Pharmaceutical Manufacturing Encyclopedia, 3rd Edition, Third Edition (Sittig's Pharmaceutical Manufacturing Encyclopedia)

Preface The Third Edition of Pharmaceutical Manufacturing Encyclopedia contains descriptions of manufacturing processes, structural formulas, trade names, therapeutic functions, and other information on 2266 pharmaceuticals now being marketed as trade-named products in America and many other countries. Information on 1295 pharmaceuticals has been taken from the Second Edition of the Pharmaceutical Manufacturing Encyclopedia (Marshall Sittig, Noyes Publications, Westwood, New Jersey, USA, 1986). Information on 971 additional pharmaceuticals, including those approved by the U.S. Food and Drug Administration (FDA) since 1986, are included in the Encyclopedia as well. The Encyclopedia comprises 4 volumes: Volume 1: A through B Volume 2: C through G Volume 3: H through P Volume 4: Q through Z, and the Raw Materials and Trade Names Indexes. The pharmaceuticals are listed in alphabetical order. INFORMATION SOURCES USED For the Second Edition, a variety of sources were used to identify the patents associated with particular commercial products and to serve as a source of process information. The sources included the following: Merck Index: followed by a citation of the entry number in the Tenth (1983) Edition.1

vi DFU: The periodical publication, Drugs of the Future,3 published by Prous Science. DOT: The periodical publication, Drugs of Today,4 published by Prous Science. Kleeman & Engel: The encyclopedic German work, Pharmazeutische Werkstoffe,5 second revised edition published in 1982. OCDS: The 3-volume reference series, The Organic Chemistry of Drug Synthesis.7 In addition, sources of pharmacological data and comparative information on trade names used in various countries were obtained from: REM: Remington's Pharmaceutical Sciences.9 Nonproprietary Name Index: The nonproprietary name index published by Paul de Haen.11 I.N.: The biannual Swiss publication, Index Nominum.12 PDR: The guide to commercially available U.S. drugs, the Physicians' Desk Reference.13

For the Third Edition, a number of new and updated sources were used, including the latest edition of The Merck Index.2 Extensive use has been made of the US, British, German, and world patent literature with regard to the process information. In addition, a variety of sources were used to identify the patents associated with particular commercial products and to serve as a source of process information. These include the encyclopedic German work Pharmazeutische Wirkstoffe (4th edition), edited by A. Kleeman and J. Engel,6 and the 6-volume reference series on the Organic Chemistry of Drug Synthesis by Daniel Lednicer8 and references [10] through [14] below.

vii In addition to the patent-derived process information, references to major pharmaceutical reference works where additional information can be obtained on synthesis methods and the pharmacology of the individual products are also cited under each drug entry. Pharmacological data and comparative information on trade names used in various countries were obtained from Organic-Chemical Drugs and Their Synonyms, 8th ed., by M. Negwer and H.-G. Scharnow. 15 July 2006 References 1. Windholz, M., editor, The Merck Index, 10th ed. Rahway, NJ: Merck & Co., Inc. (1983). 2. Smith, Ann, et al., The Merck Index: An Encyclopedia of Chemicals, Drugs, & Biologicals, 13th ed. Rahway, NJ: Merck & Co., Inc. (2001). 3. Prous, J.R., editor, Drugs of the Future, Vol. 30. Barcelona, Spain: Prous Science Publishers (2005) 4. Prous, J.R., editor. Drugs of Today, Vol. 41. Barcelona, Spain: Prous Science Publishers (2005) 5. Kleeman, A. and Engel, J., Pharmazeutische Werkstoffe: Synthesen, Patente, Anwendugen, Stuttgart, Germany: Georg Thieme Verlag, (1982). 6. Kleeman A., Engel J. Pharmazeutische Wirkstoffe. English: Pharmaceutical substances: syntheses, patents, applications, 4th ed. Stuttgart, Germany: Georg Thieme Verlag, (2001). 7. Lednicer, D., and Mitscher, L., The Organic Chemistry of Drug Synthesis, New York: John Wiley and Sons. Vol. 1 (1977); Vol. 2 (1980); Vol. 3 (1984); Vol. 4 (1990). 8. Lednicer, D., The Organic Chemistry of Drug Synthesis, New York: John Wiley and Sons. Vol. 4 (1990); Vol. 5 (1994); Vol. 6 (1998).

viii 9. Philadelphia College of Pharmacy and Science, Remington's Pharmaceutical Sciences, 17th ed. Easton, PA: Mack Publishing Co. (1985). 10. Alfonso R. Gennaro, editor. Remington: The Science and Practice of Pharmacy (Remington's Pharmaceutical Sciences), 20th ed. New York: Lippincott Williams & Wilkins (2000). 11. Paul de Haen International, Inc., Nonproprietary Name Index, 15th ed. Englewood, CO: Paul de Haen International, Inc. (1984). 12. H.P. Jasperson et al., editors. Index Nominum, Zurich, Switzerland: Swiss Pharmaceutical Society (1984). 13. Barnhart, E.R., editor, Physicians' Desk Reference, 40th ed. Oradell, NJ: Medical Economics Co., Inc. (1986). 14. Physicians Desk Reference, 55th ed. Oradell, NJ: Medical Economics Co., Inc. (2001). 15. Negwer, M., and Scharnow, H.-G., Organic-Chemical Drugs and Their Synonyms, 8th ed. New York: John Wiley and Sons (2001).

PHARMACEUTICAL MANUFACTURING ENCYCLOPEDIA Third Edition Volume 1 A through B Volume 2 C through G Volume 3 H through P Volume 4 Q through Z Raw Materials Index Trade Names Index

Copyright © 2007 by William Andrew, Inc. No part of this book may be reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, or by any information storage and retrieval system, without permission in writing from the Publisher, with the exception of the following: Cover by Brent Beckley Library of Congress Cataloging-in-Publication Data Pharmaceutical manufacturing encyclopedia. -- 3rd ed. p. ; cm. Rev. ed. of: Pharmaceutical manufacturing encyclopedia / by Marshall Sittig. c1988. Includes bibliographical references and index. ISBN-13: 978-0-8155-1526-5 (set : alk. paper) ISBN-10: 0-8155-1526-X (set : alk paper) 1. Drugs--Synthesis--Dictionaries. 2. Pharmaceutical chemistry--Dictionaries. I. Sittig, Marshall. Pharmaceutical manufacturing encyclopedia. II. William Andrew Publishing. [DNLM: 1. Pharmaceutical Preparations--Encyclopedias--English. 2. Chemistry, Pharmaceutical--Encyclopedias--English. QV 13 P536 2007] RS402.5.S58 2007 615'.19--dc22 2006023472 Printed in India This book is printed on acid-free paper. 10 9 8 7 6 5 4 3 2 1 Published by: William Andrew Publishing 13 Eaton Avenue Norwich, NY 13815 1-800-932-7045 www.williamandrew.com Exclusively distributed in the Indian Subcontinent by Affiliated East-West Press Pvt. Ltd., G-1/16, Ansari Road, Darya Ganj, New Delhi 110 002 NOTICE To the best of our knowledge the information in this publication is accurate; however the Publisher does not assume any responsibility or liability for the accuracy or completeness of, or consequences arising from, such information. This book is intended for informational purposes only. Mention of trade names or commercial products does not constitute endorsement or recommendation for their use by the Publisher. Final determination of the suitability of any information or product for any use, and the manner of that use, is the sole responsibility of the user. Anyone intending to rely upon any recommendation of materials or procedures mentioned in this publication should be independently satisfied as to such suitability, and must meet all applicable safety and health standards.

A

ABACAVIR SULFATE Therapeutic Function: Antiviral Chemical Name: 2-Cyclopentene-1-methanol, 4-(2-amino-6(cyclopropylamino-9H-purin-9-yl), sulfate (salt) (2:1), (1S,4R), sulfate Common Name: Abacavir sulfate Structural Formula:

Chemical Abstracts Registry No.: 188062-50-2; 136470-78-5 (Base) Trade Name Ziagen

Manufacturer GlaxoSmithKline

Country -

Year Introduced -

Ziagen

Glaxo Wellcome

-

-

Ziagenavir

Glaxo Wellcome

-

-

Raw Materials 2,5-Diamino-4,6-dihydroxypyrimidine (Chloromethylene)dimethylammonium chloride (1S,4R)-4-Amino-2-cyclopentene-1-methanol Triethylamine Tartaric acid, dibenzoate, (-)Orthoformate or diethoxymethyl acetate Cyclopropylamine

1

2

Abafungin

Manufacturing Process Treatment of 2,5-diamino-4,6-dihydroxypyrimidine (I) with (chloromethylene)dimethylammonium chloride yielded the dichloropyrimidine with both amino groups derivatized as amidines. Partial hydrolysis with aqueous HCl in hot ethanol gave N-(2-amino-4,6-dichloro-pyrimidin-5-yl)-N,Ndimethylformamidene (II). Subseqent buffered hydrolysis at pH 3.2 yielded the (2-amino-4,6-dichloro-pyrimididin-5-ylamino)acetaldehyde (III). Condensation chloropyrimidine (III) with (1S,4R)-4-amino-2-cyclopentene-1methanol (IV) in the presence of triethylamine and NaOH gave [2-amino-4chloro-6-(4-hydroxymethyl-cyclopent-2-enylamino)pyrimidin-5-ylamino]acetaldehyde (V). The correct enantiomer (IV) of racemic aminocyclopentene was obtained by resolution of diastereomeric salts with D-dibenzoyltartaric acid. Cyclization of (V) to the corresponding purine was accomplished with refluxing triethyl orthoformate or diethoxymethyl acetate to give nucleoside analogue [4-(2-amino-6-chloro-purin-9-yl)-cyclopent-2-enyl]methanol (VI). Displacement of chloride in the purine nucleus with cyclopropyl amine in refluxing butanol afforded abacavir. The structure of obtained compound was confirmed by 1H NMR method and elemental analysis. In practice it is usually used as sulfate salt. References Huff J.R.; Bioorg. Med. Chem., 7, (1999), 2667-2669 Daluga S.M.; European Patent No. 0,434,450; Dec. 12, 1990

ABAFUNGIN Therapeutic Function: Antibacterial, Antifungal Chemical Name: N-{4-[2-(2,4-Dimethylphenoxy)phenyl]thiazol-2-yl}1,4,5,6-tetrahydro-pyrimidinamine Common Name: Abafungin; BAY w 6341 Structural Formula:

Chemical Abstracts Registry No.: 129639-79-8 Trade Name

Manufacturer

Country

Year Introduced

Abafungin

York Pharma

-

-

Abamectin

3

Raw Materials N-(1,4,5,6-Tetrahydropyrimidinyl)thiourea 2-(2,4-Dimethylphenoxy)phenacyl chloride Manufacturing Process 15.8 g (0.12 mole) N-(1,4,5,6-tetrahydropyrimidinyl)thiourea were added to 27.45 g (0.1 mole) 2-(2,4-dimethylphenoxy)phenacyl chloride in 100 ml acetone and heated to reflux for 2 hours. On cooling the falling out product was filtered off, washed with acetone and dried. N-[4-[2-(2,4Dimethylphenoxy)phenyl]-2-thiazolyl]-1,4,5,6-tetrahydro-2-pyrimidinamine hydrochloride was prepared. Yield 91.4%; MP: 160°C. 20.72 g (0.05 mole) above product was stirred with 300 ml 1 N sodium hydroxide for 30 minutes at room temperature. The insoluble product was filtered off, washed and dried. Yield of N-[4-[2-(2,4-dimethylphenoxy)phenyl]2-thiazolyl]-1,4,5,6-tetrahydro-2-pyrimidinamine was 16.2 g (86%). MP: 191°-192°C. References Ippen. Joachim et al.; D.B. Patent No. 3,836,161 A1; Nov. 24, 1988; Bayer AG, 5090 Leverkusen, DE

ABAMECTIN Therapeutic Function: Antiparasitic Chemical Name: Avermectin B1 Common Name: Abamectin; MK-936, Zectin Chemical Abstracts Registry No.: 71751-41-2; 65195-55-3 Trade Name

Manufacturer

Country

Year Introduced

Abamectin

-

-

Kraft TM

Yellow River Enterprise Co. (a.k.a Yelori) Cheminova

-

-

Abamectin 1.8%

LIFES Labo

-

-

Abamectin

Ningbo Sega Chemical Company Institutul Pasteur Romania Merial

-

-

-

-

-

-

Merck Sharp and Dohme Ltd

-

-

Avomec Duotin Enzec

4

Abamectin

Structural Formula:

Raw Materials Streptomyces avermitilis MA-4680 Nutrient medium Manufacturing Process 1. The contents of a lyophilized tube of Streptomyces avermitilis MA-4680 is transferred aseptically to a 250 ml Erlenmeyer flask containing 305 ml of Medium 1: Dextrose 20 g, Peptone 5 g, Meat Extract 5 g, Primary Yeast 3 g, NaCl 5 g, CaCO3 (after pH adjustment) 3 g, Distilled water 1000 ml, pH 7.0. The inoculated flask is incubated for 3 days at 28°C on a rotary shaking machine at a speed of 220 RPM in a 2 inch radius circular orbit. At the end of this time, a 250 ml Erlenmeyer flask containing 50 ml of Medium 2 [Tomato Paste 20 g, Modified Starch (CPC) 20 g, Primary Yeast 10 g, CoCl2·6H2O 0.005 g, Distilled water 1000 ml, pH 7.2-7.4] is inoculated with a 2 ml sample from the first flask. This flask is incubated for 3 days at 28°C on a rotary shaking machine at a speed of 220 RPM in a 2 inch diameter circular orbit. 50 Ml of the resulting fermentation broth containing C-076 is effective against an N.dubius infection in mice.

Abamectin

5

2. A lyophilized tube of Streptomyces avermitilis MA-4680 is opened aseptically and the contents suspended in 50 ml of Medium 1 in a 250 ml Erlenmeyer flask. This flask is shaken for 3 days at 28°C on a rotary shaking machine 220 RPM with a 2 inch diameter circular orbit. A 0.2 ml portion of this seed medium is used to inoculate a Slant of Medium 3: Dextrose 10.0 g , Bacto Asparagine 0.5 g, K2HPO4 40.5 g, Bacto Agar 15.0 g , Distilled water 1000 ml, pH 7.0. The inoculated slant medium is incubated at 28°C for 10 days and stored at 4°C until used to inoculate 4 more slants of Medium 3. These slants are incubated in the dark for 8 days. One of these slants is used to inoculate 3 baffled 250 ml Erlenmeyer flasks containing 50 ml of No. 4 Seed Medium: Soluble Starch 10.0 g, Ardamine 5.0 g, NZ Amine E 5.0 g, Beef Extract 3.0 g, MgSO4·7H2O 0.5 g, Cerelose 1.0 g, Na2HPO4 0.190 g, KH2PO4 182 g, CaCO3 0.5 g, Distilled water 1000 ml, pH 7.0-7.2. The seed flasks are shaken for 2 days at 27-28°C on a rotary shaking machine at 220 RPM with a 2 inch diameter circular orbit. The contents of these flasks are pooled and used to inoculate (5% inoculum) baffled 250 ml Erlenmeyer flasks containing 40 ml of various production media. Flasks containing media 2, 5 and 6 are incubated for 4 days at 28°C on a rotary shaking machine at 220 RPM with a 2 inch diameter circular orbit. The resulting broth containing C-076 is then harvested and tested for anthelmintic activity. In all cases 6.2 ml of whole broth and the solids obtained from centrifuging 25 ml of whole broth are fully active against N.dubius helminth infections in mice. 3. The one of the four slants of Medium 3 prepared as in Example 2 is used to inoculate a baffled 250 ml Erlenmeyer flask containing 50 ml of Seed Medium No. 4. The seed flask is shaken for 1 day at 27- 28°C on a rotary shaking machine at 220 RPM with a 2 inch diameter circular orbit. The seed flask is then stored stationary at 4°C until it is ready to be used. The contents of this flask are then used to inoculate (5% inoculum) 20 unbaffled 250 ml Erlenmeyer flasks containing 40 ml of Medium No. 2. After 4 days incubation at 28°C on a rotary shaking machine at 220 RPM with a 2 inch diameter circular orbit, 19 of the flasks are harvested and pooled. The combined fermentation broths containing C-076 are filtered affording 500 ml of filtrate and 84 g of mycelia. 78 G of mycelia are extracted with 150 ml of acetone for ½ hour with stirring and the mixture filtered. The filter cake is washed with 50 ml of acetone and the filtrate and washings are combined and concentrated to 46.5 ml 30 Ml of the concentrate is adjusted to pH 4 with dilute hydrochloric acid and extracted 3 times with 30 ml portions of chloroform. The extracts are dried by filtering through dry Infusorial Earth (Super-Cel) combined and concentrated to dryness in vacuum. The oily residue of C-076 weighing 91.4 mg is dissolved in chloroform sufficient to make 3 ml of solution which represents 1% of broth volume. The C-076 (Abamectin) obtained in this recovery procedure is fully active against N.dubius infections in mice. In addition, the chloroform extraction achieved a 70 fold purification of C-076 from the whole broth. References Albers-Schonberg G., Wallick H., Ormond R.E., Miller Thomas W., Burg Richard W.; US Patent No. 4,310,519; Jan. 12, 1982; Assigned to Merck and Co., Inc. (Rahway, NJ)

6

Abanoquil mesylate

ABANOQUIL MESYLATE Therapeutic Function: Antiarrhythmic, Coronary vasodilator Chemical Name: 4-Amino, 2-(3,4-dihydro-6,7-dimethoxy-2(1H)-isoquinolyl)6,7dimethoxyquinoline monomethanesulfonate Common Name: Abanoquil mesylate Structural Formula:

Chemical Abstracts Registry No.: 118931-00-3; 90402-40-7 (Base) Trade Name Abanquil

Manufacturer Onbio Inc.

Country -

Year Introduced -

Raw Materials 6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline Acetic anhydride Phosphorus(V) oxychloride 2-Amino-4,5-dimethoxybenzonitrile Sodium hydroxide Zinc chloride Fumaric acid Manufacturing Process Synthesis of 1-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)ethanone: To a stirred solution of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (3.00 g, 15.4 mmol, 1.00 equiv.) in anhydrous pyridine (100 mL) under argon at room temperature was added acetic anhydride (14.5 mL, 154 mmol, 10.0 equiv.) over 15 min. The resulting mixture was stirred at room temperature for 2 h, and then at reflux for 6 h. The volatiles were removed by rotary evaporation at 80°C under high vacuum. The residue was flash chromatographed on silica gel (MeOH-CH2Cl2 8:92) to afford 3.21 g (89%) of 1-(6,7-dimethoxy-3,4dihydro-1H-isoquinolin-2-yl)ethanone as a viscous brown oil. The H-NMR spectrum reflected the presence of two slowly interconverting conformers in a ratio of 1.2:1 at room temperature. Synthesis of 2-[1-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2yl)ethylidineamino]-4,5-dimethoxybenzonitrile:

Abarelix

7

To a stirred solution of 1-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2yl)ethanone (1.00 g, 4.25 mmol, 1.00 equiv.) in CHCl3 at room temperature under argon was added POCl3 (143 µL, 1.53 mmol, 0.36 equiv.). After 10 min, 2-amino-4,5-dimethoxybenzonitrile (763 mg, 4.28 mmol, 1.01 equiv.) was added and the mixture was heated at reflux overnight. The mixture was cooled to room temperature and poured into 1 M aq. NaOH solution (50 mL), and the aqueous phase was extracted with CH2Cl2. The combined organic solutions were dried over MgSO4 and concentrated. The residue was flash chromatographed on silica gel (MeOH-CH2Cl2, 2 5:95) to afford 482 mg (28%) of 2-[1-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)ethylidineamino]-4,5dimethoxybenzonitrile as an yellow solid. Synthesis of 2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-6,7dimethoxyquinolin-4-ylamine hemifumarate hydrate (abanoquil): To a stirred solution of 2-[1-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2yl)ethylidineamino]-4,5-dimethoxybenzonitrile (471 mg, 1.19 mmol, 1.00 equiv.) in refluxing anhydrous N,N-dimethylacetamide (24 mL) under argon was added ZnCl2 (339 mg, 2.49 mmol, 2.10 equiv.) in three portions over 1 h. The solvent was removed by distillation at 70°C under high vacuum. Ether (40 mL) was added to the residue, which was broken up with a stirring rod, and the mixture was stirred at 0°C to precipitate the product. The supernatant was discarded, and the precipitate was washed twice more at 0°C with ether. The solid residue was stirred with 1 M aq. NaOH (25 mL) and CH2Cl2 (25 mL) for 10 min, and the aqueous phase was extracted with CH2Cl2. The combined organic solutions were dried over MgSO4 and concentrated to give 493 mg of brown oil, which was flash chromatographed on silica gel (MeOH-CH2Cl2,12:88 followed by 2-propylamine-CH2Cl2, 5:95) to afford 151 mg (38%) of 2-(6,7dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-6,7-dimethoxyquinolin-4-ylamine as a tan solid. To a solution of 2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-6,7dimethoxyquinolin-4-ylamine (150 mg) in hot CH2Cl2 (4.5 mL) and MeOH (1.5 mL) was added a solution of fumaric acid (22.8 mg, 0.196 mmol, 0.50 equiv.) in hot MeOH (3.0 mL). The resulting mixture was concentrated and the product was recrystallized from MeOH with hot filtration to afford, after filtration, 85 mg of light brown solid: m.p. 239-240°C. In practice it is usually used as mesylate. References Craig D.A., Forrey C.C., Gluchovski Ch., Branchek T.A.; US Patent No. 5,610,174; March 11, 1997; Assigned to Synaptic Pharmaceutical Corporation (Paramus, NJ)

ABARELIX Therapeutic Function: LHRH antagonist

8

Abarelix

Chemical Name: D-Alaninamide, N-acetyl-3-(2-naphthalenyl)-D-alanyl-4chloro-D-phenylalanyl-3-(3-pyridinyl)-D-alanyl-L-seryl-N-methyl-Ltyrosyl-D-asparaginyl-L-leucyl-N6-(1-methylethyl)-L-lysyl-L-prolylCommon Name: Abarelix; PPI-149 Structural Formula:

Chemical Abstracts Registry No.: 183552-38-7 Trade Name

Manufacturer

Country

Year Introduced

Plenaxis

Praecis Pharmaceuticals

-

-

Raw Materials Thioanisole Trifluoroacetic acid 1-Hydroxybenzotriazole Dicyclohexylcarbodiimide 2-Iodopropane

Methylbenzyhydramine resin Diisopropylethylamine Boc-protected amino acids Silver(I) oxide m-Chloroperbenzoic acid Boc-D-Pal (Boc-D- 3-(3'-pyridyl)alanine)

Manufacturing Process Abbreviation Residue or moiety: Nal - 3-(2-naphthyl)alaninyl 4-Cl-Phe - (4'-chlorophenyl)alaninyl Pal - 3-(3'-pyridyl)alaninyl Pal(N-O) - 3-(3'-pyridine-N-oxide)alaninyl Pal(iPr) - 3-N-(2-propyl)-3'-pyridinium)alaninyl BOC - N-t-butyoxycarbonyl

Abarelix

9

DCC - dicyclohexylcarbodiimide Abarelix was synthesized by the solid phase method using an automated synthesizer (e.g. Beckman Model 990). The amino acid residues used can be purchased from commercial sources (e.g. Aldrich Chemical Co., Milwaukee, Wis.), or can be produced from commercially available starting materials according to known methods. Amino acids which are not obtained commercially can be synthesized in a protected form for coupling, or, if appropriate, can be coupled to form a peptide and subsequently modified to the desired form. For example, Boc-D-Pal(iPr) was prepared next way: Boc-D-Pal (4.0 g, 17.7 mmol) and Ag2O (8.0 g, 34.4 mmol) in 22 ml water was stirred at room temperature for 4 hours. The reaction vessel was cooled to 0°C, and 2-iodopropane (20.4 g, 120 mmol) in 40 ml 2-propanol was added. After addition was complete, the mixture was allowed to warm to room temperature and stirred for 4 days. Additional Ag2O (2 g) and 2-iodopropane (2 g) were added after 24 hours and again after 48 hours. The mixture was filtered, and the precipitate was washed with ethanol (2x15 ml). The filtrate was evaporated to yield 4.3 g of a yellow oil. Crystallization from ethanol/ethyl acetate gave light yellow crystals (3.0 g); Yield: 63%; m.p. 182°-185°C. Synthesis of Boc-D-Pal(N-O): Boc-D-Pal (2.0 g, 7.5 mmole) was dissolved in 40 ml acetone and 2.48 g (16.5 mmol) of m-chloroperbenzoic acid (MCPBA) (57-86%; purchased from Aldrich and used as received) in 80 ml acetone was added in one portion. The mixture was stirred at room temperature for 40 hours; a small amount of white precipitate formed as the reaction proceeded. The precipitated was filtered and the mother liquor evaporated to yield a white precipitate. The combined solids were washed with ether (to remove chlorobenzoic acid) and recrystallized from ethyl acetate/hexane. Yield: 1.7 g (80%); m.p. 155°157°C. A typical coupling cycle for peptide synthesis with Boc-amino acids on a peptide synthesizer (Beckman Model 990) was as follows: Methylbenzyhydramine (MBHA) resin (1.18 g, 0.85 meq amino groups/g resin) was weighed into the reaction vessel and washed with two portions of chloroform (26 ml each). The resin was prewashed with 22% thioanisole (5 ml)/66% trifluoroacetic acid (TFA) in 14 ml dichloromethane (DCM) for 5 minutes, and then deprotected for 30 minutes with the same thioanisole/TFA mixture. The resin was washed with three portions of chloroform (20 ml each), two portions of 2-propanol (26 ml each) and two portions of DCM (26 ml each). The resin was neutralized with two portions of 12% diisopropylethylamine (DIPEA) (26 ml each), and then washed with four portions of DCM (26 ml each), followed by two portions of 1:1 DCM:dimethylformamide (DMF) (26 ml each). A solution of a Boc-protected amino acid (2.5 mole equivalents) and 1-hydroxybenzotriazole (HOBt) (2.5 mole equivalents) was introduced as a solution in 10 ml DMF, and DCC was added (256 mg in 6 DMF). Coupling was allowed to proceed for three hours,

10

Abecarnil

or overnight. Hindered residues (e.g. backbone N-methyl amino acids) required longer coupling times. The resin was washed with two 26 ml portions of DMF, followed by two 26 ml portions of 2-propanol and then two 26 ml portions of DCM. Completion of coupling was assessed by Kaiser's test (ninhydrin test). If coupling is not complete, a double coupling was performed (i.e. the resin was neutralized as above and the coupling step repeated). When complete coupling is achieved, the cycle was repeated with the next amino acid. Upon completion of the synthesis, the peptide was cleaved from the resin by treatment with liquid hydrofluoric acid (HF) for 45 minutes at 0°C. The HF was evaporated and the peptide treated with aqueous acetic acid and lyophilized. The crude peptide was then purified by high performance liquid chromatography (HPLC) on a C18 column, eluting with a mixture of acetonitrile and 0.1% TFA in water. Purified fractions (homogeneous by UV and TLC analysis) were combined and lyophilized. Analytical HPLC was used to determine the purity of the final product; peptides synthesized was at least 98% pure. References Folkers K. et al.; 1986; "Increased Potency of Antagonists of the Luteinizing Hormone Releasing Hormone Which Have D-3 Pal in Position 6"; Biochem. Biophys. Res. Comm.; 137(2):709-715 Tian, Z.P. et al.; 1994; "Design and synthesis of highly water soluble LHRH antagonists"; Pept.: Chem., Struct. Biol., Proc. Am. Pept. Symp.; 13th; 562-564 Roeske R. W.; US Patent No. 5,843,901; Dec. 1, 1998; Assigned to Advanced Research and Technology Institute, Bloomington, Ind.

ABECARNIL Therapeutic Function: Anticonvulsant, Anxiolytic Chemical Name: 9H-Pyrido[3,4-b]indole-3-carboxylic acid, 4(methoxymethyl)-6-(phenylmethoxy)-, 1-methylethyl ester Common Name: Abecarnil; SH 524 Structural Formula:

Chemical Abstracts Registry No.: 111841-85-1

Abecarnil Trade Name Abecarnil

Manufacture Schepa

Country -

11

Year Introduced -

Raw Materials Potassium carbonate Anisaldehyde Sodium hydroxide Hydrochloric acid Triethylamine

Hydrochloric acid Glycine isopropyl ester Paraformaldehyde tert-Butyl hypochlorite 5-Benzyloxy-3-(1-isopropylamino-2methoxyethyl)indole

Manufacturing Process Under nitrogen, 6 g (43.5 millimoles) of finely pulverized potassium carbonate is stirred for 10 min at 95°C in 25 ml of absolute dimethylformamide. Then, while the mixture is hot, 10 g (29.6 mmol) of 5-benzyloxy-3-(1isopropylamino-2-methoxyethyl)indole is added and the mixture is stirred approximately 10 min at 95°C until the compound has been dissolved. Thereupon, likewise at 95°C, a solution of 34.5 mmol of glycinimine (prepared from anisaldehyde and glycine isopropyl ester) in 25 ml of dimethylformamide is added dropwise in a time period of 30 min. The solution is agitated until the starting indole can no longer be detected in a thin-layer chromatogram. After cooling, the product is filtered off by suction from potassium carbonate and rinsed with toluene. After adding 100 ml of toluene, 200 ml of 1 N hydrochloric acid is added and the mixture stirred for 3 hours at room temperature. The toluene phase is separated, and the aqueous acidic phase is extracted by shaking with 100 ml of toluene. The organic phase is discarded. The acidic phase is cooled to 5°C, combined with 100 ml of toluene, and adjusted to pH 10-12 with 4 N sodium hydroxide solution. After extraction by shaking, the mixture is again extracted by shaking with 100 ml of toluene, and the combined organic phase is washed with 50 ml of water, dried, filtered, and concentrated, thus obtaining 70% 2-amino-3-(5-benzyloxyindol-3-yl)-4methoxybutyric acid isopropyl ester as an oil. A solution is prepared from 3.8 g of 2-amino-3-(5-benzyloxyindol-3-yl)-4methoxybutyric acid isopropyl ester (10 mmol) in 80 ml of xylene and added dropwise to a suspension of 360 mg of paraformaldehyde in 60 ml of xylene heated for 45 min to 100°C. The mixture is then refluxed for 2 hours on a water trap. After concentration, the residue is chromatographed over silica gel with methylene chloride:acetone=1:1 as the eluent, yielding 2.5 g of 6benzyloxy-4-methoxymethyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid isopropyl ester (65% yield as an oil); or a suspension of 2.56 g of paraformaldehyde in 8 ml of water and 0.8 ml of concentrated hydrochloric acid is refluxed at 80°C for 1 hour. One-tenth of the thus-obtained clear solution is added dropwise, after cooling to room temperature, to a solution of 3.8 g (10 mmol) of 2-amino-3-(5-benzyloxyindol-3-yl)-4-methoxybutyric acid isopropyl ester in 500 ml of water and 10 ml of concentrated hydrochloric acid (pH=3). After ½ hour of agitation, an estimate of the amount of amino compound still remaining is made by thin-layer chromatography, and a corresponding quantity of formaldehyde solution is added. Thereupon, the mixture is stirred for another hour and then extracted twice by shaking with 50 ml of toluene, respectively. The organic phase is discarded. The aqueous phase is adjusted, after adding 100 ml of toluene, to a pH of 5.3 with 27%

12

Abiraterone

strength sodium hydroxide solution. After extraction by shaking, the mixture is additionally extracted by shaking twice with 50 ml of toluene; these 3 organic phases are combined, dried over sodium sulfate, filtered, and concentrated, thus obtaining 3.3 g (85%) of 6-benzyloxy-4-methoxymethyl1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid isopropyl ester as an oil. A solution is prepared from 3.3 g (8.5 mmol) of 6-benzyloxy-4methoxymethyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid isopropyl ester in 150 ml of methylene chloride, combined under argon with 3.9 ml of triethylamine, and cooled to -15°C. At this temperature, a solution of 3.2 ml (25.6 mmol) of t-butyl hypochlorite in 50 ml of methylene chloride is added dropwise without delay to this solution. After the adding step is completed, the mixture is stirred for another 10 min, combined with 2.6 ml of triethylamine, and agitated for 2 hours at room temperature. Subsequently, the mixture is concentrated to one-half thereof and extracted once by shaking with dilute ammonia solution. The organic phase is dried, filtered, and concentrated. The residue is chromatographed over silica gel with methylene chloride:acetone=4:1 as the eluent. Recrystallization from ethyl acetate gives 1.1 g (35% yield) of 6-benzyloxy-4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester, m.p. 150-151°C. References Biere H., Huth A., Rahtz D. et al.; US Patent No. 5,414,002; May 9, 1995; Assigned to Schering Aktiengesellschaft, Berlin and Bergkamen, Germany

ABIRATERONE Therapeutic Function: Antiandrogen Chemical Name: Androsta-5,16-dien-3-ol, 17-(3-pyridinyl)-, (3β)Common Name: Abiraterone; CB 7598; Piraterone Structural Formula:

Chemical Abstracts Registry No.: 154229-19-3 Trade Name

Manufacturer

Country

Year Introduced

Abiraterone

Cougar

-

-

Ablukast sodium

13

Raw Materials Diethyl(3-pyridyl)borane 3β-Acetoxyandrosta-5,16-dien-17-yl trifluoromethanesulphonate Bis(triphenylphosphine)palladium(II) chloride Sodium carbonate Sodium hydroxide Hydrochloric acid Manufacturing Proces Diethyl(3-pyridyl)borane (3.38 g, 23 mmol) from Aldrich Chemical Co. Ltd. was added to a stirred solution of 3β-acetoxyandrosta-5,16-dien-17-yl trifluoromethanesulphonate (6.94 g, 15 mmol) in THF (75 ml) containing bis(triphenylphosphine)palladium(II) chloride (0.105 g, 0.15 mmol). An aqueous solution of sodium carbonate (2 M, 30 ml) was then added and the mixture heated, with stirring, by an oil bath at 80°C for 1 h, and allowed to cool. The mixture was partitioned between diethyl ether and water, the ether phase was dried (Na2CO3), filtered through a short plug of silica, and concentrated. Chromatography, on elution with light petroleum-diethyl ether (2:1), afforded the 3β-acetoxy-17-(3-pyridyl)androsta-5,16-diene (4.95 g, 84%) which crystallised from hexane, m.p. 144-145°C. To a solution of 3β-acetoxy-17-(3-pyridyl)androsta-5,16-diene (4.90 g, 12.5 mmol) in methanol (50 ml) was added an aqueous solution of sodium hydroxide (10% w/v, 10 ml) and the mixture heated, with stirring, on an oil bath at 80°C for 5 min, then allowed to cool. The mixture was poured into water, neutralised with hydrochloric acid (1 M), rebasified with saturated sodium bicarbonate solution, and extracted with hot toluene. The toluene extracts were combined, dried (Na2CO3), and concentrated. Chromatography, on elution with toluene-diethyl ether (2:1) afforded the 17-(3pyridyl)androsta-5,16-dien-3β-ol (3.45 g, 79%) which crystallised from toluene, m.p. 228-229°C. References Barrie S.E., Jarman M., Potter G.A., Hardcastle Ian R.; US Patent No. 5,604,213; Feb. 18, 1997; Assigned to British Technology Group Limited (London, GB2)

ABLUKAST SODIUM Therapeutic Function: Antiallergic, Anti-asthmatic Chemical Name: 2H-1-Benzopyran-2-carboxylic acid, 6-acetyl-7-[[5-(4acetyl-3-hydroxy-2-propylphenoxy)pentyl]oxy]-3,4-dihydro-, sodium salt Common Name: Ablukast sodium

14

Ablukast sodium

Structural Formula:

Chemical Abstracts Registry No.: 96565-55-8; 96566-25-5 (Base) Trade Name

Manufacturer

Country

Year Introduced

Ulpax

Roche

-

-

Raw Materials Diethyl oxalate Sodium ethylate Palladium on charcoal 4-Toluenesulfonic acid 5-Bromo-1-pentanyl acetate Acetic acid Methanesulfonyl chloride Sodium hydroxide

2',4'-Dihydroxyacetophenone Hydrochloric acid Hydrogen Boron trifluoride diethyl etherate Tetrabutylammonium hydroxide Triethylamine Tris(3,6-dioxahepyl)amine

Manufacturing Process A solution of 109.8 g (0.75 mol) of diethyl oxalate and 65 g (0.427 mol) of 2',4'-dihydroxyacetophenone in 100 mL of EtOH was added slowly under Ar, with cooling, to a stirred solution of NaOEt (from 40 g of Na and 550 mL of EtOH). The mixture was stirred at 50°C for 3 h, cooled to room temperature, and poured into a separatory funnel containing 500 mL of 2 N HCl. It was extracted with CH2CH2 washed with 500 mL of saturated NaHCO3, dried and evaporated to give a red oil, which was dissolved in 250 mL of EtOH and 10 mL of conc. HCl. The mixture was boiled under reflux for 1 h, cooled to ca. 10°C and the product was collected by filtration. It was washed with some EtOH followed by hexane to give 86.0 g (86% yield) of ethyl 7-hydroxy-4-oxo4H-1-benzopyran-2-carboxylate: m.p. 218-223°C. Crystallization of a portion from hot AcOH gave an analytical sample: m.p. 221-223°C. A solution of 80 g (0.34 mol) of ethyl 7-hydroxy-4-oxo-4H-1-benzopyran-2carboxylate in 60 mL of AcOH and 275 mL of THF was hydrogenated over 4.0 g of 10% Pd on charcoal at 45°C and 65 psi. After hydrogen absorption ceased, the catalyst was removed by filtration and the solvents were evaporated under reduced pressure. Crystallization from CCl4 gave 65 g (85%) of ethyl (R,S)-3,4-dihydro-7-hydroxy-2H-1-benzopyran-2-carboxylate: m.p. 80-82°C. A stirred mixture of 65 g (0.293 mol) of ethyl (R,S)-3,4-dihydro-7-hydroxy2H-1-benzopyran-2-carboxylate in 650 mL of AcOH, 1.5 mL of acetic anhydride, and 65 mL of BF3·OEt2 was heated at reflux for 18 h and evaporated. To the residue was added 700 mL of water, and the mixture was stirred at room temperature for 1.0 h. The product was collected by filtration

Ablukast sodium

15

and washed with hexane. It was then dissolved in 900 mL of MeOH, treated with 6.6 g of p-toluenesulfonic acid, boiled under reflux for 18 h, and cooled to 0°C. The product was collected by filtration to give 52 g (70% yield) of ethyl (R,S)-3,4-dihydro-7-hydroxy-2H-1-benzopyran-2-carboxylate: m.p. 140142°C. A 1 L, 3-necked, round-bottomed flask equipped with a mechanical stirrer and an Ar bubbler was charged with 37.5 g (0.179 moles) of 5-bromo-1-pentanyl acetate, 350 mL of anhyd. DMSO, 40.7 g (0.163 mol) of ethyl (R,S)-3,4dihydro-7-hydroxy-2H-1-benzopyran-2-carboxylate, and 51.0 g (0.369 mol) of powdered potassium carbonate. The mixture was stirred at room temperature for 18 h, poured into 1.0 L of water and extracted into EtOAc (2*1 L). The extract was washed with 1 L of brine, dried and evaporated. The residue was dissolved in 200 mL of ether, cooled to 57°C and, with stirring, diluted with petroleum ether. The product was collected by filtration, washed with a little 1:1 ether-petroleum ether (b.p. 40-60°C) and dried to give 60.0 g (97%) of methyl (R,S)-6-acetyl-3,4-dihydro-7-((5-acetoxypentyl)oxy-2H-1-benzopyran2-carboxylate: m.p.51-53°C. A solution of 72.08 g (0.19 mol) of 5-bromo-1-pentanyl acetate in 1.4 L of MeOH was treated with 38 mL of a 1.0 molar solution of tetrabutylammonium hydroxide and the mixture was stirred at room temperature for 3.0 h, 3.0 mL of AcOH was added and the solution was evaporated at 35°C. The residue was dissolved in 400 mL of EtOAc and the solution was washed with saturated NaHCO3, brine, dried, and evaporated to give 60.45 g (94% yield) of the intermediate hydroxy ester (an analytical sample may be obtained by crystallization from 70% EtOAc in hexane, m.p. 58-61°C. A stirred solution of 60.25 g of the hydroxyester in 700 mL of EtOAc was cooled to 5°C and treated with 75.5 mL (3 equiv.) of triethylamine and 32.6 mL (2.35 equiv.) of methanesulfonyl chloride. The mixture was stirred at 6°C for 2.0 h, transferred to a separatory funnel and washed sequentially with water, 2 N HCl, and brine. Concentration of the EtOAc to ca. 300 mL and dilution cooled to 0°C and treated with 75.5 mL (3 equiv.) of triethylamine and 32.6 mL (2.35 equiv.) of methanesulfonyl chloride. The mixture was stirred at 6°C for 2.0 h transferred to a separatory funnel and washed sequentially with water, 2 N HCl, and brine. Concentration of the EtOAc to ca. 300 mL and dilution with 250 mL of hexane led to crystallization (0°C, 18 h). The product was collected by filtration and washed with some cold hexane - EtOAc (1:1) to give 66 g (84% yield) of methyl (R,S)-6-acetyl-3,4-dihydro-7-[5[(methylsufonyl)oxy]pentyloxy]-2H-1-benzopyran-2-carboxylate: m.p. 7376°C. A mixture of 66.13 g (0.159 mol) of methyl (R,S)-6-acetyl-3,4-dihydro-7-[5[(methylsufonyl)oxy]pentyloxy]-2H-1-benzopyran-2-carboxylate, 30.99 g (0.159 mol) of 1-[2,4-dihydroxy-3-propylphenyl)ethanone, 33.07 g (0.239 mol) of pulverized potassium carbonate, 5.16 g (15.9 mmol) of tris(3,6dioxahepyl)amine in 900 mL of toluene was stirred under Ar at reflux for 6 h and then at room temperature overnight. The mixture was poured into 300 mL of water and the organic phase was separated, washed with brine, dried and evaporated to give 84.3 g of methyl (R,S)-6-acetyl-7-[5-(4-acetyl-3hydroxy-2-propylphenoxy)pentoxy]-3,4-dihydro-2H-1-benzopyran-2carboxilate. Crystallization from MeOH (0°C, 18 h) gave 66 g (81% yield), m.p. 77-80°C.

16

Abunidazole

A stirred solution of 55.82 g (0.109 mol) of methyl (R,S)-6-acetyl-7-[5-(4acetyl-3-hydroxy-2-propylphenoxy)pentoxy]-3,4-dihydro-2H-1-benzopyran-2carboxylate in 725 mL of MeOH was treated with 4.45 g (0.111 mol) of NaOH in 20 mL of water and the mixture was stirred at reflux for 1.25 h. It was cooled, concentrated to a volume of ca 360 mL, diluted with 310 mL of ether and left at 0°C overnight. The product was collected by filtration, dried in to give 45.76 g of (R,S)-6-acetyl-7-[[5-(4-acetyl-3-hydroxy-2propylphenoxy)pentyl]oxy]-3,4-dihydro-2H-H-benzopyran-2-carboxylic acid sodium salt (Ablukast) as the monohydrate. A further 12.27 g of product was obtained from the mother liquor to give a total yield of 99%. References Manchand P.S., Micheli R.A., Saposnik S.J.; Tetrahedron; 1992; 48, 43, 9391

ABUNIDAZOLE Therapeutic Function: Antiprotozoal Chemical Name: α-[5-(1,1-Dimethylethyl)-2-hydroxyphenyl]-1-methyl-5nitro-1H-imidazole-2-methanol Common Name: Abunidazole; PN 4478846 Structural Formula:

Chemical Abstracts Registry No.: 91017-58-2 Trade Name

Manufacturer

Country

Year Introduced

Abunidazole

ZYF Pharm Chemical

-

-

Raw Materials p-tert-Butylphenol Hydrogen chloride

Ethylmagnesium bromide 1-Methyl-5-nitroimidazolyl-2-carboxyaldehyde

Manufacturing Process 150.0 g (1 mol) of p-tert-butylphenol are dissolved in 1200 ml of anhydrous ethyl ether and the thus obtained solution is added to a 10% solution of ethylmagnesium bromide in 1000 ml of anhydrous ether, at room temperature, under stirring. After having evaporated the ether, 1000 ml of anhydrous benzene are added

Acadesine

17

and the mixture is distilled, at normal pressure, until its volume is about 2/3 of the original volume. After cooling at room temperature, 1 mol of 1-methyl5-nitroimidazolyl-2-carboxyaldehyde in 1000 ml of anhydrous benzene is added. The whole is boiled for 1 h, is cooled to about 10°C and is added with 8% HCl to adjust the pH to 7. Benzene layer is dried and concentrated up to 2/3 of the volume. The 2-(1-methyl-5-nitro)imidazolyl-1-(2-hydroxy-5-tertbutylphenylcarbinol is allowed to crystallize, melting point 158°-160°C; yield 0-60%. References Tessitore P.T.; US Patent No. 4,478,846; Oct. 23, 1984

ACADESINE Therapeutic Function: Cardiotonic, Platelet aggregation inhibitor Chemical Name: 1H-Imidazole-4-carboxamide, 5-amino-1β-D-ribofuranosylCommon Name: Acadesine; AICA riboside; Arasine Structural Formula:

Chemical Abstracts Registry No.: 2627-69-2 Trade Name

Manufacturer

Country

Year Introduced

AICA

BIOMOL

-

-

Raw Materials Sodium hydroxide Methyl iodide Formic acid Hydrogen Ammonium hydroxide

Adenosine 3', 5'-cyclic phosphate N'-oxide Sodium bicarbonate Nickel 1,5-Diazabicyclo[5.4.0]undec-5-ene

Manufacturing Process Adenosine 3', 5'-cyclic phosphate N'-oxide (76.0 g, 0.200 mole) as the

18

Acadesine

dihydrate was dissolved in a solution of 400 ml DMSO and 31.0 g (0.204 mole) 1,5-diazabicyclo[5.4.0]undec-5-ene. The solution was cooled to 15°C and 40 ml methyl iodide was added with stirring at room temperature. After 30 min, the mixture had gelled; 1.5 L ethanol was added and the solid was thoroughly homogenized by vigorous stirring. The solid was filtered, and the resulting paste was resuspended in 2 L ethanol and homogenized. The product was again filtered, washed with ethanol and ether, and dried, giving 80.4 g of 1-methoxyadenosine 3',5'-cyclic phosphate suitable for further transformation (recrystallization from aqueous methanol with ether). A solution of 30.0 g 1-methoxyadenosine 3',5'-cyclic phosphate (81.5 mmole), 20.0 g NaHCO3 (238 mmole), and 300 ml H2O was refluxed 45 mm. The pH of the solution was adjusted to 2.5 with Dowex 50x8 (H)+ while warm, and a water pump vacuum was applied to mixture to remove CO2. The pH was readjusted to 9-10 with NaOH, and the resin was removed by filtration. The solution was passed onto a column containing 400 ml Dowex 1x2 (formate, 100-200 mesh), and the column was washed well with water. The column was eluted with a gradient of 4 L water in the mixing chamber and 4 L 4 N formic acid in the reservoir. The first major product, coming after about 2 L eluate, was 5-amino-N-methoxy-1-β-D-ribofuranosylimidazole-4-carboxamidine 3',5'cyclic phosphate, giving 5.4 g (19%) after evaporation of the solvent and trituration of the residue with ethanol (recrystallization from water). A solution of 5.0 g (14.3 mmoles) 5-amino-N-methoxy-1-β-Dribofuranosylimidazole-4-carboxamidine 3',5'-cyclic phosphate in 200 ml H2 preheated to 60°C and containing approximately 5.0 g moist sponge nickel catalyst, was shaken with 2-3 atm. H2 at 60°C for 2 h. The filtered solution was evaporated to dryness to give 3.75 g of 5-amino-1-β-Dribofuranosylimidazole-4-carboxamidine 3',5'-cyclic phosphate (82%), (recrystallization from water). A mixture of 4.0 g (12.5 mmole) 5-amino-1-β-D-ribofuranosylimidazole-4carboxamidine 3',5'-cyclic phosphate and 100 ml conc. NH4OH was heated in a bomb at 100°C for 16 h, then cooled and evaporated in vacuum. The residue was taken up in 100 ml H2O and applied to a 2.5x20 cm column of Dowex 1x2 (formate form, 100-200 mesh). After washing well with H2O the column was eluted with a gradient of 1 L H2O in the mixing chamber and 1 L 3 N formic acid in the reservoir. Fractions containing the product, appearing near the end of the elution, were evaporated. Trituration of the residue with EtOH gave 2.90 g (68%) of 5-amino-1-β-D-ribofuranosylimidazole-4carboxamide 3',5'-cyclic phosphate. The 5-amino-1-β-D-ribofuranosylimidazole-4-carboxamide may be produced by hydrolysis of 5-amino-1-β-D-ribofuranosylimidazole-4-carboxamide 3',5'cyclic phosphate with NaOH. References Meyer R.B., Shuman D.A.; US Patent No. 3,919,192; Nov. 11, 1975; Assigned: ICN Pharmaceuticals, Irvine, Calif.

Acamprosate calcium

19

ACAMPROSATE CALCIUM Therapeutic Function: Psychotropic Chemical Name: 3-(Acetylamino)-1-propanesulfonic, calsium salt (2:1) Common Name: Acamprosate; N-Acetylhomotaurine Structural Formula:

Chemical Abstracts Registry No.: 77337-73-6; 77337-76-9 (Base) Trade Name Campral Campral

Manufacturer Merck Forest Pharm

Country -

Year Introduced -

Raw Materials Sodium hydroxide Aminopropanesulfonic acid

Acetic anhydride Hydrochloric acid

Manufacturing Process In a 4 liter flask provided with stirring means, a bromine funnel and a thermometer, 17.5% sodium hydroxide solution and aminopropanesulfonic acid (homotaurine) are added. After complete dissolution, at a temperature of between 25°-40°C, acetic anhydride are added so as not to exceed a temperature of between 30°-40°C. The mixture is then maintained at this temperature by heating for at least 1 h. The solution is then concentrated in vacuum, the residue is redissolved in 2.5 L of distilled water and the mixture is concentrated again. The residue is then dissolved in 1.6 L of distilled water, filtered, then concentrated almost completely. Drying is terminated in an oven in vacuum. A colorless crystalline powder of 3-acetylaminopropanesulfonate of sodium (sodium Nacetylhomotaurinate) is obtained. The 3-acetylaminopropanesulfonic acid may be produced by treatment of 3acetylaminopropanesulfonate of sodium with hydrochloric acid. In practice it is usually used as calcium salt.

20

Acaprazine

References Durlach J.P.; US Patent No. 4,355,043; Oct. 19, 1982; Assigned: Les Laboratores Meram, France

ACAPRAZINE Therapeutic Function: Adrenergic blocker, Tranquilizer Chemical Name: Acetamide, N-(3-(4-(2,5-dichlorophenyl)-1-piperazinyl) propyl)Common Name: Acaprazine Structural Formula:

Chemical Abstracts Registry No.: 55485-20-6 Trade Name

Manufacturer

Country

Year Introduced

Acaprazine

ZYF Pharm Chemical

-

-

Raw Materials Nickel Raney Sodium hydroxide Sodium carbonate Potassium phthalimide 4-(m-Chloropheny1)-1piperazinopropionitrile Acetic anhydride Triethylamine

N-(3-Chloropropyl)phthalimide 1-(2,5-Dichlorophenyl)piperazine Hydrogen chloride Hydrazine hydrate 1-(3-Chloropropyl)-4-(2,5-dichlorophenyl) piperazine Chlorosuccinimide Hydrogen

Manufacturing Process 2 methods of producing of 1-(3-acetylaminopropyl)-4-(2,5-dichlorophenyl) piperazine: 1. A mixture formed by N-(3-chloropropyl)phthalimide (23.0 g), 1-(2,5dichlorophenyl)piperazine (24.0 g), anhydrous sodium carbonate (14.0 g) and toluene (130 ml) is boiled under stirring for 30 h. The solution is then cooled, filtered, concentrated to dryness, and the residue is treated with water and ether. The ethereal extract is washed, dried and concentrated to dryness. The

Acarbose

21

residue is treated with ethyl acetate and transformed into hydrochloride with ethanolic HCl. N-[3-[4-(2,5-Dichlorophenyl)-1-piperazinyl]propyl]phthalimide hydrochloride (30.0 g) is obtained, melting point 233°C (dec.). N-[3-[4-(2,5-Dichlorophenyl)-1-piperazinyl]propyl]phthalimide (15.0 g) and 99% hydrazinehydrate (2 ml) are heated, under reflux, for 90 min. 5 N HCl (115 ml) is then added and the solution is heated for 30 min under reflux. The solution is cooled, filtered and concentrated to small volume. The residue is diluted with water, made alkaline by means of a solution of NaOH and extracted with CH2Cl2. The organic layer is dried, evaporated and distilled under reduced pressure. 7.0 g of 1-(3-aminopropyl)-4-(2,5-dichlorophenyl) piperazine are obtained. 1-(3-Aminopropyl)-4-(2,5-dichlorophenyl)piperazine (50.0 g) is dissolved in CH2Cl2, and the solution is heated under reflux. Acetic anhydride (25 ml) dissolved in CH2Cl2, (500 ml) is introduced under stirring in about 1 h. The solution is heated for 1 h and is evaporated to dryness in a rotating evaporator. The is treated with H2O, thus obtaining a solid which is separated, washed and dried at 50°C. This solid is then dissolved in ethyl acetate (about 350 ml), treated with charcoal and crystallized. 1-(3-Acetylaminopropyl)-4(2,5-dichlorophenyl)piperazine is obtained in an almost quantitative yield, melting point 114°C. 2. Chlorosuccinimide (5.4 g) is added to a solution of 4-(m-chlorophenyl)-1piperazinopropionitrile (5.0 g) in CH2Cl2 (100 ml). The solution is heated for a few hours and, after removal of the solvent, it is chromatographed on an alumina column. The solution is eluted with a 1:1 mixture of cyclohexane and benzene containing 0.3 % of triethylamine. 4-(2,5-Dichlorophenyl)-1piperazinopropionitrile (2.0 g) is thus obtained. 4-(2,5-Dichlorophenyl)-1-piperazinopropionitrile (20.0 g), acetic anhydride (100 ml), anhydrous sodium sulfate (12.0 g) and a 50% solution of Ni-Raney (6 ml) are hydrogenated at 60.0 pounds per inch at 60°C in a Parr apparatus. After about half an absorption of hydrogen is complete. The reaction mixture is cooled, the is filtered and the solution is concentrated to small volume in a rotating evaporator. The residue is treated with NaOH solution and extracted several times CH2Cl2. The organic layer is washed, dried and evaporated. The residue is crystallized from ethyl acetate. 14.0 g of the 1-(3acetylaminopropyl)-4-(2,5-dichlorophenyl)piperazine are obtained, melting point 114°C. References GB Patent No. 1,443,598; July 21, 1976; Assigned: Aziende Chemiche Riunite Angelini Franceso A.C.R.A.F. S.p.A., Italy

ACARBOSE Therapeutic Function: Antidiabetic

22

Acarbose

Chemical Name: D-Glucose, O-4,6-dideoxy-4-(((1S-(1α,4α,5β,6α))-4,5,6trihydroxy-3-(hydroxymethyl)-2-cyclohexen-1-yl)amino)-α-Dglucopyranosyl-(1-4)-O-α-D-glucopyranosyl-(1-4)Common Name: Acarbose Structural Formula:

Chemical Abstracts Registry No.: 56180-94-0 Trade Name Glicobase Glucobay Glucor Glumida Prandase

Manufacturer Formenti Bayer Limited Laboratoires Bayer Pharma Pensa Yno

Country Italy India France Spain -

Year Introduced -

Precose

Bayer

Germany

-

Precose

Cheshire Drugs

-

-

Precose Precose

Allscripts Physicians TC.

-

-

Raw Materials Microorganisms of family Actinoplanacease (by fermentation) Commercial cation exchanger based on polystyrene with a degree of crosslinking 3-4% Solution of saccharase inhibitor Lewatit Manufacturing Process The title compound was obtained from a cultural broth of fermenting a microorganism of family Actinoplanaceae in particular of strain genus Actinoplanes, according to DT-OS (German Published Specification) No. 2,347,782. 50 g of cation exchange resin (Lewatit S 1040W) in the H+ form and 30 g an anion exchanger (Lewatit M 600) in OH form were added to 300 ml of a culture broth with mycelium content of 25% and an inhibitor content of 50 SIU/ml in solution. The mixture was stirred at room temperature for 50 minutes. The solution, containing a sieving nozzle with 0.1 mm slits. For

Acebutolol

23

testing, a sample of filtered broth was centrifuged and was examined for saccharase inhibitor in the supernatant liquor. The solution contained 2.5 SIU/ml, that is to say 5%, of starting activity. This procedure improved the yield of the aminosugar from 20% in the procedure known from DT-OS (German Published Specification) No. 2,347,782, to 50-60%. It has now found that cation exchangers based on styrene, divinylbenzene and methoxymethylmethacrylamide, oxyethyl(meth)acrylic acid amide (ester), dimethylaminoethyl(meth)acrylic acid amide (ester) or oxypropyl(meth)acrylic acid amide(ester) are preferred in industrial separation procedure of acarbose. This exchanger gave a very sharp separation of the individual homologues and impurities. And it has now found the new biosynthesis of acarbose by using of gen engineering methods. References Rauenbusch E. et al.; US Patent No. 4,174,439, Nov. 13, 1979, Assigned: Bayer Aktiengesellschaft (Leverkusen, DE) Lange P.M. et al.; US Patent No. 4,666,776, May 19, 1987, Assigned: Bayer Aktiengesellschaft (Leverkusen, DE) Deutsches Patent and Markenamt, Offenlegungsschrift DE 100 21 667 A1, 8. 11.2001

ACEBUTOLOL Therapeutic Function: beta-Adrenergic blocker Chemical Name: N-[3-Acetyl-4-[2-hydroxy-3-[(1-methylethyl)-amino] propoxy]phenyl]butanamide Common Name: 5'-Butyramido-2'-(2-hydroxy-3-isopropylaminopropoxy)acetophenone Structural Formula:

Chemical Abstracts Registry No.: 37517-30-9; 34381-68-5 (Hydrochloride salt) Trade Name

Manufacturer

Country

Year Introduced

Sectral

May and Baker

UK

1975

Sectral

Specia

France

1976

Prent

Bayer

W. Germany

1977

24

Acebutolol

Trade Name

Manufacturer

Country

Year Introduced

Neptall

Rhodia Pharma

W. Germany

1977

Sectral

May and Baker

Switz.

1980

Sectral

Roger Bellon

Italy

1980

Sectral

RBJ Pharma

Italy

1980

Acetanol

Kanebo, Ltd.

Japan

1981

Prent Acecor Diasectral Neptal Secradex Sectral

Bayer S.P.A. Rhone Poulenc Rohm Pharma May and Baker Wyeth

Italy Italy UK US

1981 -

Raw Materials Butyramidophenol Aluminum chloride Sodium ethoxide

Acetyl chloride Epichlorohydrin Isopropylamine

Manufacturing Process Crude 5'-butyramido-2'-(2,3-epoxypropoxy)acetophenone (16 g), isopropylamine (20 g) and ethanol (100 ml) were heated together under reflux for 4 hours. The reaction mixture was concentrated under reduced pressure and the residual oil was dissolved in N hydrochloric acid. The acid solution was extracted with ethyl acetate, the ethyl acetate layers being discarded. The acidic solution was brought to pH 11 with 2 N aqueous sodium hydroxide solution and then extracted with chloroform. The dried chloroform extracts were concentrated under reduced pressure to give an oil which was crystallized from a mixture of ethanol and diethyl ether to give 5'-butyramido2'-(2-hydroxy-3-isopropylaminopropoxy)acetophenone (3 g), MP 119-123°C. Crude 5'-butyramido-2'-(2,3-epoxypropoxy)acetophenone used as starting material was prepared as follows: p-butyramidophenol (58 g; prepared according to Fierz-David and Kuster, Helv. Chim. Acta 1939,2282), acetyl chloride (25.4 g) and benzene (500 ml) were heated together under reflux until a solution formed (12 hours). This solution was cooled and treated with water. The benzene layer was separated and the aqueous layer was again extracted with benzene. The combined benzene extracts were dried and evaporated to dryness under reduced pressure to give p-butyramidophenyl acetate (38 g) as an off-white solid, MP 102-103°C. A mixture of p-butyramidophenyl acetate (38 g), aluminum chloride (80 g) and 1,1,2,2-tetrachloroethane (250 ml) was heated at 140°C for 3 hours. The reaction mixture was cooled and treated with iced water. The tetrachloroethane layer was separated and the aqueous layer was extracted with chloroform. The combined organic layers were extracted with 2 N aqueous sodium hydroxide and the alkaline solution was acidified to pH 5 with concentrated hydrochloric acid. The acidified solution was extracted with chloroform and the chloroform extract was dried and concentrated under reduced pressure to give 5'-butyramido-2'-hydroxyacetophenone (15.6 g), MP 114-117°C. A solution of 5'-butyramido-2'-hydroxyacetophenone (15.6 g) in

Acecainide

25

ethanol (100 ml) was added to an ethanolic solution of sodium ethoxide which was prepared from sodium (1.62 g) and ethanol (100 ml). The resulting solution was evaporated to dryness under reduced pressure and dimethylformamide (100 ml) was added to the solid residue. Approximately 10 ml of dimethylformamide was removed by distillation under reduced pressure. Epichlorohydrin (25 ml) was added and the solution was heated at 100°C for 4 hours. The solution was concentrated under reduced pressure to give a residual oil which was treated with water to give a solid. The solid was dissolved in ethanol and the resulting solution was treated with charcoal, filtered and concentrated under reduced pressure to give crude 5'-butyramido2'-(2,3-epoxypropoxy)acetophenone (16 g), MP 110-116°C. The crude compound may be purified by recrystallization from ethyl acetate, after treatment with decolorizing charcoal, to give pure 5'-butyramido-2'-(2,3epoxypropoxy)acetophenone, MP 136-138°C. References Merck Index 13 Kleeman and Engel p. 1 PDR p. 1978 OCDS Vol. 2 p. 109 (1980) DOT 11 (7) p. 264 (1975) I.N. p. 2 Wooldridge, K.R.H. and Basil, B.; US Patent 3,857,952; Dec. 31,1974; Assigned to May and Baker, Ltd.

ACECAINIDE Therapeutic Function: Antiarrhythmic Chemical Name: Benzamide, 4-(acetylamino)-N-(2-(diethylamino)ethyl)Common Name: Acecainide; NAPA Structural Formula:

Chemical Abstracts Registry No.: 32795-44-1

26

Acecarbromal

Trade Name Acecainide

Manufacturer ZYF Pharm Chemical

Country -

Year Introduced -

Raw Materials Acetyl chloride p-Amino-N-(2-diethylaminoethyl)benzamide Sodium hydroxide Manufacturing Process 1.0 g of p-amino-N-(2-diethylaminoethyl)benzamide is dissolved in chloroform. A few ice cubes are added to the solution. Acetyl chloride is added dropwise with stirring until no more white precipitate forms; the latter is separated by filtering under suction. The precipitate is washed with cold acetone and dried overnight in a vacuum oven at room temperature. The product is dissolved in a minimum amount of hot isopropanol and allowed to precipitate in the cold. The p-acetamido-N-(2-diethylaminoethyl)benzamide hydrochloride, is recrystallized a second time from hot isopropanol, melting point 190°-193°C. The free base is obtained from the hydrochloride by dissolving the latter in water, adjusting the pH to greater than 10 with dilute sodium hydroxide, and adding an equal volume of benzene. After shaking in a separatory funnel, the benzene layer is recovered and evaporated to dryness. So the p-acetamido-N(2-diethylaminoethyl)benzamide is obtained. References GB Patent No. 1,319,980; June 13, 1973; Assigned: E.R. Squibb and Sons, Inc., a corporation organized and existing under the laws of the State of Delaware, USA

ACECARBROMAL Therapeutic Function: Sedative, Hypnotic Chemical Name: Butanamide, N-((acetylamino)carbonyl)-2-bromo-2-ethylCommon Name: Acecarbromal; Acetcarbromal; Acetylcarbromal; Sedacetyl Structural Formula:

Chemical Abstracts Registry No.: 77-66-7

Aceclidine Trade Name Acetylcarbromal Afrodor 2000 Afrodor 2000 Paxarel

Manufacturer Pfaltz and Bauer Farco-Pharma Biomenta Circle Pharmaceuticals

Country -

27

Year Introduced -

Raw Materials Urea Bromine Zinc chloride

Diethylacetic acid anhydride Acetic anhydride

Manufacturing Process It was mixed 120 parts of urea and 258 parts of bromodiethylacetylbromide (prepared from diethylacetic acid anhydride and bromine). After 12 hours the mixture was heated for 3 hours at 100°C. The product was mixed with an aqueous solution of sodium bicarbonate and then was filtered. The obtained bromodiethylacetylurea was crystallized from diluted ethanol; melting point 114-118°C. The mixture of 474 parts of bromodiethylacetylurea, 1000 parts of acetic anhydride and 75 parts ZnCl2 was heated at 60°C for 1 hour. The product was stirred with 3000 parts of ice-water and then 1-acetyl-3-(αbromo-α-ethylbutyryl)urea was filtered; melting point 108-109°C. References Merck Index, Monograph number: 18, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. DE Patent 286,760, 1913; Bayer and Co. In Elberfeld DE Patent 327,129, 1917; Bayer and Co., Leverkusen

ACECLIDINE Therapeutic Function: Miotic, Cholinomimetic Chemical Name: 1-Azabicyclo[2.2.2]octan-3-ol acetate Common Name: 3-Quinuclidinol acetate Structural Formula:

Chemical Abstracts Registry No.: 827-61-2; 6109-70-2 (Hydrochloride salt)

28

Aceclidine

Trade Name

Manufacturer

Country

Year Introduced

Glacostat

MSD-Chibret

France

1966

Glaunorm

Farmigea

Italy

1969

Glaudin

Sifi

Italy

-

Raw Materials Methyl isonicotinate Potassium

Ethyl bromoacetate Hydrogen

Manufacturing Process A mixture of 274 g of methyl isonicotinate, 367 g of ethyl bromoacetate and 125 cc of ethyl alcohol was stirred without heating for 4 hours in a flask equipped with a reflux condenser. (The reaction was exothermic and precautions were taken to keep the temperature below 70°C.) The reaction mixture was then left for 15 hours at room temperature. The reaction product (1-carbethoxymethyl-4-carbornethoxy-pyridinium bromide) was obtained in crystalline form. (It formed prisms melting at 166169°C after recrystallization from a mixture of isopropanol and acetone.) It was not necessary to isolate it. For the following reduction step, the reaction mixture was brought into solution by the addition of about 1 liter of warm ethyl alcohol. It was then hydrogenated at about 30 atm pressure in the presence of 2 g of platinum oxide. The temperature rose during this reaction to about 40°C. After the calculated amount of hydrogen had been absorbed, the catalyst was filtered off, the solution was concentrated in vacuum, and the residual syrup was dissolved in ice water. Benzene was added and the mixture was made alkaline with an excess of concentrated ice cold potassium carbonate solution. The temperature was kept low by continuous addition of ice, and the benzene layer was separated and dried with sodium sulfate. The dried benzene solution was concentrated in vacuum and the residual oil was distilled in vacuum. BP 30 mm = 175-182°C, nD25= 1.4613-1.4628. During the reduction, partial alcoholysis occurred, and the product isolated was 1carbethoxymethyl-4-"carbalkoxy"-piperidine, wherein "carbalkoxy" represents a mixture of carbomethoxy and carbethoxy. 100 g of potassium were pulverized in 200 cc of hot toluene in a heated three-neck flask equipped with an efficient condenser, stirrer and dropping funnel. To the refluxing potassium suspension were added in small portions 229 g of the product of the previous step and about 700 cc of toluene. This addition had to be carried out very cautiously; the onset of the exothermic reaction is sometimes delayed. The addition was finished in about 1 hour. To complete the reaction, the refluxing and stirring were continued for about 4 hours. The reaction mixture was then cooled to about +5°C and about 50 cc isopropanol were added to decompose unreacted potassium. Then 2.5 liters of concentrated hydrochloric acid were added and the mixture was refluxed for 15 hours, and then concentrated in vacuum to dryness. To the residue was added with cooling an excess of 50% potassium hydroxide. Ether was then added and the resulting mixture was filtered through a fritted glass funnel, thus removing the precipitated potassium chloride. The ethereal and aqueous layers were separated, and the aqueous layer was extracted repeatedly with 500 cc portions of ether. The organic solutions were combined, dried over

Aceclidine

29

sodium sulfate and concentrated in vacuum. Aqueous hydrochloric acid was added to the residue until the solution became acid. The mixture was then diluted with distilled water to about 300 cc, heated with decolorizing charcoal, filtered and concentrated in vacuum to dryness. The residue was treated with isopropanol, and the precipitated crystalline product was filtered off. The product was recrystallized from a mixture of water and isopropanol and was identified as 1-azabicyclo[2.2.2]-3-octanone hydrochloride; prisms, MP 311313°C, with decomposition. A solution of 50 g of the above ketone-hydrochloride in 30 cc of water was made alkaline by the addition of 30 g of potassium hydroxide. After the alkali was dissolved, 35 g of granular potassium carbonate were added. The free basic ketone was then extracted from the viscous mixture by shaking with 4 portions of hot benzene (300 cc in each portion). The benzene extracts were decanted, filtered over sodium sulfate in order to remove any suspended alkali, and concentrated in vacuum. The residual lszabicyclo[2.2.2]-3-octanone was purified by sublimation (50-70°C/0.5 mm Hg); it can also be purified by recrystallization from petroleum ether. It formed feathery crystals melting at 147-148°C. The product was reduced as follows: A solution of 50 g of 1-azabicyclo[2.2.2]-3-octanone hydrochloride in 200 cc of water was hydrogenated at room temperature and 50 atm pressure with 1 g of platinum oxide as catalyst. After the calculated amount of hydrogen had been absorbed, the mixture was filtered and concentrated in vacuum to dryness. The residual product was recrystallized from a mixture of methanol and acetone and formed prisms melting above 300°C. It was identified as 1azabicyclo[2.2.2]-3-octanol hydrochloride. A solution of 50 g of 1-azabicyclo[2.2.2]-3-octanol hydrochloride in 30 cc water was made alkaline with 30 g of potassium hydroxide. After the alkali was dissolved 35 g of granular potassium carbonate were added. The free basic alcohol was then extracted from the viscous mixture by shaking with four portions of boiling benzene (300 cc in each portion). The benzene extracts were decanted and filtered over anhydrous sodium sulfate, to remove any suspended alkali. The combined benzene solutions were concentrated in vacuum. The residue was recrystallized from benzene and identified as lszabicyclo[2.2.2]-3-octanol, MP 221-223°C. The product can also be purified by recrystallization from acetone, or by sublimation in vacuum (120°C/20 mm Hg). The alcohol was reacted with acetic anhydride to give the product aceclidine. References Kleeman and Engel p. 2 OCDS Vol. 2 p. 295 (1980) I.N. p. 2 Sternbach, L.H.; US.Patent 2,648,667; Aug. 11,1953; Assigned to Hoffman La Roche Inc.

30

Aceclofenac

ACECLOFENAC Therapeutic Function: Analgesic, Antiinflammatory Chemical Name: Benzeneacetic acid, 2-[(2,6-dichlorophenyl)amino]-, carboxymethyl ester Common Name: Aceclofenac; Locomin Structural Formula:

Chemical Abstracts Registry No.: 89796-99-6 Trade Name Reservix Aceclofenac Airtal Kafenac Zurem Beofenac Bristaflam Bristaflam Berlofen Bristaflam Biofenac Biofenac Biofenac Locomin Proflam

Manufacturer Incepta Xian HaiXin pharmaceutical Co., Ltd. Almirall Almirall ABIOGEN PHARMA srl Almirall Egypt Company Co. BMS Co. Elea Bristol UCB BERAGENA EMRA-MED ARZNEIM UCB Eurofarma

Country -

Year Introduced -

-

-

Raw Materials Benzyl bromoacetate Sodium 2-[(2,6-dichlorphenyl)amino]phenylacetate Palladium on carbon Hydrogen Manufacturing Process 50 g of sodium 2-[(2,6-dichlorphenyl)amino]phenylacetate were dissolved in 300 ml of N,N-dimethylformamide under heating to 50°C, and 44.22 g of benzyl bromoacetate were added thereto. Under these condition stirring was

Acediasulfone sodium

31

continued for 9 hours. Upon completion of the reaction, the solvent was removed at reduced pressure, and the sodium salt were precipitated with addition of 400 ml of ether. The solution was then filtered and the ether phase was washed twice time with 100 ml of hexane. The resulting product was crystallized from the hexane/ether and then from acetone/chloroform (1:9) thus obtaining 44.1 g (61%) of benzyl 2-[(2,6dichlorphenyl)amino]phenylacetoxyacetate in the form of white crystals having a melting point of 67-69°C. 45.28 g of benzyl 2-[(2,6-dichlorphenyl)amino]phenylacetoxyacetate were dissolved in 1500 ml of ethyl acetate, and the resulting solution was mixed with 7 g of Pd/C 10% and then hydrogen ted at atmospheric pressure for 14 hours. The solution was filtered, concentrated and crystallized; thereby obtaining 23.51 g (65%) of 2-[(2,6-dichlorphenyl)amino]phenylacetoxyacetic acid; melting point 149-150°C. References Casas A.V.; US Patent No. 4,548,952; Oct. 22, 1985; Assigned to Prodes, S.A., San Justo Desvern, Spain Schickaneder H., Nikolopoulos A., Murphy T.; WO Patent No. 9,955,660; 199911-04; Assigned to Russinsky Ltd (IE), Schickaneder Helmut (IE), Nikolopoulos Aggelos (IE), Murphy Trevor (IE)

ACEDIASULFONE SODIUM Therapeutic Function: Antibacterial Chemical Name: N-p-Sulfanilylphenylglycine sodium Common Name: Acediasulfone sodium; Glycinodiasulfone sodium Structural Formula:

Chemical Abstracts Registry No.: 127-60-6; 80-03-5 (Base) Raw Materials Methyl chloroacetate Lithium hydroxide Sodium hydroxide

4,4'-Diaminodiphenyl sulfone Hydrochloric acid

32

Acedoben

Trade Name

Manufacturer

Country

Year Introduced

Solfone

Bracco

-

-

Manufacturing Process 24.8 g of 4,4'-diaminodiphenyl sulfone, 150 g of methyl chloroacetate and 150 ml of ethanol are refluxed together and refluxed for 24 hours. The alcohol and excess methyl chloroacetate are then distilled off on a steam bath under reduced pressure. The residue consisting of the hydrochloride salt of 4-amino4'-(carbomethoxymethylamino)diphenyl sulfone is mixed with of alcoholic solution containing 2.5 g lithium hydroxide and refluxed for 4 hours on the steam bath. Most of the alcohol is removed by distillation and the residual lithium salt of 4-amino-4'-(carboxymethylamino)diphenyl sulfone taken up water. The solution is filtered and dilute HCl added until no more separation occurs. The 4-amino-4'-(carboxymethylamino)diphenyl sulfone thus obtained is collected and dried. The sodium salt of 4-amino-4'-(carboxymethylamino)diphenyl sulfone is prepared by dissolving the free acid in an aqueous solution containing one equivalent of sodium hydroxide and evaporating the solution to dryness in vacuo. References Merck Index, Monograph number: 21, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. Rawlins A.L.; US Patent No. 2,589,211; Mar. 18, 1952; Assigned to Parke, Devis and Co., Detroit, Michigan Martin H., Habicht E.; US Patent No. 2,751,382; June 19, 1956; Assigned to Cilag Ltd., Schaffhausen, Switzerland

ACEDOBEN Therapeutic Function: Antiviral Chemical Name: Benzoic acid, p-acetamidoCommon Name: Acedoben Structural Formula:

Acefluranol

33

Chemical Abstracts Registry No.: 556-08-1 Trade Name 4-Acetamidobenzoic acid p-Acetamidobenzoic Acid p-Acetamidobenzoic Acid

Manufacturer ARIAC Chembay Chemical Co., LTD Sigma-Aldrich

Country -

Year Introduced -

-

-

Raw Materials Magnesium sulfate N-p-Tolylacetamide Hydrochloric acid

Sodium acetate Potassium permanganate

Manufacturing Process Into a 2 L, 3-necked flask set in a tub and equipped with a stirrer, an air condenser (drying tube), thermometer, was placed 860 ml of water, 43.0 g of MgSO4 and 43.0 g of sodium acetate and heated on water bath. Into heated solution to 70°C stirring 43.0 g of N-p-tolylacetamide were added. Then 136.0 g of KMnO4 by small portions were added at 75°-80°C. The reaction mixture allow to stand for 6 h and stirring was continue till the solution became colorless. Hot solution was filtered and filtrate treated hydrochloric acid to slightly acidic pH. After that 44.0 g (85%) of p-acetoaminobenzoic acid was obtained as white precipitate, melting point 250°C. References Berkengame A.M.; Chemistry and Technology of synthetic drugs; 1935; Moscow

ACEFLURANOL Therapeutic Function: Antiestrogen Chemical Name: (1RS,2SR)-4,4'-(1-Ethyl-2-methyl-1,2-ethanediyl)bis[6fluoro-1,2-benzenediol] tetraacetate Common Name: Acefluranol; BX 591 Structural Formula:

34

Acefluranol

Chemical Abstracts Registry No.: 80595-73-9 Trade Name

Manufacturer

Country

Year Introduced

Acefluranol

ZYF Pharm Chemical

-

-

Raw Materials erythro-3,3'-Difluoro-4,4'-dihydroxy-α-ethyl-α'-methylbibenzyl Pyridine Acetic anhydride Aluminum chloride Sodium hydroxide Hydrogen peroxide Sodium borohydride Hydrochloric acid Manufacturing Process 4.5 g erythro-3,3'-difluoro-4,4'-dihydroxy-α-ethyl-α'-methylbibenzyl in 30 ml pyridine and 10 ml acetic anhydride were left to stand for 24 h at room temperature, thereafter the reaction mixture was worked up to give a crude product, recrystallisation of which from chloroform-diethyl ether (1:4 v/v) gave 5.5 g erythro-3,3'-difluoro-4,4'-diacetoxy-α-ethyl-α'-methylbibenzyl, melting point 118°-120°C. 5.0 g of the erythro-3,3'-difluoro-4,4'-diacetoxy-α-ethyl-α'-methylbibenzyl were ground with 10.0 g aluminum chloride and the mixture was heated at 150°C for 30 min. After cooling, the mass was added portion-wise to ice, stirred and extracted with chloroform. The chloroform solution was washed with water, dried with anhydrous sodium sulfate and concentrated to half its volume. An equal volume of diethyl ether was added thereto and the solution was treated with charcoal and filtered. The filtrate was evaporated and the residue obtained was crystallized from chloroform-diethyl ether (1:1 v/v) to give 2.6 g erythro-3,3'-diacetyl-4,4'-dihydroxy-5,5'-difluoro-α-ethyl-α'methylbibenzyl, melting point 194°-196°C. 0.9 g erythro-3,3'-diacetyl-4,4'-dihydroxy-5,5'-difluoro-α-ethyl-α'methylbibenzyl were suspended in a mixture of 10 ml dioxan and 6 ml 1 N aqueous sodium hydroxide solution. The solution was cooled to 10°C and 0.8 ml 30% hydrogen peroxide added dropwise thereto. The reaction mixture was stirred at 20°C for 1.5 h and then poured into a mixture of dilute hydrochloric acid and ice. The product was extracted with peroxide-free diethyl ether, the extract was evaporated and the residue was crystallized from benzene to give a yellow solid. This was treated in 5 ml ethanol with 2.0 mg sodium borohydride, followed by acidification with hydrochloric acid, rapid extraction with diethyl ether, evaporation of the extract and immediate crystallization from benzene to give 350.0 mg of pure erythro-4,4',5,5'-tetrahydroxy-3,3'difluoro-α-ethyl-α'-methyldibenzyl, melting point 143°-145°C. 1.0 g erythro-3,3'-difluoro-4,4',5,5'-tetrahydroxy-α-ethyl-α'-methyldibenzyl in a mixture of 10 ml pyridine and 5 ml acetic anhydride was left to stand at 20°C for 20 h and at 60°-80°C for 1 h. The reaction mixture was then poured into a mixture of dilute hydrochloric acid and ice, stirred for several h and filtered. The filtrate was evaporated and the residue was taken up in

Aceglutamide aluminum

35

chloroform and the chloroform solution was washed with dilute hydrochloric acid and water, dried over anhydrous sodium sulfate and the solvent removed. The gummy residue was taken up with benzene and the benzene solution filtered through a neutral alumina. The benzene was removed from the filtrate to give 1.0 g pure erythro-3,3'-difluoro-4,4',5,5'-tetraacetoxy-α-ethyl-α'methyldibenzyl; melting point 160°-162°C (crystallised from diethyl ether). References Chan R.P.K.; US Patent No. 4,427,697; Jan. 24, 1984; Assigned: Biorex Laboratories Limited, England

ACEGLUTAMIDE ALUMINUM Therapeutic Function: Antiulcer Chemical Name: Pentakis(N2-acetyl-L-glutaminato)tetrahydroxytrialuminum Common Name: Structural Formula:

Chemical Abstracts Registry No.: 12607-92-0 Trade Name Glumal Glumal

Manufacturer Kyowa Hakko Liade

Raw Materials N-Acetyl-L-glutamine Aluminum isopropoxide

Country Japan Spain

Year Introduced 1978 -

36

Acemetacin

Manufacturing Process A mixture of 37.6 g of N-acetyl-L-glutamine and 1,000 ml of water is heated to 40°C, and 900 ml of an isopropanol solution containing 40.8 g of aluminum isopropoxide is added to the warm mixture with stirring. The stirring is continued for 10 minutes. The reaction mixture is filtered and the filtrate is concentrated under reduced pressure. Isopropanol is added to the aqueous solution and the salt precipitates in the solution. The precipitates are collected by filtration and upon drying, 48.5 g of the crystalline-like aluminum salt of Nacetyl-L-glutamine are obtained. References Merck Index 20 Kleeman and Engel p. 32 DOT 14 (2) p. 54 (1978) I.N. p. 3 Kagawa, T., Fuji, K., Tanaka, M. and Tanaka, H.; US Patent 3,787,466; Jan. 22,1974; Assigned to Kyowa Hakko Kogyo Co., Ltd.

ACEMETACIN Therapeutic Function: Antiinflammatory Chemical Name: 1-(p-Chlorobenzoyl)-5-methoxy-2-methylindole-3acetoxyacetic acid Common Name: Structural Formula:

Chemical Abstracts Registry No.: 53164-05-9 Trade Name Rantudil Rantudil

Manufacturer Bayer Tropon

Country W. Germany W. Germany

Year Introduced 1980 -

Acenocoumarol

37

Raw Materials N-(p-Methoxybenzyl)-p-chlorobenzhydrazide HCl Benzyl levulinoyloxyacetate Hydrogen Manufacturing Process 25.4 g (0.050 mol) of [1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3indoleacetoxy]-benzyl acetate were dissolved in 400 ml of glacial acetic acid and hydrogenated on 2.0 g of palladium carbon at room temperature. After the absorption of hydrogen had finished (1 hour), the catalyst was filtered off, the filtrate was concentrated by evaporation under vacuum and the compound was caused to crystallize by adding petroleum ether. The compound melted at 149.5-150.5°C (determined on the micro-Kofler bench); the yield was 19.4 g which corresponds to 93% of the theoretical yield. The starting material for the above step may be prepared as follows: 5 g (0.016 mol) of N1-(p-methoxyphenyl)-p-chlorobenzhydrazide hydrochloride and 4.75 g (0.018 mol) of benzyl levulinoyloxyacetate were heated in 25 ml of glacial acetic acid for 3 hours at 80°C. The solvent was then evaporated off under vacuum. The residue was taken up in chloroform and the solution was washed neutral by shaking with sodium bicarbonate solution and thereafter with water. After drying the chloroform solution, this was subjected to chromatography on aluminium oxide, the eluate was concentrated by evaporation and the viscous oil remaining as residue was crystallized by adding ether. The compound melted at 94-95°C. The yield was 4.1 g which corresponds to 50.7% of the theoretical yield. References Merck Index 21 DFU 2 (7) p.423 (1977) Kleeman and Engel p. 3 DOT 17 (7) p.279 (1981) I.N. p. 3 Boltze, K.H., Brendler, O., Dell, H.D. and Jacobi, H.; US Patent 3,910,952; October 7,1945; Assigned to Tropenwerke Dinklage and Co. Boltze, K.H., Brendler,O., Dell, H.D. and Jacobi, H.; US Patent 3,966,956; June 29,1976; Assigned to Tropenwerke Dinklage and Co.

ACENOCOUMAROL Therapeutic Function: Anticoagulant, Vitamin Chemical Name: 3-(α-Acetonyl-p-nitrobenzyl)-4-hydroxycoumarin Common Name: Nicoumalone Chemical Abstracts Registry No.: 152-72-7

38

Acenocoumarol

Structural Formula:

Trade Name Sintrom Sintrom Sintrom Sintrom NeoSintrom Ascumar Syncumar Synthrome Sintrom

Manufacturer Geigy Geigy Ciba Geigy Ciba Geigy Geigy Star EGYT Geigy Ciba Geigy

Country US W. Germany Switz. France Finland Hungary UK Japan

Year Introduced 1957 1959 -

Raw Materials 4-Hydroxycoumarin Nitrobenzalacetone Manufacturing Process 16 parts of 4-hydroxycoumarin and 19 parts of 4-nitrobenzalacetoneare thoroughly mixed and heated for 12-14 hours in an oil bath, the temperature of which is between 135°C and 140°C. After cooling, the melt is dissolved in a little acetone. The solution is slowly added to a lye made up from 6 parts of sodium hydroxide in 400 parts of water while stirring and then the mixture is stirred for 30 minutes. A little animal charcoal is then added, the mixture is stirred for a further 15 minutes, 400 parts of water are added and the charcoal and undissolved components are separated by filtration under suction. The clear solution is made acid to Congo red paper with hydrochloric acid and the product which is precipitated is filtered off under suction. 3-[α(4'-Nitrophenyl)-β-acetylethyl]-4-hydroxycoumarin is obtained. MP 196-199°C. It should be noted that the process is akin to that for Warfarin except that 4nitrobenzalacetone replaces benzalacetone as a raw material. References Merck Index 23 Kleeman and Engel p. 4 OCDS Vol. 1 p. 331 (1977) I.N. p.3 Stoll, W. and Litvan, F.; US Patent 2,648,682; August 11, 1953; Assigned to J.R. Geigy A.G., Switzerland.

Aceperone

39

ACEPERONE Therapeutic Function: Vasodilator, Antihypertensive, Neuroleptic Chemical Name: Acetamide, N-((1-(4-(4-fluorophenyl)-4-oxobutyl)-4-phenyl4-piperidinyl)methyl)Common Name: Aceperone; Acetabutone Structural Formula:

Chemical Abstracts Registry No.: 807-31-8 Trade Name Aceperone

Manufacturer ZYF Pharm Chemical

Country Year Introduced -

Aceperone

Vasudha Pharma Chem Limited.

-

-

Raw Materials 1-Benzyl-4-(4-phenyl)-4-(acetaminomethyl)piperidine Sodium bicarbonate 3-(4-Fluorobenzoyl)propyl bromide Thiophenol Sodium hydroxide Manufacturing Process A mixture of 1-benzyl-4-(4-phenyl)-4-(acetaminomethyl)piperidine, 3-(4fluorobenzoyl)propyl bromide, sodium bicarbonate and anhydrous acetone was stirred and heated under reflux. The resulting mixture was filtered while still hot, and the filtrate was concentrated to dryness under reduced pressure. The residue was washed with ether to give 1-benzyl-1-[3-(4-fiuorobenzoyl)propyl](4-phenyl-4-acetaminomethyl)piperidinium bromide. To a stirred mixture of thiophenol and 15% (W/W) aqueous sodium hydroxide was added the 1-benzyl-1-[3-(4-fluorobenzoyl)propyl]-(4-phenyl-4acetaminomethyl)piperidinium bromide and the mixture was heated to 85°90°C for 2 h. After cooling, solid matter precipitated was collected by filtration and washed with water to give 1-[3-(4-fluorobenzoyl)propyl]-4(acetaminomethyl)-4-phenylpiperidine, melting point 111°-112°C.

40

Acepromazine maleate

References Nakao M. et al.; US Patent No. 3,850,935; Nov. 26, 1974; Assigned: Sumitomo Chemical Company, Limited, Osaka, Japan

ACEPROMAZINE MALEATE Therapeutic Function: Neuroleptic, Antiemetic Chemical Name: Ethanone, 1-(10-(3-(dimethylamino)propyl)-10Hphenothiazin-2-yl)-, maleate (1:1) Common Name: Acepromazine maleate; Acetopramazine maleate; Notensil Structural Formula:

Chemical Abstracts Registry No.: 3598-37-6; 61-00-7 (Base) Trade Name Sedaject Anatran Sedalin

Manufacturer Bayer Korea Co. Ayerst Chassot

Country -

Year Introduced -

Raw Materials 3-Acetylphenothiazine Phosgene γ-Dimethylaminopropyl alcohol Manufacturing Process 120 g 3-acetylphenothiazine (0.479 mol) are heated to the boil in 1.2 L xylene and a rapid stream of phosgene then passed in for a period of 12 hours. The solvent is then removed by distillation and the residue taken up in 1 L benzene. The benzene solution is heated to the boil and 112 g of γdimethylaminopropyl alcohol (1.09 mol) are added within a period of 15 min and the reaction mixture boiled for a further 2 hours. After cooling, the precipitated hydrochloride of the γ-dimethylaminopropyl alcohol washed with benzene and the combined benzene solutions rapidly washed with water in order to remove excess basic alcohol. The material is dried over potash and the hydrochloride precipitated by means of ethereal hydrochloric acid. The

Aceprometazine

41

hydrochloride may also be precipitated by passing in gaseous hydrogen chloride. After recrystallisation from isopropanol, 157 g (78% of theory) of γdimethylaminopropyl 3-acetylphenothiazine-10-carboxylate are obtained. The hydrochloride melts at 212°C. In practice it is usually used as maleate salt. References Hoerlein U. et al,; DE Patent No. 1,049,865; Assigned to Farbenfabriken Bayer Aktiengesellschaft, Leverkusen-Bayerwerk GB Patent No. 808,050; Jan. 28,1959; BAYER AG

ACEPROMETAZINE Therapeutic Function: Neuroleptic, Antitussive Chemical Name: Ethanone, 1-(10-(2-(dimethylamino)propyl)-10Hphenothiazin-2-yl)Common Name: Aceprometazine Structural Formula:

Chemical Abstracts Registry No.: 13461-01-3 Trade Name

Manufacturer

Country

Year Introduced

Aceprometazine

ZYF Pharm Chemical

-

-

Raw Materials 2-Acetylphenothiazine 1-Dimethylamino-2-chloropropane Sodium hydride Manufacturing Process In a 1 liter flask, equipped with stirrer, thermometer and nitrogen inlet, 241.0 g of 2-acetylphenothiazine (1 mole) is dissolved in 300 ml of dry dimethylformamide. When the 2-acetylphenothiazine is almost completely soluble, to this solution is added 275 ml of a 4 N solution of 1-dimethylamino2-chloropropane in toluene.

42

Acesulfame potassium

The mixture is heated to 50°C and 26.0 g (1.08 moles) of sodium hydride is added portion-wise, maintaining the temperature at 50°-60°C. The addition should take about 1 h. The reaction is allowed to stir for 3 h at 50°-60°C. Any excess hydride is destroyed by the cautious addition of 10 ml methanol, and the reaction mix is poured into 800 ml of 20% acetic acid. The toluene layer is separated and extracted with 150 ml of 20% acetic acid, and discarded. The acid solutions are combined and washed once with toluene. The toluene is discarded. Fresh toluene (200 ml) is added and caustic solution is added with cooling and stirring until the pH is 9 or above. The toluene layer is separated. The aqueous layer is extracted once more with 75 ml of toluene and discarded. The toluene extracts are combined, given a small water wash, and concentrated. The residue is distilled yielding 10-[2(dimethylamino)propyl]-2-acetylphenothiazine. References Kantor M.L., Tubis S.; US Patent No. 3,100,772; August 13, 1963; Assigned: America Home Products Corporation, New York, N.Y.

ACESULFAME POTASSIUM Therapeutic Function: Pharmaceutic aid Chemical Name: 6-Methyl-1,2,3-oxathiazin-4(3H)-one 2,2-dioxide potassium salt Common Name: Acetylfame K, Acetylfame potassium Structural Formula:

Chemical Abstracts Registry No.: 55589-62-3; 33665-90-6 (Base) Trade Name Acesulfame Potassium Acesulfame K Acesulfame Potassium Acesulfame K Acesulphame K

Manufacturer Hoechst

Country -

Year Introduced -

Wuzhou international Co., Ltd. Zhang Peng International

-

-

-

-

AroKor Holdings Inc.

-

-

Acroyali Holdings Qingdao Co., Ltd.

-

-

Acetaminophen Trade Name

Manufacturer

Acesulfame K

Zhangjiagang Hope Chemicals Co., Ltd. VitaSweet Ace K VitaSweet

43

Country

Year Introduced

-

-

-

-

Raw Materials Dimethylethylamine Sulfamic acid Sulfur trioxide Manufacturing Process 80 g (1.096 mol) of dimethylethylamine were added drop-wise, with cooling, to 80 g (0.825 mol) of sulfamic acid suspended in 500 ml of glacial acetic acid. When dissolution was complete, 80 ml (1.038 mol) of diketene were added, while cooling at 25°-35°C. After 16 hours, the mixture was evaporated and the residue was stirred with acetone, whereupon crystallization of dimethylethylammonium acetoacetamide-N-sulfonate took place. Yield: 110 g (43%), melting point 73°-75°C. 12.7 g (50 mmol) of dimethylethylammonium acetoacetamide-N-sulfonate in 110 ml of methylene chloride were added drop-wise to 8 ml (200 mmol) of liquid SO3 in 100 ml of CH2Cl2 at -30°C, stirring vigorously, within 60 minutes. 30 minutes later, 50 ml of ethyl acetate and 50 g of ice were added to the solution. The organic phase was separated off, and the aqueous phase was extracted twice more with ethyl acetate. The combined organic phases were dried over sodium sulfate, evaporated and the residue was dissolved in methanol. On neutralization of the solution with methanolic KOH, the potassium salt of 6-methyl-3,4-dihydro-1,2,3-oxathiazin-4-one 2,2-dioxide precipitated out. Yield: 7.3 g (73%). The product was detected by thinlayer chromatography; the structure of it was confirmed with IR spectrum. References Clauss K. et al.; US Patent No. 5,103,046; April 7, 1992; Assigned to Hoechst Aktiengesellschaft Frankfurt am Main, DE)

ACETAMINOPHEN Therapeutic Function: Analgesic, Antipyretic Chemical Name: N-(4-Hydroxyphenyl)acetamide Common Name: Paracetamol; Acetyl-p-aminophenol; APAP Chemical Abstracts Registry No.: 103-90-2

44

Acetaminophen

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Trigesic

Squibb

US

1950

Apamide

Ames

US

1952

Nebs

Norwich Eaton

US

1955

Tylenol

McNeil

US

1955

Febrolin

Tilden Yates

US

1957

Tempra

Mead Johnson

US

1957

Fendon

Am. Pharm.

US

1958

Amdil

Breon

US

1958

Lyteca

Westerfield

US

1962

Menalgesia

Clapp

US

1963

Dial-Agesic

Borden

US

1968

Tenlap

Dow

US

1970

SK-APAP

SK and F

US

1971

Valadol Tablets

Squibb

US

1971

Tapar

Parke Davis

US

1974

Cen-Apap

Central

US

1974

Acephen

G and W

US

1978

St. Joseph Aspirin St. Joseph

US

1982

Panadol

Glenbrook

US

1983

Pain and Fever

Lederle

US

-

Accu-Tap

Accu-Med

US

-

Actamin

Buffington

US

-

Am inofen

Dover

US

-

Anuphen

Comatic

US

-

Dapa

Ferndale

US

-

Datril

Bristol-Myers

US

-

Dirox

Winthrop

US

-

Dolanex

Lannett

US

-

Febrogesic

First Texas

US

-

Halenol

Halsey

US

-

Hedex

Winthrop

US

-

Homoolan

Winthrop

US

-

Injectapap

Johnson and Johnson

US

-

Korum

Geneva

US

-

Metalid

Philips Roxane

US

-

Minotal

Carnrick

US

-

Acetaminophen

45

Trade Name

Manufacturer

Country

Year Introduced

Neopap

Webcon

US

-

Neotrend

Bristol-Myers

US

-

Nilprin

AVP

US

-

Panamax

Winthrop

US

-

Panodil

Winthrop

US

-

Parten

Parmed

US

-

Phenaphen

Robins

US

-

Phendex

Mallard

US

-

Phrenilin

Carnrick

US

-

Prompt

Delree

US

-

Proval

Reid-Provident

US

-

Robigesic

Robins

US

-

Valorin

Otis Clapp

US

-

Abrol

Rekah

Israel

-

Abrolet

Rekah

Israel

-

Acamol

Ikapharm

Israel

-

Acetalgin

Streuli

Switz.

-

Aldolor

Novis

Israel

-

Alpiny

SS Pharmaceutical

Japan

-

Alvedon

Draco

Sweden

-

Anaflon

Duphar

UK

-

Anhiba

Hokuriku

Japan

-

APA/Aparacet

Arcana

Austria

-

Apiretal

Ern

Spain

-

Arasol

Horner

Canada

-

Benmyo

Heilmittelwerke Wien Austria

-

Ben-U-Ron

Benechemie

W. Germany

-

Calpol

Calmic

UK

-

Campain

Winthrop

Canada

-

Ceetamol

Protea

Australia

-

Cetadol

Rybar

UK

-

Chemcetaphen

Chemo-Drug

Canada

-

Dipramat Infantil

Byk Gulden

W. Germany

-

Dolamin

Nyal

Australia

-

Doliprane

Bottu

France

-

Dolprone

Siegfried

W. Germany

-

Dymadon

Calmic

UK

-

Efferalgan

UPSA

France

-

Enelfa

Dolorgiet

W. Germany

-

Exdol

Merck-Frosst

Canada

-

Febrilix

Boots

UK

-

46

Acetaminophen

Trade Name

Manufacturer

Country

Year Introduced

Finimal

Mepros

Netherlands

-

Finimal

Pharmaton

Switz.

-

Gelocatil

Gelos

Spain

-

Ildamol

Rekah

Israel

-

Kinder-Finiweh

Cesmopharma

Netherlands

-

Kratofin

Kwizda

Austria

-

Labamol

Vitamed

Israel

-

Langesic

Boots

UK

-

Letamol

Letap

Switz.

-

Momentum

Much

W. Germany

-

Myalgin

Allied Labs

UK

-

Napional

Pharma Import

Austria

-

Nealgyl

Bottu

France

-

Nevral

Lepetit

Italy

-

Pacemo

Alpinapharm

Switz.

-

Pacet

Rekah

Israel

-

Painex

A.L.

Norway

-

Pamol

Marshalls Pharm.

UK

-

Panacete

Prosana

Australia

-

Panadol

Sterwin Espanola

Spain

-

Panadon

Isis

Yugoslavia

-

Panasorb

Winthrop

UK

-

Panasorb

Bayer

W. Germany

-

Panok

B.M. Labs

UK

-

Pantalgin

UCB

Belgium

-

Paracet

Zdravlje

Yugoslavia

-

Paracet

Weifa

Norway

-

Paralgin

ICN

Canada

-

Paramol

Duncan Flockhart

UK

-

Paramolan

Trima

Israel

-

Parasin

Adams

Australia

-

Paraspen

Fisons

UK

-

Para-Suppo

Orion

Finland

-

Parmol

Knoll

Australia

-

Parol

Atabay

Turkey

-

Pasolind

Stada

W. Germany

-

PCM

Napp

UK

-

Pediaphen

Ross

Canada

-

Phenipirin

Aksu

Turkey

-

Pinex

A.L.

Norway

-

Acetaminophen

47

Trade Name

Manufacturer

Country

Year Introduced

Puernol

Formenti

Italy

-

Pyrinazin

Yamanouchi

Japan

-

Pyrital

Medica

Finland

-

Reliv

ACO

Sweden

-

Rivalgyl

Rivopharm

Switz.

-

Rounox

Rougier

Canada

-

Servigesic

Servipharm

Switz.

-

Setamol

Pharmacia

Sweden

-

Setol

Dif-Dogu

Turkey

-

Supramol

Sam-On

Israel

-

Tabalgin

Bayer

W. Germany

-

Tachipirina

Angelini

Italy

-

Temperal

Prodes

Spain

-

Trenodin

Fresenius

W. Germany

-

Tymol

Reckitt and Colman

W. Germany

-

Veralydon

Lelong

France

Raw Materials Nitrobenzene Acetic anhydride Manufacturing Process About 250 ml of a reaction mixture obtained by the electrolytic reduction of nitrobenzene in sulfuric acid solution and containing about 23 grams of paminophenol by assay is neutralized while at a temperature of 60°C to 65°C, to a pH of 4.5 with calcium carbonate. The calcium sulfate precipitate which forms is filtered off, the precipitate washed with hot water at about 65°C and the filtrate and wash water then combined. The solution is then extracted twice with 25 ml portions of benzene and the aqueous phase is treated with 0.5 part by weight, for each part of p-aminophenol present, of activated carbon and the latter filtered off. The activated carbon is regenerated by treatment with hot dilute caustic followed by a hot dilute acid wash, and reused a minimum of three times. To the filtrate obtained, there are then added about 0.2 gram of sodium hydrosulfite or sodium sulfite and 15.0 grams of anhydrous sodium acetate in about 27 grams of acetic anhydride at 40°C. The reaction mixture formed is cooled to 8°C to 10°C with stirring and held at this temperature for 60 minutes. A crystalline precipitate of about 27 grams of N-acetyl-paminophenol is obtained melting at 169-171°C. This is equivalent to a yield of 85%. In lieu of utilizing calcium carbonate as the neutralizing agent, calcium hydroxide, barium hydroxide, barium chloride or other alkaline earth metal salt or hydroxide forming an insoluble sulfate may be employed.

48

Acetaminosalol

References Merck Index 39 Kleeman and Engel p. 684 PDR p. Many References OCDS Vol. 1 p. 111 (1977) DOT 16 (2) p. 59 (1980) I.N. p. 728 REM p. 1111 Wilbert,G. and De Angelis, J.; US Patent 2,998,450; August 29, 1961; Assigned to Warner-Lambert Pharmaceutical Company

ACETAMINOSALOL Therapeutic Function: Analgesic, Antineuralgic, Antirheumatic, Antipyretic Chemical Name: 2-Hydroxybenzoic acid 4-(acetylamino)phenyl ester Common Name: Acetamidosalol; Acetaminosal; Acetylparaminosalol; Acetaminosalol; Phenetsal Structural Formula:

Chemical Abstracts Registry No.: 118-57-0 Trade Name

Manufacturer

Country

Year Introduced

Acetaminosal

ZYF Pharm Chemical

-

-

Raw Materials N-Acetyl-p-aminophenol Acetyl salicylic chloride

Sodium hydroxide Acid chloride

Manufacturing Process 2 Methods of producing of acetyl salicylic acid ester of N-acetyl-paminophenol: 1. 65.0 g of N-acetyl-p-aminophenol were slurried with 400 ml of water and cooled to 10°C. 125 ml of 20% sodium hydroxide were slowly added to the mixture with stirring, the temperature being maintained 10°-15°C. To the solution obtained, 75.0 g of acetyl salicylic chloride were added with vigorous stirring over a period of 0.5 h, the solution being maintained at a temperature

Acetarsol

49

of about 10°C. Towards the end of the reaction the pH was checked and adjusted to greater than 10 by the addition of a small amount of 20% sodium hydroxide. After all the acid chloride had been added, vigorous stirring was continued for 0.5 h during which time the crude product separated out. The acetyl salicylic acid ester of N-acetyl-p-aminophenol was filtered off, washed thoroughly with water and recrystallised from ethanol. 2. 65.0 g of sodium N-acetyl-p-aminophenol were slurried with 500.0 g of dry benzene and 80.0 g of acetyl salicylic chloride added. The mixture was heated under reflux for 4 h and filtered hot. The excess benzene was removed under vacuum and the crude acetyl salicylic acid ester of N-acetyl-p-aminophenol crystallized from ethanol. References Robertson A.; US Patent No. 3,431,293; March 4, 1969; Assigned: Sterling Drug Inc., New York, N.Y.

ACETARSOL Therapeutic Function: Antiprotozoal, Tonic Chemical Name: Arsonic acid, (3-(acetylamino)-4-hydroxyphenyl)Common Name: Acetarsol; Acetarsone; Osarsol(um) Structural Formula:

Chemical Abstracts Registry No.: 97-44-9 Trade Name Acetarsol

Manufacturer Cyklo Pharma Chem Pvt. Ltd.

Country -

Year Introduced -

Acetarsol Fluoryl Gynoplix Laryngarsol Nilacid Orarsan Osarbon

Nizhpharm AFI Theraplix Sanofi-Synthelabo Sanofi-Synthelabo Boots Nizhpharm

-

-

50

Acetazolamide

Trade Name

Manufacturer

Country

Year Introduced

Pallicid

Wander

-

-

Spirocid

Hoechst

-

-

Stovarsol

Abbott

-

-

Raw Materials 4-Chloroaniline Hydrogen chloride Sodium hydroxide Sodium thiosulfate

Sodium nitrite Sodium arsenite Nitric acid/Sulfuric acid Acetic anhydride

Manufacturing Process 1 part of 4-chloroaniline is dissolved with 2 parts of concentrated hydrochloric acid (specific gravity 1.16) and 10 parts of water, and diazotised in the usual manner. 3 parts of sodium arsenite are introduced into the diazo solution thus obtained, the sodium arsenite being dissolved in 5 parts of water and 1 part of 96% ethanol. The solution is heated slowly to 70°C. When evolution of nitrogene ceased, it is filtered from separated oil and the addition of hydrochloric acid precipitates the 4-chlorophenylarsonic acid, which crystallizes out in the form of white needles. By action HNO3/H2SO4 on 4-chlorophenylarsonic acid is obtained 4-chloro-3nitrophenylarsonic acid which is converted at 100°C with 33% aqueous solution of sodium hydroxide to 4-hydroxy-3-nitrophenylarsonic acid. After reduction of NO2 group of 4-hydroxy-3-nitrophenylarsonic acid by the action of Na2S2O3 or Fe/NaOH is obtained 3-amino-4-hydroxyphenylarsonic acid. From 3-amino-4-hydroxyphenylarsonic acid and acetic anhydride is prepared N-acetyl-4-hydroxy-m-arsanilic acid. References Bart H.; GB Patent No. 568; Jan. 9, 1911 GB Patent No. 5595; 06.03.1911; Assigned to Farbwerke vorm. Meister, Lucius, and Bruning, Hoechst, Germany

ACETAZOLAMIDE Therapeutic Function: Carbonic anhydrase inhibitor, Diuretic, Antiglaucoma Chemical Name: N-[5-(Aminosulfonyl)-1,3,4-thiadiazol-2-yl]acetamide Common Name: Chemical Abstracts Registry No.: 59-66-5

Acetazolamide

51

Structural Formula:

Trade Name Diamox Hydrazole Acetamide Acetamox Acetazolam Acetazolamide Chibret Albox Atenezol Defiltran Diazomid Diamox Didoc Diluran Diuramid DirureticumHolzinger

Manufacturer Lederle Softcon Products Nessa Santen ICN Chibret

Country US US Spain Japan Canada France

Year Introduced 1953 1975 -

Kwizda Tsuruhara Jouveinal Dif-Dogu Theraplix Sawai Spofa Polfa Holzinger

Austria Japan France Turkey France Japan Czechoslovakia Poland Austria

-

Diuriwas Donmox Edemox Glauconox Glaupax Glaupax Gleupax Inidrase

Wassermann Hona Wassermann Llorens Erco Baeschlin Dispersa Omikron-Gagliardi

Italy Japan Spain Spain Denmark W. Germany Switz. Italy

-

Nephramid Oedemin Renamid Uramox Zohnox

Chemiek Astra Pliva Taro Konto

E. Germany Sweden Yugoslavia Israel Japan

-

Raw Materials Hydrazine hydrate Ammonium thiocyanate Acetic anhydride Chlorine Ammonia Bromine

52

Acetazolamide

Manufacturing Process According to REM, hydrazine hydrate is reacted with 2 mols of ammonium thiocyanate to produce 1,2-bis(thiocarbamoyl)hydrazine which by loss of ammonia and rearrangement produces 5-amino-2-mercapto-1,3,4-thiadiazole. That compound is acetyled with acetic anhydride. Then, as described in US Patent 2,554,816, the 2-acetylamido-5-mercapto1,3,4-thiadiazole is converted to the sulfonyl chloride by passing chlorine gas into a cooled (5-10°C) solution in 33% acetic acid (66 parts to 4 parts of mercapto compound) used as a reaction medium. Chlorine treatment is continued for two hours. The crude product can be dried and purified by recrystallization from ethylene chloride. The pure compound is a white crystalline solid, MP 194°C, with decomposition, when heated rapidly. The crude damp sulfonyl chloride is converted to the sulfonamide by addition to a large excess of liquid ammonia. The product is purified by recrystallization from water. The pure compound is a white, crystalline solid, MP 259°C, with decomposition. The yield of sulfonamide was 85% of theory based on mercapto compound. An alternative process is described in US Patent 2,980,679 as follows. 15 grams of finely powdered 2-acetylamino-1,3,4-thiadiazole-5-mercaptain are suspended in 200 ml of water containing 4 grams of potassium bromide. From 0.5 to 1 gram of ferric chloride are subsequently added. The mass is energetically stirred and 52 grams of liquid bromide are added by increments for about 45 minutes, while keeping the reaction temperature below 10°C, and, preferably, at 4-8°C by employing a cooling bath. Stirring is continued for a further 10 minutes, then the 2-acetylamino-1,3,4-thiadiazole-5sulfobromide is collected on a funnel equipped with a porous diaphragm, thoroughly washed with cold water and finally subjected to amidation with liquid ammonia. The reaction mixture is allowed to stand for a certain period, then the ammonia is evaporated, after which the residue is taken up with diluted ammonia and, after decolorizing with carbon, the sulfonamide is precipitated with hydrochloric acid. The yield of crude sulfonamide obtained with this process, with respect to the starting mercapto compound is abut 84%. If the amidation is carried out with 33% aqueous ammonia, the yield is slightly lower. References Merck Index 45 Kleeman and Engel p. 6 PDR pp. 830, 1008, 1606 OCDS Vol. 1 p. 249 (1977) I.N. p. 5 REM p.936 Clapp, J.W. and Roblin, R.O., Jr.; US Patent 2,554,816; May 29, 1951; Assigned to Americar Cyanamid Company Gianfranco, P.; US Patent 2,980,679; April 18, 1961; Assigned to OmikronGagliardi Societa di Fatto, Italy

Acetohexamide

53

ACETIROMATE Therapeutic Function: Antihyperlipidemic Chemical Name: Benzoic acid, 4-(4-hydroxy-3-iodophenoxy)-3,5-diiodo-, acetate Common Name: Acetiromate; Adecol Structural Formula:

Chemical Abstracts Registry No.: 2260-08-4 Trade Name

Manufacturer

Country

Year Introduced

Acetiromate

ZYF Pharm Chemical

-

-

Raw Materials 3,5-Diiodo-4-(3-iodo-4-hydroxyphenoxy)benzoic acid Acetic anhydride Manufacturing Process To 3 parts of 3,5-diiodo-4-(3-iodo-4-hydroxyphenoxy)benzoic acid 10 parts of acetic acid anhydride was added and mixture was heated on oil bath for some hours. In the result of this reaction amorphous precipitate was obtained. After recrystallization from glacial acetic acid 2.4 parts of 3,5-diiodo-4-(3-iodo-4acetoxyphenoxy)benzoic acid were obtained. References Fr. Patent No. M1610; Dec. 10, 1962; Assigned: Takeda Chemical Industries, LTD

ACETOHEXAMIDE Therapeutic Function: Hypoglycemic

54

Acetohexamide

Chemical Name: 1-[(p-Acetylphenyl)sulfonyl]-3-cyclohexylurea Common Name: Cyclamide Structural Formula:

Chemical Abstracts Registry No.: 968-81-0 Trade Name

Manufacturer

Country

Year Introduced

Dymelor

Lilly

US

1964

Dimelin

Shionogi

Japan

-

Dimelor

Lilly

UK

-

Gamadiabet

Salvat

Spain

-

Metaglucina

Perga

Spain

-

Ordimel

Lilly

Spain

-

Raw Materials Sodium nitrite Hydrogen chloride Ammonia

p-Aminoacetophenone Sulfur dioxide Cyclohexyl isocyanate

Manufacturing Process Preparation of p-Acetylbenzenesulfonamide: 100 grams of paminoacetophenone were dissolved in a solvent mixture containing 165 ml of 12 N hydrochloric acid and 165 ml of glacial acetic acid. The mixture was cooled with stirring to about 0°C. A solution containing 56.2 grams of sodium nitrite and 175 ml of water was added dropwise with stirring to the acidic solution while maintaining the temperature below 5°C. After the addition had been completed, the acidic solution containing pacetylphenyldiazonium chloride formed in the above reaction was added dropwise with stirring to a mixture of 530 ml of glacial acetic acid and 530 ml of benzene which had been previously cooled, and the cooled solution saturated with sulfur dioxide and to which had been added 34 g of cupric chloride dihydrate. After the addition had been completed, the reaction mixture was stirred at about 40°C for three hours, and was then poured into 3,000 ml of an ice-water mixture. The benzene layer containing p-acetylbenzenesulfonyl chloride formed in the above reaction was separated, and the acidic aqueous phase was extracted twice with 250 ml portions of benzene. The benzene layers were combined, the combined extracts were filtered, and the benzene was evaporated from the resulting filtrate in vacuum.

Acetohydroxamic acid

55

The solid residue comprising p-acetylbenzenesulfonyl chloride was dissolved in 100 ml of dioxane, and the solution was added to 200 ml of 14% aqueous ammonium hydroxide. The resulting solution was stirred overnight at ambient room temperature. The p-acetylbenzenesulfonamide thus prepared was collected by filtration. Recrystallization of the filter cake from aqueous ethanol yielded purified p-acetylbenzenesulfonamide melting at about 176°C to 179°C. Preparation of N-p-Acetylphenylsulfonyl-N'-Cyclohexylurea: A reaction mixture consisting of 32.7 grams of p-acetylbenzenesulfonamide and 64 grams of anhydrous potassium carbonate in 350 ml of anhydrous acetone was stirred at refluxing temperature for about 1% hours, thus forming the potassium salt of p-acetylbenzenesulfonamide. 30.9 grams of cyclohexylisocyanate were added dropwise to the reaction mixture. Refluxing and stirring were continued during the course of the addition and for an additional 16 hours. The acetone was removed by evaporation in vacuum, and about 750 ml of water were added to dissolve the resulting residue. The solution was filtered. The potassium salt of N-p-acetylphenylsulfonyl-N'-cyclohexylurea formed in the above reaction, being water-soluble, passed into the filtrate. Acidification of the filtrate with 6 N aqueous hydrochloric acid caused the precipitation of N-p-acetylphenylsulfonyl-N'-cyclohexylurea which was collected by filtration. Recrystallization of the filter cake from 90% aqueous ethanol yielded purified N-p-acetylphenylsulfonyl-N'-cyclohexylurea melting at about 188-190°C. References Merck Index 53 Kleeman and Engel p. 7 PDR p. 1049 OCDS Vol. 1 p. 138 (1977) I.N. p. 6 REM p.976 Sigal, M.V., Jr. and Van Arendonk, A.M.; US Patent 3,320,312; May 16, 1967; Assigned to Eli Lilly and Company.

ACETOHYDROXAMIC ACID Therapeutic Function: Urease inhibitor Chemical Name: Acetamide, N-hydroxyCommon Name: Acetohydroxamic acid; Uronefrex Structural Formula:

Chemical Abstracts Registry No.: 546-88-3

56

Acetophenazine dimaleate

Trade Name Lithostat Uronefrex

Manufacturer Country Mission Pharmacal Co. Robert -

Year Introduced -

Raw Materials Hydroxylamine Acetamide Nitrohydroxylamine

Ethyl acetic acid ether Acetaldehyde

Manufacturing Process 3 Methods of producing of acetohydroxamic acid: 1. Ethyl acetic acid ether was treated with hydroxylamine and acetohydroxamic acid was obtained. 2. Acetohydroxamic acid was obtained in the result of reaction of acetamide with hydroxylamine. 3. Acetohydroxamic acid was obtained by treatment of acetaldehyde with nitrohydroxylamine. References Karrer P.; Lehrbuch der organischen chemie; Stuttgart; 1959; 1216 s.

ACETOPHENAZINE DIMALEATE Therapeutic Function: Tranquilizer Chemical Name: 10-[3-[4-(2-Hydroxyethyl)-1-piperazinyl]propyl] phenothiazin-2-yl methyl ketone maleate Common Name: Structural Formula:

Acetoxolone aluminum salt

57

Chemical Abstracts Registry No.: 5714-00-1; 2751-68-0 (Base) Trade Name

Manufacturer

Country

Year Introduced

Tindal

Schering

US

1961

Raw Materials 2-Acetylphenothiazine Sodium amide 1-Bromo-3-chloropropane Maleic acid 1-(2-Hydroxyethyl)piperazine Manufacturing Process The requisite intermediate, 10-(3-chloropropyl)-2-acetylphenothiazineis prepared as follows: To a suspension of sodium amide (from 3 grams of sodium) in 300 ml of liquid ammonia is added 30 grams of 2acetylphenothiazine. After stirring for one hour, there is added 19 grams of 1bromo-3-chloropropane. The ammonia is allowed to evaporate and the residue is diluted with 200 ml of water. The mixture is extracted with ether and the ether solution is dried over anhydrous sodium sulfate, filtered and concentrated. The residue consists of crude 10-(3-chloropropy1)-2-acetylphenothiazine as a viscous oil and is used in the next step without further purification. The crude base obtained from the reaction of 10-(3-chloropropyl)-2-acetylphenothiazine with 1-(2-hydroxyethyl)piperazine is purified by conversion to its dimaleate salt, MP 167-168.5°C from ethanol. References Merck Index 64 Kleeman and Engel p. 7 OCDS Vol. 1 p. 383 (1977) I.N. p. 6 REM p. 1086 Sherlock, M.H. and Sperber, N.; US Patent 2,985,654; May 23, 1961; Assigned to Schering Corporation, Bloomfield, N.J.., a corporation of a New Jersey

ACETOXOLONE ALUMINUM SALT Therapeutic Function: Antiulcer Chemical Name: 3-(Acetyloxy)-11-oxoolean-12-en-29-oic acid aluminum salt Common Name: Chemical Abstracts Registry No.: 6277-14-1 (Base)

58

Acetoxolone aluminum salt

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Oriens

Inverni Beffa

Italy

1981

Raw Materials 3-Acetyl-18β-glycyrrhetinic acid Aluminum alcoholate Manufacturing Process The salts of 3-acetyl-18β-glycyrrhetinic acid can be prepared by reaction between 3-acetyl-18β-glycyrrhetinic acid and an aluminum alcoholate. Preferably lower alcoholates are used, i.e., alcoholates in which the alkoxy group or groups have from one to four carbon atoms. The salification reaction may be carried out at room temperature or at an elevated temperature in conventional fashion, preferably in the presence of organic solvents. As organic solvents may be used alcohols, ethers, ketones, chlorinated solvents (methylene chloride, chloroform) ethyl acetate, etc. References Merck Index 70 Bonati, A.; US Patent 3,764,618; October 9,1973; Assigned to Dott. Inverni and Della Befia S.P.A.

Acetrizoate sodium

59

ACETRIZOATE SODIUM Therapeutic Function: Diagnostic aid (radiopaque medium) Chemical Name: 3-(Acetylamino)-2,4,6-triiodobenzoic acid sodium salt Common Name: Structural Formula:

Chemical Abstracts Registry No.: 129-63-5 Trade Name Urokon Sodium Thixokon Cystokon Pyelokon-R Salpix Diaginol Diaginol Vasurix Fortombrin Iodopaque Triurol

Manufacturer Mallinckrodt Inc. Mallinckrodt Inc. Mallinckrodt Inc. Mallinckrodt Inc. Ortho May and Baker Banyu Guerbet Dagra Labaz Lundbeck

Country US US US US US UK Japan France Netherlands Switz. Denmark

Year Introduced 1950 1957 1964 -

Raw Materials 3-Amino-2,4,6-triiodobenzoic acid Acetic anhydride Sodium hydroxide Manufacturing Process 3-Amino-2,4,6-triiodobenzoic acid (51.5 g) was mixed with 125 ml of acetic anhydride containing 2 drops of concentrated sulfuric acid and refluxed for thirty minutes. The mixture was allowed to cool slightly, and then was poured into 600 ml of water at room temperature and stirred until crystallization was complete. The mixed anhydride of 3-acetylamino-2,4,6-triiodobenzoic acid with acetic acid thus prepared was then separated by filtration and washed with water. Without drying, the solid was suspended in 600 ml of water and hydrolyzed with a slight excess of ammonium hydroxide. It was necessary to warm the mixture slightly and stir it for about one-half hour in order to dissolve all the solid. The solution was then treated with activated carbon, filtered and precipitated with an excess of hydrochloric acid, filtered, washed and dried at 70°C. The yield was 51.5 g of 3-acetylamino-2,4,6-triiodobenzoic

60

Acetyl sulfisoxazole

acid which melted at 276.6-278.2°C with decomposition when placed in the melting block at 260°C and heated at the rate of 3°C per minute. Due to decomposition, the melting point varied from about 269-280°C, depending upon the rate of heating and other conditions. 3-Acetylamino-2,4,6-triiodobenzoic acid (28 g) was dissolved in a little over 50 ml of 1 N sodium hydroxide in a round-bottom flask. The pH was adjusted to slightly over 7 and the solution was evaporated on a steam bath under reduced pressure. After the residue became solid, it was further dried overnight in a vacuum desiccator containing calcium chloride. The salt weighed 31.2 g, theory being 29.0 g, indicating that the product contains about 7% water of crystallization when dried under these conditions. The finished salt was scraped from the flask and ground. References Merck Index 73 Kleeman and Engel p. 8 I.N. p.7 Wallingford, V.H.; US Patent 2,611,786; September 23, 1952; Assigned to Mallinckrodt Chemical Works

ACETYL SULFISOXAZOLE Therapeutic Function: Antimicrobial Chemical Name: N-[(4-Aminophenyl)sulfonyl]-N-(3,4-dimethyl-5-isoxazolyl) sulfanilamide Common Name: Acetylsulfafurazol Structural Formula:

Chemical Abstracts Registry No.: 80-74-0 Trade Name Gantrisin Acetyl Lipo-Gantrisin Acetyl Pediazole Raw Materials Sulfisoxazole Acetic anhydride

Manufacturer Roche Roche Ross

Country US US US

Year Introduced 1954 1954 -

Acetylcysteine

61

Manufacturing Process 267 grams (1 mol) of sulfisoxazole were suspended in 400 ml of acetone and 79 grams (1 mol) of dry pyridine at 20-25°C in a round-bottom flask equipped with a stirrer and thermometer. 132 grams (1 mol) of acetic anhydride were added within 3 minutes with stirring. The sulfisoxazole dissolved in the mixture and a clear solution resulted. The temperature rose to 39-40°C. After stirring for several minutes, the product started to crystallize as a white crystalline mush. The temperature rose to 42-43°C maintained itself at this temperature for 15-30 minutes, and then started to drop. Stirring was continued for 5 hours and the mixture was then allowed to stand for 10 hours. One liter of 2.5-3.0% ice-cold aqueous ammonia and some fresh ice were then added while stirring and the crystals were filtered without delay. The crystals were washed on the filter with 1 liter of ice-cold 1% ammonia and then with 1 liter of water. The material on the filter was well pressed off, washed with 200-300 ml of alcohol and dried at 70°C to constant weight. The N-monoacetyl sulfisoxazole melted at 193-194°C and showed a positive Bratton-Marshall reaction and a positive Hucknall-Turfat reaction. The product is in the form of colorless crystals which are somewhat water repellent. It is insoluble in alkali but is saponified upon standing in alkaline suspension (3% ammonia). It is soluble in strong acids (20-36% HCl or 10 N H2SO4) and is rapidly saponified upon standing. References Merck Index 104 Kleeman and Engel p. 13 PDR pp. 1487, 1558 I.N. p. 10 Hoffer, Max; US Patent 2,721,200; October 18, 1955; Assigned to HoffmannLa Roche Inc.

ACETYLCYSTEINE Therapeutic Function: Expectorant Chemical Name: N-Acetyl-L-cysteine Common Name: Structural Formula:

Chemical Abstracts Registry No.: 616-91-1

62

Acetylcysteine

Trade Name Mucomyst Acetein Airbron Broncholysin Brunac Fabrol Fluimucetin Fluimucetin Fluimucil Inspir Mucolyticum Mucosolvin NAC Parvolex Mucomist Mucisol Rinofluimucil A.R.B. Mucofilin

Manufacturer Mead Johnson Senju BDH Spofa Bruschettini Ciba Zambon Inpharzam Zambon Vitrum Lappe VEB Berlin Chemie Mead Johnson Duncan Flockhart Bristol Deca Inpharzam Tokyo Tanabe Eisai

Country US Japan UK Czechoslovakia Italy Italy Belgium Italy Sweden W. Germany E. Germany UK Italy Italy W. Germany Japan Japan

Year Introduced -

Raw Materials L-Cysteine HCl Acetic anhydride Manufacturing Process To a suspension of 35.2 grams (0.2 mol) of L-cysteine hydrochloride monohydrate stirred in a reaction vessel containing 87 ml of 91% aqueous tetrahydrofuran under a nitrogen atmosphere there is added 54.4 grams (0.4 mol) of sodium acetate trihydrate. The mixture is stirred for 20 minutes at room temperature to insure neutralization of the hydrochloride salt resulting in the formation of a suspension of equimolar amounts of cysteine and sodium acetate. The mixture is then chilled to 3-6°C by external cooling and 20 ml (20.8 grams, 0.21 mol) of acetic anhydride is added thereto in dropwise fashion with cooling in the above range. The resulting mobile suspension is stirred for 6 hours at room temperature, allowed to stand overnight, and finally heated at reflux (72°C) for 4 hours. The resulting suspension of sodium N-acetyl-Lcysteinate is then neutralized by treatment at 5-10°C with 8 grams of hydrogen chloride. Resulting sodium chloride is removed by filtration and the product is isolated by distilling the solvent from the filtrate in vacuum and crystallizing the residue from 35 ml of water, yield 26.3 grams (80.6%) of Nacetylcysteine as a white solid, MP 109-110°C. References Merck Index 82 Kleeman and Engel p. 8

Acetyldigitoxin

63

PDR p. 1126 DOT 16 (2) p. 42 (1980) I.N. p. 8 REM p. 867 Martin, T.A. and Waller, C.W.; US Patent 3,184,505; May 18, 1965; Assigned to Mead Johnson and Company.

ACETYLDIGITOXIN Therapeutic Function: Cardiotonic Chemical Name: Card-20(22)-enolide, 3-((O-2,6-dideoxy-β-D-ribohexopyranosyl-(1.4)-O-2,6-dideoxy-beta-D-ribo-hexopyranosyl-(1.4)-2,6dideoxy-β-D-ribo-hexopyranosyl)oxy)-14-hydroxy-, monoacetate, (3β,5β)Common Name: Digitoxin monoacetate Structural Formula:

Chemical Abstracts Registry No.: 1111-39-3 Trade Name Acylanid Acygoxine Acylanide Acylanid Sandolanid

Manufacturer Sandoz Sandoz Sandoz Sandoz Sandoz

Country US France France Italy W. Germany

Year Introduced 1954 1972 1954 1966 1968

Raw Materials Digitalis Ferruginea Leaves Manufacturing Process Acetyldigitoxin-α can be obtained from acetyldigitoxin-β by heating it in an

64

β-Acetyldigitoxin

anhydrous or aqueous organic solvent at neutral, weakly acid or weakly alkaline pH, i.e., at a pH range from about 3.5 to about 8. The acetylidigitoxin-β used for this purpose is a cardiac glycoside which can be obtained either by splitting off the glucose residue from lanatoside A, or by extraction of the leaves of Digitalis ferrugines. It is composed of the aglycone digitoxigenin and 3 molecules of digitoxose, to one of which an acetyl group is attached. Acetyldigitoxin-α, obtained from acetyldigitoxin-β by rearrangement, differs from the latter in the position of the acetyl group. The process may be carried out, for example, in the following manner: A solution of acetyldigitoxin-β in a suitable solvent, such as methanol, is boiled under reflux and then diluted with water. The unchanged acetyldigitoxin-β, which crystallizes out first, is filtered off and can again be submitted to the same process. On concentrating the filtrate, acetyldigitoxin-α separates out in crystalline form and after filtering off and recrystallizing is obtained in a pure state. The acetyldigitoxin-α crystallizes from aqueous methanol in platelets melting at 217-221°C. References Merck Index 83 Kleeman and Engel p. 9 I.N. p.8 Stoll, A. and Kreis, W.; US Patent 2,776,963; January 8, 1957; Assigned to Sandoz, AG, Switzerland.

β-ACETYLDIGOXIN Therapeutic Function: Cardiotonic Chemical Name: Card-20(22)-enolide, 3-((O-4-O-acetyl-2,6-dideoxy-beta-dribo-hexopyranosyl-(1.4)-O-2,6-dideoxy-beta-d-ribo-hexopyranosyl-(1.4)2,6-dideoxy-beta-d-ribo-hexopyranosyl)oxy)-12,14-dihydroxy-, (3β,5β,12β)Common Name: beta-Acetyldigoxin; Betagoxinum Chemical Abstracts Registry No.: 5355-48-6 Trade Name

Manufacturer

Country

Year Introduced

Novodigal

Asta Medica Arzneimittel

-

-

Novodigal

Lilly

-

-

Digoxin

Didier

-

-

Digoxin

Elkins-Sinn

-

-

Digoxin

Roxane

-

-

Digoxin

Wyeth-Ayerst

-

-

β-Acetyldigitoxin

65

Trade Name

Manufacturer

Country

Year Introduced

Lanoxin

GlaxoSmithKline

-

-

Digitek

Bertek

-

-

Digoxin

Novartis

-

-

Corotal

Rosch and Handel

-

-

Structural Formula:

Raw Materials Crude partial acetylated digoxin Dicyclohexylcarbodiimide

Digoxin Acetic acid

Manufacturing Process Dried crude product of the partial acetylation of digoxin (42 g) prepared from digitalis - is dissolved under reflux in acetone (480 ml) and n-hexane (2400 ml) is added to the solution with stirring. Fine crystals, which begin to separate immediately, are left at room temperature for 5 hours, then they are filtered with suction, washed with n-hexane and dried in vacuum at 40°C, yielding 32 g of crude β-acetyldigoxin (product 1). Product 1 (31 g) is dissolved under reflux in chloroform (500 ml) and toluene (2500 ml) is added thereto with stirring. The crystals, which separate after standing for 6 hours at room temperature, are filtered, washed with toluene and ether and dried in vacuum yielding 29 g of β-acetyldigoxin (product 2). MP: 249°-251°C. The filtrate, which results from the separation of product 1, is evaparated to dryness in vacuum. The residue, which mainly contains unreacted digoxin, is purified by recrystallization from pyridine/ether/water (3.5:5:40) and repeatedly acetylated. It can then be recycled to produce more βacetyldigoxin. The filtrate resulting from the separation of product 2 is evaporated to dryness. The resulting residue contains the di- and polyacetyl derivatives of digoxin, which are deacetylated to digoxin in a known manner

66

Acetylmethadol

and later is returned to a further acetylation process and can then be recycled to produce more β-acetyldigoxin. Beta-Acetyldigoxin may be prepared from digoxin, acetic acid and dicyclohexylcarbodiimide using the last one as a condensing agent. References Pelan B. et al.; G.B. Patent No. 2,000,145 A; June 22, 1977 Haberland G., Arzneim.Forsh. 15, 481 (1965)

ACETYLMETHADOL Therapeutic Function: Narcotic analgesic Chemical Name: Benzeneethanol, β-(2-(dimethylamino)propyl)-α-ethyl-βphenyl-, acetate (ester) Common Name: Acemethadone; Acetyldimepheptanol; Acetylmethadol; Amidolacetat; Dimepheptanolacetat; Methadyl acetate; RaceAcetylmethadol Structural Formula:

Chemical Abstracts Registry No.: 509-74-0 Trade Name

Manufacturer

Country

Year Introduced

Acetylmethadol

National Inst. for Drug Abuse

-

-

ORLAAM

Roxane Laboratories, Inc.

-

Raw Materials Vinyl propionate Novozym 435 Sodium hydroxide Dibenzo-18-crown-6 Sodium borohydride

1-Dimethylamino-2-propanol Thionyl chloride Diphenylacetonitrile Hydrogen chloride Ethyl magnesium bromide

Acetylmethadol

67

Acetyl chloride Cerium (III) chloride heptahydrate Manufacturing Process Racemic 1-dimethylamino-2-propanol (100.0 g, 0.97 mol) was stirred with vinyl propionate (63.6 ml, 0.58 mol) at 40°C and Novozym 435 (5.0 g) was added. The reaction was stirred slowly for 75 h and after this time TLC (10% methanol/dichloromethane-visualize KMnO4 solution) indicated that the reaction had gone to at least 50% conversion. The enzyme was removed by filtration and the filtrate was distilled at reduced pressure. S-(+)-1Dimethylamino-2-propanol was obtained as a colourless oil (31.6 g, 64%), boil point 35°C. A solution of thionyl chloride (37 ml, 0.48 mol) in chloroform (20 ml) was added slowly, with stirring, to a cooled (ice/water) solution of S-(+)-1dimethylamino-2-propanol (30.6 g, 0.32 mol) in chloroform (85 ml). When the addition was complete a precipitate formed. The mixture was allowed to warm to room temperature over 30 min and then heated to reflux for a further 30 min. The precipitate redissolved on heating but then the product crystallized out from the boiling solvent as it formed. More chloroform (20 ml) was needed to maintain the stirring. The cooled mixture was diluted with ether and filtered. The 45.0 g (96%) of crude product was isolated. This was recrystallised from 2-propanol as in the other series to give 30.9 g (65%) of R-(-)-1-dimethylamino-2-chloropropane, melting point 192°-193°C. A 50% w/v solution of sodium hydroxide in water (12.5 ml, 0.32 mol) was added to a mechanically stirred suspension of diphenylacetonitrile (15.0 g,0.08 mol) and dibenzo-18-crown-6 (0.5 g, cat.) in dimethylsulphoxide (12.5 ml). The color rapidly deepened to an orange/brown. R-(-)-1-Dimethylamino2-chloropropane (30.0 g, 0.095 mol) was added in portions over 30 min, this caused the temperature to rise to 30°C. After the addition was complete the mixture was warmed to 45°-50°C (water bath) and stirred for a further hour. The reaction mixture was then allowed to cool to room temperature and was poured into ice/water (250 ml) and extracted with ethyl acetate (3 times 150 ml). The combined extracts were dried (MgSO4) and filtered and evaporated down to -100 ml. The product was extracted into 1N HCl (100 ml+50 ml) and this was back washed with ethyl acetate. The aqueous was basified with 2 M sodium hydroxide and extracted into ethyl acetate (3 times 100 ml). The extracts were washed with brine (70 ml), dried (MgSO4), and evaporated down to a yellow oil. This was chilled and triturated with cold hexane (50 ml) to give a white solid which was collected by filtration and washed thoroughly with a further portion of cold hexane (100 ml). 14.65 g (33%) of S-(+)-2,2diphenyl-4-dimethylaminopentanenitrile were obtained, melting point 100°101°C (recrystallised from hexane). All apparatus was dried and the reaction was carried out under an inert atmosphere of argon. A solution of S-(+)-2,2-diphenyl-4dimethylaminopentanenitrile (10.0 g, 0.018 mol) in toluene (15 ml) was added to a stirred solution of 3 M ethyl magnesium bromide in ether (10.7 ml, 0.03 mol). The ether was removed under reduced pressure and the remaining solution heated at reflux (135°-140°C) for 3 h. The solution went slightly cloudy but there was no significant precipitation. After cooling to room temperature 2 N HCl (30 ml) was added with care and then stirring was

68

Acexamic acid

continued at 135°-140°C for a further 30 min. The two phases were allowed to separate and cool to room temperature. After scratching the sides of the flask a solid started to crystallise from the aqueous phase. The flask was cooled to complete crystallisation and the white solid was collected by filtration. This solid was recrystallised from water to yield 6.6 g (53%) of S(+)-methadone hydrochloride (6-dimethylamino-4,4-diphenyl-3-heptanone hydrochloride) were obtained, melting point 240°-241°C. S-(+)-Methadone hydrochloride (600.0 mg,1.74 mmol) was dissolved in ethanol (10 ml) and the solution was stirred whilst sodium borohydride (3.47 mmol) was added portion-wise over a period of 5 min. When the addition was complete a spatula end of cerium (III) chloride heptahydrate was added. The resultant solution was allowed to stir at room temperature for 30 min then the ethanol was removed under reduced pressure. The residue was portioned between diethyl ether (40 ml) and water (40 ml). The aqueous layer was extracted with more diethyl ether (2 times 20 ml) and then the combined organics were washed with brine (40 ml) and dried (MgSO4). The ether was removed under reduced pressure to leave 435.0 mg, (80%) of 6dimethylamino-4,4-diphenyl-3-heptanol. 6-Dimethylamino-4,4-diphenyl-3-heptanol (435.0 mg, 1.40 mmol) dissolved in ethyl acetate (10 ml) was treated with acetyl chloride (183.0 mg, 2.33 mmol). The mixture was refluxed for 2 h. After allowing the solution to cool to room temperature the solvent was removed under reduced pressure to leave a white foam, this crystallised from ethyl acetate to give 6-dimethylamino-4,4diphenyl-3-acetoxyheptane hydrochloride (levo-α-acetyl methadol hydrochloride) (420.0 mg, 79%). The 6-dimethylamino-4,4-diphenyl-3-acetoxyheptane may be produced by treatment of the 6-dimethylamino-4,4-diphenyl-3-acetoxyheptane hydrochloride with sodium hydroxide. References Scheinmann F. et al.; US Patent No. 6,143,933; Nov. 7, 2000; Assigned: Salford Ultrafine Chemicals and Research Ltd., United Kingdom

ACEXAMIC ACID Therapeutic Function: Antifibrinolytic Chemical Name: Hexanoic acid, 6-(acetylamino)Common Name: Acexamic acid; Plastesol Structural Formula:

Acexamic acid

69

Chemical Abstracts Registry No.: 57-08-9 Trade Name Acexamic acid Acide Acexamicum Plastenan

Manufacturer Flamma ZYF Pharm Chemical Sanofi Winthrop

Country -

Year Introduced -

Raw Materials Calcium hydroxide Acetylcaprolactame Hydrogen chloride Manufacturing Process 400 L of demineralized water, 5.0 kg of calcium hydroxide, and 155.0 kg (1000 moles) of acetyl-caprolactame are introduced under stirring and at a temperature of about 25°C into a 1000 L stainless double walled reactor. The temperature is raised to 30°C. 75.0 kg of calcium hydroxide are introduced stepwise in the form of successive amounts of 2.0 kg each in the medium, under stirring and at a temperature adjusted and maintained 25°30°C through external cooling, in a manner such that the time required to introduce into the reactor the whole amount of calcium hydroxide approximates 1.5 h. When the stirring is stopped, the pH is about 7.5-7.8. The obtained mixture is stirred continuously at a temperature of 30°C during 14 h. At the end of this operation the pH is again adjusted at a value 7.5-7.8. The hydrolysate is filtered on a 60 x 60 pressfilter comprising 6 compartments and equipped with fabrics of the polyester known under the designation TERGAL which have been previously coated with a suspension of a cellulose commercialized under the trademark SOLKA FLOX BW20. The duration of filtration is of 1.5 h. 580 L of the filtrate are recovered and subjected to a concentration under reduced pressure in an evaporator the volume of which is of 750 L, at a distillation temperature ranging from 45°-50°C under a reduced pressure of 10-15 Torr. The operation is ran until concentration of the solution to 280 L, the concentrated solution being then left standing. The crystallisation is already considerable 2 h after the end of the operation of concentration. Crystallisation is ended after 16-24 h. The crystals are centrifuged at a speed of 700 revolutions/minute. The centrifuged crystals of calcium acexamate are washed twice on the centrifuge with 20 l of acetone. 107.0 kg of crystals are obtained, which are dried under vacuum at 40°C. The 96.0 kg of dry calcium acexamate obtained are ground and sifted. Acexamic acid may be produced by treatment of the calcium acexamate with HCl.

70

Acipimox

References Goulay J.; US Patent No. 3,974,215; Aug. 10, 1976; Assigned: Choay S.A., Paris, France

ACIPIMOX Therapeutic Function: Antihyperlipidemic Chemical Name: 2-Pyrazinecarboxylic acid, 5-methyl-, 4-oxide Common Name: Acipimox; Zopinox Structural Formula:

Chemical Abstracts Registry No.: 51037-30-0 Trade Name

Manufacturer

Country

Year Introduced

Olbetam

Pfizer

-

-

Nedios

Byk Pharmaceuticals

-

-

Olbemox

Pharmacia

-

-

Olbemox

Pfizer

-

-

Raw Materials Ethyl chloroformate Ammonia Hydrogen peroxide Hydrochloric acid

2-Carboxy-5-methylpyazine Acetic acid Sodium hydroxide

Manufacturing Process 2-Carboxy-5-methylpyazine (9.7 g) in dry dioxan (114 ml) and tributylamine (17.7 ml) was treated with ethyl chloroformate (7.5 ml), keeping the temperature at 0-5°C. After 10 min, dioxan (190 ml) saturated with ammonia was added. The mixture was stirred for 3 h at room temperature, then dioxin was distilled off, and the residue was taken up tin saturated aqueous sodium bicarbonate (20 ml). The mixture was filtered and the product washed with water to give 2-carbamoyl-5-methylpyrazine (9.2 g), melting point 204°206°C.

Acitazanolast

71

This 2-carbamoyl-5-methylpyrazine (7.0 g) in glacial acetic acid (30 ml) and 35% (w/v) hydrogen peroxide (20 ml) was heated with stirring at 70°C for 7 h. The reaction mixture was cooled, the product which separated was filtered and washed with water to give 2-carbamoyl-5-methylpyrazine-4-oxide (5.5 g), melting point 206°-208°C. 2-Carbamoyl-5-methylpyrazine 4-oxide (5.0 g) was added to 10% by weight sodium hydroxide (50 ml) and then refluxed for 30 min. The reaction mixture was acidified with dilute hydrochloric acid and extracted in a continuous extractor with ethyl acetate. The ethyl acetate extract was concentrated to small volume and gave, after filtration 2-carboxy-5-methylpyrazine 4-oxide (3.2 g), melting point 178°-180°C. References GB Patent No. 1,361,967; July 31, 1974; Assigned: CARLO ERBA SPA an Italian body corporate of Via Carlo Imbonati 24, 20159 Milan, Italy

ACITAZANOLAST Therapeutic Function: Anti-asthmatic, Antiallergic, Bronchodilator Chemical Name: Acetic acid, oxo-((3-(1H-tetrazol-5-yl)phenyl)amino)Common Name: Acitazanolast; Azitanolast; Zepenolast Structural Formula:

Chemical Abstracts Registry No.: 114607-46-4 Trade Name

Manufacturer

Country

Year Introduced

Zepelin

Kowa

-

-

Zepelin

Wakamoto

-

-

Raw Materials 3-(1H-Tetrazol-5-yl)aniline Oxalyl chloride Hydrochloric acid

Triethylamine Sodium hydroxide

72

Acitemate

Manufacturing Process 2 Methods of preparation of 3-(1H-tetrazol-5-yl)oxanilic acid: 1. 5.0 g of 3-(1H-tetrazol-5-yl)aniline was dissolved in 25 ml of N,Ndimethylformamide, followed by adding 5.68 g of triethylamine. Then, 5.64 g of ether oxalyl chloride was dropwise added to the solution while cooling in ice water. After completion of the dropwise addition, the reaction temperature was slowly raised up to room temperature and the reaction was continued for 15 h. After the reaction was completed, the reaction mixture was poured into 100 ml of ice water and crystals separated out from the solution was filtered off to obtain 8.3 g of ethyl 3-(1H-tetrazol-5-yl)oxanilate (yield 94.1%), melting point 192°-l93°C (recrystallized from acetone/n-hexane). The ethyl 3-(1H-tetrazol-5-yl)oxanilate (5.0 g), was dissolved in 35 ml of ethanol and 100 ml of 0.5 N sodium hydroxide was dropwise added thereto under water cooling. After the dropwise addition, the reaction temperature was slowly raised up to room temperature and under such condition, the reaction was carried out for 3 h. This solution was dropwise added to 70 ml of 4 N hydrochloric acid at room temperature. Thereafter, the solution was stirred for 1 h and crystals separated out from the solution was filtered off. The resultant crystals were washed with water and 3.9 g of 3-(1H-tetrazol-5yl)oxanilic acid was recovered (yield 87.4%), melting point 241°-243°C (dec. recrystallized from isopropyl). 2. Oxalyl chloride (12.0 g) was dissolved in 50 ml of anhydrous dimethoxyethane. To this solution a solution of 3-(1H-tetrazol-5-yl)aniline (5.0 g) in 250 ml of anhydrous dimethoxyethane was dropwise added over 3 h at room temperature while stirring. Insolubles were removed by filtering the solution, then 50 ml of water was gradually added to the reaction mixture under ice cooling and stirring was continued for 1 h at room temperature. Then, 500 ml of ethyl acetate was added thereto to carry out extraction, the extract was washed with water, dried over anhydrous sodium sulfate and then the solvent was distilled off to obtain 5.4 g of the 3-(1H-tetrazol-5- yl)oxanilic acid (yield 74.8%), melting point 241°-243°C (dec. recrystallized from isopropyl). References Sawaki S. et al.; US Patent No. 4,795,754; Jan. 3, 1989Assigned: Wakamoto Pharmaceutical Co., Ltd., Tokyo, Japan

ACITEMATE Therapeutic Function: Platelet aggregation inhibitor, Antihyperlipidemic Chemical Name: 3-(Ethoxycarbonyl)-6,7,8,9-tetrahydro-6-methyl-4-oxo-4Hpyrido[1,2-a]pyrimidine-9-acetic acid Common Name: Acitemate; Vapedrine

Acitemate

73

Structural Formula:

Chemical Abstracts Registry No.: 64405-40-9 Trade Name Acitemate

Manufacturer Onbio Inc.

Country -

Year Introduced -

Raw Materials 3-Ethoxycarbonyl-7-methyl-4-oxo-6,7,8,9-tetrahydro-4Hpyrido[1,2a]pyrimidine Palladium on carbon Glyoxylic acid monohydrate Hydrogen Manufacturing Process 23.6 g of 3-ethoxycarbonyl-7-methyl-4-oxo-6,7,8,9-tetrahydro-4Hpyrido[1,2a]pyrimidine and 10.0 g of glyoxylic acid monohydrate are reacted and the obtained 3-ethoxycarbonyl-7-methyl-9-carboxy(hydroxymethyl)-4oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2a]pyrimidine is heated in 150 ml ethanol under stirring for 3 h. After cooling the crystals are filtered off and recrystallized from ethanol. Thus 3-ethoxycarbonyl-7-methyl-9(carboxymethylene)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2a]pyrimidine melting point 110°-112°C, is obtained (yield: 51%). 55.6 g of 3-ethoxycarbonyl-9-(carboxymethylene)-4-oxo-6,7,8,9-tetrahydro4H-pyrido[1,2a]pyrimidine are hydrogenated in 500 ml of ethanol in the presence of 20.0 g of 9% by weight Pd/C catalyst containing metal. When 1 mole of hydrogen has been used up, the catalyst is removed from the reaction mixture by filtration and the solution is evaporated under reduced pressure. The 3-ethoxycarbonyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9acetic acid is obtained (yield: 57%), melting point 156°-157°C (recrystallized from ethanol). References Hermecz I. et al.; US Patent No. 4,123,533; Oct. 31, 1978; Assigned: Chinoin Gyogyazer es Vegyeszeti Termekek Gyara R.T., Budapest, Hungary

74

Acitretin

ACITRETIN Therapeutic Function: Antipsoriatic Chemical Name: 2,4,6,8-Nonatetraenoic acid, 3,7-dimethyl-9-(4-methoxy2,3,6-trimethyl-phenyl)-, (all-E) Common Name: Acitretin; Etretin Structural Formula:

Chemical Abstracts Registry No.: 56079-83-9 Trade Name Acitretin Neotigason Neotigason Soriatane

Manufacturer Roche Roche Pty Limited Roche Roche Pharmaceuticals

Country Australia -

Year Introduced -

Raw Materials 5-(4-Methoxy-2,3,6-trimethylphenyl)-3-methylpenta-2,4-diene-1triphenylphosphonium bromide 3-Formylcrotonic acid butyl ester Sodium hydride Manufacturing Process 228 g of 5-(4-methoxy-2,3,6-trimethyl-phenyl)-3-methyl-penta-2,4-diene-1triphenylphosphonium bromide was added under nitrogen to 910 ml of dimethylformamide and treated at 5-10°C within 20 min. with 17.5 g of a suspension of sodium hydride (about 50% by weight) in mineral oil. The mixture was stirred for 1 hour at about 10°C, then 61.8 g of 3-formylcrotonic acid butyl ester was added dropwise at 5-8°C, a mixture was heated for 2 hours at 65°C, subsequently introduced into 8 L of ice-water, then was added 300 g of sodium chloride, and the mixture thoroughly extracted with a total 18 L of hexane. The extract was washed 5 times with 1 L of methanol/water (6:4 parts by volume) each time and 2 times with 1.5 L water each time, dried over sodium sulphate and evaporated under reduced pressure to leave 9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid butyl ester, m.p. 80-81°C. 125.8 g of this ester was introduced into 2 L of abs. ethanol and treated with a solution of 125.6 g of hydroxide in 195 ml of water. The mixture was heated

Acivicin

75

to boiling under nitrogen gassing for 30 minutes, then cooled, introduced into 10 L of ice-water and, after the addition of about 240 ml of conc. hydrochloric acid (pH 2-4), thoroughly extracted with total 9 L methylene chloride. Extract is washed with about 6 L water to neutrality, dried over calcium chloride and evaporated under reduced pressure. The residue is taken up in 700 ml of hexane. The precipitated 9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethylnona-2,4,6,8-tetraen-1-oic acid melts at 228-230°C. References W. Bollang, R. Ruegg, G. Ryser, US Patent No. 4,105,681, Aug. 8, 1978

ACIVICIN Therapeutic Function: Antineoplastic Chemical Name: 5-Isoxazoleacetic acid, α-amino-3-chloro-4,5-dihydro-, (S(R*,R*))Common Name: Acivicin; NSC-163501 Structural Formula:

Chemical Abstracts Registry No.: 42228-92-2 Trade Name

Manufacturer

Country

Year Introduced

Acivicin

ZYF Pharm Chemical

-

-

LKT-A0934-M010

LKT Laboratories, Inc.

-

-

Raw Materials cis-2-Buten-1,4-dio Trichloroacetonitrile Dibromoformaldoxime

Monotrichloroacetimidate tert-Butyl benzene Bromonitrile oxide

Manufacturing Process Starting from commercial, cis-2-buten-1,4-diol, the monotrichloroacetimidate was obtained as a colorless liquid (60%, b.p. 88°-102°C/0.2 mm Hg) by treatment with trichloroacetonitrile (1 equivalent) in tetrahydrofuran at -23°C in the presence of catalytic amount of sodium. Monotrichloroacetimidate upon refluxing in tert-butyl benzene for about 1 hour underwent, smoothly,

76

Aclarubicin

rearrangement to afford the vinylglycine synton (84%, MP: 30°C). The treatment of the last compound with bromonitrile oxide (3 equiv.) generated in situ from dibromoformaldoxime in ethyl acetate containing excess of KHCO3 and trace amounts of water afforded 3:2 mixture of cycloadducts threo- and erythro-N-[1-(3-bromo-4,5-dihydroisoxazol-5-yl)-2-hydroxyethyl]-2,2,2trichloroacetamide. The undesired threo- isomer (MP: 164°-165°C) was quantitatively removed from the mixture by fractional crystallization from chloroform. The erythro-isomer (oil) was refluxed with methanolic-HCl for 1 hour to give the chloro-alchohol (50%, syrup), which upon Jones oxidation (with H2Cr2O7/acetone) followed by deprotection of trichloroacetyl group (Ba(OH)2/H2O, H3+O) afforded racemic acivicin (66 %). The synthetic, racemic antibiotic was spectrally (UV, 1H NMR) indistinguishable from natural product, prepared from fermentation broth of Stretomyces sviceus. References Vyas D.M., Chiang Y. and Doyle T.W.; Tetrahedron Letters, vol. 25, No 5, p.p. 487-490; 1984 Mrtin D.G., Duchamp D.J. and Chidester C.G.; Tetrahedron Letters, No 27, p.p. 2549-2552, 1973

ACLARUBICIN Therapeutic Function: Antitumor, Antibiotic Chemical Name: Aclacinomycin A Common Name: Aclacinomycin A Structural Formula:

Chemical Abstracts Registry No.: 57576-44-0 Trade Name Aclacinon Aclacinomycine

Manufacturer Yamanouchi Roger Bellon

Country Japan France

Year Introduced 1981 1981

Aclarubicin

77

Raw Materials Carbohydrates Manufacturing Process An aqueous medium having the following composition was prepared: Percent Potato starch Glucose Prorich KH2PO4

1 1 1.5 0.1

K2HPO4 MgSO4·7H2O NaCl Minerals* Silicone (KM75) pH

Percent 0.1 0.1 0.3 0.125 0.05 7.0

*2.8 g CuSO4·5H2O, 0.4 g FeSO4·7H2O, 3.2 g MnCl2·4H2O, 0.8 g ZnSO4·7H2O in 500 ml water 100 ml of this medium was sterilized at 120°C for 15 min in a 500 ml Sakaguchi-shaking flask which was inoculated from an agar slant culture of Streptomyces galilaeus MA144-M1 by platinum loop. Incubation proceeded for 48 hr at 28°C on a reciprocal shaker. 10 L of the previously sterilized medium in a 20 L stainless steel jar fermenter were aseptically inoculated with 200 ml of the above seed cultures. Fermentation was carried out at 28°C for 32 hours with agitation (240 rpm) and aeration (5 L/min). The cultured broth obtained was adjusted to pH 4.5, mixed with an adsorbent siliceous earth material and filtered from the mycelium. The filtrate and cake obtained thereby were extracted separately. The cake was suspended in acetone (3 L/kg wet cake), stirred for 2 hr and filtered, and the cake was further extracted with acetone once again. The extracts thus obtained were evaporated to one-tenth volume in vacuum. The culture filtrate was adjusted to pH 6.8 and extracted twice with one-third volume of ethyl acetate, and the ethyl acetate extracts were concentrated to one-tenth volume in vacuum. Twenty grams of the resulting oily substances were mixed with 20 grams of silicic acid (Mallinckrodt Chemical Co.), applied to a column 40 cm in length and 4.5 cm in diameter filled with silicic acid, and eluted with a benzeneacetone-methanol mixture. The initial eluate which eluted with a 1:1:0 mixture was discarded and the active fractions eluted with 1:3:0 and 1:3:0.3 mixtures were collected and concentrated to dryness in vacuum. 11.5 g of this crude substance was then dissolved in a small amount of ethyl acetate and applied to the same silicic acid column as above. After discarding the initial eluates by the 1:1 and 2:1 benzene-acetone mixtures, aclacinomycin B fractions were first eluted with the above mixtures of 1:3 and 1:5 ratio, and aclacinomycin A fractions were then eluted with the 1:5:0.5 and 1:5:1

78

Aclatonium napadisylate

benzene-acetone-methanol mixtures. The eluates were dried over anhydrous sodium sulfate and concentrated to dryness in vacuum. 4.8 g of crude aclacinomycin A and 3.5 g of aclacinomycin B were obtained as yellow powder. 2.0 g of crude aclacinomycin A obtained as above were dissolved in a small amount of chloroform, applied to a column 20 cm in length and 20 cm in diameter filled with 30 g of silicic acid. After eluting off the pigments containing aglycone and aclacinomycin B and other impurities with chloroform and 1.5% methanol-containing chloroform, aclacinomycin A fractions were eluted with 2% methanol-containing chloroform, and concentrated to dryness in vacuum. 53 mg of yellow powder of aclacinomycin A was obtained. Its melting point was 129°C to 135°C. References DFU2 (3) 171 (1978) (as Aclacinomycin A) DOT 18 (10) 517 (1982) I.N. p.42 (1984) Umezawa, H., Takeuchi, T., Hamada, M., Takamatsu, A. and Oki, T.; US Patent 3,988,315; October 26, 1976; Assigned to Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai

ACLATONIUM NAPADISYLATE Therapeutic Function: Cholinergic Chemical Name: 2-[2-(Acetyloxy)-1-oxopropoxy]-N,N,N-trimethylethanaminium 1,5-naphthalenedisulfonate (2:1) Common Name: Bis[acetoxy-methyl acetic acid trimethylammoniumethyl ester]-naphthalene-1,5-disulfonate Structural Formula:

Chemical Abstracts Registry No.: 55077-30-0 Trade Name

Manufacturer

Country

Year Introduced

Abovis

Toyama

Japan

1981

Acodazole hydrochloride

79

Raw Materials Bis(choline)-naphthalene-1,5-disulfonate Lactic acid anhydride diacetate Manufacturing Process 5.2 g of bis(choline)-naphthalene-1,5-disulfonate was suspended in 30 ml of acetonitrile, and 10 g of lactic acid anhydride diacetate was added thereto. This mixture was refluxed for 3 hours. The resulting reaction mixture was allowed to stand at room temperature while cooling to precipitate the desired product crystals, which were collected by filtration. 5.5 g (76% yield) of the desired product having a melting point of 189°C to 191°C were obtained. References Merck Index 110 DFU 7 (4) 227 (1982) DOT 19 (1) 8 (1983) I.N.p.42 Miura, K., Takagawa, N., Suzuki, Y. and Matsumoto, Y.; US Patent 3,903,137; September 2, 1975; Assigned to Toyama Chemical Co., Ltd.

ACODAZOLE HYDROCHLORIDE Therapeutic Function: Antineoplastic Chemical Name: Acetamide, N-methyl-N-(4-((7-methyl-1H-imidazo[4,5f]quinolin-9-yl)amino)phenyl)-, hydrochloride Common Name: Acodazole hydrochloride; NSC-305884 Structural Formula:

Chemical Abstracts Registry No.: 55435-65-9; 79152-85-5 (Base) Trade Name

Manufacturer

Country

Year Introduced

Acodazole Hydrochloride

ZYF Pharm Chemical

-

-

80

Acodazole hydrochloride

Raw Materials Acetic anhydride Hydrogen 5-Nitrobenzimidazole Ethyl acetoacetate Acetic acid Sodium hydroxide

N-Methyl-p-nitroaniline Nickel Raney Palladium on carbon Calcium sulfate POCl3 Dowtherm®

Manufacturing Process An 82.0 g (0.5 mole) of 5-nitrobenzimidazole in 900 ml of ethanol was reduced over 4.0 g of 5% Pd/C catalyst containing 50% H2O. After filtration of the catalyst, 65.0 g (0.5 mole) of ethyl acetoacetate, 20.0 g of anhydrous calcium sulfate, and 0.5 ml of HOAc was added. After filtration, the solution was concentrated in vacuo till a solid remained. The product was filtered and washed with fresh ethanol and air-dried. The yield of ethyl 3-(5benzimidazolylamino)crotonate was 84.0 g (69%), melting point 160°-162°C. 40.0 g of ethyl 3-(5-benzimidazolylamino)crotonate was added to 80 ml of boiling Dowtherm® and the boiling was continued for 5 min. The product separated upon cooling. The product was filtered, washed with Dowtherm® and then acetone and air-dried. The yield of 7-methyl-9-imidazo[4,5f]quinolinol was 29.0 g (91%), melting point 345°-347°C. Into a 22 L, 4-necked flask set in a tub and equipped with a stirrer, an air condenser (drying tube), thermometer, and dropping funnel was placed POCl3 (4590 ml). The 7-methyl-9-imidazo[4,5-f]quinolinol (1062.0 g, 5.33 moles) was added with no heating effect noted. Dimethylformamide (4690 ml) was added dropwise over a 2.5 h period at a rate to control the temperature below 85°C. The resulting viscous solution was allowed to stand overnight at room temperature and then added cautiously to ice to a total volume of ca. 50 L. The resulting solution was then adjusted to a pH of 7 to 8 by the addition of NaOH pellets (9771.0 g). More ice was added as needed to keep the temperature below 45°C. The resulting precipitate was collected by filtration, washed well by stirring in water (3x20 L) and dried at 60°C to yield 1107.0 g (95.5%) of 9-chloro-7-methylimidazo[4,5-f]quinolone. To 500 ml of acetic anhydride was added portionwise, 100.0 g (0.658) of Nmethyl-p-nitroaniline. Following the addition, the solution was heated on a steam bath for 2 h, then stirred overnight at room temperature. The white precipitate of the N-methyl-4-nitroacetanilide was collected by filtration, washed with ether and air-dried to give 53.0 g, melting point 153°-156°C. The filtrate was concentrated in vacuum to give another 61.0 g, melting point 150°-154°C. A mixture of 114.0 g (0.587 m) of N-methyl-4-nitroacetanilide and 800 ml of ethanol was shaken with hydrogen over one teaspoon of Raney active nickel catalyst in water. A pressure drop of 127 psi was recorded (calc. 118 psi). The catalyst was removed by filtration and the ethanol filtrate refluxed overnight with 127.0 g (0.587 m) of the 9-chloro-7-methylimidazo[4,5-f]quinolone. The mixture was chilled, filtered, washed with ether and air-dried to give 75.5 g of 9-[p-(N-methylacetamido)anilino]-7-methyl-1-H-imidazo[4,5-f]quinoline

Acoxatrine

81

hydrochloride sesquihydrate, melting point 315°-318°C (recrystallized from 4,000 ml of MeOH). By treatment of 9-p-(N-methylacetamido)anilino-7-methyl-1H-imidazo[4,5f]quinolone hydrochloride sesquihydrate with NaOH may be produced the 9-p(N-methylacetamido)anilino-7-methyl-1H-imidazo[4,5-f]quinolone. References Spencer C.F., Snyder H.R.; US Patent No. 3,878,206; April 15, 1975; Assigned: Morton-Norwich Products, Inc., Norwich, N.Y.

ACOXATRINE Therapeutic Function: Vasodilator, Antihypertensive Chemical Name: Acetamide, N-((1-(1,4-benzodioxan-2-ylmethyl)-4-phenyl4-piperidyl)methyl)Common Name: Acetoxatrine; Acoxatrine Structural Formula:

Chemical Abstracts Registry No.: 748-44-7 Trade Name

Manufacturer

Country

Year Introduced

Acoxatrine

ZYF Pharm Chemical

-

-

Raw Materials Lithium aluminum hydride Acetyl chloride

DL-1-Cyano-4-phenyl-piperidine Sodium hydroxide

Manufacturing Process To a solution of 11.5 parts lithium aluminum hydride in 100 parts tetrahydrofurane is added dropwise a solution of 94 parts DL-1-cyano-4phenyl-piperidine in 240 parts tetrahydrofurane, at a temperature of about 45°C. After the addition is complete, the reaction mixture is stirred first at the same temperature for 3 h and 30 min and then refluxed for 1 h. The whole is decomposed by successive addition of 12 parts water, 9 parts sodium

82

Acriflavine hydrochloride

hydroxide 20% and 50 parts water. The mixture is filtered from inorganic matter. The filter-cake is washed with tetrahydrofurane and the combined filtrates are evaporated. The oily residue is dissolved in 240 parts 2-propanol and to this solution are added about 60 parts concentrated hydrochloric acid. After keeping at room temperature, the precipitated salt is filtered off, washed with 2-propanol and dried, yielding DL-4-(amino-methyl)-1-[1,4benzodioxanyl)methyl]-4-phenylpiperidine dihydrochloride; melting point 272°-278°C as a white amorphous powder. From 4.1 parts DL-4-(aminomethyl)-1-[2-(1,4-benzodioxanyl)methyl]-4phenylpiperidine dihydrochloride, the free base is liberated in the usual manner and extracted with chloroform. The organic layer is separated, dried and evaporated. The DL-4-(aminomethyl)-1-[2-(1,4-benzodioxanyl)methyl]-4phenylpiperidine obtained is dissolved in 128 parts anhydrous chloroform. This solution is cooled to 5°C and there is added dropwise a solution of 1.6 parts acetylchloride in 7 parts anhydrous chloroform (exothermic reaction). The reaction mixture is stirred over night at room temperature and then alkalized with about 25 parts sodium hydroxide 20% at a temperature of 20°C. The aqueous layer is separated and extracted twice with chloroform. The combined organic layers are washed with water, dried over magnesium sulfate, filtered and evaporated. The oily residue is dissolved in a mixture of 40 parts acetone and 20 parts diisopropyl ether and evaporated again. The solid residue is triturated in diisopropylether, yielding DL-4-(N-acetylaminomethyl)-1-[2-(1,4benzodioxanyl)-methyl]-4-phenylpiperidine; melting point 140°-141.1°C, as a white microcrystalline powder. References Janssen P.A.J.; US Patent No. 3,166,561; January 19, 1965; Assigned: Research Laboratorium Dr. C. Janssen N.V., a corporation of Belgium

ACRIFLAVINE HYDROCHLORIDE Therapeutic Function: Antiseptic, Topical antibacterial Chemical Name: Acridinium, 3,6-diamino-10-methyl-, chloride, monohydrochloride, mixture with 3,6-acridinediamine hydrochloride Common Name: Acid acriflavine; Acriflavin; Acriflavinium chloride; Euflavin; Flavacridinum; Xanthacridinum Structural Formula:

Acriflavine hydrochloride

83

Chemical Abstracts Registry No.: 6034-59-9; 837-73-0 (Base) Trade Name

Manufacturer

Country

Year Introduced

Acriflavine hydrochloride Acriflavine hydrochloride

ABCR GmbH and Co. KG

-

-

Advance Scientific and Chemical, Inc.

-

-

Acriflavine hydrochloride

Spectrum Chemicals and Laboratory Products, Inc.

-

Acriflavine hydrochloride Acriflavine hydrochloride

Ruger Chemical Co., Inc. -

-

AppliChem

-

-

Acriflavine hydrochloride

Amend Drug and Chemical Company

-

-

Acriflavine hydrochloride

CCA (Changzhou) Biochemical Co., Ltd.

-

-

Acridina

Fatro

-

-

Acriflavin

Koi

-

-

Acriflavin

Vipor Chemicals Pvt.Ltd.

-

-

Acriflavin

Advance Scientific and Chemical, Inc.

-

-

Acriflavin

C. Krieger + Co. Nachf. GmbH + Co.

-

-

Acriflavin

Exim-Pharm International -

-

Acriflavin

Hasco-Lek

-

-

Acriflavin

Dr Zdrowie SA

-

-

Acriflavin

Rasfer Internacional, S.A. -

-

Acriflavin

Trannspharma, Sas

-

-

Acriflavin

Mediplus International

-

-

Acriflavin

Unical (Ceylon) Limited

-

-

Acriflavin

Olita Scientific Works

-

-

Acriflavin

Hygea SA; Polska Grupa Aptekarska

-

-

Acriflavin

Internatio NV

-

-

Acrinol

Pasteur

-

-

Burnol

Boots Company PLC

-

-

Diacrid

Sidroga AG

-

-

Euflavin

Macsen Laboratories

-

-

Gonacrine

May and Baker

-

-

Panflavin

Chinosolfabrik

-

-

Trypaflavin

Zoolek

-

-

84

Acrisorcin

Raw Materials 4,4-Diaminodiphenylmethane Nitric acid Hydrochloric acid Tin Ferric chloride Acetanhydride 4-Toluolsulfomethyl ether Manufacturing Process 4,4-Diaminodiphenylmethane reacted with HNO3 and as a result of this reaction 4,4-diamino-2,2-dinitro-diphenylmethane was obtained. By reducing of 4,4-diamino-2,2-dinitro-diphenylmethane with HCl and Sn, 2,2,4,4-tetraaminodiphenylmethane was produced, which at heating to 150°C gave 3,6-diamino-9,10-dihydroacridine. The 3,6-diamino-9,10-dihydroacridine by oxidation with FeCl3 was converted to 3,6-diaminoacridine. 3,6-Diaminoacridine was reacted with acetanhydride and 3,6-bis(acetylamino)-acridine was produced. 3,6-Bis-(acetylamino)-acridine was methylated by p-toluolsulfomethyl ether and 3,6-bis-(acetylamino)-10-methylacridinumtosylate was produced. Then the 3,6-bis-(acetylamino)-10-methylacridinumtosylate was converted to 3,6-diamino-10-methylacridinum chloride (acriflavinum chloride) by reaction with hydrochloric acid. References Kleemann A., Engel J.; Pharmazeutische Wirkstoffe, GeorgThieme Verlag Stuttgart, New York, 1982

ACRISORCIN Therapeutic Function: Antifungal, Anthelmintic Chemical Name: 1,3-Benzenediol, 4-hexyl-, compd. with 9acridinamine (1:1) Common Name: Acrisorcin; Akrinol; Aminacrine hexylresorcinate Chemical Abstracts Registry No.: 7527-91-5

Acrivastine

85

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Aminacrine hexylresorcinate

ZYF Pharm Chemical

-

-

Raw Materials 4-Hexylresorcinol Hydrochloric acid

Potassium hydroxide 9-Aminoacridine

Manufacturing Process 4-Hexylresorcinol 194.0 g is added to a solution composed of 56.1 g potassium hydroxide in 1.5 L of water with stirring, and the mixture heated to about 40°C to effect complete solution. The pH of this solution is 12. A second solution of 9-aminoacridine hydrochloride is prepared as follows: 2 L of water containing 83 ml of concentrated hydrochloric acid are heated with stirring to about 80°C. Slowly 194.0 g of 9-aminoacridine are added. Heating is continued until a clear solution is obtained. About 2 ml of additional concentrated hydrochloric acid are added in small increments until the solution is slightly acid (pH of about 6). The 4-hexyl resorcinol solution is now slowly added under rapid agitation to the 9-aminoacridine hydrochloride solution. A copious precipitate is formed which, upon :stirring and continued addition of the 4-hexylresorcinol solution, becomes a creamy yellow slurry. At the end of the addition, the pH is 7-8 (indicator paper). The slurry is stirred while heated for an additional 15 min and then rapidly filtered on a 15 cm Buchner funnel. The product thus obtained is washed thoroughly, using about 1 L of cold water, to give a very pale yellow color in the last wash. The compound is then pressed dry and then oven-dried for 2-3 h at 50°C. The resultant product, 9aminoacridine 4-hexyl resorcinolate, has a melting point of 189°-190°C. References Seneca H.; US Patent No. 3,122,553; Feb. 25, 1964; Assigned: Bansen, Inc., New York, N.Y., a corporation of New York

ACRIVASTINE Therapeutic Function: Antihistaminic

86

Acrivastine

Chemical Name: 2-Propenoic acid, 3-(6-(1-(4-methylphenyl)-3-(1pyrrolidinyl)-1-propenyl)-2-pyridinyl)-, (E,E)Common Name: Acrivastine; Semprex Structural Formula:

Chemical Abstracts Registry No.: 87848-99-5 Trade Name Acrivastine Semprex Cap. Benadryl Benadryl

Manufacturer ZYF Pharm Chemical Glaxo Wellcom-Misr Co. Warner-Lambert Pfizer

Country -

Year Introduced -

Raw Materials Sulfuric acid Butyl lithium 4-Tolunitrile Sodium carbonate Ammonia Sodium hydroxide

Triphenyl-2-pyrrolidinoethylphosphonium bromide 2,6-Dibromopyridine Hydrochloric acid 4-Toluenesulfonic acid Sodium hydride Triethyl phosphonoacetate

Manufacturing Process Butyl lithium (50 ml, 1.65 mol in hexane) was added under nitrogen to a stirred suspension of 2,6-dibromopyridine (19.5 g) in dry ether (200 ml) at 50°C. After 0.75 h a solution of 4-tolunitrile (10.0 g) in ether (50 ml) was added; stirring was continued at -50°C for 3 h. The mixture was allowed to warm to -30°C and treated with hydrochloric acid (200 ml, 2 mol). The precipitated solid was collected, washed with water to give the 2-bromo-6-(4toluoyl)pyridine as colourless needles (12.2 g), melting point 97°-98°C (recrystallized from aqueous ethanol). A mixture of 2-bromo-6-(4-toluoyl)pyridine (200.0 g), ethylene glycol (85 ml), p-toluenesulphonic acid (32.0 g) and benzene (11 ml) was boiled under a Dean/Stark trap until water collection had become very slow (about 20 ml collected in 16 h). The cooled solution was poured into ice/water containing sodium carbonate (100.0 g) with stirring. The benzene layer was separated, washed with water, dried with sodium sulfate and evaporated to about 500 ml. Cooling gave a

Acrivastine

87

first crop of 2-(6-bromo-2-pyridyl)-2-(4-tolyl)-1,3-dioxolan, melting point 113°-114°C (170.0 g). Dilution with petroleum ether gave a second crop, melting point 109°-112°C (34.0 g). The residue after evaporation (31.0 g) was recycled. A solution of 2-(6-bromo-2-pyridyl)-2-(4-tolyl)-1,3-dioxolan, vide supra, (70.0 g) in dry toluene (800 ml) was added dropwise during 5 h to a stirred solution of butyl lithium (1.6 mol in hexane, 200 ml) and toluene (200 ml) at -65° to 72°C under nitrogen. After a further 30 min at -70°C, dry dimethylformamide (40 ml) was added during 35 min. Stirring continued overnight at -70° to 60°C. Hydrochloric acid (2 N, 400 ml) was added, allowing the temperature to rise to about -10°C. After 30 min, 2 N ammonia (ca. 90 ml) was added to pH 7-8. The toluene layer was separated and the aqueous phase was extracted with ether. The combined organic liquids were washed with ice/water, dried (MgSO4) and evaporated in vacuum below 50°C. The aldehyde, 2-(6-formyl-2pyridyl)-2-(4-tolyl)-1,3-dioxolan, (63.9 g) crystallized on keeping at 3°C, melting point 52-63°C. The 2-(6-formyl-2-pyridyl)-2-(4-tolyl)-1,3-dioxolan (2.5 g) was dissolved in 1,2-dimethoxyethane (10 ml) and added to a solution of the phosphonate carbanion produced from triethyl phosphonoacetate (2.0 g) and sodium hydride (0.22 g) in the same solvent. The mixture was stirred for 2 h, diluted with ether (25 ml) and treated with hydrochloric acid (5 ml, 2 mol). The organic phase was separated, washed with water, dried, and evaporated. The resulting oil was dissolved in ethanol (20 ml) containing concentrated hydrochloric acid (3 ml) and water (3 ml). After heating on the steam bath for 10 min, the solution was diluted with ice water, rendered alkaline with sodium bicarbonate solution, and extracted with ether. Evaporation gave 1.0 g ((E)-3(6-(4-toluoyl)-2-pyridyl)acrylate as colourless platelets, melting point 108°111°C (crystallized from cyclohexane). Butyl lithium (10 ml, 1.64 mol in hexane) was added under nitrogen to a stirred suspension of triphenyl-2-pyrrolidinoethylphosphonium bromide (7.2 g) in dry toluene (75 ml). After 0.5 h, ((E)-3-(6-(4-toluoyl)-2-pyridyl)acrylate, vide supra, (4.8 g) in toluene (50 ml) was added. The suspension, initially orange, became deep purple, then slowly faded to yellow during 2 h heating at 75°C. The cooled solution was diluted with ether (150 ml) and treated with hydrochloric acid (50 ml, 2 mol). The aqueous phase was separated, washed with ether, and basified with potassium carbonate (ice) and extracted with ether. The mixture of isomeric esters obtained by evaporation was dissolved in ethanol (100 ml) containing sodium hydroxide solution (20 ml, 1 mol) and partially evaporated on the steam bath under reduced pressure for 5 min. The residual aqueous solution was neutralized with sulfuric acid (20 ml, 0.5 mol) and evaporated to dryness. The solid residue was extracted with hot isopropanol (3x50 ml) and the extracts were concentrated until crystallization commenced. The (E)-3-(6-(3-pyrrolidino-1-(4-tolyl)prop-1-(E)-enyl)-2pyridyl)acrylic acid, melting point 222°C (dec. recrystallization from isopropanol) was obtained. References Coker G.G., Findlay J.W.A.; EU Patent No. 0,085,959; Feb. 3, 1983; Assigned: The Wellcome Foundation Limited 183-193 Euston Road, London NW1 2BP(GB)

88

Acrocinonide

ACROCINONIDE Therapeutic Function: Antiinflammatory, Antiallergic Chemical Name: (11β,16α)-9-Fluoro-11,21-dihydroxy-16,17-[2propenylidenebis(oxy)]pregna-1,4-diene-3,20-dione Common Name: Acrocinonide Structural Formula:

Chemical Abstracts Registry No.: 28971-58-6 Trade Name

Manufacturer

Country

Year Introduced

Acrocinonide

Onbio Inc.

-

-

Raw Materials 9-Fluoro-11β,16α,17,21-tetra-hydroxy-pregna-1,4-diene-3,20-dione Perchloric acid Sodium bicarbonate Acrolein Manufacturing Process A suspension of 1.0 g of 9-fluoro-11β,16α,17,21-tetra-hydroxy-pregna-1,4diene-3,20-dione in a mixture of 35 ml of dioxan, 15 ml of acrolein and 0.1 ml of perchloric acid was stirred for 3 h at room temperature. The clear solution thus obtained was poured into an aqueous saturated solution of sodium bicarbonate. The mixture was extracted twice with benzene, and the benzenic extract was concentrated to a small volume. The resulting crystals were collected and the 9-fluoro-11β,21-dihydroxy-16α,17-(2-propenylidenedioxy)pregna-1,4-diene-3,20-dione was obtained as white crystals, melting point 200°-205°C. References GB Patent No. 1,292,269; Oct. 11, 1972; Assigned: ROUSSEL-UCLAF SOCIETE ANONYME, a body corporate organized under the laws of France, of 35 Boulevard des Invalides, Paris 7e, France

Acronine

89

ACRONINE Therapeutic Function: Antineoplastic Chemical Name: 7H-Pyrano[2,3-c]acridin-7-one, 3,12-dihydro-6-methoxy3,3,12-trimethylCommon Name: Acronine; Acronycine; NSC-403169 Structural Formula:

Chemical Abstracts Registry No.: 7008-42-6 Trade Name

Manufacturer

Country

Year Introduced

Acronine

ZYF Pharm Chemical

-

-

Raw Materials 2-Nitrobenzoyl chloride 3-Chloro-3-methylbutyne Sodium hydride

3,5-Dimethoxyphenol Zinc Methyl iodide

Manufacturing Process The acridone alkaloids constitute a small group of natural products found exclusively in the Rutaceae family of higher plants. A sustained interest in this field has been due to the reported activity of acronycine a constituent of Acronnychia baueri and Vepris amphody as an anti-tumor agent. There are different methods of the synthetic preparation of acronycine (W. M. Bandaranayake et al., J. Chem. Soc. Perkin 1, 998 (1968); J. Hlubucek et al.; Aust. J. Chem. 23, 1881 (1970). One of them is described below. FriedelCrafts condensation between 2-nitrobenzoyl chloride and 3,5dimethoxyphenol. 2-Nitrobenzoyl chloride (12 g) and AlCl3, (anhyd., 13 g) were dissolved in dry ether (50 ml) and this mixture added to a solution of 3.5-dimethoxyphenol (5 g) in dry ether 150 ml) at 0°C and the final mixture stirred at 0°C for 3 hours, brought to 20°C and stirred for a further 3 h. Diluted HCl and ice were added and the product extracted with EtOAc (3x50 ml), this extract was washed with aq. NaHCO3, water, dried (MgSO4), filtered and evaporated under reduced pressure to yield a dark red oil. This oil was treated with 2 M aq. NaOH. (100 ml) for 1 h., acidified with diluted HCl and re-extracted with

90

Acronine

EtOAc which gave, after a similar work up, a paled red oil (5.0 g). Thin layer chromatography (TLC) showed three components one of which was the starting phenol. Column chromatography (150 g silica gel) and elution with benzene:petrol ether 40°-60°C (1:1) followed by increasing polarity of solvents (benzene through chloroform to chloroform:ether (4:1) gave 59 fractions. Fractions 1-12 were combined to gave a solid, which crystallized from benzene to give 4,6-dimethoxy-2-hydroxy-2-nitrobenzophenone, MP: 198°-199°C. Fractions 13-21 were discarded. Fractions 22-42 were combined (0.3 g), crystallized from benzene and the product added to that obtained from fractions 43-59 which crystallized from benzene to give 2,6-dimethoxy7-hydroxy-2-nitrobenzophenone (0.5 g) MP: 175°-177°C. Condensation of 3-chloro-3-methylbutyne with 2,6-dimethoxy-7-hydroxy-2nitrobenzophenone: A solution of the above benzophenone (2 g) and excess 3-chloro-3methylbutyne (4.5 g) in dry DMF (60 ml) containing anhydrous K2CO3 (4 g) and dry KI (2 g) was stirred and heated at 65°C for 14 hours (under N2). The mixture was cooled, diluted with water, acidified, extracted with chloroform (3x50 ml) and the extract was worked up in the usual way (including a NaOH wash) to give an oil, which was redissolved in DMF (20 ml) and heated at 130°C, under N2, for 7 h whence most of the starting material had disappeared. The solvent was removed under reduced pressure to give a product (0.62 g) which was purified by preparative layer chromatography on silica gel to give 6-(2-nitrobehzoyl)-5,7-dimethoxy-2,2-dimethylchromene (0.22 g) which crystallized from EtOH, MP: 92°-93°C. 6-(2-Aminobenzoyl)-5,7-dimethoxy-2,2-dimethylchromene (0.2 g) was dissolved in EtOH (30 ml) containing water (5 ml) and ammonium chloride (1 g) and Zn mossy (1.5 g) was added in portions and the mixture stirred at room temperature for 5 days. The solution was filtered, evaporated to dryness under reduced pressure and the residue dissolved in EtOAc (25 ml) and worked up in the usual way to give a solid (0.19 g). It crystallised from EtOH with MP: 123°-126°C. Cyclization of aminodimethylchromenylbenzophenone: 6-(2-aminobenzoyl)5,7-dimethoxy-2,2-dimethylchromene (0.12 g) was dissolved in DMSO (8 ml) and NaH (0.06 g) added, the mixture was stirred for 6 days at room temperature. A further addition of NaH (0.06 g) was made and the solution heated to 50°C for 0.5 h whence it was poured into water, extracted with EtOAc and worked up in the usual way to give a crude mixture (0.11 g; components). Separation of this mixture on plate (silica gel:benzene:EtOAc, 10:4) gave band 1 (Rf 0.45: 38 mg) identified as starting material. Band 2 (Rf 0.32: 42 mg; 43%) which crystallized from ethylacetate as des-Nmethylisoacronycine, MP: 293°-295°C. Band 3 (Rf 0.10; 29 mg, 29%) crystallized from ethyl acetate as des-N-methylacronycine. MP: 237°-240°C. Des-N-methylacronycine (14 mg) was dissolved in dry acetone (10 ml), anhydrous K2CO3 (1 g), and MeI (2 ml) added and the mixture refluxed for 11 hours. The solution was filtered and the solvents evaporated to give a solid (12 mg) which after purification on TLC, gave acronycine which crystallized from aqueous MeOH, MP: 171°-173°C. This product showed identical U.V. and Rf characterization when compared with acronycine and had an accurate mass

Actaplanin

91

measurement of 321.1368. C20H19NO3, required: 321.1364. UV and 1H NMR spectrum confirmed the structures of all described compounds. References Adams Joyce H. et al.; Tetrahedro,n v.37, pp 209-217, 1981 Coker G.G., Findlay J.W.A.; EU Patent No. 0,085,959; Feb. 3, 1983; Assigned: The Wellcome Foundation Limited 183-193 Euston Road, London NW1 2BP(GB)

ACTAPLANIN Therapeutic Function: Growth stimulant Chemical Name: See structure Common Name: Structural Formula: Complex of glycopeptide antibiotics produced by Actinoplanes missourinesis Chemical Abstracts Registry No.: 37305-75-2 Trade Name

Manufacturer

Country

Year Introduced

Actaplanin

Onbio Inc.

-

-

Raw Materials Potassium chloride Ferric sulfate Agar Hydrochloric acid Dextrin Yeast extract Dextrose Peptone Corn steep liquor Sulfuric acid Actinoplanes sp

Magnesium sulfate heptahydrate Yeast Pre-cooked oatmeal Glucose Soybean meal Calcium carbonate Dextrin Molasses, beet sugar Betaine Potassium phosphate dibasic

Manufacturing Process The microorganism used for the production of antibiotic Actaplanin (A-4696) has been identified as a strain of a species of Actinoplanes of the family Actinoplanaceae. The Actinoplanaceae are a new family of microorganisms of the order Actinomycetales, having been first described by Dr. John N. Couch, Jour. Elisha Mitchell Sci. Soc., 65, 315-318 (1949). The Actinoplanes sp. useful for the production of A-4696 was isolated from a sample of soil obtained from the Cascade mountain area in the state of

92

Actaplanin

Washington. Mycelial fragments of Actinoplanes sp., strain ATCC 23342 were inoculated on a nutrient agar slant having the following composition (g): pre-cooked oatmeal 60.0; yeast 2.5; K2HPO4 1.0; dried distiller's solubles 5.0; Czapek's mineral stock 5.0 ml; agar 25.0; water, deionized 1 L; Czapek's mineral stock has the following composition (g): KCl 100.0; MgSO4·7H2O 100.0; FeSO4·7H2O 2.0; (dissolve in 2 ml conc. HCl); deionized water 1 L. The slant was inoculated with ATCC 23342 and incubated for 6 days at 30°C. The culture does not normally sporulate on this medium, and it is necessary to macerate the mycelial mat with a flattened, sharpened, inoculating needle in order to increase the number of potential growth centers. The macerated mature culture was covered with sterile distilled water and scraped carefully with a sterile rod to obtain a mycelial suspension. The suspension thus obtained was used to inoculate 100 ml of a sterile vegetative medium having the following composition (g): glucose 5.0; dextrin 20.0; soybean meal 5.0; yeast extract 2.5; calcium carbonate 1.0; tap water 1 L. The inoculated vegetative medium was grown for 48 h at 30° on a rotary shaker operating at 250 rpm. 10 ml of the incubated vegetative medium was inoculated into 100 ml of a sterile "bump" medium of the same composition as given next above. The thus inoculated "bump" medium was incubated for 24 h at 30°C with constant shaking on a rotary shaker operating at 250 rpm. 0.4 ml of the incubated "bump" medium was inoculated into 100 ml portions of a production medium of the composition shown below contained in 500 ml. Erlenmeyer flasks, and sterilized at 120°C for 30 min (g): dextrose 1.0; dextrin 3.0; peptone 1.5; soybean meal 0.5; MgSO4·7H2O 0.2; molasses, beet sugar 1.5; corn steep liquor 0.5; betaine 0.1; K2HPO4 0.05; deionized water q.s. 25 L. The pH of the medium was adjusted to 7.5 with 5 N sodium hydroxide solution before sterilization. After sterilization the pH was approximately 6.9. The production fermentation was shaken for about 96 h at a temperature of 30°C on a rotary shaker operating at 250 rpm. The pH at the end of the fermentation cycle was about 7.2. The preparation of the inoculum proceeded through the incubation of the "bump" medium detailed above 25 L of a production medium as outlined above, with 0.02% Dow Corning antifoam added, was sterilized by autoclaving at 120°C for 30 min and charged into a 40 L fermentation tank. 100 ml of incubated "bump" medium was inoculated into the sterile production medium. The inoculated production medium contained in the 40 L tank was allowed to ferment for 4 days at 30°C. The fermentation was aerated with sterile air in an amount of about 0.5 volume of air per volume of culture medium per minute. The fermenting production medium was agitated with a mixer utilizing an impeller of a proper size and turning at an appropriate rpm to insure adequate mixing of air with the medium. The pH of the culture medium gradually increased from an initial level of about 6.9-7.2 as the fermentation proceeded.

Actisomide

93

The whole broth obtained from an A-4696 fermentation, was filtered with the aid of a commercial filter aid. The filtrate was set aside. The mycelial cake was washed with 32 L of water and the wash water set aside. The mycelial cake was then suspended in an additional 32 L of water and the pH of the mixture adjusted to pH 10.5 with 5 N sodium hydroxide solution. The mycelial cake water suspension was stirred for 45 min and the mixture was filtered. This filtrate and the water wash were combined with the original filtrate from the fermentation broth and the pH of combined filtrates was adjusted to pH 4.0 with H2SO4. The acidified combined filtrates was passed through a carbon column utilizing 1.0 kg of activated carbon, (Pittsburgh, 12x40). The activated carbon column was washed until the effluent was colorless. The A-4696 activity was adsorbed on the carbon column. The A-4696 activity was eluted from the carbon column utilizing a 1% H2SO4 solution in acetone: H2O (1:1). 2 L of the acidified acetone-water solution was sufficient to elute the A-4696 activity from the carbon column. The eluate containing the A-4696 activity as treated with a saturated barium hydroxide solution, in order to form a precipitate of barium sulfate, thus removing the sulfate ions from the solution. The mixture was filtered and the barium sulfate precipitate was discarded. The filtrate containing the A-4696 activity was concentrated under vacuum to dryness. The resulting residue comprising the A-4696 activity amounted to approximately 80.0 g. References Hamill R.L. et al.; US Patent No. 3,952,092; April 20, 1976; Assigned: Eli Lilly and Company, Indianapolis, Ind.

ACTISOMIDE Therapeutic Function: Cardiac depressant Chemical Name: 3H-Pyrido[1,2-c]pyrimidin-3-one, 4-(2-(bis(1-methylethyl) amino)ethyl)-4,4a,5,6,7,8-hexahydro-1-methyl-4-phenyl-, cis-(+-)Common Name: Actisomide; Dizactamide Structural Formula:

Chemical Abstracts Registry No.: 96914-39-5

94

Acyclovir

Trade Name Dizactamide

Manufacturer ZYF Pharm Chemical

Country -

Year Introduced -

Raw Materials Platinum oxide N,N-Dimethylacetamide dimethylacetal 4-Diisopropylamino-2-phenyl-2-pyridin-2-yl-butyramide Lithium aluminum hydride Manufacturing Process Hydrogenation of 4-diisopropylamino-2-phenyl-2-pyridin-2-yl-butyramide over platinum oxide catalyst reduced the pyridine ring to a piperidine to give 4diisopropylamino-2-phenyl-2-piperidin-2-yl-butyramide as a white solid, MP: 107°-108°C. Structure was confirmed by proton, carbon-13-NMR spectra and by elemental analysis. 2-(1-Acetylpiperidin-2-yl)-4-diisopropylamino-2-phenylbutyramide was prepared by acetylation of above product with N,N-dimethylacetamide dimethylacetal by heating at 80°C for about 14 hours. The acetamide melted at 191°-192°C. The treatment of that intermediate with lithium aluminum hydride led the newly introduced acetyl group to condense with the adjacent amide nitrogen. There was thus obtained 4-(2-diisopropylaminoethyl)-1methyl-4-phenyl-4,4a,5,6,7,8-hexahydropyrido[1,2-c]pyrimidin-3-one, the new anti-arrhythmic agent actisomide, MP: 70°-75°C. Its structure was confirmed by proton NMR and infrared spectra and by elemental analysis. References Adelstein G.W., Chorvat R.J.; EP Patent No. 0,104,647; Sept. 27, 1983 Lednicer D., The Organic Chemistry of Drug Synthesis; v. 5; pp. 149-150; 1995; Wiley and Sons Inc.

ACYCLOVIR Therapeutic Function: Antiviral Chemical Name: 2-Amino-1,9-dihydro-9-[(2-hydroxyethoxy)methyl]-6Hpurin-6-one Common Name: Acycloguanosine; 9-(2-Hydroxyethoxymethyl)guanine Structural Formula:

Acyclovir

95

Chemical Abstracts Registry No.: 59277-89-3 Trade Name Zovirax Zovirax Zovirax Zovirax Zovirax Zovirax

Manufacturer Burroughs-Wellcome Burroughs-Wellcome Burroughs-Wellcome Burroughs-Wellcome Burroughs-Wellcome Burroughs-Wellcome

Country UK US Switz. W. Germany Sweden France

Year Introduced 1981 1982 1982 1983 1983 1983

Raw Materials Sodium nitrite 2-Chloro-9-(2-hydroxyethoxymethyl)adenine Ammonia Manufacturing Process Solid sodium nitrite (0.97 g) was added at room temperature with stirring over a period of one hour to a solution of 2-chloro-9-(2hydroxyethoxymethyl)adenine (0.5 g) in glacial acetic acid (10 ml). The reaction mixture was stirred for an additional 4½ hours. The white solid was removed by filtration, washed with cold acetic acid and then well triturated with cold water to remove the sodium acetate present. The solid product was retained. The combined acetic acid filtrate and wash was evaporated at reduced pressure and 40°C bath temperature and the residual oil triturated with cold water. The resulting solid material was combined with the previously isolated solid and the combined solids dried and recrystallized from ethanol to give 2-chloro-9-(2-hydroxyethoxymethyl)-hypoxanthine (0.25 g), MP>310°C. Elemental analysis and NMR spectrum were consistent with this structure. A mixture of 2-chloro-9-(2-hydroxyethoxymethyl)-hypoxanthine (0.375 g) and methanol (80 ml) saturated with anhydrous ammonia was heated in a bomb at 125°C for 5 hours. The bomb was cooled in an ice bath and the reaction mixture removed. Solvent and excess ammonia were removed under reduced pressure at 50°C. After the residue was triturated with cold water to remove the ammonium chloride formed, the remaining solid was dried and then recrystallized from methanol to give pure 9-(2-hydroxyethoxymethyl) guanine (0.24 g), MP 256.5-257°C. References Merck Index 140 DFU 4 (11) 842 (1979) Kleeman and Engel p. 14 PDR p. 773 OCDS Vol. 3 p. 229 DOT 18 (2) 52 (1982) REM p. 1231 Schaeffer, H.J.; US Patent 4,199,574; April 22, 1980; Assigned to BurroughsWellcome Co.

96

Adafenoxate

ADAFENOXATE Therapeutic Function: Nootropic, Psychostimulant Chemical Name: 2-(1-Adamantylamino)ethyl (p-chlorophenoxy)acetate Common Name: Adafenoxate Structural Formula:

Chemical Abstracts Registry No.: 82168-26-1 Trade Name

Manufacturer

Country

Year Introduced

Adafenoxate

Laboratorios Wassermann

-

-

Raw Materials 1-Aminoadamantine-2-ethanol p-Chlorophenoxyacetyl chloride p-Chlorophenoxyacetic acid Manufacturing Process Preparation of the p-chlorophenoxyacetate of 1-aminoadamantine-2-ethanol, starting from a p-chlorophenoxyacetic acid halide: 22 g (0.11 mol) of 1-aminoadamantine-2-ethanol dissolved in 250 ml of benzene are poured into a 500 ml flask fitted with a mechanical stirrer, using a decanting funnel. 23 g (0.11 m) of p-chlorophenoxyacetyl chloride are added in drops while stirring, the mixture then being stirred for 30 minutes. 120 ml of a 10% solution of sodium carbonate is then added, and the resulting mixture is stirred for 10 minutes. The organic phase is decanted, and the benzene is then removed by distillation. The residue is crystallized with petroleum ether. This yields 37 g (93%) of a white solid. Preparation of the p-chlorophenoxyacetate of 1-aminoadamantine-2-ethanol, starting from p-chlorophenoxyacetic acid: In a 1 liter flask, provided with a Dean-Stark separator tube and reflux refrigerant, a mixture of 20.5 g (0.011 m) of p-chlorophenoxyacetic acid, 22 g (0.11 m) of 1-aminoadamantine-2-ethanol, 98 g of conc. sulfuric acid and 700 ml of toluene is heated to boiling point over a period of 24 hours. At the end

Adamexine

97

of this period, the mixture is treated with an aqueous solution of 5% sodium carbonate to an alkali pH, and is then washed with water. The mixture is then dried on anhydrous sodium sulphate, and the toluene is removed by distillation at reduced pressure. The crude product so obtained is crystallized with petroleum ether. The yield is 35.2 g (88%) of a white solid. Preparation of the chlorhydrate of p-chlorophenoxyacetate of 1aminoadamantine-2-ethanol: A solution of 60 g (0.16 m) of p-chlorophenoxyacetate of 1-aminoadamantine2-ethanol in 300 ml of ether is subjected to the passage of HCl gas until the precipitation of a solid product is completed. It is left to cool in a refrigerator over a period of 6 hours and it is then filtered. The resulting solid is recrystallized with a mixture of ether and methanol. 61 g (92%) of the product are obtained. References Andreoli R.R. et al; US Patent No. 4,476,319; Oct. 9, 1984; Assigned to Sociedad Espanola de Espacialides Formaco-Terapeuticas S.A., Barselona, Spain

ADAMEXINE Therapeutic Function: Mucolytic Chemical Name: Acetamide, N-(2,4-dibromo-6-((methyltricyclo [3.3.1.13,7]dec-1-ylamino)methyl)phenyl)Common Name: Adamexine; Broncostyl Structural Formula:

Chemical Abstracts Registry No.: 54785-02-3 Trade Name

Manufacturer

Country

Year Introduced

Adamexine

ZYF Pharm Chemical

-

-

Broncostyl

Robert

-

-

98

Adapalene

Raw Materials 2-Bromomemtyl-4,6-dibromo-N,N,diacetylaniline N-Methyladamantyl Manufacturing Process 4.3 g 2-brommemtyl-4,6-dibromo-N,N-diacetylaniline and 1.65 g Nmethyladamantyl amine in 100 ml of absolute ethanol were heated to reflux for 8 hours. The ethanol was removed and a residue was washed with some times with ether. The resulting hard mass was refluxed with 150 ml 2 N HCl for 2 hours. The obtained product was cooled and stood for 10-12 hours at 4°C in a refrigerator. The crystalline 2-(N-(1-adamantyl)-Nmethylaminomethyl-4',6'-dibromacetanilid hydrochloride (adamexine) was filtered off and thoroughly washed with distilled water. It was recrystallized from a mixture glacial acetic acid/water 2:1 (v/v) to give a white crystalline powder, melting at 250°-254°C. The hydrochloride is better for a pharmaceutical composition because of solubility in water. The free base may be prepared by adding of an equivalent of any basic compound (NaOH, NaHCO3 and so on). References B.D. Patent No. 2,436,909; July 31, 1974; Ferrer Internacional, S. A. Barcelona (Spain)

ADAPALENE Therapeutic Function: Antiacne Chemical Name: 2-Naphthalenecarboxylic acid, 6-(4-methoxy-3-tricyclo (3.3.1.13,7))dec-1-ylphenyl)Common Name: Adapalene Structural Formula:

Chemical Abstracts Registry No.: 106685-40-9

Adapalene

99

Trade Name

Manufacturer

Country

Year Introduced

Adaferin

Laboratoires Galderma

France

-

Adapalene

Laboratoires Galderma

France

-

Differin

Laboratoires Galderma

France

-

Raw Materials 4-Bromophenol 1-Adamantanol Sodium hydride Methyl iodide Dibromoethane Zinc chloride Nickel chloride/1,2-(diphenylphosphino)ethane-complex Manufacturing Process Preparation of 6-(3-(1-adamantyl)-4-methoxyphenyl)-2-naphthoic acid consist of 4 steps. 1. 2-(1-Adamantyl)-4-bromophenol. 34.6 g (200 mmol) of p-bromophenol and 30.4 g (200 mmol) of 1adamantanol are dissolved in 100 ml of dichloromethane. To the resulting solution there are slowly added 10 ml of concentrated sulfuric acid. The mixture is stirred for 8 hours at ambient temperature, poured into water, neutralized with sodium bicarbonate, extracted with methylehe chloride, dried and evaporated. After recrystallization in isooctane 52.8 g of the expected product are obtained. Yield - 86%. MP: 140°-141°C. 2. 2-(1-Adamantyl)-4-bromoanisole. To suspension of sodium hydride (80% in oil, 4.32 g, 144 mmol) in 50 ml of THF, there are slowly added while maintaining the temperature at 20°C, 36.8 g (120 mmol) of 2-(1-adamantyl)-4-bromophenol. The mixture is stirred for 1 hour at ambient temperature at which point 9 ml of methyl iodide are added. The mixture is then stirred for 2 hours at 20°C, poured into water, extracted with ether, dried and evaporated. The product is purified by passage through a silica column (10x30), eluting with a mixture of hexane (90%) and dichloromethane (10%). On evaporation, 26.2 g of a white solid are obtained. Yield - 68%. MP: 138°-139°C. 3. Methyl ester of 6-(3-(1-adamantyl)-4-methoxyphenyl)-2-naphthoic acid. To a suspension of magnesium (1.64 g, 67.5 mmol in 30 ml of THF, there is added a solution of 1.4 g (4.5 mmol) of 2-(1-adamantyl)-4-bromoanisole and 0.39 ml of dibromoethane in 10 ml of THF. The mixture is stirred until the reaction is initiated and then there is slowly added a solution of (40.8 mmol) of 2-(1-adamantyl)-4-bromoanisole in 90 ml of THF. The mixture is refluxed for 2 hours, and then cooled to 20°C. After that 6.2 g (45 mmol) of anhydrous ZnCl2 are added. The mixture is stirred for 1 hour at 20°C at which point 7.95 g (30 mmol) of methyl 6-bromo-2-naphthoate are added followed by addition of 300 g of NiCl2/1,2-(diphenylphosphino)ethane-complex as the catalyst. The mixture is stirred again for 2 hours at 20°C, poured into water, extracted with CH2Cl2 dried and evaporated. The product is isolated by column

100

Adatanserin hydrochloride

chromatography, eluting with a mixture of heptane (70%) and dichloromethane (30%) and then recrystallized in ethyl acetate. 12.2 g of the expected product are obtained. Yield - 78%. MP: 222°-223°C. 4. 6-(3-(1-Adamantyl)-4-methoxyphenyl)-2-naphthoic acid. 10.5 g of the ester obtained above (step 3) are treated with a solution of soda in methanol (200 ml, 4.2 N). The mixture is heated at reflux for 48 hours. The solvents are evaporated and the resulting residue is taken up in water and acidified with concentrated HCl. The solid is filtered and dried under vacuum over phosphoric anhydride. The resulting white solid is recrystallized in a mixture of THF and ethyl acetate. 8.2 g of expected product are obtained. Yield - 81%. MP: 325°-327°C. References Shroot B. et al.; US Patent No. 4,940,696; July 10, 1990; Assigned to Centre International de Recherches Dermatologioues (CIRD), Valbonne, France

ADATANSERIN HYDROCHLORIDE Therapeutic Function: Anxiolyticá Antidepressant Chemical Name: Tricyclo[3.3.1.13,7]decane-1-carboxamide, N-(2-(4-(2pyrimidinyl)-1-piperazinyl)ethyl)-, hydrochloride Common Name: Adatanserin hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 144966-96-1; 127266-56-2 (Base) Trade Name

Manufacturer

Country

Year Introduced

WY-50324

Centre de Recherche Pierre Fabre

-

-

Adatanserin hydrochloride

ESTEVE QUIMICA SA

-

-

Raw Materials [4-(2-Pyrimidinyl)piperazino]ethylamine Triethylamine Adamantane-1-carboxylic acid chloride

Ademetionine

101

Manufacturing Process To a stirred solution of [4-(2-pyrimidinyl)piperazino]ethylamine (2.0 g, 0.01 mol) in 50 ml of methylene chloride, adamantane-1-carboxylic acid chloride (3.6 g, 0.018 mol) and triethylamine (2.9 g, 0.015 mol) were added. Stirring was continued at room temperature overnight. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The remaining residue was subjected to preparative HPLC. The residue was dissolved in ethyl acetate (10 ml) and subjected to flash chromatography using a 9 inch column of silica gel and ethyl acetate as the eluent. The N-[2-[4-(2-pyrimidinyl)-1piperazinyl]ethyl]tricyclo[3.3.1.1(3,7)] decane-1-carboxamide was separated. In practice it is usually used as hydrochloride. References Abou Gharbia M. A.-M. et al.; GB Patent No. 2,218,988A; Oct. 29, 1989

ADEMETIONINE Therapeutic Function: Metabolic, Antiinflammatory Chemical Name: S-Adenosyl-DL-methionine Common Name: Ademethionium; Ademetionine; Adenosylmethionine Structural Formula:

Chemical Abstracts Registry No.: 29908-03-0 Trade Name

Manufacturer

Country

Year Introduced

Donamet

Ravizza

-

-

Geptral

Knoll

-

-

Gumbaral

AWD.Pharma

-

-

Gumbaral

Asta Pharma AWD -

-

Legend

Fidia

-

-

102

Ademetionine

Trade Name

Country

Year Introduced

S-Amet parenteral Europharma

Manufacturer

-

-

Transmetil

Knoll

-

-

Twin

San Carlo

-

-

FO-1501

Sampl-Gibipharma -

-

Samyr

Knoll

-

-

Raw Materials Glucose Polypeptone Yeast extract Sucrose Urea Methionine, LBoric acid Potassium iodide Acetic acid Sulfuric acid

Potassium phosphate monobasic Magnesium sulfate heptahydrate Calcium chloride dihydrate Zinc sulfate heptahydrate Ferric sulfate heptahydrate Copper sulfate pentahydrate Cobalt(II) chloride hexahydrate Perchloric acid Potassium hydrocarbonate

Manufacturing Process S-Adenosyl methionine (SAM) is produced is prepared by cultivating of Saccharomyces cerevisiae. One loopful of each of the microorganism strains (IFO 2342, IFO 2343, IFO 2345, IFO 2346, IFO 2347) was inoculated in 10 ml of a heat-sterilized culture medium adjusted to pH 6.0 and composed of 5.0 g/dl of glucose, 0.5 g/dl of polypeptone, 0.4 g/dl of KH2PO4, 0.4 g/dl of K2HPO4, 0.02 g/dl of MgSO4·7H2O and 0.2 g/dl of yeast extract, and cultivated with shaking at 28°C for 24 h. 1 L of a culture medium adjusted to pH 6.0 and composed of 10.0 g/dl of sucrose, 1.0 g/dl of yeast extract, 0.4 g/dl of K2HPO4, 0.01 g/dl of MgSO4·7H2O, 1.5 g/dl of urea (separately sterilized), 0.75 g/dl of Lmethionine, 0.02 g/dl of CaCl2·2H2O, 0.25 mg/dl of ZnSO4·7H2O, 0.25 mg/dl of FeSO4·7H2O, 125.0 mg/dl of MnSO4·6H2O, 2.0 µg/dl of CuSO4·5H2O, 2.0 µg/dl of H3BO3, 0.2 µg/dl of CoCl2·6H2O and 1.0 µg/dl of KI was put in a 2liter fermentor and sterilized. Then, 5 ml of the seed culture broth prepared as above was inoculated in the culture medium and cultivated at 28°C for 72 h with aeration and agitation. After the cultivation, the microbial cells were collected by centrifugal separation, washed once with physiological saline, suspended in 100 ml of 1.5 N perchloric acid, and shaken at room temperature for 1 h. The suspension was then centrifuged to remove the microbial cells, and the resulting liquid was adjusted to pH 4.5 by adding potassium hydrogen carbonate. The resulting precipitate of potassium perchlorate was removed by centrifugal separation to give an extract containing SAM. The amount of SAM in the extract was determined, and the amount of SAM based on the dry cells.

Adenosine triphosphate

103

The extract in an amount of 0.2 g as SAM was passed through a column filled with 50 ml of Amberlite IRC-50 (H+ form), a weakly acidic cation exchange resin, to cause adsorption of SAM. 0.005 N acetic acid was passed through the column to wash it until the absorbance at 260 nm of the eluate becames less than 0.1. Thus, impurities were removed. Then, 0.1 N sulfuric acid was passed through the column, and SAM was eluted until the absorbance at 260 nm of the eluate becames less than 0.05. The eluate was treated with Amberlite IRA 900 resin (OH- form) to adjust its pH to 3.0, and then lyophilized to obtain SAM sulfate. The SAM based may be produced from SAM sulfate by treatment with potassium hydrogen carbonate. The purity of SAM was measured by cellulose thin-layer chromatography, paper chromatography and high-performance liquid chromatography. The yield of SAM based on the dry cells: IFO 2343-12.1%; IFO 2346-18.8%; IFO 2347-16.7%. References Shiozaki S. et al.; US Patent No. 4,562,149; Dec. 31, 1985; Assigned: Nippon Zeon Co., Ltd., Tokyo, Japan

ADENOSINE TRIPHOSPHATE Therapeutic Function: Coenzyme, Vasodilator Chemical Name: Adenosine 5'-(tetrahydrogen triphosphate) Common Name: ATP; Triphosadenine Structural Formula:

Chemical Abstracts Registry No.: 56-65-5 Trade Name

Manufacturer

Country

Year Introduced

Atepodin

Medix

Spain

-

Atriphos

Biochimica

Switz.

-

Estriadin

Boizot

Spain

-

Striadyne

Auclair

France

-

Triphosphodine

I.C.I.

UK

-

104

Adimolol hydrochloride

Raw Materials 1,3-Dicyclohexylguanidinium adenosine 5'-phosphoramidate Bis-Triethylammonium pyrophosphate Manufacturing Process With a solution of 0.29 part by weight of well dried 1,3dicyclohexylguanidinium adenosine 5'-phosphoramidate in 5 parts by volume of ortho-chlorophenol is admixed a solution of 0.95 part by weight of bistriethylammonium pyrophosphate in a mixed solvent composed of 1 part by volume of ortho-chlorophenol and 2 parts by volume of acetonitrile. The mixture is left standing at 20°C for 2 days. Then 30 parts by volume of water is added to the mixture. After washing with three 15 parts by weight volumeportions of diethyl ether, the aqueous layer is separated, and the remaining diethyl ether in the aqueous layer is removed under reduced pressure. Five parts by weight of activated charcoal is added to the aqueous layer and the mixture is stirred for 30 minutes. The activated charcoal is filtered and further 1 part by weight of activated charcoal is added to the filtrate. After 20 minutes agitation, the activated charcoal is taken out by filtration. The combined activated charcoal is washed with a little water, and eluted twice with respective 300 and 200 parts by volume-portions of 50% (volume) ethanol containing 2% (volume) of concentrated aqueous ammonia. The eluate is concentrated to 40 parts by volume, then is passed through a column packed with 20 parts by volume of a strongly basic anion exchange resin in bead form (chloric type) (polystyrene trimethylbenzyl ammonium type resin sold under the name of Dowex-1 from Dow Chemical Company, Mich. USA). Then, the column is washed with 750 parts by volume of an acid aqueous saline solution containing 0.01 normal hydrochloric acid and 0.02 normal sodium chloride and then eluted with 600 parts by volume of an acid aqueous saline solution composed of 0.01 normal hydrochloric acid and 0.2 normal sodium chloride. After neutralizing with a diluted sodium hydroxide solution, the eluate is treated with activated charcoal to adsorb ATP as its sodium salt. The separated activated charcoal is washed with water and eluted with 60% (volume) ethanol containing 2% (volume) of concentrated aqueous ammonia. The eluate is concentrated to 0.5 part by volume, then 5 parts by volume of ethanol is added. The precipitate thus deposited is centrifuged and dried at low temperature to obtain 0.155 part by weight of tetra-sodium salt of ATP containing 4 mols of water of crystallization as a colorless crystalline powder. The yield is 47% relative to the theoretical. References Merck Index 146 I.N.p. 983 Tanaka, K.and Honjo, M.; US Patent 3,079,379; February 26, 1963; Assigned to Takeda Pharmaceutical Industries, Ltd.

ADIMOLOL HYDROCHLORIDE Therapeutic Function: Alpa- and Beta-adrenergic blocker

Adiphenine hydrochloride

105

Chemical Name: ()-1-(3-((2-Hydroxy-3-(1-naphthyloxy)propyl)amino)-3methylbutyl)-2-benzimidazolinone hydrochloride Common Name: Adimolol hydrochloride; Imidolol hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 75708-29-1; 78459-19-5 (Base) Trade Name

Manufacturer

Country

Year Introduced

Adimolol hydrochloride

ZYF Pharm Chemical

-

-

Raw Materials 1-(3-Amino-3,3-dimethyl-n-propyl)benzimidazolidinone-2 1-[Naphthyl-1-oxyl]propylene-(2,3)-epoxide Manufacturing Process A mixture consisting of 3 g of 1-(3-amino-3,3-dimethyl-n-propyl) benzimidazolidinone-2, 3.3 g of 1-[naphthyl-(1)-oxyl]propylene-(2,3)-epoxide and 12 ml of 98% ethanol were refluxed for three hours. Thereafter, the ethanol was distilled off, the residue was taken up in some methanol, and the solution was acidified with 1 N hydrochloric acid and then extracted with ethyl acetate. The ethyl acetate was distilled out of the extract solution, and ether and some water were added to the residue, whereupon a crystalline substance separated out. The product was recrystallized from ethanol, yielding 60% of theory of ()-1-(3-((2-hydroxy-3-(1-naphthyloxy)propyl)amino)-3methylbutyl)-2-benzimidazolinone, which had a melting point of 161°C. In practice it is usually used as hydrochloride. References Koppe H. et al.; US Patent No. 4,255,430; March 10, 1981; Assigned to Boehringer Ingelheim GmbH, Ingelheim am Rhein, Fed. Rep. of Germany

ADIPHENINE HYDROCHLORIDE Therapeutic Function: Anticholinergic, Spasmolytic, Smooth muscle relaxant

106

Aditeren

Chemical Name: Benzeneacetic acid, α-phenyl-, 2-(diethylamino)ethyl ester, hydrochloride Common Name: Adiphenine hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 50-42-0; 64-95-9 (Base) Trade Name Adiphenine hydrochloride

Manufacturer Country Spectrum Chemicals and Laboratory Products, Inc.

Year Introduced -

Neuro-Trasentin Paxil Paxil Paxil Trasentine

Aleve Frosst SKB GlaxoSmithKline Ciba

-

-

Raw Materials α,α-Diphenylacetic acid Thionyl chloride Diethylaminoethanol Manufacturing Process 10.6 parts of α,α-diphenylacetic acid are treated with thionyl chloride and the diphenylacetylchloride thus produced is caused to react with 5.9 parts of diethylaminoethanol at 120°C. The α,α-diphenylacetic acid, 2(diethylamino)ethanol ester hydrochloride thus produced is crystallized from ethyl acetate; it melts at 113-114°C. References Merck Index, Monograph number: 160, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. Miescher K., Hoffmann K., US Patent No. 2,079,962; May 11, 1937; Assigned to Society of Chemical Industry, Basel, Switzerland

ADITEREN Therapeutic Function: Diuretic

Aditeren

107

Chemical Name: 2,4-Diamino-5-(4-amino-3,5-dimethoxybenzyl)pyrimidine Common Name: Aditeren Structural Formula:

Chemical Abstracts Registry No.: 56066-19-4 Trade Name

Manufacturer

Country

Year Introduced

Aditeren

Onbio Inc.

-

-

Raw Materials Aniline p-Anilinepropionitrtile Sodium nitrite Guanidine carbonate Aluminum oxide 4-Toluenesulfonic acid Acetamide Bromosuccinimide Bromine Palladium on carbon Dimethylsulfone Sodium hydride Sodium methylate Sodium borohydride 3-Hydroxy-5-keto-3-cyclohexenecarboxylic acid Manufacturing Process A solution of 6.9 g of sodium in 1 liter of absolute ethanol were treated with 54 g of guanidine carbonate and 31.0 g of 4-amino-α-(anilinemethylene)-3,5dimethoxyhyrocinnamic acid nitrile and boiled under reflux for 20 hours. 500 ml of water were added and the alcohol was removed in vacuum. After standing at room temperature for 2 hours, the crystallized 2,4-diamino-5-(4amino-3,5-dimethoxybenxyl)pyrimidine was filtered off under suction, washed with water and recrystallised from methanol; melting point 215°-216°C. The starting material was prepared as follows: 13.8 g of sodium were dissolved in 900 ml of methanol. To this solution were added 46.8 g of 3-hydroxy-5-keto-3-cyclohexenecarboxylic acid. This mixture was stirred, held between -4° and -8°C by means of a cooling bath and treated during 30 minutes with a phenyl-diazonium chloride solution [prepared from 27.9 g of aniline, 450 ml of water, 72 ml of concentrated hydrochloric acid and 21.0 g of sodium nitrite in 90 ml of water]. The resulting mixture was stirred for a further 1 hour at -5°C to -10°C. The deposited, red reaction product was filtered off under vacuum and washed with ca 1000 ml of water. There was obtained 3-hydroxy-5-keto-4-phenyl-azo-3-cyclohexenecarboxylic acid of melting point 218°C.

108

Aditeren

60 g of 3-hydroxy-5-keto-4-phenyl-azo-3-cyclohexenecarboxylic acid, 200 ml of methanol, 1200 ml of benzene and 5 g of p-toluenesulphonic acid were boiled together under reflux on a water separator for 18 hours. After cooling, the solution was washed with 500 ml of a 5% sodium bicarbonate solution, then washed with water, dried and evaporated. The residue was dissolved in ethyl acetate and purified on an aluminum oxide column [500 g; activity stage I]. After evaporation of the ethyl acetate and recrystallisation of the residue from benzene/petroleum ether, there was obtained 3-hydroxIy-5-keto-4phenyl-azo-3-cyclohexenecarboxylic acid methyl ester as a solid of melting point 144°C. 54.8 g of 3-hydroxy-5-keto-4-phenyl-axe-3-cyclohexenecarboxylic acid methyl ester, 12.0 g of acetamide and 2.0 g of bromosuccinimide were stirred in 600 ml of chloroform and treated dropwise with 32.0 g of bromine in 400 ml of chloroform [the reaction temperature being held below 35°C]. The separation of acetamide hydrobromide soon began. The mixture was stirred for a further 30 minutes at room temperature, the acetamide hydrobromide filtered off and the filtrate evaporated to dryness. The residue was taken up in a small amount of ethanol, filtered off under vacuum and washed with ethanol. There was obtained 3,5-dihydroxy-4-phenylazobenzoic acid methyl ester of melting point 216°-218°C. A mixture of 27.2 g of 3,5-dihydroxy-4-phenylazobenzoic acid methyl ester, 150 ml of methanol and 64 g of dimethyl sulfate was treated during 45 minutes with a solution of 23 g of sodium hydroxide in 50 ml of water while stirring. Care was taken that the temperature did not exceed 55°C by means of a cooling bath. The mixture was stirred at room temperature for a further 1 hour, cooled with ice water, filtered off under vacuum and recrystallized from 400 ml of ethanol. Red crystals of 3,5-dimethoxy-4-phenylazobenzoic acid methyl ester were obtained; melting point 130°-132°C. 12 g of 3,5-dimethoxy-4-phenylazobenzoic acid methyl ester were dissolved in 400 ml of ethanol and, after the addition of 0.80 g of palladium on carbon, hydrogenated under atmospheric pressure and at room temperature. With slight warming, 2 moles of hydrogen were taken up during 1.5 hours. The catalyst was filtered off and the filtrate concentrated in vacuum. The resulting aniline was distilled off with steam. After cooling, the 4-amino-3,5dimethoxybenzoic acid methyl ester which remained as an aqueous suspension, was filtered off under vacuum, dried and recrystallised from cyclohexane; melting point 115°-116°C. A suspension of 214 g of dimethylsulphone and 78.2 g of sodium hydride (50% dispersion in oil) in 400 ml of absolute dimethyl sulfoxide was stirred at 50°C under nitrogen and with exclusion of moisture for 3 hours. The mixture was cooled to 30°C, whereupon 137 g of 4-amino-3,5-dimethoxybenzoic acid methyl ester were added, the temperature rising to 50°C. After stirring under nitrogen and at room temperature for ca 1 hour, the resulting mixture was left to stand for 3 hours and then dissolved in 2 liters of water under addition of ice. The solution was adjusted to pH 6-7 with glacial acetic acid. After stirring under ice-cooling for 1 hour, the crystallized 4'-amino-3',5'-dimethoxy-2methylsulfonyl-acetophenone was filtered off under suction, washed with water, dried and recrystallised from ethyl acetate; MP: 166°-167°C. A suspension of 123 g of 4'-ammo-3',5'-dimethoxy-2-methylsulphonyl-

Adosopine

109

acetophenone and 68 g of sodium borohydride in 1.5 liters of alcohol was stirred at room temperature for 20 hours. The suspension was diluted with 1.5 liters of water. The alcohol was evaporated in vacuum and the resulting 4amino-3,5-dimethoxy-α-(methylsulfonylmethyl)benzyl alcohol was filtered off under suction, washed with water and dried; melting point 178°-179°C. A mixture of 8.64 g of sodium methylate, 14.6 g of p-anilinepropionitrtile and 22.0 g of 4-amino-3,5-dimethoxy-α-(methylsulfonylmethyl)benzyl alcohol in 50 ml of absolute dimethyl sulfoxide was stirred at 50°C for 1 hour under nitrogen and with the exclusion of moisture. The solution was poured into 500 ml of ice-water and the resulting emulsion was extracted with two 500 ml portions of ethyl acetate. The ethyl acetate extracts were washed with two 250 ml portions of water, dried over magnesium sulfate and evaporated in vacuum. The residue was dissolved in 60 ml ethyl acetate. After standing at room temperature for 20 hours, the crystallized 4-amino-α(anilinemethylene)-3,5-dimethoxyhydrocinnamic acid nitrile was filtered off under suction, washed with a small amount of ethyl acetate and dried; MP: 150°-151°C. References G.B. Patent No. 1,484,481; Sept. 11, 1974; F. Hoffmann-La Roche and CO., Aktiengesellschaft, Swiss Company, 124-184 Grenzacherstrasse Basle, Switzerland

ADOSOPINE Therapeutic Function: Urinary incontinence agent Chemical Name: N-(6,11-Dihydro-5-methyl-6,11-dioxo-5H-dibenz[b,e] azepin-10-yl)acetamide Common Name: Adosopine Structural Formula:

Chemical Abstracts Registry No.: 88124-26-9 Trade Name

Manufacturer

Country

Year Introduced

Adosopine

Menarini Group

-

-

110

Adrafinil

Raw Materials Acetic anhydride Sodium methylate

1-Aminoanthraquinone Methyl iodide

Manufacturing Process 2 ml of acetic anhydride are added to 2.5 g of 10-amino-5,6-dihydro-11Hdibenzo[b,e]azepine-6,11-dione (prepared from 1-aminoanthraquinone in accordance with Caronna and Palazzo-Gaz. Chim. It. 83, 533, 1953) in 50 ml of dioxane. After maintaining for 2 h under reflux, the mixture is evaporated almost to dryness under reduced pressure, the residue is then poured into water, filtered and dried to give 2.0 g of crude product. The 2.0 g of previously obtained crude product is suspended in 20 ml of N,Ndimethylformamide, and 710.0 mg of sodium methylate in 10 ml of methanol are added. After maintaining for 30 min at room temperature, 2.5 ml of methyl iodide are added, and mixture is allowed to stand for 24 h after which the mixture is poured into water, the product filtered off, dried and crystallized from ethanol, to give 5-methyl-10-acetamino-5,6-dihydro-11H-dibenzo[b,e] azepine-6,11-dione, melting point 199°-201°C. References Pestellini V. et al.; US Patent No. 4,551,451; Nov. 5, 1985; Assigned: A.Menarini S.a.S., Italy

ADRAFINIL Therapeutic Function: Psychostimulant Chemical Name: Acetamide, 2-((diphenylmethyl)sulfinyl)-N-hydroxyCommon Name: Adrafinil; Olmifon Structural Formula:

Chemical Abstracts Registry No.: 63547-13-7 Trade Name

Manufacturer

Country

Year Introduced

Olmifon

Cephalon

-

-

Adrafinil

111

Raw Materials 3-Chloroacetic acid Sulfuric acid Sodium methylate Hydrogen peroxide Chlorodiphenylmethane

Sodium carbonate Hydroxylamine hydrochloride Hydrogen chloride Thiourea Sodium hydroxide

Manufacturing Process 7.6 g (0.1 mol) of thiourea and 100 ml of dematerialized water are introduced into a 500 ml three-neck flask equipped with a magnetic stirrer, a dropping funnel and a condenser; the mixture is heated to 50°C and 20.25 g (18 ml; 0.1 mol) of chlorodiphenylmethane are then added all at once. The solution is left refluxing until it has become limpid, and is then cooled to 20°C, and 200 ml of 2.5 N NaOH are added dropwise. So the sodium benzhydrylthiolate is obtained. A solution of sodium 3-chloroacetate is added to the solution of sodium benzhydrylthiolate at about 60°C. Thereafter the temperature is raised to the boil, the mixture is left under reflux for about 0.5 h and is then cooled, filtered over charcoal and acidified with concentrated HCl, and 3(benzhydrylthio)acetic acid are thus precipitated. To the solution of 3-(benzhydrylthio)acetic acid in 1,2-dichloroethane, methanol and concentrated H2SO4 have been added. The whole is heated to the reflux temperature for about 5 h, cooled, and decanted, the aqueous phase is discarded and the organic phase is washed with a saturated sodium bicarbonate solution and then with water until the wash waters have a neutral pH. After drying over MgSO4 and evaporating the solvent, the 3(benzhydrylthio)acetic acid methyl ester is obtained. The 3-(benzhydrylthio)acetic acid methyl ester dissolved in methanol, is added to a solution of hydroxylamine base [prepared by neutralising 0.15 mol (10.4 g) of hydroxylamine hydrochloride with 0.15 mol of sodium methylate]. The whole is left at ordinary temperature (15°-25°C) for 48 h, the sodium chloride is filtered off, the methanol is evaporated, the residue is taken up with aqueous alkali, the solution is filtered over charcoal, the filtrate is acidified with concentrated HCl, and the 3-(benzhydrylthio)acethylhydroxamic acid (recrystallised from benzene) is thus obtained. The 3-(benzhydrylthio)acethylhydroxamic acid, dissolved in anhydrous CH3COOH, is reacted with H2O2. The mixture is left at 40°-45°C for about 1.5 h, the acetic acid is evaporated and the residue is taken up in 50 ml of ethyl acetate; the 2-[(diphenylmethyl)sulfinyl]-N-hydroxyacetamide (CRL 40028) crystallises (recrystallised from isopropanol). References Lafon L.; US Patent No. 4,066,686; Jan. 3, 1978; Assigned: Laboratoire L. Lafon, Maisons Alfort, France

112

Afalanine

ADRENALONE Therapeutic Function: Hemostatic, Sympathomimetic, Vasoconstrictor Chemical Name: Ethanone, 1-(3,4-dihydroxyphenyl)-2-(methylamino)Common Name: Adrenalone; Adrenone Structural Formula:

Chemical Abstracts Registry No.: 99-45-6 Trade Name

Manufacturer

Adrenalone

Yick-Vic Chemicals and Pharmaceuticals (HK) Ltd.

Country

Year Introduced -

Raw Materials ω-Chloro-3,4-dihydroxyacetophenone Methylamine Manufacturing Process To a suspension of 1 part ω-chloro-3,4-dihydroxyacetophenone (prerared from chloroacetyl chloride and benzcatechole, see J. Russ. Phys. Chem. Ges., 25, 154) was added dropwise 1 part 60% solution of methylamine. Immediately was formed a residue of the salt of methylamine and ω-chloro-3,4dihydroxyacetophenone. The dissolution of the salt was carried out by heating of the mixture. Then the salt was converted in crude 3,4-dihydroxy-αmethylaminoacetophenone. The product was dissolved in dilute hydrochloric acid. To this solution was added dropwise aqueous ammonium solution to prepare light yellow crystal of 3,4-dihydroxy-α-methylaminoacetophenone. The base and the hydrochloride of 3,4-dihydroxy-α-methylaminoacetophenone decomposed at temperature near 230°C and 240°C respectively. References Merck Index, Monograph number: 170, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. DE Patent No. 152,814; 1903.08.15; Assigned to Farbwerke vorm. Meister and Bruening in Hoechst a. M.

AFALANINE Therapeutic Function: Antidepressant

Afloqualone

113

Chemical Name: DL-Phenylalanine, N-acetylCommon Name: Afalanine Structural Formula:

Chemical Abstracts Registry No.: 2901-75-9 Trade Name

Manufacturer

Country

Year Introduced

Afalanine

Sankyo

-

-

Raw Materials Phenylalanine Sodium hydroxide Acetylbromide Manufacturing Process The phenylalanine was dispersed in water. A 1 N aqueous solution of sodium hydroxide was slowly added to this dispersion, and the pH of the solution reached a value of 7-8. Then acetylbromide was dissolved in this solution, to give a Nacetylphenylalanine. References Shiogari T. et al.; EU Patent No. 0,178,911; April 23, 1986; Assigned: Sankyo company limited. N 1-6, 3-chome Nihonbashi Honcho Chuo-ku Tokyo (JP)

AFLOQUALONE Therapeutic Function: Muscle relaxant Chemical Name: 6-Amino-2-(fluoromethyl)-3-(o-tolyl)-4(3H)-quinazolinone Common Name: Chemical Abstracts Registry No.: 56287-74-2; 56287-75-3 (Hydrochloride salt)

114

Afloqualone

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Arofuto

TANABE SEIYAKU

Japan

1983

Raw Materials Fluoroacetyl chloride Acetic anhydride

N-(2-Amino-5-nitrobenzyl)-o-toluidine Hydrogen

Manufacturing Process 14.4 g (0.053 mol) of N-(2-amino-5-nitrobenzoyl)-o-toluidine and 6.3 g (0.08 mol) of pyridine are dissolved in 300 ml of tetrahydrofuran. 12.2 g (0.126 mol) of fluoroacetyl chloride are added to the solution for 10 minutes under ice-cooling. The solution is stirred at the same temperature for 30 minutes and then at room temperature for 2.5 hours. The reaction solution is allowed to stand at room temperature overnight. The crystalline precipitate is collected by filtration, washed with water and then dried. 16.4 g of N-(2fluoroacetamido-5-nitrobenzoyl)-o-toluidine are obtained. Yield: 93.7%; MP 238-239°C. 16.5 g (0.05 mol) of N-(2-fluoroacetamido-5-nitrobenzoyl)-o-toluidine and 25.5 g (0.25 mol) of acetic acid anhydride are dissolved in 250 ml of glacial acetic acid. The solution is refluxed for 2 hours under heating. Then, the reaction solution is evaporated to remove solvent. The residue thus obtained is poured into ice-water, and the aqueous mixture is adjusted to pH 9 with potassium carbonate. The crystalline precipitate is collected by filtration. 15.5 g of 2-fluoromethyl-3-(o-tolyl)-6-nitro-4(3H)-quinazolinone are obtained. Yield: 98.7%; MP 155-158°C (recrystallized from ethanol). A mixture of 2.0 g (0.064 mol) of 2-fluoromethyl-3-(o-tolyl)-6-nitro-4(3H)quinazolinone, 0.2 g of 5% palladium-carbon and 100 ml of acetic acid is shaken for 30 minutes in hydrogen gas. The initial pressure of hydrogen gas is adjusted to 46 lb and the mixture is heated with an infrared lamp during the reaction. After 30 minutes of this reaction, the pressure of hydrogen gas decreases to 6 lb. After the mixture is cooled, the mixture is filtered to remove the catalyst. The filtrate is evaporated to remove acetic acid, and the residue is dissolved in chloroform. The chloroform solution is washed with 5% aqueous sodium hydroxide and water, successively. Then, the solution is dried and evaporated to remove solvent. The oily residue thus obtained is dissolved in 2 ml of chloroform, and the chloroform solution is passed through a column of 200 g of silica gel. The silica gel column is eluted with ethyl acetatebenzene (1:1). Then, the eluate is evaporated to remove solvent. The crude crystal obtained is washed with isopropyl ether and recrystallized from

Afurolol

115

isopropanol. 0.95 g of 2-fluoromethyl-3-(o-tolyl)-6-amino-4(3H)-quinazolinone is obtained. Yield: 52.5%; MP 195-196°C. References DFU 7 (8) 539 (1982) DOT 19 (1) 581 (1983) Inoue, L., Oine, T., Yamado, Y., Tani, J., Ishida, R. and Ochiai, T.; US Patent 3,966,731; June 29, 1976; Assigned to Tanabe Seiyaku Co., Ltd.

AFUROLOL Therapeutic Function: Beta-adrenergic blocker Chemical Name: 7-[3-[(1,1-Dimethylethyl)amino]-2-hydroxypropoxy]-1(3H)isobenzofuranone Common Name: Afurolol Structural Formula:

Chemical Abstracts Registry No.: 65776-67-2 Trade Name

Manufacturer

Afurolol

ZYF Pharm Chemical -

Country

Year Introduced -

Raw Materials 7-Hydroxyphthalide 1-Chloro-2,3-epoxypropane t-Butylamine Manufacturing Process A mixture of 18.0 g (0.12 mole) 7-hydroxyphthalide, 180.0 g of 1-chloro-2,3epoxypropane (2 moles) and 0.5 ml of piperidine is heated at 100°C for about 5 h and then the unreacted 1-chloro-2,3-epoxypropane is distilled off in vacuum to yield 12.0 g (48%) of 7-(2,3-epoxypropoxy)phthalide, melting point 88°-90°C, (crystallized successively from methanol and ethyl acetate). The 7-(2,3-epoxypropoxy)phthalide is dissolved in methanol and t-butylamine are added to the solution at about 20°C. The solution is allowed to stand

116

Aganodine

overnight and, the mixture is evaporated in vacuum and the residue is dried to give 7-(2-hydroxy-3-t-butylamino-propoxy)phthalide. References Bellasio E.; US Patent No. 3,935,236; Jan. 27, 1976; Assigned: Gruppo Lepetit, S.p.A., Milan, Italy

AGANODINE Therapeutic Function: Antihypertensive Chemical Name: Guanidine, (4,7-dichloro-2-isoindolinyl)Common Name: Aganodine Structural Formula:

Chemical Abstracts Registry No.: 86696-87-9 Trade Name

Manufacturer

Country

Year Introduced

Aganodine

ZYF Pharm Chemical

-

-

Raw Materials 3,6-Dichlorophthalic anhydride Lithium aluminum hydride Cyanamide

Carbazic acid, tert-butyl ester Hydrochloric acid Sodium bicarbonate

Manufacturing Process The solution of 3,6-dichlorophthalic anhydride in 300 ml of N,Ndimethylformamide are heated to the boiling point over 15 min with tbutylcarbazate. Subsequent to evaporation of the solvent, N-(tbutyloxycarbonylamino)-3,6-dichlorophthalimide is obtained from ethanol. The solution of N-(t-butyloxycarbonylamino)-3,6-dichlorophthalimide in 400 ml of absolute tetrahydrofuran are slowly dripped into a suspension of aluminum lithium hydride in absolute tetrahydrofuran. The mixture is heated to the boiling point. Conventional processing yields N-(t-butyloxycarbonylamino)-4,7dichloroisoindoline.

Ajmaline

117

N-(t-Butyloxycarbonylamino)-4,7-dichloroisoindoline are introduced into concentrated hydrochloric acid and stirred at room temperature. The hydrochloride of 2-amino-4,7-dichloroisoindoline precipitates in the form of crystals is obtained, melting point 230°-232°C. 2-Amino-4,7-dichloroisoindoline hydrochloride and cyanamide are heated over 2 h to the boiling point in n-amyl alcohol. The solvent is evaporated off and the residue recrystallized from isopropyl alcohol and ethyl ether, yielding the (4,7-dichloroisoindolin-2-yl)guanidine in the form of hydrochloride, melting point 235°-237°C. To obtained the base (4,7-dichloroisoindolin-2-yl)guanidine the salt (4,7dichloroisoindolin-2-yl)guanidine hydrochloride is treated with sodium bicarbonicum. References Cohnen E, Armah B.; US Patent No. 4,526,897; July 2, 1985; Assigned: Beiersdorf Aktiengesellschaft, Hamburg, Fed.Rep. of Germany

AJMALINE Therapeutic Function: Antiarrhythmic Chemical Name: Ajmalan-17,21-diol, (17R,21α)Common Name: Ajmaline; Rauwolfine Structural Formula:

Chemical Abstracts Registry No.: 4360-12-7 Trade Name

Manufacturer

Country

Year Introduced

Ajmaline

Solvay Pharma

-

-

Aritmina

Farmacie Petrone

-

-

Aritmina

Solvay

-

-

Neo-Aritmina

Giulini Pharma

-

-

Gilurytmal

Solvay

-

-

Gilurytmal

Solvay Arzneimittel

-

-

118

Alacepril

Trade Name

Manufacturer

Country

Year Introduced

Gilurytmal

Solvay Pharmaceuticals (Spolka z o.o.)

-

-

Gilurytmal

Solvay Pharmaceuticals

-

-

Gilurytmal

Solvay Pharma, Klosterneuburg

-

-

Neo-Gilurytmal

Solvay Pharmaceuticals

-

-

Rauwolfine

Extrasynthese

-

-

Ritmos

Inverni

-

-

Serenol

Laboratoires Plantes et Medecines

-

-

Tachmalin

Arzneimittelwerk Dresden

-

-

Raw Materials Rauwolfia canescens L. roots Acetic acid Ammonia Manufacturing Process Ajmaline isolated from Rauwolfia sp. roots: Rauwolfia serpentine Benth., Rauwolfia vomitoria Afr., Rauwolfia canescens L. Threshed roots of Rauwolfia canescens L. extracted with 5% solution of acetic acid at room temperature for 24 h. Then extract was decanted to flask. This extract was alkalified with ammonia (alkaloid salts were converted to alkaloid bases). The obtained thus method solution was extracted with chloroform 3 or more times. Then chloroform extract was chromatographed on column through Al2O3 sorbent. After chromatography ajmalin was obtained, which had melting point at 205°C (recyrstallization from methanol). References Belikov A.S.; Alkaloids of Rauwolfia canescens L.//Chemistry of natural compounds 1969, 3. P.64

ALACEPRIL Therapeutic Function: Antihypertensive Chemical Name: L-Phenylalanine, N-(1-(3-(acetylthio)-2-methyl-1oxopropyl)-L-prolyl)-, (S)-

Alacepril

119

Common Name: Alacepril; Cetapril Structural Formula:

Chemical Abstracts Registry No.: 74258-86-9 Trade Name

Manufacturer

Country

Year Introduced

Alacepril

Sumika Fine Chemicals Co., Ltd.

-

-

Alacepril

ZYF Pharm Chemical

-

-

Cetapril

Dainippon Pharmaceutical Co., Ltd.

-

-

Raw Materials N-Methylmorpholine 1-(D-3-Acetylthio-2-methylpropanoyl)-L-proline Phenyl chloroformate L-Phenylalanine t-butyl ester hydrochloride Sodium bicarbonate Hydrochloric acid Anisole Trifluoroacetic acid Manufacturing Process N-Methylmorpholine (1.03 g) was added to a solution of 1-(D-3-acetylthio-2methylpropanoyl)-L-proline (2.65 g) in dry tetrahydrofuran (50 ml). The resulting solution was stirred and cooled at -20° to -15°C. Phenyl chloroformate (1.61 g) was added, and after 5 min, a solution of Lphenylalanine t-butyl ester hydrochloride (2.4 g) and N-methylmorpholine (1.03 g) in dry tetrahydrofuran (30 ml) was added. The mixture was stirred at -20° to -15°C for 1 h and then at room temperature overnight. After removal of insoluble materials by filtration, the filtrate was concentrated under reduced pressure and the residue was dissolved in chloroform. The chloroform solution was washed successively with 1 N sodium hydroxide, water, 10% citric acid, and water, dried and concentrated under reduced pressure. The residue was chromatographed on silica gel with chloroformmethanol (99:1) to give 4.2 g the 1-(D-3-acetylthio-2-methylpropanoyl)-Lprolyl-L-phenylalanine tert-butyl ester. 1-(D-3-Acetylthio-2-methylpropanoyl)-L-prolyl-L-phenylalanine tert-butyl ester

120

Alafosfalin

(2.5 g) was dissolved in a mixture of anisole (18 ml) and trifluoroacetic acid (37 ml). The solution was allowed to stand at room temperature for 1 h and then concentrated to dryness under reduced pressure. The residue was crystallized from diethyl ether. The 1-(D-3-acetylthio-2-methylpropanoyl)-Lprolyl-L-phenylalanine was obtained (1.8 g), melting point 155°-156°C (recrystallization from ethanol/n-hexane). References Sawayama T. et al.; US Patent No. 4,248,883; Feb. 3, 1981; Assigned: Dianippon Pharmaceutical Co., Ltd., Osaka, Japan

ALAFOSFALIN Therapeutic Function: Antibacterial Chemical Name: Phosphonic acid, ((1R)-1-(((2S)-2-amino-1-oxopropyl) amino)ethyl)Common Name: Alafosfalin; Alaphosfalin Structural Formula:

Chemical Abstracts Registry No.: 60668-24-8 Trade Name

Manufacturer

Country

Year Introduced

Alafosfalin

Roche Product Limited

-

-

Raw Materials N-Hydroxysuccinimide ester of N-benzyloxycarbonyl-L-alanine (1R,S)-1-Aminoethylphosphonic acid Benzylamine Palladium on carbon 1R-(L-Alanylamino)ethanephosphonous acid Mercuric chloride Propylene oxide Manufacturing Process 14.1 g (0.168 mol) of solid sodium bicarbonate were added to a solution of 7 g (0.056 mol) of (1R,S)-1-aminoethylphosphonic acid in 280 ml of water and 140 ml of ethanol while stirring at 0°C. While stirring this mixture at 0°C, a solution of 17.9 g (0.056 mol) of the N-hydroxysuccinimide ester of N-

Alafosfalin

121

benzyloxycarbonyl-L-alanine in 140 ml of warm ethanol was added dropwise over ca 15 minutes. The latter solution was washed in with 70 ml of ethanol. The heterogeneous mixture was stirred for 1 hour at 0°C and then for a further 16 hours at room temperature, the mixture becoming homogeneous. The mixture was evaporated and re-evaporated with 200 ml of water to give a gum, which was dissolved in 500 ml of water. The solution was extracted firstly with 500 ml of chloroform and then with 250 ml portions of chloroform, acidified to pH 2 with ca 80 ml of 2 N hydrochloric acid and again extracted with 500 ml of chloroform followed by two 250 ml portions of chloroform. The aqueous layer was concentrated and passed down a column of cation exchange resin (B.D.H., Zerolit 225, SRC 13, RSO3H; 750 g; freshly regenerated in the acid cycle). The column was eluted with water and there were collected six 250 ml fractions. The first four fractions were combined, evaporated and re-evaporated with water to remove hydrogen chloride. There was obtained a final residue of (1R,S)-1-[(N-benzyloxycarbonyl-L-alanyl)amino]ethylphosphonic acid which was separated as follows: The latter residue was dissolved in 400 ml of water and titrated with 1 M benzylamine to pH 4.5. The resulting solution was concentrated and crystallized from water to give 5.3 g of the benzylamine salt of (1S)-1-[(Nbenzyloxycarbonyl-L-alanyl)amino]ethylphosphonic acid of melting point 210215°C. Concentration of the mother liquors followed by further recrystallization from water gave the benzylamine salt of (1R)-1-[(Nbenzyloxycarbonyl-L-alanyl)amino]ethylphosphonic acid in a first crop of 0.59 g [melting point 226-228°C (decomposition); [α]D20 = -32.3° (c = 1% in acetic acid)] and a second crop of 0.825 g] melting point 225-227°C (decomposition); [α]D20 = -33.0° (c = 1% in acetic acid)]. Recrystallization of the first crop from water gave 0.333 g of pure benzylamine salt of the Rstereoisomer; melting point 226-228°C (decomposition); [α]D20 = -33.1° (c=1% in acetic acid). 1.1 g (2.5 mmol) of the benzylamine salt of (1R)-1-[(N-benzyloxycarbonyl-Lalanyl)amino]-ethylphosphonic acid were dissolved in 4 ml of 2 N ammonium hydroxide, passed down a column of cation exchange resin (B.D.H., Zerolit 225, SRC 13, RSO3H; 120 g; freshly regenerated in the acid cycle) and eluted with water. There were collected 200 ml of acid eluate, which was concentrated to 100 ml. To this were added 100 ml of methanol, 0.3 g of 5% palladium-on-charcoal catalyst and 3 drops of glacial acetic acid. The mixture was hydrogenated at room temperature and atmospheric pressure. The catalyst was filtered off and the solvent evaporated. The residual gum was reevaporated with three 50 ml portions of n-propanol to give 0.6 g of a gummy solid of melting point ca 275-280°C (decomposition). After further recrystallization from water and ethanol, there was obtained 0.2 g of (1R)-1(L-alanylamino)-ethylphosphonic acid of melting point 295-296°C (decomposition); [α]D20 = -44.0° (c=1% in water). The different ways of synthesis of alafosfalin were described: 1). 1R-1-(L-alanylamino)-ethanephosphonous acid (0.034 M), mercuric chloride (0.068 M) and water (175 ml) were mixed and heated to reflux for 1 hour The white insoluble mercuric chloride which formed was removed by filtration and the aqueous filtrate was evaporated to dryness. The oily residue was dissolved in ethanol (20 ml) and propylene oxide was added until

122

Alanosine

precipitation was complete. Filtration gave 1R-1-(L-alanylamino)ethylphosphonic acid, which was recrystallised from ethanol/water. MP: 293295°C, [α]D20 =-49.3° (1%, H2O). Yield was 100% of theory. 2). Papain (50 mg; 2.2 U/mg) was added to the solution of 0.5 mmol Z-L-Ala, 1.15 mmol racemic diisopropyl ester of 1-aminoethylphosphonic acid and 50 ml 2-mercaptoethanol in the mixture of 2.3 ml acetonitrile and 0.2 ml water The suspension was shaken for about 2 days until all the Z-ala was consumed (TLC-control). The enzyme was filtered off and washed with 10% KHSO4, water, saturated NaHCO3, dried with anhydrous Na2SO4 and evaporated under reduced pressure. The resulting phosphonopeptide was dissolved in 2 ml of 40% HBr in glacial acetic acid and left overnight. Anhydrous ether (10 ml) was added and the mixture was stirred for 10 min and upper phase decanted. The residue was evaporated, the remaining gum was dissolved in 2 ml of methanol and treated with excess of propylene oxide. The precipitated material was filtered off and crystallized from water water-ethanol to give pure alafosfalin, yield 60%, MP: 273-276°C (decomposition); [α]D20 =-45° (0.2% in water). Only L-aminophosthonate is involved in the peptide bond formation because of papain presence. References Atherton F.R. et al.; US Patent No. 4,016,146; April 5, 1977; Assigned to Hoffmann-La Roche Inc., Nutely, N.Y. Baylis E.; US Patent No. 4,331,591; May 25, 1982; Assigned to Ciba-Geigy Corporation, Ardsley, N.Y. Solodenko V., Kukar V.; Tetrahedron Letters, v. 30, No. 49, pp 6917-6918, 1989

ALANOSINE Therapeutic Function: Antineoplastic Chemical Name: 3-(Hydroxynitrosoamino)-L-alanine Common Name: Alanosine Structural Formula:

Chemical Abstracts Registry No.: 5854-93-3 Trade Name

Manufacturer

Country

Year Introduced

Alanosine

Triangle Pharmaceuticals

-

-

Alanosine

123

Raw Materials Streptomyces alanosinicus n. sp. ATCC 15710 Peptone-agar-glucose-yeast extract medium Glucose Dried whale meat (Pascor) 6% of Darco G-60 charcoal Sodium methoxide Manufacturing Process Alanosine is an antibiotic isolated from the fermentation broth of Streptomyces alanosinicus n. sp. Oat meal agar slants seeded with Streptomyces alanosinicus n. sp. ATCC 15710 were incubated at 20°C for 7 to 10 days and then used to inoculate 100 ml of a peptone-agar-glucose-yeast extract medium contained in 500 ml Erlenmeyer flask. The composition of this fermination medium is: Meat extract Peptone Yeast extract Enzymatic casein hydrolysate Cerelose NaCl

5.0 5.0 5.0 3.0 2.0 1.5

g./liter g./liter g./liter g./liter g./liter g./liter

The medium is adjusted to pH 7.2 prior to sterilization for 20 minutes at 121°C and 15 Ibs steam pressure. The germination flasks are incubated at 28°C for 48 hours on rotary shaker having a 2 inch throw and making 240 rpm. A 3% transfer is made from the germination flask to 500 ml Erlenmeyer fermentation flaks containing 100 ml of medium TVF/5 having the following composition: Glucose Dried whale meat (Pascor) CaCO4 (NH4)2SO4 MgSO4·7H2O CuSO4 sol. 0.5% FeSO4 sol. 0.1% ZnSO4 sol. 0.2% MnSO4 sol. 0.8%

50.0 g/L 10.0 g/L 5.0 g/L 1.0 g/L 1.0 g/L 1 ml 1 ml 1 ml 1 ml

The medium is adjusted to pH 7.0 prior to sterilization for 20 minutes at 121°C. The fermentation flasks are incubated and agitated under similar conditions as the germination flasks. After 72 hours the mycelium was separated by centrifugation and the untreated broth assayed by the streak dilution method. 30 liters of broth are centrifuged and 6% of Darco G-60 charcoal is added to the clear solution, which is stirred for 30 minutes; then the charcoal is filtered off to give an almost colorless solution which is concentrated in vacuum at 45-50°C to 1.5 liters. The concentrated solution is poured under stirring into 5 liters of methanol, the formed precipitate is

124

Alatrofloxacin mesylate

filtered, washed with much acetone and dried in vacuum. Yield 230 g of crude product assaying about 10%. Purification: The above crude product is suspended in 400 ml of water and to the suspension, cooled to 4°C and kept stirred, sulfuric acid is added to pH 2.02.5; the undissolved residue is filtered off, the solution is further diluted with 400 ml of water and 1.6 liters of methanol are added to precipitate the antibiotic. The mixture is kept at 4°C for some hours to complete precipitation, then it is filtered, washed with acetone and dried in vacuum over P2O5. Yield 62 g of a product assaying 27%. The dried product is suspended in anhydrous methanol and the mixture is kept stirred; perchloric acid (75%) is added at about 4°C to reach a pH of 3.0, the undissolved portion is filtered off and the antibiotic is precipitated by adjusting the pH 5.5 with sodium methoxide. The suspension is allowed to decant for some hours at 4°C, then it is filtered and the precipitate is washed with diethyl ether. Yield 30 g (titer 43%). An amount of 3.2 g of the obtained antibiotic is dissolved in 60 ml of H2O and the pH is adjusted to 8; the undissolved portion is filtered off and by the addition of glacial acetic acid, the pH is adjusted to 4-4.5. On cooling at 4°C, 1.2 g of antibiotic in crystalline form (assaying 75%) are obtained. An amount of 2.9 g of said crystalline antibiotic is dissolved in 900 ml of water heating the solution to 70-80°C, then it is filtered, concentrated to 200 ml and allowed to stand 8-10 hours at 4°C; then it is filtered and washed with cold water. Yield 1.45 g (97%). By further concentrating the solution to 100 ml a further amount of antibiotic is obtained: 1 g (80%). Alanosine melts at 190°C, [α]D25= -37.8° (c=0.5, water). Antibiotic was also prepared by syntheses from anhydrous hydroxylamine and methyl-2-acetamido-3-chloropropionate followed by reaction with NaNO2 in dilute acetic acid. The prepared racemic product was separated on individual isomers. References Thiemann J. et al.; US Patent No. 3,676,490; July 11, 1972; Assigned to Lepetit S.P.A., Milan, Italy Lancini G.C.A, Diena and E. Lassari; Tetrahedron Letters No. 16, pp. 17691772, 1966

ALATROFLOXACIN MESYLATE Therapeutic Function: Antibacterial Chemical Name: L-Alaninamide, L-alanyl-N-(3-(6-carboxy-8-(2,4difluorophenyl)-3-fluoro-5,8-dihydro-5-oxo-1,8-naphthyridin-2-yl)-3azabicyclo[3.1.0]hex-6-yl)-, (1α,5α,6α)-, monomethanesulfonate Common Name: Alatrofloxacin mesilate

Alatrofloxacin mesylate

125

Structural Formula:

Chemical Abstracts Registry No.: 146961-77-5; 146961-76-4 (Base) Trade Name

Manufacturer

Country

Year Introduced

Alatrofloxacin mesylate Alatrofloxacin mesylate

Pfizer

-

-

Fairview Pharm

-

-

Alatrofloxacin mesilate

Cipla

-

-

Trovan Preservative Free

Pfizer

-

-

Trovan iv

Pfizer

-

-

Turvel iv

Roerig Farmaceutici Italiana S.p.A. Pfizer

-

-

-

-

Turvel iv Raw Materials

Diphenylphosphinous azide Dihydropyrrole Ethyldiazoacetate Palladium Alanylalanine 1-(2,4-Difluoro-phenyl)-6,7-difluoro-4-oxo-1,4-dihydro[1,8] naphthylridine-3-carboxylic acid ethyl ester Manufacturing Process The dipolar cycloaddition of ethyldiazoacetate to the protected dihydropyrrole (with carbobenzyloxy (CBZ) protecting group) gives the fused pyrrazolidine(CBZ-3-ethylperoxy-1,3a,4,5,6,6a-hexahydro-pyrrolo{3,4-c}pyrazole). Pyrolysis results in loss of nitrogen and formation of the cyclopyrrolidine ring. The ester is then saponified to the corresponding carboxylic acid (CBZ-6-azabicyclo[3.1.0]hexene-3-carboxylic acid).This acid undergoes a version of the

126

Albendazole

Curtius rearrangement when treated with diphenylphosphinous azide to afford transient isocyanate. That reactive function adds tert-butanol from the reaction medium to afford the product as its butoxycarbonyl (BOC) derivative. CBZ-protecting group is removed by catalytic hydrogenation on Pd to afford the BOC-protected secondary amine - BOC-6-aza-bicyclo[3.1.0]hex-3-ylamine. In a standard quinolone reaction, this amine is then used to displace the more reactive fluorine at 7-position in the quinolone - 1-(2,4 difluoro-phenyl)-6,7difluoro-4-oxo-1,4-dihydro[1,8]naphthylridine-3-carboxylic acid ethyl ester. Treatment of the displacement product with hydrogen chloride cleaves the BOC protecting group to afford the antibiotic trovafloxacin. The peptide-like alanylalanylamide derivative, alatrofloxacin can in principle be prepared by reaction of the ester precursor of trovafloxacin with alanylalanine followed by saponification and treatment by methane sulphonic acid (mesylate). References Lednicer D., The organic Chemistry of Drug Synthesis, vol. 5, Wiley, NY, p.123 (1985) Brighty K.E.; US Patent No. 5,164,402; Nov. 17, 1992, Assigned to Pfizer Inc., New York, N.Y. Lednicer D., The organic Chemistry of Drug Synthesis, vol.6, Wiley, NY, p.154 (1999)

ALBENDAZOLE Therapeutic Function: Anthelmintic Chemical Name: [5-(Propylthio)-1H-benzimidazol-2-yl]carbamic acid methyl ester Common Name: Structural Formula:

Chemical Abstracts Registry No.: 54965-21-8 Trade Name

Manufacturer

Country

Year Introduced

Zentel

SK and F

France

1981

Raw Materials 3-Chloro-6-nitroacetanilide Hydrogen Methyl chloroformate

Propyl Mercaptan Cyanamide

Albifylline

127

Manufacturing Process A mixture of 6.65 g of 3-chloro-6-nitroacetanilide, 3.2 ml of propylmercaptan, 5.6 g of 50% sodium hydroxide and 100 ml of water is heated at reflux overnight. The cooled mixture is filtered to give the desired 2-nitro-5propylthioaniline, MP 69.5-71.5°C after recrystallization from ethanol then hexane-ether. NMR (CDCl3) 40%. The aniline (2.5 g) is hydrogenated with 1.9 ml of concentrated hydrochloric acid, 100 ml ethanol and 5% palladium-on-charcoal to give 4-propylthio-ophenylene-diamine hydrochloride. A mixture of 2.5 ml of 50% sodium hydroxide in 5 ml of water is added to a mixture of 1.9 g of cyanamide, 2.2 g of methylchloroformate, 3.5 ml of water and 3 ml of acetone over 45 minutes below 10°C, pH raised to 6.5. A molar equivalent solution of the diamine in 100 ml of ethanol is added. The mixture is heated until the easily volatile solvents are expelled, to about 85°C, then maintained at this temperature with some water added for one-half hour. The product, methyl 5-propylthio-2-benzimidazolecarbamate, is separated, washed to give a colorless crystalline solid, MP 208-210°C. References Merck Index 197 DFU 2 (2) 81 (1977) OCDS Vol.2 p. 353 (1980) DOT 15 (3) 89 (1979) I.N. p. 50 Gyurik, R.J. and Theodorides, V.J.; US Patent 3,915,986; October 28, 1975; Assigned to Smith Kline Corp.

ALBIFYLLINE Therapeutic Function: Vasodilator Chemical Name: 3,7-Dihydro-1-(5-hydroxy-5-methylhexyl)-3-methyl-1Hpurine-2,6-dione Common Name: Albifylline Structural Formula:

Chemical Abstracts Registry No.: 107767-55-5

128

Albifylline

Trade Name

Manufacturer

Country

Year Introduced

HWA-138

Hoechst-Roussel

-

-

Raw Materials 1-Chloro-5-hexanone 3-Methylxanthine Palladium on carbon

Methyl magnesium chloride Benzyl bromide

Manufacturing Process 1-(5-Hydroxy-5-methylhexyl)-3-methylxanthine may be prepared next way: 1). 1-Chloro-5-hydroxy-5-methylhexane: A solution of 67.3 g (0.5 mol) of 1-chloro-5-hexanone in 50 ml of anhydrous ether is added dropwise to 44.9 g (0.6 mol) of methyl magnesium chloride in the form of a 20% strength solution in tetrahydrofuran and 200 ml of dry ether at 0° to 5°C, while stirring. The mixture is then subsequently stirred initially at room temperature for one hour and then while boiling under reflux for a further hour, the tertiary alkanolate formed is decomposed by addition of 50% strength aqueous ammonium chloride solution, the ether phase is separated off and the aqueous phase is extracted by shaking with ether. The combined ethereal extracts are washed in succession with aqueous sodium bisulfite solution and sodium bicarbonate solution as well as a little water, dried over sodium sulfate, filtered and concentrated in vacuo and the liquid residue is subjected to fractional distillation under reduced pressure. Yield: 64.1 g (85.1% of theory), boiling point (20 mbar) 95-97°C, refractive index nD25 =1.4489. 2). 7-Benzyl-3-methylxanthine: 20 g (0.5 mol) of sodium hydroxide dissolved in 200 ml of water are added to a suspension of 83 g (0.5 mol) of 3-methylxanthine in 500 ml of methanol, the mixture is stirred at 70°C for one hour, 85.5 g (0.5 mol) of benzyl bromide are then added dropwise at the same temperature and the reaction mixture is kept between 70°C and 80°C for 5 hours. It is then cooled and filtered cold with suction, the product on the suction filter is washed with water and dissolved in 1000 ml of 1 N sodium hydroxide solution under the influence of heat, the solution is filtered and the pH is brought slowly to 9.5 with 4 N hydrochloric acid, while stirring. The crystals are filtered off from the still warm solution, washed with water until free from chloride and dried in vacuum. Yield: 81.7 g (63.8% of theory), melting point: 262-264°C. 3). 7-Benzyl-1-(5-hydroxy-5-methylhexyl)-3-methylxanthine: A mixture of 20.5 g (0.08 mol) of 7-benzyl-3-methylxanthine, 12.4 g (0.09 mol) of potassium carbonate and 13.61 g (0.09 mol) of above 1-chloro-5hydroxy-5-methylhexane in 300 ml of dimethylformamide is heated at 110° to 120°C for 8 hours, while stirring, and is then filtered hot and the filtrate is evaporated under reduced pressure. The residue is taken up in chloroform, the mixture is washed first with 1 N sodium hydroxide solution and then with

Albuterol

129

water until neutral and dried, the solvent is distilled off in vacuum and the solid residue is recrystallized from ethyl acetate, with the addition of petroleum ether Yield: 23.8 g (80.3% of theory), melting point: 109-111°C. 4). 1-(5-Hydroxy-5-methylhexyl)-3-methylxanthine: 14.8 g (0.04 mol) of the above mentioned 7-benzylxanthine are hydrogenated in 200 ml of glacial acetic acid over 1.5 g of palladium (5%) on active charcoal at 60°C under 3.5 bar in the course of 24 hours, while shaking. After cooling, the mixture is blanketed with nitrogen, the catalyst is filtered off, the filtrate is concentrated under reduced pressure and the solid residue is recrystallized from ethyl acetate. Yield of albifylline: 9.6 g (85.6% of theory), MP: 192-193°C. References Gebert U. et al.; US Patent No. 4,833,146; May 23, 1989; Assigned to Hoechst Aktiengeselschaft, Frankfurt am Main, Fed. Rep. of Germany

ALBUTEROL Therapeutic Function: Bronchodilator Chemical Name: α1-[[(1,1-Dimethylethyl)amino]methyl]-4-hydroxy-1,3benzenedimethanol Common Name: Salbutamol, α'-tert-Butylaminomethyl-4-hydroxy-m-xyleneα1,α3-diol Structural Formula:

Chemical Abstracts Registry No.: 18559-94-9; 51022-70-9 (Sulfate) Trade Name Ventolin Sultanol Ventoline Ventolin Ventolin Ventolin Ventolin Broncollenas Buto-Asma Proventil

Manufacturer Allen and Hanburys Glaxo Glaxo Glaxo Sankyo Glaxo Glaxo Llenas Aldo Union Schering

Country UK W. Germany France Italy Japan Switz. US Spain Spain US

Year Introduced 1969 1971 1971 1973 1973 1981 1981 -

130

Albuterol

Trade Name Rotacaps Salbumol Salbutol Salbuvent Salbuvent

Manufacturer Schering Medica Iltas Leiras Nyegaard

Country Finland Turkey Finland Norway

Year Introduced -

Raw Materials 5-(N-Benzyl-N-tert-butylglycyl)salicylic acid methyl ester hydrochloride Lithium aluminum hydride Hydrogen Manufacturing Process (a) α1-Benzyl-tert-butylaminomethyl-4-hydroxym-xylene-α1,α3-diol: 3.0 g of 5-(N-benzyl-N-tert-butylglycyl)-salicylic acid methyl ester hydrochloride in 40 ml of water was basified with sodium bicarbonate solution and extracted into ether. The ethereal solution was dried over MgSO4 and evaporated and the basic residue in 20 ml of dry tetrahydrofuran was added with stirring to 1.0 g of lithium aluminum hydride in 100 ml of dry tetrahydrofuran, over a period of 5 minutes. The light gelatinous precipitate that formed was stirred and refluxed for 8 hours after which time 7 ml of water was carefully added and the solvents were removed under reduced pressure. The residue was acidified with dilute hydrochloric acid and brought to pH 8 with sodium hydroxide and sodium bicarbonate. The mixture was filtered and the filtrate and orange solid were separately extracted with chloroform. The combined, dried, chloroform solutions were evaporated to give 22 g of the crude basic triol as an orange solid, when triturated with ether. A portion of the material was recrystallized from ether/light petroleum (BP 40-60°C) to give a white solid, MP 109-111°C. In an alternative process, sodium borohydride was used as the reducing agent, as follows: 36 g of 2-(benzyl-tert-butylamino)-4'-hydroxy-3'-hydroxymethyl acetophenone, hydrochloride was shaken with 100 ml of 10% sodium carbonate solution and 100 ml of ethyl acetate. The ethyl acetate layer was separated, washed with water, dried over anhydrous sodium sulfate and evaporated in vacuum. The residual gum was dissolved in 360 ml of ethanol and cooled to 15°C in an ice/water bath, 8 g of sodium borohydride was then added in portions over 30 minutes while maintaining the temperature at 15-20°C. After a further 30 minutes at 20°C the solution was stirred at room temperature for 2 hours. The solution was again cooled in ice and 250 ml of 2 N sulfuric acid were slowly added, then the solution was evaporated in vacuum until the ethanol had been removed. The clear aqueous solution was then treated with 250 ml of 10% sodium carbonate solution and the oil which precipitated was extracted into ethyl acetate. The ethyl acetate layer was washed with sodium carbonate solution, then with water, and was dried over anhydrous sodium

Alclofenac

131

sulfate and evaporated in vacuum, to a small volume. Petroleum ether (BP 40-60°C) was added, and after standing overnight a white solid was obtained. This was filtered off to give 23 g of the product, MP 110-114°C. (b) α1-tert-Butylaminomethyl-4-hydroxy-m-xylene-α1,α3-diol: 0.8 g of α1benzyl-tert-butyl-aminomethyl-4-hydroxy-m-xylene-α1,α3-diol in 20 ml of ethanol and 2 ml of water was shaken with hydrogen in presence of 0.50 g of pre-reduced 10% palladium on charcoal catalyst. When uptake of hydrogen was complete, the solution was filtered and evaporated under reduced pressure to give 0,4 g of the base as a colorless oil which yielded a white solid, MP 144-145°C when triturated with ether/cyclohexane. Recrystallization from ethyl acetate-cyclohexane gave a white solid, MP 147-149°C. References Merck Index 206 DFU 4 (9) 629 (1979) Kleeman and Engel p. 813 PDR 40 pp. 916, 1649 OCDS Vol. 2 p. 43 (1980) DOT 16 (8) 269 (1980) I.N. p. 860 REM p. 881 Lunts, L.H.C. and Toon, P.; US Patent 3,644,353; February 22, 1972; Assigned to Allen and Hanburys Ltd.

ALCLOFENAC Therapeutic Function: Antiinflammatory Chemical Name: 3-Chloro-4-(2-propenyloxy)benzene-acetic acid Common Name: (4-(Allyloxy)-3-chlorophenyl]acetic acid Structural Formula:

Chemical Abstracts Registry No.: 22131-79-9 Trade Name Mervan Prinalgin Neoston

Manufacturer Cooper Berk Beiersdorf

Country Switz. UK W. Germany

Year Introduced 1971 1972

132

Alclometasone dipropionate

Trade Name

Manufacturer

Country

Year Introduced

Allopydin

Chugai

Japan

1976

Zumaril

Abbott

Italy

1976

Epinal

Kyorin

Japan

1976

Darkeyfenac

Cuatrecasas-Darkey

Spain

-

Desinflam

Sintyal

Argentina

-

Medifenac

Medici

Italy

-

Mervan, Mirvan

Continental Pharma

Belgium

-

Vanadian

Federico Bonet

Spain

-

ZumariI

Sidus

Italy

-

Rentenac

Tosi

Italy

-

Raw Materials 3-Chloro-4-allyloxyphenyl acetonitrile Potassium hydroxide Manufacturing Process 103.7 grams of 3-chloro-4-allyloxyphenylacetonitrile in 500 cc of ethanol, 100 grams of potassium hydroxide and 100 cc of water are refluxed for 4 hours. Maximum of alcohol is evaporated, the residue is diluted with water and ice, and acidified with 20% HCl. The solid is filtered and washed with petroleum ether. 91.5 grams of acid are obtained (Yield: 81%) which is recrystallized from aqueous methanol; MP 92-93°C. References Merck Index 209 Kleeman and Engel p. 19 OCDS Vol. 2 p. 68 (1980) DOT 8 No. 9, 329 (1972) I.N. p. 50 British Patent 1,174,535; December 17, 1969; Assigned to Madan AG, Switzerland

ALCLOMETASONE DIPROPIONATE Therapeutic Function: Antiinflammatory, Antiallergic Chemical Name: Pregna-1,4-diene-3,20-dione, 7-chloro-11-hydroxy-16methyl-17,21-bis(1-oxopropoxy)-, (7α,11β,16α)Common Name: Alclometasone dipropionate; Perderm; Modrasone Chemical Abstracts Registry No.: 66734-13-2

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133

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Alclovate

GlaxoSmithKline

-

-

Afloderm

Belupo

-

-

Miloderme

Schering-Plough

-

-

Raw Materials 16α-Methyl-1,4,6-pregnatriene-11β,17α,21-triol-3,20-dione 17,21dipropionate Hydrogen chloride Sodium borohydride Manufacturing Process A). Add 16α-methyl-1,4,6-pregnatriene-11β,17α,21-triol-3,20-dione 17,21dipropionate (2.0 g) to dioxane (24 ml) which has been saturated with dry hydrogen chloride gas. Stir at room temperature for 16 hours, pour into ice water (600 ml), separate the resultant precipitate by filtration, wash the precipitate with water and dry in air. Separate the components in the foregoing precipitate on silica gel via thin layer chromatography utilizing as developing solvent ether:hexane (2:1), and elute with ethyl acetate the band containing 7α-chloro-16α-methyl-1,4-pregnadiene-11β,17α,21-triol-3,20-dione 17,21-dipropionate as shown by ultraviolet light. Evaporate the combined ethyl acetate eluates and triturate the resultant residue with acetone:ether, then filter and dry the triturated precipitate to obtain 7α-chloro-16α-methyl1,4-pregnadiene-11β,17α,21-triol-3,20-dione 17,21-dipropionate. Alternatively, the 7α-chloro-16α-methyl-1,4-pregnadiene-17α,21-diol-3,11,20trione 17,21-dipropionate is prepared according to following procedures B and C. B). Saturate dry tetrahydrofuran (137 ml) at 0°C with dry hydrogen chloride gas. Add 16α-methyl-1,4,6-pregnatriene-17α,21-diol-3,11,20-trione 17,21dipropionate (6.85 g) and stir the reaction mixture at 0°C for 1 hour. Pour into ice water (1 liter) and stir for ½ hour. Separate the resultant precipitate by filtration, wash with water, and air dry to give 7v-chloro-16α-methyl-1,4pregnadiene-17α,21-diol-3,11,20-trione 17,21-dipropionate. Purify from methanol:acetone containing a trace of propylene oxide; [α]D26 +76.2°

134

Alcuronium chloride

(dimethylformamide). C). To a solution of 7v-chloro-16α-methyl-1,4-pregnadiene-17α,21-diol3,11,20-trione 17,21-dipropionate (3.2 g) in tetrahydrofuran (24 ml) and methanol (8 ml) at 0°C under an atmosphere of nitrogen add sodium borohydride (0.697 g) and stir the reaction mixture for 15 min at 0°C. Pour into ice water (1.8 liters) and 250 ml of 1 N hydrochloric acid. Separate the resultant precipitate by filtration and air dry to give 7α-chloro-16α-methyl11β,17α,21-triol-3,20-dione 17,21-dipropionate. Purify by crystallizing twice from acetone:methanol:isopropyl ether; m.p. 212°-216°C; [α]D26 +42.6° (dimethylformamide). λmax 242 nm (methanol, ε 15,600). By saponification of 7α-chloro-16α-methyl-1,4-pregnadiene-17α,21-diol3,11,20-trione 17,21-dipropionate is prepared (7α,11β,16α)-7-chloro11,17,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione. References Green M., Shue Ho-Jane; US Patent No. 4,124,707; Nov. 7, 1978; Schering Corporation (Kenilworth, NJ)

ALCURONIUM CHLORIDE Therapeutic Function: Muscle relaxant Chemical Name: N,N'-Diallylnortoxiferinium dichloride Common Name: Structural Formula:

Aldosterone

135

Chemical Abstracts Registry No.: 15180-03-7 Trade Name

Manufacturer

Country

Year Introduced

Alloferin

Roche

UK

1966

Alloferin

Roche

W. Germany

1968

Alloferine

Roche

France

1968

Dialferin

Nippon Roche

Japan

1969

Toxiferin

Roche

-

-

Raw Materials Diallyl Nortoxiferine Diiodide Chloride Ion Exchange Resin Manufacturing Process 31 g of diallylnortoxiferine diiodide are suspended in 1 liter of water and shaken with 1,100 ml of Amberlite IRA-400 [chloride ion form, described Merck Index, 7th edition, Merck and Co., Inc., Rahway, New Jersey (1960), page 1584], for 2 hours. The diiodide thereby goes into solution. The ion exchanger is filtered off and then washed in 3 portions with a total of 1 liter of water. The combined filtrates are then allowed to run through a column of 300 ml of Amberlite IRA-400 (chloride ion form), rinsed with 300 ml of water and the eluate evaporated to dryness in a vacuum while excluding air. The residue gives on recrystallization from methanol/ethanol crystalline pure colorless diallylnortoxiferine dichloride in a yield of 18.6 g. The compound contains 5 mols of water of crystallization after equilibration in air. References Merck Index 215 Kleeman and Engel p. 19 I.N. p.51 Boller, A., Els, H. and Furst, A.; US Patent 3,080,373; March 5, 1963; Assigned to Hoffman La Roche, Inc.

ALDOSTERONE Therapeutic Function: Mineralocorticoid Chemical Name: Pregn-4-en-18-al, 11,21-dihydroxy-3,20-dioxo-, (11β)Common Name: Aldosterone; Elektrocortin; Oxocorticosterone; Reichstein's substance X Chemical Abstracts Registry No.: 52-39-1

136

Aldosterone

Structural Formula:

Trade Name Aldosterone Aldosterone Aldocorten

Manufacturer Sigma Chemical Company Andard-Mount Company Limited Ciba

Country -

Year Introduced -

-

-

-

-

Raw Materials 3α,11β-Dihydroxy-D-homo-18noretiocholan-17α-one Sodium hydride Potassium hydroxide Acrylonitrile 4-Toluenesulfonic acid monohydrate Acetic acid Sodium borohydride Ozone Sodium metaperiodate Sodium arsenite Sodium bicarbonate Potassium iodide Piperidine Pyridine Acetic anhydride Zinc Diazomethane Lithium Bromobenzene Thyonyl chloride Palladium Chromic oxide Dinitrophenylhydrazine Furfural Hydrogen chloride Manufacturing Process In 1.0 L of methanol (purified by distillation from potassium hydroxide) was dissolved 27.02 g of 3α,11β-dihydroxy-D-homo-18-noretiocholan-17α-one (melting point 169°-173°C Patent No. 2,847,457; May 26, 1955). The solution was cooled to 5°C, and 54 ml of freshly distilled furfural was added. The air in the flask was replaced by nitrogen, 400 ml of 15% aqueous potassium hydroxide was added and the flask was sealed tightly. The solution was allowed to stand at room temperature overnight. The precipitate was collected on a filter, washed generously with water, and was dried to constant weight in vacuo, yielding 28.45 g of 3α,11β-dihydroxy-D-homo-18-noretiocholan-17furfurylidene-17α-one as colorless lustrous plates, melting point 193°-194°C (after repeated recrystallization from methanol and acetone-petroleum ether). A solution of 48 mg of sodium hydride in 6 ml of anhydrous methanol was cooled to 5°C, and to it was added slowly 1.20 ml of acrylonitrile (b.p. 75°78°C). The solution was allowed to stand at room temperature for an 1 h and then cooled again to 5°C. The 3α,11β-dihydroxy-D-homo-18-noretiocholan-17-

Aldosterone

137

furfurylidene-17α-one was added and the solution was stirred at room temperature for 2 h and then heated at reflux for 2 h. After a total of 8 h of heating at reflux the mixture was cooled to 5°C, and acetic acid was added until the solution was acidic. It was then diluted with water and extracted with ethyl acetate. The extract was washed with aqueous sodium bicarbonate and water, dried over magnesium sulfate, and distilled to dryness under reduced pressure. The product was crystallized from a small volume of acetone, and the crystals were washed with hot petroleum ether and then ether. This gave 750 mg of 3α,11β-dihydroxy-13α-(2-cyanoethyl)-D-homo-18-noretiocholan17-furfurylidene-17α-one as colorless plates, melting point 193°-194°C (after repeated recrystallization from methanol). A solution of 1.02 g of 3α,11β-dihydroxy-13α-(2-cyanoethyl)-D-homo-18noretiocholan-17-furfurylidene-17α-one in 60 ml of methanol and 5 ml of pyridine was cooled to -70°C, and a stream of oxygen containing ozone was passed through until the solution turned a faint blue color (25 min). The solution was quickly put under reduced pressure to remove any dissolved ozone, and after 3 min a solution of 1.0 g of sodium borohydride in 10 ml of water was added slowly, allowing the solution to warm to 0°C. Within two min after the borohydride was added (an acidified portion of the solution gave no starch-iodide test, indicating absence of ozonide). An additional 3.0 g of borohdride was added in 1 g portions at 1 h intervals, and the solution was allowed to stand for a total of 35 h. Acetic acid was added slowly and stirring until the solution yield pH 5. The methanol was distilled, under reduced pressure, the last portions being co-distilled with ethyl acetate and water. The aqueous solution was then extracted three times with ethyl acetate. The extracts were washed in turn with 5% aqueous hydrochloric acid (cold), water, aqueous sodium bicarbonate, and water. The combined ethyl acetate solutions were dried over sodium sulfate and concentrated to dryness under reduced pressure. The crude product (71%) of 3α,11β,17,17a-tetrahydroxy-13α-(2cyanoethyl)-D-homo-18-noretiocholan was obtained as colorless rods, melting point 137°-140°C (several recrystallization from aqueous methanol). To a solution of 280 mg of 3α,11β,17,17a-tetrahydroxy-13α-(2-cyanoethyl)-Dhomo-18-noretiocholan in 17 ml of methanol at room temperature contained in a 25 ml volumetric flask there was added 162 mg of sodium metaperiodate in 8 ml of water. A small amount of water was added to bring the volume to 25 ml. After 15 min an aliquot was withdrawn and added to a measured amount of sodium arsenite solution containing sodium bicarbonate and potassium iodide. After 10 min, the solution was titrated with standard iodine solution. The solution was diluted with water and extracted twice with ethyl acetate, each extract being washed in turn with sodium combined, dried over magnesium sulfate and concentrated to dryness under reduced pressure, yielding 265 mg of a colorless, amorphous product of 4b-methyl-1β-(2formylethyl)-2β-formyl-2-(2-cyanoethyl)-4β,7αdihydroxyperhydrophenanthrene. A solution of 240 mg of 4b-methyl-1β-(2-formylethyl)-2β-formyl-2-(2cyanoethyl)-4β,7α-dihydroxyperhydrophenanthrene dissolved in 30 ml of anhydrous methanol containing 20 mg of p-toluenesulfonic acid monohydrate was allowed to stand at room temperature for 36 h. Aqueous sodium bicarbonate was added and the methanol was evaporated under reduced pressure. An ether extraction of the aqueous layer afforded 260 mg of a benzene soluble oil, which was chromatographed on 12 g of florisil. The 4b-

138

Aldosterone

methyl-1β-(2-formylethyl)-2β-formyl-2-(2-cyanoethyl)-4β,7αdihydroxyperhydrophenanthrene 1β-methyl acetal 2β,4β-lactol methyl ether was eluted between 20% benzene in ether and ether. A solution of 560 mg of the 4b-methyl-1β-(2-formylethyl)-2β-formyl-2-(2cyanoethyl)-4β,7α-dihydroxyperhydrophenanthrene 1β-methyl acetal 2β,4βlactol methyl ether in 10 ml of pyridine and 5 ml of acetic anhydride was heated at 100°C for 10 min. The solution was cooled and poured on iced aqueous sodium bicarbonate. The mixture was extracted with ether, the extract being washed with water, dried over magnesium sulfate and concentrated to dryness at aspirator pressure. The pyridine was removed at 2 mm with as little heating as possible. From a small volume of methanol, the colorless oil remaining gave a heavy precipitate of crystals which was washed with petroleum ether (b.p. 32°-35°C). The pure 4b-methyl-1β-(2-formylethyl)2β-formyl-2-(2-cyanoethyl)-4β,7α-dihydroxyperhydrophenanthrene 1β-methyl acetal 2β,4β-lactol methyl ether 7α-acetate was obtained as colorless prisms, melting point 126°-127°C, by several recrystallizations from methanol. The 4b-methyl-1β-(2-formylethyl)-2β-formyl-2-(2-cyanoethyl)-4β,7αdihydroxyperhydrophenanthrene 1β-methyl acetal 2β,4β-lactol methyl ether 7α-acetate (360 mg) was stirred in 3 ml of ether. Upon the addition of 9 ml of 70% aqueous acetic acid the crystals dissolved immediately. The solution was allowed to stand at room temperature for 16 h and was then extracted with ether. The extract was washed thoroughly with water and aqueous sodium bicarbonate, dried over magnesium sulfate and concentrated to dryness under reduced pressure, yielding 337 mg of oil. On trituration with ether there was obtained 305 mg of crystals of 4b-methyl-1β-(2-formylethyl)-2β-formyl-2-(2cyanoethyl)-4β,7α-dihydroxyperhydrophenanthrene 2β,4β-lactol methyl ether 7α-acetate as platelets, melting point 85°-105°C after recrystallizations from benzene-petroleum ether. After standing at room temperature for 10 min, a solution of 710 mg of the 4b-methyl-1β-(2-formylethyl)-2β-formyl-2-(2-cyanoethyl)-4β,7αdihydroxyperhydrophenanthrene 2β,4β-lactol methyl ether 7α-acetate in 5 ml of piperidine and 10 ml of benzene was heated at brisk reflux in a nitrogen atmosphere. After 3 h the solvents were removed under reduced pressure, leaving 820 mg of 4b-methyl-1β-[3-(1-piperidyl)-2-propenyl]-2β-formyl-2-(2cyanoethyl)-4β,7α-dihydroxyperhydrophenanthrene 2β,4β-lactol methyl ether 7α-acetate as colorless oil. Through a solution of 810 mg of crude 4b-methyl-1β-[3-(1-piperidyl)-2propenyl]-2β-formyl-2-(2-cyanoethyl)-4β,7α-dihydroxyperhydrophenanthrene 2β,4v-lactol methyl ether 7α-acetate in 60 ml of methylene chloride and 1.5 ml of pyridine at -70°C was passed a stream of oxygen containing ozone until the solution turned blue (17 min). 3 g of zinc dust and 6 ml of glacial acetic acid were added immediately. The stirred solution was allowed to warm to 0°C and to remain at that temperature for 30 min. The solution was filtered and washed with aqueous sodium bicarbonate. The organic solvent was dried over magnesium sulfate and was distilled below room temperature, affording 750 mg of a benzene soluble, pale yellow oil. The product was chromatographed and eluted 310 mg (45%) of 4b-methyl-1β-(2-formylmethyl)-2β-formyl-2-(2cyanoethyl)-4β,7α-dihydroxyperhydrophenanthrene 2β,4β-lactol methyl ether 7α-acetate.

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139

A solution of 310 mg of the chromatographed noncrystalline 4b-methyl-1β-(2formylmethyl)-2β-formyl-2-(2-cyanoethyl)-4β,7αdihydroxyperhydrophenanthrene 2β,4β-lactol methyl ether 7α-acetate in 60 ml of anhydrous methanol containing 40 mg of p-toluenesulfonic acid monohydrate was allowed to stand at room temperature for 9 h. Aqueous sodium bicarbonate was added, and methanol was evaporated under reduced pressure. The remaining mixture was extracted with ether and extract was dried over magnesium sulfate and concentrated to dryness in vacuo, affording 325 mg of oil. This was chromatographed on 12 g of florisil. Ether eluted 285 mg of oil which crystallized from petroleum ether, giving 230 mg of 4bmethyl-1β-(2-formylmethyl)-2β-formyl-2-(2-cyanoethyl)-4β,7αdihydroxyperhydrophenanthrene 1β-methyl acetal 2β,4β-lactol methyl ether 7α-acetate as irregular prisms, melting point 149°-152°C. A solution of 220 mg of the 4b-methyl-1β-(2-formylmethyl)-2β-formyl-2-(2cyanoethyl)-4β,7α-dihydroxyperhydrophenanthrene 1β-methyl acetal 2β,4βlactol methyl ether 7α-acetate in 5 ml of methanol and 10 ml of 10% aqueous potassium hydroxide was heated at reflux 17 h. The methanol was distilled off and the remainder was extracted with chloroform. The aqueous solution was cooled to 5°C and was acidified to pH 4 with cold 3 N hydrochloric acid. The solution was rapidly extracted twice with cold ethyl acetate, each extract being washed in turn 3 times with water. To the combined extracts (300 ml) was added 10 ml of methanol followed by solution excess diazomethane in 50 ml of ether. After 10 min the diazomethane was blown off, and the solvent was evaporated under reduced pressure, affording 235 mg of an oil. Chromatography of this material on 6 g of florisil and elution gave 220 mg of 4b-methyl-1β-(2-formylmethyl)-2β-formyl-2-(2-methylcarboxyethyl)-4β,7αdihydroxyperhydrophenanthrene 1β-methyl acetal 2β,4β-lactol methyl ether. Excess phenyllithium (prepared from 0.210 g of lithium wire and 2.4 g of bromobenzene following the directions given by J.C.W. Evans and C.F.H. Allen, Org. Syntheses, vol. 2, p. 22 (1943)) in 20 ml of ether was added to 215 mg of the 4b-methyl-1β-(2-formylmethyl)-2β-formyl-2-(2-methylcarboxyethyl)4β,7α-dihydroxyperhydrophenanthrene 1β-methyl acetal 2β,4β-lactol methyl ether in 20 ml of anhydrous ether under an atmosphere of nitrogen. After the solution was stirred at room temperature for 2 h, the excess reagent was decomposed by the drop wise addition of ethanol. Water was added, and the mixture was extracted with ether. The extract was washed with water, dried over magnesium sulfate and concentrated to dryness under reduced pressure, yielding 310 mg of an oil which was chromatographed ed on 6 g of florisil; ether eluted 267 mg of an oil which giving 252 mg of 4b-methyl-1β-(2formylmethyl)-2β-formyl-2-(3,3,3-hydroxydiphenylpropyl)-4β,7αdihydroxyperhydrophenanthrene 1β-methyl acetal 2β,4β-lactol methyl ether as needles, melting point 116°-119°C (from ether). A solution of 250 mg of the 4b-methyl-1β-(2-formylmethyl)-2β-formyl-2(3,3,3-hydroxydiphenylpropyl)-4β,7α-dihydroxyperhydrophenanthrene 1βmethyl acetal 2β,4β-lactol methyl ether, in 10 ml of pyridine and 5 ml of acetic anhydride was heated at 100°C for 10 min. The solution was cooled and poured onto iced aqueous sodium bicarbonate. The mixture was extracted with ether, dried over magnesium sulfate and concentrated to dryness under reduced pressure, affording 255 mg (95.2%) of the colorless 4b-methyl-1β(2-formylmethyl)-2β-formyl-2-(3,3,3-hydroxydiphenylpropyl)-4β,7αdihydroxyperhydrophenanthrene 1β-methyl acetal 2β,4β-lactol methyl ether

140

Aldosterone

7α-acetate. To a solution of 250 mg of the 4b-methyl-1β-(2-formylmethyl)-2β-formyl-2(3,3,3-hydroxydiphenylpropyl)-4β,7α-dihydroxyperhydrophenanthrene 1βmethyl acetal 2β,4β-lactol methyl ether 7α-acetate in 10 ml of benzene and 1.0 ml of pyridine at 0°C was added 0.5 ml of thyonyl chloride. After standing at 0°C for 15 min, the solution was poured onto iced sodium bicarbonate, and resulting mixture was extracted with ether. The extract was dried over magnesium sulfate, and the ether was removed under reduced pressure. Pyridine (20 ml) was added and solution was heated at 100°C for 20 min. The solution was then concentrated to dryness under reduced pressure and the residue was dissolved in a small volume of benzene. The benzene solution was poured on 6 g of florisil; elution with ether provided 230 mg of colorless 4bmethyl-1β-(2-formylmethyl)-2β-formyl-2-(3,3-diphenyl-2-propenyl)-4β,7αdihydroxyperhydrophenanthrene 1β-methyl acetal 2β,4β-lactol methyl ether 7α-acetate. Through a solution of 225 mg of the 4b-methyl-1β-(2-formylmethyl)-2βformyl-2-(3,3-diphenyl-2-propenyl)-4β,7α-dihydroxyperhydrophenanthrene 1βmethyl acetal 2β,4β-lactol methyl ether 7α-acetate in 30 ml of methylene dichloride and 0.15 ml of pyridine at -70°C was passed a stream of oxygen containing ozone. When the solution turned a faint blue color, 3 g of zinc dust and 6 ml of glacial acetic were added immediately. The solution was stirred at 0°C until it gave a negative starch iodide test (10 min); the mixture was filtered, washing the zinc with additional methylene dichloride. The organic solution was washed with aqueous sodium bicarbonate, dried over magnesium sulfate and concentrated to dryness in vacuo, giving 230 mg of oil. This was chromatographed on 5 g of florisil; elution with ether gave 110 mg of 4bmethyl-1β,2α-bis-(2-formylmethyl)-2β-formyl-4β,7αdihydroxyperhydrophenanthrene 1β-methyl acetal 2β,4β-lactol methyl ether 7α-acetate. In 1 ml of ether was dissolved 20 mg of the crude 4b-methyl-1β,2α-bis-(2formylmethyl)-2β-formyl-4β,7α-dihydroxyperhydrophenanthrene 1β-methyl acetal 2β,4β-lactol methyl ether 7α-acetate. To this was added 3 ml of 70% aqueous acetic acid, and the homogeneous solution was allowed to stand at room temperature to 10 h. The material was extracted with ether, and extract was washed with aqueous sodium bicarbonate, dried over magnesium sulfate and concentrated to dryness under reduced pressure, yielding 15 mg of 4bmethyl-1β,2α-bis-(2-formylmethyl)-2β-formyl-4β,7αdihydroxyperhydrophenanthrene 2β,4β-lactol 7α-acetate. A benzene solution (5 ml) of 15 mg of the 4b-methyl-1β,2α-bis-(2formylmethyl)-2β-formyl-4β,7α-dihydroxyperhydrophenanthrene 2β,4β-lactol 7α-acetate containing 3.4 mg of piperidine and 6.2 mg of acetic acid was heated at 60°C in slow stream of nitrogen with an azeotropic separator. After 1 h, half the solution was withdrawn, diluted with benzene, and washed with diluted aqueous hydrochloric acid and with aqueous sodium bicarbonate. The benzene extract dried over magnesium sulfate and concentrated to dryness under reduced pressure, giving 3α-acetoxy-17-formyl-16-etiocholen-11β-ol18-one 11β,18-lactol as colorless oil. The 3α-acetoxy-17-formyl-16-etiocholen-11β-ol-18-one 11β,18-lactol can be converted to aldosterone by conventional methods as follows.

Alendronate sodium trihydrate

141

The unsaturated 3α-acetoxy-17-formyl-16-etiocholen-11β-ol-18-one 11β,18lactol is hydrogenated in the presence of palladium catalyst to saturate the 16,17-double bond, and then saturated aldehyde are oxidized by treatment with chromic oxide in pyridine to give 3α-acetoxy-11β-ol-18-one-pregnane 11β,18-lactone 17-carboxylic acid. Then as a result of reaction of 3α-acetoxy-11β-ol-18-one-pregnane 11β,18lactone 17-carboxylic acid and HCl the 3α-acetoxy-11β-ol-18-one-pregnane 11β,18-lactone 17-carboxylic acid chloride was obtained. The 3α-acetoxy-11βol-18-one-pregnane 11β,18-lactone 17-carboxylic acid chloride was treated with diazomethane to give 3α-acetoxy-11β-ol-18-one-pregnane 11β,18-lactone 17-diazoketone. The saponification of acetoxy group and reacting of 3α-acetoxy-11β-ol-18one-pregnane 11β,18-lactone 17-diazoketone with acetic acid were carried out to afford acetic acid 3α,11β-dihydroxy-18,20-dione-pregnane 11β,18-lactone 17-oxoethyl ether. The 3-keto-δ4 system is introduced by conventional methods, that is, by oxidation of the 3-hydroxy group to a 3-keto group with chromic oxide. Bromination at the 4-position, and finally dehydrobromination with dinitrophenylhydrazine or with lithium chloride in dimethylformamide were carried out to give acetic acid 11β-hydroxy-3,18,20-trione-pregn-4-ene 11β,18-lactone 17-oxoethyl ether. 2 Methods of producing of aldosterone: 1. Further, acetic acid 11β-hydroxy-3,18,20-trione-pregn-4-ene 11β,18-lactone 17-oxoethyl ether has been converted to 11β,21-dihydroxy-3,18,20-trionepregn-4-ene by methods of reduction of the lactone group and deacetylation of 17-oxoethyl group, described by Schmidlin, Anner, Biller and Wettstein (Experimentia, XI, 365 (1955). 2. Further, acetic acid 11β-hydroxy-3,18,20-trione-pregn-4-ene 11β,18-lactone 17-oxoethyl ether has been converted to 11β-hydroxy-18-one-pregn-4-ene 11β,18-lactone-3,20-bis-ethylenketal 17-oxoethyl ether, which was reduced with lithium-aluminum hydride to 3,20-bis-ethylenketal aldosterone. Then by hydrolisation of 3,20-bis-ethylenketal aldosterone with HClO4 aldosterone can be obtained. References Johnson W.S., Johns W.F.; US Patent No. 3,049,539; August 14, 1962; Assigned: Wisconsin Alumini Research Foundation, Madison,Wis., a corporation of Wisconsin Chaletsky A.M.; Pharmaceutical Chemistry, 'Medicina', L., 1966. 761p.

ALENDRONATE SODIUM TRIHYDRATE Therapeutic Function: Antiosteoporotic

142

Alendronate sodium trihydrate

Chemical Name: (4-Amino-1-hydroxybutylidene)diphosphonic acid monosodium salt trihydrate Common Name: Alendronate sodium Structural Formula:

Chemical Abstracts Registry No.: 129318-43-0; 66376-36-1 (Base) Trade Name

Manufacturer

Country

Year Introduced

Adronat

Neopharmed

Italy

-

Adronat

Tecnifar

Portugal

-

Alendronate sodium

BARR

-

-

Arendal

Syncro

Argentina

-

Alendros

Abiogen

Italy

-

Brek

TRB

Argentina

-

Dronal

Sigma Tau

Italy

-

Elandur

Sidus

Argentina

-

Endronax

Sintofarma

Brazil

-

Fosalan

Merck Pharmaceutical Corporation

-

-

Fosamax

Merck Sharp and Dohme

Netherlands

-

Holadren

Laboratorio Chile S.A.

-

-

Lafedam

Elvetium

Argentina

-

Marvil

Elisium

Argentina

-

Onclast

Teijin Pharma Ltd.

Japan

-

Osteoral

Ache

-

-

Phostarac

Rontag

Argentina

-

Regenesis

Elea

Argentina

-

Teiroc

Teijin Pharma Ltd.

Japan

-

Raw Materials Phosphorous acid Phosphorus trichloride 4-Aminobutyric acid

Alentamol

143

Manufacturing Process 4-Amino-1-hydroxybutylidene-1,1-diphosphonic acid (ABDT). Orthosphophorous acid (102.7 g; 1.25 moles) is introduced into a 2 liter-flask with condenser, stirrer and dropping funnel, placed on a thermostatized bath; the air is then removed with a nitrogen stream which is continued during all the reaction. The acid is melted by heating the bath to 95°C. When melting is complete, 4-aminobutyric acid (103.3; 1 mole) is added under stirring which is continued till obtaining a doughy fluid. Phosphorous trihalide (176 ml; 2 moles) is added dropwise causing the mixture to boil and evolution of gaseous hydrochloric acid which is damped by means of a suitable trap. The addition rate is adjusted so as to keep a constant reflux for about 60 minutes. When the addition is nearly over, the mixture swells, slowly hardening. Stirring is continued as long as possible, whereafter the mixture is heated for further 3 hours. Without cooling, but removing the bath, water (300 ml) is added, first slowly and then quickly. Heating and stirring are started again. Decolorizing charcoal is added and the mixture is boiled for about 5 minutes, then hotfiltered on paper and the filtrate is refluxed for 6 hours. After cooling is slowly poured in stirred methanol (1500 ml) causing thereby the separation of a white solid which collected and dried (161 g; 64.6%). The structure of ABDT is confirmed by IR spectrum, proton magnetic and nuclear magnetic resonance spectrum and elemental analysis. The sodium salt of this acid may be prepared by adding of equivalent of sodium hydroxide. References G. Staibano; US Patent No. 4,705,651; Nov. 10, 1987; Assigned to Instituto Gentili S.p.A., Pisa, Italy

ALENTAMOL Therapeutic Function: Antipsychotic, Dopamine agonist Chemical Name: 1H-Phenalen-5-ol, 2-(dipropylamino)-2,3-dihydro-, hydrobromide, (+/-) Common Name: Alentamol Structural Formula:

144

Alentamol

Chemical Abstracts Registry No.: 121514-27-0 Trade Name

Manufacturer

Country

Year Introduced

U 68553B

Upjohn Company

-

-

Raw Materials Triethylamine Hydrogen chloride Trifluoroacetic acid Sodium hydroxide n-Propyl bromide

5-Methoxy-2,2-dicarboxy-2,3-dihydro-1H-phenalene Diphenyl phosphoryl azide t-Butyl carbamate Hydrogen bromide Potassium carbonate

Manufacturing Process The solid 5-methoxy-2,2-dicarboxy-2,3-dihydro-1H-phenalene, was decarboxylated (one carboxyl group removed) by heating in an oil bath at 190°-210°C for 50 min. The resulting liquid was cooled, and the solid was ground to a fine powder to obtain 37.1 g (98% yield) of the subtitled 2carboxyl-5-methoxy-2,3-dihydro-1H-phenalene, melting point 194°-196°C. A mixture of the 5-methoxy-2,3-dihydro-1H-phenalen-2-yl-carboxylic acid, (37.1 g; 0.153 mole), 42.1 g (0.153 mole) of diphenyl phosphoryl azide, 17.0 g (0.168 mole) of triethylamine and 1950 ml of dry tert-butyl alcohol was refluxed for 21 h. The initially formed solution became a suspension. The solvent was evaporated in vacuo and the residue was taken up in a chloroform/water mixture. The resulting suspension was filtered. The filtrate was separated, the aqueous phase was extracted with chloroform, and the combined organic liquid phases was washed with 5% w/v sodium hydroxide aqueous solution (3x100 ml), with water and with saturated sodium chloride salt solution and then dried over magnesium sulfate and evaporated.The resulting residual yellow solid, 35.9 g, was extracted with boiling SKELLYSOLVE B brand of hexanes (5x200 ml), the resulting solution was concentrated to about 300 ml, clarified with diethyl ether and allowed to crystallize at 0°C to obtain 28.6 g of the 5-methoxy-2-(tertbutoxycarbonylamino)-2,3-dihydro-1H-phenalene, melting point 113°-115°C. Trifluoroacetic acid, 85 ml, was added to 30.5 g (0.0958 mole) of the 5methoxy-2-(tert-butoxycarbonylamino)-2,3-dihydro-1H-phenalene. The resulting solution was stirred for 20 min. Ice was then added, and the resulting mixture was made pH basic with 20% w/w sodium hydroxide in water solution and stirred for 1 h at room temperature. The mixture was extracted well with chloroform, the chloroform extract was separated and washed with water, with saturated sodium chloride solution; dried with magnesium sulfate, and evaporated to give 18.8 g (92% yield) of the 2amino-5-methoxy-2,3-dihydro-1H-phenalene as a brown oil. This 2-amino-5-methoxy-2,3-dihydro-1H-phenalene was converted to its hydrochloride salt in methanol with 1.5 N hydrogen chloride in diethyl ether solution to give 18.11 g of the 2-amino-5-methoxy-2,3-dihydro-1H-phenalene hydrochloride as colorless needle crystals, melting point 252°C (dec.). A mixture of 2-amino-5-methoxy-2,3-dihydro-1H-phenalene, 2.6 g (0.0122 mole), released from its hydrochloride, 6.46 g (0.0525 mole) of n-propyl

Alexidine

145

bromide, 7.25 g (0.0525 mole) of potassium carbonate and 50 ml of acetonitrile was refluxed for 20 h. Another 3.3 g of n-propyl bromide, 3.6 g of potassium carbonate and 25 ml of acetonitrile were added to the reaction mixture. The mixture was refluxed for 26 h. GC analysis of a sample of the reaction mixture indicated complete reaction. The mixture was evaporated, and the residue was taken up in a diethyl ether/water mixture. The organic liquid layer was washed with saturated sodium chloride (salt) solution and dried with magnesium sulfate, and evaporated. The residue was dissolved in petroleum ether (boiling point 30°-60°C), and filtered from some insoluble brown material, and the filtrate was evaporated to leave the 2-(di-npropylamino)-5-methoxy-2,3-dihydro-1H-phenalene. The 2-(di-n-propylamino)-5-methoxy-2,3-dihydro-1H-phenalene was dissolved in diethyl ether, treated with ethereal hydrogen chloride which resulted in the formation of the crude gummy solid hydrogen chloride salt. 2.67 g (66% yield) of the 2-(di-n-propylamino)-5-methoxy-2,3-dihydro-1H-phenalene hydrochloride, melting point 196°-197°C (crystallized from a methanol/diethyl ether). A mixture of 2-(di-n-propylamino)-5-methoxy-2,3-dihydro-1H-phenalene, (1.65 g; 5.55 mmol), released from the hydrochloride salt, and 20 ml of 48% aqueous hydrogen bromide solution was heated for 15 min in an oil bath at 125°-130°C. The reaction mixture was evaporated, the residue was dissolved in a minimum amount of methanol, diethyl ether was added until the mixture became cloudy, and the mixture was filtered through a filter aid (CELITE) to remove some oily impurity. The filtrate was diluted with diethyl ether and seeded. There was obtained 1.28 g (63% yield) of the 2-(di-n-propylamino)2,3-dihydro-lH-phenalen-5-ol hydrobromide, melting point 233°-234°C (dec.). References Szmuszkovicz J. et al.; Patent Coop. Treaty (WIPO), 1987, 87/04153; July 16, 1987; Assigned: The UPJOHN COMPANY [US/US]; 301 Henrietta Street, Kalamazoo, MI 49001 (US)

ALEXIDINE Therapeutic Function: Antiseptic Chemical Name: 2,4,11,13-Tetraazatetradecanediimidamide, N,N''-bis(2ethylhexyl)-3,12-diiminoCommon Name: Alexidine Chemical Abstracts Registry No.: 22573-93-9 Trade Name

Manufacturer

Country

Year Introduced

Alexidine

Science Lab.

-

-

Alexidine

Chemos GmbH

-

-

146

Alfacalcidol

Structural Formula:

Raw Materials 1,1'-Hexamethylene-bis(3-cyanoguanidine) Ethylhexylamine hydrochloride Manufacturing Process A mixture of 16 g (0.09 mole) 1,1'-hexamethylene-bis(3-cyanoguanidine) and 20 d (0.12 mole) 2-ethylhexylamine hydrochloride is heated at 150-155°C for 3 hours. The mixture is cooled and the product is dissolved in 75 ml of hot water. The solution is treated with activated charcoal. 1,1'-Hexamethylene-bis(5-(ethylhexyl)biguanide) is recrystalluized from methanol-ether, melting point 220.6-223.4°C. References Fr. Patent No. 1,463,818; Apr. 8, 1965; Assigned to Sterling Drug Inc. Residant in USA

ALFACALCIDOL Therapeutic Function: Calcium regulator, Vitamin Chemical Name: 9,10-Secocholesta-5,7,10(19)-triene-1,3-diol Common Name: 1α-Hydroxycholecalciferol; 1α-Hydroxyvitamin D3 Structural Formula:

Alfacalcidol

147

Chemical Abstracts Registry No.: 41294-56-8 Trade Name One-Alpha Eins-Alpha Alfarol One-Alpha Delakmin Etalpha Un-Alfa

Manufacturer Leo Thomae Chugai Teljin Roussel Leo Leo

Country UK W. Germany Japan Japan France Denmark -

Year Introduced 1978 1980 1981 1981 -

Raw Materials Cholesta-1,5,7-trien-3β-ol m-Chloroperbenzoic acid

4-Phenyl-1,2,4-triazoline-3,5-dione Lithium aluminum hydride

Manufacturing Process 1. Preparation of 1,4-cyclized adduct of cholesta-1,5,7-trien-β-ol and 4phenyl-1,2,4-triazoline-3,5-dione: a solution of 400 mg of cholesta-1,5-7trien-3β-ol in 30 ml of tetrahydrofuran is cooled with ice, and 190 mg of 4phenyl-1,2,4-triazoline-3,5-dione is added little by little to the solution under agitation. The mixture is agitated at room temperature for 1 hour and the solvent is distilled under reduced pressure. The residue is purified by chromatography using a column packed with silica gel. Fractions eluted with ether-hexane (7:3 v/v) are collected and recrystallization from ether gives 550 mg of a 1,4-cyclized adduct of cholesta-1,5,7-trien-3β-ol and 4-phenyl1,2,4-triazoline-3,5-dione having a melting point of 178°C to 182°C. 2. Preparation of 1,4-cyclized adduct of cholesta-5,7-dien-3β-ol-1α-epoxide and 4-phenyl-1,2,4-triazoline-3,5-dione: 1.25 g of the 1,4-cyclized adduct of cholesta-1,5,7-trien-3β-ol and 4-phenyl-1,2,4-triazoline-3,5-dione is dissolved in 50 ml of chloroform, and 560 mg of m-chloroperbenzoic acid is added to the solution. The mixture is agitated for 20 hours at room temperature, and 200 mg of m-chloroperbenzoic acid is further added and the mixture is agitated again for 20 hours. The reaction mixture liquid is diluted with chloroform, washed with a 10% aqueous solution of potassium carbonate and dried with magnesium sulfate. Then, the solvent is distilled under reduced pressure. The residue is purified by silica gel chromatography, and first effluent fractions eluted with ether are collected, and recrystallization from methanol gives 680 g of a crystal melting at 172°C to 173°C. The second ether effluent fractions are collected, and recrystallization from methanol gives 400 mg of a 1,4-cyclized adduct of cholesta-5,7-dien-3β-ol-1α,2α-epoxide and 4-phenyl-1,2,4-triazoline-3,5-dione having a melting point of 152°C to 154°C. 3. Preparation of cholesta-5,7-diene-1α,3β-diol: a solution of 500 mg of the 1,4-cyclized adduct of cholesta-5,7-dien-3β-ol-1α,2α-epoxide and 4-phenyl1,2,4-triazoline-3,5-dione in 40 ml of tetrahydrofuran is added dropwise under agitation to a solution of 600 mg of lithium aluminum hydride in 30 ml of THF. Then, the reaction mixture liquid is gently refluxed and boiled for 1 hour and cooled, and a saturated aqueous solution of sodium sulfate is added to the reaction mixture to decompose excessive lithium aluminum hydride. The organic solvent layer is separated and dried, and the solvent is distilled. The

148

Alfadolone

residue is purified by chromatography using a column packed with silica gel. Fractions eluted with ether-hexane (7:3 v/v) are collected, and recrystallization from the methanol gives 400 mg of cholesta-5,7-diene-1α,3βdiol. 4. Preparation of 1α,3β-dihydroxyprovitamin D3: a solution of 25 mg of cholesta-5,7-diene-1α,3β-diol in 650 ml of ether is subjected to radiation of ultraviolet rays for 14 minutes in an argon gas atmosphere by passing it through a Vycor filter using a 200-W high pressure mercury lamp (Model 654A-36 manufactured by Hanobia). The solvent is distilled at room temperature under reduced pressure. This operation is repeated twice, and 50 mg of the so obtained crude product is fractionated by chromatography using a column packed with 20 g of Sephadex LH-20. The first effluent fractions eluted with chloroform-hexane (65:35 v/v) give 13.5 mg of oily 1α,3βdihydroxyprovitamin D3. The composition exhibits a maximum ultraviolet absorption at 260 nm in an ether solution. 5. Preparation of 1α-hydroxycholecalciferol: a solution of 13.5 mg of 1α,3βdihydroxyprovitamin D3 in 200 mi of ether is allowed to stand still in the dark at room temperature in an argon gas atmosphere for 2 weeks. During this period, the position of the maximum ultraviolet absorption is shifted from 260 nm to 264 nm, and the absorption intensity becomes 1.6 times as high as the original intensity. The solvent is distilled at room temperature under reduced pressure, and the residue is purified by chromatography using a column packed with 10 g of Sephadex LH-20. The fractions eluted with chloroformhexane (65:35 v/v) give 6.5 mg of oily 1α-hydroxycholecalciferol. References Merck Index 4730 Kleeman and Engel p. 21 DOT 6 (3) 104 (1970); 14 (10) 441 (1978) I.N. p. 52 Ishikawa, M., Kaneko, C., Suda, T., Yamada, S., Eguchi, Y., Sugimoto, A. and Sasaki, S.; US Patent 3,929,770; December 30, 1975; Assigned to Wisconsin Alumni Research Foundation

ALFADOLONE Therapeutic Function: Anesthetic Chemical Name: 5α-Pregnane-11,20-dione, 3α,21-dihydroxyCommon Name: Alfadolone; Alphadolone Chemical Abstracts Registry No.: 14107-37-0 Trade Name

Manufacturer

Country

Year Introduced

Alphadolone

RiboTargets Ltd.

-

-

Alfadolone

149

Structural Formula:

Raw Materials Acetic acid Potassium hydroxide Potassium acetate Hydrogen Lead tetraacetate

3β-Acetoxy-5α-pregn-16-ene-11,20-dione 4-Toluenesulfonyl chloride Palladium on carbon Boron trifluoride etherate Sodium bicarbonate

Manufacturing Process A solution of 3β-acetoxy-5α-pregn-16-ene-11,20-dione (Chamberlin et al., J.Amer. Chem Soc., 1951, 73, 2396) (25.7 g) in dioxan (Analar, 500 ml) was treated with potassium hydroxide (10 g) and water 250 ml and the mixture allowed to stand at room temperature for 1 h. After a further 1 h at 40°C the mixture was diluted with water and the product filtered off. The crude material was dissolved in chloroform and filtered through a column of grade III neutral alumina (100 g). The material obtained was crystallized from acetonepetroleum to give pure 3β-hydroxy-5α-pregn-16-ene-11,20-dione (17.65 g, 77.5%) as small plates, melting point 217.5°C. A solution of 3β-hydroxy-5α-pregn-16-ene-11,20-dione (39.6 g) in dry pyridine (165 ml) was treated with toluene-p-sulfonyl chloride (43.9 g) to give the toluene sulfonate (56.7 g), melting point 147-151°C. A portion (10.7 g) of this material was crystallized from ethyl acetate-petroleum to give the pure 3β-toluene-p-sulfonyloxy-5α-pregn-16-ene-11,20-dione (9.2 g) as plates, melting point 154°-155°C. 2 Methods of producing of 3α-hydroxy-5α-pregn-16-ene-11,20-dione from 3βtoluene-p-sulfonyloxy-5α-pregn-16-ene-11,20-dione: 1. A solution of 3β-toluene-p-sulfonyloxy-5α-pregn-16-ene-11,20-dione (19.1 g) in N,N-dimethylformamide (160 ml) and water (16.0 ml) was treated with potassium acetate (29.2 g) and the mixture heated at 115°C for 2.5 h. The solvents were removed in vacuo and residue partitioned between chloroform and water. The chloroform extract was washed with water, dried and evaporated. The residue was taken up in methanol (500 ml) and solution flushed with nitrogen. Potassium hydroxide (17 g) in water (70 ml) was added and the solution refluxed for 1 h. Glacial acetic acid was added to bring the pH to about 6 and most of the methanol evaporated in vacuo. Dilution with water gave a gummy precipitate which was extracted into chloroform to give the crude product. This material was extracted with ether and the residue boiled with benzene. The insoluble material was crystallized from chloroformpetroleum to give 3α-hydroxy-5α-pregn-16-ene-11,20-dione (3.28 g) as large

150

Alfadolone

prisms, melting point 243°-244°C. 2. A mixture of the 3β-toluene-p-sulfonyloxy-5α-pregn-16-ene-11,20-dione (60 g; 0.124 mole) in N,N-dimethylformamide (350 ml) and potassium acetate (92 g, 0.94 mole) in water (935 ml) was stirred at 115°C for 4 h. The brown solution was cooled and most of the N,N-dimethylformamide removed by evaporation at 50°C and 4 mm to give a brown solid mass. Another run with to sylate (58 g, 0.12 mole), potassium acetate (90 g, 0.91 mole), N,Ndimethylformamide (350 ml) and water (35 ml) was carried out as described above. The combined aqueous fractions were extracted with chloroform (3 x 100 ml) and dried over magnesium sulfate. The chloroform was removed in vacuo and residual N,N-dimethylformamide was evaporated at 50°C and 4 mm to give the crude 3α-acetate-5α-pregn-16-ene-11,20-dione (92 g) as a brown solid. A solution of 3α-acetate-5α-pregn-16-ene-11,20-dione (92 g) in dioxin (1000 ml) was mixed with a solution of potassium hydroxide (45 g, 0.8 mole) in water (500 ml) to give a two-phase system. A homogeneous solution was obtained by the addition of dioxin (440 ml) and water (625 ml). Nitrogen was bubbled through the solution which was heated at 50°C for 2 h. The port colored solution was treated with glacial acetic acid (40 ml) to bring the pH about 7 and two thirds of the solvent was removed by distillation in vacuo (water pump). Water (3 L) was added to the resultant mixture (which had already begun to crystallize) and the precipitated solid was filtered off, washed with water and dried over phosphorus pentoxide to give the crude 3αhydroxy-5α-pregn-16-ene-11,20-dione (73.9 g). Producing of 3α,21-dihydroxy-5α-pregnane-11,20-dione from 3α-hydroxy-5αpregn-16-ene-11,20-dione: A solution of 3α-hydroxy-5α-pregn-16-ene-11,20-dione (200 mg) in freshly distilled tetrahydrofuran (8 ml) with 5% palladium on carbon (100 mg) was hydrogenated till hydrogen uptake ceased. The mixture was filtered through a pad of kieselguhr and the tetrahydrofuran removed in vacuo to give 3αhydroxy-5α-pregnane-11,20-dione (196 mg), melting point 171°-172°C. Boron trifluoride etherate (37.9 ml) was added to a stirred solution of 3αhydroxy-5α-pregnane-11,20-dione (6.64 g, 20 mmol) and lead tetraacetate (10.1 g, 22 mmol) in dry benzene (280 ml) and methanol (15.1 ml) at room temperature. After 2 h the mixture was poured into water (2 L) and extracted with ether (1 L). The combined ether extracts were washed successively with sodium bicarbonate solution and water, dried over magnesium sulfate, and concentrated in vacuo to give a white crystalline mass. Four recrystallizations from acetone-petroleum (b.p. 40°-60°C) gave 21-acetoxy-3α-hydroxy-5αpregnane-11,20-dione as fine needles (4.22 g, 54%), melting point 172°173°C. The 3α,21-dihydroxy-5α-pregnane-11,20-dione is conveniently prepared by the deacylation of 21-acetoxy-3α-hydroxy-5α-pregnane-11,20-dione under basic conditions, for example, in the presence of potassium or sodium hydrogen carbonate, conveniently in the presence of a solvent e.g. methanol, ethanol or tetrahydrofuran, reesterifying the resultant product.

Alfaxalone

151

References Davis B. et al.; US Patent No. 3,781,435; December 25, 1973

ALFAXALONE Therapeutic Function: Anesthetic component Chemical Name: 3-Hydroxypregnane-11,20-dione Common Name: Alphaxolone Structural Formula:

Chemical Abstracts Registry No.: 23930-19-0 Trade Name

Manufacturer

Country

Year Introduced

Althesin

Glaxo

UK

1972

Alfadion

Nippon Glaxo

Japan

1978

Alfathesin

Glaxo

France

-

Aurantex

Glaxo

W. Germany

-

Raw Materials 3α-Hydroxy-5α-pregn-16-ene-11,20-dione Hydrogen Manufacturing Process A solution of 3α-hydroxy-5α-pregn-16-ene-11,20-dione (200 mg) in freshly distilled tetrahydrofuran (8 ml) with 5% palladium on carbon (100 ml) was hydrogenated until hydrogen uptake ceased. The mixture was filtered through a pad of kieselguhr and the tetrahydrofuran removed in vacuum to give 196 mg, MP 171°C to 172°C. References Merck Index 225 Kleeman and Engel p. 23 DOT 8 (11) 407 (1972)

152

Alfentanil hydrochloride

I.N. p. 53 Davis, B., Pearce, D.R. and Phillips, G.H., British Patent 1,317,184; May 16, 1973; Assigned to Glaxo Laboratories, Ltd. Davis, B. and Phillips, G.H.; US Patent 3,714,352; January 30, 1973; Assigned to Glaxo Laboratories, Ltd.

ALFENTANIL HYDROCHLORIDE Therapeutic Function: Narcotic analgesic Chemical Name: N-[1-[2-(4-Ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)ethyl]4-(methoxy-methyl)-4-piperidinyl]-N-phenylpropaneamide hydrochloride Common Name: Structural Formula:

Chemical Abstracts Registry No.: 69049-06-5 Trade Name

Manufacturer

Country

Year Introduced

Rapifen

Janssen

Belgium

1983

Rapifen

Janssen

Netherlands

1983

Rapifen

Janssen

W. Germany

1983

Rapifen

Janssen

UK

1983

Rapifen

Janssen

Switz.

1983

Raw Materials 1-Ethyl-1,4-dihydro-5H-tetrazol-5-one 1-Bromo-2-chloroethane N-[4-(Methoxymethyl)-4-piperidinyl]-N-phenylpropanamide Manufacturing Process A mixture of 22 parts of 1-ethyl-1,4-dihydro-5H-tetrazol-5-one, 45 parts of 1bromo-2-chloroethane, 26 parts of sodium carbonate, 0.3 part of potassium iodide and 240 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with water-separator. The reaction mixture is cooled, water is added and the layers are separated. The aqueous phase is extracted three times with

Algestone acetophenide

153

dichloromethane. The combined organic phases are dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using trichloromethane as eluent. The pure fractions are collected and the eluent is evaporated, yielding 28.4 parts (80%) of 1-(2-chloroethyl)-4-ethyl1,4-dihydro-5H-tetrazol-5-one as a residue. A mixture of 1.8 parts of 1-(2-chloroethyl)-4-ethyl-1,4-dihydro-5H-tetrazol-5one, 3.45 parts of N-[4-(methoxymethyl)-4-piperidinyl]-Nphenylpropanamide, 5 parts of sodium carbonate, 0.2 part of potassium iodide and 240 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with water-separator. The reaction mixture is poured onto water and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified by column-chromatography over silicagel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is converted into the hydrochloride salt in 2-propanone. The salt is filtered off and crystallized from 2-propanone, yielding 1.5 parts (33.3%) of N-[1-[2-(4-ethyl4,5-dihydro-5-oxo-1H-tetrazol-1-yl]-4-(methoxymethyl)-4-piperidinyl]-Nphenylpropanamide monohydrochloride monohydrate; melting point 140.8°C. References DFU 6 (6)335 (1981) OCDS Vol. 3 p. 118 (1984) DOT 19 (12) 683 (1983) I.N. p. 53 Janssens, F.; US Patent 4,167,574; September 11, 1979; Assigned to Janssen Pharmaceutica NV.

ALGESTONE ACETOPHENIDE Therapeutic Function: Progestin, Contraceptive Chemical Name: 16,17-[(1-Phenylethylidene)bis(oxy)]pregn-4-ene-3,20dione Common Name: 16α,17α-Dihydroxyprogesterone acetophenide; Alphasone acetophenide Structural Formula:

Chemical Abstracts Registry No.: 24356-94-3

154

Alibendol

Trade Name Neolutin Depo Neolutin Depositum Droxone Decadroxone Decadroxate

Manufacturer Medici Orma Squibb Squibb Sauibb

Country Italy Italy US -

Year Introduced 1982 -

Raw Materials 16α,17α-Dihydroxyprogesterone Acetophenone Manufacturing Process To a suspension of 500 mg of 16α,17α-dihydroxyprogesterone in 25 ml of freshly redistilled acetophenone is added 0.125 ml of 72% perchloric acid and the mixture is agitated at room temperature for one hour. The clear solution is washed with dilute sodium bicarbonate to remove excess acid and the acetophenone layer, after addition of chloroform is separated from the aqueous phase. The organic layer is dried over sodium sulfate and after removal of the chloroform and acetophenone in high vacuum the residue is crystallized from 95% alcohol. The pure acetophenone derivative has a melting point of about 142°C to 144°C. References Merck Index 227 Kleeman and Engel p. 24 OCDS Vol. 2 p. 171 (1980) DOT 19 (2) 110 (1983) I.N. p. 54 Fried, J.; US Patent 2,941,997; June 21, 1960; Assigned to Olin Mathieson Chemical Corp. Fried, J. and Diassi, P.A.; US Patent 3,008,958; November 14, 1961; Assigned to Olin Mathieson Chemical Corp.

ALIBENDOL Therapeutic Function: Choleretic, Spasmolytic Chemical Name: 2-Hydroxy-N-(2-hydroxyethyl)-3-methoxy-5-(2-propenyl) benzamide Common Name: Chemical Abstracts Registry No.: 26750-81-2 Trade Name

Manufacturer

Country

Year Introduced

Cebera

Bouchara

France

1981

Alifedrine hydrochloride

155

Structural Formula:

Raw Materials 2-Hydroxy-3-methoxy-5-allylbenzoic acid Ethanol Ethanolamine Manufacturing Process 36 g of ethyl ester of 2-hydroxy-3-methoxy-5-allyl-benzoic acid [obtained by the process described by Pearl, et al., J. Amer. Chem. Soc., Vol. 71, 10671068 (1949)] and 61 g of ethanolamine were admixed and left to stand for 1 hour at ambient temperature after which it was heated for 1 hour at 120°C. The mixture was extracted with chloroform and the organic phases were washed with half diluted hydrochloric acid, then with water, and the chloroform evaporated off. The residue, after recrystallization from benzene, was a 78% yield of 2-hydroxy-3-methoxy-5-allyl-N-(β-hydroxyethyl)benzamide having a melting point of 95°C. The product appeared in the form of colorless crystals which were insoluble in water and soluble in dilute sodium hydroxide. References Merck Index 230 DOT 18 (10) 525 (1982) Clemence, F. and Le Martret, O.; US Patent 3,668,238; June 6, 1972; Assigned to Roussel Uclaf.

ALIFEDRINE HYDROCHLORIDE Therapeutic Function: Sympathomimetic; Cardiotonic Chemical Name: 1-Propanone, 1-cyclohexyl-3-((2-hydroxy-1-methyl-2phenylethyl)amino)-, (R-(R*,S*))-, hydrochloride Common Name: Alifedrine Chemical Abstracts Registry No.: 72913-80-5

156

Alifedrine hydrochloride

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Alifedrine hydrochloride

Chemiewerk Homberg

-

-

Raw Materials 1-Acetyl-1-cyclohexene 1-Norephedrine Palladium on carbon Aluminum chloride

Dimethylamine hydrochloride Cyclohexanecarboxylic acid chloride Cyclohexyl-β-chloroethyl ketone

Manufacturing Process There are some means to produce aliflurane: 1). 2.2 g (0.01 mol) of (2-dimethylaminoethyl)cyclohexylketone hydrochloride (produced by Mannich reaction from 1-acetyl-1-cyclohexene with formaldehyde and dimethylamine hydrochloride and subsequent hydrogenation with Pd/C as catalyst) and 1.5 g (0.01 mol) of 1-norephedrine were dissolved in 20 ml of warm isopropanol. The product crystallizing out in the cooling was filtered off with suction and recrystallized from ethanol. Yield of desired 1-propanone, 1-cyclohexyl-3-((2-hydroxy-1-methyl-2phenylethyl)amino)-, (R-(R*,S*) hydrochloride 24%, M.P: 219-221°C. 2). 13.8 g (0.1 mol) of cyclohexylvinyl ketone (obtainable by the splitting off of HCl during the distillation of cyclohexyl-β-chloroethyl ketone) and 15.1 g (0.1 mol) of 1-norephedrine were dissolved in 50 ml of isopropanol. The desired compound crystallized out as the free base in the standing overnight. The hydrochloride was made with isopropanolic hydrochloric acid. M.P. of the hydrochloride: 219-221°C. 3). The oily cyclohexyl-β-chloroethyl ketone obtained from a solution of 200 g (1.36 mol) of cyclohexanecarboxylic acid chloride in 500 ml of dried 1,2dichloroethane by portion-wise addition of 182 g (1.3 mol) of AlCl3 at -5°C, then leading ethylene through, subsequent hydrolysis with 500 ml of water at room temperature and concentration of the organic phase dried with Na2SO4 in a vacuum (analogous to U.S. Pat. No. 2,792,406) was added to a solution of 164 g (1.09 mol) of 1-norephedrine in 1000 ml of dioxane. The desired product crystallized out overnight, was filtered off with suction and recrystallized from ethanol/water 1:1 (by volume). Yield: 67% (based on the cyclohexane carboxylic acid chloride). M.P. of the hydrochloride: 219-221°C.

Alimadol

157

References Engel J. et al.; US Patent No. 4,542,159; September 17, 1985; Assigned to Degussa Aktiengeselschaft, Frankfurt, Fed. Rep. of Germany

ALIMADOL Therapeutic Function: Analgesic Chemical Name: N-(3-Methoxy-3,3-diphenylpropyl)allylamine Common Name: Alimadol Structural Formula:

Chemical Abstracts Registry No.: 52742-40-2 Trade Name

Manufacturer

Country

Year Introduced

Alimadol

ZYF Pharm Chemical

-

-

Raw Materials Trifluoroacetic anhydride Allyl bromide

3,3-Diphenyl-3-methoxypropylamine Hexamethyl phosphoric acid amide

Manufacturing Process 12 g 3,3-diphenyl-3-methoxypropylamine, 13.5 g trifluoroacetic acid anhydride, 6.0 g pyridine and 100 ml benzene was heated by stirring for 1 hour at 40°C. Then in was cooled to 0°C and poured in water. The organic layer was separated, washed with diluted HCl and water, and evaporated to dryness. The residue N-(3,3-diphenyl-3-methoxypropyl)trifluoroacetamide melted at 108°-110°C. Yield: 98%. 8 g above amide was in 80 ml hexamethyl phosphoric acid amide dissolved mixed with 1.7 g sodium hydride and stirred for 3 hours. Then 5.7 g allyl bromide was added dropwise and the mixture was stirred for 30 minutes. It was diluted with water and extracted with benzene. Benzene layer was separated, evaporated to dryness. The residue was mixed with 100 ml of 75% ethanol and 1 g sodium hydroxide and heated for 1 hour. Ethanol was distilled off and reaction product was extracted with ether. Yield of N-(3-methoxy-3,3diphenylpropyl)allylamin (or 1,1-diphenyl-1-methoxy-3-allylaminopropane) was 6.5 g (97%). MP: 40°-50°C. Hydrochloride melted at 137°-138°C.

158

Alinastine

References Hollinger R. et al.; DE Patent No. 2,339,528; Sept. 11, 1972; Lenia GmdH, Chem. u. pharm. Erzeugnisse-Indusriebedarf, 8000 Munchen

ALINASTINE Therapeutic Function: Antihistaminic, Antiallergic Chemical Name: Benzimidazole, 2-(1-(p-tert-butylphenethyl)-4-piperidyl)-1(2-ethoxyethyl)Common Name: Alinastine Structural Formula:

Chemical Abstracts Registry No.: 154541-72-7 Trade Name Alinastine

Manufacturer Fabrica Espanola de Productos Quimicos y Farmaceuticos

Country -

Year Introduced -

Raw Materials Sodium hydride 2-(2-Ethoxyethyl)tosylate 2-[1-(2-(4-(1,1-Dimethylethyl)phenyl)ethyl)piperidin-4-yl]-1Hbenzimidazole Manufacturing Process 1.5 g of a sodium hydride suspension in oil are added to another suspension of 10.83 g of 2-[1-(2-(4-(1,1-dimethylethyl)phenyl)ethyl)piperidin-4-yl]-1Hbenzimidazole in 150 ml of dimethylformamide and the mixture is stirred for 1 h at room temperature, then a solution of 2-(2-ethoxyethyl)tosylate in dimethylformamide are slowly added. The mixture is heated at 60°C for 16 h, poured onto water and extracted with ether. The extracts are washed with water, dried over anhydrous sodium sulfate and concentrated. The obtained oil is purified by column chromatography yielding 6.0 g of 1-(2-ethoxyethyl)-2[1-(2-(4-(1,1-dimethylethyl)phenyl)ethyl)piperidine-4-yl]-1H-benzimidazole, melting point 138°-140°C.

Alinidine hydrobromide

159

References Orjales-Venero A., Rubio-Royo V.; US Patent No. 5,322,850; June 21, 1994; Assigned: Fabrica Espanola de Productos Quimicos y Farmaceuticos, S.A., Leiva-Lamiaco, Spain

ALINIDINE HYDROBROMIDE Therapeutic Function: Antiarrhythmic, Bradycardic, Analgesic Chemical Name: N-(2,6-Dichlorophenyl)-4,5-dihydro-N-2-propenyl-1Himidazol-2-amine monohydrobromide Common Name: Alinidine hydrobromide Structural Formula:

Chemical Abstracts Registry No.: 71306-36-0 Trade Name

Manufacturer

Country

Year Introduced

Alinidine hydrobromide

Boehringer Ingelheim Laboratories

-

-

Raw Materials 2-(2',6'-Dichlorophenylamino)-2-imidazoline Allyl bromide Manufacturing Process 2-(N-Allyl-N-(2,6-dichlorophenyl)amino)-2-imidazoline: A mixture consisting of 2.0 g of 2-(2',6'-dichlorophenylamino)-2-imidazoline, 3 ml of allyl bromide, 1 ml of pyridine and 10 ml of absolute methanol was heated for about 15 hours at 100°C in a closed tube. Thereafter, the reaction mixture was evaporated to dryness in vacuum, the residue was dissolved in a small amount of dilute hydrochloric acid, the resulting solution was purified by extraction with ether, and the ether extracts were discarded. The acidic aqueous solution was made alkaline with 5 N sodium hydroxide where upon an oily substance separated out which crystallized through upon standing for some time on an ice bath. The crystalline product was collected by vacuum filtration, washed with distilled water and dried. 1.5 gm (83% of theory) of the compound having a melting point of 130-131°C was obtained.

160

Alizapride

References Stahle H. et al.; US Patent No. 3,708,485; January 2, 1973; Assigned to Bohehringer Ingelheim am Rein, Germany

ALIZAPRIDE Therapeutic Function: Neuroleptic, Antiemetic Chemical Name: 6-Methoxy-N-[[1-(2-propenyl)-2-pyrrolidinyl]methyl]-Hbenzotriazole-5-carboxamide Common Name: Structural Formula:

Chemical Abstracts Registry No.: 59338-93-1 Trade Name Plitican Vergentan

Manufacturer Delagrange Delagrange

Country France W. Germany

Year Introduced 1981 1981

Raw Materials 2-Methoxy-4,5-azimidobenzoic acid 1-Allyl-2-aminomethylpyrrolidine Phosphoric anhydride Manufacturing Process 38.6 g (0.2 mol) of 2-methoxy-4,5-azimidobenzoic acid were dissolved in anhydrous toluene and 56 g (0.4 mol) of 1-allyl-2-amino-methylpyrrolidine were added. The mixture was heated to 50°C and then 42 g (0.3 mol) of phosphoric anhydride were added. The mixture was warmed at reflux temperature for 3 hours and then cooled to 80°C. After adding water, the aqueous layer was alkalized. The crystals were filtered, washed with water and then dissolved in 450 ml of acetone. After crystallization, the product was

Alkofanone

161

filtered, washed and dried. 40.4 g (yield 65%) of N-(1'-allyl-2'-pyrrolidylmethyl)-2-methoxy-4,5azimidobenzamide having a melting point of 139°C were obtained. References Merck Index 231 DFU 6 (1) 11 (1981) DOT 18 (4) 162 (1982) I.N. p.55 Bulteau, G., Acher, J., Collignon, C. and Monier, J.C.; US Patent 4,039,672; August 2, 1977; Assigned to Societe D'Etudes Scientifiques et Industrielles de I'lle-de-France

ALKOFANONE Therapeutic Function: Antidiarrheal Chemical Name: 3-[(4-Aminophenyl)sulfonyl]-1,3-diphenyl-1-propanone Common Name: Structural Formula:

Chemical Abstracts Registry No.: 7527-94-8 Trade Name

Manufacturer

Country

Year Introduced

Clafanone

Roche

US

1956

Raw Materials Benzal acetophenone p-Aminobenzene sulfinic acid Manufacturing Process 38 g benzal-acetophenone and 25 g p-aminobenzene-sulfinic acid are refluxed

162

Allantoin

for 5 hours in 700 cc of 85% ethyl alcohol. Fine crystals soon begin to appear and fill the reaction vessel. While still hot, the mixture is suction-filtered. The reaction product is washed first with 750 cc warm absolute alcohol, then with 500 cc water, and finally again with 300 cc alcohol, and then dried in vacuum. Yield 32 g. MP 210-212°C with decomposition. References Merck Index 240 Goldberg, M.W.; US Patent 2,421,836; June 10, 1947; Assigned to HoffmannLa Roche, Inc.

ALLANTOIN Therapeutic Function: Vulnerary, Antiulcer (topical), Antipsoriatic Chemical Name: Urea, (2,5-dioxo-4-imidazolidinyl)Common Name: Allantoin Structural Formula:

Chemical Abstracts Registry No.: 97-59-6 Trade Name

Manufacturer

Country

Year Introduced

Allantoin

Arocor Holdings Inc.

-

-

Allantoin

Hunan Xinyu

-

-

Allantoin

Akema Fine Chemicals

-

-

Allantoin

Allan Chemical Corporation

-

-

Allantoin

Hangzhou Greenda Chemical Co., Ltd.

-

-

Allantoin

Kunshan Hua Xin Daily Chemicals Co., Ltd.

-

-

Allantoin

Omikron

-

-

Allantoin

-

-

Cutemol

Xiamen Linyo Technology Co., Ltd. Summers Laboratories Inc.

-

-

Egopsoryl

Ego Pharmaceuticals

-

-

Egopsoryl

SMP Vet

-

-

Herker

Herker Industries

-

-

Soothex

Jamieson Laboratories Ltd.

-

-

Allobarbital

163

Raw Materials Urea Sulfuric acid Sodium nitrite Ammonium sulfate

Glyoxal Cobalt(II) nitrate hexahydrate Hydrogen chloride

Manufacturing Process To a mixture of 13.14 kg 40% solution of glyoxal in water and a solution of 0.5 L of concentrated HCl in 3 L of water was added 1.8 g Co(NO3)2·6H2O. The mixture was heated at 50-60°C, to the solution was added 20 g of sodium nitrite and then at 40-60°C was added dropwise the mixture of 6 L of concentrated HNO3, 4.2 L of water and 30 g of sodium nitrite. The product obtained was mixed with 2.4 kg ammonium sulfate and filtrated. The filtrate was heated with 14.5 kg urea at 70°C for 10 hours. Allantoin was filtrated and recrystallized from the water; M.P. 233-235°C. References Merck Index, Monograph number: 255, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. DE Patent No. 1,939,924, 18 Feb., 1971 Christmann et al.; US Patent No. 2,802,011; Aug. 6, 1957; Assigned to Carbogen Corporation, New York DE Patent No. 2,714,938; 11.05.1978

ALLOBARBITAL Therapeutic Function: Sedative, Hypnotic Chemical Name: Barbituric acid, 5,5-diallylCommon Name: Diallylbarbituric acid, Allobarbital, Diallymal Structural Formula:

Chemical Abstracts Registry No.: 52-43-7 Trade Name

Manufacturer

Country

Year Introduced

Allobarbital

Fluorochem Ltd.

-

-

Dorm

Funke

-

-

164

Alloclamide hydrochloride

Raw Materials Allyl bromide Barbituric acid Sodium hydroxide Manufacturing Process To a mixture of 43 parts barbituric acid, 200 parts of water and 5 parts of cuprous sulfate in 10 parts of water is added 82 parts of allylbromide. Then at room temperature is added 27 parts of sodium hydroxide (10% aqueous solution). 5,5-Diallylbarbituric acid is isolated by filtration. After recrystallization from water 5,5-diallylbarbituric acid has melting polint 169170°C. References Patent DE 268158; 30.June 1911; Assigned to Geselschaft fur Chemische Industrie in Basel Patent DE 526854; 22. Feb. 1930; Assigned to F.Hoffmann-La Roche and Co. Act.-Ges. in Basel

ALLOCLAMIDE HYDROCHLORIDE Therapeutic Function: Antitussive Chemical Name: Benzamide, 4-chloro-N-(2-(diethylamino)ethyl)-2-(2propenyloxy)-, monohydrochloride Common Name: Alloclamide hydrochloride; Depryn; Pectex Structural Formula:

Chemical Abstracts Registry No.: 5107-01-7; 5486-77-1 (Base) Trade Name

Manufacturer

Country

Year Introduced

Alloclamide hydrochloride

ZYF Pharm Chemical

-

-

Alloclamide hydrochloride

165

Raw Materials 2-Hydroxy-4-chlorobenzoic aci β-Diethylaminoethylamine

Allyl bromide Thionyl chloride

Manufacturing Process (a) 200 g of 2-hydroxy-4-chlorobenzoic acid and 1 liter of methanol are brought to reflux. Dry hydrogen chloride gas is bubbled through the mixture during a time period of 8 hours. The excess of methanol is evaporated, the residue is poured into cold water, neutralized and extracted with ether. After evaporation of the solvent the product is distilled under vacuum. The boiling point of the compound at 15 mm Hg is 127°C, and the yield is 85% of the theoretical. (b) The production of 2-allyloxy-4-chloromethyl benzoate: 4-Chloro-2-hydroxymethyl benzoate 186 g (1 mole), 152 g anhydrous potassium carbonate, 133 g redistilled allyl bromide in 350 ml acetone are heated of refluxing under agitation. At the end of 6 hours the reaction is completed. The reaction mixture is filtered for removal of the mineral salts. The acetone is evaporated. There is thus obtained an oily residue, which rapidly crystallizes. After recrystallization from methanol the obtained product is a white crystal solid, which melts at 56°C. The yield is 84%. (c) The production of 2-allyl-oxy-4-chlorobenzoyl chloride: The 2-allyloxy-4-chloromethyl benzoate obtained under (b) above is saponified under the usual conditions on for obtaining the corresponding acid, and the corresponding acid is obtained in a yield of 91%, the acid melting at 87°C. The chloride of the acid is prepared by treating 1 mol of the acid with 1.5 moles of thionyl chloride (freshly rectified on linseed oil) in the presence of benzene. There is thus obtained a pale yellow viscous liquid, which can be further used without preliminary distillation. (d) Preparation of the amide and of the hydrochloride: 115.5 g (0.5 mol) of the benzoyl chloride produced under (c) above is dissolved in 500 ml of anhydrous chloroform. There is added to this solution drop by drop while agitating and under cooling in an ice bath 116 g of βdiethylaminoethylamine. After the addition is completed the agitation is continued for 1 hour at ambient temperature. The reaction mass is then washed with water, the chloroform is evaporated, the residue is taken up the minimum of absolute alcohol, and there is then added a slight excess of absolute alcohol saturated with hydrogen chloride. The hydrochloride crystallizes by the addition of anhydrous ether. After recrystallization in absolute alcohol plus ether there is obtained white crystals, which are soluble in water and in alcohol. The 2-allyloxy-4-chloro-N-(βdiethylaminoethyl)benzamide hydrochloride melts at 125°-127°C.

166

Allomethadione

References Mauvernay R-Y.; US Patent No. 3,160,557; Dec. 8, 1964; Assigned to Centre European de Recherches Mauvernay, Chateau de Bardon, Riom, Puy-deDome, France

ALLOMETHADIONE Therapeutic Function: Anticonvulsant, Antiepileptic Chemical Name: 2,4-Oxazolidinedione, 5-methyl-3-(2-propenyl)Common Name: Allomethadione, Aloxidone Structural Formula:

Chemical Abstracts Registry No.: 526-35-2 Trade Name

Manufacturer

Country

Year Introduced

Aloxidone

ZYF Pharm Chemical

-

-

Raw Materials Allyl bromide Urea

5-Methyloxazolidine-2,4-dione Ethyl lactate

Manufacturing Process A mixture of 11.4 parts of 5-methyloxazolidine-2,4-dione and 15 parts anhydrous potassium carbonate in 150 parts of dry acetone is stirred for 0.5 hour. 15 parts of allyl bromide are then added and the mixture boiled under reflux with stirring for 4 hours. After cooling and filtering, the solvent and any unchanged allyl bromide are removed by distillation. The residue is extracted with ether end the extract washed with saturated aqueous sodium bicarbonate until the subsequent water-washings are either neutral or just alkaline to litmus paper. The solvent is then distilled and the residue fractionated when 3allyl-5-methyloxazolidine-2,4-dione is obtained in 65% yield as a colorless oil, BP: 88°-90°C/1.8 mm, nd20 = 1.4710. The dry sodium salt of 5-methyloxazolidine-2,4-dione, obtained from 4.6 parts of sodium, 100 parts of ethanol, 12 parts of urea and 23.6 parts of ethyl lactate, is suspended in 100 parts of dry benzene and 30.25 parts of allyl bromide are added. The mixture is boiled under reflux for 20 hours and the benzene decanted or filtered from any solid. The solution is washed with

Allopurinol

167

saturated aqueous sodium bicarbonate until the subsequent water-washings are neutral or just alkaline to litmus paper. The dried benzene solution is then distilled to remove solvent and the residue fractionated, when 3-allyl-5methylosazolidine-2,4-dione is obtained in 27% yield as a colorless oil, BP: 89°-90°C/1 mm, nd20 = 1.4712. The dry sodium salt of 5-methyloxazolidine-2,4-dione obtained as above is mixed with 100 parts of dry dioxane and 31.25 parts of allyl bromide are added. After boiling under reflex for 24 hours, decanting the solution and distilling off the dioxane under reduced pressure, the residue is dissolved in ether and the ethereal extract mashed with aqueous sodium bicarbonate as above. Fractionation of the residue after removing the olvent furnishes 3-allyl5-methyloxazolidine-2,4-dione in 48.5% yield as a colorless oil; BP: 94°95°C/11.75 mm; nd20 = 1.4710. References Davis J.S.H. and Hook W.H.; GB Patent No. 632,423; June 28, 1948; British Schering Research Laboratories, Great Britain

ALLOPURINOL Therapeutic Function: Xanthine oxidase inhibitor, Gout therapy Chemical Name: 1H-Pyrazolo[3,4-d]pyrimidin-4-ol Common Name: Structural Formula:

Chemical Abstracts Registry No.: 315-30-0 Trade Name

Manufacturer

Country

Year Introduced

Zyloprim

Burroughs-Wellcome

US

1966

Zyloric

Wellcome

Switz.

-

Zyloric

Burroughs-Wellcome

UK

1966

Zyloric

Wellcome

W. Germany

1967

Zyloric

Wellcome

Italy

1968

Zyloric

Wellcome

Japan

1969

Zyloric

Wellcome

France

1969

Lopurin

Boots

UK

1980

Adenock

Tanabe

Japan

-

Adenock

Shiraimatsu

Japan

-

Allopin

Yeni

Turkey

-

168

Allopurinol

Trade Name Allomaron Alloprim Alloprin Allopur Allopur Allopurinol Allopurinol Allopurinol Allopurinol Allopurinol Allopurinol Allorin Allozym Allural Allural Allurit Aloc Alositol Anoprocin Antigot Anzief Aprinol Apurin Apurin Apurol Bleminol Caplenal Capurate Cellidrin Cosuric Dabroson Embarin Epidropal Flogorex Foligan Geapur Gichtex Ketawrift Ketobun A Lopurin Lysuron Masaton Melianin Mephanol Milurit

Manufacturer Nattermann Iltas ZCN Gea Nyegaard Sigfried Efeka Woelm Pharma Lederle Kowa Showa Towa Sawai Nativelle Pan Quimica Schoum Toho Iyaku Tanabe Nippon Shoji Yurtoglu Nippon Chemiphar Daisan Gea Madica Siegfried Desitin Berk Fawns and McAllan Henning DDSA Hoyer Diabetylin Fresenius Lancet Henning Gea Gerot Ohta Isei Generics Corp. Boehringer Mannheim Zensei Kohjin Mepha EGYT

Country W. Germany Turkey Canada Denmark Norway W. Germany W. Germany W. Germany Japan Japan Japan Japan Japan Italy Spain Italy Japan Japan Japan Turkey Japan Japan Denmark Finland Switz. W. Germany UK Australia W. Germany UK W. Germany W. Germany W. Germany Italy W. Germany Denmark Austria Japan Japan US W. Germany Japan Japan Switz. Hungary

Year Introduced -

Allopurinol

169

Trade Name

Manufacturer

Country

Year Introduced

Monarch

SS Pharmaceutical

Japan

-

Nektronan

W. Germany

-

Neufan

ICN Pharmaceuticals Inc. Teikoku

Japan

-

Neufan

Teisan

Japan

-

Novopurol

Novopharm

Canada

-

Progout

Protea

Australia

-

Puricos

Lennon

S. Africa

-

Purinol

Horner

Canada

-

Riball

Mitsui

Japan

-

Roucol

Rougier

Canada

-

Serviprinol

Servipharm

Switz.

-

Suspendol

Merckle

W. Germany

-

Takanarumin

Takata

Japan

-

Urbol

Heilit

W. Germany

-

Urbol

Gea

Denmark

-

Uredimin

Chassot

Switz.

-

Uricemil

Farnex

Italy

-

Uricemil

Fardeco

Italy

-

Uriconorm

Streuli

Switz.

-

Uridocid

Reig Jofre

Spain

-

Uriscel

Armour Med.

Italy

-

Urobenyl

Endopharm

W. Germany

-

Urolit

Magis

Italy

-

Urosin

Boehringer Mannheim

W. Germany

-

Urozyl-SR

Restan

S. Africa

-

Urtias

Sabona

W. Germany

-

Vedatan

Corvi

Italy

-

Xanturat

Gruenenthal

W. Germany

-

Zylol

Teva

Israel

-

Raw Materials Cyanoacetamide Morpholine

Triethylorthoformate Hydrazine hydrate

Manufacturing Process 3-Morpholino-2-cyanoacrylamide: A stirred mixture of cyanoacetamide (63 g), triethylorthoformate (134 g), morpholine (82.5 g) and acetonitrile (37.5 ml) was heated under reflux for 4 hours. The initial reflux temperature was 117°C and the final reflux temperature was 82°C. At the end of the reflux period the mixture was cooled to 30°C and the heavy

170

Allylestrenol

crystalline precipitate was collected and washed with 2 x 75 ml of ethanol. The product was dried in vacuum at 30°C. Wt = 111 g. Yield = 82%, MP 173175°C. 3-Aminopyrazole-4-carbxamide hemisulfate: To water (253 ml) at 60°C was added 3-morpholino-2-cyanoacrylamide (63.4 g) and 85% technical hydrazine hydrate (22.7 g). The mixture was rapidly heated to 95°C and the temperature was maintained at >90°C for 20 minutes. The mixture was then cooled to 60°C and the pH carefully adjusted to 1.5 by the addition of a mixture of sulfuric acid (45.7 g) and ice. The acidified reaction was cooled to 5°C and the crystalline product collected and washed with cold water (2 x 100 ml) and acetone (2 x 50 ml). The product was dried in vacuum at 80°C. Wt =5.8 g. Yield =95%, MP 237-239°C. 4-Hydroxypyrazolo[3,4-d]pyrimidine: A suspension of 3-aminopyrazole-4carboxamide hemisulfate (113 g) in formamide (325 g) was stirred and heated to 145°C. The reaction was held at 145°C for 5 hours. The reaction was then cooled to 30°C and the product collected and washed with formamide (2 x 50 ml), water (2 x 150 ml) and acetone (2 x 100 ml). Wt of crude product = 79 g. The crude product was recrystallized by dissolution in a solution made from sodium hydroxide (25 g) in water (1,200 ml) with treatment at 25°C with charcoal (8 g), followed by reprecipitation by the addition of concentrated hydrochloric acid to pH 5. The product was collected and washed with cold water (2 x 300 ml), acetone (2 x 200 ml) and dried in vacuum at 60°C. Wt = 70 g. Yield = 80%. References Merck Index 273 Kleeman and Engel p. 27 PDR pp. 685,774,830,993,1606 OCDS Vol. 1 pp. 152, 269 (1977) I.N. p. 57 REM p. 1111 Druey, J. and Schmidt, P.; US Patent 2,868,803; January 13, 1959; Assigned to Ciba Pharmaceutical Products Inc. Hitchings, G.H. and Falco, E.A.; US Patent 3,474,098; October 21, 1969; Assigned to Burroughs Wellcome and Co. Cresswell, R.M. and Mentha, J.W.; US Patent 4,146,713; March 27, 1979; Assigned to Burroughs Wellcome and Co.

ALLYLESTRENOL Therapeutic Function: Progestin; Antiandrogen Chemical Name: 17α-Allylestr-4-en-17β-ol Common Name: Alilestrenol; Allylestrenol; Allyloestrenol Chemical Abstracts Registry No.: 432-60-0

Allylestrenol

171

Structural Formula:

Trade Name Alilestrenol Alilestrenol PA Allyloestrenol Allyloestrenol Anin Astanol Gestanin Gestanin Gestanon Tab. Gestin Gestormone Gravidin Gynonys Fetugard Fulterm Maintane Tab. Nidagest Orageston Pregular Profar Premaston Profar Turinal Turinal Turinal Turinal Turinal Tab.

Manufacturer Terapia AAA Principio Activo Belco Pharma Huei-Ho Industries Ind-Swift Ltd. Rekvina Pharma Organon Donmed Organon Walter Bushnell Zorka Alidac Sankyo Biddle Sawyer Micro Nova Jagsonpal Systopic Akzo Helios Infar Kalbe Infar Richter Co. Gedeon Richter Medimpex Mekim October Pharma Co.

Country -

Year Introduced -

Raw Materials Methylamine Chromium trioxide Acetic acid Allyl bromide

Lithium Oestradiol-3-methylether Magnesium

Manufacturing Process To 145 ml of dry methylamine which is cooled to -20°C 1.5 g of lithium cut to

172

Almagate

small pieces are added. To the solution which is blue in color after 10-20 min, a solution of 3.0 g of oestradiol-3-methylether in 145 ml of absolute ether is added drop wise. Subsequently the reaction mixture is stirred at -10°C for 40 h, after which 50 ml of absolute ethanol are added. Then the methylamine is distilled off at law pressure. To the remaining solution 50 ml of ether and 50 ml of water are added. The water layer is separated and extracted with ether. The ethereal layer is washed with a 2 N hydrochloric acid solution, subsequently with a saturated sodium bicarbonate solution, and then with water. The ethereal solution is dried and evaporated to dryness. The resulting crude reaction product is dissolved in a mixture of benzene and petroleum ether (1:3) and chromatographed over aluminium oxide. The δ4-17β-hydroxy-oestrene obtained after chromatographic purification has a melting point of 80°-90°C and 95°-100°C after repeated crystallization from petroleum ether. A solution of 13.2 g of chromium trioxide in a mixture of 120 ml of water and 20 ml of acetic acid is added, with stirring, to a solution of 20 g of δ4-17βhydroxy-oestrene in 400 ml of benzene. Subsequently the reaction mixture is vigorously stirred at room temperature for 16 h, after which the benzene layer is separated. The remaining aqueous layer is extracted a few times with benzene and the benzene extracts collected are then added to the separated benzene layer. The benzene extracts are successively washed with dilute sulfuric acid and water and then evaporated to dryness. The residue is crystallized from acetone, and the δ4-17β-oxo-oestrene, melting point 114°-116°C is obtained. To a mixture of 22.4 ml of absolute ether and 1.84 g of magnesium, a mixture of 2.72 ml of allyl bromide and 2.72 ml of absolute ether is added in nitrogen atmosphere. Subsequently a solution of 2 g of δ4-17β-oxo-oestrene in 30 ml of absolute ether is added to this reaction mixture, after which the whole is stirred for 4 h. Then the reaction mixture is poured into acidified ice water. The aqueous mixture is extracted with ether; the ether layer is separated, washed with water, dried over sodium sulfate and evaporated to dryness. The residue is recrystallized from a mixture of ether and petroleum ether, giving δ4-17β-hydroxy-17α-allyl-oestrene, melting point 79.5°-80°C. References GB Patent No. 841,411; April 2, 1958; Assigned: Organon Laboratories Limited, a British Company of Brettenham House, Lancaster Place, London

ALMAGATE Therapeutic Function: Antacid Chemical Name: Magnesium, (carbonato(2-))heptahydroxy(aluminum)tri-, dihydrate

Almasilate

173

Common Name: Almagate Structural Formula: AlMg3(CO3)(OH)7 Trade Name Almagate

Manufacturer AGARWAL PHARCHEM (I) PVT. LTD.

Country -

Year Introduced -

Chemical Abstracts Registry No.: 66827-12-1 Raw Materials Aluminum hydroxide Triethylamine Water

Magnesium hydroxide Ammonium hydroxide

Manufacturing Process 2 Methods of producing of basic aluminium magnesium carbonate: 1. A suspension of aluminum hydroxide (9.57 g, corresponding to 5.09 g of Al2O3 0.05 mol), magnesium hydroxide of 92.09% purity (18.87 g; 0.3 mol), concentrated ammonium hydroxide (4.89 ml; 0.33 mol) and water (500 ml) was boiled under reflux for 6 h while a stream of carbon dioxide was passed through the mixture. Then the reaction mixture was cooled, and the insoluble compound was filtered off, washed several times with water and dried in vacuum at a temperature of 60°C. Basic aluminum magnesium carbonate (31.1 g) was obtained. 2. A suspension of aluminium hydroxide (9.57 g, corresponding to 5.09 g of Al2O3 0.05 mol) magnesium hydroxide of 92.09% purity (18.87 g; 0.3 mol), triethylamine (33.4 g; 0.33 mol) and water (500 ml) was boiled under reflux for 8 h while a stream of carbon dioxide was passed through the mixture. After cooling, the insoluble compound was filtered off, washed several times with water and dried at 60°C under reduced pressure. Basic aluminum magnesium carbonate (30.8 g) was obtained. References Spickett R.G.W. et al.; US Patent No. 4,447,417; May 8, 1984; Assigned: Anphar S.A., Madrid, Spain

ALMASILATE Therapeutic Function: Antacid Chemical Name: Magnesium aluminosilicate (MgAl2Si2O8) hydrate Common Name: Simagel; Almasilate

174

Almasilate

Structural Formula: MgAl2Si2O8·H2O Trade Name

Manufacturer

Megalac Almasilat

Krewel Meuselbach -

Country

-

Simagel

Philopharm

-

-

Year Introduced

Chemical Abstracts Registry No.: 71205-22-6 Raw Materials Magnesium chloride Caustic soda Aluminum sulfate Sodium silicate (Na2O, 9%, SiO2, 29%) Manufacturing Process 203 g of crystalline magnesium chloride such as is used as a food additive, containing 46% MgCl2, is dissolved in 600 ml of water, to which 96 g of caustic soda dissolved in 250 ml of water is added with stirring and a solution comprising 50 ml of water with 207 g of sodium silicate (Na2O, 9%, SiO2, 29%) is further added and is then vigorously stirred to produce basic sodium magnesium silicate (which is designated as Slurry A). Secondly 593 g of aluminum sulfate containing 17.2% Al2O3, dissolved in 1,700 ml of water is gently added with stirring to 216 g of caustic soda dissolved in 600 ml of water, to which 50 ml of water added to 207 g of sodium silicate (Na2O 9%, SiO2, 29%) is slowly added and is then vigorously stirred to produce tetrabasic dialuminum silicate (which is designated as Slurry B). Slurry A and Slurry B are mixed up vigorously with stirring for 3 hours at room temperature. The thus obtained white gel-like precipitate is washed by decantation to remove free alkali, sodium sulfate, sodium chloride, etc. produced as reaction by-products. The residue is filtered and dried at 105°-110°C and 340 g of white powder of fine particle size is obtained as the final product. The molar ratio of MgO to Al2O3, to SiO2, in this product is approximately 1: 1: 2. 203 g of crystalline magnesium chloride such as is used as a food additive, containing 46% MgCl2, and 593 g of aluminum sulfate containing 17.2% Al2O3, are dissolved in 2,300 ml of water, to which a solution comprising 272 g of caustic soda with 800 ml of water, is slowly added with stirring. Thereafter, a solution comprising 414 g of sodium silicate (Na2O, 9%, SiO2, 29%) with 100 ml of water is added, the mixture is heated and is stirred for five hours, while keeping the temperature at 60°C. When the reaction mixture becomes neutral it is allowed to cool and to stand, the supernatant fluid is withdrawn and the white gel-like precipitate is washed by decantation to remove the impurities and dried at 105°-110°C and 350 g of white powder of fine particle size is obtained as the final product (almasilate). References Hidetaka Uoda et al.; GB Patent No. 1,153,513; Feb. 17, 1967; Fuji Kagaku Kogyo Kaushiki Kaisha, a Japanese Company, of 55 Yokohooji, Kamiichimachi, Naka-Niikawa-gun, Toyama-ken, Japan

Alminoprofen

175

ALMINOPROFEN Therapeutic Function: Analgesic, Antiinflammatory Chemical Name: Benzeneacetic acid, α-methyl-4-((2-methyl-2-propenyl) amino)Common Name: Alminoprofen; Minalfene Structural Formula:

Chemical Abstracts Registry No.: 39718-89-3 Trade Name Alminoprofen

Manufacturer ZYF Pharm Chemical

Country -

Year Introduced -

Minalfene

Bouchara-Recordati

-

-

Raw Materials Methyl 2-(p-nitrophenyl)acrylate Methallyl chloride

Palladium on charcoal Pyridine

Manufacturing Process Methyl 2-(p-aminophenyl)propionate: Methyl 2-(p-nitrophenyl)acrylate (52 g) is hydrogenated in ethanol (500 ml) in the presence of 5% palladium-over-charcoal, while maintaining the temperature at +5°C. The theoretical amount of hydrogen is taken up within one hour. After separation of the catalyst and concentration to dryness, the resulting material gives methyl 2-(p-aminophenyl)proprionate which crystallizes: MP: = 40°-43°C. Methyl 2-(p-methallylaminophenyl)propionate hydrochloride: A mixture of methyl 2-(p-aminophenyl)propionate (44.75 g), methallyl chloride (34 g) and pyridine (30 ml) in isopropanol (400 ml) is boiled during 30 hours. The solvent is removed in vacuo and the residue is taken up into water and ether. After separation, the organic phase is washed repeatedly with water, after which it is dried and concentrated in vacuo. The resulting oil is fractionally distilled in vacuo (0.1 mm Hg; 5 g of oil essentially consisting of methyl 2-(p-aminophenyl)propionate are collected at 115°-120°C; 30 g of oil consisting of a mixture of mono- (80%) and disubstituted (20%) amines is collected at 128°-130°C. This oil is used to prepare the hydrochloride, which is recrystallized from ethyl acetate, to give white crystals (22.7 g) melting at

176

Almitrine

115°C. Saponification in the cold methanolic hydroxide gives the desired 2-(4(methallylamino)phenyl)propionic acid (alminoprofen). MP: 120°C. References Bouchara E.; US Patent No. 3,957,850; May 18, 1976

ALMITRINE Therapeutic Function: Respiratory stimulant Chemical Name: 1,3,5-Triazine-2,4-diamine, 6-(4-(bis(4-fluorophenyl) methyl)-1-piperazinyl)-N,N'-di-2-propenylCommon Name: Almitrine Structural Formula:

Chemical Abstracts Registry No.: 27469-53-0 Trade Name Armanor Duxaril Duxil Vectarion

Manufacturer Les Laboratoires Servier Les Laboratoires Servier Servier-Egypt Co. Les Laboratoires Servier

Country -

Year Introduced -

Raw Materials 4,6-Bis(allylamino)-2-chloro-s-triazine 1-p,p'-Difluorobenzhydryl piperazine dihydrochloride Sodium hydroxide Manufacturing Process A solution of 4,6-bis(allylamino)-2-chloro-s-triazine, melting point 204°C

Almotriptan malate

177

(Kofler) and dihydrochloride of 1-p,p'-difluorobenzhydryl piperazine, melting point 178°-180°C (capillary) in anhydrous dimethylformamide are heated under reflux. On completion of this operation the solvent is removed under vacuum and the residue taken up in a mixture of chloroform and of water (1:1). The organic phase is separated, and repeatedly extracted with aqueous N-methanesulphonic acid and the aqueous acidic layers separated. The aforementioned acidic solutions are then combined and rendered alkaline (pH 10) with dilute aqueous sodium hydroxide, the base extracted with ether, the extract dried over anhydrous potassium carbonate, and filtered. The etheral filtrate, upon evaporation yields the 2,4-bis(allylamino)-6-(4-(bis(pfluorophenyl)methyl)-1-piperazinyl)-s-triazine, melting point 175°-180°C. References Regnier G. et al.; US Patent No. 3,647,794; March 7, 1972; Assignee: Societe en nom collectiff "Science Union et Cie", Societe Francaise de Recherche Medicale

ALMOTRIPTAN MALATE Therapeutic Function: Migraine therapy Chemical Name: Pyrrolidine, 1-[[[3-[2-(dimethylamino)ethyl]-1H-indol-5yl]methyl]sulfonyl]-, hydroxybutanedioate salt (1:1) Common Name: Almotriptan malate Structural Formula:

Chemical Abstracts Registry No.: 181183-52-8; 154323-57-6 (Base) Trade Name Almogran Axert Axert Axert

Manufacturer Lundbeck Aetna Inc. Jannsen-Ortho Pharmacia Corporation

Country -

Year Introduced -

Raw Materials 1-[[2-Carboxy-3-(2-dimethylaminoethyl)-5-indolyl]methanesulphonyl]pyrrolidine Quinoline Copper oxide

178

Alniditan dihydrochloride

Manufacturing Process To a solution of previously dried 1-[[2-carboxy-3-(2-dimethylaminoethyl)-5indolyl]methanesulphonyl]-pyrrolidine (1.6 g; 0.0442 moles) in anhydrous quinoline (75 ml) and under atmosphere of nitrogen, cuprous oxide (160 mg; 0.0011 moles) was added. The reaction mixture was heated to 190°C for 15 minutes, stirred to room temperature, poured into a mixture of 1 N hydrochloric acid (150 ml) and ethyl acetate (50 ml), shaken and decanted. The aqueous solution was washed several times with ethyl acetate, then solid sodium bicarbonate was added until pH = 7.8, and washed with n-hexane to eliminate the quinoline. The aqueous solution was made alkaline with solid potassium carbonate and extracted with ethyl acetate. The organic solution was dried (Na2SO4), the solvent removed under reduced pressure when a dark oil was obtained (1.3 g; yield 92%). This product was purified by column chromatography with silica gel and methylene chloride:ethanol:ammonium hydroxide (60:8:1) as eluent and a white foam (0.8 g) of 1-[[3-(2dimethylaminoethyl)-5-indolyl]methanesulphonyl]-pyrrolidine was obtained. To a solution of the above product (0.8 g) in acetone (30 ml), a few drops of hydrogen chloride saturated dioxan solution, were added. The precipitated solid was collected by filtration, washed with acetone and dried to give 1-[(3(2-(dimethylamino)ethyl)-5-indolyl)methanesulphonyl]-pyrrolidine hydrochloride (0.75 g). Melting point 218°-220°C. In practice it is usually used as malate salt. References F. Former et al.; WO 94/02460; 28.07.92 D. Lednicer; The organic chemistry of drug synthesis; p. 124, 1999; Wiley and Sons

ALNIDITAN DIHYDROCHLORIDE Therapeutic Function: Migraine therapy Chemical Name: 1,3-Propanediamine, N-((3,4-dihydro-2H-1-benzopyran-2yl)methyl)-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-, dihydrochloride, (2R)Common Name: Alniditan dihydrochloride; Pasmigren Structural Formula:

Chemical Abstracts Registry No.: 155428-00-5; 152317-89-0 (Base)

Alniditan dihydrochloride Trade Name Pasmigren

Manufacturer Janssen-Cilag

Country -

179

Year Introduced -

Raw Materials Methylbenzene 2-Chloropyrimidine Thionyl chloride Thiophene Hydrogen Potassium acetate Sodium hydroxide Nickel Raney

3,4-Dihydro-2H-1-benzopyran-2carboxylic acid, (+)2,2'-Oxybispropane Acetamide, N,N-dimethylPalladium on charcoal Benzenemethanamine 2-Propenenitrile Sodium carbonate

Manufacturing Process To a stirred and heated +80°C mixture of 3,4-dihydro-2H-1-benzopyran-2carboxylic acid and methylbenzene were added dropwise thionyl chloride during a period of 85 min. Upon complete addition, stirring was continued for 2 h at 80°C. After cooling to room temperature, the reaction mixture was evaporated. The residue was taken up in methylbenzene and the solvent was evaporated again, yielding (R)-3,4-dihydro-2H-1-benzopyran-2-carbonyl chloride. A mixture of (R)-3,4-dihydro-2H-1-benzopyran-2-carbonyl chloride in N,Ndimethylacetamide and 2,2'-oxybispropane was hydrogenated in the presence of palladium-on-charcoal catalyst (10%) and a solution of thiophene in methanol (4%). After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was added to a mixture of benzenemethanamine, potassium acetate and methanol. This mixture was hydrogenated again in the presence of palladium-on-charcoal catalyst (10%) and a solution of thiophene in methanol (4%). After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was poured into water and the whole was basified with NaOH (50%). The product was extracted with dichloromethane and the extract was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2/CH3OH 95:5). The eluent of the desired fraction was evaporated and the residue was converted into the hydrochloride salt in 2-propanone by adding 2-propanol saturated with HCl. The salt was filtered off and dried, yielding (R)-3,4-dihydro-N-(phenylmethyl)-2H-1benzopyran-2-methanamine. A mixture of 28.0 g of (R)-3,4-dihydro-N-(phenylmethyl)-2H-1-benzopyran-2methanamine and 300 ml of methanol was hydrogenated in the presence of 2.0 g of palladium-on-charcoal catalyst (10%). After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 18.2 g (100%) of (-)-(R)-3,4-dihydro-2H-1-benzopyran2-methanamine as crude residue. A mixture of 18.0 g of (-)-(R)-3,4-dihydro-2H-1-benzopyran-2-methanamine, 60.0 g of 2-propenenitrile and 400 ml of ethanol was stirred for 4 h at reflux temperature. The reaction mixture was evaporated and the residue was dried, yielding 20.0 g (84%) of (-)-(R)-3-[[(3,4-dihydro-2H-1-benzopyran-2yl)methyl]amino]propanenitrile.

180

Alonacic

A mixture of 20.0 g (-)-(R)-3-[[(3,4-dihydro-2H-1-benzopyran-2yl)methyl]amino]propanenitrile and 300 ml of methanol was hydrogenated in the presence of 5.0 g of Raney Nickel. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 21.0 g (100%) of (-)-(R)-N-[(3,4-dihydro-2H-1benzopyran-2-yl)methyl]-1,3-propanediamine as crude residue. A mixture of (-)-(R)-N-[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]-1,3propanediamine, 2-chloropyrimidine, sodium carbonate and ethanol was stirred for 4 h at reflux temperature. The reaction mixture was evaporated. The residue was purified by column chromatography (silica gel; CHCl3/CH3OH 90:10). The eluent of the desired fraction was evaporated and the residue was converted into the hydrochloride salt in 2-propanol. The salt was filtered off and dried in vacuum, yielding (-)-(R)-N-[(3,4-dihydro-2H-1-benzopyran-2yl)methyl]-N'-(2-pyrimidinyl)-1,3-propanediamine dihydrochloride hemihydrate. A mixture of 3.6 g of (-)-(R)-N-[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]N'-(2-pyrimidinyl)-1,3-propanediamine dihydrochloride hemihydrate in 150 ml of methanol and 20 ml of 2-propanol saturated with HCl was hydrogenated in the presence of 1.5 g of palladium-on-charcoal catalyst (2%). After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The product was crystallized from acetonitrile, filtered off and dried, yielding 2.7 g (74.0%) of (-)-(R)-N-[(3,4-dihydro-2H-1benzopyran-2-yl)methyl]-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3propanediamine dihydrochloride hemihydrate; melting point 200.2°C. The base (-)-(R)-N-[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]-N'-(1,4,5,6tetrahydro-2-pyrimidinyl)-1,3-propanediamine may be obtained by treatment of (-)-(R)-N-[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]-N'-(1,4,5,6tetrahydro-2-pyrimidinyl)-1,3-propanediamine dihydrochloride hemihydrate with NaOH. References Van Lommen G.R.E. et al.; US Patent No. 5,541,180; July 30, 1996; Assigned: Janssen Pharmaceutica N.V., Beerse, Belgium

ALONACIC Therapeutic Function: Mucolytic Chemical Name: N-(((2RS,4R)-2-Methyl-4-thiazolidinyl)carbonyl)-β-alanine, methyl ester Common Name: Alonacic Chemical Abstracts Registry No.: 105292-70-4

Alonacic

181

Structural Formula:

Trade Name Alonacic

Manufacturer Onbio Inc.

Country -

Year Introduced -

Raw Materials β-Alanine methyl ester hydrochloride N-Methylmorpholine Dicyclohexylcarbodiimide N-Hydroxybenzotriazole N-t-Butoxycarbonyl-2-methylthiazolidine-4-carboxylic acid Manufacturing Process Preparation of (2-methylthiazolidin-4-carbonyl)-β-alanine methyl ester: To a solution of β-alanine methyl ester hydrochloride (5.08 g, 36.4 mmol) in dimethylformamide (35 ml) kept under stirring at -5°C, N-methylmorpholine (4.01 ml, 36.4 mmol) and then a solution of N-t-butoxycarbonyl-2methylthiazolidine-4-carboxylic acid (9 g, 36.4 mmol) in dimethylformamide (15 ml) were added. To the resulting solution kept under stirring at -5°C, dicyclohexylcarbodiimide (9 g, 43.68 mmol) and N-hydroxybenzotriazole (5.89 g, 43.68 mmol) were added. After 24 hours under stirring at +4°C, the precipitate (dicyclohexylurea) was filtered and the filtrate was evaporated to dryness. An oil was obtained which was dissolved in ethyl acetate and the solution was washed with an aqueous solution of citric acid at 10%, with an aqueous sodium bicarbonate solution at 10% and with water. The organic solution, dried on sodium sulphate was evaporated to dryness under vacuum at 40°C. (N-t-Butoxycarbonyl-2-methylthiazolidine-4-carbonyl)-β-alanine methyl ester (10.7 g) was thus obtained as oil. The obtained product (7.9 g) was treated at room temperature under nitrogen, with ethyl acetate (90 ml) containing 13% (w/v) of hydrogen chloride. After 1 hour the solution was evaporated to dryness under vacuum at 35°C. The residue, after crystallization from isopropyl alcohol diethyl ether, afforded (2-methylthiazolidine-4-carbonyl)-β-alanine methyl ester hydrochloride (5.4 g). [α]D20=-85° (c=1, CH3OH); MP:=124°-125°C. The base form may be prepared by adding of equivalent of any basic product (NaHCO3, Et3N and so on). References Pilotto A. et al.; US Patent No. 4,761,399; Aug. 2, 1988; Assigned to Zambon S.P.A., Vicenza, Italy

182

Alonimid

ALONIMID Therapeutic Function: Sedative, Hypnotic Chemical Name: Spiro[naphthalene-1(4H),3'-piperidine]-2',4,6'-trione, 2,3dihydroCommon Name: Alonimid Structural Formula:

Chemical Abstracts Registry No.: 2897-83-8 Trade Name Alonimide Alomid

Manufacturer ZYF Pharm Chemical Merrel

Country -

Year Introduced -

-

-

Raw Materials Phenylacetonitrile Ethyl acrylate Polyphosphoric acid Manufacturing Process To a stirred mixture of 58.6 g (0.5 M) of phenyl-acetonitrile and 150 g (1.5 M) of ethyl acrylate was carefully added sodium methoxide in small increments (about 0.1 g). The exothermic reaction was controlled by ice bath cooling to keep the reaction mixture at 50°C. When further additions of sodium methoxide were no longer exothermic, the reaction mixture was stirred for one half hour more and the excess ethyl acrylate removed under reduced pressure on a steam bath. The resulting oil was added to 1.500 g of polyphosphoric acid and stirred on a steam bath for three hours. After cooling to about 50°C, 0.5 liter of chloroform was added followed by additions of crushed ice until the aqueous phase was free flowing. The chloroform layer was separated and combined with three 150 ml chloroform extracts of the aqueous layer. The organic phase was then dried over anhydrous magnesium sulfate, filtered and concentrated to a semi-solid residue. Recrystallization from acetone gave 2,3-dihydrospiro[naphthalene-1(4H),3'piperidine]-2',4,6'-trione, melting point 197°-199°C.

Alosetron hydrochloride

183

References Carr et al.; US Patent No. 3,647,797; March, 7, 1972; Assigned to Richardson-Merrell Inc., New York, N.Y.

ALOSETRON HYDROCHLORIDE Therapeutic Function: Antidiarrheal Chemical Name: 1H-Pyrido[4,3-b]indol-1-one, 2,3,4,5-tetrahydro-5-methyl2-[(5-methyl-1H-imidazol-4-yl)methyl]-, monohydrochloride Common Name: Alosetron hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 122852-69-1; 122852-42-0 (Base) Trade Name Alosetron hydrochloride Lotronex

Manufacturer GlaxoSmithKline

Country -

Year Introduced -

GlaxoSmithKline

USA

-

Raw Materials Thionyl chloride Maleic acid Sodium hydride Polyphosphoric acid

1-(Triphenylmethyl)-1H-imidazole-4-methanol Hydroxylamine hydrochloride 3,4-Dihydro-4-methylcyclopent[b]indol-1-(2H)-one

Manufacturing Process 4-(Chloromethyl)-1-(triphenylmethyl)-1H-imidazole. Thionyl chloride (0.829 g) was added over 1 min to a stirred suspension of 1(triphenylmethyl)-1H-imidazole-4-methanol (1.3 g) in a mixture of dichloromethane (50 ml) and DMF (1.0 ml) at 23°C. The solution so obtained was stirred for 15 min. and extracted with 8% sodium bicarbonate solution (80 ml). The organic phase was washed with water (50 ml), dried and evaporated to give an oil which solidified. The solid was slurried in hexane and filtered to give the title compound (1.28 g), m.p. 139-141°C. 3,4-Dihydro-4-methylcyclopent[b]indol-1(2H)-one oxime.

184

Alosetron hydrochloride

3,4-Dihydro-4-methylcyclopent[b]indol-1(2H)-one (1.7 g) and hydroxylamine hydrochloride (1.925 g) in pyridine were heated at 60°C for 18 h and cooled. The reaction mixture was evaporated in vacuo to a residue to which was added 8% sodium bicarbonate (150 ml). Extraction with ethyl acetate (300 ml) produced a suspension in the organic layer; this layer and associated solid was separated from the aqueous layer. The aqueous layer was re-extracted with ethyl acetate (250 ml). The combined organic extracts (and suspended solid) were evaporated to a residue, boiled with a mixture of ethanol (150 ml) and methanol (150 ml) and cooled to 50°C. The residue was adsorbed from this solution on to FCC silica and applied to an FCC column. Elution with ethyl acetate/3-10% methanol provided the title compound (1.69 g), m.p. 219224°C (decomp.). 2,3,4,5-Tetrahydro-5-methyl-1H-pyrido[4,3-b]indol-1-one. 3,4-Dihydro-4-methylcyclopent[b]indol-1(2H)-one oxime (1.53 g), polyphosphoric acid (409 g) and dioxan (15 ml) were heated at 110-120°C for 2.2 h under nitrogen. The reaction mixture was cooled, and treated with 2 N sodium carbonate solution (1 L). The suspension was extracted with ethyl acetate (4x400 ml) and the combined extracts were dried. Evaporation gave a solid (1.43 g) which was recrystallised from ethyl acetate/cyclohexane. This solid was purified by FCC, eluting with dichloromethane:ethanol:ammonia solution (200:10:1) to give a solid (1.26 g) which was recrystallised from ethanol to provide the title compound (960 mg), m.p. 234-238°C. 2,3,4,5-Tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1Hpyrido[4,3-b]indol-1-one maleate. A mixture of 2,3,4,5-tetrahydro-5-methyl-1H-pyrido[4,3-b]indol-1-one (0.6 g) and 78% sodium hydride dispersion in mineral oil (0.109 g) in dry DMF (15 ml) was stirred under nitrogen at 50°C until hydrogen evolution ceased (ca. 1.5 h). The mixture was cooled to 40°C and a solution of 4-(chloromethyl)-5methyl-1-(triphenylmethyl)-1H-imidazole (1.12 g) in dry THF (15 ml) was added. The reaction was then stirred at 40°C for 3 h, at 20°C for 16 h and a further portion of 4-(chloromethyl)-5-methyl-1-(triphenylmethyl)-1H-imidazole (1.12 g) in dry THF (15 ml) was added. The resulting mixture was heated at 40°C for 3 h, quenched with water (20 ml) and acetic acid (20 ml), and heated at 100°C for 2 h. The mixture was then concentrated in vacuo to ca. 60 ml, diluted with 1 M hydrochloric acid (40 ml) and washed with ethyl acetate (3x50 ml). The organic phase was discarded and the acidic aqueous phase was basified (pH=9) with potassium carbonate and extracted with ethyl acetate:ethanol (20:1; 3x100 ml). The extracts were combined, dried and evaporated to give a brown gum (ca. 1 g). This gum was adsorbed onto silica and purified by FCC eluting with dichloromethane:ethanol:ammonia solition (100:8:1) to give a pale brown solid (0.8 g); m.p. 238-240°C (decomp.). This solid was dissolved in a mixture of (hot ethanol and methanol (1:1; 100 ml) and treated with an ethanolic solution of maleic acid (3.18 g). The resulting solution was concentrated to ca. 20 ml and diluted with dry diethyl ether (ca. 8 ml) to precipitate the title compound (0.75 g) as an off-white solid melting point 160-162°C. Hydrochloride may be prepared by treating the above solid with an equivalent of an ethanolic solution of HCl.

Alpertine

185

References Harold I.H. et al.; European Patent Office No 0 306 323 A2; 02.09.88

ALPERTINE Therapeutic Function: Antipsychotic; Neuroleptic Chemical Name: 1H-Indole-2-carboxylic acid, 5,6-dimethoxy-3-(2-(4-phenyl1-piperazinyl)ethyl)-, ethyl ester Common Name: Alpertine Structural Formula:

Chemical Abstracts Registry No.: 27076-46-6 Trade Name Alpertine Win 31665

Manufacturer ZYF Pharm Chemical Sterling-Winthrop

Country -

Year Introduced -

Raw Materials γ-Butyrolactone Ethyl oxalate 3,4-Dimethoxyphenylhydrazine hydrochloride Manufacturing Process 1-[2-(2-Carbethoxy-5,6-dimethoxy-3-indolyl)ethyl]-4-phenylpiperazine: To a suspension of 23 g (1.0 mole) of sodium pellets in 800 ml of absolute ether was added 80 ml of a mixture of 86 g (1.0 mole) of γ-butyrolactone and 146 g (1.0 mole) of ethyl oxalate. The reaction mixture began to boil gently and was allowed to reflux spontaneously for two hours, after which time the remainder of the γ-butyrolactone and ethyl oxalate mixture was added

186

Alphaprodine hydrochloride

cautiously. When addition was complete, the mixture was refluxed for one hour, allowed to stand overnight, and the ether removed in vacuo. The residue was mixed with ice, acidified with cold, dilute sulfuric acid, extracted with ether, and the ether extracts dried over sodium sulfate and taken to dryness. Distillation of the residue in vacuo at 0.05 mm afforded 98 g of α-ethoxalyl-γbutyrolactone, collected between 110-126°C. Forty grams (0.215 mole) of the latter were heated under reflux in 100 ml of 2 N sulfuric acid until the evolution of carbon dioxide ceased, giving a solution of α-keto-δ-valerolactone. 3,4-Dimethoxyphenylhydrazine hydrochloride (44 g, 0.22 mole) was dissolved in 300 ml of water, treated with a solution of 12.3 g (0.22 mole) of potassium hydroxide in 50 ml of water, and cooled. To this mixture was added the above described solution of α-keto-δ-valerolactone, and the pH of the mixture was adjusted to about 2 with 10% sodium hydroxide. The mixture was warmed on a hot plate for five minutes, allowed to cool, extracted with chloroform, and the extracts dried over magnesium sulfate and concentrated to dryness giving 66 g of crude hydrazone. The latter was dissolved in 100 ml of absolute ethanol, the mixture acidified with 400 ml of saturated ethanolic hydrogen chloride, and a stream of hydrogen chloride gas was passed through the mixture causing the temperature to rise to 80°C. The solid which separated from the reaction mixture was collected after standing overnight, and washed with cold absolute ethanol to give 38 g of crude 2-carboxy-5,6 -dimethoxy-3-(2hydroxyethyl)indole. The latter was suspended in 300 ml of absolute ethanol and the solution saturated with anhydrous hydrogen chloride for one hour. The mixture was allowed to stand for two hours, and the solid which separated was collected and dried to give 24 g of 2-carbethoxy-5,6-dimethoxy-3-(2-chloroethyl)indole, M.P. 179-181°C. The latter was added to 15 ml of 1-phenylpiperazine and the mixture heated at 140-160°C for one hour and twenty minutes. The cooled mixture was triturated with 100 ml of ether, filtered, and the ether filtrate concentrated to dryness. The residue was mixed with water and acetic acid, the pH adjusted to about 5.0, and the insoluble material was collected by filtration giving 5 g of crude product which was recrystallized from methanol to give 2.2 g of 1-[2(2-carbethoxy-5,6-dimethoxy-3-indolyl)ethyl]-4-phenylpiperazine, M.P. 142.5144.0°C. References Archer S.; US Patent No. 3,562,278; Feb. 9, 1971; Assigned to Sterling Drug Inc., New York, N.Y., a corporation of Delawere

ALPHAPRODINE HYDROCHLORIDE Therapeutic Function: Narcotic analgesic

Alphaprodine hydrochloride

187

Chemical Name: cis-1,3-Dimethyl-4-phenyl-4-piperidinolpropanoate hydrochloride Common Name: Structural Formula:

Chemical Abstracts Registry No.: 77-20-3 (Base); 49638-24-6 (Hydrochloride salt) Trade Name

Manufacturer

Country

Year Introduced

Nisentil

Roche

US

1949

Raw Materials Lithium Bromobenzene Hydrogen chloride

1,3-Dimethyl-4-piperidone Propionic anhydride

Manufacturing Process In a round-bottom flask provided with stirrer, dropping funnel, condenser and a gas outlet for keeping the system under nitrogen, 200 cc of dry ether is placed and 4.6 grams of lithium cut into thin strips is added. 52 grams of bromobenzene in 50 cc of dry ether are added dropwise and after addition, the mixture is refluxed for 2 hours. This procedure results in the formation of phenyl-lithium. Other aryl-lithium compounds can be prepared in a similar manner by reacting lithium metal or a lithium compound capable of transferring lithium and a compound having an exchangeable halogen group as, for example, bromonaphthalene. The solution of phenyl-lithium is cooled to -20°C and to this a solution of 12.7 grams of 1,3-dimethyl-4-piperidone, prepared according to the method of Howton, J. Org. Chem. 10, 277 (1945), in ether is added dropwise with stirring. After the addition, the stirring is continued for a further 2 hours at 20°C. The lithium complex, 1,3-dimethyl-4-phenyl-4-oxylithium piperidine, which forms is soluble in the ether and can be recovered there from. To prepare the piperidinol, the lithium complex, while in the reaction mixture is decomposed by the addition of an ice and hydrochloric acid mixture. The acidified layer is separated, basified and extracted with ether. After drying the ether solution and removing the solvent, the residue on distillation in vacuum distills chiefly at 155°C/10 mm, yielding the product, 1,3-dimethyl-4-phenyl4-hydroxypiperidine, which, on crystallization from n-hexane melts at 102°C. On treatment with propionic anhydride catalyzed with a trace of sulfuric acid,

188

Alpidem

1,3-dimethyl-4-propionoxy-4-phenylpiperidine is attained. The latter compound can be converted into the hydrochloride salt by reaction with hydrogen chloride. This salt after crystallization from acetone has a melting point of 209°C. References Merck Index 302 Kleeman and Engel p. 29 PDR p. 1494 OCDS Vol. 1 pp. 304 and 2328 (1977) I.N. p.60 REM p. 1107 Lee, J. and Ziering, A.; US Patent 2,498,433; February 21, 1950; Assigned to Hoffmann-La Roche Inc.

ALPIDEM Therapeutic Function: Anxiolytic Chemical Name: Imidazo[1,2-a]pyridine-3-acetamide, 6-chloro-2-(4chlorophenyl)-N,N-dipropylCommon Name: Ananxil Structural Formula:

Chemical Abstracts Registry No.: 82626-01-5 Trade Name

Manufacturer

Country

Year Introduced

Ananxil

Synthelabo

-

-

Raw Materials Formic acid 6-Chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridine-3-acetonitrile Hydrogen chloride Ammonia Potassium hydroxide Acetic acid

Alprazolam

189

Manufacturing Process Two methods of synthesis of 6-chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridine-3-N,N-dimethylacetamide: 1. 22 g (0.0788 mol) of 6-chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridine-3acetonitrile are added to 85 ml of 99% formic acid and the solution is treated with a stream of dry hydrogen chloride for 3 to 4 hours. When all the nitrile has been converted, the solution is heated slightly to degas it, and the cooled solution is then poured into 1 liter of water; the mixture is stirred for 10 min and then rendered alkaline with 200 ml of concentrated ammonia solution. The solid is filtered off, washed copiously with water and dried under a waterpump vacuum. The 6-chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridine-3acetamide is recrystallised from ethanol. Melting point = 285-287°C. 2. 19.2 g of 6-chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridine-3-acetamide and 19 g of KOH are added successively to 550 ml of 75% ethanol. The suspension is heated at the reflux temperature for 10-16 hours. When the reaction has ended, the solution is concentrated in vacuo and the residue is dissolved in ½ liter of water. The small amount of insoluble material is filtered off and the filtrate is treated with 50 ml of acetic acid. The expected acid precipitates and it is filtered off and roughly dried. The crude product is taken up in 500 ml of acetone and the 6-chloro-2-(4-chlorophenyl)imidazo[1,2a]pyridine-3-acetic acid is filtered off hot. Melting point=258-260°C. References Kaplan J.-P., George Pascal; US Patent No. 4,460,592; July 17, 1984; Assigned to Synthelabo

ALPRAZOLAM Therapeutic Function: Tranquilizer Chemical Name: 8-Chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4] benzodiazepine Common Name: Structural Formula:

190

Alprazolam

Chemical Abstracts Registry No.: 28981-97-7 Trade Name Xanax Xanax Xanax Xanax

Manufacturer Upjohn Upjohn Upjohn Upjohn

Country US Switz. UK Australia

Year Introduced 1981 1982 1983 1983

Raw Materials 2,6-Dichloro-4-phenylquinoline Hydrazine hydrate Triethyl orthoacetate Sodium periodate Paraformaldehyde Phosphorus tribromide Ammonia Manufacturing Process 6-Chloro-2-hydrazino-4-phenylquinoline: A stirred mixture of 2,6-dichloro-4phenylquinoline (2.7 g, 0.01 mol) and hydrazine hydrate (6.8 g) was refluxed under nitrogen for 1 hour and concentrated in vacuum. The residue was suspended in warm water, and the solid was collected by filtration, dried and recrystallized from ethyl acetate-Skelly B hexanes to give 1.81 g (67% yield) of 6-chloro-2-hydrazino-4-phenylquinoline of melting point 156.5-157°C. 7-Chloro-1-methyl-5-phenyl-s-trizolo[4,3-a]quinoline: A stirred mixture of 6chloro-2-hydrazino-4-phenylquinoline (1.4 g, 0.0052 mol), triethylorthoacetate (0.925 g, 0.0057 mol) and xylene (100 ml) was refluxed, under nitrogen, for 2 hours 40 minutes. During this period the ethanol formed in the reaction was removed by distillation through a short, glass helix-packed column. The mixture was concentrated to dryness in vacuum and the residue was crystallized from methanol-ethyl acetate to give: 1.28 g of 7-chloro-1methyl-5-phenyl-s-triazolo[4,3-a]quinoline (83.9% yield). The analytical sample was crystallized from methylene chloride:methanol and had a melting point 252.5-253.5°C. 5-Chloro-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone (Oxidation of 7chloro-1-methyl-5-phenyl-s-trizolo[4,3-a]quinoline): A stirred suspension of 7chloro-1-methyl-5-phenyl-s-triazolo[4,3-a] quinoline (2,94 g, 0.01 mol) in acetone (110 ml) was cooled in an ice-bath and treated slowly with a solution prepared by adding sodium periodate (2 g) to a stirred suspension of ruthenium dioxide (200 mg) in water (35 ml). The mixture became dark. Additional sodium periodate (8 g) was added during the next 15 minutes. The ice-bath was removed and the mixture was stirred for 45 minutes. Additional sodium periodate (4 g) was added and the mixture was stirred at ambient temperature for 18 hours and filtered. The solid was washed with acetone and the combined filtrate was concentrated in vacuum. The residue was suspended in water and extracted with methylene chloride. The extract was dried over anhydrous potassium carbonate and concentrated. The residue was chromatographed on silica gel (100 g) with 10% methanol and 90% ethyl acetate; 50 ml fractions were collected. The product was eluted in fractions 10-20 and was crystallized from ethyl acetate to give: 0.405 g of melting

Alprazolam

191

point 168-169.5°C and 0.291 g of melting point 167.5-169°C (23.4% yield) of 5-chloro-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone. The analytical sample had a melting point of 168°C. 5-Chloro-2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone: A stirred mixture of 5-chloro-2-(3-methyl-4H-1,2,4-triazolo-4yl)benzophenone, (2.98 g, 0.01 mol) paraformaldehyde (3 g) and xylene (100 ml) was warmed under nitrogen, in a bath maintained at 125°C for 7 hours. The mixture was then concentrated in vacuum. The residue was chromatographed on silica gel (150 g) with 3% methanol-97% chloroform. Fifty ml fractions were collected. The product was eluted in fractions 20-44. The fractions were concentrated and the residue was crystallized from ethanol-ethyl acetate to give: 1.64 g of melting point 138-142°C; 0.316 g of melting point 138.5-141°C; 0.431 g of melting point 139-141°C (72.8% yield) of 5-chloro-2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4yl]benzophenone. The analytical sample had a melting point of 138-139°C. 5-Chloro-2-[3-(bromomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]-benzophenone: A solution of 5-chloro-2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone (328 mg, 0.001 mol) in dry, hydrocarbon-stabilized chloroform (5 ml) was cooled in an ice-bath and treated with phosphorus tribromide (0.1 ml). The colorless solution was kept in the ice-bath for 55 minutes, at ambient temperature (22-24°C), for 5 hours. The resulting yellow solution was poured into a mixture of ice and dilute sodium bicarbonate. This mixture was extracted with chloroform. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was crystallized from methylene chloride-ethyl acetate to give: 0.285 g of melting point 200240°C (decomposition) and 0.030 g of melting point 200-220°C (decomposition) of 5-chloro-2-[3-(bromomethyl)-5-methyl-4H-1,2,4-triazol-4yl]benzophenone. The analytical sample had a melting point of 200-240°C. 8-Chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine: A stirred suspension of 5-chloro-2-[3-(bromomethyl)-5-methyl-4H-1,2,4-triazol4-yl]-benzophenone (391 mg, 0.001 mol) in tetrahydrofuran (15 ml) was cooled in an ice-bath and treated with a saturated solution of ammonia in methanol (12.5 ml). The resulting solution was allowed to warm to ambient temperature and stand for 24 hours. It was then concentrated in vacuum. The residue was suspended in water, treated with a little sodium bicarbonate and extracted with methylene chloride. The extract was washed with brine, dried with anhydrous potassium carbonate and concentrated. The residue was crystallized from methylene chloride-ethyl acetate to give 0.220 g of crude product of melting point 227-228.5°C. Recrystallization of this material from ethyl acetate gave 0.142 g of melting point 228-229.5°C of 8-chloro-1methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine. References Merck Index 303 DFU 1 (12) 551 (1976) Kleeman and Engel p. 30 PDR p. 1865 OCDS Vol. 3 p. 197 (1984) DOT 11 (5) 179 (1975) I.N. p. 60

192

Alprenolol hydrochloride

Hester, J.B., Upjohn Hester, J.B., Upjohn Hester, J.B., Upjohn

Jr.; US Patent 3,681,343; August 1, 1972; Assigned to The Company Jr.; US Patent 3,781,289; December 25, 1973; Assigned to The Company Jr.; US Patent 3,709,898; January 9, 1973; Assigned to The Company

ALPRENOLOL HYDROCHLORIDE Therapeutic Function: Beta-adrenergic blocker Chemical Name: 1-[(1-Methylethyl)amino]-3-[2-(2-propenyl)phenoxy]-2propanol hydrochloride Common Name: Structural Formula:

Chemical Abstracts Registry No.: 13655-52-2 (Base); 13707-88-5 (Hydrochloride salt) Trade Name

Manufacturer

Country

Year Introduced

Aptol

Globopharm

Switz.

-

Aptin

Astra France

W. Germany

1967

Aptine

Lematte/Boinot

France

1971

Aprobal

Fujisawa

Japan

1971

Aptin

Byk Gulden

Italy

1972

Apllobal

Hassle

Sweden

-

Aptina

Made

Spain

-

Aptol-Duriles

Astra

-

-

Betacard

Beecham

UK

-

Elperl

Sawai

Japan

-

Gubernal

Geigy

France

-

Regletin

Teikoku

Japan

-

Sinalol

Kaken

Japan

-

Yobir

Maruko

Japan

-

Alprostadil

193

Raw Materials Ammonia Hydrogen chloride Acetone

o-Allyl epoxy propoxy benzene Sodium borohydride

Manufacturing Process A solution of 24.6 g of o-allyl-epoxypropoxybenzene dissolved in 250 ml of absolute ethanol saturated with ammonia was placed in an autoclave and heated on a steam-bath for 2 hours. The alcohol was then removed by distillation and the residue was redissolved in a mixture of methanol and ethylacetate. Hydrogen chloride gas was introduced into the solution. The hydrochloride salt was then precipitated by the addition of ether to yield 11.4 g of product. Five grams of the amine-hydrochloride thus formed were dissolved in 50 ml of methanol and 9 ml of acetone. The resulting solution was cooled to about 0°C. At this temperature 5 g of sodium borohydride were added over a period of 1 hour. Another 2.2 ml of acetone and 0.8 g of sodium borohydride were added and the solution was kept at room temperature for 1 hour, after which 150 ml of water were added to the solution. The solution was then extracted with three 100-ml portions of ether which were combined, dried over potassium carbonate, and evaporated. The free base was then recrystallized from petrol ether (boiling range 40-60°C) to yield 2.7 g of material having a melting point of 57°C. The corresponding hydrochloride was prepared by dissolving 2 g of the product, prepared above, in 20 ml of acetone, and adding to the resulting solution acetone saturated with hydrogen chloride until the pH was reduced to about 3. The precipitated hydrochloride salt was then recrystallized from acetone. References Merck Index 304 Kleeman and Engel p. 31 OCDS Vol. 1 p. 177 (1977) DOT 9 (6) 245 (1973) I.N. p. 60 Brandstrom, A.E., Corrodi, H.R. and Alblad, H.R.G.; US Patent 3,466,376; September 9, 1969; Assigned to Aktiebolaget Hassie

ALPROSTADIL Therapeutic Function: Vasodilator, Abortifacient, Antihypertensive, Bronchodilator Chemical Name: Prost-13-en-1-oic acid, 11,15-dihydroxy-9-oxo-, (11α,13E,15S)Common Name: Alprostadil; Prostaglandin E1

194

Alprostadil

Structural Formula:

Chemical Abstracts Registry No.: 745-65-3 Trade Name Alprostadil Alprostapint Alprostan Alpostin Alprox-TD Befar Bondil Caverject Muse Prostin VR Topiglan Vazaprostan

Manufacturer Schwarz Pharmacia BAG Leciva Samarth Pharma Pvt. Ltd. NexMed, Inc. Nexmed Pharmaceutical Meda Pharmacia and Upjohn Meda Pharmacia India (P) Ltd. MacroChem Copr. Schwarz Pharma

Country Germany Czech Republic India

Year Introduced -

USA Belgium UK India Germany

-

Raw Materials 3α,6,7,7α-Tetrahydro-4-methyl-2-oxo-1β-indaheptanoic acid methyl ester 4-Toluenesulfonic acid monohydrate Ethylene glycol Sodium hydride Sodium periodate Trifluoroperacetic acid Etheral diazomethane Sodium methoxide Osmium tetroxide Potassium t-butoxide Manufacturing Process Manufacturing process for prostaglandin E1 includes 15 steps. 1. A mixture of 11.8 g of (+/-)-3α,6,7,7α-tetrahydro-4-methyl-2-oxo-1βindaheptanoic acid methyl ester, 27 ml of ethylene glycol and 300 mg of ptoluene sulfonic acid mono-hydrate in 600 ml of benzene was refluxed with stirring for 18 hours using a Dean-Stark trap to separate the water formed in the reaction. The reaction mixture was cooled and added to 300 ml of cold 5% potassium bicarbonate. The aqueous layer extracted twice with 2:1 benzene-hexene. The combined organic fractions were washed 3 times with saturated aqueous NaCl, dried over sodium sulfate and evaporated to dryness

Alprostadil

195

affording 12.6 g of (+/-)-3α,6,7,7α-tetrahydro-4-methyl-2-oxo-1βindaheptanoic acid methyl ester, 2-cyclic ethylene acetal. 2. To 5.69 g of this acetal in 410 ml of t-butanol and 11 ml of water was added a mixture of 5.80 g of potassium carbonate, 22,8 g of sodium periodate, and 270 mg of potassium permanganate in 1230 ml of water. The reaction mixture was stirred at 20-25°C for 20 hours and concentrated in vacuo to remove t-butanol. Ethylene glycole (0.5 ml) was added and reaction mixture extracted with 1:1 ether-benzene to remove neutral material. The aqueous layer acidified with solid sodium dihydrogen phosphate and extracted 4 times with 1:1 ethyl acetate-benzene. The organic layer was dried over sodium sulfate and evaporated to dryness in vacuo affording (+/-)-3-acetyl2α-(2-carboxyethyl)-5-oxo-1β-cyclopentaneheptanoic acid methyl ester, 5cyclic ethylene acetal as a mixture of the 3α and 3β isomers. 3. (+/-)-3β-Acetyl-2α-(2-methoxycarbonylethyl)-5-oxo-1βcyclopentaneheptanoic acid methyl ester, 5-cyclic ethylene acetal, NMR (CDCl3) δ 2.13 [3H - CH3CO], was prepared from above (+/-)-3-acetyl-2α-(2carboxyethyl)-5oxo-1β-cyclopentaneheptanoic acid methyl ester, 5-cyclic ethylene acetal with etheral diazomethane and subsequent stirring with sodium methoxide in methanol for 18 hours at room temperature. 4. (+/-)-3β-Acetoxy-2α-(2-methoxycarbonylethyl)-5-oxo-1βcyclopentaneheptanoic acid methyl ester, 5-cyclic ethylene acetal was produced by stirring the solution of 4.5 g of (+/-)-3β-acetyl-2α-(2methoxycarbonylethyl)-5-oxo-1β-cyclopentaneheptanoic acid methyl ester, 5cyclic ethylene acetal in 25 ml methylene chloride, containing 60 g of solid disodium monohydrogen phosphate, with 85 ml freshly prepared 0.3 M trifluoroperacetic acid in methylene chloride for 42 hours at room temperature. The reaction mixture was filtered, the precipitate washed with methylene chloride and the organic extract was washed with cold aqueous potassium iodide and cold thiosulfate. Organic layer was washed with potassium bicarbonate, dried over sodium sulfate and evaporated in vacuo. 5. The reaction 4.25 g of (+/-)-3β-acetoxy-2α-(2-methoxycarbonylethyl)-5oxo-1β-cyclopentaneheptanoic acid methyl ester, 5-cyclic ethylene acetal in 25 ml of methanol with 6 ml of 1.00 N sodium methoxide under nitrogen at room temperature for 2 hours produced pure (+/-)-2α-(2-methoxycarbonylethyl)3β-hydroxy-5-oxo-1β-cyclopentaneheptanoic acid methyl ester, 5-cyclic ethylene acetal after chromatographical purification with silica gel (eluent 25% acetone in chloroform). 6. (+/-)-2α-(2-Carboxyethyl)-3β-hydroxy-5-oxo-1β-cyclopentaneheptanoic acid methyl ester δ-lactone, 5-cyclic ethylene acetal was prepared as follows: 1.66 g of (+/-)-2α-(2-methoxycarbonylethyl)-3β-hydroxy-5-oxo-1βcyclopentaneheptanoic acid methyl ester, 5-cyclic ethylene acetal in 350 ml of benzene was refluxed with 0.25 ml of 0.66 M potassium t-butoxide in butanol and 140 ml of benzene in a nitrogen atmosphere for 4 hours. Above lacton was produced after washing of organic fraction with of saturated aqueous solutions of sodium dihydrogen phosphate and NaCl and evaporating in vacuo to dryness. 7. 210 mg of 50% sodium hydride was added to a stirred solution above δlactone under nitrogen at 0°C. The mixture was stirred for 1 hour at 0°C and

196

Alprostadil

4 hours at 20°C. The solvent was removed in vacuo and residue washed with ether and filtered. The residue was recrystallized from ether-hexane affording (+/-)-2α-(2-carboxy-2-formylethyl)-3β-hydroxy-5-oxo-1βcyclopentaneheptanoic acid methyl ester δ-lactone, 5-cyclic ethylene acetal, m.p. 88-90°C. 8. A solution of 460 mg of (+/-)-2α-(2-carboxy-2-formylethyl)-3β-hydroxy-5oxo-1β-cyclopentaneheptanoic acid methyl ester δ-lactone, 5-cyclic ethylene acetal in 6 ml of methylene chloride and 4.4 ml of pyridine was treated with a 5% ozone-oxygen mixture at - 70°C until the mixture had persistent pale blue color. The excess of ozone was evaporated by bubbling nitrogen into reaction and the solvents were removed in vacuo. The residue was tirturaed with ether affording crystalline (+/-)-2α-(2-carboxy-2-oxoethyl)-3β-hydroxy-5-oxo-1βcyclopentaneheptanoic acid methyl ester δ-lactone, 5-cyclic ethylene acetal, m.p. 114-116°C. 9. The product of ozonolysis was acetylated in 6 ml of pyridine and 3 ml acetic anhydride at room temperature for 17 hours, 6 ml xylene was added and the reaction mixture evaporated in vacuo. The residue was triturated with etherhexane affording crystalline (+/-)-2α-(2-acetoxy-2-carboxyvinyl)-3β-hydroxy5-oxo-1β-cyclopentaneheptanoic acid methyl ester δ-lactone, 5-cyclic ethylene acetal, m.p. 82-84°C. 10. 14 mg of osmium tetroxide in 1.4 ml methanol was added to a stirred solution of δ-lactone (step 9) in 16 ml of methanol. The reaction mixture darkened in 10-15 minutes and 440 mg of sodium periodate was added portionwise over 3 hours. The mixture was stirred 1 additional hours and filtered, filtrate evaporated to dryness in vacuo. The residue was dissolved in 2.5 ml of 1:1 ethyl acetate - benzene and the solution washed in usual way, dried over sodium sulfate and evaporated according (+/-)-2α-formyl-3β[(methoxyalyl)oxy]-5-oxo-1β-cyclopentaneheptanoic acid methyl ester δlactone, 5-cyclic ethylene acetal as an oil. 11. 230 mg of dimethyl-2-oxoheptyl phosphonate in 4 ml of tetrahydofuran was stirred with 50 mg of 50% sodium hydride in 10 ml tetrahydrofuran under a nitrogen at 0°C for 30 minutes. A solution of 420 mg of (+/-)-2α-formyl-3β[(methoxyalyl)oxy]-5-oxo-1β-cyclopentaneheptanoic acid methyl ester δlactone, 5-cyclic ethylene acetal in 4 ml of tetrahydrofuran was added dropwise over 5 min. After 10 min the mixture was allowed to warm to room temperature and stirred 2 hours. The reaction mixture was added to saturated aqueous dihydrogen phosphate at 10°C and extracted with ethyl acetate. After usual washing and drying procedure, extract was evaporated to dryness affording (+/-)-3β-[(methoxyalyl)oxy]-2α-(3-oxo-1-octenyl)-5-oxo-1βcyclopentaneheptanoic acid methyl ester, 5-cyclic ethylene acetal. 12. The above product was dissolved in 7.5 ml of methanol and 60 mg of ethylenediamine in 5 ml of methanol was added dropwise at 0°C and the mixture stirred for 45 min at 20°C. And the solvent evaporated in vacuo. The residue was chromatographed on 35 g silica gel eluting with 30% acetone and chloroform taking 40 fractions of 4 ml each. Fraction 5-14 was evaporated to dryness in vacuo affording 250 mg (+/-)-3β-hydroxy-2α-(3-oxo-1-octenyl)-5oxo-1β-cyclopentaneheptanoic acid methyl ester, 5-cyclic ethylene acetal, λmax (methanol, 232 nm, E 12500).

Alrestatin sodium

197

13. Prostaglandin E1, methyl ester, cyclic ethylene acetal was prepared from 245 mg of (+/-)-3β-hydroxy-2α-(3-oxo-1-octenyl)-5-oxo-1βcyclopentaneheptanoic acid methyl ester, 5-cyclic ethylene acetal, in 6 ml of methanol by stirring with 23 mg of sodium borohydride in 2 ml of methanol at -10°C for 40 min. After usual washing and evaporating to dryness the residue was chromatographed on 20 g of silica gel eluting with 50% acetonechloroform. (+/-)-3β-hydroxy-2α-(3β[R]-hydroxy-1-octenyl)-5-oxo-1βcyclopentaneheptanoic acid methyl ester, 5-cyclic ethylene acetal and (+/-)3β-hydroxy-2α-(3β[S]-hydroxy-1-octenyl)-5-oxo-1β-cyclopentaneheptanoic acid methyl ester, 5-cyclic ethylene acetal, m.p. 54-56°C were afforded. 14. 40 mg of (+/-)-3β-hydroxy-2α-(3β[S]-hydroxy-1-octenyl)-5-oxo-1βcyclopentaneheptanoic acid methyl ester, 5-cyclic ethylene acetal in 1 ml was saponificated with a solution of 45 mg of KOH in 2.5 ml of water at 0°C in nitrogen atmosphere. The mixture was allowed to warm to room temperature and stirred for 3 hours. After usual procedures of evaporating, extracting, washing, drying and evaporating, (+/-)-prostaglandin E1, (+/-)-3β-hydroxy2α-(3β[S]-hydroxy-1-octenyl)-5-oxo-1β-oxocyclopentaneheptanoic acid, 5cyclic ethylene acetal, m.p. 82-84°C, was afforded. 15. A mixture of 37 mg of (+/-)-prostaglandin E1 and 3 ml 1:1 acetic acidwater was stirred at 25°C for 3 hours. Saturated aqueous Na2HPO4 solution was added and the mixture extracted with 1:1 ethyl acetate-benzene. The organic layer was washed, evaporated to dryness affording the crystalline residue (+/-)-prostaglandin E1, m.p. 111-113°C (recrystallized from ethyl acetate-benzene). References Wendler N.L. et al.; US Patent No. 3,870,747; Mar. 11, 1975; Assigned: Merck and Co., Inc., Rahway, N.J. Nelson N.A.; US Patent No. 3,933,897; Jan. 20, 1976; Assigned: The Upjohn Company (Kalamazoo, MI)

ALRESTATIN SODIUM Therapeutic Function: Aldose reductase inhibitor Chemical Name: 1H-Benz[de]isoquinoline-2(3H)-acetic acid, 1,3-dioxo-, sodium salt Common Name: Alrestatin sodium Structural Formula:

198

Alsactide

Chemical Abstracts Registry No.: 51876-97-2; 51411-04-2 (Base) Trade Name

Manufacturer

Country

Year Introduced

Alrestatin

BIOMOL

-

-

Raw Materials 1,8-Naphthalic acid anhydride Glycine Manufacturing Process 1,3-Dioxo-1H-benz[de]isoquinoline-2(3H)-acetic acid: 1,8-Naphthalic acid anhydride (110 g, 0.556 mole), glycine (48 g, 0.64 mole) and dimethylformamide (750 ml) are heated and stirred at reflux for 2 hr. The homogeneous dark solution is cooled to about 100°C and 750 ml of hot water is added slowly to the stirred solution. The reaction mixture is cooled and allowed to stand in a refrigerator for 16 hr. The precipitate is collected and recrystallized from ethanol, using decolorizing charcoal, to give the title compound, MP: 271°-272°C. In practice it is usually used as sodium salt. References Sestanj K. et al.; US Patent No. 3,821,383; June 28, 1974; Assigned to A. Mc and Harrison Limited, Larent, Quebec, Canada

ALSACTIDE Therapeutic Function: Adrenocorticotropin Chemical Name: α1-17-Corticotropin, 1-β-alanine-17-(N-(4-aminobutyl)-Llysinamide)Common Name: Alisactide ;Alsactide Chemical Abstracts Registry No.: 34765-96-3 Trade Name

Manufacturer

Country

Year Introduced

Alsactide

ZYF Pharm Chemical

-

-

Raw Materials Z-Lys(Boc) OTCP Triethylamine Palladium N-Ethylmorpholine

Z-Lys(Boc)-NH-(CH2)4-NH-Boc 4-Toluenesulfonic acid Z-Lys(Boc)-Pro-Val-Gly-Lys(Boc)-OH 1-Hydroxybenzotriazole

Alsactide

199

Trifluoroacetic acid Dicyclohexylcarbodiimide Thioglycolic acid Boc-β-Ala-Tyr-Ser-Met-Glu-(OBut)-His-Phe-Arg-Trp-Gly-OH·4H2O Structural Formula:

Manufacturing Process Abbreviations: Boc - tert-butoxycarbonyl; TCP - 2,4,5-trichlorophenyl; Z - carbobenzyloxy. (a) β-Ala-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-Gly-Lys-Lys-LysNH-(CH2)4-NH2-acetate, aq. Z-Lys(Boc)-NH-(CH2)4-NH-Boc: 7.0 g (31 mmols) of Boc-NH-(CH2)4-NH2-HCl and 4.2 ml (30 mmols) of triethylamine in 100 ml of dimethylformamide are stirred for 20 hours together with 16.8 g (30 mmols) of Z-Lys(Boc) OTCP. The product is filtered off the triethylammonium chloride and the filtrate is evaporated to dryness in vacuo. The residue is dissolved in ethyl acetate, thoroughly shaken at 0°C with 2 N citric acid, 1 N bicarbonate and H2O and dried over sodium sulfate. After distilling off the solvents, the residue is recrystallized two times from isopropanol/ether. Yield: 14.1 g (83%), M.P. 83°-85°C. (b) H-Lys(Boc)-NH-(CH2)4-NH-Boc-tosylate: 11.4 g of the Z-compound prepared according to (a) are hydrogenated in the presence of Pd in 80 ml of methanol with, while adding methanolic toluene-sulfonic acid at pH 5. After the reaction is complete, the product is filtered to remove the catalyst, the methanol is distilled off in vacuo and the residue is triturated with ether. For purification purposes it is dissolved in warm isopropanol and precipitated with ether. Yield: 10.3 g (88%).

200

Alteconazole

(c) Z-Lys(Boc)-Pro-Val-Gly-Lys(Boc)-Lys(Boc)-Lys(Boc)-NH-(CH2)4-NH-Boc: 10.9 g (10 mmols) of Z-Lys(Boc)-Pro-Val-Gly-Lys(Boc)-OH and 5.89 g (10 mmols) of Boc-NH-(CH2)4-NH2-tosylate in 100 ml of dimethylformamide are combined with 12.8 ml (10 mmols) of N-ethylmorpholine and 2.7 g (20 mmols) of 1-hydroxybenzotriazole. 2.2 g of dicyclohexylcarbodiimide (11 mmols) are added at -10°C. The whole is then allowed to come to room temperature. The stirring is continued for 3 hours, the solvent is distilled off in vacuo. The residue is digested with 1 N bicarbonate and water and, after drying, recrystallized from acetonitrile. Yield: 10.6 g (74.2%). M.P. 150°155°C (while foaming). [α]D20: -24.0° (c=1 in dimethylformamide). (d) H-Lys(Boc)-Pro-Val-Gly-Lys(Boc)-Lys(Boc)-Lys(Boc)-NH-(CH2)4-NH-Boctosylate-dihydrate: 15.1 g (10 mmols) of the Z-compound prepared according to (c) are catalytically hydrogenated in the presence of Pd in 300 ml of methanol, a pH of 5 being maintained by simultaneously adding methanolic toluene-sulfonic acid. After complete reaction, the methanol is distilled off and the residue is reprecipitated from pyridine/ ether and methanol/water. The oil, which first precipitates becomes solid after a short time. Yield: 12.1 g (77.5%). (e) 1.65 g (1.1 mmols) of Boc-β-Ala-Tyr-Ser-Met-Glu-(OBut)-His-Phe-Arg-TrpGly-OH·4H2O and 1.56 g (1 mmol) of H-Lys(Boc)-Pro-Val-Gly-Lys(Boc)-Lys(Boc)-Lys(Boc)-NH-(CH2)4-NH-Boc-tosylate-dihydrate are dissolved together with 540 mg (4 mmols) of 1-hydroxybenzotriazole in 30 ml of dimethylformamide. A solution of 1.25 g (6 mmols) of dicyclohexylcarbodiimide in 4 ml of dimethylformamide is prepared and 1/3 of this solution is added to the above solution. The whole is stirred for 1 hour, then another third is added and, after a further hour, the last third is fed in. After a further 2 to 3 hours of stirring, the reaction product is precipitated with ether. Yield: 3.1 g. Without further purification, the compound is freed from the protective groups by standing for 1 hour in 80-90% trifluoroacetic acid containing some thioglycolic acid, and is subsequently precipitated by adding 150 ml of ether. Yield: 3.06 g of crude peptide-trifluoroacetate. After purification on carboxymethyl cellulose, 1.45 g of the chromatographically pure peptide are obtained in the form of acetate. [α]D20:-68.6°-2° (c=0.5 in 1% acetic acid). Amino acid analysis: Ser0.86Glu0.99Pro0.97Gly2.00Val1.03Met0.98Tyr0.02Phe1.00βAla1.01Lys4.00His1.02Arg0.94. References Geiger R. et al.; US Patent No. 3,749,709; July 31, 1973; Assigned to Farbwerke Hoechst Aktiengesellschaft vormals Meister Lucius and Bruning, Frankfurt am, Main, Germany

ALTECONAZOLE Therapeutic Function: Antifungal

Alteconazole

201

Chemical Name: (cis)-1-[[2-(4-Chlorophenyl)-3-(2,4-dichlorophenyl)oxiranyl] methyl]-1H-1,2,4-triazole Common Name: Alteconazole Structural Formula:

Chemical Abstracts Registry No.: 93479-96-0 Trade Name

Manufacturer

Country

Year Introduced

Alteconazole

Onbio Inc.

-

-

Raw Materials Potassium t-butylate 4-Chloroacetophenone 2,2'-Azoisobutyrodinitrile 1,2,4-Triazole

2,4-Dichlorobenzyltriphenylphosphonium chloride N-Bromosuccinimide 3-Choroperoxybenzoic acid Sodium hydride

Manufacturing Process 63.6 g of potassium t-butylate in 300 ml of dry methanol were introduced into a solution of 229 g of 2,4-dichlorobenzyltriphenylphosphonium chloride in 800 ml of dry methanol at 10°C, and 77.2 g of 4-chloroacetophenone were added after half an hour. The reaction solution was refluxed for 3 hours, the precipitated salt was filtered off at room temperature, the filtrate was evaporated down under reduced pressure, the residue was digested with petroleum ether at from 50°C to 70°C to free it from triphenylphosphine oxide, and the solution was evaporated down under reduced pressure. The residue was taken up in 1 liter of carbon tetrachloride, and the solution was refluxed with 81.7 g of N-bromosuccinimide and 4 g of 2,2'azoisobutyrodinitrile. After the reaction was complete, the succinimide was filtered off, the filtrate was evaporated down under reduced pressure and the residue was recrystallized from methanol. 73.4 g (38.8%) of Z-1-(2,4dichlorophenyl)-2-(4-chlorophenyl)-3-bromoprop-1-ene of melting point 128°C was obtained. 58.9 g of Z-1-(2,4-dichlorophenyl)-2-(4-chlorophenyl)-3-bromoprop-1-ene were refluxed with 52.3 g of 3-choroperoxybenzoic acid in 590 ml of chloroform. After the reaction was complete, the chloroform phase was

202

Althiazide

washed acid-free with aqueous sodium bicarbonate solution and water, dried over sodium sulfate and evaporated down under reduced pressure, and the residue was recrystallized from methanol to give two crystalline fractions: 41.3 g (70.2%) of 2-bromomethyl-2-(4-chlorophenyl)-3-(2,4-dichlorophenyl) oxirane (isomer A) of melting point 98-99°C, and, 12 g (20.4%) of 2bromomethyl-2-(4-chlorophenyl)-3-(2,4-dichlorophenyl)oxirane (isomer B) of melting point 93-95°C. 20.9 g of 1,2,4-triazole and 4.4 g of sodium hydride (50% strength dispersion in mineral oil) were dispersed in 150 mL of N,N-dimethylformamide, and a solution of 39.2 g of 2-bromomethyl-2-(4-chlorophenyl)-3-(2,4dichlorophenyl)oxirane (isomer A) and 16.6 g of potassium iodide in 150 ml of N,N-dimethylformamide was added at room temperature. After 8 hours, the reaction solution was worked up, and the product was recrystallized from diisopropyl ether. 31 g (81.9%) of 2-(1,2,4-triazol-1-ylmethyl)-2-(4chlorophenyl)-3-(2,4-dichlorophenyl)oxirane (isomer A) - alteconazole was obtained. MP: 119°C. References Janssenet B. al.; US Patent No. 4,464,381; August 7, 1984; Assigned to BASF Aktiengesellschaft, Fed. Rep. of Germany

ALTHIAZIDE Therapeutic Function: Diuretic, Antihypertensive Chemical Name: 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4dihydro-3-((2-propenylthio)methyl)-, 1,1-dioxide Common Name: Althiazide; Altizide Structural Formula:

Chemical Abstracts Registry No.: 5588-16-9 Trade Name

Manufacturer

Country

Year Introduced

Althiazide

Solchem

-

-

Altizide

Bayer

-

-

Altretamine

203

Raw Materials 4-Amino-2-chloro-5-(methylsulfamyl)benzenesulfonamide Dimethyl allylmercaptoacetal Manufacturing Process To 6.75 g (0.0225 mole) of 4-amino-2-chloro-5-(methylsulfamyl) benzenesulfonamide in 45 ml of dimethylformamide is added 4.86 g (0.03 mole) of dimethyl allylmercaptoacetal followed by 1.5 ml ethyl acetate saturated with hydrogen chloride gas. The solution is refluxed for 1.5 hours, cooled and added dropwise with stirring to ice/water. The resulting precipitate is filtered, dried and recrystallized from isopropanol. The recrystallization gave 4.0 g of 2-methyl-3-allylthiomethyl-6-chloro-7-sulfamyl-3,4-dihydro-1,2,4benzothiadiazine-1,1-dioxide; M.P. 168.5-170°C. References Merck Index, Monograph number: 326, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. GB Patent No. 902,658; Aug. 9, 1962 McManus J.M. et al.; US Patent No. 3,102,882; Sept. 3, 1963; Assigned to Chas. Pfizer and Co., Inc., New York

ALTRETAMINE Therapeutic Function: Antitumor Chemical Name: 2,4,6-Tris(dimethylamino)-1,3,5-triazine Common Name: Hexamethylmelamine Structural Formula:

Chemical Abstracts Registry No.: 645-05-6 Trade Name

Manufacturer

Country

Year Introduced

Hexastat

Roger Bellon

France

1979

Hexastat

Rhone Poulenc

Switz.

1981

Altretamine

Rhone Poulenc

W. Germany

1982

204

Aluminum nicotinate

Raw Materials Hexamethylolmelamine-Hexamethyl Ether Hydrogen Manufacturing Process 50 g of hexamethylolmelamine-hexamethyl ether in 950 cc methanol are hydrogenated, at 90°C to 100°C, in the presence of 2 g Raney nickel with 100 atmospheres excess pressure of hydrogen in a steel autoclave holding 2 L until the absorption of hydrogen is terminated. After the catalyst has been filtered off with suction, the methanol is distilled off. As a result, 23.1 g (86% of the theoretical) of crude hexamethylmelamine are formed having a melting point of 158°C to 162°C. After recrystallization from methanol, the pure product is obtained having a melting point of 168°C. References Merck Index 310 DFU 5 (10) 492, 635 (1980) DOT 18 (4) 165 (1982) I.N. p. 61 von Brachel, H. and Kindler, H.; US Patent 3,424,752; January 28, 1969; Assigned to Casella Farbwerke Mainkur AG

ALUMINUM NICOTINATE Therapeutic Function: Vasodilator Chemical Name: 3-Pyridinecarboxylic acid aluminum salt Common Name: Tris(nicotinato)aluminum Structural Formula:

Chemical Abstracts Registry No.: 1976-28-9 Trade Name Nicalex Alunitine

Manufacturer Merrell Dow Continental Pharma

Country Belgium US

Year Introduced 1960 -

Alverine citrate

205

Raw Materials Nicotinic acid Aluminum hydroxide Manufacturing Process Aluminum nicotinate is prepared by dissolving nicotinic acid in hot water and adding a slurry of aluminum hydroxide to it. A slight excess of aluminum hydroxide is used in order that the final product would be free of nicotinic acid. The precipitate is collected on a filter and dried. The final product contains a mixture of aluminum nicotinate and a small but acceptable amount of aluminum hydroxide. References Merck index 346 Kleeman and Engel p. 33 I.N.p.62 Miale, J.P.; US Patent 2,970,082; January 31, 196l; Assigned to Walker Laboratories, Inc.

ALVERINE CITRATE Therapeutic Function: Anticholinergic, Spasmolytic Chemical Name: Benzenepropanamine, N-ethyl-N-(3-phenylpropyl)-, citrate Common Name: Alverine citrate Structural Formula:

Chemical Abstracts Registry No.: 5560-59-8; 150-59-4 (Base) Trade Name

Manufacturer

Country

Year Introduced

Alverine citrate

Kemikos

-

-

Alverine citrate

Norgine

-

-

Alverine citrate

Bristhar Laboratorios -

-

Alvercol

Norgine

-

-

206

Amadinone

Trade Name

Manufacturer

Country

Year Introduced

Antispasmin

Balkanpharma Dupnitza Co.

-

-

Spasmaverine

Bellon

-

-

Spasmonal

Norgine

-

-

Spasmonal

Ying-Yuan Chemical Pharmaceutical Co., Ltd.

-

Raw Materials Ethylamine Hydrogen Platinum

3-Phenylpropylchloride Potassium hydroxide Barium sulfate

Manufacturing Process 2 Methods of producing of alverine: 1. 3-Phenylpropylchloride reacted with ethylamine in the presence potassium hydroxide and N-ethyl-3,3'-diphenyldipropylamine (alverine) was obtained. 2. 3-Phenylpropenal reacted with ethylamine in the presence hydrogen and Pt as catalyst and BaSO4 and N-ethyl-3,3'-diphenyldipropylamine (alverine) was obtained. In practice it is usually used as citrate. References Kleemann A., Engel J.; Pharmazeutische Wirkstoffe, GeorgThieme Verlag Stuttgart. New York, 1982

AMADINONE Therapeutic Function: Progestin Chemical Name: 19-Norpregna-4,6-diene-3,20-dione, 6-chloro-17-hydroxyCommon Name: Amadinone, 19-Norchlormadinone Chemical Abstracts Registry No.: 30781-27-2 Trade Name

Manufacturer

Country

Year Introduced

Amadinone

ZYF Pharm Chemical

-

-

Amadinone

207

Structural Formula:

Raw Materials δ(4)-3,20-Dioxo-6α,7α-oxido-17α-acetoxy-19-norpregnene Hydrochloric acid Methanesulfonyl chloride Sodium acetate Manufacturing Process A solution of 250.0 mg of δ4-3,20-dioxo-6α,7α-oxido-17α-acetoxy-19norpregnene in 15 ml of 1 N hydrochloric acid in dioxan is kept for 1 h at 25°C, then poured into water and neutralized with sodium bicarbonate solution. The precipitated crude product is dissolved in a 5:1 mixture of ether and methylene chloride, washed with water until the washings run neutral, and the solution is dried and evaporated under vacuum to give the δ4-3,20dioxo-6-chloro-7α-hydroxy-17α-acetoxy-19-nor-pregnene. The crude δ4-3,20-dioxo-6-chloro-7α-hydroxy-17α-acetoxy-19-nor-pregnene is dissolved in 3 ml of pyridine, mixed at 5°-0°C with 0.3 ml of methanesulphonyl chloride while being stirred, and the mixture is kept for 2 days at 10°C. The reaction product is then poured into dilute sodium bicarbonate solution, dissolved in ether, and the ethereal solution is washed until the washings run neutral, dried and evaporated under vacuum and the δ4-3,20-dioxo-6-chloro-7α-mesyloxy-17α-acetoxy-19-norpregnene is obtained. The δ4-3,20-dioxo-6-chloro-7α-mesyloxy-17α-acetoxy-19-norpregnene is dissolved in 25 ml of dimethyl formamide, mixed with 4.5 g of anhydrous sodium acetate, and the whole is heated for 75 min at 85°C under nitrogen while being stirred. The cooled reaction mixture is diluted with water, extracted with a 5:1-mixture of ether and methylene chloride, and the organic layer is washed with 100 ml of water, dried and evaporated. The resulting crude product is dissolved in benzene and chromatographed on 15 times its own weight of alumina (activity II). The afore-mentioned solvent elates 105.0 mg of pure δ4,6-3,20-dioxo-6-chloro-17α-acetoxy-19-norpregnadiene, melting point 159°-161°C (recrystallized from methylene chloride:hexane). The δ4,6-3,20-dioxo-6-chloro-17-hydroxy-19-norpregnadien, melting point 159°-161°C, may be produced by hydrolysis of δ4,6-3,20-dioxo-6-chloro-17αacetoxy-19-norpregnadiene.

208

Amafolone hydrochloride

References GB Patent No. 1,007,758; Dec. 29, 1961; Assigned: Ciba Limited, a body corporate organized according to the laws of Switzerland, of Basle, Switzerland

AMAFOLONE HYDROCHLORIDE Therapeutic Function: Antiarrhythmic Chemical Name: (2β,3α,5α)-3-Amino-2-hydroxyandrostan-17-one hydrochloride Common Name: Amafolone hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 51740-76-2; 50588-47-1 (Base) Trade Name

Manufacturer

Country

Year Introduced

Amafolone hydrochloride

ZYF Pharm Chemical

-

-

Raw Materials Perchloric acid Acetic acid Ammonia

N-Bromoacetamide 5α-Androst-2-en-17-one Potassium hydroxide

Manufacturing Process A solution of 70% perchloric acid (60 ml) in water (280 ml) was added to a stirred solution of 5α-androst-2-en-17-one (200.0 g) in ether (1.15 l) at 15°C followed by portionwise addition of N-bromacetamide (112.0 g) over 10 min. After stirring for 1 h the precipitated white crystalline solid was filtered off, washed neutral with ether and water and crystallised to give 2β-hydroxy-3αbromo-5α-androstan-17-one (172.0 g). The ether layer of the filtrate was washed neutral, dried (Na2SO4) and concentrated to give a second crop (28.0 g). The two crops (200.0 g) were suspended in methanol (1 L), 10 N aqueous potassium hydroxide solution (100 ml) added and the mixture slowly distilled over 45 min. Addition of water precipitated the product as a white solid which

Amanozine hydrochloride

209

was filtered off, washed with water, dried and 88.0 g of 2β,3β-epoxy-5αandrostan-17-one were obtained (crystallisation from ether:light petrol). A solution of the 2β,3β-epoxy-5α-androstan-17-one (30.0 g) in ethanol (130 ml), water (15 ml) and liquid ammonia was heated in an autoclave at 150°C for 6 h and the resultant crystalline suspension evaporated to dryness. Water (35 ml) and acetic acid (36 ml) were added and the solution kept at 90°C for 1 h, cooled and excess water added. The precipitated material was filtered off and the filtrate made alkaline with aqueous 10 N potassium hydroxide solution to precipitate a white solid which was filtered off, washed neutral with water, dissolved in methylene chloride, the solution dried (Na2SO4) concentrated and ether added to give 2β-hydroxy-3α-amino-5α-androstan-17-one (14.3 g), melting point l92°-195°C. In practice it is usually used as hydrochloride. References Hewett C.L., Savage D.S.; US Patent No. 3,862,196; Jan. 21, 1975; Assigned: Akzona Incorporated, Asheville, N.C.

AMANOZINE HYDROCHLORIDE Therapeutic Function: Diuretic Chemical Name: N-Phenyl-1,3,5-triazine-2,4-diamine monohydrochloride Common Name: Amanozine, Amenozine Structural Formula:

Chemical Abstracts Registry No.: 6011-10-5; 537-17-7 (Base) Trade Name

Manufacturer

Country

Year Introduced

Amanozine

Onbio Inc.

-

-

Raw Materials 1-Phenylbiguanide hydrochloride Sodium carbonate

210

Amantanium bromide

Manufacturing Process 21.3 g (0.1 mole) of 1-phenylbiguanide hydrochloride were dissolved in hot water and the solution was added to 5.3 g (0.05 mole) sodium carbonate by stirring. On cooling 15 g of the needle crystals have fallen. They were heated to reflux with 80 ml of dry formic acid. Then 40-50 ml formic acid was distilled off. The residue was with water diluted, cooled with ice and the conc. alkali was added. The precipitate fallen. It was filtered off and recrystallized from 40-50% ethanol. The pure product 4-amino-2-anilino-1,3,5-triazine had MP: 232°-233°C. Monochlorohydrate of it crystallized as long colorless needles melted at 258°260°C. References Clauder O. et al.; Austrian Patent No. 168,063; April 10, 1959; Richter Gedeon Vegyeszeti R.T. in Budapest Kleemann A., Engel J.; Pharmazeutische Wirkstoffe, GeorgThieme Verlag Stuttgart. New York, 1982

AMANTANIUM BROMIDE Therapeutic Function: Antiseptic Chemical Name: (2-(1-Tricyclo[3.3.1.13,7]decylcarbonyloxy)ethyl) decyldimethyl-ammonium bromide Common Name: Amantanium bromide Structural Formula:

Chemical Abstracts Registry No.: 58158-77-3 Trade Name

Manufacturer

Country

Year Introduced

Amantanium bromide

Onbio Inc.

-

-

Amantidine hydrochloride

211

Raw Materials 2-Dimethylaminoethanol 1-Bromodecan

1-Adamantanecarboxylic acid chloride Sodium hydroxide

Manufacturing Process A solution of 21.7 g (0.11 mole) 1-adamantanecarboxylic acid chloride in 100 ml ether was added to a solution of 19.4 g (0.22 mole) 2dimethylaminoethanol in 200 ml ether. The reaction mixture was stirred overnight at room temperature. Then additional 15.0 g (0.17 mole) 2dimethylaminoethanol was added and the reaction mixture again stirred overnight. The reaction mixture was poured into 300 ml water and treated with 20 ml of 10% NaOH solution. From the ether layer was recovered 23.0 g of 2-dimethylaminoethyl 1-adamantanecarboxylate as oil. The 2-dimethylaminoethyl 1-adamantanecarboxylate was mixed with 1bromodecan and allowed to stand for about 6 weeks. The resultant crystalline mass was washed with ether and dried to gave 2-(1’adamantanecarbonyloxy)ethyldimethyldecylammonium bromide as white crystals, melting point 183°-184.5°C (two recrystallizations from ethyl acetate). References Bauman R.A.; US Patent No. 3,928,411; Dec. 23, 1975; Assigned: ColgatePalmoliv Company, New York, N.Y.

AMANTIDINE HYDROCHLORIDE Therapeutic Function: Antiviral, Antiparkinsonian Chemical Name: 1-Adamantanamine hydrochloride Common Name: 1-Aminoadamantane hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 665-66-7 Raw Materials Adamantane Sodium hydroxide

Hydrocyanic acid Hydrogen chloride

212

Amantidine hydrochloride

Trade Name Symmetrel Symmetrel Symmetrel Mantadan Mantadix Symmetrel Amantadin Amantan Amazolon Antadine Atarin Contenton Influenol Paramantin Paritrel PK-Mertz Protexin Solu-Contenton Trivaline Viregyt Virofral Virofral Virosol

Manufacturer DuPont (Endo) Geigy Geigy De Angeli Theraplix Fujisawa Ratiopharm Byk Gulden Sawai DuPont Medica SK Dauelsberg Santos Orion Trima Mertz Landerlan SK and F Farmex EGYT Duphar Ferrosan Phoenix

Country US W. Germany UK Italy France Japan W. Germany Japan Australia Finland W. Germany Spain Finland Israel W. Germany Spain W. Germany France Hungary Belgium Denmark Argentina

Year Introduced 1966 1966 1971 1971 1973 1975 -

Manufacturing Process 360 ml of 96% sulfuric acid and a solution of 13.6 grams (0.1 mol) of adamantane in 100 ml of n-hexane were emulsified in the apparatus described and provided with an inclined centrifugal stirrer. Then a mixture of 46 grams (1.7 mols) of liquid hydrocyanic acid and 29.6 grams (0.4 mol) of tertiary butanol was added dropwise within 1.5 hours at about 25°C. After 30 minutes of postreaction, the product was poured on ice. The granular mass which precipitated [N-(adamantyl-1)formamide] was sucked off and washed with water. The raw product (37 grams) was then refluxed for 10 hours with a solution of 60 grams of NaOH in 600 ml of diethylene glycol. After cooling, the solution was diluted with 1.5 liters of water and subjected to three extractions with ether. The amine was extracted from the ethereal solution with 2 N HCl and liberated therefrom by the addition of solid NaOH (while cooling). The alkaline solution was extracted with ether and the ethereal solution was dried with solid NaOH. Distillation resulted in 10.6 grams (70% of the theory) of 1-aminoadamantane which, after sublimation, melted at 180°C to 192°C (seal capillary). It is converted to the hydrochloride. References Merck Index 373 Kleeman and Engel p. 33

Amantocillin

213

PDR p. 862 OCDS Vol. 2 p. 18 (1980) DOT 3 (1) 6 (1967) and 7 (2) 44 (1971) I.N. p. 63 REM p. 927 Haaf, W.; US Patent 3,152,180; October 6, 1964; Assigned to Studiengesellschaft Kohle GmbH, Germany

AMANTOCILLIN Therapeutic Function: Antibiotic Chemical Name: 4-Thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, 6(((3-aminotricyclo[3.3.1.13,7]dec-1-yl)carbonyl)amino)-3,3-dimethyl-7oxo-, (2S-(2α,5α,5β))Common Name: Amantocillin Structural Formula:

Chemical Abstracts Registry No.: 10004-67-8 Trade Name

Manufacturer

Country

Year Introduced

Amantocillin

Onbio Inc.

-

-

Raw Materials Sulfuric acid Sodium hydroxide Thionyl chloride Triethylamine

3-Bromoadamantane-1-carboxylic acid Acetic acid 6-Aminopenicillanic acid

Manufacturing Process A mixture of 3-bromoadamantane-1-carboxylic acid (5.8 g), acetonitrile (45 ml) and concentrated sulphuric acid (9 ml) was refluxed for 20 h. After cooling, the mixture was poured into water (250 ml), and the resulting suspension concentrated in vacuo to remove most of the acetonitrile. Aqueous sodium hydroxide (33%) was added until the pH was 4.0 (about 24 ml). The precipitate was filtered off, washed with water, and dried to yield 4.4 g of the 3-acetaminoadamantane-1-carboxylic acid, melting point 254°-258°C (two recrystallizations from methanol-aceto nitrile).

214

Ambazone

A solution of 3-acetamino-adamantane-1-carboxylic acid (3.0 g) in 4 N sodium hydroxide (40 ml) was refluxed for 5 h. After cooling, the pH of the solution was adjusted to 7 with acetic acid. The crystalline precipitate was filtered off, washed with ethanol and dried to yield 2.20 g of the desired compound, melting point over 330°C. In order to purify the compound, 2.0 g of it was suspended in water (10 ml), 4 N NaOH (2 ml) was added, and the resulting solution filtered through a filter aid known under the registered trademark 'Dicalite'. The filtrate was adjusted to a pH of 6.5 with acetic acid. The resulting crystalline precipitate was filtered off, washed with a little water followed by alcohol, and dried to yield 1.55 g of pure 3-amino-adamantane-1carboxylic acid. 3-Aminoadamantane-1-carboxylic acid (1.0 g) was refluxed with thionyl chloride (4.6 ml) for 1 h. Excess of thionyl chloride was removed in vacuo. The residue was dissolved in benzene (3 ml), and the resulting solution evaporated under reduced pressure to remove traces of thionyl chloride. This process was repeated to leave 1.3 g of a 3-thionyliminoadamantane-1carboxylic acid chloride, almost colourless. 500.0 mg of 3-thionyliminoadamantane-1-carboxylic acid chloride were dissolved in dry acetone (8 ml), and the resulting solution was added during 20 min at room temperature with stirring, to a suspension of 6aminopenicillanic acid (520.0 mg) in 50% aqueous acetone (20 ml), previously adjusted to a pH of 7.0 with triethylamine. During the process, a pH value of 7.0 was maintained by the addition of a 1 N solution of triethylamine in 50% aqueous acetone from an automatic titrator. At the end of the reaction, a clear solution was obtained. Acetone was removed in vacuo, and 70% of the theoretical amount of 3-amino-adamantyl-1-penicillin was formed. The aqueous solution was concentrated in vacuo to a volume of 4 ml. Addition of acetone (40 ml) gave an oily precipitate which after decanting and addition of fresh acetone gave 900.0 mg of a semicrystalline solid which contained 50% of the theoretical amount of 3-aminoadamantyl-1-penicillin. References Godtfredsen W.O.; US Patent No. 3,564,049; Feb. 16, 1971; Assigned: Lovens Kemiske Fabrik Produktionsaktieselskab, Ballerup, Denmark, a firm

AMBAZONE Therapeutic Function: Antiseptic Chemical Name: Guanidine, ((4-oxo-2,5-cyclohexadien-1-ylidene)amino)-, thiosemicarbazone monohydrate Common Name: Ambazone; Guanothiazone Chemical Abstracts Registry No.: 6011-12-7; 539-21-9 (Base)

Ambenonium chloride

215

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Ambazone

Generic

-

-

Ambazone

Terapia

-

-

Ambazone

East-Asia Pharmaceutical Chemical Co., Ltd.

-

Faringosept

Terapia

-

-

Faringosept

Interprindera

-

-

Iversal

Bayer

-

-

Primal

Bayer

-

-

Raw Materials Quinone monoguanylhydrazone nitrate Thiosemicarbazide Nitric acid Manufacturing Process To a solution of 22.7 g of quinone monoguanylhydrazone nitrate in 250 ml water is added dropwise hot aqueous solution of 9.1 g thiosemicarbazide, then is added slowly a solution of 5 ml concentrated nitric acid in 10 ml of water. The mixture is stirred at 60°C for 1 hour. The product is dissolved in 1-1.2 L of water at 100°C. The solution is filtered and added to an aqueous ammonium solution. Blue residue of p-benzoquinone amidinohydrazone thiosemicarbazone is filtered and dried, melting point 188°C (decomp.). References Merck Index, Monograph number: 395, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. Petersen S., Domagk G.; DE Patent No. 965,723; 1957-06-19; Assigned to Bayer AG

AMBENONIUM CHLORIDE Therapeutic Function: Cholinesterase inhibitor Chemical Name: N,N'-[(1,2-Dioxo-1,2-ethanediyl)bis(imino-2,1-ethanediyl)] bis[2-chloro-N,N-diethylbenzenemethanaminium] dichloride

216

Ambenonium chloride

Common Name: Structural Formula:

Chemical Abstracts Registry No.: 115-79-7 Trade Name Mytelase CL Mytelase Mytelase Mytelase Mytelase Mysuran

Manufacturer Winthrop Winthrop Winthrop Winthrop Nippon Shoji Winthrop

Country US W. Germany France UK Japan -

Year Introduced 1956 1950 1970 -

Raw Materials 2-Diethylaminoethylamine Ethyl oxalate 2-Chlorobenzyl chloride Manufacturing Process N,N'-Bis(2-Diethylaminoethyl)Oxamide: A solution of 150 grams (1.32 mol) of 2-diethylaminoethylamine in 250 ml of xylene was gradually added to a solution of 73.0 grams (0.5 mol) of ethyl oxalate in 250 ml of xylene, with external cooling. The mixture was then refluxed for eight hours, cooled and diluted with ether. The ether-xylene solution was extracted with 10% hydrochloric acid, and the hydrochloric acid extracts were in turn extracted with ether and then made alkaline with 35% sodium hydroxide solution. The organic material which separated was extracted with ether, and the ether solution was dried over anhydrous sodium sulfate and concentrated, giving 106.5 grams of N,N'-bis(2-diethylaminoethyl)oxamide, MP 40-42°C. N,N'-Bis(2-Diethylaminoethyl)Oxamide Bis(2-Chlorobenzochloride): A solution of 7 grams (0.025 mol) of N,N'-bis(2-diethylaminoethyl)oxamide and 16.1 grams (0.1 mol) of 2-chlorobenzyl chloride in 100 ml of acetonitrile was refluxed for eleven hours. The solid which separated upon cooling was collected by filtration and recrystallized by dissolving it in ethanol and adding ether to cause the product to separate. After drying at about 60°C (1-3 mm) there was obtained 4.1 grams of N,N'-bis(2-diethylaminoethyl)oxamide bis(2chlorobenzochloride), MP 196-199°C.

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References Merck Index 378 Kleeman and Engel p. 34 I.N. p. 64 REM p. 898 Kirchner, F.K.; US Patent 3,096,373; July 2, 1963; Assigned to Sterling Drug Inc. Behr, L.C. and Schreiber, R.S.; US Patent 2,438,200; March 23, 1948; Assigned to E.I. du Pont de Nemours and Co.

AMBENOXAN Therapeutic Function: Muscle relaxant Chemical Name: 2,3-Dihydro-N-[2-(2-methoxyethoxy)ethyl]-1,4benzodioxine-2-methanamine Common Name: Structural Formula:

Chemical Abstracts Registry No.: 2455-84-7 Trade Name

Manufacturer

Country

Year Introduced

Ambenoxan

ZYF Pharm Chemical

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Raw Materials 2-Aminomethyl-1,4-benzodioxane β-Methoxyethoxy ethyl chloride Potassium carbonate Manufacturing Process 2-Aminomethyl-1,4-benzodioxane (17 g) and β-methoxyethoxy ethyl chloride (7 g) were heated at 160°C for 2 hours. The reaction mixture was cooled and chloroform (30 ml) and a solution of potassium carbonate (7 g) in water (20 ml) added thereto.The chloroform layer was removed and the aqueous layer extracted twice with chloroform (10 ml each time). The chloroform extracts were combined and dehydrated over anhydrous sodium sulfate. Filtration, followed by distillation gave 2-(β-methoxyethoxyethyl)amino-methyl-1,4benzodioxane (yield 7.7 g) as a pale yellow oil boiling at 180-186°C/11.5 mm. The base was converted to a white hydrochloride having a melting point of

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104-106°C by the addition of alcoholic hydrogen chloride to an ether solution of the base and isolation of the salt which separated. References Shapero M., Green P.N.; US Patent No. 3,308,136; Mar. 7, 1967; Assigned to Ward Blenkinsop and Company Limited, Middlesex, England, a British company

AMBICROMIL Therapeutic Function: Antiallergic, Histamine H1 antagonist Chemical Name: 4H,6H-Benzo[1,2-b:5,4-b']dipyran-2,8-dicarboxylic acid, 4,6-dioxo-10-propylCommon Name: Probicromil; Ambicromil Structural Formula:

Chemical Abstracts Registry No.: 58805-38-2 Trade Name

Manufacturer

Country

Year Introduced

Probicromil

ZYF Pharm Chemical

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Raw Materials Benzyltrimethylammonium hydroxide Dimethyl acetylenedicboxylate Chlorosulfonic acid Manufacturing Process 4,6-Dioxo-10-propyl-4H,6H-benzo[1,2-b:5,4-b']dipyran-2,8-carboxylic acid: 2 ml of benzyltrimethylammonium hydroxide was added to a solution of 18.3 g 2-propylresorcine and dimethyl acetylenedicboxylate in 500 ml of ethanol and the mixture obtained was heated for 20 hours at reflux. The solution was cooled, 30 g sodium hydroxide in 150 ml of water was added and all mass was heated for 2 hours at reflux. On cooling the reaction mixture was poured into 2 L of water and washed with ethyl acetate. The water layer was acidified with conc. hydrochloric acid and a precipitate fallen was collected, washed

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with water, and dried in vacuum at 80°C to give 21 g cream-colored solid product. 21 g above product was in portion added to 200 ml of chlorosulfonic acid by ice cooling. The temperature of reaction was not higher 10°C. Then the reaction mixture was heated for 2.5 hours at 50°C. On cooling it was poured into 3 L of ice/water, the fallen precipitate was filtered off, washed with water and dried in vacuum. The solid product was heated with 100 ml of ethanol, an insoluble part was collected and boiled with 100 ml of ethyl acetate. Insoluble product was centrifuged and dried in vacuum at 60°C. Yield of title product hydrate 10.5 g. 4,6-Dioxo-10-propyl-4H,6H-benzo[1,2-b:5,4-b']dipyran-2,8carboxylic acid melted at 310°-311°C (deg). References Cairns H. et al.; D.E. Patent No. 2,851,440; Nov. 11, 1978

AMBROXOL Therapeutic Function: Expectorant Chemical Name: 4-[[(2-Amino-3,5-dibromophenyl)methyl]amino] cyclohexanol Common Name: Structural Formula:

Chemical Abstracts Registry No.: 18683-91-5 Trade Name Mucosolvan Mucosolvan Mucosolvon

Manufacturer Thomae De Angeli Boehringer Ingelheim

Country W. Germany Italy Switz.

Year Introduced 1980 1981 1982

Fluixol Fluibron Muciclar

Ripari-Gero Chiesi Piam

Italy Italy Italy

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Raw Materials N-(trans-p-Hydroxycyclohexyl)-(2-aminobenzyl)-amine Bromine

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Manufacturing Process 6.5 g of N-(trans-p-hydroxycyclohexyl)-(2-aminobenzyl)-amine were dissolved in a mixture of 80 cc of glacial acetic acid and 20 cc of water, and then 9.6 g of bromine were added dropwise at room temperature while stirring the solution. After all of the bromine had been added, the reaction mixture was stirred for two hours more and was then concentrated in a water aspirator vacuum. The residue was taken up in 2 N ammonia, the solution was extracted several times with chloroform, and the organic extract solutions were combined and evaporated. The residue, raw N-(trans-phydroxycyclohexyl)-(2-amino-3,5-dibromobenzyl)-amine, was purified with chloroform and ethyl acetate over silica gel in a chromatographic column, the purified product was dissolved in a mixture of ethanol and ether, and the solution was acidified with concentrated hydrochloric acid. The precipitate formed thereby was collected and recrystallized from ethanol and ether, yielding N-(trans-p-hydroxycyclohexyl)-(2-amino-3,5-dibromobenzyl)-amine hydrochloride, MP 233-234.5°C (decomposition). References Merck Index 383 DFU 1 (3) 95 (1976) Kleeman and Engel p. 35 I.N. p. 64 Kack, J., Koss, F.W., Schraven, E. and Beisenherz, G.; US Patent 3,536,713; October 27, 1970; Assigned to Boehringer Ingelheim G.m.b.H.

AMBRUTICIN Therapeutic Function: Antifungal Chemical Name: 2H-Pyran-2-acetic acid, 6-(2-(2-(5-(6-ethyl-3,6-dihydro-5methyl-2H-pyran-2-yl)-3-methyl-1,4-hexadienyl)-3-methylcyclopropyl) ethenyl)tetrahydro-4,5-dihydroxyCommon Name: Ambruticin; SMP-78 Structural Formula:

Chemical Abstracts Registry No.: 58857-02-6

Ambruticin Trade Name Ambruticin

Manufacturer Universitet Karlsruhe (TH)

Country -

Ambruticin

Kosan Biosciences Inc.

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Raw Materials Methyltriphenylphosphonium Methyl 2,3-di-O-benzyl-α-Dbromide glucopyranoside Tributyltin hydride t-Butyldiphenylsilyl chloride DMAP Tetrabutylammonium fluoride (-)-Dimenthyl succinate 2,2,6,6-Tetramethylpiperidine 1,1-Bromochloroethane Potassium hydroxide Diborane-THF complex Periodinane Triphenylphosphine Diisobutylaluminum hydride Triphenylmethyl chloride 1,1'-Thiocarbonyldiimidazole Diazomethane Sodium methoxide Sulfuric acid Acetic anhydride Glycosyl fluoride 4-Toluenesulfonic acid Triethylamine Diethylaminosulfur trifluoride Doss-Martin's periodinane PDC Sodium hydride Aldehyde Hydroquinone Imidazole Glyoxylic acid Potassium fluoride 2,4'-Dibromoacetophenone Oxalyl chloride (+)-α-Methylbenzylamine Methyl magnesium bromide trans-Propenyltrimethyltin Acetic anhydride N,N-Diisopropylamine Sodium hydrogen carbonate Butyl lithium Hydrogen hydrochloride 4-Toluenesulfonyl fluoride Lithium hydroxide Lithium Tetrabromomethane Sodium Tetramethylammonium acetate Ammonium chloride Benzylchlorobis(triphenylphosphine)palladium (II) Manufacturing Process Preparation of methyl 2,3-di-O-benzyl-1,4-dideoxy-1α/1β-fluoro-Dglucoheptopyranuronate: To a stirred solution of the methyl 2,3-di-O-benzyl-α-D-glucopyranoside (1.01 g, 2.70 mmol) in DMF (10 ml) was added imidazole (0.37 g, 5.40 mmol) followed by a solution of t-butyldiphenylsilyl chloride (0.89 g, 3.24 mmol) in DMF (3.5 ml) at 0°C. The resulting solution was stirred at room temperature for 2 h, cooled to 0°C, H2O (1 ml) was added, and the mixture was stirred for 10 min. The resulting solution was poured into H2O (100 ml) and extracted with Et2O (3x100 ml). The organic layers were combined, washed with brine, dried over sodium sulfate and filtered. The solvent was removed in vacuum to give a colorless oil, which was purified by column chromatography over silica gel (hexane-Et2O, 7:3) to afford 1.64 g (99%) of methyl 2,3-di-O-benzyl-6-Ot-butyldiphenylsilyl-α-D-glucopyranoside as a colorless viscous oil.

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To a stirred solution of methyl 2,3-di-O-benzyl-6-O-t-butyldiphenylsilyl-α-Dglucopyranoside (0.617 g, 1.01 mmol) in toluene (5 ml) was added 1,1'thiocarbonyldiimidazole (0.359 g, 2.01 mmol) at room temperature. The solution was heated at reflux. The reaction mixture was poured into 0.5 N HCl (50 ml) and extracted with CH2Cl2 (3x50 ml). The organic layers were combined, washed with sat. sodium bicarbonate solution followed by brine, dried over sodium sulfate and filtered. The solvent was removed in vacuum to give a crude yellow oil, which was purified by column chromatography over silica gel (hexane-EtOAc, 7:3) to afford 0.676 g (93%) of methyl 2,3-di-Obenzyl-6-O-t-butyldiphenylsilyl-4-O-imidazolyl-thiocarbonyl-α-Dglucopyranoside as a colorless viscous oil. To a stirred solution of nBu3SnH (0.24 g, 0.83 mmol) in toluene (4.2 ml) was added a solution of methyl 2,3-di-O-benzyl-6-O-t-butyldiphenylsilyl-4-Oimidazolyl-thiocarbonyl-α-D-glucopyranoside (0.30 g, 0.42 mmol) in toluene (2 ml) over 2 min at 100°C. The resulting solution was heated at reflux for 12 h. The solvent was removed in vacuum and the resulting crude oil was purified by column chromatography over silica gel (hexane-Et2O, 9:1) to afford 0.20 g (83%) of the methyl 2,3-di-O-benzyl-6-O-t-butyldiphenylsilyl-4deoxy-α-D-glucopyranoside as a colorless viscous oil. To a stirred solution of the methyl 2,3-di-O-benzyl-6-O-t-butyldiphenylsilyl-4deoxy-α-D-glucopyranoside (25.9 g, 43.4 mmol) in THF (400 ml) was added dropwise a 1 M solution of nBu4NF 65.1 ml in THF over 30 min at room temperature. The resulting solution was stirred at room temperature for 18 h and then poured into H2O (500 ml). The mixture was extracted with Et2O (3x500 ml). The organic extracts were combined, washed with brine, dried over sodium sulfate and filtered. The solvent was removed in vacuum to give a colorless oil, which was purified by column chromatography over silica gel (hexane-EtOAc, 1:1) to afford 14.81 g (95%) of methyl 2,3-di-O-benzyl-4deoxy-α-D-glucopyranoside as a colorless viscous oil. To a stirred solution of methyl 2,3-di-O-benzyl-4-deoxy-α-D-glucopyranoside (6.12 g, 17.1 mmol) in DMF ( 69 ml) was added 21.81 g (58 mmol) of PDC at room temperature. The resulting red-brown viscous solution was stirred at room temperature for 20 h. The reaction mixture was diluted with Et2O (100 ml) and stirred for 10 min. The clear yellow liquid was collected by decantation. The gummy brown residue was extracted with Et2O (3x100 ml). The extracts were combined, and concentrated in vacuum to give a yellow viscous oil, which was purified by column chromatography over silica gel (CH2Cl2 -MeOH, 10:1) to give 5.60 g (88%) of methyl 2,3-di-O-benzyl-4deoxy-α-D-glucopyranosiduronic acid as an amorphous powder. To a stirred solution of the methyl 2,3-di-O-benzyl-4-deoxy-α-Dglucopyranosiduronic acid (1.73 g, 4.65 mmol) in CH2Cl2 (30 ml) was added oxalyl chloride (0.943 g, 0.65 ml, 7.43 mmol) followed by DMF (0.23 mmol) at room temperature. The resulting clear solution was stirred at room temperature for 2 h, and then concentrated in vacuo. To a solution of the crude acyl chloride derivative in Et2O (50 ml) was added a solution of diazomethane in Et2O (30 ml) at 0°C over 20 min. The resulting clear yellow solution was stirred at room temperature for 30 min and then

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evaporated in vacuo at under 20°C to give a crude yellow oil, which was purified by column chromatography over silica gel (hexane-Et2O, 1:1) to afford 1.44 g (78%) of the corresponding diazoketone as a yellow viscous oil. A solution of the diazoketone prepared above (1.39 g, 3.52 mmol) in MeOH (60 ml) was placed in a 100 ml pyrex test tube, and irradiated by a Hanovia 30620 type medium pressure UV arc under constant cooling by running H2O for 48 h. The reaction mixture was concentrated in vacuo to give a yellow oil, which was purified by column chromatography over silica gel (hexane-Et2O, 3:2) to afford 0.96 g (68%) of methyl (methyl 2,3-di-O-benzyl-4-deoxy-α-Dglucoheptopyranosiduronate as a colorless viscous oil. To a stirred solution of the methyl (methyl 2,3-di-O-benzyl-4-deoxy-α-Dglucoheptopyranosiduronate (0.705 g, 1.76 mmol) in acetic anhydride (7 ml) was added 1 ml of a 10% solution of H2SO4 in acetic anhydride at -30°C. The resulting solution was stirred at -20°C for 10 min. The reaction mixture was poured into a sat. sodium bicarbonate solution (100 ml) and stirred well for 30 min at room temperature to destroy the excess of acetic anhydride. The resulting mixture was extracted with Et2O (3x100 ml). The organic extracts were combined, washed with brine, dried over sodium sulfate and filtered. The solvent was removed in vacuum to give a colorless oil, which was purified by column chromatography over silica gel (hexane-Et2O, 3:2) to afford 0.664 g (88%) of 82:18 mixture of methyl (acetyl 2,3-di-O-benzyl-4-deoxy-α/β-Dglucoheptopyranosiduronate). To a freshly prepared solution of sodium methoxide (1.931 mmol) in MeOH (15 ml) was added a solution of methyl (acetyl 2,3-di-O-benzyl-4-deoxy-α/βD-glucoheptopyranosiduronate) (413.0 mg, 0.966 mmol) in MeOH (5 ml) at 0°C. The resulting solution was stirred at 0°C for 10 min and then poured into H2O (50 ml). The mixture was extracted with Et2O (3x50 ml). The organic extracts were combined, washed with brine, dried over sodium sulfate and filtered. The solvent was removed in vacuum to give a residue, which was purified by column chromatography over silica gel (hexane-EtOAc, 3:2) to afford 360.0 mg (97%) of the mixture of methyl 2,3-di-O-benzyl-4-deoxy-α/βD-glucoheptopyranuronate. To a stirred solution of methyl 2,3-di-O-benzyl-4-deoxy-α/β-Dglucoheptopyranuronate (472.0 mg, 1.22 mmol) in CH2Cl2 (12 ml) was added diethylaminosulfur trifluoride (DAST) (590.0 mg, 3.66 mmol) at -30°C. The resulting colorless solution was stirred at 0°C for 20 min and then cooled again to -30°C. MeOH (1 ml) was added to the reaction mixture to destroy the excess of DAST. After stirring at 0°C for 10 min, the solution was poured into a sat. sodium bicarbonate solution (50 ml) and extracted with Et2O (3x50 ml). The organic extracts were combined, washed with brine, dried over sodium sulfate and filtered. The solvent was removed in vacuum to give a colorless oil, which was purified by column chromatography over silica gel (hexane-Et2O, 3:2) to afford 454.0 mg (96%) of 27:73 mixture of methyl 2,3di-O-benzyl-1,4-dideoxy-1α/1β-fluoro-D-glucoheptopyranuronate. Preparation of methyl (8E,10S,11S,12S)-2,3-di-O-benzyl-1,4-dideoxy-1β-[11methyl-12-formylcyclopropylethenyl]-D-glucoheptopyranuronate.

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A dry, 1.0 L, three-necked, round-bottomed flask containing a magnetic stirring bar, and a thermometer was charged with freshly distilled 2,2,6,6tetramethylpiperidine (29.7 ml, 176 mmol) and dry THF (240 ml). The solution was cooled to 0°C and nBuLi 2.5 M in hexane, 70.4 ml, 176 mmol) was added dropwise over 45 min. Following the addition, the mixture was stirred for 20 min at 0°C, then cooled to -78°C. A solution of (-)-dimenthyl succinate (31.56 g, 80 mmol) in THF (80 ml) was added dropwise over 1 h. The resulting yellow solution of succinate dianion was stirred for 1 h. To the reaction mixture was added a solution of 1,1-bromochloroethane (10.1 g, 70.4 mmol) in THF (15 ml) over a 5 h-period. After the reaction mixture was stirred for 2.5 h, it was poured into ice-cooled 0.5 N HCl (320 ml) and the product extracted with Et2O (3x300 ml). The combined organic phases were washed with brine (1x400 ml), dried over sodium sulfate, filtered, and concentrated in vacuum. The residue was chromatographed over silica gel (hexane-Et2O 20:1) to give 13.23 g (45 %) of dimenthyl (1S,2S)-3methylcyclopropane-1,2-dicarboxylate as colorless crystals, melting point 98°99°C. To a solution of the dimenthyl (1S,2S)-3-methylcyclopropane-1,2dicarboxylate (2.5 g, 5.94 mmol) in THF (10 ml) was added a 10% KOH solution in 9:1( EtOH-H2O (3.94 ml, 7.02 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3.5 days, then the solvent was evaporated, diluted with H2O, and extracted with Et2O. The aqueous layer was acidified with a 10% HCl solution to pH ~ 3 and extracted several times with Et2O. The combined organic layers were washed successively with H2O, brine, and dried over sodium sulfate. Evaporation of the solvent in vacuum afforded 1.4 g (83%) of the menthyl (1S,2S,3S)-2carboxy-3-methylcyclopropane-1-carboxylate as a clear oil. To a solution of the menthyl (1S,2S,3S)-2-carboxy-3-methylcyclopropane-1carboxylate (1.32 g, 4.68 mmol) in dry THF (40 ml) cooled to 0°C was added dropwise a 1.0 M solution of B2H6-THF complex (5.62 ml, 5.62 mmol) over a 20 min-period. The reaction mixture was allowed to warm to room temperature and stirred for 8 h, followed by the addition of a second equivalent of B2H6-THF complex (5.617 ml, 5.617 mmol). When all the starting material had disappeared, the reaction mixture was carefully quenched at room temperature by a dropwise addition of 1:1, H2O-AcOH (1 ml) with stirring until no more gas evolution occurred. The reaction mixture was concentrated at room temperature, and the slurry was diluted with EtOAc (80 ml) and washed with H2O (30 ml). The aqueous phase was extracted with EtOAc (3x80 ml). The combined organic layers were washed with a sat. sodium bicarbonate solution, brine, and then dried over sodium sulfate. Solvent removal and purification of the residue by chromatography (hexaneEtOAc, 8:2) gave 1.25 g (100%) of menthyl (1S,2S,3S)-2-hydroxymethyl-3methylcyclopropane-1-carboxylate as a white solid, melting point 85°-86°C. A solution of the menthyl (1S,2S,3S)-2-hydroxymethyl-3-methylcyclopropane1-carboxylate (0.536 g, 2 mmol) in CH2Cl2 (10 ml) was added to a suspension of periodinane (1.017 g, 2.4 mmol) in CH2Cl2 (10 ml) with stirring. The reaction mixture was stirred at room temperature for 1.5 h, followed by the addition of a second equivalent of the periodinane reagent. When all the starting material had disappeared, the reaction mixture was filtered through

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Celite, and the filter cake was washed with CH2Cl2. The solvent was evaporated in vacuum, and the residue was chromatographed over silica gel (hexane-EtOAc, 95:5) to give 0.51 g (96%) of menthyl (1S,2S,3S)-2-formyl3-methylcyclopropane-1-carboxylate as a white crystalline solid, melting point 66°-67°C. A solution of triphenylphosphine (1.42 g, 5.41 mmol) in CH2Cl2 (15 ml) was cooled to 0°C and treated with CBr4 (0.896 g, 2.70 mmol). A solution of menthyl (1S,2S,3S)-2-formyl-3-methylcyclopropane-1-carboxylate (0.360 g, 1.35 mmol) in CH2Cl2 (10 ml) was then added dropwise. The yellow solution was stirred at 0°C for 30 min. The solvent was evaporated in vacuum, and the residue was chromatographed over silica gel (hexane-EtOAc, 96:4) to give 0.56 g (98%) of menthyl (1S,2S,3S)-2-(2,2-dibromovinyl)-3methylcyclopropane-1-carboxylate as a white solid, melting point 75°-76°C. To a stirred solution of the menthyl (1S,2S,3S)-2-(2,2-dibromovinyl)-3methylcyclopropane-1-carboxylate (3.96 g, 9.37 mmol) in toluene (50 ml) was added a 1 M solution of diisobutylaluminum hydride (DIBALH) (28.1 ml, 28.1 mmol) in hexane at -78°C. The resulting solution was stirred at -78°C for 10 min and then at 0°C for 30 min. The reaction mixture was poured into 0.2 N HCl (200 ml) and extracted with Et2O (3x200 ml). The organic extracts were combined, washed with brine, dried over sodium sulfate and filtered. The solvent was removed in vacuum to give a colorless crude oil, which was purified by column chromatography over silica gel (hexane-Et2O, 1:1) to afford 2.29 g (90%) of the corresponding cyclopropylcarbinol as a colorless oil. To a stirred solution of the cyclopropylcarbinol obtained above (2.33 g, 8.64 mmol) in DMF (35 ml) was added triphenylmethyl chloride (9.64 g, 34.6 mmol) followed by Et3N (9.63 ml, 69.1 mmol) and DMAP (0.21 g, 1.73 mmol) at room temperature. The resulting mixture was stirred at room temperature for 72 h, poured into an aqueous ammonium chloride solution (100 ml), and then extracted with Et2O (3x200 ml). The organic layer was combined, washed with brine, dried over sodium sulfate and filtered. The solvent was removed in vacuum to give a colorless oil, which was purified by column chromatography over silica gel (hexane-CH2Cl2, 8:1) to afford 3.98 g (90%) of the (1S,2S,3S)-2-(2,2-dibromovinyl)-3-methyl-1triphenylmethoxymethylcyclopropane as a colorless viscous oil. To a stirred solution of the (1S,2S,3S)-2-(2,2-dibromovinyl)-3-methyl-1triphenylmethoxymethyl-cyclopropane (128.6 mg, 0.251 mmol) in THF (5 ml) was added dropwise a 1.42 M solution of nBuLi (0.35 ml, 0.50 mmol) in hexane at -78°C. After stirring at -78°C for 10 min, the solution was poured into H2O (30 ml) and extracted with Et2O (3x30 ml). The organic extracts were combined, washed with brine, dried over sodium sulfate and filtered. The solvent was removed in vacuum to give a colorless residue, which was purified by column chromatography over silica gel (hexane-Et2O, 20:1) to afford 81.4 mg (92%) of (1S,2S,3S)-3-ethynyl-2-methylcyclopropylmethyl triphenylmethyl ether as a colorless viscous oil. To a stirred solution of the (1S,2S,3S)-3-ethynyl-2-methylcyclopropylmethyl triphenylmethyl ether (333.0 mg, 0.945 mmol) in hexane (3 ml) was added a

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1.0 M solution of DIBALH (0.95 ml, 0.95 mmol) in hexane at 40°C. The resulting solution was stirred at 50°C for 2 h. After cooling to room temperature, the reaction mixture was diluted with toluene (4 ml). To this in situ-generated vinylalane solution was added a solution of methyl 2,3-di-Obenzyl-1,4-dideoxy-1α/1β-fluoro-D-glucoheptopyranuronate (anomeric mixture, α:β=27:73, 282.0 mg, 0.727 mmol) in toluene (1 ml) at -20°C. The resulting colorless solution was stirred at -20°C for 10 min then at room temperature for 30 min. The reaction mixture was poured into 0.2 N HCl (20 ml) and extracted with Et2O (3x30 ml). The organic extracts were combined, washed with brine, dried over sodium sulfate and filtered. The solvent was removed in vacuum to give a colorless crude residue, which was purified by column chromatography over silica gel (hexane-CH2Cl2-EtOAc, 20:20:1) to afford 0.256 g (49%) of methyl (8E,10S,11S,12S)-2,3-di-O-benzyl-1,4dideoxy-1β-[11-methyl-12-triphenylmethoxymethylcyciopropylethenyl]-Dglucoheptopyranuronate and 0.150 g (28%) of methyl (8E,10S,11S,12S)-2,3di-O-(benzyl-1,4-dideoxy-1α-[11-methyl-12triphenylmethoxymethylcyclopropylethenyl]-D-glucoheptopyranuronate as colorless oils. To a stirred solution of methyl (8E,10S,11S,12S)-2,3-di-O-benzyl-1,4-dideoxy1β-[11-methyl-12-triphenylmethoxymethylcyclopropylethenyl]-Dglucoheptopyranuronate (173.0 mg, 0.24 mmol) in CH2Cl2 (2 ml) was added a solution of p-toluenesulfonic acid (9.0 mg, 0.048 mmol) in MeOH (2 ml) at room temperature. The resulting solution was stirred at room temperature for 2 h and then poured into a sat. sodium bicarbonate solution (20 ml). This mixture was extracted with Et2O (3 x 30 ml). The organic extracts were combined, washed with brine, dried over sodium sulfate and filtered. The solvent was removed in vacuum to give a colorless residue, which was purified by preparative thin layer chromatography (hexane-EtOAc, 1:1) to afford 106.0 mg (92%) of the methyl (8E,10S,11S,12S)-2,3-di-O-benzyl-1,4-dideoxy-1β[11-methyl-12-hydroxymethylcyclopropylethenyl]-D-glucoheptopyranuronate as a colorless oil. To a stirred solution of the methyl (8E,10S,11S,12S)-2,3-di-O-benzyl-1,4dideoxy-1β-[11-methyl-12-hydroxymethylcyclopropylethenyl]-Dglucoheptopyranuronate (96.2 mg, 0.20 mmol) in CH2Cl2 (5 ml) was added Doss-Martin's periodinane (127.0 mg, 0.30 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 30 min and then diluted with Et2O (20 ml). This mixture was poured into a sat. sodium bicarbonate solution (10 ml) containing sodium thiosulfate (0.5 g). The organic layer was separated and the aqueous layer was washed with Et2O (2x20 ml). The organic extracts were combined, washed with brine, dried over sodium sulfate and filtered. The solvent was removed in vacuum to give a crude residue, which was purified by preparative thin layer chromatography (hexane-EtOAc, 3:1) to afford 86.5 mg (90%) of methyl (8E,10S,11S,12S)2,3-di-O-benzyl-1,4-dideoxy-1β-[11-methyl-12-formylcyclopropylethenyl]-Dglucoheptopyranuronate as a colorless oil. Preparation of (+)-6-ethyl-5-methyl-2-(4-sulfotolyl-1,3-dimethyl-but-1-ene)yl-3,6-dihydro-2H-pyran: Sodium hydride (16.0 g, 0.4 mol, as a 60% dispersion in mineral oil) in a 1.0 L three-necked flask was washed with hexane (3x50 ml) to remove the

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mineral oil. The flask was then equipped with rubber stoppers, a reflux condenser, and a mechanical stirrer. The system was alternatively evacuated and filled with nitrogen; DMSO (140 ml) was introduced rapidly, and the mixture was heated at 75°-80°C for 60 min, or until the evolution of hydrogen ceased. The resulting black-greenish solution of methylsulfinyl carbanion was cooled in an ice-H2O bath, and methyltriphenylphosphonium bromide (142.8 g, 0.4 mol) in warm DMSO (320 ml) was added at 15°-20°C. The resulting solution was allowed to warm to it and stirred for 10 min, then at 30°-32°C for 10 min or until a red-brownish color developed. The reaction mixture was cooled to 15°C and the aldehyde (43.34 g, 0.44 mol) was added dropwise (through a cannula), keeping the temperature between 15°-20°C. The reaction mixture was stirred at room temperature for 25 min, then at 30°32°C for 20 min. The reaction was immediately distilled in the presence of a cat. amount of hydroquinone under reduced pressure to give 32.0 g (75%) of 3-methyl-1,3-hexadiene collected in a solid carbon dioxide trap, boiling point 35°-37°C/59 mm Hg. Freshly distilled 3-methyl-1,3-hexadiene (15.6 g, 0.162 mol) was placed into a Carius tube containing a cat. amount of hydroquinone, glyoxylic acid monohydrate (22.45 g, 0.244 mol), and CHCl3 (80 ml). The tube was sealed and heated at 115°-120°C for 12 h. The reaction mixture was cooled to 0°C and diluted with H2O (30 ml), the organic phase was separated and the aqueous phase was extracted with CH2Cl2 (3x60 ml). The combined organic extracts were washed with H2O (1x100 ml), brine (1x100 ml), and dried over sodium sulfate. Complete removal of solvent afforded 22.5 g (81%) of a 4:1 mixture of (cis:trans) 6-ethyl-5-methyl-3,6-dihydro-2H-pyran-2-carboxylic acid as a reddish viscous oil, which was used directly in the next step without further purification. A mixture of potassium fluoride (33.83 g, 0.582 mol), 2,4'dibromoacetophenone (80.93 g, 0.291 mol), and DMF (350 ml) was stirred at room temperature for 5 min. A solution of 4:1 mixture of (cis:trans) acids (45.0 g, 0.265 mol) in DMF (50 ml) was then added to the reaction mixture and the whole stirred at room temperature for 3 h, then at 100°C for 30 min. The reaction mixture was cooled to room temperature and diluted with H2O (200 ml). The aqueous solution was extracted with Et2O (4x400 ml). The combined ethereal extracts were washed with H2O (3x400 ml) and dried over sodium sulfate. After the solvent was partially removed in vacuo, a precipitate was formed. The slurry was the filtered to give 51.0 g (53%) of pbromophenacyl ester of 6-ethyl-5-methyl-3,6-dihydro-2H-pyran-2-carboxylic acids as a white solid material, melting point 137°-138°C. To a solution of the p-bromophenacyl ester of 6-ethyl-5-methyl-3,6-dihydro2H-pyran-2-carboxylic acids (46.0 g, 0.125 mol) in glacial AcOH (650 ml) was slowly added zinc (dust, 49.31 g, 0.754 mol) in a 60 min-period at room temperature. The reaction mixture was stirred at room temperature for 8 h, then filtered on Celite, and the zinc residue washed with AcOH (200 ml), then THF (200 ml). Most of the solvent was evaporated and the crude reaction mixture diluted with Et2O and washed with H2O (2x150 ml). The organic layer was treated with a diluted NaOH solution to pH ~ 10. The aqueous phase was washed with Et2O several times, then acidified with a 1.0 N HCl solution to pH ~ 4, and extracted with Et2O. The combined organic extracts were

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successively washed with H2O, brine, and dried over sodium sulfate. After evaporation of the solvent, 19.23 g (90%) of pure (+)-6-ethyl-5-methyl-3,6dihydro-2H-pyran-2-carboxylic acid was obtained as a yellowish solid, melting point 61°-63°C. This acid was used in the next step without further purification. To a solution of (+)-6-ethyl-5-methyl-3,6-dihydro-2H-pyran-2-carboxylic acid (21.0 g, 0.123 mol) in MeOH (125 ml) was added (+)-α-methylbenzylamine (14.97 g, 0.123 mol) with stirring. The solvent was partially evaporated in vacuo and Et2O (100 ml) was added. The solvents were partially evaporated and more Et2O was added. The process was repeated until crystallization occurred. The reaction mixture was cooled to 0°C and filtered to give 19.0 g of the salt. The recrystallization process was repeated four more times or until the optical rotation of the corresponding acid was constant. After five recrystallizations, 6.0 g of the corresponding salt were obtained. This salt was then acidified with a 1.0 N HCl solution to pH ~ 4 and extracted with Et2O several times. The organic phase was successively treated with H2O, brine, and then dried over sodium sulfate. Evaporation of the solvent in vacuo gave 3.4 g (32%, from the racemic acid) of the optically pure acid (+)-6-ethyl-5methyl-3,6-dihydro-2H-pyran-2-carboxylic acid as a clear viscous oil. To a stirred solution of the (+)-6-ethyl-5-methyl-3,6-dihydro-2H-pyran-2carboxylic acid (3.0 g, 17.65 mmol) in CH2Cl2 (60 ml), and DMF (0.12 ml) at 0°C was added oxalyl chloride (1.82 ml, 21.18 mmol) over a 30 min-period. The reaction mixture was stirred at 0°C for 1 h, then at room temperature for 2 h. The solvent was evaporated in vacuum, and the residue was used directly in the next reaction without further purification. In a 50 ml, two-necked, round-bottomed flask equipped with a Teflon-covered magnetic stirring bar, a drierite filled trap, and a thermometer was placed the crude acid chloride in HMPA (16 ml). Freshly prepared trans-propenyltrimethyltin (4.34 g, 21.18 mmol) was then added followed by the addition of benzylchlorobis(triphenylphosphine)palladium (II) (13.6 mg, 0.02 mmol). The yellow solution was heated at 65°-70°C with stirring under an air atmosphere for 3 h. The reaction mixture was cooled to room temperature and H2O (15 ml) was added. The mixture was extracted with Et2O (3x60 ml). The ethereal solutions were combined and washed with H2O, brine, dried over sodium sulfate, and the solvent removed in vacuum. The residue was purified by chromotography over silica gel (hexane-EtOAc, 98:2) to give 3.1 g (90%) of (+)-6-ethyl-5-methyl-2-(but-2-ene-1-one)-yl-3,6-dihydro-2H-pyran as a colorless volatile oil. A solution of the α,β-(+)-6-ethyl-5-methyl-2-(but-2-ene-1-one)-yl-3,6dihydro-2H-pyran (3.02 g, 15.44 mmol) in THF (80 ml) was cooled to 0°C and MeMgBr (3.1 M solution in Et2O, 6.5 ml, 20.1 mmol) was added dropwise over a 30 min-period. After the addition, the reaction mixture was stirred at 0°C for 2 h under argon. The reaction mixture was quenched at 0°C by addition of a sat. ammonium chloride solution (14 ml), then H2O (14 ml). The mixture was extracted with Et2O (3x70 ml). The ethereal solutions were combined and washed with brine (1x50 ml), dried over sodium sulfate and the solvent removed by evaporation. The residue was purified by chromatography over silica gel (hexane-EtOAc, 98:2) to give 3.0 g (92 %) of the (+)-6-ethyl-5methyl-2-(1-methyl-1-hydroxy-2-buten)-yl-3,6-dihydro-2H-pyran-as a clear

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volatile liquid. Acetic anhydride (3.02 ml, 31.96 mmol) was added to a stirred solution of (+)-6-ethyl-5-methyl-2-(1-methyl-1-hydroxy-2-buten)-yl-3,6-dihydro-2Hpyran (3.36 g, 15.98 mmol), Et3N (4.46 ml), and DMAP (0.39 g, 3.2 mmol) in CH2Cl2 (15 ml) at room temperature. The solution was stirred at room temperature for 3 days in a sealed tube. Excess of anhydride was quenched by the addition of MeOH. Evaporation of the solvents gave a reddish-oily residue, which was suspended in Et2O and successively treated with 1.0 N HCl, aqueous sodium hydrogen carbonate, and sodium chloride sat. solution. The organic layer was dried over sodium sulfate and evaporated in vacuum. Purification of the residue by chromatography over silica gel (hexane-EtOAc, 98:2) gave 2.9 g (72%) of the acetic acid (+)-6-ethyl-5-methyl-2-(1-methyl1-hydroxy-2-buten)-yl-3,6-dihydro-2H-pyran ester as a colorless oil. To a stirred solution of dry N,N-diisopropylamine (1.1 ml, 7.85 mmol) in THF (10 ml) cooled to 0°C was added nBuLi (2.5 M in hexanes, 3.14 ml, 7.85 mmol) over several min. After the solution was stirred for 10 min following the addition, the reaction mixture was cooled to -78°C, and an additional 1 ml of THF was added. The acetic acid (+)-6-ethyl-5-methyl-2-(1-methyl-1hydroxy-2-buten)-yl-3,6-dihydro-2H-pyran ester (1.65 g, 6.54 mmol) in THF (7 ml) was slowly added over a 40 min-period at -78°- (-70)°C. After the reaction was stirred for 5 min, TBSCl (1.18 g) in THF-HMPA (1:1,6 ml) was added in one portion. The cooling bath was then removed, and the reaction mixture was allowed to warm to 0°C and stirred for 1 h, then at room temperature for an additional 1 h, and finally 1.5 h at 65°C. The yellow solution was cooled to room temperature and diluted with THF (60 ml), then treated with a 10% HCl aqueous solution (16 ml). The reaction mixture was stirred at room temperature for 3 h The solvent was evaporated and the residue diluted with Et2O and treated with a 1.0 N KOH aqueous solution; the organic phase was discarded, and the aqueous solution was washed with Et2O. The basic solution was acidified with 10% HCl and the product isolated by ether extraction. This afforded 1.0 g (61%) of a 12:1 mixture of (+)-6-ethyl5-methyl-2-(3-methyl-hex-4-enoic acid)-3,6-dihydro-2H-pyran as a colorless oil. This mixture was carried through the next reaction without further purification. A solution of (+)-6-ethyl-5-methyl-2-(3-methyl-hex-4-enoic acid)-3,6-dihydro2H-pyran (1.0 g, 3% mmol) in Et2O (20 ml) was treated with an excess of diazomethane. The solvent was then evaporated, and the two isomers were cleanly separated by chromatography over silica gel (hexane-EtOAc, 98:2) to give 0.97 g (92%) of the methyl (+)-6-ethyl-5-methyl-2-(3-methyl-hex-4enoic acid)-3,6-dihydro-2H-pyran ester as a clear liquid. A solution of N,N-diisopropylamine (0.24 ml, 1.7 mmol) in THF (3 ml) was treated with nBuLi (2.5 M in hexane, 0.68 ml, 1.7 mmol) at 0°C, under a nitrogen atmosphere. After 20 min at 0°C, the solution was cooled to -78°C, and a solution of the methyl (+)-6-ethyl-5-methyl-2-(3-methyl-hex-4-enoic acid)-3,6-dihydro-2H-pyran ester (266.0 mg, 1 mmol) in THF (3 ml) was slowly added. After 1 h at -78°C, p-toluenesulfonyl fluoride (348.0 mg, 2.0 mmol) in THF (2 ml) was added all at once. The reaction mixture was allowed to warm to room temperature and stirred for 24 h, then cooled to 0°C, quenched by careful addition of a sat. ammonium chloride solution, and

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extracted with EtOAc several times. The combined organic extracts were washed with H2O and brine, dried over sodium sulfate, and concentrated in vacuum. The residue was chromatographed over silica gel (hexane-EtOAc, 9:1) to give 180.0 mg (43% isolated yield) of methyl (+)-6-ethyl-5-methyl-2(2-sulfonyl-benzene-3-methyl-hex-4-enoic acid)-3,6-dihydro-2H-pyran ester, melting point 129°-131°C as a mixture of diastereomers. This diastereomeric mixture was used directly in the next step without further purification. To a stirred solution of methyl (+)-6-ethyl-5-methyl-2-(2-sulfonyl-benzene-3methyl-hex-4-enoic acid)-3,6-dihydro-2H-pyran ester (130.0 mg, 0.31 mmol) in HMPA (2 ml) was added (Me)4N+ -OAc (370.0 mg, 2.78 mmol) and the mixture was heated at 96°-100°C for 17 h. The reaction mixture was cooled and diluted with EtOAc, washed with H2O several times, brine, dried over magnesium sulfate, and the solvent removed in vacuum. The residue was purified by chromatography over silica gel (hexane-EtOAc 9:1) to give 0.08 g (71%) of (+)-6-ethyl-5-methyl-2-(4-sulfotolyl-1,3-dimethyl-but-1-ene)-yl-3,6dihydro-2H-pyran as a clear liquid. Preparation of (+)-Ambruticin: To a stirred solution of (+)-6-ethyl-5-methyl-2-(4-sulfotolyl-1,3-dimethyl-but1-ene)-yl-3,6-dihydro-2H-pyran (54.4 mg, 0.15( mmol) in dry Et2O (1 ml) cooled to 0°C was added dropwise a solution of nBuLi (1.5 M in hexane, 0.18 mmol). The yellow solution was stirred at 0°C for 10 min, then at -42°C for 15 min. Dry hexane (0.5 ml) was added, and a solution of the methyl (8E,10S,11S,12S)-2,3-di-O-benzyl-1,4-dideoxy-1β-[11-methyl-12formylcyclopropylethenyl]-D-glucoheptopyranuronate (60.0 mg, 0.125 mmol) in Et2O (0.5 ml) was added dropwise. The reaction mixture was stirred at 42°C for 2 h, then quenched with ammonium chloride, and extracted with EtOAc several times. The combined organic extracts were washed with brine, dried over sodium sulfate, and the solvent removed in vacuum. The residue was chromatographed over silica gel (hexane-EtOAc, 8:2) to give 53.7 mg (51%) of a mixture of diastereomers. The mixture was used in the next reaction without further purification. To a stirred solution of this mixture (10.0 mg, 0.012 mmol) in a mixture of MeOH-THF 1:1 (0.8 ml) cooled to -35°C was added an excess of Na(Hg) 6% (300.0 mg) in one portion. The reaction mixture was stirred at -35°C for 3.5 h, then diluted with Et2O and filtered through Celite; the cake was washed several times with Et2O. To the ether solution was added a sat. solution of ammonium chloride and then 1.0 N HCl solution until pH - 4. The aqueous phase was extracted several times with EtOAc, and the combined organic phase was washed with H2O, brine, dried over sodium sulfate, and concentrated in vacuum. The residue was chromatographed over silica gel (hexane-EtOAc, 9:1) to give 13(E)-tetraene (methyl 5α,6βdibenzyloxypolyangioate) as the main product, in 63% overall yield, as a clear colorless liquid. Careful chromatography of this E/Z mixture eluted with CH2Cl2/hexane/Et2O (10:10:1) produced pure 13(E) product. To a stirred solution of 13(E) methyl 5α,6β-dibenzyloxypolyangioate (7.0 mg, 0.0105 mmol) in THF (1.5 ml) was added a solution of LiOH (1.3 mg, 0.0525 mmol) in H2O (0.5 ml) at room temperature. The resulting solution was

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231

stirred at room temperature for 18 h and then poured into 0.2 N HCl (10 ml). This mixture was extracted with Et2O (3x20 ml). The organic extracts were combined, washed with brine, dried over sodium sulfate and filtered. The solvent was removed in vacuum to give 7.0 mg of crude 5α,6βdibenzyloxypolyangioic acid as a colorless oil. This crude acid was used in next debenzylation step without further purification. To a stirred solution of the crude 5α,6β-dibenzyloxypolyangioic acid (7.0 mg, 0.0105 mmol) in liquid ammonia (10 ml, distilled from sodium) and EtOH (2 ml) at -78°C was added 0.7 mg (0.105 mmol) of lithium wire. The resulting mixture was stirred at -78°C for 30 min. Ammonium chloride (20.0 mg) was added to this mixture to quench the excess lithium and stirred for 30 min at 78°C. To the resulting mixture was added CH2Cl2 (10 ml), stirred for 1 h at room temperature, then poured into 0.2 N HCl (10 ml), and extracted with CHCl3 (3x20 ml). The organic extracts were combined, washed with brine, dried over sodium sulfate and filtered. The solvent was removed in vacuum to give a colorless oil, which was purified by preparative thin layer chromatography (EtOAc-i-PrOH-H2O, 85:10:5) to afford 3.2 mg (63% from 5 L) of ambruticin as an amorphous powder. References Kende A.S. et al.; Total synthesis of natural (+)-ambruticin; Tetrahedron Vol. 49, N 36, pp. 8015-8038, 1993

AMBUCAINE Therapeutic Function: Local anesthetic Chemical Name: Benzoic acid, 4-amino-2-butoxy-, 2-(diethylamino)ethyl ester Common Name: Ambucaine; Ambutoxate; 2-Butoxyprocaine Structural Formula:

Chemical Abstracts Registry No.: 119-29-9 Trade Name Ambucaine Ambucaine

Manufacturer ZYF Pharm Chemical Onbio Inc.

Country -

Year Introduced -

232

Ambucaine

Raw Materials Potassium carbonate Sodium carbonate Hydrochloric acid Hydrogen Ammonia

4-Nitro-2-hydroxybenzoic acid n-Butylbenzenesulfonate Nickel Raney Diethylaminoethyl chloride

Manufacturing Process A stired mixture of 4-nitro-2-hydroxybenzoic acid, anhydrous potassium carbonate and n-butyl benzenesulfonate in xylene was refluxed under a continuous water separator for about 19 h. The insoluble potassium salts were filtered off and washed with hot dry toluene. The combined filtrate and washings were distilled under reduced pressure to remove the solvents, thereby leaving a residual oil which solidified on cooling. The solid yields of greater than 95% of n-butyl 4-nitro-2-n-butoxybenzoate (recrystallized from methanol). The n-butyl 4-nitro-2-n-butoxybenzoate obtained was dissolved in 50% aqueous ethanol. To this solution was added 2 - 3 molecular equivalents of sodium carbonate, and the resulting mixture, was stirred under reflux for about 16 h. After the ethanol has been distilled off under reduced pressure, the remaining aqueous solution was diluted with water and made acidic with concentrated hydrochloric acid. The precipitated yellow solid was filtered, washed with water, dried in a vacuum oven at 90°C and recrystallized from ethyl acetate. There was thus obtained a 4-nitro-2-n-butoxy-benzoic acid (95.5% yield), melting point 120.9°-122.8°C (corr.). A mixture of 4-nitro-2-n-butoxybenzoic acid, anhydrous potassium carbonate and 400 ml of dry toluene was refluxed and stirred under a continuous water separator. When the evolution of water had ceased (3 h), the water separator was removed and there was added diethylaminoethyl chloride. The mixture was then refluxed with stirring for about 20 h, filtered while hot, and the solvent was removed from the filtrate by distilling in vacuo. The residual oil was dissolved in dilute hydrochloric acid, the solution was decolorized with activated carbon and the base was liberated by the addition of excess ammonia. The base was extracted with ethyl acetate, the solution was dried, and the ethyl acetate was removed by distilling in vacuo, yielding 2diethylaminoethyl 4-nitro-2-n-butoxybenzoate as a pale yellow oil. The 2-diethylaminoethyl 4-nitro-2-n-butoxybenzoate in ethanol is hydrogenated using 50 lbs. pressure of hydrogen at 25°C in the presence of Raney nickel (alternatively platinum oxide monohydrate). After the rapid exothermic reaction, the catalyst is filtered off and the filtrate evaporated to dryness to give the 2-diethylaminoethyl 4-amino-2-n-butoxybenzoate. References Clinton R.O., Laskowski S.C.; US Patent No. 2,689,248; Sept. 14, 1954; Assigned: Sterling Drug Inc., New York, N.Y., a corporation of Delaware

Ambuphylline

233

AMBUPHYLLINE Therapeutic Function: Diuretic, Smooth muscle relaxant Chemical Name: 3,7-Dihydro-1,3-dimethyl-1H-purine-2,6-dione compound with 2-amino-2-methyl-1-propanol (1:1) Common Name: Theophylline aminoisobutanol; Bufylline Structural Formula:

Chemical Abstracts Registry No.: 5634-34-4 Trade Name

Manufacturer

Country

Year Introduced

Butaphyllamine

Merrell Dow

US

1944

Buthoid

Merrell Dow

US

-

Raw Materials Theophylline 2-Amino-2-methyl-1-propanol Manufacturing Process Equimolecular proportions of theophylline and 2-amino-2-methyl-1-propanol are dissolved in water and the water is evaporated until crystallization is almost complete. The crystals are filtered off and dried. The product has a melting point of 254-256°C, softening at 245°C. It has a water solubility of about 55%. It may be compounded in the form of tablets, for oral administration, or may be prepared in solution for distribution in ampoules. For the manufacture of solutions for packaging in ampoules, it is more convenient to simply dissolve the theophylline and the butanolamine in water, without going through the intermediate step of separating the crystalline salt. References Merck Index 385 I.N. p. 64 Shelton, R.S.; US Patent 2,404,319; July 16, 1946; Assigned to The Wm. S. Merrell Co.

234

Ambuside

AMBUSIDE Therapeutic Function: Diuretic, Antihypertensive Chemical Name: N'-Allyl-4-chloro-6-[(3-hydroxy-2-butenylidene)amino]-mbenzenedisulfonamide Common Name: Structural Formula:

Chemical Abstracts Registry No.: 3754-19-6 Trade Name

Manufacturer

Country

Year Introduced

Hydrion

Robert and Carriere

France

1970

Raw Materials 2-Allylsulfamyl-5-chloro-4-sulfamylaniline Acetaldehyde dimethylacetal Manufacturing Process Preparation of 2-Allylsulfamyl-4-Sulfamyl-5-Chloro-N-(3-Hydroxy-2Butenylidene)Aniline or Ambuside: 2-allylsulfamyl-5-chloro-4sulfamylanilinemonohydrate (6.9 grams, 0.020 mol) was dissolved in 14 ml acetylacetaldehyde dimethylacetal at room temperature and the viscous solution was filtered. Addition of 6 drops of 10:1 H2O/concentrated HCl, and stirring for 20 hours gave a heavy suspension. Dilution with 150 ml of ethanol, collection of the solid, washing twice with 40 ml portions of ethanol, and drying gave 6.2 grams (78%) of product, MP 204-206°C. References Merck Index 386 Kleeman and Engel p. 35 OCDS Vol.2 p. 116 (1980) I.N. p. 64 Robertson, J.E.; US Patent 3,188,329; June 8, 1955; Assigned to ColgatePalmolive Co.

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235

AMCINAFIDE Therapeutic Function: Antiinflammatory, Antiallergic Chemical Name: 9-Fluoro-11,21-dihydroxy-16,17-[(1-phenylethylidene) bis(oxy)]pregna-1,4-diene-3,20-dione Common Name: Amcinafide Structural Formula:

Chemical Abstracts Registry No.: 7332-27-6 Trade Name

Manufacturer

Country

Year Introduced

Amcinafide

Onbio Inc.

-

-

Raw Materials Triamcinolone Perchloric acid Acetophenone Manufacturing Process 1 ml 72% perchloric acid was added to a suspension of 4 g triamcinolone in 100 ml of fresh distilled acetophenone and the mixture was stirred at a room temperature before all triamcinolone solved (for about 2 hours). The solution was neutralized with help of 8 ml of 1.1 N sodium hydroxide and sufficient quantity of sodium bicarbonate. Then chloroform and water were added. Organic layer was separated and concentrated in vacuum. The residue was recrystallized from acetone-hexane and thoroughly washed from acetophenone with hexane. Triamcinolone acetophenide (amicinafide) was prepared. It had MP: 281°-283°C (decomp.);αD23 = +23°. (c = 0.98 in CHCl3). References Fried J.; D. E. Patent No. 1,099,529; August 6, 1958; Olin Mathieson Chemical Corporation New York, N.Y. (USA)

236

Amcinonide

AMCINONIDE Therapeutic Function: Topical corticosteroid, Antiinflammatory Chemical Name: 16α,17α-Cyclopentylidenedioxy-9α-fluoro-11β,21-dihydroxy1,4-pregnadiene-3,20-dione-21-acetate Common Name: Amcinopol Structural Formula:

Chemical Abstracts Registry No.: 51022-69-6 Trade Name

Manufacturer

Country

Year Introduced

Cyclocort

Lederle

US

1979

Amcinonid

Cyanamid

W. Germany

1981

Visderm

Lederle

Japan

1982

Penticort

Lederle

France

-

Mycoderm

Lederle

-

-

Raw Materials 16α,17α-Cyclopentylidenedioxy-9α-fluoro-11β,21-dihydroxy-1,4pregnadiene-3,20-dione Acetic anhydride Manufacturing Process An 11.1 g (24.1 mmol) portion of the compound 16α,17αcyclopentylidenedioxy-9α-fluoro-11β,21-dihydroxy-1,4-pregnadiene-3,20-dione is placed in a 250 ml round-bottom flask. A 100 ml portion of pyridine is added and the mixture is stirred to a complete solution. A 5.5 ml (54.6 mmol) portion of acetic anhydride is added dropwise and the mixture is stirred for 2% hours. An 11 ml portion of methanol is added and the mixture is stirred an additional hour. This mixture is concentrated under reduced pressure to about 10 to 15 ml and then poured slowly into a mixture of ice, water and dilute hydrochloric acid. This mixture is stirred and the solid which forms is collected by filtration, washed with water to a neutral pH and air dried yielding 11.5 g. This solid is taken up in hot acetone, treated with activated charcoal and filtered while hot through diatomaceous earth. The filtrate is concentrated on a steam bath while adding n-hexane to the point of incipient crystallization. This mixture is allowed to cool to room temperature. The solid which forms is

Amebucort

237

collected by filtration, washed with acetone-n-hexane (1:14) and air dried yielding 7.0 g of the desired product. References Merck Index 389 DFU 3 (5) 337 (1978) Kleeman and Engel p. 36 PDR p. 1007 DOT 16 (10) 322 (1980) I.N. p. 65 REM p.972 Schultz, W., Sieger, G.M. and Krieger, C.; British Patent 1,442,925; July 14, 1976; Assigned to American Cyanamid Company.

AMEBUCORT Therapeutic Function: Antiinflammatory, Antiallergic Chemical Name: 21-Acetoxy-17-butyryloxy-11β-hydroxy-6α-methyl-4pregnene-3,20-dione Common Name: Amebucort Structural Formula:

Chemical Abstracts Registry No.: 83625-35-8 Trade Name Amebucort

Manufacturer ZYF Pharm Chemical

Country -

Raw Materials 17,21-Dihydroxy-6α-methyl-4-pregnene-3,20-dione Pyridinium tosylate Trimethyl orthoformate

Year Introduced -

238

Amebucort Sweetwort slant with Curvularia lunata (NRRL 2380) Glucose Germination culture Butyric anhydride Sulfuric acid

Manufacturing Process (a) 100 g of 17,21-dihydroxy-6α-methyl-4-pregnene-3,20-dione and 10 g of pyridinium tosylate are dissolved in 700 ml of dimethylformamide at room temperature and under agitation, and the clear solution is diluted with 3.5 L of toluene. The solution is then warmed up in a glycerin bath and, at a temperature of 120°C, 1.2 L of toluene is distilled off to remove traces of water. Under agitation, 240 ml of trimethyl orthoformate is gradually poured into the hot reaction solution; the latter is reacted for 30 min and thereafter additional toluene and other readily volatile reaction components are removed by 1 hour of distillation. The mixture is combined with 120 ml of pyridine, cooled to 60°C, and concentrated under vacuum at a bath temperature of 70°C. The mixture is then diluted with 400 ml of dimethylformamide, and the solution is poured under agitation into 10 L of water, thus obtaining the product in the form of a yellowish-white, crystalline precipitate. The mixture is stirred for another 2 hours, vacuum-filtered, washed with water, and dried for 24 hours at 40°C in a vacuum over phosphorus pentoxide, thus obtaining 111.6 g of 17,21-(1-methoxyethylidenedioxy)-6α-methyl-4-pregnene-3,20dione, melting point 85-87°C. (b) A 7-14 day old sweetwort slant with Curvularia lunata (NRRL 2380) is freed of the supernatant with 3 ml of physiological sodium chloride solution, and this supernatant is used to inoculate a 2-liter Erlenmeyer flask containing 500 ml of a nutrient solution of 2% glucose and 2% cornsteep, sterilized for 30 min at 120°C in an autoclave and adjusted to pH 6.5. After 60 hours of shaking on a rotary shaker at 30°C, 250 ml of this germination culture is used to inoculate the preliminary fermentor. A 20-liter prefermentor charged with 15 L of a nutrient medium of the same composition as the germination medium and sterilized at 121°C and 1 bar gauge pressure is inoculated with 250 ml of germination culture. With the addition of silicone SH as the defrother, germination is now conducted up to 29°C and 0.6 bar pressure under aeration (15 L/min) and agitation (220 rpm) for 24 hours. The main fermentor is inoculated with 1.5 L of this prefermentor culture. A 20-liter main fermentor, filled with 13.5 L of a sterilized nutrient medium made up of 3% cornsteep liquor and 0.7% glucose, adjusted to pH 5.5, is inoculated with 1.5 L of prefermentor culture. After an incubation phase of 12 hours under prefermentation conditions, a sterile-filtered solution of 12.18 g of 17,21-(1methoxyethylidenedioxy)-6α-methyl-4-pregnene-3,20-dione in 130 ml of dimethylformamide is added thereto and the mixture is further agitated and aerated. 4 hours after addition of the substrate, the pH value of the culture broth is set at pH 4.5 and held at this value. The pH 0.2 by automatic control with 16% sodium hydroxide solution and 20% sulfuric acid until the end of the fermentation. After a contact period of 51 hours, the microbiological conversion is complete. The content of the fermentor is then treated in a continuous centrifuge, and the culture filtrate as well as the centrifuged fungal mycelium are extracted separately with methyl isobutyl ketone. The extracts are combined and first concentrated in a forced-circulation evaporator to 1 liter at 40°C under vacuum, and then entirely evaporated to dryness in a 2-

Amesergide

239

liter round flask on a rotary evaporator under vacuum at a bath temperature of 40°C. The remaining oily residue is combined with 400 ml of hexane and decanted after vigorous shaking. Subsequently, the residue is once again combined with 400 ml of hexane and agitated at room temperature for 2 hours. The now completely crystallized residue is vacuum-filtered, washed with 100 ml of hexane, and dried for 4 hours at 60°C in a vacuum. Yield: 9.9 g of 17-acetoxy-11β,21-dihydroxy-6α-methyl-4-pregnene-3,20-dione which, after recrystallization from acetone-diisopropyl ether, melts at 192-194°C. A solution of 1.0 g of 17-acetoxy-11β,21-dihydroxy-6α-methyl-4-pregnene3,20-dione in 20 ml of pyridine is combined with 3 ml of butyric anhydride and stirred at room temperature for 2 hours. The reaction solution is then allowed to flow into 150 ml of cooled 8% sulfuric acid and agitated for another 5 hours; the product, initially precipitated in oily form, becomes completely crystallized. The product is vacuum-filtered, washed with water, and dried for 6 hours at 80°C in a vacuum. For purifying purposes, the crude product is recrystallized from acetone-diisopropyl ether, thus obtaining 940 mg of 17acetoxy-21-butyryloxy-11β-hydroxy-6α-methyl-4-pregnene-3,20-dione, melting point 98-120°C. References Annen K., Petzoldt K., Laurent H., Wiechert R., Hofmeister H.; US Patent No. 4,912,098; March 27, 1990; Assigned to Schering Aktiengesellschaft (Berlin and Bergkamen, DE)

AMESERGIDE Therapeutic Function: Serotonin antagonist Chemical Name: Ergoline-8-carboxamide, N-cyclohexyl-6-methyl-1-(1methylethyl)-, (8β)Common Name: Amesergide Structural Formula:

Chemical Abstracts Registry No.: 121588-75-8 Trade Name

Manufacturer

Country

Year Introduced

Amesergide

Onbio Inc.

-

-

LY 237733

Lilly

-

-

240

Amezepine

Raw Materials (8β)-1-Isopropyl-6-methylergoline-8-carboxylie acid Potassium carbonate Isobutyl chloroformate Cyclohexylamine Ammonium hydroxide Manufacturing Process To a 250 ml three-neck round bottom flask was added 10.0 g (32.01 mmol) of (8β)-1-isopropyl-6-methylergoline-8-carboxylie acid, 4.43 g (32.1 mmol) of potassium carbonate and 200 ml of N,N-dimethylformamide. The mixture was refluxed and 25 ml of a distillate was collected. The remaining solution was cooled in an ice bath, and then with an acetonitrile/carbon dioxide bath which lowered the temperature of the reaction mixture to about -45°C this mixture was added 4.59 g (33.62 mmol) of isobutyl chloroformate dropwise. The resulting mixture was stirred for approximately 5 min and 3.49 g (35.21 mmol) of cyclohexylamine was added. The reaction mixture was allowed to warm to room temperature and stirred for approximately 19 h. To the mixture was added 500 ml of ice water containing 25 ml of concentrated ammonium hydroxide. The mixture was cooled and the precipitated solid was collected by vacuum filtration. The resulting solid was washed with water and dried in vacuo to provide 10.13 g (yield 76.8%) of the (8β)-N-cyclohexyl-1-isopropyl6-methylergoline-8-carboxamide having a purity of 92.3%. The resulting solid was combined with three other lots of the desired compound previously synthesized to provide a total weight of 33.6 g. This material was dissolved in 1200 ml of hot methanol and the resulting solution was filtered. The filtrate was allowed to cool to room temperature and 600 ml of water was added dropwise. The mixture was cooled in the freezer and the precipitated crystals were collected by vacuum filtration. The crystals were washed with methanol and dried in vacuo to provide 26.95 g of the desired compound having a purity of 96.5% as determined by HPLC. The dried solid was dissolved in 1100 ml of hot methanol, and the resulting solution was filtered hot and allowed to cool. To this mixture was added 600 ml of water and again the precipitated solid was collected by vacuum filtration. The solid was washed with water and dried in vacuo to provide 25.82 g of the (8β)-Ncyclohexyl-1-isopropyl-6-methylergoline-8-carboxamide, melting point 250°C. The assayed material indicated 98.7% purity. References Foreman M.M. et al.; European Patent Application 0,296,748; June 6, 1988; Hudson, Christopher Mark et al Erl Wood Manor Windlesham Surrey GU20 6PH (GB)

AMEZEPINE Therapeutic Function: Antidepressant

Amezepine

241

Chemical Name: 5H-Dibenz[b,f]azepine, 5-methyl-10-(2-methylamino) ethyl)Common Name: Amezepine Structural Formula:

Chemical Abstracts Registry No.: 60575-32-8 Trade Name Amezepine Amezepine

Manufacturer ZYF Pharm Chemical Onbio Inc.

Country -

Year Introduced -

Raw Materials Potassium Sodium hydroxide Fumaric acid Hydrochloric acid Caustic potash

9-Methoxycarbony-10-methylacridinium methosulphate Potassium borohydride Lithium aluminum hydride Phosphorus pentoxide 1-Dimethylamino-2-chloroethane hydrochloride

Manufacturing Process 78.0 g 9-methoxycarbony-10-methylacridinium methosulphate salt (obtained according to a process analogous to that described by Rauhut et al. [J. Org. Chem.,(30, 3587 (1965)], 800 ml ethanol and 40 ml distilled water are mixed; then 80.0 g potassium borohydride are added over the course of 45 min, at room temperature. The mixture is agitated for 30 min, poure into a water-ice mixture, agitated for 2 h, and extracted with ether; the extract is dried by vacuum distillation. 51.0 g 9-methoxycarbonyl-10-methylacridan, melting point 106°C (recrystallized from isopropyl ether) are obtained. 250.0 g 1-dimethylamino-2-chloroethane hydrochloride and 250 ml water are mixed and cooled; 250 ml sodium hydroxide solution are added at a temperature below 10°C; the mixture is agitated for 15 min at 5°C and extracted with ether. The ethereal phases are washed with water and dried over magnesium sulfate; the ether is distilled off and the residue is redistilled. 130.0 g 1-dimethylamino-2-chloroethane, boiling point 106°-108°C, are obtained. 36.5 g 9-methoxycarbonyl-10-methylacridan and 1 L of toluene are mixed; 50 ml toluene are distilled off and the mixture is cooled. 5.56 g potassium are

242

Amezepine

added at a temperature below +10°C; the mixture is agitated for 2 h at room temperature, refluxed for 30 min, and cooled. A solution of 52.5 ml 1-dimethylamino-2-chloroethane in 200 ml toluene is added at a temperature below 20°C; the mixture is refluxed for 20 h and cooled, and 100 ml t-butanol are added. The mixture is agitated for 1 h at room temperature, 35 ml ethanol are added, and the mixture is again agitated for 30 min at room temperature. It is then extracted with 2 N hydrochloric acid; the acidic phases are washed with ether, made alkaline by the addition of sodium hydroxide solution, and extracted with ether; the ethereal phases are washed with water, dried over magnesium sulphate and then distilled to dryness under a vacuum. The residue is dissolved in 100 ml methanol; 300 ml of a saturated solution of fumaric acid in methanol are added; the methanol is distilled off and replaced by ethyl acetate. Crystallization is allowed to commence and the mixture is cooled with ice for 30 min and suction-filtered; the precipitate is washed with water and dried. 37.0 g 9-(2-dimethylaminoethyl)-9-methoxycarbonyl-10-methylacridan fumarate are obtained, melting point 176°C (recrystallized from methanolethyl acetate). 50.0 g of the 9-(2-dimethylaminoethyl)-9-methoxycarbonyl-10-methylacridan fumarate are suspended in 500 ml water; the suspension is cooled and 30 ml sodium hydroxide solution are added. The mixture is extracted with dichloromethane and the organic phases are washed with water, dried over magnesium sulphate and then distilled to dryness under a vacuum 36.0 g 9(2-dimethylaminoethyl)-9-methoxycarbonyl-10-methylacridan are obtained. 400 ml tetrahydrofuran are cooled and 20.0 g lithium aluminum hydride are added over the course of 15 min, followed by a solution of 36.0 g 9-(2dimethylaminoethyl)-9-methoxycarbonyl-10-methylacridan in 400 ml tetrahydrofuran added over the course of 30 min. The mixture is refluxed for 2 h and cooled, and 200 ml tetrahydrofuran containing 20% water are added at a temperature below 0°C. The mixture is filtered, washed with dichloromethane, and distilled to dryness under a vacuum; the residue is dissolved in dichloromethane and the organic phases are washed with water, dried over magnesium sulfate, and concentrated, ethyl acetate being added to replace the dichloromethane. Crystallization is allowed to commence and the mixture is cooled with ice for 1 h, suction-filtered, washed with water, and dried. 24.5 g 9-(2-dimethylaminoethyl)-9-hydroxymethyl-10-methylacridan, melting point 150°C (recrystallized from dichloromethane - ethyl acetate) are obtained. On concentration of the mother liquors, a second yield of 1.6 g of product is obtained (total yield: 79%). A mixture of 24.5 g 9-(2-dimethylaminoethyl)-9-hydroxymethyl-10(methylacridan) 1 L of m-xylene and 125.0 g phosphorus pentoxide are refluxed for 3 h; the reacture mixture is cooled, poured on to ice, agitated for 15 min, alkaline by the addition of sodium hydroxide solution, and extracted with ethyl acetate; the organic phases are washed with water, dried over magnesium sulfate, and dried by vacuum distillation. The residue is dissolved in ether, filtered, and concentrated to a small volume; pentane is added with distillation to remove the ether. The mixture is filtered and concentrated to about 100 ml; crystallization is allowed to commence and the mixture is

Amezinium methyt sulfate

243

cooled with ice for 1 h and suction-filtered; the precipitate is washed with water and dried in vacua. After chromatographing on magnesium silicate, eluting with ether 16.0 g 5-methyl-10-(2-dimethylaminoethyl)-5Hdibenz[b,f]azepine, melting point 78°C (recrystallized from pentane) are obtained (yield: 70%). 32.5 ml benzene and 5 ml ethyl chloroformate are mixed; a solution of 6.5 g 5-methyl-10-(2-dimethylaminoethyl)-5H-dibenz[b,f] azepine in 32.5 ml benzene are added; the mixture is refluxed for 5 h and cooled; ethyl acetate is added and the mixture is agitated in the presence of N-hydrochloric acid; the organic phase is decanted off, washed with water, dried over magnesium sulfate, and distilled to dryness under a vacuum; 5.0 g 5-methyl-10-[2-(Nethoxycarbonyl-N-methylamino)ethyl]-5H-dibenz[b,f]azepine are obtained. (Yield: 64%). 5.0 g caustic potash in 50 ml n-butanol is added to 5.0 g 5-methyl-10-[2-(Nethoxycarbonyl-N-methylamino)ethyl]-5H-dibenz[b,f]azepine; the mixture is agitated and refluxed for 20 h, and the butanol is distilled off in vacua; the residue is taken up with water, the mixture is extracted with ethyl acetate, and the organic phases are washed with water and dried over magnesium sulfate, and then distilled to dryness under vacuum; the residue is dissolved in 10 ml ether and the solution is chromatographed on magnesium silicate, eluting with ether, and distilled to dryness under a vacuum; 3.5 g crude 5methyl-10-(2-methylamino-ethyl)-5H-dibenz[b,f] azepine are obtained. References GB Patent No. 1,316,361; May 9, 1973; Assigned: ROUSSEL UCLAF, a French Body Corporate of 35 Boulevard des Invalidies, Paris 7e, France

AMEZINIUM METHYL SULFATE Therapeutic Function: Antihypotensive Chemical Name: 4-Amino-6-methoxy-1-phenylpyridazinium methyl sulfate Common Name: Structural Formula:

Chemical Abstracts Registry No.: 30578-37-1 Trade Name Regulton Regulton

Manufacturer Nordmark Knoll

Country W. Germany Switz.

Year Introduced 1981 1983

244

Amfecloral

Raw Materials 1-Phenyl-4-aminopyridazone Dimethyl sulfate Manufacturing Process 18.7 parts of 1-phenyl-4-aminopyridazone-(6) and 19 parts of dimethyl sulfate in 400 parts of xylene are kept at 120°C for one hour while mixing well. The reaction mixture is suction filtered, 28 parts (89.5% of the theory) of 1-phenyl-4-amino-6-methoxypyridazinium methosulfate is obtained having a melting point of 173°C to 174°C after recrystallization from acetonitrile. The perchlorate has a melting point of 179°C to 182°C. References Merck Index 395 DFU 5 (4) 207 (1980) DOT 18 (7) 317 (1982) I.N. p. 66 Reicheneder. F. and Kropp, R.; US Patent 3,631,038; December 28, 1971; Assigned to Badische Anilin und Soda-Fabrik A.G.

AMFECLORAL Therapeutic Function: Anorexic Chemical Name: 1-Phenyl-N-(2,2,2-trichlorethylidene)-2-propylamine Common Name: Amfecloral; Amphecloral Structural Formula:

Chemical Abstracts Registry No.: 5581-35-1 Trade Name

Manufacturer

Country

Year Introduced

Amphecloral

ZYF Pharm Chemical

-

-

Raw Materials d-Amphetamine Chloral hydrate Manufacturing Process Molar equivalents of d-amphetamine base and chloral hydrate were dissolved

Amfenac sodium

245

in benzene and the solution was heated to distill off benzene and water, azeotropically. Two molar equivalents of water were separated in this manner. The remainder of the benzene was distilled off, leaving a liquid residue which was then fractionally distilled to yield the clear, colorless liquid condensation product, N-[2-(1-phenylpropyl)]-2,2,2-trichloroethylidenimine, which boiled at 95°C/0.5 mm and had an index of refraction, nD20 of 1.530 and a specific optical rotation of +49.9(+/-)0.3° [in dioxane]. Following the above procedure but using dl-amphetamine, the DL-form of N[2-(1-phenyl-propyl)]-2,2,2-trichloroethylidemmine was also prepared. It had the same boiling point and index of refraction as the (-)-form above but its specific optical rotation was zero. References Ch. J. Cavallito; US Patent No. 2,923,661; Feb. 2, 1960; Assigned to Irwin, Neigler and Co., Decatur, III.; a corporation of Illinoi

AMFENAC SODIUM Therapeutic Function: Antiinflammatory Chemical Name: 2-Amino-3-benzoylbenzeneacetic acid sodium salt Common Name: Amfenac sodium, Fenamate Structural Formula:

Chemical Abstracts Registry No.: 61618-27-7; 51579-82-9 (Base) Trade Name Amfenac sodium Fenazox

Manufacturer Country Yungjin Pharmacetical Co. Ltd. Chemos GmbH -

Year Introduced -

Raw Materials Hydrochloric acid Acetic acid Sodium hydroxide

Ethyl 2-acetamido-3-benzoylphenylacetate 2-Acetamido-3-benzoylphenylacetic acid

246

Amflutizole

Manufacturing Process 7-Benzoylindolin-2-one: Method A. A mixture of 2.5 g (0.0077 mole) of ethyl 2-acetamido-3benzoylphenylacetate in 50 ml of 3 N hydrochloric acid was refluxed for one hour. The reaction mixture was filtered and the filtrate was poured into a mixture of ice and water. The precipitate was collected and recrystallized from acetone; yield of 7-benzoylindolin-2-one 1 g (55%); melting point 154°C. Method B. A solution of 1.3 g (0.0044 mole) of 2-acetamido-3benzoylphenylacetic acid in 15 ml of 3 N hydrochloric acid and 15 ml of acetic acid was refluxed for three hours. The cooled solution was poured into ice water and the 7-benzoylindolin-2-one which precipitated was collected and dried. 2-Amino-3-benzoylphenylacetic acid: A mixture of 1.0 g (0.004 mole) of 7-benzoylindolin-2-one was added to 30 ml of 3 N sodium hydroxide and the basic solution was refluxed for 45 min under nitrogen. The mixture was filtered and the filtrate was neutralized with glacial acetic acid. The precipitate was filtered off, washed with water and dried. The 2-amino-3-benzoylbenzeneacetic acid melted at 122°C (dec.). The yield was 0.8 g (72%). References Welstead, Jr., William J., Moran H. W.; US Patent No. 4,045,576; August 30, 1977; Assigned to A. H. Robins Company, Incorporated (Richmond, VA)

AMFLUTIZOLE Therapeutic Function: Uricosuric Chemical Name: 5-Isothiazolecarboxylic acid, 4-amino-3-(3-(trifluoromethyl) phenyl)Common Name: Amflutizole Structural Formula:

Amicarbalide isethionate

247

Chemical Abstracts Registry No.: 82114-19-0 Trade Name LY 141894 Amflutizole

Manufacturer Eli Lilly Onbio Inc.

Country -

Year Introduced -

Raw Materials 3-Trifluoromethyl-α-(p-toluenesulfonyloxyimino)benzylcyanide Methyl thioglycolate Triethylamine Potassium hydroxide Manufacturing Process To a stirred solution of 3-trifluoromethyl-α-(p-toluenesulfonyloxyimino) benzylcyanide in methanol containing methyl thioglycolate was added dropwise over a 30 min period triethylamine. The reaction mixture was stirred at room temperature for 4 h following complete addition, and then was cooled to 0°C and filtered. The precipitate which was collected was recrystallized from hexane and ethyl acetate to provide methyl 3-(3-trifluoromethylphenyl)4-amino-5-isothiazolecarboxylate, melting point 94°-95°C. A solution of methyl 3-(3-trifluoromethylphenyl)-4-amino-5isothiazolecarboxylate and potassium hydroxide in methanol was heated at reflux for 6 h. The reaction mixture was then poured into ice containing 12 N aqueous hydrochloric acid. The free acid precipitated from the acidic solution, and after all of the ice had melted, the aqueous acidic mixture was filtered. The precipitate was crystallized from ethanol and water to provide 3-(3trifluoromethylphenyl)-4-amino-5-isothiazolecarboxylic acid, melting point 179°-180°C. Yield 80%. References Beck J.R. et al.; US Patent No. 4,346,094; August 24, 1982; Assigned: Eli Lilly and Company, Indianapolis, Ind.

AMICARBALIDE ISETHIONATE Therapeutic Function: Antiprotozoal Chemical Name: 3,3'-(Carbonyldiimino)bis[benzenecarboximidamide] isethionate (1:2) Common Name: Amicarbalide isethionate; Diampron Chemical Abstracts Registry No.: 3671-72-5; 3459-96-9 (Base)

248

Amicarbalide isethionate

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Diampron

May and Baker

-

-

Amicarbalide isethionate

Onbio Inc.

-

-

Raw Materials Phosgene Hydrogen chloride

Saturated anhydrous ethanolic ammonia m-Aminobenzonitrile

Manufacturing Process m-Aminobenzonitrile (50 g) in anhydrous pyridine (200 ml) was treated with a solution of phosgene (15 ml) in anhydrous toluene (100 ml) over 10 min with mechanical stirring. The red solution was heated for 0.5 hour on the steam bath, cooled, and added to water (2 litres). The pale grey precipitate was filtered off, washed with ether, and crystallised from methanol (250 ml). N,N1Di(m-cyanophenyl)urea separated as grey prisms, melting point 205-206°C. A suspension of N,N1-di(m-cyanophenyl)urea (42 g) in anhydrous chloroform (420 ml), containing anhydrous ethanol (70 ml), was saturated with anhydrous hydrogen chloride at 0-5°C. After setting aside for 2 hours, a clear solution was obtained, which began to crystallise. After a week, the crystals were filtered off, washed well with anhydrous ether, and dried over calcium chloride. The iminoether hydrochloride so obtained (72 g) was added to saturated anhydrous ethanolic ammonia (720 ml), and the suspension heated at 55-60°C for 6 hours. After cooling to 20°C the crystals were filtered off, and recrystallized from 2 N hydrochloric add (300 ml). 3,31Diamidinodiphenylurea dihydrochloride monohydrate separated as white prisms, melting point 286°C (decomp.). In practice it is usually used as isethonate salt. References GB Patent No. 888,965; Feb. 7, 1962; Assigned to May and Baker Limited, a British Copmpany, of Dagenham, Essex

Amidephrine mesylate

249

AMIDEPHRINE MESYLATE Therapeutic Function: Vasoconstrictorá Nasal decongestant Chemical Name: N-(3-(1-Hydroxy-2-(methylamino)ethyl)phenyl) methanesulfonamide monomethanesulfonate Common Name: Amidefrine mesilateæ Amidephrine mesylate Structural Formula:

Chemical Abstracts Registry No.: 1421-68-7; 3354-67-4 (Base) Trade Name

Manufacturer

Country

Year Introduced

Amidefrine mesylate

Pharm. Chemical Shanghai Lansheng Corporation

-

-

Raw Materials N-Benzylmethylamine Methanesulfonic acid Hydrogen

3-(2-Bromoacetyl)methanesulfonanilide Palladium on carbon Sodium hydroxide

Manufacturing Process A solution of N-benzylmethylamine 7.27 g (0.06 mole) in 25 ml of acetonitrile is added dropwise during 10 min to a solution of 8.76 g (0.03 mole) of 3-(2bromoacetyl)methanesulfonanilide (M.P. 118-121°C) in 100 ml of acetonitrile. External cooling is employed to maintain a reaction temperature of 10°C during the addition. The cooling bath is then removed and the solution stirred for an additional 20 min. Concentration of the reaction mixture yields a yellow oil which is dissolved in 300 ml of ether and washed with water to remove byproduct N-benzylmethylamine hydrobromide. The ethereal solution is dried over magnesium sulfate and the solvent distilled leaving a viscous oil. The oil is purified by dissolving in ether (250 ml), and filtering the ether solution through diatomaceous earth to remove insoluble colored impurities. The treated ether solution is diluted with 100 ml of acetonitrile. Treatment of the ether-acetonitrile solution with an ether solution of methanesulfonic acid yields 3-(2-benzylmethylaminoacetyl)methanesulfonanilide methanesulfonate as a white precipitate which is collected and washed with 100 ml of 1:1 acetonitrile-ether and dried. It weighs 9.0 g (70%), and exhibits M.P. 197.5201°C. It is recrystallized from 96% ethanol, yielding 8.0 g (62.3%) of the 3(2-benzylmethylaminoacetyl)methanesulfonanilide methanesulfonate as a crystalline product, M.P. 206-209°C.

250

Amifloverine

A solution of 31.8 g (0.74 mole) of 3-(2-benzylmethylaminoacetyl) methanesulfonanilide methanesulfonate in 700 ml of absolute ethanol is reduced in an atmospheric hydrogenation unit (2 to 5 p.s.i. g positive pressure) during 24 hours with a 10% palladium catalyst prepared from 320 mg of palladium chloride and 2.0 g of pulverized charcoal. After absorption of the calculated amount of hydrogen, the catalyst is filtered, the filtrate concentrated to about 100 ml, mixed with about 500 ml of ether, resulting in precipitation of a white solid weighing 24.3 g (96%), M.P. 201-203.5°C. Two recrystallizations from ethanol (35 ml/g of solid) yield the analytically pure 3(2-methylamino-1-hydroxyethyl)methanesulfonanilide methanesulfonate, 19.6 g (75%), M.P. 207-209°C. 3-(2-Methylamino-1-hydroxyethyl)methanesulfonanilide methanesulfonate, 17.0 g (0.05 mole) is dissolved in 50 ml of 1 N sodium hydroxide, yielding a yellow solution having pH 8. The water is removed from the solution by evaporation in vacuo and the residue is treated with several portions of ethanol which are evaporated to remove last traces of moisture. The bulk of the sodium methanesulfonate byproduct is then removed from the residue by dissolving the product in 350 ml of hot absolute ethanol and clarifying by filtration through a diatomaceous earth filter aid. The ethanolic filtrate is evaporated to dryness. Last traces of sodium methanesulfonate are then removed by washing the residue with 15 ml of cold water and then with two 15 ml portions of 1:1 cold water-isopropanol, and finally with ether, yielding 7.7 g of 3-(2-methylamino-1-hydroxyethyl)methanesulfonanilide as a white solid, M.P. 159-161°C. In practice it is usually used as monomethanesulfonate salt. References Merck Index, Monograph number: 418, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. Larsen A.A., Uloth R.H.; US Patent No. 3,341,584; Sept. 12, 1967; Assigned to Mead Johnson and Co., Evansville, Ind., Indiana

AMIFLOVERINE Therapeutic Function: Spasmolytic Chemical Name: 2-(3,5-Diethoxyphenoxy)-N,N-diethylethanamine Common Name: Amifloverine Structural Formula:

Amifostine

251

Chemical Abstracts Registry No.: 54063-24-0 Trade Name

Manufacturer

Country

Amifloverine

ZYF Pharm Chemical -

-

Amifloverine

Onbio Inc.

-

-

Year Introduced

Raw Materials Sodium 1-Chloro-2-diethylaminoethane hydrochloride 3,5-Dimethoxyphenol Manufacturing Process 4.6 g of sodium was reacted with 125 ml of ethanol and, when the sodium had disappeared, 15.4 g of 3,5-dimethoxyphenol in 50 ml of absolute ethanol was added, followed by 17.2 g of 1-chloro-2-diethylaminoethane hydrochloride in suspension in 25 ml of ethanol. The mixture was refluxed for 6 hours. Then the precipitated sodium chloride was separated and the alcoholic solution was concentrated. The residue was taken up in 50 ml of ether and etheral hydrogen chloride was slowly added under reduced pressure. The mixture was filtered after cooling in ice and was dried under reduce pressure over potassium carbonate. For purification, the product (2-(3,5-diethoxyphenoxy)N,N-diethylethanamine) was recrystallized from 200 ml of boiling isopropanol using vegetable carbon black. 16.4 g (yield 56.7%) of white crystals melting at 127°C was obtained. References Lafon L.; US Patent No. 3,740,397; June 19, 1973; Assigned to Societe Orsymonde, Paris, France

AMIFOSTINE Therapeutic Function: Radioprotective, Chemoprotectant, Mucolytic Chemical Name: 2-[(3-Aminopropyl)amino]ethanethiol dihydrogen phosphate (ester) Common Name: Amifostine; Ethiofos; Fosteamine Structural Formula:

Chemical Abstracts Registry No.: 20537-88-6

252

Amifostine

Trade Name

Manufacturer

Country

Year Introduced

Ethyol

MedImmune, Inc.

-

-

Amifostine

Haorui PharmaChem Inc.

-

-

Ethyol

Schering-Plough

-

-

Raw Materials 2-(3-Aminopropylamino)ethanol Hydrobromic acid Trisodium phosphorothioate Manufacturing Process A solution of 2-(3-aminopropylamino)ethanol (25.0 g, 0.212 mole) in 48 % hydrobromic acid (200 ml) was distilled until 35 ml of distillate had been collected. The solution was refluxed and, periodically, more distillate was collected. The total volume of distillate removed in 7 distillation periods was 160 ml, or 80 % of the original volume of 48% hydrobromic acid, and the time of continuous boiling was approximately 48 hours. The residual solution was then evaporated to dryness under reduced pressure with the aid of several added portions of methanol. The crystalline residue was thoroughly triturated with acetone, collected, and washed on the funnel with acetone. After the product had been pressed as dry as possible on the funnel, it was dissolved in a slight excess of boiling methanol and the solution was filtered. Addition of acetone to the filtrate precipitated pure N-(2-bromoethyl)-1,3propanediamine dihydrobromide as colorless crystals, which were dried in vacuum over phosphorus pentoxide: yield 58.0 g (80%), melting point 205206°C. Trisodium phosphorothioate (6.93 g, 38.5 mmoles) was gradually added in small portions with vigorous stirring to water (38 ml) cooled externally by means of a water bath (15°-20°C). To the resulting suspension was added N-(2-bromoethyl)-1,3-propanediamine dihydrobromide (13.3 g, 38.8 mmoles). After a few minutes, complete solution occurred, and N,Ndimethylformamide (19 ml) was added with continued external cooling at 15°20°C. After the solution had been stirred at about 20°C for 90 min, it was poured into methanol (250 ml), and the mixture was refrigerated at 4°C overnight. The white precipitate that formed was collected and pressed as dry as possible on the funnel. The solid was dissolved in water (40 ml), and the solution was filtered. Addition of methanol (250 ml) reprecipitated the product. After the mixture had been refrigerated about 1 hour, the product was collected and washed on the funnel, first with methanol and finally with ether. The white solid was dried in vacuo at room temperature, then exposed to ambient conditions of the laboratory for 5 hours, and bottled under nitrogen and stored in a freezer. The yield of S-2-(3-aminopropylamino)ethyl dihydrogen phosphorothioate monohydrate, melting point (from methanol) 160-161°C, dec., was 8.15 g (91%). References Piper J.R., Johnston Th. P.; US Patent No. 3,892,824, July 1, 1975; Assigned to Southern Research Institute, Birmingem, Ala.

Amikacin

253

AMIKACIN Therapeutic Function: Antibacterial Chemical Name: (S)-O-3-Amino-3-deoxy-α-D-glucopyranosyl-(1-6)-O-[6amino-6-deoxy-α-D-glucopyranosyl-(1-4)]-N1-(4-amino-2-hydroxy-1oxobutyl)-2-deoxy-D-streptamine Common Name: 1-N-[L(-)-4-Amino-2-hydroxybutyryl]kanamycin A Structural Formula:

Chemical Abstracts Registry No.: 37517-28-5; 39831-55-5 (Sulfate) Trade Name Amikin Amiklin Biklin Amikin Biklin BB-K8 Amiglyde-V Amisin Biklin Briclin Kaminax Likacin Novamin Amikacin

Manufacturer Bristol Bristol Gruenenthal Bristol Bristol Banyu Bristol Bristol Faro Frika Mead Johnson Ausonia Lisapharma Bristol Banyu

Country US France W. Germany UK Japan Italy Turkey Austria Italy Italy Japan

Year Introduced 1976 1976 1976 1976 1977 1978 -

Raw Materials N-Hydroxysuccinimide Sulfuric acid

L-(-)-γ-Amino-α-hydroxybutyric acid 6'-Monobenzyloxy-carbonyl-kanamycin A

254

Amikacin Sodium hydroxide Hydrogen

Carbobenzoxy chloride Palladium on carbon

Manufacturing Process Preparation of L-(-)-γ-benzyloxycarbonylamino-α-hydroxybutyric acid: L-(-)-γamino-α-hydroxybutyric acid (7.4 g, 0.062 mol) was added to a solution of 5.2 grams (0.13 mol) of sodium hydroxide in 50 ml of water. To the stirred solution was added dropwise at 0-5°C over a period of 0.5 hour, 11.7 grams (0.068 mol) of carbobenzoxy chloride and the mixture was stirred for another hour at the same temperature. The reaction mixture was washed with 50 ml of ether, adjusted to pH 2 with dilute hydrochloric acid and extracted with four 80 ml portions of ether. The ethereal extracts were combined, washed with a small amount of saturated sodium chloride solution, dried with anhydrous sodium sulfate and filtered. The filtrate was evaporated in vacuum and the resulting residue was crystallized from benzene to give 11.6 grams (74%) of colorless plates; MP 78.5°C to 79.5°C. Preparation of N-Hydroxysuccinimide Ester of L-(-)-γ-Benzyloxycarbonylaminoα-hydroxybutyric acid: A solution of 10.6 grams (0.042 mol) of L-(-)-γbenzyloxycarbonylamino-α-hydroxybutyric acid and 4.8 grams (0.042 mol) of N-hydroxysuccinimide in 200 ml of ethyl acetate was cooled to 0°C and then 8.6 grams (0.042 mol) of dicyclohexylcarbodiimide was added. The mixture was kept overnight in a refrigerator. The dicyclohexylurea which separated was filtered off and the filtrate was concentrated to about 50 ml under reduced pressure to give colorless crystals of L-(-)-γ-benzyloxycarbonylaminoα-hydroxybutyric acid which were collected by filtration; 6.4 grams, MP 121122.5°C. The filtrate was evaporated to dryness in vacuum and the crystalline residue was washed with 20 ml of a benzene-n-hexane mixture to give an additional amount of L-(-)-γ-benzyloxycarbonylamino-α-hydroxybutyric acid. The total yield was 13.4 grams (92%). Preparation of 1-[L-(-)-γ-Benzyloxycarbonylamino-α-Hydroxybutyryl]-6'Carbobenzoxykanamycin A: A solution of 1.6 grams (4.6 mmol) of L-(-)-γbenzyloxycarbonylamino-α-hydroxybutyric acid in 40 ml of ethylene glycol dimethyl ether (DME) was added dropwise to a stirred solution of 2.6 grams (4.2 mmol) of 6'-monobenzyloxycarbonylkanamycin A in 40 ml of 50% aqueous ethylene glycol dimethyl ether and the mixture was stirred overnight. The reaction mixture was evaporated under reduced pressure to give a brown residue 1-[L-(-)-γ-benzyloxycarbonylarnino-α-hydroxybutyryl]-6'carbobenzoxykanamycin A which was used for the next reaction without further purification. Preparation of 1-[L-(-)-γ-Amino-α-Hydroxybutyryl] Kanamycin A: The crude product 1-[L-(-)-γ-benzyloxycarbonylamino-α-hydroxybutyryl]-6'carbobenzoxykanamycin A was dissolved in 40 ml of 50% aqueous dioxane and a small amount of insoluble material was removed by filtration. To the filtrate was added 0.8 ml of glacial acetic acid and 1 gram of 10% palladiumon-charcoal and the mixture was hydrogenated at room temperature for 24 hours in a Parr hydrogenation apparatus. The reaction mixture was filtered to remove the palladium catalyst and the filtrate was evaporated to dryness in vacuum. The residue was dissolved in 30 ml of water and chromatographed on a

Amiloride hydrochloride

255

column of CG-50 ion exchange resin (NH4+ type, 50 cm x 1.8 cm). The column was washed with 200 ml of water and then eluted with 800 ml of 0.1 N NH4OH, 500 ml of 0.2 N NH4OH and finally 500 ml of 0.5 N NH4OH. Ten milliliter fractions were collected and fractions 146 to 154 contained 552 mg (22%. based on carbobenzoxykanamycin A, 6'monobenzyloxycarbonylkanamycin A) of the product which was designated BB-K8 lot 2. MP 187°C (dec). Relative potency against B. subtilis (agar plate) = 560 mcg/mg (standard: kanamycin A free base). A solution of 250 mg of BB-K8 lot 2 in 10 ml of water was subjected to chromatography on a column of CG-50 (NH4+ type, 30 cm x 0.9 cm). The column was washed with 50 ml of water and then eluted with 0.2 N NH4OH. Ten milliliter fractions were collected. Fractions 50 to 63 were combined and evaporated to dryness under reduced pressure to give 98 mg of the pure product base. Preparation of the Monosulfate Salt of 1-[L-(-)-γ-Amino-α-Hydroxybutyryl] Kanamycin A: One mol of 1-[L-(-)-γ-amino-α-hydroxybutyryl] kanamycin A is dissolved in 1 to 3 liters of water. The solution is filtered to remove any undissolved solids. To the chilled and stirred solution is added one mol of sulfuric acid dissolved in 500 ml of water. The mixture is allowed to stir for 30 minutes, following which cold ethanol is added to the mixture till precipitation occurs. The solids are collected by filtration and are determined to be the desired monosulfate salt. References Merck Index 405 Kleeman and Engel p. 38 PDR p. 692 DOT 12 (5) 202 (1976) I.N. p. 68 REM p. 1180 Kawaguchi, H., Naito, T. and Nakagawa, S.; US Patent 3,781,268; December 25, 1973; Assigned to Bristol-Myers Company Schreiber, R.H. and Kell, J.G.,; US Patent 3,974,137; August 10, 1976; Assigned to Bristol-Myers Company

AMILORIDE HYDROCHLORIDE Therapeutic Function: Diuretic Chemical Name: 3,5-Diamino-N-(aminoiminomethyl)-6-chloropyrazine carboxamide hydrochloride Common Name: Guanamprazine; Amipramidin; Amipramizide Chemical Abstracts Registry No.: 2016-88-8; 2609-46-3 (Base)

256

Amiloride hydrochloride

Structural Formula:

Trade Name Midamor Modamide Arumil Midamor Colectril Moducren Moduretic Nilurid Pandiuren Puritrid

Manufacturer Merck Merck Sharp and Dohme Merck Merck DohmeGhibret Merck Merck Sintyal Leiras

Country UK France W. Germany US US France Argentina Finland

Year Introduced 1971 1973 1975 1981 -

Raw Materials Sulfuryl chloride Ammonia Guanidine

Methyl-3-aminopyrazinoate Sodium Hydrogen chloride

Manufacturing Process Step A: Preparation of methyl 3-amino-5,6-dichloropyrazinoare: Methyl 3aminopyrazinoate (765 g, 5 mols) is suspended in 5 liters of dry benzene. While stirring under anhydrous conditions sulfuryl chloride (1.99 liters, 3.318 g, 24.58 mols) is added over a period of 30 minutes and stirring is continued for 1 hour. During this period, the temperature rises to about 50°C and then begins to drop. The mixture is heated cautiously to reflux (60°C), refluxed for 5 hours and then stirred overnight at room temperature. The excess sulfuryl chloride is distilled off at atmospheric pressure (distillation is stopped when vapor temperature reaches 78%). The dark red mixture is chilled to 6°C. The crystals are filtered off, washed by displacement with two 100 ml portions of cold (8°C) benzene, then washed with 300 ml petroleum ether and dried in vacuum at room temperature, yielding 888 g (80%) of methyl 3-amino-5,6dichloropyrazinoate in the form of red crystals, MP 228-230°C. The crude product is dissolved in 56 liters of boiling acetonitrile and passed through a heated (70-80°C) column of decolorizing charcoal (444 g). The column is washed with 25 liters of hot acetonitrile, the combined eluate concentrated in vacuum to about 6 liters and chilled to 5°C. The crystals that form are filtered, washed three times with cold acetonitrile, and air dried to constant weight, yielding 724 g (82% recovery, 66% overall) of methyl 3-amino-5,6dichloropyrazinoate in the form of yellow crystals, MP 230-234°C. After additional recrystallizations from acetonitrile the product melts at 233-234°C. Step B: Preparation of methyl-3,5diamino-6-chloropyrazinoete: In a 2-liter, 3-

Amineptine hydrochloride

257

necked flask fitted with a a mechanical stirrer, thermometer and gas inlet tube is placed dry dimethyl sulfoxide (1 liter). Methyl 3-amino-5,6dichloropyrazinoate (100 g, 0.45 mol) is added and the mixture stirred and heated at 65°C on a steam bath until solution is effected. A stream of dry ammonia gas is admitted to the solution with continuous stirring, over a period of 45 minutes while the temperature is maintained at 65-70°C. The solution is cooled to about 10°C with continuous stirring and ammonia gas is admitted for an additional 1 1/4 hours. The yellow reaction mixture is poured, with stirring, into cold water (2 liters) and the light yellow solid that separates is removed by filtration, thoroughly washed with water, and dried in a vacuum desiccator to give 82.5 g (91%) of methyl 3,5-diamino-6-chloropyrazinoate, MP 210-212°C. Recrystallization from acetonitrile gives material melting at 212-213°C. Step C: Preparation of the base: A 300 ml one-necked, round-bottomed flask, equipped with a water-cooled condenser, calcium chloride tube and magnetic stirrer is charged with anhydrous methanol (150 ml) and sodium metal (5.75 g, 0.25 g atom). When the reaction is complete, the solution is treated with dry guanidine hydrochloride (26.3 g, 0.275 mol) and stirred for 10 minutes. The sodium chloride that forms is removed by filtration. The solution is concentrated in vacuum to a volume of 30 ml and the residue treated with the product of Step B, heated one minute on a steam bath and kept at 25°C for 1 hour. The product is filtered, washed well with water, dissolved in dilute hydrochloric acid and the free base precipitated by addition of sodium hydroxide to give the amiloride product base, a solid which melts at 240.5241.5°C. To produce the hydrochloride, the base is suspended in water (70 ml) and treated with sufficient 6 N hydrochloric acid to dissolve the free base. The solution is filtered and treated with concentrated hydrochloric acid (5 ml). The hydrochloride salt (22 g, 97%) separates and is recrystallized from water (50 ml) containing concentrated hydrochloric acid (3 ml). References Merck Index 406 Kleeman and Engel p.40 PDR p. 1199 OCDS Vol. 1 p. 278 (1977) DOT 19 (3) 172 (1983) I.N. p. 69 REM p. 941 Cragoe, E.J., Jr.; US Patent 3,313,813; April 11,1967; Assigned to Merck and Co., Inc.

AMINEPTINE HYDROCHLORIDE Therapeutic Function: Central stimulant Chemical Name: 7-[10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylamino]heptanoic acid hydrochloride

258

Amineptine hydrochloride

Common Name: Structural Formula:

Chemical Abstracts Registry No.: 57574-09-1 (Base); 30272-08-3 (Hydrochloride salt) Trade Name

Manufacturer

Country

Year Introduced

Survector

Eutherapie

France

1978

Survector

Servier

Italy

1982

Maneon

Poli

Italy

1982

Raw Materials 5-Chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene Ethyl 7-aminoheptanoate Manufacturing Process 6.5 g of 5-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene in 60 ml of nitromethane and 10.8 g of ethyl 7-aminoheptanoate in 12ml of nitromethane were mixed at ambient temperature. The reaction was slightly exothermic. The reaction mixture was left to stand overnight and the solvent was evaporated in vacuum. The residue was taken up in normal hydrochloric acid and the resulting precipitate was filtered off. 10.5 g of crude ethyl 7-[dibenzo(a,d)cycloheptadiene-5-yl]aminoheptanoate hydrochloride were obtained, of which a sample recrystallized from benzene gave a pure product melting instantaneously at 166°C to 168°C. The hydrochloride of the crude ester obtained above was added to 25 ml of 2 N hydrochloric acid. The whole was kept under reflux for 2 hours. The material dissolved and a new hydrochloride then reprecipitated. After cooling, the hydrochloride of the crude acid was filtered off, washed with iced water and then recrystallized from distilled water. 5.7 g of 7[dibenzo(a,d)cycloheptadienb-yl] aminoheptanoic acid hydrochloride were obtained, melting instantaneously at 226°C to 230°C. References Merck Index 409 Kleeman and Engel p. 40 DOT 19 (10) 547 (1983)

Aminobenzoic acid

259

I.N. p. 69 Melen, C., Danree, B. and Poignant, J.C.; US Patent 3,758,528; September 11, 1973; Assigned to Societe en nom Collectif Science Union et Cie; Societe Francaise de Recherche Medicale Melen, C., Danree, B. and Poignant, J.C.; US Patent 3,821,249; June 28, 1974; Assigned to Societe en nom Collectif Science Union et Cie; Societe Francaise de Recherche Medicale

AMINOBENZOIC ACID Therapeutic Function: Sunscreen agent, Antirickettsial Chemical Name: p-Aminobenzoic acid Common Name: Vitamin H; Vitamin Bx; PABA Structural Formula:

Chemical Abstracts Registry No.: 150-13-0 Trade Name

Manufacturer

Country

Year Introduced

Pabalate

Robins

US

1949

Hachemina

Medea

Spain

-

Pabafilm

Owen

US

-

Pabagel

Owen

US

-

Pabanol

Elder

US

-

Potaba

Westwood

US

-

Pre-Sun

Westwood

US

-

Sunbrella

Dorsey

US

-

Raw Materials Xylene Ammonium sulfate Sodium hypochlorite Manufacturing Process The following example illustrates in detail the preparation of amino benzoic acids from the hot reaction product obtained by the oxidation of a xylene and containing a mixture of salt, amide salt and diamide of a phthalic acid. 800 cc of hot aqueous oxidation product, obtained from the oxidation of pxylene with ammonium sulfate, hydrogen sulfide and water are boiled and

260

Aminobenzoic acid

agitated for 4 hours to remove carbon dioxide, hydrogen sulfide and ammonia, sufficient water being added to maintain a constant volume. The mixture is filtered to remove a precipitate containing elemental sulfur. 12 grams of activated charcoal are added to the filtrate and the mixture held at a temperature of 180°F for 20 minutes. Filtration through diatomaceous earth removes color bodies formed during the oxidation process and yields a pale yellow filtrate. The filtrate is acidified with sulfuric acid to a pH of 3 or less to precipitate approximately 49 grams of white solid, comprising a mixture of terephthalic acid and amides of terephthalic acid, which are removed by filtration. This solid is then washed with water at 200°F and redissolved in 200 cc of water containing 28.6 grams of sodium hydroxide. A mixture of sodium hypochlorite and sodium hydroxide is prepared by adding 27.5 grams of chlorine to a vessel equipped with cooling means and containing a solution of 50 grams of sodium hydroxide in 375 cc of water, thereafter adding sufficient water to produce 500 cc of solution. 190 cc of this cold solution are slowly added to the acid-amide solution previously prepared so as to keep the temperature of the mixture below 55°F. The mixture is stirred for 15 minutes and then heated rapidly to 200°F and maintained at that temperature for one hour. 2 grams of sodium thiosulfate are added to consume excess sodium hypochlorite. The solution is acidified to a pH of 3 or less and filtered hot. The filter cake, comprising about 26.9 grams of terephthalic acid, is then suspended in 300 cc of dilute sulfuric acid of pH about 2, heated to 200°F and filtered hot. The filtrates are combined, cooled, and extracted with three successive 200 cc portions of ether. The pH of the filtrate is then raised to 3.5 with sodium hydroxide and the filtrate extracted with six successive 200 cc portions of ether to yield the balance of the product. The crude p-aminobenzoic acid product is recovered by evaporation of ether and is suspended in hot benzene, cooled and filtered to remove benzoic and toluic acids together with small amounts of impurities soluble in the filtrate. Recrystallization of the product from 200 cc of water yields 14.5 grams of light tan needles of p-aminobenzoic acid having an acid number of 411 (theoretical value 409). Aminobenzoic acid can be then purified and decolorized by a process described in US Patent 2,735,865. References Merck Index 423 PDR pp.926, 1894 I.N. p.1012 REM p.787 Toland, W.G. and Heaton, C.D.; US Patent 2,878,281; March 17, 1959; Assigned to California Research Corporation Spiegler, L.; US Patent 2,947,781; August 2, 1960; Assigned to E.I. Du Pont de Nemours and Company Lyding, A.R.; US Patent 2,735,865; February 21, 1956; Assigned to Heyden Chemical Corporation

Aminocaproic acid

261

AMINOCAPROIC ACID Therapeutic Function: Antifibrinolytic Chemical Name: 6-Aminohexanoic acid Common Name: Epsilcapramin Structural Formula:

Chemical Abstracts Registry No.: 60-32-2 Trade Name Epsilon Epsilon-Aminoca Capramol Amicar Epsikapron Acikaprin Amicar Capracid Capracid Capralense Capramol Caprolisin EACA Ekaprol Epsilon Hemocaprol Capusumine Hemotin Ipsilon Resplamin

Manufacturer Roche Roche Choay Lederle Kabi Vitrum Polfa Lederle Kabi Vitrum Bonomelli-Hommel Choay Intalfarmaco Malexi Kasi Vitrum Difrex Star Delagrange Nichiiko Hokuriku Daiichi Kyorin

Country W. Germany W. Germany France US UK Poland US Sweden Italy France Italy Italy Sweden Australia Finland France Japan Japan Japan Japan

Year Introduced 1962 1962 1963 1964 1967 -

Raw Materials Caprolactam Water Manufacturing Process 5 kg of caprolactam were heated with 40 liters of water in a pressure vessel

262

Aminoglutethimide

at 250°C for a period of four hours. These quantities of reactants correspond to a water:lactam molecular ratio of 50:1. After cooling, the small quantity of the nonsoluble substance that is formed is filtered off, and the filtrate is evaporated as far as possible. The resulting concentrate is mixed with three times its volume of strong alcohol, thereby causing the desired product, epsilon-aminocaproic acid (6-aminohexanoic acid), to crystallize out. After separating the crystalline product thus obtained, a further quantity of epsilonaminocaproic acid can be obtained from the mother liquid if desired. References Merck Index 433 Kleeman and Engel p. 41 PDR pp. 872, 997 I.N. p. 13 REM p. 831 Koch, T.; US Patent 2,453,234; November 9, 1948; Assigned to American Enka Corporation

AMINOGLUTETHIMIDE Therapeutic Function: Cytostatic Chemical Name: 3-(4-Aminophenyl)-3-ethyl-2,6-piperidinedione Common Name: α-(p-Aminophenyl)-α-ethylglutarimide Structural Formula:

Chemical Abstracts Registry No.: 124-84-8 Trade Name

Manufacturer

Country

Year Introduced

Ellipten

Ciba

US

1960

Cytadren

Ciba Geigy

US

1980

Orimeten

Ciba Geigy

Switz.

1981

Orimeten

Ciba Geigy

UK

1982

Raw Materials α-Phenyl-α-ethyl glutarimide Nitric acid Hydrogen

Aminolevulinic acid hydrochloride

263

Manufacturing Process The α-(p-nitrophenyl)-α-ethyl-glutarimide starting material can be prepared as follows: 217 g of α-phenyl-α-ethyl-glutarimide are dissolved in 800 g of concentrated sulfuric acid with subsequent cooling to about -10°C and nitration is carried out at -10°C to +10°C by slow addition of a mixed acid consisting of 110 g of concentrated sulfuric acid and 110 g of 63% nitric acid. The nitration solution is stirred into ice, the separated nitro compound taken up in methylene or ethylene chloride, the solution washed with water and sodium carbonate solution until neutral and the solvent evaporated under vacuum. The residue is crystallized from methanol or ethyl acetate, whereby a yellowish crystal powder of MP 128-136°C is obtained in a yield of about 85% which consists for the most part of α-(p-nitrophenyl)-α-ethyl-glutarimide. By recrystallization from methanol the pure p-nitrophenyl compound is obtained of MP 137-139°C. From the residues of the mother liquors a small quantity of the isomeric α-(o-nitrophenyl)-α-ethyl-glutarimide of MP 170-172°C can be obtained. 26.2 g of α-(p-nitrophenyl)-α-ethyl-glutarimide of MP 137-139°C dissolved in ethyl acetate, are reduced in the presence of nickel with hydrogen in a shaking flask at 50-70°C until the absorption of hydrogen falls off. The catalyst is then filtered off with suction and the solution concentrated and cooled, as a result of which colorless crystals of MP 146-149°C are obtained. Recrystallization from methanol gives pure α-(p-aminophenyl)-α-ethylglutarimide of MP 149-150°C (yield 97%). Instead of ethyl acetate another solvent can be used in the above reduction, such as methanol or ethanol. The hydrochloride of MP 223-225°C is obtained by dissolving the base with alcohol and the corresponding quantity of hydrochloric acid gas in the hot with subsequent cooling of the solution. Colorless crystals are formed of MP 223225°C, which are easily soluble in water. References Merck Index 443 PDR p. 794 OCDS Vol. 1 p.257 (1977) I.N. p. 71 REM p. 1143 Hoffmann, K. and Urech, E.; US Patent 2,848,455; August 19, 1958; Assigned to Ciba Pharmaceutical Products, Inc.

AMINOLEVULINIC ACID HYDROCHLORIDE Therapeutic Function: Photosensitizer Chemical Name: Pentanoic acid, 5-amino-4-oxo-, hydrochloride

264

Aminolevulinic acid hydrochloride

Common Name: Aminolevulinic acid hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 5451-09-2; 106-60-5 (Base) Trade Name

Manufacturer

Country

Year Introduced

Levulan Kerastick

DUSA Pharmaceuticals Inc.

-

-

Raw Materials N-Furfurylphthalimide Rose Bengal Palladium on carbon Manufacturing Process 1) Oxidation Step 2.27 g (10.0 mmol) of N-furfurylphthalimide was charged into a three-necked glass flask equipped with an oxygen feed tube, a thermometer, and a reflux condenser, and dissolved in 100 ml of anhydrous pyridine. After the addition of 7.0 mg of Rose Bengal, oxygen gas was fed at a rate of 20 ml/min at 10°20°C under irradiation by light. A 27 W white fluorescent lamp was used as a light source and the radiation was performed from the outside of the flask. After 7 hours, the irradiation was terminated and the pyridine was evaporated under reduced pressure to obtain 2.47 g of a light brown, semi-crystalline product. 2) Reduction Step (Hydrogenation) 2.00 g of the semi-crystalline solid obtained in (1) was dissolved in 40 ml of methanol and stirred at 50°C in a hydrogen atmosphere under atmospheric pressure in the presence of 200 mg of 5% palladium-on-carbon catalyst. After five hours, the reaction was terminated and the mixture was allowed to cool to room temperature. The catalyst was removed by filtration and methanol was evaporated to obtain 2.11 g of white crystals. The crystals were identified to be 5-phthalimidolevulinic acid by NMR analysis. The yield was 97%. 3) Hydrolysis Step 100 ml of 6 N hydrochloric acid was added to 2.11 g of the white crystals (2), and the mixture was heated under reflux for 5 hours.

Aminometradine

265

After evaporating the hydrochloric acid under reduced pressure, a brown solid product was obtained and dissolved in ethanol. Acetone was added to the solution and the crystals produced were collected by filtration to obtain 0.689 g of 5-aminolevulinic acid hydrochloride. The yield based on Nfurfurylphthalimide was 51%. NMR spectrum data conformed to 5-aminolevulinic acid hydrochloride References Takeya H. et al.; US Patent No. 5,380,935; Jan. 10, 1995; Assigned Cosmo Research Institute; Cosmo Oil Co., Ltd., both of Tokyo, Japan

AMINOMETRADINE Therapeutic Function: Diuretic Chemical Name: 6-Amino-3-ethyl-1-(2-propenyl)-2,4(1H,3H)pyrimidinedione Common Name: Aminometramide Structural Formula:

Chemical Abstracts Registry No.: 642-44-4 Trade Name

Manufacturer

Country

Year Introduced

Mincard

Searle

US

1954

Mictine

Searle

-

-

Raw Materials Monoallyl urea Sodium hydroxide

Cyanoacetic acid Diethyl sulfate

Manufacturing Process 85 parts of monoallylurea are dissolved in 105 parts of acetic anhydride, and 85 parts of cyanoacetic acid are added gradually and the mixture is maintained at 65°C for 2.5 hours. The mixture is distilled at 20 mm until a syrup remains. 50 parts of water are added to this syrup and distillation is resumed. The resulting syrup is dissolved in 96% ethanol at 60°C, stirred with charcoal and filtered. One to one and one-half volumes of ether are added to the filtrate at 40°C. Upon cooling the N-cyanoacetyl-N'-allylurea precipitates.

266

Aminopentamide

It is collected on a filter and washed with ether. The white crystals melt at about 142-143°C. The N-cyanoacetyl-N'-allylurea is dissolved by warming with 10% sodium hydroxide. Sufficient 70% sodium hydroxide is added to raise the pH to 10. The solution is maintained at 60°C for five minutes. After cooling the crystals are collected on a filter and recrystallized from water. 1-Allyl-6amino-1,2,3,4-tetrahydro-2,4-pyrimidinedione is obtained in the form of white crystals melting at 270-272°C. 334 parts of 1-allyl-6-amino-1,2,3,4-tetrahydro-2,4-pyrirnidinedione are dissolved in a solution of 88 parts of sodium hydroxide in 1,100 parts of water. While this mixture is stirred rapidly at 50°C, 430 parts of diethyl sulfate are added in the course of 30 minutes. Stirring is continued at 50-55°C for one hour longer, and an alkaline reaction is maintained by occasional additions of small portions of 20% aqueous sodium hydroxide solution, about 300 parts in all being required. On cooling, the 1-allyl-3-ethyl-6-amino-1,2,3,4tetrahydro-2,4-pyrimidinedione separates as the monohydrate; it is filtered off, washed with cold water, and recrystallized from water containing a small amount of sodium hydroxide to hold in solution any unreacted 1-allyl-6amino-1,2,3,4-tetrahydro-2,4-pyrimidinedione. The air dried product thus obtained contains 1 mol of crystal water and melts over a wide range with dehydration at 75-115°C. After dehydration by treatment with anhydrous ether, the anhydrous 1-allyl-3-ethyl-6-amino-1,2,3,4-tetrahydro-2,4pyrimidinedione melts sharply at about 143-144°C. References Merck Index 455 OCDS Vol. 1 p. 265 (1977) I.N. p. 72 Papesch, V. and Schroeder, E.F.; US Patent 2,650,922; September 1, 1953; Assigned to G.D. Searle and Co.

AMINOPENTAMIDE Therapeutic Function: Anticholinergic Chemical Name: 4-(Dimethylamino)-2,2-diphenylvaleramide Common Name: Dimevamide Structural Formula:

Aminophylline

267

Chemical Abstracts Registry No.: 60-46-8 Trade Name

Manufacturer

Country

Year Introduced

Centrine

Bristol

US

1953

Raw Materials α,α-Diphenyl-γ-dimethylaminovaleronitrile Hydroxylamine hydrochloride Manufacturing Process A mixture of 14 g (0.05 mol) of α,α-diphenyl-γ-dimethylaminovaleronitrile, 16 g (0.2 mol) of sodium acetate, 14 g (0.2 mol) of hydroxylamine hydrochloride and 75 ml of ethyl alcohol was refluxed 18 hours. The mixture was cooled, poured into water and neutralized with ammonium hydroxide. The heavy white precipitate solidified on standing. The material was filtered and recrystallized from isopropanol. After three recrystallizations the aminopentamide product melted at 177° to 179°C. The product is often used as the acid sulfate which is produced as follows: 252.0 g (0.85 mol) of α,α-diphenyl-γ-dimethylaminovaleronitrile was dissolved in one liter of isopropanol, and 70 ml of concentrated sulfuric acid was added as rapidly as possible. The mixture was heated until clear, then filtered and diluted with 1,500 ml of anhydrous ethyl acetate. The solution was cooled and filtered, and the white crystalline product was dried in vacuum over P2O5. References Merck Index 463 I.N. p. 342 Specter, M.E.; US Patent 2,647,926; August 4, 1953; Assigned to Bristol Laboratories, Inc.

AMINOPHYLLINE Therapeutic Function: Diuretic, Cardiac stimulant, Smooth muscle relaxant, Vasodilator Chemical Name: 1H-Purine-2,6-dione, 3,7-dihydro-1,3-dimethyl-, compd. with 1,2-ethanediamine (2:1) Common Name: Aminophelline; Teofyllamin; Theophyllin-Athylendiamin; Theophylline; Theophyl(l)amin; Ethylenediamine Chemical Abstracts Registry No.: 317-34-0

268

Aminophylline

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Memcophylline

Memphis Co.

-

-

Memcophylline IV

Memphis Co.

-

-

Aminophyl

Neon Laboratories Ltd.

-

-

Aminophylline

Wellcome

-

-

Aminophylline

AroKor Holdings Inc.

-

-

Aminophylline

West-ward Pharmaceutical Corp.

-

-

Aminophylline, Anhydrous

Spectrum Chemicals and Laboratory Products, Inc.

-

-

Afonilum

Knoll

-

-

Aminodur

Berlex

-

-

Cardophylin

Rhone Poulenc

-

-

Euphyllina

Byk Gulden

-

-

Pecram

Novartis

-

-

Phyllocontin

Purdue Frederick

-

-

Phyllotemp

Mundipharma

-

-

Planphylline

Asta

-

-

Pulmovet

Solvay

-

-

Tefamin

Recordati

-

-

Ventax

Yamanouchi Europe

-

-

Diffumal 24

Malesci Instituto Pharmabiologico

-

-

Durofilin

Zdravle

-

-

Retafyl

Orion Pharma International

-

-

Slow-Bid

Rhone-Poulenc Rorer

-

-

Spophyllin Retard

Slovakofarma

-

-

Theo

Amoun

-

-

Theostat

Pierre Fabre Medicament

-

-

Teotard

Krka

-

-

Uni-Dur

Schering-Plough

-

-

Aminocardol

Wander

-

-

Aminofilin

Srbolek

-

-

Aminopromazine fumarate

269

Trade Name

Manufacturer

Country

Year Introduced

Aminofilina

Ariston

-

-

Aminofilina

Biochimico

-

-

Aminofilina

IMA

-

-

Aminofilina

Sandoz

-

-

Aminofilina

Uniao Quimica Farm.

-

-

Aminofilina

Vital Brazil

-

-

Aminofilina

Azevedos

-

-

Aminofilina

C.P. Higiene

-

-

Aminofilina

Apteka im.T.Kosciusz

-

-

Theophyllaminum

Leiras

-

-

Theodrox

Suomen Astra

-

-

Theodrox

3 M Riker

-

-

Raw Materials Theophylline Ethylenediamine hydrate Manufacturing Process A mixture of 198 g (1 mol) theophylline and 60-78 g (0.75-1 mol) ethylenediamine hydrate in 300 g of water was stirred at 50°C and then the mixture was concentrated in vacuo. The product (aminophylline) was separeted by suction filtration. Aminophylline was used as an aqueous solution. References Byk H., DE Patent No. 223,695, June 30, 1910; Assigned to Chemische Werke

AMINOPROMAZINE FUMARATE Therapeutic Function: Spasmolytic Chemical Name: 10-(2,3-Bis(dimethylamino)propyl)phenothiazine fumarate (2:1) Common Name: Aminopromazine fumarate; Proquamezine fumarate; Tetrameprozine Chemical Abstracts Registry No.: 3688-62-8;58-37-7 (Base)

270

Aminopromazine fumarate

Structural Formula:

Trade Name Jenotone Jenotone Lispamol Lorusil Myspamol Sedofarmolo

Manufacturer Coopers Schering-Plough Specia Biochemie May and Baker Centralvet

Country -

Year Introduced -

Raw Materials Phenothiazine Sodium amide 1,3-Bis(dimethylamino)-2-chloropropane Manufacturing Process Phenothiazine (20 g) is heated under reflux for 1 hour with sodium amide (5 g) in xylene (80 ml). A solution of 1,3-bis(dimethylamino)-2-chloropropane (27 g) (prepared by a method analogous to that described in Ingold and Rothstein J.C.S. 1931, 1676) in xylene (30 ml) is then added over 2 hours. Heating is continued for a further 1 hour and then the mixture is taken up in water (270 ml) and hydrochloric acid (d=1.19; 20 ml). The decanted acid layer is treated with caustic soda (d 1.33; 25 ml) and the base is extracted with ether (2 x 50 ml) which is then dried over potassium carbonate. On distillation there is obtained at 218-220°C/0.6 mm Hg a mixture (20 g) containing a major proportion of 10-[2,3-bis(dimethylamino)-1propyl]phenothiazine and a minor proportion of 10-[1,3-bis(dimethylamino)-1propyl]phenothiazine. A mixture of bases (11 g) obtained is dissolved in isopropanol (25 ml). Ether (25 ml) containing dry hydrogen chloride (2 g) is added, the mixture is left to crystallise overnight in a refrigerator and the product is filtered off, washed and dried. There is thus obtained a salt (2.5 g), M.P. 244°C, which is 10-[1,3bis(dimethylamino)-1-propyl]phenothiazine hydrochloride. On evaporation of the mother liquors from the above hydrochloride a residue is obtained from which is isolated its isomer, 10-[2,3-bis(dimethylamino)-1propyl]phenothiazine, the base crystallising from ethanol and melting at 58°C. The structure of these two isomers has been confirmed by comparison of their infra-red adsorption spectra with those of related products of known structure. In practice it is usually used as fumarate.

Aminopterin hydrate

271

References Merck Index, Monograph number: 487, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. GB Patent No. 800,635; Nov.4,1955; Assigned to Socciete des Usines Chimiques Rhone-Poulenc, a French body corporate

AMINOPTERIN HYDRATE Therapeutic Function: Antineoplastic Chemical Name: L-Glutamic acid, N-(4-(((2,4-diamino-6-pteridinyl)methyl) amino)benzoyl)-, hydrate Common Name: 4-Amino-4-deoxyfolic acid; 4-Aminofolsäure; 4-Amino-PGA; Aminopterin; 4-Aminopteroylglutamic acid; 4-Aminopteroylglutaminsäure; Antifolic acid; Antifolsäure Structural Formula:

Chemical Abstracts Registry No.: 54-62-6 (Base) Trade Name

Manufacturer

Country

Year Introduced

Aminopterin

Sigma Chemical Company

-

-

Raw Materials 1,3-Dihydroxyacetone Bromine Cysteine hydrochloride hydrate Triphenylphosphine

Barium chloride dihydrate N-(4-Aminobenzoyl)-L-glutamic acid 2,4,5,6-Tetraaminopyrimidine sulfate hydrate

Manufacturing Process 2,4,5,6-Tetraaminopyrimidine·H2SO4·H2O (75.0 g, 0.293 mole) was added to a stirred solution of BaCl2·2H2O (71.5 g, 0.293 mole) in H2O (1.45 L) at 8590°C. The mixture was stirred rapidly at about 90°C for 15 min, cooled to 40°C, and filtered from BaSO4, which was washed thoroughly on a funnel with

272

Aminopterin hydrate

H2O. The clear, yellow filtrate was then diluted further with H2O to give a volume of 4.35 L. This solution of the tetraaminopyrimidine·2HCl was then added to a solution of NaOAc (4.35 L of 4 N) in which 1,3-dihydroxyacetone (79.3 g, 0.88 mole) and cysteine·HCl·H2O (51.5 g, 0.293 mole) had just been dissolved. The resulting solution was stirred mechanically at room temperature while a slow stream of air was continuously passed through it for 26 hours. (Yellow-orange solid began separating after 2 hours). The mixture was then kept in a refrigerator for 16 hours before the solid was collected, washed successively with cold H2O, EtOH, and Et2O before it was dried to constant weight in vacuo over P2O5 at 25°C. [The crude product mixture (47 g) was weighed in order to obtain an estimate of the volume of 48% HBr required to form hydrobromide salts]. A mechanically stirred mixture of the dried solid and EtOH (6.05 L) was heated to 70°C, and a solution of 48% HBr (28 ml) in EtOH (490 ml) was added in a thin stream while the mixture was maintained at 70-75°C. The mixture was then refluxed for about 5 min with rapid stirring while nearly all of the solid dissolved. The hot solution was treated with Norit and filtered through a Celite mat. The clear yellow filtrate was kept in a refrigerator overnight while a first crop of orange colored solid separated. The collected solid was washed with EtOH, then dried in vacuo (56°C over P2O5) to give 17.2 g of product. The filtrate was concentrated by evaporation (rotary evaporator) to about 2 L and then refrigerated to give a second crop of 10.2 g, which was dried as before; total yield of crude 2,4diamino-6-pteridinemethanol hydrobromide 27.4 g (34%). The PMR spectrum of this material in CF3CO2D showed it to contain a barely detectable amount of methyl-substituted 2,4-diaminopteridine·HBr. Bromine (59.6 g, 0.373 mole) was added dropwise over a 30 min to a stirred solution of triphenylphosphine (97.7 g, 0.373 mole) in anhydrous dimethylacetamide (486 ml) kept at 10°C (ice bath) and protected from atmospheric moisture. (Bromine remaining in the funnel was rinsed with 10 ml of dimethylacetamide). A smooth suspension containing finely divided, crystalline triphenylphosphine dibromide resulted. The 2,4-diamino-6pteridinemethanol·HBr (25.4 g, 0.093 mole) described above was added in one portion through a powder funnel (with the aid of 10 ml dimethylacetamide). The ice bath was removed, and the stirred mixture was allowed to warm to 20-25°C. After about 1 hour, complete solution had occurred. The solution, which gradually developed a dark red color, was kept at 20-25°C for 1 hour longer and was then chilled (ice bath) before it was treated with EtOH (72 ml). After overnight refrigeration, the solvents were removed by evaporation in vacuo. The dark, semisolid residue was stirred with two 300 ml of C6H6 (to remove triphenylphosphine oxide), and each portion was removed from the C6H6 insoluble product by decantation. The solid that remained was dissolved with stirring in glacial AcOH (660 ml) which had been preheated to 80°C. The mixture was kept in a bath at 80°C until solution was complete. Tan crystalline solid separated as the dark solution was allowed to cool. Overnight refrigeration caused the AcOH to partially freeze. When it had thawed, the solid was collected, washed with chilled AcOH followed by Et2O, and dried in vacuo (over P2O5 and NaOH pellets) at successive temperatures of 25°C, 56°C, and 110°C. (The higher temperature was necessary for complete removal of AcOH). The yield was 15.3 g (49%). (Some runs afforded 60% yield). This sample was further purified by reprecipitation from MeOH solution (Norit) by addition of Et2O followed by drying in vacuo (25°C, P2O5), yield 13.0 g (42%) of 2,4-diamino-6-(bromomethyl)pteridine hydrobromide as

Aminosalicylic acid

273

a pale yellow solid. A mixture of 2,4-diamino-6-(bromomethyl)pteridine hydrobromide (168 mg, 0.500 mmole) and N-(4-aminobenzoyl)-L-glutamic acid (400 mg, 1.50 mmoles) in dimethylacetamide (2 ml) was stirred at 25°C under N2 in a stoppered flask protected from light. Solution occurred after 2 hours. After 18 hours, the orange solution was mixed with H2O (15 ml) with stirring to give a finely divided, yellow precipitate. The mixture was centrifuged, and the supernatant removed by decantation. The yellow solid was stirred with four 15 ml portions of H2O, each of which was removed by decantation after centrifugation. The solid was then suspended in EtOH (15-20 ml), collected by filtration, washed with Et2O, and dried in vacuo (25°C, P2O5) to give hydrated N-[4-[[(2,4-diamino-6-pteridinyl)methyl]amino]benzoyl]-L-glutamic acid (Aminopterin) hydrate (4:7) in 68% yield (160 mg). Examination by TLC revealed one UV-absorbing spot and no fluorescence at any point. References Merck Index, Monograph number: 493, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. James R.P., Montgomery J.A.; US Patent No. 4,079,056; Mar. 14; Assigned to The Unites States of America, Departament of Health, Education and Welfare, Washington

AMINOSALICYLIC ACID Therapeutic Function: Antitubercular Chemical Name: 4-Amino-2-hydroxybenzoic acid Common Name: Structural Formula:

Chemical Abstracts Registry No.: 65-49-6 Trade Name

Manufacturer

Country

Year Introduced

Pamisyl

Parke Davis

US

1948

Parasal

Panray

US

1950

Rexipas

Squibb

US

1954

Aminacyl

Wander

UK

-

B-Pas

Salvoxyl-Wander

France

-

Enseals

Lilly

US

-

Nemasol

I.C.N.

Canada

-

274

Aminosalicylic acid

Trade Name

Manufacturer

Country

Year Introduced

Neopasalate

Mallinckrodt Inc.

US

-

Panacyl

-

Paramisan

Pharma W. Germany Rheinpreussen Smith and Nephew UK

Para-Pas

Gold Leaf

US

-

Pas

Sumitomo

Japan

-

Pasido

Ferrosan

Sweden

-

Propasa

-

-

Rezipas

Merck Sharp and Dohme Squibb

US

-

Sanpas

Sanyo

Japan

-

Sta-Pas

Debat

France

-

Tebacin Acid

Consol. Midland

US

-

-

Raw Materials Sodium-p-aminosalicylate m-Aminophenol Ammonium carbonate Manufacturing Process As described in US Patent 427,564, aminosalicylic acid may be prepared from m-aminophenol by heating with ammonium carbonate in solution under pressure. Alternatively, aminosalicylic acid may be made from sodium p-aminosalicylate as described in US Patent 2,844,625 as follows: 196 grams of commercial sodium para-aminosalicylate (18.5% H2O) was dissolved in 196 ml of water and 150 ml of isopropanol. 6 grams of sodium bisulfite was dissolved in the solution and the solution filtered. While stirring and keeping the temperature between 25-31°C, seven grams of 85% formic acid and 27.5 grams of 95% sulfuric acid in 150 ml of water was added during 1 ½ hours. The mixture was stripped 1 hour longer, cooled to 23°C and filtered. The filter cake was washed with 100 cubic centimeters of water, further washed with 100 cc of 25% isopropanol and 100 cc of water, and vacuum dried to constant weight at 4550°C. Weight of p-aminosalicylic acid was 76.5 grams (92.7% yield) exhibiting a bulk density of 47 cc/oz. References Merck Index 485 Kleeman and Engel p. 43 I.N. p. 74 REM p. 1213 Gnehm, R.and Schmid, J.; US Patent 427,564; May 13, 1890 Centolella, A.P.; US Patent 2,844,625; July 22, 1958; Assigned to Miles Laboratories, Inc. Doub, L.; US Patent 2,540,104; February 6, 1951; Assigned to Parke Davis and Co.

Amiodarone hydrochloride

275

AMIODARONE HYDROCHLORIDE Therapeutic Function: Coronary vasodilator Chemical Name: (2-Butyl-3-benzofuranyl)[4-(2-diethylamino)ethoxyl-3,5diiodophenyl]methanone hydrochloride Common Name: Structural Formula:

Chemical Abstracts Registry No.: 1951-25-3 (Base) Trade Name Cordarone Cordarone Cordarone X Cordarone Cordarexne Amiodacore Atlansil Miodarone Procor Ritmocardyl Trangorex Uro-Septra

Manufacturer Labaz Sigma Tau Labaz Labaz Labaz C.T.S. Roemmers Biosintetica Unipharm Bago Labaz Biosintetica

Country France Italy UK Switz. W. Germany Israel Argentina Brazil Israel Argentina Brazil

Year Introduced 1971 1980 1981 1982 -

Raw Materials 2-n-Butyl-3-(3,5-diiodo-4-hydroxybenzoyl)benzofuran Sodium methoxide β-Diethylaminoethyl chloride Manufacturing Process 135 grams of 2-n-butyl-3-(3,5-diiodo-4-hydroxybenzoyl)benzofuran dissolved in 600 cc of ethyl carbonate were treated with 5.7 grams of sodium in the form of sodium methoxide in methanol. Then, β-diethylaminoethyl chloride which had been obtained from 51.6 grams of the hydrochloride in ethyl

276

Amiphenazole

carbonate was introduced into a suspension of the sodium salt. The mixture was heated to a temperature of approximately 90°C which was maintained for approximately 2 hours. The mixture was cooled and allowed to stand overnight during which time the sodium chloride settled down. The toluene solution containing diethylaminoethyl ether was extracted with increasingly diluted aqueous hydrochloric acid solutions while stirring. Extraction was continued until the alkalized solution produced no further precipitate. The combined aqueous solutions were washed with ether and then made strongly alkaline with aqueous sodium hydroxide. Extraction with ether was carried out three times. The organic layers were washed with water and then dried over anhydrous potassium carbonate. In order to produce the hydrochloride, the carbonate was filtered off and then the hydrochloride was precipitated from the ether solution with an ethereal hydrochloric acid solution. After the solution had been allowed to stand for a few hours, decantation was carried out and the syrupy hydrochloride residue was taken up in 500 cc of boiling acetone. The salt crystallized out by cooling. The substance was allowed to stand overnight at 0°C, and centrifuged, washed with ethyl acetate and then with ether and dried. 130 grams of 2-n-butyl-3(3,5-diiodo-4-β-N-diethylaminoethoxybenzoyl)benzofuran hydrochloride in the form of a crystalline powder which melts at 156°C were obtained. References Merck Index 491 Kleeman and Engel p. 43 DOT 5 (4) 123 (1969) I.N. p. 75 Tondeur, R. and Binon, F.; US Patent 3,248,401; April 26, 1966; Assigned to Societe Beige de I'Azote et des Produits Chimiques du Marly, SA, Belgium

AMIPHENAZOLE Therapeutic Function: Respiratory stimulant, Barbiturate antagonist, Morphine antagonist Chemical Name: Thiazole, 2,4-diamino-5-phenylCommon Name: Amifenazole; Amiphenazole Structural Formula:

Chemical Abstracts Registry No.: 490-55-1

Amisometradine

277

Trade Name

Manufacturer

Country

Year Introduced

Aamphisol

RJR

-

-

Raw Materials Thiourea α-Bromophenylacetonitrile Manufacturing Process Thiourea reacted with α-bromophenylacetonitrile and as a result of this reaction 2-(cyanophenylmethyl)isothiourea was obtained. By cyclisation of the 2-(cyanophenylmethyl)isothiourea 2,4-diamino-5phenylthiazole (amiphenazol) was produced. References Kleemann A., Engel J.; Pharmazeutische Wirkstoffe, GeorgThieme Verlag Stuttgart. New York, 1982

AMISOMETRADINE Therapeutic Function: Diuretic Chemical Name: 6-Amino-3-methyl-1-(2-methyl-2-propenyl)-2,4(1H,3H)pyrimidinedione Common Name: Structural Formula:

Chemical Abstracts Registry No.: 550-28-7 Trade Name

Manufacturer

Country

Year Introduced

Rolicton

Searle

US

1956

Raw Materials Methallylamine Cyanoacetic acid

Methyl isocyanate Sodium hydroxide

278

Amisulpride

Manufacturing Process Preparation of the ethyl analog is as follows (methyl isocyanate is used in amisometradine manufacture). To a cooled and stirred solution of 142 parts of methallylamine in 900 parts of benzene, 156 parts of ethyl isocyanate are added dropwise. Upon concentration in vacuum N-ethyl-N'-methallylurea is obtained. 260 parts of this urea derivative are dissolved in 500 parts of acetic anhydride and treated with 157 parts of cyanoacetic acid at 60°C and heated at that temperature for 2 hours. The solution is then concentrated in vacuum to a syrup. 100 parts of water are added and the vacuum distillation is repeated. The remaining syrup contains a mixture of N-cyanoacetyl-N-ethyl-N'methallylurea and a small quantity of N-cyanoacetyl-N-methallyl-N'-ethylurea. This syrup is treated with sufficient 20% sodium hydroxide solution to raise the pH to 10. A violent reaction occurs. The reaction mixture is diluted with 50 parts of water, stirred, cooled and filtered. The material collected on the filter is recrystallized from 10% ethanol to yield a mixture of 1-methallyl-3-ethyl-6amino-1,2,3,4-tetrahydro-2,4-pyrimidinedione and 1-ethyl-3-methallyl-6amino-1,2,3,4-tetrahydro-2,4-pyrimidinedione melting at about 157-159°C. References Merck Index 493 OCDS Vol. 1 p. 266 I.N. p. 76 Papesch, V. and Schroeder, E.F.; US Patent 2,729,669; January 3, 1956; Assigned to G.D. Searle and Co.

AMISULPRIDE Therapeutic Function: Antipsychotic Chemical Name: Benzamide, 4-amino-N-((1-ethyl-2-pyrrolidinyl)methyl)-5(ethylsulfonyl)-2-methoxyCommon Name: Aminosultopride; Amisulpride Structural Formula:

Amisulpride

279

Chemical Abstracts Registry No.: 71675-85-9 Trade Name Solian Amitrex Socian

Manufacturer Lorex-Synthelabo Synthelabo Sanofi-Synthelabo GmbH

Country -

Year Introduced -

Raw Materials 2-Methoxy-4-amino-5-mercaptobenzoic acid Caustic soda Ethyl sulfate Manufacturing Process 2-Methoxy-4-amino-5-ethylthiobenzoic acid: 159 g of 2-methoxy-4-amino-5-mercaptobenzoic acid, 355 ml of water and 160 ml of caustic soda solution are placed in a flask fitted with a condenser. The mixture is heated until the solid dissolves, then 123 g of ethyl sulfate is added. The mixture is heated to reflux, treated with 10 ml of 30% caustic soda solution, then heated to reflux for 1 hour. After cooling, 800 ml of water is added and the solution is filtered. The precipitate obtained by adding 100 ml of concentrated hydrochloric acid in the presence of ether is drained, washed with water and dried. 162 g of 2-methoxy-4-amino-5-ethylthiobenzoic acid is obtained (yield=88%). 2-Methoxy-4-amino-5-ethylsulfonylbenzoic acid: 123 g of 2-methoxy-4-amino-5-ethylthiobenzoic acid is dissolved hot in 542 ml of acetic acid. The solution obtained is cooled to 35°C, then 185 ml of hydrogen peroxide is added in small quantities while the temperature is raised to 80°C. The temperature is lowered to 40°C and the mixture is kept at that temperature for some hours and then cooled to 10°C. The precipitate formed is drained, washed with acetic acid and dried, then dissolved in 600 ml of water and 100 ml of 20% ammonia. The precipitate formed by adding 70 ml of concentrated hydrochloric acid is cooled, drained, washed with water and dried. 61.5 g of 2-methoxy-4-amino-5-ethylsulfonylbenzoic acid is obtained (yield 42%, M.P. 95-100°C). 4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2methoxybenzamide: 81 g of 2-methoxy-4-amino-5-ethylsulphonylbenzoic acid and 297 ml of acetone are placed in a flask fitted with an agitator, a thermometer and a dropping funnel, followed by 33 g of triethylamine. The solution is cooled to 0°C, then 30 g of ethyl chloroformate is added drop by drop between 0° and 5°C. When the mixture has been agitated 51 g of 1-ethyl-2aminomethylpyrrolidine is added drop by drop between 5° and 10°C. The mixture is agitated at 10°C then at ambient temperature. The triethylamine hydrochloride which precipitates is drained, then the acetone is distilled. The residue is dissolved in 600 ml of water in the presence of caustic soda

280

Amitraz

solution. The base crystallizes after seeding and is drained, washed with water and dried. When the crystals have been purified by passing them through hydrochloride and recrystallising them in acetone, 66 g of 4-amino-N-[(1ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamideis obtained (yield 61%, M.P. 126-127°C). References Thominet M., Acher J., Monier J.; US Patent No. 4,401,822; Aug. 30, 1983; Assigned to Societe de'Etudes Scientifiques et Industrielles de l'Ile-de France (Paris, FR)

AMITRAZ Therapeutic Function: Acaricide, Scabicide, Tickicide, Appetite stimulant Chemical Name: Methanimidamide, N'-(2,4-dimethylphenyl)-N-(((2,4dimethylphenyl)imino)methyl)-N-methylCommon Name: Amitraz; Ectodex; Topline Structural Formula:

Chemical Abstracts Registry No.: 33089-61-1 Trade Name Aludex Ectodex

Manufacturer Hoechst Roussel Vet Ltd. Intevet

Country -

Year Introduced -

-

-

Raw Materials Sodium hydroxide N-Methylformamide

2,4-Dimethylaniline hydrochloride 4-Toluenesulfonyl chloride

Manufacturing Process A mixture of 55.1 g 2,4-dimethylaniline hydrochloride, 83.7 g ptoluenesulphonyl chloride and 150 ml N-methylformamide was stirred with occasional cooling to maintain the temperature at 20°-35°C. When the exothermic reaction had subsided, the mixture was stirred at room temperature for 4 h, poured into a mixture of ice and water, and basified with 10 N sodium hydroxide solution, keeping the temperature of the mixture

Amitriptyline hydrochloride

281

below 10°C. The precipitated solid was filtered, washed with water until free from alkali, dried at room temperature, to give N-2,4-dimethylphenyl-N'methylformamidine, melting point 75°-76°C (recrystallized from cyclohexane). A solution of 19.4 g N-2,4-dimethylphenyl-N'-methylformamidine and 0.3 g ptoluenesulphonic acid in 195 ml dry xylene was refluxed under anhydrous conditions for 48 h, causing the evolution of methylamine. The xylene was distilled off under reduced pressure to give 1,5-di-(2,4-dimethylphenyl)-3methyl-1,3,5-triaza-penta-1,4-diene, melting point 88°-89°C (crystallized twice from isopropyl). References Harrison I. R. et al.; US Patent No. 3,781,355; Dec. 25, 1973; Assigned: Boots Pure Drug Company Limited, Nottingham, England

AMITRIPTYLINE HYDROCHLORIDE Therapeutic Function: Antidepressant Chemical Name: 3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)N,N-dimethyl-1-propaneamine hydrochloride Common Name: Structural Formula:

Chemical Abstracts Registry No.: 549-18-8; 50-48-6 (Base) Trade Name Elavil HCl Elavil Triptizol Laroxyl Endep Amitril Amitid Arnavil

Manufacturer Merck Sharp and Dohme DDSA Merck Sharp and Dohme

Country US

Year Introduced 1961

UK Italy

1962 1962

Roche Roche WL/PD Squibb Mallard

Italy US US US US

1962 1975 1978 1979 1980

282

Amitriptyline hydrochloride

Trade Name

Manufacturer

Country

Year Introduced

Enovil

Hauck

US

1982

Adepril

Lepetit

Italy

-

Adepress

Essex-Shionogi

Japan

-

Ami-Aneiun

Lorente

Spain

-

Amilent

Warner Lambert

US

-

Amiprin

Kobayashi

Japan

-

Amiptanol

Kanto

Japan

-

Amitrip

Glebe

Australia

-

Amitriptol

Bracco

Italy

-

Annolytin

Kodama

Japan

-

Annolytin

Nippon Shoji

Japan

-

Deprestat

Script Intal

S. Africa

-

Domical

Berk

UK

-

Elatrol

ICN

Canada

-

Elatrol

Teva

Israel

-

Elatrolet

Teva

Israel

-

Lantron

Yamanouchi

Japan

-

Lentizol

Warner Lambert

US

-

Levate

ICN

Canada

-

Limbitrol

Roche

France

-

Limbitrol

Roche

US

-

Mareline

Elliott-Marion

Canada

-

Meravil

Medic

Canada

-

Miketorin

Mitsui

Japan

-

Mitaptyline

Toyo Pharm.

Japan

-

Mutanxion

Cetrane

France

-

Mutaspline

Cetrane

France

-

Normaln

Sawai

Japan

-

Novotriptyn

Novopharm

Canada

-

Redomex

Labaz

-

-

Saroten

Lundbeck

W. Germany

-

Saroten

Tropon

W. Germany

-

Saroten

Warner

UK

-

Sarotex

Lundbeck

W. Germany

-

Schuvel

Tokyo Hosei

Japan

-

Sensival

Pfizer Taito

Japan

-

Teperin

EGYT

Hungary

-

Trepiline

Lennon

S. Africa

-

Triavil

Merck Sharp and Dohme Kimya Evi

US

-

Turkey

-

Triptilin

Amitriptyline hydrochloride

283

Trade Name

Manufacturer

Country

Year Introduced

Triptyl

Farmos

Finland

-

Tryptal

Unipharm

Israel

-

Tryptanol

Merck-Banyu

Japan

-

Tryptizol

Sharp and Dohme W. Germany

-

Tryptizol

Sharp and Dohme UK

-

Raw Materials Phthalic anhydride Hydrochloric acid Phenylacetic acid

3-(Dimethylamino)propyl chloride Hydrogen

Manufacturing Process Phthalic anhydride is reacted with phenylacetic acid to form 3benzylidenephthalide which is then hydrogenated to 2-phenethylbenzoic acid. Conversion to the acid chloride followed by intramolecular dehydrochlorination yields the ketone, 5H-dibenzo[a,d]cyclohepten-5-one. The ketone undergoes a Grignard reaction with 3-(dimethylamino)propyl chloride to give 5-(γdimethylaminopropylidene)-5H-dibenzo[a,d]cycloheptene. Then, as described in US Patent 3,205,264, a solution of 5-(γdimethylaminopropylidene)-5H-dibenzo[a,d]cycloheptene (42 grams; 0.153 mol) in 105 ml of ethanol is hydrogenated over Raney nickel (1.5 grams) at 65°C under an initial hydrogen pressure of 450 lb. After 1 mol of hydrogen is absorbed (3.5 hours), the reaction mixture is filtered to remove the catalyst and is acidified with 80 ml of 2.5 N hydrochloric acid (0.2 mol). The acidic solution is concentrated to dryness under vacuum and is flushed three times with 100 ml of benzene to remove residual water. The solid residue then is dried under vacuum at 40°C to yield 44.9 grams (94% of theory) of the product, MP 187-189.5°C, equivalent weight 307, ultraviolet absorption A% 2380432. Recrystallization from isopropyl alcohol and ether affords the product in high purity. In practice it is usually used as hydrochloride. References Merck Index 496 Kleeman and Engel p. 44 PDR pp. 673, 993, 1174, 1217, 1314, 1509, 1513, 1569, 1606, 1617 OCDS Vol. 1 pp. 151, 404 DOT 9 (6) 219 (1973) I.N. p. 76 REM p. 1093 Tristram, E.W. and Tull, R.J.; US Patent 3,205,264; September 7, 1965; Assigned to Merck and Co., Inc.

284

Amitriptyline oxide

AMITRIPTYLINE OXIDE Therapeutic Function: Antidepressant Chemical Name: 3-(3'-Dimethylaminopropylidene)dibenzo[a,d]cyclohepta1,4-diene N-oxide Common Name: Structural Formula:

Chemical Abstracts Registry No.: 4317-14-0 Trade Name

Manufacturer

Country

Year Introduced

Equilibrin

Nattermann

W. Germany

1980

Ambivalon

Nattermann

W. Germany

-

Raw Materials Dibenzo[a,d]cyclohepta-1,4-diene-5-one 3-Dimethylaminopropanol magnesium chloride Hydrogen peroxide Manufacturing Process 31.3 g (0.1 mol) of 3-(3'-dimethylaminopropylidene)dibenzo[a,d]cyclohepta1,4-diene hydrochloride are dissolved in water, and the free base is liberated by means of a 28% aqueous solution of sodium hydroxide. The free base is sucked off, washed with water, and dissolved in 100 ml of methanol. To the solution are added 31 ml of 30% hydrogen peroxide. After 7 days, the reaction mixture is diluted with 200 ml of water, and the major part of the methanol is evaporated in vacuum. The precipitated N-oxide crystals are filtered off, washed with water, and dried, yielding 27 g of the dihydrate of 3(3'-dimethylaminopropylidene)dibenzo[a,d]cyclohepta-1,4-diene N-oxide with melting point of 102° to 103°C. In dehydrated state the melting point is 228°C to 230°C. By dissolving the N-oxide in acetone, and bubbling dry hydrogen chlorine gas through the solution until slightly acid reaction, the hydrochloride of the Noxide is precipitated as a white crystalline substance with melting point of 172°C to 173.6°C.

Amixetrine hydrochloride

285

The starting material can be prepared in known manner from dibenzo[a,d]cyclohepta-1,4-diene-5-one by a Grignard reaction with 3dimethylaminopropyl magnesium chloride, hydrolysis and dehydration of the resulting carbinol. References Merck Index 497 DFU 5 (7) 329 (1980) Kleeman and Engel p. 45 DOT 18 (3) 110 (1982) I.N. p. 77 Pedersen, J.B.; British Patent 991,651; May 12, 1965; Assigned to A/S Dumex (Dumex, Ltd.) Merck and Co., Inc.; British Patent 1,095,786; December 20, 1967 Pedersen, J.B.; US Patent 3,299,139; January 17, 1967; Assigned to A/S Dumex (Dumex, Ltd.)

AMIXETRINE HYDROCHLORIDE Therapeutic Function: Antiinflammatory, Anticholinergic, Antidepressant Chemical Name: N-(2-Phenyl-2-isoamyloxy)ethylpyrrolidine hydrochloride Common Name: Structural Formula:

Chemical Abstracts Registry No.: 24622-52-4; 24622-72-8 (Base) Trade Name

Manufacturer

Country

Year Introduced

Somagest

Riom

France

1972

Raw Materials Styrene Hydrogen chloride Pyrrolidine

Isoamyl alcohol t-Butyl hypobromite

Manufacturing Process There is heated under reflux with stirring for 10 hours: 117 g of (2-phenyl-2-

286

Amlexanox

isoamyloxy)ethyl bromide, 61.5g of pyrrolidine and 250 ml of toluene. After filtration of the pyrrolidine hydrobromide, the toluene is removed under reduced pressure. The residue is then taken up with 4 N HCl. The aqueous solution is washed with ether. It is made alkaline by a solution of 50% NaOH. It is extracted with ether. The ethereal phase is dried over anhydrous sodium sulfate, and rectified under reduced pressure after removing the solvent. There is thus obtained 90 g of a colorless oil with an amine odor. The hydrochloride is prepared in the usual manner by dissolving the amine in anhydrous ether and adding to it the requisite amount of dry gaseous hydrochloric acid, dissolved in absolute alcohol. There is obtained a white crystalline powder melting at 150°C, very soluble in water and alcohol, very slightly soluble in ether and ethyl acetate. The starting material above is prepared by reacting styrene with isoamyl alcohol and then reacting that product with t-butyl hypobromite. References Merck Index 499 Kleeman and Engel p. 46 DOT 8 (9) 334 (1972) I.N. p. 77 Centre Europeen de Recherches Mauvernay, RIOM; British Patent 1,253,818; November 17, 1971

AMLEXANOX Therapeutic Function: Antiulcer (topical) Chemical Name: 5H-[1]Benzopyrano[2,3-b]pyridine-3-carboxylic acid, 2amino-7-(1-methylethyl)-5-oxoCommon Name: Amlexanox, Amoxanox Structural Formula:

Chemical Abstracts Registry No.: 68302-57-8 Trade Name

Manufacturer

Country

Year Introduced

Aphthasol

Block Drug Company

-

-

Apthasol

Access Pharmaceuticals

-

-

Amlodipine besylate

287

Trade Name Apthera OraDisc

Manufacturer Paladin Labs Access Pharmaceuticals

Country -

Year Introduced -

OraRinse

Paladin Labs

-

-

Raw Materials Morpholine Piperidine

6-Isopropyl-4-oxo-4H-1-benzopyran-3-carbonitrile Ethyl cyanoacetate

Manufacturing Process A mixture of 2 ml of morpholine, 3 ml of dimethylformamide and 10 ml of water was heated to 60°C and under stirring the equal molecular quantity of 6-isopropyl-4-oxo-4H-1-benzopyran-3-carbonitrile was added for 5 minutes. The mixture was heated at that temperature for one hour and the resultant precipitate was filtered, rained with water recrystallized from acetic acid and washed with chloroform. By the above procedure was obtained 2-amino-6isopropyl-4-oxo-4H-1-benzopyran-3-carboxaldehyde melting at 206°-208°C. A mixture of 4 ml ethyl cyanoacetate, 50 ml of ethanol, 5 ml of piperidine and the equal molecular quantity of 2-amino-6-isopropyl-4-oxo-4H-1-benzopyran3-carboxaldehyde was refluxed for 30 minutes and, after cooling, the crystalline precipitate was filtered and washed with chloroform. By above procedure was obtained ethyl-2-amino-7-isopropyl-1-azaxanthone-3carboxylate, melting after recrystallization from ethanol at 243°-244°C. A mixture of 10 ml of acetic acid and 10 ml of 55% sulfuric acid the equal molecular quantity and 2-ethyl-amino-7-isopropyl-1-azaxanthone-3carboxylate was stirred at 130°C for 4 hours and, after water was added, the precipitate was collected by filtration and recrystalllized from dimethylformamide to give the 2-amino-7-(1-methylethyl)-5-oxo-5H[1]benzopyrano[2,3-b]pyridine-3-carboxylic acid, melting point 300°C. References Nohara Akira et al.; US Patent No. 4,143,042; March, 6, 1979; Assigned Takeda Chemical Industries, Ltd., Osaka, Japan

AMLODIPINE BESYLATE Therapeutic Function: Antianginal, Antihypertensive Chemical Name: 2-[(2-Aminoethoxy)methyl]-4-(2-chlorophenyl)-3ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine monobenzenesulfonate Common Name: Amlodipine besylate Chemical Abstracts Registry No.: 111470-99-6; 881150-42-9 (Base)

288

Amlodipine besylate

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Amlodin

-

-

Amlodipine besilate

Sumitomo Pharmaceuticals Co., Ltd. Ultra-tech Spc. Pvt. Ltd.

India

-

Amlogard

Pfizer

-

-

Amlovas

India

-

India

-

Normodipine

Unique Pharmaceutical Laboratories Macleods Pharmaceuticals Pvt. Ltd. Gedeon Richter

Hungary

-

Norvasc

Lincoln

-

-

Stamlo

Dr. Reddy's Laboratories Ltd. PT Pfizer

India

-

Indonesia

-

Amlovas

Tensivask Raw Materials

Hydrazine hydrate Phthalimide Ethylacetoacetate

2-Chlorobenzaldehyde Methyl-3-aminocrotonate

Manufacturing Process 2-[(2-Aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5methoxycarbonyl-6-methyl-1,4-dihydropyridine (amlodipine) was prepared from 2-(phthalimidoaminoethoxy)acetoacetate, 2-chlorobenzaldehyde and methyl-3-aminocrotonate under refluxing in ethanol for 24 hours. The ketoester was prepared by the method of Troostwijk and Kellog (JCS Chem. Comm., 1977, p.932). Methyl-3-aminocrotonate can be prepared by known method. Phthalimido-amino-protecting group was removed using hydrazine hydrate in ethanol at the reflux temperature. Although amlodipine is effective as the free base, in practice it is best administered form of a salt of a pharmaceutically acceptable acid.

Amobarbital

289

Benzensulphonic salt of amlodipine was prepared as follows: Amlodipine base (65.6 g, 0.161 mols) was slurried in industrial methylated spirit (denatured alcohol, 326.4 ml) and cooled to 5°C. Benzensulphonic acid (26.2 g, 0.168 mols) was dissolved in industrial methylated spirit (65.6 ml) at 5°C and added to base. The resulting slurry was then granulated, filtered and washed with 2 volumes the same solvent (65.6 ml). The damp solid was slurred at 5°C for 1 hr in 327.6 ml industrial methylated spirit, filtered, washed with 2 volumes of the same solvent (65.6 ml) and dried under vacuum at 55°C for 24 hr. A yield of besylate salt of amlodipine 65 g. References Campbell S.F. et al.; US Patent No. 4,572,909, Feb. 25, 1986; Assigned: Pfizer Inc. (New York, NY) (Preparation 2a) Davison E. et al.; US Patent No. 4,879,303, Nov. 7, 1989; Assigned: Pfizer Inc. (New York, NY)

AMOBARBITAL Therapeutic Function: Hypnotic, Antiepileptic Chemical Name: Barbituric acid, 5-ethyl-5-isopentylCommon Name: 5-Ethyl-5-isopentylbarbituric acid; Amobarbitone; Amylbarbitone; Pentymal Structural Formula:

Chemical Abstracts Registry No.: 57-43-2 Trade Name Hypnotal Isonal Sednotic Transital

Manufacturer Pharmacal Leiras Dista Miquel

Country -

Year Introduced -

Raw Materials Malonic acid diethyl ester Ethyl bromide

Sodium ethylate Isopentyl bromide

Manufacturing Process By interaction of malonic acid diethyl ester with sodium ethylate (molar ratio 1:1) and then with ethyl bromide (molar ratio 1:1) was prepared ethylmalonic

290

Amocarzine

acid diethyl ester. From ethylmalonic acid diethyl ester and sodium ethylate (molar ratio 1:1) and then with isopentylbromide was synthesized α-ethyl-αisopentylmalonic acid diethyl ester. By condensation of α-ethyl-αisopentylmalonic acid diethyl ester with urea in the presence of sodium ethylate was obtained ethyl-isopentylbarbituric acid. References Layraud E.; GB Patent No. 191,008; Oct. 25, 1923 Shonle H.A.; US Patent No. 1,856,792; May 3, 1932; Assigned to Eli Lilly and Company, of Indianapolis, Indiana, a Corporation of Indiana

AMOCARZINE Therapeutic Function: Anthelmintic Chemical Name: 1-Piperazinecarbothioamide, 4-methyl-N-(4-((4-nitrophenyl) amino)phenyl)Common Name: Amocarzine; Phenthiourezine Structural Formula:

Chemical Abstracts Registry No.: 36590-19-9 Trade Name

Manufacturer

CGP 6140

CIBA-GEIGY Corp. -

Country

Year Introduced -

Raw Materials 4-Nitro-4'-isothiocyanodiphenylamine N-Methylpiperazine Manufacturing Process A solution of 4-nitro-4'-isothiocyanodiphenylamine in toluene was treated at 50°C with stirring with a solution N-methylpiperazine in toluene. After 3 hours the solution was filtered from the precipitate obtained. By recrystallization the crude product from methanol the 4-methyl-N-[4-[(4nitrophenyl)amino]phenyl]-1-piperazinecarbothioamide was obtained; melting point 191-196°C.

Amodiaquin

291

References Ruediger Spaun et al.; US Patent No. 3,781,290; Dec. 25, 1973; Assigned to Ciba-Geigy Corporation, Ardsley, N.Y.

AMODIAQUIN Therapeutic Function: Antimalarial Chemical Name: 4-[(7-Chloro-4-quinolinyl)amino]-2-[(diethylamino)methyl] phenol Common Name: 4-(3'-Diethylaminomethyl-4'-hydroxyanilino)-7chloroquinoline Structural Formula:

Chemical Abstracts Registry No.: 86-42-0 (Base); 69-44-3 (Dihydrochloride salt) Trade Name Camoquin HCl Flavoquine Corbutyl Camoquin

Manufacturer Parke Davis Roussel I.S.H. Parke Davis

Country US France France UK

Year Introduced 1950 1979 -

Raw Materials 4,7-Dichloroquinoline Diethylamine

p-Aminophenol hydrochloride Paraformaldehyde

Manufacturing Process 72.8 g (0.5 mol) of p-aminophenol hydrochloride is dissolved in 500 cc of water and added to 99 g (0.5 mol) of 4,7-dichloroquinoline. After a few minutes of warming in a steam bath, 4-(4'-hydroxyanilino)-7-chloroquinoline hydrochloride, of sufficient purity for use in further experiments, precipitates as a yellow crystalline solid. Recrystallized from methanol, the MP is over 300°C. A mixture consisting of 13.5 g of 4-(4'-hydroxyanilino)-7-chloroquinoline hydrochloride dissolved in absolute ethanol is treated with a solution of 4.38 g

292

Amoproxan hydrochloride

of diethylamine and 1.8 g of paraformaldehyde in 20 cc of absolute ethanol. The reaction mixture is heated under reflux for 16 hours, evaporated to onehalf volume and the warm solution treated with an excess of hydrogen chloride dissolved in absolute ethanol. Acetone is added to the warm solution until it becomes turbid and then the solution is cooled. The crude dihydrochloride which separates is collected and purified by recrystallization from methanol; MP 240-242°C. By using an equivalent amount of 4-(4'-hydroxyanilino)-7-bromoquinoline in the above procedure, 4-(3'-diethylaminomethyl-4'-hydroxyanilino)-7bromoquinoline dihydrochloride is obtained; MP (base) 206-208°C dec. References Merck Index 593 Kleeman and Engel p. 47 I.N. p.78 REM p. 1217 Burckhalter, J.H., Jones, E.M., Rawlins, A.L., Tendick, F.H, and Holcomb, W.F.; US Patent 2,474,821; July 5, 1949; Assigned to Parke, Davis and Co.

AMOPROXAN HYDROCHLORIDE Therapeutic Function: Antiarrhythmic, Antianginal Chemical Name: 3,4,5-Trimethoxybenzoic acid 1-[(3-methylbutoxy)methyl]2-(4-morpholinyl)ethyl ester hydrochloride Common Name: Amoproxan hydrochloride, Aproxim Structural Formula:

Chemical Abstracts Registry No.: 22661-96-7 Trade Name

Manufacturer

Country

Year Introduced

Bisolaryn

Boehringer Ingelheim

-

-

Ambrobeta

Betapharm

-

-

Exabrol

Pharmacos

-

-

Amoproxan hydrochloride

293

Raw Materials Isoamyl alcohol Boron trifluoride Epichlorohydrin Morpholine Hydrogen chloride (3,4,5-Trimethoxy)benzoyl chloride Manufacturing Process To a mixture of 176 g (2 M) of isoamyl alcohol and 4 ml of a 10% solution of BF3 in anhydrous ether, were added, with stirring, 278 g (3 M) of epichlorohydrin while maintaining the temperature at approximately 45°C. After the addition, the reaction was maintained for an additional hour at 60°C. It was then cooled and a solution of 160 g of NaOH in pellets in 200 ml H2O was added while maintaining the temperature at approximately 15°C. Stirring was continued for an additional 2 hours, the NaCl formed was filtered and the organic phase decanted. Vacuum fractionation gave 142 g of 3-isoamyloxy1,2-epoxypropane. Boiling point 67-68°C. To a solution of 115.2 g (0.8 M) of 3-isoamyloxy-1,2-epoxypropane in 200 ml of absolute ethanol were added 76 g of morpholine. The temperature rose to approximately 40°C. Heating under reflux was continued for one additional hour, the solvent was distilled and the reaction mixture vacuum fractionated to obtain 166 g of 4-[3-isoamyloxy-2-hydroxy]propyltetrahydro-1,4-oxazine. Boiling point 163°C, nD21 = 1.4620, yield=90%. In a 2 liter three-neck flask, provided with a tight-fitting stirrer and a reflux condenser, were charged: 115.5 g (0.5 M) of 4-[3-isoamyloxy-2hydroxy]propyl tetrahydro-1,4-oxazine in 750 ml of anhydrous benzene, 50.5 g of triethylamine and 115.25 g of (3,4,5-trimethoxy)benzoyl chloride. The mixture was slowly brought to reflux, which was maintained for 4 hours. After cooling, it was filtered, the solvent was stripped off under vacuum, the residue taken up in 4 N HCl (in the cold) and the aqueous solution washed with ether. The aqueous solution was then treated with sodium carbonate and the oil formed extracted with the ether. It was dried over anhydrous sodium sulfate and the solvent tripped off to obtain a highly viscous oily residue, which was taken up in 600 ml of ethyl acetate; the required quantity of absolute ethanol, with 30% HCl gas, was then added, affording the hydrochloride. After standing for several hours in the ice-box, it was filtered, and after recrystallization from anhydrous isopropyl alcohol and drying under vacuum at 60°C to constant weight, 155 g of (3,4,5-trimethoxy)benzoyl chloride were obtained. Yield=67%, melting point 145°C. References Mauvernay R. Y., Busch N., Simond J., Moleyre J.; US Patent No. 3,790,569; Feb. 1, 1974; Assigned to Centre Europeen de Recherches Mauvernay, Riom, France

294

Amosulalol hydrochloride

AMOSULALOL HYDROCHLORIDE Therapeutic Function: Alpha-adrenergic blocker, Beta-adrenergic blocker, Antihypertensive Chemical Name: (+/-)-5-(1-Hydroxy-2-((2-(o-methoxyphenoxy)ethyl)amino) ethyl)-o-toluenesulfonamide monohydrochloride Common Name: Amosulalol hydrochloride; Lowgan Structural Formula:

Chemical Abstracts Registry No.: 70958-86-0; 85320-68-9 (Base) Trade Name

Manufacturer

Country

Year Introduced

Amosulalol hydrochloride

Yamanouchi

-

-

Raw Materials Methyl ethyl ketone Sodium borohydride Hydrogen chloride Hydrogen

N-Benzyl-2-(2-methoxyphenoxy)ethylamine 5-Bromoacetyl-2-methylbenzenesulfonamide Palladium on charcoal

Manufacturing Process A mixture of N-benzyl-2-(2-methoxyphenoxy)ethylamine, methyl ethyl ketone, and 5-bromoacetyl-2-methylbenzenesulfonamide was refluxed with stirring. After cooling the reaction mixture, ethyl ketone was distilled off under reduced pressure and the residue formed was dissolved in benzene. Then, ether was added to the solution and after removing the hydrobromide of N-benzyl-2-(2methoxyphenoxy)ethylamine precipitated, the solvent was distilled off under reduced pressure to provide a viscous oily product. The viscous oily product was dissolved in ethanol and after adding to the solution an excess amount of sodium borohydride, the mixture was stirred at room temperature followed by distilling off ethanol under reduced pressure. The residue was dissolved in ethyl acetate and the ethyl acetate layer recovered was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to provide a viscous oily product. The product was subjected to a silica gel column chromatography and eluted using benzene and then a mixture of benzene and ethyl acetate of 10:1 by volume ratio to provide 5-{1-hydroxy-2-[N-benzyl-2-(2methoxyphenoxy)ethylamino]ethyl}-2-methyl-benzenesulfonamide as a viscous oily product.

Amoxapine

295

In 200 ml of methanol was dissolved 20.0 g of 5-{1-hydroxy-2-[N-benzyl-2(2-methoxyphenoxy)ethylamino]ethyl}-2-methyl-benzenesulfonamide. After adding thereto 20 ml of ethanol containing about 10% hydrogen chloride and 1.0 g of 10% palladium charcoal, the mixture was shaken in hydrogen gas stream. When the absorption of hydrogen stopped, the catalyst was filtered away and the filtrate was distilled off under reduced pressure. The residue was dissolved in 100 ml of ethanol while it was hot and the solution was allowed to stand overnight in ice chamber, whereby 12.8 g of the α-type crystals of 5-{1-hydroxy-2-[2-(2-methoxyphenoxy)ethylamino]ethyl}-2methylbenzenesulfonamide were obtained as the colorless crystals, melting point 169°-171°C. In practice it is usually used as monohydrochloride References Imai K. et al.; US Patent No. 4,217,305; August 12, 1980; Assigned: Yamanouchi Pharmaceutical Co., Ltd., Tokyo, Japan

AMOXAPINE Therapeutic Function: Antidepressant Chemical Name: 2-Chloro-11-(1-piperazinyl)dibenz[b,f][1,4]oxazepine Common Name: Structural Formula:

Chemical Abstracts Registry No.: 14028-44-5 Trade Name

Manufacturer

Country

Year Introduced

Asendin

Lederle

US

1980

Moxadil

Lederle

France

1980

Amoxan

Lederle

Japan

1981

Omnipress

Cyanamid

W. Germany

1983

Demolox

Lederle

-

-

296

Amoxapine

Raw Materials N-Carbethoxypiperazine o-(p-Chlorophenoxy)aniline hydrochloride Ethyl chlorocarbonate Phosphorus pentoxide Manufacturing Process A mixture of 125 g of o-(p-chlorophenoxy)aniline hydrochloride and 100 ml of dry pyridine is treated cautiously with a solution of 90 ml of ethyl chlorocarbonate in 150 ml of ether. The mixture is kept at room temperature for 3 days, diluted with about 500 ml of water and extracted with 300 ml of ether, The ethereal extract is washed with 300 ml of water, dried over calcium chloride, filtered and concentrated. The resulting ethyl o-(pchlorophenoxy)carbanilate is obtained in a viscous oil suitable for use in the next step without further purification. A solution of 70 g of ethyl o-(p-chlorophenoxy)carbanilate and 120 g of Ncarbethoxypiperazine in 100 ml of benzene containing a little sodium methoxide is heated on a steam bath for about 5 days. The solvent is removed by distillation and the residue is triturated with water. The resulting solid is dissolved in ether and dried over sodium sulfate. Filtration and concentration then yields ethyl 4-[[o-(p-chlorophenoxy)phenyl]carbamoyl]-1piperazinecarboxylate, melting at 89°C to 91°C, and suitable for cyclization. A mixture of 10 g of the above piperazine carboxylate ester, 8 g of phosphorus pentoxide and 20 ml of phosphorus oxychloride is heated under reflux for about 1 day, diluted with 100 ml each of chloroform and benzene and quenched with 200 g of ice. The mixture is made basic with 10% sodium hydroxide. The organic layer is isolated and extracted with 150 ml of dilute hydrochloric acid. The product is precipitated from the aqueous layer by addition of 10% sodium hydroxide, extracted with benzene and dried over potassium carbonate. Recrystallization from benzene-petroleum ether gives 2chloro-11-(1-piperazinyl)dibenz[b,f][1,4]oxazepine which melts at 175°C to 176°C. References Merck Index 598 PDR p. 1005 DOT 8 (2) 78 (1972) and 15 (3) 73 (1979) REM p. 1094 DFU 1 (11) 511 (1976) OCDS Vol. 2 p. 478 (1980) I.N. p. 79 Howell, C.F., Hardy, R.A., Jr. and Quinones, N.Q.; US Patent 3,663,696; May 16, 1972; Assigned to American Cyanamid Company Howell, C.F., Hardy, R.A., Jr. and Quinones, N.Q.; US Patent 3,681,357; August 1, 1972; Assigned to American Cyanamid Company

Amoxicillin

297

AMOXICILLIN Therapeutic Function: Antibacterial Chemical Name: 6-([Amino-(4-hydroxyphenyl)acetyl]amino)-3,3-dimethyl-7oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Common Name: p-Hydroxyampicillin Structural Formula:

Chemical Abstracts Registry No.: 26787-78-0; 61336-70-7 (Trihydrate) Trade Name

Manufacturer

Country

Year Introduced

Arnoxil

Bencard

UK

1972

Clamoxyl

Beecham

W. Germany

1973

Clamoxyl

Beecham

France

1974

Larotid

Roche

US

1974

Amoxil

Beecham

US

1974

Polymox

Bristol

US

1975

Sawacillin

Fujisawa

Japan

1975

Pasetocin

Kyowa Hakko

Japan

1975

Velamox

Zambeletti

Italy

1975

Wymox

Wyeth

US

1978

Utimox

WL/PD

US

1979

Agerpen

Cepa

Spain

-

A-Gram

Inava

France

-

Alfamox

Alfa

Italy

-

Alfida

Esteve

Spain

-

Alfoxil

Fako

Turkey

-

Am-73

Medici

Italy

-

Amocilline

Inpharzam

Belgium

-

Amoclen

Spofa

Czechoslovakia

-

Amodex

Robert and Carriere

France

-

Amo-Flamisan

Mazuelos

Spain

-

Amoksilin

Nobel

Turkey

-

Amoksina

Mustafa Nevzat

Turkey

-

298

Amoxicillin

Trade Name

Manufacturer

Country

Year Introduced

Arnolin

Takeda

Japan

-

Amorion

Orion

Finland

-

Amosin

Sanli

Turkey

-

Amox

Lusofarmaco

Spain

-

Amox

Prodes

Spain

-

Amoxamil

Lafi

Brazil

-

Amoxaren

Areu

Spain

-

Arnoxi-Basileos

Basileos

Spain

-

Amoxibiotic

Aristochimica

Italy

-

Amoxicil

Dincel

Turkey

-

Amoxicillin

Toho

Japan

-

Amoxidal

Roemmers

Argentina

-

Amoxidin

Normon

Switz.

-

Amoxi-Gobens

Lagap

Spain

-

Amoxillin

Esseti

Italy

-

Amoximedical

Medical

Spain

-

Amoxipen

Gibipharma

Italy

-

Amoxipenil

Montpellier

Argentina

-

Amoxiroger

Roger

Spain

-

Amoxi-Tabs

Beecham

-

-

Amoxypen

Gruenenthal

W. Germany

-

Amplimox

Ausonia

Italy

-

Amplimox

Iton

Italy

-

Ampy-Penyl

Proto

Switz.

-

Apitart

Isei

Japan

-

Ardine

Antibioticos

Spain

-

Aspenil

Chemil

Italy

-

Augmentin

Beecham

US

-

Ax-1000

Durachemie

W. Germany

-

Axbiot

Galepharma Iberica

Spain

-

Becabil

Alfar

Spain

-

Benzoral

Biosintetica

Brazil

-

Bioxidona

Faes

Spain

-

Bristamox

Bristol

-

-

Cabermox

Caber

Italy

-

Chitacillin

Banyu

Japan

-

Cidanamox

Cidan

Spain

-

Clamox

Roussel-Diamant

Morocco

-

Clamoxyl

Wulfing

W. Germany

-

Amoxicillin

299

Trade Name

Manufacturer

Country

Year Introduced

Clarnoxyl

Beecham-Sevigne

France

-

Dacala

Guadalupe

Spain

-

Damoxicil

Elmu

Spain

-

Daxipen

Recofarma

Brazil

-

Delacillin

Sankyo

Japan

-

Demoksil

Deva

Turkey

-

Doksilin

Iltas

Turkey

-

Draximox

Novo

-

-

Efpenix

Toyo Jozo

Japan

-

Eupen

Uriach

Spain

-

Flemoxin

Gist Brocades

-

-

Fullcilina

Sintyal

Argentina

-

Grinsil

Argentia

Argentina

-

Hiconcil

Allard

France

-

Himinomax

Kaken

Japan

-

Hosboral

Hosbon

Spain

-

Ibiamox

IBI

Italy

-

Imacillin

Astra

-

-

Infectomycin

Heyden

W. Germany

-

Isimoxin

ISI

Italy

-

Kapoxi

Kappa

Spain

-

Largopen

Bilim

Turkey

-

Majorpen

Cyanamid

US

-

Megacillin

Mulda

Turkey

-

Metifarma

Novofarma

Spain

-

Morgenxil

Morgens

Spain

-

Moxacin

C.S.L.

Australia

-

Moxal

Roger Bellon

Italy

-

Moxalin

Mead Johnson

US

-

Moxilean

Organon

-

-

Moxipin

Gamir

Spain

-

Moxypen

Teva

Israel

-

Novamoxin

Novopharm

Canada

-

Nuvosyl

Mepha

Switz.

-

Optium

Disprovent

Argentina

-

Ospanox

Biochemie

Austria

-

Pamocil

Lancet

Italy

-

Paradroxil

Bristol

-

-

Pasetocin

Kyowa

Japan

-

300

Amoxicillin

Trade Name

Manufacturer

Country

Year Introduced

Penamox

Beecham

-

-

Penimox

Ibsa

Switz.

-

Piramox

Pharmax

Italy

-

Precopen

Fides

Spain

-

Primasin

Eczacibasi

Turkey

-

Raudopen

Alter

Spain

-

Raylina

Robert

Spain

-

Reloxyl

Biologia Marina

Spain

-

Remoxil

Kimya Evi

Turkey

-

RivoxicilIin

Rivopharm

Switz.

-

Robamox

Robins

US

-

Sancixomal

Santos

Spain

-

Sawamezin

Sawai

Japan

-

Sigamopen

Siegfried

Switz.

-

Simplamox

ISF

Italy

-

Sinacilin

Galenika

Yugoslavia

-

Sint edix

Castillon

Spain

-

Sintoplus

Aesculapius

Italy

-

Sumox

Reid-Provident

US

-

Superpeni

Efeyn

Spain

-

Tolodina

Estedi

Spain

-

Triamoxil

Squibb

US

-

Trifamox

Bago

Argentina

-

Trimoksilin

Abdi Ibrahim

Turkey

-

Trimox

Squibb

US

-

Unicillin

Tobishi

Japan

-

Uro-Clamoxyl

Beecham

-

-

Utimox

Parke Davis

-

-

Wassermox

Wassermann

Spain

-

Widecillin

Meiji

Japan

-

Zamocillin

Zambon

Italy

-

Zimox

Farmitalia

Italy

-

Raw Materials 6-Aminopenicillanic acid Sodium bicarbonate Ethyl chlorocarbonate Hydrogen O,N-Dibenzyloxycarbonyl-p-oxy-di-α-aminophenylacetic acid Manufacturing Process Ethyl chlorocarbonate (2.2 ml) was added to an ice cold solution of O,N-

Amperozide

301

dibenzyloxycarbonyl-p-oxy-dl-α-aminophenylacetic acid (10 grams) and triethylamine (3.85 ml) in dry acetone (193 ml). The mixture was stirred at 0°C for 5 minutes during which triethylamine hydrochloride precipitated. The suspension was cooled to -30°C and stirred vigorously while adding as rapidly as possible an ice cold solution of 6-aminopenicillanic acid (5.85 grams) in 3% aqueous sodium bicarbonate (193 ml), the temperature of the mixture never being allowed to rise above 0°C. The resulting clear solution was stirred for 30 minutes at 0°C, and then for a further 30 minutes, without external cooling, and finally extracted with diethyl ether (3 x 200 ml) only the aqueous phase being retained. This aqueous solution was brought to pH 2 by the addition of hydrochloric acid and the 6-(O,N-dibenzyloxycarbonyl-p-oxy-dl-αaminophenylacetamido)penicillanic acid so liberated was extracted into diethyl ether (50 ml and 2 portions of 30 ml). The ether phase was washed with water (3 x 5 ml) and the water washings were discarded. Finally, the penicillin was converted to the sodium salt by shaking the ether solution with sufficient 3% sodium bicarbonate to give a neutral aqueous phase, separating the latter and evaporating it at low pressure and temperature below 20°C. The product was finally dried over phosphorus pentoxide in vacuo to give sodium 6-(O,N-dibenzyloxycarbonyl-p-oxy-dl-αaminophenylacetamido)-penicillanate (9.2 grams). A suspension of palladium on calcium carbonate (36 grams of 5%) in water (150 ml) was shaken in an atmosphere of hydrogen at room temperature and atmospheric pressure for 1 hour. A neutral solution of sodium 6-(O,Ndibenzyloxycarbonyl-p-oxy-dl-α-aminophenylacetamido)penicillanate (9 grams) in water (100 ml) was then added and shaking in hydrogen was resumed for one hour. The suspension was then filtered and the collected catalyst was washed well with water without being allowed to suck dry between washings. The combined filtrate and washings were then brought to pH 6.5 with dilute hydrochloric acid and evaporated to dryness at reduced pressure and temperatures below 20°C. The product was finally dried over phosphorus pentoxide in vacuo to give a solid (5.4 grams) containing 6-(phydroxy-dl-α-aminophenylacetamido)penicillanic acid. References Merck Index 600 Kleeman and Engel p. 48 PDR pp.658, 673, 705, 993, 1315, 1606, 1769, 1997 OCDS Vol. 1 p. 414 DOT 19 (3) 169 (1983) I.N. p. 79 REM p. 1193 Nayler, J.H.C. and Smith, H.; US Patent 3,192,198; June 29, 1965

AMPEROZIDE Therapeutic Function: Anti-aggressive, Antiarrhythmic

302

Amperozide

Chemical Name: 4-[4,4-Bis(4-fluorophenyl)butyl]-N-ethyl-1piperazinecarboxamide Common Name: Amperozide; Hogpax Structural Formula:

Chemical Abstracts Registry No.: 75558-90-6 Trade Name

Manufacturer

Country

Year Introduced

Amperozide

Ferrosan

-

-

FG 5606

Kabi Pharmacia

-

-

Raw Materials Sodium bicarbonate Hydrogen chloride Potassium carbonate Phenyl N-ethylcarbamate

N'-Ethyl-1-piperazinecarboxamide 4-Chloro-1,1-(di-p-fluorophenyl)butane 1-[4,4-(Di-p-fluorophenyl)butyl]piperazine

Manufacturing Process (1). A stirred mixture of 4.7 g (0.03 mole) of N'-ethyl-1piperazinecarboxamide, 10.1 g (0.036 mole) of 4-chloro-1,1-(di-pfluorophenyl)butane, 5.0 g of sodium bicarbonate and 10 ml of ethanol was heated at reflux for 60 hours. 50 ml of water was added. The mixture was extracted twice with ether. The combined extracts were dried over sodium sulfate and concentrated. The residue was dissolved in ethanol-ether and the hydrochloride was precipitated with hydrogen chloride in ethanol. The solid was collected by filtration and recrystallised from 2-butanone-isopropanol 4:1 to give 6.4 g of N'-ethyl-4-[4,4-(di-p-fluorophenyl)butyl]-1piperazinecarboxamide hydrochloride. Melting point 177-178°C. (2). A stirred mixture of 9.9 g (0.03 mole) of 1-[4,4-(di-pfluorophenyl)butyl]piperazine, 5,0 g (0,03 mole) of phenyl N-ethylcarbamate, 6,6 g of potassium carbonate and 100 ml of toluene was heated at reflux for 45 minutes. The mixture was filtered and the solvent was removed. The residual oil was dissolved in ethanol-ether and the hydrochloride was precipitated with hydrogen chloride in ethanol. The solid was collected by filtration and recrystallized from 2-butanone-isopropanol 4:1 to give 6.8 g of N'-ethyl-4-[4,4-(di-p-fluorophenyl)butyl]-1-piperazinecarboxamide hydrochloride. Melting point 177-178°C.

Amphetamine phosphate

303

References Bjork Anders K. K., Olsson Knut G., Abramo Aina L., Christensson Erik G.; US Patent No. 4,308,387; December 29, 1981; Assigned to AB Ferrosan (Malmo, SE)

AMPHETAMINE PHOSPHATE Therapeutic Function: Central stimulant Chemical Name: 1-Phenyl-2-aminopropane monophosphate Common Name: Structural Formula:

Chemical Abstracts Registry No.: 139-10-6 Trade Name Raphetamlne Amphate Leptamine Monophos Profetamine

Manufacturer Strasenburgh Storck Bowman Durst Clark and Clark

Country US US US US US

Year Introduced 1950 -

Raw Materials Phenyl nitropropylene Phosphoric acid Manufacturing Process 1 mol of phenyl-nitropropylene, C6H5CH=C(CH3)NO2, is dissolved with a solvent prepared by mixing one liter of ethanol with one-half liter of acetic acid and one-half liter of 12 N sulfuric acid. The resultant solution is placed in the cathode compartment of a divided electrolytic cell containing a metallic cathode of mercury, copper, or other metal of similar nature. Current is passed, using a current density of ~0.2 amp/cm2 of cathode surface. The temperature is kept at about 40°C during the electrolysis which is continued until at least eight Faradays of electricity have been passed. When the reduction is completed, the 1-phenyl-2-aminopropane may be separated from the solution. A convenient way of doing this is by removing

304

Amphomycin calcium

the ethanol and ethyl acetate present by evaporation and then making the residual solution strongly alkaline by addition of caustic alkali. The basic layer thus formed is separated from the aqueous solution and contains the desired 1-phenyl-2-aminopropane. 135 g (1 mol) of amphetamine (1-phenyl-2-aminopropane) were stirred into 300 cc of acetone in a stainless-steel vessel. To the resultant solution there were slowly added under constant agitation 115.3 g of 85% phosphoric acid (containing 1 mol of H3PO4), care being taken to avoid any sudden rise in temperature or local overheating due to the considerable amount of heat that is evolved. During the addition of the phosphoric acid a fine, white, flocculent precipitate appears which becomes more and more dense and abundant, as the quantity of added acid increases. When the entire quantity of the phosphoric acid has thus been added, agitation of the mixture is continued for about a half-hour or more to insure complete conversion. The precipitate is then allowed to settle, the supernatant liquid is drawn off, and the residue is filtered. The precipitate thus separated may, if desired, be washed with acetone and is then dried by evaporation to constant weight. It forms a fine, white, impalpable powder consisting of pure monobasic amphetamine phosphate. References Merck Index 607 I.N. p. 80 Alles, G.A.; US Patent 1,879,003; September 27, 1932 (amphetamine base mfg.) Goggin, T.C.; US Patent 2,507,468; May 9, 1950; Assigned to Clark and Clark Co. (amphetamine conversion to phosphate)

AMPHOMYCIN CALCIUM Therapeutic Function: Antibiotic Chemical Name: Amphomycin calcium Common Name: Glumamicin Chemical Abstracts Registry No.: 1402-82-0 (Base) Trade Name

Manufacturer

Country

Year Introduced

Amphocortrin CR

Warner Lambert

US

1963

Raw Materials Amphomycin Calcium hydroxide

Amphomycin calcium

305

Structural Formula:

Manufacturing Process The process for producing amphomycin comprises cultivating a strain of Streptomyces canus in an aqueous, nutrient-containing carbohydrate solution under submerged aerobic conditions until substantial antibacterial activity is imparted to the solution and then recovering the so-produced amphomycin from the fermentation broth. The process of decolorizing solutions of amphomycin then involves treatment with activated charcoal, followed by the steps of (1) extracting the antibiotic into a water-immiscible organic solvent under strongly acid conditions or precipitating the amphomycin from aqueous solution by adjusting the pH to a point within the range of pH 3.0 to 4.0, (2) removing impurities from strongly acid, aqueous solution of amphomycin by extraction of the impurities with methyl isobutyl ketone and amyl acetate, (3) extracting the amphomycin from a strongly acid solution in butanol by the use of water having a pH higher than 4, (4) extracting the amphomycin from solution in water-immiscible organic solvent into water whose pH is greater than 6.0, (5) precipitating amphomycin from solution by formation of insoluble derivatives of the basic function, and (6) precipitating amphomycin from solution by formation of insoluble derivates of the acidic function.

306

Amphotalide

The amphomycin is then converted to the calcium salt with calcium hydroxide. References Merck Index 609 Heinemann, B., Cooper, I.R. and Kaplan, M.A.; US Patent 3,126,317; March 24, 1964; Assigned to Bristol-Myers Co.

AMPHOTALIDE Therapeutic Function: Antischistosomal Chemical Name: 1H-Isoindole-1,3(2H)-dione, 2-(5-(4-aminophenoxy) pentyl)Common Name: Amphotalide; Schistomide Structural Formula:

Chemical Abstracts Registry No.: 1673-06-9 Trade Name Amphotalide

Manufacturer ZYF Pharm Chemical

Country -

Year Introduced -

Amphotalide

May and Baker Ltd.

-

-

Raw Materials 5-Phthalimidopentyl bromide Hydrogen

Potassium p-nitrophenoxide Platinum oxide

Manufacturing Process A mixture of 5-phthalimidopentyl bromide (Drake and Garman, J.Amer. Chem. Sec, 1949, 71, 2426) (296.0 g) and potassium p-nitrophenoxide (177.0 g) in ethanol (1.5 L) was stirred mechanically, boiled under reflux for 20 h, concentrated to half its volume, cooled and filtered. The product was washed with water, dried and crystallised from acetone, giving 1-p-nitrophenoxy-5phthalimidopentane, melting point 123°-124°C. The foregoing 1-p-nitrophenoxy-5-phthalimidopentane (100.0 g) in ethanol (1 L) was reduced by hydrogen over 2% of platinum oxide at 74°C/73 lb. per sq. in. The filtered solution on cooling gave L-p-aminophenoxy-5-

Amphotericin B

307

phthalimidopentane, melting point 111°-112° C (recrystallisation from ethanol). References Barber H.J. et al.; GB Patent No. 769,706; April 20, 1955; Assigned: May and Baker Limited, British Company, of Dagenham, Essex

AMPHOTERICIN B Therapeutic Function: Antifungal Chemical Name: Amphotericin B Common Name: Structural Formula:

Chemical Abstracts Registry No.: 1397-89-3 Trade Name

Manufacturer

Country

Year Introduced

Fungizone

Squibb

US

1958

Ampho-Moronal

Heyden

W. Germany

-

Fungizone

Squibb

France

1969

Amphocycline

Squibb

France

-

Amphozone

Squibb

-

-

Fungilin

Squibb

UK

-

Fungilin

Squibb

Italy

-

Fungizone

Squibb-Sankyo

Japan

-

Mysteclin

Heyden

W. Germany

-

Raw Materials Carbohydrates Streptomyces nodosus

308

Ampicillin

Manufacturing Process The process for producing amphotericin comprises cultivating a strain of Streptomyces nodosus in an aqueous nutrient medium comprising an assimilable, fermentable carbohydrate and an assimilable organic nitrogen source, under submerged aerobic conditions, until substantial antifungal activity is imparted to the medium and recovering amphotericin from the medium. References Merck Index 611 Kleeman and Engel p. 50 PDR pp. 1743, 1752 DOT 7 (5) 192 (1971) I.N. p. 81 REM p. 1226 Dutcher, J.D., Gold, W., Pagano, J.F. and Vandeputte, J.; US Patent 2,908.611; October 13, 1959; Assigned to Olin Mathieson Chemical Corporation

AMPICILLIN Therapeutic Function: Antibacterial Chemical Name: 6-[D-Amino-(2-phenylacetamido)]-3,3-dimethyl-7-oxo-4thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Common Name: Di-α-aminobenzylpenicillin Structural Formula:

Chemical Abstracts Registry No.: 69-53-4 Trade Name

Manufacturer

Country

Year Introduced

Binotal

Bayer

W. Germany

1962

Penicline

Delagrange

France

1963

Penbritin

Ayerst

US

1963

Penbritin

Beecham

UK

1963

Omnipen

Wyeth

US

1966

Ampisint

Proter

Italy

1969

Acucillin

Fuji

Japan

-

Ampicillin

309

Trade Name

Manufacturer

Country

Year Introduced

Adobacillin

Tobishi

Japan

-

Albipen

Gist Brocades

-

-

Alfasilin

Fako

Turkey

-

Almopen

Gist Brocades

-

-

Alpen

Lederle

US

-

Amblosen

Hoechst

W. Germany

-

Amcill

Parke Davis

US

-

Amfipen

Gist Brocades

UK

-

Amfipen

Schering

W. Germany

-

Amipenix

Toyo Jozo

Japan

-

Ampen

Medosan

Italy

-

Ampen

ICN

Canada

-

Ampensaar

Chephasaar

W. Germany

-

Ampibeta

Violani-Farmavigor Italy

-

Ampibiotic

Ottolenghi

Italy

-

Ampicil

Ausonia

Italy

-

Ampicillina Pharmax

Pharmax

Italy

-

Ampicillina Pierrel

Pierrel

Italy

-

Ampicina

Sigma Tau

Italy

-

Ampicyn

Protea

Australia

-

Ampifen

Intersint

Italy

-

Ampikel

Dreikehl

Spain

-

Ampilan

Ibern

Italy

-

Ampiland

Landerlan

Spain

-

Ampilisa

Lisapharma

Italy

-

Ampilux

Tubi Lux Pharma

Italy

-

Ampimed

Aristochimica

Italy

-

Ampinebiot

Bertran Hathor

Spain

-

Ampinova

Spain

-

Ampinoxi

Cheminova Espanola Therapia

Spain

-

Ampiopen

Ibern

Italy

-

Ampi-Plena Simple Pradel

Spain

-

Ampisil

Dif-Dogu

Turkey

-

Ampisina

Mustafa Nevzat

Turkey

-

Ampi-Tablinen

Sanorania

W. Germany

-

Ampitex

Neopharmed

Italy

-

Ampivax

Ripari-Gero

Italy

-

Ampixyl

Pharma-Plus

Switz.

-

Amplenil

Orma

Italy

-

310

Ampicillin

Trade Name

Manufacturer

Country

Year Introduced

Amplibios

Panther-Osfa

Italy

-

Amplicid

Cifa

Italy

-

Amplipen

Labif

Italy

-

Amplipenyl

ISF

Italy

-

Ampliscocil

I.C.I.

Italy

-

Amplisom

Isom

Italy

-

Amplital

Farmitalia

Italy

-

Amplizer

O.F.F.

Italy

-

Anhypen

Gist Brocades

-

-

Anidropen

Wyeth

Italy

-

Anticyl

San Carlo

Italy

-

A-Pen

Orion

Finland

-

Argocillina

Beta

Italy

-

Austrapen

CSI

Australia

-

Benusel

ICN

-

-

Bio-Ampi

Donatello

Italy

-

Biocellina

Magis

Italy

-

Bionacillin

Takata

Japan

-

Bonapicillin

Taiyo

Japan

-

Britapen Oral

Federico Bonet

Spain

-

Britcin

DDSA

UK

-

Bropicilina

Byk Gulden

-

-

Cilleral

Bristol Banyu

Japan

-

Citicil

C.T.

Italy

-

Combipenix

Toyo Jozo

Japan

-

Copharcilin

Cophar

Switz.

-

Deripen

Schering

W. Germany

-

Doktacillin

Astra

-

-

Domicillin

Dainippon

Japan

-

Drisilin

Drifen

Turkey

-

Espectrosira

Clariana

Spain

-

Eurocillin

Borromeo

Italy

-

Farmampil

Gazzini

Italy

-

Fidesbiotic

Fides

Spain

-

Fortapen

Continental Pharma

Belgium

-

Geycillina

Geymonat

Italy

-

Gramcillina

Caber

Italy

-

Grampenil

Argentia

Argentina

-

Guicitrina

Perga

Spain

-

Hostes Pedriatico

Lando

Argentina

-

Ampicillin

311

Trade Name Ikapen Isocillin Iwacillin Lampocillina Orale Lifeampil Marisilan Makrosilin Maxicilina Napacil NC-Cillin Negopen Nuvapen Orocilin Overcillina Overcillina Pen Ampil

Manufacturer Ikapharm Kanto Iwaki Sidus Lifepharma Wakamoto Atabay Antibioticos Montefarmaco Nippon Chemiphar Deva Cepa Isa Lepetit Archifar Nuovo. Const. Sanit. Naz.

Country Israel Japan Japan Italy Spain Japan Turkey Spain Italy Japan Turkey Spain Brazil Italy Italy Italy

Year Introduced -

Penbrock Penibrin Penimic Peninovel Penisint B.G. Penoral Penorsin Pentrex Pentrexyl Pharcillin Platocillina Plumericin Policilin Polycillin Principen Quimetam Radiocillina Recenacillin Resan Rivocillin Saicil Sentapent Sernabiotic Sesquicillina Sintopenyl SK-Ampicillin Togram

Beecham Teva SS Pharmaceutical Larma Boniscontro Nobel Wassermann Banyu Galenika Toyo Pharm. Crosara Torlan Bristol Bristol Squibb Ouimicos Unidos Radiumpharma Maruko Alacan Rivopharm Libra Kimya Evi Libra Ita Aesculapius SK and F Morgens

Israel Japan Spain Italy Turkey Spain Japan Yugoslavia Japan Italy Spain US US Spain Italy Japan Spain Switz. Italy Turkey Italy Italy Italy US Spain

-

312

Ampicillin

Trade Name

Manufacturer

Country

Year Introduced

Tokiocillin

Isei

Japan

-

Totacillin

Beecham

Japan

-

Totaclox

Beecham

Japan

-

Totalciclina

Benvegna

Italy

-

Totapen

Bristol

France

-

Trafarbiot

Novopharm

Spain

-

Ultrabion

Lifasa

Spain

-

Vastacyn

Ankerfarm

Italy

-

Vexampil

Ifi

Italy

-

Vicclilin

Meiji

Japan

-

Raw Materials α-Aminophenylacetic acid 6-Aminopenicillanic acid Hydrogen

Ethyl chlorocarbonate Benzyl chlorocarbonate

Manufacturing Process α-Carbobenzyloxyaminophenylacetic acid (0.1 mol), which is obtained by the reaction of equivalent quantities of α-aminophenylacetic acid and benzyl chlorocarbonate in aqueous sodium hydroxide, dissolved in dry acetone is stirred and cooled to approximately -5°C. To this there is added dropwise with continued cooling and stirring a solution of ethyl chlorocarbonate (0.1 mol). After approximately 10 minutes, the acylating mixture is cooled to about -5°C and then is slowly added to a stirred ice-cold mixture of 6-aminopenicillanic acid (0.1 mol), 3% sodium bicarbonate solution (0.1 mol) and acetone. This reaction mixture is allowed to attain room temperature, stirred for an additional thirty minutes at this temperature and then is extracted with ether. The extracted aqueous solution is covered with butanol and the pH adjusted to 2 by the addition of HCl. The acidified aqueous phase is extracted with butanol, the pH of the aqueous phase being adjusted to pH 2 each time. The combined butanol solutions which contain the free acid, αcarbobenzyloxyaminobenzylpenicillin, are washed with water, and are then shaken with water to which sufficient 3% sodium bicarbonate has been added to bring the aqueous phase to pH 7. The process of washing and shaking is repeated with fresh water and bicarbonate solution. The combined aqueous solutions are washed with ether and then are evaporated under reduced pressure and low temperature. The product, the sodium salt of αcarbobenzyloxyaminobenzylpenicillin, is obtained as a yellow solid in a yield of 65%. A suspension of palladium on barium carbonate (3.7 grams of 30%) in water (20 ml) is shaken in an atmosphere of hydrogen at room temperature. The catalyst is then filtered and washed well with water, care being taken that it does not become dry. A solution of the sodium salt of αcarbobenzyloxyaminobenzylpenicillin (4 grams) in water (20 ml) is added to the pretreated catalyst and the suspension is shaken in an atmosphere of hydrogen at room temperature and pressure for one hour. The catalyst is then

Ampicillin trihydrate

313

filtered off, washed well with water, and the combined filtrate and washings adjusted to pH 7 with hydrochloric acid. The resulting solution is evaporated in vacuum at a temperature below 20°C to give α-aminobenzylpenicillin (2.4 grams, 74% yield), which is assayed at approximately 48% pure by the manometric method. References Merck Index 612 Kleeman and Engel p. 50 PDR pp.673, 703, 1314, 1722, 1964 OCDS Vol. 1 p. 413; Vol. 2 p. 437 I.N. p. 81 REM p. 1194 Doyle, F.P., Nayler, J.H.C., and Smith, H.; US Patent 2,985,648; May 23, 1961 Kaufmann, W. and Bauer, K.; US Patent 3,079,307; Feb. 26, 1963; Assigned to Farben-fabriken Bayer AG, Germany Johnson, D.A. and Wolfe, S.; US Patent 3,140,282; July 7, 1964; Assigned to Bristol-Myers Company Grant, N.H. and Alburn, H.E.; US Patent 3,144,445; August 11, 1964; Assigned to American Home Products Corporation

AMPICILLIN TRIHYDRATE Therapeutic Function: Antibacterial Chemical Name: 6-[D-Amino-(2-phenylacetamido)]-3,3-dimethyl-7-oxo-4thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid trihydrate Common Name: Structural Formula:

Chemical Abstracts Registry No.: 7177-48-2 Trade Name

Manufacturer

Country

Year Introduced

Polycillin

Bristol

US

1963

Principen

Squibb

US

1967

314

Ampicillin trihydrate

Trade Name

Manufacturer

Country

Year Introduced

Amcill

Parke Davis

US

1968

Alpen

Lederle

US

1969

Totacillin

Beecham

US

1970

Pensyn

Upjohn

US

1972

Ro-Ampen

Rowell

US

1972

Pen A

Pfizer

US

1972

Trimox

Squibb

US

1978

AB-PC

Tojo Jozo

Japan

-

Acillin

ICN

-

-

Amblosin

Hoechst

-

-

Amcap

Circle

US

-

Amperil

Geneva

US

-

Ampexin

Therapex

Canada

-

Ampicsl

Uva

France

-

Ampichelle

Rachelle

US

-

Ampicil

Jeba

Spain

-

Ampiciman

Liberman

Spain

-

Ampi-Co

Coastal

US

-

Ampifar

Benedetti

Italy

-

Ampikel

Dreikehl

Spain

-

Ampilag

Lagap

Switz.

-

Ampileta

Lagap

Switz.

-

Ampi-Oral

Biologia Marina

Spain

-

Ampiorus

Horus

Spain

-

Ampiscel

Rachelle

US

-

Ampixyl

Pharma-Plus

Switz.

-

Ampi-Zoja

Zoja

Italy

-

Amplin

Winston

US

-

Arcocillin

ICN

-

-

Benusel

ICN

-

-

Binotal

Bayer

-

-

Cetampin

CTA Pharma

Switz.

-

Cetampin

Scarium

Switz.

-

Cimexillin

Cimex

Switz.

-

Cymbl

Dolorgiet

W. Germany

-

Citicil

C.T.

Italy

-

D-Amp

Dunhall

US

-

D-Cillin

Dunhall

US

-

Delcillin

Marlop

US

-

Divercillin

Ascher

US

-

Dumopen

Dumex

Denmark

-

Dur Ampicillin

Durachemie

W. Germany

-

Ampicillin trihydrate

315

Trade Name

Manufacturer

Country

Year Introduced

Espimin-Cilin

Spyfarma

Spain

-

Fuerpen

Hermes

Spain

-

Gobemicina Simple Normon

Spain

-

Helvecillin

Helvepharm

Switz.

-

Lifeampil

Lifepharma

Spain

-

Morepen

Morejon

Spain

-

Novoexpectro

Aldon

Spain

-

Penbristol

Bristol-Myers

Austria

-

Penimaster

Liade

Spain

-

Peninovel

Larma

Spain

-

Pentraxyl

Bristol

-

-

Pentrexyl Oral

Antibioticos

Spain

-

Pentricine

Ibsa

Switz.

-

Poenbiotico

Poen

Argentina

-

Prestacilina

Pental

Spain

-

Q I Damp

Mallinckrodt Inc.

US

-

Rosampline

Rosa-Phytopharma France

-

Servicillin

Servipharm

Switz.

-

Standacillin

Biochemie

Austria

-

Sumipanto Oral

Asla

Spain

-

Texcillin

First Texas

US

-

Trafarbior

Novopharm

Spain

-

Trafacilina

Bago

Argentina

-

Vampen

Vangard

US

-

Vidopen

Berk

UK

-

Raw Materials Ampicillin beta-naphthalene sulfonate Secondary amines Manufacturing Process The known methods for the preparation of D-(-)-α-aminobenzylpenicillin by the acylation of 6-aminopenicillanic acid result in the preparation of aqueous mixtures which contain, in addition to the desired penicillin, unreacted 6aminopenicillanic acid, hydrolyzed acylating agent, and products of side reactions such as the products of the acylating agent reacted with itself and/or with the desired penicillin, as well as other impurities. The D-(-)-α-aminobenzylpenicitlin may then be recovered from the aqueous reaction mixture by concentration to small volume and recovering the product by filtration. However, due to the fact that anhydrous D-(-)-αaminobenzylpenicillinis soluble in water to the extent of about 20-25 mg/ml at 20°-25°C, it is very difficult to recover the product in high yields.

316

Ampiroxicam

Furthermore, the recovered D-(-)-α-aminobenzylpenicillin may be obtained in the form of a monohydrate. The monohydrates (as well as the dihydrates) of D-(-)-α-aminobenzylpenicillin possess poor biological stability. The trihydrate which is obtained in high yields, is relatively insoluble in water, possesses high biological stability and can be obtained by contacting, at a temperature not above 60°C, an acid addition salt of D-(-)-αaminobenzylpenicillin with an amine in a water immiscible solvent containing at least 3 mols of water per mol of such penicillin. The following is an example of the conduct of such a process. To a vigorously agitated mixture of 100 ml of methyl isobutyl ketone there are added at 25° to 30°C 15 ml of water and 10 ml of a mixture of secondary amines. To this mixture there is then added slowly over a period of 30 minutes 10 grams of D-(-)-α-aminobenzylpenicillin α-naphthalenesulfonate. The mixture is agitated for 3 hours at 25-30°C. The product, D-(-)-α-aminobenzylpenicillin trihydrate precipitates and is collected by filtration. The filter cake of the product is washed several times with methyl isobutyl ketone and is dried at 40°C. The product is obtained in about a 90% yield and has a potency of 865 mcg/mg. It is determined by Karl Fischer analysis to have a moisture content of 13.4% by weight. References Merck Index 612 Kleeman and Engel p. 81 PDR pp. 993, 1606, 1758 I.N. p. 50 Johnson, D.A. and Hardcastle, G.A., Jr.; US Patent 3,157,640; November 17, 1964; Assigned to Bristol-Myers Company

AMPIROXICAM Therapeutic Function: Antiinflammatory Chemical Name: Carbonic acid ethyl 1-[[2-methyl-3-[(2-pyridinyl) aminocarbonyl]-2H-1,2-benzothiazin-4-yl]oxy]ethyl ester, S,S-dioxide Common Name: Ampiroxicam Structural Formula:

Amprenavir

317

Chemical Abstracts Registry No.: 99464-64-9 Trade Name Ampiroxicam

Manufacturer Country NANJING PHARMA -

Year Introduced -

Raw Materials Piroxicam Potassium carbonate

α-Chloroethyl ethyl carbonate Sodium iodide

Manufacturing Process To a round bottomed flask equipped with a reflux condenser and stirring bar were added 2-methyl-N-(2-pyridyl)-4-hydroxy-2H-1,2-benzodiazine-3carboxamide 1,1-dioxide (piroxicam, 10.0 g, 30.2 mmol), potassium carbonate (8.35 g, 60.4 mmol), α-chloroethyl ethyl carbonate (12.35 mL, 13.81 g, 90.6 mmol) and acetone (350 mL). The heterogenous reaction mixture was heated to reflux under a nitrogen atmosphere. After 19 hours, anhydrous sodium iodide (22.6 g, 150.7 mmol) was added and reflux continued for an additional 5 hours. The acetone was removed in vacuum leaving a brown residue which was treated with water (250 mL) and methylene chloride (250 mL). The organic layer was separated and the aqueous layer extracted with additional methylene chloride (250 mL). The combined organic extracts were washed with water (250 mL), brine (250 mL), dried (Na2SO4) and concentrated in vacuum to a brown oil. Column chromatography on silica gel (1:9 ethyl acetate:methylene chloride) afforded a pale yellow foam (10.67 g, 79.0%). The 4-[1-(ethoxycarbonyloxy)ethoxy]2-methyl-N-(2-pyridyl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide was recrystallized from toluene to give 9.50 g of pure white crystals; melting point 159-161°C. References European Patent No.147,177 Marfat A.; US Patent No. 4,551,452; Nov. 5, 1985; Assigned to Pfizer Inc. (New York, NY)

AMPRENAVIR Therapeutic Function: Antiviral Chemical Name: Carbamic acid, ((1S,2R)-3-(((4-aminophenyl)sulfonyl)(2methylpropyl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-, (3S)tetrahydro-3-furanyl ester Common Name: Amprenavir Chemical Abstracts Registry No.: 161814-49-9

318

Amprenavir

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Agenerase

GlaxoSmithKline

UK

-

Amprenavir

Vertex Pharmaceuticals Inc

-

Amprenavir

GlaxoSmithKline

UK

-

KVX-478

Glaxo Wellcome

-

-

Prozei

Kissei Pharmaceutical Co., Ltd.

-

-

VX-478

Glaxo Wellcome

-

-

141W94

Glaxo Wellcome

-

-

Raw Materials Isobutylamine (1-Oxiranyl-2-phenylethyl)-carbamic acid t-butyl ester Benzyl chloroformate Diisopropylethylamine (S)-(+)-3-Hydroxytetrahydrofuran Phosgene p-Nitrobenzenesulfonyl chloride Manufacturing Process (1-Oxiranyl-2-phenylethyl)-carbamic acid t-butyl ester may be synthesized from available starting materials (see B. E. Evans et al., J. Org. Chem., 50, p.4615 (1985)). The amprenavir may be preparated with the next steps. 1. (1-Benzyl-3-isobutylaminopropyl)-carbamic acid t-butylester. A solution of 4.1 g of epoxide (1-oxiranyl-2-phenylethyl)-carbamic acid t-butyl ester in 30 ml of ethanol was treated with 22.4 ml of isobutylamine and heated under reflux for 1 h. The mixture was concentrated to yield the title compound as a white solid which was used without subsequent purification. 2. To a solution of the above compound (2.5 g, 7.43 mmol) in CH2Cl2 (50 ml) was added triethylamine (2.1 ml, 14.9 mmol) followed by addition of benzyl chloroformate (1.2 ml, 8.1 mmol). The mixture was allowed to stir at ambient temperature for 6 h. The solution was diluted with 1 L of CH2Cl2 and washed with water. The organics were dried over anhydrous MgSO4, concentrated

Amprenavir

319

under reduced pressure, then purified via silica gel chromatography. Gradient solvent system: CH2Cl2 followed by 3:97 methanol/CH2Cl2. (3-tButoxycabonylamino-4-phenylbutyl)-isobutylcarbamic acid benzyl ester (2.97 g) was obtained as a colorless oil. TLC: Rf= 0.14, 3:97 methanol/CH2Cl2. 3. BOC - protecting group was removed as followed: to a solution of 1.5 g (3.187 mmol) of the above compound of in ethyl acetate (25 ml) at - 20°C was bubbled anhydrous HCl gas for 10 min. The ice bath was removed and after an additional 15 min the reaction mixture was sparged with nitrogen, then concentrated in vacuo to provide 1.29 g of deprotected product as a white solid which was used directly for the next reaction TLC: Rf= 0.14, 10% methanol/CH2Cl2. 4. Isobutyl[4-phenyl-(S)-3-tetrahydrofuran-3-yl-oxycarbonylamino)-butyl]carbamic acid benzyl ester. To a solution of 1.077 g of the above resultant crude compound (2.647 mmol) in acetonitrile (10 ml) was added sequentially at ambient temperature under an atmosphere of nitrogen, 1.61 ml (9.263 mmol) of diisopropylethylamine and 910 mg (3.97 mmol) of the Nsuccinimidyl-(S)-3-tetrahydrocfuryl carbonate. The last one was prepared from phosgene and (S)-(+)-3-hydroxytetrahydrofuran by usual procedure. After stirring for 3 h, an additional 223 mg (0.973 mmol) of the N-succinimidyl-(S)3-tetrahydrocfuryl carbonate was added. The mixture was stirred for 16 h and then concentrated in vacuo. The residue was taken up in ethyl acetate and washed with water, 0.5 N HCl, saturated sodium bicarbonate, saturated brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by low pressure silica gel column chromatography using a gradient 10% to 25% ethyl acetate in CH2Cl2 eluent to yield 1.025 g of the title product as a white solid. TLC: Rf= 0.10, 10% ethyl acetate/CH2Cl2. 5. A solution of 872 mg (1.799 mmol) isobutyl[4-phenyl-(S)-3tetrahydrofuran-3-yl-oxycarbonylamino)-butyl]-carbamic acid benzyl ester in (10 ml) of ethyl alcohol was added, at ambient temperature under a nitrogen atmosphere, to a slurry of 87 mg (10% by weight) of 10% palladium on carbon in (5 ml) ethyl alcohol and hydrogenated for 16 h under a slight positive pressure of hydrogen. The mixture was filtered and concentrated in vacuo to yield 553.2 mg of the carbamic acid as a colorless glass which was used directly for ensuing reaction. TLC: Rf = 0.46, 10% methanol/CH2Cl2. 6. A solution of 102 mg of the resultant compound of a step 5 in 4:1 CH2Cl2/saturated aqueous NaHCO3 was treated sequentially, at ambient temperature under an atmosphere of nitrogen, with 65 mg of pnitrobenzenesulfonyl chloride and 51 mg of sodium bicarbonate. The mixture was stirred for 14 h, diluted with CH2Cl2, washed with saturated NaCl, then dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by low pressure silica gel chromatography using 20% diethyl ether/CH2Cl2 as eluent to provide 124 mg of the 1-benzyl-3-[isobutyl-(4nitrobenzenesylfonyl)-amino]-propylcarbamic acid tetrahydrofuran-3(S)-yl] ester as a white solid. TLC: Rf = 0.36, 20% diethyl ether/CH2Cl2, HPLC: Rt = 15.15 min. (1H)-NMR (CDCl3) consist with structure. 7. A solution of 124 mg of the resultant compound of the step 6 in ethyl acetate was treated, at ambient temperature, with 13 mg of 10% palladium

320

Amprolium chloride

on carbon. The mixture was stirred for 14 h under an atmosphere of hydrogen, filtered through a pad of celite filter agent, and concentrated in vacuo. The residue was subjected to preparative HPLC to yield 82 mg of the ((1S,2R)-3-(((4-aminophenyl)sulfonyl)(2-methylpropyl)amino)-2-hydroxy-1(phenylmethyl)propyl)-, (3S)-tetrahydro-3-furanyl carbamic ester a white solid. TLC: Rf= 0.10, 20% ether/CH2Cl2, HPLC: Rt= 13.16 min. (1H)-NMR (CDCl3) consistent with structure. References Tung et al.; US Patent No. 5,691,372; Nov. 25, 1997; Assigned Vertex Pharmaceuticals Incorporated Tung et al.; WO 94/05639, March 1994

AMPROLIUM CHLORIDE Therapeutic Function: Coccidiostatic Chemical Name: Pyridinium, 1-((4-amino-2-propyl-5-pyrimidinyl)methyl)-2methyl-, chloride Common Name: Amprocidum; Amprolium chloride; Mepyrium Structural Formula:

Chemical Abstracts Registry No.: 121-25-5 Trade Name

Manufacturer

Country

Year Introduced

Neoprol

SIMB

-

-

Raw Materials 4-Toluenesulfonyl chloride 2-n-Propyl-4-amino-5-hydroxy-methyl pyrimidine 2-Methylpyridine Hydrochloric acid Manufacturing Process 1.9 grams of p-toluene sulfonyl chloride was added gradually with shaking to a cooled (0-5°C) solution of 1.67 grams of 2-n-propyl-4-amino-5-hydroxymethyl pyrimidine in 10 ml of 2-methylpyridine. The reaction mixture, after

Amrinone

321

standing three hours in an ice bath, and 15 hours at room temperature, was evaporated to dryness in vacuo. The residue was dissolved in 20 ml of water, acidified with hydrochloric acid and poured over a column of Amberlite IRA400 ion exchange resin on the chloride cycle. The eluate was evaporated to dryness to give a residue of 1-(2-n-propyl-4-amino-5-pyrimidylmethyl)-2methyl pyridinium chloride hydrochloride. On recrystallization from a methanol-ethanol mixture, the quaternary had melting point 246°C (dec.). References Rogers E.F., Sarett L.H.; US Patent No. 3,020,277; Feb. 6, 1962; Assigned to Merck and Co, Inc., Rahway, N.J.., a corporation of New Jersey

AMRINONE Therapeutic Function: Cardiotonic Chemical Name: 3-Amino-5-(4-pyridinyl)-2(1H)-pyridinone Common Name: Structural Formula:

Chemical Abstracts Registry No.: 60719-84-8 Trade Name Inocor Inocor

Manufacturer Sterling Winthrop Sterling Winthrop

Country Philippines Mexico

Year Introduced 1982 1983

Raw Materials 3-Nitro-5-(4-pyridinyl)-2(1H)-pyridinone Hydrogen Manufacturing Process A mixture containing 10g of 3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone, 200 ml of dimethylformamide and 1.5 g of 10% palladium-on-charcoal was hydrogenated under pressure (50 psi) at room temperature until the uptake of hydrogen ceased (about 30 minutes). The reaction mixture was filtered through infusorial earth and the filtrate was heated in vacuum to remove the solvent. The residual material was crystallized from dimethylformamide, washed successively with ethanol and ether, and dried in a vacuum oven at 80°C for 8 hours to yield 6 g of 3-amino-5-(4-pyridinyl)-2(1H)-pyridinone, melting point 294° to 297°C with decomposition.

322

Anagestone acetate

References Merck Index 616 DFU 4 (4) 245 (1979) PDR p. 1909 OCDS Vol. 3 p. 147 DOT 18 (10) 547 (1982) and 19 (10) 581 (1983) I.N. p.85 Lesher, G.Y. and Opalka, C.J.; US Patent 4,004,012; January 18, 1977; Assigned to Sterling Drug Inc. Lesher, G.Y. and Opalka, C.J.; US Patent 4,107,315; August 15, 1978; Assigned to Sterling Drug Inc.

ANAGESTONE ACETATE Therapeutic Function: Progestin Chemical Name: Pregn-4-en-20-one, 17-hydroxy-6α-methyl-, acetate Common Name: Anagestone acetate; Anapregnone Structural Formula:

Chemical Abstracts Registry No.: 3137-73-3 Trade Name ORF 1658 Anagestone acetate

Manufacturer ZYF Pharm Chemical Ortho Pharm

Country -

Year Introduced -

Raw Materials Ethanedithiol Nickel Acetic acid Acetic anhydride

6α-Methyl-4-pregnen-17α-ol-3,20-dione Pyridine chlorhydrate 4-Toluenesulfonic acid

Manufacturing Process To solution of 6α-methyl-4-pregnen-17α-ol-3,20-dione (1.0 g) in ethane-

Anagrelide hydrochloride

323

dithiol (1 ml) and methylene chloride (2 ml) pyridine chlorhydrate (1 g) was added and mixed 3 min at room temperature. Then to reaction mixture methanol (30 ml) was added and cooled in ice bath during of 2 min. Precipitate was filtered and washed with cool methanol. 6α-Methyl-4-pregnen17α-ol-20-one-3-thioacetal was obtained (0.9 g), melting point 186°-188°C (recrystalisation from methanol-dichlormethane). To the solution of 6α-methyl-4-pregnen-17α-ol-20-one-3-thioacetal (2 g) in 95% ethanol (200 ml) Ni (Renney) (50 g) was added and mixed at heating. Then reaction mixture was cooled to room temperature. The mixture was filtered, and filtrate was evaporated, obtaining residue was crystallisated from methanol with dichloromethane and in the result 6α-methyl-4-pregnen-17αol-20-one (0.95 g) was produced, melting point 190°-193°C. To the solution of 6α-methyl-4-pregnen-17α-ol-20-one (1.5 g) in acetic acid (75 ml) and acetic anhydride (15 ml) p-toluenesulfonic acid was added and the reaction mixture allayed to stand at room temperature any time. Then crystals were recrystallised from methanol with dichlormethane. Acetate 6αmethyl-4-pregnen-17α-ol-20-one (1.3 g) was obtained, melting point 173°175°C. References BE Patent No. 624,370; Oct. 31, 1962; Assigned: Ortho Pharmaceutical Corporation

ANAGRELIDE HYDROCHLORIDE Therapeutic Function: Platelet aggregation inhibitor Chemical Name: 6,7-Dichloro-1,5-dihydroimidazo[2,1-b]quinazolin-2(3H)one hydrochloride Common Name: Anagrelide hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 58579-51-4; 68475-42-3 (Base) Trade Name Agrylin

Manufacturer Shire Pharmaceuticals

Country -

Year Introduced -

Agrelin Anagrelide Hydrochloride

Pharma Internacional Cipla Limited

India

-

324

Anastrazole

Raw Materials 6-Chloro-2-nitrobenzylchloride Cyanogen bromide Ethylglycine hydrochloride Ferric chloride anhydrous Chlorine Bromine Manufacturing Process 6,7-Dicloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one was produced from 6-chloro-7-bromo-1,2,3,5-tetrahydroimidazo[2,1-b]quinozolin-2-one by substitution the bromine an equimolar quantity chlorine. 6-Chloro-7-bromo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one was produced next way: to a solution of 1.30 g (8 mmole) of anhydrous ferric chloride in 30 ml of nitromethane was added 1.30 g (5 mmole) of solid 6chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one and 0.80 g (5 mmole) of bromine. The system was stoppered, warmed to 50°C in an oil bath overnight, cooled to room temperature and the solvent removed in vacuo. The resulting solid was suspended in water (50 ml), the mixture was made basic (pH=10) with sodium bicarbonate and stirred at home temperature for 20 min. The solid was filtered under suction, washed with water, then isopropyl alcohol and dried yielding 1.19 g of 6-chloro-7-bromo1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one (78% yield). Purification was effected by formation of the hydrochloride salt (mp 275°C) from acetonitrile. 6-Chloro-1,2,3,5,-tetrahydroimidazo[2,1-b]quinazolin-2-one was produced from 6-chloro-2-nitrobenzylchloride, ethylglycine hydrochloride and cyanogen bromide in 3 steps. References Beveriung Jr. et al.; US Patent No. 3,932,407; Jan. 13, 1976; Assigned: Bristol-Myers Company (New York, NY)

ANASTRAZOLE Therapeutic Function: Antitumor Chemical Name: 1,3-Benzenediacetonitrile, α,α,α',α'-tetramethyl-5-(1H1,2,4-triazol-1-ylmethyl)Common Name: Anastrozole Chemical Abstracts Registry No.: 120511-73-1

Anastrazole

325

Structural Formula:

Trade Name

Manufacturer

Altraz

Alkem Laboratories Ltd. India

Country

Year Introduced -

Anastrozole

AstraZeneca

UK

-

Arimidex

AstraZeneca

UK

-

Raw Materials N-Bromosuccinimide 1,2,4-Triazole sodium salt Tetrabutylammonium bromide Iodomethane

Benzoyl peroxide 3,5-Bis(bromomethyl)toluene Potassium cyanide Sodium hydride

Manufacturing Process A mixture of 2,2-(5-methyl-1,3-phenylene)di(2-methylpropionitrile) (2.26 g), N-bromosuccinimide (1.78 g), benzoylperoxide (0.05 g) and carbon tetrachloride (50 ml) was refluxed for 2 hours, cooled and filtered, and the filtrate was evaporated to dryness under reduced pressure. The residue was dissolved in dimethylformamide (20 ml), sodium triazole (1.8 g) was added, and the mixture was stirred at room temperature for 18 h. Water (100 ml) was added, and the mixture was extracted twice with ethyl acetate, dried and evaporated to dryness and the residue was purified by flash column chromatography, eluting with ethyl acetate to give 2,2-[5-(1H-1,2,4-triazol-1ylmethyl)-1,3-phenylene]di(2-methylpropionitrile), mp 81-82°C after crystallization from ethyl acetate/cyclohexane. The 5-methyl-1,3-phenylene compound used as starting material in above process may be prepared as follows. The mixture of 3,5bis(bromomethyl)toluene (30 g), tetrabutyl-ammonium bromide (1 g), KCN (17.6 g), dichloromethane (100 ml) and water (30 ml) was stirred vigorously and refluxed for 3 h. The mixture was cooled, diluted with water (100 ml) and extracted three times with ethyl acetate, dried and evaporated to dryness, the residue was purified by flash chromatography, eluting with petroleum ether/ethyl acetate (3:1) to give 2,2-(5-methyl-1,3-phenylene)diacetonitrile, mp 73-74°C after crystallization from carbon tetrachloride. A mixture of this diacetonitrile (11.5 g), iodomethane (42 g) and dimethylformamide (150 ml) was cooled in an ice and stirred while sodium hydride (50% dispersion in mineral oil, 15 g) was added slowly, over 1 hour, then the mixture was allowed to warm to room temperature, stirred for 2 h, 500 ml of water was added, and the mixture was extracted twice with ethyl acetate, the extracts were dried and evaporated to dryness and the residue was crystallized from carbon tetrachloride to give the required 5-methyl-1,3-phenylene starting

326

Anaxirone

material, mp 126-127°C. References Edwards P.N. et al.; US Patent No. RE36,617 Mar. 14, 2000; Assigned: Zeneca Limited (London, GB) Thomson and Siiteri, J. Biol. Chem., 249, 5364 (1974)

ANAXIRONE Therapeutic Function: Antineoplastic Chemical Name: 1,2,4-Triazolidine-3,5-dione, 1,2,4-tris(oxiranylmethyl)Common Name: Anaxirone; Triglycidylurazol Structural Formula:

Chemical Abstracts Registry No.: 77658-97-0 Trade Name

Manufacturer

Country

Year Introduced

Anaxirone

Onbio Inc.

-

-

Raw Materials Triazolidine-3,5-dione Epichlorohydrin Triethylamine Manufacturing Process In a 4-liter three-necked flask equipped with a stirrer, thermometer and reflux condenser, 101 g (1 mole) of triazolidine-3,5-dione, 2775 g (30 moles) of epichlorohydrin and 2 ml of triethylamine are heated to 80°C by means of an oil bath. The mixture reacts exothermically so that the oil bath may be removed. After the exothermic reaction has abated, the reaction mixture is stirred at 80°C. The total reaction time is 10 hours. 250 g of 50% sodium hydroxide solution are added dropwise to the solution obtained over a period of 4 hours at from 30 to 40°C in such a way that the water added and the water formed during the reaction is continuously removed by azeotropic

Ancarolol

327

distillation at from 30 to 60 Torr using a water separator. To complete the reaction, the reaction mixture is stirred for another hour and the sodium chloride formed is separated by filtration. The sodium chloride is washed twice with 200 g of epichlorohydrin and the combined epichlorohydrin solutions are washed with 200 ml of water. After the organic phase has been dried over sodium sulfate, the solvent is removed by concentration in a rotary evaporator and the residue is dried, ultimately at 80°C/0.2 mbar, to constant weight. 240 g of a light brown viscous oil are obtained. It was found to have an epoxide value of 0.93 and has a chlorine content of 2.75%. The viscous oil crystallizes after standing for from a few hours to days. The practically pure 1,2,4triglycidyl triazolidine-3,5-dione melting at from 98° to 103°C crystallizes by dissolution in methanol and cooling to 5°C. IR- and NMR-spectra in conjunction with elemental analysis and epoxide determination confirm the assumed structure. Melting point 94-96°C. References Rottmaier Ludwig, Merten Rudolf; US Patent No. 4,283,546; Aug. 11, 1981; Assigned to Bayer Aktiengesellschaft (DE)

ANCAROLOL Therapeutic Function: Beta-adrenergic blocker Chemical Name: N-[2-[3-[(1,1-Dimethylethyl)amino]-2-hydroxypropoxy] phenyl]-2-furancarboxamide (+/-) Common Name: Ancarolol Structural Formula:

Chemical Abstracts Registry No.: 75748-50-4 Trade Name

Manufacturer

Country

Year Introduced

Ancarolol

ZYF Pharm Chemical

-

-

Ancarolol

Onbio Inc.

-

-

Raw Materials 2'-(2,3-Epoxypropoxy)-furan-2-carboxylic acid anilide t-Butylamine

328

Ancitabine hydrochloride

Manufacturing Process A mixture of 23 g of 2'-(2,3-epoxypropoxy)-furan-2-carboxylic acid anilide, 7.3 g of t-butylamine and 50 ml of isopropanol is boiled under reflux for 10 hours. On cooling, 2'-(2-hydroxy-3-t-butylaminopropoxy)-furan-2-carboxylic acid anilide (ancarolol) crystallizes out from the solution. The chromatographically pure base is obtained in the form of a white solid of melting point 112°-113°C by recrystallization from ethyl acetate. The yield is 12 g. The colorless, crystalline base is dissolved in alcohol, alcoholic HCl is added and the hydrochloride is induced to crystallize by adding ether dropwise. After isolation, the salt is recrystallized again from ethanol. This gives 10 g of the hydrochloride, melting point 189°-191°C. References Ulendorf J. et al.; US Patent No. 4,269,855; May 26, 1981; Assigned to A. Nattermann and Cie, GmbH, Cologne, Fd.Rep. of Germany

ANCITABINE HYDROCHLORIDE Therapeutic Function: Antineoplastic Chemical Name: 2,3,3a,9a-Tetrahydro-3-hydroxy-6-imino-6Hfuro[2',3';4,5]oxazolo[3,2-a]pyrimidine-2-methanol hydrochloride Common Name: Structural Formula:

Chemical Abstracts Registry No.: 10212-25-6; 31698-14-3 (Base) Trade Name

Manufacturer

Country

Year Introduced

Cyclo-C

Kohjin

Japan

1975

Raw Materials Uridine Imidazole Hydrogen sulfide Acetic anhydride Ammonia Hydrogen chloride

Trityl chloride Thiophosgene Acetic acid Phosphorus pentasulfide Bromine

Ancrod

329

Manufacturing Process A series of reaction steps may be employed in which: (1) Uridine is reacted with trityl chloride to give 5'-o-trityluridine; (2) Imidazole is reacted with thiophosgene and that product reacted with the 5'-o-trityluridine to give 2,2'anhydro-1-(5'-o-trityl-β-D-arabinofuranosyl)uracil; (3) The preceding uracil product is converted to the thiouracil using hydrogen sulfide; (4) The trityl group is removed by treatment with 80% acetic acid; (5) A triacetylated product is obtained using acetic anhydride; (6) A dithiouracil is prepared from the uracil intermediate using phosphate pentasulfide. Preparation of 1-(β-D-arabinofuranosyl)-2-thiocytosine: A solution of 2.0 g of 1-(2',3',5'-O-triacetyl-β-D-arabinofuranosyl)-2,4-dithiouracilin 100 ml of methanol is saturated with anhydrous ammonia at 0°C. The mixture, in a glass liner, is heated in a pressure bomb at 100°C for three hours. The reaction mixture is concentrated to a gum in vacuum, and most of the byproduct acetamide is removed by sublimation at 60°C/0.1 mm. The residue is chromatographed on 100 g of silica gel. Elution of the column with methylene chloride-methanol mixtures with methanol concentrations of 2-25% gives fractions containing acetamide and a series of brown gums. The desired product is eluted with 30% methanol-methylene chloride to give a total yield of 0.386 g (30%), MP 175-180°C (dec.). Recrystallization from methanolisopropanol furnishes an analytical sample, MP 180-182°C (dec.). To a solution of 80 mg of 1-(β-D-arabinofuranosyl)-2-thiocytosine in 12 ml of water is added dropwise 3 ml of a 1 M bromine solution in carbon tetrachloride. At this point the color of the bromine persists for about 2-3 minutes after each addition. The unreacted bromine is blown off with a stream of nitrogen, and the reaction mixture is concentrated to a syrup in vacuum using a bath temperature less than 50°C. The residue is evaporated three times with 10 ml portions of ethanol, whereupon it crystallizes. The product is triturated with cold ethanol and with ether to obtain 17 mg of 2,2'-anhydro-1(β-D-arabinofuranosyl)cytosine hydrobromide, MP 240°C (dec.). Treatment of the hydrobromide with a slight excess of ethanolic ammonia yields the base which may then be converted to the hydrochloride. References Merck Index 654 Kleeman and Engel p. 53 DOT 12 (8) 304 (1976) I.N. p.87 Shen, T.Y. and Ruyle, W.V.; US Patent 3,463,850; August 26, 1969; Assigned to Merck and Co., Inc.

ANCROD Therapeutic Function: Anticoagulant Chemical Name: Agkistrodon serine proteinase

330

Ancrod

Common Name: Ancrod; Venacil Chemical Abstracts Registry No.: 9046-56-4 Trade Name Viprinex Arvin

Manufacturer Country Knoll Pharmaceuticals Knoll AG/BASF Pharma -

Year Introduced -

Raw Materials Venom of the Malayan pit-viper Agkistrodon rhodostoma Triethylaminoethyl cellulose powder (Serva) tris(Hydroxymethyl)aminomethane Manufacturing Process Triethylaminoethyl cellulose powder (Serva) of capacity 0.71 m.equiv./gm is suspended in 2 M sodium chloride buffered with 0.1 M tris/phosphate pH 6.0 and the slurry is packed into a glass column 3.6 cm in diameter until the height of the packed material reaches 20 cm. The column is washed with a further 2 L of the solvent used for preparing the slurry and is then equilibrated with 0.01 M tris/phosphate buffer pH 8.5. Tris is an abbreviation for tris(hydroxymethyl)aminomethane. 330-360 mg of crude A. rhodostoma venom is dissolved in 20 ml of 0.01 M tris/phosphate buffer pH 8.5, centrifuged to remove insoluble material, and the clear supernatant is applied to the column. The fractionation is carried out at room temperature at a flow rate of 90-100 ml (35 ml/hour). The protein concentration in the eluate is estimated from the extinction of the solution at 280 m/t in 1 cm cells. The chromatogram is developed with the following buffers. In all cases the molarity of the buffers are with respect 40 to tris. 0.01 M tris/phosphate pH 8.5 (to wash venom onto the column) (fractions 1, 2, 3). 0.01 M tris/phosphate pH 7.0 (fraction 4), 0.02 M tris/phosphate pH 6.0, 0.04 M tris/phosphate pH 6.0 (fraction 5), 0.10 M tris/phosphate pH 6.0 (fraction 6), 0.10 M tris/phosphate + 0.10 M NaCl pH 6.0 (fraction 7). The changes in eluting buffer are made after the column has equilibrated with the buffer. The protein fractions obtained in this way are assayed for coagulant activity. Less than 1% of the applied coagulant activity is recovered in fraction Nos. 1, 2, 3, 4. Fraction 1 however possesses proteolytic activtity which in concentrated solutions would dissolve fibrin clots. The thrombin-like activity is eluted from these columns in significant amounts at a buffer strength of 0.04 M or greater. The eluate is freeze dried to give a light powdery product. Yield: 18-20 mg per 350 mg dry venom. Calculation of molecular weight of the protein based on the amino acid composition gives a value of 30.000 which is in a very good agreement with that obtained by physical methods.

Anetholtrithion

331

References Reid H.A. et al.; US Patent No. 3,657,416; April 18, 1972; Assigned to Natinal Research Development Corporation, London, England

ANETHOLTRITHION Therapeutic Function: Salivation stimulant, Choleretic, Neuroprotective Chemical Name: 3H-1,2-Dithiole-3-thione, 5-(4-methoxyphenyl)Common Name: Anethole dithiolthione; Trithioparamethoxyphenylpropene; Anethole trithione Structural Formula:

Chemical Abstracts Registry No.: 532-11-6 Trade Name

Manufacturer

Country

Year Introduced

Sialor

Paladin Labs

-

-

Anetholtrithion

Shanghai Jinsai Medicine Chemical Industry Co. Ltd.

-

Anetholtrithion

-

-

Anetholtrithion

Tianjin Mid-Chem Co., Ltd. Shanghai Lansheng Corporation

-

-

Secrebil

Wassermann

-

-

Secrebil

Vicente Scavone y CIA. C.I.S.A.

-

Bilitherap

Kaigen

-

-

Felviten

Nippon Shinyaku

-

-

Halpen

Toho Kagaku

-

-

Mucinol

-

Sialor

Sanofi-Synthelabo OTC, D-Berlin Solvay-Kingswood -

Sonicur

Kalifarma

-

-

Sufralen

Solvay

-

-

Sulfarlem

Solvay

-

-

-

332

Angiotensin amide

Trade Name

Manufacturer

Sulfarlem

Solvay-Kingswood -

Country

Year Introduced -

Sulfarlem

UCM

-

-

Sulfarlem

Tobishi

-

-

Sulfarlem

Ouiheng

-

-

Sulfarlem

Frik

-

-

Sulfarlem

Ethimed

-

-

Raw Materials Anethol (1-Methoxy-4-propenyl-benzene) Sulfur Manufacturing Process 1 mol anethol (1-methoxy-4-propenyl-benzene) and 3 mol sulfur were heated in an open vessel to temperature 190°-200°C. H2S was removed at this temperature. On cooling the reaction mixture was getting solid. The solid product was recrystallizated from acetone or ethanol to give the orange-red needles of 5-(4-methoxyphenyl)-3H-1,2-dithiole-3-thione; MP 108.5°C. References Boettcher B.; D.B. Patent No. 869,799; May 8, 1940

ANGIOTENSIN AMIDE Therapeutic Function: Vasoconstrictor Chemical Name: L-Asparaginyl-L-arginyl-L-valyl-L-tyrosyl-L-valyl-L-histidyl-Lprotyl-L-phenylalanine Common Name: Chemical Abstracts Registry No.: 53-73-6 Trade Name

Manufacturer

Country

Year Introduced

Hypertensin

Ciba

W. Germany

1961

Hypertensin

Ciba

US

1962

Raw Materials L-Asparaginyl-L-arginyl-L-valyl-L-tyrosyl-L-valyl-L-histidyl-L-prolyl-Lphenylalanine methyl ester trihydrochloride Sodium hydroxide

Anilamate

333

Structural Formula:

Manufacturing Process 48 mg (0.042 mmol) of L-asparaginyl-L-arginyl-L-valyl-L-tyrosyl-L-valyl-Lhistidyl-L-prolyl-L-phenylalanine methyl ester trihydrochloride are suspended in 0.5 ml of methanol, and treated gradually in the course of one hour with 0.3 ml of N-caustic soda solution (about 7 equivalents) so that the pH value of the solution is maintained between 10.5 and 11.5. After a further 30 minutes the solution is freed from methanol under vacuum at room temperature, adjusted with 1 N acetic acid to pH 7.4 and lyophilized. The residual mixture of free peptide and inorganic salts (79 mg) is fractionated by countercurrent distribution in the system butanol/0.1 N ammonium hydroxide. The pure octapeptide is obtained as a colorless powder which is soluble in water and methanol, more sparingly soluble in ethanol, and insoluble in acetone. References Merck Index 674 Kleeman and Engel p. 55 I.N. p. 89 Schwyzer, R., Iselin, B., Kappeler, H., Ritter, W. and Riuiker, B.; US Patent 2,978,444; April 4, 1961; Assigned to Ciba Pharmaceutical Products, Inc.

ANILAMATE Therapeutic Function: Antiinflammatory Chemical Name: 2-[[(Methylamino)carbonyl]oxy]-N-phenylbenzamide Common Name: Anilamate

334

Anileridine dihydrochloride

Structural Formula:

Chemical Abstracts Registry No.: 5591-49-1 Trade Name

Manufacturer

Country

Year Introduced

Anilamate

Onbio Inc.

-

-

Raw Materials Salicylanilide Triethylamine Methyl isocyanate Manufacturing Process 32 g of salicylanilide was dissolved in 1000 ml of diethyl ether, 2 ml of triethylamine and 25 ml of a 50% solution of methyl isocyanate in toluene were added to the solution and the reaction mixture was allowed to stand overnight at about 25°C. The resulting crystals of salicylanilide methylcarbamate were removed by filtration, washed with 100 ml of diethyl ether, and dried in vacuo to provide 37.5 g (92% yield) of salicylanilide methylcarbamate having melting point of 160-161°C. References Strube R.E.; US Patent No. 3,091,633; May 28, 1963; Assigned to The Upjon Company, Kalamazoo, Mich., a corporation of Delawere

ANILERIDINE DIHYDROCHLORIDE Therapeutic Function: Narcotic analgesic Chemical Name: 1-[2-(4-Aminophenyl)ethyl]-4-phenyl-4-piperidinecarboxylic acid ethyl ester dihydrochloride Common Name: Chemical Abstracts Registry No.: 126-12-5; 144-14-9 (Base)

Anileridine dihydrochloride

335

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Leritine HCl

US

1958

Apodol Tabs

Merck Sharp and Dohme Squibb

US

1965

Leritine

Merck-Frosst

Canada

-

Raw Materials Sodium carbonate Hydrogen chloride

β-(p-Aminophenyl)ethyl chloride 4-Phenyl-4-carbethoxypiperidine carbonate

Manufacturing Process A mixture of 7.8 grams (0.05 mol) of β-(p-aminophenyl)ethyl chloride hydrochloride, 12.5 grams (0.025 mol) of 4-phenyl-4-carboethoxypiperidine carbonate, 10.5 grams (0.125 mol) sodium bicarbonate, and 100 cc of anhydrous ethanol are mixed, stirred and heated under reflux for a period of approximately 40 hours and then concentrated in vacuum to dryness. The residual material is triturated with 50 cc of water, decanted, washed by decantation with an additional 50 cc of water, and then dried in vacuum to give N-[β-(p-aminophenyl)ethyl]-4-phenyl-4-carboethoxypiperidine. The N-[β-(p-aminophenyl)ethyl]-4-phenyl-4-carboethoxypiperidine is dissolved in 50 cc of hot anhydrous ethanol, an excess (about 20 cc) of 20% alcoholic hydrochloric acid solution is added; upon scratching the side of the container crystals form. One hundred cubic centimeters of ether are then added to the mixture, the ethereal mixture is cooled, and the crystalline material which precipitates is recovered by filtration, washed with ether, and dried to give 12.7 grams of N-[β-(p-aminophenyl)ethyl]-4-phenyl-4-carboethoxypiperidine dihydrochloride which can be further purified by recrystallization from ethanol or methanal to give substantially pure material; MP 275-277°C. References Merck Index 680 Kleeman and Engel p. 56 OCDS Vol. 1 p. 300 (1977) I.N. p. 90 Weijlard, J. and Pfister, K., III; US Patent 2,966,490; December 27, 1960; Assigned to Merck and Co., Inc.

336

Anipamil

ANIPAMIL Therapeutic Function: Coronary vasodilator, Antihypertensive Chemical Name: 2-[3-[(m-Methoxyphenethyl)methylamino]propyl]-2-(mmethoxyphenyl)tetradecanenitrile Common Name: Anipamil; LU 42668 Structural Formula:

Chemical Abstracts Registry No.: 83200-10-6 Trade Name

Manufacturer

Country

Year Introduced

Anipamil

Onbio Inc.

-

-

Anipamil

ZYF Pharm Chemical

-

-

Raw Materials 3-Methoxyphenylacetonitrile 1-Bromododecane 1-Bromo-3-chloropropane

1-Cyano-1-(3-methoxyphenyl)tridecane N-Methyl-β-(3-methoxyphenyl)ethylamine Sodium amide

Manufacturing Process 1,7-Bis-(3-ethoxyphenyl)-3-methylaza-7-cyano-nonadecane: 0.06 mole of 1-cyano-1-(3-methoxyphenyl)tridecane (prepared by phase transfer-catalyzed alkylation of 3-methoxyphenylacetonitrile with 1bromododecane) and 0.06 mole of 1-chloro-4-methylaza-6-(3methoxyphenyl)hexane [prepared from N-methyl-β-(3methoxyphenyl)ethylamine and 1-bromo-3-chloropropane by a method similar to that described in Arzneim.-Forsch. 28 (II) (1978), 2048] were dissolved in 100 ml of dry toluene in a three-necked flask provided with a stirrer, dropping funnel, reflux condenser and thermometer. 9.3 g (0.07 mole) of a 30% strength suspension of sodium amide in toluene were then added dropwise at from 100° to 110°C, with stirring, and stirring was continued under reflux for a further 90 minutes.

Aniracetam

337

The resulting reaction solution was poured into 200 ml of ice water, and the toluene phase was separated off and washed twice with water. The required amount of hydrochloric acid was added to the toluene solution, the toluene was distilled off under reduced pressure and the residue, which remained was recrystallized from acetone to give 1,7-bis-(2-methoxyphenyl)-3-methylaza-7cyanononadecane hydrochloride or α-dodecyl-3-methoxy-α-[3-[[2-(3methoxyphenyl)ethyl]methylamino]propyl]benzene-acetonitrile (anipamil); MP: 60°-69.5°C. References Ehrmann O. et al.; US Patent No. 4,438,131; March 20, 1984; Assigned to BASF Aktiengesellshaft, Fed. Rep. of Germany

ANIRACETAM Therapeutic Function: Nootropic Chemical Name: 2-Pyrrolidinone, 1-(4-methoxybenzoyl)Common Name: Aniracetam; Memodrin Structural Formula:

Chemical Abstracts Registry No.: 72432-10-1 Trade Name Pergamid AM Ro13-5057

Manufacturer Rontag ABATRA Technology Co., Ltd.

Country -

Year Introduced -

Memodrin

Lavipharm Group

-

-

Raw Materials 2-Pyrrolidinone Triethylamine Sodium hydride

p-Methoxybenzoyl chloride p-Methoxybenzoic acid pentachlorophenyl ester 1-Trimethylsilyl-2-pyrrolidinone

Manufacturing Process There are a few versions of synthesis of title compound.

338

Aniracetam

Preparation of 1-(p-methoxybenzoyl)-2-pyrrolidinone: 1. 40.0 g of p-methoxybenzoyl chloride, 25.0 g of 2-pyrrolidinone and 110 ml of absolute diethyl ether are treated at between 0°C and 10°C while stirring with 52.5 ml of triethylamine. The mixture is stirred at room temperature for a further 30 minutes and at reflux for 3 hours, then cooled down and treated at 2°C with cold water. The insoluble constituents are filtered off under suction and washed with water and diethyl ether. The thus obtained solid substance is recrystallized from alcohol after drying over phosphorus pentoxide. There is obtained 1-(p-methoxybenzoyl)-2-pyrrolidinone which melts at 121°-122°C. 2. 20.2 g of the sodium salt of 2-pyrrolidinone (prepared using sodium hydride) suspended in 270 ml of dimethylformamide are added in four portions at -10°C to a solution of 37.0 g of p-methoxybenzoyl chloride in 50 ml of dimethylformamide. Subsequently, the mixture is stirred at room temperature for 1 hour and then at 40°C for 4 hours. The solvent is evaporated and the residue is treated with diethyl ether and with cold sodium bicarbonate solution. The insoluble crystalline constituents are filtered off, washed with water and diethyl ether and dried in vacuum over phosphorus pentoxide. There is obtained 1-(p-methoxybenzoyl)-2-pyrrolidinone having a melting point of 120°-121°C. 3. 20 g of p-methoxybenzoyl chloride and 20 g of 2-pyrrolidinone are boiled at reflux in 20 ml of diethyl ether for 16 hours and then diethyl ether, ice and 2 N aqueous ammonia are added to the mixture. The insoluble constituents are filtered off and washed ion-free with diethyl ether and water. The filter cake is dried and there is obtained 1-(p-methoxybenzoyl)-2-pyrrolidinone having a melting point of 119.5°-120.5°C. 4. 20 g of p-methoxybenzoyl chloride and 20 g of 2-pyrrolidinone are boiled at reflux in 20 ml of diethyl ether for 16 hours and then diethyl ether, ice and 2 N aqueous ammonia are added to the mixture. The insoluble constituents are filtered off and washed ion-free with diethyl ether and water. The filter cake is dried and there is obtained 1-(p-methoxybenzoyl)-2-pyrrolidinone having a melting point of 119.5°-120.5°C. The procedure described in item is followed, but the starting materials are heated in 20 ml of toluene instead of diethyl ether. The resulting 1-(p-methoxybenzoyl)-2-pyrrolidinone melts at 117°118°C. 5. 10 g of 2-pyrrolidinone and 10 g of p-methoxybenzoyl chloride are heated at 80°-90°C (internal temperature) in the absence of a solvent for 1 hour. The mixture is then left to cool down and is worked-up as described in item 3. After recrystallization from alcohol, there is obtained 1-(p-methoxybenzoyl)-2pyrrolidinone having a melting point of 120°-121°C. 6. 24.4 g of p-methoxybenzoyl chloride and 22.5 g of 1-trimethylsilyl-2pyrrolidinone are mixed and the mixture is stirred at room temperature for 10 minutes. Then, the resulting trimethylchlorosilane is distilled off under reduced pressure in an oil bath at 80°C. The residue is triturated with 100 ml of diethyl ether. The mixture is filtered and the filter cake is recrystallized from ethanol. There is obtained 1-(p-methoxybenzoyl)-2-pyrrolidinone having a melting point of 120°-121°C. 7. 7.0 g of the sodium salt of 2-pyrrolidinone (prepared using sodium hydride)

Anirolac

339

suspended in 120 ml of dimethylformamide are added at -10°C to a solution of 20.0 g of p-methoxybenzoic acid pentachlorophenyl ester in 100 ml of dimethylformamide. Subsequently, the mixture is stirred at room temperature for 1 hour and at 55°C for 8 hours. The solvent is evaporated, the residue is treated with cold aqueous acetic acid solution and the mixture is extracted with ethyl acetate. The organic phase is washed with cold sodium bicarbonate solution and water, dried over sodium sulfate, filtered and evaporated. The residue is taken up in ethanol and stirred in an ice bath. The separated crystals are filtered off and there is obtained 1-(p-methoxybenzoyl)-2pyrrolidinone having a melting point of 119°-120°C. References Kyburz E. et al.; US Patent No. 4,369,139; Jan. 18, 1983; Assigned to Hoffmann-La Roche Inc., Nutaey, N.J.

ANIROLAC Therapeutic Function: Antiinflammatory, Analgesic Chemical Name: 1H-Pyrrolizine-1-carboxylic acid, 2,3-dihydro-5-(4methoxybenzoyl)-, (+-)Common Name: Anirolac Structural Formula:

Chemical Abstracts Registry No.: 66635-85-6 Trade Name Anirolac Anirolac

Manufacturer Syntex Inc. Onbio Inc.

Country -

Year Introduced -

Raw Materials N,N-Dimethyl-p-methoxybenzamide Phosphorous oxychloride Isopropyl 1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate Manufacturing Process A solution of 1.1 equivalent of N,N-dimethyl-p-methoxybenzamide and 1

340

Anisacril

equivalent of phosphorous oxychloride in 2 ml of 1,2-dichloroethane is refluxed for 30 minutes. To this solution is added a solution of 1 equivalent of isopropyl 1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate in 2 ml of 1,2dichloroethane. The reaction mixture is refluxed under an argon atmosphere for 8 hours, treated with equivalent of sodium acetate and refluxed for a further 5 hours. The resultant mixture is then evaporated to dryness and the residue is chromatographed on 12 g of silica gel, eluting with hexane: ethyl acetate (3:1), monitoring the course of the reaction by TLC. Isopropyl 5-pmethoxybenzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate was obtained as an oil. UV, IR, NMR spectrum confirmed the structure of obtained compound. A solution of 1 equivalent of isopropyl 5-p-methoxybenzoyl-1,2-dihydro-3Hpyrrolo[1,2-a]pyrrole-1-carboxylate in 10 ml of methanol is treated with a solution of 1 equivalent of potassium carbonate in 5 ml of water. The reaction mixture is refluxed under nitrogen atmosphere for 30 minutes, cooled, and evaporated to dryness. The residue is taken up in 10 ml of 10% aqueous hydrochloric acid and 50 ml of water and the resultant mixture extracted with ethyl acetate (2x50 ml). The combined extracts are dried over magnesium sulfate and evaporated to dryness under reduced pressure. Crystallization of the residue from ethyl acetate-hexane affords 5-p-methoxybenzoyl-1,2dihydro-3H-pyrrolo[1, 2-a]pyrrole-1-carboxylic acid (anirolac); MP: 187°187.5°C. References Syntex (USA) Inc.; G.B. Patent No. 1,554,075; Oct. 17, 1979

ANISACRIL Therapeutic Function: Anorexic, Antihyperlipidemic Chemical Name: Acrylic acid, 2-(o-methoxyphenyl)-3,3-diphenylCommon Name: Anisacril Structural Formula:

Chemical Abstracts Registry No.: 5129-14-6 Trade Name

Manufacturer

Country

Year Introduced

SCF 16046

Smith Kline

-

-

Anisindione

341

Raw Materials o-Bromoanisole Hydrochloric acid Sodium hydroxide

Magnesium Diphenyl pyruvic acid

Manufacturing Process A solution of Grignard reactive (prepared from 247 g of o-bromoanisole and 31.6 g of magnesium in 1500 ml of ether) is added dropwise to a solution of 91 g of diphenyl pyruvic acid in ether. The mixture is refluxed for 2 hours. After cooling to the reaction mixture is added 5% hydrochloric acid and the product is extracted with 5% solution of sodium hydroxide. α-(o-Anisyl)-β,βdiphenyl lactic acid is precipitated by addition of concentrated hydrochloric acid; yield 62 g, melting point 194-195°C. 4 g of α-(o-anisyl)-β,β-diphenyl lactic acid is heated at 210-215°C for 10-15 min. The α-(o-anisyl)-β,β-diphenyl acrylic acid is recrystallized from benzene, yield 2.85 g (74%), melting point 195-196°C. References FR Patent No. 1,442,295; Oct. 8, 1964; Assigned to Smith Kline and French Laboratories residant aux Etats-Unis d'Amerique

ANISINDIONE Therapeutic Function: Anticoagulant Chemical Name: 2-(4-Methoxyphenyl)-1H-indene-1,3(2H)-dione Common Name: Anisindandione Structural Formula:

Chemical Abstracts Registry No.: 117-37-3 Trade Name Miradon Unidone Unidone

Manufacturer Schering Unilabo Centrane

Country US France France

Year Introduced 1960 1964 -

342

Anisopirol

Raw Materials p-Methoxybenzaldehyde Sodium ethoxide Phthalide Manufacturing Process To a hot solution of 20.6 g of sodium in 400 ml of absolute ethanol, there is added a solution of 110 g of phthalide and 110 g of p-methoxybenzaldehyde. A vigorous reaction ensues and one-half of the alcohol is distilled off over a two hour period. Ice and water are added to the red solution and the diluted solution is acidified with hydrochloric acid. The resulting gum solidifies and the aqueous phase is removed by decantation. The crude solid is recrystallized twice from two liters of ethanol yielding 2-(p-methoxyphenyl)-1,3-indandione as pale yellow crystals, MP 155-156°C. References Merck Index 690 Kleeman and Engel P.57 OCDS Vol. 1 p. 147 (1977) I.N. p.90 REM p.828 Sperber, N.; US Patent 2,899,358; August 11, 1959; Assigned to Schering Corporation

ANISOPIROL Therapeutic Function: Neuroleptic Chemical Name: (+/-)-α-(4-Fluorophenyl)-4-(2-methoxyphenyl)-1piperazinebutanol Common Name: Anisopirol Structural Formula:

Chemical Abstracts Registry No.: 442-03-5 Trade Name

Manufacturer

Country

Year Introduced

Anisopirol

ZYF Pharm Chemical

-

-

Anisotropine metylbromide

343

Raw Materials γ-Chloro-4-fluorobutyrophenone 1-(2-Methoxyphenyl)piperazine Sodium borohydride Manufacturing Process A mixture of 6.6 parts of γ-chloro-4-fluorobutyrophenone and 12.5 parts of 1(2-methoxyphenyl)piperazine, heated for 10 hours at a temperature of 110°C. The reaction mixture is treated with 800 parts of ether and fiItered. The ether layer is washed with water, dried over anhydrous potassium carbonate and filtered, whereupon hydrogen chloride gas is introduced into the solution. The precipitate is collected on a filter and dissolved in a mixture of 240 parts of 2propanol and 80 parts of acetone to yield 1-[γ-(4-fluorobenzoyl)propyl]-4-(2methoxyphenyl)piperazine hydrochloride. This monohydrochloride is collected on a filter and dissolved in 240 parts of 2-propanol. Anhydrous, gaseous hydrogen chloride is passed through the solution. On cooling, the 1-[γ-(4fluorobenzoyl)propyl]-4-(2-methoxyphenyl)piperazine hydrochloride precipitates. A second crop of product is obtained by passing hydrogen chloride gas through the solution of mother liquors. The pale-brown, amorphous powder is collected on a filter and found to melt at about 205°-205.5°C. This salt is dissolved in water and treated with sodium hydroxide. The precipitated base is recovered by filtration and recrystallized from diisopropylether. The white crystals melt about 67.5°-68.5°C. By dissolving 4 parts of 1-[γ-(4-fluorobenzoyl)propyl]-4-(2-methoxyphenyl) piperazine dihydrochloride in 800 parts of water, rendering alkaline, extracting with 400 parts of ether, drying over calcium chloride, filtering, and evaporating the resulting solution, the free base of 1-[γ-(4-fluorobenzoyl) propyl]-4-(2-methoxyphenyl)piperazine is obtained. This product is dissolved in 120 parts of absolute ethanol and 0.03 part of sodium borohydride is added portionwise at 35°C. After decomposition with 150 parts of 1 N hydrochloric acid, the mixture is diluted with 500 parts of water, made alkaline with 4 N sodium hydroxide, and further diluted to a volume of 1,000 parts. Upon cooling for 4 hours at 0°C the precipitate formed is filtered, dried, and recrystallized from diisopropyl ether to yield 1-(4-fluorophenyl)-4-[4-(2methoxyphenyl)piperazine]-1-butanol (anisopirol). The white granular powder of this compound has a melting point of about 105°-106°C. References Jansen P. A.J.; US Patent No. 2,997,474; August 22, 1961

ANISOTROPINE METHYLBROMIDE Therapeutic Function: Anticholinergic

344

Anisotropine metylbromide

Chemical Name: endo-8,8-Dimethyl-3-[(1-oxo-2-propylpentyl)oxy]-8azoniabicyclo[3.2.1]octane bromide Common Name: Octatropine methyl bromide Structural Formula:

Chemical Abstracts Registry No.: 80-50-2 Trade Name

Manufacturer

Country

Year Introduced

Valpin

Endo (Du Pont)

US

1963

Valpinax

Crinos

Italy

1966

Valpin

Lacer

Spain

-

Valpin

Sankyo

Japan

-

Raw Materials Tropine Di-n-propyl acetyl chloride Methyl bromide Manufacturing Process Preparation of Di-n-propyl acetyl tropine hydrochloride: Tropine (11.12 grams) was dissolved in 100 ml of anhydrous pyridine and to this solution was added 15.64 grams of di-n-propyl acetyl chloride. The mixture was refluxed for 6 hours. This solution was then cooled and the pyridine removed in vacuum. The residue was dissolved in chloroform. The chloroform solution was washed with 10% hydrochloric acid to remove the residual trace of pyridine. The hydrochloride of the product ester is soluble in chloroform and is not extracted from chloroform by hydrochloric acid. This is an unexpected property. The chloroform solution of the hydrochloride was dried over anhydrous calcium sulfate, and evaporated to dryness, leaving a semisolid residue of product ester hydrochloride. This was recrystallized from chloroform-hexane mixture, MP 186°C. Preparation of the Anisotropine Methyl Bromide: To the acetone solution of the free base was added an acetone solution, containing an excess of methyl bromide. Within a few minutes the methobromide started to crystallize. The mixture was allowed to stand for several hours. The crystallized solid was filtered, and additional product was obtained by evaporation of the filtrate. The yield was nearly quantitative. After recrystallization from acetone, the product melted at 329°C.

Anistreplase

345

References Merck Index 693 Kleernan and Engel p. 655 PDR p. 865 I.N. p. 699 REM p.913 Weiner, N. and Gordon, S.M.; US Patent 2,962,499; November 29, 1960; Assigned to Endo Laboratories, Inc.

ANISTREPLASE Therapeutic Function: Thrombolytic Chemical Name: Anisoylated plasminogen streptokinase activator complex Common Name: Eminase; Fibrit; Iminase; Multilase; Anisoylated plasminogen streptokinase activator complex Structural Formula: Binary complex of streptokinase and human plasminogen Chemical Abstracts Registry No.: 81669-57-0 Trade Name

Manufacturer

Country

Year Introduced

Anistreplase

Beecham

-

-

Raw Materials Streptokinase (250,000 units, Kabi, Stockholm, Sweden) 0.1 M p-amidinophenyl p'-anisate in dimethylsulphoxide Human lys-plasminogen [Kabi, Stockholm] L-Lysine-sepharose 4B 0.1 M ε-aminocaproic acid Manufacturing Process Preparation of freeze dried p-anisoyl streptokinase/plasminogen complex without internal peptide bond cleavages: Streptokinase (250,000 units, Kabi, Stockholm, Sweden) was dissolved in 0.1 M trishydroxymethylmethane hydrochloride pH 7.4 (2.5 ml) and a solution of 0.1 M p-amidinophenyl p'-anisate in dimethylsulphoxide (0.25 ml) added. A slight cloudiness resulted. To this mixture was added 0.5 ml of a solution of human lys-plasminogen (8.99 mg/ml in the above buffer) [Kabi, Stockholm] and the solution was thoroughly and rapidly mixed. After standing on ice for 15 minutes, the solution was stored on ice until use. After approximaely 2 hours 0.4 ml (40,000 units) of the material was diluted with 3.0 ml of a slurry of L-lysine-sepharose 4B (a 33% wet wt/volume suspension in the above buffer) and stood at 0°C for 1 hour. The gel was filtered on a glass sinter

346

Anitrazafen

funnel at 4°C under suction and washed with the buffer (100 ml). The gel was eluted under gentle suction with the same buffer containing 0.1 M εaminocaproic acid (3 lots of 5 ml). The combined filtrates were dialysed for 2 hours at 4°C against ammonium bicarbonate buffer (50 mM pH 7.0) containing 2.5% w/v mannitol. The product was then freeze dried to 0.799 g of a white solid. Approximately 195 mg of this material was analysed by slab gel polyacrylamide gel electrophoresis using 10% w/v gels in the presence of sodium dodecyl sulphate. Two main polypeptide bands were observed corresponding to lys-plasminogen (m.w. 84,000) and streptokinase (m.w. 47,000). There was also a trace of contaminating human serum albumin derived from the commercial streptokinase preparation. References Smith R.A.G. et al.; US Patent No. 4,808,405; Feb. 28, 1989; Assigned Beecham Group P.L.C., England

ANITRAZAFEN Therapeutic Function: Antiinflammatory Chemical Name: 1,2,4-Triazine, 5,6-bis(4-methoxyphenyl)-3-methylCommon Name: Anitrazafen Structural Formula:

Chemical Abstracts Registry No.: 63119-27-7 Trade Name

Manufacturer

Country

Year Introduced

Lilly 122512

Eli Lilly

-

-

Raw Materials 3-Hydroxy-5,6-bis(4-methoxyphenyl)-1,2,4-triazine Anisil (4,4'-dimethoxybenzil) Semicarbazide hydrochloride Phosphorous oxychloride Methyltriphenylphosphonium bromide Butyl lithium

Anpirtoline hydrochloride

347

Manufacturing Process Preparation of 5,6-bis(4-methoxyphenyl)-3-methyl-1,2,4-triazine: (A) 3-Hydroxy-5,6-bis(4-methoxyphenyl)-1,2,4-triazine 2 moles, 540 g of anisil (4,4'-dimethoxybenzil), 222 g (2 moles) of semicarbazide hydrochloride, 180 g (2.2 moles) of sodium acetate, and 2.5 liters of acetic acid were heated at reflux overnight. The cooled reaction mixture was poured into 5 liters of water. The crude solid product was collected by filtration, washed with water, and recrystallized from acetic acid, giving 434 g of 3-hydroxy-5,6-bis(4methoxyphenyl)-1,2,4-triazine; MP: about 272°-274°C. (B) 3-Chloro-5,6-bis(4-methoxyphenyl)-1,2,4-triazine: 10 grams of 3-hydroxy-5,6-bis(4-methoxyphenyl)-1,2,4-triazine and 50 ml of phosphorous oxychloride were heated at reflux for 1.5 hours. The cooled mixture was poured onto crushed ice and the resultant mixture was extracted with diethyl ether. The extract was washed successively with 2% sodium hydroxide and water until the washings were neutral. The ether extract was dried over anhydrous sodium sulfate and evaporated. The residue was taken up in ether, filtered, and the filtrate was evaporated to yield 9.0 g of 3-chloro5,6-bis(4-methoxyphenyl)-1,2,4-triazine; MP: about 130°-132°C. (C) 5,6-Bis(4-methoxyphenyl)-3-methyl-1,2,4-triazine: To a slurry of 11.7 g (0.33 mole) of methyltriphenylphosphonium bromide in 150 ml of dry tetrahydrofuran at -35°C was added, over a 15-minute period, 20 ml (0.033 mole) of n-butyl lithium. The reaction mixture was stirred for one hour. To the reaction mixture at -35° to -40°C was added over a 10minute period a solution of 5.7 g (0.0165 mole) of 3-chloro-5,6-bis(4methoxyphenyl)-1,2,4-triazine in 50 ml of tetrahydrofuran. The reaction mixture was allowed to warm to ambient temperature and was stirred overnight. A solution of 1.05 g (0.0165 mole) of sodium carbonate in 50 ml of water was added dropwise to the reaction mixture which then was heated at reflux for three hours. The reaction mixture was cooled, poured over ice, and extracted with diethyl ether. The diethyl ether extract was washed with water, dried over anhydrous sodium sulfate, and concentrated. The concentrate was chromatographed over silica gel, with three fractions being collected. After evaporation of solvent, the third fraction solidified; MP: about 109°-113°C. The solid was identified as 5,6-bis(4-methoxyphenyl)-3-methyl-1,2,4-triazine by nuclear magnetic resonance analysis, mass spectrographic analysis, and elemental microanalysis. References Lacefield W.B.; US Patent No. 4,190,725; Feb. 26, 1980; Assigned to Eli Lilly and Company, Indianapolis, Ind.

ANPIRTOLINE HYDROCHLORIDE Therapeutic Function: Analgesic, Antidepressant

348

Anpirtoline hydrochloride

Chemical Name: 2-Chloro-6-(4-piperidinylthio)pyridine monohydrochloride Common Name: Anpirtoline hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 99201-87-3; 98330-05-3 (Base) Trade Name

Manufacturer

Country

Year Introduced

Anpirtoline Hydrochloride

YQBio (Shanghai) Co. Ltd.

-

-

Anpirtoline Hydrochloride

Biomol Research Lab.

-

-

Raw Materials Sodium hydride Silica gel

4-Mercaptopiperidine hydrochloride 2,6-Dichloropyridine

Manufacturing Process 2-Chloro-6-(4-piperidinylthio)pyridine: The reaction is carried out under an argon atmosphere. 0.27 g of 80% sodium hydride (0.009 mol) are suspended in 10 ml of dimethylacetamide; the mixture is cooled with ice and then 0.615 g (0.004 mol) of solid 4mercaptopiperidine hydrochloride are added and stirred for 10 minutes. A solution of 0.588 g (0.004 mol) of 2,6-dichloropyridine in 5 ml of dimethylacetamide are then added dropwise to this mixture and the reaction mixture is stirred for 2.5 hours at room temperature. Working up of the reaction mixture: 25 ml of water are added dropwise with cooling, 20 ml of methylene chloride are then added, the organic phase is separated off, the aqueous phase is then extracted twice with 15 ml of methylene chloride each time, the combined organic phase is washed twice, in each case with 10 ml of water, dried with sodium sulfate, the solution is concentrated on a rotary evaporator, the residue is mixed with 10 ml of absolute ethanol and then reconcentrated. The product which is obtained on removal of the eluant is diluted with 10 ml of ether, an equivalent quantity of HCl in isopropanol is added dropwise and the mixture is placed for several hours in a deep freezer after addition of seed crystals. The hydrochloride of the 2-chloro-6-(4-piperidinylthio)pyridine which crystallizes out is filtered off with suction, washed with ether and dried under oil pump vacuum at 50°C. Melting point of the hydrochloride 132°-133°C.

Ansoxetine

349

References Engel J. et el.; US Patent No. 4,643, 995; Feb. 17, 1987; Assigned to Deguss Akkktiengesellschaft, Frankfurt am Main, Fed. Rep. of Germany

ANSOXETINE Therapeutic Function: Antidepressant Chemical Name: 6-[3-(Dimethylamino)-1-phenylpropoxy]-2-phenyl-4H-1benzopyran-4-one Common Name: Ansoxetine Structural Formula:

Chemical Abstracts Registry No.: 79130-64-6 Trade Name

Manufacturer

Country

Year Introduced

Ansoxetine

ZYF Pharm Chemical

-

-

Raw Materials 1-Chloro-1-phenyl-3-dimethylaminopropane Manufacturing Process A solution of 1 gram-equivalent of 6-hydroxyflavanone in equivalent of 0.5 N ethanolic NaOH is evaporated, the residue is dissolved in 200 ml of DMF and the solution is heated to 150°C; a solution of g-eguivalent of 1-chloro-1phenyl-3-dimethylaminopropane in 50 ml of DMF is added, while stirring. The mixture is stirred for 1.5 hours at 150°C and 6-(1-phenyl-3dimethylaminopropoxy)flavonone is precipitated by adding water. References Hausberg H.-H. et al.; US Patent No. 4,780,478; October 25, 1988; Assigned to Merck Patent Gesellschaft mit Berschrankter Heftung, Darmstadt, Fed.Rep. of Germany

350

Antazoline hydrochloride

ANTAZOLINE HYDROCHLORIDE Therapeutic Function: Antihistaminic Chemical Name: 4,5-Dihydro-N-phenyl-N-(phenylmethyl)-1H-imidazole-2methanamine hydrochloride Common Name: Imidamine Structural Formula:

Chemical Abstracts Registry No.: 2508-72-7; 91-75-8 (Base) Trade Name Antistine HCl Antistine Antistine Antasten Arithmin Azalone Histotab Phenazoline

Manufacturer Ciba Ciba Geigy Ciba Ciba Lannett Smith, Miller and Patch Boots Polfa

Country US France W. Germany US US

Year Introduced 1948 -

UK Poland

-

Raw Materials 2-Chloromethylimidazoline hydrochloride N-Benzylaniline Hydrogen chloride Manufacturing Process 15.4 parts of 2-chloromethylimidazoline hydrochloride, 45.8 parts of Nbenzylaniline and 150 parts of alcohol are heated in an oil bath at 100° to 110°C. After distilling off the alcohol, the reaction mass is maintained at this temperature for a further 3 hours and then triturated with water and 10 parts of sodium bicarbonate. The unconsumed benzylaniline is extracted with ether and the aqueous solution neutralized with dilute hydrochloric acid. By evaporating this solution and extracting the residue with alcohol there is obtained 2-(N-phenyl-N-benzylaminomethyl)imidazoline hydrochloride in the

Antienite

351

form of colorless crystals of melting point 227° to 229°C. References Merck Index 701 Kleeman and Engel p. 57 OCDS Vol. 1 p. 242 (1977) I .N. p. 91 Miescher, K. and Klarer, W.; US Patent 2,449,241; September 14, 1948; Assigned to Ciba Pharmaceutical Products, Inc.

ANTIENITE Therapeutic Function: Anthelmintic Chemical Name: Imidazo[2,1-b]thiazole, 5,6-dihydro-6-(2-thienyl)-, (+/-)Common Name: Antienite; Thiazothielite Structural Formula:

Chemical Abstracts Registry No.: 5029-05-0 Trade Name Antienite Antienite

Manufacturer Onbio Inc. ZYF Pharm Chemical

Country -

Year Introduced -

Raw Materials 2-Iminothiazoline Acetic anhydride Thionyl chloride Oxalic acid dihydrate

Bromomethyl-2-thienylketone Sodium borohydride Phosphoroxy chloride

Manufacturing Process A mixture of 4 parts of 2-iminothiazoline, 8.3 parts of bromomethyl-2thienylketone and 40 parts of absolute ethanol is stirred and refluxed for 2 hours in a water-bath. After cooling, the precipitated hydrobromide is filtered off. From this salt the free base is liberated on treating with ammonium hydroxide solution and it is extracted with chloroform. The organic extract is separated, treated with activated charcoal, filtered and the filtrate is first dried over magnesium sulfate and then evaporated. The solid residue is recrystallized from 24 parts 2-propanol, to yield 2-imino-3-[(2thienylearbonyl)-methyl]-thiazoline; MP: 117.5°-118.5°C.

352

Antienite

A mixture of 4 parts of 2-imino-3-[(2-thienylcarbonyl)methyl]thiazoline, 50 parts of acetic anhydride and 1.15 parts of sodium acetate is stirred and refluxed for 15 minutes. The formed sodium bromide is filtered off. From the filtrate, the excess of acetic anhydride is distilled and the residual solid is recrystallized from 2-propanol. The solid is filtered off and dried in vacuum, yielding 2-(acetylimino)-3-[(2-thienylcarbonyl)methyl]thiazoline; MP: 146°147.5°C. To a stirred mixture of 13 parts of 2-(acetylimino)-3-(2thienylcarbonyl)methyl]thiazoline hydrobromide and 64 parts of ethanol are added portion wise 3 parts of sodium borohydride (exothermic reaction). After the addition is complete, the whole is stirred and refluxed for one hour. The solvent is evaporated. The solid residue is dissolved in hydrochloric acid 4 N. After keeping at room temperature, it crystallizes again. The solid is filtered off and dissolved in water. The aqueous solution is rendered alkaline with ammonium hydroxide and extracted with chloroform. The chloroform extract is dried over magnesium sulfate and evaporated. The solid residue is recrystallized twice: first from 4-methyl-2-pentanone and once more from 400 parts of water. After drying in vacuum, DLl-2-(acetylimino)-3-[2-hydroxy-2-(2thienyl)ethyl]thiazoline is obtained; MP: 132.5°-133°C. A solution of 2 parts of DL-2-(acetylimino)-3-[2-hydroxy-2-(2thienyl)ethyl]thiazoline in 16 parts of thionylchloride and 45 parts chloroform is stirred and refluxed for one hour. After cooling the whole is extracted with water. The acid aqueous solution is separated, washed with toluene, alkalized with ammonium hydroxide solution and extracted with chloroform. The extract is dried over magnesium sulfate and evaporated. The oily residue is dissolved in 40 parts boiling 2-propanol. To this warm solution is added a warm solution of an equivalent quantity of oxalic acid dihydrate in 2-propanoL After cooling to room temperature, the precipitated oxalate is filtered off and dried in vacuum, yielding DL-5,6-dihydro-6-(2-thienyl)imidazo[2,1-b]thiazole oxalate; MP: 192°-193°C. A mixture of 6 parts DL-2-(acetylimno)-3-[2-hydroxy-2-(2thienyl)ethyl]thiazoline and 80 parts phosphoroxy-chloride is heated in a water-bath for 2 hours at a temperature of 100°C. On cooling, the reaction mixture is poured into water. The whole is alkalized with ammonium hydroxide solution and extracted with toluene. The extract is dried over magnesium sulfate and evaporated in vacuum. The oily residue is dissolved in 40 parts boiling 2-propanol. To this warm solution is added a warm solution of an equivalent quantity of oxalic acid dihydrate in 2-propanol. After cooling to room temperature, the precipitated salt is filtered off and dried in vacuum, yielding DL-5,6-dihydro-6-(2-thienyl)imidazo[2,1-b]thiazole oxalate; MP: 193°-194°C. An aqueous solution of this salt is alkalized with ammonium hydroxide and extracted with toluene. The extract is dried over magnesium sulfate and evaporated. The oily residue is crystallized from 12 parts xylene. The solid is filtered off and dried in vacuum, yielding DLl-5,6-dihydro-6-(2thienyl)imidazo[2,1-b]thiazole; MP: 58°-62°C. To a solution of 1.2 parts of DL-5,6-dihydro-6-(2-thienyl)imidazo[2,1b]thiazole in 24 parts acetone is added a slight excess of a solution of hydrogen chloride in 2-propanol. The oily precipitate solidifies on seeding with

Antrafenine

353

the solid hydrochloride salt and scratching. The salt is filtered off and dried, to yield DL-5,6-dihydro-6-(2-thienyl)imidazo[2,1-b]thiazole hydrochloride; M.P. 159°-160.5°C. References Raenmaekers A. et al.; US Patent No. 3,274,209; Sept. 20, 1966; Assigned to Janssen Pharmaceutica N.V., a corporation of Belgium

ANTRAFENINE Therapeutic Function: Analgesic Chemical Name: 2-(4'-m-Trifluoromethylphenylpiperazino)ethyl 2-(7'trifluoromethyl-4'-quinolylamino)benzoate Common Name: Structural Formula:

Chemical Abstracts Registry No.: 55300-29-3 Trade Name Stakane

Manufacturer Dausse

Country France

Year Introduced 1977

Raw Materials Allyl 2-(7'-trifluoromethyl-4'-quinolinylamino)benzoate 2-(4'-m-Trifluoromethylphenylpiperazino)ethanol Sodium Manufacturing Process A mixture of 18.65 g (0.05 mol) of allyl 2-(7'-trifluoromethy-4'quinolylamino)benzoate, 16.2 g (0.059 mol) of 2-(4'-mtrifluoromethylphenylpiperazino)ethanol, 150 ml of anhydrous toluene and 0.03 g of sodium is heated under reflux for 2 ½ hours, while the allyl alcohol formed during the reaction is slowly removed by distillation. A slight amount of insoluble matter is filtered off and the toluene is evaporated from the filtrate. The residue is dissolved in a mixture of methylene chloride and acetone (8:2) and this solution is passed through a silica column. Elution is carried out with the same mixture of solvents and the eluate is collected in 50

354

Antramycin

ml fractions. These fractions are examined by thin layer chromatography. Those which contain the desired almost pure ester are combined and the solvent is driven off from them. The residual product is triturated in a mixture of ether and petroleum ether, filtered off and dried. 16.8 g (yield 57%) of 2(4'-m-trifluoromethylphenylpiperazino)ethyl 2-(7'-trifluoromethyl-4'quinolylamino)benzoate, melting point 88° to 90°C, are thus isolated. References Merck Index 746 DFU 2 (12) 786 (1977) Kleeman and Engel p. 57 DOT 14 (2) 55 (1978) I.N. p. 94 Giudicelli, D.P.R.L., Najer, H., Manory, P.M.J. and Dumas, A.P.F.; US Patent 3,935,229; January 27, 1976; Assigned to Synthelabo

ANTRAMYCIN Therapeutic Function: Antineoplastic Chemical Name: 2-Propenamide, 3-(5,10,11,11a-tetrahydro-9,11-dihydroxy8-methyl-5-oxo-1H-pyrrolo[2,1-c][1,4]benzodiazepin-2-yl)-, (11R[2(E),11α11aβ])Common Name: Anthramycin; Antramycin; Refuin Structural Formula:

Chemical Abstracts Registry No.: 4803-27-4 Trade Name Anthramycin Antramycin

Manufacturer ZYF Pharm Chemical Onbio Inc.

Country -

Year Introduced -

-

-

Raw Materials Streptomyces sp. NRRL 1143 Bacto yeast extract Enzyme hydrolyzed casein

Bacto tryptone Bacto soytone Enzyme hydrolyzed soy protein

Antramycin

355

Manufacturing Process Several loopfuls of spores of Streptomyces sp. NRRL 1143 are transferred from a mature (2-3 day old) 45° stock agar slant to 100 ml of germination medium composed as follows in g/liter: Bacto tryptone Bacto yeast extract Bacto soytone Soluble starch Mannitol Magnesium sulfate·7H2O Ferrous ammonium sulfate·6H2O Zinc chloride Manganous chloride·4H2O Copper sulfate·5H2O Cobalt nitrate·6H2O Boric acid

5g 2g 2g 10 g 5g 200 mg 10 mg 2.1 mg 1.8 mg 0.3 mg 0.5 mg 0.6 mg

The medium is contained in a 1000 ml Pyrex Blake mottle. After inoculation the medium is incubated at 45°C with constant vigorous agitation, on a rotary shaker for 16 hours. During this period a vigorous growth of the organism ensues. The contents of two such incubated Blake bottles are pooled into a 500 ml Pyrex inoculum transfer bottle fitted with a tubulature at the bottom and containing 150 ml of sterile water. The entire contents of the inoculum transfer bottle are transferred to a 100gallon stainless steel fermentor, which is prepared for it as follows: To 25 gallons of clean tap water contained in a stainless steel fermentor fitted for controlled agitation, aeration, and temperature control are added the following inegredients: Potato starch Bacto yeast extract Enzyme hydrolyzed casein Enzyme hydrolyzed soy protein Aqueous extract of yeast Mannitol Magnesium sulfate·7H2O Ferrous ammonium sulfate·6H2O Zinc chloride Manganous chloride·4H2O Copper sulfate·5H2O Cobalt nitrate·6H2O Boric acid Dow Coming Silicone A emulsion

1500 g 2g 750 g 300 g 300 g 750 g 30 g 1.5 g 315 mg 270 mg 45 mg 75 mg 90 mg 2.5 g

When all the ingredients are dissolved the volume is brought to 40 gallons (150 liters) with tap water and the pH adjusted to 7.2 with about 60 ml of 5 N potassium hydroxide. The fermentor is then closed and the contents sterilized by being brought to a temperature of 120°C and maintained at that

356

Antramycin

temperature from 30-40 minutes. The batch is then cooled to 48°C and inoculated as described above. After inoculation the batch is aerated with 3 cubic feet per minute of sterile air and agitated at a shaft speed of 400 r.p.m., the while maintaining a temperature of 48°C. Foam is controlled by the addition, as needed, of a sterile 2.5% suspension of Dow Silieone Emulsion AF. About 3000 ml of defoamer suspension is used during the batch. Hourly samples are taken aseptically from the 12th hour on and assayed for in vitro potency. This batch reaches its maximum potency in 18-20 hours. The above process is repeated ten times, the broths obtained are combined, the pH is adjusted to 6, the combined broths are filtered, and the resulting filtrate is extracted countercurrently at the rate of 128 gallons per hour with about the same rate of butanol, in a 12" diameter by 11 ft. high Karr extraction column. A water backwash of 0.2 times the butanol rate is employed at the top of the extraction column to minimize the carry-over of water soluble components. The butanol extract is concentrated to approximately a 5% solution which comprises the feed to the center of a 3" diameter by 20 ft. high Karr fractional liquid extraction column. This column is operated at a water to butanol ratio of about 10 to 1, and the butanol extract contains the product. The butanol extract is concentrated by evaporation to a solution or paste containing about 5 to about 20% ent solids; then about 25 to about 50 volumes of n-hexane are added, and the resulting slurry filtered. The precipitated product is then vacuum-dried to give a solid compound. 7 g of the product prepared by the above process is dissolved in 350 ml of chloroform-isopropanol (1:1) which was previously equilibrated with water. This solution is introduced into the center of a one-inch diameter by twentyfoot high Karr extraction column at the rate of 0.5 ml/min. Simultaneously 60 ml/min of equilibrated aqueous phase is introduced at the bottom of the column and 14.6 ml/min of equilibrated solvent phase is introduced at the top of the column. Most of the product is extracted into the aqueous phase leaving the top of the column. The aqueous phase is re-extracted countercurrently in a one-inch diameter by ten-foot high extraction column employing a 1:1 isopropanol-chloroform solvent at a solvent to water ratio of 1:1. The product passes into the isopropanol-chloroform solvent, which leaves at the bottom of the extraction column. This solution is concentrated to 58 ml, filtered, and then treated with 2.9 liters of technical hexane to precipitate the product. The product is filtered and dried. The dried product, which is 90% pure is crystallized from acetone to yield a highly active purified material. 20 g of the product above was distributed between 120 ml each of upper and lower phases of a solvent system consisting of isopropanol;chloroform: water (1:1:2). The phases were then introduced into the first three tubes of a 200tube Craig countercurrent distribution apparatus and run at room temperature for 197 transfers. The upper and lower phases of tubes 45 to 75 were combined, the organic phase evaporated at a temperature below 35°C in vacuum and the residue added to the corresponding aqueous phase, and the aqueous phase lyophylized. The lyophylized residue was crystallized from acetone to yield a purified antibiotic antramycin. Yellow prisms decomposed at 188°-194°C; [α]

25 D

= +930° (DMF).

Apalcillin sodium

357

References Berger J. et al.; US Patent No. 3,361,742; January 2, 1966; Assigned to Hoffmann-La Roche Inc.,Nutley, N.J.,a corporation of New Jersey

APALCILLIN SODIUM Therapeutic Function: Antibacterial Chemical Name: 6-[[[[(4-Hydroxy-1,5-naphthyridin-3-yl)carbonyl] amino]phenylacetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0]heptane-2-carboxylic acid sodium salt Common Name: D-α-(4-Hydroxy-1,5-naphthyridine-3-carbonamido) benzylpenicillin sodium Structural Formula:

Chemical Abstracts Registry No.: 58795-03-2; 63469-19-2 (Base) Trade Name Lumota

Manufacturer Thomae

Country W. Germany

Year Introduced 1982

Raw Materials Phenacyl-6-aminopenicillate hydrochloride D-Phenylglycyl chloride hydrochloride 4-Hydroxy-1,5-naphthyridine-3-carboxylic acid N-succinimide ester Sodium bicarbonate Sodium thiophenoxide Triethylamine Manufacturing Process (a) Preparation of 6-D-α-aminobenzylpenicillin phenacyl ester: To a suspension of phenacyl 6-aminopenicillanate hydrochloride (1.85 g) and Dphenylglycyl chloride hydrochloride (1.29 g) in dichloromethane (20 ml), sodium bicarbonate (1.05 g) was added, and the resultant mixture was stirred

358

Apaxifylline

while cooling with ice for 6 hours. The reaction mixture was filtered to eliminate the by-produced sodium chloride. The filtrate was admixed with isopropanol and concentrated under reduced pressure by the aid of a rotary evaporator. After the evaporation of dichloromethane, the precipitate was collected by filtration to give the objective compound in the form of the hydrochloride (2.19 g) MP 142° to 148°C (decomposition). (b) Preparation of D-α-(4-hydroxy-1,5-naphthyridine-3carbonamido)benzylpenicillin: To a solution of 6-D-α-aminobenzylpenicillin phenacyl ester (hydrochloride) (2.01 g) and triethylamine (0.808 g) in dimethylformamide (20 ml), 4-hydroxy-1,5-naphthyridine-3-carboxylic acid Nsuccinimide ester [MP 310° to 311°C (decomposition)] (1.15 g) was added while cooling with ice, and the resultant mixture was stirred for 1 hour. Stirring was further continued at room temperature for 2 hours. After cooling with ice, 1% sodium bicarbonate solution (100 ml) was added thereto. The precipitated crystals were collected by filtration, washed with water and dried over phosphorus pentoxide to give D-(α-4-hydroxy-1,5-naphthyridine-3carboxamido)benzylpenicillin phenacyl ester (2.17 g). The above product was dissolved in dimethylformamide (65 ml), sodium thiophenoxide (0.89 g) was added thereto, and the resultant mixture was stirred at room temperature for 1 hour. To the resultant mixture, acetone (650 ml) was added, and the separated crystals were collected by filtration and washed with acetone and ether in order to give the objective compound in the form of the sodium salt (1.3 g). In the above procedure, the use of 4-hydroxy-1,5-naphthyridine-3-carbonyl chloride in place of 4-hydroxy-1,5-naphthyridine-3-carboxylic acid Nsuccinimide ester can also afford the same objective compound as above. The use of sodium thio-n-propoxide in place of sodium thiophenoxide can also give the objective compound in the form of the sodium salt. References Merck Index 748 DFU 4 (3) 225 (1979) DOT 19 (2) 110 (1983) I.N. p. 94 Yamada, H., Tobiki, H., Nakatsuka, I., Tanno, N., Shimago, K. and Nakagome, T.; US Patent 4,005,075; January 25, 1977; Assigned to Sumitomo Chemical Co., Ltd.

APAXIFYLLINE Therapeutic Function: Adenosine A1-antagonist, Nootropic Chemical Name: (S)-3,7-Dihydro-8-(3-oxocyclopentyl)-1,3-dipropyl-1Hpurine-2,6-dione Common Name: Apaxifylline

Apaxifylline

359

Structural Formula:

Chemical Abstracts Registry No.: 151581-23-6 Trade Name Apaxifylline

Manufacturer Boehringer Ingelheim/Upjohn

Country -

Year Introduced -

Raw Materials 3-Oxocyclopentancarboxylic acid methyl ester Carbonyldiimidazole 1,6-Diamino-1,3-di-n-propyluracil Manufacturing Process 1,3-Dipropyl-8-(3-oxocyclopentyl)xanthyne: 1). 100 g 3-oxocyclopentancarboxylic acid methyl ester (0.7 moles) was heated with 1000 ml of 2 M hydrochloric acid to reflux for 10 hours. On cooling the solution was evaporated in vacuum. Residual water was removed by azeotropic dehydratation. The residue was distilled in high vacuum to give 3-oxocyclopentancarboxylic acid as colorless oil, b.p.: 116°-121°C/0.002 mm; yield 74.0 g (82 %). 2). 11.6 g carbonyl diimidasole was added to 8.8 g 3oxocyclopentancarboxylic acid (0.072 moles) in 240 ml methylene chloride at 20°-25°C and stirred for 2 hours at room temperature. Then 16.0 g 1,6diamino-1,3-di-n-propyluracil (0.072) at 20°-25°C was added and was stirred 3 hours at room temperature. The mixture was evaporated in vacuum to dryness. The residue oil was diluted with 3200 ml water, 35 g of calcium hydroxide was added and all taken was heated at 80°C for 0.5 hour by stirring. The mixture was cooled to 5°C, acidified with pH 1-2 with hydrochloric acid and extracted with CH2Cl2 (3x100 ml). The organic phase was washed with 1x100 ml water and dried over magnesium sulfate. The solution was purified with of 350 g silica gel S 160. CH2Cl2 : CH3OH (99:1) was used as eluent. Refined residue was evaporated and treated with 100 ml ether. 11.5 g 1,3-dipropyl-8-(3-oxocyclopentyl)xanthyne (apaxifylline) obtained (50.2 %). MP: 164-168°C. References Kufter-Muuhl U. et al.; Europe Patent No. 0,374,808; Dec. 18, 1989; Boehringer Ingelheim International G.M.B.H.

360

Apazone

APAZONE Therapeutic Function: Antiarthritic Chemical Name: 5-(Dimethylamino)-9-methyl-2-propyl-1H-pyrazolo[1,2a][1,2,4]benzotriazine-1,3(2H)-dione Common Name: Azapropazone Structural Formula:

Chemical Abstracts Registry No.: 113539-598 Trade Name Prolixan Prolixan Cinnamin Rheumox Prolixan Prolixan Prolixan Prodisan Prodisan Prolix Prolixano Rheumox Xani

Manufacturer Siegfried Siegfried Nippon Chemiphar Robins Logeais Malesci Embil Embil Roche Roche Leo Robins Farmakos

Country W. Germany Switz. Japan UK France Italy Turkey Turkey US Yugoslavia

Year Introduced 1970 1970 1971 1976 1976 1977 -

Raw Materials 3-Dimethylamino-(1,2-dihydro1,2,4-benzotriazine) Diethyl propyl malonate Sodium Triethylamine

3-Dimethylamino-1,2,4benzotriazine oxide Propyl malonyl chloride Hydrogen

Manufacturing Process The following describes two alternatives for the synthesis of the closely related butyl analog.

Apicycline

361

Alternative (a): In a three-neck flask with descending condenser to 3.8 grams of 3-dimethylamino-(1,2-dihydro-1,2,4-benzotriazine) are added 0.52 gram metallic sodium, dissolved in a small volume of absolute alcohol, 4.5 g of diethylbutylmalonate (diethylpropylmalonate for Apazone) and 15 ml of xylene, in a nitrogen atmosphere. The mixture is heated for 2 hours to 70°C, then for 3 hours to 110-130°C and for one more hour to 150°C, slowly distilling off the alcohol and most of the xylene. To the resulting light brown colored mass are added 200 ml of water. The resulting solution is extracted twice with ether or benzene and afterwards acidified with HCl. Yield 3.6 g of 1,2-butylmalonyl-3-dimethylamino-(1,2-dihydro-1,2,4-benzotriazine). After crystallization from alcohol the melting point is 189-190°C. Alternative (b): 3-Dimethylamino-1,2,4-benzotriazine oxide is shaken in the presence of Raney nickel in 15 volume parts of an alcohol-acetic acid (9:1) mixture in a hydrogen atmosphere. The mixture absorbs 2 mols hydrogen per 1 mol starting material. Hydrogenation can also be effected using a palladium catalyst with a suitable solvent. After reduction it is filtered on a Buchnerfunnel through a Hyflow-layer and the solvent is evaporated in vacuum under nitrogen. The residue is dissolved in 20 parts of water-free dioxane and treated at 60°C with the calculated amount of butylmalonyl chloride (propyl malonyl chloride for Apazone) (1 mol/mol) and triethylamine (2 mol/mol). The separated triethylamine hydrochloride is filtered, the dioxane-solution is evaporated under vacuum to dryness, and the residue is dissolved in 7 volume parts of boiling acetic acid. After cooling, the product separates in lightly yellowish crystals. They are dissolved in the calculated amount of 0.25 N NaOH, treated with a small amount of carbon and precipitated with HCl. Melting point of the purified product is 187°C. Yield: approximately 60% of the theoretical amount. References Merck Index 750 Kleeman and Engel p. 66 OCDS Vol. 2 p. 475 (1980) I.N. p. 110 Molnar, I., Wagner-Jauregg, T., Jahn, U. and Mixich, G.; US Patent 3,349,088; October 24, 1967; Assigned to Siegfried AG, Switzerland Molnar, I., Wagner-Jauregg, T., Jahn, U. and Mixich, G.; US Patent 3,482,024; December 2, 1969; Assigned to Siegfried AG.

APICYCLINE Therapeutic Function: Antibiotic Chemical Name: α-(4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro3,6,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2naphthacenecarboxamido)-4-(2-hydroxyethyl)-1-piperazineacetic acid Common Name: Apicycline; Traserit Chemical Abstracts Registry No.: 15599-51-6

362

Apicycline

Structural Formula:

Trade Name Travert Travert

Manufacturer Country Baxter Pharmacia Upjohn -

Year Introduced -

Raw Materials Glyoxylic acid monohydrate N-(2-Hydroxyethyl)piperazine| Tetracycline base trihydrate Manufacturing Process Glyoxylic acid monohydrate (1.96 g, 20 mrnoles) is dissolved in 200 ml of methanol, and a solution of 2.60 g (20 mmoles) of N-(2-hydroxyethyl) piperazine in 50 ml of methanol is slowly added thereto with stirring. Stirring is maintained for 15 minutes and the medium is cooled to 5°C. There is then added 10.2 g (20 mmoles) of tetracycline base trihydrate and the reaction medium is maintained for 20 hours at 5°C under stirring. After that reaction time, the solution is concentrated up to 50 ml and 0.25 liter of acetone is added for precipitating a yellowish product which is filtered and dried to yield N-[(carboxy)(4-β-hydroxyethylpiperazino)methyl] tetracycline (apicycline). When tested for antibiotic potency against Bacillus cereus var. mycoides ATCC 9634 (diffusion method), the product is shown to present an antibiotic potency equivalent to 97% of the tetracycline present therein. Anhydrous tetracycline base (0.90 g, 2 mmoles) is dissolved in 30 ml of nbutanol at about 40°C. There is then added thereto under stirring a solution of 0.26 g (2 mmoles) of N-(2-hydroxyethyl)piperazine in 10 ml of butanol and 0.191 g (2 mmoles) of glyoxylic acid monohydrate. A precipitate appears after a few minutes and the suspension is maintained for six hours under stirring and at room temperature. After that reaction time, precipitation is completed by addition of 120 ml of ether. The yellowish precipitate is filtered and dried to yield N-[(carboxy)(4-βhydroxyethylpiperazino)methyl]tetracycline (apicycline). Yellow, amorphous powder with slight amine odor, MP: 144.5°C (dec). Freely solves in water. [α]D =-123° (c = 0.5 in methanol); [α]D =-133° (c = 0.5 in water).

Apomorphine hydrochloride

363

The pH value of a 2% aqueous solution of this product is 6.2. When tested for antibiotic potency against Bacillus cercus var. mycoides ATCC 9634 (diffusion method), the product is shown to present an antibiotic potency equivalent to 95% of the tetracycline present therein. References Rondelet J.; US Patent No. 3,456,007; July 15, 1969; Assigned to Recherche et Industrie Therapeutiques R.I.T., Genval, Belgium, a corporation of Belgium

APOMORPHINE HYDROCHLORIDE Therapeutic Function: Emetic, Expectorant, Hypnotic, Antiparkinsonian, Dopamine agonist Chemical Name: 4H-Dibenzo(de,g)quinoline-10,11-diol, 5,6,6a,7-tetrahydro6-methyl-, (R)-, hydrochloride Common Name: Apafinum; Apomorfin; Apomorphine Structural Formula:

Chemical Abstracts Registry No.: 314-19-2; 58-00-4 (Base) Trade Name Apomorphine hydrochloride Apofin Apofin Apokyn Apokyn Apokinon Apomine Britaject Ixense Uprima

Manufacturer Nastech Pharmaceuticals Company, Inc. Chiesi Farmaceutici Amro Trust Company (Suisse) SA Mylan Bertek Pharmaceuticals Bertek Pharmaceuticals Aguettant Faulding Britannia Takeda Abbott Laboratories

Country -

Year Introduced -

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364

Apovincamine

Raw Materials Morphine Phosphoric acid Hydrogen hydrochloride Manufacturing Process 2 Methods of producing of apomorphine 1. The apomorphine was obtained by dehydratation of morphine at heating to 120°C in the presence phosphoric acid and rendering of HCl gas over reaction mixture. 2. The morphine was converted to β-chloromorphine and then to dichlorodihydrodesoxymorphine at heating to 140°-150°C in the presence hydrochloric acid. Then apomorphine is obtained by dehydratation of dichlorodihydrodesoxymorphine. References Chaletsky A.M.; Pharmaceutical chemistry, Medicina, L., 1966, 761p. Belikov V.G.; Pharmaceutical chemistry, Pyatigorsk, 2003, 713p. Fiser L., Fiser M.; The chemistry of natural compounds of phenantren line. 1953, 656 p.

APOVINCAMINE Therapeutic Function: Vasodilator Chemical Name: Eburnamenine-14-carboxylic acid methyl ester, (3α,16α)Common Name: Apovincamine Structural Formula:

Chemical Abstracts Registry No.: 4880-92-6 Trade Name Apovincamine

Manufacturer GC Promochem

Country -

Year Introduced -

Apraclonidine hydrochloride

365

Raw Materials Vincamine Tartaric acid, dibenzoate, (-)Manufacturing Process Apovincamine is semisynthethetic derivative of (+)-vincamine. Vincamine is alkaloid of Vinca minor. Alcoloid of Tabernaemontana rigida (Apocynaceae) also is used as raw material for preparing of apovincamine. (+)- Vincamine was transformed into oxime ester by reaction with NaNO2 in acetic acid at 0°C -(+/-)-methyl-3-((12bR)-1-ethyl-1,2,3,4,6,7,12,12b-octahydroindolo[2,3a]quinolizin-1-yl)-2-(hydroxyimino)propanoate, which was resolved on the isomers with dibenzoyl D-tartratic acid. (-)-Methyl 3-((12bR)-1-ethyl1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizin-1-yl)-2(hydroxyimino)propanoate was re-crystallized from methanol to afford (-)methyloxime ester, MP: 195°C. 2 g of above oxime methyl ester was heated in mixture of methanol (37.5 ml) and conc. H2SO4 (13.5 ml) on water bath for 1 hour. The solution was poured into ice-water (80 ml), basified with conc. NH4OH to pH 9, and extracted with CH2Cl2 (3x20 ml). The combined extracts were dried (MgSO4), filtered, evaporated in vacuum and the residue was re-crystallized from MeOH (5 ml) to yield 1.32 g (72.5%) of (+)-apovincamine, MP: 160°-162°C. References Szabo L. et al., Tetrahedron; V. 39, No 22, pp 3737-3737; 1983

APRACLONIDINE HYDROCHLORIDE Therapeutic Function: Antiglaucoma Chemical Name: 1,4-Benzenediamine, 2,6-dichloro-N1-(4,5-dihydro-1Himidazol-2-yl)-, hydrochloride Common Name: p-Aminoclonidine hydrochloride; Apraclonidine hydrochloride; Aplonidine hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 73218-79-8; 66711-21-5 (Base)

366

Apraclonidine hydrochloride

Trade Name Alfadrops Iopidine

Manufacturer Cipla Limited Alcon

Country India -

Year Introduced -

Raw Materials 2,6-Dichloro-4-nitroaniline t-Butyl methyl ether Methanol Ethylenediamine Hexane

Nickel Raney Thiophosgene 2-Propanol Toluene

Manufacturing Process The preparation of p-aminoclonidine (apraclonidine) consists of 6 steps. In the first step 2,6-dichloro-4-nitroaniline was converted to 2,6-dicloro-4nitrophenylisothiocyanate by addition of thiophosgene in toluene according to the method described in Great Britain Patent No.: 1,131,780 (Beck et al.). The second step involved the conversation of 2,6-dichloro-4-nitrophenylisothiocyanate to 1-(2-aminoethyl)-3-(2,6-dichloro-4-nitrophenyl)-thiourea ethylenediamine solvate. The solution of 2,6-dicloro-4-nitrophenylisothiocyanate (432 g, 1.73 mol) in 2 L of toluene was added dropwise to the cooled (0°C) solution ethylenediamine (244 ml, 3.66 mol, 2.1 eq.) in toluene (4 L) under a nitrogen atmosphere. 2-Propanol (1 L) was added and after 5 minutes, the solid was collected by filtration, washed with 20% 2propanol/toluene, and dried to a constant weight of 602 g (94%). This product is hygroscopic, mp 120°C (dec.). The third step was the conversation of 1-(2-aminoethyl)-3-(2,6-dichloro-4nitrophenyl)-thiourea ethylenediamine solvate to 2-[(2,6-dicloro-4nitrophenyl)imino]imidazoline ethylenediamine solvate. (500 g, 1.35 mol) of above prepared thiourea solvate was suspended with toluene (4 L) and was heated at reflux for 15 hours. The mixture was cooled to 23°C and 1 M aqueous hydrochloric acid (4 L) was added. After stirring for 10 min the biphasic mixture was filtered to remove a sticky insoluble material. The aqueous phase was neutralized to pH=7.0 using 50% NaOH. After stirring for 1 hour the yellow solid was collected by filtration, washed with water (4 L) and t-butyl methyl ether (2 L) and dried in air to constant weight of 195 g (52%), m.p. 289-292°C. The fourth step was the conversation of 2-[2,6-dichloro-4-nitrophenyl) imino]imidazoline (150 g, 0.55 mol) in methanol (1,5 L) to 2-[(2,6-dichloro-4aminophenyl)imino]imidazoline by hydrogen with 30 g Raney nickel catalyst at 23°C for 22 hours. After removing the catalyst hydrogen chloride gas was bubbled into solution until pH of the reaction mixture was 1.0. The solvent was rotary removed in vacuum and the residual solid was slurried with 2propanol (1 L). The solvent was again removed by rotary evaporation, the cream solid was triturated with 2-propanol (600 ml). After aging for 1 hour, the solid was collected by filtration, washed with 2-propanol and t-butyl methyl ether, and dried for 15 hours at 6°C and t-butyl methyl ether, and dried for 15 hours at 60°C and 20 mm Hg. Yield of dihydrochloride 167 g

Aprindine hydrochloride

367

(96%), mp 260°C (dec.). The dihydrochloride was converted to the monochloride (step 5) by adding 5 M aqueous sodium hydroxide dropwise to pH=6.5 at 5°C for 2 hours. Yield of hydrochloride 87%. The last step was recrystallization of product from water. The recrystallized material had m.p. 300°C. Calculated for: C9H10Cl2N4HCl: C, 38.39; H, 3.94; N, 19.90; Cl, 37.78. Found: C, 38.36; H, 3.91; N, 19.83; Cl, 37.77. References Councel, J. Med Chem., v 30, p.1214 (1987) Pierce D.R., Dean W.D., Deason M.E.; Patent WO9521818; 17.08.1995; Assigned to Alcon Laboratories Inc.

APRINDINE HYDROCHLORIDE Therapeutic Function: Antiarrhythmic Chemical Name: N-[3-(Diethylamino)propyl]-N-phenyl-2-indanamine hydrochloride Common Name: Structural Formula:

Chemical Abstracts Registry No.: 33237-74-0; 37640-71-4 (Base) Trade Name Amidonal Fiboran Fibocil Fiboran Ritmusin

Manufacturer Madaus Sedaph Lilly Christiaens Gebro

Country W. Germany France US Belgium Austria

Year Introduced 1976 1977 -

Raw Materials N-Phenyl-2-aminoindane Sodium hydroxide Hydrogen chloride

γ-Chloropropyl diethylamine Sodium amide

368

Aprobarbital

Manufacturing Process 104.6 g (0.5 mol) N-phenyl-2-aminoindane and 2.5 liters benzene are introduced into a reaction vessel of 5 liters, under an atmosphere of nitrogen. 37 g (0.95 mol) sodium amide are added and the mixture is stirred during 3 hours at room temperature. 119.7 g (0.8 mol) of γ-chloropropyl diethylamine are then quickly added. After agitation during 1 hour at room temperature, the reaction mixture is refluxed and stirred under nitrogen during 21 hours. The mixture is then allowed to cool and poured onto ice. The obtained aqueous phase is extracted by means of 500 cm3 of benzene. The benzene extract is washed two times with 200 cm3 of water and the benzene is then evaporated. The residue is treated with 500 cm3 of hydrochloric acid (2 N). The obtained solution is evaporated to dryness and the oily residue is recrystallized from ethanol. 176.9 g (yield 89.4%) of dihydrochloride of N-phenyl-Ndiethylaminopropyl-2-aminoindane are obtained, MP 208° to 210°C. The dihydrochloride is converted into monohydrochloride by dissolving 26.36 g (0.066 mol) of dihydrochloride into 158 cm3 of water, adding drop by drop a suitable amount (0.066 mol) of caustic soda (1 N), evaporating the aqueous solution to dryness, drying by means of benzene, filtering the formed sodium chloride (3.8 g) and crystallizing the cooled obtained benzene solution. 22.6 g (95%) of monohydrochloride are obtained, MP 120° to 121°C. References Merck Index 776 Kleeman and Engel p. 58 OCDS Vol. 2 p. 208 DOT 10 (4) 120 (1974) REM p. 860 Vanhoof, P. and Clarebout, P.; British Patent 1,321,424; June 27, 1973; Assigned to Manufacture de Produits Pharmaceutiques A. Christiaens, SA

APROBARBITAL Therapeutic Function: Sedative, Hypnotic Chemical Name: 5-Allyl-5-isopropylbarbituric acid Common Name: Allopropylbarbital; Allylcarbamidum; Allypropymal; Aprobarbital; Aprobarbitone Chemical Abstracts Registry No.: 77-02-1 Raw Materials Isopropylbarbituric acid

Aprofene

369

Sodium hydroxide Allyl bromide Structural Formula:

Trade Name Alurate Aprobarbital Isonal

Manufacturer Roche Arocor Holdings Inc. Leo

Country -

Year Introduced -

Manufacturing Process 170 parts of isopropylbarbituric acid are mixed with 500 parts of water and dissolved by adding 135 parts of a 30 percent of the solution of sodium hydroxide. To this solution are added 130 parts of 130 parts of allylbromide. An emulsion obtained is stirred at an inner temperature of about 25°C. The reaction is at first accompanied by a slight development of heat. After 12 hours the reaction is brought to a close. When cooled down the isopropylallylbarbituric acid is drawn off. The yield is more than 80 percent of the theoretically calculated quantity. By crystallization from diluted alcohol the pure isopropylallylbarbituric acid is obtained in colorless crystals of the melting point 137-138°C. References Merck Index, Monograph number: 794, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. Kurz F. and Kappeler V.W.; US Patent No. 1,444,802; Feb. 13, 1923; Assigned to Ernst Preiswerk

APROFENE Therapeutic Function: Spasmolytic Chemical Name: Benzeneacetic acid, α-methyl-α-phenyl-, 2-(diethylamino) ethyl ester Common Name: Aprofene; Aprophene Chemical Abstracts Registry No.: 3563-01-7

370

Aprotinin

Structural Formula:

Trade Name Aprofene Aprofene

Manufacturer ZYF Pharm Chemical ICN Pharmaceuticals

Country -

Year Introduced -

Raw Materials Diphenylpropionic acid Thionyl chloride Diethylaminoethanol Diphen (CIS prep.) Manufacturing Process 32 parts of α,α-diphenylpropionic acid chloride (made from diphenylpropionic acid and thionyl chloride, B.P./12 mm 170°C) are mixed with 50 parts of diethylaminoethanol. The mixture is heated for two hours to 150°-160°C. It is then suspended in dilute hydrochloric acid. The solution is treated with ether. After separation of the aqueous solution, the base is precipitated with sodium hydroxide solution and suspended in ether. After removal of the ether by distillation, the residue is distilled in a vacuum. α,α-Diphenylpropionic acid β-diethylaminoethyl ester is obtained as a thick oil by distilling under 2 mm pressure at 180°-185°C. It is readily soluble in diluted acids. References Wander A.; G.B. Patent No. 641,573; Dec. 19, 1947; Switzerland

APROTININ Therapeutic Function: Proteinase inhibitor Chemical Name: Trypsin inhibitor, pancreatic basic Common Name: Aprotinin; Frey inhibitor; Kallikrein-trypsin inhibitor Chemical Abstracts Registry No.: 9087-70-1

Aprotinin

371

Structural Formula:

Trade Name Trasylol Antagosan Antilysin Spofa Apronin Aprotimbin Contrykal Gordox Iniprol Inibil Kallikrein-trypsin inhibitor Kontrikal Trasylol

Manufacturer Bayer Hoechst Marion R. d.o.o Spofa Chandra Bhagat Pharma Pvt. Ltd. Biochemie GmbH AWD GmbH and Co.KG Gedeon Richter Sanofi-Winthrop Sclavo Bayer

Country -

Year Introduced -

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Pliva d. d. Bayer

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Raw Materials Parotid of cattle Acetic acid

Acetone Ammonia

372

Aptazapine maleate

Manufacturing Process 1 kg of parotid of cattle, which were freed of fat and flesh are comminuted in a meat chopper and twice extracted with 5 L of acetone. The acetone was removed as far as possible by sucking off and the moist material is digested for 2.5 hours in 1.2 L of 1 N acetic acid and 2.8 L of 96% ethanol at 50°C. The filtrate containts about 230.000 inactivator units. The alcoholic solution is concentrated to 1.2 L by evaporating in vacuo and shaken with an equal amount of ether. Dark coloring matters and residues of fat are thus dissolved. The aqueous phase is now mixed with acetone until a precipitate occurs and the dissolved in dilute acetic acid. The solution is brought to a weakly alkaline pH by addition of ammonia. It is then centrifuged and the inactivator is precipitated with five times the amount of ethanol. The yield amounts to about 180.000 kallikrein inactivator units in 0.4-0.5 g of substance. References Kraut H., Koerbel R.; US Patent No. 2,890,986; June 16, 1959; Assigned to Farbenfabriken Bayer Aktiengesellschaft, Leverkusen, Germany, a corporation of Germany

APTAZAPINE MALEATE Therapeutic Function: Antidepressant Chemical Name: 2H,10H-Parazino[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine, 1,3,4,14b-tetrahydro-2-methyl-, maleate (1:1) Common Name: Aptazapine maleate Structural Formula:

Chemical Abstracts Registry No.: 71576-40-4 (Base); 71576-41-5 Trade Name

Manufacturer

Country

Year Introduced

Aptazapine maleate

ZYF Pharm Chemical

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Aptazapine maleate

373

Raw Materials Diborane N-Potassium phthalimide Hydrazine hydrate Chloroacetonitrile Platinum oxide Palladium on charcoal

Maleic acid o-Nitrobenzyl chloride 2,5-Dimethoxytetrahydrofuran N-Methylbenzylamine Diethyl oxalate

Manufacturing Process To the suspension of 12.8 g of 2-methyl-3,4-dioxo-1,3,4,14b-tetrahydro-10Hpyrazino[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine in 460 ml of tetrahydrofuran, 200 ml of 1-molar diborane in tetrahydrofuran are added while stirring and cooling with ice. The mixture is refluxed for one hour, again cooled and combined with 25 ml of acetic acid. It is evaporated, the residue taken up in 50 ml of 30% aqueous sodium hydroxide and the mixture extracted with methylene chloride. The extract is dried, evaporated, the residue dissolved in diethyl ether, the solution filtered and the filtrate evaporated, to yield the crude 2-methyl-1,3,4,14b-tetrahydro-10Hpyrazino[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine. It is triturated with ethyl acetate-diethyl ether, chromatographed on 70 g of silica gel and eluted with methanol-chloroform (1:9). The eluate is evaporated and the residue salified. 9.7 g thereof are dissolved in the minimum amount of isopropanol and the solution acidified with a concentrated solution of 4.45 g of maleic acid is isopropanol. The precipitate formed is collected and recrystallized from methanol-diethyl ether, to yield the corresponding mono-maleate melting at 180°-182°C. The starting material is prepared as follows: the mixture of 54.0 g of Npotassium phthalimide, 50.0 g of o-nitrobenzyl chloride and 120 ml of dimethylformamide is refluxed for 3 hours and poured into 900 ml of icewater while stirring. After 30 minutes, it is filtered, and the residue washed with water, to yield the N-o-nitrobenzyl-phthalimide melting at 190°-209°C. The mixture of 70.0 g thereof, 14.6 g of hydrazine hydrate and 600 ml of ethanol is refluxed for 4 hours and combined with 50 ml of concentrated hydrochloric acid. After 30 minutes, it is cooled to room temperature, filtered and the residue washed with water. The filtrate is concentrated, the aqueous concentrate filtered and the filtrate basified with 3 N aqueous sodium hydroxide. It is extracted with diethyl ether, the extract dried and evaporated, to yield the o-nitrobenzylamine. To the solution of 7.6 g thereof in 25 ml of glacial acetic acid, 6.6 g of 2,5dimethoxytetrahydrofuran are added and the mixture is refluxed for one hour. It is evaporated, the residue poured into ice water and the mixture extracted with ethyl acetate. The extract is washed with saturated aqueous sodium bicarbonate, dried and evaporated. The residue is taken up in diethyl ether, the solution decolorized with charcoal, filtered and evaporated, to yield the 1(o-nitrobenzyl)pyrrole. Through the mixture of 13.42 g thereof, 140 ml of diethyl ether and 6.85 ml of chloroacetonitrile, hydrogen chloride is bubbled while stirring and cooling in

374

Aptiganel hydrochloride

an ice-salt bath. The saturated mixture is stirred at room temperature overnight, filtered and the residue suspended in 100 ml of water. It is extracted 3 times with 100 ml of ethyl acetate, warmed on the steam bath while stirring until all is dissolved, and the solution evaporated, to yield the 1o-nitrobenzyl-2-chloroacetylpyrrole. To the solution of 16.2 g thereof in 450 ml of ethanol, 14.10 g of N-methylbenzylamine are added and the mixture is refluxed for 3 hours. It is evaporated, the residue taken up in methylene chloride, the solution washed with saturated aqueous sodium carbonate dried, filtered and evaporated. The residue is triturated with diethyl ether, to yield the 1-(o-nitrobenzyl)-2-(Nmethyl-N-benzylaminoacetyl)pyrrole. The solution of 3.0 g thereof in 30 ml of glacial acetic acid is hydrogenated over 100 mg of platinum oxide at 2.7 atm and room temperature until the theoretical amount of hydrogen has been absorbed. It is filtered, the filtrate evaporated, the residue taken up in methylene chloride-diethyl ether and the solution washed with saturated aqueous sodium bicarbonate. It is dried, evaporated, the residue chromatographed on 30 g of silica gel and eluted with methanol-chloroform (1:9), to yield the 11-(N-methyl-N-benzylaminomethyl)10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine melting at 147°-149°C. The solution of 500 mg thereof in 35 ml of ethanol and 5 ml of glacial acetic acid is hydrogenated over 250 mg of 5% palladium on charcoal at 2.7 atm and 40°C for 7 hours. The mixture is filtered, the filtrate evaporated and the residue taken up in methylene chloride. The solution is washed with saturated aqueous sodium carbonate, the aqueous phase extracted with methylene chloride and the combined organic solutions dried and evaporated, to yield the 11-(N-methylaminomethyl)-10,11-dihydro-5H-pyrrolo[2,1c][1,4]benzodiazepine. The mixture of 300 mg thereof and 232 mg of diethyl oxalate is slowly heated to 140°C during 45 minutes and to 180°C during 15 minutes, at which temperature it is maintained for 30 minutes. It is cooled, diluted with benzene, chromatographed on silica gel and eluted with methanol-chloroform (1:9), to yield the 2-methyl-3,4-dioxo-1,3,4,14b-tetrahydro-10H-pyrazino[1,2a]pyrrolo[2,1-c][1,4]benzodiazepine melting at 178°-179°C. In practice it is usually used as maleate salt. References Wasley J.W.F., Chatham; US Patent No. 4,316,900; February 23, 1982; Assigned to Ciba-Geigy Corporation, Ardsley, N.Y.

APTIGANEL HYDROCHLORIDE Therapeutic Function: NMDA antagonist

Aptiganel hydrochloride

375

Chemical Name: N-(3-Ethylphenyl)-N-methyl- N'-1-naphthalenylguanidine monohydrochloride Common Name: Cerestat; Aptiganel hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 137160-11-3 Trade Name Aptiganel Cerestat

Manufacturer Oregon State University Cambridge NeuroScience

Country -

Year Introduced -

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Raw Materials m-Ethylphenylcyanamide Methyl iodide Sodium hydroxide

Sodium hydride 1-Aminonaphthalene Hydrochloric acid

Manufacturing Process A solution of m-ethylphenylcyanamide (1.46 g, 10 mmol) and sodium hydride (480 mg, 20 mmol, prewashed with hexane) in anhydrous THF (10 ml) was heated at 80-85°C for 2.5 hours. After it was allowed to cool to room temperature, methyl iodide (3.5 g, 25 mmol) was added and stirring continued at room temperature for 2 hours. Methanol (10 ml) followed by water (20 ml) was added and the reaction mixture was extracted with dichloromethane (3x25 ml). Concentration of the organic layer followed by flash chromatography on SiO2 afforded N-(m-ethylphenyl)-N-methylcyanamide (960 mg, 60%) as a colorless liquid: IR (film): 2220, 3400cm-1. A mixture of m-ethylphenyl-N-methylcyanamide (520 mg, 3.25 mmol) and 1aminonaphthalene hydrochloride (508 mg, 3.25 mmol) was placed in a preheated oil bath at 160°C for 3 hours and then allowed to cool to room temperature. The resulting solid was taken into dichloromethane and washed with 10% sodium hydroxide solution. The organic layer was concentrated and the resulting residue was dissolved in absolute ethanol (2 ml) and treated with dilute hydrochloric acid. It was concentrated and the solid was twice

376

Aranidipine

recrystallized from absolute ethanol-ether to give N-(1-naphthyl)-N'-(methylphenyl)-N'-methylguanidine hydrochloride (403 mg, 37%) as off-white needles, melting point 223-225°C. References Weber Eckard, Keana John F. W.; US Patent No. 5,262,568; November 16, 1993; Assigned to State of Oregon (Portland, OR)

ARANIDIPINE Therapeutic Function: Antihypertensive Chemical Name: 3,5-Pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-4(2-nitrophenyl)-, methyl 2-oxopropyl ester Common Name: Aranidipine; Asanidipine Structural Formula:

Chemical Abstracts Registry No.: 86780-90-7 Trade Name Aranidipine

Manufacturer Shiono Chemical Co., Ltd.

Country -

Year Introduced -

Aranidipine

INTERCHEMICAL(chongqing) CO. LTD Verychem Co. Taiho Pharmaceutical Co., Ltd.

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Aranidipine Sapresta

Raw Materials Sodium hydride Diketene Ammonia

2,2-Ethylenedioxypropanol Methyl 2'-nitrobenzylidene acetoacetate Hydrochloric acid

Araprofen

377

Manufacturing Process 100.0 mg of 50% sodium hydride was added to a mixture of 20.0 g of 2,2ethylenedioxypropanol and 100 ml of benzene, and 20.0 g of diketene was added dropwise to the mixture while refluxing the mixture. After refluxing the mixture for 2 h, the solvent was distilled off and the resulting residue was distilled under reduced pressure to obtain 21.5 g (70% yield) of 2,2ethylenedioxypropyl acetoacetate as a colorless oil, boiling point of 90°C (6 mm Hg). Ammonia gas was passed through a mixture of 19.0 g of 2,2ethylenedioxypropyl acetoacetate and 100 ml of methanol for 2.5 h under icecooling while stirring. The solvent was then distilled off and the residue was distilled under reduced pressure to obtain 16.0 g (84% yield) of 2,2ethylenedioxypropyl 3-aminocrotonate as a pale yellow oil, boiling point of 120°C (5 mm Hg). A mixture of methyl 2'-nitrobenzylidene acetoacetate, 2,2-ethylenedioxypropyl 3-aminocrotonate and ethanol was refluxed for 10 h. The resulting reaction solution was allowed to stand overnight, and the precipitated crystals were collected by filtration and recrystallized from ethanol to obtain methyl 2,2ethylenedioxypropyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5dicarboxylate. Methyl 2,2-ethylenedioxypropyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4dihydropyridine-3,5-dicarboxylate was refluxed in an ethanol solution containing 10% hydrochloric acid for 6 h. The solvent was then distilled off and the residue was crystallized from diethyl ether to give methyl 2-oxopropyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate as yellow prisms, melting point 155°C (recrystallized from a mixture of ethyl acetate and hexane). References Ohno S. et al.; US Patent No. 4,446,325; May 1, 1984; Assigned: Maruko Seiyaku Co., Ltd., Nagoya, Japan

ARAPROFEN Therapeutic Function: Antiinflammatory, Analgesic Chemical Name: (+/-)-4-[(2-Carboxyphenyl)amino]-α-methylbenzeneacetic acid Common Name: Araprofen; Camprofen Chemical Abstracts Registry No.: 15250-13-2 Trade Name

Manufacturer

Country

Year Introduced

Araprofen

Onbio Inc.

-

-

378

Arbaprostil

Structural Formula:

Raw Materials Potassium carbonate Copper Sulfuric acid

2-(4-Aminophenyl)propionic acid Potassium o-chlorobenzoate

Manufacturing Process A mixture of 2-(4-aminophenyl)propionic acid (52.2 g), potassium ochlorobenzoate (61.5 g), potassium carbonate (43.6 g) and copper powder (0.3 g) in amyl alcohol (620 ml) is heating under reflux for 16 h. The major proportion of the solvent is then removed by steam distillation. The residual aqueous solution is treated with decolorising charcoal (20.0 g) and acidified with 4 N sulfuric acid (220 ml). The cream product which crystallises is dissolved in diethyl ether (500 ml). The aqueous mother liquors are extracted with methylene chloride (900 ml). The organic phases are combined, washed with water (800 ml) and dried over anhydrous sodium sulfate. After filtration, the filtrate is concentrated to dryness under a pressure of 20 mm Hg to give a semicrystalline paste (65.0 g) which is recrystallised from acetonitrile (550 ml). The crystals are filtered off, and the product recovered (32.0 g) is recrystallised from acetonitrile (600 ml). There is thus obtained 2-[4-(2-carboxyphenyl)aminophenyl]propionic acid (18.4 g) melting point 191°-192°C. References GB Patent No. 1,053,269; Dec. 30, 1966; Assigned: Rhone-Poulenc S.A., a French Body Corporate, 22, Avenue Montaigne, Paris, France

ARBAPROSTIL Therapeutic Function: Gastric antisecretory; Antiulcer Chemical Name: Prosta-5,13-dien-1-oic acid, 11,15-dihydroxy-15-methyl-9oxo-, (5Z,11α,13E,15R)Common Name: Arbaprostil

Arbaprostil

379

Structural Formula:

Chemical Abstracts Registry No.: 55028-70-1 Trade Name Arbaprostil

Manufacturer ZYF Pharm Chemical

Country -

Year Introduced -

Raw Materials Prostaglandin E2 Hexamethyldisilazane Ammonium chloride Potassium hydroxide Diazomethane

2,3-Dichloro-5,6-dicyano-1,4-benzoquinone Trimethylchlorosilane Methyl magnesium bromide Hydrochloric acid

Manufacturing Process 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone is added to a solution of PGF2a [(5Z,11α,13E)-11,15-dihydroxy-9-oxoprosta-5,13-dien-1-oic acid or Prostaglandin E2] in dioxane. The mixture is stirred 24 h at 50°C under nitrogen, and then is cooled to 20°C and filtered. The filtered solids are washed with dichloromethane. Evaporation of the combined filtrate and washings at reduced pressure gives a residue which is chromatographed on silica gel (Silicar CC-4; Malincrodt), eluting with 50% ethyl acetate in Skellysolve B (a mixture of isomeric hexanes). Evaporation of the eluates gives 15-oxo-PGF2a. A mixture of hexamethyldisilazane and tri-methylchlorosilane is added to a solution of 15-oxo-PGF2a in tetrahydrofuran. This mixture is stirred 16 h at 25°C under nitrogen, and is then filtered. The filtrate is evaporated under reduced pressure. Xylene is added to the residue and the mixture is evaporated at 60°C under reduced pressure. This addition of xylene and evaporation is repeated twice. The resulting residue is the tris-(trimethylsilyl) derivative of 15-oxo-PGF2a. A 3 M diethyl ether solution of methylmagnesium bromide is added dropwise to a stirred solution of the tris-(trimethylsilyl) derivative of 15-oxo-PGF2a in diethyl ether at 25°C.

380

Arbekacin

The mixture is stirred 30 min at 25°C, after which an additional the methylmagnesium bromide solution is added and stirring is continued an additional 30 min. The resulting reaction mixture is poured into saturated aqueous ammonium chloride solution at 0°C. After stirring several minutes, the mixture is extracted repeatedly with diethyl ether. The combined diethyl ether extracts are washed with saturated aqueous sodium chloride solution and then dried with anhydrous sodium sulfate. Evaporation of the diethyl ether gives a yellow oil which is dissolved in ethanol. That solution is diluted with water, and the mixture is stirred 4 h at 25°C. The ethanol in the resulting solution is evaporated at reduced pressure, and the aqueous residue is saturated with sodium chloride and then extracted with ethyl acetate. Solution, dried with anhydrous sodium sulfate, and evaporated under reduced pressure to give a mixture of 15-methyl-PGF2a and 15-methyl-15(R)-PGF2a. The 520.0 mg mixture of 15-methyl-PGF2a and 15-methyl-15(R)-PGF2a is dissolved in diethyl ether and cooled to 0°C. Excess diazomethane dissolved in diethyl ether is then added, and the mixture is maintained 5 min at 0°C and then 5 min at 25°C. The solution is evaporated in a stream of nitrogen, and the residue is chromatographed on 500.0 g of neutral silica (Merck), eluting successively with 20%, 40%, and of 50% ethyl acetate in Skellysolve B. The corresponding eluates emerging from the column are discarded. Elution is continued successively with gradients of 4 L of 50% and 4 L of 60% ethyl acetate in Skellysolve B, and 5 L of 60% and 5 L of 75% ethyl acetate in Skellysolve B, and then with 4 L of 75% ethyl acetate in Skellysolve B, collecting the corresponding eluates in 500 ml fractions. Elution is further continued successively with 5 L of 75% ethyl acetate in Skellysolve B and with 6 L of 100% ethyl acetate, collecting the corresponding eluates in 200 ml fractions. Eluate fractions 29-35 are combined and evaporated to give 109.0 mg of 15-methyl-15(R)-PGF2a methyl ester. Aqueous potassium hydroxide solution is added to a solution of 15-methyl15(R)-PGF2a methyl ester in a mixture of methanol and of water under nitrogen. The resulting solution is stirred 2 h at 25°C, and is then poured into several volumes of water. The aqueous mixture is extracted with ethyl acetate, acidified with 3 N hydrochloric acid, saturated with sodium chloride, and then extracted repeatedly with ethyl acetate. The latter ethyl acetate extracts are combined, washed successively with water and saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate, and evaporated under reduced pressure. The crystalline residue is recrystallized from a mixture of ethyl acetate and Skellysolve B to give 15-methyl-15(R)-PGF2a. References Bundy G.L.; US Patent No. 3,804,889; April 16, 1974; Assigned: Upjohn Company, Kalamazoo, Mich.

ARBEKACIN Therapeutic Function: Antibiotic

Arbekacin

381

Chemical Name: L-Streptamine, O-3-amino-3-deoxy-α-D-glucopyranosyl-(16)-O-(2,6-diamino-2,3,4,6-tetradeoxy-α-D-erythro-hexopyranosyl-(1-4))N1-(4-amino-2-hydroxy-1-oxobutyl)-2-deoxy-, (S)Common Name: Arbekacin; Habekacin Structural Formula:

Chemical Abstracts Registry No.: 51025-85-5 Trade Name Habekacin Habekacin

Manufacturer Meiji-Seika Co. Ltd. Choong Wae Pharma. Co

Country -

Year Introduced -

Arbeka

Reyon Pharmaceutical Co. Ltd.

-

-

Raw Materials 3',4'-Dideoxykanamycin Benzyloxycarbonyl chloride Ammonia Acetic acid Hydrogen Palladium on carbon N-Hydroxysuccinimide ester of (S)-4-benzyloxycarbonylamino-2hydroxybutyric acid Manufacturing Process 13.53 g (30 mmole) of 3',4'-dideoxykanamycin (abbreviated as DKB) in the form of the free base was dissolved in 135 ml of water, and to this solution was added dropwise 5.61 g (33 mmole) of benzyloxycarbonyl chloride over 1 h under stirring and under ice-cooling (0°-5°C). After the addition, the mixture was further stirred for 1 h at room temperature and filtered to remove the precipitate. The filtrate was washed with 135 ml of ethyl ether. The aqueous phase was neutralized by addition of aqueous ammonia and then concentrated under reduced pressure. The concentrated solution was passed through a column of 480 ml of a cation-exchange resin essentially consisting of a copolymer of methacrylic acid and divinylbenzene (available under a trade name "Amberlite

382

Arbekacin

CG 50", a product of Rohm and Haas Co., U.S.A. the ammonium form) to effect the adsorption of the benzyloxycarbonylated DKB by the resin. The resin column was washed with water (1920 ml) and then eluted with 0.1 N aqueous ammonia. 960 ml of the first running of the eluate was discarded, and the subsequently running fraction of the eluate amounting to 780 ml was collected, concentrated and freeze-dried to give 5.43 g (yield 31%) of 6'-Nbenzyloxycarbonyl DKB as a colorless powder, melting point 113°-115°C (dec.). 4.04 g (6.9 mmole) of the 6'-N-benzyloxycarbonyl DKB was dissolved in 26 ml of water, and to this solution was added a solution of 2.94 g (8 mmole) of Nhydroxysuccinimide ester of (S)-4-benzyloxycarbonylamino-2-hydroxybutyric acid in 45 ml of dimethoxyethane. The admixture was stirred at room temperature for 90 min and then the reaction mixture was concentrated to dryness. The residue was taken up in a volume of water and the aqueous solution was poured into a column of 560.0 g of silica gel. The elution was conducted using methanol-chloroform-17% aqueous ammonia (4:2:1), and such eluate fractions containing the unreacted materials were discarded. The fractions containing the mixed acylated products were collected and concentrated to give 5.63 g of the mixed acylated products. The mixed acylated products were dissolved in a mixture of 67 ml of glacial acetic acid, 63 ml of methanol and 17 ml of water, and the solution so obtained was admixed with 1.6 g of 5% palladium-carbon and hydrogenated with hydrogen at atmospheric pressure for 4 h to remove the benzyloxycarbonyl groups of the acylated products. The reaction mixture was filtered to remove the catalyst, and the filtrate was concentrated to under reduced pressure to give 5.20 g of a powder of the acetate of the acylated products comprising 1-N[(S)-4-amino-2-hydroxybutyryl] DKB acetate. The aqueous solution of 1-N-[(S)-4-amino-2-hydroxybutyryl] DKB acetate was poured into a column of 250 ml of a cation-exchange resin made of a copolymer of methacrylic acid and divinylbenzene (commerically available as "Amberlite CG 50" ammonium form). The resin column was washed with water and eluted successively with aqueous ammonia (0.1 N 850 ml, 0.3 N 830 ml, 0.63 N 830 ml and 1 N 830 ml). The eluate was collected in 17 ml fractions. 320 ml of the fractions which were eluted by using 1 N aqueous ammonia and which showed high antibacterial activity to Bacillus subtilis PC 1219 and Escherichia coli JR 66/W 677 were combined together and concentrated to dryness to give 301.0 mg of a powder. This powder was rechromatographed again into a column of 11 ml of a cation-exchange resin made of a copolymer of methacrylic acid with divinylbenzene (commercially available as "Amberlite CG 50", ammonium form). Thus, the resin column was at first washed with 40 ml of water and then with 90 ml of 0.5 N aqueous ammonia, and subsequently the elution was made using 0.75 N aqueous ammonia. Such fractions of the eluate were combined together to a total volume of 26 ml and concentrated to dryness to give 61.0 mg (yield 1.6%) of 1-N-[(S)-4-amino-2-hydroxybutyryl]DKB as a colorless crystalline powder, melting point 178°C (dec.). References Umezawa H. et al.; US Patent No. 4,107,424; August 15, 1978; Assigned: Zaidan Hojin Biseibutsu Kagaku Kenkyu Kal, Tokyo, Japan

Arbutamin hydrochloride

383

ARBUTAMIN HYDROCHLORIDE Therapeutic Function: Cardiotonic Chemical Name: 1,2-Benzenediol, 4-((1R)-1-hydroxy-2-((4-(4hydroxyphenyl)butyl)amino)ethyl)-, hydrochloride Common Name: Arbutamine hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 125251-66-3; 128470-16-6 (Base) Trade Name

Manufacturer

Country

Year Introduced

Genesa

Genesia Automedics

UK

-

Raw Materials 3,4-Dihydroxybenzaldehyde t-Butyldimethylsilyl chloride Nitromethane (S)-6,6'-Bis(triethylsilylethynyl)-1,1'-dihydroxy-2,2-binaphthalene Butyl lithium 4-(4-Methoxymethoxyphenyl)butanoic acid Diethylphosphorylcyanide Triethylamine Lithium aluminum hydride Manufacturing Process (R)-Arbutamin was produced as follows: 89.3 mg of (-)-1-di(tbutyldimethylsiloxy)phenyl)-2-aminoethanol, 50.0 mg of 4-(4methoxymethoxyphenyl)butanoic acid, diethylphosphorylcyanide, and triethylamine were dissolved in N,N-dimethylformamide at 0°C, reacted at room temperature, so as to obtain 108.6 mg (in a yield of 82%) of amide compound. The amide compound obtained was reduced lithium aluminium hydride in an ether solvent at reflux temperature, so as to quantitative obtain amine. And 55.6 mg of (R)-arbutamin which is intended compound was obtained by deprotecting the hydroxyl-protecting group of amine in a methanol-THF solvent at room temperature using hydrochloric acid. [α]D25 = -17 (c 1.15, EtOH). (-)-1-(Dibutyldimethylsiloxy)phenyl)-2-aminoethanol was obtained by a hydrogenization of (R)-1-(3,4-di(t-butyldimethylsiloxyphenyl)-2-nitroethanol

384

Arclofenin

on 10% Pd/C. The last compound was prepared as follows: the hydroxyl groups of 3,4dihydroxy-benzaldehyde was protected using t-butyldimethylsilylchloride (1). 100 mg (0.26 mmol) of 3,4-di(t-butyl-methylsiloxy)benzaldehyde was dissolved in 1 ml tetrahydrofurane under atmosphere of argon at -40°C, and 0.30 ml of metal complex from (S)-6,6'-bis(triethylsilylethynyl)-1,1-dihydroxy2,2'-binaphtalene (2) mixed with a solution of n-butyllitium in hexane.After stirring for 30 minutes, 79.4 mg (1.3 mmol) of nitromethane was added dropwise to the mixture. After 67 hour reaction time, 2 ml of 1 N aqueous solution of hydrochloric acid added to stop the reaction. Product was extracted with 50 ml ethyl acetate, dehydrated with anhydrous sodium sulfate and concentrated within evaporator followed by silica gel chromatography (nhexane/acetone = 10/1), after which (R)-1-(3,4-di(t-butyldimethylsiloxy) phenyl)-2-nitroethanol with an optical purity of 92% e.e. was obtained in a yield of 93%. References Aldrich, Catalogue Handbook of Fine Chemicals, 2000, p.312 Shibasaki et al.; US Patent No. 6,632,955B1; Oct. 14, 2003 Monte W.T. et al.; US Patent No. 5,874,601; Feb. 23, 1999; Assigned: Abbott Laboratories (Abbott Park, IL)

ARCLOFENIN Therapeutic Function: Diagnostic aid Chemical Name: Glycine, N-(2-((2-benzoyl-4-chlorophenyl)amino)-2oxoethyl)-N-(carboxymethyl) Common Name: Arclofenin Structural Formula:

Chemical Abstracts Registry No.: 87071-16-7

Arfendazam

385

Trade Name

Manufacturer

Country

Year Introduced

Arclofenin

ZYF Pharm Chemical

-

-

Raw Materials Acetic anhydride Pyridine Nitrilotriacetic acid Sodium hydroxide 2-Amino-5-chlorobenzophenone Manufacturing Process A round bottom flask is charged with dimethylformamide 72.0 g, acetic anhydride 25.0 g, pyridine 2.0 g, and nitrilotriacetic acid (NTA) 38.2 g and the suspension is nitrogen purged for several minutes. The flask is stoppered and the mixture is stirred at room temperature for 3 days. A small amount of unreacted NTA is filtered out. The bulk of the solvent 79 ml is removed in vacuo at a bath temperature of 60°-70°C. The resulting viscous solution is twice roto-vacued after two successive additions of 40 ml dimethylformamide. So the 2,6-diketo-N-carboxymethyl morpholine (NTA anhydride) is prepiared. To the viscous solution of NTA anhydride is added 300 ml toluene. The mixture is stirred at room temperature until uniform. Then 46.3 g of 2-amino5-chlorobenzophenone dissolved in 300 ml toluene is added to the stirred solution of NTA anhydride and heated at 90°-100°C for 1 h. After cooling, the reaction mixture is flashed to dryness. The residue is taken up in 400 ml of 1N sodium hydroxide and filtered. The filtrate is extracted with chloroform, ether and charcoaled. The charcoal is removed by filtration. The product is precipitated from the filtrate by the careful addition of 6 N HCl. The precipitate is removed by filtration to give the N-[N'-(2-benzoyl-4chlorophenyl)carbamoylmethyl]iminodiacetic acid, melting point 180°-186°C (dec., recrystallized from hot methanol/water). References Roleston R.E.; US Patent No. 4,454,107; June 12, 1984; Assigned: Merck and Co., Inc., Rahway, N.J.

ARFENDAZAM Therapeutic Function: Tranquilizer Chemical Name: 1H-1,5-Benzodiazepine-1-carboxylic acid, 7-chloro-2,3,4,5tetrahydro-4-oxo-5-phenyl-, ethyl ester Common Name: Arfendazam Chemical Abstracts Registry No.: 37669-57-1

386

Argatroban hydrate

Structural Formula:

Trade Name Arfendazam

Manufacturer ZYF Pharm Chemical

Country -

Year Introduced -

Raw Materials Phosgene Ethanol 8-Chloro-1-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-2-one Manufacturing Process A phosgene was mixed with ethanol, then cooling by ice-water the solution of 8-chloro-1-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-2-one in chloroform was added dropwise, mixed and allowed to stand. Then the reaction mixture was concentrated, and crystals was filtered off. So the 7chloro-2,3,4,5-tetrahydro-4-oxo-5-phenyl-1H-1,5-benzodiazepine-1-carboxylic acid ethyl ester was obtained, melting point 172°-173°C (dec.). References Bub O. et al.; SU 474,986; Oct. 25, 1975; Assigned: Knol AG, FRG. Karrer, Lehrbuch der organischen chemie, 1959

ARGATROBAN HYDRATE Therapeutic Function: Anticoagulant Chemical Name: (2R,4R)-4-methyl-1-[N2-3-methyl-1,2,3,4-tetrahydro-8quinolinsulfonyl-L-arginyl]-2-piperidinecarboxylicacid hydrate Common Name: Argatroban; Argipidine Chemical Abstracts Registry No.: 141396-28-3; 74863-84-6 (Base) Raw Materials Triethylamine N(G)-Nitro-N(2)-(tert-butoxycarbonyl)-L-arginine Isobutyl chloroformate

Argatroban hydrate

387

Ethyl 4-methyl-2-piperidinecarboxylate Palladium 3-Methyl-8-quinolinesulfonyl chloride Structural Formula:

Trade Name Acova Argatroban

Manufacturer SmithKline Beecham Texas Biotechnology Corporation

Country -

Year Introduced -

Novastan

Mitsubishi Chemical Corp.

Japan

-

Slonnon

Mitsubishi Chemical Corp.

Japan

-

Manufacturing Process To a stirred solution of 28.3 g of NG-nitro-N2-(tert-butoxycarbonyl)-L-arginine in 450 ml of dry tetrahydrofuran were added in turn 9.0 g of triethylamine and 12.2 g of isobutyl chloroformate while keeping the temperature at -20°C. After 10 minutes, to this was added 15.2 g of ethyl 4-methyl-2piperidinecarboxylate and the mixture was stirred for 10 minutes at -20°C. At the end of this period, the reaction mixture was warmed to room temperature. The solvent was evaporated and the residue taken up in 400 ml of ethyl acetate, and washed successively with 200 ml of water, 100 ml of 5% sodium bicarbonate solution, 100 ml of 10% citric acid solution and 200 ml of water. The ethyl acetate solution was dried over anhydrous sodium sulfate. The solution was evaporated to give 31.5 g (75 %) of ethyl 1-[NG-nitro-N2(tert-butoxycarbonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylate in the form of a syrup. To a stirred solution of 30 g of ethyl 1-[NG-nitro-N2-(tert-butoxycarbonyl)-Larginyl]-4-methyl-2-piperidinecarboxylate in 50 ml of ethyl acetate was added 80 ml of 10% dry HCl-ethyl acetate at 0°C. After 3 hours, to this solution was added 200 ml of dry ethyl ether to precipitate a viscous oily product. This was filtered and washed with dry ethyl ether to give ethyl 1-[NG-nitro-L-arginyl]-4methyl-2-piperidinecarboxylate hydrochloride as an amorphous solid.

388

Arginine aspartate

To a stirred solution of ethyl 1-(NG-nitro-L-arginyl)-4-methyl-2piperidinecarboxylate hydrochloride in 200 ml of chloroform were added in turn 18.5 g of triethylamine, and 14.7 g of 3-methyl-8-quinolinesulfonyl chloride at 5°C, and stirring was continued for 3 hours at room temperature. At the end of this period, the solution was washed twice with 50 ml of water. The chloroform solution was dried over anhydrous sodium sulfate. Upon evaporation of the solvent, the residue was chromatographed on 50 g of silica gel packed in chloroform, washed with chloroform and eluted with 3% methanol-chloroform. The fraction eluted from 3% methanol-chloroform was evaporated to give 32.1 g (91%) of ethyl 1-[NG-nitro-N2-(3-methyl-8quinolinesulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylate in the form of an amorphous solid. A solution of 30 g the above product in 100 ml of ethanol and 100 ml of 1 N sodium hydroxide solution was stirred for 24 hrs at room temperature. At the end of this period, the solution was neutralized with 1 N hydrochloric acid and then concentrated to 70 ml. The solution was adjusted to pH=11 with 1 N sodium hydroxide solution, washed three times with 100 ml of ethyl acetate, acidified with 1 N hydrochloric acid and then extracted three times with 100 ml of chloroform. The combined chloroform solution was dried over anhydrous sodium sulfate and evaporated to give 28.0 g (97%) of 1-[NG-nitro-N2-(3methyl-8-quinolinesulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylic acid as an amorphous solid. IR (KBr): 3,300, 1,720, 1,630 cm-1. To a solution of 3.00 g of 1-[NG-nitro-N2-(3-methyl-8-quinolinesulfonyl)-Larginyl]-4-methyl-2-piperidinecarboxylic acid in 50 ml of ethanol was added 0.5 g of palladium black and then the mixture was shaken under 10 kg/cm2 H2 pressure at 100°C for 8 hrs. At the end of this period, the ethanol solution was filtered to remove the catalyst and evaporated to give 2.50 g (90%) of 1[N2-(3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl]-4-methyl-2piperidinecarboxylic acid as an amorphous solid. IR (KBr): 3,400, 1,620, 1,460, 1,380 cm-1. References Okamoto S. et al.; US Patent No. 4,201,863; May 6, 1980; Assigned: Mitsubishi Chemical Industries, Limited (Tokyo, JP) Mano T. et al.; US Patent No. 5,506,241; Apr. 9, 1996; Assigned: Mitsubishi Chemical Corporation (Tokyo, JP)

ARGININE ASPARTATE Therapeutic Function: Tonic, Stimulant, Hepatoprotectant Chemical Name: L-Aspartic acid, compound with L-arginine (1:1) Common Name: Arginine aspartate; Aspargininum Chemical Abstracts Registry No.: 7675-83-4

Arginine aspartate

389

Structural Formula:

Trade Name Arginine aspartate

Manufacturer Microbase Biotech Co., Ltd. Flamma S.P.A. Euro-Labor' Grunenthal

Country -

Year Introduced -

-

-

Bio-Energol Bio-Energol Desfatigan Dynamisan Dynamisan

Medicum Yamanouchi IMA Mipharm S.p.A Novartis Santé Familiale SAS

-

-

Dynamisan Eubiol Lacorene Pargine Pargine Potenciator Sangenor Sargenor Sorbenor Targifor Targifor

Famar, S.A. Chephasaar Spedrog Caillon Viatris Asta Medica Valderrama Roche Viatris S.p.A Casen Fleet, SA. Aventis Pharma Silva Araujo Roussel S.A.

-

-

Taurargin

Laboratorios Baldacci S.A.

-

-

Arginine aspartate Asparten

Raw Materials Calcium aspartate Arginine dihydrochloride Manufacturing Process 1000 ml of polystyrene-trimethylbenzylammonium ion exchange resin were converted into the chloride form by passing aqueous hydrochloride acid over the resin. The resin was washed with distilled water to remove all traces of

390

Arginine glutamate

hydrochloric acid and a 1 N aqueous solution of calcium aspartate was then passed over the resin. A 10% excess of the calcium aspartate solution over the theoretical ion-exchange capacity of the resin was used and the resin was then washed with water until the wash water was free of chloride ions. At the end of this treatment, the resin was in the aspartic acid form. An aqueous solution containing 168.56 g of calcium aspartate and 49.44 g of arginine dihydrochloride per litre was prepared, and this solution was passed slowly over the aspartic acid form resin. The effluent liquid was collected in fractions of 200 ml, then of 100 ml, and towards the end, in fractions of 50 ml. After about 1000 ml of eluate had been collected, the succeeding fractions were examined very carefully for the presence of chloride ion. All the eluate fractions prior to the first one containing traces of chloride, i.e. all the chloride-free eluate fractions, were combined; the combined chloride eluates amounted to about 1300 ml. The arginine present was determined by Sakaguchis method and the total nitrogen in the combined eluates was also determined. These determinations showed that the eluates contained from 270 to 300 g of arginine aspartare per litre. The combined eluates were evaporated to a volume of about 500 ml and allowed to crystallize at a low temperature (0°-4°C). After seeding with a crystal of arginine aspartate, colourless crystals were obtained; they were filtered off, washed with aqueous ethanol, and then dried. About 210 g, i.e. 70% of the theoretical yield, of crystals having a decomposition point of 220°C was obtained. The mother liquor from the first crystallization was evaporated down to a volume of about 150 ml. Ethanol was added to the solution until cloudiness which persisted was obtained, the solution was cooled to 0°C and a second crop of crystals was obtained. The size of this second crop was increased by adding further ethanol after the major portion of the second crop had crystallized and allowing the mixture to stand for 48 hours at 0°C. After separation, the second fraction consisted of 75 g of a crystalline mass which had the same physico-chemical and chemical properties as the main fraction. References GB Patent No. 1,045,060; Sept. 15, 1965; Assigned to Mundipharma S.A.

ARGININE GLUTAMATE Therapeutic Function: Ammonia detoxicant (hepatic failure) Chemical Name: Glutamic acid compound with L-arginine Common Name: Chemical Abstracts Registry No.: 4320-30-3 Raw Materials L-Arginine L-Glutamic acid

Aripiprazole

391

Structural Formula:

Trade Name Modamate Eucol

Manufacturer Abbott Lefranco

Country US France

Year Introduced 1960 1970

Manufacturing Process This salt may be prepared by mixing L-arginine with L-glutamic acid in water and crystallizing the resulting salt from the water by the addition of a polar water miscible organic solvent to the water. For instance, when 17.2 g of Larginine and 14.5 g of L-glutamic acid were dissolved in 155 g of water, a clear homogeneous solution resulted which had a pH of 5.3. This solution was filtered and the filtrate was evaporated at 50°C under reduced pressure to a solution having a solids content of about 45%. Absolute methanol (220 g) was added to the concentrated solution of the salt and this mixture cooled to 5°C for one hour. The resulting solid salt was removed from the mixture by filtration and washed with absolute methanol. After being dried preliminarily in the air, the salt was further dried in a vacuum oven at 60°C for 3 hours. The resulting salt, L-arginine-L-glutamate, weighed 30 g (94.6% of the theoretically possible yield based on the amount of L-arginine and L-glutamic acid employed) and melted at 193-194.5°C with decomposition. References Merck Index 798 DFU 3 (1) 10 (1978) DOT 17 (3) 87 (1981) I.N. p.98 Barker, N.G. and Chang, R.W.H., US Patent 2,851,482; September 9, 1958; Assigned to General Mills, Inc.

ARIPIPRAZOLE Therapeutic Function: Antipsychotic Chemical Name: 2(1H)-Quinolinone, 7-(4-(4-(2,3-dichlorophenyl)-1piperazinyl)butoxy)-3,4-dihydro-

392

Aripiprazole

Common Name: Aripiprazole Structural Formula:

Chemical Abstracts Registry No.: 129722-12-9 Trade Name

Manufacturer

Country

Year Introduced

Abilify

Bristol-Myers Squibb

USA

-

Abilify

Otsuka America Pharmaceutical, Inc.

USA

-

Abilitat

Bristol-Myers Squibb

USA

-

Aripiprazole

Bristol-Myers Squibb

USA

-

Aripiprazole

Otsuka Pharmaceutical Japan Company, Ltd.

-

Raw Materials 2,3-Chloroaniline 7-Hydroxy-3,4-dihydrocarbostyril 1,4-Dibromobutane Di(2-bromethyl)amine Triethylamine Manufacturing Process To a solution of 4.06 g of K2CO3 with 400 ml of water was added 40 g of 7hydroxy-3,4-dihydrocarbostyril [1] and 158 g of 1,4-dibrombutane. The mixture was refluxed for 3 hours. Then it was extracted with dichloremethane, dried with anhydrous MgSO4, the solvent was removed by evaporation. The residue was purified by means of silica gel chromatography (eluent: dichloromethane) and recrystallized from n-hexane-ethanol to yield 50 g of 7(4-bromobutoxy)-3,4-dihydrocarbostyril, mp 110.5°-110.0°C. 47 g of 7-(4-bromobutoxy)-3,4-dihydrocarbostyril, 35 g of NaJ in 600 ml of acetonitrile was refluxed for 30 minutes. To this suspension was added 40 g of 1-(2,3-dichlorophenyl)piperazine (it was prepareted from 2,3-chloroaniline and di(2-bromoethyl)amine [1]) and 33 ml of triethylamine. The mixture was refluxed for 3 hours. After removing of the solvent, the residue was dissolved in chloroform, washed with water and dried with anhydrous MgSO4. The solvent was removed by evaporation, and residue was recrystallized from ethanol twice to yield 57.1 g of 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydrocarbostyril. Melting point: 139.0°-139.5°C.

Arnolol

393

References J. Pharmacol. Exp. Ther., 277, 137-143 (1996) Banno K. et al.; US Patent No. 4,734,416; March 29, 1988; Assigned: Otsuka Pharmaceutical Co., Ltd. (JP) Oshiro Y. et al.;. US Patent No. 5,006,528; April 9, 1991; Assigned: Otsuka Pharmaceutical Co., Ltd. (Tokyo, JP)

ARNOLOL Therapeutic Function: Beta-adrenergic blocker (ophthalmic) Chemical Name: 2-Butanol, 3-amino-1-(4-(2-methoxyethyl)phenoxy)-3methylCommon Name: Arnolol Structural Formula:

Chemical Abstracts Registry No.: 87129-71-3 Trade Name Arnolol

Manufacturer ZYF Pharm Chemical

Country -

Year Introduced -

Raw Materials Palladium on charcoal 1-[4-(2-Methoxyethyl)phenoxy]-3-nitro-3-methylbutan-2-ol Acetic acid Sodium hydroxide Zinc Hydrochloric acid Manufacturing Process 2 methods of producing of 1-[4-(2-methoxyethyl)-phenoxy]-3-amino-3methyl-butan-2-ol: 1). 19.0 g of 1-[4-(2-methoxyethyl)phenoxy]-3-nitro-3-methylbutan-2-ol are hydrogenated at 60°C and under a pressure of 6 bar in a mixture of 250 ml of ethanol and 50 ml of glacial acetic acid in the presence of 4.0 g of palladiumon-charcoal (10% Pd). After the mixture has been filtered and the solvent has been evaporated off, the residue is rendered alkaline with 2 N NaOH and the

394

Arotinolol hydrochloride

mixture is extracted with CH2Cl2. The organic phase is washed with water and dried with Na2SO4 to give, after evaporation, 15.0 g of the 1-[4-(2methoxyethyl)phenoxy]-3-amino-3-methylbutan-2-ol, melting point 120°122°C (dec.). 2). 18.3 g of zinc dust are gradually added to 20.0 g of 1-[4-(2-methoxyethyl) phenoxy]-3-nitro-3-methylbutan-2-ol in 400 ml of ethanol and 60 ml of concentrated hydrochloric acid at 50°-60°C. The mixture is stirred at this temperature for 1 h and filtered and the solvent is evaporated off. After 200 ml of 40% strength NaOH have been added, the product is extracted with methylene chloride. Solvent is distilled and the 1-[4-(2-methoxyethyl) phenoxy]-3-amino-3-methylbutan-2-ol is produced, melting point 120°-122°C (dec.). References Cohnen E., Heilwigstrasse, Fed. Rep. of Germany

AROTINOLOL HYDROCHLORIDE Therapeutic Function: Beta-adrenergic blocker Chemical Name: 2-Thiophenecarboxamide, 5-(2-((3-((1,1-dimethylethyl) amino)-2-hydroxypropyl)thio)-4-thiazolyl)-, monohydrochloride Common Name: Arotinolol hydrochloride; Tarotiolol hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 68377-92-4 (Base); 68377-91-3 Trade Name

Manufacturer

Country

Year Introduced

Arotinolol hydrochloride

ZYF Pharm Chemical

-

-

Raw Materials 2-Mercapto-4-(5'-carbamoyl-2'-thiophenyl)thiazole Sodium hydroxide 1-Chloro-3-t-butylaminopropanol

Arprinocid

395

Manufacturing Process To a solution of 2-mercapto-4-(5'-carbamoyl-2'-thiophenyl)thiazole, 3.2 g in 20 ml of 0.3 % aqueous sodium hydroxide solution, 1-chloro-3-tbutylaminopropanol, 12.64 g in 20 ml of methanol was added, while the temperature was maintained at 20°C. The reaction solution was stirred at room temperature for 4 h, and then condensed to a half volume in vacuo. The residual solution, added with 100 ml of water, was extracted with chloroform. The chloroform extract was washed with water, dried over anhydrous magnesium sulfate and evaporated in vacuo to give 4.8 g of 2-(3'-t-butylamino-2'-hydroxypropylthio)-4-(5'-carbamoyl-2'thiophenyl)thiazole, as crystals, melting point 234°-235.5°C (dec., recrystallized from methanol/water). In practice it is usually used as hydrochloride. References Hibino T. et al.; US Patent No. 3,932,400; January 13, 1976; Assigned: Sumitomo Chemical Company, Limited, Japan

ARPRINOCID Therapeutic Function: Coccidiostatic Chemical Name: 9H-Purin-6-amine, 9-((2-chloro-6-fluorophenyl)methyl)Common Name: Arprinocid Structural Formula:

Chemical Abstracts Registry No.: 55779-18-5 Trade Name Arprinocid

Manufacturer Country NANJING PHARMA CHEMICAL PLANT

Year Introduced -

Arprinocid

Hallochem Pharma Co., Ltd.

-

Arprinocid

Shanghai abochem chemical co., Ltd.

-

396

Arpromidine

Raw Materials Adenine 2-Chloro-6-fluorobenzyl chloride Potassium t-butoxide Manufacturing Process To a solution of potassium t-butoxide in absolute ethanol slowly adding dry adenine. This mixture was stirred for about 2 h, and then 2-chloro-6fluorobenzyl chloride was added over a period of about 4 h. The resulting mixture was heated to reflux with stirring and allowed to react for about 42 h, after which it was cooled to about 10°C. The crude product thus formed was isolated by filtration and then washed with ice cold ethanol and ice cold water to yield a 6-amino-9-(2-chloro-6-fluorobenzyl)purine. References Lira E.P. et al.; US Patent No. 3,846,426; Nov. 5, 1974; Assigned: International Minerals and Chemical Corporation, Libertyville, III. G.B. Patent No. 1,123,457; 11 August 11, 1966; Warner Lambert Pharmaceutical Company, a Corporation of Delaware, USA

ARPROMIDINE Therapeutic Function: Histamine H2-receptor agonist Chemical Name: Guanidine, N-(3-(4-fluorophenyl)-3-(2-pyridinyl)propyl)-N'(3-(1H-imidazol-4-yl)propyl)Common Name: Arpromidine Structural Formula:

Chemical Abstracts Registry No.: 106669-71-0 Trade Name

Manufacturer

Country

Year Introduced

Arpromidine

Onbio Inc.

-

-

Arpromidine

397

Raw Materials Sodium hydride Sodium hydroxide Sulfuric acid Ammonia Hydrochloric acid

(4-Fluorophenyl)-pyrid-2-yl acetonitrile N-(2-Bromoethyl)phthalimide 3-(Imidazol-4-yl)-propylamine N-Benzoyldiphenylimidocarbonate

Manufacturing Process 42.4 g (0.2 mol) of (4-fluorophenyl)-pyrid-2-yl-acetonitrile are dissolved in 50 ml of dimethylformamide and introduced dropwise into a suspension, cooled with ice, of 5.0 g of sodium hydride (put into the process as a dispersion in mineral oil) in 150 ml of dimethylformamide. The reaction mixture is then stirred at room temperature for 15 min and thereafter heated under reflux for 5 h after the addition of 53.4 g (0.21 mol) of N-(2-bromoethyl)phthalimide. When the resulting reaction mixture has cooled down, it is diluted with 500 ml of ether and the organic phase is washed with water until neutral, dehydrated over sodium sulfate and then concentrated by evaporation under vacuum. The N-[3-(cyano-3-(4-fluorophenyl)-3-(pyrid-2-yl)propyl]phthalimide, oily residue, melting point 154°C (crystallizing from methanol), yield: 48.5 g (63%). 46.25 g (0.12 mol) of N-[3-cyano-3-(4-fluorophenyl)-3-(pyrid-2yl)propyl]phthalimide in 100 ml of 75% sulfuric acid are heated to 150°C for 5 h. When the reaction mixture is cold, it is poured out on ice, filtered through a glass filter, alkalized with sodium hydroxide solution and extracted with ether. The combined extracts are washed with water, dehydrated over sodium sulfate and concentrated by evaporation under vacuum, and the product obtained is isolated by distillation at 150°-155°C/0.8 mm Hg. 19.1 g (yield: 69%) of the 3-(4-fluorophenyl)-3-(pyrid-2-yl) propylamine are obtained. 1.15 g (5 mmol) of 3-(4-fluorophenyl)-3-(pyrid-2-yl)-propylamine and 1.59 g (5 mmol) of N-benzoyl-diphenylimidocarbonate are stirred together in 20 ml of methylene chloride for 15 min at room temperature. The solvent is distilled off under vacuum and the residue is taken up with 30 ml of pyridine and then heated under reflux for 60 min after the addition of 0.69 g (5.5 mmol) of 3(imidazol-4-yl)-propylamine. The reaction mixture is concentrated by evaporation under vacuum and the residue is dissolved in dilute acid and extracted with ether to remove the phenol formed in the reaction. Alkalization of the aqueous phase with ammonia is followed by extraction with methylene chloride, and the organic phase is washed with water, dehydrated over sodium sulfate and concentrated by evaporation under vacuum. The crude product is purified by preparative layer chromatography (silica gel 60 PF254, containing gypsum; solvent: chloroform/methanol 99+1, ammoniacal atmosphere). 1.4 g (yield 58%) of N-benzoyl-N'-[3-(4-fluorophenyl)-3-(pyrid-2-yl)propyl]-N"-[3(imidazol-4-yl)propyl]-guanidine a non-crystalline solid (foam) are obtained (crystallisation from ethyl acetate). 0.97 g (2 mmol) of N-benzoyl-N'-[3-(4-fluorophenyl)-3-(pyrid-2-yl)propyl]-N"[3-(imidazol-4-yl)propyl]-guanidine are heated under reflux in 45 ml of 18% hydrochloric acid for 6 h. When the reaction mixture has cooled down, the benzoic acid formed is removed by extraction with ether, the aqueous phase is evaporated to dryness under vacuum and the residue is dehydrated in a high vacuum: 0.9 g (yield 92%) of a hygroscopic, non-crystalline N-[3-(4-

398

Arsanilic acid

fluorophenyl)-3-(pyrid-2-yl)propyl]-N'-[3-(imidazol-4-yl)propyl]-guanidine is obtained. References Buschauer A. et al.; US Patent No. 5,021,431; June 4, 1991; Assigned: Heumann Pharma GmbH and Co., Nuremberg, Fed. Rep. of Germany

ARSANILIC ACID Therapeutic Function: Antibacterial Chemical Name: Arsonic acid, (4-aminophenyl)Common Name: Acidum arsanilicum; Arsanilic acid Structural Formula:

Chemical Abstracts Registry No.: 98-50-0 Trade Name Arsanilic acid Arsanilic acid Arsanilic acid Acidum arsanilicum

Manufacturer Fleming Laboratories, Inc. AroKor Holdings Inc. Idea'l Nutrition Science And Development Co., LTD ZYF Pharm Chemical

Country -

Year Introduced -

-

-

Raw Materials Arsenic acid Aniline Hydrochloric acid Sodium hydroxide Manufacturing Process 342.0 g (2 mol) of 83% arsenic acid were added during 75 min to a rapidly stirred mixture of 372.5 g (4 mol) aniline and 111.0 g chlorobenzene while the temperature of the mixture was kept at 147°-150°C. After the addition of arsenic acid was complete the mixture was stirred for an additional 8 h while being maintained at 149°-153°C. Water was continuously removed by distillation, and the organic phase of the distillate was continuously recycled

Arsthinol

399

back into the reaction mixture. At the end of that time a total of 121.0 g of water, containing the condensation of aniline and arsenic acid has been removed. The mixture was then allowed to cool to 110°C. 562.0 g (2.81 mol) of 20% sodium hydroxide were added over a 2 h period while water, chlorobenzene and excess aniline were distilled off at a temperature of from 102°-113°C. The distillation was continued for an additional 2 h while the volume of the mixture was kept at about 700 ml by the addition of water. The mixture was then diluted with water to a volume of 1400 ml and allowed to cool to 23°C. At this point, 52.0 g of by-product material, which was predominantly tri-(p-aminophenyl)-arsineoxide, were filtered out. The pH of the filtrate was then brought from 8.7 to 5.1 by the addition of 1.8 mol of hydrochloric acid while the volume of the mixture was increased to 2,200 ml by the addition of water. The mixture was stirred for 5 h at room temperature and again filtered. 108.0 g of by-product material comprising predominantly di-(p-aminophenyl)-arsinic acid was filtered off at this point. The pH of the filtrate was lowered to 4.5 by the addition of 0.2 mole of hydrochloric acid, and an additional 5.0 g of by-products, the composition of which was not determined, was filtered off. The filtrate was then brought to a pH of 3.2 by addition of 0.6 mole of hydrochloric acid, and 128.0 g (29.5% based upon arsenic acid) of arsanilic acid were recovered as a precipitate. The arsanilic acid filtrate was combined with the by-products filtered off during each of the three filtration steps. 2.8 mol of hydrochloric acid were added to the combined arsanilic acid filtrate and the mixture was heated at 80°C for 5 days. Arsanilic acid was then precipitated from the remaining hydrolyzed mixture in the manner described for the primary reaction product, and an additional 120.0 g (27.5% based on arsenic acid) were recovered. The filtrate contained 14.0 g (3.2%) of arsanilic acid which could be recovered at least partially in subsequent processing. Thus it can be seen from this example that an arsanilic acid yield of 59% was obtained. References Hoffmannn H., Green H.E.; US Patent No. 3,763,201; October 2, 1973

ARSTHINOL Therapeutic Function: Antiprotozoal Chemical Name: 3-Hydroxypropylene ester of 3-acetamido-4hydroxydithiobenzene-arsonous acid Common Name: Arsthinenol; Arsthinol; Mercaptoarsenical; Mercaptoarsenol Chemical Abstracts Registry No.: 119-96-0

400

Arteflene

Structural Formula:

Trade Name Arsthinol

Manufacturer ZYF Pharm Chemical

Country -

Year Introduced -

Raw Materials 4-Hydroxy-3-acetylaminophenyl-arsenoxide 2,3-Dimercaptopropanol Manufacturing Process 0.1 mol of 4-hydroxy-3-acetylaminophenyl-arsenoxide is suspended in 50 times its weight of water, and to the suspension 3 mols of sodium carbonate and 11 ml (110 mmols) of 2,3-dimercaptopropanol are added with rapid stirringfor 60 min. The resulting precipitate is filtered off, washed with water and dried in vacuo. So the N-[2-hydroxy-5-[4-(hydroxymethyl)-1,3,2-dithiarsolan-2-yl]phenyl] acetamide, melting point 163°-166°C is obtained. References Friedheim E.A.H.; US Patent No. 2,772,303; November 27, 1956

ARTEFLENE Therapeutic Function: Antimalarial Chemical Name: 2,3-Dioxabicyclo[3.3.1]nonan-7-one, 4-(2-(2,4-bis (trifluoromethyl)phenyl)ethenyl)-4,8-dimethyl- (1S-(1α,4β(Z),5α,8α))Common Name: Arteflene Structural Formula:

Arteflene

401

Chemical Abstracts Registry No.: 123407-36-3 Trade Name Arteflene

Manufacturer Roche

Country -

Year Introduced -

Raw Materials Carvone, (-) Sulfuric acid Sodium sulfite Butyl lithium Zinc chloride Hydrogen bromide Sodium methanolate Silver trifluoroacetate

3-Chloroperbenzoic acid Sodium hydroxide Sodium metaperiodate Sodium bicarbonate n-Butyltriphenylphosphonium bromide Hydrogen peroxide Sodiumbis(trimethylsilyl)amide 2,4-Bis(trifluoromethyl)benzyltriphenylphosphonium bromide

Manufacturing Process A solution of 3-chloroperbenzoic acid (55%) in methylene chloride is cooled in an ice bath. (5R)-(-)-Carvone are added dropwise thereto so that the temperature does not rise above 20°C. The reaction mixture is stirred at room temperature for 3.5 h, whereby a precipitate of 3-chlorobenzoic acid forms. This suspension is stirred for 30 min and cooled with ice in order to complete the precipitation. The precipitate is filtered off and washed with hexane/methylene chloride (9:1). The filtrate is evaporated carefully. The thus-obtained oil (epoxide) is suspended in ice-water and treated with 3 N sulfuric acid while cooling in an ice bath so that the temperature does not rise above 20°C. The mixture is stirred at room temperature for 15 h. The pH is adjusted to 6.5 by adding 3 N sodium hydroxide solution. A small amount of 3-chlorobenzoic acid is filtered off. The aqueous phase is cooled to 0°C, whereupon sodium (meta)periodate are added in portions over 30 min so that the temperature does not rise above 20°C. After stirring at room temperature for 2 h sodium sulfite and sodium bicarbonate are added in succession. The suspension is filtered and the filtrate is extracted three times with methylene chloride each time. The combined organic phases are dried over sodium sulfate and evaporated. There is obtained (5R)-5-acetyl-2-methyl-2cyclohexen-1-one (crystallized from hexane/ethyl acetate at 0°C). n-Butyltriphenylphosphonium bromide are suspended in dry tetrahydrofuran under argon and cooled to -50°C. 1.33 N n-butyl lithium in hexane are added thereto. The orange coloured suspension is warmed to room temperature and then again cooled to -50°C. (5R)-5-Acetyl-2-methyl-2-cyclohexen-1-one dissolved in dry tetrahydrofuran are added dropwise thereto over a period of 20 min. The cooling bath is then removed and the suspension is left to warm to room temperature. After stirring for 2 h the reaction mixture is filtered through siliceous earth. The filtrate is evaporated, the dark residue is dissolved in ethyl acetate and washed twice with water each time. The organic phase is dried over sodium sulfate and evaporated. The thus-obtained oil is purified by column chromatography on silica gel with hexane/ethyl acetate (95:5) as the elution agent. There is obtained (5R)-2-methyl-5-[(Z)-1-methyl1-pentenyl]-2-cyclohexen-1-one. (5R)-2-Methyl-5-[(Z)-1-methyl-1-pentenyl]-2-cyclohexen-1-one are dissolved

402

Artilide fumarate

in methylene chloride and cooled to 0°C. After adding a catalytic amount zinc chloride the solution is saturated with hydrogen bromide gas. After 30 min the solution is filtered through silica gel and evaporated carefully. The resulting oily residue is dissolved in dry ether, cooled to 0°C and treated with 100% hydrogen peroxide. Silver trifluoroacetate dissolved in dry ether are added dropwise over a period of 30 min. The excess of silver ions is precipitated by adding 1 N hydrochloric acid and the suspension obtained is filtered through silica gel. In order to remove the excess hydrogen peroxide, the filtrate is washed 5 times with water each time. The ether phase is then evaporated carefully and the residue is taken up methanol. A catalytic amount of sodium methanolate is added to this solution, whereupon the mixture is left to stand at room temperature for 15 h. The methanol is distilled off and the residue is purified and separated into the two diastereomers (1:1) by chromatography on silica gel while eluting with hexane/ethyl acetate (7:3). There are obtained (1S,4R,5R,8S)-4-butyl-4,8-dimethyl-2,3-dioxabicyclo[3.3.1]nonan-7-one. (1S,4R,5R,8S)-4-Butyl-4,8-dimethyl-2,3-dioxabicyclo[3.3.1]nonan-7-one is dissolved in methylene chloride. 2,4-Bis(trifluoromethyl) benzyltriphenylphosphonium bromide and sodium bis(trimethylsilyl)amide are added thereto and the solution is left to stand at room temperature for 24 h. The methylene chloride is distilled off and the (1S,4R,5R,8S)-4-[(Z)-2,4bis(trifluoromethyl)styryl-4,8-dimethyl-2,3-dioxabicyclo[3.3.1]nonan-7-one, melting point 124°C is obtained. References Hofneinz W. et al.; US Patent No. 4,977,184; December 11, 1990; Assigned: Hoffmann-La Roche Inc., Nutley, N.J.

ARTILIDE FUMARATE Therapeutic Function: Antiarrhythmic Chemical Name: Methanesulfonamide, N-(4-(4-(dibutylamino)-1hydroxybutyl)phenyl)-, (R)-, fumarate (2:1) (salt) Common Name: Artilide fumarate Chemical Abstracts Registry No.: 133267-19-3 (Base); 133267-20-6 Raw Materials Aniline Aluminum chloride Sodium bicarbonate 1-Hydroxybenzotriazole Lithium aluminum hydride 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride

Methanesulfonyl chloride Succinic anhydride Hydrogen hydrochloride Dibutylamine Sodium potassium tartrate

Artilide fumarate

403

Structural Formula:

Trade Name Artilide fumarate

Manufacturer Upjohn (Pharmacia)

Country -

Year Introduced -

Manufacturing Process A mechanically stirred solution of aniline (139.7 g, 1.5 mol) in pyridine (2 L), under N2 is cooled in an icebath. Methanesulfonyl chloride (171.8 g, 1.5 mol) is added dropwise to this solution while the temperature is maintained at 15°20°C, which results in a red-orange color change in the reaction mixture. After the addition is complete the ice bath is removed and the reaction is allowed to continue at room temperature for 2.5 h. The reaction mixture is concentrated in vacuo and the residue is combined with 700 ml of water which results in crystallization of a dark red material. This material is filtered and washed several times with water. The filtered material is dissolved in CH2Cl2, washed with brine, dried (Na2SO4), and concentrated in vacuo to give four crops (157.37 g, 19.27 g, 26.55 g, 5.07 g) of methanesulfonanilide, melting point 93°C (decolorizing with Darco carbon and crystallization from ethyl acetate). A mechanically stirred suspension of aluminum chloride (88.0 g, 0.66 mol) and 150 ml of carbon disulfide under N2 is cooled in an ice bath. Methanesulfonanilide (30.0 g, 0.175 mol) and succinic anhydride (17.5 g, 0.175 mol) are combined and added rapidly to the cooled reaction mixture. The ice bath is removed and the mixture is stirred at room temperature for 6 h. The reaction mixture is then heated to 55°C and allowed to continue for 18 h. The reaction mixture is separated into two layers the bottom of which solidifies. The upper layer is decanted and the remaining solid layer is decomposed with ice. The resulting suspension is filtered and the solid is washed several times with methylene chloride and dissolved in a mixture of saturated sodium bicarbonate (500 ml) and water (500 ml). This solution is

404

Ascorbic acid

acidified (pH 2) with HCl and the resulting precipitate is collected by filtration, redissolved in NaHCO3 and reprecipitated with HCl. The solid is collected by filtration and dried to give 4-[(methylsulfonyl)amino]-γ-oxobenzenebutanoic acid, melting point 198°-200°C. A mixture of 4'-[(methylsulfonyl)amino]-γ-oxobenzenebutanoic acid and 1hydroxybenzotriazole in dimethylformamide (DMF) under nitrogen, is treated with dibutylamine in DMF. The mixture is cooled in an ice bath and 1-ethyl-3(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC) added in portions over 5 min. The mixture is stirred in the cold 1 h and overnight at room temperature. The solvent is removed in vacuo (bath temperature 35°C). The residue is treated with ice and ethyl acetate and the organic layer washed sequentially with 0.5 N monopotassium sulfate, cold 4% NaHCO3, cold water and finally brine. The organic solution is dried (Na2SO4) and concentrated in vacuo. The N,N-dibutyl-γ-oxo-4-[(methylsulfonyl)amino]benzenebutan-amide (crystallized from ethyl acetate-hexane) is obtained. Lithium aluminum hydride is suspended in dry tetrahydrofuran (THF), under nitrogen and the mixture cooled in an ice bath. To this mixture is added N,Ndibutyl-γ-oxo-4-[(methylsulfonyl)amino]benzenebutanamide, (partly as a suspension in THF added over 10 min and partly as a solid added in portions over 30 min). The mixture is stirred for 2.5 h in the cold. The cold reaction mixture is then treated cautiously with a saturated solution of sodium potassium tartrate in water and stirred for 10 min in the cold. This mixture is extracted with EtOAc. The pooled ethyl acetate extracts are washed with brine, dried (Na2SO4) and concentrated in vacuo to give a solid. The aqueous residue from the above extractions is diluted with 10 ml of water and extracted with ethyl acetate. The pooled extract is washed with brine, dried (Na2SO4) and concentrated to give solid. The two solids are recrystallized separately from EtOAc to give N-4[4-(dibutylamino)-1-hydroxybutyl]phenyl]methanesulfonamide (recrystallized from EtOAc-hexane). By recrystallyzation of stereo-isomers of N-4-[4-(dibutylamino)-1hydroxybutyl]phenyl]methanesulfonamide may be obtained the (R)-N-4-[4(dibutylamino)-1-hydroxybutyl]phenyl]methanesulfonamide, melting point 179°-180°C. References Boling H.J.; EU Patent No. 0,164,865; May 1, 1985; Assigned: Perry, Robert Edward et al., GILL JENNINGS and EVERY 53-64 Chancery Lane London WC2A 1HN (GB)

ASCORBIC ACID Therapeutic Function: Vitamin Chemical Name: 3-Keto-L-gulofuranolactone

Ascorbic acid

405

Common Name: Acide ascorbique; Acido ascorbico; Acidium ascorbicum; Acidum ascorbinicum; Ascorbic acid; Ascorbinsaure; Askorbinsyra; Cevitamic acid; C-Vitamin; Hexuronic acid; Hexuronsaure; Vitamin C; Witamina C Structural Formula:

Chemical Abstracts Registry No.: 50-81-7 Trade Name Ascorbic acid Cebion Celin Chewable Plivit C

Manufacturer Natur Product Merck KGaA Glaxo Pliva

Country France Germany India Croatia

Year Introduced -

Styptovit

Dr. Reddy's Laboratories Ltd.

India

-

Upsavit Vitamin C Vitamin C

UPSA Hemofarm

Vitamin CInjektopas Vitamin C Nycomed Vitrum Plus Vitamin C

Pascoe Naturmedizin

France Serbia and Montenegro Germany -

Nycomed Pharma A/S

Norway

-

Unipharm

USA

-

Raw Materials Glucose Nickel Raney Acetone Sodium hypochlorite Manufacturing Process D-Glucose was reduced to the D-sorbitol with a hydrogen over Ni Raney, then it was turned into the L-sorbose with the acetobacter suboxydans and the hydroxyl groups of L-sorbose were protected with acetone treatment yielded the diaceton-L-sorbose. Subsequent treatment with NaOCl/Raney Ni produced di-O-isopropylidene-2-oxo-L-gulonic acid. Partial hydrolysis with aqueous HCl gave deprotected 2-oxo-L-gulonic acid, which yielded ascorbinic acid by heating with HCl.

406

Asobamast

References Reichstein T., Grusser A.; Helv. Chim. Acta, 17, 311 (1934) Kirk-Othmer, Encyclopedia of Chemical Technology, 2 Aufl. Vol. 2, s.747 ff

ASOBAMAST Therapeutic Function: Antiallergic, Anti-asthmatic Chemical Name: 2-Ethoxyethyl (4-(3-methyl-5-isoxazolyl)-2-thiazolyl) oxamate Common Name: Asobamast; Sobamast Structural Formula:

Chemical Abstracts Registry No.: 104777-03-9 Trade Name Asobamast

Manufacturer Onbio Inc.

Country -

Year Introduced -

Raw Materials Bromine 3-Methyl-5-acetylisoxazole Thiourea 2-Ethoxyethyloxalyl chloride Manufacturing Process 1). 179 mmol of bromine in 20 ml of chloroform were added dropwise in 10 minutes to a solution of 172 mmol of 3-methyl-5-acetylisoxazole, (Gass. Chim. Ital. 72, 242, 194) containing 4.9 ml of glacial acetic acid while the reaction mixture was maintained under stirring at 48°-50°C. After 5 minutes the mixture was poured into 300 g of water and crushed ice. The organic layer was separated, washed with water, dried and evaporated to residual 3methyl-5-bromoacetylisoxazole. Yield 87%; white crystalline compound, MP: 44°-46°C (isopropyl ether).

Asocainol hydrochloride

407

2). A mixture of 50 mmol of 3-methyl-5-bromoacetylisoxazole and 100 mmol of thiourea in 164 ml of ethyl alcohol was refluxed for 90 minutes and then cooled for 1 hour with an ice bath. The precipitate was collected by filtration and added to a mixture of 25 ml of a 10% aqueous solution of sodium hydroxide and 100 ml of ethyl acetate under vigorous stirring. The organic layer was separated, washed, dried and evaporated to dryness after recrystallization from acetonitrile the 2-amino-4-(3-methyl-5isoxazolyl)thiazole melts at 208°-210°C. Yield, 57%. 3). To a mixture of 20.5 mmol of 2-amino-4-(3-methyl-5-isoxazolyl)thiazole in 37.4 ml of pyridine maintained under stirring at 5°C were added dropwise 23.6 mmol of 2-ethoxyethyloxalyl chloride. The reaction mixture was maintained under stirring overnight, then poured into 100 g of crushed ice, made acid with concentrate hydrochloric acid and extracted with chloroform. The chloroform extracts were washed with water, dried and evaporated to dryness. The residual 2-ethoxyethyl-4-(3-methyl-5-isoxazolyl)thiazole-2oxamate was re-crystallized from 65 ml of acetonitrile. Yield, 91%; MP: 155°156°C. References Carenzi A. et al.; US Patent No. 4,766,137; August 23, 1988; Assigned: Zambon S.p.A., Vicenza, Italy

ASOCAINOL HYDROCHLORIDE Therapeutic Function: Antiarrhythmic Chemical Name: (+/-)-6,7,8,9-Tetrahydro-2,12-dimethoxy-7-methyl-6-(2phenylethyl)-5H-dibenz[d,f]azonin-1-ol hydrochloride Common Name: Asocainol hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 77400-65-8 (Base); 91574-89-9 Trade Name

Manufacturer

Country

Year Introduced

Asocainol hydrochloride

ZYF Pharm Chemical

-

-

408

Asparaginase

Raw Materials Phenethyl bromide Activated magnesium turnings Thebaine Ammonium chloride Manufacturing Process A solution of a Grignard reagent is prepared from 5.5 g (0.23 mol) activated magnesium turnings and 41.5 g (0.24 mol) phenethyl bromide in 200 ml anhydrous diethyl ether. To this is added dropwise, at 35-40°C, a solution of 31.5 g (0.1 mol) thebaine in 0.4 liters dry benzene. After heating under reflux for 2 hours, the reaction mixture is decomposed with a solution of 48 g ammonium chloride in 200 ml water. The usual working up, after conversion of the base into the hydrochloride by means of hydrogen chloride in ethyl acetate, gives 7.3 g (21% of theory) (+/-)-2,12-dimethoxy-1-hydroxy-7methyl-6-phenethyl-5,6,8,9-tetrahydro-7H-dibenz[d,f]azonine hydrochloride; melting point 227.6°C, after recrystallization from propan-2-ol. References Satzinger Gerhard, Herrmann Manfred, Fritschi Edgar, Bahrmann Heinrich, Ganser Volker, Wagner Bernd, Steinbrecher Wolfgang; US Patent No. 4,689,339; Nov. 15, 1983; Assigned to Godecke Aktiengesellschaft (Freiburg, DE)

ASPARAGINASE Therapeutic Function: Antineoplastic (acute leukemia) Chemical Name: See Structural Formula Common Name: Colapase; L-Asnase Structural Formula: L-Asparagine amidohydrolase (an enzyme of MW 133,000 ± 5,000 believed to consist of 4 equivalent subunits) Trade Name Crasnitin Crasnitin Leunase Kidrolase Crasnitin Elspar

Manufacturer Bayer Bayer Kyowa Hakko Specia Bayer Merck Sharp and Dohme

Country W. Germany Italy Japan France UK US

Year Introduced 1969 1971 1971 1971 1971 1978

Kidrolase Leucogen

Rhone Poulenc Bayer

Canada -

-

Aspartame

409

Chemical Abstracts Registry No.: 9015-68-3 Raw Materials Erwinia bacteria Nutrient medium Manufacturing Process Therapeutically active L-asparaginase is isolated from bacteria from the genus Erwinia, a known genus pathogenic towards plants. L-asparaginase is conveniently isolated from this genus by growing the bacteria upon a suitable nutrient medium until a desired quantity is obtained and then extracting the L-asparaginase either by conventional cell disruption methods, or preferably, by processes more fully described in US Patent 3,660,238. References Merck Index 849 Kleernan and Engel p. 62 PDR p. 1176 I.N. p. 102 REM p. 1143 Wade, H.E.; US Patent 3,660,238; May 2, 1972 Herbert, D. and Wade, H.E.; US Patent 3,686,072; August 22, 1972

ASPARTAME Therapeutic Function: Sugar supplement Chemical Name: N-L-α-Aspartyl-L-phenylalanine 1-methyl ester Common Name: Structural Formula:

Chemical Abstracts Registry No.: 22839-47-0

410

Aspartame

Trade Name Canderel Canderel Equal Canderel Canderel Nutrasweet

Manufacturer Searle Searle Searle Wander Muro Searle

Country France Switz. US W. Germany US US

Year Introduced 1979 1981 1982 1983 -

Raw Materials L-Phenylalanine methyl ester hydrochloride N-Benzyloxycarbonyl-L-aspartic acid α-p-nitrophenyl, β-benzyl diester Hydrogen Manufacturing Process A solution of 88.5 parts of L-phenylalanine methyl ester hydrochloride in 100 parts of water is neutralized by the addition of dilute aqueous potassium bicarbonate, then is extracted with approximately 900 parts of ethyl acetate. The resulting organic solution is washed with water and dried over anhydrous magnesium sulfate. To that solution is then added 200 parts of Nbenzyloxycarbonyl-L-aspartic acid α-p-nitrophenyl, β-benzyl diester, and that reaction mixture is kept at room temperature for about 24 hours, then at approximately 65°C for about 24 hours. The reaction mixture is cooled to room temperature, diluted with approximately 390 parts of cyclohexane, then cooled to approximately -18°C in order to complete crystallization. The resulting crystalline product is isolated by filtration and dried to afford βbenzyl N-benzyloxycarbonyl-L-aspartyl-L-phenylalanine methyl ester, melting at about 118.5-119.5°C. To a solution of 180 parts of β-benzyl N-benzyloxycarbonyl-L-aspartyl-Lphenylalanine methyl ester in 3,000 parts by volume of 75% acetic acid is added 18 parts of palladium black metal catalyst, and the resulting mixture is shaken with hydrogen at atmospheric pressure and room temperature for about 12 hours. The catalyst is removed by filtration, and the solvent is distilled under reduced pressure to afford a solid residue, which is purified by recrystallization from aqueous ethanol to yield L-aspartyl-L-phenylalanine methyl ester. It displays a double melting point at about 190°C and 245247°C. References Merck Index 852 DOT 16 (2) 65 (1980) I.N. p. 102 Schlatter, J.M.; US Patent 3,492,131; January 27, 1970; Assigned to G.D. Searle and Co.

Aspirin

411

ASPIRIN Therapeutic Function: Analgesic, Antipyretic, Antiinflammatory Chemical Name: 2-(Acetyloxy)benzoic acid Common Name: Acetylsalicylic acid Structural Formula:

Chemical Abstracts Registry No.: 50-78-2 Trade Name Entab Easprin Ecotrin Zorprin Verin AAS Acesal Acetard Acetisal Acetisal Acetisal Acetical Acetophen Acetylin Acetylo Acetylosal Acetyl-Sal Acetysal Acetysal Acetysal Acimetten Acisal Adiro Alaspine Albyl Algo Alka-Seltzer

Manufacturer Mayrand WL/PD Menley and James Boots Verex Sterwin Espanola Oranienbourg Benzon Alkaloid Farmakos Galenika Rekah Merck-Frosst Heyden Chemedica Maria Heil Hartz Jugoremedija Krka Zdravlje Kwizda Pliva Bayer Liba AFI Lokman Miles

Country US US US US US Spain E. Germany Denmark Yugoslavia Yugoslavia Yugoslavia Israel Canada W. Germany Switz. Austria Canada Yugoslavia Yugoslavia Yugoslavia Austria Yugoslavia Turkey Norway Turkey Italy

Year Introduced 1982 1982 1983 1983 1983 -

412

Aspirin

Trade Name Ancasal Antidol Apernyl Apyron

Manufacturer Anca Gebro Bayer Lingner and Fischer

Country Canada Austria Japan W. Germany

Year Introduced -

Asart Asatard Asdol Aspalgin Aspec

SK and F De Angeli Srbolek Krka Kempthorne Prosser Egic Otis Clapp Buffington Bayer Dover Miles Bayer Nicholas Pan Quimica Rivopharm Medic Atabay Pfizer Deva Boots Izal Teva Buffington Dover Yer Sinclair Liade Theraplix Cederroths Bayer Nicholas Nicholas Nicholas Fass Bayer Spitzner

US Italy Yugoslavia Yugoslavia New Zealand

-

France US US W. Germany US US W. Germany Italy Spain Switz. Canada Turkey US Turkey UK UK Israel US US Spain UK Spain France Sweden Italy UK France Spain W. Germany W. Germany

-

Rougier Maggioni Medici Domus Andromaco

Canada Italy Italy Argentina

-

Aspegic Aspercin Aspermin Aspirin Aspirtab Aspirvess Aspisol Aspro Aspro Asrivo Astrin Ata spin Babypyrin Bebaspin Bi-Prin Breoprin Bufacyl Buffaprin Buf fasal Calmo Yer Caprin Casprium Catalgine Cedrox Cemerit Claradin Claragine Clariprin Codalgina Colfarit ContrheumaRetard Coryphen Diaforil Domupirina Ecasil

Aspirin Trade Name Ecoprin Ecotrin Empirin Endospirin Endyol Entericin Enterosarine Entrophen Eskotrin Extren Flectadol Genasprin Godamed Globentyl Globoid Glucetyl Hagedabletten Halgon Idotyl Juveprine Kilios Levius Levius Licyl Longasa Magnecyl Magnyl Measurin Medisyl Mejoral Infantil Micristin Neopirine Neutracetyl Nibol Nova-Phase Novasen Pharmacin Premaspin Pyronoval Rectosalyl Reunyl Rhodine Rhonal Rhonal

Manufacturer Sam-On SK and F BurroughsWellcome Enila-Lotecia Guidotti Bristol-Myers Sarein Merck-Frosst SK and F Vicks Maggioni Fisons Pfleger Nyegaard Nyegaard Technicopharm Hageda Togal Ferrosan Sarget Farmitalia Pharmitalia Montedison A.L. Squibb ACO DAK Breon Medica Sterwin Espanola Gyogyert Casgrain and Charbonneau Promedica Bosnalijek Nova Novopharm Optrex Laake Hoechst Bouty Hassle Specia Specia Rhodia Iberica

413

Country Israel US US

Year Introduced -

Brazil Italy US France Canada US US Italy UK W. Germany Norway Norway Switz. W. Germany W. Germany Denmark France Italy UK W. Germany Norway US Sweden Denmark US Finland Spain Hungary Canada

-

France Yugoslavia Canada Canada UK Finland W. Germany Italy Sweden France France Spain

-

414

Aspirin

Trade Name Rhusal Riphen Rodina Sal Adult Sal Infant Sargepirine Saspryl Seclopyrine Servisprin Solprin Solpyron Solucetyl Solusal St. Joseph Supasa Tasprin Temagin Triaphen Trineral Winsprin

Manufacturer G.P. Riva Farmitalia Beecham Beecham Sarget Teva Seclo Servipharm Reckitt Beecham Sarbach Hamilton Plough Nordic Ticen Beiersdorf Trianon Beiersdorf Winthrop

Country Australia Canada Italy UK UK France Israel France Switz. UK UK France Australia US Canada UK W. Germany Canada W. Germany US

Year Introduced -

Raw Materials Salicylic acid Acetic anhydride Ketene Manufacturing Process As described in US Patent 2,731,492, a glass-lined reactor of 1,500 gallons capacity, fitted with a water-cooled reflux condenser, thermometers with automatic temperature registers and an efficient agitator, is employed. To start the process, a mother liquor is made by dissolving 1,532 kg of acetic anhydride (15 mols) in 1,200 kg of toluene. To this mother liquor, add 1,382 kg of salicylic acid (10 mols), heat the reaction mixture under an efficient reflux condenser, to 88-92°C and maintain within this temperature range for 20 hours. The reaction mixture is now transferred to aluminum cooling tanks, and is allowed to cool slowly, over a period of 3 to 4 days, to a terminal temperature of 15-25°C (room temperature). The acetylsalicylic acid precipitates as large, regular crystals. The mother liquor is now filtered or centrifuged from the precipitated acetylsalicylic acid and the filter cake is pressed or centrifuged as free of mother liquor as possible. The crystals are washed with distilled water until completely free of acetic acid, pressed or centrifuged as dry as possible and the filter cake is then dried in a current of warm air at a temperature of 60-70°C.

Aspoxicillin

415

The filtrate from this first batch will comprise a solution of 180 to 270 kg of unprecipitated acetylsalicylic acid (1.0 to 1.5 mols), 510 kg of acetic anhydride (5.0 mols), 600 kg of acetic acid (10.0 mols) (obtained as a byproduct in the acetylation step) and 1,200 kg of the diluent toluene. Into this filtrate, at a temperature of 15° to 25°C, ketene gas is now passed through a sparger tube or diffuser plate, with good agitation, until a weight increase of 420.5 kg of ketene (10 mols) occurs. The reaction mixture will now contain 180-270 kg of unprecipitated acetylsalicylic acid (1.0-1.5 mols) and 1,532 kg of acetic anhydride (15 mols) in 1,200 kg of toluene. This mother liquor is recycled to the first step of the process for reaction with another batch of 1,382 kg of salicylic acid. On recirculating the mother liquor, the yield of pure acetylsalicylic acid is 1,780 to 1,795 kg per batch. References Merck Index 863 Kleeman and Engel p. 12 PDR (Many References) DOT 16 (10) 359 (1980) REM p. 1112 Kamlet, J.; US Patent 2,731,492; January 17, 1956 Hamer, W.E. and Phillips, G.V.; US Patent 2,890,240; June 9, 1959; Assigned to Monsanto Chemicals, Limited, England Edmunds, R.T.; US Patent 3,235,583; February 15, 1966; Assigned to The Norwich Pharmacal Company

ASPOXICILLIN Therapeutic Function: Antibiotic Chemical Name: Glycinamide, N-methyl-D-asparaginyl-N-(2-carboxy-3,3dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-6-yl)-D-2-(4hydroxyphenyl)-,(2S-(2-α,5-α,6-β))Common Name: Apaxicillin; Aspoxicillin; Doyle Structural Formula:

Chemical Abstracts Registry No.: 63358-49-6

416

Aspoxicillin

Trade Name Aspoxicillin Aspoxicillin Aspoxicillin

Manufacturer Shiono Chemical Co., Ltd. ZYF Pharm Chemical INTERCHEMICAL(chongqing) CO. LTD

Country -

Year Introduced -

-

-

Raw Materials D-2-Amino-3-N-methylcarbamoyl-propionic acid hydrochloride (D-N'methylasparagine HCl) Benzyloxycarbonyl chloride Dicyclohexylcarbodiimide N-Hydroxysuccinimide p-Hydroxy-D-phenylglycine Citric acid 6-Aminopenicillanic acid Triethylamine Palladium on barium carbonate Manufacturing Process 1). 3 g (23.6 millimoles) of D-2-amino-3-N-methylcarbamoyl-propionic acid hydrochloride (D-N'-methylasparagine HCl), 4.5 g of benzyloxycarbonyl chloride, 30 g of water, 30 ml of tetrahydrofuran and 12 g of potassium carbonate are mixed at 5° to 10°C. Then, the mixture is stirred at the same temperature for 2 hours. During the reaction, the mixture is kept at a slightly alkaline pH (pH 8) with potassium carbonate. 10 ml of water are added to the reaction mixture, and insoluble materials are filtered off. The filtrate is washed twice with ethyl acetate, acidified with citric acid and then extracted three times with 50 ml of ethyl acetate. The ethyl acetate extracts are washed with water, dried and evaporated to remove solvent. 5.1 g of D-2benzyloxycarbonylamino-3-N-methylcarbamoyl-propionic acid are obtained. MP: 142°-143°C. 2). 2.8 g (10 millimoles) of D-2-benzyloxycarbonylamino-3-Nmethylcarbamoyl-propionic acid, 2.27 g of dicyclohexylcarbodiimide, 1.27 g of N-hydroxysuccinimide and 120 ml of tetrahydrofuran are mixed at 0° to 5°C, and the mixture is stirred at the same temperature for 16 hours. Insoluble materials are filtered off. Then, the filtrate is evaporated at 20°C under reduced pressure to remove the solvent, and the crystalline precipitates thus obtained are washed with a mixture of benzene-ether. 2.6 g of N-(D-2benzyloxycarbonylamino-3-N-methylcarbamoyl-propionyloxy)succinimide are obtained. MP: 132°-134°C. 3). 3.75 g of N-(D-2-benzyloxycarbonylamino-3-Nmethylcarbamoylpropionyloxy)succinimide are dissolved in 50 ml of tetrahydrofuran. 12.5 ml of an aqueous 1 N-sodium hydroxide solution containing 2.3 g of p-hydroxy-D-phenylglycine are added to the solution. The mixture is stirred at room temperature for 24 hours. 20 ml of ethyl acetate and 20 ml of water are added to the reaction mixture, and said mixture is shaken. Then, the aqueous layer is separated, adjusted to pH 3 with citric acid

Astemizole

417

and extracted with a mixture of 20 ml of tetrahydrofuran and 10 ml of ethyl acetate. The extract is washed with water, dried and evaporated to remove solvent. The residue thus obtained is washed with ether. 3.0 g of D-2-(D-2benzyloxycarbonylamino-3-N-methylcarbamoylpropionamido)- 2-phydroxyphenylacetic acid are obtained as colorless crystalline powder. MP: 154°-156°C(decomp.). 4). 429 mg of D-2-(D-2-benzyloxycarbonylamino-3-Nmethylcarbamoylpropionamido)-2-p-hydroxyphenylacetic acid and 382 mg of 6-aminopenicillanic acid triethylamine salt are dissolved in 10 ml of dimethylformamide. 303 mg of diphenylphosphoric azide [N3PO(OC6H5)2] and 110 mg of triethylamine are added to the solution at -5°C, and the mixture is stirred at -5°C for 15 hours. After the reaction, the mixture is adjusted to pH 3 with an aqueous 5% citric acid solution and extracted with a mixture of 15 ml of tetrahydrofuran and 10 ml of ethyl acetate. The extract is washed with water, dried and then evaporated at below 40°C to remove the solvent. Ether is added to the residue obtained, and precipitates are collected by filtration. 509 mg of 6-[D-2-(D-2-benzyloxycarbonylamino-3-Nmethylcarbamoylpropionamido)-2-p-hydroxyphenylacetamido]penicillanic acid are obtained as a colorless powder. 5). 627 mg of 6-[D-2-(D-2-benzyloxycarbonylamino-3-N-methylcarbamoylpropionamido)-2-p-hydroxyphenylacetamido]penicillanic acid and 400 mg of 30% palladium-BaCO3 are suspended in 10 ml of methanol. The suspension is shaken at room temperature for 30 minutes. Said shaking step is carried out in a hydrogen gas atmosphere under atmospheric pressure. After the reaction is completed, the catalysts are removed by filtration. The filtrate is evaporated at below 40°C to remove the solvent, and ether is added to the residue. Then, a colorless crystalline powder is collected by filtration and washed with tetrahydrofuran. 443 mg of 6-[D-2-(D-2-amino-3-N-methylcarbamoylpropionamido)-2-p-hydroxyphenylacetamido]penicillanic acid are obtained. MP: 198°-201°C(decomp.). References Kawazu M. et al.; US Patent No. 4,053,609; October 11, 1977; Assigned to Tanabe Seiyaku Co., Ltd., Osaka, Japan

ASTEMIZOLE Therapeutic Function: Antiallergic, Antihistaminic Chemical Name: 1-[(4-Fluorophenyl)methyl]-N-[1-[2-(4-methoxyphenyl) ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine Common Name: Chemical Abstracts Registry No.: 68844-77-9

418

Astemizole

Structural Formula:

Trade Name Hismanal

Manufacturer Janssen

Country UK

Year Introduced 1983

Raw Materials 2-(4-Methoxyphenyl)ethyl methane sulfonate 1-[(4-Fluorophenyl)methyl]-N-(4-piperidinyl)-1H-benzimidazol-2-amine dihydrobromide Sodium carbonate Manufacturing Process A mixture of 2.3 parts of 2-(4-methoxyphenyl)ethyl methanesulfonate, 4.9 parts of 1-[(4-fluorophenyl)methyl]-N-(4-piperidinyl)-1H-benzimidazol-2amine dihydrobromide, 3.2 parts of sodium carbonate, 0.1 part of potassium iodide and 90 parts of N,N-dimethylformamide is stirred overnight at 70°C. The reaction mixture is poured onto water. The product is extracted with methylbenzene. The extract is washed with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2,2'-oxybispropane, yielding 2.2 parts (48%) of 1(4-fluorophenylmethyl)-N-[1-[2-(4-methoxyphenyl)ethyl]-4-piperidinyl]-1Hbenzimidazol-2-amine; MP 149.1°C. References Merck Index A-1 DFU 7 (1) 10 (1982) OCDS Vol. 3 p. 177 DOT 19 (7) 412 (1983) I.N.p. 102 Janssens, F., Stokbroekx, R., Torremans, J. and Luyckx, M; US Patent 4,219,559; August 26, 1980; Assigned to Janssen Pharmaceutica N.V.

Astromicin sulfate

419

ASTROMICIN SULFATE Therapeutic Function: Antibiotic Chemical Name: L-chiro-Inositol, 4-amino-1-((aminoacetyl)methylamino)1,4-dideoxy-3-O-(2,6-diamino-2,3,4,6,7-pentadeoxy-β-L-lyxoheptopyranosyl)-6-O-methyl-, sulfate (1:2) Common Name: Astromicin sulfate; Fortimicin A Structural Formula:

Chemical Abstracts Registry No.: 55779-06-1 (Base); 72275-67-3 Trade Name Fortimicin sulfate Astromicin sulfate

Manufacturer Youngjin Pharma AroKor Holdings Inc.

Country -

Year Introduced -

Astromicin sulfate

ZYF Pharm Chemical Abbott Kyowa Hakko Kogyo Co., Ltd.

-

-

-

-

Abbott-44747 Fortimicin A Raw Materials

Micromonospora olivoasterospora MK-70 (ATCC 21819) Yeast extract Starch Corn steep liquor Magnesium sulfate heptahydrate Calcium carbonate Amberlite

Glucose Peptone Calcium carbonate Soybean meal Potassium phosphate, dibasic Potassium chloride Radiolite No. 600 Dowex

Manufacturing Process Aminoglycoside antibiotic complex produced by Micromonospora

420

Astromicin sulfate

olivoasterospora. Micromonospora olivoasterospora MK-70 (ATCC 21819) (FERM-P No. 1560) is used as a seed strain. One loopful of the seed strain is inoculated into 10 ml of a seed medium containing 2% glucose, 0.5% peptone, 0.5% yeast extract and 0.1% calcium carbonate (pH 7.5 before sterilization) in a 50 ml large test tube. Culturing is carried out at 30°C for 5 days. 10 ml of the seed culture broth is then inoculated into 30 ml of a second seed medium in a 250 ml Erlenmeyer flask. The composition of the second seed medium is the same as that of the first seed medium. The second seed culturing is carried out at 30°C for 2 days with shaking. Then 30 ml of the second seed culture broth is inoculated into 300 ml of a third seed medium in a 2 L Erlenmeyer flask provided with baffles. The composition of the third seed medium is the same as that of the first seed medium. The third seed culturing is carried out at 30°C for 2 days with shaking and 1.5 L of the third seed culture broth (corresponding to the content of five flasks) is inoculated into 15 L of a fourth seed medium in a 30 L glass jar fermenter. The composition of the fourth seed medium is the same as that of the first seed medium. Culturing in the jar fermenter is carried out at 37°C for 2 days with aeration and stirring (revolution: 350 r.p.m.; aeration: 15 L/min). Thereafter, 15 L of the fourth seed culture broth is inoculated into 150 L of a main fermentation medium in a 300 L fermenter. The main fermentation medium comprises 4% soluble starch, 2% soybean meal, 1% corn steep liquor, 0.05% K2HPO4, 0.05% MgSO4·7H2O, 0.03% KCl and 0.1% CaCO3 (pH 7.5 before sterilization). Culturing in the fermenter is carried out at 37°C for 4 days with aeration and stirring (revolution: 150 r.p.m.; aeration: 80 L/min). After the completion of culturing, the resulting fermentation broth is adjusted to a pH of 2.5 with concentrated sulfuric acid, and stirred for 30 minutes. Then, about 7 kg of a filter aid, Radiolite No. 600 (product of Showa Kagaku Kogyo Co., Ltd., Japan) is added thereto and the microbial cells are removed by filtration. The filtrate is adjusted to a pH of 7.5 with 6 N sodium hydroxide and passed through a column packed with about 20 L of a cation exchange resin, Amberlite IRC-50 (ammonium form), and the effluent is discarded. Active substances are adsorbed on the resin. After washing the resin with water, the adsorbed active substances are eluted out with 1 N aqueous ammonia. Activity of the eluate is determined by a paper disc method, using an agar plate of Bacillus subtilis No. 10707. The active fractions are collected and the mixture is concentrated to about 1 L under reduced pressure. The concentrate is passed through a column packed with 500 ml of an anion exchange resin, Dowex 1x2 (OH- form). Then, about 2 L of water is passed through the column, whereby impurities are removed and active substances are eluted out. The thus obtained active fractions are collected, and concentrated to about 100 ml under reduced pressure, and the resulting concentrate is passed through a column packed with about 50 ml of active carbon powder. The active substances are adsorbed onto the carbon powders. Then, the column is washed with water and the effluent and the washing water are discarded. Then, the adsorbed active substances are eluted out with 0.2 N sulfuric acid. Activity of the eluate is determined by the paper disc method using Bacillus subtilis, and the active fractions are collected. The thus obtained fractions are passed through a column of Dowex 44 (OH- form), and active substances are eluted out with water. The active fractions are again collected and concentrated to about 50 ml. The thus obtained concentrate is lyophilized, whereby about 32 g of a crude powder containing Fortimicin A is

Atamestane

421

obtained. The crude powder exhibits an activity of 575 unit/mg (the activity of 1 mg of a pure product corresponds to 1000 units). Then 10 g of the crude powder is placed as a thin and uniform layer on 500 ml of silica gel packed in a glass column. The glass column is prepared by suspending the silica gel in a solvent of the lower layer of a mixture comprising chloroform, isopropanol and 17% aqueous ammonia (2:1:1 by volume), and then packing the suspension tightly in the column as a uniform layer, and thereafter washing with the same solvent. After placing the crude powder at the head of the column, elution is carried out with the abovedescribed solvent by gradually pouring into the column from its top, and thereafter elution is carried out at a flow rate of about 50 ml/hour. The eluate is obtained as fractions of 20 ml each, and the activity of each fraction is determined by a paper disc method. Fortimicin B is eluted out at first. Thereafter, fractions containing Fortimicin A are obtained. The active fractions are subjected to paper chromatography, and the fractions containing Fortimicin A are collected and concentrated under reduced pressure to completely remove the solvent. The concentrate is then dissolved in a small amount of water. After freeze-drying the solution, about 1.8 g of purified preparate of the free base of Fortimicin A is obtained. The activity of the preparate is about 970 unit/mg. White amorphous powder, MP: >200° (dec.). [α] D25 +87.5° (c = 0.1 in water); solves in water and lower alcohols, insoluble in organic solvents. References Nara T. et al.; US Patent No. 3,946,768; August 24, 1976; Assigned to Abbott Laboratories, North Chicago Ill.

ATAMESTANE Therapeutic Function: Aromatase inhibitor Chemical Name: Androsta-1,4-diene-3,17-dione, 1-methylCommon Name: Atamestane Structural Formula:

Chemical Abstracts Registry No.: 96301-34-7

422

Atenolol

Trade Name Atamestane

Manufacturer Schering AG

Country -

Year Introduced -

Raw Materials 17β-Hydroxy-1-methylandrosta-1,4-dien-3-one Chromic acid Manufacturing Process 6.01 g of 17β-hydroxy-1-methylandrosta-1,4-dien-3-one is dissolved in 100 ml of acetone. At room temperature, 22 ml of a chromic acid solution (prepared from 6.67 g of CrO3, 6 ml of concentrated sulfuric acid, replenished with water to 100 ml) is added dropwise to this solution. The mixture is stirred for one hour and then precipitated into ice water; the product is suctioned off and dried, thus obtaining after recrystallization from acetone/hexane 5.25 g of 1-methylandrosta-1,4-diene-3,17-dione, melting point 165-166°C. References Kerb Ulrich, Sauer Gerhard, Wiechert Rudolf, Henderson David, Nishino Yukishige, Beier Sybille; US Patent No. 4,591,585; May 27, 1986; Assigned to Schering Aktiengesellschaft (Berlin and Bergkamen, DE)

ATENOLOL Therapeutic Function: Beta-adrenergic blocker Chemical Name: 4-[2-Hydroxy-3-[(1-methylethyl)amino]propoxy] benzeneacetamide Common Name: Structural Formula:

Chemical Abstracts Registry No.: 29122-68-7 Trade Name Tenormin Tenormin

Manufacturer Stuart I.C.I.

Country UK W. Germany

Year Introduced 1976 1976

Atenolol

Trade Name Tenormin Tenormin Tenormin Tenormin Atenol Blokium Ibinolo Myocord Normiten Seles Beta Tenoretic Vericordin

Manufacturer I.C.I. I.C.I. I.C.I. Stuart C.T. Prodes I.B.I. Szabo-Kessler Abic Farmitalia Stuart Lazar

Country Switz. Italy France US Italy Spain Italy Argentina Israel Italy US Argentina

423

Year Introduced 1978 1979 1979 1981 -

Raw Materials p-Hydroxyphenylacetamide Epichlorohydrin Isopropylamine Manufacturing Process 1 gram of 1-p-carbamoylmethylphenoxy-2,3-epoxypropane and 10 ml of isopropylamine in 25 ml of methanol is heated in a sealed tube at 110°C for 12 hours. The mixture is evaporated to dryness and the residue is partitioned between 50 ml of chloroform and 50 ml of aqueous 2 N hydrochloric acid. The aqueous acidic layer is separated, made alkaline with sodium carbonate and extracted twice with 50 ml of chloroform each time. The combined extracts are dried and evaporated to dryness and the residue is crystallized from ethyl acetate. There is thus obtained 1-p-carbamoylmethyiphenoxy-3isopropylamino-2-propanol, MP 146-148°C. The 1-p-carbamoylmethylphenoxy-2,3-epoxypropane used as starting material may be obtained as follows: a mixture of 3.2 grams of phydroxyphenylacetamide, 25 ml of epichlorohydrin and 6 drops of piperidine is heated at 95-100°C for 6 hours. The mixture is cooled and filtered and the solid product is crystallized from methanol. There is thus obtained 1-pcarbamoylmethylphencxy-2,3-epoxypropane, MP 158-160°C. References Merck Index 868 DFU 1 (1) 7 (1976) Kleeman and Engel p. 62 PDR pp. 1786, 1788 OCDS Vol. 2 p. 109 (1980) DOT 13 (2) 49 (1977) and 16 (1) 30 (1980) I.N. p. 103 REM p. 904 Barrett, A.M., Carter, J., Hull, R., Le Count, D.J. and Squire, C.J.; US Patent 3,663,607; May 16, 1972; Assigned to Imperial Chemical Industries Limited, England

424

Atevirdine mesylate

Barrett, A.M., Carter, J., Hull, R., Le Count, D.J. and Squire, C.J.; US Patent 3,836,671; September 17, 1974; Assigned to Imperial Chemical Industries Limited, England

ATEVIRDINE MESYLATE Therapeutic Function: Antiviral Chemical Name: Piperazine, 1-(3-(ethylamino)-2-pyridinyl)-4-((5-methoxy1H-indol-2-yl)carbonyl)-, monomethanesulfonate Common Name: Atevirdine mesylate Structural Formula:

Chemical Abstracts Registry No.: 136816-75-6 (Base); 138540-32-6 Trade Name Atevirdine mesylate

Manufacturer Upjohn

Country -

Year Introduced -

Raw Materials 1,1'-Carbonyldiimidazole Chlorotrimethylsilane Methanesulfonic acid

5-Methoxyindole-2-carboxylic acid 1-(3-N-Ethylamino-2-pyridinyl)piperazine

Manufacturing Process 1-[5-Methoxyindolyl-2-carbonyl]-4-[3-(ethylamino)-2-pyridinyl]piperazine: 1,1'-Carbonyldiimidazole (0.55 g) is added to a 20°-25°C solution of 5methoxyindole-2-carboxylic acid (0.59 g) in tetrahydrofuran (7.0 ml). After stirring 1 hour, the reaction is transferred via cannnula into a solution of 1-(3N-ethylamino-2-pyridinyl)piperazine (0.70 g) in tetrahydrofuran (7 ml) at 12°C (ice/acetone bath). The reaction is stirred at -10°C for 30 minutes, then slowly warmed to 20°-25°C and stirred a further 18 hours. After diluting with

Atibeprone

425

ether (60 ml), the mixture is washed with saturated aqueous sodium bicarbonate (70 ml), saline (70 ml) and dried over anhydrous sodium sulfate. The mixture is concentrated under reduced pressure to a residue which is purified by flash chromatography (2 cm x 20 cm) eluting with methanol/chloroform (2/98) to give the title compound, mp 153°-154°C. 1-[5-Methoxyindolyl-2-carbonyl]-4-[3-(ethylamino)-2-pyridinyl]piperazine hydrochloride: 1-(Ethyl)-3-(dimethylaminopropyl)carbodiimide (1.25 g) is added to a solution of 1-(3-ethyl-2-pyridinyl)piperazine (1.12 g) in THF (15 ml). The reaction is stirred at 20°-25°C for 3 hr; then it is dissolved in chloroform (50 ml) and extracted with saturated aqueous sodium bicarbonate, saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by flash column chromatography (200 g silica) eluting with ethyl acetate/hexane (50/50), the appropriate fractions are pooled and concentrated to give the title compound, The product is dissolved in methanol (150 ml) with heating, cooled to 20°-25°C and chlorotrimethylsilane (4.70 mmol) is added. The mixture is concentrated to half-volume, ether is added until cloudy and the flask is stored at 0°C overnight. Filtration gives the hydrochloride salt, MP: 194°-195°C. The mesylate salt is formed by dissolving the free base in methanol and by adding methanesulfonic acid (1 eq). The solution is diluted with diethyl ether until the salt crystallizes out of solution. The crystals are collected and dried to afford the mesyl salt of the title compound, MP: 215°-216°C. References Allen M.M. et al.; WO Patent No. 91/09849; 1991/07/11; Pharmacia and Upjohn Company, U.S.

ATIBEPRONE Therapeutic Function: Antidepressant Chemical Name: 7-((5-Isopropyl-1,3,4 thiadiazol-2-yl)methoxy)-3,4dimethylcoumarin Common Name: Atibeprone Structural Formula:

426

Atipamezole

Chemical Abstracts Registry No.: 153420-96-3 Trade Name Atibeprone

Manufacturer BASF

Country -

Year Introduced -

Raw Materials 7-Methoxy-3,4-dimethylcoumarin Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4diphosphetane 2,4-disulfide) Manufacturing Process 10 mmol of 7-methoxy-3,4-dimethylcoumarin were stirred with 10 mmol (4.04 g) of Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4diphosphetane 2,4-disulfide) in 20 ml of toluene at 90°C for 1-2.5 h. After cooling, the solvent was distilled off, the residue was taken up in DMF, and water was added. The precipitate was filtered off with suction and the crude 3,4-dimethyl-7-(2-isopropyl-1,3,4-thiadiazol-5-ylmethoxy)-2-thiocoumarin was purified by recrystallization from methanol or by column chromatography (silica gel, methylene chloride). Yield: 98%, melting point: 134-135°C. References Rendenbach-Mueller Beatrice, Karl Ulrich, Weifenbach Harald; US Patent No. 5,414,006; May 9, 1995; Assigned to BASF Aktiengesellschaft (Ludwigshafen, DE)

ATIPAMEZOLE Therapeutic Function: Antihypertensive Chemical Name: 4-(2-Ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole Common Name: Structural Formula:

Chemical Abstracts Registry No.: 104054-27-5 Trade Name Antisedan MPV 1248

Manufacturer Novartis Orion Farmos Group Ltd.

Country -

Year Introduced -

Atolide

427

Raw Materials 2-Acetyl-1-indanone Sodium carbonate Bromine Palladium on carbon

Ethyl bromide Sodium borohydride Hydrochloric acid

Manufacturing Process (a). 2-Acetyl-1-indanone (Liebigs Ann. Chem. 1906, 347, 112) is alkylated with ethylbromide in acetone in the presence of sodium carbonate to 2-acetyl2-ethyl-1-indanone. The acetyl group is brominated with bromine in methanol and to imidazole by heating in formamide as before. The melting point of the 4(5)-(2,3-dihydro-2-ethyl-1-oxo-1H-inden-2-yl)imidazole is 126-127°C (from ethyl acetate). (b). The carbonyl group of 4(5)-(2,3-dihydro-2-ethyl-1-oxo-1H-inden-2yl)imidazole is reduced to the alcohol group with sodium borohydride in ethanol. The product is the mixture of cis-trans stereoisomers, the purification of which is accomplished by liquid chromatography: cis-isomer as hydrochloride (melting point 184-185°C); 1H NMR (80 MHz, MeOH-d4): 0.73 (3H, t), 1.86 (2H, m), 3.36 (2H, m), 3.61 (3H, s), 5.15 (1H, s), 7.06 (1H, d), 7.2-7.4 (4H, m), 8.69 (1H, d), and trans-isomer as hydrochloride; 1H NMR (80 MHz, MeOH-d4): 0.80 (3H, t), 1.84 (2H, m), 3.15 (2H, m), 3.24 (3H, s), 5.15 (1H, s), 6.87 (1H, d), 7.2-7.4 (4H, m), 8.54 (1H, d). The oxo derivative prepared in step (a) or the hydroxy derivative prepared in step (b) is hydrogenated in 2 N hydrochloric acid in the presence of 10% palladium on carbon at 70°C. When the uptake of hydrogen ceases, the reaction mixture is filtered and made alkaline. The product is extracted with methylene chloride which is washed with water, dried and evaporated to dryness. From the residue, which is the product as base, is made the hydrochloride of 4(5)-(2,3-dihydro-2-ethyl-1H-inden-2-yl)imidazole using dry hydrogen chloride in ethyl acetate. It has melting point 211-215°C. References Karjalainen Arto J., Virtanen Raimo E., Karjalainen Arja L., Kurkela Kauko O.A.; US Patent No. 4,689,339; August 25, 1987; Farmos Yhtyma oy (Turku, FI)

ATOLIDE Therapeutic Function: Anticonvulsant Chemical Name: 2-Amino-N-[4-(diethylamino)-2-methylphenyl]benzamide Common Name: Atolide Chemical Abstracts Registry No.: 16231-75-7

428

Atorvastatin calcium

Structural Formula:

Trade Name Atolide

Manufacturer ZYF Pharm Chemical

Country -

Year Introduced -

Raw Materials 2-Amino-5-diethylaminotoluene Isatoic acid anhydride Manufacturing Process 0.8 kg (4.5 moles) of freshly distilled 2-amino-5-diethylaminotoluene is mixed thoroughly with 0.75 kg (4.5 moles) of isatoic acid anhydride and the mixture heated to 100°C with stirring for three hours. The product formed is taken up before cooling in 2.5 liters of boiling ethyl acetate and the solution filtered. On cooling the filtrate 1.1 kg (83% of theory) of 2-amino-4'-(diethylamino)-2'methylbenzanilide precipitates out. After re-crystallzation from n-propanol the colorless crystalline product obtained melts at 152°C. References G.B. Patent No. 1,123,457; 11 August 11, 1966; Warner Lambert Pharmaceutical Company, a Corporation of Delaware, USA

ATORVASTATIN CALCIUM Therapeutic Function: Anticholesteremic Chemical Name: (βR,δR)-2-(4-Fluorophenyl)-β,δ-dihydroxy-5-[(1methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1) Common Name: Atorvastatin calcium Chemical Abstracts Registry No.: 134523-03-08; 134523-00-5 (Base) Raw Materials n-Butyl diisopropyl amine t-Butylcarboxylic acid

Sodium borohydride Butyl lithium

Atorvastatin calcium

429

Triethylborane Bromine Magnesium S-(+)-2-Acetoxy-1,1,2-triphenylethanol 5-(4-Fluorophenyl)-2-(1-methylethyl)-1-(3-oxopropyl)-N,4-diphenyl-1Hpyrrole-3-carboxamide Structural Formula:

Trade Name Cardyl Citalor

Manufacturer Pfizer Pfizer Pharmaceuticals

Country Spain Ireland

Year Introduced -

Lipibec Lipibec Lipitor Lipitor Xarator

IVAX Arg. Syncro Parke Davis Pfizer Pfizer Italy S.p.A.

Argentina Italy

-

Manufacturing Process 285 ml 2.2 M n-butyl lithium in hexane was added dropwise to 92 ml diisopropylamine at -50-60°C under nitrogen. The well stirred solutions warmed to about -20°C, then it was cannulated into a suspension of 99 g of S(+)-2-acetoxy-1,1,2-triphenylethanol in 500 ml absolute tetrahydrophuran (THF) at -70°C and the reaction mixture was allowed to warm to -10°C for 2 hours. A suspension of MgBr2 was made from 564 ml (0.63 mol) of bromine and 15.3 g of magnesium (0.63 mol) in 500 ml THF cooled to -78°C. The enolate solution was cannulated into this suspension within 30 min and was stirred for 60 min at -78°C. 150 g 5-(4-fluorophenyl)-2-(1-methylethyl)-1-(3oxopropyl)-N,4-diphenyl-1H-pyrrole-3-carboxamide in 800 ml absolute THF was added dropwise over 30 min; stirred 90 min at -78°C, then was added 200 ml acetic acid, this is removed to a cool bath, 500 ml of H2O was added and the mixture concentrate in vacuo at 40-50°C. After adding of 500 ml of 1:1 EtOAc/heptane the mixture was filtered. The filtrate was washed extensively with 0.5 N HCl, then several times with H2O and finally

430

Atosiban

EtOAc/heptane (3:1) and cooled with dry ice to -20°C. The light brown crystalline product was dried in vacuum oven at 40°C. The yield was 194 g. 112 g of the same product was produced by evaporation of mother liquor after recrystallization and chromatographic purification on a silicagel. 162 g of this substance was suspended in methanol/THF (5:3) and was stirred with 11.7 g of sodium methoxide until everything was dissolved and kept in the freezer overnight. Later it was quenched with AcOH concentrated in vacuo, was added to 500 ml H2O and extracted twice with EtOAc (300 ml). The combined extracts was washed with saturated NaHCO3 brine and dried over anhydrous MgSO4, purified on silica-gel and gave 86.1 g of white crystals m.p. 125-126°C, αD20=4.23° (1.17 M, CH3OH). 81 g of the last product in 500 ml absolute THF was added as quickly as possible to the mixture of 77 ml THF at diisopropylamine, 200 ml 2.2 M of nbutyl lithium and 62 ml of t-butylacetate in 200 ml THF -40-42°C under nitrogen. Stirring was continued for 4 hours at -70°C. The reaction mixture was concentrated in vacuo, the residue was taken up in EtOAc, washed with water, then saturated NH4Cl, NaHCO3 (saturated), dried over anhydrous MgSO4, filtred and the solvent evaporated. The organic phase was dried and concentrated in vacuo to yield 73 g crude product, that was dissolved in 500 ml absolute THF, 120 ml triehtylborane and 0.7 g t-butylcarboxylic acid, 70 ml methanol and 4.5 g sodium borohydride was added. The mixture was stirred at -78°C under a dry atmosphere for 6 hours, poured slowly into 4:1:1 mixture of ice/30%H2O2/H2O and stirred overnight. CHCl3 (400 ml) was added and organic layer washed extensively with H2O until no peroxide could be found, was dried over MgSO4, filtered and was treated by chromatography on silica gel to yield 51 g. The product was dissolved in THF/methanol and saponificated with NaOH and, concentrated to remove organic solvents at room temperature, added 100 ml H2O, and extracted with Et2O twice. Organic layer was thoroughly dried and it was left at room temperature for the next 10 days, then concentrated. Chromatography on silica gel yielded 13.2 g racemate of lactone - trans-(+/)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-di-diphenyl-1-[2-(tetrahydro-4hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide. This racemate was divided by chiral synthesis which was made analogously the method in US Pat. No. 4,581,893. Then each isomer was saponificated with NaOH and purificated by HPLC. The calcium salt corresponding acid was prepared by reaction with 1 eq. of CaCl2·2H2O in water. References Roth B.D.; US Patent No. 5,273,995; Dec. 28, 1993; Assigned: WarnerLambert Company (Morris Plains, NJ)

ATOSIBAN Therapeutic Function: Oxytocin antagonist

Atosiban

431

Chemical Name: Oxytocin, 1-(3-mercaptopropanoic acid)-2-(O-ethyl-Dtyrosine)-4-L-threonine-8-L-ornithineCommon Name: Atosiban; Tractotile Structural Formula:

Chemical Abstracts Registry No.: 90779-69-4 Trade Name Tractocile Antocin Antocin Tractotile Atosiban

Manufacturer Ferring srl Ortho Ferring Ferring ASI Bio-tech's products

Country -

Year Introduced -

Raw Materials BocGly resin O-Ethyl-D-tyrosine Boc-L-ornithine Ammonia sodium BOC-L-Asparagine Diisopropylethylamine Dicyclohexylcarbodiimide

3-Mercaptopropanoic acid Boc-L-threonine 4-Ethoxyphenyl-D-alanine Boc-L-cysteine Boc-isoleucyne Hydroxybenzotriazole

Manufacturing Process BocGly resin (3.0 g, 3 meq) was placed in the reaction vessel of a Vega Model 50 semiautomatic peptide synthesizer. The peptide was built up by increments on the resin in accordance with Tables 1 and 2. TABLE 1 Solid phase synthesis

432

Atosiban

Step Solvent/Reagent 1 Dichloromethane 2 50% trifluoroacetic acid/dichloromethane

Vol. [ml] 70 70

Time [min] 3 15

Number of cycles 2 2

3 4 5

Isopropanol Dichloromethane 10% diisopropylethylamine in dichloromathane

70 70 70

3 3 3

2 2 2

6 7 8 9

Dichloromethane Activated amino acid Isopropanol Dichloromethane

70 70 70 70

3 120* 3 3

2 1 2 2

*30 for BocAsn and BocGln TABLE 2 Termination procedure Step Solvent/Reagent 1

2

1 M Imidazole: dichloromethane + acetic acid anhydride Isopropanol

3

Dichloromethane

Vol. [ml] Time [min]

Number of cycles

70 + 7

30

1

70

3

2

70

3

4

Activation of the amino acid was carried out by dissolving 10 meq of a suitably protected amino acid, 15 meq of hydroxy benzotriazole and 10 meq of dicyclohexylcarbodiimide in DMF (70 ml), whereupon the mixture was left at room temperature for 1 h (asparagine and glutamine were activated at 0°C for 15 min), whereupon the precipitate was filtered off, and the filtrate was treated the activated amino acid in Table 1 (step 7). The completion of the coupling step was checked by the method of Kaiser (Anal. Biochem. 34, 595 (1970)) after the cycle had been completed (step 9). If the test was positive (coupling yield below 99%), the cycle was repeated starting from step 7. If the test was negative, the termination procedure was performed according to Table 2. When the whole sequence had been coupled, the resin was placed on a filter and washed repeatedly with methanol. The dried product was placed in a glass vessel and cooled in an ethanol-dry ice bath and suspended in methanol (about 100 ml). The mixture was then saturated with sodium-dried ammonia to achieve approximately 50% concentration. Then the vessel was placed in a steel cylinder and left at room temperature for two days. After the pressure had been relieved, the product was filtered, and the residue was extracted with hot (about 100°C) DMF (2x100 ml). The filtrate and the extract were combined and evaporated. The residue was dissolved in a small amount of hot DMF, and methanol was added to the coupling point. The precipitate was collected by filtration and washed on the filter with methanol. After drying in vacuum, the purity was checked by thin-layer chromatography. Yield about 2.8 g. 100 mg of the above described protected peptide were placed in a 100 ml

Atovaquone

433

round-bottom flask, and dry nitrogen was flushed through for about 15 min. 50 ml of sodium-dried ammonia were distilled in, and the protective group was removed from the product by adding sodium until blue color remained in the solution for 15 sec. The excess of sodium was destroyed by adding of ammonium chloride. Ammonia was removed in a nitrogen stream, and the residue was dissolved in 1 liter of methanol. The pH of the solution was adjusted to about 4 with concentrated acetic acid, and the solution was then titrated with 0.1 mM of iodine in methanol to brownish color. The mixture was stirred with 3 g of Dowex 50x2 ion exchanger in chloride form for 10 min at room temperature. The ion exchanger was removed by filtration, and the filtrate was evaporated to dryness. The residue was dissolved in 3 ml of 20% acetic acid and purified by chromatography on Sephadex G-25 with 20% acetic acid as eluent. The final purification was achieved by reverse phase HPLC. The purity of the product was determined on a HPCL column µBondapak C-18 in 45% ethanol and 55% 5 mM trifluoroacetic acid in water. The column was supplied by Water Associates, Inc., Millford, Mass., U.S.A. The purity of the product was also shown by amino acid analysis. References Per O.R. Melin et al.; US Patent No. 4,504,469; March 12, 1985; Assigned to Ferring AB, Malmo, Sweden

ATOVAQUONE Therapeutic Function: Antiprotozoal Chemical Name: 2-(trans-4-(p-Chlorophenyl)cyclohexyl)-3-hydroxy-1,4naphthoquinone Common Name: Atovaquone Structural Formula:

Chemical Abstracts Registry No.: 95233-18-4 Trade Name

Manufacturer

Country

Year Introduced

Atovaquone

GlaxoSmithKline

-

-

Mepron

GlaxoSmithKline

USA

-

434

Atovaquone

Trade Name

Manufacturer

Country

Year Introduced

Tropine

India

-

Wellvone

Neon Laboratories Ltd. GlaxoSmithKline

USA

-

Wellvone Suspension

GlaxoSmithKline Australia Pty Ltd.

Australia

-

Raw Materials 2-Chloro-1,4-napthohinone Acetyl chloride Carbon disulfide Aluminum chloride Silver nitrate Cyclohexene Ammonium persulfate Bromine Sodium metabisulphite Manufacturing Process Preparation of intermediate 4-(4-chlorophenyl)cyclohexane-1-carboxylic acid was needed at first. It was made as follows: acetyl chloride (30 g), aluminium chloride (60 g) in carbon disulfide (120 ml) were stirred at -50°C. Cyclohexen (30 g) previously cooled to -50°C was added dropwise during 10 minutes and the mixture was stirred for 60 minutes at -50°C. The solvent was decanted and 300 ml chlorobenzene was added, the so-obtained solution heated at 40°C for 3 hours with stirring, poured onto a mixture of ice and concentrated hydrochloric acid and the organic layer washed with 2 M HCl, 2 M NaOH and water, dried over anhydrous Na2SO4. The product was distilled in vacuo, the fraction boiling at 140°-154°C (0.1 mm Hg) collected, diluted with an equal volume of petroleum ether, cooled to -6°C and a stream of nitrogen gas bubbled through. 3.1 g above obtained hexahydroacetophenone was dissolved in dioxan (15 ml) and the fresh preparated hypobromite (8 ml) in a solution of NaOH (6.2 g) in water (42 ml) at 0°C was added at below 20°C. The mixture was stirred at ambient temperature for 6 hours then allowed to stand overnight. Excess hypobromite was destroyed with sodium metabisulphite, cooled and then acidified to give a colourless solid. It was filtered off, washed with water, dried and recrystallysed from ethanol to give 4-(4-chlorophenyl)cyclohexane-1carboxylic acid, m.p. 254°-256°C. A mixture of this acid, 2-chloro-1,4naphthoquinone and silver nitrate was added to ammonium persulfate to give the corresponding naphthoquinone which was saponificated with KOH and was yielded 2-trans-4-(p-chlorophenyl)cyclohexyl)-3-hydroxy-1,4 naphthoquinone, m.p. 216°-219°C, shown by NMR to be the pure trans isomer. References Hudson A.T. et al.; US Patent No. 5,053,432; Oct. 1, 1991; Assigned: Burroughs Wellcome Co. (Research Triangle Park, NC)

Atracurium besylate

435

ATRACURIUM BESYLATE Therapeutic Function: Neuromuscular blocker Chemical Name: N,N'-4,10-Dioxa-3,11-dioxotridecylene-1,13-bistetrahydropapaverine dibenzenesulfonate Common Name: Structural Formula:

Chemical Abstracts Registry No.: 64228-81-5 Trade Name

Manufacturer

Country

Year Introduced

Tracrium

Burroughs-Wellcome

US

1983

Tracrium

Burroughs-Wellcome

UK

1983

Tracrium

Burroughs-Wellcome

Switz.

1983

Raw Materials Acryloyl chloride Tetrahydropapaverine

Pentane-1,5-diol Methyl benzene sulfonate

Manufacturing Process Acryloyl chloride (0.2 mol) in dry benzene (60 ml) was added over 0.5 hour with mechanical stirring to pentane-1,5-diol (0.1 mol), triethylamine (0.2 mol) and pyrogallol (0.1 g) in dry benzene (100 ml). Further dry benzene (ca 100 ml) was added followed by triethylamine (10 ml), and the mixture stirred at 50°C for 0.5 hour. The triethylamine hydrochloride was filtered off and the solvent removed in vacuum to leave a yellow oil which was distilled in the presence of a trace of p-methoxyphenol, excluding light, to give 1,5pentamethylenediacrylate (12.9 g; 61%; BP 90° to 95°C/0.01 mm Hg). A solution of tetrahydropapaverine (4.43 g) and 1,5-pentamethylene diacrylate (1.30 g) in dry benzene (15 ml) was stirred under reflux for 48 hours excluding light. The solvent was removed in vacuum and the residual pale red oil dissolved in chloroform (10 ml). Addition of ether (ca 400 ml), followed by saturated ethereal oxalic acid solution (ca 500 ml) gave a flocculent white precipitate, which was filtered off, washed with ether and

436

Atreleuton

dried. Crystallization (twice) from ethanol gave N,N'-4,10-dioxa-3,11dioxotridecylene-1,13-bis-tetrahydropapaverine dioxalate as a white powder (3.5 g; 51%; MP 117° to 121°C). The free base, N,N'-14,10-dioxa-3,11-dioxotridecylene-1,13-bistetrahydropapaverine, was obtained by basifying an aqueous solution of the dioxalate with sodium bicarbonate solution, followed by extraction with toluene and evaporation of the solvent, to give a colorless viscous oil. Scrupulously dried base (0.5 g) in spectroscopically pure acetonitrile (8 ml) was treated with methyl benzene sulfonate at room temperature for 22 hours. The filtered reaction mixture was added dropwise to mechanically stirred, filtered, dry ether (ca 450 ml). The flocculent white precipitate was filtered off, washed with dry ether, and dried in vacuum over P2O5 at 50°C to yield the product, an off-white powder melting at 85° to 90°C. In practice it is usually used as dibenzenesulfonate. References Merck Index A-2 DFU 5 (11) 541 (1980) PDR p.766 DOT 19 (2) 111 (1983) I.N. p.104 REM p.925 Stenlake, J.B., Waigh, R.D., Dewar, G.H., Urwin, J. and Dhar, N.C.; US Patent 4,179,507 December 18,1979; Assigned to Burroughs Wellcome Company

ATRELEUTON Therapeutic Function: Antiallergic, Anti-asthmatic Chemical Name: 1-((R)-3-(5-(p-Fluorobenzyl)-2-thienyl)-1-methyl-2propynyl)-1-hydroxyurea Common Name: Atreleuton; ABT 761 Structural Formula:

Chemical Abstracts Registry No.: 154355-76-7

Atreleuton Trade Name Abbott-85761

Manufacturer Abbott

Country -

437

Year Introduced -

Raw Materials Thiophene Butyl lithium N-Iodosuccinimide Sodium thiosulfate Triethylamine Hydroxylamine Sodium hydroxide Triphenylphosphine Copper (I) iodide

tetrakis(Triphenylphosphine)palladium(O) Bis(acetonitrile)palladium(II) chloride 4-Fluorobenzylbromide p-Toluenesulfonyl chloride (S)-3-Butyn-2-ol Hydrogen chloride Potassium cyanate (R)-N-Hydroxy-N-(3-butyn-2-yl)urea Diethylamine

Manufacturing Process A solution of thiophene (12.6 g, 0.15 mol) in a mixture of anhydrous ether (230 ml) and anhydrous THF (70 ml) was treated dropwise at 0°C with a 2.5 M solution of n-butyl lithium in hexane (54.0 ml, 0.134 mol). The mixture was stirred at 0°C for 1.5 h and then transferred by cannula into a -78°C solution of 4-fluorobenzylbromide (23.6 g, 0.125 mol) containing tetrakis(triphenylphosphine)palladium(O) (1.25 g) in anhydrous THF (200 ml). The reaction mixture was stirred for 17 h at room temperature and then quenched with saturated aqueous NH4Cl solution (100 ml) and partitioned between ether and additional NH4Cl solution. The ether layer was dried over MgSO4, concentrated in vacuum and the residue subjected to vacuum distillation to give 19.4 g (81%) of 2-(4-fluorophenylmethyl)thiophene, boiling point 74°-83°C at 0.6-0.7 mm of Hg. A mixture of 2-(4-fluorophenylmethyl)thiophene (3.85 g, 20.0 mmol) and Niodosuccinimide (4.50 g, 20.0 mmol) in 1:1 chloroform-acetic acid (40 ml) was stirred at room temperature for 1 h and then diluted with an equal volume of water. The organic layer was washed with saturated aqueous NaHCO3 solution (2 times 50 ml), 10% aqueous sodium thiosulfate solution (2 times 50 ml) and once with brine. After drying over MgSO4, the organic layer was concentrated in vacuum to give 6.07 g (95%) of 2-iodo-5-(4fluorophenylmethyl)thiophene as a gold colored oil. To a solution of (S)-O-p-toluenesulfonyl-3-butyn-2-ol (11.2 g, 50.0 mmol), prepared by addition of p-toluenesulfonyl chloride and triethylamine to (S)-3butyn-2-ol, in methanol (100 ml), was added 55% aqueous hydroxylamine (30 ml, 0.50 mol) and the reaction mixture was stirred at room temperature for 40 h. The reaction mixture was cooled to 10°C and concentrated HCl (50 ml) was added dropwise. The reaction mixture was concentrated in vacuum and the residue was partitioned between H2O (50 ml) and ethyl acetate (200 ml). The 2-phase mixture was cooled to 10°C and taken to pH 8 with 50% aqueous NaOH solution (60 ml). After stirring for 15 min the layers were separated and the aqueous phase was extracted twice with 200 ml of ethyl acetate. The combined ethyl acetate extracts were cooled to 10°C and a solution of KOCN (8.1 g, 0.10 mmol) in H2O (30 ml) was added, followed by dropwise addition of 11 ml of concentrated HCl, and the reaction mixture was

438

Atrimustine

stirred for 30 min. The ethyl acetate layer was separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuum to give 5.9 g (92% yield) of (R)-N-hydroxy-N-(3-butyn-2-yl)urea, melting point 129°C. To a solution of 2-iodo-5-(4-fluorophenylmethyl)thiophene (5.30 g, 16.6 mmol), in anhydrous DMF (5.0 ml) was added (R)-N-hydroxy-N-(3-butyn-2yl)urea (2.12 g, 16.6 mmol), triphenylphosphine (84.0 mg, 0.32 mmol), bis(acetonitrile)palladium(II) chloride (40.0 mg, 0.16 mmol), copper(I) iodide (16.0 mg, 0.08 mmol), and diethylamine (5.6 ml). The mixture was stirred under nitrogen at room temperature for 22 h and concentrated in vacuum at 32°C. The residue was subjected to chromatography on silica eluting with 27% MeOH in CH2Cl2, crystallization from ethyl acetate-hexane and trituration in CH2Cl2 to afford (R)-N-{3-[5-(4-fluorophenylmethyl)thien-2-yl]-1-methyl-2propynyl}-N-hydroxyurea as a cream-colored solid 0.94 g (18%), melting point 135°-136°C, (dec). References Brooks D.W. et al.; US Patent No. 5,506,261; April 9, 1996; Assigned: Abbott Laboratories, Abbott Park, Ill.

ATRIMUSTINE Therapeutic Function: Antineoplastic Chemical Name: Estra-1,3,5(10)-triene-3,17-diol, (17β)-, 3-benzoate, 17((4-(4-(bis(2-chloroethyl)amino)phenyl)-1-oxobutoxy)acetate) Common Name: Atrimustine; Busramustine Structural Formula:

Chemical Abstracts Registry No.: 75219-46-4

Atrimustine

Trade Name Atrimustine

Manufacturer Onbio Inc.

Country -

439

Year Introduced -

Raw Materials 1,3,5(10)-Estratriene-3,17β-diol Monobromoacetyl bromide Dimethyl sulfoxide Manufacturing Process Preparation of 3-hydroxy-1,3,5(10)-estratriene-17β-[4-{p-[bis(2chloroethyl)amino]phenyl}butyryloxy]acetate: Preparation of 3-hydroxy-1,3,5(10)-estratriene-17β-monobromoacetate. 10 g of 1,3,5(10)-estratriene-3,17β-diol was dissolved in 400 ml of anhydrous tetrahydrofuran (THF), and then, 8.8 g of pyridine was added. A solution of 22.5 g of monobromoacetyl bromide in 74 g of carbon tetrachloride was added dropwise to the resulting solution at about -5°C to -7°C. The mixture was kept for one night. After the reaction, the resulting precipitate was separated by a filtration. The solvent was distilled off from the filtrate. The residue was dissolved in ether and recrystallized from ether to obtain 1,3,5(10)-estratriene-3,17β-bis(monobromoacetate). 2 g of the product was dissolved in 900 ml of methanol and the solution was cooled to -5°C. A solution of 0.24 g of K2CO3 in 20 ml of water was added dropwise to the resulting solution. After the reaction for 30 minutes, 1000 ml of water was added and the resulting precipitate was separated and dried. It was confirmed that the product was 3-hydroxy-1,3,5(10)-estradiene-17β-monobromoacetate by the elementary analysis and the IR spectrum. Preparation of 3-hydroxy-1,3,5(10)-estratriene-17β-[4{p-[bis(2chloroethyl)amino]phenyl}butyryloxy]acetate: 200 mg of silver [4-{p-[bis(2-chloroethyl)amino]phenyl}butyrate (silver salt of Chlorambucil) was added in 10 ml of DMSO to form a white colloidal solution. Then, 190.8 mg of 3-hydroxy-1,3,5(10)-estratriene-17βmonobromoacetate was added and the mixture was stirred at room temperature for 64 hours in the dark. The precipitate was changed to yellowish green color. A small amount of acetone was added and the precipitate was separated by a filtration through G-4 filter. The precipitate was changed from yellowish green color to blackish green color by the irradiation of light. The filtrate was colorless and transparent. DMSO was distilled off under a reduced pressure on a water bath at 80°C and 100 ml of water was added to precipitate white crystals. The crystals were kept for 1 hour to remove DMSO and the crystals were separated through G-4 filter and thoroughly washed with distilled water and dried under a reduced pressure in a desiccator. A crude yield was 330.5 mg. Purification of the product 330.5 mg of crude crystals were dissolved in a mixed solvent of 50 vol. parts of cyclohexane and 10 vol. parts of ethyl acetate. The solution was slowly passed through a column filling 40 g of silica gel and the product was gradually separated to obtain 188.2 mg (yield: 62.86%) of pure product. It was confirmed that the product was 3-hydroxy-

440

Atrinositol sodium

1,3,5(10)-estratriene-17β-[4{p-[bis(2-chloroethyl)amino]phenyl} butyryloxy]acetate by the elementary analysis and the IR spectrum. References Asano K. et al.; US Patent No. 4,332,797; June 1, 1982; Assigned to Kureha Kagaku Kogyo Kabushiki Kaisha, Tokyo, Japan

ATRINOSITOL SODIUM Therapeutic Function: Neuropeptide antagonist, Antiinflammatory Chemical Name: D-myo-Inositol 1,2,6-tris(dihydrogen phosphate) pentasodium salt Common Name: Atrinositol sodium; Minosifate sodium; α-Trinositol sodium Structural Formula:

Chemical Abstracts Registry No.: 136033-48-2 Trade Name

Manufacturer

Country

Atrinositol sodium Perstorp (Sweden) -

Year Introduced -

Raw Materials Borane-methyl sulphide complex 4-Toluenesulfonyl chloride cis-3,5-Cyclohexadiene-1,2-diol 1'-Dynamax 83,123-6 column Silver oxide Sodium hydride Palladium on charcoal Tetrabenzylpyrophosphate

Mandelic acid, (S)-,(+)Lithium aluminum hydride m-Chloroperbenzoic acid Benzyl bromide Cyclohexene N,N,N',N'-Tetramethylenediamine Diisopropylamine Butyl lithium

Atrinositol sodium

441

Manufacturing Process Pseudomonas putida oxidation of benzene affords cis-3,5-cyclohexadiene-1,2diol which is used as a novel precursor for the synthesis of D- and L-myoinositol trisphosphates, which was prepared in 11 steps: 1). (R)-(+)-sec-Phenethyl alcohol: Borane-methyl sulfide complex (68 ml, 0.71 mol) was added dropwise to a solution of (S)-(+)-mandelic acid (98.5 g, 0.65 mol) in THF (900 ml) at room temperature (RT) under a flow of argon over 3 h. The reaction was stirred for 6 h. Then methanol was added dropwise and stirring continued for a further 13 h. The volatiles were then removed in vacuum, the residue stirred in methanol, and the process repeated 3 times. Column chromatography (MeOHethyl acetate-petrol, gradient elution) of the residue afforded the diol (57.3 g, 64%). p-Toluenesulphonyl chloride (80 g, 98% 0.41 mol) was then added portionwise to a solution of the diol in pyridine (700 ml) at 0°C over 8 h. The reaction was stirred at RT for 13 h, then the volatiles removed in vacuum. The residue was washed with water, dried (MgSO4), and the residual pyridine removed in vacuum to afford the tosylate as an orange oil. A solution of the tosylate in ether/THF (500 ml) was added dropwise to a stirred suspension of lithium aluminium hydride (15.6 g, 0.41 mol) in ether (500 ml) at RT under argon. The reaction was stirred for 16 h, then water (15.6 ml), aqueous sodium hydroxide solution (15.6 ml), and water (46.8 ml) were successively added dropwise. After 4 h, sodium sulfate was added and stirring continued. The mixture was filtered through a pad of celite, washed with dichloromethane, and the solvents evaporated in vacuum. Column chromatography (0-100% ether-petrol, gradient elution) followed by distillation (b.p. 96°C/20mmHg) afforded the title alcohol (24.1 g, 48%) as a colourless liquid, [α]D27+41.48°. 2). (3aα,6α,7α,7aα)-6,7-Epoxy-3a,6,7,7a-tetrahydrobenzo[d]-1,3-dioxol-2-one and (3aα,6β,7β,7aα)-6,7-Epoxy-3a,6,7,7a-tetrahydrobenro[d]-1,3-dioxol-2one: Freshly prepared sodium methoxide (0.1 ml of a 1 M solution in methanol, 10 mmol) was added dropwise to a solution of cis-3,5-cyclohexadiene-1,2-diol (112 mg, 1 mmol) in dimethyl carbonate (1.7 ml) and methanol (0.2 ml) at RT under argon, and stirred for 20 min. A small aliquot was removed, solvent evaporated in vacuum (bath T 22°C) and the resulting solid was washed with a small volume of chilled (-20°C) ether and chilled (-20°C) petrol (b.p. 30°40°C) to afford the 3a,7a-dihydrobenzo[1,3]dioxol-2-one (cyclic carbonate) as a beige-coloured solid, mp 90°C (dec.). The remaining solution was diluted with DCM (2 ml), and m-chloroperbenzoic acid (mCPBA) (0.30 g, 2.0 mmol) was added portionwise. After stirring at RT for 40 h, the mixture was extracted with DCM and washed successively with aqueous sodium sulfite solution, aqueous sodium bicarbonate solution and water, dried (MgSO4) and evaporated in vacuum. Column chromatography (45-70% ether-petrol, gradient elution) of the residue afforded the title epoxides (3aα,6α,7α,7aα)-6,7-epoxy-3a,6,7,7a-tetrahydrobenzo[d]-1,3-dioxol2-one (73 mg, 47%) mp 87°-89°C and (3aα,6β,7β,7aα)-6,7-epoxy-3a,6,7,7a-

442

Atrinositol sodium

tetrahydrobenro[d]-1,3-dioxol-2-one, (16 mg 10%) mp 107.5°-108.5°C. 3). [3aR-[3aα,4α,5β(R),7aα]-3a,4,5,7a-Tetrahydro-4-hydroxy-5-(1phenylethoxy)benzo[d]-1,3-dioxol-2-one and [3aS-[3aα,4α,5β(R),7aα]3a,4,5,7a-tetrahydro-4-hydroxy-5-(1-phenylethoxy)benzo[d]-1,3-dioxol-2one: Tetrafluoroboric acid-diethyl ether complex (catalytic amount) was added to a stirred solution of epoxide (+/-)-(3aα,6α,7α,7aα)-6,7-epoxy-3a,6,7,7atetrahydrobenzo[d]-1,3-dioxol-2-one (32 mg, 0.2 mmol) and (R)-(+)-secphenethyl alcohol (0.048 ml, 0.4 mmol) in DCM at RT under argon. After 30 min, water was added and the mixture extracted with DCM (3 times). The combined organic phase was dried (MgSO4) and evaporated in vacuum. Column chromatography (30-75% ether-petrol, gradient elution) of the residue afforded the alcohols [3aR-[3aα,4α,5β(R),7aα]-3a,4,5,7a-tetrahydro4-hydroxy-5-(1-phenylethoxy)benzo[d]-1,3-dioxol-2-one and [3aS[3aα,4α,5β(R),7aα]-3a,4,5,7a-tetrahydro-4-hydroxy-5-(1phenylethoxy)benzo[d]-1,3-dioxol-2-one. (37 mg, 67%) as a thick oil and a 1:1 mixture of diastereomers. Subsequent HIPLC (1'-Dynamax 83,123-6 column; 6% isopropanol-petrol, 15 ml/min) effected separation of the diastereomers. Less polar [3aR-[3aα,4α,5β(R),7aα]-3a,4,5,7a-tetrahydro-4hydroxy-5-(1-phenylethoxy)benzo[d]-1,3-dioxol-2-one had retention time 16.3 min; [α]D20 +90.1° (c 1.1, CHCl3). 4. [3aS-[3aα,6β(R),7α,7aα]-7-Benzyloxy-3a,6,7,7a-tetrahydro-6-(1phenylethoxy)benzo[d]-1,3-dioxol-2-one): Freshly prepared silver oxide (88 mg, 0.38 mmol) was added to a stirred solution of the alcohol [3aR-[3aα,4α,5β(R),7aα]-3a,4,5,7a-tetrahydro-4hydroxy-5-(1-phenylethoxy)benzo[d]-1,3-dioxol-2-one (53 mg, 0.19 mmol) and benzyl bromide (0.080 ml, 0.67 mmol) in DMF (2 ml) at RT under argon and the mixture stirred vigorously in the dark for 64 h. The mixture was diluted with ether, filtered through a pad of silica which was then washed copiously with ether and DCM, and the filtrate evaporated in vacuum. The residue was dissolved in ether, washed with water and brine, dried (MgSO4) and evaporated in vacuum. Column chromatography (30-100% ether-petrol, gradient elution) of the residue afforded the title benzyl erher. (70 mg, 100%) as needles, m.p. 97°-99°C; [α]D20 +102.9° (c 1.0, CHCl3). 5). [1S-[1α,2α,5α(R),6β]-6-Benzyloxy-5-(1-phenylethoxy)-3-cyclohexene-1,2diol: The carbonate (0.459 g, 1.25 mmol) was stirred in 1:5:1 triethylamine/methanol/water (12 ml) at RT. After 72 h, the volatiles were removed in vacuum and the residue freeze-dried. The crude product was purified by column chromatography (50-100% ethyl acetate-petrol, gradient elution) to afford the title diol (0.421 g, 99%) as a white solid, mp 46°-47°C; [α]D20 +82.4° (c 2.5, CHCl3). 6. [1R-[1α,2α,3β,4α(R),5α,6α)-3-Benzyloxy-5,6-epoxy-4-(1-phenylethoxy) cyclohexane-1,2-diol: mCPBA (2.68 g, 80% 12.4 mmol) was added to a stirred solution of olefin

Atrinositol sodium

443

(2.111 g, 6.2 mmol) in DCM (30 ml) at RT under argon. After stirring for 48 h, cyclohexene was added dropwise (excess) and the mixture stirred for 90 min. The solvents were removed in vacuum to afford the title epoxydiol (1.93 g, 92%) as a foam and a 17:1 mixture of epoxide stereoisomers. Column chromatography (10-50% ethyl acetate-petrol, gradient elution) yielded the major epoxide (1.928 g, 87%) as a foam, [α]D20 +98.9° (c 0.92, CHCl3). 7). [3aR-[3aα,4α,5β(R),6β,7β,7aα)-4-Benzyloxy-6,7-epoxy-5-(1-phenylethoxy) hexahydro-2,2-dimethylbenzo[d]-1,3-dioxole: Camphorsulphonic acid monohydrate (catalytic amount) was added to a stirred solution of [1R-[1α,2α,3β,4α(R),5α,6α)-3-benzyloxy-5,6-epoxy-4-(1phenylethoxy)cyclohexane-1,2-diol (0.321 g, 0.9 mmol) in 2,2dimethoxypropane (10 ml) at RT under argon. After 16 h, the mixture was poured into DCM and washed with aqueous sodium bicarbonate solution and water. The aqueous layers were reextracted with DCM and the combined organic extracts dried (MgSO4) and evaporated in vacuum column chromatography (50% ether-petrol) of the residue afforded the title epoxy acetonide (0.317 g, 89%) as needles, m.p. 114°-115°C (recrystallized from ether-petrol); [α]D20+134.1° (c 1.00, CHCl3). 8). [2(R)]-L-3-O-Benzyl-4,5-O-isopropylidene-6-O-[2-(5,5-dimethyl-1,3dioxan-2-yl)ethyl]-2-O-(1-phenylethyl)-muco-inositol and [S(R)]-D-4-OBenzyl-2,3-O-isopropylidene-6-O-[2-(5,5-dimethyl-1,3-dioxan-2-yl)ethyl]-5-O(1-phenylethyl)-myo-inositol: The 1,3-dioxane-2-ethanol (2 ml) was added dropwise to sodium hydride (396 mg of 60% dispersion, 10 mmol) at RT under argon. When the effervescence had ceased, N,N,N',N'-tetramethylenediamine (TMEDA) (1 ml) was added, the mixture stirred for a further 4 h and then a solution of the epoxide (396 mg, 1.0 mmol) in TMEDA (1.0 ml) was added dropwise. The mixture was stirred at 100-110°C for 3 days and then allowed to cool to RT. Water was added and, after 5 min the mixture extracted with ether. The extract was washed with water and the aqueous phase reextracted with ether. The combined organic extracts were dried (MgSO4) and evaporated in vacuum column chromatography (4% MeOH-10% ether-86% petrol) of the residue afforded [2(R)]-L-3-O-Benzyl-4,5-O-isopropylidene-6-O-[2-(5,5-dimethyl-1,3-dioxan-2yl)ethyl]-2-O-(1-phenylethyl)-muco-inositol (176 mg, 31%), [α]D20 +63.4° (c 1.4, CHCl3); and [S(R)]-D-4-O-Benzyl-2,3-O-isopropylidene-6-O-[2-(5,5dimethyl-1,3-dioxan-2-yl)ethyl]-5-O-(phenylethyl)-myo-inositol (273 mg, 48%), mp 108°-110°C, [α]D20+29.3° (c 0.76, CHCl3) as a thick oil and a white solid respectively, and starting epoxide (65 mg, 16%). 9). D-6-O-[2-(5,5-Dimethyl-1,3-dioxan-2-yl)ethyl]-2,3-O-isopropylidene-myoinositol: 10% Palladium on activated charcoal (Fluka) (catalytic amount) was added to a solution of [S(R)]-D-4-O-benzyl-2,3-O-isopropylidene-6-O-[2-(5,5-dimethyl1,3-dioxan-2-yl)ethyl]-5-O-(phenylethyl)-myo-inositol (105 mg, 0.18 mmol) in ethanol (10 ml) at RT under argon. The flask was flushed through with hydrogen and the mixture stirred vigorously under a hydrogen atmosphere. After 16 h, the flask was refluxed with argon and the mixture filtered through a pad of celite, which was washed copiously with ether and then DCM.

444

Atropine

Evaporation of the solvents in vacuum afforded. D-6-O-[2-(5,5-Dimethyl-1,3dioxan-2-yl)ethyl]-2,3-O-isopropylidene-myo-inositol (65 mg, 100%) as a white solid, mp 96.5°-97.5°C; [α]D20 +24.7° (c 0.45, CHCl3). 10). D-6-O-[2-(5,5-Dimethyl-1,3-dioxan-2-yl)ethyl]-2,3-O-isopropylidenemyo-inositol 1,4,5-tris(dibenqylphosphate): n-Butyl lithium (0.172 ml of a 2.5 M solution in hexanes, 0.43 mmol) was added dropwise to a solution of the above compound (45 mg, 0.12 mmol) in THF (4 ml) at -30°C under argon. Diisopropylamine (0.073 ml, 0.52 mmol) was then added and the mixture stirred at -30°-(-25)°C for 20 min. Tetrabenzylpyrophosphate (242 mg, 0.45 mmol) was added in one portion and the reaction allowed to warm gradually to +2°C over 4 h. The precipitated lithium dibenzylphosphate was filtered off, the cake washed with THF and the solvent evaporated in vacuum. Column chromatography (30-100% ethyl acetate-petrol, gradient elution) of the residue afforded the triphosphate (95 mg, 67% ) as a thick oil, [α]D20 -4.5° (c 1.13, CHCl3). 11). D-(-)-myo-lnositol 1,4,5-trisphosphate: 10% Palladium on activated charcoal (Fluka) (catalytic amount) was added to a solution of the protected trisphosphate (243 mg, 0.21 mmol) in ethanol (10 ml) at RT under argon. The flask was flushed through with hydrogen and the mixture stirred vigorously under a hydrogen atmosphere. After 48 h, the flask was refluxed with argon, the mixture filtered and washed with ethanol. The volatiles were removed in vucuo and the residue freeze-dried to afford fully debenzylated material. This was stirred in 80% aqueous trifluoroacetic acid (cu. 6 ml) at RT for 4 h. After removing the volatiles in vacuum, the residue was again freeze-dried. Purification of the crude product by HPLC (Spherisorb S5SAX column, 202 mm x 250 mm; 0.2 M ammonium formate buffer at pH 4, 12 ml/min) afforded atrinositol (64 mg, 88%), retention time 42 min, [α]D20 22°-24° (c 0.15, H2O, pH 6.9). UR, 1H-NMR, 31P-NMR spectra confirmed the structure of described compounds. References Ley S.V. et al.; Tetrahedron; vol. 46, No 13/14, pp. 4995-5026; 1990

ATROPINE Therapeutic Function: Anticholinergic Chemical Name: 1-α-H,5-α-H-Tropan-3-α-ol (+/-)-tropate (ester) Common Name: Atropine; DL-Hyoscyamine Chemical Abstracts Registry No.: 51-55-8

Atropine methonitrate

445

Structural Formula:

Trade Name Atromed Atropen Atropinol

Manufacturer Promed Exports Meridian Wenzer

Country India USA Denmark

Year Introduced -

Raw Materials Plants from botanic family Slanaceae: Atropa belladonna, Atropa acminata, Atropa boetica, Hyocyamus niger Chloroform Manufacturing Process Atropin was obtained from belladonna roots and by racemisation of Lhyoscyamine with dilute alkali or by heating in chloroform solution. The alkaloid was crystallised from alcohol on addition of water, or from chloroform on addition of light petroleum, or from acetone in long prisms, m.p. 118°C, sublimed unchanged when heated rapidly. It is soluble in alcohol or chloroform, less soluble in ether or hot water, sparingly so in cold water (in 450 L at 25°C) and almost insoluble in light petroleum. Atropine is optically inactive. References Ann., 1833, 5, 43 6, 44, 7 269. Arch. Pharm., 1850 74, 245, Pesci, Gazzetta, 1882 12, 59, Will and Bredig, Ber., 1888 21, 1717, 2797, Schmidt, ibid. 1829 Gadamer, Arch. Pharm., 1901, 239, 294 Chemnitius, J. pr. Chem., 1927 [ii], 116, 276 Dilius, Chem. Zeit., 1930, 54, 182

ATROPINE METHONITRATE Therapeutic Function: Anticholinergic, Mydriatic, Spasmolytic Chemical Name: 8-Azoniabicyclo[3.2.1]octane, 3-(3-hydroxy-1-oxo-2phenylpropoxy)-8,8-dimethyl-, (3-endo)-, nitrate (salt)

446

Atropine methonitrate

Common Name: Methylatropine nitrate; Atropine methonitrate Structural Formula:

Chemical Abstracts Registry No.: 52-88-0 Trade Name Methylatropine nitrate

Manufacturer Paganfarma

Country -

Methylatropine nitrate

Yick-Vic Chemicals and Pharmaceuticals (HK) Ltd.

-

Atropine methyl nitrate

Sigma

-

-

Year Introduced -

Raw Materials Atropine Atropine sulfate

Methyl nitrate Barium nitrate

Manufacturing Process There are 2 methods of synthesis of methyl atropine nitrate: 1) To a solution of 28.9 g atropine of in 100 g of methanol was added at 110°C for 2 hours 7.7 g methyl nitrate. Methanol was evaporated and methyl atropine nitrate was crystallysed, M.P. 163°C. 2) To a solution of 70.4 g methyl atropine sulfate (prepared from methyl atropine chloride and silver nitrate) in water was added aqueous solution of 26.1 g barium nitrate. Barium sulfate was deleted by filtration. Filtrate was concentrated and the methyl atropine nitrate was obtained. References DE Patent No. 138,443; Nov. 28, 1901; Assigned to Farbenfabriken vorm. Friedr. Bayer and Company in Elberfeld DE Patent No. 137,622; Nov.28, 1902; Assigned to Farbenfabriken vorm. Friedr. Bayer and Company in Elberfeld

Auranofin

447

AURANOFIN Therapeutic Function: Antiarthritic Chemical Name: S-Triethylphosphine gold 2,3,4,6-tetra-O-acetyl-1-thio-β-Dglucopyranoside Common Name: Structural Formula:

Chemical Abstracts Registry No.: 34031-32-8 Trade Name Ridaura Ridaura

Manufacturer SK and F SK and F

Country W. Germany Switz.

Year Introduced 1982 1983

Raw Materials Thiodiglycol Triethylphosphine S-(2,3,4,6-Tetra-O-acetylglucopyranosyl)thiopseudourea hydrobromide Gold acid chloride trihydrate Potassium carbonate Manufacturing Process (A) Triethylphosphine gold chloride: A solution of 10.0 g (0.08 mol) of thiodiglycol in 25 ml of ethanol is mixed with a solution of 15.76 g (0.04 mol) of gold acid chloride trihydrate in 75 ml of distilled water. When the bright orange-yellow solution is almost colorless, it is cooled to -5°C and an equally cold solution of 5.0 g (0.0425 mol) of triethylphosphine in 25 ml of ethanol is added dropwise to the stirred solution. After the addition is complete, the cooled mixture is stirred for ½ hour. Solid that separates is removed and the filtrate is concentrated to about 30 ml to yield a second crop. The combined solid is washed with aqueous-ethanol (2:1) and recrystallized from ethanol by adding water to the cloud point. The product is obtained as white needles, MP 85° to 86°C. (B) Auranofin: A cold solution of 1.66 g (0.012 mol) of potassium carbonate in

448

Aurothioglycanide

20 ml of distilled water is added to a solution of 5.3 g (0.011 mol) of S(2,3,4,6-tetra-O-acetylglucopyranosyl)-thiopseudourea hydrobromide [Methods in Carbohydrate Chemistry, vol 2, page 435 (1963)] in 30 ml of water at -10°C. A cold solution of 3.86 g (0.011 mol) of triethylphosphine gold chloride in 30 ml of ethanol containing a few drops of methylene chloride is added to the above mixture before hydrolysis of the thiouronium salt is complete. After the addition is complete, the mixture is stirred in the cold for ½ hour. The solid that separates is removed, washed first with aqueous ethanol then water and dried in vacuum. There is obtained colorless crystals, MP 110° to 111°C, of S-triethylphosphine gold 2,3,4,6-tetra-O-acetyl-1-thio-βD-glucopyranoside. References Merck Index 882 DFU 1 (10) 451 (1976) PDR p. 1721 DOT 18 (9) 463 (1982) I.N. p. 106 REM p. 1122 McGusty, E.R. and Sutton, B.M.; US Patent 3,708,579; January 2, 1973; Assigned to Smith Kline and French Laboratories Nemeth, P.E. and Sutton, B.M.; US Patent 3,635,945; January 18, 1972; Assigned to Smith Kline and French Laboratories

AUROTHIOGLYCANIDE Therapeutic Function: Antiarthritic Chemical Name: [[(Phenylcarbamoyl)methyl]thio]gold Common Name: Aurothioglycollic acid anilide Structural Formula:

Chemical Abstracts Registry No.: 16925-51-2 Trade Name Lauron

Manufacturer Endo

Raw Materials Potassium bromoaurate Sulfur dioxide Thioglycolic acid anilide

Country US

Year Introduced 1945

Avilamycin

449

Manufacturing Process The product is made preferably by reacting thioglycolic acid anilide with an aurous bromide (AuBr). Prior art methods for making the starting material, HSCH2CONHC6H5 are disclosed in an article by Beckurts et al. in Journ. Praktische Chemie (2) 66 p. 174, and in the literature referred to in the mentioned article. Ten grams of the potassium salt of bromoauric acid are dissolved in 100 cc of 96% ethyl alcohol. This salt is also designated as potassium auribromide. Sulfur dioxide (SO2) is then led through this solution, through a fine capillary tube, for several minutes. This reaction produces aurous bromide (AuBr). The solution of the aurous bromide is then allowed to stand for 2 to 3 hours until it is colorless. A precipitate of KBr is thus formed. This precipitate is separated from the solution of the aurous bromide which is added to a solution of three grams of the thioglycolic acid anilide in 50 cc of ethyl alcohol. This is done at about 20°C. Then 300 cc of water are added to this mixture, at 20°C. The water is then removed by decantation or any suitable method, and the mixture is repeatedly thus treated with water, in order to remove all impurities which can thus be removed. The product is then centrifuged twice with 96% ethyl alcohol. It is then centrifuged three times with 100% or absolute ethyl alcohol, and then centrifuged three times with water-free ligroin (petroleum ether), i.e., the 40-60°C fraction which is distilled from petroleum. After each centrifuging, the product is separated from the liquid which has been used during the centrifuging. The product is then dried in a high vacuum with the use of phosphorus pentoxide (P2O5). References Merck Index 889 I.N. p. 106 Lewenstein, M.J.; US Patent 2,451,841; October 19, 1948

AVILAMYCIN Therapeutic Function: Antibiotic Chemical Name: Avilamycin A, mixture of small quantities of avilamycin B, C, D1, D2 and E Common Name: Avilamycin; Maxus Chemical Abstracts Registry No.: 11051-71-1

450

Avilamycin

Structural Formula:

Trade Name Maxus Avilamicina

Manufacturer Eli Lilly Eli Lilly

Country -

Year Introduced -

Raw Materials Meat meal Peptone Glucose Meat extract

Salt extract Calcium carbonate Streptomyces viridochromogenes NRRL 2860 Sodium chloride

Manufacturing Process Avilamycin is produced from Streptomyces viridochromogenes NRRL 2860: A nutrient solution is prepared which contains 20.0 g of meat meal, 20.0 g of salt extract, 10.0 g of calcium carbonate and 1 L of tap water and adjusted to pH=7. This solution, or a multiple thereof, is charged into conical flasks of 500 ml capacity (100 ml of nutrient solution each) or into fermenters of 500 L capacity (300 L of nutrient solution each) and sterilized for 20-30 min under a pressure of 1 atm. The contents of the flasks are then inoculated with up to 10% of a partially sporulating vegetative culture of Streptomyces viridochromogenes NRRL 2860 and incubated at 27°C with thorough shaking or stirring, and in the fermenters with aerating with about 1 volume of sterile air per volume of nutrient solution per minute. The cultures are allowed to grow for 24-48 h, mixed with about 1.5% of a filtration assistant and then filtered depending on the volume, through a suction filter or a filter press or a rotary filter to free the antibiotically active aqueous solution from the mycelium and other solid constituents. The medium described above is replaced the nutrient media: 10.0 g of crude glucose, 5.0 g of peptone, 3.0 g of meat extract (Oxo Lab- Lemco), 5.0 g of sodium chloride, 10.0 g of calcium carbonate and 1 L of tap water; pH - prior

Avizafone hydrochloride

451

to sterilization: 7.5, analogous sterilization, inoculation with Streptomnyces viridochromogenes NRRL 2860, incubation at 27°C and filtration likewise yield aqueous antibiotically active solutions. 90 L of culture filtrate are extracted with 20 L of ethyl acetate, and the extract is concentrated to 400 ml. When the concentrate is kept for 20 h at 2°C, avilamycin precipitates in the form of a dense floccular substance which is filtered off. After having been dried in an exsiccator, the practically colorless crystal cake consisting of strongly felted small needles weighs 3.07 g. The mother liquors are concentrated to about 200 ml and mixed with twice the amount of ether. When the concentrate is kept for 4 days at 0°C, a further 3.28 g of avilamycin crystallize out. 3.0 g of the crystallizate are dissolved in 50 ml of acetone, and a small amount of insoluble sludge is filtered off. The clear filtrate is mixed with ether and concentrated. On cooling, 2.0 g of colorless fine needles crystallize out. Concentration of the mother liquors to about one quarter their volume produces a further 0.48 g of crystals. For analysis a test portion of these crystals is recrystallized 4 times from acetone+ether and dried for 20 h in a high vacuum at 70°C. The analytically pure antibiotic avilamycin have a melting point 188°-189.5°C. Optical rotation [α]D20=+0.8° (c=1.165 in absolute ethanol). References Gaeumann E., Prelog V.; US Patent No. 3,131,126; April 28, 1964; Assigned: Ciba Corporation, a corporation of Delaware

AVIZAFONE HYDROCHLORIDE Therapeutic Function: Anxiolytic, Anticonvulsant Chemical Name: 2'-Benzoyl-4'-chloro-2-((S)-2,6-diaminohexanamido)-Nmethylacetanilide dihydrochloride Common Name: Avizafone hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 65617-86-9 (Base); 60067-16-5

452

Avizafone hydrochloride

Trade Name Avizafone hydrochloride Avizafone hydrochloride

Manufacturer Onbio Inc.

Country -

Year Introduced -

Roche Product Ltd.

-

-

Raw Materials N-Benzyloxycarbonylglycine Isobutylchloroformate N-Methylmorpholine 5-Chloro-2-methylaminobenzophenone Hydrogen bromide N(α),N(ε)-Bisbenzyloxycarbonyl-L-lysyl N-hydroxysuccinimide ester Amberlite Manufacturing Process (a) 20.9 g of N-benzyloxycarbonylglycine were suspended in 1500 ml of dry 1,2-dimethoxyethane and the suspension was cooled to -20°C. 10.1 g of Nmethylmorpholine and 13.7 g of isobutylchloroformate were added, the resulting solution was stirred at -20°C for 1 hour and then filtered. The filtrate was added portion-wise over a period of several hours to a refluxing solution of 24.55 g of 5-chloro-2-methylaminobenzophenone in 200 ml of 1,2dimethoxyethane, the resulting mixture was boiled overnight and then evaporated to dryness in vacuum. The yellow residue was dissolved in ethyl acetate, washed with two portions of water and one portion of saturated sodium chloride solution, dried over anhydrous magnesium sulfate and then evaporated. Column chromatography of the residue on Florisil (Trade Mark) using mixtures of benzene and chloroform yielded 35 g (80%) of pure 2-(Nbenzyloxycarbonylamino)-N-(2-benzoyl-4-chlorophenyl)-N-methylacetamide as a pale yellow gum. 43.7 g of 2-(N-benzyloxycarbonylamino)-N-(2-benzoyl-4-chlorophenyl)-Nmethylacetamide were dissolved in 200 ml of a 30% solution of hydrogen bromide in glacial acetic acid and the resulting solution was stirred overnight at room temperature. The mixture was added slowly to a large excess (2000 ml) of dry diethyl ether with vigorous stirring. The product, which separated was allowed to settle and the supernatant liquors were decanted off. The residue was triturated with 150 ml of acetone and the product filtered off, washed consecutively with the minimum amount of acetone and dry diethyl ether and dried in vacuum to give 29.5 g (77%) of 2-amino-N-(2-benzoyl-4chlorophenyl)-N'-methylacetamide hydrobromide as a white hygroscopic powder of melting point 194°-195°C (decomposition). (b) 84 g of N-benzyloxycarbonylglycine were suspended in 500 ml of alcoholfree chloroform and the suspension was cooled to -200°C. The stirred suspension was treated portion-wise over a period of 15 minutes with 90 g of phosphorus pentachloride and the stirring was continued until a clear solution was obtained. At this point, the cold mixture was added dropwise over a period of 30 minutes to a cold (-5°C) vigorously stirred emulsion consisting of 82 g of 5-chloro-2-methylaminobenzophenone, 347 g of potassium bicarbonate, 700 ml of chloroform and 1400 ml of water. The resulting

Avizafone hydrochloride

453

mixture was stirred for a further 1 hour at -5°C and then overnight at room temperature. The stirring was then discontinued and the liquid phases allowed to separate. The chloroform layer was washed three times with 500 ml of water each time and evaporated in VW to give 150.7 g of a viscous yellow gum which was shown by physical methods to be almost pure (above 95%) 2(N-benzyloxycarbonylamino)-N-(2-benzoyl-4-chlorophenyl)-Nmethylacetamide. The product above obtained was dissolved in 650 ml of a 30% solution of hydrogen bromide in glacial acetic acid and treated in an identical manner to that described in part (a) to give 2-amino-N-(2-benzoyl4chlorophenyl)-N-methylacetamide hydrobromide in a 77% overall yield from 5-chloro-2-methylaminobenzophenone. (c) 1 mole of Nα,Nε-bisbenzyloxycarbonyl-L-lysyl N-hydroxysuccinimide ester was dissolved in 50 ml of dry dimethylformamide. The resulting solution was cooled to -20°C and there were added 1 mole of 2-amino-N-(2-benzoyl-4chlorophenyl)-N-methylacetamide hydrobromide followed by the dropwise addition of 1 mole of N-ethylmorpholine. The resulting mixture was vigorously stirred for 1 hour at -20°C and then overnight at room temperature. The solvent was evaporated in vacuum and the residue dissolved in a mixture of dichloromethane and water. The organic and aqueous layers were separated and the aqueous phase extracted with further portions of dichloromethane. The combined organic phases (250 ml) were washed three times with 50 ml of water each time, dried over anhydrous magnesium sulfate and evaporated in vacuum to give a yellow oily residue, which was shown by physical methods to consist of Nα,Nε-bisbenzyloxycarbonyl-L-lysyl-N-(2-benzoyl-4-chlorophenyl)N-methylglycinamide as an almost colorless light-sensitive gum; [α]D20= -9.3° (c=1 in ethanol). Nα,Nε-Bisbenzyloxycarbonyl-L-lysyl-N-(2-benzoyl-4-chlorophenyl)-Nmethylglycinamide was converted using a 30% solution of hydrogen bromide in glacial acetic acid into L-lysyl-N-(2-benzoyl-4-chlorophenyl)-Nmethylglycinamide dihydrobromide which was obtained as a hygroscopic powder of melting point 145°C (decomposition); [α]D20= + 15.6° (c=1 in water). Treatment of the foregoing dihydrobromide in aqueous solution by passage over an excess of an anion-exchange resin such as 'Amberlite' IRA-401 in the chloride form followed by lyophilisation of the eluate gave, in quantitative yield, L-lysyl-N-(2-benzoyl-4-chlorophenyl)-N-methylglycinamide dihydrochloride (avizafone) as a hygroscopic white light-sensitive powder of melting point 125°-145°C (slow decomposition); [α]D20= +19.3° (c= 1 in water). References Hassall G.H. et Limited; a Hassall G.H. et Limited; a

al.; GB Patent No. 1,517,165; May 21, 1975; Roche Product British Company al.; GB Patent No. 1,517,166; August 11, 1975; Roche Product British Company

454

Avobenzone

AVOBENZONE Therapeutic Function: Sunscreen agent Chemical Name: 1,3-Propanedione, 1-(4-(1,1-dimethylethyl)phenyl)-3-(4methoxyphenyl)Common Name: Avobenzone; Episol Structural Formula:

Chemical Abstracts Registry No.: 70356-09-1 Trade Name Avobenzone Avobenzone Clarins Episol

Manufacturer AroKor Holdings Inc. Vivimed Labs Ltd Clarins Schering-Plough

Country -

Year Introduced -

-

-

Raw Materials p-t-Butylbenzoic acid Sodium carbonate Acetylanisole Methanol

Sulfuric acid Sodium amide Hydrochloric acid

Manufacturing Process 356.0 g (2 mol) of p-t-butylbenzoic acid, 243.0 g (7.6 mol) of methyl alcohol and 35.0 g of sulfuric acid (96%) are added to a four-necked round flask which is provided with a stirrer and a condenser. The mixture is held for 8 h at reflux temperature with slight stirring. The condenser is then replaced by a distillation column and the excess methyl alcohol is distilled off, towards the end under a slight vacuum but without the temperature exceeding 100°C. The mixture is cooled and poured on to ice. The phases are left to separate, the organic phase is washed with ice-water, with a saturated sodium carbonate solution in the presence of ice and finally with ice until neutral. The organic phase is dried over sodium sulfate and there is thus obtained a precipitate. By distillation on a Widmer column (120 mm) there are obtained 345.0 g (90% yield) of the p-t-butylbenzoic acid methyl ester, boiling point 76°C/0.02 mmHg. 2 methods of producing of 4-(1,1-dimethylethyl)-4'-methoxydibenzoylmethane

Avorelin

455

from p-t-butylbenzoic acid methyl ester: 1). To a round flask which has been well dried and flushed with nitrogen are added 85.0 g (1.1 mol) of sodium amide (50% suspension in toluene) and 180.0 g of isopropyl ether and there are now added dropwise thereto at a temperature of 50°-60°C 150.2 g (1 mol) of acetylanisole in 180.0 g of isopropyl ether. Reaction sets in immediately and a white paste-like mass forms. After completion of the addition, the mixture is stirred for a further 0.5 h and then 192.3 g of p-t-butylbenzoic acid methyl ester are added rapidly at 25°-30°C. The mixture is stirred for 0.5 h at room temperature, then for 3 h at 60°-70°C and left to stand for 12 h. 200.0 g of ice are then added and the mixture is acidified with 128.0 g (1.1 mol) of technical hydrochloric acid and 200 ml of ice-water. The mixture is stirred until the sodium salt of the product has dissolved. The phases are separated and the organic phase is washed with ice-water until neutral. The organic phase is concentrated on a rotary evaporator and there are thus recovered 290.0 g of isopropyl ether. The yield of 4-(1,1-dimethylethyl)-4'-methoxydibenzoylmethane, melting point 83.5°C is 199.8 g (64.5%) (recrystallisation from methanol). 2). 36.0 g (1.2 mol) of 80% sodium amide and 300.0 g of dry toluene are added to a round flask which was flushed with nitrogen. The mixture is heated to 50°C and 150.2 g (1 mol) of acetylanisole in 309.0 g of toluene are added within 1.5 h. After completion of the addition, the mixture is held at 50°C for 15 min and there are then added thereto at this temperature within 1 h 50 min 192.3 g (1 mol) of p-t-butylbenzoic acid methyl ester. The mixture is stirred for a further 1 h at 50°C and then heated at 100°C for 1 h, after which time the product has separated out in the form of a solid precipitate. The mixture is left to stand for 12 h and there are then added thereto 300 ml of ice-water followed by a mixture of 100 ml of pure hydrochloric acid and 250 ml of ice-water. The phases are separated and the organic phase is washed twice with water. The organic phase is dried over sodium sulfate and treated simultaneously with 20.0 g of active carbon. After filtration, the filtrate is concentrated until crystallisation begins. 50 ml of hexane are added, the mixture is cooled and then filtered over a Buchner funnel. There is obtained a total yield of 220.91 g (71.2%) of the desired 4-(1,1-dimethylethyl)-4'methoxydibenzoylmethane, of melting point 83.5°C (recrystallisation from 600 ml of methanol). References De Polo K.-F.; US Patent No. 4,387,089; June 7, 1983; Assigned: Givaudan Corporation, Clifton, N.J.

AVORELIN Therapeutic Function: LHRH agonist Chemical Name: 10-deglycinamideluteinizing hormone-releasing factor (pig), 6-(2-methyl-D-tryptophan)-9-(N-ethyl-L-prolinamide)Common Name: Avorelin

456

Avorelin

Structural Formula:

Chemical Abstracts Registry No.: 140703-49-7 Trade Name

Manufacturer

Country

Year Introduced

Avolerin

Mediolanum

-

-

Raw Materials Benzhydrylamine resin Diisopropylcarbodiimide Aminoacids: 5-oxoproline, histidine, typthophan, serine, tyrosine, leucyne, arginine,N-ethyl proline amide Trifluoroacetic acid Hydrogen fluoride Sephadex G-50 F column Manufacturing Process It is well known that the incorporation or substitution of a D-tryptophan residue into a biologically active peptide chain enhances the activity of that chain. Furthermore, such incorporation or substitution will prolong the biological activity. The prolonged and enhanced effectiveness of such peptides probably relates the increased resistance to degradation by peptidases. [D-2-Methyl-Trp6] LHRH and [Des-Gly10-D-2-methyl-Trp6-Pro-ethylamide9]

Avridine

457

LHRH. 2-Methyl-tryptophan is known (cf. H.N. Rydon, J. Chem. Soc. 1948, 705) and the homologous alkylated derivatives are conveniently prepared from the corresponding 2-alkyl indoles by well known methods (cf. J.P. Li et al., Synthesis (1), 73, 1988). The resolution of the racemic tryptophan derivatives to give the D-enantiomers can also be achieved by a variety of methods (cf. Amino Acids, Peptides and Proteins, Vol. 16, pages 18-20, The Royal Society of Chemistry, London, 1985). The both solution phase or the solid phase method of peptide synthesis can be used to make 5-oxo-L-prolyl-L-histidyl-Ltryptophyl-L-seryl-L-tyrosyl-2-methyl-D-tryptophyl-L-leucyl-L-arginyl-N-ethylL-prolinamide (cf. R. Geiger et al., "The Peptides", Academic Press, New York 1981). If the solid phase method is used, peptide synthesizers such as the Applied Biosystem 430A, Bioresearch Sam 9500 or the Beckman Model 990 are preferably used. According to this methodology, the first amino acid is linked to the benzhydrylamine resin and the remaining protected amino acids are then coupled in a stepwise manner using the standard procedures recommended by the manufacturers of the synthesizers. For instance, amino acid couplings are performed by using symmetrical anhydrides in the Applied Biosystems Synthesizer and diisopropylcarbodiimide in the Bioresearch or Beckman machines. The amino acid derivatives are protected by the tertiary butoxy-carbonyl groups on the α-amino function during the synthesis. The functional groups present in the amino-acid in the side chain are previously protected. For instance, the functional groups of histidine are protected by benzyloxymethyl (His(Bom)), tosyl (His(Tos)), the functional groups of tryptophan by formyl (Trp(For)), those of serine by benzyl (Ser(Bzl)), those of tyrosine by 2-Br-benzyloxycarbonyl (Tyr(2-Br-Z)), those of arginine by tosyl (Arg(Tos)); those of proline by O-benzyl HCl (Pro(OBzl HCl)). The Boc protective groups on the α-aminic function are removed at each stage by treatment with 60% trifluoroacetic acid ("TFA") in dichloromethane. The crude peptides after HF cleavage are purified on a Sephadex G-50 F column in 50% acetic acid or by preparative reverse phase HPLC using gradients of acetonitrile and water containing 0.1% trifluoroacetic acid. References DEGHENGHI, Romano [It/CH]; Chesaux Dessus B1, CH-1264 S.-Cergue (CH); W.O. 91/18016

AVRIDINE Therapeutic Function: Antiviral Chemical Name: Ethanol, 2,2'-((3-(dioctadecylamino)propyl)imino)bisCommon Name: Avridine Chemical Abstracts Registry No.: 35607-20-6

458

Avridine

Structural Formula:

Trade Name Avridine

Manufacturer Chemical Formulations, LLC

Country -

Year Introduced -

Raw Materials Dioctadecylamine Acrylonitrile N-Propionyl chloride Manufacturing Process N,N-Dioctadecyl-1,3-propanediamine: A). A two-gallon autoclave is charged with 3-(dioctadecylamino)propionitrile (100 g), ethanol (3750 ml) containing anhydrous ammonia (100 g) and Raney nickel (20 g dry basis) and purged with nitrogen, then with hydrogen. It is then sealed and the hydrogen pressure raised to 250 psi. The autoclave is agitated, the temperature raised to 70°C and the mixture held at this temperature for 1.5 hours at which time hydrogen absorption has ceased. The autoclave is cooled to 20°C, vented, and the contents removed. The catalyst is filtered off, washed with ethanol, and the combined washings and reaction mixture concentrated in vacuum to a viscous green-yellow oil (82 g) which solidified upon standing; MP: 39°-41°C. 3-(Dioctadecylamino)propionitrile is prepared by refluxing a mixture of dioctadecylamine (200 g) and acrylonitrile (1903.8 ml) for eighteen hours. The mixture is then concentrated to a waxy semi-solid which is slurried in acetone, filtered, and air dried overnight. B). The monoacyl derivatives of N,N-dioctadecyl-1,3-propanediamine are prepared as follows: To a solution of methylene chloride (500 ml per 0.1 mole of reactants) containing equimolar amounts of N,N-dioctadecyl-1,3-propanediamine and triethylamine and cooled in an ice-bath is added an equimolar amount of the appropriate acyl chloride in methylene chloride (25 ml per 0.1 mole of acyl chloride) over a period of 15 minutes. The mixture is stirred for ten minutes then brought to room temperature and stirred for one hour. The methylene chloride phase is separated and extracted with water (3x25 ml). The water is

Azabon

459

in turn extracted with methylene chloride (2x25 ml) and the combined methylene chloride phases dried (Na2SO4) then evaporated under reduced pressure. The residue is taken up in benzene and the solution passed through a silica gel column. The column is eluted with benzene, then with benzene containing increasing amounts of ethyl acetate; e.g., 5, 10, 25, and 50 %. The eluate is subjected to thin layer chromatography (ethyl acetate) and those fractions, which show only one spot, combined and evaporated to give N,N-dioctadecyl-N',N'-bis(2-hydroxyethyl)propanediamine M.P. 48.5°-49°C. References GB Patent No. 1,369,247; August 7, 1970; Pfizer Inc. St Delaware, USA

AZABON Therapeutic Function: Central stimulant Chemical Name: 3-[(4-Aminophenyl)sulfonyl]-3-azabicyclo[3.2.2]nonane Common Name: Azabon Structural Formula:

Chemical Abstracts Registry No.: 1150-20-5 Trade Name Azabon

Manufacturer ZYF Pharm Chemical

Country -

Year Introduced -

Raw Materials Sodium hydroxide 1,4-Cyclohexane-bis(methylamine) Nickel Raney 4-Nitrobenzenesulfonyl chloride Hydrogen Manufacturing Process The 1,4-cyclohexane-bis(methylamine) feed line was connected to the top of the preheater in a pyrolysis tube. The pyrolysis section was heated by external electric heaters. For a typical run, the pyrolysis temperature was

460

Azacitidine

maintained at 385°-395°C; the feed rate was 8.4 g per minute of 1,4cyclohexanebis(methylamine) and 1.47 g per minute of nitrogen this is a ratio of 0.885 mole of nitrogen per mole of 1,4-cyclohexanebis(methylamine) per h. The crude reaction product was collected in a chilled flask and the nitrogen and reaction gases were vented to a hood. These conditions were maintained for 15.5 h, during which time 7,849 g (55 moles) of 1,4cyclohexanebis(methylamine) was fed to the unit. Tile total crude product obtained weighed 7,269 g. Distillation of the crude product at atmospheric pressure to a base temperature of 260°-270°C yielded 1,480 g of 3azabicyclo[3.2.2]nonane (recrystallized from an equal weight of acetone). Gas chromatography of the filtrates of this first fraction through a 6-foot column packed with 15% Carbowax 20M on white Chromosorb indicated 1,854 g of 1,4-cyclohexanebis(metnylamine) and 721.0 g of 3-azabicyclo[3.2.2]nonane present. The remainder of the crude product was distilled at 1-5 mm to a base temperature of 200°-225°C. Thus, a total of 2,201 g (17.6 moles, 62.1% yield) of 3-azabicycla[3.2.2]nonane was produced. To a 3 L, three-neck flask equipped with a stirrer, thremometer, and condenser was charge 30.0 g (0.24 mole) of 3-azabicyclo[3.2.2]nonane, 44.3 g (0.2 mole) of p-nitrobenzenesulfonyl chloride and 2 L of water. The pH of the reaction mixture was adjusted to 14 with a 10% solution of sodium hydroxide; the reaction mixture was then slowly heated to 75°C and heating stopped. The reaction mixture was cooled to 20°C and 44.0 g (71% of theory) of crude 3-(p-nitrobenzenesulfonyl)-3-azabicyclo[3.2.2]nonane was collected by filtration. The crude 3-(p-nitrobenzenesulfonyl)-3-azabicyclo[3.2.2]nonane (44.0 g, 0.14 mole), 5.0 g alcohol wet Raney nickel, and 400 ml methyl alcohol were charged to an autoclave and reduced at 70°C at 1000 p.s.i. hydrogen pressure until absorption of hydrogen had stopped. The crude reduced product was filtered hot to remove the Raney nickel catalyst. The filtrate was cooled to 20°C and the solid 3-(p-ammobenzenesulfonyl)-3-azabicyclo[3.2.2]nonane was collected by filtration (38.9 g 98% theory), melting point 149°-151°C. References Pircio A.W. et al.; US Patent No. 3,351,528; Nov. 7, 1967; Assigned: BristolMyers Company, New York, N.Y.

AZACITIDINE Therapeutic Function: Antineoplastic Chemical Name: 1,3,5-Triazin-2(1H)-one, 4-amino-1β-D-ribofuranosylCommon Name: Azacitidine; 5-Azacytidine; Ladakamycin Chemical Abstracts Registry No.: 320-67-2

Azacitidine

461

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

5-Azacytidine

AroKor Holdings Inc.

-

-

5-Azacytidine

Xinxiang Tuoxin BiochemicTechnology and Science Co., Ltd.

-

-

Mylosar

Upjohn

-

-

Raw Materials 1-(2,3,5-tri-O-Benzoyl-β-D-ribofuranosyl)-4-methylthio-1,2-dihydro1,3,5-triazin-2-one Ammonia Potassium hydroxide Sodium methoxide Manufacturing Process A mixture of 1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-4-methylthio-1,2dihydro-1,3,5-triazin-2-one (0.5875 g), absolute methanol (5 ml) and a normal methanolic sodium methoxide solution (1.2 ml) is stirred at room temperature with the exclusion of atmospheric moisture (a guard tube filled with potassium hydroxide pellets is fitted to the reaction vessel). The starting compound passes into solution in the course of 5 min. The resulting solution is allowed to stand at room temperature for 45 min and then the cations are removed by passage of the solution through a column packed with 10 ml of a weakly acidic cation exchange resin in the H+ form prewashed with water and methanol. The methanolic effluent (60 ml) is evaporated under reduced pressure at 30°C, the residue is dissolved in methanol (20 ml) and the solution once again is evaporated and the 1-β-D-ribofuranosyl-4-methoxy-1,2dihydro-1,3,5-triazin-2-one was obtained. The residual crude crystalline 1β-D-ribofuranosyl-4-methoxy-1,2-dihydro1,3,5-triazin-2-one is dissolved in a 10% solution of dry ammonia in absolute methanol (4 ml) and the whole reaction mixture is allowed to stand in a stoppered flask for 30 min at room temperature (the product begins to deposit in the course of 5 min) and for 12 h in a refrigerator at -10°C. The resulting 5-azacytidine is collected with suction, washed with methanol and dried under reduced pressure. A yield of 0.216 g (88.6%) of 5-azacytidine, that is [1-β-D-ribofuranosyl-4-amino-1,3,5-triazin-2(1H)-one], melting point 232°-234°C (dec.), is obtained.

462

Azaconazole

References GB Patent No. 1,227,691; April 7, 1971; Assigned: Ceskoslovenska akademie ved, a Corporation organized and existing under the law of Czechoslovakia of N 3 Narodni, Prague 1, Czechoslovakia

AZACONAZOLE Therapeutic Function: Antifungal Chemical Name: 1H-1,2,4-Triazole, 1-((2-(2,4-dichlorophenyl)-1,3-dioxolan2-yl)methyl)Common Name: Azaconazolel; Azoconazole Structural Formula:

Chemical Abstracts Registry No.: 60207-31-0 Trade Name Azaconazole

Manufacturer Chemical Formulations, LLC

Country -

Year Introduced -

Raw Materials Hydrochloric acid Acetic acid Sodium hydroxide 1H-1,2,4-Triazole Sodium

1-(2,4-Diaminopheny1)-1-ethanone Sodium nitrite Bromine 4-Methylbenzenesulfonic acid

Manufacturing Process A stirred and cooled (0°C) solution of 1-(2,4-diaminophenyl)-1-ethanone in a concentrated hydrochloric acid solution, water and acetic acid was diazotated with a solution of sodium nitrite in water. After stirring at 0°C, the whole was poured onto a solution of copper (I) chloride in a concentrated hydrochloric acid solution while stirring. The mixture was heated at 60°C. After cooling to room temperature, the product was extracted twice with 2,2'-oxybispropane. The combined extracts were washed successively with water, a diluted sodium hydroxide solution and again twice with water, dried, filtered and evaporated, yielding 1-(2,4-dichlorophenyl)-1-ethanone.

Azacosterol hydrochloride

463

1-(2,4-Dichlorophenyl)-1-ethanon were dissolved in 1,2-ethanediol at heating. While stirring bromine were added dropwise, without external heating. After stirring at room temperature, 4-methylbenzenesulfonic acid and benzene were added. The whole was stirred and refluxed overnight with water-separator. The reaction mixture was evaporated and the residue was taken up in 2,2'oxybispropane. The resulting solution was washed successively once with a dilute sodium hydroxide solution and 3 times with water, dried, filtered and evaporated. The residue was distilled, yielding 2-(bromomethyl)-2-(2,4dichlorophenyl)-1,3-dioxolane. 6.9 parts of 1H-1,2,4-triazole in 150 parts of dimethylformamide were added to a stirred solution of 2.3 parts of sodium in 120 parts of methanol. The methanol was removed at normal pressure until the internal temperature of 130°C was reached. Then, 25 parts of 2-(bromomethyl)-2-(2,4dichlorophenyl)-1,3-dioxolane were added. The reaction-mixture was stirred and refluxed for 3 h. It was allowed to cool to room temperature and poured onto water. The precipitated product was filtered off, yielding 12 parts of 1-[2(2,4-dichlorophenyl)-1,3-dioxolan-2-yl-methyl]-1H-1,2,4-triazole; melting point 109.9°C (crystallized from diisopropylether; activated charcoal). References GB Patent No. 1,522,657; August 23, 1978; Assigned: Janssen Pharmaceutica N.V., a Belgian Body Corporate, of Turnhoutsebaan 30, Beerse, Belgium

AZACOSTEROL HYDROCHLORIDE Therapeutic Function: Hypocholesteremic Chemical Name: Androst-5-en-3β-ol, 17β-((3-(dimethylamino)propyl) methylamino)-, dihydrochloride Common Name: Azacosterol hydrochloride; Diazacholesterol dihydrochloride; Diazasterol hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 1249-84-9; 313-05-3 (Base) Trade Name

Manufacturer

Country

Ornitrol

Avitrol Corporation -

Year Introduced -

464

Azacosterol hydrochloride

Raw Materials 3β-Hydroxyandrost-5-en-17-one 3-Dimethylaminopropylamine Lithium aluminum hydride Manufacturing Process A solution of 15 parts of 3β-hydroxyandrost-5-en-17-one and 30 parts of 3dimethylaminopropylamine in 36.6 parts of formic acid is heated in an oil bath at about 170-180°C for about 24 hours. The cooled mixture is diluted with about 500 parts of water, and the resulting aqueous mixture is extracted with chloroform, containing a small amount of methanol. The organic layer is separated, washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The viscous residue is dissolved in a mixture of 80 parts of isopropyl alcohol and 420 parts of ether, and this solution is treated with isopropanolic hydrogen chloride. The resulting precipitate is collected by filtration and washed with acetone to afford 17β-[N(3-dimethylaminopropyl)formamido-1-androst-5-en-3β-ol hydrochloride. A solution of this hydrochloride in aqueous methanol is made alkaline by the addition of dilute aqueous sodium hydroxide, and the resulting colloidal precipitate is extracted with chloroform. The chloroform extracts washed with water, dried over anhydrous sodium sulfate and concentrated to dryness to afford a residue, which is crystallized from acetone, resulting in 17β-[N-(3dimethylaminopropyl)formamido]androst-5-en-3β-ol, which displays a double melting point at about 116-118°C and 143-148°C; [α]D= -67.5° (chloroform). To a slurry of 4 parts of LiAlH4 in 150 parts of dioxane is added dropwise with stirring, at the reflux temperature a solution of 10 parts of 17β-[N-(3dimethylaminopropyl) formamido]androst-5-en-3β-ol in 150 parts of dioxane. This reaction mixture is heated at reflux for about 18 hours longer, and then treated dropwise successively, at the reflux temperature, with a solution of 4 parts of water in 25 parts of dioxane, 3 parts of 20% aqueous sodium hydroxide, and 14 parts of water. The resulting mixture is clarified by filtration, and the residue on the filter is washed with fresh dioxane. The filtrates are combined, evaporated to dryness under reduced pressure, and the resulting residue is recrystallized from acetone-methanol to produce 17β-[N-methyl-N-(3dimethylaminopropyl)amino]androst-5-en-3β-ol, M.P. about 146-148°C; [α]D= -54.5° (chloroform). A solution of this amine in ether-isopropyl alcohol is treated with isopropanolic hydrogen chloride to afford the corresponding dihydrochloride; [α]D= -32° (methanol). References Merck Index, Monograph number: 924, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. Counsell R.E. et al.; US Patent No. 3,084,156; Apr. 2, 1963; Assigned to G.D. Searle and Co., Chicago, Ill., a corporation of Delawere

Azacyclonol

465

AZACYCLONOL Therapeutic Function: Tranquilizer Chemical Name: α,α-Diphenyl-4-piperidinemethanol Common Name: γ-Pipradol Structural Formula:

Chemical Abstracts Registry No.: 115-46-8; 1798-50-1 (Hydrochloride salt) Trade Name

Manufacturer

Country

Year Introduced

Frenquel

Merrell

US

1955

Frenoton

Draco

Sweden

-

Frenquel

Inibsa

Spain

-

Frenquel

Merrell-Tourade

France

-

Frenquel

Shionogi

Japan

-

Raw Materials α-(4-Pyridyl)-benzhydrol Hydrogen Manufacturing Process A mixture of 26 g (0.1 mol) of α-(4-pyridyl)-benzhydrol, 1.5 g of platinum oxide, and 250 ml of glacial acetic acid is shaken at 50-60°C under hydrogen at a pressure of 40-50 lb/in2. The hydrogenation is complete in 2 to 3 hours. The solution is filtered and the filtrate evaprated under reduced pressure. The residue is dissolved in a mixture of equal parts of methanol and butanone and 0.1 mol of concentrated hydrochloric acid is added. The mixture is cooled and filtered to give about 30 g of α-(4-piperidyl)benzhydrol hydrochloride, MP 283285°C, as a white, crystalline substance. The free base is readily obtained from the hydrochloride salt by treatment with ammonia and when so obtained has a melting point of 160-161°C. References Merck Index 898 Kleeman and Engei p. 65 OCDS Vol. 1 p. 47

466

Azalanstat hydrochloride

I.N.p. 109 Schumann, E.L., Van Campen, M.G., Jr. and Pogge, R.C.; US Patent 2,804,422; August 27, 1957; Assigned to The Wm. S. Merrell Co.

AZALANSTAT HYDROCHLORIDE Therapeutic Function: Antihyperlipidemic Chemical Name: Benzenamine, 4-(((2-(2-(4-chlorophenyl)ethyl)-2-(1Himidazol-1-ylmethyl)-1,3-dioxolan-4-yl)methyl)thio)-, (2S,4S)-, hydrochloride Common Name: Azalanstat hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 143393-27-5 (Base); 143484-82-6 Trade Name Azalanstat hydrochloride

Manufacturer Syntex

Country -

Year Introduced -

Raw Materials 4-Chlorophenethyl alcohol N-Bromosuccinimide Peracetic acid Potassium carbonate Imidazole Triethylamine Sodium hydroxide Methanesulfonyl chloride

Triphenylphosphine Vinyl bromide Sodium acetate Sodium hydride Oxalyl chloride Glycerol 4-Toluenesulfonic acid monohydrate 4-Aminothiophenol

Manufacturing Process A stirred solution of 4-chlorophenethyl alcohol (131.0 g) and triphenylphosphine (241.3 g) in dry THF (500 ml) at 0°C was treated portionwise over 30 min with N-bromosuccinimide (163.75 g). The resulting black solution was stirred overnight at room temperature, whereupon the THF was evaporated and the residue stirred with ether. The solution was filtered and the filtrate evaporated and treated with hexane. The stirred mixture was filtered, evaporated, and the residue distilled under reduced pressure to give 100.0 g of 4-chlorophenethyl bromide as a colorless liquid, boiling point 85°C

Azalanstat hydrochloride

467

(3 mm Hg). To a flame-dried flask containing magnesium turnings under ether was added 4-chlorophenethyl bromide in anhydrous ether at such a rate as to maintain a gentle reflux. When the addition was complete, the mixture was heated under reflux for an additional hour and then treated dropwise over 1 h with vinyl bromide in ether maintaining a gentle reflux. The resulting mixture was stirred overnight at room temperature and then poured onto ice-cold dilute sulfuric acid. The product was extracted with ethyl acetate and the combined extracts were washed with dilute aqueous potassium carbonate, dried MgSO4 and evaporated. The resulting brown oil was distilled under reduced pressure to give 4-(4-chlorophenyl)but-1-ene. To a solution of 4-(4-chlorophenyl)but-1-ene in dichloromethane was added dropwise with stirring a mixture of 40% peracetic acid and sodium acetate. The resulting mixture was heated under reflux, cooled, and stirred with water. The dichloromethane layer was separated, washed with dilute aqueous potassium carbonate until neutral, water, and dried (MgSO4) and evaporated to give 4-(4-chlorophenyl)-1,2-epoxybutane as a colorless oil. To a suspension of sodium hydride (50% dispersion in mineral oil) in dry DMF under nitrogen was added imidazole in dry DMF with stirring at such a rate as to keep the temperature below 65°C (ice bath). When the evolution of gas had ceased, 4-(4-chlorophenyl)-1,2-epoxybutane was added dropwise and the mixture stirred overnight at room temperature. The resulting brown solution was added water, extracted with ethyl acetate and the combined extracts were washed with water 3 times, dried (MgSO4) and evaporated to give an oil which crystallized. Washing the solid with ether and filtration give 1-(4-(4chlorophenyl)-2-hydroxybutyl)imidazole. A solution of oxalyl chloride (74.8 g) in dry dichloromethane (1350 ml) at below -70°C under a nitrogen atmosphere was treated with dry dimethylsulfoxide (91.5 ml) in methylene chloride (270 ml) dropwise over 1520 min while maintaining the temperature of the reaction mixture below 50°C. After an additional 5 min a solution of (+/)-1-(4-(4-chlorophenyl)-2hydroxybutyl)imidazole (128.3 g) in a mixture of dimethylsulfoxide (50 ml) and methylene chloride (200 ml) was added over a period of 20 min keeping the reaction mixture at temperatures below -65°C. After a further 15 min dry triethylamine (300 ml) was added rapidly and after 15 min the reaction mixture was allowed to warm to 0°C. Water (20 ml) was then added to the reaction mixture, the methylene chloride then removed by evaporation and the resulting slurry was then treated with water and filtered. The filter cake was washed well with ice water, cold ethyl acetate and then dried in air to yield 118.0 g of 4-(4-chlorophenyl)-1-(imidazol-1-yl)butan-2-one. A mixture of 4-(4-chlorophenyl)-1-(imidazol-1-yl)butan-2-one (50.0 g), ptoluenesulfonic acid monohydrate (42.07 g) and glycerol (37.0 g) in toluene (200 ml) was heated under reflux, with stirring, through a Dean-Stark trap for 6 h. The two layers were allowed to separate and the hot toluene (upper layer) decanted and discarded. The lower layer was poured into 2 N sodium hydroxide (500 ml), the transfer completed by washing the flask with 1 N sodium hydroxide and methylene chloride, and the product extracted with methylene chloride (4x200 ml). The extracts were dried (MgSO4) evaporated

468

Azaloxan fumarate

and the residue recrystallized from toluene to give 61.4 g of (cis/trans)-2-(2(4-chlorophenyl)ethyl)-2-(imidazol-1-yl)methyl-4-hydroxymethyl-1,3dioxolane, melting point 96°-110°C. (cis/trans)-2-[2-(4-Chlorophenyl)ethyl]-2-(imidazol-1-yl)methyl-4hydroxymethyl-1,3-dioxolane (39.7 g) in pyridine (150 ml) at 0°C was treated drop-wise with stirring with methanesulfonyl chloride (10.6 ml) and the mixture stirred overnight. The resulting solid mass was stirred with ether (500 ml) to break up the solid, filtered and washed well with ether to give (cis/trans)-2-[2-(4-chlorophenyl)ethyl]-2-(imidazol-1-yl)methyl-4(methylsulfonyloxy)methyl-1,3-dioxolane hydrochloride, melting point 107°110°C (recrystallized from dichloromethane/isopropanol). The (cis/trans)-2-[2-(4-chlorophenyl)ethyl]-2-(imidazol-1-yl)methyl-4(methylsulfonyloxy)methyl-1,3-dioxolane hydrochloride was basified with aqueous potassium carbonate solution, extracted with ethyl acetate (2x400 ml) and the extracts washed, dried (MgSO4) and evaporated. The resulting semicrystalline mass was chromatographed on silica gel (900.0 g) eluting with dichloromethane, aqueous ethyl acetate (2.2% water) to give 25.4 g of (+/-)cis-2-(2-(4-chlorophenyl)ethyl)-2-(imidazol-1-yl)methyl-4(methylsulfonyloxy)methyl-1,3-dioxolane, as a snow white solid, melting point 93.5°-96°C. Further elution gave, after a small mixed fraction, pure (+/-)trans-2-[2-(4-chlorophenyl)ethyl]-2-(imidazol-1-yl)methyl-4(methylsulfonyloxy)methyl-1,3-dioxolane, as a white solid, melting point 93°95°C. A mixture of (+/-)-cis-2-[2-(4-chlorophenyl)ethyl]-2-(imidazol-1-yl)methyl-4(methylsulfonyloxy)methyl-1,3-dioxolane (31.0 g), 4-aminothiophenol (12.6 g) and anhydrous potassium carbonate (23.1 g) in acetone (250 ml) was stirred overnight under reflux under nitrogen. The reaction mixture was then evaporated to dryness, and the resulting residue was extracted with methylene chloride (300 ml) and filtered. The solid filter cake was then washed with methylene chloride (200 ml). The methylene chloride extracts were then combined and concentrated and flash chromatographed on a silica gel eluting with methylene chloride followed by 30% acetone in methylene chloride. The pure product was dissolved in a minimum amount of hot ethyl acetate (125 ml), the solution diluted with an equal volume of hot hexane and seeded to give 30.0 g of (+/-)-cis-2-[2-(4-chlorophenyl)ethyl]-2-(imidazol-1yl)methyl-4-(4-amino-phenylthio)methyl-1,3-dioxolane, melting point 121°122.5°C. In practice it is usually used as hydrochloride. References Walker K.A. et al.; US Patent No. 5,158,949; Oct. 27, 1992; Assigned: Syntex (U.S.A.) Inc., Palo Alto, Calif.

AZALOXAN FUMARATE Therapeutic Function: Antidepressant

Azaloxan fumarate

469

Chemical Name: (S)-1-[1-[2-(1,4-Benzodioxan-2-yl)-ethyl]-4-piperidyl]-2imidazolidinone fumarate Common Name: Azaloxan fumarate Structural Formula:

Chemical Abstracts Registry No.: 72822-56-1 (Base); 86116-60-1 Trade Name

Manufacturer

Country

Year Introduced

Idulian

Unicet

-

-

CGS7135A

Ciba-Geigy

-

-

Azaloxan Fumarate

ZYF Pharm Chemical

-

-

Raw Materials Bromine Catechol Allyl cyanide Sulfuric acid 4-Aminopyridine Hydrogen Furmaric acid

Acetic acid 4-Toluenesulfonyl chloride Sodium bis(2-methoxyethoxy)aluminum hydride Potassium carbonate Sodium methanolate 2-Chloroethylisocyanate Ruthenium on carbon

Manufacturing Process The producing of starting materials 1 and 2: 1). The solution of 16.0 g of bromine in 10 ml of petroleum ether is slowly added to the solution of 6.7 g of allyl cyanide in 30 ml of the same solvent, while stirring and keeping the temperature at about -15°C. After removal of the solvent the oily 3,4-dibromo-butyronitrile is obtained [J.A. C.S. 67, 400 (1945)]. 227.0 g of 3,4-dibromobutyronitrile are added dropwise in 5 equal parts to the stirred mixture of 85.0 g of catechol and 50. g of anhydrous potassium carbonate in 100 ml of refluxing acetone each. Another 50.0 g of potassium carbonate are added, followed by a slow addition of another part of nitrile. After 3 more cycles, using 40.0 g of potassium carbonate, 1 part nitrile each and sufficient acetone to allow stirring, the mixture is refluxed for 20 h. It is

470

Azaloxan fumarate

filtered, the filtrate evaporated, the residue distilled and the fraction boiling at 105°C/0.15 mm Hg collected, to yield the 1,4-benzodioxan-2-yl-acetonitrile [Belgium Pat. No. 643,853-Aug. 14, 1964]. The mixture of 111.0 g of 1,4-benzodioxan-2-yl-acetonitrile, 63.5 ml of sulfuric acid, 160 ml of acetic acid and 160 ml of water is refluxed for 48 h. It is poured on ice, the resulting solid collected to yield the 1,4-benzodioxan-2yl-acetic acid, melting point 100°C, (recrystallized from benzene-petroleum ether) [Belgium Pat. No. 613,211-July 30, 1962]. The solution of 5.8 g of 1,4-benzodioxan-2-yl-acetic acid in 100 ml of benzene is added dropwise to 16.5 ml of a refluxing, 70% benzene solution of sodium bis(2-methoxyethoxy)aluminum hydride under nitrogen. When addition is complete, the mixture is refluxed for 4 h, cooled and poured slowly into 20 ml of 25% sulfuric acid. After filtration and removal of the solvent, the residue is taken up in methylene chloride, the solution washed several times with saturated aqueous sodium bicarbonate, dried and evaporated, to yield the oily 2-(2-hydroxyethyl)-1,4-benzodioxan. The mixture of 3.6 g of 2-(2-hydroxyethyl)-1,4-benzodioxan, 5.7 g of ptoluenesulfonyl chloride and 20 ml of dry pyridine is stirred and cooled in an ice bath for 2 h. Ice is then added to the mixture, the resulting solid is filtered off to yield the 2-(2-tosyloxyethyl)-1,4-benzodioxan, melting point 82°-83°C (recrystallized from ethyl acetate-petroleum ether). 2). To the solution of 1.6 g of 4-aminopyridine in 7 ml of dimethylformamide 2.0 g of 2-chloroethylisocyanate are added while stirring and keeping the temperature below 40°C. After 2 h 28 ml of water are added and stirring is continued for 2 h at room temperature. The precipitate formed is filtered off, washed with water, dried to yield the 1-(4-pyridyl)-3-(2-chloroethyl)urea, melting point 120°-122°C, (recrystallized from aqueous ethanol). To the suspension of 2.66 g of 1-(4-pyridyl)-3-(2-chloroethyl)urea in 4 ml of boiling methanol, 2.68 g of 30.8% methanolic sodium methanolate are added while stirring and the mixture is refluxed for 1 h. It is filtered hot, washed with hot methanol, the filtrate evaporated, to yield the 1-(4-pyridyl)-2imidazolidinone, melting point 204°-207°C, (recrystallized from 90% aqeuous ethanol). The solution of 5.0 g of 1-(4-pyridyl)-2-imidazolidinone in 45 ml of water is hydrogenated over 0.8 g of 10% ruthenium on carbon at 120°C and 120 atm until the hydrogen absorption ceases. It is filtered, the filtrate evaporated, the residue taken up in chloroform, the solution dried, evaporated to yield the 1(4-piperidyl)-2-imidazolidinone, melting point 155°-157°C (recrystallized from methylene chloride-petroleum ether). The producing of (cis)-(S)-1-[1-[2-(1,4-benzodioxan-2-yl)ethyl]-4-piperidyl]2-imidazolidinone fumarate: The mixture of 4.9 g of 2-(2-tosyloxyethyl)-1,4-benzodioxan, 2.54 g of 1-(4piperidyl)-2-imidazolidinone, 5.0 g of anhydrous sodium carbonate and 100 ml of 4-methyl-2-pentanone is stirred and refluxed for 3 days. It is filtered, evaporated, to yield the 1-[1-[2-(1,4-benzodioxan-2-yl)-ethyl]-4-piperidyl]-2imidazolidinone, melting point 125°C, (recrystallized from isopropanol).

Azanidazole

471

To the solution of 2.0 g of 1-[1-[2-(1,4-benzodioxan-2-yl)-ethyl]-4-piperidyl]2-imidazolidinone in the mini-mum amount of ethanol, the saturated solution of 0.78 g of furmaric acid in boiling ethanol is added. The mixture is cooled to 0°C and the precipitate collected, to yield the 1-[1-[2-(1,4-benzodioxan-2-yl)ethyl]-4-piperidyl]-2-imidazolidinone fumarate, melting point 190°C. The (cis)-(S)-form may be produced by chromatographic division of isomers of 1-[1-[2-(1,4-benzodioxan-2-yl)ethyl]-4-piperidyl]-2-imidazolidinone fumarate. References Huebner Ch. F.; US Patent No. 4,329,348; May 11, 1982; Assigned: CibaGeigy Corporation, Ardsley, N.Y.

AZANIDAZOLE Therapeutic Function: Antiprotozoal, Antibacterial Chemical Name: 2-Amino-4-[2-(1-methyl-5-nitroimidazol-2-yl)vinyl] pyrimidine Common Name: Nitromidine Structural Formula:

Chemical Abstracts Registry No.: 62973-76-6 Trade Name

Manufacturer

Country

Year Introduced

Triclose

Ist. Chemioter.

Italy

1977

Triclose

I.C.I.

Italy

-

Raw Materials 2-Amino-4-methylpyrimidine 2-Formyl-1-methyl-5-nitroimidazole Sulfuric acid Manufacturing Process Into a mixture of 1.6 g of 2-amino-4-methylpyrimidine with 10 ml of glacial acetic acid is slowly added 2.13 g of concentrated sulfuric acid. A mixture of 2.4 g of 2-formyl-1-methyl-5-nitroimidazole in 20 ml of glacial acetic acid is slowly added to the mixture of the pyrimidine under stirring. The reaction

472

Azaperone

mixture is maintained at a temperature of about 55°C for 4 hours. The resultant mixture is then diluted with 200 ml of distilled water and neutralized with a saturated aqueous solution of sodium bicarbonate. A brownish-yellow precipitate (MP 232° to 235°C) is formed and recovered. The product is analyzed by infrared spectroscopy and is found to conform to 2-amino-4-[2(1-methyl-5-nitro-2-imidazolyl)vinyl]pyrimidine. References Merck Index 902 DOT 14 (6) 234 (1978) I.N. p. 109 Garzia, A.; US Patent 3,882,105; May 6, 1975; Assigned to Istituto Chemioterapico Italiano SpA Garzia, A.; US Patent 3,969,520; July 13, 1976; Assigned to Istituto Chemioterapico Italiano SpA

AZAPERONE Therapeutic Function: Neuroleptic, Hypnotic Chemical Name: 1-Butanone, 1-(4-fluorophenyl)-4-(4-(2-pyridinyl)-1piperazinyl)Common Name: Azaperone; Sedaperone Structural Formula:

Chemical Abstracts Registry No.: 1649-18-9 Trade Name

Manufacturer

Azaperone

Dayang Chemicals Co. Ltd.

-

Azaperolo

C.E.R. Laboratoire D'Hormonologie

-

Azaperone

C.E.R. Laboratoire D'Hormonologie

-

Raw Materials γ-Chloro-4-fluorobutyrophenone 1-(2'-Pyridyl)piperazine

Country

Year Introduced

Azapetine phosphate

473

Manufacturing Process A mixture of γ-chloro-4'-fluorobutyrophenone and 1-(2'-pyridyl)piperazine is heated on an oil bath. The mixture is then boiled in diisopropyl ether and the precipitates is collected and boiled with water and benzene. The benzene layer is treated with activated charcoal, added to the ethereal filtrate, and evaporated to give a residue which is taken up in diisopropyl ether. After cooling an oil is precipitated, which after decantation and drying yields 1-[γ(4'-fluorobenzoyl)propyl]-4-(2'-pyridyl)piperazine. References Janssen P.A.J.; US Patent No. 2,958,694; Nov. 1, 1960

AZAPETINE PHOSPHATE Therapeutic Function: Adrenergic blocker Chemical Name: 6,7-Dihydro-6-(2-propenyl)-5H-dibenz[c,e]azepine phosphate Common Name: Structural Formula:

Chemical Abstracts Registry No.: 130-83-6; 146-36-1 (Base) Trade Name

Manufacturer

Country

Year Introduced

Ilidar

Roche

US

1954

Ilidar

Roche

W. Germany

-

Raw Materials Diphenic acid Lithium aluminum hydride Allyl bromide

Ammonia Acetic anhydride Phosphoric acid

474

Azapetine phosphate

Manufacturing Process 29 grams of diphenic acid were stirred in 900 cc of acetic anhydride at 120°C for one hour, The cooled mixture was filtered and washed with acetic acid to give diphenic anhydride, colorless crystals, MP about 222-226°C. 24.11 grams of diphenic anhydride were mixed with 50 cc of concentrated ammonia. The mixture warmed up and cooling was applied, after which the mixture was stirred until a clear solution formed and for 1½ hours afterward. The mixture was acidified and allowed to stand overnight. Water was added, initiating precipitation. The mixture was chilled and filtered to yield diphenamic acid, a colorless solid, MP about 191-193°C. 23.5 grams of diphenamic acid were heated at 200°C in an oil bath, first for about 20 hours at atmospheric pressure and then for about 10 hours at about 20 mm. Melting points were taken at intervals in order to gain an idea of the extent of reaction. The final residue was boiled with alcohol but since the solid exhibited insufficient solubility in the hot solvent, the mixture was filtered. The residue consisted of tan crystals, MP about 220-221°C, and the filtrate on cooling gave an additional crop of tan crystals, MP about 219-221°C. The two materials were identical and consisted of diphenimide. 5.58 g of diphenimide were placed in a Soxhlet thimble and extracted for about 3 days with a boiling mixture of 9.0 g of lithium aluminum hydride in 600 cc of sodium-dried ether. Excess lithium aluminum hydride was then decomposed cautiously with water and the mixture was filtered through a filter aid by suction. The filtrate consisted of two layers. The ether layer was separated and dried with anhydrous potassium carbonate and acidified with alcoholic hydrochloric acid to give 6,7-dihydro-5H-dibenz[c,e]azephine hydrochloride, MP about 287-289°C. One gram of 6,7-dihydro-5H-dibenz[c,e]azepine hydrochloride was dissolved in water, made alkaline with concentrated ammonia, and the resultant base extracted twice with benzene, The benzene layers were combined, dried with anhydrous potassium carbonate, and mixed with 0.261 g of allyl bromide at 25-30°C. The reaction solution became turbid within a few minutes and showed a considerable crystalline deposit after standing 3½ days. The mixture was warmed 1 3/4 hours on the steam bath in a loosely-stoppered flask, then cooled and filtered. The filtrate was washed twice with water and the benzene layer evaporated at diminished pressure. The liquid residue was dissolved in alcohol, shaken with charcoal and filtered. Addition to the filtrate of 0.3 gram of 85% phosphoric acid in alcohol gave a clear solution which, when seeded and rubbed, yielded 6-allyl-6,7-dihydro-5H-dibenz[c,e]azepine phosphate, MP about 211-215°C with decomposition. References Merck Index 904 Kleeman and Engel p. 65 I.N. p. 109 Schmidt, R.A. and Wenner, W.; US Patent 2,693,465; November 2, 1954; Assigned to Hoffmann-La Roche, Inc.

Azaquinzole

475

AZAQUINZOLE Therapeutic Function: CNS depressant Chemical Name: 1,3,4,6,7,11b-Hexahydro-2H-pyrazino[2,1-a]isoquinoline Common Name: Azaquinzole Structural Formula:

Chemical Abstracts Registry No.: 5234-86-6 Trade Name

Manufacturer

Country

Year Introduced

Azaquinzole

Onbio Inc.

-

-

Raw Materials Diethyl ester of oxalic acid Lithium aluminum hydride 1-Aminomethyl-1,2,3,4-tetrahydroisoquinoline Ethylene dibromide Potassium carbonate Sodium hydroxide Manufacturing Process 2 Methods of producing of 1,2,3,6,7,11b-hexahydro-4H-pyrazino-[2,1a]isoquinoline: 1). 214.0 g diethyl ester of oxalic acid are mixed with a solution of 238.0 g 1aminomethyl-1,2,3,4-tetrahydroisoquinoline in 200 ml alcohol are boiled for 7 h. After cooling, the obtained crystals of 1,2,3,6,7,11b-hexahydro-4Hpyrazino[2,1-a]isoquinoline-3,4-dione are vacuum-filtered and washed with acetone and dried, melting point 220°C. Yield: 240.0 g. 55.0 g lithium aluminum hydride are dissolved in 650 ml absolute tetrahydrofuran and mixed dropwise with a suspension of 120.0 g 1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline-3,4-dione in 300 ml absolute tetrahydrofuran. After 7 h of boiling, the residual hydride is decomposed by the addition of water, and the reaction solution is worked up. The obtained 1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline is distilled in vacuum, boiling point 98°-100°C/0.01 mm. Yield: 86.0 g. 2). 16.2 g 1-aminomethyl-1,2,3,4-tetrahydroisoquinoline and 18.7 g ethylene dibromide are boiled for 4 h in n-butanol, with the addition of 13.8 g potassium carbonate. After the solvent is evaporated, the residue is treated

476

Azaserine

with water, mixed with sodium hydroxide solution, and shaken out with chloroform. The chloroform solution is dried, concentrated by evaporation, and the resulting 1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline is distilled at 98°-100°C/0.01 mm. The yield amounts to 7.5 g. References Thesing J. et al.; US Patent No. 3,393,195; July 16, 1968; Assigned: E. Merch Aktiengeselischaft, Darmstadt, Germany

AZASERINE Therapeutic Function: Antineoplastic, Antifungal Chemical Name: L-Serine diazoacetate (ester) Common Name: Azaserine Structural Formula:

Chemical Abstracts Registry No.: 115-02-6 Trade Name

Manufacturer

Country

Year Introduced

Azaserine

TG International Chemical Co. Sigma

-

-

-

-

Azaserine

CalbiochemNovabiochem Corp.

-

-

Azaserine

ICN Biomedicals Inc.

-

-

Azaserine

Raw Materials Streptomyces fragilis Soybean expeller oil meal Yeast Sodium hydroxide Ammonium nitrate Mineral oils

Glucose Acid hydrolyzed casein Sodium chloride Calcium carbonate Castile soap

Manufacturing Process The azaserine is produced by microbiological synthesis using culture of Streptoniyces fragili:

Azaserine

477

10 gallons of a nutrient medium having the following composition (%):glucose 1.0; soybean expeller oil meal 1.0; acid hydrolyzed casein 0.5; debittered yeast 0.5; sodium chloride 0.5; water sufficient to make 100.0% is placed in a 30 gallon stainless steel fermenter, the pH adjusted to 7.5 with 6 N sodium hydroxide solution and 0.1% calcium carbonate added. The medium is sterilized by heating at 121°C for 30 min after which the pH of the medium is 6.85. The medium is cooled and inoculated with the spares from two fourteen day old Moyer's sporulation agar slant cultures of Streptoniyces fragilis suspended in 20 ml of sterile 0.01% castile soap solution. The culture mixture is incubated at 27°C for 24 h during which time aeration is supplied through a sparger at the rate of one volume of air per volume of medium per minute. The incubated culture thus obtained is used to inoculate the main culture as described below. 150 gallons of a medium having the following composition (%): glucose 1.0; soybean expeller oil meal 1.0; acid hydrolyzed casein 0.5; debittered yeast 0.5; sodium chloride 0.5; ammonium nitrate 0.25; water sufficient to make 100.0 percent. 6 N sodium hydroxide solution-sufficient to bring the pH to 7.5;calcium carbonate - (added after pH adjustment) is placed in a 200-gallon stainless steel fermenter and sterilized by heating at 121°C for 30 min. The medium is cooled, inoculated with the 10-gallon culture of Streptomyces fragilis prepared as described above, and incubated at 26°C for 44 h. During the incubation period air is supplied through a sparger at the rate of 1.5-volumes of air per volume of medium per min and the mixture stirred at the rate of 150 r.p.m. for the first 12 h and at 300 r.p.m. for the final 32 h, 1.5 gallons of a sterilized mixture of crude lard and mineral oils containing mono- and diglycerides being added as needed to control foaming. The solid material present in the incubated fermentation mixture is removed by filtration and the filter cake washed with water. The washings are combined with the main filtrate and 110 gallons of this solution stirred with 2079.0 g of activated carbon for about 1 h. The carbon is removed by filtration and the filter cake washed with deionized water. The combined filtrate and washes (136 gallons) are concentrated in vacuum to a volume of about 20 gallons. Three volumes of acetone are added to the concentrate with stirring, and the precipitate which forms removed by filtration and the filter cake washed with 75% aqueous acetone. The combined aqueous acetone filtrate and washings is concentrated in vacuum to a volume of about 19.5 gallons, the concentrate so obtained frozen and dried from the frozen state under high vacuum. 1.0 kg of dry powder is extracted with one 10-liter portion of 90% (by volume) ethanol followed by extraction with one 2-liter portion of the same solvent. The combined extracts (about 12 L) are diluted with sufficient water to reduce the ethanol concentration to 75% by volume, and this alcoholic solution passed through an adsorption column prepared as described below. 3.0 kg of alumina are stirred with dilute hydrochloric acid so that the pH remains constant at 7.7. The alumina is removed, washed with water and activated by heating at 200°C for 4 h. The alumina is stirred with 75% aqueous ethanol and packed into an adsorption column having a diameter of 4 inches. The total packed volume is approximately 3500 ml. The alcoholic solution prepared above is added to the adsorption column at the rate of 6 L/h and the percolate discorded. The column is washed with 35 L of 75% ethanol (by volume), the washing discarded and the column finally washed with 21 L of 50% ethanol. Some O-diazoacetyl-L-serine may be

478

Azasetron hydrochloride

detected in the last wash solution. After the washing has been completed the adsorbed O-diazoacetyl-L-serine is eluted from the adsorption column by passing 17.5 L of distilled water through the column. The aqueous eluate is concentrated and frozen and the concentrate dried from the frozen state under high vacuum. The powder thus obtained, a O-diazoacetyl-L-serine content of 5.8%. 500.0 g of the material assaying 5.8% O-diazoacetyl-L-serine is dissolved in 1,320 ml of water. A column of activated charcoal is prepared. A mixture of 2.0 kg of activated charcoal (Darco (1-60) and 2.0 kg of diatomaceous earth is packed as a thick slurry in a 6 inch column. The pH of the water is 5.2-5.5. With this bed, a head of 4 feet of solvent is necessary to achieve a suitable flow rate. After packing, the column is washed with water for several hours to settle and remove solubles. The solution is applied to the column with positive pressure equivalent to a head of four foot of water. One retention volume of 9 L of water is then applied to the column. This is followed by a 5% acetone solution. The total solvent flow is 36 L. The colorless eluate is discarded. The elution front which is easily detected is a light yellowish-green solution. This solution is retained. The solution is concentrated by vacuum distillation until a concentration of 20-25 mg/ml is reached. This solution is applied to a column prepared in an identical manner as described herein and treated by the same procedure as the primary adsorption. The percolate is concentrated by vacuum distillation until a concentration of 60-75 mg/ml is reached. The quantity of solution is now approximately 300 ml. Absolute alcohol (450 ml) is added. The solution is gently warmed to complete solution and then stored at 5°C for several hours. The O-diazoacetyl-L-serine which separates in crystalline form is collected and purified by recrystallization from 60-70% ethanol; is an aqueous buffer of pH 7. References Ehrlich J. et al.; US Patent No. 2,996,435; Aug. 15, 1961; Assigned: Parke, Davis and Company, Detroit, Moch., a corporation of Michigan

AZASETRON HYDROCHLORIDE Therapeutic Function: Antiemetic Chemical Name: (+/-)-N-1-Azabicyclo[2.2.2]oct-3-yl-6-chloro-3,4-dihydro-4methyl-3-oxo-2H-1,4-benzoxazine-8-carboxamide monohydrochloride Common Name: Azasetron hydrochloride; Nazasetron hydrochloride Chemical Abstracts Registry No.: 123040-69-7 (Base); 141922-90-9 Raw Materials 2-(2-Carboxy-4-chlorophenoxy)acetic acid Nitric acid Ferric sulfate heptahydrate Potassium t-butoxide

Sulfuric acid Ammonia Hydrochloric acid Methyl iodide

Azasetron hydrochloride 3-Amino-8-azabicyclo[3.2.1]octane Ethyl chlorocarbonate Sodium hydrogen carbonate

479

Triethylamine Potassium hydroxide

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Azasetron hydrochloride Azasetron hydrochloride

Pharm Chemical

-

-

HangZhou Ohua Pharmaceutical Technology Co., Ltd. Yoshimoti

-

-

-

-

Serotone

Manufacturing Process To a solution of 2-(2-carboxy-4-chlorophenoxy)acetic acid in concentrated sulfuric acid is added dropwise a mixed liquid of fuming nitric acid and concentrated sulfuric acid under stirring with keeping at a temperature below 10°C. After the addition, the reaction mixture is stirred and poured into 10 L of ice-cold water. The precipitated crystals are collected by filtration, washed with 2 L of water four times and them dried to give 2-(2-carboxy-4-chloro-6nitrophenoxy)acetic acid. To a solution of ferrous sulfate heptahydrate in of hot water is added a solution of 2-(2-carboxy-4-chloro-6-nitrophenoxy)acetic acid and aqueous concentrated ammonia solution in water under stirring. After stirring, to the reaction mixture is twice added aqueous concentrated ammonia solution. While the reaction mixture becomes exothermic, stirring is continued. The resultant mixture is filtered through a celite layer under reduced pressure and washed with hot water twice. The filtrate is cooled and made acid with concentrated hydrochloric acid. The precipitated crystals are washed with water and dried to give 6-chloro-3,4-dihydro-3-oxo-2H-1,4-benzoxazine-8carboxylic acid. A mixture of 6-chloro-3,4-dihydro-3-oxo-2H-1,4-benzoxazine-8-carboxylic acid, methanol and concentrated sulfuric acid is refluxed under heating with stirring, and then cooled. The precipitated crystals are collected by filtration, washed with methanol and dried to give methyl 6-chloro-3,4-dihydro-3-oxo2H-1,4-benzoxazine-8-carboxylate, melting point 239°-241°C. To a solution of methyl 6-chloro-3,4-dihydro-3-oxo-2H-1,4-benzoxazine-8-

480

Azastene

carboxylate in dimethylformamide is added potassium t-butoxide and solution stirred at room temperature. To the resultant solution is added dropwise a solution of methyl iodide in dimethylformainide under stirring. After the reaction solution is stirred, water is added thereto. The insoluble substance is collected by filtration, washed with water and dried to give methyl 6-chloro3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazine-8-carboxylate. A mixture of methyl 6-chloro-3,4-dihydro-4-methyl-3-oxo-2H-1,4benzoxazine-8-carboxylate, ethanol and 4% aqueous potassium hydroxide solution is refluxed with heating. The resultant solution is cooled and water is added thereto followed by filtration. The filtrate is made acid with concentrated hydrochloric acid. The precipitated crystals are collected by filtration, washed with water and dried, and then recrystallized from ethanol to give 6-chloro-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazine-8-carboxylic acid, melting point 241°-243°C. A solution of 6-chloro-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazine-8carboxylic acid in tetrahydrofuran and dimethylformamide is cooled to below 0°C and triethylamine is added under stirring thereto. Further, ethyl chlorocarbonate is added and the mixture is stirred at room temperature. To the resultant mixture is added 3-amino-8-azabicyclo[3.2.1]octane and the mixture stirred. After completion of the reaction, aqueous sodium hydrogen carbonate and ethyl acetate are added. The organic layer is separated, washed with water and dried over magnesium sulfate. The solvent is distilled off to give 6-chloro-3,4-dihydro-4-methyl-N-(8-azabicyclo[3.2.1]oct-3-yl)-3oxo-2H-1,4-benzoxazine-8-carboxamide. In practice it is usually used as hydrochloride. References Tahara T. et al.; US Patent No. 4,892,872; Jan. 9, 1990; Assigned: Yoshitomi Pharmaceutical Industries, Ltd., Osaka, Japan

AZASTENE Therapeutic Function: Contraceptive Chemical Name: Androsta-2,5-dieno[2,3-d]isoxazol-17-ol, 4,4,17-trimethyl-, (17β)Common Name: Azastene Structural Formula:

Azastene

481

Chemical Abstracts Registry No.: 13074-00-5 Trade Name

Manufacturer

Country

Year Introduced

Azastene

ZYF Pharm Chemical

-

-

Raw Materials 4,4,17α-Trimethyl-2,5-androstdien-17β-ol-3-one Sodium Methanol Ethyl formate Hydrochloric acid Sodium acetate Hydroxylamine hydrochloride Acetic acid Manufacturing Process A solution of 4,4,17α-trimethyl-androsta-2,5-dien-17β-ol-3-one in benzene was added to sodium methoxide (from sodium and of absolute methanol, concentrating the solution and drying the residue for 1 h at 150°-160°C and 15 mm). Ethyl formate was then added with stirring in a nitrogen atmosphere. The reaction mixture was stirred for 4 h at room temperature, allowed to stand for about 15 h, stirred for 2 h and then poured into water. The reaction mixture was extracted with benzene, the aqueous layer warmed until clear, filtered and cooled below room temperature. Concentrated hydrochloric acid and ice were added to the filtrate until the mixture was acid to Congo red, and the product was extracted with chloroform. The chloroform extracts were washed with water, dried over anhydrous sodium sulfate, filtered and concentrated vacuum, whereupon there separated 2-hydroxymethylene4,4,17α-trimethyl-androsta-2,5-dien-17β-ol-3-one. To a solution of sodium acetate in acetic acid was added hydroxylamine hydrochloride, and methanol was added until solution resulted. This solution was added to a solution of 2-hydroxymethylene-4,4,17α-trimethyl-androsta2,5-dien-17β-ol-3-one in absolute methanol, and the combined solution was refluxed for 40 min on a steam bath. The reaction mixture was concentrated, the residue extracted with ethyl acetate, and the ethyl acetate extracts were washed with ethyl acetate, and the ethyl acetate extracts were washed with 5% hydrochloric acid, dried over anhydrous sodium sulfate and concentrated whereupon there separated solid material. The mother liquors were concentrated to dryness and the residue recrystallized from ether to give solid product. The latter was chromatographed on a column of silica gel in benzene solution, recrystallized from ethyl acetate and dried at 75°C for 20 h to give 17β-hydroxy-4,4,17αtrimethyl-androsta-2,5-dien[2,3-d]isoxazole. The crude product was chromatographed on silica gel in benzene solution, eluted with benzene containing 5% of ether and recrystallized from ethanol to give 17β-hydroxy-4,4,17α-trimethyl-androsta-2,5-dien[2,3-d]isoxazole.

482

Azatadine maleate

References Clinton R.O., Manson A.J.; US Patent No. 3,135,743; June 2, 1964; Assigned: Sterling Drug Inc., New York, N.Y., a corporation of Delaware

AZATADINE MALEATE Therapeutic Function: Antihistaminic Chemical Name: 6,11-Dihydro-11-(1-methyl-4-piperidinylidene)-5Hbenzo[5,6]cyclohepta[1,2-b]pyridine maleate Common Name: Structural Formula:

Chemical Abstracts Registry No.: 3978-86-7 Trade Name

Manufacturer

Country

Year Introduced

Idulian

Unilabo

France

1968

Optimine

Schering

US

1977

Optimine

Warrick

UK

1978

Optimine

Warrick

Italy

1983

Optimine

Byk-Essex

W. Germany

1983

Trinalin

Schering

US

-

Verben

Schering

-

-

Zadine

Schering

-

-

Raw Materials N-Methyl-4-chloropiperidine Polyphosphoric acid 4-Aza-10,11-dihydro-5-H-dibenzo-[a,d]cycloheptene-5-one Ethyl bromide

Azatepa

483

Magnesium Maleic acid Manufacturing Process Preparation of 4-aza-5-(N-methyl-4-piperidyl)-10,11-dihydro-5Hdibenzo[a,d]cycloheptene-5-ol: Add 17.4 g of N-methyl-4-chloropiperidine to a stirred mixture containing 3.2 g of magnesium, 20 ml of anhydrous tetrahydrofuran, 1 ml of ethyl bromide and a crystal of iodine. Reflux for two hours, cool to 30-35°C and add a solution of 13 g of 4-aza-10,11-dihydro-5Hdibenzo[a,d]cycloheptene-5-one in 25 ml of tetrahydrofuran. Stir for five hours, remove the solvent by distillation in vacuum and add 250 ml of ether. Add 100 ml of 10% ammonium chloride solution and extract the mixture with chloroform. Concentrate the chloroform solution to a residue and recrystallize from isopropyl ether obtaining 20 g of the carbinol, MP 173-174°C. Preparation of 4-aza-5-(N-methyl-4-piperidylidene)-10,11-dihydro-5Hdibenzo[a,d]cycloheptene: Heat 5.4 g of the carbinol and 270 g of polyphosphoric acid for 12 hours at 140-170°C. Pour into ice water and make alkaline with sodium hydroxide. Extract with ether. Dry ether solution and concentrate to a residue. Crystallize from isopropyl ether, MP 124-126°C. Preparation of 4-aza-5-(N-methyl-4-piperidylidene)-10,11-dihydro-5Hdibenzo[a,d]cycloheptene dimaleate: To a solution containing 4.3 g of 4-aza(N-methyl-4-piperidylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene in 55 ml of ethyl acetate, add a solution of 3.45 g of maleic acid dissolved in ethyl acetate. Filter the resulting precipitate and recrystallize the desired product from an ethyl acetate-methanol mixture to yield 4-aza-5-(N-methyl-4piperidylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene dimaleate, MP 152-154°C. References Merck Index 906 PDR pp. 1643, 1657 OCDS Vol. 2 p. 424 DOT 5 (2) 47 (1969) I.N. p. 110 REM p. 1131 Villani, F.J.; US Patents 3,326,924; January 20, 1967; 3,357,986; December 12, 1967; and 3,419,565; December 31, 1968; all Assigned to Schering Corp.

AZATEPA Therapeutic Function: Antineoplastic Chemical Name: Phosphinic amide, P,P-bis(1-aziridinyl)-N-ethyl-N-1,3,4thiadiazol-2-ylCommon Name: Azatepa; Azetepa; Thiatriamide

484

Azathioprine

Structural Formula:

Chemical Abstracts Registry No.: 125-45-1 Trade Name

Manufacturer

Country

Year Introduced

Azatepa

ZYF Pharm Chemical

-

-

Raw Materials 2-Ethylamino-1,3,4-thiadiazole hydrochloride Phosphorus oxychloride Ethylenimine Triethylamine Manufacturing Process N-Ethyl-N-(1,3,4-thiadiazol-2-yl)amidophosphoryl chloride is prepared by refluxing 16.4 parts of 2-ethylamino-1,3,4-thiadiazole hydrochloride with 84 parts of phosphorus oxychloride for 6 h and then removing the excess phosphorus oxychloride by distillation under reduced pressure. The residual oil is washed with cold petroleum ether, dried and dissolved in 310 parts of dry benzene. The solution of N-ethyl-N-(1,3,4-thiadiazol-2-yl)amidophosphoryl chloride is added slowly at 10°C to a mixture of 9.5 parts of ethylenimine, 30.3 parts of triethylamine, and 44 parts of warm dry benzene. Agitation is continued for 2 h without cooling after which the triethylamine hydrochloride is filtered off. The benzene is distilled from the filtrate under reduced pressure, and the N,N'-diethylene-N''-ethyl-(N'-(1,3,4-thiadiazo-2-yl)phosphoramide is recrystallized from hexane, melting point 95°-96°C. References GB Patent No. 885,370; Dec. 28, 1961; Assigned: American Cyanamid Company, State of Maine, USA

AZATHIOPRINE Therapeutic Function: Immunosuppressive Chemical Name: 6-[(1-Methyl-4-nitroimidazol-5-yl)thio]purine Common Name: Azothioprine

Azathioprine

485

Structural Formula:

Chemical Abstracts Registry No.: 446-86-6 Trade Name

Manufacturer

Country

Year Introduced

Imuran

Wellcome

UK

1964

Imurel

Wellcome

France

1967

Imurek

Wellcome

W. Germany

1967

Imuran

Wellcome

US

1968

Imuran

Wellcome

Italy

1968

Imuran

Tanabe

Japan

1969

Azamun

Medica

Finland

-

Azanin

Tanabe

Japan

-

Azapress

Lennon

S. Africa

-

Raw Materials N,N'-Dimethyloxaldiamide Nitric acid

Phosphorus pentachloride 6-Mercaptopurine

Manufacturing Process N,N'-Dimethyloxaldiamide is reacted with PCl5, to give 4-chloro-1-methyl imidazole. This is nitrated with HNO3 to give 5-nitro-1-methyl-4chloroimidazole. Then, a mixture of 4.6 grams of anhydrous 6mercaptopurine, 5 grams of 1-methyl-4-chloro-5-nitroimidazole and 2.5 grams of anhydrous sodium acetate in 100 ml of dry dimethyl sulfoxide was heated at 100°C for 7 hours. After standing overnight at room temperature, the mixture was poured into 200 ml of cold water and the yellow precipitate of 6-(1'-methyl-4'-nitro-5'imidazolyl)mercaptopurine (7.0 grams) collected. After recrystallization from 50% aqueous acetone, the product melted at 243-244°C, dec., and had an UV spectrum with λ maximum = 280 nm at pH 1 and λ max. = 285 nm at pH 11. References Merck Index 907 Kleeman and Engel p. 67 PDR p. 744 OCDS Vol. 2 p. 464 DOT 16 (10) 360 (1980) I.N.p. 110

486

Azelaic acid

REM p. 1143 Hitchings, G.H. and Elion, G.B.; US Patent 3,056,785; October 2, 1962: Assigned to Burroughs Wellcome and Co.

AZELAIC ACID Therapeutic Function: Antiacne, Depigmentor Chemical Name: 1,7-Heptanedicarboxylic acid Common Name: Acide azelaique; Acidum azelaicum; Anchoic acid; Azelaic acid; Azelainsaure; Lepargylic acid Structural Formula:

Chemical Abstracts Registry No.: 123-99-9 Trade Name

Manufacturer

Country

Year Introduced

Azelaic acid

Schering Health Care

-

-

Azelan

Schering-Plough

-

-

Azelex

Schering-Plough

-

-

Aziderm

Micro Labs

India

-

Skinoran

Schering

-

-

Skinoren

Schering

-

-

Raw Materials Oleic acid Hydrogen peroxide Nitric acid

Linoleic acid Formic acid Sodium metavanadate

Manufacturing Process Two step oxidation of tall oil fatty acid using peroxyformic acid and nitric acid/sodium metavanadate were used to produce azelaic acid. Step 1 (derivatization of the double bond): A hydroxy acyloxy derivative of tall oil fatty acid (TOFA) was prepared by mixing 200 g of TOFA (63% oleic acid, 31% linoleic acid) with 500 mL of

Azelaic acid

487

formic acid. The resulting mixture was vigorously stirred by magnetic action. Hydrogen peroxide solution, 180 mL of 35% by weight, was added in aliquots to the mixture throughout the course of the reaction. A third of the total amount of peroxide solution was added at once to initiate the reaction. The peroxyformic acid in this case was prepared in situ. The start of the reaction was signalled by heat evolution and a dramatic color change, from pale yellow to deep rust red. The exothermicity of the reaction required external cooling to control the temperature. The reaction was maintained at 40°C to minimize oxygen loss through the decomposition of the peroxide. As required, the temperature of the reaction was maintained with an external heating source. A total reaction time of 5 to 6 hours was necessary for complete reaction. The end of the reaction was indicated by a color change; the reaction mixture changed from rust red back to yellow. One last aliquot of peroxide solution was added at the end of the reaction period to provide a peroxide atmosphere during the reaction work-up. TOFA as a substrate produced a mixture of mono- and dihydroxy formoxystearic acid from the oleic and linoleic acid components, respectively. The final product was obtained in essentially 100% yield by removing the unreacted formic acid and hydrogen peroxide as well as water. It was obtained as a viscous, syrupy yellow oil that upon gas chromatographic analysis of the methyl esters of the reaction mixture gave no evidence of unreacted substrate. Step 2 (oxidation of derivative obtained from step 1): A 2 L three neck flask fitted with an air condenser attached to a gas scrubbing apparatus was filled with 500 mL of concentrated nitric acid (70% by weight). The acid was stirred by magnetic action and 1 g of sodium metavanadate was added to it. The resulting mixture was heated slowly to 40°-50°C. At this point a small amount of product as obtained from Step 1 was added to the acid-catalyst mixture. Heating was continued until a sharp temperature increase accompanied by evolution of NOx gases was observed. The reaction temperature was self-sustained with the addition of aliquots of the hydroxy formoxy ester mixture obtained from Step 1. (External cooling may be required throughout the substrate addition period to keep the temperature within 65°-70°C). At the end of the addition period the reaction temperature was maintained for an additional 1.5 to 2 hours, for a total reaction time of 3 hours. The final products were obtained by quenching the reaction by adding excess water and extracting the organic layer with purified diethyl ether. The ether extract was dried over anhydrous sodium sulfate overnight before its removal with a roto-vap apparatus. Addition of petroleum ether (boiling range 35°60°C) to the product mixture caused precipitation of the diacid component. Vacuum filtration was used to remove the solid diacids from the liquid monoacid mixture. The latter was obtained by removing the excess petroleum ether from the resulting filtrate. Quantitative analysis by gas chromatography of the methyl esters showed that the products to be 96% yield of diacid (66% azelaic, 30% suberic). References Malek A. et al.; US Patent No. 5,380,928; Jan. 10, 1995; Assigned: Synergistic Industries, Inc., Canada

488

Azepindole

AZEPINDOLE Therapeutic Function: Antidepressant Chemical Name: 1H-[1,4]Diazepino[1,2-a]indole, 2,3,4,5-tetrahydroCommon Name: Azependole Structural Formula:

Chemical Abstracts Registry No.: 26304-61-0 Trade Name

Manufacturer

Country

Year Introduced

Azependole

ZYF Pharm Chemical

-

-

McN-2453

McNeil Laboratories, Inc.

-

-

Raw Materials Ethyl indole-2-carboxylate Acetic acid Acetic anhydride Hydrogen Lithium aluminum hydride

Acrylonitrile Tenzyltrimethylammonium hydroxide Nickel Raney Sodium hydride

Manufacturing Process Ethyl indole-2-carboxylate (9.84 g, 0.052 mole) is dissolved in 150 ml dioxane. Acrylonitrile (3.11 g, 0.0588 mole) and benzyltrimethylammonium hydroxide (Triton B) (2 ml) are added and the mixture is warmed, with stirring, at 50°-55°C for 45 min. The solution is cooled to room temperature and stirred overnight. The reaction mixture is added to 500 ml water containing 3 ml glacial acetic acid. The mixture is extracted with methylene chloride, the organic layer washed with 2x25 ml water and dried over magnesium sulfate. The solvent is removed under reduced pressure. The remaining oil is dissolved in ether and filtered through alumina with ether as eluant. Evaporation of the ether gives a solid. The product obtained is ethyl N(β-cyanoethyl)indole-2-carboxylate, melting point 84°-86°C. A 2.42 g (0.01 mole) of ethyl N-(β-cyanoethyl)indole-2-carboxylate is suspended in acetic anhydride (20 ml). The suspended compound is hydrogenated on a Parr shaker in the presence of Raney nickel. The uptake of hydrogen is complete after 1.5 h. The product recovered is recrystallized from benzene-hexane. The product obtained is ethyl 1-(3-acetamidopropyl)indole2-carboxylate, melting point 83.5°-84.5°C.

Azetirelin

489

Ethyl 1-(3-acetamidopropyl)indole-2-carboxylate (1.44 g, 0.005 mole) is cyclized in the presence of sodium hydride (0.30 g, 0.00625 molar in hydride) in xylene under reflux. A few drops of absolute ethanol are added after 1 h reflux. Total reflux time is 2 h. The product recovered is crystallized from benzenehexane. The product obtained is 2,3,4,5-tetrahydro-1H-1,4diazepino[1,2-a]indol-1-one, melting point 181°-183°C. 2,3,4,5-Tetrahydro-1H-1,4-diazepino[1,2-a]indol-1-one (6.0 g, 0.03 mole) in 200 ml of monoglyme is added dropwise to a stirred suspension of lithium aluminum hydride (2.8 g, 0.08 mole) in 200 ml of monoglyme, and the mixture heated under reflux overnight. Water is added to the cooled mixture, and the mixture filtered. The filtrate is dried with anhydrous magnesium sulfate and concentrated in vacuum, giving an oil which solidifies on standing to give about 85% theoretical yield of the free amine, 2,3,4,5-tetrahydro-1H1,4-diazepino[1,2a]indol, melting point 75°-77°C. References Reynolds B.E., Carson J.R.; US Patent No. 3,867,374; February 18, 1975; Assigned: McNeil Laboratories, Incorporated, Ft. Washington, Pa.

AZETIRELIN Therapeutic Function: TRH analogue Chemical Name: L-Prolinamide, N-((4-oxo-2-azetidinyl)carbonyl)-L-histidyl-, (S)Common Name: Azetirelin Structural Formula:

Chemical Abstracts Registry No.: 95729-65-0 Trade Name

Manufacturer

Country

Year Introduced

Azetirelin

ZYF Pharm Chemical

-

-

Azetirelin

Yamanouchi

-

-

490

Azidamfenicol

Raw Materials L-Histidyl-L-prolinamide 2-hydrobromide Triethylamine (S)-2-Azetidinone-4-carboxylic acid Hydroxybenzotriazole Dicyclohexylcarbodiimide Manufacturing Process In 13 ml of DMF was dissolved 826.0 mg of L-histidyl-L-prolinamide 2hydrobromide and then 2 ml of a DMF solution of 405.0 mg of triethylamine was added to the solution under ice-cooling. After maintaining 30 min under ice-cooling, the precipitates thus formed were filtered off to provide L-histidylL-prolinamide. In 10 ml of DMF was dissolved 230.0 mg of (S)-2-azetidinone-4-carboxylic acid and then 351.0 mg of N-hydroxy-1,2,3-benzotriazole and 453.0 mg of dicyclohexylcarbodiimide were added to the solution under ice-cooling. Then, after stirring the mixture for 15 min, the reaction was maintained for 15 min at room temperature. The reaction mixture was ice-cooled again and 15 ml of a DMF solution of foregoing L-histidyl-L-prolinamide was added to the reaction mixture followed by reaction overnight at 0°C. The precipitates thus formed were filtered off, the filtrate was concentrated to dryness, the residue was dissolved in 10 ml of chloroform-methanol (4:1) and subjected to silica gel column chromatography. The eluates by chloroform-methanol (7:3) were collected and concentrated to dryness to provide 509.0 mg of crude product. When the product was subjected to silica gel column chromatography again and eluted by a mixture of chloroform, methanol, and aqueous ammonia (40:10:1) to provide 394.0 mg of pure Nepsilon-[(S)-2-azetidinone-4-carbonyl]L-histidyl-L-prolinamide, melting point 183°-185°C (crystallization from a small amount of methanol). References Tamura T. et al.; US Patent No. 4,636,567; January 13,1987; Assigned: Yamanouchi Pharmaceutical Co., Ltd., Tokyo, Japan

AZIDAMFENICOL Therapeutic Function: Antibiotic Chemical Name: Acetamide, 2-azido-N-((1R,2R)-2-hydroxy-1(hydroxymethyl)-2-(4-nitrophenyl)ethyl)Common Name: Azidamfenicol; Azidoamphenicol Chemical Abstracts Registry No.: 13838-08-9

Azidocillin

491

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

BerlicetinAugentropfen

Chauvin

-

-

Berlicetin

Chauvin Ankerpharm

-

-

Leucomycin-N

Bayer

-

-

Posifenicol

Ursapharm

-

-

Thilocanfol

Alcon

-

-

Raw Materials D-(-)-Threo-1-p-nitrophenyl-2-aminopropane-1,3-diol Azidoacetonitrile Hydrochloric acid Manufacturing Process 21.2 g of D-(-)-threo-1-p-nitrophenyl-2-aminopropane-1,3-diol are stirred with 10 g of azidoacetonitrile (B.P. 68°C/25 mm) in a mixture of 125 ml of methanol and 125 ml of water at 30-40°C for a few days. The mixture is filtered off from a little undissolved base and the solvent is distilled in vacuo. The residue is treated with a little normal hydrochloric acid until acid to Congo red and extracted with ethylacetate. By evaporating the solvent and recrystallizing the residue from ethylene chloride is obtained D-(-)-threo-1-pnitrophenyl-2-azidoacetylamino-propane-1,3-diol; M.P. 107°C. References Merck Index, Monograph number: 941, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. Meisser W. et al.; US Patent No. 2,882,275; Apr. 14, 1959; Assigned to Farbenfabriken Bayer Aktiengesellschaft, Germany

AZIDOCILLIN Therapeutic Function: Antibacterial Chemical Name: 6-(D-2-Azido-2-phenylacetamido)-3,3-dimethyl-7-oxo-4thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid

492

Azidocillin

Common Name: α-Azidobenzylpenicillin Structural Formula:

Chemical Abstracts Registry No.: 17243-38-8 Trade Name

Manufacturer

Country

Year Introduced

Nalpen

Beecham

W. Germany

1972

Longatren

Bayer

Italy

1981

Longatren

Bayer

Japan

-

Astracilina

Astra

Sweden

-

Finacillin

Sedequil

Portugal

-

Syncillin

Tropon

W. Germany

-

Raw Materials α-Azidophenylacetic acid 6-Aminopenicillanic acid Thionyl chloride

Ethyl chloroformate Triethylamine

Manufacturing Process Example 1: α-Azidobenzylpenicillin via the Mixed Anhydride - A solution of αazidophenylacetic acid (8.9 grams, 0.05 mol) of triethylamine (5.1 grams, 0.05 mol) in 50 ml of dry dimethylformamide was stirred and chilled below 5°C. At this temperature ethyl chloroformate (4.7 ml) was added in portions so that the temperature was never above -5°C. After the mixture had been stirred for 20 minutes, dry acetone (100 ml), chilled to -5°C, was added in one portion, immediately followed by an ice-cold solution of 6aminopenicillanic acid (10.8 grams, 0.05 mol) and triethylamine (5.1 grams, 0.05 mol) in 100 ml of water, and the stirring was continued for 1½ hours at 0°C. The pH of the mixture was adjusted to 7.5 by adding a saturated sodium bicarbonate solution. After being washed twice with diethyl ether, the reaction solution was acidified to pH 2 with dilute hydrochloric acid and extracted with ether. The ether solution containing the free penicillin was washed twice with water and then extracted with 50 ml of N potassium bicarbonate solution. After freeze drying of the obtained neutral solution, the potassium salt of αazidobenzylpenicillin was obtained as a slightly colored powder (11.2 grams, 54% yield) with a purity of 55% as determined by the hydroxylamine method (the potassium salt of penicillin G being used as a standard).

Azimilide hydrochloride

493

The infrared spectrum of this substance showed the presence of an azido group and a beta-lactam system. The substance inhibited the growth of Staph. aureus Oxford at a concentration of 0.25 mcg/ml. Example 2: α-Azidobenzylpenicillin via the Acid Chloride - 6-aminopenicillanic acid (18.5 grams, 0.085 mol) and sodium bicarbonate (21 grams, 0.025 mol) were dissolved in 200 ml of water and 100 ml of acetone. To this solution, chilled in ice, was added α-azidophenylacetyl chloride (16.6 grams, 0.085 mol), diluted with 10 ml of dry acetone. The temperature is held at 0° to 5°C and the reaction mixture was stirred for 2½ hours. The resulting solution was treated as described in Example 1 to give the potassium salt of α-azidobenzylpenicillin as a white powder (29.4 grams, 84% yield) with a purity of 83% as determined by the hydroxylamine method (the potassium salt of penicillin G being used as a standard). The product showed the same properties as the product obtained in Example 1;. it inhibits the growth of Staph. aureus Oxford at a concentration of 0.13 mcg/ml. The α-azidophenylacetyl chloride was prepared by treating α-azidophenylacetic acid with thionylchloride in portions at room temperature and then heating the solution under reflux for one hour. The α-azidophenylacetyl chloride distils at 115°C under a pressure of 10 mm Hg. References Merck Index 913 Kleeman and Engel p. 68 DOT 7 (5) 186 (1971) and 8 (7) 248 (1972) I.N.p. 111 Sjoberg, B.O.H. and Ekstrom, B.A.; US Patent 3,293,242; December 20, 1966; Assigned to Beecham Group Limited, England

AZIMILIDE HYDROCHLORIDE Therapeutic Function: Antiarrhythmic Chemical Name: 1-{[5-(4-Chlorophenyl)furan-2-ylmethylene]amino}-3-[4(4-methylpiperazin-1-yl)butyl]imidazolidine-2,4-dione dihydrochloride Common Name: Azimilide hydrochloride; Stedicor Chemical Abstracts Registry No.: 149908-53-2 (Base); 149888-94-8 Trade Name

Manufacturer

Country

Year Introduced

Stedicor

Procter and Gamble

-

-

494

Azimilide hydrochloride

Structural Formula:

Raw Materials 1-Bromo-4-chlorobutane Sodium hydride 1-Methylpiperazine Hydrogen chloride Hydrogen Sodium iodide

1-(Benzylideneamino)hydantoin Sodium iodide Sodium bicarbonate Palladium on carbon 5-(4-Chlorophenyl)-2-furancarboxaldehyde

Manufacturing Process 1-Phenylmethylenamino-3-(4-chlorobutyl)-2,4-imidazolidinedione dihydrochloride is prepared by adding 60% sodium hydride in mineral oil (7.8 g, 0.1944 mole) over 1 h to a stirred solution o f 1(benzy1ideneamino)hydantoin [prepared as described by J. Gut, A Novacet, and P. Fiedler, Coll. Czech. Chern. Comrnun., Vol. 33, pp. 2087-2096; No. 71, 1968] (39.5 g , 0.1944 mole) in dimethyl formamide (1000 ml). After complete addition, the solution is heated at steam bath temperature (approximately 100°C) for 1.5 h. The resulting mixture is allowed to cool to room temperature (30°C). While stirring at room temperature, 1-bromo-4-chlorobutane (100 g ,0.5832 mole, 3 eq.) is added in one portion. The mixture becomes exothermic reaching around 35°C in approximately 30 min. The near-solution is heated a t approximately 80°C by steam bath for 4 h, cooled and stirred for approximately 8 h at room temperature (30°C). The cloudy mixture is filtered, removing a small amount of insoluble solid. The filtrate is concentrated under reduced pressure to a semi-solid residue. This residue is triturated with H2O (400 ml), collected, recrystallized from acetonitrile, and then air-dried to give 43.1 g (0.1467 mole) of 1-phenylmethyleneamino-3-(4-chlorobutyl)-2,4imidazolidinedione. A mixture of 1-phenylmethyleneamino-3-(4-chlorobutyl)-2,4imidazolidinedione (43.1 g, 0.1467 mole), acetone (1200 ml) and sodium iodide (48.4 9, 0.3227 mole) is heated to reflux. Reflux is maintained for 5 h. The mixture is filtered, collecting the insoluble. The filtrate is recharged with sodium iodide (10.0 g) and reflux is resumed and is maintained for 15 h. After cooling to room temperature, the mixture is filtered, removing the insoluble NaCl (total recovery, 9.5 g, 110%). The filtrate is poured into H2O (2000 ml) while stirring. After stirring for 30 min, the solid is collected and air-dried to yield 51.5 g (0.1337 mole) of 1-phenylmethyleneamino-3-(4-iodobutyl)-2,4imidazolidinedione.

Azimilide hydrochloride

495

A solution of 1-phenylmethyleneamino-3-(4-iodobutyl)-2,4-imidazolidinedione (10.0 g, 0.0260 mole), dimethylformamide (150.0 mg) and 1methylpiperazine (11.5 ml, 10.4 9, 0.1040 mole) is heated to reflux. Reflux is maintained for 3 h. After cooling to approximately 40°C, the solution is concentrated under reduced pressure by rotary evaporator to an oily-solid residue. This residue is dissolved in H2O (200 ml) then made basic with saturated NaHCO3 (200 ml). The resulting mixture is stirred for 2 h. The solid is collected and air-dried, and is next dissolved in absolute ethanol (150 ml), next filtered, then made acidic to wet litmus with EtOH/HCl. After cooling several hours, the solid is collected and air-dried to give 8.04 g (0.0187 mole) of 1-phenylmethyleneamino-3-[4-(4-methyl-1-piperazinyl)butyl]-2,4imidazolidinedione dihydrochloride. A mixture of 1-phenylmethyleneamino-3-[4-(4-methyl-1-piperazinyl)butyl]2,4-imidazolidinedione dihydrochloride (8.04 g, 0.0187 mole), 2 N HCl (125 ml) and 5% Pd/C: 50% H2O (1.5 g) is subjected to hydrogen on a Parr apparatus at 40 psi at room temperature. After 2 h, the catalyst is removed by filtration. The filtrate is divided into two equal portions. Each is concentrated under reduced pressure on a rotary 10 evaporator to an oily residue of 1-amino-3-[4-(4-methyl-1-piperazinyl)butyl]-2,4-imidazolidinedione hydrochloride. A solution of 1-amino-3-[4-(4-methyl-1-piperazinyl)butyl]-2,4imidazolidinedione hydrochloride (0.0094 mole), dimethylformamide (75 ml) and 5-(4-chlorophenyl)-2-furancarboxaldehyde [prepared as described in U.S. Patent No. 20 4,882,354, to Huang et al., assigned to Norwich Eaton Pharmaceuticals, Inc., issued November 21, 1984; see Cols. 7 and 8] (1.94 g , 0.0094 mole) is stirred at room temperature for 72 h. The mixture is filtered, collecting the solid. Recrystallization from absolute ethanol/H2O and air-drying gives 2.63 g (0.0050 mole) of 1-[[[5-(4-chlorophenyl)-2furanyl]methylene]amino]3-[4-(4-methyl-1-piperazinyl)butyl]-2,4imidazolidinedion hydrochloride. 1-[[[5-(4-Chlorophenyl)-2-furanyl]methylene]amino]-3-[4-(4-methyl-1piperazinyl)butyl]-2,4-imidazolidinedione hydrochloride, (6.56 g, 0.0124 mole) is dissolved in H2O (300 ml) and washed with (1x100 ml). The aqueous phase is made basic with saturated NaHCO3 solution. The resulting mixture is extracted with CH2Cl2 (4x100 ml). The extract is washed with saturated NaCl (2x50 ml), dried over MgSO4 (activated charcoal), filtered and concentrated under reduced pressure to a solid residue. This solid is triturated in anhydrous ether, collected and air-dried. Recrystallization once from absolute EtOH and then from toluene (activated charcoal), next washing with anhydrous ether and air drying gives 2.05 g (0.0045 mole) of 1-[[[5-(4-chlorophenyl)-2furanyl]methylene]amino]-3-[4-(4-methyl-1-piperazinyl)butyl]-2,4imidazolidinedione. References Pelosi S.S., Calcagno M.A.; WO Patent No. 93/04061; March 4, 1993; Assigned: Procter and Gamble Pharmaceuticals [US/US]; NY (US)

496

Azintamide

AZINTAMIDE Therapeutic Function: Choleretic Chemical Name: (6-Chlorpyridazin-3-ylthio)diethylacetamide Common Name: Azintamide; Azinthiamide Structural Formula:

Chemical Abstracts Registry No.: 1830-32-6 Trade Name

Manufacturer

Country

Year Introduced

Azintamide

Bristhar Laboratorios

-

-

Azintamide

Nycomed Austria GmbH Pharm Chemical Shanghai Lansheng Corporation

-

-

-

-

Biluen

Byk Argentina

-

-

Colerin

Laboratorios LAB, LDA

-

-

Ora-Gallin purum

Nycomed

-

-

Oragallin

Austerreichcshe Shtkttofwerke

-

-

Soragallin

Misr Co.

-

-

Soragallin

Linz Co.

-

-

Azintamide

Raw Materials 3-Chloro-6-mercaptopyridazine Chloroacetic acid diethyl amide Caustic soda Manufacturing Process 7.3 parts of 3-chloro-6-mercaptopyridazine are neutralised with 20 parts of 10% caustic soda solution, diluted with 60 parts of 50% ethanol, and heated to 60°C. 7.5 parts of chloroacetic acid diethyl amide dissolved in 20 parts of ethanol are added to this solution over a period of 10 min and the resulting mixture is heated to 60°C for 30 min. The reaction solution is then cooled, the

Azithromycin

497

resulting crystallisate is removed by suction, and the filtrate is extracted with ethyl acetate. The solvent is removed by evaporation and the concentration residue is combined with the crystallisate. After two recrystallisations from benzene, 11 parts of 3-chloro-pyridazine-6-mercaptoacetic acid diethyl amide, having a melting point of from 139° to 140°C are yielded. References Merck Index, Monograph number: 945, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. Stormann, Arzneim.-Forsch., 1964, 14, 266

AZITHROMYCIN Therapeutic Function: Antibiotic Chemical Name: Azithromycin Common Name: Azithromycin Structural Formula:

Chemical Abstracts Registry No.: 83905-01-5 Trade Name

Manufacturer

Country

Year Introduced

ATM

Indoco Remedies Ltd.

India

-

AZ-1

Kopran Limited

India

-

Azee Rediuse

Protech Biosystems

-

-

Azicare

Olcare Laboratories

India

-

Azifast

Innova (IPCA)

India

-

Azilide

Micro Nova Pharmaceuticals Ltd.

India

-

498

Azithromycin

Trade Name

Manufacturer

Country

Year Introduced

Azithral

Alembic Ltd.

India

-

Azithro-250

Ind-Swift Ltd.

India

-

Azithromycin

Alembi

India

-

Azitop

Talent Laboratories

India

-

Aziwok

Wockhardt Ltd.

India

-

Hemomycin

Hemofarm

Serbia and Montenegro

-

Licathrom

Replica Remedies

India

-

Sumamed

Pliva

Croatia

-

Vicon

Pfizer

-

-

Zady

Mankind Pharma Pvt. Ltd.

India

-

Zathrin

FDC Ltd.

India

-

Zithromax

Teuto/Neo Quimica

-

-

Zithromax

Pfizer

-

-

Zycin

IRM Pharma

India

-

Raw Materials 11-Aza-10-deoxo-10-dihydroerythromycin A Formic acid Formaldehyde Manufacturing Process To a solution of 0.54 g (0.000722 mole) of 11 aza-10-deoxo-10dihydroerythromycin A in 20 ml CHCl3 were added 0.0589 ml (0.000741 mole) of formaldehyde (approx. 35% w./w.) and 0.00283 g (0.000735 mole) of formic acid (approx. 98 to 100% w./w.). The reaction mixture was stirred for 8 hours while heating under reflux, then cooled to ambient temperature, whereupon were added 15 ml of water (pH 5.8). The pH of the reaction mixture was adjusted to 5.0 by means of 2 N HCl, whereupon the CHCl3 layer was separated. To the aqueous part was added 15 ml of CHCl3, the pH of the reaction suspension was adjusted to 7.5 by means of 20% NaOH, the layers were separated and subsequently the aqueous layer was extracted three times with 15 ml of CHCl3. The combined chloroform extracts having pH 7.5 were dried over K2CO3 and evaporated under reduced pressure, yielding 0.45 g (82.4%) of N-methyl-11-aza-10-deoxo-10-dihydro erythromycin A (azithromycin), m.p. 113°-115°C. [α]D20= - 37.0 (1% in CHCl3). References Murphu H.W. et al.; US Patent No. 3,417,077; Dec. 17, 1968 Kobrehel G. et al.; US Patent No. 4,328,334; May 4, 1982; Assigned: PLIVA Pharmaceutical and Chemical Works (Zagreb, YU) Bright G.M.; US Patent No. 4,474,768; Oct. 2, 1984; Assigned: Pfizer Inc. (New York, NY)

Azlocillin

499

AZLOCILLIN Therapeutic Function: Antibacterial Chemical Name: D-α-(Imidazolidin-2-on-1-yl-carbonylamino)benzylpenicillin, sodium salt Common Name: Structural Formula:

Chemical Abstracts Registry No.: 37091-66-0; 37091-65-9 (Sodium Salt) Trade Name

Manufacturer

Country

Year Introduced

Securopen

Bayer

W. Germany

1977

Securopen

Bayer

Switz.

1980

Securopen

Bayer

UK

1980

Azlin

Miles

US

1982

Securopen

Bayer

France

1983

Raw Materials D-(-)-α-[(Imidazolidin-2-on-1-yl)carbonylamino]phenyl acetic acid 6-Aminopenicillanic acid Manufacturing Process 3.8 parts by weight of D-(-)-α-[(imidazolidin-2-on-1-yl)carbonylamino]phenylacetic acid were dissolved in 65 parts by volume of dichloromethane. 2.7 parts by weight of 1-methyl-2-chloro-δ1-pyrrolinium chloride were added, and after cooling to -10°C 2.0 parts by volume of triethylamine were added gradually. This reaction mixture was then stirred for one hour at -5°C (mixture A). 4.0 parts by weight of 6-aminopenicillanic acid in 80 parts by volume of dichloromethane were treated with 4.4 parts by volume of triethylamine and 4.0 parts by weight of anhydrous sodium sulfate and then stirred for two hours at room temperature. After filtration, the solution was cooled to -20°C and combined with the mixture A. The reaction mixture was left to reach 0°C of its own accord, and was then stirred for a further hour at 0°C. The solvent was removed in a rotary evaporator, the residue was dissolved in water, and the solution was covered with a layer of ethyl acetate

500

Azolimine

and acidified with dilute hydrochloric acid at 0° to 5°C, while stirring, until pH 1.5 was reached. The organic phase was then separated off, washed with water, dried over magnesium sulfate while cooling, and filtered, and after dilution with an equal amount of ether the sodium salt of the penicillin was precipitated from the filtrate by adding a solution of sodium 2-ethylcaproate dissolved in ether containing methanol. Yield: 1.3 parts by weight. References Merck Index 916 Kleeman and Engel p. 69 PDR p. 1247 OCDS Vol. 3 p. 206 (1984) DOT 13 (10) 409 (1977) I.N.p. 111 REM p. 1200 Konig, H.B., Schrock, W., Disselknotter, H. and Metzger, K.G.; US Patents 3,933,795; January 20, 1976; 3,936,442; February 3, 1976; 3,939,149; February 17, 1976; 3,974,140; August 10, 1976; 3,978,223; August 31, 1976 and 3,980,792; September 14, 1976; all

AZOLIMINE Therapeutic Function: Diuretic Chemical Name: 4-Imidazolidinone, 2-imino-3-methyl-1-phenylCommon Name: Azolimine Structural Formula:

Chemical Abstracts Registry No.: 40828-45-3 Trade Name

Manufacturer

Country

Year Introduced

Azolimine

ZYF Pharm Chemical

-

-

Raw Materials Sodium hydroxide Phenylcyanamide N-Methylchloroacetamide Sodium methoxide Phenylcyanamide hemihydrate

Azosemide

501

Manufacturing Process 2 methods of producing of 1-phenyl-2-imino-3-methyl-4-oxoimidazolidine: 1). In 29 ml of water containing 1.0 g of sodium hydroxide was dissolved 3.55 g of phenylcyanamide. To the clear solution was added 2.7 g of Nmethylchloroacetamide. The reaction mixture was left to stir for 120 h at room temperature. The solvent was therefore stripped off on a rotary evaporator under vacuum. The solid residue was slurried in dilute alkali and filtered to yield 1.0 g (21%) of 1-phenyl-2-imino-3-methyl-4-oxoimidazolidine, melting point 163°-165°C. 2). 133.0 g of phenylcyanamide hemihydrate was dissolved in 1500 ml of absolute alcohol. To this solution was added 55.0 g of sodium methoxide. This mixture was stirred for 30 min and 113.0 g of N-methylchloroacetamide then added. This mixture was heated to reflux for 4 h and allowed to stand overnight. The white precipitate was filtered and washed with ethanol. This ethanol filtrate was concentrated on the rotating evaporator and cooled giving additional product. Both crops of product were combined, washed with water and dried to give 87.0 g (47%) of 1-phenyl-2-imino-3-methyl-4oxoimidazolidine, melting point 169°-170°C. References Hanifin J.W. et al.; US Patent No. 4,044,021; August 23, 1977; Assigned: American Cyanamid Company, Stamford, Conn.

AZOSEMIDE Therapeutic Function: Diuretic Chemical Name: 5-(4'-Chloro-2'-thenylamino-5'-sulfamoylphenyl)tetrazole Common Name: Structural Formula:

Chemical Abstracts Registry No.: 27589-33-9

502

Azotomycin

Trade Name

Manufacturer

Country

Year Introduced

Diurapid

Boehringer Mannheim

W. Germany

1981

Raw Materials 4-Chloro-2-fluoro-5-sulfamoyl benzonitrile Thenylamine Sodium azide Manufacturing Process The 4-chloro-5-sulfamoyl-2-thenylaminobenzonitrile used as starting material is obtained by the reaction of 4-chloro-2-fluoro-5-sutfamoyl-benzonitrile with thenylamine in anhydrous tetrahydrofuran. Then the 5-(4'-chloro-5'-sulfamoyl-2'-thenylamino)phenyltetrazole (MP 218° to 221°C; yield 37% of theory) is obtained by the reaction of 4-chloro-5sulfamoyl-2-thenylaminobenzonitrite (MP 170° to 174°C) with sodium azide and ammonium chloride, References Merck Index 922 DFU 4 (6)393 (1979) OCDS Vol. 3 p. 27 (1984) Popelek, A., Lerch, A., Stach, K., Roesch, E. and Hardebeck, K.; US Patent 3,665,002; May 23, 1972; Assigned to Boehringer Mannheim GmbH

AZOTOMYCIN Therapeutic Function: Antineoplastic Chemical Name: L-Norleucine, 6-diazo-N-(6-diazo-N-L-γ-glutamyl-5-oxo-Lnorleucyl)-5-oxoCommon Name: Azotomycin; Duazomycin B Structural Formula:

Azotomycin

503

Chemical Abstracts Registry No.: 7644-67-9 Trade Name

Manufacturer

Country

Year Introduced

Azotomycin

ZYF Pharm Chemical

-

-

Raw Materials γ-OBzl-N-Boc-L-Glu Trifluoroacetic acid N-Methylmorpholine Oxalyl chloride Sephadex LH-20

Diazomethane Isobutyl chloroformate Palladium on carbon Triethylamine

Manufacturing Process Azotomycin is anticancer antibiotic produced by Streptomyces ambofaciens. Total sythesis of it from γ-benzyl-N-tert-butyloxycarbonyl-L-glutamic acid (γOBzl-N-Boc-L-Glu) has been accomplished in nine steps. The mixed carbonic anhydride method was chosen for peptide bond formation. Commerically available γ-OBzl-N-Boc-L-Glu was esterified with ethereal diazomethane, deprotected with trifluoroacetic acid-methylene chloride (1:1), and converted to hydrochloride γ-benzyl-L-glutamic acid α-methyl ester (γ-OBzl-L-Glu-α-OMe HCl) by treatment with dry hydrogen chloride in ethyl ether, MP: 129°-135°C (dec.); [α]D25= + 13.3° (CHCl3). Reaction of γ-OBzl-N-Boc-L-Glu with isobutyl chloroformate and Nmethylmorpholine followed by addition of γ-OBzl-L-Glu-α-OMe HCl afforded dipeptide γ-OBzl-N-Boc-L-Glu-γ-OBzl-L-Glu-α-OMe; yield 93%, MP: 58.5°60°C; [α]D25= + 7.10° (CHCl3). After cleaving (trifluoroacetic acid-methylene chloride) the Boc group of above dipeptide, N-Tfa-L-Glu-OMe (Tfatrifluoroacetyl) was condensed with the product to afford tripeptide N-(γ-NTfa-L-Glu-α-OMe)-v-OBzl-N-Boc-L-Glu-γ-OBzl-L-Glu-α-OMe as colorless crystals, MP: 120°-122°C, [α]D25= + 7.7° (CHCl3). Following hydrogenolysis of benzyl esters using palladium-on-carbon (10%), diacid N-(γ-N-Tfa-L-Glu-αOMe)-L-Glu-L-GluOMe was obtained in yield 94% as colorless crystals, MP: 181°-184°C; [α]D25= - 37.6° (CH3OH). Selectively protected above diacid was converted to (γ-N-Tfa-L-Glu-α-OMe)-LGlu-L-Glu-tetra-OMe next way. To a solution of N-(γ-N-Tfa-L-Glu-α-OMe)-L-GluL-Glu-α-OMe (0.18 g) in dry acetone (20 ml cooled to 0°C was added with magnetic stirring ethereal diazomethane (0.8 mole) until yellow color persisted. After evaporation of solvent, the colorless solid was recrystallized from methylene chloride-hexanes to afford 0.17 g (92%) of colorless crystals of (γ-N-Tfa-L-Glu-α-OMe)-L-Glu-L-Glu-tetra-OMe; MP: 150°-152°C; [α]D25= 8.5° (CHCl3). A 1.00 g (1.9 mmoles) of (γ-N-Tfa-L-Glu-α-OMe)-L-Glu-L-Glu-tetra-OMe was dissolved under argon in dry dimethoxyethane (30 ml) with warming and magnetic stirring, and triethylamine (0.55 ml, 3.97 mmoles) was added. The reaction mixture was cooled to -30°C (dry ice isopropyl alcohol), and oxalyl chloride (0.35 ml, 3.97 mmoles) was added followed by dimethylformamide (2

504

Aztreonam

drops). The reaction mixture was warmed to 0°C by addition of hot isopropyl alcohol to the dry ice bath, stirred for 40 min, and then cooled to -78°C. The cold acid chloride solution was slowly (30 min) added through the sintered-glass filter into ethereal solution of diazomethane (0.5 moles, 30 ml) cooled to -23°C (dry ice-carbon tetrachloride). After the mixture was stirred 30 min at -23°C and 30 min at 0°C, solvent was evaporated by steam argon, and the residue was chromatographed in 19:1 ethyl acetate-methanol on column of silica gel (70 g). The fraction (24:1 ethyl acetate-methanol) with TLC Rf 0.16 were collected and solvent evaporated to 0.30 g (38 %) of light yellow crystals of N-Tfa(-)-azotomycin-di-OMe, which upon recrystallization from chloroform-ethyl ether, melted at 134°-136°C; [α]D25= - 22.9°. To a mixture of N-Tfa(-)-azotomycin-di-OMe (106 mg, 0.18 mmoles) and methanol (0.12 ml) was added 1.0 N sodium hydroxide (0.83 ml, 8.3 mmoles) at room temperature and stirred for 30 min. Then the solution was acidified to pH 6.9 with 0.1 N hydrochloric acid and extracted with chloroform (2x25 ml). The aqueous phase was dissolved in methanol and passed through a column of Sephadex LH-20 (250 g), and fractions containing the magor product (TLC Rf 0.31, methanol, tailing) were collected. Solvent was evaporated and the residue was freeze-dried to yield 54.3 mg (65%) of (-)-azotomycin as a light yellow solid, which slowly decomposed at ambient temperature; [α]D25= 4.3°; IR, UV, 1H NMR, 13C NMR spectrum confirmed the structures of all described compounds. References Pettit G.R., Nelson P.S.; J Org.Chem.; v.51, No 8, pp 1282-1286; 1986

AZTREONAM Therapeutic Function: Antibiotic Chemical Name: Propanoic acid, 2-(((Z)-(1-(2-amino-4-thiazolyl)-2(((2S,3S)-2-methyl-4-oxo-1-sulfo-3-azetidinyl)amino)-2-oxoethylidene) amino)oxy)-2-methylCommon Name: Azthreonam; Aztreonam Chemical Abstracts Registry No.: 78110-38-0 Trade Name

Manufacturer

Country

Year Introduced

Azactam

Bristol-Myers Squibb

USA

-

Azenam

Aristo Pharmaceutical Ltd. Bristol-Myers Squibb

India

-

-

-

Aztreonam

Aztreonam

505

Structural Formula:

Raw Materials Arrobacterium radiobacter A.T.C.C. No. 31700 Carbohydrates Dimethybenzylammonium chloride Sodium tiocyanate Glucose Manufacturing Process The solutions for fermentation having the following composition was preparated: Yeast extract Glucose Oatmeal Tomato paste

2% 10% 2% 2%

This mixture was sterilized for 15 minutes at 121°C at 15 lbs/inch2 steam pressure prior to use. The fermentation flasks were incubated at 25°C for 40 to 45 hours on a of rotary shaker. A 250 liter batch of Agrobacterium radiobacter A.T.C.C. No. 31700 is fermented in a 100 gallon steel vessel with a media and operating conditions described below. Culture of Agrobacterium radiobacter grown out on agar slants, pH 7.3 consisted of yeast extract (1 g), beef extract (1 g), NZ amine A (2 g), glucose (10 g), agar (15 g) in 1000 ml distilled water. Loopful of surface growth from agar slant was used as the source of incolumn. Medium of oatmeal (20 g), tomato paste (20 g) tapped water to 1000 ml, pH 7, was sterilized for 15 min at 121°C at 15 lbs/inch2 steam pressure prior to use. 100 ml of the medium, containing incolumn is incubated at 25°C for about 24 hours on a rotary shaker. It was added to a mixture of yeast extract (5 g), glucose (10 g) in 1 L distilled water and incubated for about 42 hours at 25°C in 100 gallon stainless steel fermentation vessel. During incubation, the broth is agitated at 155 r.p.m. and aerated at rate of 10.0 cubic feet per minute. An antifoam agent (Ucon LB625, Union Carbide) was added as needed. The fermentation beer was adjusted to pH 4 with aqueous HCl and calls separated by centrifugation. The supernatante (200 L)

506

Azumolene sodium

was extracted with 40 L of 0.05 m cetyldimethylbenzyl ammonium chloride in dichloromethane and extract concentrated in vacuo to 5.5 L. The concentrate was then extracted with solution of 177 g of sodium thiocyanate in 2 L of water, adjusting the mixture of pH 4.35 with phosphoric acid. The aqueous extract was concentrated in vacuo to 465 ml and added to 1840 ml of methanol. Solids are filtrated yielded 194 g of crude solid product. It was dissolved and chromatographed on a 5x106.5 cm column of Sephadex G-10 three times and after concentrating in vacuo gave 3.5 g of crude antibiotic M53 (azetreonam) which was chromatographed at first on QAE Sephadex A25 (liner gradient, prepared from 2.5 L of water and 2.5 L of 0.25 M sodium nitrate). Then the residue (fractions 26-75) gave M53 (natrium salt) after evaporation. It was triturated with methanol and the souble fraction, 0.40 g was chromatographed on a 2.5x20 cm column of Diaion HP20AG, eluting at 2 ml per minute with water and collecting 20 ml fractions. Fractions 26-75 gave 51.9 mg of antibiotic M53 (sodium salt). In practice it is usually used as free base. References Sykes R.B. et al.; US Patent No. 4,321,326; Mar. 23, 1982; Assigned: E. R. Squibb and Sons, Inc. (Princeton, NJ)

AZUMOLENE SODIUM Therapeutic Function: Muscle relaxant Chemical Name: 2,4-Imidazolidinedione, 1-(((5-(4-bromophenyl)-2-oxazolyl) methylene)amino)-, sodium salt Common Name: Azumolene sodium Structural Formula:

Chemical Abstracts Registry No.: 64748-79-4 (Base) Trade Name

Manufacturer

Country

Year Introduced

Azumolene sodium

ZYF Pharm Chemical

-

-

Azumolene sodium

Procter and Gamble

-

-

Azumolene sodium

507

Raw Materials 2-Bromo-4'-bromoacetophenone Hexamethylenetetramine [[(2,4-Dioxo-1-imidazolidinyl)imino]methyl]formyl chloride Hydrogen chloride Amine hydrochloride Phosphorus oxychloride Manufacturing Process To a stirred solution of 2-bromo-4'-bromoacetophenone (100.0 g, 0.36 mole) in chloroform (500 ml) was added hexamethylenetetramine (50.0 g, 0.36 mole). The mixture was stirred for 2.5 h and 143.0 g of the product was collected by filtration (100%). The product above was combined with a solution of methanol (300 ml) and conc. HCl (410 ml), and the mixture was stirred for 52 h. The solid was collected by filtration and was washed with isopropanol. The product was recrystallized from methanol (Darco) to give 55.0 g (61%, in three crops), melting point 284°-287°C. To a stirred mixture of the above amine hydrochloride (55.0 g, 0.22 mole) and [[(2,4-dioxo-1-imidazolidinyl)imino]methyl]formyl chloride (42.0 g, 0.22 mole) was added a solution of 440 ml of dimethylformamide and 44 ml of pyridine. The mixture was stirred for 20 h and poured into 2 L of water. The solid was collected by filtration and washed with ethanol and ether to give 36.0 g (28%) of N-[2-(4-bromophenyl)-2-oxoethyl]-[[(2,4-dioxo-1-imidazolidinyl)imino]methyl]formamide, melting point 267°-269°C (recrystallization from 2200 ml acetic acid). The of N-[2-(4-bromophenyl)-2-oxoethyl]-[[(2,4-dioxo-1-imidazolidinyl) imino]methyl]formamide (22.0 g, 0.061 mole) was combined with phosphorus oxychloride (310 ml) and the mixture was stirred and refluxed for 7 h. The solid was filtered off and stirred into an ice and water mixture (1 L). The 15.0 g (70%) of 1-[[[5-(4-bromophenyl)-2-oxazolyl]methylene]amino]-2,4imidazolidinedione was collected by filtration, melting point 290°-292°C (recrystallization from 700 ml acetic acid). In practice it is usually used as sodium salt. References White R.L.; US Patent No. 4,049,650; September 20, 1977; Assigned: Morton-Norwich Products, Inc., Norwich, N. Y.

B

BACAMPICILLIN Therapeutic Function: Antibacterial Chemical Name: 6-[(Aminophenylacetyl)amino]-3,3-dimethyl-7-oxo-4-thia1-azabicyclo-[3.2.0]heptane-2-carboxylic acid 1-[(ethoxycarbonyl)oxy]ethyl ester Common Name: 1'-Ethoxycarbonyloxyethyl 6-(D-α-aminophenylacetamido) penicillinate Structural Formula:

Chemical Abstracts Registry No.: 50972-17-3; 37661-08-8 (Hydrochloride salt) Trade Name Penglobe Bacacil Penglobe Bacacil Ambaxin Spectrobid Bacacil Penglobe Bamaxin Ambacamp Bacampicin Velbacil

Manufacturer Astra Pfizer Lematte/Boinot Pfizer Upjohn Pfizer Pfizer Taito Yoshitomi Upjohn Upjohn Upjohn Pfizer

Country W. Germany Switz. France Italy UK US Japan Japan Canada W. Germany -

508

Year Introduced 1977 1978 1978 1980 1981 1981 1981 1981 1982 -

Bacitracin

509

Raw Materials Sodium 6-(D-α-azidophenylacetamido)penicillinate α-Chlorodiethyl carbonate Sodium bicarbonate Hydrogen Palladium on carbon Manufacturing Process 1'-Ethoxycarbonyloxyethyl 6-(D-α-azidophenylacetamido)penicillinate (98 g) was prepared from sodium 6-(D-α-azidophenylacetamido)penicillinate (397 g, 1 mol), α-chlorodiethylcarbonate (458 g, 3 mols) and sodium bicarbonate (504 g, 6 mols). The product showed strong IR absorption at 2090 cm-1 and 1780-1750 cm-1 showing the presence of azido group and β-lactam and ester carbonyls. It was dissolved in ethyl acetate (700 ml) and hydrogenated at ambient conditions over a palladium (5%)on carbon catalyst (18 g). The catalyst was removed by filtration and washed with ethyl acetate. The combined filtrates were extracted with water at pH 2.5 by addition of dilute hydrochloric acid. Lyophilization of the aqueous phase gave the hydrochloride of 1'ethoxycarbonyloxyethyl 6-(D-α-aminophenylacetarnido)penicillinate (94 g), MP 171°-176°C. References Merck Index 933 Kleeman and Engel p. 69 PDR p. 1531 OCDS Vol. 3 p. 204 (1984) DOT 11 (11) 428 (1975) and 13 (10) 415 (1977) I.N.p.113 REM p. 1200 Ekstrom, B.A. and Sjoberg, B.O.H.; US Patents 3,873,521; March 25, 1975;and 3,939,270; February 17, 1976; both assigned to Astra Lakemedal A.B.

BACITRACIN Therapeutic Function: Antibacterial Chemical Name: Complex polypeptide mixture containing predominantly bacitracin A Common Name: Chemical Abstracts Registry No.: 1405-87-4; 21373-17-1 (Bacitracin A)

510

Bacitracin

Structural Formula:

Trade Name Baciguent Topitracin Bacitracine Bacitracine Bacitracin Bacitracin Batrax Cicatrin Cicatrex Enterostop Fortracin Hydroderm

Manufacturer Upjohn Comm. Solvents Novopharm Djamant Kayaku Upjohn Gewo Calmic Wellcome Schiapparelli A.L. Merck Sharp and Dohme

Country US US Switz. France Japan US W. Germany UK W. Germany Italy US UK

Year Introduced 1948 1948 1953 -

Medicrucin Nebacetin Neobacrin Neo-Caf Neo-Polycin Neosporin

Medice Byk Gulden Glaxo Francia Dow BurroughsWellcome

W. Germany W. Germany UK Italy US US

-

Orobicin Polybactrin Polybactrin Polycin Polyfax Polysporin

Fulton Calmic Wellcome Dow Wellcome BurroughsWellcome

Italy UK W. Germany US UK US

-

Rikospray Topitracin

Riker Reed Carnrick

UK US

-

Bacitracin

511

Raw Materials Bacillus subtilis Nutrient medium Manufacturing Process The early patent, US Patent 2,498,165 first disclosed bacitracin and described a process for preparing bacitracin, comprising cultivating Bacillus subtilis Tracy I in a nutritive medium, at substantially pH 7 and 37°C, for more than three days, extracting the antibiotic from the resulting medium with a low molecular weight alcohol, concentrating the resulting alcoholic solution in vacuo, acidifying the resulting concentrate, extracting the antibiotic from the resulting solution, and precipitating the antibiotic from the resulting solution, with a precipitating agent for the antibiotic, selected from the group consisting of Reinecke's salt, phosphotungstic acid, phosphomolybdic acid, molybdic acid, picric acid, ammonium rhodanilate, and azobenzene-p-sulfonicacid. A subsequent patent, US Patent 2,828,246 described a commercial process for bacitracin production. A 1,230 gallon portion of a medium containing 10% soybean oil meal, 2.50% starch and 0.50% calcium carbonate having a pH of 7.0 was inoculated with a culture of bacitracin-producing bacteria of the Bacillus subtilis group and the inoculated medium incubated for a period of 24 hours with aeration such that the superficial air velocity was 12.1. An assay of the nutrient medium following the fermentation revealed a yield of bacitracin amounting to 323 units/ml. This was more than twice the yields previously obtained. Then, a patent, US Patent 2,834,711 described the purification of bacitracin. In this process for purifying bacitracin, the steps comprise adding a watersoluble zinc salt to a partially purified aqueous solution of bacitracin, adjusting the pH to from 5 to 9, recovering the precipitate which forms, dissolving the precipitate in water at a pH not substantially in excess of 4, and removing the zinc ion by passing the aqueous solution through a cation exchange resin and drying the resulting solution to obtain dry solid bacitracin. Another patent, US Patent 2,915,432describes a process of recovering and concentrating bacitracin from aqueous filtered fermentation broth containing on the order of 3% protein-aceous solids which comprises intimately contacting the broth with a synthetic organic cation exchange resin having as its functional groups nuclear sulfonic acids and having a crosslinkage of the order of 1 to 2%, with the resin being in the hydrogen form, and eluting the adsorbed bacitracin from the resin with a weak base. Bacitracin recovery is described in US Patents 3,795,663 and 4,101,539. References Merck Index 937 Kleeman and Engel p.70 PDR p.888 I.N. p.113 REM p.1201

512

Baclofen

Chaiet, L. and Cochrane, T.J., Jr.; US Patent 2,915,432; December 1, 1959; assigned to Merck and Co., Inc. Johnson,R.A. and Meleney, F.L.; US Patent 2,498,165; February 21, 1950; assigned to US Secretary of War Freaney, T.E. and Allen, L.P.; US Patent 2,828,246; March 25, 1958; assigned to Commercial Solvents Corporation Zinn, E. and Chornock, F.W.; US Patent 2,834,711; May 13, 1958; assigned to Commercial Solvents Corporation Miescher, G.M.; US Patent 3,795,663; March 5, 1974; assigned to Commercial Solvents Corp. Kindraka,J.A. and Gallagher, J.B.; US Patent 4,101,539; July 18, 1978; assigned to IMC Chemical Group, Inc.

BACLOFEN Therapeutic Function: Muscle relaxant Chemical Name: γ-Amino-β-(p-chlorophenyl)butyric acid Common Name: Structural Formula:

Chemical Abstracts Registry No.: 1134-47-0 Trade Name Lioresal Lioresal Lioresal Lioresal Lioresal Lioresal Lioresal Gabalon Baclon Spastin

Manufacturer Ciba Geigy Ciba Geigy Ciba Geigy Ciba Geigy Ciba Geigy Ciba Geigy Ciba Geigy Daiichi Medica Yurtoglu

Country Switz. W. Germany UK France US Japan Japan Japan Finland Turkey

Raw Materials β-(p-Chlorophenyl)glutaric Acid Imide Sodium hydroxide Bromine

Year Introduced 1971 1972 1974 1974 1977 1979 1979 -

Bacmecillinam

513

Manufacturing Process 42.45 g of β-(p-chlorophenyl)glutaric acid imide are stirred into a solution of 8.32 g of sodium hydroxide in 200 ml of water. The mixture is heated for 10 minutes at 50°C, and the solution thus formed is cooled to 10° to 15°C. At this temperature there are then added dropwise a solution of 40.9 g of sodium hydroxide in 200 ml of water and then, in the course of 20 minutes, 38.8 g of bromine. When all has been dropped in, the batch is stirred for 8 hours at 20° to 25°C. The reaction solution is then cautiously adjusted with concentrated hydrochloric acid to pH 7, whereupon finely crystalline γ-aminoβ-(p-chlorophenyl)butyric acid settles out. To purify it, it is recrystallized from water. Melting point is 206°to 208°C. References Merck Index 939 Kleeman and Engel p.71 PDR p.894 OCDS Vol.2 p.121 (1980) DOT 8 (2) 49 (1972) I.N. p.114 REM p.925 Keberle, H., Faigle, J.W. and 1969; assigned to Ciba Keberle, H., Faigle, J.W. and 1972; assigned to Ciba

Wilhelm, M.; US Patent 3,471,548; October 7, Corporation Wilhelm, M.; US Patent 3,634,428; January 11, Corporation

BACMECILLINAM Therapeutic Function: Antibiotic Chemical Name: 4-Thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, 6(((hexahydro-1H-azepin-1-yl)methylene)amino)-3,3-dimethyl-7-oxo-, 1((ethoxycarbonyl)oxy)ethyl ester, (2S-(2α,5α,6β))Common Name: Bacmecillinam; KW-1100 Structural Formula:

514

Balazipone

Chemical Abstracts Registry No.: 50846-45-2 Trade Name

Manufacturer

Country

Year Introduced

Bacmecillinam

ZYF Pharm Chemical

-

-

Bacmecillinam

LHA CHEMPHARMA CO. LTD.

-

-

Raw Materials 1-Hexamethyleneiminocarboxaldehyde dimethylacetate Triethylamine 1’-Ethoxycarbonyloxyethyl 6-aminopenicillanate Manufacturing Process 1-Hexamethyleneiminocarboxaldehyde dimethylacetate (3.1 g) in chloroform (50 ml) was added dropwise at -30°C to a solution of 1’ethoxycarbonyloxyethyl 6-aminopenicillanate (5.0 g) and triethylamine (1.9 ml) in chloroform (150 ml) during 15 min. Then, the temperature is allowed to rise to 0°C during 30 min, and the mixture is stirred at 0°C for another 60 min. Water (120 ml) is added, and stirring is continued for 10 min. The water phase is separated and the organic layer is washed with water and stripped. There was obtained 5.0 g of the 1’-ethoxycarbonyloxy-ethyl 6-(hexahydro-1Hazepin-l-yl) methyleneaminopenicillanate. References Bamberg P. et al.; US Patent No. 4,089,963; May 16, 1978; Assigned: Astra Pharmaceutical Products, Inc., Framingham, Mass.

BALAZIPONE Therapeutic Function: Immunomodulator Chemical Name: 3-(2-Acetyl-3-oxo-1-butenyl)benzonitrile Common Name: Balazipone; OR-1364 Structural Formula:

Chemical Abstracts Registry No.: 137109-71-8 Trade Name Balazipone

Manufacturer Orion

Country -

Year Introduced -

Balofloxacin

515

Raw Materials 3-Cyanbenzaldehyde Acetic acid

2,4-Pentanedione Piperidine

Manufacturing Process A mixture containing 3-cyanbenzaldehyde, 2,4-pentanedione, piperidine and acetic acid in toluene was refluxed for some hours. After standing over night at room temperature the crystals were filtered and washed with toluene and dried. There was obtained the 3-[(2-cyanophenyl)methylene]-2,4pentanedione. References Backstrom R.J.; EU Patent No. 0,440,324 A2; August 7, 1991

BALOFLOXACIN Therapeutic Function: Antibacterial Chemical Name: 3-Quinolinecarboxylic acid, 1-cyclopropyl-6-fluoro-1,4dihydro-8-methoxy-7-(3-(methylamino)-1-piperidinyl)-4-oxoCommon Name: Balfloxacin; Balofloxacin Structural Formula:

Chemical Abstracts Registry No.: 127294-70-6 Trade Name Balofloxacin Balofloxacin

Manufacturer Country Hangzhou Greenda Chemical Co., Ltd. Shanghai Acychem Trade Co, Ltd.

Year Introduced -

Raw Materials Ethyl 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3carboxylate 3-Acetamidopiperidine

516

Balofloxacin Dimethyl sulfoxide Sodium methoxide Triethylamine

Manufacturing Process (1) A mixture of ethyl 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4oxoquinoline-3-carboxylate (933 mg), 3-acetamidopiperidine (710 mg), triethylamine (400 mg) and dimethylsulfoxide (10 ml) was heated at 100°C for 2 hours with stirring. Thereafter the mixture was cooled down and ice water was added thereto. The resulting mixture was extracted with chloroform and the chloroform layer was washed with water three times before being dried over anhydrous sodium sulfate. Removal of the solvent in vacuum followed by purification by silica gel column chromatography (chloroformethanol) gave ethyl 7-(3-acetamidopiperidin-1-yl)-1-cyclopropyl-6,8-difluoro1,4-dihydro-4-oxo quinoline-3-carboxylate (930 mg). Re-crystallization from ethanol-ether afforded a colorless crystalline substance (MP: 217°-218°C). (2) Ethyl 7-(3-acetamidopiperidin-1-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro4-oxo-quinoline-3-carboxylate obtained from the foregoing step: (a) (433 mg) of above product was dissolved in 6 N hydrochloric acid (5 ml) and heated at 100°C. for 2.5 hours with stirring. After the removal of the solvent in vacuum, methanol was added to the residue and the insoluble materials were filtered off. Removal of the solvent followed by purification by silica gel column chromatography (chloroform-methanol) gave hydrochloride of 7-(3-aminopiperidin-1-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4oxoquinoline-3-carboxylic acid (colorless, crystalline-powder). MP: color change at about 272°C; decomposition at about 280°C. (b) A mixture of 7-(3-acetamidopiperidin-1-yl)-1-cyclopropyl-6,8-difluoro-1,4dihydro-4-oxoquinoline-3-carboxylic acid (4.05 g), sodium methoxide (2.16 g) and N,N-dimethylformamide (120 ml) was stirred for 2 hours at 100°-140°C. The reaction mixture was concentrated in vacuum and water was added to the residue. The mixture was neutralized with 1 N hydrochloric acid and the neutralized mixture was then concentrated in vacuum. Purification of the concentrated mixture by silica gel column chromatography (chloroformmethanol) gave 7-(3-acetamidopiperidin-1-yl)-1-cyclopropyl-6-fluoro-1,4dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid. MP: 248°-250°C. (c) 7-(3-Acetamidopiperidin-1-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8methoxy-4-oxoquinoline-3-carboxylic acid (1.25 g) above obtained was suspended in 6 N hydrochloric acid (30 ml) and ethanol (5 ml) and heated at 100°C for 3 hours. Then the reaction mixture was concentrated in vacuum and the residue was purified by silica gel column chromatography (chloroform:methanol:ammonium hydroxide=100:30:5) to afford 7-(3aminopiperidin-1-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4oxoquinoline-3-carboxylic acid. MP: 176°-177°C. References Nagano, Hiroyuki (Saitama, JP); Yokota, Takeshi (Chiba, JP); Katoh, Yasuyuki; US Patent No. 5,051,509; September 24, 1991; Assigned to Chugai Seiyaku Kabushiki Kaisha (Tokyo, JP)

Balsalazide disodium salt

517

BALSALAZIDE DISODIUM SALT Therapeutic Function: Antiinflammatory Chemical Name: Benzoic acid, 5-((4-(((2-carboxyethyl)amino)carbonyl) phenyl)azo)-2-hydroxy-, (E)-, disodium salt Common Name: Balsalazide sodium; Balsalazine disodium Structural Formula:

Chemical Abstracts Registry No.: 213594-60-6; 80573-04-2 (Base) Trade Name Colazal Colazide

Manufacturer Salix Pharmaceuticals, Inc. Shire Pharmaceuticals

Country USA

Year Introduced -

-

-

Raw Materials 4-Nitrobenzoyl chloride Palladium on charcoal Salicylic acid

Alanine, βSodium nitrite

Manufacturing Process 125 g finely powdered 4-nitrobenzoyl chloride were added portionwise, while stirring, to a solution of 70 g β-alanine in 500 ml water containing 65 g sodium hydroxide and cooled to 5°C. The reaction mixture was stirred for 3 hours and then added to a mixture of ice and hydrochloric acid. The precipitate obtained was filtered off, washed with water and dried by suction. After crystallisation of the dried product from hot acetone, there were obtained 130 g 4-nitrobenzoyl-β-alanine; M.P. 164°-166°C. A suspension of 15 g finely powdered 4-nitrobenzoyl-β-alanine in 200 ml ethanol was stirred in an atmosphere of hydrogen in the presence of 1 g of palladium-charcoal (5%), while cooling gently. When the absorption of hydrogen had ceased, the reaction mixture was filtered and the filtrate concentrated to a small volume. Upon adding diethyl ether and cooling 4aminobenzoyl-β-alanine was obtained. The yield was 11.5 g; M.P. 156°-158°C.

518

Bamaluzole

8.8 g 4-aminobenzoyl-β-alanine were triturated with 12 ml hydrochloric acid and the paste obtained was dissolved in 100 ml water. The solution was cooled to -5°C and a solution of 3 g sodium nitrite in 20 ml water, cooled to 0°C, was added dropwise, while stirring. The diazotised solution was left for 1 hour at 0°C and was then added dropwise at -5°C to a solution of 6 g salicylic acid in 70 ml water containing 3.6 g sodium hydroxide and 7 g sodium carbonate. The final reaction mixture was adjusted to a pH of about 8, stirred for 2 to 3 hours and added to a mixture of dilute hydrochloric acid and ice. The precipitate obtained was filtered off, washed with water and suction dried. Crystallisation from hot ethanol gave 11.9 g 5-[(2-carboxy-ethylcarbamoyl)phenylazo]-2-hydroxy-benzoic acid; M.P. 254°-255°C. 10.7 g of the free acid were dissolved in 300 ml warm ethanol and treated with a solution of 2.4 g sodium hydroxide in 25 ml ethanol. The precipitate obtained was filtered off, washed with ethanol and diethyl ether and dried in a vacuum at 50°C to give 11.5 g of the disodium salt of 5-[(2-carboxyethylcarbamoyl)-phenylazo]-2-hydroxy-benzoic acid; M.P. >350°C. References Chan R.P.K.; US Patent No. 4,412,992; Nov. 1, 1983; Assigned to Biorex Laboratories Limited, England Lednicer D., The organic chemistry of drug synthesis, V. 6, p.49, 1999, John Wiley and Sons, Inc.

BAMALUZOLE Therapeutic Function: Anticonvulsant Chemical Name: 4-[(2-Chlorophenyl)methoxy]-1-methyl-1H-imidazo[4,5c]pyridine Common Name: Bamaluzole Structural Formula:

Chemical Abstracts Registry No.: 87034-87-5 Trade Name

Manufacturer

Country

Year Introduced

Bamaluzole

Onbio Inc.

-

-

Bambuterol

519

Raw Materials 1-Chlorophenyl-2-methanol 4-Methylamino-3-nitropyridine Formic acid Acetic anhydride

Sodium hydride Hydrogen chloride Tin(II) chloride

Manufacturing Process 1-Chlorophenyl-2-methanol is dissolved in dimethylformamide; NaH is added and the mixture is stirred at 20°C for 1 h. After a solution of 4-chloro-1methyl-1H-imidazo[4,5-c]pyridine [melting point 132°-134°C; obtainable by reaction of 4-methylamino-3-nitropyridine with HCl/SnCl2 to give 3-amino-2chloro-4-methylaminopyridine (melting point 170°-173°C) and reaction with HCOOH/acetic anhydride] in dimethylformamide has been added, the mixture is stirred at 90°-95°C for 15 h. The mixture is evaporated and the residue is worked up in the customary manner to give 4-o-chlorobenzyloxy-1-methyl1H-imidazo[4,5-c]pyridine, melting point 132°-135°C (crystallize from ethyl acetate-tetrahydofuran). References Irmscher K. et al.; US Patent No. 4,654,350; March 31, 1987; Assigned: Merck Patent Gesellschaft Mit Beschrankter Haftung, Darmstadt, Fed. Rep. of Germany

BAMBUTEROL Therapeutic Function: Anti-asthmatic Chemical Name: 5-(2-(tert-Butylamino)-1-hydroxyethyl)-m-phenylene bis(dimethylcarbamate) Common Name: Bambuterol; Terbutaline bis(dimethylcarbamate) Structural Formula:

Chemical Abstracts Registry No.: 81732-65-2

520

Bambuterol

Trade Name Bambuterol Bambec Oxeol Oxeol Bambuterol

Manufacturer Paranova AstraZeneca Orifarm AstraZeneca King Sun Chemical and Pharmaceutical Co., Ltd.

Country -

Year Introduced -

Raw Materials Palladium on carbon Bromine N-Benzyl-t-butylamine

3,5-Dihydroxyacetophenone N,N-Dimethylcarbamoyl chloride Benzyl chloride

Manufacturing Process Preparation of 1-[bis-(3',5'-N,N-dimethylcarbamoyloxy)phenyl]-2-N-tbutylaminoethanol hydrochloride: A solution of 78 g of bis-3',5'-(N,N-dimethylcarbamoyloxy)-2-(N-benzyl-tbutyl)aminoacetophenone in 300 ml of ethanol was hydrogenated in a Parr equipment in the presence of 25 ml of benzyl chloride and 3.5 g of 10% Pd/C. The hydrogenation time was 24 hrs at a pressure of 345 KPa (50 psig) and a temperature of 50°C. The catalyst was filtered off, and the filtrate was evaporated to dryness. The residue was dissolved in isopropanol, filtered, and to the filtrate was added diethylether to precipitate the title compound. The identity of the title product obtained was confirmed with NMR. Yield: 46.5 g. The bis-3',5'-(N,N-dimethylcarbamoyloxy)-2-(N-benzyl-tbutyl)aminoacetophenone which was used as starting material was prepared as follows: (1a). Bis-3,5-(N-N-dimethylcarbamoyloxy)acetophenone: To a solution of 152 g of 3,5-dihydroxyacetophenone in 700 ml dry pyridine was added 280 ml of N,N-dimethylcarbamoyl chloride. The mixture was stirred for 18 hrs at 60°-70°C. After evaporation in vacuum the residue was treated with a mixture of diethylether and water. The water phase was extracted with diethylether, whereafter the combined diethylether phases were washed with water, and dried over MgSO4. After evaporation, the residue was recrystallized from isopropylalcohol-petroleum ether b.p. 40°-60°C. The identity of the product was confirmed with NMR. Yield: 180.4 g. (1b). Bis-3',5'-(N,N-dimethylcarbamoyloxy)-2-bromoacetophenone: To a solution of 180 g of bis-3,5-(N,N-dimethylcarbamoyloxy)acetophenone obtained in step 1a in 700 ml of dioxane was added dropwise a solution of 31 ml of bromine in 200 ml of dioxane. The mixture was stirred at 35°C for 1 hr. The residue obtained after evaporation in vacuum was recrystallized from isopropylalcohol-petroleum ether b.p. 40°-60°C. The identity of the product was confirmed with NMR. Yield: 174 g.

Bamifylline hydrochloride

521

(1c). Bis-3',5'-(N,N-dimethylcarbamoyloxy)-2-(N-benzyl-tbutyl)aminoacetophenone: To a solution of 5.6 g of the bromoacetophenone obtained in step 1b in 75 ml of acetone was added a solution of 4.9 g of N-benzyl-t-butylamine in 30 ml of acetone. The mixture was refluxed under stirring for 18 hrs, filtered, and evaporated in vacuum. The residue was dissolved in diethyl ether, petroleum ether b.p. 61°-70°C was added, and the yellow precipitate formed filtered off. After washing with water followed by a 1:1 mixture of isopropylalcoholpetroleum ether white crystals were obtained. The identity of the product was confirmed with NMR. Yield: 4.6 g. References Torsten Olsson O. A.; US Patent No. 4,419,364; December 6, 1983; Assigned to aktiebolaget Draco, Lund Sweden

BAMIFYLLINE HYDROCHLORIDE Therapeutic Function: Bronchodilator, Coronary vasodilator Chemical Name: 7-[2-[Ethyl(2-hydroxyethyl)amino]ethyl]-3,7-dihydro-1,3dimethyl-8-(phenylmethyl)-1H-purine-2,6-dione monohydrochloride Common Name: Bamifylline hydrochloride; Benzetamophylline; Bamiphylline hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 2016-63-9 (Base); 20684-06-4 Trade Name Bamifylline hydrochloride

Manufacturer ZYF Pharm Chemical

Bamifix Trentadil

Farmalab Laboratoires Evans Medical

Country -

Year Introduced -

522

Bamipine

Trade Name Airest Bamifix

Manufacturer Caber Chiesi Farmaceutici spa

Bamifix BB

Chiesi Farmaceutici spa TEOFARMA Laboratoires Evans Medical

Briofil Bamifylline hydrochloride

Country -

Year Introduced -

-

-

-

-

Raw Materials 8-Benzyltheophilline Sodium carbonate

N-Ethylethanolamine Hydrochloric acid

Manufacturing Process A mixture of 100 kg of 8-benzyltheophilline, 36 L of N-ethylethanolamine, 300 L of 1,2-dichlorethane and 71 kg of sodium carbonate was refluxed for 24 hours. Then 36 L of N-ethylethanolamine was added and the reaction mixture was refluxed. After cooling to the mixture was added the water and hydrochloric acid. The organic phase was extracted with hydrochloric acid. The acidic phase was neutralized with sodium carbonate and the 7-(N-ethyl-N-βhydroxyethylaminoethyl)-8-benzyltheophilline was extracted with dichloromethane. The solvent was evaporated and the free base of 7-(N-ethylN-β-hydroxyethylaminoethyl)-8-benzyltheophilline was dissolved in methanol. Hydrochloride of 7-(N-ethyl-N-β-hydroxyethylaminoethyl)-8-benzyltheophilline was obtained by addition to the solution the hydrochloric acid; yield 81%, melting point 185-186°C. References Ridder R.R.; DE Patent No. 3,120,909; 1982-04-08; Applicant CYRISNIAENS SAA (BE)

BAMIPINE Therapeutic Function: Antihistaminic, Antiallergic Chemical Name: 1-Methyl-N-phenyl-N-(phenylmethyl)-4-piperidinamine Common Name: Bamipine; Piperamine Chemical Abstracts Registry No.: 4945-47-5 Raw Materials Aniline Acetic acid

1-Methyl-piperidone-4 Activated borings of aluminum

Bamipine

523

Structural Formula:

Trade Name Bamipine

Manufacturer Pharm Chemical Shanghai Lansheng Corporation

Country -

Year Introduced -

Soventol Soventol Soventol Comp. Soventol Comp.

Knoll Rentschler Adco Co. Knoll

-

-

Manufacturing Process 80 g of 1-methyl-piperidone-4 and 70 g of aniline are boiled, using a water separator in 350 ml of toluene to which several drops of glacial acetic acid have been added, until the theoretical quantity of water (12.7 ml) has separated out. The toluene is then distilled off and the remains are fractionated at reduced pressure. At a boiling point of 156°C/13 mm of Hg pressure, 118 g of a weakly yellow colored oil of the anil of 1-methyl-1piperidone-4 are obtained. 100 g of the above described anil of 1-methyl-1-piperidone-4 are boiled for 8 hours, using a reflux condenser, with 30 g of activated borings of aluminum in 300 ml of methanol diluted with 60 ml of water. The liquid phase is then separated from the solid phase, the solvent is evaporated and the residuum is fractionated at reduced pressure, 95 g of a colorless oil being obtained boiling at 163-165°C at 15 mm of Hg pressure. The oil solidifies at once to a mass of crystals of 4-N-phenylaimno-1-methylpiperidine. After having been recrystallized from dibutyl ether the base melts at 87°C, its dihydrochloride has the melting point of 246°C. 95 g of 4-N-phenylamino-1-methylpiperidine are boiled together with 22 g of pulverized sodium amide in 300 ml of benzene, using a reflux condenser, while nitrogen is passed through the reaction mixture, until the evolution of ammonia has ceased. 64 g of benzyl chloride are then gradually added drop by drop to the boiling reaction product and boiling is continued for several hours. After having been cooled the solution is shaken with water and subsequently dried with potassium carbonate. The solvent having been evaporated the remaining base of 4-(N-phenyl-N-benzyl)-amino-1methylpiperidine solidifies with the formation of crystals, the yield amounting to 123 g. The base is recrystallized from dibutyl ether and has a melting point of 115°C; its dihydrochloride melts at 189°C.

524

Barbexaclone

References Merck Index, Monograph number: 983, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. Kallischnigg R., US Patent No. 2,683,714; July 13, 1954; Knoll A.G., Ludwigschaffen (Rhine), Germany

BARBEXACLONE Therapeutic Function: Antiepileptic Chemical Name: (-)-N-α-Dimethylcyclohexaneethylamine compound with 5ethyl-5-phenyl-5-phenylbarbituric acid Common Name: Structural Formula:

Chemical Abstracts Registry No.: 4388-82-3 Trade Name

Manufacturer

Country

Year Introduced

Maliasin

Knoll

Italy

1983

Raw Materials Phenyl ethyl barbituric acid 1-Cyclohexyl-2-methylamino propane hydrochloride Manufacturing Process 25.4 g of sodium salt of phenyl ethyl barbituric acid and 19.1 g of 1cyclohexyl-2-methylamino propane hydrochloride are boiled under reflux in a mixture of 125 cc of acetic acid ethyl ester and 125 cc of ethanol. After boiling for half an hour, the solution is filtered, while still hot, to separate the precipitated sodium chloride. The filtrate is concentrated by evaporation to about half its volume. After cooling 42.5 g of the salt of 1-cyclohexyl-2methylamino propane and of phenyl ethyl barbituric acid are obtained in crystalline form. Its melting point is 130°-133°C.

Barmastine

525

References Kleeman and Engel p. 73 I.N. p. 115 Suranyi, L.; US Patent 3,210,247; October 5, 1965; assigned to Knoll A.G.

BARMASTINE Therapeutic Function: Antihistaminic Chemical Name: 4H-Pyrido[1,2-a]pyrimidin-4-one, 3-(2-(4-((3-(2furanylmethyl)-3H-imidazo[4,5-b]pyridin-2-yl)amino)-1-piperidinyl)ethyl)2-methylCommon Name: Barmastine; Ramastine Structural Formula:

Chemical Abstracts Registry No.: 99156-66-8 Trade Name Barmastine

Manufacturer ZYF Pharm Chemical

Country -

Year Introduced -

Raw Materials Thiophene Ammonia Hydrogen Sulfur Acetic acid Hydrobromic acid

N-(3-Nitro-2-pyridinyl)-2-furanylmethanamine Platinum on charcoal Mercury (II) oxide Ethyl 4-isothiocyanato-1-piperidinecarboxylate Potassium hydroxide Sodium carbonate 3-(2-Hydroxyethyl)-2-methyl-pyrido[2,1b]pyrimidin-4-one

Manufacturing Process A mixture of N-(3-nitro-2-pyridinyl)-2-furanylmethanamine, of a solution of thiophene in ethanone 4% and of methanol saturated with ammonia was hydrogenated at normal pressure and at room temperature with platinum-on-

526

Barmastine

charcoal catalyst 5%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was crystallized from acetonitrile, yielding the N2-(2-furanylmethyl)-2,3pyridinediamine. A mixture of 54 parts of ethyl 4-isothiocyanato-1-piperidinecarboxylate, 48 parts of N2-(2-furanylmethyl)-2,3-pyridinediamine and 450 parts of tetrahydrofuran was stirred and refluxed overnight. The reaction mixture was evaporated and the residue was crystallized from a mixture of 2-propanone and 2,2'-oxybispropane. The product was filtered off and dried, yielding 76 parts (75%) of ethyl 4-[[[2-[(2-furanylmethyl)amino]-3pyridinyl]aminothioxomethyl]amino]-1-piperidinecarboxylate; melting point 132.7°C. A mixture of 74 parts of ethyl 4-[[[2-[(2-furanylmethyl)amino]-3pyridinyl]aminothioxomethyl]amino]-1-piperidinecarboxylate, 96 parts of mercury (II) oxide, 0.1 parts of sulfur and 800 parts of ethanol was stirred and refluxed for 3 h. The reaction mixture was filtered over Hyflo and the filtrate was evaporated to give 52.5 parts (79%) of ethyl 4-[[3-(2furanylmethyl)-3H-imidazo[4,5-b]pyridin-2-yl]amino]-1-piperidinecarboxylate; melting point 149.2°C (crystallized from acetonitrile). A mixture of ethyl 4-[[3-(2-furanylmethyl)-3H-imidazo[4,5-b]pyridin-2yl]amino]-1-piperidinecarboxylate and of a hydrobromic acid solution 48% in water was stirred and heated for 3 h at about 80°C. The reaction mixture was evaporated and the residue was dried, yielding the 3-(2-furanylmethyl)-N-(4piperidinyl)-3H-imidazo[4,5-b]pyridin-2-amine dihydrobromide (crystallized from methanol). A mixture of 3-(2-hydroxyethyl)-2-methyl-pyrido[2,1-b]pyrimidin-4-one, of acetic acid and of a hydrobromic acid solution 67% in acetic acid was stirred and heated to reflux. Stirring was continued overnight at reflux temperature. The reaction mixture was evaporated and the solid residue was triturated in 2propanone. The product was filtered off and dried, yielding 3-(2-bromoethyl)2-methyl-pyrido[1,2-a]pyrimidin-4-one monohydrobromide. A mixture of 3-(2-bromoethyl)-2-methyl-pyrido[1,2-a]pyrimidin-4-one monohydrobromide, 3-furan-2-yl-methyl-(3H-imidazo[4,5-b]pyridine-2yl)-4piperidinyl)-amine dihydrobromide, of sodium carbonate and of N,Ndimethylformamide was stirred and heated overnight at about 70°C. The reaction mixture was poured onto water. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (94:6 by volume), saturated with ammonia, as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 3-(2-(4-((3-(2furanylmethyl)-3H-imidazo[4,5-b]pyridin-2-yl)amino)-1-piperidinyl)ethyl)-2methyl-4H-pyrido[1,2-a]pyrimidin-4-one; melting point 202°C. References Janssens F.E. et al.; US Patent No. 5,025,014; June18, 1991; Assigned: Janssen Pharmaceutica N.V., Beerse, Belgium

Barnidipine hydrochloride

527

BARNIDIPINE HYDROCHLORIDE Therapeutic Function: Coronary vasodilator Chemical Name: (+)-(3'S,4S)-1-Benzyl-3-pyrrolidinyl methyl 1,4-dihydro2,6-dimethyl-4-(m-nitrophenyl)-3,5-pyridinedicarboxylate monohydrochloride Common Name: Barnidipine hydrochloride; Mepirodipine hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 104713-75-9 (Base); 104757-53-1 Trade Name

Manufacturer

Country

Year Introduced

Barnidipine hydrochloride

Yamanouchi

-

-

Cyress

Yamanouchi

-

-

Libradin

Sigma-Tau Industrie Farmaceutiche Riunite spa

-

Libradin

Andromaco

-

-

Vasexten

Yamanouchi

-

-

Vasexten

Fournier

-

-

Raw Materials 3-Nitrobenzaldehyde 1-Benzyl-3-acetoacetyloxypyrrolidine β-Aminocrotonic acid Manufacturing Process In 5 ml of isopropyl alcohol were dissolved 1.5 g (0.01 mole) of 3nitrobenzaldehyde, 2.6 g (0.01 mole) of 1-benzyl-3-acetoacetyloxypyrrolidine, and 1.3 g (0.01 mole) of β-aminocrotonic acid methyl ester and then the solution was refluxed for 8 hours. The solvent was distilled off under reduced pressure, the residue obtained was dissolved in a small amount of chloroform, and the solution was applied to silica gel column chromatography (column diameter 1.5 cm, height 20 cm, and about 200 ml of chloroform was used as the eluent). The eluates were collected and concentrated to give 3.4 g of oily

528

Batebulast hydrochloride

2,6-dimethyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3(1-benzylpyrrolidin-3-yl)ester-5-methyl ester: [α]D20=+64.8° (c = 1 in methanol). In practice it is usually used as monohydrochloride. References Kojima Tadao, Takenaka Toichi; US Patent No. 4,220,649; September 2, 1980; Assigned to Yamanouchi Pharmaceutical Co., Ltd. (Tokyo, JP)

BATEBULAST HYDROCHLORIDE Therapeutic Function: Antiallergic, Anti-asthmatic Chemical Name: p-tert-Butylphenyl trans-4-(guanidinomethyl) cyclohexanecarboxylate monohydrochloride Common Name: Batebulast hydrochloride; Telbulast hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 81907-78-0 (Base); 83373-31-3 Trade Name Batebulast hydrochloride

Manufacturer Onbio Inc.

Country -

Batebulast hydrochloride

Nippon Chemiphar -

Raw Materials trans-4-Guanidinomethylcyclohexanecarboxylic acid p-t-Butylphenol Dicyclohexylcarbodiimide

Year Introduced -

Batimastat

529

Manufacturing Process A mixture of 9.4 g of trans-4-guanidinomethylcyclohexanecarboxylic acid, 7.2 g of p-t-butylphenol and 10.0 g of dicyclohexylcarbodiimide was suspended in a solution of 61 ml of dry pyridine and ml of dry dimethylformamide, and the suspension was stirred at room temperature for 24 h.The solvent was removed under reduced pressure.The residue was washed and dried.There was obtained the 4’-t-butylphenyl trans-4-guanidinomethylcyclohexanecarboxylate. In practice it is usually used as hydrochloride. References Muramatsu M. et al.; US Patent No. 4,465,851; August 14, 1984; Assigned: Nippon Chemiphar Co., Ltd., Tokyo, Japan

BATIMASTAT Therapeutic Function: Antineoplastic Chemical Name: Butanediamide, N4-hydroxy-N1-(2-(methylamino)-2-oxo-1(phenylmethyl)ethyl)-2-(2-methylpropyl)-3-((2-thienylthio)methyl)-, (2R(1(S*),2R*,3S*))Common Name: Barinatrix; Batimastat Structural Formula:

Chemical Abstracts Registry No.: 130370-60-4 Trade Name Batimastat

Manufacturer British Biotech

Country -

Raw Materials Leucine, DSulfuric acid Sodium bicarbonate Potassium t-butoxide

Potassium bromide Sodium nitrite Dibenzyl malonate Hydroxy benztriazole

Year Introduced -

530

Batimastat N-Methylmorpholine Palladium on charcoal Piperidine Thiophenethyol N-(Dimethylaminoethyl)-N’ethylcarbodiimide

Ammonium formate Phenylalanine-N-methylamide Formaldehyde Dicyclohexylcarbodiimide

Manufacturing Process D-Leucine (100.0 g, 0.76 mol) and potassium bromide (317.5 g, 2.67 mol) were dissolved in aqueous acid (150 ml concentrated sulfuric acid in 500 ml of water). The solution was cooled to -2°C and sodium nitrite (69.6 g, 0.95 mol in water) was added over 1 h taking care to maintain the temperature between -1°C and -2°C. After addition was complete the mixture was kept at 0°for a further hour, then DCM was added and the mixture stirred for a few minutes. The layers were separated and the aqeous phase was washed with further portions of DCM (5 x 250 ml). The combined organic layers were dried over magnesium sulfate then the solvent removed to give the 2R-bromo-5methylpentanoic acid as a pale yellow oil (123.1 g, 0.63 mol, 83%). 2R-Bromo-5-methylpentanoic acid (123.0 g, 0.63 mol) was dissolved in DCM (400 ml) and the solution cooled to -40°C while isobutene was condensed in to roughly double the volume. Maintaining the temperature at -40°C concentrated sulfuric acid (4 ml) was added dropwise. When the addition was complete the reaction was allowed to warm to room temperature overnight. The resultant solution was concentrated to half the volume by removing the solvent at reduced pressure, then the DCM was washed twice with an equal volume of 10% sodium bicarbonate solution. The organic layer was dried over magnesium sulfate and the solvent removed under reduced pressure to leave the t-butyl 2R-bromo-5-methylpentanoate as a yellow oil (148.1 g, 0.59 mol, 94%). Dibenzyl malonate (124.5 g, 0.44 mol) was taken up in dry DMF and potassium t-butoxide (49.2 g, 0.44 mol) was added portionwise with stirring and cooling. When a homogeneous solution had formed it was cooled to 0°C, then t-butyl-2R-bromo-5-methylpentanoate (110.1 g, 0.44 mol) in DMF (200 ml) was added dropwise over 1 h. When addition was complete the reaction was transfered to a cold room at 5°C and left for 4 days. The reaction mixture was partitioned between ethyl acetate and saturated ammonium chloride then the aqueous layer extracted with further ethyl acetate (4 x 500 ml), drying and solvent removal left an oil (228.0 g) heavily contaminated with DMF. This oil was taken into ether (1 L) and washed with brine (2 x 11) then the organic layer dried (magnesium sulfate), solvent removed under reduced pressure to leave the benzyl (2-benzyloxycarbonyl-3R-(t-butoxycarbonyl)-5methylhexanoate (179.0 g) contaminated with a small amount of dibenzyl malonate. Benzyl (2-benzyloxycarbonyl-5-methyl-3R-t-butoxycarbonyl)hexanoate (281.4 g, 0.56 mol) was taken up in 5% water in TFA (410 ml) and allowed to stand at 5°C overnight. After this time the TFA was evaporated under reduced pressure then the residue partitioned between DCM (1 L) and brine (200 ml). Solvent removal left an oil which crystallised on standing (230.0 g). The crude acid from this reaction was dissolved in DMF (1 L), then hydroxy benztriazole (95.3 g, 0.64 mol), N-methylmorpholine (64.0 g, 0.64 mol) and

Batimastat

531

phenylalanine-N-methylamide (113.1 g, 0.64 mol) were added at room temperature. The mixture was cooled to 0°C before dropwise addition of dicyclohexylcarbodiimide (131.0 g, 0.64 mol) in THF (1 L). This solution was stirred to room temperature over the weekend. The precipitated dicyclohexylurea was removed by filtration then the solvents were removed from the filtrate under reduced pressure to leave an oil. This oily residue was dissolved methyl acetate then washed with 10% citric acid, 10% sodium bicarbonate and saturated brine. The organic layer was dried (magnesium sulfate), filtered then the solvent removed under reduced pressure to give the title compound as an oil (400.0 g). This material was columned on silica using gradient elution (0-50% ethyl acetate in hexane) to remove impurities and separate a small amount of the minor diastereoisomer. The material from the column (195.0 g) was recrystallised from diisopropyl ether to give the [4benzyloxy-3-benzyloxycarbonyl-2R-isobutylsuccinyl]-L-phenylalanine-Nmethylamide as a white crystalline solid (140.2 g, 0.25 mol, 47%), melting point 98°-99°C. The 4-benzyloxy-3-benzyloxycarbonyl-2R-isobutylsuccinyl]-L-phenylalanine-Nmethylamide (29.6 g, 53 mmol) was taken up in ethanol, ammonium formate (16.7 g, 265 mmol) added followed by 10% palladium on charcoal (6.0 g) as a slurry in isopropyl alcohol. After 30 min at room temperature the catalyst was removed by filtration, then washed with ethanol to give a solution of the crude diacid. To this was added piperidine (5.0 g) and the mixture stirred at room temperature for 15 min before addition of aqueous formaldehyde (40% solution, 25 ml). After 18 h at room temperature the mixture was refluxed for 1 h. Solvents were removed under reduced pressure and the residue partitioned between ethyl acetate and citric acid. The acid layer was extracted with further portions of ethyl acetate (2 x 250 ml), the combined organic layers were extracted with potassium carbonate (3 x 200 ml). These base extracts were acidified to pH 4 and reextracted with DCM then the organic layer dried over magnesium sulfate. Solvent removal under reduced pressure gave the [4-hydroxy-2R-isobutyl-3-ethenylsuccinyl]-L-phenylalanine-Nmethylamide as a white solid (9.35 g, 27.0 mmol, 51%), melting point 149°151°C. The [4-hydroxy-2R-isobutyl-3-ethenylsuccinyl]-L-phenylalanine-N-methylamide (400.0 mg, 1.16 mmol) was dissolved in thiophenethyol and the mixture stirred in the dark under nitrogen at 60°C for 2 days. Ether was added to the cooled reaction mixture and the precipitated product collected by filtration. The solid was washed with large volumes of ether and dried under vacuum to give the [4-N-hydroxy-2R-isobutyl-3S-(thienylthiomethyl)succinyl]-Lphenylalanine-N-methylamide (320.0 mg, 0.73 mmol, 63%), melting point 184°-186°C. The [4-N-hydroxy-2R-isobutyl-3S-(thienylthiomethyl)succinyl]-Lphenylalanine-N-methylamide and hydroxy benztriazole were dissolved in DCM/DMF (4:1) and the mixture cooled to 0°C before adding N(dimethylaminoethyl)-N’-ethylcarbodiimide and N-methylmorpholine. The mixture was stirred at 0°C or 1 h to ensure complete formation of the activated ester. Hydroxylamine hydrochloride and NMM were dissolved in DMF then this mixture added dropwise to the cooled solution of the activated ester. After 1 h the reaction was poured into ether/water (1:1) whereupon the desired product precipitated as white crystals. These were collected by filtration, further washed with ether and water then dried under vacuum at

532

Batoprazine hydrochloride

50°C. So the [4-(N-hydroxyamino)-2R-isobutyl-3S-(thienylthiomethyl) succinyl]-L-phenylalanine-N-methylamide was obtained, melting point 236°238°C (recrystallised from methanol/ water 1:1). References Campion C. et al.; US Patent No. 5,240,958; August 31,1993; Assigned: British Bio-Technology Limited, Oxford, England

BATOPRAZINE HYDROCHLORIDE Therapeutic Function: Psychotropic Chemical Name: 8-(1-Piperazinyl)-2H-1-benzopyran-2-one monohydrochloride Common Name: Batoprazine hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 105684-52-4 Trade Name Batoprazine hydrochloride

Manufacturer Duphar

Country -

Year Introduced -

Raw Materials 5-Amino-1-benzopyran-2-one Sodium hydroxide Bis-(2-chloroethyl)amine hydrochloride Manufacturing Process 5-Amino-1-benzopyran-2-one and bis-(2-chloroethyl)amine hydrochloride were suspended in chlorobenzene. The mixture was heated at 130°C for about 66 h while stirring.

Batroxobin

533

The reaction mixture was cooled to 90°C and diluted with ethyl acetate. The solid was filtered off, washed with ethyl acetate and dried. So the 1-[5-(1benzopyran-2-one)]piperazine hydrochloride was obtained, melting point 250°C (dec.; recrystallized from ethanol). To obtained the base, 1-[5-(1-benzopyran-2-one)]piperazine, the 1-[5-(1benzopyran-2-one)]piperazine hydrochloride was treated by solution of sodium hydroxide. References Hartog J. et al.; EU Patent No. 0,189,612; August 6, 1986

BATROXOBIN Therapeutic Function: Hemostatic Chemical Name: See under structural formula; no defined name Common Name: Structural Formula: It is a complex enzyme of molecularweight no greater than 40,000 in monomeric form. Chemical Abstracts Registry No.: 9039-61-6 Trade Name

Manufacturer

Country

Year Introduced

Defibrase

Serono

W. Germany

1982

Botrophase

Ravizza

Italy

-

Ophidiase

Labaz

Switz.

-

Reptilase

Disperga

Austria

-

Reptilase

Knoll

W. Germany

-

Raw Materials Venom of Bothrops Atrox (A Pit Viper) Phenol Manufacturing Process The process for preparing the enzyme composition comprises treating an aqueous solution of the snake venom at a pH of about 4 to 6 with phenol or a phenol derivative in order to precipitate an insoluble complex containing the active venom fraction and decomposing the complex in order to release the thrombinlike enzyme composition. References Merck Index 1010

534

Baxitozine

DOT 18 (4) 169 (1982) I.N.p. 117 Percs, E.E., Stocker, K.F., Blomback, B., Blomback, M.and Hessel, B.;US Patent 3,849,252; November 19, 1974; assigned to Pentapharm A.G.

BAXITOZINE Therapeutic Function: Gastric cytoprotective; Antiulcer Chemical Name: 2-Butenoic acid, 4-oxo-4-(3,4,5-trimethoxyphenyl)-, (E)Common Name: Baxitozine; RU 38086 Structural Formula:

Chemical Abstracts Registry No.: 84386-11-8 Trade Name Baxitozine

Manufacturer ZYF Pharm Chemical

Country -

Year Introduced -

Raw Materials Glyoxylic acid Acetic acid Sodium carbonate

Hydrochloric acid 3,4,5-Trimethoxy acetophenone

Manufacturing Process 29.6 g of glyoxylic acid of 50% by weight are heated in water under reduced pressure until elimination of 80% of the water present, whereupon, after cooling, 84.1 g of 3,4,5-trimethoxy acetophenone are introduced into the reaction mixture. Heating is effected for 2 h at 95°-100°C under reduced pressure (about 50 mm/Hg), at the same time distilling off the residual water present. After cooling of the medium, 120 ml of water containing 11.6 g of sodium carbonate and ether are introduced, the aqueous phase is decanted and washed with : ether, whereupon the aqueous phase is acidified to a pH of 1 with 50% hydrochloric acid. The desired product is extracted with ethyl acetate. After elimination of the extraction solvent 31.5 g of the 4-(3,4,5trimethoxyphenyl)-4-oxo-2-hydroxy butanoic acid, melting point 119°-120°

Bazinaprine

535

are obtained (recrystallization from 1,2-dichloroethane). 15.8 g of 4-(3,4,5-trimethoxyphenyl)-4-oxo-2-hydroxy butanoic acid, 20 ml of acetic acid and 20 ml of concentrated hydrochloric acid (d-1.18) are heated for 2.5 h under reflux. The reaction medium is cooled and precipitated by water. The precipitate formed is filtered off. 10.5 g of the (E)-4-(3,4,5trimethoxyphenyl)-4-oxo-2-butenoic acid, melting point 140°C are obtained (recrystallization from ethanol-water 1:1). References Christidis Y, Fournex R.; US Patent No. 4,450,292; May 22, 1984; Assigned: Roussel Uclaf, Paris, France

BAZINAPRINE Therapeutic Function: Antidepressant Chemical Name: 4-Pyridazinecarbonitrile, 3-((2-(4-morpholinyl)ethyl)amino)6-phenylCommon Name: Bazinaprine; SR 95191 Structural Formula:

Chemical Abstracts Registry No.: 94011-82-2 Trade Name SR 95.191

Manufacturer Clin Midy/Sanofi Winthrop

Country -

Year Introduced -

Raw Materials Ethyl malonate Potassium iodide Hydrazine hydrate Ammonia Sulfuric acid Sodium hydroxide

Potassium carbonate Phenacyl chloride Acetic acid Phosphorus oxychloride N-(2-Aminoethyl)morpholine Bromine

536

Bazinaprine

Manufacturing Process 240.25 g of ethyl malonate, 138.0 g of potassium carbonate, 5.0 g of potassium iodide and 154.0 g of phenacylchloride in 2 L of anhydrous acetone are heated under reflux overnight. After the inorganic salts have been filtered off, the filtrate is evaporated to dryness and the excess ethyl malonate is then distilled off under reduced pressure (pressure: 0.5 mbar; temperature: about 60°C). The distillation residue is chromatographed on a silica column using a cyclohexane/ethyl acetate mixture (9:1) as the eluent. The ethyl phenacylmalonate is obtained in the form of a red oil. Yield: 80.3%. 40.5 g of the ethyl phenacylmalonate are dissolved in 70 ml of absolute ethanol, and 7.25 g of hydrazine hydrate are added dropwise to the reaction medium at 0°C, with stirring. When the reaction medium has returned to room temperature, it is stirred for 24 h and the beige precipitate obtained, which corresponds to the expected pyridazinone, is then filtered off. The filtrate is treated with 3.62 g of hydrazine hydrate. After stirring for 24 h, an additional quantity of pyridazinone can be filtered off. The same operation is repeated once more on the filtrate. After purification by passage through a silica column using a cyclohexane/ethyl acetate mixture (1:1) as the eluent, the 4-ethoxycarbonyl-6-phenyl-4,5-dihydro-2H-pyridazin-3-one is obtained. Yield: 37%. 9.0 g of the 4-ethoxycarbonyl-6-phenyl-4,5-dihydro-2H-pyridazin-3-one are dissolved in 200 ml of acetic acid, and 11.18 g of bromine are then added to the solution, with stirring. Decolouration of the medium occurs after 5 min. After 2 h at room temperature, and with stirring, the medium is poured into 200 ml of water, the mixture is then extracted with methylene chloride and the organic phase is evaporated to dryness. The residue is taken up 3 times with cyclohexane. The beige powder obtained is chromatographed on a silica column using a cyclohexane/ethyl acetate mixture (1:1) as the eluent. The 4ethoxycarbonyl-6-phenyl-2H-pyridazin-3-one, melting point 150°C is obtained. Yield: 51%. 2.0 g of the 4-ethoxycarbonyl-6-phenyl-2H-pyridazin-3-one are added to 40 ml of concentrated ammonia solution and the mixture is stirred overnight at room temperature. The solid is filtered off and dried to give the 6-phenyl-3oxo-2H-pyridazine-4-carboxamide, melting point >300°C. Yield: 86%. 1.5 g of the 6-phenyl-3-oxo-2H-pyridazine-4-carboxamide are dissolved in 20 ml of phosphorus oxychloride and the solution is then heated at 80°C for 5 h. The mixture is poured into 50 ml of water. A precipitate appears, which is filtered off and dried. There are obtained 58.3% of 3-chloro-4-cyano-6phenylpyridazine, melting point 206°C. 7.3 g of the 3-chloro-4-cyano-6-phenylpyridazine are dissolved in 60 ml of nbutanol, and 8.0 g of N-(2-aminoethyl)-morpholine are added. The mixture is heated under reflux for 3 h and then poured into 1000 ml of water. The organic phase is extracted with ether and the ether solution is then extracted with a 1 N solution of sulfuric acid. The aqueous phase is separated off, rendered alkaline with sodium hydroxide and extracted with ether. The ether phase is dried over magnesium sulfate and the solvent is then evaporated off to dryness in vacuo to give the 3-(2-morpholinoethylamino)-4- cyano-6phenylpyridazine, as yellow solid, melting point 138°C. Yield: 81.3%.

Beclamide

537

References Kan J.-P. et al.; US Patent No. 4,631,280; December 23, 1986; Assigned: Sanofi, Paris, France

BECLAMIDE Therapeutic Function: Anticonvulsant Chemical Name: 3-Chloro-N-(phenylmethyl)propanamide Common Name: Benzchloropropamide; Benzylchloropropionamide; Chloroethylphenamide Structural Formula:

Chemical Abstracts Registry No.: 501-68-8 Trade Name Posedrine Posedrine Beclamid Neuracen Nydrane Nydrane Posedrine Posedrine Posedrine Seclar

Manufacturer Biosa Aron Aron Promonta Lipha Aron Lasa Byk Gulden Spemsa Andromaco

Country Switz. France W. Germany W. Germany UK France Spain Italy Argentina

Year Introduced 1970 1975 -

Raw Materials Benzylamine p-Chloropropionyl chloride Sodium hydroxide Manufacturing Process A 100 gallon lined jacketed kettle provided with cooling is charged with 100 lb of benzylamine and 150 liters of water. The mixture is cooled to 5°C and with stirring 119 lb of β-chloropropionyl chloride and a solution of 45 lb of sodium hydroxide pellets in 40 liters of water are added simultaneously at such a rate that the temperature does not exceed 10°C. During this period the pH of the

538

Beclobrate

mixture should be on the alkaline side but below pH 9.5. When the addition is complete the pH should be about 8. The mixture is stirred overnight in the cold, and the solid product is filtered. The filter cake is reslurred with about 80 gallons of water, filtered, and air-dried. Yield, 128 pounds. The crude material is recrystallized by dissolving it in the minimal quantity of hot methanol (about 50 gallons), adding Norite, and filtering hot. Upon cooling slowly (finally to about 5°C) large crystals separate: they are filtered and air-dried. Yield, 109 pounds. Melting point 92° to 93°C. References Merck Index 1017 Kleeman and Engel p. 74 I.N. p. 118 Cassell, R.T. and Kushner, S.; US Patent 2,569,288; September 25, 1951: assigned to American Cyanamid Company

BECLOBRATE Therapeutic Function: Antihyperlipidemic Chemical Name: Butanoic acid, 2-(4-((4-chlorophenyl)methyl)phenoxy)-2methyl-, ethyl ester, (+/-)Common Name: Beclobrate; Turec Structural Formula:

Chemical Abstracts Registry No.: 55937-99-0 Trade Name Beclobrate Beclipur

Manufacturer ZYF Pharm Chemical SIEGFRIED HOLDING AG

Country -

Raw Materials 4-Chloro-4'-hydroxydiphenylmethane Potassium carbonate 2-Bromo-2-ethyl-2-methylacetic acid ethyl ester

Year Introduced -

Beclomethasone dipropionate

539

Manufacturing Process 87.0 g (0.4 mol) of 4-chloro-4'-hydroxydiphenylmethane are heated together with 27.0 g (0.2 mol) of anhydrous potassium carbonate in 350 ml of anhydrous xylene for 30 min to reflux temperature, whereafter a solution of 83.5 g (0.4 mol) of 2-bromo-2-ethyl-2-methyl acetic acid ethyl ester in 50 ml of anhydrous xylene is added. The mixture is kept for 24 hours and with vigorous stirring at reflux temperature. After filtering off the precipitated potassium bromide and evaporating the solvent in a Buchi rotary evaporator, the residue is taken up in ether and extracted with normal sodium hydroxide solution. The ether extracts are washed with water, dried over MgSO4 and concentrated by evaporation. The brown oil (82.0 g) thereby obtained is dissolved in n-hexane and filtered through a column of 200 g of basic Al2O3. After evaporating the solvent and distillation at reduced pressure, 34.7 g of pure ethyl (+/-)-2-((α-(p-chlorophenyl)-p-tolyl)oxy)-2-methylbutyrate are obtained with the boiling point 200-204°C/0.01-0.1 mm Hg. References Thiele K., Quazi A., Adrian R., Jahn U.; US Patent No. 4,483,999; November 20, 1984; Assigned to Siegfried Aktiengesellschaft (Zofingen, CH)

BECLOMETHASONE DIPROPIONATE Therapeutic Function: Topical antiinflammatory, Glucocorticoid Chemical Name: 9-Chloro-11β,17,21-trihydroxy-16β-methylpregna-1,4diene-3,20-dione dipropionate Common Name: Structural Formula:

Chemical Abstracts Registry No.: 5534-09-8; 4419-39-0 (Base)

540

Beclomethasone dipropionate

Trade Name Propaderm Eecotide

Manufacturer Kyowa Hakko Allen and Hanburys

Country Japan UK

Year Introduced 1972 1972

Cleniderm Sanasthmyl Becotide Beconase Vanceril Beclotide Nasal Becotide Aldesin Beclovent Becotide Becloforte

Chiesi Glaxo Glaxo Glaxo Schering Glaxo Glaxo Shionogi Glaxo Glaxo Allen and Hanburys

Italy W. Germany France W. Germany US Italy Japan Japan US Switz. UK

1974 1975 1976 1976 1976 1977 1978 1978 1979 1981 1982

Aldecin Anceron Beclacin Beclacin Beclamet Beclo-Asma Beclomet Beclosona Beclovent Becotide Betozon Betozon Bronco-Turbinal Clenil Dermisone Beclo Entyderma Gnadion Hibisterin Inalone Korbutone Proctisone Propaderm Propavent Rino-Clenil Turbinal Vaderm Viarex Viarex Viarox Zonase Zonide

Schering Essex Kaigai Morishita Orion Aldo Union Orion Spyfarma Meyer Pliva Ohta Ono Valeas Chiesi Frumtost Taiyo Pliva Nippon Zoki Lampugnani Nippon Glaxo Chiesi Duncan Glaxo Chiesi Valeas Schering Essex Schering Byk-Essex Script Intal Script Intal

Argentina Japan Japan Finland Spain Finland Spain US Yugoslavia Japan Japan Italy Italy Spain Japan Yugoslavia Japan Italy Japan Italy Italy UK Italy Italy Italy US W. Germany S. Africa S. Africa

-

Beclomethasone dipropionate

541

Raw Materials 16β-Methyl-1,4-pregnadiene-11β,17α,21-triol-3,2-dione-21-acetate Methanesulfonyl chloride Sodium methoxide N-Chlorosuccinimide Perchloric acid Manufacturing Process 6 grams of 6β-methyl-1,4-pregnadiene-11β,17α,21-triol-3,20-dione-21-acetate is dissolved in a mixture of 35 ml of dimethylformamide and 6 ml of pyridine. To the resulting solution is added 2.5 ml of methanesulfonyl chloride and the reaction mixture maintained at 80°-85°C for about 1 hour. The resulting red solution is cooled in an ice bath and treated successively with 55 ml of methanol, 240 ml of 5% aqueous sodium bicarbonate and finally with 360 ml of water. The resulting reaction mixture is then allowed to stand at room temperature overnight after which the precipitated product is removed by filtration, washed repeatedly with water and dried to a constant weight in air at about 50°C to produce 6β-methyl-1,4,9(11)-pregnadiene-11α,21-diol-3,20dione-21-acetate. Hydrolysis of the acetate ester with alkali, e.g., sodium methoxide in methanol, affords the free alcohol, 16β-methyl-1,4,9(11)-pregnadiene-17α,21diol-3,20-dione. To a suspension of 3 grams of 6β-methyl-1,4,9(11)pregnadiene-17α,21-diol-3,20-dione-21-acetate 40 ml of acetone is added at 0°C with stirring 2 grams of N-chlorosuccinimide and then 7 ml of a perchloric acid solution prepared by dissolving 0.548 ml of 70% perchloric acid in 33 ml of water. The resulting reaction mixture is stirred at 0° for about 4 hours 45 minutes. The excess of N-chlorosuccinimide is destroyed by the addition of about 15 drops of allyl alcohol and 180 ml of water is then added with stirring. This mixture is held at 0°C for about one hour. The precipitated 16β-methyl-1,4pregnadiene-9α-chloro-11β,17α,21-triol-3,20-dione-21-acetate is recovered filtration. A solution of 250 mg of the chlorohydrin in 5 ml of 0.25N perchloric acid in methanol is stirred for about 18 hours at room temperature to produce 16β-methyl-9α-chloro-11β,17α,21-trihydroxy-1,4-pregnadiene-3,20-dione which is recovered by adding water to the reaction mixture and allowing the product to crystallize. Propionic anhydride is then used to convert this material to the dipropionate. References Merck Index 1018 Kleeman and Engel p.74 PDR pp.906, 1659 DOT 9 (8) 335 (1973) I.N. p.118 REM p. 962 Merck and Co., Inc. British Patent 912,378; December 5, 1962 Taub, D., Wendler, N.L. and Slates, H.L.; US Patent 3,345,387; October 3, 1967; assigned to Merck and Co., Inc.

542

Befunolol

BEFUNOLOL Therapeutic Function: Beta-adrenergic blocker Chemical Name: 2-Acetyl-7-(2-hydroxy-3-isopropylaminopropoxy)benzofuran Common Name: Structural Formula:

Chemical Abstracts Registry No.: 39552-01-7 Trade Name Bentos

Manufacturer Kakenyaku Kako

Country Japan

Year Introduced 1983

Raw Materials 2-Acetyl-7-hydroxybenzofuran Epichlorohydrin Isopropylamine Manufacturing Process To 8.8 g of 2-acetyl-7-hydroxybenzofuran were added 80 ml of epichlorohydrin and 0.2 g of piperidine hydrochloride and the mixture was heated at 105°C for 3 hours. After the reaction, the excess of epichlorohydrin was evaporated and the resultant was distilled under reduced pressure to give 9.3 g of 2-acetyl-7-(2,3-epoxypropoxy)benzofuranhaving a boiling point of 175° to 176°C/0.7 mm Hg. 6 g of the product was dissolved in 30 ml of ethanol and to the solution was added 10 ml of isopropylamine. After refluxing the mixture for 40 minutes, the solvent was evaporated from the reaction mixture. The resulting residue was recrystallized from cyclohexane-acetone to give 6 g of 2-acetyl-7-(2-hydroxy-3-isopropylaminopropoxy)benzofuran having a melting point of 115°C. References Merck Index 1022 DFU 6 (10) 601 (1981) Ito, K., Mashiko, I., Kimura, K. and Nakanishi, T.; US Patent 3,853,923; December 10, 1974; assigned to Kakenyaku Kakko Co., Ltd.

Bekanamycin sulfate

543

BEKANAMYCIN SULFATE Therapeutic Function: Antibacterial Chemical Name: D-Streptamine, O-3-amino-3-deoxy-α-D-glucopyranosyl-(16)-O-[2,6-diamino-2,6-dideoxy-α-D-glucopyranosyl-(1-4)]-2-deoxy sulfate (1:1) Common Name: Aminodeoxykanamycin Structural Formula:

Chemical Abstracts Registry No.: 29701-07-3; 4696-76-8 (Base) Trade Name Kanendomycin Stereocidin Coltericin Kanendomicina Kanendos Visumetazone Antibiotica Visumicina

Manufacturer Meiji Seika Crinos Argentia Lefa Crinos ISF

Country Japan Italy Argentina Spain Italy Italy

Year Introduced 1969 1980 -

ISF

Italy

-

Raw Materials Bacterium S. Kanamyceticus Nutrient broth Manufacturing Process 200 liters of the medium containing 2.0% starch, 1.0% soybean meal, 0.05% KCl, 0.05% MgSO4·7H2O, 0.3% NaCl, 0.2% NaNO3 was placed in the 400 liter fermenter, the pH was adjusted to 7.5, and the medium was then sterilized (pH after the sterilization was 7.0) for 30 minutes at 120°C, inoculated with 1,000 ml of 40 hour shake-cultured broth of S. kanamyceticus (a selected subculture of K2-J strain) and tank-cultured at 27°-29°C. As antifoam,

544

Bemesetron

soybean oil (0.04%)and silicone (0.04%) were added. The broth after 48 hours was found to contain 250 mcg/ml of kanamycin. A portion (950 ml) of the rich eluate was adjusted to pH 6.0 by the addition of sulfuric acid. Ultrawet K (7.0 g) in 70 ml water was added slowly to the neutralized eluate to precipitate kanamycin B dodecylbenzenesulfonate which was collected by filtration after adding filter aid (Dicalite). The cake was washed with water and extracted with 100 ml methanol. After filtering and washing with methanol, sulfuric acid was added to the filtrate until no more kanamycin B sulfate precipitated. After addition of an equal volume of acetone to provide more complete precipitation, the kanamycin B sulfate was collected by filtration, washed with methanol and dried in vacuo at 50°C. References Merck Index 5118 Kleeman and Engel p. 75 I.N. p. 120 REM p. 1181 Umezawa, H., Maeda, K. and Ueda, M.; US Patent 2,931,798; April 5, 1960. Johnson, D.A. and Hardcastle, G.A.; US Patent 2,967,177; January 3,1961; assigned to Bristol-Myers Co. Rothrock, J.W. and Potter, I.; US Patent 3,032,547; May 1, 1962; assigned to Merck and Co., Inc.

BEMESETRON Therapeutic Function: Serotonin antagonist Chemical Name: Benzoic acid, 3,5-dichloro-, (endo)-8-methyl-8-azabicyclo [3.2.1]oct-3-yl ester Common Name: Bemesetron Structural Formula:

Chemical Abstracts Registry No.: 40796-97-2 Trade Name Bemesetron

Manufacturer Merrel Dow

Country -

Year Introduced -

Benactyzine hydrochloride

545

Raw Materials Tropine 3,5-Dichlorobenzoylchloride Manufacturing Process Tropine (34.24 g) is treated with anhydrous diethyl ether and ethereal hydrogen chloride and the precipitated hydrochloride is isolated by evaporation of the solvent. 3,5-Dichlorobenzoylchloride (51.7 g) is added and the mixture stirred at 140°C for 15 minutes during which time the mixture liquifies, evolves hydrogen chloride gas and resolidifies. After heating for a further 15 minutes the cooled solid is dissolved in water, an excess of an aqueous solution of potassium carbonate is added, and the base is extracted with ethyl acetate. Evaporation of the dried ethyl acetate solution yields a solid, which is recrystallized from aqueous methanol to yield 3,5dichlorobenzoic acid 8-methyl-8-aza-bicyclo[3.2.1]oct-1-yl ester (endo). MP: 95°C (51.8 g). References Fozard J. R. et al.; US Patent No. 4,563,465; January 7, 1986; Assigned to Merrell Dow Pharmazeuticals Inc., Cincinnati, Ohio

BENACTYZINE HYDROCHLORIDE Therapeutic Function: Tranquilizer; Anticholinergic Chemical Name: α-Hydroxy-α-phenylbenzene acetic acid-2-(diethylamino) ethyl ester hydrochloride Common Name: β-Diethylaminoethylbenzilate hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 57-37-4; 302-40-9 (Base) Trade Name Suavitil Phebex

Manufacturer Merck Sharp and Dohme Hoechst

Country US

Year Introduced 1957

US

1958

546

Benactyzine hydrochloride

Trade Name Cedad Cevanol Deprol Lucidil Morcain Nutinal Parasan Parpon Phobex Phobex

Manufacturer Recordati I.C.I. Wallace Smith and Nephew Tatsumi Boots Medix Santen Lloyd Dabnev and Westerfield

Country Italy UK US UK Japan UK Spain Japan -

Year Introduced -

Raw Materials Ethyl benzilate β-Diethylaminoethanol

Sodium Hydrogen chloride

Manufacturing Process 114 parts of ethyl benzilate, 175 parts of β-diethylaminoethanol and 0.2 part of metallic sodium were placed in a flask attached to a total-reflux variable take-off fractionating column. The pressure was reduced to 100 mm and heat was applied by an oil bath the temperature of which was slowly raised to 90°C. During three hours of heating 17 parts of ethanol distilled (35.5°C). When the distillation of the ethanol became slow, the bath temperature was raised to 120°C. When the vapor temperature indicated distillation of the amino alcohol the take off valve was closed and the mixture was refluxed for one hour. At the end of this period the vapor temperature had dropped and two more parts of ethanol were distilled, The remaining aminoalcohol was slowly distilled for three hours. The pressure was then reduced to 20 mm and the remainder of the aminoalcohol distilled at 66°C. During the reaction the color of the solution changed from yellow to deep red. The residue was dissolved in 500 parts of ether, washed once with dilute brine, and three times with water, dried over sodium sulfate and finally dried over calcium sulfate. 500 parts of a saturated solution of HCl in absolute ether was added and the resulting precipitate filtered. Dry HCl gas was passed into the filtrate to a slight excess and the precipitate again filtered. The combined precipitates were washed with cold acetone. The 106 parts of product was purified by recrystallization from acetone as fine white crystals which melt at 177°178°C. References Merck Index 1028 Kleeman and Engel p.76 PDR p.1874 OCDS Vol.1 p.93 (1977) DOT 9 (6) 241 (1973) I.N. p.120 Hill, A.J. and Holmes, R.B.; US Patent 2,394,770; February 12, 1946; assigned to American Cyanamid

Benapryzine hydrochloride

547

BENAPRYZINE HYDROCHLORIDE Therapeutic Function: Anticholinergic, Antiparkinsonian Chemical Name: α-Hydroxy-α-phenylbenzeneacetic acid 2(ethylpropylamino)ethyl ester hydrochloride Common Name: 2-Ethylpropylaminoethyl diphenylglycollate hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 3202-55-9; 22487-42-9 (Base) Trade Name Brizin

Manufacturer Beecham

Country UK

Year Introduced 1973

Raw Materials Sodium methoxide Hydrogen chloride

2-Ethylpropylaminomethanol Methyl α,α-diphenyl glycollate

Manufacturing Process A methanolic solution of sodium methoxide [from sodium (0.2 gram) and dry methanol (3 ml)] was added dropwise during 20 minutes to a boiling solution of methyl α,α-diphenylglycollate (11 grams) and 2-ethylpropylaminoethanol (6 grams) in light petroleum (150 ml, BP 80°-100°C) and the methanol that separated was removed by using a Dean and Starke apparatus. At the end of 5 hours no further separation of methanol occurred and the reaction mixture after being washed with water (3 x 20 ml) was extracted with 1N hydrochloric acid (3 x 30 ml). The acid extracts (after washing with 50 ml ether) were made alkaline with aqueous 5 N sodium hydroxide solution, the liberated base was extracted into ether (4 x 50 ml) and the ether extracts were dried (MgSO4). Treatment of the extracts with hydrogen chloride gave the hydrochloride (11 grams, 70%), which was obtained as rectangular plates, MP 164° to 166°C, after several crystallizations from butanone. References Merck Index 1030 Kleeman and Engel p. 77

548

Benazepril hydrochloride

OCDS Vol.2 p.74 (1980) DOT 9 (6) 241 (1973) I.N. p.121 Mehta, M.D. and Graham, J.; US Patent 3,746,743; July 17, 1973; assigned to Beecham Group Limited

BENAZEPRIL HYDROCHLORIDE Therapeutic Function: Antihypertensive Chemical Name: 1H-1-Benzazepine-1-acetic acid, 2,3,4,5-tetrahydro-3-((1(ethoxycarbonyl)-3-phenylpropyl)amino)-2-oxo-, monohydrochloride,(S(R*,R*))-, monohydrochloride Common Name: Benazepril hydrochloride; Labopal Structural Formula:

Chemical Abstracts Registry No.: 86541-74-4; 86541-75-5 (Base) Trade Name

Manufacturer

Country

Year Introduced

Lotensin

Novartis

-

-

Benazepril hydrochloride

DSM Catalytica Pharmaceuticals, Inc.

-

-

Cibace

Ciba-Geigy

-

-

Cibacen

Novartis

-

-

Labopal

Morrith

-

-

Labopal

Beecham

-

-

Normacen

Normal

-

-

Tensanil

CRINOS Industria Farmacobiologica S.p.A

-

Zinadril

ERREKAPPA EUROTERAPICI

-

-

Bendacort

549

Raw Materials Sodium azide 1,2,4,5-Tetrahydrobenzo[b]azepin-2-one Sodium cyanoborohydride 2-Oxo-4-phenylbutyric acid ethyl ester Manufacturing Process The synthesis of benzazepril based on a benzazepinone. It started by chlorination of lactam - 1,2,4,5-tetrahydrobenzo[b]azepin-2-one to the dichloro derivative 3,3-dichloro-1,2,4,5-tetrahydrobenzo[b]azepin-2-one. Catalytic reduction removed one of the gem chloro substituents to give 3chloro-1,2,4,5-tetrahydrobenzo[b]azepin-2-one; the halogen was then displaced with sodium azide to give 3-azido-1,3,4,5tetrahydrobenzo[b]azepin-2-one. Alkylation of the amide with ethyl bromoacetate in the presence of base yielded the ester (3-azido-2-oxo2,3,4,5-tetrahydrobenzo[b]azepin-1-yl)acetic acid ethyl ester. Hydrogenation then converted the azide to an amino group to give 3-amino-2-oxo-2,3,4,5tetrahydrobenzo[b]azepin-1-yl)acetic acid ethyl ester. It was then resolved by classical salt formation and crystallization. Saponification of the S enantiomer - S-(3-amino-2-oxo-2,3,4,5-tetrahydrobenzo[b]azepin-1-yl)acetic acid ethyl ester with sodium hydroxide afforded (3-amino-2-oxo-2,3,4,5tetrahydrobenzo[b]azepin-1-yl)acetic acid. Reductive alkylation of it with 2oxo-4-phenylbutyric acid ethyl ester and sodium cyanoborohydride gave the desired product as 70:30 mixture of diastereoisomers. The isolation of the predominant isomer gave benazepril. The epimerization occurred thermally and therefore required a sufficiently high temperature. The high temperature condition can be achieved by either using a high boiling-point solvent such as xylene or by heating the reaction mixture under pressure to increase its boiling-point temperature. Good results can be achieved in both polar and non-polar solvent systems. For example, both p-xylene and ethylene glycolwater systems are found suitable to conduct this process. The crude product acid 3-[(1-ethoxycarbonyl)-3-phenyl-(1S)-propylamino]-2,3,4,5-tetrahydro-2oxo-1H-1-benzazepine-1-acetic acid was heated to reflux temperature for 30 hours in p-xylene. The mixture was cooled down to room temperature. Solvent removal resulted in a solid, which was then dried at reduced pressure to give a 98:2 diasteriomeric mixture as determined by HPLC, MP: 287°290°C. IR and 1H-NMR spectrum analysis. was confirmed the structure of product. References Lednicer D., The Organic Chemistry of Drug Synthesis; v. 5; pp. 135-136; 1995; Wiley and Sons Inc. W-Hong Tseng et al.; US Patent No. 6,548,665B2; April 15, 2003; Assigned to Scinopharm, Taiwan, Ltd., Tainan (CN)

BENDACORT Therapeutic Function: Glucocorticoid

550

Bendazac

Chemical Name: 21-Ester of [(1-benzyl-1H-indazol-3-yl-oxy]-acetic acid with 11β,17α-dihydroxy-pregn-4-ene 3,20-dione Common Name: Ester of Bendazac with hydrocortisone Structural Formula:

Chemical Abstracts Registry No.: 53716-43-1 Trade Name Versacort

Manufacturer Angelini

Country Italy

Year Introduced 1978

Raw Materials Hydrocortisone Bendazac chloride ([(1-benzyl-1H-indazol-3-yl)oxy]acetic acid chloride) Manufacturing Process Hydrocortisone (25 g) and bendazac chloride (21 g) are suspended in anhydrous dioxane (250 ml). Pyridine (6 ml) is added and the solution is kept under stirring for 2 hours at room temperature. Pyridine hydrochloride which separates is filtered and the clear dioxane solution is added, under strong stirring, to a solution of sodium bicarbonate (20 g) in distilled water (2,500 ml). The colorless precipitate which is formed is filtered, washed with water and dried on a porous plate. The substance crystallizes from ethanol. Needles. MP 174°-176°C. Yield: 75%. References Merck Index 4689 Baiocchi, L.; US Patent 4,001,219; January 4, 1977

BENDAZAC Therapeutic Function: Antiinflammatory

Bendazac

551

Chemical Name: [(1-Benzyl-1H-indazol-3-yl)oxy]acetic acid Common Name: Bendazolic acid Structural Formula:

Chemical Abstracts Registry No.: 20187-55-7 Trade Name Versus Zildasac Hubersil Versus

Manufacturer Angelini Chugai Hubber Werfft Chemie

Country Italy Japan Spain Austria

Year Introduced 1970 1979 -

Raw Materials 1-Benzyl-3-oxy-indazole Chloroacetonitrile Hydrogen chloride Manufacturing Process 11 grams of the sodium salt of 1-benzyl-3-oxy-indazole are dissolved in 70 ml of absolute ethanol by heating the resulting solution to boiling and stirring. 3.5 grams of chloroacetonitrile dissolved in 5 ml of absolute ethanol are then added within 2-3 minutes and after 10 minutes a further portion of 1.7 grams of chloroacetonitrile are added. The reaction is finally brought to completion with an additional 45 minutes of boiling. The reaction mixture is allowed to cool at room temperature and is then filtered. The alcohol solution is evaporated to dryness under reduced pressure; the resulting residue is taken up again with ether and the ether solution is washed in sequence with dilute HCl, water, NaOH and water. The solution is dried on Na2SO4 and then the solvent is removed. The residue consists of (1-benzyl-indazole3)oxyacetonitrile which is crystallized from methanol. It has a melting point of 93°C. 1 gram of the (1-benzyl-indazole-3)oxyacetonitrile is pulverized and is added with stirring to 5 ml concentrated HCl. By heating on a boiling water bath for 2-3 minutes, the nitrile product melts and soon thereafter solidifies. The precipitate is cooled, then filtered and washed well in a mortar with water. After dissolution in 10% Na2CO3 it is precipitated again with dilute HCl. After

552

Bendroflumethiazide

crystallization from ethanol, 1-benzyl-indazole-3-oxyacetic acid is obtained. It has a melting point of 160°C. References Merck Index 1033 Kleeman and Engel p.79 OCDS Vol.2 p.351 (1980) I.N. p.121 Palazzo, G.; US Patent 3,470,194; September 30, 1969; assigned to Aziende Chimiche Riunite Angelini, Francesco ACRAF SPA, Italy

BENDROFLUMETHIAZIDE Therapeutic Function: Diuretic, Antihypertensive Chemical Name: 3,4-Dihydro-3-(phenylmethyl)-6-(trifluoromethyl)-2H-1,2,4benzothiadiazine-7-sulfonamide 1,1-dioxide Common Name: Benzydroflumethiazide; Benzylhydroflumethiazide; Bendrofluazide Structural Formula:

Chemical Abstracts Registry No.: 73-48-3 Trade Name Naturetin Sinesalin Naturine Leo Benuron Aprinox Benzide Berkozide Bristuric Bristuron Centyl Centyl Corzide Neo-Naclex Neo-Rontyl

Manufacturer Squibb I.C.I. Leo Bristol Boots Protea Berk Bristol Bristol Leo Leo-Sankyo Squibb Glaxo Leo

Country US W. Germany France US UK Australia UK US Denmark Japan US UK Denmark

Year Introduced 1959 1961 1965 -

Bendroflumethiazide Trade Name Notens Pluryl Polidiuril Poliuron Rauzide Salural Salures Seda-Repicin Sinesalin Sodiuretic Tensionorm Urizid

Manufacturer Farge Leo Bios Lepetit Squibb ICE Ferrosan Boehringer Ingelheim Arcana Squibb Leo Rekah

553

Country Italy Denmark Italy Italy US Italy Denmark W. Germany

Year Introduced -

Austria Italy France Israel

-

Raw Materials α,α,α-Trifluoro-m-toluidine ω-Ethoxystyrene Phenylacetaldehyde

Ammonia Chlorosulfonic acid

Manufacturing Process The process is described in US Patent 3,392,168 as follows: (A) Preparation of 5-Trifluoromethylaniline-2,4-Disulfonylchloride - 113 ml of chlorosulfonic acid is cooled in an ice bath, and to the acid is added dropwise while stirring 26.6 grams of α,α,α-trifluoro-m-toluidine. 105 grams of sodium chloride is added during 1-2 hours, where after the temperature of the reaction mixture is raised slowly to 150° - 160°C which temperature is maintained for three hours. After cooling the mixture, ice-cooled water is added, whereby 5-trifluoromethylaniline-2,4-disulfonyl chloride separates out from the mixture. (B) Preparation of 5-Trifluoromethyl-2,4-Disulfamylaniline - The 5trifluoromethylaniline-2,4-disulfonyl chloride obtained in step (A) is taken up in ether and the ether solution dried with magnesium sulfate. The ether is removed from the solution by distillation, the residue is cooled to 0°, and 60 ml of ice-cooled, concentrated ammonia water is added while stirring. The solution is then heated for one hour on a steam bath and evaporated in vacuo to crystallization. The crystallized product is 5-trifluoromethyl-2,4disulfamylaniline, which is filtered off, washed with water and dried in a vacuum-desiccator over phosphorus pentoxide. After recrystallization from a mixture of 30% ethanol and 70% water, the compound has a MP of 247°248°C. (C) Preparation of 3-Benzyl-6-Trifluoromethyl-7-Sulfarnyl-3,4-Dihydro-1,2,4Benzothiadiazine-1,1-Dioxide - 6.4 grams of 5-trifluoromethyl-2,4disulfamylaniline is dissolved in 12 ml of dioxane, 2.7 ml of phenylacetaldehyde and a catalytic amount of p-toluenesulfonic acid are added. After boiling for a short time under reflux, the reaction mixture crystallizes, and, after filtration and recrystallization from dioxane, the desired

554

Benfluorex hydrochloride

product is obtained with a MP of 224.5°-225.5°C. (D) Alternative to (C) - 9.6 grams of 5-trifluoromethyl-2,4-disulfarnylaniline and 4.9 grams of ω-ethoxystyrene are dissolved in 35 ml of n-butanol. 0.5 grams of p-toluenesulfonic acid is added, and the mixture is heated on a steam bath while stirring. When the solution is clear, 55 ml of hexane is added, whereafter the mixture is heated further for one and a half hours. After cooling, the substance identical to that of Example (C) is filtered off and has a MP of 222°-223°C. Sterile compositions containing Bendroflumethiazide for parenteral administration may be prepared as described in US Patent 3,265,573. References Merck Index 1036 Kleeman and Engel p.79 PDR pp.1741, 1753, 1767 OCDS Vol.1 p.358 (1977) DOT 16(3) 94 (1980) I.N. p.122 REM p.938 Goldberg, M.; US Patent 3,265,573; August 9, 1966; assigned to E.R. Squibb and Sons, Inc. Lund, F., Lyngby, K. and Godtfredsen, W.O.; US Patent 3,392,168; July 9, 1968; assigned to Lovens Kemiske Fabrik ved A. Kongsted, Denmark

BENFLUOREX HYDROCHLORIDE Therapeutic Function: Antihyperlipidemic, Cardiovascular Chemical Name: 1-(m-Trifluoromethylphenyl)-2-(β-benzoyloxyethyl) aminopropane hydrochloride Common Name: Structural Formula:

Chemical Abstracts Registry No.: 23642-66-2; 23602-78-0 (Base)

Benfotiamine Trade Name Mediator Mediaxal Mediaxal Minolip

Manufacturer Servier Stroder Servier Chiesi

Country France Italy Switz. Italy

555

Year Introduced 1976 1981 1982 -

Raw Materials 1-(m-Trifluoromethylphenyl)-2-(β-hydroxyethyl)amino propane Benzoyl chloride Manufacturing Process To a solution of 24.7 parts of 1-(m-trifluoromethylphenyl)-2-(βhydroxyethyl)amino propane in 140 parts of anhydrous benzene, there were added successively 15 parts of 4.7N hydrochloric ether and a solution of 14 parts of benzoyl chloride in 24 parts of anhydrous benzene. The addition required 10 minutes, the reaction mixture was then refluxed for 8 hours. The solid product was collected by filtration and after recrystallization from 230 parts of ethyl acetate, there were obtained 15 parts of 1-(mtrifluoromethylphenyl)-2-(β-benzoyloxyethyl)amino propane hydrochloride melting at 161°C. 10 parts hydrochloride are put in suspension in 100 parts of water, 80 parts ether are added, then 10 parts of a concentrated solution of ammonium hydroxide. The mixture is stirred a few minutes until the salt is dissolved, then the ethered solution is poured off and dried. After the ether is eliminated, 9 parts of 1-(m-trifluoromethylphenyl)-2-(βbenzoyloxyethyl)amino propane are obtained; the base is a colorless oil. References Merck Index 1037 DFU 2 (8) 557 (1976) Kleeman and Engel p.80 DOT 13 (1) 12 (1977) I.N. p.122 Beregi, L. Hugon, P. and Le Douarec, J.C.; US Patent 3,607,909; September 21, 1971; assigned to Science Union et Cie Societe Francaise de Recherche Medicale

BENFOTIAMINE Therapeutic Function: Analgesic Chemical Name: Benzoic acid, thio-, S-ester with N-((4-amino-2-methyl-5pyrimidinyl)methyl)-N-(4-hydroxy-2-mercapto-1-methyl-1-butenyl) formamide dihydrogen phosphate (ester)

556

Benfotiamine

Common Name: Benfotiamine; Benphothiamin; Benzoylthiamine monophosphate Structural Formula:

Chemical Abstracts Registry No.: 22457-89-2 Trade Name Biotamin

Manufacturer Sankyo

Country -

Year Introduced -

Vitanevril

Sanofi Winthrop

-

-

Milgamma

Worwag Pharma GmbH and Co

-

-

Benfogamma

Worwag Pharma GmbH and Co

-

-

Bio-Towa

Towa Pharmaceutical Co., Ltd.

-

-

Benfothiamin

Shanghai BR Chemical Co., Ltd.

-

Benfotiamin

Shanghai Lansheng Corporation

-

-

Raw Materials Phosphoric acid Thiamine hydrochloride Benzoyl chloride Manufacturing Process 28.6 g 84% phosphoric acid was heated to temperature about 270°C. After cooling to 100°C 4 g thiamine hydrochloride (vitamin B1 hydrochloride) was added and left at temperature 100°C before an isolation of HCl was ended. After adding of an ice water and acetone, phosphate ester of vitamin B1 was fallen. The precipitate was dissolved in 17 ml 1 N HCl and stood at ambient temperature 7 days for a hydrolysis. Then a solution was with acetone diluted and the mixture was cooled, whereupon vitamin B1 monophosphate hydrochloride was isolated.

Benfurodil hemisuccinate

557

The solution of 4.3 parts vitamin B1 monophosphate hydrochloride in 16 parts of water was diluted with 11 parts 15% NaOH, 2.1 parts benzoyl chloride was dropwise added with stirring and cooling. The obtained mixture was neutralized, evaporated in vacuum, acidified with concentrated HCl to pH 3.54, whereupon a crude S-derivative of vitamin B1 monophosphate ester was precipitated. The product was suspended in water, was bringing with NaOH to pH 7 and was acidified to pH 4. 3.4 g refined S-benzoylthiamine Omonophosphate was prepared; MP: 165°C (with decomposition). References Sankyo Kabushiki Kaisha, Tokyo; D.B. Patent No. 1,130,811; April 14, 1960

BENFURODIL HEMISUCCINATE Therapeutic Function: Coronary vasodilator; Cardiotonic Chemical Name: Succinic acid monoester with 4-[2-(1-hydroxyethyl)-3methyl-5-benzofuranyl]-2(5H)-furanone Common Name: Structural Formula:

Chemical Abstracts Registry No.: 3447-95-8 Trade Name Eucilat Clinodilat Eucilat Eucilat

Manufacturer Clin Midy Mack-Midy Midy Clin-Comar-Byla

Country France W. Germany Italy France

Raw Materials Aluminum chloride Succinic anhydride Acetyl chloride 4-(4-Methoxyphenyl)-2oxo-2,5-dihydrofuran

Chloroacetone Hydrogen chloride Sodium borohydride

Year Introduced 1970 1981 1981 -

558

Benfurodil hemisuccinate

Manufacturing Process (A) Preparation of 4-(3-Acetyl-4-Hydroxyphenyl)-2-Oxo-2,5-Dihydrofuran (1567 CB): A solution of 57 grams of 4-(4-methoxyphenyl)-2-oxo-2,5dihydrofuran (0.3 mol) in 300 ml of methylene chloride is added slowly to 200 grams of anhydrous powdered aluminum chloride, while stirring and cooling in a bath of iced water. When this is completed, one removes the bath and leaves the reagents in contact for 10 minutes, and then introduces 72 grams of acetyl chloride at a speed sufficient to maintain refluxing of the solvent. One subsequently heats under reflux for 3 hours 30 minutes, decomposes by pouring on to crushed ice, filters off the crystalline product and washes it with water. 56 g, MP = 200°C. Yield: 80%. The product is recrystallized from acetic acid and then melts at 201°-202°C. (B) Preparation of 4-[3-Acetyl-4-(2-Oxopropyloxy)Phenyl]-2-Oxo-2,5Dihydrofuran: 5.45 grams (0.025 mol) of compound 1567 CB prepared according to (A) dissolved in 50 ml of dimethyl formamide is stirred at room temperature for 15 minutes with 5 grams of potassium carbonate and 1 gram of sodium iodide, and 5 grams of chloracetone are then added drop by drop. The temperature spontaneously rises a few degrees. The disappearance of the phenolic compound is checked by testing with an alcoholic solution of ferric chloride; this test should be negative at the end of the reaction (approximately 2 hours). One then dilutes with 10 volumes of water, filters the product which crystallizes out under these conditions and recrystallizes it from acetic acid. It has the form of yellow needles (4 grams yield: 63%). MP, = 155°-157°C. (C) Preparation of 2-Acetyl-3-Methyl-5-(2-Oxo-2,5-Dihydro-4Furyl)Benro[b]Furan (3556 CB): (1) A suspension of 2 grams of the compound prepared according to (B) in 20 ml of concentrated hydrochloric acid, is heated to about 50°C, just until it dissolves. There after it is heated for 2 minutes to 70°C, just until precipitation commences. The mixture is allowed to cool, diluted with water, filtered, the residue washed, dried, and sublimed at 200°C and 0.1 mm pressure. 1.4 grams of product (Yield: 70%) is obtained. MPc=218°-221°C. A second sublimation produces a chemically pure product. MPc= 221°-222°C. (2) Compound 1567 CB and chloracetone are caused to react as in (B), the mineral salts subsequently filtered, 12 ml of concentrated hydrochloric acid are added to the solution in dimethyl formamide without dilution with water, and the mixture heated for 40 minutes on a water bath. The product crystallizes in the warm mixture, the mixture is cooled to room temperature, filtered, the residue washed with water and crystallized from acetic acid. MPc= 222°C. Yield: 60% based on compound 1567 CB. (D) Preparation of 2-(1-Hydroxyethyl)-3-Methyl-5-(2-Oxo-2,5-Dihydro-4Furyl)Benzo[b]-Furan (3574 CB): 13.2 grams of compound 3556 CB of which the preparation is described in (C) are treated successively with 66 ml of methylene chloride, 27 ml of methanol and, with stirring, 1.6 grams of sodium borohydride added in stages. The reaction takes 1 hour. The mixture is poured into water acidified with a sufficient amount of acetic acid, the solvents are stripped under vacuum, the crystalline product removed, washed with water, and recrystallized from ethyl acetate. Yield: 90%. MPk= 158°C. (E) Preparation of 2-(1-Succinyloxyethyl)-3-Methyl-5-(2-Oxo--2,5-Dihydro-4-

Benmoxin

559

Furyl)Benzo[b]-Furan (4091, CB): 8.65 grams of compound 3574 CB in 43 ml of pyridine are warmed for 30 minutes, on a water bath, with succinic anhydride. At the end of this, the pyridine is stripped off in vacuo. The mixture is treated with dilute sulfuric acid and with ether, the crystalline product filtered off, washed with water and with ether, and recrystallized from ethyl acetate (9.35 grams). MPc=144°C (measured after drying at 90°C and 0.1 mm). Yield: 77%. The product yields an equimolecular compound with morpholine. MPc=136°C (from ethyl acetate). References Kleeman and Engel p.81 OCDS Vol.2 p.355 (1980) DOT 6 (6) 203 (1970) I.N. p. 123 Schmitt, J.; US Patent 3,355,463; November 28, 1967; assigned to Etablissements Clin-Byla, France

BENMOXIN Therapeutic Function: Antidepressant Chemical Name: 1-Benzoyl-2-(alpha-methylbenzyl)hydrazine Common Name: Benmoxin; Mebamoxine Structural Formula:

Chemical Abstracts Registry No.: 7654-03-7 Trade Name Neuralex

Manufacturer Millot

Country -

Year Introduced -

Raw Materials Acetylhydrazine Hydrogen

Acetophenone Palladium on carbon

Manufacturing Process A mixture of 29.6 parts of acetylhydrazine, 48 parts of acetophenone and 140 parts of ethanol is heated under reflux for 18 hours and is then cooled to 20-

560

Benorylate

25°C and filtered. The solid residue, M.P. 135-136°C, is washed with diethyl ether and dried at 40°C. 28.5 parts of this dried product in 180 parts of methanol is shaken in an atmosphere of hydrogen under a pressure of 100 atmospheres and at a temperature of 25°C in the presence of 3 parts of a 5% palladium on carbon catalyst until the theoretical amount of hydrogen is absorbed. The mixture is filtered and the filtrate is evaporated. The residue is fractionally distilled under reduced pressure and there is thus obtained 1-(αmethylbenzyl)-2-acetylhydrazine, B.P. 182-186°C/15 mm, M.P. 72-74°C. References Merck Index, Monograph number: 1072, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. Crowther A.F. et al.; US Patent No. 3,297,530; Jan. 10, 1967; Assigned to Imperial Chemical Industrie Limited, London, England Brevet DInvention FR Patent No. 1,314,362; Dec. 22, 1962; Assigned to Imperial Chemical Industries Limited residant en Gdande-Bretagne

BENORYLATE Therapeutic Function: Analgesic, Antiinflammatory, Antipyretic Chemical Name: 2-(Acetyloxy)benzoic acid 4-(acetylamino)phenyl ester Common Name: Fenasprate; p-N-Acetamidophenyl acetylsalicylate Structural Formula:

Chemical Abstracts Registry No.: 5003-48-5 Trade Name

Manufacturer

Country

Year Introduced

Benortan

Winthrop

Switz.

-

Benoral

Winthrop

UK

1972

Benortan

Winthrop

W. Germany

1975

Benortan

Winthrop

France

1976

Benorile

Rubio

Spain

-

Benortan

Pharmacal

Finland

-

Bentum

Inpharzam

Belgium

-

Salipran

Bottu

France

-

Benoxaprofen

561

Trade Name

Manufacturer

Country

Year Introduced

Sinalgin

Robin

Italy

-

Triadol

Sterling Heath

UK

-

Winorylate

Sterwin Espanola

Spain

-

Raw Materials N-Acetyl-p-aminophenol Acetyl salicoyl chloride Manufacturing Process Example 1: 65 grams of N-acetyl-p-aminophenol were slurried with 400 ml of water and cooled to 10°C. 125 ml of 20% sodium hydroxide were slowly added to the mixture with stirring, the temperature being maintained between 10°and 15°C. To the solution obtained, 75 grams of acetyl salicoyl chloride were added with vigorous stirring over a period of 1/2 hr, the solution being maintained at a temperature of about 10°C. Towards the end of the reaction the pH was checked and adjusted to greater than 10 by the addition of a small amount of 20% sodium hydroxide. After all the acid chloride had been added, vigorous stirring was continued for half an hour during which time the crude product separated out. This product was filtered off, washed thoroughly with water and recrystallized from ethanol. Example 2: 65 grams of sodium N-acetyl-p-aminophenol were slurried with 500 grams of dry benzene and 80 grams of acetyl salicoyl chloride added. The mixture was heated under reflux for four hours and filtered hot. The excess benzene was removed under vacuum and the crude acetyl salicyclic acid ester of N-acetyl-p-aminophenol crystallized from ethanol. References Merck Index 1043 Kleeman and Engel p.82 DOT 8 (6) 208 (1972) I.N. p.123 Robertson, A.; US Patent 3,431,293; March 4, 1969; assigned to Sterling Drug, Inc.

BENOXAPROFEN Therapeutic Function: Antiinflammatory, Analgesic Chemical Name: 2-(2-p-Chlorophenyl-5-benzoxazolyl)propionic acid Common Name: Chemical Abstracts Registry No.: 51234-28-7

562

Benoxaprofen

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Opren

Dista Lilly

UK

1980

Coxigon

Lilly

W. Germany

1981

Inflamid

Lilly

France

1981

Coxigon

Lilly

Switz.

1982

Coxigon

Schweiz. Serum I

Switz.

1982

Oraflex

Lilly

US

1982

Bexopron

Lilly

-

-

Raw Materials Ethyl-2-(3-hydroxy-4-amlnophenyl)propionate p-Chlorobenzoyl chloride Manufacturing Process The 6-benzoxazolyl analog of the 5-benzoxazolyl product is prepared as follows: (a) Ethyl 2-(2-p-chlorophenyl-6-benzoxazolyl)propionate: A solution of ethyl 2-(3-hydroxy-4-aminophenyl)propionate (2.5 g) in pyridine (15 ml) was treated with p-chlorobenzoyl chloride (1.65 ml) at 5°C. After stirring for 2 hours at room temperature the solution was evaporated to dryness. The residue was heated at 220°C until no more water was evolved, then was allowed to cool. This yielded ethyl 2-(2-p-Chlorophenyl-6benzoxazolyl)propionate. (b) 2-(2-p-Chlorophenyl-6-benzoxazolyl)propionic acid: A solution of ethyl 2(2-chlorophenyl-6-benzoxazolyl)propionate (4 g) in aqueous sodium hydroxide (30 ml) was heated on a steam bath for one-half hour. On cooling the black solution was washed with chloroform. On acidification of the black solution with hydrochloric acid the mixture was extracted with chloroform. This solution on evaporation yielded 2-(2-p-chlorophenyl-6-benzoxazolyl)propionic acid, MP 196°C. References Merck Index 1044 DFU 2 (9)565 (1977) Kleeman and Engel p. 82 OCDS Vol. 2 p. 356 (1980) DOT 16 (9) 283 (1980)

Benoxinate hydrochloride

563

I.N.p. 123 Evans, D., Dunwell, D.W. and Hicks, A.; US Patent 3,912,748; October 14, 1975; assigned to Lillv Industries Ltd. Evans, D., Dunwell, D.W. and Hicks, T.A.; US Patent 3,962,441; June 8, 1976; assigned to Lilly Industries, Ltd. Evans, D., Dunwell, D.W. and Hicks, T.A.; US Patent 3,962,452; June 8, 1976; assigned to Lilly Industries, Ltd.

BENOXINATE HYDROCHLORIDE Therapeutic Function: Local anesthetic Chemical Name: 4-Amino-3-butoxybenzoic acid 2-(diethylamino)ethyl ester hydrochloride Common Name: Oxybuprocaine Structural Formula:

Chemical Abstracts Registry No.: 5987-82-6; 99-43-4 (Base) Trade Name

Manufacturer

Country

Year Introduced

Dorsacaine HCl

Dorsey

US

1953

Novesine

Marck-Chibret

France

1960

Anemixin

Zeria

Japan

-

Benoxil

Santen

Japan

-

Benoxinate

Barnes Hind

US

-

Cebesine

Chauvin-Blache

France

-

Colirio Anestesico

Collado

Spain

-

Collu-Blache

Chauvin-Blache

France

-

Conjuncain

Mann

W. Germany

-

Lacrimin

Santen

Japan

-

Minims Benoxinate

Smith and Nephew

UK

-

Novesin

Wander

Switz.

-

Novesin

Dispersa

Switz.

-

Prescaina

Llorens

Spain

-

Scarlene

Chauvin-Blache

France

-

564

Benoxinate hydrochloride

Raw Materials 3-Oxy-4-nitrobenzoic acid Potassium hydroxide Thionyl chloride Hydrogen Ethanol Butanol Diethylaminoethanol Hydrogen chloride Manufacturing Process 25 grams of 3-oxy-4-nitrobenzoic acid are esterified (ethyl ester) and 26 grams of the ester are dissolved in 200 cc of absolute ether and treated with 7 grams of caustic potash in 20 cc of absolute methanol. The red potassium phenolate with 7 grams of pure butyl bromide and 7 grams of absolute alcohol are heated for 5 hours in the oven to 150°C. When cool, the alcohol is evaporated in vacuo and the butoxy-nitrobenzoic acid ethyl ester is precipitated with water. The substance is sucked off and saponified for 15 minutes with a solution of 2.5 grams of caustic potash in 30 cc of alcohol on a water bath. The alcohol is evaporated in vacuo and the 3-butoxy-4nitrobenzoic acid is precipitated with hydrochloric acid. It forms needles which melt at 174°C. 7.9 grams of dry acid are boiled for 45 minutes under a reflux condenser with 25 cc of thionyl chloride. The excess of thionyl chloride is then removed in vacuo, and the oil is distilled. The acid chloride has a yellow color and solidifies. 7.3 grams of the acid chloride are treated with 6.6 grams of diethyl-aminoethanol in 20 cc of absolute benzene. The mixture is then warmed for 1 hour on a water bath. When cold, it is treated with a solution of soda and washed with ether. After drying over potash, the ether and benzene are removed by distillation and 3-butoxy-4-nitrobenzoic acid diethylamino-ethyl ester is obtained, having a BP 215°C/2.5 mm. 5.0 grams of this product are hydrogenated in absolute alcohol solution with fresh Raney nickel. When the absorption of hydrogen ceases (5 hours), the solution is filtered and the alcohol evaporated in vacuo. The 3-butoxy-4aminobenzoic acid diethyl-amino-ethyl ester boils at 215°-218°C at 2 mm pressure; it is an almost colorless oil. By precipitation of a solution of the ester in absolute ether with hydrogen chloride gas, the dihydrochloride is obtained; upon recrystallization from alcohol/ether, it forms crystals which melt at 196°-197°C. References Merck Index 1045 Kleeman and Engel p. 671 I.N. p.716 REM p. 1057 Dr. A. Wander, AG, Switzerland; British Patent 654,484; June 20,1951

Benperidol

565

BENPERIDOL Therapeutic Function: Tranquilizer Chemical Name: 1-[1-[4-(4-Fluorophenyl)-4-oxobutyl]-4-piperidinyl]-1,3dihydro-2H-benzimidazol-2-one Common Name: Benzperidol Structural Formula:

Chemical Abstracts Registry No.: 2062-84-2 Trade Name Frenactil Gliahimon Anquil

Manufacturer Clin-Comar-Byla Tropon Janssen

Country France W. Germany UK

Year Introduced 1965 1966 1973

Raw Materials γ-Chloro-4-fluorobutyrophenone 1-(4-Piperidyl)-2-benzimidazoline HCl Manufacturing Process A mixture of 3.4 parts of γ-chloro-4-fluorobutyrophenone, 4 parts of 1-(4piperidyl)-2-benzimidazolinone hydrochloride, 6 parts of sodium carbonate and 0.1 part of potassium iodide in 176 parts of 4-methyl-2-pentanone is stirred and refluxed for 48 hours. The reaction mixture is cooled and 120 parts of water is added. The separated organic layer is dried over magnesium sulfate and the solvent is evaporated to leave an oily residue which is dissolved in dilute hydrochloric acid and boiled. The acidic solution is filtered and cooled at room temperature whereupon there crystallizes from solution 1-(1-[γ-(4fluorobenzoyl)propyl] -4-piperidyl)-2-benzimidazolinone hydrochloride hydrate melting at about 134°-142°C. References Merck Index 1046 Kleeman and Engel p. 83

566

Benproperine

OCDS Vol. 2 p. 290 (1980) I.N.p. 124 British Patent 989,755; April 22, 1965; assigned to N.V. Research Laboratorium Dr. C. Janssen Janssen, P.A.J.: US Patent 3,161,645; December 15, 1964; assigned to Research Laboratorium Dr. C. Janssen N.V.

BENPROPERINE Therapeutic Function: Antitussive Chemical Name: 1-[1-Methyl-2-[2-(phenylmethyl)phenoxy]ethyl]piperidine Common Name: Structural Formula:

Chemical Abstracts Registry No.: 2156-27-6 Trade Name Tussafug Blascorid Flaveric Tussafugsaft Pirexyl Blascorid Pectipront

Manufacturer Medipharm Guidotti Pfizer Taito Robugen Pharmacia Pharmacia Mack

Country Switz. Italy Japan W. Germany Sweden Sweden W. Germany

Year Introduced 1968 1970 1976 -

Raw Materials o-Benzylphenoxy-β-chloropropane Piperidine Manufacturing Process A mixture of 26.1 g of o-benzylphenoxy-β-chloropropane and 17 g of piperidine is refluxed over a period of 32 hours until the temperature is about 124°C and a nearly solid mixture is formed due to the precipitation of a salt. The mixture is then refluxed over a period of 48 hours at about 160°C and the reaction product obtained is cooled and dissolved in methanol. The solution is concentrated under reduced pressure to yield an oil which is added

Benserazide

567

to 200 ml 3N hydrochloric acid whereupon the mixture is shaken with ether, 3 x 100 ml, until the aqueous phase is clear. The ether solution is washed with water, 3 x 50 ml, and the water present in the combined aqueous phase and water used for washing is evaporated under reduced pressure methanol being added three times when the residue appears to be dry. The impure hydrochloride of o-benzylphenoxy-β-N-piperidinopropane, 41 g, obtained is dissolved in 100 ml water and 100 ml 30% aqueous sodium hydroxide solution are added, whereupon precipitated oil is extracted with ether, 1 x 100 and 2 x 50 ml. The ether solution is washed with water, 4 x 50 ml, dried with magnesium sulfate and the ether is removed under reduced pressure. The residue, 25.2 g, is distilled under reduced pressure and the main fraction, 23.2 g, BP 159°-161°C/0.2 mm. References Merck Index 1047 Kleeman and Engel p. 83 OCDS Vol. 2 p. 100 (1980) DOT 13 (6) 223 (1977) I.N. p. 124 Rubinstein, K.; US Patent 3,117,059; January 7, 1964; assigned to A.B. Pharmacia

BENSERAZIDE Therapeutic Function: Antiparkinsonian Chemical Name: DL-Serine 2-[(2,3,4-trihydroxyphenyl)methyl]hydrazide Common Name: Structural Formula:

Chemical Abstracts Registry No.: 322-35-0 Trade Name

Manufacturer

Country

Year Introduced

Madopar

Roche

Italy

1974

Madopar

Roche

UK

1975

Modopar

Roche

France

1975

Madopar

Roche

W. Germany

1975

Neodopasol

Daiichi

Japan

1980

568

Bentazepam

Trade Name Madopar EC-Doparyl Madopark Prolopa

Manufacturer Nippon Roche Kyowa Hakko Roche Roche

Country Japan Japan -

Year Introduced 1980 1980 -

Raw Materials DL-Seryl hydrazide HCl Pyrogallolaldehyde Hydrogen Manufacturing Process 35.5 grams of DL-seryl-hydrazide hydrochloride was dissolved in 350 ml of water and 35 grams of pyrogallolaldehyde (2,3,4-trihydroxy-benzaldehyde) added thereto at one time. In about 5-10 minutes a clear solution resulted, whereupon slow crystallization occurred and the temperature rose to about 6°-7°C. The crystallization was permitted to continue overnight at 5°C, and the very fine precipitate was then isolated by centrifugation and in the centrifuge washed with water, ethanol, and ether, yielding the dihydrate of DLseryl-(2,3,4-trihydroxy-benzylidene) hydrazide hydrochloride, which melted at 134°-136°C and was poorly soluble in cold water, but very readily dissolved in hot water. The condensation was also effected in absolute ethanol yielding the anhydrous form of the hydrazone, which melted at 225°-228°C. 33.5 grams of the hydrazone-dihydrate was suspended in 330 ml of methanol and hydrogenated with 2.5 grams of palladium-carbon. After the absorption of 2.8 liters of hydrogen, the catalyst was filtered off and the solution evaporated in vacuo to a weight of about 52-55 grams. It was then immediately mixed with 160 ml of absolute ethanol and permitted to crystallize for 24 hours at room temperature and then for a further 24 hours at 0°C. The product was then filtered off with suction and washed with absolute ethanol and absolute ether. The so-obtained DL-seryl-(2,3,4-trihydroxy-benzyl)-hydrazide hydrochloride formed a white crystalline powder which was readily soluble in water and which melted at 146°-148°C. References Merck Index 1048 Kleernan and Engel p. 84 DOT 10 (9) 322 (1974) I.N.p. 124 Hegedus, B.and Zeller, P.; US Patent 3,178,476; April 13, 1965; assigned to Hoffmann-La Roche Inc.

BENTAZEPAM Therapeutic Function: Anticonvulsant, Tranquilizer

Bentiromide

569

Chemical Name: 2H-[1]Benzothieno[2,3-e]-1,4-diazepin-2-one, 1,3,6,7,8,9hexahydro-5-phenylCommon Name: Bentazepam; Liberan Structural Formula:

Chemical Abstracts Registry No.: 29462-18-8 Trade Name Bentazepam Tiadipona Bentazepam

Manufacturer Laboratorios Made S. A. Knoll ZYF Pharm Chemical

Country -

Year Introduced -

Raw Materials N-Phthalimidoacetic acid 2-Amino-3-benzoyl-4,5-tetramethylene thiophene Manufacturing Process To a solution of 3.4 kg N-phthalimidoacetic acid in 20 L of methylene chloride was added a solution of 2.8 kg of 1,1-carbonyl diimidazol in 20 L of methylene chloride. The mixture was refluxed for 1 hour. After cooling to the obtained solution was added a solution of 4.3 kg of 2-amino-3-benzoyl-4,5tetramethylene thiophene in 30 L of methylene chloride and the reaction mixture was refluxed for 16 hours. After cooling the mixture was washed with 30 L of water, dried with sodium sulfate and filtered. After removing the solvent was obtained the 2-(N-phthalimidoacetylamino)-3-benzoyl-4,5tetramethylene thiophene, yield 70%, melting point 230°C. References ES Patent No. 8,602,009; 1986-03-01; Assigned to MADE LABOR SA [ES]

BENTIROMIDE Therapeutic Function: Diagnostic aid (pancreatic function)

570

Bentiromide

Chemical Name: 4-[[2-(Benzoylamino)-3-(4-hydroxyphenyl)-1-oxopropyl] amino]benzoic acid Common Name: N-Benzoyl-L-tyrosyl-p-aminobenzoic acid Structural Formula:

Chemical Abstracts Registry No.: 37106-97-1 Trade Name

Manufacturer

Country

Year Introduced

PFD Oral Sol

Eisai

Japan

1980

PFT Roche

Roche

Switz.

1982

Chymex

Adria

US

-

Raw Materials L-Tyrosine N-Methylmorpholine

Benzoyl chloride p-Aminobenzoic acid

Manufacturing Process A mixture was made of L-tyrosine (18.1 g, 0.1 mol) benzoyl chloride (7.0 g, 0.05 mol) and 200 ml anhydrous THF. After stirring at reflux for 2 hours, the mixture was cooled to room temperature, and the precipitate of tyrosine hydrochloride filtered off (11 g, 46 meq. Cl-). The THF was evaporated and the residue extracted with CCl4 (3 X 100 ml at reflux, discarded) and then dissolved in ethyl acetate (200 ml) filtering off insolubles. The ethyl acetate solution was evaporated to yield 132 g solid product, MP 159°-162°C (93%). The tyrosine was recovered (8 g) by neutralization with aqueous alkali, from the hydrochloride. A solution was made of N-benzyl-L-tyrosine (5.7 g, 20 mmols) and Nmethylmorpholine (2.04 g, 20 mmols) in 60 ml of THF, at -15°C, and to it was added ethyl chloroformate (2.08 g, 20 mmols). After 12 minutes, paminobenzoic acid (2.74 g, 20 mmols) dissolved in 25 ml of THF and 0.38 g of p-toluenesulfonic acid (2 mmols) were added, and the temperature allowed to rise to 5°C. After 2 hours and forty minutes, the mixture was poured into l liter of 0.1 N cold HCl, stirred one-half hour, filtered and dried, to give 8,7 g, MP 192°-223°C. The product was recrystallized from 90 ml methanol and 40 ml water, to give 6 g (74%) of product, N-benzoyl-L-tyrosyl-p-aminobenzoic

Benzarone

571

acid, MP 240°-242°C. References Merck Index 1050 OCDS Vol. 3 p. 60 (1984) DOT 16 (10) 354 (1980) I.N. p. 125 De Benneville, P.L. and Greenberger, N.J.; US Patent 3,745,212; July 10,1973; assigned to Rohm and Haas Co.

BENZARONE Therapeutic Function: Antihemorrhagic Chemical Name: Methanone, (2-ethyl-3-benzofuranyl)(4-hydroxyphenyl)Common Name: Benzarone; Venagil Structural Formula:

Chemical Abstracts Registry No.: 1477-19-6 Trade Name Fragivix Fragivix Fragivix Fragivix Vasoc Benzarone Venagil

Manufacturer Labaz Sigma-Tau Schwarz Pharma AG C.P. Higiene Lindopharm Tohira Pharma Ltd. Erbamont Italia

Country -

Year Introduced -

Raw Materials Salicylic aldehyde Hydrazine hydrate Tin tetrachloride

Coloroacetone 2-Metoxybenzoyl chloride Pyridine hydrochloride

Manufacturing Process The process of preparation of the 2-ethyl-3-(4'-hydroxybenzoyl)benzofurane

572

Benzbromarone

includes the next steps: 1. To 1 mol of potassium hydroxide in absolute ethanol is added 1 mole of salicylic aldehyde. The mixture is brought to boiling point in water bath until the potassium salt formed is dissolved. One mole of coloroacetone is gradually added and the solution boiled in a reflux condenser for 2 hours. On cooling the potassium chloride precipitate is separated off by filtration. The residue is distilled to give 2-acetyl-1-benzofurane, BP: 135°C/15 mm Hg. 2. It was reduced by hydrazine hydrate in an alkaline medium (by process of Hyuang-Minlon, J.A.C.S., 1946, 68, 2487) to give 2-ethyl-1-benzofurane BP: 211°-212°C. 3. 2-Ethyl-1-benzofurane is condensed with 2-metoxybenzoyl chloride in the presence of tin tetrachloride (according to the process described by Bisagni, J.C.S., 1955, 3694). Thus 2-ethyl-3-(4-methoxybenzoyl)-1-benzofyrane is obtained. BP: 226°C/15 mm Hg. 4. 1 part of 2-ethyl-3-(4-methoxybenzoyl)-1-benzofyrane is mixed with 2 parts of pyridine hydrochloride and heated at an oil bath at 210°C in N2 current for 1 hour. On cooling 10 parts of 0.5 N HCl are added. A water layer is mixed with 20 parts of 1% NaOH. The alkaline layer is separated, acidified with diluted HCl. The dropped precipitate (2-ethyl-3-(4'-hydroxybenzoyl) benzofurane) is recrystallized from acetic acid. MP: 124.3°C. References G.B. Patent No. 836,272; Dec. 12, 1957; Societe des Labaz, a Belgiam Body Corporate, of 168 Louise, Brusseles, Belgium Shalk W. et al.; D.B. Patent No. 1,076,702; March 20, 1960; Societe des Laboratories Labaz, Bruessel Hoi N.P.B., Beaudet C.; US Patent No. 3,012,042; Dec. 5, 1961; Assigned to Societe Belge l'Azote et Produits Chimiques du Marly, Liege, Belgium

BENZBROMARONE Therapeutic Function: Uricosuric, Antiarthritic Chemical Name: (3,5-Dibromo-4-hydroxyphenyl)-(2-ethyl-3-benzofuranyl) methanone Common Name: Structural Formula:

Benzbromarone

573

Chemical Abstracts Registry No.: 3562-84-4 Trade Name

Manufacturer

Country

Year Introduced

Desuric

Labaz

Switz.

-

Uricovac

Labaz

W. Germany

1971

Desuric

Labaz

France

1976

Desuric

Sigma Tau

Italy

1977

Urinorm

Torii

Japan

1979

Azubromaron

Azupharma

W. Germany

-

Allomaron

Nattermann

W. Germany

-

Exurate

Mead Johnson

US

-

Hipuric

Labaz

-

-

Max-Uric

Labinca

Argentina

-

Minuric

Labaz

-

-

Narcaricin

Heumann

W. Germany

-

Normurat

Gruenenthal

W. Germany

-

Obaron

Mepha

Switz.

-

Raw Materials Chloroacetone Bromine Anisoyl chloride

Hydrazine hydrate Salicylic aldehyde

Manufacturing Process The propyl analog of the benzbromarone intermediate containing an ethyl group is prepared as follows: to a solution of potassium hydroxide (56 g = 1 mol) in absolute ethyl alcohol (750 cc) is added one mol of salicylic aldehyde (122 grams). The mixture is brought to boiling point in a water-bath until the potassium salt formed is dissolved. One mol of ethyl chloromethyl ketone (106.5 grams) (methyl chloromethyl ketone or chloracetone in the case of benzbromarone) is gradually added and the solution boiled in a reflux condenser for two hours. After cooling, the potassium chloride precipitate is separated off by filtration, and the greater part of the solvent removed by distillation. The residue is then puritied by distillation. In this way, 140 grams of 2-propionyl coumarone are obtained, boiling at 135°C under 15 mm Hg. A mixture is then prepared as follows: 215 grams of 2-propionyl coumarone, 550 cc of diethylene glycol and 200 grams of hydrazine hydrate at 85% and maintained at boiling point in a reflux condenser for 10 minutes. After cooling, 180 grams of potassium hydroxide are added and the mixture brought up to 120°-130°C. This temperature is maintained until no more nitrogen is liberated (about 1 hour). The mixture is then distilled by means of super-heated steam (150°-160°C). The distillate is neutralized by means of concentrated HCl, decanted, and the aqueous layer extracted by means of ether. The oily layer and the ethereal extract are mixed, washed with diluted HCl, then with water, and finally dried over sodium sulfate. The solvent is removed and the residue rectified under

574

Benzethonium chloride

reduced pressure. In this way, 130 grams of 2-propyl coumarone are obtained, boiling at 112°C under 17 mm of mercury. The following substances are then placed in a 250 cc flask fitted with a stirrer and a separatory funnel: 12.96 grams of 2-propyl coumarone, 55 cc of carbon sulfide and 14 grams of anisoyl chloride. The mixture is cooled by means of iced water and 21.5 grams of stannic chloride introduced dropwise, while the mixture is stirred. Stirring is continued for three hours at 0°C, after which the mixture is allowed to stand overnight. 50 cc of carbon sulfide is added and the mixture is treated, while being stirred, with the following: 20 cc of HCl and 100 cc of iced water. The organic layer is decanted and washed with water, dried over silica gel and rectified. 16.16 grams of 2-propyl-3-anisoyl coumarone are obtained (Yield: 72%), boiling at 189°C under 0.5 mm Hg. The methoxylated coumarone so obtained is mixed as follows: 1 part of 2-propyl-3-anisoylcoumarone and 2 parts of pyridine hydrochloride and the mixture maintained for one hour under a stream of dry nitrogen in an oil bath at 210°C (under a vertical condenser). After cooling, the mixture is triturated with 0.5 N hydrochloric acid (10 parts). The aqueous layer is separated and the residue extracted with ether. The ethereal extract is treated with 20 parts of 1% caustic soda. The alkaline layer is separated by decanting and acidified by means of diluted HCl. The precipitate is purified by recrystallization in aqueous acetic acid. 0.8 part of 2-propyl-3p-hydroxybenzoyl coumarone is obtained, melting at 123°C. Then the dibromo counterpart of benzbromarone may be prepared as follows: 8.05 g of 3-ethyl-2-p-hydroxybenzoyl coumarone, prepared as described above, are dissolved in very silght excess of 3% caustic soda. To this solution is gradually added a slight excess of bromine dissolved in a 25% aqueous solution of potassium bromide. The resultant solution is acidified with a 20% solution of sodium bisulfite, centrifuged, washed with water and then dried under vacuum. The product is then recrystallized in acetic acid and 13.6 g of 2-(4'-hydroxy-3',5'-dibromo-benzoyl)-3-ethyl coumarone obtained. MP 151°C. References Merck Index 1062 Kleeman and Engel p. 87 OCDS Vol. 2 p. 354 (1980) I.N. p. 127 Hoi, N.P.B. and Beaudet, C.; US Patent 3,012,042; December 5, 1961; assigned to Societe Belge de I'Azote et des Produits Chirniques du Marly, Belgium

BENZETHONIUM CHLORIDE Therapeutic Function: Topical antiinfective Chemical Name: N,N-Dimethyl-N-[2-[2-[4-(1,1,3,3-tetrarmethylbutyl) phenoxy]ethyl]benzenemethanaminium chloride

Benzethonium chloride

575

Common Name: Structural Formula:

Chemical Abstracts Registry No.: 121-54-0 Trade Name Phemerol Premithyn Benzalcan Dalidyne Desamon Hyarom Sterilette Uni Wash

Manufacturer Parke Davis Flint Siegfried Dalin Streuli Teva Farmitalia United

Country US US Switz. US Switz. Israel Italy US

Year Introduced 1942 1959 -

Raw Materials p-Diisobutylphenol Benzyl chloride Dichlorodiethyl ether Dimethylamine Manufacturing Process A mixture of 32 g of p-(α,α,γ,γ-tetramethylbutyl)phenoxyethoxyethyldimethylamine and 12.7 parts of benzyl chloride was warmed in 50 g of benzene for 2 hours. The benzene was then evaporated. The residual viscous mass gave a foamy, soapy solution in water. The original starting materials are p-diisobutylphenol, dichlorodiethyl ether and dimethylamine. References Merck Index 1072 PDR pp. 829, 1826 I.N.p. 127 REM p. 1166 Bruson, H.A.; US Patents 2,115,250; April 26, 1938; 2,170,111; August 22, 1939; and 2,229,024; January 21, 1941; all assigned to Rohm and Haas Co.

576

Benzilonium bromide

BENZILONIUM BROMIDE Therapeutic Function: Anticholinergic Chemical Name: Pyrrolidinium, 1,1-diethyl-3-((hydroxydiphenylacetyl)oxy)-, bromide Common Name: Benzilonium bromide; Ulcoban Structural Formula:

Chemical Abstracts Registry No.: 1050-48-2; 16175-92-1 (Base) Trade Name Benzilonium bromide

Manufacturer Pharm Chemical Shanghai Lansheng Corporation

Country -

Year Introduced -

Ulcoban

Parke-Davis

-

-

Raw Materials 1-Ethyl-3-hydroxypyrrolidine Diphenylchloroacetyl chloride

Ethylbenzilate Ethyl bromide

Manufacturing Process A mixture containing of 23 g of 1-ethyl-3-hydroxypyrrolidine, 51.2 g of ethylbenzilate and 1.50 ml of benzene is subjected to azeotropic distillation to remove traces of water and then 250 mg of metallic sodium added to the residual solution. The mixture heated under reflux for about 8 hours while slowly drawing off the benzene-alcohol azeotrope formed. The reaction mixture is cooled, treated with 1 ml of acetic acid and washed with water. The benzene is removed by distillation and the residue distilled in vacuo to obtain the desired 1-ethyl-3-pyrrolidinyl benzilate as a viscous oil; yield 44 g, 68.1%; b.p. 164-170°C at 0.2 mm. If desired, this same product can be prepared by adding 8 g of 1-ethyl-3hydroxypyrrolidine in about 40 ml of dry methylene dichloride to 18.4 g of diphenylchloroacetyl chloride in about 40 ml of boiling methylene dichloride and refluxing the mixture for 1 hour. The solvent is evaporated and the residue heated on a steam bath with 200 ml of water for 5 min and then

Benziodarone

577

allowed to stand at room temperature for 2 days. The mixture is treated with potassium carbonate, extracted with benzene and the benzene distilled from the extract to obtain crude l-ethyl-3-pyrrolidinyl benzilate. Distillation in vacuo yields the pure l-ethyl-3-pyrrolidinyl benzilate; yield 8 g (31%); b.p. 197°C at 2 mm. 22 g of 1-ethyl-3-pyrrolidinyl benzilate prepared by either of the above methods is mixed with 32 g of ethyl bromide in 100 ml of isopropanol and refluxed for 1 hour to give 23 g of 1,1-diethyl-3-pyrrolidinium bromide benzilate, m.p.196-197°C. References Merck Index, Monograph number: 1110, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. Nguen Phac Bao Hoi, GB Patent No. 821,436; Dec. 5, 1961; Assigned to Societe Belge de l'Azote et des Produits Chimiques du Marly, Liege, Belqium DE Patent No. 1,136,338; Fev. 12, 1957; Assigned to Parke, Davis and Co., Detroit, Michigan

BENZIODARONE Therapeutic Function: Coronary vasodilator, Uricosuric Chemical Name: Methanone, (2-ethyl-3-benzofuranyl)(4-hydroxy-3,5diiodophenyl)Common Name: Benziodarone; Ethofuridione Structural Formula:

Chemical Abstracts Registry No.: 68-90-6 Trade Name Amplivix Amplivix Amplivix Amplivix Dilafurane Plexocardio

Manufacturer Sigma-Tau Sanofi Pharma AG Sumitomo C.P. Higiene Sanofi-Winthrop Benvegna

Country -

Year Introduced -

578

Benzoctamine hydrochloride

Raw Materials Salicylic aldehyde Tin tetrachloride Potassium iodide

Chloroacetone 4-Methoxy-benzoylchloride Iodine

Manufacturing Process The starting product 2-ethyl-3-benzofuranyl p-hydroxyphenyl ketone (benzaron) was prepared in 4 steps: 1. First step was a reaction of salicylic aldehyde with chloroacetone to produce 2-acetyl-1-benzofuran. 2. It was reduced by hydrazine hydrate in an alkaline medium by process of Hyuang-Minlon, J.A.C.S., 1946, 68, 2487 to give 2-ethyl-1-benzofurane. 3. 2-Ethyl-3-(4-methoxybenzoyl)-1-benzofuran was obtained from 2-ethyl-1benzofuran and 4-methoxy-benzoylchloride in a presence of tin tetrachloride. 4. It was heated with pyridine hydrochloride at 200°-220°C to give 2-ethyl-3benzofuranyl p-hydroxyphenyl ketone (benzaron) as described in N.P.B.Hoi, C.Beaudet; US Patent No. 3,012,042; Dec. 5, 1961. Benzaron (1 part) was dissolved in a very slight excess of 3% caustic soda. To this solution is gradually added a slight excess of iodine dissolved in a 25% aqueous solution of potassium iodide. The resultant solution is acidified with a 20% solution of sodium bisulphite, centrifuged, washed with water and then recrystallized in acetic acid to give of 2-ethyl-3-benzofuranyl 4-hydroxy-3,5diiodophenyl ketone. MP: 167°C. References GB Patent No. 836,272; Dec. 17, 1957; Societe des Labaz, a Belgiam Body Corporate, of 168 Louise, Brusseles, Belgium

BENZOCTAMINE HYDROCHLORIDE Therapeutic Function: Sedative, Muscle relaxant Chemical Name: N-Methyl-9,10-ethanoanthracene-9(10H)-methanamine hydrochloride Common Name: Chemical Abstracts Registry No.: 10085-81-1; 17243-39-9 (Base)

Benzonatate

579

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Tacitin

Ciba Geigy

Switz.

-

Tacitine

Ciba Geigy

France

1970

Tacitin

Ciba Geigy

UK

1971

Tacitin

Ciba Geigy

Italy

1971

Tacitin

Ciba Geigy

W. Germany

1972

Raw Materials Anthracene Methylamine

Acrolein Hydrogen

Manufacturing Process A solution of 10 g of 9:10-dihydro-9:10-ethano-(1:2)-anthracene-(9)aldehyde (made from anthracene and acrolein) and 10 g of monomethylamine in 100 cc of ethanol is heated at 80°C for 4 hours in an autoclave. The reaction mixture is then evaporated to dryness under reduced pressure to leave a crystalline residue which is dissolved in 150 cc of ethanol and, after the addition of 2 g of Raney nickel, hydrogenated at 40°C under atmospheric pressure. When the absorption of hydrogen has subsided, the catalyst is filtered off and the filtrate evaporated under reduced pressure. An oil remains which is covered with 100cc of 2N hydrochloric acid, The 9-methylamino-methyl-9:10-dihydro-9:10ethano-(9:10)-anthracene hydrochloride crystallizes immediately; after crystallization from methanol it melts at 320°-322°C. References Merck Index 1087 Kleeman and Engel p. 88 DOT 6 (4) 123 (1970) I.N. p. 129 Schmidt, P., Wilhelm, M. and Eichenberger, K.; US Patent 3,399,201; August 27, 1968; assigned to Ciba Corp.

BENZONATATE Therapeutic Function: Antitussive

580

Benzonatate

Chemical Name: 4-(Butylamino)benzoic acid 3,6,9,12,15,18,21,24,27nonaoxaoctacos-1-yl ester Common Name: Benzononatine Structural Formula:

Chemical Abstracts Registry No.: 104-31-4 Trade Name

Manufacturer

Country

Year Introduced

Tessalon

Endo (Du Pont)

US

1958

Ventusasin

Warren Teed

US

1964

Tessalon

Ciba Geigy

Switz.

-

Raw Materials p-Butylaminobenzoic acid ethyl ester Nonaethylene glycol monomethyl ether Manufacturing Process 4.42 parts of para-butylamino-benzoic acid ethyl ester are put with 16.0 parts of a mixture of polyethylene glycol monomethyl ethers, boiling at 180°-220°C at a pressure of 0.01 mm of mercury, in a closed reaction vessel which is fitted with an adjustable inlet tube for solvents and a connection for distilling off in vacuo. In order to dry the mixture completely, it is heated for an hour at 100°-105°C and absolute xylene is introduced under the surface of the mixture in vacuo at a pressure of 12 mm of mercury. There is thus a constant stream of xylene steam passing through the whole apparatus, which removes the last traces of moisture and any other volatile impurities. The xylene is condensed in a cooler. The whole is cooled to 20°-30°C and 0.06 part of sodium methylate dissolved in 0.6 part of methanol is added.

Benzphetamine hydrochloride

581

Thereupon xylene is introduced again in vacuo at a temperature of 100°105°C whereby all the methanol and the ethanol formed during reesterification evaporates. The re-esterification is continued under these conditions until a specimen of the reaction mass is clearly soluble in cold water, which occurs after about 2-3 hours. There is now obtained in almost quantitative yield the ester of the formula wherein n stands for approximately 7 to 9, which still contains an excess of polyethylene glycol monomethyl ether. The ester is purified by dissolving in benzene and being washed several times with a sodium carbonate solution of 5% strength. It is advantageous to agitate all the washing solutions with fresh benzene. In this distribution between benzene and sodium carbonate solution the new ester remains in the benzene, the excess polyethylene glycol monomethyl ether and a small amount of brown impurities are taken up by the dilute soda solution. By evaporating the dried and filtered benzene solution there is obtained the new ester in the form of a colorless to very faintly yellow oil which is easily soluble in most organic solvents with the exception of aliphatic hydrocarbons. The new ester is precipitated from aqueous solutions when heated to about 42°C. but it dissolves again readily on cooling. References Merck Index 1099 Kleeman and Engel p.89 PDR p. 862 I.N.p. 130 REM p. 870 Matter, M.; US Patent 2,714,608; August 2, 1955; assigned to Ciba Pharmaceutical Products, Inc.

BENZPHETAMINE HYDROCHLORIDE Therapeutic Function: Antiobesity Chemical Name: N-α-Dimethyl-N-(phenylmethyl)benzeneethanamine hydrochloride Common Name: Structural Formula:

Chemical Abstracts Registry No.: 5411-22-3; 156-08-1 (Base) Trade Name Didrex Inapetyl Didrex

Manufacturer Upjohn Upjohn Upjohn

Country US France UK

Year Introduced 1960 1969 -

582

Benzpyrinium bromide

Raw Materials Benzyl chloride Sodium hydroxide

d-Desoxyephedrine hydrochloride Hydrogen chloride

Manufacturing Process Fifty grams of d-desoxyephedrine hydrochloride was dissolved in a small amount of water and a molar excess of sodium hydroxide was .added thereto. The resulting forty grams of precipitated oily d-desoxyephedrine was collected in ether and the whole was thereafter dried with anhydrous potassium carbonate. The ether was then removed, the resulting oily residue having an nD22 of 1.5045 was stirred in a flask with 40 grams of anhydrous sodium carbonate at 120°C, and 34.6 grams of benzyl chloride was added dropwise thereto over a period of thirty minutes. Stirring was continued for 2 hours, whereafter the reaction mixture was extracted with benzene. The benzene was distilled from the extract and the residue of d-N-methyl-Nbenzyl-β-phenylisopropylamine was distilled at reduced pressure. The thus obtained free base, distilling at 127°C at a pressure of 0.2 mm of mercury and having an nD19 of 1.5515, was dissolved in ethyl acetate and a molar equivalent of ethanolic hydrogen chloride was added thereto. Anhydrous ether was added to the mixture and d-N-methyl-N-benzyl-β-phenylisopropylamine hydrochloride precipitated from the reaction mixture as an oil which was crystallized from ethyl acetate to give crystals melting at 129° to 130°C. References Merck Index 1122 Kleeman and Engel p.89 PDR p.1841 OCDS Vol. 1 p.70 (1977) I.N. p.131 REM p.891 Heinzelman, R.V. and Aspergren, B.D.; US Patent 2,789,138; April 16, 1957; assigned to The Upjohn Company

BENZPYRINIUM BROMIDE Therapeutic Function: Cholinergic Chemical Name: 3-[[(Dimethylamino)carbonyl]oxy]-1-(phenylmethyl) pyridinium bromide Common Name: Chemical Abstracts Registry No.: 587-46-2

Benzpyrinium bromide

583

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Stigmonene

Warner Lambert

US

1949

Raw Materials Dimethylcarbamyl chloride 3-Pyridol Benzyl bromide Manufacturing Process 56 grams of dimethylcarbamyl chloride were gradually added over a period of 50 minutes to a solution of 45 grams of 3-pyridol in a mixture of 300 cc of benzene and 69 grams of triethylamine. The reaction mass was then agitated at 80°C for 3 hours and permitted to cool. The triethylamine hydrochloride was removed by filtration and solvents distilled from the filtrate under vacuum in a nitrogen atmosphere. The residual oil was then fractionated under vacuum whereby, after removal of unchanged dimethylcarbamyl chloride, a product distilling at 90°C at 0.3 mm was obtained; this product was the dimethylcarbamyl ester of 3-pyridol. 60 grams of the ester prepared as above described were dissolved in 225 cc of benzene and 92.5 grams of benzyl bromide were added thereto. The solution was stirred at room temperature for 24 hours and refluxed for 3 additional hours. At the end of this time the crude product which formed was separated, washed with benzene and dissolved in water. The aqueous solution was extracted with ether, filtered through charcoal and then evaporated to dryness in a nitrogen atmosphere; traces of water were removed by redissolving the oily residue in absolute alcohol, adding benzene and then evaporating the mixture to dryness under vacuum. The yellow oil thus obtained was then dissolved in a mixture of 300 cc of benzene and 55 cc of absolute alcohol under reflux, the solution cooled, and 340 cc of absolute ether added. The solution was then seeded and maintained at 5°C for two days. The crystalline product obtained was filtered and dried, a product melting between 115°C and 116°C being obtained. This product was the desired 1 benzyl-3-(dimethylcarbamyloxy)-pyridinium bromide. References Merck Index 1124 I.N. p. 131 Wuest, H.M.; US Patent 2,489,247; November 22, 1949; assigned to William R. Warner and Co., Inc.

584

Benzquinamide

BENZQUINAMIDE Therapeutic Function: Tranquilizer, Antinauseant Chemical Name: 2-(Acetyloxy)-N,N-diethyl-1,3,4,6,7,11b-hexahydro-9,10dimethoxy-2H-benzo[a]quinolizine-3-carboxamide Common Name: Structural Formula:

Chemical Abstracts Registry No.: 63-12-7; 30046-34-5 (Hydrochloride salt) Trade Name

Manufacturer

Country

Year Introduced

Emete-Con

Roerig

US

1974

Promecon

Endopharm

W. Germany

1983

Quantril

Pfizer

US

-

Raw Materials 2-Oxo-3-carboxy-9,10-dimethoxy-1,2,3,4,6,7-hexahydro-11b-Hbenzopyridocoline Diethylamine Hydrogen Hydrogen chloride Manufacturing Process According to US Patent 3,055,894, a solution consisting of 3.4 grams (0.01mol) of 2-oxo-3-carboethoxy-9,10-dimethoxy-1,2,3,4,6,7-hexahydro11b-H-benzopyridocoline and 0.8 grams (0.011 mol) of freshly distilled diethylamine dissolved in 50 ml of xylene was refluxed under a nitrogen atmosphere for 24 hours. After cooling to room temperature, the reaction mixture was successively extracted with four 100 ml portions of water. The aqueous phase was then discarded and the xylene layer was passed through a paper filter containing a bed of sodium sulfate and activated charcoal. The resulting filtrate was then heated under reduced pressure (65 mm Hg) via a water bath at 50°C in order to remove the xylene solvent, and the residual oil so obtained was cooled to approximately 5°C and held at that point until a semisolid formed (required approximately 16 hours). Recrystallization of the

Benzquinamide

585

semisolid from aqueous ethanol in the presence of activated charcoal afforded light yellow crystals of 2-oxo-3-(N,N-diethylcarboxamido)-9,10-dimethoxy1,2,3,4,6,7-hexahydro-11b-H-benzopyridocoline, MP 150°-152°C. Then, as described in US Patent 3,053,845, one hundred grams (0.278 mol) of 2-oxo-3-(N,N-diethylcarboxamido)-9,10-dimethoxy-1,2,3,4,6,7-hexahydro11b-H-benzopyridocoline was dissolved in 1,500 ml of hot methanol and the resulting solution was allowed to cool to room temperature. After removal of all the dissolved oxygen therein by saturation of the solution with dry nitrogen, 5.0 grams of Adams' platinum oxide catalyst was introduced into the system in one portion while still maintaining same under a nitrogen atmosphere. The reaction flask and its contents were then shaken at room temperature under slightly greater than one atmosphere of hydrogen pressure until the total hydrogen uptake was completed. Dissolved hydrogen gas was then removed from the reaction solution by saturation of same with respect to dry nitrogen, while the platinum black was removed by means of gravity filtration. Concentration of the resulting filtrate under reduced pressure on a steam bath then afforded a nearly quantitative yield of 2-hydroxy-3-(N,Ndiethyicarboxamido)-9,10-dimethoxy-1,2,3,4,6,7-hexahydro-11b-Hbenzopyridocoline as a yellow crystalline solid (mixture of the axial and equatorial forms). A mixture consisting of 2 grams of 2-hydroxy-3-(N,N-diethylcarboxamido)9,10-dimethoxy-1,2,3,4,6,7-hexahydro-11 b-H-benzopyridocoline (OH-axial) hydrochloride (prepared by treating the base with hydrogen chloride gas in absolute ether) dissolved in 7 ml of acetic anhydride containing 3 ml of pyridine was heated at 100°C for 2 hours under a nitrogen atmosphere. At the end of this period, a crystalline precipitate had formed and the resultant mixture was subsequently diluted with an equal volume of diethyl ether and filtered. The crystalline hydrochloride salt so obtained, i.e., the solid material collected on the filter funnel, was then converted to the corresponding free base by distribution in 10 ml of a benzene-aqueous 5% sodium carbonate system. The product recovered from the benzene extracts was then recrystallized from diisopropyl ether to afford 1.46 grams of 2-acetoxy-3-(N,Ndiethylcarboxamido)-9,10-dimethoxy-1,2,3,4,6,7-hexahydro-11b-Hbenzopyridocoline (CH3COO-axial), MP 130°-131.5°C. References Merck Index 1125 Kleeman and Engel p.90 PDR p.1523 OCDS Vol.1 p.350 (1977) DOT 11 (1) 11 (1975); 9 (6) 233 (1973) I.N. p. 131 REM p.807 Tretter, J.R.; US Patent 3,053,845; September 11, 1962; assigned to Chas. Pfizer and Co., Inc. Lombardino, J.G. and McLamore, W.M.; US Patent 3,055,894; September 25, 1962; assigned to Chas. Pfizer and Co., Inc.

586

Benzthiazide

BENZTHIAZIDE Therapeutic Function: Diuretic, Antihypertensive Chemical Name: 6-Chloro-3-([(phenylmethyl)thio]methyl)-2H-1,2,4benzothiadiazine-7-sulfonamide 1,1-dioxide Common Name: Structural Formula:

Chemical Abstracts Registry No.: 91-33-8 Trade Name Exna Dytide Diteriam Aquatag Edemex Lemazide Aquapres Aquastat Aquatag Decaserpyl Dihydrex Exosalt Fovane Hydrex Hy-Drine Proaqua Regulon Tensimic Urese

Manufacturer Robins SK and F Roussel Tutag Savage Lemmon Coastal Lemmon Reid-Provident Roussel Astra Bayer Taito Pfizer Trimen Zemmer Reid-Provident Yamanouchi Roussel Pfizer

Country US UK France US US US US US US France Sweden W. Germany Japan US US US Japan France US

Raw Materials 2,4-Disulfamyl-5-chloroaniline Chloroacetaldehyde Benzyl mercaptan Manufacturing Process The preparation of the dihydro analog is as follows:

Year Introduced 1960 1960 1962 1965 1970 1970 -

Benztropine mesylate

587

(A) Preparation of 3-Chloromethyl-6-Chloro-7-Sulfamyl-3,4-DihydroBenzothiadizine-1,1-Dioxide - To 8 ml of 40-50% chloroacetaldehyde aqueous solution and 7 ml of dimethylformamide are added 10 grams of 2,4disulfamyl-5-chloroaniline. The mixture is heated on a steam bath for 2 hours after which it is concentrated at reduced pressure. The residue is triturated with water. The solid material is recrystallized from methanol-ether after treatment with activated carbon to give 7.2 grams of product, MP 229°230°C. (B) Preparation of Benzylthiomethyl-6-Chloro-7-Sulfamyl-3,4Dihydrobenzothiadiazine-1,1-Dioxide - A mixture of 3-(chloromethyl)-6-chloro7-sulfamyl-3,4-dihydrobenzothiadiazine-1,1-dioxide (0.02 mol) and benzylmercaptan (0.024 mol) in 20 ml of 10% sodium hydroxide and 20 ml of dimethylformamide is stirred at room temperature for 6 hours. After heating for 10 minutes on a steam bath, the mixture is cooled and acidified with 6 N HCl. The product, after recrystallization from acetone, melts at 210°-211°C. References Merck Index 1126 Kleeman and Engel p. 90 PDR pp. 1458, 1807 I.N.p. 132 REM p.938 McLamore, W.M. and Laubach, G.D.; US Patent 3,111,517; November 19, 1963; assigned to Chas. Pfizer and Co., Inc.

BENZTROPINE MESYLATE Therapeutic Function: Antiparkinsonian Chemical Name: 3-(Diphenylmethoxy)-8-methyl-8-azabicyclo[3.2.1]octane methanesulfonate Common Name: Tropine benzohydryl ether methanesulfonate; Benzatropine Mesylate; Benztropine methanesulfonate Structural Formula:

Chemical Abstracts Registry No.: 132-17-2

588

Benztropine mesylate

Trade Name Cogentin

Manufacturer Merck Sharp and Dohme

Country US

Year Introduced 1954

Cogentinol Cogentine Cogentin Akitan Bensylate

Astra Merrell Merck-Banyu Farmos ICN

W. Germany France Japan Finland Canada

1966 -

Raw Materials Diphenyldiazomethan Hydrogen bromide Methanesulfonic acid

Tropine Sodium hydroxide

Manufacturing Process Diphenyldiazomethane was prepared by shaking 7.9 grams of benzophenone hydrazone and 8.8 grams of yellow mercuric oxide in petroleum ether, filtering and evaporating off the petroleum ether from the filtrate under reduced pressure. To the residual diphenyldiazomethane 2.83 grams of tropine and 4.5 ml of benzene were added. The mixture was warmed in a pan of hot water at about 85°C under reflux for 24 hours after which time the original purple color had been largely discharged. The reaction mixture was dissolved by adding benzene and water containing hydrochloric acid in excess of the quantity theoretically required to form a salt. A rather large amount of water was required since the tropine benzohydryl ether hydrochloride was not very soluble and tended to separate as a third phase. The aqueous layer was separated, washed with benzene and with ether and made alkaline with an excess of sodium hydroxide. The resulting insoluble oil was extracted with benzene. The benzene extracts were dried over potassium carbonate and evaporated under reduced pressure, leaving a residue of 4.1 grams. The residue (tropine benzohydryl ether) was dissolved in ether and treated with hydrogen bromide gas until an acidic reaction was obtained. The precipitate soon became crystalline and was collected on a filter and dried. The tropine benzohydryl ether hydrobromide weighed 4.1 grams. Recrystallization from absolute ethanol gave 3.3 grams of first crop melting at 247°-248°C (dec.). Twelve grains of tropine benzohydryl ether hydrobromide was converted to the free base by warming with dilute aqueous sodium hydroxide. The oily base was extracted with toluene. The toluene extract was washed with water and then extracted with about 100 ml of water containing 28.1 ml of 1.10 N methanesulfonic acid, (an equimolecular quantity). The toluene solution was extracted twice more with fresh portions of water. The combined water extracts were evaporated under reduced pressure. Residual water was removed by dissolving the residue in absolute ethanol and evaporating under reduced pressure several times. Residual alcohol was then removed by dissolving the residue in acetone and evaporating under reduced pressure several times. The resulting residue was recrystallized by dissolving in acetone and adding ether. The crystalline precipitate was collected on a filter, washed

Benzydamine hydrochloride

589

with ether and dried at 56°C in vacuo. The tropine benzohydryl ether methanesulfonate weighed 10.2 grams, MP 138°-140°C. References Merck Index 1127 Kleeman and Engel p.86 PDR pp.1149, 1606 DOT 18 (2) 91 (1982) I.N.p.127 REM p.928 Phillips, R.F.; US Patent 2,595,405; May 6, 1952; assigned to Merck and Co., Inc.

BENZYDAMINE HYDROCHLORIDE Therapeutic Function: Analgesic, Antiinflammatory, Antipyretic Chemical Name: 1-Propanamine, N,N-dimethyl-3-((1-(phenylmethyl)-1Hindazol-3-yl)oxy)-, monohydrochloride Common Name: Benzidammina; Benzydamine hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 132-69-4; 642-72-8 (Base) Trade Name

Manufacturer

Country

Year Introduced

Tantum

-

-

Afloben

Angelini Pharmaceuticals Esseti

-

-

Afloben

Benedetti SpA

-

-

Andolex

3M Pharma

-

-

Benalgin

Polfa-Pabianice

-

-

Benzyrin

Yoshitomi

-

-

Benzydamine Hydrochloride

Shanghai Lansheng Corporation

-

-

590

Bephenium hydroxynaphthoate

Trade Name Difflam Enzamin Salyzoron Saniflor Saniflor Verax Lonol Lonol

Manufacturer Carnegie Kowa Hishiyama Esseti Benedetti Tosi Promero Boehringer Ingelheim Promeco

Country -

Year Introduced -

Multum

Lampugnani

-

-

Raw Materials Hydrochloric acid Sodium nitrite

Anthranilic acid methyl ester Sodium hydroxide

Manufacturing Process To a solution of 175 g of anthranilic acid methyl ester in 2 L of water and 120 ml of concentrated hydrochloric acid at 25°C was added concentrated solution of 80 g sodium nitrite. The product was dissolved in solution of 500 g NaOH in 1.5 L of water. To this solution under nitrogen was added 400 g of sodium bisulfite. The mixture was stirred for 6 hours at 75°C under nitrogen. The obtained solid product was dissolved in water and then to the solution was added 750 ml glacial acetic acid. The yield of 1-benzyl-3-(3-(dimethylamino) propoxy)-1H-indazole 70%, M.P. 154-156°C. In practice it is usually used as monohydrochloride salt. References Merck Index, Monograph number: 1157, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. Fr. Patent No. 1,382,855; 21.02.1964; Assigned to Aziende Chimiche Riunite Angeloni Francesco, residant en Italie

BEPHENIUM HYDROXYNAPHTHOATE Therapeutic Function: Anthelmintic Chemical Name: N,N-Dimethyl-N-(2-phenoxyethyl)benzenemethanaminium hydroxynaphthoate Common Name: Chemical Abstracts Registry No.: 7181-73-9

Bephenium hydroxynaphthoate

591

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Alcopar

Wellcome

UK

1960

Alcopar

Wellcome

France

1965

Alcopara

Burroughs-Wellcome

US

1967

Alcopar

Wellcome-Tanabe

Japan

-

Raw Materials Chloro-2-phenoxyethane Dimethyl amine

Benzyl chloride 2-Hydroxy-3-naphthoic acid

Manufacturing Process First, dimethylamino-2-phenoxyethanewas made by reacting chloro-2phenoxyethane with dimethylamine. Benzyl chloride (10 grams) was then added to a solution of 1-dimethylamino-2-phenoxyethane (12.3 grams) in acetone (35 ml). The mixture warmed spontaneously and N-benzyl-N,Ndimethyl-N-2-phenoxyethylammonium chloride slowly crystallized. After 24 hours, this solid was filtered off, washed with fresh acetone and dried immediately in vacuo, MP 135°-136°C. 2-Hydroxy-3-naphthoic acid (1.88 grams) was dissolved in hot aqueous sodium hydroxide (0.5N; 20 ml) and the resulting solution was slowly added to a solution of N-benzyl-N,N-dimethyl-N-2-phenoxyethylammonium chloride (2.9 grams) in water (5 ml). A gum separated at first but it solidified on scratching. After the addition was complete, the mixture was allowed to stand at room temperature for 2 hours and then filtered. The residue was washed with water and dried in vacuo to give N-benzyl-N,N-dimethyl-N-2phenoxyethylammonium 2-hydroxy-3-naphthoate, MP 170°-171°C. References Merck Index 1159 Kleeman and Engel p.93 DOT 4 (3) 114 (1968) I.N. p. 134 Copp, F.C.; US Patent 2,918,401; December 22, 1959; assigned to BurroughsWellcome and Co.. Inc.

592

Bepotastine besilate

BEPOTASTINE BESILATE Therapeutic Function: Antiallergic Chemical Name: 1-Piperidinebutanoic acid, 4-((S)-(4-chlorophenyl)-2pyridinylmethoxy)-, monobenzenesulfonate Common Name: Bepotastine besilate; Betotastine besilate Structural Formula:

Chemical Abstracts Registry No.: 190786-44-8; 190786-43-7 (Base) Trade Name

Manufacturer

Country

Year Introduced

Bepotastine besilate Talion

Ube

-

-

TANABE SEIYAKU

-

-

Raw Materials Trioxane Palladium on carbon 4-Toluenesulfonic acid monohydrate Lithium aluminum hydride Magnesium beta-Propiolactone t-Butyldimethylsilyl chloride Pyridine Cerium (III) chloride heptahydrate Dimethyl 3-methyl-2-oxo-hept5-yne-phosphonate

Dicyclohexylcarbodiimide Hydrogen Sodium hydrogen carbonate Thionyl chloride Copper iodide Diazomethane Imidazole Trifluoroacetic acid Sodium methoxide 7-Bromo-3a,8b-cis-3a,8b-dihydro3H-5-cyclopenta[b] benzofurancarboxylic acid

Manufacturing Process Methyl 2-endo-hydroxy-1-exo-hydroxymethyl-3a,8b-cis-2,3,3a,8b-tetrahydro1H-5-cyclopenta[b]benzofurancarboxylate: To a suspension of 4 g of trioxane in 28 ml of acetic acid was added 1.2 ml of concentrated sulfuric acid, and the mixture was heated to 80°C with stirring.

Bepotastine besilate

593

To the solution was added in small portions 2 g of 7-bromo-3a,8b-cis-3a,8bdihydro-3H-5-cyclopenta[b]benzofurancarboxylic acid. After being stirred at 80°C for 14 hours, the reaction mixture was cooled, and the acetic acid was removed under reduced pressure. The residue was subjected to azeotropic operation with toluene two times, and ether was added to the residue. The precipitate derived from trioxane was removed by filtration and washed with ether, and the combined ethereal solutions were concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed with water and aqueous saturated solution of sodium chloride, was dried, and was concentrated to give 4 g of an oily material. The oily material was dissolved in 20 ml of methanol and to the solution was added 20 ml of aqueous 1 N solution of sodium hydroxide, and the mixture was stirred for 14 hours at room temperature. After removal of methanol under reduced pressure, water was added to the mixture, and this solution was acidified to pH 3 with aqueous 2 N hydrochloric acid. The mixture was extracted five times with ethyl acetate, and the ethyl acetate extract was dried and concentrated to give 3.5 g of crude crystals. After addition of ethanol to the crude crystals, the crude crystals were filtered. The filtrate was concentrated, and to the residue was added ethanol and ethyl acetate, and precipitate was collected by filtration. The combined amount of the crude crystals was 1.6 g. After the combined crude crystals were methylated with diazomethane, the reaction product was dissolved in 20 ml of ethyl acetate. To this solution was added 1.5 g of sodium acetate and 300 mg of 10% palladium-carbon, and the mixture was stirred for 2 hours under hydrogen. Then, the reaction product was filtered, and after addition of aqueous saturated solution of sodium hydrogen carbonate to the filtrate, the mixture was extracted two times with ethyl acetate. The extract was washed with an aqueous saturated solution of sodium chloride, dried, and concentrated to give 1.3 g of crude crystals. The crude crystals were recrystallized from ethyl acetate to yield 765 mg of the title compound (melting point 134-135°C, yield 43%). Methyl 3-methyl-trans-4a-cisoid-4a,5a-cis-5a-1,4a,5,5a,10b,10c-hexahydro-7dioxin o[5,4-a]cyclopenta[b]benzofurancarboxylate: To a stirred suspension of 3 g of methyl 2-endo-hydroxy-1-exohydroxymethyl-3a,8b-cis-2,3,3a,8b-tetrahydro-1H-5-cyclopenta[b]benzofurancarboxylate in 30 ml of anhydrous tetrahydrofuran was added 1.5 ml of a solution which is obtained by dissolving 10 ml of 1,1-diethoxyethane and 200 mg of p-toluenesulfonic acid monohydrate into 10 ml of tetrahydrofuran followed by drying over molecular sieves, and the mixture was stirred for 14 hours at 60°C and then cooled. To the reaction mixture was added 100 mg of sodium hydrogen carbonate, and the mixture was stirred for 10 min at room temperature. Then, water was added to the reaction mixture and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed with water and aqueous saturated solution of sodium chloride, was dried, and was concentrated to give 3.5 g of the crude crystals. The crude crystals were recrystallized from benzene-hexane to yield 2 g of the title compound (m.p. 162-163°C). The filtrate was concentrated and the residue was dissolved again in 10 ml of anhydrous tetrahydrofuran. To this solution were added 2.5 ml of 1,1diethoxyethane and 1 ml of the above-mentioned solution of p-toluenesulfonic

594

Bepotastine besilate

acid monohydrate in tetrahydrofuran and the mixture was stirred for 14 hours at 60°C and then cooled. To the reaction mixture was added 100 mg of sodium hydrogen carbonate, and the mixture was stirred for 10 min at a room temperature. After addition of water, the mixture was extracted three times with ethyl acetate. The combined organic layers were washed with water and aqueous saturated solution of sodium chloride, dried, and concentrated to give 1.5 g of crude crystals of methyl 3-methyl-trans-4a-cisoid-4a,5a-cis-5a1,4a,5,5a,10b,10c-hexahydro-7-dioxino[5,4-a]cyclopenta[b]benzofurancarboxylate. The crude crystals were recrystallized from benzene-hexane to yield 740 mg of the title compound (m.p. 154-156°C, yield 83%). 3-Methyl-trans-4a-cosoid-4a,5a-cis-5a-1,4a,5,5a,10b,10c-hexahydro-7dioxino[5,4-a]cyclopenta[b]benzofuranylmethanol: To a suspension of 1 g of lithium aluminum hydride in 10 ml of anhydrous tetrahydrofuran cooled in an ice bath was added dropwise a solution of 1.94 g of methyl 3-methyl-trans-4a-cisoid-4a,5a-cis-5a-1,4a,5,5a,10b,10chexahydro-7-dioxino[5,4-a]cyclopenta[b]benzofurancarboxylate in 40 ml of anhydrous tetrahydrofuran. After being stirred for 30 min at room temperature, the reaction mixture was cooled in an ice bath. The excess of lithium aluminum hydride was decomposed by the addition of ethyl acetate, and aqueous saturated solution of potassium sodium tartarate was added to the reaction mixture. After filtration of the mixture, the filtrate was concentrated and the residue was dissolved in 10 ml of methanol. After addition of 2 g of potassium carbonate to the solution, the mixture was stirred for 3 hours at room temperature and was concentrated. After water was added to the residue, the aqueous mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed with water and saturated aqueous solution of sodium chloride, dried, and concentrated to give 2 g of crude crystals. The crude crystals were recrystallized from ethyl acetatehexane to yield 1.49 g of the pure crystals of the titled compound (m.p. 124125°C, yield; 85%). 7-Chloromethyl-3-methyl-trans-4a-cisoid-4a,5a-cis-5a-1,4a,5,5a,10b,10chexahydrodioxino[5,4-a]cyclopenta[b]benzofuran: To a solution of 1.14 g of 3-methyl-trans-4a-cisoid-4a,5a-cis-5a1,4a,5,5a,10b,10c-hexahydro-7-dioxino[5,4-a]cyclopenta[b]benzofuranylmethanol in 10 ml of dimethoxyethane cooled in an ice bath was added 0.43 ml of anhydrous pyridine and 0.38 ml of thionyl chloride, and the mixture was stirred for 3 hours at room temperature. After addition of ether to the reaction mixture, the precipitate was filtered, and water was added to the filtrate and the mixture was extracted three times with ether. The extract was washed with aqueous saturated solution of copper sulfate, water, aqueous saturated solution of sodium hydrogen carbonate and aqueous saturated solution of sodium chloride, dried, and concentrated to give 1.2 g of crude crystals. The crude crystals were recrystallized from ethyl acetate-hexane to yield 1 g of the pure titled chloride (m.p. 94-95°C, yield; 83%). 4-[3-Methyl-trans-4a-cisoid-4a,5a-cis-5a-1,4a,5,5a,10b,10c-hexahydro-7dioxino[5,4-a]cyclopenta[b]benzofuranyl]butyric acid: A solution of 482 mg of 7-chloromethyl-3-methyl-trans-4a-cisoid-4a,5a-cis5a-1,4a,5,5a,10b,10c-hexahydrodioxino[5,4-a]cyclopenta[b]benzofuran in 5

Bepotastine besilate

595

ml of anhydrous tetrahydrofuran was added dropwise to 84 mg of turnings of metallic magnesium with stirring to prepare a Grignard reagent. To the thus prepared Grignard reagent cooled in an ice bath were added 30 mg of cuprous iodide and 0.1 ml of beta-propiolactone, and the mixture was stirred for one hour. Aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was acidified with 1 N hydrochloric acid to PH 3-4 to decompose the excess of magnesium. The resulting solution was extracted 5 times with ether, and the combined ethereal layers were washed with water and aqueous saturated solution of sodium chloride, dried and concentrated to give 500 mg of crude crystals. The crude crystals were recrystallized from ethyl acetate-hexane to yield 279 mg of the pure crystals of the carboxylic acid (melting point 148-149°C, yield; 54%). Methyl 4-[2-endo-hydroxy-1-exo-hydroxymethyl-3a,8b-cis-2,3,3a,8btetrahydro-1H-5- cyclopenta[b]benzofuranyl]butyrate: To a solution of 390 mg of 4-[3-methyl-trans-4a-cisoid-4a,5a-cis-5a1,4a,5,5a,10b,10c-hexahydro-7-dioxino[5,4-a]cyclopenta[b]benzofuranyl] butyric acid in 5 ml of ethyl acetate cooled in an ice bath was added an excess of an ethereal solution of diazomethane, and after being stirred for 5 min the mixture was concentrated. The resulting oily material was dissolved in 3 ml of methanol, and to the solution was added 1 ml of 1 N hydrochloric acid and the mixture was stirred for 3 hours at room temperature. After concentration of the reaction mixture and addition of 1 ml of water, the mixture was extracted 3 times with each 5 ml of ethyl acetate. The combined layers of ethyl acetate were washed with 3 ml of water and 3 ml of aqueous saturated solution of sodium chloride, dried and concentrated to give 380 mg of crude crystals. The crude crystals were recrystallized from ethyl acetatehexane to yield 200 mg of the pure captioned product (m.p. 56-57°C, yield; 53%). Methyl 4-[2-endo-acetoxy-1-exo-hydroxymethyl-3a,8b-cis-2,3,3a,8btetrahydro-1H-5-cyclopenta[b]benzofuranyl]butyrate: To a solution of 350 mg of methyl 4-[2-endo-hydroxy-1-exo-hydroxymethyl3a,8b-cis-2,3,3a,8b-tetrahydro-1H-5-cyclopenta[b]benzofranyl]butyrate in 3.5 ml of anhydrous dimethylformamide cooled in an ice bath were added 140 mg of imidazole and 360 mg of t-butyldimethylsilyl chloride, and after the mixture was stirred for 3 hours at room temperature, dimethylformamide was removed under reduced pressure. The residue was dissolved in a mixture of 10 ml of acetic anhydride and 5 ml of pyridine. After the mixture was stirred for 2 hours at room temperature, the reaction mixture was concentrated. Then the residual oil was dissolved in 5 ml of acetic acid, and to the solution were added 5 ml of tetrahydrofuran and 2 ml of water. After the mixture was stirred for 14 hours at 50°C and concentrated, the residue was subjected to azeotropic operation two times with toluene. The residue was purified by column chromatography on silica gel using ethyl acetate-cyclohexane (1:2) to give 280 mg of the pure compound (yield; 70%). Methyl ester of 11,15-dideoxy-11-acetoxy-16-methyl-15-oxo-18,19tetradehydro-5,6,7-trinor-4,8-inter-m-phenylene PGI2: In 1.4 ml of a solution of 0.3 ml of pyridine in 10 ml of benzene was dissolved 178 mg of methyl 4-[2-endo-acetoxy-1-exo-hydroxymethyl-3a,8b-cis-

596

Bepotastine besilate

2,3,3a,8b-tetrahydro-1H-5- cyclopenta[b]benzofranyl]butyrate. To the solution were added 0.42 ml of the solution obtained by dissolving 0.14 ml of trifluoroacetic acid in 10 ml of dimethylsulfoxide and 320 mg of dicyclohexylcarbodiimide, and the mixture was stirred for 14 hours at room temperature. The precipitate was filtered and washed well with benzene. The filtrate was washed with water (3x3 ml), dried and concentrated to give 250 mg of crude aldehyde. In the next step, 118 mg of sodium hydride (55% dispersion in mineral oil) was suspended in 20 ml of dimethoxyethane under argon. To the suspension was added a solution of 689 mg of dimethyl 3-methyl-2-oxohept-5-ynephosphonate in 10 ml of dimethylformamide, and the mixture was stirred for 30 min at a room temperature. To the thus prepared mixture was added a solution of 250 mg of the abovementioned crude aldehyde in 5 ml of dimethoxyethane, and the mixture was stirred for 30 min at a room temperature. After neutralization (pH 7) with acetic acid the mixture was concentrated. The residue was dissolved in 10 ml of pentane and ether (1:1), and the precipitate was filtered, and the filtrate was concentrated to give 800 mg of an oily material. The oily material was purified by column-chromatography using ethyl acetate and cyclohexane (1:3) as an eluent to yield 162 mg of the pure captioned product (yield 70%). 11-Deoxy-11-acetoxy-16-methyl-18,19-tetradehydro-5,6,7-trinor-4,8-inter-mphenylene PGI2: To a stirred solution of 122 mg of 11,15-dideoxy-11-acetoxy-16-methyl-15oxo-18,19-tetradehydro-5,6,7-trinor- 4,8-inter-m-phenylene PGI2 in 10 ml of methanol was added 150 mg of cerium chloride heptahydrate, and then the solution was cooled in an ice bath, and 15 mg of sodium borohydride was added to the solution. After 10 min, to the mixture was added 2 ml of aqueous saturated solution of sodium hydrogen carbonate, and the mixture was further stirred for 10 min. After concentration of the reaction mixture, 5 ml of ethyl acetate was added to the residue, and the precipitate was filtered and washed with ethyl acetate (2x2 ml). The combined organic layers were washed with water and aqueous saturated solution of sodium chloride, dried and concentrated to give 130 mg of an oily material. The oily material was purified by column-chromatography on silica gel using ethyl acetate and cyclohexane (1:2) as eluent to give 54 mg of the captioned compound. Methyl ester of 16-methyl-18,19-tetradehydro-5,6,7-trinor-4,8-inter-mphenylene PGI2: To a solution of 54 mg of methyl ester of 11-deoxy-11-acetoxy-16-methyl18,19-tetradehydro-5,6,7-trinor-4,8-inter-m-phenylene PGI2 in 4.5 ml of anhydrous methanol was added 0.001 ml of 4.8 N sodium methoxide under argon, and the reaction mixture was stirred for 1.5 hours at room temperature. After addition of acetic acid to the reaction mixture and concentration of the mixture, the residue was dissolved in 20 ml of ethyl acetate, and the solution

Bepridil

597

was washed with aqueous saturated solution of sodium hydrogen carbonate, water and aqueous saturated solution of sodium chloride, dried and concentrated to afford 55 mg of an oily material. This oily material was purified by column chromatography using ethyl acetate and cyclohexane (3:1) as eluent to give 48 mg of the methyl ester of 16methyl-18,19-tetradehydro-5,6,7-trinor-4,8-inter-m-phenylene PGI2. References EP Appl. 84,856 Ohno Kiyotaka, Nagase Hiroshi, Matsumoto Kazuhisa, Nishio Shintaro; US Patent No. 4,474,802; October 2, 1984 ; Assigned to Toray Industries, Inc. (Tokyo, JP)

BEPRIDIL Therapeutic Function: Antianginal Chemical Name: 1-[2-(N-Benzylanilino)-3-isobutoxypropyl)pyrrolidine Common Name:Structural Formula:

Chemical Abstracts Registry No.: 49571-04-2 Trade Name Cordium Angopril Angopril

Manufacturer Riom Cerm Riom

Country France France France

Year Introduced 1981 -

Raw Materials N-Benzylaniline Sodium amide

1-(3-Isobutoxy-2-hydroxy)propyl pyrrolidine Thionyl chloride

Manufacturing Process The first step involves the preparation of 1-(3-isobutoxy-2-chloro)propyl

598

Bermoprofen

pyrrolidine as an intermediate. 345 ml of thionyl chloride dissolved in 345 ml of chloroform are added, drop by drop, to 275 g of 1-(3-isobutoxy-2hydroxy)propyl pyrrolidine dissolved in 350 ml of chloroform, while maintaining the temperature at approximately 45°. The reaction mixture is heated to reflux until gas is no longer evolved. The chloroform and the excess of thionyl chloride are removed under reduced pressure. The residue is poured on to 400 g of crushed ice. The reaction mixture is rendered alkaline with soda and the resulting mixture is extracted twice with 250 ml of diethyl ether. The combined ethereal extracts are dried over anhydrous sodium sulfate. After evaporation of the solvent the residue is distilled under reduced pressure. 220 g of product are obtained having the following properties: boiling point = 96°C/3 mm, nD24 = 1.4575. The final product is prepared as follows. 23.4 g of sodium amide is added little by little to a solution of 92 g of N-benzylaniline in 500 ml of anhydrous xylene. The reaction mixture is then heated at 130°-135°C for 6 hours. While maintaining the temperature at 110°C, 110 g of the product of the first step dissolved in 150 ml of xylene is added and the product heated for 6 hours at 120°C. The product having been allowed to cool to ambient temperature, 200 ml of cold water are added. The organic phase is separated and extracted with an aqueous solution of hydrochloric acid. After twice washing with 100 ml of diethyl ether, the aqueous phase is made alkaline with 50% caustic soda solution. The liberated base is twice extracted with 150 ml of diethyl ether. After the ether has been evaporated, the residue is distilled under reduced pressure and has a boiling point of 184°C/0.1 mm, nD20 = 1.5538. 77 g of the pure base in the form of a viscous liquid is thus obtained. The hydrochloride, which is prepared in conventional manner, has a melting point of 128°C. References Merck Index 1160 DFU 2 (11) 713 (1977) Kleeman and Engel p.93 OCDS Vol. 3 p. 46 (1984) DOT 18 (9) 422 (1982) I.N.p. 135 Mauvernay, R.Y., Busch, N., Moleyre, J., Monteil, A. and Simond, J.; US Patent 3,962,238; June 8,1976; assigned to Centre Europeen de Recherches Mauvernay "CERM"

BERMOPROFEN Therapeutic Function: Antiinflammatory, Antipyretic

Besipirdine hydrochloride

599

Chemical Name: 10,11-Dihydro-α,8-dimethyl-11-oxodibenz[b,f]oxepin-2acetic acid Common Name: Bermoprofen Structural Formula:

Chemical Abstracts Registry No.: 78499-27-1 Trade Name

Manufacturer

Country

Year Introduced

Bermoprofen

ZYF Pharm Chemical

-

-

Raw Materials DL-2-[4-(2'-Carboxymethyl-4'-methylphenoxy)phenyl]propionic acid Polyphosphoric acid Manufacturing Process A mixture of dl-2-[4-(2'-carboxymethyl-4'-methylphenoxy)phenyl]propionic acid (15.3 g) and polyphosphoric acid (92 g) was heated with stirring at 110120°C for 2 hours. To the reaction mixture was added water and the resulting mixture was extracted with chloroform. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated. The residue was chromatographed on silica gel (75 g) using chloroform as an eluent to give a crude product, which was recrystallized from toluene to give the dl-2-(8methyl-10,11-dihydro-11-oxodibenz[b,f]oxepin-2-yl)propionic acid (9.4 g, 65.3%), m.p. 128-129°C. References EP Appl. 3,893; Uno Hitoshi, Nagai Yasutaka, Nakamura Hideo; US Patent No. 4,238,620; Dec. 9, 1980; Assigned to Dainippon Pharmaceutical Co., Ltd. (Osaka, JP)

BESIPIRDINE HYDROCHLORIDE Therapeutic Function: Cognition activator Chemical Name: 1H-Indol-1-amine, N-propyl-N-4-pyridinyl-, monohydrochloride

600

Besipirdine hydrochloride

Common Name: Besipirdine Structural Formula:

Chemical Abstracts Registry No.: 130953-69-4 Trade Name

Manufacturer

Country

Year Introduced

Besipirdine hydrochloride

Hoechst-Roussel Pharmaceuticals, Inc.

-

-

Besipirdine hydrochloride

Aventis Pharmaceuticals, Inc.

-

-

Raw Materials N-(4-Pyridinyl)-1H-indol-1-amine 1-Bromopropane Hydrochloric acid

Sodium hydride Maleic acid

Manufacturing Process Part A: N-Propyl-N-(4-pyridinyl)-1H-indol-1-amine maleate: A solution of N-(4-pyridinyl)-1H-indol-1-amine (6 g) in 25 ml of dimethylformamide was slowly added to an ice-cooled suspension of NaH (1.3 g of 60% NaH dispersion in mineral oil was washed with hexanes, the liquid was decanted and the residual solid was dispersed in 5 ml of dimethylformamide). After anion formation, a solution of 1-bromopropane (4 g) in 5 ml of dimethylformamide was added. After one hour of stirring at ambient temperature, the reaction mixture was stirred with ice-water and extracted with dichloromethane. The organic extract was washed with water and saturated sodium chloride solution, was dried over anhydrous magnesium sulfate, filtered and concentrated to 8 g of oil. This oil was purified by HPLC (silica, ethyl acetate) and thereafter by column chromatography (alumina, ether) to give 6.4 g oil. This oil was converted to the maleate salt and recrystallized from methanol/ether to give 6.8 g of crystals, m.p. 115-116°C. Part B: N-Propyl-N-(4-pyridinyl)-1H-indol-1-amine hydrochloride: N-Propyl-N-(4-pyridinyl)-1H-indol-1-amine maleate was converted to the free base by action of alcaline agent. Then the free base oil was converted to the hydrochloride salt which was recrystallized from methanol; m.p. 212-214°C.

Betaine aspartate sodium

601

References Effland R.C., Klein J. T., Davis Larry Olsen, Gordon E.; US Patent No. 4,970,218; November 13, 1990; Hoechst-Roussel Pharmaceuticals Inc. (Somerville, NJ) Kongsamut S., Smith C. P., Woods A. T.; US Patent No. 5,356,910; October 18, 1994; Assigned to Hoechst-Roussel Pharmaceuticals Inc. (Somerville, NJ) Klein J.T., L. Davis, G.E. Olsen, G.S. Wong, M. Cornfeldt, F.P. Huger, C.P. Smith, W.W. Petko, J.C. Wilker, R.D. Blitzer, E. Landau, V. Hartoutunian, L.L. Martin and R.C. Effland. Synthesis and structure-activity relationships of N-propyl-N-(4-pyridinyl)-

BETAINE ASPARTATE SODIUM Therapeutic Function: Hepatoprotectant Chemical Name: L-aspartic acid, ion (1-), 1-carboxy-N,N,N-trimethylaminium sodium salt Common Name: Somatyl Structural Formula:

Chemical Abstracts Registry No.: 52921-08-1 Trade Name

Manufacturer

Country

Year Introduced

Somatyl

TEOFARMA Srl

-

-

Somatyl

Anphar-Rolland

-

-

Raw Materials Betaine L-Aspartic acid Manufacturing Process Betaine aspartate was prepared from betaine and L-aspartic acid (molar ratio 1:1) in aqueous solution at pH 5.7-5.0.

602

Betamethasone

In practice it is usually used as sodium salt. References Cote M.R.; FR Patent No. 1,356,945, Dec. 14, 1961 FR-M 2,462, Oct. 9, 1962

BETAMETHASONE Therapeutic Function: Glucocorticoid Chemical Name: 9-Fluoro-11β,17,21-trihydroxy-16β-methylpregna-1,4diene-3,20-dione Common Name: Structural Formula:

Chemical Abstracts Registry No.: 378-44-9 Trade Name

Manufacturer

Country

Year Introduced

Celestone

Schering

US

1961

Becort

Rachelle

US

-

Betacortil

Pfizer

US

-

Betalone

Firma

Italy

-

Betamamallet

Showa

Japan

-

Betapred

Glaxo

UK

-

Betasolon

Pharmax

Italy

-

Betnelan

Glaxo

UK

-

Betnesail

Glaxo

UK

-

Betnesol

Glaxo

UK

-

Celestan

Aesca

Austria

-

Celestene

Cetrane

France

-

Celestone

Essex

Spain

-

Cuantin

I.C.N.

Canada

-

Betamethasone acetate

603

Trade Name

Manufacturer

Country

Year Introduced

Dermovaleas

Valeas

Italy

-

Desacort-Beta

Caber

Italy

-

Diprosone

Byk-Essex

W. Germany

-

Diprosone

Unilabo

France

-

Diprostene

Centrane

France

-

Hormezone

Tobishi

Italy

-

Linosal

Wakamoto

Japan

-

Minisone

IDI

Japan

-

No-Rheumar

Janus

Italy

-

Pertene Vita

Vita

Italy

-

Rinderon

Shionogi

Japan

-

Sanbetason

Santen

Japan

-

Sclane

Promesa

Spain

-

Unicort

Unipharm

Israel

-

Valisone

Schering

US

-

Raw Materials Betamethasone acetate Hydrogen chloride Manufacturing Process Betamethasone acetate is converted to betamethasone by means of hydrochloric acid in a methanol-chloroform-water mixture as described in US Patent 3,164,618. References Merck Index 1196 Kleeman and Engel p.95 PDR p.1610 OCDS Vol.1 p.198 (1977) I.N. p.137 REM p.962 Amiard, G., Torelli, V. and Cerede, J.; US Patent 3,104,246; September 17, 1963; assigned to Roussei-UCLAF, SA, France Rausser, R. and Oliveto, E.P.; US Patent 3,164,618; January 5, 1965; assigned to Schering Corporation

BETAMETHASONE ACETATE Therapeutic Function: Glucocorticoid

604

Betamethasone acetate

Chemical Name: 9-Fluoro-11β,17,21-trihydroxy-16β-methylpregna-1,4diene-3,20-dione-21-acetate Common Name: Structural Formula:

Chemical Abstracts Registry No.: 987-24-6 Trade Name

Manufacturer

Country

Year Introduced

Celestone Soluspan

Schering

US

1965

Betafluorene

Lepetit

France

-

Celestone Cronodose

Essex

Italy

-

Raw Materials 17β,21-Dihydroxy-16β-methyl-4,9(11)-pregnadiene-3,20-dione 21acetate N-Bromosuccinimide Sodium methoxide Hydrogen fluoride Perchloric acid Acetic anhydride Selenium dioxide Manufacturing Process The synthesis is long and complex. For brevity, only the last steps are given here. Refer to the patents cited below for full details. Preparation of 9α-Bromo-11β,17α,21-Trihydroxy-16β-Methyl-4-Pregnene-3,20Dione 21-Acetate: To a mixture of 620 mg of 17α,21-dihydroxy-16β-methyl4,9(11)-pregnadiene-3,20-dione 21-acetate and 330 mg of Nbromosuccinimide in 10 ml of dioxane and 3.2 ml of water cooled to 10°C was added 1.8 ml of cold 1 M aqueous perchloric acid. The mixture was stirred at 15°C for 3 hours. Excess N-bromosuccinimide was destroyed by addition of aqueous sodium thiosulfate and most of the dioxane was removed in vacuo. About 30 ml of water was added and crystalline bromohydrin, 9α-bromo11β,17α,21-trihydroxy-16β-methyl-4-pregnene-3,20-dione 21-acetate, was

Betamethasone adamantoate

605

filtered, washed with water, and dried in air. Preparation of 9β,11β-Epoxy-17α-21-Dihydroxy-16β-Methyl-4-Pregnene-3,20Dione 21-Acetate: To a stirred solution of 100 mg of the 9α-bromo11β,17α,21-trihydroxy-16β-methyl-4-pregnene-3,20-dione 21-acetate in 3 ml of tetrahydrofuran and 1 ml of methanol under nitrogen was added 1.02 ml of 0.215N methanolic sodium methoxide. After 10 minutes at 25°C, 0.2 ml of acetic acid was added and the methanol removed in vacuo. The residue was acetylated with 1.00 ml of pyridine and 0.5 ml of acetic anhydride at 60°C for 70 minutes. The mixture was taken to dryness in vacuo, water added, and the product extracted into chloroform. The residue was crystallized from etheracetone to give pure 9β,11β-epoxy-17α,21-dihydroxy-16β-methyl-4-pregnene3,20-dione 21-acetate. Preparation of 9α-Fluoro-11β,17α,21-Trihydroxy-16β-Methyl-4-Pregnene-3,20Dione 21-Acetate: To a solution of 200 mg of 9β,11β-epoxy-17α,21-dihydroxy16β-methyl-4-pregnene-3,20-dione 21-acetate in 2 ml of chloroform and 2 ml of tetrahydrofuran in a polyethylene bottle at -60°C was added 2 ml of a 2:1 (by weight) mixture of anhydrous hydrogen fluoride and tetrahydrofuran. After 4 hours at -10°C the mixture was cooled to -60°C and cautiously added to a stirred mixture of 30 ml or 25% aqueous potassium carbonate and 25 ml of chloroform kept at -5°C. The aqueous phase was further extracted with chloroform and the latter phase washed with water and dried over magnesium sulfate. The residue on crystallization from acetone-ether gave pure 9α-fluoro11β,17α,21-trihydroxy-16β-methyl-4-pregnene-3,20-dione 21-acetate. Preparation of 9α-Fluoro-11β,17α,21-Trihydroxy-16β-Methyl-4-Pregnadiene3,20-Dione 21-Acetate 100 mg of 9α-fluoro-11β,17α,21-trihydroxy-16βmethyl-4-pregnene-3,20-dione 21-acetate was treated with selenium dioxide to produce the corresponding 9α-fluoro-11β,17α,21-trihydroxy-16β-methyl-4pregnadiene-3,20-dione 21-acetate. Alternately, Bacillus sphaericus may be utilized. References Merck Index 1196 Kleeman and Engel p.97 PDR p.1612 I.N. p.137 REM p.963 Taub, D., Wendler, N.L. and Slates, H.L.; US Patent 3,053,865; September 11, 1962; assigned to Merck and Co., Inc. Rausser, R. and Oliveto, E.P.; US Patent 3,164,618; January 5, 1965; assigned to Schering Corporation.

BETAMETHASONE ADAMANTOATE Therapeutic Function: Glucocorticoid Chemical Name: 9-Fluoro-11β,17-dihydroxy-16β-methylpregna-1,4-diene3,20-dione 21-(tricyclo(3.3.1.13,7)dec-1-ylformate)

606

Betamethasone adamantoate

Common Name: Betamethasone adamantoate Structural Formula:

Chemical Abstracts Registry No.: 40242-27-1 Trade Name

Manufacturer

Country

Year Introduced

Betamethasone Adamantoate

Zhejiang Xianju Pharmaceutical Co., Ltd.

-

-

Raw Materials Betamethasone Trifluorcacetic anhydride Pyridine

Adamantane carboxylic acid Sodium bicarbonate Triethylamine adamantane carbonyl chloride

Manufacturing Process 3 Methods of producing of betamethasone 21-adamantane-1'-carboxylate: 1. A suspension of betamethasone (740.0 mg) in dioxan (20 ml) was treated with adamantane carboxylic acid (1.96 g) and trifluorcacetic anhydride (0.75 ml). The mixture was stirred at room temperature for 23 h during which time the steroid completely dissolved. Addition of sodium bicarbonate (2.0 g) and water gave a waxy semi-solid which was separated from the supernatant liquid by decantation. Water and a little methanol were added to the solid and the resulting granular material was removed by filtration and washed well with water. Fractional crystallization from methanol afforded adamantane carboxylic anhydride as the less soluble component and betamethasone 21-adamantane1'-carboxylate as the more soluble component. 2. 9α-Fluoro-11β,17-dihydroxy-21-iodo-16β-methylpregna-1,4-diene-3,20dione (76.65 g) was dissolved in warm acetone (400 ml) and then adamantanecarboxylic acid (54.0 g) and triethylamine (52.5 ml) was added and washed in with more acetone (100 ml). The solution was refluxed for 1 h and then poured with good stirring into cold water (2.5 L). Filtration of the precipitated material and recrystallisation from aqueous methanol with charcoaling afforded betamethasone 21-admantane-1'-carboxylate showing extensive melting 245°-250°C.

Betamethasone benzoate

607

3. A solution of betamethasone (1.0 g) in dry tetrahydrofuran (40 ml) was treated with adamantane carbonyl chloride (about 2.2 equivalents) in dry tetrahydrofuran (5 ml) and then pyridine (0.8 ml) was added. The mixture was refluxed for 6 h and then most of the solvent was boiled off and the residue extracted with chloroform to afford a froth. The ether soluble portion of this froth was dissolved in chloroform and extracted repeatedly with dilute sodium bicarbonate solution. Evaporation of the chloroform layer gave a froth which was further purified by chromatography and crystallisation from chloroform-petroleum ether to yield betamethasone 21-adamantane-1'carboxylate melting point 256°-259°C (dec.). References Phillipps G.H., English A.F.; GB Patent No. 1,391,443; July 5, 1971; Assigned: Glaxo Laboratories Limited, a British Company, of Greenford, Middlesex

BETAMETHASONE BENZOATE Therapeutic Function: Glucocorticoid Chemical Name: 9-Fluoro-11β,17,21-trihydroxy-16β-methylpregna-1,4diene-3,20-dione-17-benzoate Common Name: Structural Formula:

Chemical Abstracts Registry No.: 22298-29-9 Trade Name

Manufacturer

Country

Year Introduced

Benisone

Warner Lambert

US

1973

Flurobate Gel

Texas Pharm

US

1973

Beben

Parke Davis

Italy

1974

Uticort Gel

Warner Lambert

US

1977

608

Betamethasone dihydrogen phosphate

Trade Name

Manufacturer

Country

Year Introduced

Benisone

Cooper Vision

US

1979

Bebate

Warner

UK

-

Beben

Vister

Italy

-

Dermizol

Roux-Ocefa

Argentina

-

Euvaderm

Sasse

W. Germany

-

Parbetan

Parke Davis

W. Germany

-

Skincort

Parke Davis

W. Germany

-

Uticort

Parke Davis

US

-

Raw Materials Betamethasone Methyl orthobenzoate Manufacturing Process A mixture of 50 g of betamethasone, 50 cc of dimethylformamide, 50 cc of methyl orthobenzoate and 1.5 g of p-toluenesulfonic acid is heated for 24 hours on oil bath at 105°C while a slow stream of nitrogen is passed through the mixture and the methanol produced as a byproduct of the reaction is distilled off. After addition of 2 cc of pyridine to neutralize the acid catalyst the solvent and the excess of methyl orthobenzoate are almost completely eliminated under vacuum at moderate temperature. The residue is chromatographed on a column of 1,500 g of neutral aluminum oxide. By elution with ether-petroleum ether 30 g of a crystalline mixture are obtained consisting of the epimeric mixture of 17α,21-methyl orthobenzoates. This mixture is dissolved without further purification, in 600 cc of methanol and 240 cc of methanol and 240 cc of aqueous 2N oxalic acid are added to the solution. The reaction mixture is heated at 40°-50°C on water bath, then concentrated under vacuum, The residue, crystallized from acetone-ether, gives betamethasone 17-benzoate, MP 225°-231°C. References Merck Index 1196 Kleeman and Engel p.98 PDR p.1393 DOT 10 (1) 9 (1974) I.N. p. 137 Ercoli, A. and Gardi, R.; US Patent 3,529,060; September 15, 1970; assigned to Warner-Lambert Pharmaceutical Co.

BETAMETHASONE DIHYDROGEN PHOSPHATE Therapeutic Function: Glucocorticoid

Betamethasone dihydrogen phosphate

609

Chemical Name: Pregna-1,4-diene-3,20-dione, 9-fluoro-11,17-dihydroxy-16methyl-21-(phosphonooxy)-, (11βa,16β)-, disodium salt Common Name: Bentelan; Betnesol; Celestan; Durabetason; VistaMethasone Structural Formula:

Chemical Abstracts Registry No.: 360-63-4 Trade Name

Manufacturer

Country

Year Introduced

Bentelan

Biofutura

-

-

Bentelan

Glaxo Wellcome

-

-

Celestan solubile

Essex

-

-

Raw Materials Bistriethylamine phosphate Phosphoric acid Silver phosphate Triethylamine Hydrogen chloride 9α-Fluoro-11β,17α,21-trihydroxy-16α-methyl-1,4-pregnadiene-3,20-dione 21-methanesulfonate Manufacturing Process A solution of bistriethylamine phosphate was prepared by slowly adding 2.36 ml of 85% phosphoric acid to 20 ml of acetonitrile containing 9.9 ml, of triethylamine at 20°C. This solution was added to a stirred mixture of 4.70 g of 9α-fluoro-11β,17α,21-trihydroxy-16α-methyl-1,4-pregnadiene-3,20-dione 21-methanesulfonate and 20 ml of acetonitrile. The mixture was heated under reflux for 4 h and then evaporated under reduced pressure to a volume of 12 ml. This mixture was a concentrated solution of 9α-fluoro-11β,17α,21trihydroxy-16α-methyl-1,4-pregnadiene-3,20-dione 21-phosphate triethylamine salt with some inorganic phosphate. The salt of 9α-fluoro-11β,17α,21-trihydroxy-16α-methyl-1,4-pregnadiene3,20-dione 21-phosphate may be converted to 9α-fluoro-11β,17α,21trihydroxy-16α-methyl-1,4-pregnadiene-3,20-dione 21-phosphate by treatment with acid (for example HCl).

610

Betamethasone dipropionate

References Metuchen J.M. Ch. et al.; US Patent No. 2,939,873; June 7, 1960; Assigned: Merck and Co., Inc., Rahway, N.J., a corporation of New Jersey

BETAMETHASONE DIPROPIONATE Therapeutic Function: Glucocorticoid Chemical Name: Pregna-1,4-diene-3,20-dione, 9-fluoro-11β,17,21trihydroxy-16β-methyl-, 17,21-dipropionate Common Name: Structural Formula:

Chemical Abstracts Registry No.: 5593-20-4 Trade Name

Manufacturer

Country

Year Introduced

Betnovate

Glaxo

UK

1961

Bentelan

Glaxo

Italy

1962

Betnesol

Glaxo

France

1963

Betnesol

Glaxo

W. Germany

1965

Diprosone

Schering

US

1975

Rinderon DP

Shionogi

Japan

1980

Diprolene

Schering

US

1983

Alphatrex

Savage

US

-

Beloderm

Belupo Ltd.

Yugoslavia

-

Diproderm

Essex Espana

Spain

-

Diproderm

Aesca

Austria

-

Diproderm

Schering

US

-

Diprogenta

Byk-Essex

W. Germany

-

Diprosalic

Unilabo

France

-

Betamethasone valerate

611

Trade Name

Manufacturer

Country

Year Introduced

Diprosalic

Schering

UK

-

Diprostene

Cetrane

France

-

Lortisone

Schering

US

-

Vanceril

Schering

US

-

Raw Materials 9α-Fluoro-11β-hydroxy-16β-methyl-17α,21-(1'-ethyl-1'-ethoxymethylenedioxy)pregna-1,4-diene-32,0-dione Acetic acid Propionyl chloride Manufacturing Process A solution of 9α-fluoro-11β-hydroxy-16β-methyl-17α,21-(1'-ethyl-1'ethoxymethylenedioxy)pregna-1,4-diene-3,20-dione (538 mg) in acetic acid (20 ml), containing 2 drops of water, was allowed to stand at room temperature for 5 hours. Dilution of the mixture with water gave a white solid (457 mg) which, after being filtered off and dried, was recrystallized from acetone to afford 9α-fluoro-11β,21-dihydroxy-16β-methyl-17αpropionyloxypregna-1,4-diene-3, 20-dione (361 mg), MP 230°-235°C. Bethmethasone 17-propionate (812 mg) in pyridine (10 ml) was treated with propionyl chloride (0.21 ml) at 0°C for 1 hour. Dilution with water and acidification with dilute hydrochloric acid gave the crude diester. Recrystallization from acetone-petroleum ether afforded betamethasone 17,21-dipropionate (649 mg), MP 117°C (decomposition). References Merck Index 1196 Kleeman and Engel p.99 PDR pp.888, 1429, 1601, 1614, 1631 I.N. p.138 Elks, J., May, P.J. and Weir, N.G.; US Patent 3,312,590; April 4, 1967; assigned to Glaxo Laboratories, Ltd.

BETAMETHASONE VALERATE Therapeutic Function: Corticosteroid Chemical Name: 9-Fluoro-11β,17,21-trihydroxy-16β-methylpregna-1,4diene-3,20-dione-17-valerate Common Name: Chemical Abstracts Registry No.: 33755-46-3; 38196-44-0 (Divalerate)

612

Betamethasone valerate

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Valisone

Schering

US

1967

Beta Dival

Fardeco

Italy

1978

Beta Val

Lemmon

US

1980

Cordel

Taisho

Japan

1981

Betatrex

Savage

US

1983

Betacort

ICN

Canada

-

Betacorten

Trima

Israel

-

Betaderm

K-Line

Canada

-

Betnesol

Glaxo

W. Germany

-

Betnelan

Glaxo

UK

-

Betnevate

Daiichi

Japan

-

Celestan

Schering

W. Germany

-

Celestoderm

Cetrane

France

-

Celestoderm

Essex Espana

Spain

-

Dermosol

Iwaki

Japan

-

Dermovaleas

Valeas

Italy

-

Ecoval

Glaxo

Italy

-

Metaderm

Riva

Canada

-

Muhibeta

Nippon Shoji

Japan

-

Novobetamet

Novopharm

Canada

-

Procto-Celestan

Byk-Essex

W. Germany

-

Recto-Betnesol

Glaxo

W. Germany

-

Retenema

Glaxo

UK

-

Rinderon

Shionogi

Japan

-

Rolazote

Lando

Argentina

-

Stranoval

Glaxo

Italy

-

Raw Materials Betamethasone Methyl orthovalerate

Betanidine sulfate

613

Manufacturing Process The valerate is made from betamethasone as a starting material as follows: A suspension of 9α-fluoro-11β,17α,21-trihydroxy-16β-methylpregna-1,4-diene3,20-dione(betamethasone) (2 grams) in sodium dried benzene (500 ml) was distilled vigorously for a few minutes, toluene-p-sulfonic acid monohydrate (30 mg) and methyl orthovalerate (5 ml) were added and distillation was continued for 10 minutes. The mixture was then boiled under reflux for 1.5 hours after which time unreacted betamethasone alcohol (400 mg) was removed by filtration. The benzene solution was treated with solid sodium .bicarbonate and a few drops of pyridine, filtered and evaporated to dryness at about 50°C. The residue, in ether, was filtered through grade III basic alumina (20grams) to remove traces of unreacted betamethasone alcohol, the ether removed in vacuo and the residue of crude betamethasone 17,21methyl orthovalerate was treated with acetic acid (20ml) and a few drops of water and left overnight at room temperature. The acetic acid solution was poured into water (100 ml) and extracted with chloroform. The chloroform extracts were washed in turn with water, saturated sodium bicarbonate solution and water, dried and evaporated in vacuo. The residual gum was triturated with ether and a white crystalline solid (1.16 grams) isolated by filtration. Recrystallization from ether (containing a small amount of acetone)-petroleum ether gave 9α-fluoro-11β,21-dihydroxy-16βmethyl-17α-valeryloxypregna-1,4-diene-3,20-dione (871 mg) as fine needles. References Merck Index 1196 Kleeman and Engel p.101 PDR pp.888, 1034, 1428, 1602, 1658 I.N. p.138 REM p. 963 Elks, J., May, P.J. and Weir, N.G.; US Patent 3,312,590; April 4, 1967; assigned to Glaxo Laboratories Limited, England

BETANIDINE SULFATE Therapeutic Function: Antihypertensive Chemical Name: Guanidine, 1-benzyl-2,3-dimethyl-, sulfate (2:1) Common Name: Betanidine sulfate; Bethanidine sulfate; Regulin Chemical Abstracts Registry No.: 55-73-2 (Base); 114-85-2 Raw Materials 2-Bromobenzylamine S-Methylthiouronium sulfate

614

Betaxolol hydrochloride

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Bendogen

Lagap Pharmaceuticals SA

-

-

Benzoxine

Plant Products

-

-

Bethanidine sulfate

Robins AH

-

-

Regulin

Gea

-

-

Regulin

Medica

-

-

Regulin

Nyco

-

-

Tenathan

Robins AH

-

-

Manufacturing Process A mixture of 2-bromobenzylamine (12.5 g) and S-methylthiouronium sulfate (10 g) in water (20 ml) was heated for 1.5 hours on a steam bath in a hood, during which methylmercaptan escaped (as evidenced by a foul odour). The reaction mixture was then cooled and diluted with ethanol (100 ml). A colourless solid of 2-bromobenzylguanidine sulfate was separeted, and washed with ethanol. This solid melted at 230-232°C; it was recrystallized from water and then melted at 247-248°C. By action of a basic agent the salt obtained may be converted into free base. References Walton E., Ruffell G.K.; GB Patent No. 973,882; Dec. 15, 1960; Assigned to the Wellcome Foundation Ltd., London

BETAXOLOL HYDROCHLORIDE Therapeutic Function: Beta-adrenergic blocker Chemical Name: 1-[4-[2-(Cyclopropylmethoxy)ethyl]phenoxy]-3-[(1methylethyl)amino]-2-propanol hydrochloride Common Name: -

Betaxolol hydrochloride

615

Structural Formula:

Chemical Abstracts Registry No.: 63659-18-7 Trade Name Kerlone Kerlon

Manufacturer Carriere Kramer

Country France Switz.

Year Introduced 1983 1983

Raw Materials Sodium hydroxide Hydrogen chloride Isopropylamine

4-[2-(Cyclopropylmethoxy)ethyl]phenol Epichlorohydrin

Manufacturing Process (1) 1 g of sodium hydroxide pellets (0.025 mol) is added to a suspension of 3.8 g of 4-[2-(cyclopropylmethoxy)-ethyl]-phenol in 30 ml of water. When the solution becomes homogenous, 2.3 ml of epichlorohydrin are added and the mixture is stirred for 8 hours. It is then extracted with ether and the extract is washed with water, dried over sodium sulfate and evaporated to dryness. The compound is purified by passing it over a silica column. 2.4 g of 1-[4-[2(cyclopropylmethoxy)ethyl]-phenoxy]-2,3-epoxy-propane are thus obtained. (2) 4.9 g of the preceding compound (0.02 mol) are condensed with 25 ml of isopropylamine by contact for 8 hours at ambient temperature and then by heating for 48 hours at the reflux temperature. After evaporation to dryness, the compound obtained is crystallized from petroleum ether. 5 g (yield 80%) of 2-[[4-(2-cyclopropylmethoxy)-ethyl]-phenoxy]-3-isopropylaminopropan-2-ol are thus obtained, melting point 70° to 72°C. The hydrochloride is prepared by dissolving the base in the minimum amount of acetone and adding a solution of hydrochloric acid in ether until the pH is acid. The hydrochloride which has precipitated is filtered off and is recrystallized twice from acetone, melting point 116°C. References Merck Index 1197 DFU 4 (12) 867 (1979) DOT 18 (10) 552 (1982) Manoury P.M.J., Cavero, I.A.G., Majer, H. and Guidicelli, D.P.R.L.; US Patent 4,252,984; February 24, 1981; assigned to Synthelabo

616

Betazole

BETAZOLE Therapeutic Function: Diagnostic aid (gastric secretion) Chemical Name: 1H-Pyrazole-3-ethanamine Common Name: β-Aminoethyipyrazole; Ametazole Structural Formula:

Chemical Abstracts Registry No.: 105-20-4; 138-92-1 (Dihydrochloride salt) Trade Name Histalog Betazol Histimin

Manufacturer Lilly Lilly Shionogi

Country US W. Germany Japan

Year Introduced 1953 -

Raw Materials γ-Pyrone Hydrazine hydrate Hydrogen Manufacturing Process A solution of 55 grams (1.1 mol) of hydrazine hydrate in 100 ml of methanol was cooled in a water bath and stirred while a solution of 48 grams (0.50 mol) of pure γ-pyrone in 100 ml of methanol was added over a period of about 15 minutes. After the addition was complete, the solution was allowed to stand at room temperature for about 1 hour, and was placed in a 1 liter hydrogenation bomb. 25 ml of liquid ammonia were added cautiously with stirring, followed by about 15 cc of Raney nickel catalyst. The bomb was charged with hydrogen to 1,800 pounds pressure, heated to 90°C and agitated. The quantity of hydrogen required to convert the hydrazone into the desired aminoethylpyrazole was taken up in about 3 hours. The bomb was cooled and opened, and the contents filtered. The filtrate was evaporated under reduced pressure to remove the methanol and the residual liquid was distilled under reduced pressure, whereby there were obtained 44.5 grams (81% yield) of 3-β-aminoethylpyrazole boiling at 118°-123°C at a pressure of 0.5 mm of Hg.

Bethanechol chloride

617

References Merck Index 1198 Kleeman and Engel p.102 I.N. p.139 REM p.1124 Jones, R.G.; US Patent 2,785,177; March 12, 1957; assigned to Eli Lilly and Company

BETHANECHOL CHLORIDE Therapeutic Function: Cholinergic Chemical Name: 2-[(Aminocarbonyl)oxyl-N,N,N-trimethyl-1-propanamium chloride Common Name: Carbamylmethylcholine chloride Structural Formula:

Chemical Abstracts Registry No.: 590-63-3 Trade Name

Manufacturer

Country

Year Introduced

Urecholine CI

MSD

US

1949

Urecholine CI

MSD

Switz.

-

Duvoid

Norwich Eaton

US

1978

Besacolin

Elsai

Japan

-

Bethachorol

Nichiiko

Japan

-

Mechothane

Farillon

UK

-

Mictone

Kenyon

US

-

Mictrol

Misemer

US

-

Mycholine

Glenwood

US

-

Myo Hermes

Hermes

Spain

-

Myotonachol

Glenwood

US

-

Myotonine

Glenwood

UK

-

Paracholin

Kanto

Japan

-

Perista

Nissin

Japan

-

Urocarb

Hamilton

Australia

-

Urolax

Century

US

-

618

Bevantolol hydrochloride

Raw Materials β-Methylcholine Chloride Phosgene Ammonia Manufacturing Process About 3 grams of β-methylcholine chloride are stirred at room temperature with an excess of phosgene dissolved in 50 grams of chloroform, for about 2 hours. Excess phosgene and hydrochloric acid are removed by distillation under vacuo. Additional chloroform is added to the syrup and the mixture is poured into excess ammonia dissolved in chloroform and cooled in solid carbon dioxide-acetone. The solid is filtered and extracted with hot absolute alcohol. The solid in the alcohol is precipitated with ether, filtered, and recrystallized from isopropanol. The carbaminoyl-β-methylcholine chloride obtained has a melting point of about 220°C. References Merck Index 1200 Kleeman and Engel p.102 PDR pp.830, 926, 1219, 1276 I.N. p.139 REM p.895 Major, R.T. and Bonnett, H.T.; US Patent 2,322,375; June 22, 1943; assigned to Merck and Co., Inc.

BEVANTOLOL HYDROCHLORIDE Therapeutic Function: Antiarrhythmic, Beta-adrenergic blocker Chemical Name: 2-Propanol, 1-((2-(3,4-dimethoxyphenyl)ethyl)amino)-3-(3methylphenoxy)-, hydrochloride Common Name: Bevantolol hydrochloride; Vantol Structural Formula:

Chemical Abstracts Registry No.: 59170-23-9 (Base); 42864-78-8

Bevantolol hydrochloride

619

Trade Name

Manufacturer

Country

Year Introduced

Bevantolol hydrochloride

Parke, Davis (Pfizer)

-

-

Raw Materials Epichlorohydrin 3-Cresol Sodium hydoxide β-(3,4-Dimethoxyphenyl)ethylamine Hydrogen chloride Manufacturing Process To a solution of 50 g (1.25 mol) of NaOH in 1200 ml H2O was added 108 g (1 mol) of m-cresol freshly distilled and at 15°C in one lot 117ml (1.5 mol) of epichlorohydrin. The emulsion was stirred at room temperature for 16 hours in a creased flask. The product was taken up in 1000 ml of toluene and washed with 500 ml water. Distillation yielded 135.7 g=82% of 3-(m-tolyloxy)-1,2epoxypropane, b.p. 61°C at 0.05 mm. Preparation of bevantolol hydrochloride: To a suitable reactor under a nitrogen blanket is added 13.7 kg of β-(3,4dimethoxyphenyl)ethylamine. The amine is cooled to 5°C and 12.5 kg of 3(m-tolyloxy)-1,2-epoxypropane is added maintaining the temperature between 5-10°C. After 10 hours, the mixture is seeded with bevantolol free base; seeding is repeated approximately every 2 hours until it is evident that crystallization has started. After stirring for 48 hours at 10°C, 26 L of hexane is added. The temperature is raised to 25°C and stirring is continued for 48 hours. The slurry is filtered and the collected solid is dried under vacuum. The product is dissolved in 60 L of isopropyl alcohol and the solution is filtered. The reactor and filter are rinsed with 186 L of isopropyl alcohol and 2.7 kg of anhydrous hydrogen chloride is added to the combined filtrate. The batch is heated to reflux for 2 hours. The temperature is adjusted to 65°C and the solution is seeded with bevantolol hydrochloride crystals. The mixture is held at this temperature with stirring until a heavy sand-like slurry is present. The mixture is allowed to cool to ambient temperature without stirring or artificial cooling. It is then cooled to 20°C. The slurry is centrifuged and the product rinsed with isopropyl alcohol until the filtrate is colorless. After being vacuum dried at 50-55°C the product is milled if necessary; yield of bevantolol hydrochloride 22.7 kg (78.6%); melting point 137-138°C. References Hoekstra M.S.; US Patent No. 4,994,618; February 19, 1991; Assigned to Warner-Lambert Company (Morris Plains, NJ) Holmes A., Meyer R.F.; US Patent No. 3,857,891; Dec. 31, 1974; Assigned to Parke, Davis and Vcompany, Detroit, Mich.

620

Bexarotene

BEXAROTENE Therapeutic Function: Antineoplastic Chemical Name: Benzoic acid, 4-(1-(5,6,7,8-tetrahydro-3,5,5,8,8pentamethyl-2-naphthalenyl)ethenyl)Common Name: Bexarotene Structural Formula:

Chemical Abstracts Registry No.: 153559-49-0 Trade Name

Manufacturer

Country

Year Introduced

LGD1069

Ligand Pharmaceuticals Inc. R.P. Scherer St. Petersburg Elan Pharmaceuticals, Inc.

-

-

USA

-

-

-

Ligand Pharmaceuticals Inc. Ligand Pharmaceuticals Inc.

USA

-

USA

-

Targretin Targretin Targretin Targrexin Raw Materials

Aluminum chloride 1,2-Dichloroethane 1,2,3,4-Tetrahydro-1,1,4,4,6-pentamethylnaphthalene 4-Carbomethoxybenzoyl chloride Potassium hexamethyldisilazide Methyltriphenylphosphonium bromide Manufacturing Process (a) Methyl [4-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) carbonyl]benzoate (1): To a suspension of aluminum chloride (1.10 g, 8.25 mmol) in 30 mL of 1,2dichloroethane under argon at room temperature was added a solution of 1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylnaphthalene (1.52 g, 7.5 mmol) (Kagechika, H. et al., J. Med. Chem, 31:2182 (1988)) and 4carbomethoxybenzoyl chloride (1.57 g, 7.87 mmol) in 15 mL of 1,2-

Bexarotene

621

dichloroethane. The reaction mixture was stirred overnight and poured onto ice water and extracted with 40% ethyl acetate/hexane. The combined organic layers were washed with saturated aqueous NaHCO3and brine. The solution was dried over anhydrous MgSO4, filtered and concentrated to afford a brown solid (2.56 g). Flash chromatography (60% dichloromethane/hexane) yielded the desired product (1) as a white, crystalline solid (1.733 g, 64 %): m.p. 146°-149°C; Rf 0.11 (50% CH2Cl2/hexane). The structure of the product was also confirmed using IR, 1H NMR and mass spectroscopy. (b) [4-(5,6,7,8-Tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) carbonyl]benzoic acid (2): To a suspension of the ester (1) (0.120 g, 0.329 mmol) in 75% aqueous methanol (2 mL) was added potassium hydroxide (0.055 g). The reaction mixture was stirred at 60°C for 1 h during which time the material dissolved. The solution was cooled to room temperature, acidified with 1 N aqueous hydrochloric acid, and then extracted with 80% ethyl acetate/hexane. The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated to afford a white solid (0.109 g). Recrystallization from benzene/hexane afforded (2) as a white, crystalline solid (0.102 g, 89%): m.p. 209°-212°C. The structure of the product was also confirmed using IR, 1H NMR and mass spectroscopy. (c) Methyl 4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)-1ethenyl]benzoate (3): To a suspension of methyltriphenylphosphonium bromide (0.196 g, 0.55 mmol) in 1 mL of benzene under argon at room temperature was added a 0.5 M solution of potassium hexamethyldisilazide in toluene (1.2 mL, 0.6 mmol), and the yellow solution was stirred for 5 min. A solution of keto-ester (1) (0.1 g, 0.274 mmol) in 1.5 mL of benzene was added and the orange solution was stirred for 3 h at room temperature. The reaction mixture was filtered through a plug of silica gel with 40% ethyl acetate/hexane. The filtrate was concentrated to afford a solid. Flash chromatography (30%; 40% dichloromethane/hexane) yielded the desired product (3) as a white solid (0.077 g, 78%): m.p. 167°-168°C; Rf 0.4 (50% dichloromethane/hexane). The structure of the product was also confirmed using IR, 1H NMR and mass spectroscopy. (d) [4-[1-(5,6,7,8-Tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)-1ethenyl]benzoic acid (4): To a suspension of the ester (3) (0.058 g, 0.16 mmol) in 75% aqueous methanol (2 mL) was added one pellet of potassium hydroxide (0.1 g). The mixture was stirred at 70°C for 1 h during which time the material dissolved. The solution was cooled to room temperature, acidified with 1 N aqueous hydrochloric acid and then extracted with 80% ethyl acetate/hexane. The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated to afford a white solid. Recrystallization from dichloromethane/hexane afforded the desired acid (4) as a white, crystalline solid (42 mg, 91%): melting point 230°-231°C. The structure of the product was also confirmed using IR, 1H NMR and mass spectroscopy.

622

Bezafibrate

References Dawson M.L. et al.; US Patent No. 5,466,861; Nov., 14, 1995; Assigned: SRI International (Menlo Park, CA); La Jolla Cancer Research Foundation (La Jolla, CA)

BEZAFIBRATE Therapeutic Function: Antihyperlipidemic Chemical Name: Propanoic acid, 2-(4-(2-((4-chlorobenzoyl)amino)ethyl) phenoxy)-2-methylCommon Name: Bezafibrate; Detrex Structural Formula:

Chemical Abstracts Registry No.: 41859-67-0 Trade Name

Manufacturer

Country

Year Introduced

Bezafibrate

Eipico Co.

-

-

Bezalip

Glaxo Wellcom-Misr Co.

-

-

Cholestenorm

Natur Produkt

-

-

Azufibrat

Azupharma GmbH and Co. Hennig Arzneimittel GmbH and Co. KG

-

-

-

-

Befizal

Roche

-

-

Befizal

Boehringer Mannheim France Pharma SA

-

-

Beza 1 A Pharma

AbZ-Pharma GmbH

-

-

Beza 200 von ct

AbZ-Pharma GmbH

-

-

Beza AbZ

AbZ-Pharma GmbH

-

-

Bezabeta

Betapharm Arzneimittel GmbH

-

-

Bezacur

Hexal

-

-

Detrex

Vargas

-

-

Bezafibrate

Topharman Shanghai Co., Ltd.

-

-

Befibrat

Bezitramide

623

Raw Materials Tyramine Sodium

p-Chlorobenzoyl chloride 2-Bromo-2-methyl-propionic acid ethyl ester

Manufacturing Process 0.292 moles p-chlorobenzoyl chloride and 50 ml dry pyridine were added dropwise to 0.146 moles tyramine in 60 ml dry pyridine for 10 minutes. Then the mixture was poured in about 500 g of ice with water. The fallen-out crystals was filtered off, washed with diluted HCl, water and NaHCO3 solution and dried. It was recrystallized from acetone to give di(4-chlorobenzoyl) tyramine; yield 98 %; MP: 203°-205°C. 0.11 moles above product in 400 ml methanol was mixed with 130 ml 2 N KOH and heated at 40°-45°C for 1 hour. On cooling 130 ml 2 N HCl was added. The fallen-out precipitate was filtered off, filtrate was distilled off to dryness. The residue was washed with water, NaHCO3 solution and recrystallized from ethanol to give N-(4-chlorobenzoyl)tyramine; yield 91%; MP: 174°-176°C. 2.14 g sodium was dissolved in 50 ml of absolute methanol and mixed with 0.93 mole N-(4-chlorobenzoyl)tyramine. Methanol was removed in vacuum to dryness. The residue was slurried in 100 ml absolute toluene and 0.137 moles 2-bromo-2-methylpropionic acid ethyl ester was added. The suspension was heated for 25 hours at 80°C. Then it was distilled in vacuum to dryness and the residue was dissolved in CH2Cl2, washed with diluted HCl, NaOH and water, and dried over CaCl2. On removing of the solvent, the crude 2-{4-[2(4-chlorobenzoylamino)ethyl]phenoxy}-2-methylpropionic acid ethyl ester was obtained. After recrystallization from ether/ ligroin and acetone it had MP: 96°-97°C; yield 67 %. 0.1 mole above ester in 1.5 L of dioxane was slowly mixed with 200 ml 1 N KOH at ambient temperature and stood for 2 hours, then it was heated at 40°C for 1 hour. The substance was dissolved completely. On cooling the mixture was neutralized with 200 ml 1 N HCl. The solvents were removed in vacuum. The residue was washed with water and recrystallized from acetone to give 2-{4-[2-(4-chlorobenzoylamino)ethyl]phenoxy}-2-methylpropionic acid; yield 84%; MP: 186°C. References Witte E-Ch. et al; D.B. Patent No. 2,149,070; October 1, 1971; Assigned to Boehriger Mannheim GmbH, 6800 Mannheim

BEZITRAMIDE Therapeutic Function: Narcotic analgesic, Antitussive

624

Bezitramide

Chemical Name: 2-Benzimidazolinone, 1-(1-(3-cyano-3,3-diphenylpropyl)-4piperidyl)-3-propionylCommon Name: Bezitramide Structural Formula:

Chemical Abstracts Registry No.: 15301-48-1 Trade Name

Manufacturer

Country

Year Introduced

Bezitramide

ZYF Pharm Chemical

-

-

Raw Materials 4-Bromo-2,2-diphenylbutyronitrile 4-(2-Oxo-1-benzimidazolinyl)piperidine Propionic anhydride

Sodium carbonate Potassium iodide

Manufacturing Process A mixture of 6.9 parts 4-bromo-2,2-diphenylbutyronitrile, 5 parts 4-(2-oxo-1benzimidazolinyl)piperidine, 7.3 parts sodium carbonate, a few crystals of potassium iodide in 160 parts 4-methyl-2-pentanone is stirred and refluxed for 12 hours. After cooling the reaction mixture, 100 parts water is added. The aqueous layer is separated and extracted with 4-methyl-2-pentanone. The combined organic layer are dried over MgSO4 and evaporated. The oily residue is dissolved in a mixture of 24 parts diisopropylether and 24 parts isopropanol. After cooling overnight to -20°C, 5.3 parts product are obtained. This crop is boiled in 72 parts 4-methyl-2-pentanone and cooled to 0°C, yielding 1-(3-cyano-3,3-diphenylpropyl)-4-(2-oxo-1-benzimidazolinyl) piperidine, melting point 225-226°C, as a grey-white amorphous powder. A mixture of 5 parts 1-(3-cyano-3,3-diphenylpropyl)-4-(2-oxo-1benzimidazolinyl)piperidine, 7.5 parts propionic acid anhydride and 80 parts benzene is stirred and refluxed for 16 hours. After cooling, the reaction mixture is washed twice with 100 parts water. The aqueous layer is dried over potassium carbonate, filtered and evaporated. The residue is recrystallized from 60 parts of ether, yielding 4 parts crude 1-(3-cyano-3,3-diphenylpropyl)4-(2-oxo-3-propionyl-1-benzimidazolinyl)piperidine. This crop is recrystallized from 20 parts m-methyl-2-pentanone 4-ethyl-2-pentanone, yielding 1-(3-

Bialamicol

625

cyano-3,3-diphenylpropyl)-4-(2-oxo-3-propionyl-1-benzimidazolinyl)piperidine with melting point: 124.5-126°C as a pale yellow amorphous powder. References Janssen P.A.J.; US Patent No. 3,196,157; July 20, 1965; Assigned to Research Laboratorium Dr.C.Janssen N.V., a corporation of Belgium

BIALAMICOL Therapeutic Function: Antiamebic Chemical Name: 3,3'-Bis[(diethylamino)methyl]-5,5'-di-(2-propenyl)-[1,1biphenyl]-4,4'-diol Common Name: Biallylamicol Structural Formula:

Chemical Abstracts Registry No.: 493-75-4 Trade Name

Manufacturer

Country

Year Introduced

Camoform HCl

Parke Davis

US

1956

Raw Materials Paraformaldehyde Diethylamine 3,3'-Diallyl-4,4'-biphenol Manufacturing Process Paraformaldehyde (7.59) (0.25mol) and 18.3 g (0.25 mol) of diethylamine are mixed in 25 cc of alcohol and warmed until a clear solution is obtained. The

626

Bicalutamide

solution is cooled and mixed with 26.6 g (0.10 mol) of 3,3'-diallyl-4,4'biphenol in 25 cc of alcohol. After standing several hours, the solution is warmed for one hour on the steam bath, allowing the alcohol to boil off. The residue is then taken up in ether and water, the ether layer separated and washed with 2% sodium hydroxide solution and finally with water. The washed ether solution is dried over solid potassium carbonate, and filtered. After acidifying with alcoholic hydrogen chloride, the ether is distilled off and the alcoholic residue diluted with an equal volume of acetone. The crystalline hydrochloride is filtered off, triturated with alcohol, diluted with several volumes of acetone, filtered and dried; MP 209°-210°C. References Merck Index 1209 I.N. p.141 Rawlins, A.L., Holcomb, W.F., Jones, E.M., Tendick, F.H. and Burckhalter, J.H.; US Patent 2,459,338; January 18,1949; assigned to Parke, Davis and Co.

BICALUTAMIDE Therapeutic Function: Antitumor Chemical Name: Propanamide, N-(4-cyano-3-(trifluoromethyl)phenyl)-3-((4fluorophenyl)sulfonyl)-2-hydroxy-2-methyl- (racemic mixture) Common Name: Bicalutamide Structural Formula:

Chemical Abstracts Registry No.: 90357-06-5

Bicalutamide

627

Trade Name

Manufacturer

Country

Year Introduced

Bicalutamide

AstraZeneca

-

-

Biprosta

India

-

Calutide-50

Cytomed (A div. of Alembic) Cipla Limited

India

-

Casodex

AstraZeneca

-

-

Cosudex

AstraZeneca

-

-

Raffolutil

AstraZeneca

-

-

Raw Materials Bromal Dioxolanone 4-Fluorbenzenethiol Thionyl chloride

Citramalic acid 2-Mercaptopyridine-N-oxide 4-Amino-2-trifluoromethylbenzonitrile

Manufacturing Process [(4S)-4-Methyl-5-oxo-2-(tribromomethyl)-1,3-dioxolan-4-yl]acetic acid. Bromal (25.0 g; 89.1 mmol) and (S)-citramalic acid (11.0 g; 74.2 mmol) were cooled to 0°C under inert atmosphere. Sulfuric acid/acetic acid (1/1; 25 ml) was added dropwise with stirring. After 2 h the contents were a yellow solution with a white precipitate. The ice bath was removed and the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with ice and extracted 4 times with ethyl acetate. The organic layer was back extracted with water and then was dried with MgSO4. After filtration, the filtrate was concentrated to an oil. The product was obtained as a white solid after crystallization from toluene/hexanes. Yield: 23.2 g (77%); mp 151°C (sublime). (5R)-5-(Bromomethyl)-5-methyl-2-(tribromo-methyl)-l,3-dioxolan-4-one. The above obtained [(4S)-4-Methyl-5-oxo-2-(tribromomethyl)-1,3-dioxolan-4yl]acetic acid (102.5 mg; 0.250 mmol) and 2-mercaptopyridine- N-oxide (34.4 mg; 0.280 mmol) were suspended in CBrCl3 (1.5ml). The reaction mixture was heated to reflux and a solution of dicyclohexyl carbodiimide (DCC) (103 mg; 0.500 mmol) in CBrCl3 (1.0 ml) was added slowly over the course of 30 min. The reaction mixture was stirred for an additional hour. The product was purified by silica gel chromatography (CH2Cl2/hexanes (1:2)) and was obtained as white needles from the same solvents. Yield: 72 mg (65%); mp 110-113°C. (2R)-3-[(4-Fluorophenyl)thio]-2-hydroxy-2-methyl-propanoic acid. The above prepared protected hydroxyacid (184 mg; 0.413 mmol) was dissolved in 4 ml of a 1:1 mixture of isopropanol:1 M NaOH. After 3 h, the reaction mixture was a solution and no starting material was detectable by TLC. 4-Fluorobenzenethiol (70 ml; 0.65 mmol) was then added and the reaction mixture was stirred overnight. The reaction mixture was then

628

Bietamiverine

adjusted to pH 8 with HCl and was extracted twice with CH2Cl2. The aqueous layer was then adjusted to pH 1 and was extracted with CH2Cl2. This organic layer was concentrated to an oil, which crystallized on standing. The hydroxyacid was either used in the next reaction without further purification or was recrystallized from chloroform/petroleum ether. Yield 76 mg (80%). (2R)-N-[4-Cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenul)thio]-2hydroxy-2-methylpropanamide was prepared from above hydroxyacid (1.89 g; 8.22 mmol) and 4-amino-2-trifluoromethylbenzonitrile (2.05 g; 11.0 mol) were in dry DMA (15 ml) under inert atmosphere. After the solution had been cooled to -10°C, the thionyl chloride (0.75 ml; 10 mmol) was added slowly. The reaction mixture was stirred for 15 min at -10°C and then the ice bath was removed. After stirring overnight at room temperature, the reaction mixture was deluted with CH2Cl2 and was extracted one time with saturated NaHCO3. The organic layer was dried with MgSO4 and concentrated. The product was purified by silica gel chromatography (6% ethyl acetate in CH2Cl2). Yield 1.38 g (42%). (2R)-N-[4-Cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2hydroxy-2-methylpropanamide. To a solution of the sulfide (1.27 g; 3.19 mmol) in CH2Cl2 (43 mL) was added mCPBA (1.65 g; 9.57 mmol). After stirring overnight at room temperature, the reaction mixture was diluted with ethyl acetate and extracted with Na2SO3 and NaHCO3 (2x). The organic layer was dried with MgSO4 and concentrated. After purification by silica gel chromatography using a step gradient of ethyl acetate in CHCl3, the product was obtained as white crystals from benzene/petroleum ether. Yield 1.29 g (94%); ee>>99%; mp 178°C. (2S)-N-[4-Cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2hydroxy-2-methylpropanamide ee>>99%. Product may be prepared from the starting materials. References James K.D., Ekwuribe N.N.; Tetrahedron, V. 58, Is. 29, pp.5905-5908, (2002) Tucker H.; US Patent No. 4,636,505; Jan. 13, 1987; Assigned: Imperial Chemical Industries PLC (London, GB2)

BIETAMIVERINE Therapeutic Function: Spasmolytic Chemical Name: 1-Piperidineacetic acid, alpha-phenyl-, 2-(diethylamino) ethyl ester Common Name: Bietamiverine; Dietamiverine

Bietaserpine

629

Structural Formula:

Chemical Abstracts Registry No.: 479-81-2 Trade Name

Manufacturer

Country

Year Introduced

Bietamiverine

Shanghai Lansheng Corporation Tokyo Tanabe

-

-

-

-

Sparine Raw Materials

Phenylchloroacetic acid Diethylaminoethanol Piperidine Manufacturing Process To a solution of 117 g of diethylaminoethanol in 1000 ml of benzene was added a solution of 94.5 g phenylchloroacetic acid in 400 ml benzene (time of addition 1 hour). Then the reaction mixture was refluxed for 2 hours. To the obtained solution was added an aqueous solution of sodium carbonate. Then to the solution which was dried with sodium sulfate was added 85 g of piperidine and the solution was refluxed for 2 hours. The obtained solution was washed with water, dried with sodium sulfate and distilled. Yield of αphenyl-1-piperidineacetic acid 2-diethylaminoethyl ester 115 g, Kp1 180°C. References Merck Index, Monograph number: 1252, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. Reez Th.; DE Patent No. 859,892; July 8, 1949; Assigned to Nord-Werke G.m.b.H., Hamburg

BIETASERPINE Therapeutic Function: Antihypertensive Chemical Name: 1-[2-(Diethylamino)ethyl]-11,17-dimethoxy-18-[(3,4,5trimethoxybenzoyl)oxy]yohimban-16-carboxylic acid methyl ester

630

Bietaserpine

Common Name: 1-[2-(Diethylamino)ethyl]reserpine Structural Formula:

Chemical Abstracts Registry No.: 53-18-9 Trade Name

Manufacturer

Country

Year Introduced

Tensibar

Lefranco

France

1967

Pleiatensin

Guidotti

Italy

-

Pleiatensin

Byla

France

-

Raw Materials Naphthalene Sodium

Diethylaminochloroethane Reserpine

Manufacturing Process The first stage is to prepare the naphthyl sodium solution in the following way: To a solution of 0.6 g naphthalene in 10 ml tetrahydrofurane, anhydrous, used as solvent, add 96 mg sodium under a nitrogen atmosphere. After a few minutes, an intensive dark green coloration develops, while the sodium dissolves. The reaction is completed after a period of time ranging between 30 and 60 minutes. Then add to the above solution a solution of 2.42 g reserpine in 60 ml anhydrous dioxan at 50°C. After heating for 15 minutes (which corresponds to carrying out reaction a), add 0.6 g, diethylaminochloroethane, while the mixture is kept boiling under reflux, for 6 hours. Reaction b is then completed. Then cool the mixture and evaporate the dioxan under reduced pressure. The pasty residue is dissolved in a mixture of 50 ml benzene and 20 ml ether, and washed several times with water. The aqueous solutions resulting from the washing are also extracted with

Bifemelane hydrochloride

631

ether, and the ether portions are added to the main ether-benzene solution. This solution is extracted several times with 5% acetic acid, until the silicotungstate test (an identification test for alkaloids) yields a negative result, and the acetic solutions are washed with 10 ml ether. After combining the acetic extracts, the solution is adjusted to a pH of 9 with sodium carbonate, which precipitates the base, which is insoluble in water. The oily suspension obtained in this way is extracted several times with chloroform. The chloroform solutions are then washed, each with 10 ml water, then they are combined and dried over anhydrous potassium carbonate. After filtering and evaporating the solvent under reduced pressure, the pasty residue, constituted by the enriched product, is diluted with 30 ml ether and in this way 0.225 g reserpine (which has not taken part in the reaction) is isolated by filtration. After evaporation of the ether under reduced pressure, 1.525 g of the crude resinous base is obtained, which constitutes the required product in a crude and impure condition. This product is purified in the following way: After dissolving in 15 ml of dry benzene, the resulting solution is filtered on an alumina column, which fixes the base. After consecutive elutions with pure benzene, and benzene containing increasing proportions of chloroform,0.748 g of 1-diethylaminoethylreserpineis isolated in the form of a resin. The crystalline acid bitartrate prepared in ethyl acetate melts at 145°-150°C, with decomposition. References Merck Index 1217 Kleeman and Engel p.105 I.N. p.142 Societe Nogentaise De Produits Chimiques and Buzas, A.; British Patent 894,866; April 26, 1962

BIFEMELANE HYDROCHLORIDE Therapeutic Function: Antidepressant, Antiulcer, Nootropic Chemical Name: N-Methyl-4-[2-(phenylmethyl)phenoxy]-1-butanamine hydrochloride Common Name: Bifemelane hydrochloride; Neurocine Chemical Abstracts Registry No.: 90293-01-9 (Base); 62232-46-6

632

Bifonazole

Structural Formula:

Trade Name Bifemelane hydrochloride

Manufacturer ABATRA Technology Co., Ltd.

Country -

Year Introduced -

Alnert Celeport Alemelano Cordinal Neurocine Neurolea

Fujisawa Eisai ELVETIUM-ALET Roemmers Armstrong Elea

-

-

Raw Materials Methylamine Sodium hydroxide

2-(5-Bromopentyloxy)diphenylmethane Hydrogen chloride

Manufacturing Process N-Methyl-4-[2-(phenylmethyl)phenoxy]-1-butanamine was prepared from 2(5-bromopentyloxy)diphenylmethane and of methylamine in ethanol is at 50°C in a sealed tube (heating for 3 hours). Ethanol and excess methylamine are distilled in vacuo, 2 N NaOH aqueous solution is added, and the reaction product is extracted with ether. Dry hydrogen chloride gas is passed into the ether solution, and the precipitate collected by filtration. Recrystallization from ethanol-ether gives N-methyl-4-[2-(phenylmethyl)phenoxy]-1-butanamine hydrochloride, m.p. 87.5-89.5°C. References Kikumoto Ryoji, Tobe Akihiro, Tonomura Shinji, Ikoma Hidenobu; US Patent No. 4,091,114; May 23, 1978; Assigned to Mitsubishi Chemical Industries Limited (Tokyo, JA) Tobe Akihiro, Tanaka Tadashi; EP No. 698,390; 1996-02-28; Assigned to MITSUBISHI CHEM CORP (JP)

BIFONAZOLE Therapeutic Function: Antifungal

Bifonazole

633

Chemical Name: 1-[(1,1'-Biphenyl)-4-yl-phenylmethyl]-1H-imidazole Common Name: (Biphenyl-4-yl)-imidazol-1-yl-phenylmethane Structural Formula:

Chemical Abstracts Registry No.: 60628-96-8 Trade Name Mycospor

Manufacturer Bayer

Country W. Germany

Year Introduced 1983

Raw Materials 4-Phenylbenzophenone Sodium borohydride

Imidazole Thionyl chloride

Manufacturing Process 38.8g (0.15 mol) of 4-phenylbenzophenone are dissolved in 200 ml of ethanol and 39 (0.075 mol) of sodium borohydride are added. After heating for 15 hours under reflux, and allowing to cool, the reaction mixture is hydrolyzed with water containing a little hydrochloric acid. The solid thereby produced is purified by recrystallization from ethanol. 36 g (89% of theory) of (biphenyl4-yl)-phenyl-carbinol [alternatively named as diphenyl-phenyl carbinol or α(biphenyl-4-yl)benzylalcohol] of melting point 72°-73°C are obtained. 13.6 g (0.2 mol) of imidazole are dissolved in 150 ml of acetonitrile and 3.5 ml of thionyl chloride are added at 10°C. 13 g (0.05 mol) of (biphenyl-4-yl)phenyl-carbinol are added to the solution of thionyl-bis-imidazole thus obtained. After standing for 15 hours at room temperature, the solvent is removed by distillation in vacuo. The residue is taken up in chloroform and the solution is washed with water. The organic phase is collected, dried over sodium sulfate and filtered and the solvent is distilled off in vacuo. The oily residue is dissolved in ethyl acetate and freed from insoluble, resinous constituents by filtration. The solvent is again distilled off in vacuo and the residue is purified by recrystallization from acetonitrile, 8.7 g (56% of theory) of (biphenyl-4-yl)-imidazol-1-yl-phenylmethane [alternatively named as diphenyl-imidazolyl-(1)-phenyl-methane or as 1-(α-biphenyl-4ylbenzyl)imidazole] of melting point 142°C are obtained. References Merck Index A-3 DFU 7 (2) 87 (1982)

634

Biotin

DOT 19 (6) 341 (1983) I.N. p.142 Regal, E., Draber, W., Buchel, K.H. and Plempel, M.; US Patent 4,118,487; October 3,1978; assigned to Bayer A.G.

BIOTIN Therapeutic Function: Vitamin Chemical Name: 1H-Thieno(3,4-d)imidazole-4-pentanoic acid, hexahydro-2oxo-, (3aS,4S,6aR)Common Name: Bios II; Biotin; Coenzym R; Skin factor; Vitamin B7; Vitamin Bw Structural Formula:

Chemical Abstracts Registry No.: 58-85-5 Trade Name Biotin Biotin Biotin Gabunat Medebiotin Priorin-Biotin

Manufacturer Solgar Nature's Way Twinlab Strathmann AG Medea Roche Nicholas

Country Germany France

Year Introduced -

Raw Materials 4,5-Dihydrothiophene Ammonium formate Sodium hydroxide Manufacturing Process 4-Carbomethoxy-2-(4,5-dihydrothiophen-3(2H)-one)valeric acid methyl ester was prepared from 4,5-dihydrothiophene as it was described in Baker et al., J. Org. Chem., 12, 167 (1947).

Biperiden

635

A solution of 60.0 g (0.182 mole) this ester in 550 ml absolute ethanol was treated with 91.6 g (1.45 moles) of ammonium formate. The reaction mixture refluxed for 5.0 hours. Then it was cooled, concentrated, and partitionated in a separatory funnel between 200 ml dichloromethane and 150 ml water. The aqueous phase was extracted three times with 50 ml portions of dichloromethane. The organic extracts were collected, dried over anhydrous sodium sulfate, and evaporated. 50 g (0.182 mole, 100%) 3-amino-4carbomethoxy-2,5-dihydro-2-thiophenevaleric acid methyl ester was obtained as a colorless oil. To a solution of 27.3 g (1 mole) of 3-amino-4-carbomethoxy-2,5-dihydro-2thiophenevaleric acid methyl ester in 250 ml dry methanol was added 4.0 g (0.1 mole) of sodium hydroxide pellets. The reaction mixture was refluxed 4.0 hrs, cooled and concentrated to a volume of 50 ml. The residue was taken up in 80 ml dichloromethane and transfered to a separatory funnel. After the addition of 150 ml of 10% by weight aqueous sodium bicarbonate solution, the aqueous layer was extracted twice with 50 ml portions of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and evaporated to yield 6.4 g (0.0234 mole) of recovered starting material. The aqueous phase was adjusted to pH 1 with 6 N hydrochloric acid and extracted three times with 75 ml portions of dichloromethane. The organic phases were pooled, dried over anhydrous sodium sulfate, and evaporated to yield 18.3 g (0.071 mole, 71%) of 3amino-4-carbomethoxy-2,5-dihydro-2-thiophenevaleric acid as a tan solid, upon trituration with pet. ether. The recovered starting material, 6.4 g (0.0234 mole) was dissolved in 70 ml dry methanol and treated with 1.0 g (0.025 mole) sodium hydroxide. The mixture was refluxed 5.0 hrs, cooled concentrated, and taken up in 80 ml dichloromethane. The organic phase was treated in a separatory funnel with 100 ml of 10% by weight aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with 40 ml portions of dichloromethane. The aqueous phase was acidified to pH 1 with 6 N hydrochloric acid and extracted two times with 50 ml portions of dichloromethane. The organic phases were cooled, dried over anhydrous sodium sulfate, and evaporated to dryness to afford an additional 5.3 g (0.021 mole, 21%) of 3-amino-4-carbomethoxy2,5-dihydro-2-thiophenevaleric acid; m.p. 98°-102°C. References Confalone et al.; US Patent No. 3,979,396; Sept. 7, 1976; Assigned: Hoffmann-La Roche Inc. (Nutley, NJ)

BIPERIDEN Therapeutic Function: Antiparkinsonian Chemical Name: α-Bicyclo[2.2.1]hept-5-en-2-yl-α-phenyl-1piperidinepropanol Common Name: -

636

Biperiden

Structural Formula:

Chemical Abstracts Registry No.: 514-65-8; 1235-82-1 (Hydrochloride salt) Trade Name Akineton HCl Akineton HCl Akineton HCl Akinophyl Akineton Akineton Akineton Dekinet Ipsatol Paraden Tasmolin

Manufacturer Knoll Knoll Knoll Biosedra Abbott Dainippon Medinsa Rafa Orion Yurtoglu Yoshitomi

Country US W. Germany Switz. France UK Japan Spain Israel Finland Turkey Japan

Year Introduced 1959 1970 -

Raw Materials Acetophenone Hydrogen chloride Magnesium

5-Chloro-2-norbomene Piperidine hydrochloride Formaldehyde

Manufacturing Process 65 grams of 3-piperidino-1-phenyl propanone-1 of the summary formula C14H29ON, produced according to Mannich's reaction by reacting acetophenone with formaldehyde and piperidine hydrochloride are dissolved in 300 cc of benzene. The resulting solution is added to an organo-magnesium solution prepared from 96 grams of [δ5-bicyclo-(2,2,1)-heptenyl-2]-chloride (also known as 5-chloro-2-norbomene) 18.5 grams of magnesium shavings, and 300 cc of ether. The reaction mixture is boiled for half an hour under reflux. Thereafter the ether is removed by distillation, until the inside temperature reaches 65°70°C. The resulting benzene solution is added to 95 cc concentrated hydrochloric acid containing ice for further processing. Thereby, 3-piperidino1-phenyl-1-[δ5-bicyclo-(2,2,1)-heptenyl-2]-propanol-1 of the summary formula C21H29ON is obtained. The compound melts at 101°C and its chlorohydrate has a melting point of about 238°C. The compound is difficultly soluble in water, slightly soluble in ethanol, and readily soluble in methanol.

Bisacodyl

637

References Merck Index 1231 Kleeman and Engel p.107 PDR p.975 OCDS Vol.1 p.47 (1977) DOT 18 (2) 90 (1982) I.N. p.144 REM pp.928, 929 Klavehr, W.; US Patent 2,789,110; April 16, 1957; assigned to Knoll AG Chemische Fabriken, Germany

BISACODYL Therapeutic Function: Laxative Chemical Name: 4,4'-(2-Pyridylmethylene)bisphenol diacetate Common Name: Structural Formula:

Chemical Abstracts Registry No.: 603-50-9 Trade Name Dulcolax Dulcolax Dulcolax Contalax Bicol Biscolax Theralax Alaxa Anan Bisacolax Biomit Brocalax

Manufacturer Boehringer Ingelheim Thomae Boehringer Ingelheim Riker Wampole Fleet Beecham Angelini Ono ICN Sampo BrocadesSteethman

Country US

Year Introduced 1958

W. Germany Switz.

-

France US US US Italy Japan Canada Japan Netherlands

1959 1974 1975 1976 -

638

Bisacodyl

Trade Name Cathalin Coditax Contalax Darmoletten Deficol Delco-Lax Durolax

Manufacturer Hokuriku Pharbil Fischer Omegin Vangard Delco Boehringer Ingelheim

Country Japan Belgium Israel W. Germany US US W. Germany

Year Introduced -

Endokolat Ercolax Ethanis Eulaxen Evac-Q-Kwik Godalax Hillcolax Ivilax Laco Laksodil Lax Laxadin Laxagetten Laxanin N Laxbene Laxematic Med-Laxan Metalax Mormalene Neodrast Neo-Salvilax Novolax Obstilax Organolax Perilax Prontolax Pyrilax Rytmil Sanvacual Satolax Serax Stadalax Telemin Toilax Toilex Ulcolax Vemas Vencoll Vinco

Weiskopf Erco Taisho Ferring Adria Pfleger Hillel Bieffe Paul Maney Uranium Kanto Teva Tempelhof Schwarzhaupt Merckle Kemifarma Med Star Montefarmaco Werner Schnur Para-Pharma Krka Zirkulin Azuchemie Nordex Streuli Berlin-Chemie Vicks Santos Sato Hameln Stada Funai Erco Protea Ulmer Nippon Zoki Maruko OTW

W. Germany Denmark Japan W. Germany US W. Germany Israel Italy Canada Turkey Japan Israel W. Germany W. Germany W. Germany Denmark W. Germany Finland Italy W. Germany Switz. Yugoslavia W. Germany W. Germany Norway Switz. E. Germany US Spain Japan W. Germany W. Germany Japan Denmark Australia US Japan Japan W. Germany

-

Bisantrene hydrochloride

639

Raw Materials α-Pyridine Aldehyde Phenol Acetic anhydride Manufacturing Process Preparation of (4,4'-Dihydroxy-Diphenyl)-(Pyridyl-2)-Methane 70.0 grams of α-pyridine aldehyde are fed portionwise with stirring and cooling to a mixture of 200 grams of phenol and 100 cc of concentrated sulfuric acid. The reaction mixture is allowed to stand for a while with repeated stirring, whereby it becomes syrupy, neutralized with sodium carbonate, dissolved in methanol and filtered. The filtrate is introduced into a large quantity of water and the resulting precipitate is recrystallized from a methanol/water mixture. Colorless crystals are obtained of MP 254°C. When using zinc chloride or tin tetrachloride and warming to a temperature of about 50°C, a corresponding result is obtained. Preparation of Bisacodyl: 5 grams of (4,4'-dihydroxy-diphenyl)-(pyridyl-2)methane are heated with 5 grams of anhydrous sodium acetate and 20 cc of acetic anhydride for three hours over a boiling water bath. The cooled reaction mixture is poured into water, whereby after a while a colorless substance precipitates, which is filtered off with suction, washed with water and recrystallized from aqueous ethanol. Colorless bright crystals, MP 138°C are obtained. References Merck Index 1238 Kleeman and Engel p.107 PDR pp.561, 677, 879, 1569 I.N. p.145 REM p.800 Kottler, A. and Seeger, E.; US Patent 2,764,590; September 25, 1956; assigned to Dr. Karl Thomae GmbH, Germany

BISANTRENE HYDROCHLORIDE Therapeutic Function: Antineoplastic Chemical Name: 9,10-Anthracenedicarboxaldehyde, bis((4,5-dihydro-1Himidazol-2-yl)hydrazone), dihydrochloride Common Name: Bisantrene hydrochloride Chemical Abstracts Registry No.: 78186-34-2 (Base); 71439-68-4

640

Bisantrene hydrochloride

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Bisantrene hydrochloride

ZYF Pharm Chemical

-

-

Raw Materials Hydrazine hydrate Hydrochloric acid Silver oxide

2-Methylthio-2-imidazoline hydroiodide 9,10-Anthracenedicarboxaldehyde

Manufacturing Process A 33.0 g (0.135 mole) of 2-methylthio-2-imidazoline hydroiodide is dissolved in 300 ml of water and treated with 8 ml (0.16 mole) of hydrazine hydrate. The mixture is stirred at room temperature for 20 hours and then taken to dryness under reduced pressure. The residue is dissolved in 250 ml of water and again taken to dryness under reduced pressure. The residue is redissolved in 250 ml of water and added to a mixture of 250 ml of water, 25 ml of concentrated hydrochloric acid and 25 g of silver oxide. The resulting mixture is stirred on a steam bath for 4 hours and then filtered. The filtrate is reduced to dryness under reduced pressure. The residue is dissolved in 300 ml of ethanol and 20 ml of water at the boil, clarified and cooled at -10°C. The precipitate is collected, washed with ethanol and ether and dried at 60°C and then 110°C under reduced pressure. Yield of the 2-hydrazino-2imidazoline hydrochloride 11.6 g, melting point 177-180°C. The 2-hydrazino-2-imidazoline monohydrochloride is converted to the dihydrochloride by treatment with ethanol and concentrated hydrochloric acid. A suspension of 3.46 g of the 2-hydrazino-2-imidazoline dihydrochloride and 2.34 g of 9,10-anthracenedicarboxaldehyde in 100 ml of ethanol is stirred and heated under reflux for two hours. The mixture is cooled and the solid is collected and washed with ethanol giving the desired product as a crystalline orange solid, m.p. 288-289°C (dec.). References Murdock Keith C., Durr; Frederick E.; US Patent No. 4,258,181; March 24, 1981; Assigned to American Cyanamid Company (Stamford, CT) Tomcufcik Andrew Stephen, Wilkinson Raymond George, Child Ralph Grassing; US Patent No. 3,931,152; January 6, 1976; Assigned to American Cyanamid Company (Stamford, CT)

Bismuth sodium triglycollamate

641

BISMUTH SODIUM TRIGLYCOLLAMATE Therapeutic Function: Lupus erythematosus suppressant Chemical Name: Nitrilotriacetic acid bismuth complex sodium salt Common Name: Structural Formula:

Chemical Abstracts Registry No.: 5798-43-6 Trade Name

Manufacturer

Country

Year Introduced

Bistrimate

Smith, Miller and Patch

US

1946

Raw Materials Bismuth Oxide Triglycollamic Acid Sodium carbonate Manufacturing Process A mixture of 2.33 g of bismuth oxide (Bi2O3), 3.71 g of anhydrous sodium carbonate, and 7.64 g of triglycollamic acid and 40 cc of water was heated at 80°C on the water bath until all was dissolved. The solution was evaporated on the water bath to a syrup. The syrup was allowed to cool, during which time partial solidification occurred. It was then triturated with 300 cc of alcohol, and the solid anhydrous salt was collected on a filter, washed with alcohol, ground fine, and dried in a vacuum desiccator. This substance has a water solubility at 25°C of 31,8% by weight. It decomposes on heating in the melting point bath. References Merck Index 1279 I.N. p. 147 Lehman, R.A. and Sproull, R.C.; US Patent 2,348984; May 16, 1944

642

Bisoprolol fumarate

BISOPROLOL FUMARATE Therapeutic Function: Beta-adrenergic blocker Chemical Name: 2-Propanol, 1-(4-((2-(1-methylethoxy)ethoxy)methyl) phenoxy)-3-((1-methylethyl)amino)-, (E)-2-butenedioate (2:1) (salt) Common Name: Bisoprolol fumarate Structural Formula:

Chemical Abstracts Registry No.: 104344-23-2 Trade Name Bilol Biso-BASF

Manufacturer Ecosol AG BC Biochemie Pharma GmbH

Country Switz. -

Year Introduced -

Bisobloc

Azupharma GmbH and Co. Rusan Healthcare Pvt. Ltd. Merck AG 1A Pharma Alpharma-Isis GmbH Merck AG E. Merck (India) Ltd. Merck AG AWD Pharma GmbH and Co. KG

-

-

India

-

Switz. India Switz. -

-

Procter and Gamble

Germany

-

Bisocar HT Bisomerck Biso 1A Pharma Biso-Puren Concor Concor Concor Cor Cordalin Fondril Raw Materials

1-(p-2-Isopropoxyethoxymethylphenoxy)-2,3-epoxypropane Ammonia Nickel Raney Manufacturing Process A solution of 10 g of 1-(p-2-isopropoxyethoxymethylphenoxy)-3-

Bivalirudin

643

isopropylideneamino-propan-2-ol [obtainable by reacting 1-(p-2isopropoxyethoxymethylphenoxy)-2,3-epoxy propane with ammonia to give 1(p-2-isopropoxyethoxymethylphenoxy)-3-amino-propan-2-ol and subsequently reacting this with acetone] in 250 ml of ethanol was hydrogenated on 0.5 g of Raney nickel at 25°C under 1 atmosphere of pressure until 1 equivalent of H2 had been absorbed. The mixture was filtered and the filtrate evaporated to give 1-(p-2-iso-propoxyethoxymethyl-phenoxy)-3-isopropylamino-propan-2-ol, fumarate, m.p. 100°C (after addition of equimolecular quantity of fumaric acid). References Jonas R. et Patent Jonas R. et Patent

al.; US Patent No. 4,171,370; Oct. 16, 1979; Assigned: Merck Gesellschaft mit beschrankter Haftung (Darmstadt, DE) al.; US Patent No. 4,258,062; Mar. 24, 1981; Assigned: Merck Gesellschaft mit beschrankter Haftung (Darmstadt, DE)

BIVALIRUDIN Therapeutic Function: Anticoagulant Chemical Name: L-Leucine, D-phenylalanyl-L-prolyl-L-arginyl-Lprolylglycylglycylglycylglycyl-L-asparaginylglycyl-L-α-aspartyl-Lphenylalanyl-L-α-glutamyl-L-α-glutamyl-L-isoleucyl-L-prolyl-L-α-glutamylL-α-glutamyl-L-tyrosyl Common Name: Bivalirudin Chemical Abstracts Registry No.: 128270-60-0 Trade Name Angiomax Angiomax Bivalirudin Hirulog

Manufacturer Oryx Medicines Co. Medicines Co. Braine-L' Alleud

Country Belgium

Year Introduced -

Raw Materials BOC-L-Leucine-O-divinylbenzene resin BOC-L-Glutamic acid (γ-benzyl ester) BOC-L-Proline BOC-L-Phenylalanine BOC-L-Asparagine BOC-L-Arginine 4-Cresol Trifluoroacetic acid

BOC-O-2,6-Dichlorobenzyl tyrosine BOC-L-Aspartic acid (β-benzyl ester) BOC-L-Isoleucine BOC-Glycine BOC-L-Phenylalanine Hydrogen fluoride Ethylmethyl sulfate

644

Bivalirudin

Structural Formula:

Manufacturing Process A 20 amino acid polypeptide [1], bivalirudin (hirulog) is a synthetic version of hirudin. Its amino-terminal D-Phe-Pro-Arg-Pro domain, which interacts with the active site of thrombin, is linked via four Gly residues to a dodecapeptide analogue of the carboxy-terminal of hirudin. Like hirudin, bivalirudin also forms a 1:1 stoichiometric complex with thrombin. Once bound, however, the Arg-Pro bond at the amino-terminal of bivalirudin is cleaved by thrombin, thereby restoring active site functions of the enzyme complexes of α-thrombin [2]. Hirulog-8 has the formula: H-(D-Phe)-Pro-Arg-Pro-(Gly)4-Asn-Gly-Asp-PheGlu-Glu-Ile-Pro-Glu-Glu-Tyr-Leu-OH. Hirulog-8 was synthesized by conventional solid-phase peptide synthesis employing an Applied Biosystems 430 A Peptide Synthesizer. This peptide was synthesized using BOC-L-LeucineO-divinylbenzene resin. Additional t-BOC-amino acids (Peninsula Laboratories,

Bleomycin hydrochloride

645

Belmont, Calif.) used included BOC-O-2,6-dichlorobenzyl tyrosine, BOC-Lglutamic acid (γ-benzyl ester), BOC-L-proline, BOC-L-isoleucine, BOC-Lphenylalanine, BOC-L-aspartic acid (β-benzyl ester), BOC-glycine, BOC-Lasparagine, BOC-L-phenylalanine, and BOC-L-arginine. In order to achieve higher yields in synthesis, the (Gly)4 linker segment was attached in two cycles of manual addition of BOC-glycylglycine (Beckman Biosciences, Inc., Philadelphia, Pa.). After completion of synthesis, the peptide was fully deprotected and uncoupled from the divinylbenzene resin by treatment with anhydrous HF:p-cresol:ethylmethyl sulfate (10:1:1, v/v/v). Following removal from the resin, the peptide was lyophilized to dryness. Crude Hirulog-8 was purified by reverse-phase HPLC employing an Applied Biosystems 151A liquid chromatographic system and a Vydac C18 column (2.2x25 cm). The column was equilibrated in 0.1% TFA/water and developed with a linear gradient of increasing acetonitrile concentration from 0 to 80% over 45 minutes in the 0.1% TFA at a flow-rate of 4.0 ml/min. The effluent stream was monitored for absorbance at 229 nm and fractions were collected manually. We purified 25-30 mg of crude Hirulog-8 by HPLC and recovered 15-20 mg of pure peptide. The structure of purified Hirulog-8 was confirmed by amino acid and sequence analyses. References Maraganore J.M., Bourdon P., Jablonski J., Ramachandran K.L., Fenton J.W.; Design and characterization of hirulogs: a novel class of bivalent peptide inhibitors of thrombin. J. Clin. Invest. 1990;29:7095-101 Skrzypczak-Jankun E., Carperos V.E., Ravichandran K.G., Tulinsky A., Westbrook M., Maraganore J.M.; Structure of the hirugen and hirulog 1 complexes of alpha-thrombin. J. Mol. Biol. 1991;221:1379-93 Maraganore J. et al.; US Patent No. 5,196,404; Mar. 23, 1993; Assigned Biogen, Inc., Cambridge, Mass.; Health Research, Inc., Albany, N.Y.

BLEOMYCIN HYDROCHLORIDE Therapeutic Function: Antibiotic Chemical Name: Bleomycin B1, mixture of several derivatives which differ from each other in the terminal amino function Common Name: Bleomicina hydrochloride; Bleomycin hydrochloride Chemical Abstracts Registry No.: 67763-87-5; 11056-06-7 (Base) Trade Name Bleomycin Hydrochloride

Manufacturer Nippon Kayaku, Co.

Country Japan

Year Introduced -

646

Bleomycin hydrochloride

Structural Formula:

Raw Materials 3-Amino-propyldimethylsulfonium bromide hydrobromate Streptomyces verticillus (ATCC No 15003) Millet jelly Soybean powder Glucose Manufacturing Process To a medium having a composition of 6.4 % of millet jelly, 0.5 % of glucose, 3.5 % of soybean powder, 0.75 % of corn steep liquor, 0.3 % of sodium chloride, 0.1 % of potassium secondary phosphate, 0.05 % of zinc sulfate, 0.01 % of copper sulfate, 0.2 % of sodium nitrate and 0.01 % of Toho No. 1 (trade name for a surface active agent composed of polyoxyethylene manufactured by Toho Chemical Industry Co. Ltd., Japan) was added 3-aminopropyl-dimethylsulfonium bromide hydrobromate in a proportion of 0.4 mg/ml to adjust the pH of the medium to 6.5. Each 100 ml of the thus treated medium was separately charged into a Sakaguchi flask and was then sterilized. Subsequently, Streptomyces verticillus (ATCC No. 15003) was inoculated in the medium and was cultured at 27°C for 8 days with stirring at 130 r.p.m. Thereafter, the culture liquors (4.5 L) were collected and filtered to obtain 3.0 L of a filtrate (potency 38.8 mg/ml, total potency 416.4 mg). This culture filtrate was passed through and adsorbed on a column packed with 200 ml of Amberlite IRC-50 and was washed with water and was eluted with 0.5 N hydrochloric acid. 1.0 L of the eluate was neutralized, was passed through and adsorbed on a column packed with 100 ml of active carbon, was washed and was then eluted by use of a 1:1 (by volume) mixture of acetone - 0.02 N aqueous hydrochloric acid solution, and fractions active to Mycobacterium 607 were collected and concentrated to dryness. The resulting residue was dissolved in 5 ml of an 80 % aqueous methanol solution and was charged into a column packed with 30 ml of neutral alumina, followed by elution with an 80 % aqueous methanol solution. Subsequently, bleomycin-containing fractions were collected and concentrated to dryness to obtain 195 mg of bleomycin hydrochloride (potency 650.7 mcg/mg, total potency 172 mg). The yield from the culture filtrate was 30.5 %.

Blonanserin

647

References Products of Toho Chemical Industry Co Ltd., Japan Patent Specification (London), 1,038,242, Aug 10, 1966 Umezawa H. et al.; US Patent No. RE30,451; Dec. 16, 1980; Assigned: Zaidan Jojin Biseibutsu Kagaku Kenkyu Kai (Tokyo, JP)

BLONANSERIN Therapeutic Function: Antipsychotic Chemical Name: Cycloocta[b]pyridine, 2-(4-ethyl-1-piperazinyl)-4-(1fluorophenyl)-5,6,7,8,9,10-hexahydroCommon Name: Blonanserin; AD 5423 Structural Formula:

Chemical Abstracts Registry No.: 132810-10-7 Trade Name

Manufacturer

Country

Year Introduced

Lonasen

Dainippon Pharmaceutical Almirall

-

-

-

-

Blonanserin Raw Materials

2-Chloro-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine N-Ethylpiperazine Potassium iodide Manufacturing Process Preparation of 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10hexahydrocyclooc ta[b]pyridine:

648

Bluensomycin

A mixture of 2-chloro-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta [b]pyridine (2.0 g), N-ethylpiperazine (2.4 g), and potassium iodide (1.1 g) is stirred at 170°C for 5 hours. After cooling, the reaction mixture is dissolved in ethyl acetate and water. The organic layer is washed with water and extracted with 5% hydrochloric acid. The extract is made alkaline with potassium carbonate, and extracted with ethyl acetate. The extract is washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. (a) The residue is recrystallized from acetonitrile to give the desired product (1.2 g), MP: 123°-124°C. This product obtained in the above (a) is converted to the following salt thereof by treating the product with various acids. References Hino K.; US Patent No. 5,021,421; June 4. 1991; Assigned to Dainippon Pharmaceutical Co., Ltd., Osaka, Japan

BLUENSOMYCIN Therapeutic Function: Antibiotic Chemical Name: Antibiotic obtained from cultures of Streptomyces verticillus, or the same substance produced by any other means Common Name: Bluensomycin; Glebomycin Structural Formula:

Chemical Abstracts Registry No.: 11011-72-6

Bluensomycin Trade Name Bluencomycin Glebomycin Glebomycin

649

Manufacturer Shanghai Lansheng Corporation Banyu Pharm. Co., Ltd.

Country -

Year Introduced -

-

-

DSMZ-Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH

-

-

Raw Materials Streptomyces bluensis NRRL 2876 Polyacrylic acid cation exchange resin Sea sand, adsorbent cotton and fossil flour Carbon Manufacturing Process Bluensomycin was obtained from cultures of Streptomyces verticillus, or the same substance produced by any other means. For example antibiotic was prepared by growing of Streptomyces bluensis NRRL 2876 biological way and isolation from cultural solution by adsorption with a cation-exchange resin or a capillary adsorption method by elution with water-acid solution at pH from 1 to 6 or acidic water solution of acetone. 5350 L of cultivating liquid with pH 8.2 was mixed with 16 kg oxalic acid acidified with 1 N sulfuric acid to pH 2.9 and was filtered through about 160 kg fossil flour and washed with 500 L water. The filtrate (about 5400 L) was alkalified to pH 7.8-8 with 10% sodium hydroxide and was filtered through fossil flour filter. Then it was passed through two column with polyacrylic acid cation exchange resin in sodium form (US Patent No. 2,915,432). Each column was 35 cm in diameter and contained 0.126 kg of above resin. The filtrate (5300 L) was passed with rate 19 L/minute. Then the columns were washed with deionized water, 1 N sulfuric acid to pH 1.2-1.5, and at last eluted with 4x100 L water. About 200 L of column effluent was alkalifed to pH 6.4 with 10% sodium hydroxide. The 1-st column effluent was mixed with 1200 g of activated carbon, the second effluent was mixed with 850 g of coal (1 g coal per 1 g dissolved product). The mixture was thoroughly stirred and filtered. Each coal precipitate was washed 3x10 L with water and 200 L 15% water acetone. Water acetone effluent from the 1-st column (187 L) was dried and gave 1034 g of bluensomycin, the second gave 777 g. The portions of antibiotic were combined and purified by chromatography. The column (high 1.2 m, volume 155 L, with sea sand, adsorbent cotton and fossil flour as the carrier) was used. It was washed with 150 L of deionized water and 300 L 10% water acetone (rate 410 ml per minute). A fraction 101-127 L water acetone gave 640 g bluensomycin after drying. The IR and UV spectra, element analysis confirmed the structure of prepared product and its purity.

650

Bolandiol

References Eble T.E., Johnson L-R, E.; D.B. Patent No. 1,183,631; July 19, 1962; the Upjion Company, Kalamazoo, Mich. (V.St. A.)

BOLANDIOL Therapeutic Function: Anabolic Chemical Name: (3β,17β)-Estr-4-ene-3,17-diol Common Name: Bolandiol Structural Formula:

Chemical Abstracts Registry No.: 19793-20-5 Trade Name 19-Norandrostenediol

Manufacturer Epochem Co., Ltd.

Country -

Year Introduced -

Raw Materials 19-Nortestosterone Lithium aluminum hydride Manufacturing Process To a suspension of 6 parts of lithium aluminum hydride in 2100 parts of ether there are added, with stirring, 7.2 parts of 19-nortestosterone in 700 parts of ether. The mixture is stirred with heating on the steam bath for 45 min, after which the unreacted lithium aluminum hydride is decomposed by addition of acetone. The mixture is diluted with water and the organic layer is separated and washed with water and saturated aqueous sodium chloride solution. After drying over anhydrous sodium sulfate, the ether solution is evaporated under vacuum and the residue is dissolved in benzene and thus applied to a chromatography column containing 760 parts of silica gel. The column is developed with benzene and then with 5 and 10% solutions of ethyl acetate in benzene. Further elution with a 15% solution of ethyl acetate in benzene and concentration of the eluate yields a residue which is recrystallized from acetone and water, ethyl acetate and petroleum ether, and again from acetone and water to yield the 4-estrene-3β,17β-diol, melting point 169°-172°C.

Bolasterone

651

References Colton F.B.; US Patent No. 2,843,608; July 15, 1958; Assigned: G.D. Searle and Co., Chicago, III., a corporation of Delsaware

BOLASTERONE Therapeutic Function: Anabolic Chemical Name: Androst-4-en-3-one, 17-hydroxy-7,17-dimethyl-, (7α,17β)Common Name: Bolasterone; Dimethyltestosterone Structural Formula:

Chemical Abstracts Registry No.: 1605-89-6 Trade Name

Manufacturer

Country

Year Introduced

Myagen

Upjohn

-

-

Bolasterone

ThermoLife

-

-

Methosarb

Upjohn

-

-

Raw Materials Copper chloride Methyl magnesium bromide Hydrochloric acid 6-Dehydro-17-methyltestosterone Sodium carbonate Manufacturing Process A mixture of 0.4 g of cuprous chloride, 20 ml of 4 M methylmagnesium bromide in ether and 60 ml of redistilled tetrahydrofuran was stirred and cooled in an ice bath during the addition of a mixture of 2.0 g of 6-dehydro17-methyltestosterone, 60 ml of redistilled tetrahydrofuran and 0.2 g of cuprous chloride. The ice bath was removed and stirring was continued for 4 h. Ice and water were than carefully added, the solution acidified with 3 N hydrochloric acid and extracted several times with ether. The combined ether extracts were washed with a brine-sodium carbonate solution, brine and then

652

Boldenone undecylenate

dried over anhydrous magnesium sulfate, filtered and then poured over a 75.0 g column of magnesium silicate (Florisil) packed wet with hexanes (Skellysolve B). The column was eluted with 250 ml of hexanes, 0.5 liter of 2% acetone, two liters of 4% acetone and 3.5 L of 6% acetone in hexanes. The residues from fractions 8 to 16 were combined and rechromatographed over a 125.0 g column of magnesium silicate. The column was eluted with 6% acetone in hexanes. Fractions 18 to 29 were combined and dissolved in acetone, decolorized with charcoal, and recrystallized from acetone. 1.0 g of a crystalline mixture of the 7-epimers of 7,17-dimethyltestosterone was obtained melting at 120° to 140°C. The 7α-isomer are separated according to following procedure: To obtain the 7(α)-isomer of 7,17-dimethyltestosterone the crystalline mixture of the 7 stereoisomers of 7,17-dimethyltestosterone was refluxed in tertiary butyl alcohol with recrystallized chloranil under nitrogen. The reaction mixture was concentrated under a fast stream of nitrogen, diluted with methylene chloride and the solution washed with dilute sodium hydroxide, water and then dried, filtered and the solvent removed. The residue, was combined with the product from an identical run and chromatographed through a magnesium silicate column developed with solvent of the following composition and order: two each of hexane hydrocarbons (Skellysolve B), hexanes plus 4% acetone, hexanes plus 8% acetone, hexanes plus 12% acetone, hexanes plus 14% acetone, hexanes plus 16% acetone, hexanes plus 18% acetone, hexanes plus 20% acetone, hexanes plus 24% acetone, hexanes plus 28% acetone, and two of acetone. The residues, eluted with mixture: water-acetone, were combined and chromatographed through a 50 g 1:1 charcoal (Darco)-diatomaceous earth (Celite) column. The column was developed with solvent of the following composition and order: methanol, a 1:1 mixture of methanol and acetone, a 1:2 mixture of methanol and acetone, acetone and a 1:4 mixture of acetone and methylene chloride. Fractions, containing 7(α)-epimer were combined, the solvent evaporated and the residue crystallized from acetone to give the 7α,17-dimethyltestosterone, melting point at 163° to 165°C. References Babcock J.C., Campbell J.A.; US Patent No. 3,341,557; Sept. 12, 1967; Assigned: The Upjohn Company, Kalamazoo, Mich a corporation of Delaware

BOLDENONE UNDECYLENATE Therapeutic Function: Anabolic Chemical Name: Androsta-1,4-dien-3-one, 17β-hydroxy-, 10-undecenoate Common Name: Boldenone undecylenate; Boldone; Vebonol

Boldenone undecylenate

653

Structural Formula:

Chemical Abstracts Registry No.: 13103-34-9 Trade Name Boldenone undecylenate

Manufacturer Country Shandong Xinfa Pharmaceutical Co., Ltd. Epochem Co., Ltd. -

Year Introduced -

Equipoise Equipoise Bold 200 Boldane Vebonol

Genfar Squibb Quality Vet Squibb Ciba-Geigy Agrochemicals

-

-

Vebonol Pace Parenabol

Ciba-Geigy Jurox Labs Ciba

-

-

Boldenone undecylenate

-

Raw Materials L-Dehydrotestosterone Undecylene chloride Manufacturing Process To a solution 5 g of L-dehydrotestosterone in 25 ml of benzene was added 3 ml of pyridine and 7.1 ml undecylene chloride. The mixture was heated for 2 heurs at 70°C. After cooling pyridine hydrochloride was filtered off. The filtrat was purified via chromatography on neutral aluminum oxide. Benzenic eluate was concentrated to obtain 1-dehydrotestosteron 17-undecylenate (boldenone undecylenate) as an oil; λmax 243-244 nm. References Belg. Patent No. 623,277, Oct. 10, 1961; Assigned to E. Merck Aktiengesellschaft, Darmstadt, Germany

654

Bopindolol

BOPINDOLOL Therapeutic Function: Beta-adrenergic blocker Chemical Name: 2-Propanol, 1-((1,1-dimethylethyl)amino)-3-((2-methyl-1Hindol-4-yl)oxy)-, benzoate (ester), (+/-)Common Name: Bopindolol; Sandonorm; Wandonorm Structural Formula:

Chemical Abstracts Registry No.: 62658-63-3 Trade Name Bopindolol

Manufacturer Country Sandoz (Novartis) -

Year Introduced -

Raw Materials Benzoic acid Hexamethylphosphoric acid triamide 1-t-Butylamino-3-(2-methyl-indole-4-yloxy)-2-propanol Benzoic acid anhydride Tartaric acid Manufacturing Process 4-(2-Benzoyloxy-3-t-butylaminopropoxy)-2-methyl-indole: 26 g of benzoic acid are dissolved, while heating, in 50 ml of hexamethylphosphoric acid triamide and 3.5 g of 1-t-butylamino-3-(2-methylindole-4-yloxy)-2-propanol are added. After cooling, 3.0 g of benzoic acid anhydride are added and stirred for 20 hours at room temperature. The resulting clear, yellow solution is poured onto ice 0.5 liters of ether are added and stirred for 2 hours. After making the liquid alkaline with concentrated ammonia, the ether phase is separated, shaken out with tartaric acid, made alkaline with caustic soda solution while cooling with ice and extracted with methylene chloride. After evaporating the solvent, the residue is crystallized with 1 mol of fumaric acid from methanol and acetone.

Bornaprolol hydrochloride

655

References Troxler F. et al.; US Patent No. 4,340,541; July 20, 1982; Assigned to Sandoz Ltd., Basel, Switzerland

BORNAPROLOL HYDROCHLORIDE Therapeutic Function: Beta-adrenergic blocker Chemical Name: 1-(Isopropylamino)-3-(o-2-exo-norbornylphenoxy)-2propanol hydrochloride Common Name: Bornaprolol hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 66451-06-7 (Base); 69319-47-7 Trade Name Bornaprolol hydrochloride

Manufacturer Onbio Inc.

Country -

Year Introduced -

Raw Materials 2-(2-Norbornylexo)phenol Epichlorohydrin

Sodium Isopropylamine

Manufacturing Process 1-Isopropylamino-3-[2-(2-norbornylexo)phenoxy]propan-2-ol: 24.5 g (0.13 moles) 2-(2-norbornylexo)phenol (L. A. KHEIFITS and A. E. GOL'DOVSKII, Zh. Obshch. Khim., 1963, 33, 2048), 350 ml anhydrous toluene and 3 g (0.13 mole) metallic sodium are introduced into a three-neck flask through which a stream of nitrogen flows. The reaction mixture is refluxed until the liberation of hydrogen ceases, then the solvent is driven off under reduced pressure and the residue is taken up in 250 ml tetrahydrofuran. 24 g (0.26 mole) epichlorohydrin are then added and the mixture is heated under reflux for 6 hours. An extraction with ether is then undertaken, the organic phase is washed with water, dried and the solvent is evaporated. 25 g 2-(2norbornylexo)-1-phenoxy-2,3-epoxypropane are thus obtained in the form of

656

Bosentan

an oil. 15 g (0.06 mole) of the preceding product are dissolved in 50 ml isopropylamine. After 4 days contact, the excess amine is evaporated under reduced pressure, then an extraction with ether is carried out. After washing with water and drying, the ethereal phase is saturated with gaseous hydrochloric acid. The precipitate formed is washed abundantly with ether then crystallized from an acetone/ethanol mixture (3/2). 16 g of the desired product in the form of the hydrochloride are thus obtained, having a melting point of 189°-191°C. References Mardiguuian J.; US Patent No. 4,157,400; June 5, 1979; Assigned to MARPHA, Societe d'Etude et d'Explotation de Marques, Paris, France

BOSENTAN Therapeutic Function: Endothelin receptor antagonist Chemical Name: Benzenesulfonamide, 4-(1,1-dimethylethyl)-N-(6-(2hydroxyethoxy)-5-(2-methoxyphenoxy)(2,2'-bipyrimidin)-4-yl)Common Name: Bosentan; Tracleer Structural Formula:

Chemical Abstracts Registry No.: 147536-97-8 Trade Name Bosentan

Manufacturer Roche

Country -

Year Introduced -

Raw Materials Pyrimidine-2-carboxamidine hydrochloride 5-(2-Methoxyphenoxy)-2-(pyrimidin-2-yl)tetrahydropyrimidine-4,6-dione 4,6-Dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine 4-t-Butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl)pyrimidin-4-yl]benzenesulfonamide

Botiacrine

657

Sodium Ethylene glycol Tartaric acid Manufacturing Process A solution of 0.11 g of sodium in 3.0 ml of ethylene glycol and equivalent of 4-t-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl)-pyrimidin-4yl]benzenesulphonamide were heated to 100°C, cooled for a further 4 hours, poured on to ice and adjusted to pH 3 with 1 M tartaric acid. The suspension obtained was extracted with ethyl acetate, the organic extracts were combined, washed with water, dried with sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel with CH2Cl2-ethyl acetate 9:1 and yielded 4-t-butyl-N-[6-(2-hydroxyethoxy)-5-(2methoxyphenoxy)-2-(pyrimidin-2-yl)-pyrimidin-4-yl]benzenesulphonamide as a solid. Sodium salt melted at 195°-198°C. The 4-t-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-pyrimidin-2-yl)-pyrimidin4-yl]benzenesulfonamide was prepared starting from pyrimidine-2carboxamidine hydrochloride via rac-5-(2-methoxyphenoxy)-2-(pyrimidin-2yl)tetrahydropyrimidine-4,6-dione and 4,6-dichloro-5-(2-methoxyphenoxy)2,2'-bipyrimidine. References Burri K. et al.; US Patent No. 5,292,740; March 8, 1994; Assigned to Hoffmann-La Roche Inc., Nutley, N.J.

BOTIACRINE Therapeutic Function: Antiparkinsonian Chemical Name: 10-Acridancarbothioic acid, 9,9-dimethyl-, S-(2(dimethylamino)ethyl) ester Common Name: Botiacrine Structural Formula:

Chemical Abstracts Registry No.: 4774-53-2

658

Boxidine

Trade Name Botiacrine

Manufacturer ZYF Pharm Chemical

Country -

Year Introduced -

Raw Materials Dimethylaminoethanethiol 9,9-Dimethylacridan Phosgene Manufacturing Process To 1 gramm-equivalent (g-eq) of dimethylaminoethanethiol in 150 ml of ether, a suspension of g-eq of 50% sodium hydride in 50-ml of anhydrous ether was added. After boiling for 1 hour, the reaction mixture was cooled to 0°C, whereupon g-eq of 9,9-dimethylacridan-10-carboxylic acid chloride (prepared from 9,9-dimethylacridan and phosghene - cf. Swiss Specification No. 426,821) were added and the mixture was heated for a further 6 hours to boiling temperature. After cooling to ambient temperature, the precipitated sodium chloride was filtered in a Buchner funnel fitted with a filter cell. The corresponding 9,9-dimethylacridan-10-carboxylic aciddimethylaminoethanethiol ester was immediately precipitated out of filtrate as base, which melted at 110.5°-111°C. Ethanesulphonic acid salt melted at 147°-150°C. References Molnar I. et al.; US Patent No. 3,630,918; August 20, 1974; Assigned to Siegfried Aktiengesellschaft, Zofingen, Switzerland

BOXIDINE Therapeutic Function: Antihyperlipidemic Chemical Name: Pyrrolidine, 1-(2-((4'-(trifluoromethyl)(1,1'-biphenyl)-4-yl) oxy)ethyl)Common Name: Boxidine Structural Formula:

Chemical Abstracts Registry No.: 10355-14-3

Boxidine Trade Name Boxidine

Manufacturer Onbio Inc.

Country -

659

Year Introduced -

Raw Materials p-Iodobenzotrifluoride Copper 2-Pyrrolidinylethyl chloride p-Bromobenzotrifluoride Methyl iodide Nitrobenzene

p-Iodoanisole Hydrobromic acid 4-Hydroxy-4'-trifluoromethylbiphenyl 4-Methoxycyclohexanone Palladium on carbon

Manufacturing Process The title compound may be prepared 2 ways: 1). 1-(2-[4'-(Trifluoromethyl)-4-biphenylyloxy]ethyl)pyrrolidine: A suspension consisting of 89.8 g (0.33 mole) of p-iodobenzotrifluoride, 132.5 g (0.65 mole) of p-iodoanisole, and 322.7 g of Cu powder in DMF (175 ml) was heated (225-230°C) with stirring in a resin pot for about 5 days. After cooling, the solid reaction mass was pulverized and continuously extracted (heptane) for 2 days. Evaporation of the solvent left a dark brown residue (ca. 50 g) which was dissolved (heptane, 200 ml), decolorized (charcoal), and concentrated to 100 ml. On standing ca. 20 g of impure 4,4'dimethoxybiphenyl were deposited as colorless crystals. Fractional crystallization was continued until the crops of crystalline material were free of impurities by TLC (80:20 heptane-ethyl acetate). Pure 4-methoxy-4'trifluoromethylbiphenyl was isolated as colorless granules, 21.6 g (26%), MP: 124-126°C. A solution consisting of 21.6 g (0.09 moles) of 4-methoxy-4'trifluoromethylbiphenyl dissolved in glacial acetic acid and HBr (48%) was refluxed for approximately 24 hr. After cooling the acetic reaction mixture was poured into H2O (1.5 L) and the solid which separated was collected and air dried. 18.0 g (83%) of the crude product was isolated and taken up in Et2O (100 ml), decolorized (charcoal), filtered, and concentrated to one-third of the original volume. The material which separated from the Et2O solution (m.p. 147-148°C) was pure enough for the next synthetic step (structure verified by NMR). 1.5.6 g (0.06 mole) of the sodium derivative of 4-hydroxy-4'trifluoromethylbiphenyl (prepared from 4-hydroxy-4'-trifluoromethylbiphenyl and sodium hydride) allowed to react with 8.0 g (0.06 mole) of 2pyrrolidinylethyl chloride in refluxing DMF (100 ml) for 18 hr. The resulting suspension was cooled, filtered, and the clear filtrate was concentrated to semisolid residue. Two 100 ml portions of water were used to triturate the crude product which was then dissolved in benzene; the solution was decolorized (char coal) and dried (Na2SO4) and the benzene was removed. Several fractional crystallizations from acetone afforded 9.8 g (49%) of pure 1-1 2- [4'-(trifluoromethyl)-4-biphenylyloxy]ethyl)pyrrolidine MP: 109-110°C. 2). p-Bromobenzotrifluoride (1.37 g, 0.7 mole) and ca. 1.0 g of MeI dissolved in dry Et2O (200 ml) was added to 19 g (0.8 g-atom) of 11 g suspended in Et2O (20 ml) under the usual conditions. Addition of the aromatic halide was regulated to maintain a gentle reflux and refluxing was continued an

660

Bretazenil

additional 1 hr after addition was complete. 4-Methoxycyclohexanone (64 g, 0.5 mole) dissolved in 75 ml of dry Et2O was added to the freshly formed Grignard reagent with vigorous stirring and, after addition of the ketone was complete, the reaction mixture was refluxed with stirring for approximately 1 hr. Decomposition of the Grignard reagent-ketone addition product was achieved by adding excess cold, aqueous ammonia chloride (53 g in 1 L of H2O), and the crude product was removed using two 100-ml portions of Et2O. The combined extracts were decolorized (charcoal), filtered, and dried (Na2SO4). Removal of the Et2O left a brown, oily residue which was distilled in vacuum affording 51.3 g (38%) of 1-(p-trifluoromethylphenyl)-4methoxycyclohexanol, b.p. 121-122°C (0.4-0.5 mm), m.p. 53-54°C. The 4-methoxycyclohexanol derivative (27 g, 0.1 mole), purified as described above, was added to a vigorously stirred concentrated H2SO2-glacial acetic acid (10:40 ml) solution. When a clear solution resulted (ca. 2 min), the reaction mixture was poured all at once into a previously cooled (5-10% mixture of H2O (300 ml) covered with Et2O (300 ml)). The Et2O layer was separated, dried (Na2SO4), and concentrated to a brown, oily residue. Fractionation of the crude oil yielded 18.3 g (717) of 1-(ptrifluoromethylphenyl)-4-methoxycyclohexene, b.p. 104-103°C (0.3-0.4 mm). Dehydrogenation of the purified 4-methoxycyclohexene derivative, obtained as described above, was accomplished using a modification of the method described by Anisworth (J.A.C.S., 76, 4446 (1954)). A suspension consisting of 1-(p-trifluoromethylphenyl)-4-methoxycyclohexene (500 g, 1.95 moles), 166 g of Pd/C and nitrobenzene was refluxed for 22 hr. Aliquots of the reaction mixture taken periodically and analyzed by TLC (heptane-ethyl acetate (4:1) solvent system) indicated that aromatization was complete after this period of time, Removal of the nitrobenzene under reduced pressure left 442 g (89.9%) of the crude biphenyl derivative. Two recrystallizations (petroleum ether) produced material identical with that obtained from the 1 procedure described above. References Bach FL et al.; J. Med. Chem.; 1968, 11, 987

BRETAZENIL Therapeutic Function: Anxiolytic Chemical Name: (S)-8-Bromo-11,12,13,13a-tetrahydro-9-oxo-9Himidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylic acid 1,1dimethylethyl ester Common Name: Bretazenil Chemical Abstracts Registry No.: 84379-13-5

Bretazenil

661

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Bretazenil

Hoffman-La Roche, Inc.

-

-

Raw Materials 6-Bromoisatoic acid anhydride Sodium hydride Potassium t-butylate

Proline, LDiethylchlorophosphate t-Butyl isocyanoacetate

Manufacturing Process 50.6 mmol of 6-bromoisatoic acid anhydride are stirred at 110°C for 2 hours with 50.6 mmol of L-proline in 80 ml of dimethyl sulphoxide. The solution is evaporated and the residue is crystallized from ethyl acetate. There is obtained (S)-6-bromo-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1c][1,4]benzodiazepine-5,11(10H)-dione. A suspension of 29.8 mmol of sodium hydride (55 percent oil dispersion) in 40 ml of dry dimethylformamide is treated at 20-30°C with 27.1 mmol of (S)-6bromo-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10H)dione, the mixture is stirred in the above temperature range for 45 min and then at -35°C 27.1 mmol of diethylchlorophosphate are added dropwise thereto. Separately, 3.0 g (27.1 mmol) of potassium t-butylate are dissolved in 9.0 ml of dry dimethylformamide, cooled in an acetone/dry-ice bath, treated with 3.9 g (27.1 mmol) of t-butyl isocyanoacetate and the solution obtained is added dropwise at -15°C to the mixture obtained according to the preceding paragraph. The mixture is warmed to 15°C, neutralized with 1.5 ml of glacial acetic acid, poured into 100 ml of water and extracted four times with methylene chloride. The methylene chloride solution is washed twice with water, dried over magnesium sulfate, evaporated and the crude product obtained is chromatographed on silica gel using ethyl acetate for the elution. By recrystallization from ethyl acetate/n-hexane there is obtained t-butyl (S)8-bromo-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1c][1,4]benzodiazepine-1-carboxylate. References Hunkeler W., Kyburz E.; US Patent No. 4,353,827; October 12, 1982; Assigned to Hoffmann-La Roche Inc. (Nutley, NJ)

662

Bretylium tosylate

BRETYLIUM TOSYLATE Therapeutic Function: Adrenergic blocker; Antiarrhythmic Chemical Name: 2-Bromo-N-ethyl-N,N-dimethylbenzenemethanaminium 4methylbenzene sulfonate Common Name: Structural Formula:

Chemical Abstracts Registry No.: 61-75-6 Trade Name Bretylate Bretylate Bretylol Critifib Darenthin

Manufacturer Wellcome Wellcome Am. Crit. Care Arnar-Stone BurroughsWellcome

Country UK France US US US

Year Introduced 1973 1974 1978 -

Raw Materials N-o-Bromobenzyl-N,N-dimethylamine Ethyl-p-toluene sulfonate Manufacturing Process N-o-Bromobenzyl-N,N-dimethylamine (100g) and ethyl p-toluenesulfonate (94 g) were mixed and warmed to 50°-60°C; after standing for either (a) a minimum of 96 hours at 15°-20°C or (b) a minimum of 18 hours at 50°-60°C and cooling to room temperature, a hard, crystalline mass was formed. Recrystallization of this product from acetone (2.0 ml/g of crude solid), followed by filtration and drying to 60°C gave N-o-bromobenzyl-N-ethyl-N,Ndimethylammonium p-toluenesulfonate as a white, crystalline solid, MP 97°99°C. For this procedure it was necessary that the reactants were substantially colorless and of a high purity.

Brimonidine

663

References Merck Index 1348 PDR p.574 OCDS Vol.1 p.55 (1977) DOT 16 (10) 359 (1980) I.N. p.152 REM p. 860 Copp, F.C. and Stephenson, D.; US Patent 3,038,004; June 5, 1962; assigned to Burroughs Wellcome and Co.

BRIMONIDINE Therapeutic Function: Antiglaucoma Chemical Name: 6-Quinoxalinamine, 5-bromo-N-(4,5-dihydro-1H-imidazol-2yl)Common Name: Brimonidine Structural Formula:

Chemical Abstracts Registry No.: 59803-98-4 Trade Name Alphagan P Brimonidine

Manufacturer Allergan Ratiopharm

Country Australia -

Year Introduced -

Raw Materials 6-Aminoquinoxaline Thiophosgene Sodium bisulfite

Bromine Ethylenediamine

Manufacturing Process 6-Aminoquinoxaline (2.08 g, 14.4 mmol) was dissolved in 11.5 ml glacial acetic acid. The solution was cooled in water while a solution of bromine (0.74 ml, 2.3 g, 14.4 mmol) in 1.5 ml glacial acetic acid was added slowly over 15 min. After stirring for an additional 30 min. the orange red solid formed was filtered off and washed thoroughly with dry ether. The solid was dried in vacuo overnight to yield 4.44 g crude product (a yield of 100%). The compound, 6amino-5-bromoquinoxaline hydrobromide, had no definite melting point. A

664

Brimonidine

phase change (from fine powder to red crystals) was noticed at about 220°C. Decomposition was observed at about 245°C. It was used directly for the next step. The crude 6-amino-5-bromoquinoxaline from above was dissolved in water and saturated sodium bisulfite solution was added until the resulting solution tested negative with starch-iodide paper. The solution was then basified with 2 N sodium hydroxide and extracted thoroughly with ethyl acetate. The organic extract was dried over magnesium sulfate and concentrated under reduced pressure to give the free base. The crude product was recrystallized from boiling benzene to give yellow crystals, m.p. 155°-156°C. Using various analytical procedures, the yellow crystals were determined to be 6-amino-5bromoquinoxaline. The yield was 82%. The crude hydrobromide product previously noted (4.27 g, 14.0 mmol) was dissolved in 60 ml of water and thiophosgene (1.28 ml, 16.8 mmol) was added in small portions with vigorous stirring. After 2 hours, the red color of the solution was discharged. The solid formed was filtered off and washed thoroughly with water. After drying in vacuo at 25°C 3.38 g (a yield of 90%) of brick red crystals was obtained, m.p. 157°-158°C. A portion of this material was further purified by column chromatography to give white crystals, m.p. 157°-158°C. Using various analytical procedures, these crystals were determined to be 5-bromo-6-isothiocyanatoquinoxaline. A solution of the isothiocyanate (3.25 g, 12.2 mmol) in 145 ml benzene was added to a solution of ethylenediamine (5.43 g, 90.0 mmol) in 18 ml benzene at 25°C over 2 hours. After stirring for a further 30 min., the supernatant was poured off. The oil which remained was washed by swirling with dry ether three times and used directly for the next step. A portion of this product was further purified by column chromatography (SiO2, CHCl3) for characterization. A white solid was decomposed at 175°C. This white solid was determined to be 5-bromo-6-(N-2-(aminoethyl)thioureido)quinoxaline. The crude product from above was dissolved in 100 ml dry methanol and the brown solution was refluxed for 19 hours until hydrogen sulfide gas was no longer evolved. The mixture was cooled to room temperature and concentrated to about 50 ml. The yellow solid was filtered off and dried in vacuo; weight 2.52 g (a yield of 70%), m.p. 242°-244°C. As the crude product was insoluble in most common organic solvents, initial purification was achieved by an acid-base extraction procedure. 23 g of the crude product was dissolved in 100 ml 0.5 N hydrochloric acid. The turbid yellow solution was filtered to give a clear orange yellow solution which was extracted twice with ethyl acetate (2x10 ml). The aqueous phase was cooled to 0°C and basified with 6 N sodium hydroxide, keeping the temperature of the solution below 15°C at all times. The yellow solid which precipitated was filtered off and washed thoroughly with water until the washings were neutral to pH paper. The solid was dried overnight in vacuo to give 1.97 g yellow solid, m.p. 249°-250°C. The recovery was about 88%. Further purification was achieved by recrystallization as described below. The partially purified product from above was dissolved in N,N-dimethylformamide (about 17 ml/g) at 100°C with vigorous stirring. The solution was filtered hot and set aside to cool overnight. The bright yellow crystals were collected by filtration, m.p. 252°-253°C. Recovery was from 65-77%. Using various

Brinzolamide

665

analytical procedures the bright yellow solid was determined to be 5-bromo-6(2-imidazolin-2-ylamino)quinoxaline. References Danielewicz J.C. et al.; US Patent No. 3,890,319; June 17, 1975; Assigned: Pfizer Inc., NewYork, N.Y. Burke J.A. et al.; US Patent no. 5,756,503; May 26, 1998; Assigned: Allergan (Waco, TX)

BRINZOLAMIDE Therapeutic Function: Antiglaucoma Chemical Name: (R)-4-Ethylamino-2-(3-methoxypropyl)-3,4-dihydro-2Hthieno[3,2-e]-1,2-thiazine-6-sulfonamide-1,1-dioxide Common Name: Brinzolamide Structural Formula:

Chemical Abstracts Registry No.: 138890-62-7 Trade Name

Manufacturer

Country

Year Introduced

Azopt

Alcon

-

-

Raw Materials 3-(2,5,5-Trimethyl-1,3-dioxane2-yl)thiophene 2-Bromoethyl methylether 2-(Bromomethyl)ethyl methyl ether Propylamine

Sulfur dioxide Hydroxylamine-O-sulfonic acid Pyridinium bromide perbromide Sodium borohydride Butyl lithium

Manufacturing Process To a solution of 3-(2,5,5-trimethyl-1,3-dioxane-2-yl)thiophene (2.5 g, 11.7 mmol) in hexane (30 mL) cooled to 0°C was added via syringe n-butyl lithium in hexane (2.5 M, 10.3 mL, 25.7 mmol) over 5 min. The mixture was stirred at 0°C for 20 min, the ice bath was removed and the stirring was continued for 30 min. At this time a white precipitate formed. The mixture was cooled to

666

Brinzolamide

-60°C and THF (20 mL) was added. Sulfur dioxide was then passed through the surface of the mixture for 30 min. The mixture was warmed to ambient temperature and stirred for an additional 15 min. The volatiles were evaporated and to the residue was added water (50 mL) and sodium acetate trihydrate (9.55 g, 70.2 mmol). The solution was cooled on an ice bath and hydroxylamine-O-sulfonic acid (4.62 g, 40.9 mmol) was added. The mixture was stirred at ambient temperature for 1 h, extracted with ethyl acetate (3x100 mL) and the combined extracts were washed with a sodium bicarbonate solution, brine and dried over molecular sieves. Evaporation to dryness gave a viscous liquid (4.93 g), which was chromatographed (silica, eluting with 33% ethyl acetate-hexane) to give a solid 3-(2,5,5-trimethyl-1,3dioxane-2-yl)-2-thiophenesulfonamide (2.47 g, 72%): m.p. 200°-202°C. The last compound (9.45 g, 32.5 mmol) and 1 N HCl (100 mL) in THF (100 mL) was heated at reflux for 1 h. The THF was evaporated and the aqueous solution was made basic by the addition of sodium bicarbonate. The mixture was cooled using an ice bath and the precipitate was filtered, washed with cold water and dried in vacuo to give 5.83 g (88%) of a solid 3-acetyl-2thiophenesulfonamide: m.p. 193°-196°C. The last product (5.73 g, 28.0 mmol) was dissolved in hot THF (200 mL). The solution was cooled to 10°C and pyridinium bromide perbromide (10.73 g, 33.5 mmol) was added. The mixture was allowed to stir at ambient temperature for 1 h. The volatiles were evaporated and the residue was mixed with water. The precipitate was filtered, washed with cold water and dried in vacuo overnight to give 7.77 g of a solid. A portion of this solid (3.49 g, 12.3 mmol) was suspended in ethanol (100 mL) and treated with sodium borohydride (266 mg, 7.04 mmol). The suspension turned clear after 10 min and was heated at reflux for 1 h. The ethanol was evaporated and the residue was extracted with ethyl acetate, washed with brine and evaporated to give 3,4-dihydro-4-hydroxy-2H-thieno[3,2-e]-1,2-thiazine 1,1-dioxide (1.80 g, 71%): m.p. 138°-140°C. A solution of the above product (19.2 g, 0.093 mol) in DMF (125 mL) was added to a suspension of sodium hydride (3.08 g, 80% oil dispersion, 0.103 mol) in DMF at 006. When the addition was completed the ice bath was removed and the reaction 20 mixture stirred at ambient temperature for 1 h. The reaction mixture was cooled to 0°C and 2-bromoethyl methylether (13.6 mL, 0.14 mol) was added. The reaction mixture was stirred at ambient temperature for 18 h after which time it was evaporated to dryness. The residue was suspended in brine (100 mL) and extracted with methylene chloride (4x80 mL). The combined extracts were dried (MgSO4), filtered and evaporated to a solid which was recrystallized from ethyl acetate to give the desired subject (17.4 g). Chromatography of the mother liquor (silica, 3% ethanol/methylene chloride) furnished more subject which was combined with the first batch to give a total of 19.3 g (78%) of 3,4-dihydro-4-hydroxy-2-(2methoxy)ethyl-2H-thieno[3,2-e]-1,2-thiazine 1,1-dioxide. 3,4-Dihydro-4-hydroxy-2-(2-methoxy)ethyl-2H-thieno[3,2-e]-1,2-thiazine 1,1dioxide (4.9 g, 50 18.6 mmol) was converted to the 4-(1-ethoxy)ethoxy-3,4dihydro-2-(2-methoxy)ethyl-2H-thieno[3,2-e]-1,2-thiazine 1,1-dioxide (6.2 g, 99%) using the reaction with p-toluensulfonic acid and ethylvinyl ether at 0°C in tetrahydrofuran for 2 hrs.

Bromazepam

667

The last one (6.2 g, 18.4 mmol) was converted into 3,4-dihydro-4-hydroxy-2(2-methoxy)ethyl-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide (4.87 g, 77%) m.p. 187°C by using the reaction with n-butyl lithium in anhydrous THF at -40°C for 40 min, and then bubbling sulfur dioxide gas for 20 min after which time the mixture was warmed to room temperature. After 30 min at room temperature the mixture was concentrated the residue was dissolved in water, cooled (0°C), sodium acetate trihydrate was added followed by hydroxylamine-O-sulfonic acid. The reaction mixture was stirred at room temperature for 18 h after which time was basified with solid sodium bicarbonate and extracted with ethyl acetate. 3,4-Dihydro-2-(2-methoxy)ethyl-4-propylamino-2H-thieno[3,2-e]-1,2-thiazine6-sulfonamide-1,1-dioxide hydrochloride was obtained by the reaction of 3,4dihydro-4-hydroxy-2-(2-methoxy)ethyl-2H-thieno[3,2-e]-1,2-thiazine-6sulfonamide-1,1-dioxide in THF containing triethylamine with tosyl chloride at -16°C and the next stirring for 18 hrs at room temperature. After which time the mixture was cooled to 0°C and propylamine was added, the desired product (0.57 g, 46%) was obtained: m.p. 178°-181°C. The desired 4-ethylamino-3,4-dihydro-2-(3-methoxy)propyl-2H-thieno[3,2-e]1,2-thriazine-6-sulfonamide-1,1-dioxide was prepared according to described above procedure for 3,4-dihydro-4-hydroxy-2-(2-methoxy)ethyl-2Hthieno[3,2-e]-1,2-thiazine-6-sulfonamide-1,1-dioxide substituting 2bromoethylmethylether for 2-(bromomethyl)ethyl-methylether. References Dean T.R. et al.; US Patent No. 5,240,923; Aug. 31, 1993; Assigned: Alcon Laboratories, Inc. (Fort Worth, TX)

BROMAZEPAM Therapeutic Function: Tranquilizer Chemical Name: 7-Bromo-1,3-dihydro-5-(2-pyridinyl)-2H-1,4-benzodiazepin2-one Common Name: Structural Formula:

Chemical Abstracts Registry No.: 1812-30-2

668

Bromazepam

Trade Name Lexotan Lexotan Lexotanil Lexotanil Lexomil Lexotan Compedium Creosidin Lectopam Lenitin Lexaurin Lexilium Normoc

Manufacturer Roche Roche Roche Roche Roche Roche Polifarma Osiris Hoffmann - La Roche Inc. Ikapharm Krka Alkaloid Merckle

Country Italy Japan W. Germany Switz. France UK Italy Argentina US

Year Introduced 1975 1977 1977 1977 1981 1982 -

Israel Yugoslavia Yugoslavia W. Germany

-

Raw Materials 2-(2-Aminobenzoyl)pyridine Bromine Bromoacetyl bromide Ammonia

Acetic anhydride Hydrogen chloride Water

Manufacturing Process Example: 32.8 grams of 2-(2-aminobenzoyl)-pyridine and 200 cc of acetic anhydride were stirred at room temperature for 3 hours and then permitted to stand overnight. Evaporation to dryness and digestion of the residue with 200 cc of water containing a little sodium bicarbonate to make the pH slightly alkaline gave 2-(2-acetamidobenzoyl)-pyridine as a light tan powder, which upon crystallization from methanol formed colorless crystals melting at 151°153°C. A solution of 8.6 cc of bromine in 100 cc of acetic acid was added slowly over a 3.5 hour period to a stirred solution of 38.5 grams of 2-(2acetamidobenzoyl)-pyridinein 250 cc of acetic acid. The dark solution was stirred for another 3 hours, permitted to stand over night, stirred for 1 hour with N2 sweeping, and evaporated at diminished pressure in the hood. The gummy residue (75 grams) was treated with water and ether, made alkaline with dilute sodium bicarbonate solution, and separated. Both phases contained undissolved product which was filtered off. Additional crops were obtained by further extraction of the aqueous phase with ether and evaporation of the resulting ether solutions. All these materials were recrystallized from methanol (decolorizing carbon added) yielding 2-(2-acetamido-5-bromobenzoyl)pyridineas yellow crystals melting at 131.5°-133°C. 20.85 grams of 2-(2-acetamido-5-bromobenzoyl)-pyridinein 250 cc of 20% hydrochloric acid in ethanol were heated to reflux for 2 hours. 100 cc of alcohol were added after one hour to maintain fluidity. The mixture stood overnight, was chilled and filtered to give 20.5 grams of colorless crystalline 2-(2-amino-5-bromobenzoyl)-pyridinehydrochloride. Digestion of this

Bromazepam

669

hydrochloride with 0.5liter hot water hydrolyzed this product to the free base, 2-(2-amino-5-bromobenzoyl)-pyridine which formed yellow crystals, melting at 98°-100°C. Evaporation of the alcoholic mother liquor, water digestion of the residue, and alkalization of the water digests afforded additional crops of 2-(2-amino-5-bromobenzoyl)pyridine. 0.145 kg of 2-(2-amino-5-bromobenzoyl)-pyridine, was dissolved in 2.0 liters of glacial acetic acid. The resultant solution was placed in a 3 liter, 3-necked, round bottom flask fitted with a stirrer, thermometer and dropping funnel. The system was protected by a drying tube filled with anhydrous calcium chloride. To the solution, with stirring at room temperature, were carefully added 46.7 ml of bromoacetyl bromide. After the addition was completed, the stirring was continued for two hours. The mixture was then warmed to 40°C, stirred at that temperature for 1.5 hours, chilled and filtered. The residue, after being washed with glacial acetic acid, was dried in vacuo over flake potassium hydroxide to give 2-(2-bromoacetamido-5-bromobenzoyl)pyridinehydrobromide orange crystals, MP 205°-206°C, dec. The hydrobromide was hydrolyzed to the free base as follows: 0.119 kg of 2(2-bromoacetamido-5-bromobenzoyl)-pyridine hydrobromide was stirred with 1.2 liters of cold water for 3.5 hours. The mixture was chilled and filtered, and the residue washed with cold water and dried to give 2-(2-bromoacetamido-5bromobenzoyl)-pyridine, MP 101°C (sinters), 103°-106°C, dec. 93.0 grams of 2-(2-bromoacetamido-5-bromobenzoyl)-pyridinewas carefully added to 0.5 liter of anhydrous ammonia in a 1 liter, 3-necked, round bottom flask equipped with stirrer and reflux condenser and cooled by a Dry Iceacetone bath. The system was protected from moisture by a drying tube containing anhydrous calcium chloride. After stirring for 2 hours, the cooling bath was removed. The mixture was then stirred for 6 hours, during which time the ammonia gradually boiled off. 0.4 liter of water was added to the solid residue and stirrind was resumed for about 2 hours. The solid was then filtered off, washed with water and dried in vacuo over potassium hydroxide flakes. The residue was dissolved on a steam bath in 1.4 liters of ethyl alcohol-acetonitrile (1:1) (decolorizing charcoal added). The solution was filtered hot and the filtrate chilled overnight. The crystalline deposit was filtered off, washed with cold ethyl alcohol and dried in vacuo over flake potassium hydroxide to give 54.2 grams. 7-Bromo-1,3-dihydro-5-(2-pyridyl)2H-1,4-benzodiazepin-2-one, MP 238°C (sinters), 239°-240.5°, dec. Further processing of the mother liquor yielded additional product. References Merck Index 1357 Kleeman and Engel p.110 DOT 9 (6) 238 (1973) and 11 (1) 31 (1975) I.N. p. 154 REM p. 1064 Fryer, R.I., Schmidt, R.A. and Sternbach, L.H.; US Patent 3,100,770; August 13, 1963; assigned to Hoffmann-LaRoche Inc. Fryer, R.I., Schmidt, R.A. and Sternbach, L.H.; US Patent 3,182,065; May 4, 1965; assigned to Hoffmann-LaRoche Inc. Fryer, R.I., Schmidt, R.A. and Sternbach, L.H.; US Patent 3,182,067; May 4, 1965; assigned to Hoffmann-LaRoche Inc.

670

Bromelain

BROMELAIN Therapeutic Function: Antiinflammatory Chemical Name: Complex proteolytic enzyme Common Name: Structural Formula: Complex protein, molecular weight 33,000 Chemical Abstracts Registry No.: 9001-00-7 Trade Name Ananase Bromelain Resolvit Ananase Ananase Extranase Bromelain Ananase Ananase Bromelain Dayto Anase Inflamen Mexase Pinase Proteolvis Resolvit Rogorin Traumanase

Manufacturer Rorer Nadrol Mepha Rorer Rorer Rorer Towa Yakuhin Pharmax Yamanouchi Permicutan Dayton Hokuriku Ciba Geigy Dainippon Benvegna Mepha Saba Arznei MullerRorer

Country US W. Germany Switz. Italy UK France Japan UK Japan W. Germany US Japan France Japan Italy Switz. Italy W. Germany

Year Introduced 1962 1965 1965 1965 1966 1969 1981 -

Raw Materials Pineapple Juice Acetone Manufacturing Process According to US Patent 3,002,891, the following describes pilot plant production of bromelain. Stripped pineapple stumps were passed four times through a three roll sugar mill press, In the second and following passes through the press, water was added to the pulp to increase the efficiency of the extraction procedure. The crude juice was screened to remove the coarse particles. Hydrogen sulfide gas was bled into the collected juice to partially saturate it. The pH was adjusted to pH 4.8 and then the juice was centrifuged. To 50 gallons of juice were added 30 gallons of cold acetone. The precipitate which formed was removed by centifuging in a Sharples centrifuge. This

Bromfenac sodium

671

precipitate was discarded. To the supernatant liquor an additional 35 gallons of acetone was added and the precipitate was collected in a Sharples centrifuge. The wet precipitate was dropped into fresh acetone, mixed well, and then recovered by settling. The paste was then dried in a vacuum oven at a shelf temperature of 110°F. Yield: 8 pounds of enzyme per 100 gallons of juice. Activity: 4,000 MCU/g. References Merck Index 1360 Kleeman and Engel p.112 PDR p.831 I.N. p.154 REM p.1038 Gibian, H. and Bratfisch, G.; US Patent 2,950,227; August 23, 1960; assigned to Schering AG, Germany Heinicke, R.M.; US Patent 3,002,891; October 3, 1961; assigned to Pineapple Research Institute of Hawaii

BROMFENAC SODIUM Therapeutic Function: Analgesicá Antiinflammatory Chemical Name: 2-Amino-3-(4-bromobenzoyl)benzeneacetic acid, sodium salt Common Name: Bromfenac sodium Structural Formula:

Chemical Abstracts Registry No.: 91714-93-1; 91714-94-2 (Base) Trade Name Duract Xibrom

Manufacturer Wyeth-Ayerst ISTA Pharmaceuticals, Inc.

Country -

Year Introduced -

Raw Materials (2-Aminophenyl)-(4-bromophenyl)methanone t-Butyl hypochlorite

Methylsulfanylacetic acid ethyl ester Nickel Raney

672

Bromhexine

Manufacturing Process Reaction of (2-aminophenyl)-(4-bromophenyl)-methanone with methylsulfanylacetic acid ethyl ester and tert-butyl hypochlorite gives a corresponding sulfonium salt. This salt was transformed to initially to the betaine. Electrocyclic rearrangement of that transient intermediate leads, after rearomatization, to the homoanthranilic acid. Internal ester-amine interchange leads then to 4-bromophenyl-(3-(methylthio)indolin-7-yl)methanone. The thiomethyl group is then removed with Raney nickel to give 4-bromophenyl(indolin-7-yl)methanone. Saponification of this intermediate affords the (2amino-3-(4-bromobenzoyl)-phenyl)-acetic acid (Bromfenac). In practice it is usually used as sodium salt. References Merck Index, Monograph number: 1411, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. Walsh D.A. et al.; J. Med. Chem.; 1984, 27, 1379 Gassman P.G. et al.; J. Amer. Chem. Soc.; 1973, 95, 6508

BROMHEXINE Therapeutic Function: Expectorant; Mucolytic Chemical Name: 2-Amino-3,5-dibromo-N-cyclohexyl-N-methylbenzenemethanamine Common Name: N-(2-Amino-3,5-dibromobenzyl)-N-methyl-cyclohexylamine Structural Formula:

Chemical Abstracts Registry No.: 3572-43-8; 611-75-6 (Hydrochloride salt) Trade Name Bisolvon Bisolvon Bisolvon Bisolvon

Manufacturer Boehringer Ingelheim Thomae Boehringer Ingelheim Boehringer Ingelheim

Country Switz. W. Germany Italy UK

Year Introduced 1963 1963 1968 1968

Bromindione Trade Name Bisolvon Lebelon L-Customed Aletor Auxit Bendogen Bromeksin Broncokin Bronkese Dakryo Fulpen Mucovin Ophthosol Solvex Viscolyt

Manufacturer Boehringer Ingelheim Towa Yakuhin Roha Cantabria Heyden Gea Mulda, Yurtoglu Geymonat Lennon Basotherm Sawai Leiras Winzer Ikapharm Gea

Country France Japan W. Germany Spain W. Germany Denmark Turkey Italy S. Africa W. Germany Japan Finland W. Germany Israel Denmark

673

Year Introduced 1969 1981 1982 -

Raw Materials 2-Nitrobenzyl bromide Hydrazine

Cyclohexylmethylamine Bromine

Manufacturing Process In initial steps, 2-nitrobenzylbromide and cyclohexylmethylamine are reacted and that initial product reacted with hydrazine to give N-(2-aminobenzyl)-Nmethyl-cyclohexylamine. A solution of 29.3 g of bromine in 50 cc of glacial acetic acid was slowly added dropwise to a solution of 159 g of N-(2-aminobenzyl)-N-methylcyclohexylamine, accompanied by stirring. The glacial acetic acid was decanted from the precipitate formed during the addition of the bromine solution, and the precipitate was thereafter shaken with 200 cc of 2N sodium hydroxide and 600cc of chloroform until all of the solids went into solution. The chloroform phase was allowed to separate from the aqueous phase. The chloroform phase was decanted, evaporated to dryness and the residue was dissolved in absolute ether. The resulting solution was found to be a solution of N-(2-amino-3,5-dibromobenzyl)-N-methyl-cyclohexylamine in ethanol. Upon introducing hydrogen chloride into this solution, the hydrochloride of N-(2amino-3,5-dibromobenzyl)-N-methyl-cyclohexylamine precipitated out. It had a melting point of 232°-235°C (decomposition). References Merck Index 1361 Kleeman and Engel p.113 OCDS Vol.2 p.96 (1980) I.N. p. 154 Keck, J.; US Patent 3,336,308; August 15, 1967; assigned to Boehringer Ingelheim G.m.b.H.

674

Bromisovalum

BROMINDIONE Therapeutic Function: Anticoagulant Chemical Name: 2-p-Bromophenylindandione Common Name: Bromindione; Bromophenindione; Brophenadione Structural Formula:

Chemical Abstracts Registry No.: 1146-98-1 Trade Name

Manufacturer

Country

Year Introduced

Bromindione

Chemical Formulations

-

-

Raw Materials Sodium Phthalide

Ethanol p-Bromobenzaldehyde

Manufacturing Process To a solution of 1.85 g of sodium in 40 ml of ethanol, was added 10 g of phthalide and 14.0 g of p-bromobenzaldehyde, and the reaction mixture was heated on the steam bath for one hour. Water was then added, and the alcohol was distilled off. Then after adding additional water, the reaction mixture was acidified with hydrochloric acid to precipitate the crude product, which was filtered off, dried and recrystallized from methanol. The 2-pbromophenylindandione is in the form of dark red crystals, having a melting point of 133-135°C. References Merck Index, Monograph number: 1414, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. Freedman L. et al.; US Patent No. 2,847,474; Aug. 12, 1958; Assigned to U.S. Vitamin Corporation, New York

BROMISOVALUM Therapeutic Function: Sedative, Hypnotic

Bromisovalum

675

Chemical Name: 2-Bromo-3-methylbutyrylurea Common Name: Bromisoval; Bromisovalerianyl carbamidum; Bromyl; Bromovalcarbamide; Bromovalharnstoff; Bromovaluree; Bromvaletone; Bromvalerocamidum; Bromvalerylurea Structural Formula:

Chemical Abstracts Registry No.: 496-67-3 Trade Name Bromisovalum Albroman Bromisoval Milocardin Sedual Alluval Bromural Bromoval Calmotin Dormigene Isobromyl Isoval Pivadorm Sedural Somnol Somnurol Valural

Manufacturer Linhai Duqiao Fine Chemical Factory Chinoin Slovakofarma Polpharma Pharmed Berlin-Chemie Knoll Sicomed Takeda Pharmaceutical Company Ltd.

Country -

Year Introduced -

-

-

Pharmacobel Clin-Comar-Byla Mission Specia Rekah Pharmaceutical Industry Ltd. Grindex Synochem Medica

-

-

-

-

Raw Materials 2-Bromoisovalerylbromide Urea Manufacturing Process A mixture of 2 kg 2-bromoisovalerylbromide and 1 kg dry urea is heated at 70°C. Then to the reaction mixture is added sodium hydrogen carbonate. 2Bromo-3-methylbutyrylurea is recrystallized from toluene or water, melting point 149°C.

676

Bromocriptine

References Merck Index, Monograph number: 1418, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. DE Patent No. 185,962; Mar 3, 1907; Assigned to Knoll and Ludwigschafen

BROMOCRIPTINE Therapeutic Function: Prolactin inhibitor Chemical Name: 2-Bromo-12'-hydroxy-2'-(1-methylethyl)-5'α-(2methylpropyl)ergotaman-3',6',18-trione Common Name: 2-Bromoergocryptine Structural Formula:

Chemical Abstracts Registry No.: 25614-03-3; 22260-51-1 (Mesylate salt) Trade Name

Manufacturer

Country

Year Introduced

Parlodel

Sandoz

UK

1975

Pravidel

Sandoz

W. Germany

1977

Parlodel

Sandoz

Switz.

1977

Parlodel

Sandoz

US

1978

Parlodel

Sandoz

France

1978

Parlodel

Sandoz

Japan

1979

Parlodel

Sandoz

Italy

1979

Bromergon

Lek

Yugoslavia

-

Raw Materials N-Bromosuccinimide Ergocryptine

Bromodiphenhydramine

677

Manufacturing Process A solution of 3.4 grams of N-bromosuccinimide in 60 cc of absolute dioxane is added drop wise in the dark, during the course of 5 minutes, to a stirred solution, heated to 60°C, of 9.2 grams of ergocryptine in 180 cc of absolute dioxane. The reaction mixture is stirred at this temperature for 70 minutes and is concentrated to a syrup-like consistency in a rotary evaporator at a bath temperature of 50°C. The reaction mixture is subsequently diluted with 300 cc of methylene chloride, is covered with a layer of about 200 cc of a 2 N sodium carbonate solution in a separating funnel and is shaken thoroughly. The aqueous phase is extracted thrice with 100 cc amounts of methylene chloride. The combined organic phases are washed once with 50 cc of water, are dried over sodium sulfate and the solvent is removed under a vacuum. The resulting brown foam is chromatographed on a 50-fold quantity of aluminum oxide of activity II-III with 0.2% ethanol in methylene chloride as eluant, whereby the compound indicated in the heading is eluted immediately after a secondary fraction which migrates somewhat more rapidly than the fractions containing the heading compound. The last fractions to leave the aluminum oxide contain varying amounts of starting material together with the heading compound, and may be subjected directly, as mixed fractions, to an afterbromination in accordance with the method described above. The fractions containing the pure heading compound are combined and crystallized from methyl ethyl ketonehopropy1 ether. Melting point 215°-218°C (decomp.), [α]D20-195° (c = 1 in methylene chloride). References Merck Index 1386 Kleeman and Engel p.114 PDR p.1589 DOT 12 (3) 87 (1976) I.N. p.155 REM pp.929, 955 Fluckiger, E., Troxler, F. and Hofmann, A.; US Patent 3,752,814; August 14, 1973; assigned to Sandoz Ltd., Switzerland Fluckiger, E., Troxler, F. and Hofmann, A.; US Patent 3,752,888; August 14, 1973; assigned to Sandoz Ltd., Switzerland

BROMODIPHENHYDRAMINE Therapeutic Function: Antihistaminic Chemical Name: p-Bromo-α-phenylbenzyloxy-N,N-dimethylethylamine Common Name: Bromazine; Bromdiphenhydraminum; Histabromazine; Bromodiphenhydramine Chemical Abstracts Registry No.: 118-23-0

678

Bromodiphenhydramine

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Bromazine

-

-

Ambodryl

Shanghai Lansheng Corporation Parke Davis and Co. Ltd.

-

-

Bromo-Benadryl

Parke Davis and Co. Ltd.

-

-

Raw Materials p-Bromobenzhydrylbromide Ethylene chlorohydrin Calcined sodium carbonate Dimethylethylamine Manufacturing Process 28.1 parts of p-bromobenzhydrylbromide are heated to boiling, under reflux and with stirring, with 50 parts of ethylene chlorohydrin and 5.3 parts of calcined sodium carbonate. The reaction product is extracted with ether and the etheral solution washed with water and dilute hydrochloric acid. The residue from the solution in ether [p-bromobenzhydryl(β-chloroethyl)ether]. 28.1 parts of this ether are heated with 12 parts of dimethylethylamine in a sealed tube for 4 hours at 110°C. The product of the reaction is extracted several time with dilute hydrochloric acid. The acid solution made alkaline, in the cold, with concentrated caustic soda solution, and the base which separates taken up in ether. The ether extract is washed with concentrated potassium carbonate solution, evaporated down, and the residue distilled in vacuo. Boiling point of p-bromo-α-phenylbenzyloxy)-N,N-dimethylethylamine 151-154°C under 0.3 mm. p-Bromo-α-phenylbenzyloxy)-N,N-dimethylethylamine may be used as a hydrochloride. References GB Patent No. 670,622; April 23, 1952; Assigned to Parke Davis and Corporation, USA

Bromopride

679

BROMOPRIDE Therapeutic Function: Antiemetic Chemical Name: 4-Amino-4-bromo-N-[2-(diethylamino)ethyl]-2methoxybenzamide Common Name: Structural Formula:

Chemical Abstracts Registry No.: 4093-35-0 Trade Name

Manufacturer

Country

Year Introduced

Praiden

Italchemi

Italy

1977

Valopride

Vita

Italy

1977

Cascapride

Cascan

W. Germany

1978

Artomey

Syncro

Argentina

-

Emepride

Roche

Switz.

-

Emoril

Roemmers

Argentina

-

Opridan

Locatelli

Italy

-

Plesium

Chiesi

Italy

-

Viaben

Schurholz

W. Germany

-

Raw Materials Bromine Dimethyl sulfate Methanol

4-Aminosalicylic acid Acetic anhydride

Manufacturing Process To 119 g (0.45 mol) of N-(2-diethylaminoethyl)-2-methoxy-4-aminobenzamide dissolved in 200 cc of acetic acid are added in the cold in small portions 69 g of acetic anhydride (0.45 mol + 50% excess). The starting material is made by esterifying 4-aminosalicylic acid with methanol, then acetylating with acetic anhydride and then methylating with dimethyl sulfate. The solution obtained is heated for 2 hours on a water bath and then boiled for 15 minutes. It is cooled at 25°C. While agitating constantly and maintaining the temperature between 25° and 30°C, there is added to the solution drop by drop 72 g of bromine dissolved in 60 cc of acetic acid. It is agitated for one hour. The

680

Brompheniramine maleate

mixture obtained is added to one liter of water and the base is precipitated by the addition of 30% soda, The precipitated base is extracted with 40 cc of methylene chloride. After evaporation of the solvent, the residue is boiled for two hours with 390 g of concentrated hydrochloric acid in 780 cc of water. It is cooled, diluted with one liter of water, 12 g of charcoal are added, and the mixture filtered. The base is precipitated with 30% soda. The N-(2diethylaminoethyl)-2-methoxy-4-amino-5-bromobenzamide formed crystallizes, is centrifuged and washed with water. A yield of 85 g of base having a melting point of 129°-130°C is obtained. To produce the dihydrochloride, the free base is dissolved in 110 cc of absolute alcohol, 9.6 g of dry hydrochloric acid dissolved in 35 cc of alcohol are added, followed by 2.8 cc of water. The dihydrochloride precipitates, is centrifuged, washed, and dried at 40°C. It was a solid white material having a melting point of 134°-135°C. References Merck Index 1404 Kleeman and Engel p.115 DOT 14 (5) 193 (1978) I.N. p. 156 Thominet, M.L.; US Patents 3,177,252; April 6, 1965; 3,219,528; November 23,1965; 3,357,978; December 12, 1967; all assigned to Societe d'Etudes Scientifiques et Industrielles de I'lle-de-France

BROMPHENIRAMINE MALEATE Therapeutic Function: Antihistaminic Chemical Name: (4-Bromophenyl)-N,N-dimethyl-2-pyridinepropanamine maleate Common Name: Parabromdylamine Structural Formula:

Brompheniramine maleate

681

Chemical Abstracts Registry No.: 980-71-2; 86-22-6 (Base) Trade Name

Manufacturer

Country

Year Introduced

Dimetane

Robins

US

1957

Dimegan

Dexo

France

1962

Symptom 3

WL/PD

US

1977

Brombay

Bay

US

1983

Antial

Ellem

Italy

-

Atronist

Adams

US

-

Bromfed

Muro

US

-

Bromphen

Schein

US

-

Bromrun

Hokuriku

Japan

-

Dimetapp

Scheurich

W. Germany

-

Dimotane

Robins

UK

-

Drauxin

Francia

Italy

-

Dura-Tap

Dura

US

-

Ebalin

Allergo Pharma

W. Germany

-

E .N .T. Syrup

Springbok

US

-

Febrica

Dexo

France

-

Gammistin

IBP

Italy

-

Ilvico

Bracco

Italy

-

Ilvin

Merck

W. Germany

-

Martigene

Martinet

France

-

Nagemid Chronule Ortscheit

W. Germany

-

Poly Histine

Bock

US

-

Probahist

Legere

US

-

Rupton

Dexo

France

-

Velzane

Lannett

US

-

Raw Materials Sulfuric acid Dimethylaminoethyl chloride 2-Chloropyridine

Sodium amide 4-Bromobenzyl cyanide Maleic acid

Manufacturing Process Initially, 4-bromobenzyl-cyanide is reacted with sodium amide and 2chloropyridine to give bromophenyl-pyridyl acetonitrile. This is then reacted with sodium amide then dimethyl amino ethyl chloride to give 4-bromophenyldimethylaminoethyl-pyridyl acetonitrile. This intermediate is then hydrolyzed and decarboxylated to bromphenirame using 80% H2SO4 at 140°-150°C for 24 hours. The brompheniramine maleate may be made by reaction with maleic acid in ethanol followed by recrystallization from pentanol.

682

Bronopol

References Merck Index 1417 Kleeman and Engel p.116 PDR pp.555, 674, 865, 993, 1033, 1268, 1454, 1606, 1735 OCDS Vol.1 p.77 (1977) I.N. p.157 REM p.1126 Sperber, N., Papa, D. and Schwenk, E.; US Patent 2,567,245; September 11, 1951; assigned to Schering Corporation Sperber, N., Papa, D. and Schwenk, E.; US Patent 2,676,964; April 27, 1954; assigned to Schering Corporation

BRONOPOL Therapeutic Function: Antiseptic Chemical Name: 2-Bromo-2-nitropropane-1,3-diol Common Name: Structural Formula:

Chemical Abstracts Registry No.: 52-51-7 Trade Name

Manufacturer

Country

Year Introduced

Bronosol

Green Cross

Japan

1977

Bronopol

Boots

UK

-

Raw Materials Nitromethane Formaldehyde Bromine Manufacturing Process A mixture of 441 g (3 mols) of calcium chloride dihydrate, 61 g (1 mol) of nitromethane, 163 g (2 mols) of formalin (37% formaldehyde solution) and 470 ml of water was cooled to 0°C and mixed with 5 g of calcium hydroxide while stirring. The temperature thereby rose to 30°C. As soon as the temperature had fallen again, a further 32 g of calcium hydroxide (total of 0.5

Broperamole

683

mol) were added. The mixture was then cooled to 0°C and with intensive cooling and stirring, 159.8 g (1 mol, 51 ml) of bromine were dropped in at a rate so that the temperature remained at around 0°C. After the addition was ended, the mixture was stirred for a further 2 hours, when the reaction product separated in crystalline form. The product was quickly filtered on a suction filter and the crystalline sludge obtained was taken up in 450 ml of ethylene chloride and dissolved at reflux. Then by addition of magnesium sulfate, undissolved inorganic salts were separated and the solution was slowly cooled whereby 140 g (70% yield) of 2-bromo-2-nitropropane-1,3-diol precipitated in colorless crystals melting at 123°-124°C. References Merck Index 1421 I.N. p.158 Wessendorf, R.; US Patents 3,658,921; April 25, 1972; and 3,711,561; January 16, 1973; both assigned to Henkel and Cie G.m.b.H.

BROPERAMOLE Therapeutic Function: Antiinflammatory Chemical Name: Piperidine, 1-(3-(5-(3-bromophenyl)-2H-tetrazol-2-yl)-1oxopropyl)Common Name: Broperamole Structural Formula:

Chemical Abstracts Registry No.: 33144-79-5 Trade Name

Manufacturer

Country

Year Introduced

Broperamole

Onbio Inc.

-

-

Raw Materials 3-[5'-(3"-Bromophenyl)-2'H-tetrazole]propionic acid Thionyl chloride Piperidine

684

Brotizolam

Manufacturing Process A mixture of 32 g (0.108 mole) of 3-[5'-(3"- bromophenyl)-2'Htetrazole]propionic acid and 80 g of thionyl chloride in 250 ml of dry chloroform was stirred under reflux for 16 hours. Evaporation of the solvent and excess reagent under reduced pressure gave a tan oil which was redissolved in 300 ml of dry tetrahydrofuran. To this was added 20 ml of redistilled piperidine in 100 ml of dry tetrahydrofuran. The mixture was stirred for 15 min at room temperature. The tetrahydrofuran was then removed under reduced pressure and the residue well triturated with one liter of 0.1 N hydrochloric acid. The resulting semi-solid was taken up in 700 ml of ether and extracted with 300 ml of 3% aqueous sodium bicarbonate solution. The ether solution was then dried over calcium chloride, filtered, and cooled in the refrigerator. This deposited 25 g (69 %) of tan needles of N-3-[5'-(3"bromophenyl)-2'H-tetrazole]propionyl piperidine; melting point 69°C. References Buckler R. Th.; US Patent No. 3,681,336; Aug. 1, 1972; Assigned to Miles Laboratories, Inc., Elkhart, Ind.

BROTIZOLAM Therapeutic Function: Psychotropic Chemical Name: 8-Bromo-6-(o-chlorophenyl)-1-methyl-4H-s-triazolo-[3,4c]thieno-[2,3e]-1,4-diazepine Common Name: Structural Formula:

Chemical Abstracts Registry No.: 57801-81-7 Trade Name

Manufacturer

Country

Year Introduced

Lendormin

Boehringer Ingelheim

Switz.

1983

Lendorm

Boehringer Ingelheim

Switz.

-

Broxyquinoline

685

Raw Materials 7-Bromo-5-(o-chlorophenyl)-3H-[2,3-e]thieno-1,4-diazepin-2-one Phosphorus pentasulfide Hydrazine hydrate Manufacturing Process (a) 11.5 g of 7-bromo-5-(o-chlorophenyl)-3H-[2,3e]-thieno-1,4-diazepin-2one (see German Patent 2,221,623), were heated at 55° to 60°C with 100 cc of absolute pyridine and 6.5 g of phosphorus pentasulfide for 4 hours while stirring. The mixture was allowed to cool and was then poured into 100 cc of saturated ice-cold NaCl solution. The precipitate was collected by suction filtration, washed with water, dissolved in 100 cc of methylene chloride, the solution was dried and evaporated, and the residue was treated with a little methylene chloride. After suction filtration, 6 g of brown crystalline 7-bromo5-(o-chlorophenyl)-3H-[2,3e]-thieno-1,4-diazepine-2-thione, melting point 214°C (decomposition) were obtained. (b) 6.0 g of this compound were suspended in 100 cc of tetrahydrofuran, and the suspension was stirred at room temperature with 1.2 g of hydrazine hydrate for 20 minutes. After evaporation to about 10 cc, 20 cc of ether were added, and the crystals were collected by suction filtration. Yield: 5.2 g of 7bromo-5-(o-chlorophenyl)-2-hydrazino-3H-[2,3e]-thieno-1,4-diazepine, melting point about 300°C (decomposition). (c) 5.2 g of this compound were suspended in 50 cc of orthotriethyl acetate, and the suspension was heated to 80°C. After about 30 minutes a clear solution was first formed from which later colorless crystals separated out. The mixture was allowed to cool, and the crystals were collected by suction filtration and washed with ether. Yield: 5 g of the compound, melting point 211° to 213°C. References Merck Index 1423 DFU 4 (2) 85 (1979) I.N. p.159 Weber, K.H., Bauer,A., Danneberg, P. and Kunn, F.J.; US Patent 4,094,984; June 13, 1978; assigned to Boehringer Ingelheim GmbH

BROXYQUINOLINE Therapeutic Function: Antibacterial Chemical Name: 5,7-Dibromo-8-hydroxyquinoline Common Name: Bromoxine; Broxichinolium; Broxychinolinum; Broxyquinoline; Dibromohydroxyquinoline

686

Bucainide maleate

Structural Formula:

Chemical Abstracts Registry No.: 521-74-4 Trade Name Brodiar Colepur Fenilor Intensopan Enterin Paramibe Paramibe Starogyn

Manufacturer Intervet Draco UCB Sandoz Leiras Ucepha Cid Co. Oy Leiras Finland Ab

Country -

Year Introduced -

Raw Materials 8-Hydroxyquinoline Bromine Hydrobromic acid Manufacturing Process To a suspension of 14.5 g of 8-hydroxyquinoline in 400 ml of water was added dropwise a solution of 32.3 g bromine and 30 g 8% aqueous hydrobromide in 30 ml water. A temperature of reaction mixture decreased to 33°C. Stirring was continued for 30 min, a fine yellow 5,7-dibromo-8-hydroxyquinoline was collected by filtration, washed with water and dried; yield 29.8 g (98.4%), melting point 201°C. References Merck Index, Monograph number: 1474, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. Jenkner H., DE Patent No. 2,515,476; Oct. 21, 1976; Assigned to Chemische Fabrik Kalk GmbH, 5000 Koeln

BUCAINIDE MALEATE Therapeutic Function: Antiarrhythmic Chemical Name: 1-Propanamine, N-((4-hexyl-1-piperazinyl) phenylmethylene)-2-methyl-, maleate (1:2)

Bucainide maleate

687

Common Name: Bucainide maleate Structural Formula:

Chemical Abstracts Registry No.: 51481-62-0 (Base); 51481-63-1 Trade Name

Manufacturer

Country

Year Introduced

Bucainide maleate

ZYF Pharm Chemical

-

-

Raw Materials N-Hexylpiperazine N-Isobutyl-benzimidoyl chloride Maleic acid Manufacturing Process To a solution of 13.6 g (0.08 mol) of N-hexylpiperazine and 8.1 g (11.2 ml), (0.08 mol) of triethylamine in 120 ml toluene, was added 15.6 g (0.08 mol) of N-isobutyl-benzimidoyl chloride over a period of 15 minutes. The reaction mixture was stirred at room temperature for a period of 2 hours. The triethylamine hydrochloride was filtered off and the filtrate concentrated under vacuum. The residual oily base was washed with 20 ml water, extracted with 50 ml ether and dried over anhydrous magnesium sulfate. The dry ethereal solution was then added to a solution of 18.6 g (0.16 mol) maleic acid in 800 ml ether to obtain the dimaleate salt. Two recrystallizations from ethanol yielded 22.5 g (50.2%) of N-[(4-hexyl-1-piperazinyl)phenylmethylene]-2methyl-1-propanamine product, M.P. 175°-176°C. References Shroff J.R. et al.; US Patent No. 3,793,322; February 19, 1974; Assigned to USV Pharmaceutical Corporation, Tuckahoe, N.Y.

688

Bucetin

BUCETIN Therapeutic Function: Analgesic Chemical Name: Butanamide, N-(4-ethoxyphenyl)-3-hydroxyCommon Name: Bucetin Structural Formula:

Chemical Abstracts Registry No.: 1083-57-4 Trade Name Bucetin

Manufacturer ZYF Pharm Chemical

Country -

Year Introduced -

Raw Materials Acetoacetic acid p-phenetidide Nickel Raney

Nickel on kiesel-guhr Aluminum amalgam

Manufacturing Process Bucetin may be prepared from acetoacetic acid p-phenetidide as follows: 5.5 parts of acetoacetic acid p-phenetidide, suspended in 600 parts by volume of methanol, are hydrogenated at 80°-85°C with a nickel catalyst supported on kiesel-guhr. When the theoretical quantity of hydrogen has been absorbed, the solution is cooled, then filtered, and the filtrate is concentrated. The solid residue is recrystallized from six times its weight of isopropanol. βHydroxybutyric acid p-phenetidide is obtained in an almost quantitative yield in the form of white crystals which melt at 160°C. 55 parts of acetoacetic acid p-phenetidide, suspended in 500 parts by volume of methanol, are hydrogenated with Raney nickel at 70°C. When the theoretical quantity of hydrogen has been absorbed, the solution is cooled, then filtered, and the filtrate is concentrated. The solid residue is recrystallized from six times its weight of isopropanol. 51 parts (93 % of the theoretical yield) of β-hydroxybutyric acid p-phenetidide are obtained in the form of white crystals, which are sparingly soluble in water and melt at 160°C. A mixture of 5 g of aluminum amalgam, 5 g of acetoacetic acid p-phenetidide and 50 ml of ethanol are gently heated for 30 minutes. After filtering off the reducing agent with suction, water is added to the filtrate, and the latter is then acidified with 2 N hydrochloric acid. β-Hydroxybutyric acid p-phenetidide melting at 160°C crystallizes in almost quantitative yield in the form of white crystals.

Buciclovir

689

References Ehrhart G. et al.; US Patent No. 2,830,087; April 8, 1975; Assigned to Farbwerke Hoechst Aktiengesellschaft vormals Meister Lucius and Bruning, Frankfurt am Main, Germany

BUCICLOVIR Therapeutic Function: Antiviral Chemical Name: 6H-Purin-6-one, 2-amino-9-(3,4-dihydroxybutyl)-1,9dihydro-, (R)Common Name: Buciclovir Structural Formula:

Chemical Abstracts Registry No.: 86304-28-1 Trade Name

Manufacturer

Country

Year Introduced

Buciclovir

Astra Lakemedel

-

-

Buciclovir

ZYF Pharm Chemical

-

-

Raw Materials Dimethyl maleate, R-, (+)Perchloric acid N-Bromosuccinimide

Lithium aluminum hydride Triphenylphosphine 2-Amino-6-chloropurine

Manufacturing Process Preparation of R-(+)-9-(3,4-dihydroxybutyl)guanine: Step A: preparation of R-(+)-1,2,4-butantriol: R-(+)-Dimethyl maleate (1.62, 10 mmol), prepared according to Boger, D.L. and Panek, J.S., J. Org. Chem. 1981, 46, 1208-10, was dissolved in THF (10 ml) and added dropwise to a prewarmed suspension of lithium aluminium hydride (0.63 g, 16.5 mmol) in THF (15 ml). The reaction mixture was stirred overnight at 55°C. After sequential addition of water (0.62 ml), 10% sodium hydroxide (1.20 ml) and water (1.90 ml) the mixture was filtered and the solid residue was boiled twice with THF (2x20 ml) and filtered. The combined

690

Buciclovir

filtrates were pooled and evaporated under reduced pressure (30°C) leaving crude 1,2,4-butantriol (0.7 g, 6.6 mmol) 66%. Step B: preparation of R-(+)-isopropylidenbutan 1,2,4-triol: R-(+)-1,2,4-butantriol (0.7 g, 6.6 mmol), prepared as described in step (a) above, was stirred for 1.5 hr in acetone (50 ml) containing 3 drops of conc. perchloric acid a satured solution of sodium bicarbonate in water (5 ml) was added and the stirring was continued for additional 10 min. The precipitate was filtered off and the filtrate evaporated under reduced pressure [2.7 kPa,(20 mm Hg), 30°C]. The residue was taken up in ethyl acetate, washed with satured aqueous sodium bicarbonate (5 ml) and brine (5 ml), and dried over magnesium sulfate. Evaporation of the solvent and distillation gave the title compound as a colourless oil (0.3 g, 2.05 mmol, 31%): b.p. 104°106°C/20 mm Hg; nD20=1.4390. Step C: preparation of R-(+)-4-bromo-isopropylidenebutan-1,2-diol: R-(+)-Isopropylidene-butan-1,2,4-triol (0.3 g, 2.05 mmol) and triphenylphosphine (0.63 g, 2.4 mmol) were dissolved in methylene chloride (5 ml) and cooled to 0°C. N-Bromosuccinimide (0.38 g, 2.16 mmol) was added in small portions with stirring at 0°C. After additional 1 hr of stirring at 0°C hexane (15 ml) was added and the resulting precipitate was removed by filtration and washed twice with hexane (2x5 ml). The combined hexane solution was passed through a short column of silica gel (5 g). Elution with hexane (15 ml) gave after evaporation and distillation the title compound as a colorless oil (0.2 g, 0.96 mmol, 47%): b.p. 74°-76°C/20 mm Hg, nD20=1.4630. [α]D20=+27.7° (C=20, CHCl3). Step D: preparation of R(+)-4-(2-amino-6-chloropurin-9-yl)isopropylidenebutane-1,2-diol: 2-Amino-6-chloropurin (162 mg, 0.96 mmol), R-(+)-4-bromo-isopropylidenebutandiol (200 mg, 0.96 mmol) and potassium carbonate (132 mg) was mixed in DMF (10 ml). After stirring for 16 hr the reaction mixture was filtered through celite and the solvent evaporated under reduced pressure [13 Pa (0.1 mm Hg), 50°C]. The residue was triturated with warm chloroform (5 ml) and undissolved material was filtered off. Evaporation of the solvent gave a pale yellow crystalline solid consisting mainly of the 9- and 7-isomers. These were separated by silica gel flash chromatography. Elution with chloroform/methanol (15:1) gave the title compound in pure form (106 mg, 0.36 mmol, 37%): MP: 129°-130°C, [α]D21 =+57.5° (C=6.97, CHCl3). Step E: preparation of R-(+)-9-(3,4-dihydroxybutyl)guanine: R-(+)-4-(2-Amino-6-chloropurin-9-yl)isopropylidene-butane-1,2-diol (100 mg, 0.33 mmol) prepared according to step (d) above was dissolved in hydrochloric acid (1 mol/L) and refluxed for 1 hr. The solution was concentrated in vacuum and the residue dissolved in water (5 ml) and made alkaline by addition of aqueous ammonium hydroxide. After evaporation the solid residue was recrystallized from water giving the title compound as white needles (40 mg, 0.17 mmol, 51%). [α]D21=+30.8° (C=0.25, water). (+/-)Form had MP: 260°-261°C.

Bucillamine

691

References Hugberg C-E. et al.; January 22, 1985; Assigned to Astra Lakemedel Aktiebolag, Sodertalje, Sweden

BUCILLAMINE Therapeutic Function: Antirheumatic, Immunomodulator Chemical Name: L-Cysteine, N-(2-mercapto-2-methyl-1-oxopropyl)Common Name: Bucillamine; Tiobutarit Structural Formula:

Chemical Abstracts Registry No.: 65002-17-7 Trade Name

Manufacturer

Country

Year Introduced

Bucillamine

ZYF Pharm Chemical

-

-

Bucillamine

Bioray Pharma LLC

-

-

Rimatil

Santen Pharmaceutical Co., Ltd.

-

-

Raw Materials S-Benzyl-L-cysteine Thionyl chloride Sodium

2-Benzylmercaptoisobutyric acid Ammonia

Manufacturing Process Preparation of N-(2-benzylmercaptoisobutyryl)-S-benzyl-L-cysteine: 1). 73.9 g of S-benzyl-L-cysteine were dissolved in 700 ml of 1 N sodium hydroxide solution. The solution was cooled in an ice bath and stirred. 2Benzylmercaptoisobutyryl chloride, which was obtained by reacting 63.1 g of 2-benzylmercaptoisobutyric acid with 39.3 g of thionyl chloride, was added dropwise to this solution. The resulting mixture was then stirred for one hour, acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over sodium sulfate and evaporated to dryness. The residue was chromatographed on silica gel with benzene/ethylacetate (1:1) as an eluant. The eluate was evaporated to dryness and an oily residue

692

Bucindolol hydrochloride

weighing 46.9 g, representing a yield of 74%, was obtained. 2). The obtained in (1) above were dissolved in 500 ml of liquid ammonia and 21.1 g of metallic sodium were added slowly with stirring. After completion of reaction, 59.4 g of ammonium chloride were added and thereafter the ammonia was removed by distillation. Water was added to the residue to dissolve the solid. The resulting water layer was separated, washed with ethyl acetate, and acidified with hydrochloric acid under cooling. The precipitates thus obtained were extracted with ethyl acetate. The extract was washed with water, dried over sodium sulfate and evaporated to dryness. The product weighed 43.6 g, representing a yield of 88%. After recrystallization from ethyl acetate, the desired compound, melting at 139°-140°C, was obtained. [α]D25=+32.3° (c=1.0, ethanol). References Fujita T. et al.; US Patent No. 4,305,958; December 15, 1981; Assigned to Santen Pharmaceutical Co., Ltd., Osaka, Japan

BUCINDOLOL HYDROCHLORIDE Therapeutic Function: Antihypertensive Chemical Name: Benzonitrile, 3-(2-hydroxy-3-((2-(1H-indol-3-yl)-1,1dimethylethyl)amino)propoxy)- monohydrochloride Common Name: Bucindolol hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 70369-47-0 Trade Name

Manufacturer

Country

Year Introduced

Bucindolol hydrochloride

Bristol Myers (BMS)

-

-

Bucindolol hydrochloride

693

Raw Materials 2-Cyanophenol Sodium hydroxide 2-Nitropropane Nickel Raney

Epichlorohydrin Gramine Acetic acid Hydrazine hydrate

Manufacturing Process A solution of 2-cyanophenol (25.0 g, 0.21 mole), epichlorohydrin (117.0 g, 1.26 mole), and piperidine (10 drops) was stirred and heated at 115-120°C in an oil bath for 2 h. The reaction mixture was then concentrated (90/30 mm) to remove unreacted epichlorohydrin. The residue was diluted with toluene and taken to dryness twice to help remove the last traces of volatile material. The residual oil was dissolved in 263 ml of THF, and the solution stirred at 4050°C for 1 h with 263 ml of 1 N NaOH. The organic layer was separated and concentrated to give an oil which was combined with the aqueous phase. The mixture was extracted with CH2Cl2 and the extract dried (MgSO4) and concentrated to give 36.6 g (100%) of 2-[(2,3-epoxy)propoxy]benzonitrile as oil, which slowly crystallized to a waxy solid. A mixture of gramine (120.0 g, 0.69 mole), 2-nitropropane (443 ml), and NaOH (28.8 g, 0.72 mole) was stirred and gradually heated to reflux under N2. After a 6.5 h reflux period, the reaction mixture was allowed to stand at room temperature overnight, and then diluted with 600 ml of 10% aqueous AcOH. The mixture was extracted with 1.5 l of Et2O and the organic layer washed with H2O (4x 500 ml). Concentration of the Et2O solution in vacuum gave an oil which was dissolved in 500 ml of 95% EtOH. This solution was diluted with 300 ml of H2O. After cooling, the yellow solid was collected on a filter to give 105.0 g (70%) of nitro intermediate, melting point 72-74°C. The nitro compound was dissolved in 1.3 L of 95% EtOH, and Raney nickel (70.0 g, EtOH-washed) and added. The mixture was heated to reflux, and a solution of 85% hydrazine hydrate (116.0 g, 2.3 mole) in 95% EtOH (110 ml) was added dropwise at a rate to maintain gentle reflux. The mixture was then heated at reflux for an additional 1.5 h, cooled, and filtered. Concentration of the filtrate gave crude product as a solid. A solution of the solid in 400 ml of EtOAc was diluted with 500 ml of (i-Pr)2O and cooled. The white, cottony solid which separated was collected on a filter to give 91.0 g (100%) of 2-(3indolyl)-1,1-dimethylethylamine, melting point 122-126°C. A solution of 2-[(2,3-epoxy)propoxy]benzonitrile (18.3 g, 0.10 mole) and 2(3-indolyl)-1,1-dimethylethylamine (15.2 g, 0.08 mole), in 500 ml of abs. EtOH was stirred at reflux overnight. After concentration of the reaction mixture to approximately 200 ml and seeding, crude product began to precipitate. The mixture was then cooled and the precipitate separated by filtration to give 24.8 g of the free base form of the product, white solid, melting point 120-123°C. The crude solid was dissolved in 400 ml of boiling MeOH, and the solution was cooled with stirring, as a by-product 1,1’-[[1,1dimethyl-2-(1H-indol-3-yl]ethyl]imino]bis-[3-(2-cyanophenoxy)-2-propanol] precipitated. The by-product was collected on a filter and air dried to give 2.2 g, of 2-[2-hydroxy-3-[[2-(3-indolyl)-1,1-dimethylethyl]amino]propoxy] benzonitrile, melting point 180-187°C.

694

Buclizine hydrochloride

In practice it is usually used as hydrochloride. References Kreighbaum W.E., Comer W.T.; US Patent No. 4,234,595; November 18, 1980; Assigned: Mead Johnson and Company, Evansville

BUCLIZINE HYDROCHLORIDE Therapeutic Function: Antihistaminic, Antiallergic, Antinauseant, Tranquilizer, Appetite stimulant Chemical Name: Piperazine, 1-((4-chlorophenyl)phenylmethyl)-4-((4-(1,1dimethylethyl)phenyl)methyl)-, hydrochloride Common Name: Buclizine hydrochloride; Histabutazine; Histabutizine Structural Formula:

Chemical Abstracts Registry No.: 129-74-8; 82-95-1 (Base) Trade Name

Manufacturer

Country

Year Introduced

Longifine

UCB

-

-

Longifene

Bios-Coutelier

-

-

Buclina

Sanofi Winthrop

-

-

Posdel

UCB

-

-

Postafen

Rhodia

-

-

Vibazine

Pfizer

-

-

Bucladin-S

Stuart Pharms

-

-

Buclizine Dihydrochloride

Toronto Research Chemicals Inc. (TRC)

-

-

Aphilan R

UCB Pharma

-

-

Histalon

Majer-Meyer

-

-

Postafeno

GSK

-

-

Quantum

Andromaco

-

-

Buclosamide

695

Raw Materials 4-Chlorobenzhydryl chloride Piperazine 1-carboxylic acid ethyl ester 4-tert-Butylbenzyl chloride Manufacturing Process 1 mol 4-chlorobenzhydril chloride was heated in toluene to reflux with 1 mol ethyl ester of piperazine 1-carboxylic acid at about 150°C in a presence of an excess of triethyl amine. On cooling the triethyl amine hydrochloride was filtered off, a solvent was removed in vacuum and the residue [(4-chlorophenyl)-phenyl-methyl]piperazine carboxylic acid ethyl ester was boiled straight away with potassium hydroxide in ethanol for 48 hours. After removing ethanol in vacuum to dryness, the residue was dissolved in benzene and washed with water. The benzene solution was dried, benzene removed in vacuum. The residue was distilled to give 4-chlorobezhydryl-piperazine. It had given the desired 1-(p-tert-butylbenzyl)-4-(p-chloro-α-phenylbenzyl)piperazine, buclizine, by a reaction with 4-tert-butylbenzyl chloride in the presence of any halogen hydrochloride acceptor (triethyl amine, sodium or potassium carbonate and so on). The obtained product had BP: 230°240°C/0.001 mm Hg. References Morren H.; DB Patent No. 964048; Feb. 15, 1951; Forest-Brussel (Belgium)

BUCLOSAMIDE Therapeutic Function: Antifungal Chemical Name: N-Butyl-4-chlorosalicylamide Common Name: Buclosamide Structural Formula:

Chemical Abstracts Registry No.: 575-74-6

696

Bucloxic acid

Trade Name Fungit Jadit

Manufacturer Dragon Hoechst

Country -

Year Introduced -

Raw Materials 4-Chloro-2-hydroxy-benzoic acid n-butyl-ester n-Butylamine Manufacturing Process 4-Chloro-2-hydroxy-benzoic acid n-butyl-amide A mixture consisting of 114 g of 4-chloro-2-hydroxy-benzoic acid n-butylester, 64 grams of methanol and 130 g of n-butyl-amine is heated for 22 hours at 80°C; then the parts volatile up to 130°C are distilled off under reduced pressure. The residue crystallizing in the cold is dissolved in 200 ml of methanol and the solution obtained is slowly added dropwise and while stirring into dilute hydrochloric acid, if necessary, after treatment with animal charcoal. The precipitate which is at first semi-solid soon crystallizes completely. It is filtered with suction, washed with dilute hydrochloric acid, then thoroughly washed again with water, and the product obtained in good yield is dried in the air. After having been recrystallized twice from carbon tetrachloride the 4-chloro-2-hydroxybenzene acid n-butylamide melts at 9092°C. References Merck Index, Monograph number: 1485, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. Ruschig H. et al.; US Patent No. 2,923,737; Feb. 2, 1960; Assigned to Farbwerke Hoechst Aktiengesellschaft vormais Meister Lucius and Bruning, Frankfurt am Main, Germany

BUCLOXIC ACID Therapeutic Function: Antiinflammatory Chemical Name: 3-Chloro-4-cyclohexyl-α-oxo-benzenebutanoic acid Common Name: 4-(4-Cyclohexyl-3-chlorophenyl)-4-oxobutyric acid Structural Formula:

Bucromarone

697

Chemical Abstracts Registry No.: 32808-51-8 Trade Name

Manufacturer

Country

Year Introduced

Esfar

Clin Midy

France

1974

Raw Materials Phenylcyclohexane Succinic anhydride Chlorine Manufacturing Process Phenylcyclohexane and succinic acid (Bernstein Acid) anhydride are reacted in the presence of AlCl3to give 4-(4'-cyclohexylphenyl)-4-keto-n-butyric acid. 177 grams of anhydrous aluminum chloride are introduced into a 3-necked 1 liter flask. A hot solution of 144 grams of 4-(4'-cyclohexylphenyl)-4-keto-nbutyric acid in 330 ml of methylene chloride is added slowly from a dropping funnel. Slight reflux is observed during this addition. 33.2ml of liquefied chlorine are then introduced slowly, drop by drop. This addition requires 5 hours. The solution is then poured on to 1 kg of ice containing 100 ml of concentrated hydrochloric acid. The aqueous phase is extracted twice, each time with 200 ml of methylene chloride, the organic phase is washed with water to pH 6.5 and dried and the organic solvent then evaporated. The desired acid is recrystallized from 500 ml of toluene. The yield is 64%. MP: 159°C. References Merck Index 1431 Kleeman and Engel p.118 OCDS Vol.2 p.126 (1980) DOT 10 (11) 294 (1974) British Patent 1,315,542; May 2, 1973;assigned to Ets Clinbyla, France

BUCROMARONE Therapeutic Function: Antiarrhythmic, Coronary vasodilator Chemical Name: 4H-1-Benzopyran-4-one, 2-(4-(3-(dibutylamino)propoxy)3,5-dimethylbenzoyl)Common Name: Bucromarone Chemical Abstracts Registry No.: 78371-66-1

698

Bucromarone

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Bucromarone

Transphyto

-

-

Raw Materials Aluminum chloride Hydrochloric acid Potassium carbonate

2,6-Dimethylphenol 2-Carboxylic chromone acid chloride 3-N,N-Dibutylamino-1-chloropropane

Manufacturing Process 1.2 mol of an electrophilic catalyst, advantageously aluminum chloride, was slowly added to a solution of 48.8 g (0.4 mol) of 2,6-dimethyl phenol in 400 ml of dichloroethane and agitated at room temperature for an hour. The mixture was cooled to 0°C and a solution of 84.0 g (0.4 mol) of 2-carboxylic chromone acid chloride in 400 ml of a dichloroethane, was slowly added. Agitation was continued at 0°C for 5 h and then at room temperature for 4 days. The reaction mixture was poured into 1.6 L of iced 50% hydrochloric acid. The resulting precipitate was filtered, washed with water, dried and 106.0 g (72% yield) of 2-(3,5-dimethyl-4-hydroxybenzoyl)chromone, melting point 216°C (recrystallised from dioxane) were obtained. 6.9 g (0.05 mol) of potassium carbonate was added to a solution of 29.4 g (0.1 mol) of 2-(3,5-dimethyl-4-hydroxybenzoyl)chromone in 250 ml of dimethyl formamide and kept at 100°C for an hour. A solution of 20.5 g (0.1 mol) of 3-N,N-dibutylamino-1-chloropropane in 100 ml of diethyl formamide was then added and the resulting solution heated to 130°C for 3 h. The solution was filtered, the dimethyl formamide was concentrated, dissolved in 300 ml water and extracted twice with 200 ml of benzene. The organic phase was dried on magnesium sulfate and the hydrochloride was precipitated by adding hydrochloric ether. 40.0 g (yield 80%) of 2-[4-(3-N,N-dibutylaminopropoxy)-3,5-dimethylbenzoyl]chromone were obtained (recrystallised from an acetone/ether mixture). References Chibret H.; US Patent No. 4,220,645; September 2, 1980; Assigned: Thea (Therapeutique et Applications) SA, France

Bucumolol hydrochloride

699

BUCUMOLOL HYDROCHLORIDE Therapeutic Function: Beta-adrenergic blocker Chemical Name: 8-(2-Hydroxy-3-t-butylaminopropoxy)-5-methyl coumarin hydrochloride Common Name: Structural Formula:

Chemical Abstracts Registry No.: 58409-59-9 (Base) Trade Name

Manufacturer

Country

Year Introduced

Bucumarol

Sankyo

Japan

1982

Raw Materials t-Butylamine 8-(2-Hydroxy-3-chloropropoxy)-5-methyl coumarin Manufacturing Process A mixture of 3 g of 8-(2-hydroxy-3-chloropropoxy)-5-methyl coumarin, 4.3 g of t-butylamine and 60 ml of ethanol is heated at 100°C in a sealed tube for 15 hours. The reaction mixture is concentrated under reduced pressure to dryness. The residue is recrystallized from a mixture of ethanol and ether to give 2.1 g of the desired product melting at 226° to 228°C (with decomposition). In practice it is usually used as hydrochloride. References Merck Index 1434 DFU 3 (9) 638 (1978) DOT 19 (1) 10 (1983) Sato, Y., Kobayashi, Y., Taragi, H., Kumakura, S., Nakayama, K. and Oshima, T.; US Patent 3,663,570; May 16, 1972; assigned to Sankyo Co., Ltd.

700

Budesonide

BUDESONIDE Therapeutic Function: Corticosteroid Chemical Name: Pregna-1,4-diene-3,20-dione, 16,17-(butylidenebis(oxy))11,21-dihydroxy-, (11β,16α)Common Name: Budesonide Structural Formula:

Chemical Abstracts Registry No.: 51333-22-3 Trade Name Budecort Budesonide Busonid Entocort EC Pulmicort Respules Ribujet

Manufacturer AstraZeneca Genpharm Inc. Biosintetica AstraZeneca AstraZeneca Chiesi Wasserman

Country -

Year Introduced -

Raw Materials Desonide (16α-hydroxyprednisolone-16,17-acetonide) Butyraldehyde Hydrofluoric acid Manufacturing Process 50 grams of desonide (16α-hydroxyprednisolone-16,17-acetonide) and immediately thereafter 12.5 ml of butyraldehyde were added to 500 ml of 70% hydrofluoric acid solution at -5°C, and the mixture was stirred at 0°C one hour and then poured into 5 liters of demineralized water at 0°C. The precipitate was filtered, washed to neutrality with water and dried under vacuum to give 51 g of pure budesonide with an A/B epimer ratio of 9/91. References Brattsand R.L. et al.; US Patent No. 3,983,233; Sept. 28, 1976; Assigned: AB Bofors (Bofors, SW)

Budipine

701

Brattsand R.L. et al.; US Patent No. 3,929,768; Dec., 30, 1975; Assigned: AB Bofors, Bofors, Sweden

BUDIPINE Therapeutic Function: Antiparkinsonian, Antidepressant Chemical Name: Piperidine, 1-(1,1-dimethylethyl)-4,4-diphenylCommon Name: Budipine Structural Formula:

Chemical Abstracts Registry No.: 57982-78-28 Trade Name

Manufacturer

Country

Year Introduced

Budipine

Byk Gulden (Altana)

-

-

Parkinsan

Promonta

-

-

Raw Materials 1-(tertiary Butyl)-4-hydroxy-4-phenylpiperidine Aluminum chloride Sodium hydroxide Manufacturing Process 24.4 g of 1-(t-butyl)-4-hydroxy-4-phenylpiperidine are suspended in 150 ml of anhydrous benzene. 61.5 g of finely pulverized anhydrous aluminum chloride are added in portions thereto within 25 min while stirring. The reaction temperature increases on starting addition of aluminum chloride to about 45°C. After about 20 min the temperature is increased to and maintained at about 50° to 55°C for about 1 hour. The resulting reaction solution is cooled to about 20°C and is poured into a mixture of ice and concentrated hydrochloric acid. After warming the mixture to room temperature, the hydrochloric acid layer together with the dark oil formed on decomposition is separated from the benzene layer and is washed with benzene. Water is added to said hydrochloric acid -oil phase, while stirring, in portions and in an amount sufficient to produce an almost clear solution. Said acid solution is rendered alkaline by the addition of 40% sodium hydroxide solution whereby

702

Budotitane

the mixture is well cooled. The alkalized mixture is repeatedly extracted with ether. The combined ether extracts are dried over anhydrous potassium carbonate and are concentrated by evaporation of the ether. 24 g of the crude base are obtained as residue in the form of yellowish oil. A water clear oil boiling at 129-131°C/0.005 mm Hg is recovered by distillation of said crude oil in a high vacuum. The oil solidifies to crystals on standing for a short period of time. After recrystallization from aqueous dimethylformamide, the resulting 1-methyl-4,4-diphenylpiperidine has a melting point of 72-74°C. Its hydrochloride is produced by dissolving the base in acetic acid ethyl ester and adding an ethereal hydrochloric acid solution thereto. After recrystallization from acetic acid ethyl ester, the melting point of the hydrochloride is 152-154°C. References Menge Heinz Gunter, Klosa Josef; US Patent No. 4,016,280; April 5, 1977; Assigned to Byk Gulden Lomberg Chemische Fabrik GmbH (DT)

BUDOTITANE Therapeutic Function: Antineoplastic Chemical Name: Diethoxybis(1-phenyl-1,3-butanedionato-O,O')titanium Common Name: Budotitane Structural Formula:

Chemical Abstracts Registry No.: 85969-07-9 Trade Name

Manufacturer

Country

Year Introduced

Budotitane

ZYF Pharm Chemical

-

-

Raw Materials Titantetraethoxid Benzoylaceton

Budralazine

703

Manufacturing Process 11.4 g (0.05 mol) of titantetraethoxid were mixed with solution of 15.8 g (0.097mol) of benzoylaceton in 200 ml n-hexan. Reaction mixture was mixed for 2 h at heating in N2 atmosphere. The precipitate obtained was filtered, then the product was washed with hexan also and filtered. So there was obtained the diethoxybis-(1-phenyl-1,3-butandionato)-titan, melting point 110°C. References Keller H.J. et al.; WO Patent 84/03042; February 9, 1983; Assigned: BYK GULDEN LOMBERG CHEMISCHE FABRIK GESELLSCHAFT MIT BESCHRaNKTER HAFTUNG [DE/DE]; Byk-Gulden-Strasse 2, D-7750 Konstanz (DE)

BUDRALAZINE Therapeutic Function: Antihypertensive Chemical Name: 1(2H)-Phthalazinone-(1,3-dimethyl-2-butenylidene)hydrazone Common Name: Mesityl oxide (1-phthalazinyl) hydrazone Structural Formula:

Chemical Abstracts Registry No.: 36798-79-5 Trade Name

Manufacturer

Country

Year Introduced

Buterazine

Daiichi Seiyaku

Japan

1983

Raw Materials 1-Hydrazinophthalazine HCl Mesityl oxide Manufacturing Process A mixture of 2.0 g of 1-hydrazinophthalazine hydrochloride, 1.1 g of mesityl oxide (isoproplyideneacetone) and 100 ml of ethanol, was refluxed for 3 hours. The reaction mixture was concentrated in vacuo and the residue was

704

Bufenadrine

dissolved in water. The water solution was neutralized with sodium bicarbonate, salted out and the product was extracted with benzene. The benzene layer was passed through a comparatively short column of alumina and the solvent was removed. The residue was crystallized from ether to give 0.7 g of 1-(1,3-dimethyl-2-butenylidene) hydrazinophthalazine, melting point 131°-132°C. References Merck Index 1437 DFU 2 (12) 788 (1977) DOT 18 (10) 553 (1982) and 19 (10) 582 (1983) Ueno, K., Miyazaki, S. and Akashi, A.; US Patent 3,840,539; October 8, 1974; assigned to Daiichi Seiyaku Co., Ltd.

BUFENADRINE Therapeutic Function: Antiemetic, Antihistaminic, Antiparkinsonian Chemical Name: 2-[[2-(1,1-Dimethylethyl)phenyl]phenylmethoxy]-N,Ndimethylethanamine Common Name: Bufenadinum; Bufenadrine Structural Formula:

Chemical Abstracts Registry No.: 604-74-0 Trade Name

Manufacturer

Country

Year Introduced

Bufenadrine

Onbio Inc.

-

-

Raw Materials ο-t-Butyl-α-phenylbenzyl alcohol Sodium hydride N,N-Dimethylmonochloroacetamide Lithium aluminum hydride

Bufeniode

705

Manufacturing Process The ο-t-butyl-α-phenylbenzyl alcohol and N,N-dimethylmonochloroacetamide are dissolved in anhydrous diethyl ether. Portionwise 50% sodium hydride in the form of an oily suspension is added to the solution with stirring. After all the sodium hydride is added, the mixture is stirred at room temperature for another 3 h and then water is added to decompose excess sodium hydride. The ethereal layer is separated, dried with sodium sulfate, filtered and concentrated by removal of the solvent. The residue crystallizes upon addition of petroleum ether (boiling range 80-100°C) to which some diethyl ether is added. There is obtained 2-[ο-t-butyl-α-phenylbenzyl)oxy]-N,N-dimethyl acetamide, melting point 90-91°C (81% yield). To a solution of 2-[ο-t-butyl-α-phenylbenzyl)oxy]-N,N-dimethyl acetamide in anhydrous diethyl ether is added portionwise with stirring and while refiuxing lithium aluminum hydride. After the addition is completed, refluxing is continued overnight. The reaction mixture still contains some lithium aluminum hydride which is decomposed by the addition of water. The mixture is filtered, the ethereal solution separated and dried over sodium sulfate. Diethyl ether is removed from the ethereal solution by distillation. There is obtained 2-[(ο-t-butyl-α-phenylbenzyl)oxy]-N,N-dimethylethylamine. References Stelt C.; US Patent No. 3,463,815; August 26, 1969; Assigned: N.V. Koninklijke Pharmaceutische Fabrieken v/h Brocades-Stheeman and Pharmacia Amsterdam, Netherlands, a corporation of the Netherlands

BUFENIODE Therapeutic Function: Antihypertensive Chemical Name: 4-Hydroxy-3,5-diiodo-α-[1-[(1-methyl-3-phenylpropyl) amino]ethyl]benzyl alcohol Common Name: Diiodobuphenine Structural Formula:

Chemical Abstracts Registry No.: 22103-14-6

706

Bufetolol hydrochloride

Trade Name

Manufacturer

Country

Year Introduced

Proclival

Houde

France

1970

Bufeniod

Weiskopf

W. Germany

1974

Diastal

Bayropharm

Italy

1982

Raw Materials 4-Hydroxypropiophenone Hydrogen Bromide

3-Butyl-1-phenylamine Benzyl chloride Iodine

Manufacturing Process Buphenine is the starting material. See under the alternative name "Nylidrin" in this publication for synthesis. 24 grams of buphenine hydrochloride are suspended in a mixture of 440 ml of 34% ammonia (specific gravity = 0.89) and 315 ml of water. 41 grams of iodine dissolved in 1,080 ml of 96% alcohol are added little by little, with good stirring. During this addition, effected in about 30 min, buphenine hydrochloride dissolves fairly rapidly, and then the diiodobuphenine precipitates out as a crystalline powder. Stirring is continued for a further hour. The precipitate is suction filtered, and then washed with water, with alcohol and with ether and is finally dried in vacuo in the exsiccator in the presence of phosphoric anhydride. Thus, about 23 grams of diiodobuphenine solvated with 1 mol of ethanol are obtained in the form of a microcrystalline white powder. MP (slow) = 185°C (dec.). MP (inst.): 212°C. References Merck Index 1440 Kleeman and Engel p.119 DOT 7 (2) 52 (1971) and 11 (8) 306 (1975) I.N. p.161 South African Patent 680,046; January 3, 1968; assigned to Laboratoires Houde, France

BUFETOLOL HYDROCHLORIDE Therapeutic Function: Antiarrhythmic, Beta-adrenergic blocker Chemical Name: Propanol, 1-(1,1-(dimethylethyl)amino)-3-(2-((tetrahydro2-furanyl)methoxy)phenoxy)-, hydrochloride Common Name: Bufetolol hydrochloride; Bufuronol hydrochloride Chemical Abstracts Registry No.: 35108-88-4

Bufetrol

707

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Bufetolol hydrochloride

ZYF Pharm Chemical

-

-

Raw Materials 1-Bromo-3-[2-(tetrahydro-furan-2-yloxy)phenoxy]propan-2-ol t-Butylamine Fumaric acid Manufacturing Process To a solution of 1 gramm equivalent (g-eq.) of 1-bromo-3-[2(tetrahydrofuran-2-yloxy)phenoxy]propan-2-ol in 30 ml of ethanol is added 1 g-eq. of t-butylamine, the mixture is refluxed for 6 hours, and then the ethanol is distilled off. The residue is dissolved in benzene and the solution is extracted twice with 5% oxalic acid. The aqueous extract is made alkaline with potassium hydroxide and the isolated oil is extracted with benzene. The benzene extract is dried over potassium carbonate and the benzene is distilled off to give of oily 1-(t-butylamino)-3-(o-((tetrahydrofurfuryl)oxy)phenoxy)-2propanol. The corresponding acid fumarate melts at 128°-132°C. References Nakanishi M. et al.; US Patent No. 3,723,476; March 27, 1973; Assigned to Yoshitomi Pharmaceutical Industries Ltd., Osaka, Japan

BUFETROL Therapeutic Function: Antiarrhythmic Chemical Name: 1-(tert-Butylamino)-3-[2-[(tetrahydro-2-furanyl)methoxy] phenoxy]-2-propanol Common Name: Bufetolol Chemical Abstracts Registry No.: 53684-49-4

708

Bufetrol

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Adobiol

Yoshitomi

Japan

1974

Raw Materials 2-(2-Tetrahydrofurfuryloxy)phenol Epichlorohydrin t-Butylamine Manufacturing Process The preparation of a similar compound in which a methoxyethoxy group replaces the tetrahydrofurfuryloxy group in Bufetrol is described in the following example. Nine grams of o-(2-methoxyethoxy)phenol is suspended in 50 milliliters of water containing 3.7 grams of potassium hydroxide, and 5.5 grams of epichlorhydrin is added thereto with stirring. The mixture is stirred at room temperature for 7 hours, and then extracted with two 50 milliliter portions of benzene. The extract is washed with water, dried over anhydrous magnesium sulfate and the benzene is distilled off to give 8.5 grams of oily 1(2,3-epoxypropoxy)-2-(2-methoxyethoxy)benzene showing nD20 = 1.5257. This compound has the methoxyethoxy group in place of the 2tetrahydrofurfuryloxy group in Bufetrol. To a solution of 1-(2,3-epoxypropoxy)-2-(2-tetrahydrofurfuryloxy)benzene in methanol are added tert-butylamine and water, the mixture is allowed to stand at 25°-30°C for 72 hours, and then the methanol is distilled off. The residue is dissolved in toluene and the solution is extracted twice with 5% oxalic acid. The aqueous extract is dried over potassium carbonate and concentrated to give Bufetrol. References Merck Index 1441 Kleeman and Engel p.119 DOT 10 (12) 332 (1974) I.N. p.161 Nakanishi. M.. Muro, T., Imamura, H. and Yamaguchi, N.; US Patent 3,723,476; March 27, 1973; assigned to Yoshitomi Pharmaceutical Industries, Ltd., Japan

Bufexamac

709

BUFEXAMAC Therapeutic Function: Antiinflammatory, Analgesic, Antipyretic Chemical Name: 4-Butoxy-N-hydroxybenzeneacetamide Common Name: Structural Formula:

Chemical Abstracts Registry No.: 2438-72-4 Trade Name

Manufacturer

Country

Year Introduced

Parfenac

Lederle

UK

1973

Feximac Cream

Nicholas

UK

1973

Parfenac

Lederle

France

1974

Parfenac

Cyanamid

Italy

1975

Parfenac

Cyanamid

W. Germany

1976

Parfenac

Opopharma

Switz.

1976

Anderm

Lederle-Takeda

Japan

1977

Droxan

Continental Pharma

Belgium

-

Droxarol

Continental Pharma

W. Germany

-

Flogocid

Continental Pharma

-

-

Malipuran

Scheurich

W. Germany

-

Norfemac

Nordic

Canada

-

Paraderm

Continental Pharma

Belgium

-

Viafen

Zyma

Switz.

-

Raw Materials p-Hydroxyacetophenone Sodium hydroxide Butyl bromide Ethanol

Sulfur Hydroxylamine hydrochloride Morpholine

Manufacturing Process (1) 136 g of p-hydroxyacetophenone, 140 g of butyl bromide, 152 g of potassium carbonate, 17 g of potassium iodide and 275 cc of ethanol are mixed and then refluxed for 48 hours. The reaction mixture is cooled, diluted with water, then extracted with ether. The ethereal phase is washed with a

710

Bufezolac

10% sodium hydroxide solution, then with water, followed by drying, ether is evaporated and the product distilled under reduced pressure. 168 g of pbutyloxyacetophenone are obtained with yield of 87% (160°-162°C at 11 mm Hg). (2) 192 g of p-butyloxyacetophenone, 42 g of sulfur and 130 g of morpholine are mixed and then refluxed for 14 hours. The resulting solution is poured into water and stirred until crystallization of the sulfurated complex. The latter is filtered, washed with water and dried, Production: 270 g (88% yield). (3) 200 g of sodium hydroxide are dissolved in 1,500 cc of ethanol and then 293 g of the thus-obtained sulfurated complex are added. The mixture is refluxed overnight, The mixture is distilled to separate the maximum of the alcohol and then diluted with water. The resulting solution is acidified with hydrochloric acid, and extracted with ether. The ethereal phase is washed with water, followed by extraction with a 10% sodium carbonate solution. The carbonated solution is acidified with 10% hydrochloric acid, and the resulting precipitate of p-n-butyloxyphenylacetic acid is filtered and dried. 100 g of this product are obtained (70% yield). (4) 208 g of p-n-butyloxyphenylacetic acid, 368 g of ethanol and 18 cc of sulfuric acid are refluxed for 5 hours. The mixture is diluted with water, after which it is extracted with ether. The ethereal phase is successively washed with water, then with carbonate, and again with water, following which it is dried and distilled to remove solvent. The ester is then distilled at a reduced pressure. 200 g of ethyl p-butyloxyphenylecetate are thus obtained with yield of 61% (186°C at 8 mm Hg). (5) 7 g of hydroxylamine hydrochloride are dissolved in 100 cc of methanol. A solution of 5 g of sodium in 150 cc of methanol is added and the salt precipitate is separated by filtration. 22 g of ethyl p-n-butyloxyphenylacetate are added to the filtrate and the mixture is refluxed for 1 hour. The mixture is cooled and acidified with 20% hydrochloric acid. 14.7 g of p-nbutyloxyphenylacetohydroxamic acid are thus obtained with yield of 71% (melting point: 153°-155°C). References Merck Index 1442 Kleeman and Engel p. 120 DOT 12 (11) 435 (1976) I.N. p.161 Buu-Hoi, N.P., Lambelin, G., Lepoivre, C., Gillet, C. and Thiriaux, J.; US Patent 3,479,396; November 18, 1969; assigned to Madan A.D.

BUFEZOLAC Therapeutic Function: Antiinflammatory Chemical Name: 1-(2-Methylpropyl)-3,4-diphenyl-1H-pyrazole-5-acetic acid

Bufezolac

711

Common Name: Bufezolac; LM 22070 Structural Formula:

Chemical Abstracts Registry No.: 50270-32-1 Trade Name

Manufacturer

Country

Year Introduced

Bufezolac

Onbio Inc.

-

-

Raw Materials Maleic anhydride Isobutylamine Sodium nitrite Perchloric acid Sodium carbonate

Triethylamine Hydrochloric acid Acetic anhydride Diphenylacetylene

Manufacturing Process 50.0 g of maleic anhydride and 180 ml of methanol are heated for 1 h under reflux while stirring. The reaction mixture is cooled to room temperature and the excess methanol is evaporated under reduced pressure. 67.0 g of monomethyl maleate are obtained. The monomethyl maleate is then cooled to 0°C after which 90 ml of triethylamine and then 34.0 g of isobutylamine are introduced over a period of 1 h. The reaction mixture is heated under reflux for 1 h, then cooled to 50°C and 200 ml of acetone added; as a result of filtering off the crystals which separate there are obtained 73.7 g of methyl Nisobutyl-β-aspartate, melting point 250°C. Over a period of 10 min 860 ml of concentrated hydrochloric acid are added to a suspension of 340.0 g of methyl N-isobutyl-β-aspartate in 860 ml of water whilst stirring. The solution is cooled to 0°C and 128.0 g of sodium nitrite dissolved in 280 ml of water are introduced over a period of 1 h 20 min. The reaction mixture is stirred for 2 h at 0°C and extraction is then carried out thrice with a total of 3000 ml of diethyl ether. The organic phase is thrice washed with a total of 1500 ml of water, dried over magnesium sulfate and the ether evaporated under reduced pressure. The residue, when dissolved in a mixture of 1400 ml of petroleum ether and 230 ml of ether, gives, after cooling to 3°C, 325.0 g of methyl N-isobutyl-N-nitroso-β-aspartate, melting point 95°C.

712

Buflomedil

Over a period of 15 min and whilst stirring 158.0 g of methyl N-isobutyl-Nnitroso-β-aspartate are added to 340 ml of acetic anhydride and then, drop by drop, 0.95 ml of 70% perchloric acid. The reaction mixture is then stirred for 2 h at room temperature. The acetic anhydride is evaporated under reduced pressure, and the residue is then successively dissolved once in 100 ml of chloroform, thrice in 100 ml of benzene each time and twice in 100 ml of diethyl ether each time, the solvent being evaporated each time under reduced pressure. 155.0 g of red oil are obtained which are dissolved in 2 volumes of hot di-isopropyl ether and cooled. After 1 min at 3°C the crystals which separate are filtered and there are thus obtained 78.0 g of methyl 3isobutyl-4-sydnonyl acetate, melting point 39°C. 120.0 g of methyl 3-isobutyl-4-sydnonylacetate and 110.0 g of diphenylacetylene dissolved in 600 ml of xylene are heated under reflux whilst being stirred for 70 h. The solution is cooled to room temperature and the xylene is evaporated under reduced pressure. The residue is dissolved in a mixture of 800 ml of 1 N sodium carbonate and 800 ml of acetone. The resulting solution is heated under reflux for 4 h whilst stirring and is then cooled to room temperature and separated. The aqueous phase has 1000 ml of water added thereto and is then extracted thrice with a total of 900 ml of benzene. The aqueous phase is then made acid by the addition of 68 ml of concentrated hydrochloric acid. The oil which separates from the acidified mixture is extracted using a total of 1000 ml of chloroform in five extractions. The combined chloroform extracts are dried over magnesium sulfate and the chloroform is evaporated under reduced pressure. 78.0 g of a brown oil are obtained which are submitted to chromatography upon silica gel using a mixture of chloroform-methanol 99:1 parts. So the 1-isobutyl-3,4diphenylpyrazolyl-5-acetic acid, melting point 181°C (recrystallisation from acetonitrile) is obtained. References Gueremy C., Renault C.; GB Patent No. 1,387,306; March 12, 1975; Aassigned: SOCIETE GENERALE DE RECHERCHES ET D'APPLICATIONS SCIENTIFIQUES SOGERAS, a Franch Body Corporate of 10, Rue Clement Marot, 75008 Paris, France

BUFLOMEDIL Therapeutic Function: Vasodilator Chemical Name: 4-(1-Pyrrolidinyl)-1-(2,4,6-trimethoxyphenyl)-1-butanone Common Name: Chemical Abstracts Registry No.: 55837-25-7; 35543-24-9 (Hydrochloride salt)

Buflomedil

713

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Fonzylane

Lafon

France

1976

Loftyl

Abbott

Italy

1981

Bufedil

Abbott

W. Germany

1982

Loftyl

Abbott

Switz.

1983

Buflan

Pierrel

Italy

-

Irrodan

Biomedica Foscama

Italy

-

Raw Materials 4-Chlorobutyronitrile Pyrrolidine 1,3,5-Trimethoxybenzene Manufacturing Process Introduce 33.6 g (0.2 mol) of 1,3,5-trimethoxybenzene and 100 ml of chlorobenzene into a 500 ml three-neck flask with stirrer, hydrochloric acid bubbler and condenser. Stir to dissolve and add 27.7 g of 4pyrrolidinobutyronitrile (from 4-chlorobutyronitrile and pyrrolidine). Cool to about 15°-20°C and bubble hydrochloric acid gas in for 4 hours. Cool to about 5°C and add 200 cm3 of water. Stir. Decant the aqueous layer, wash again with 150 cm3 of water. Combine the aqueous layers, drive off the traces of chlorobenzene by distilling 150 cm3 of water, and heat under reflux for one hour. Cool and render alkaline by means of 60 ml of sodium hydroxide solution of 36° Baume. Extract twice with 100 ml of ether. Wash the ether with 100 ml of water. Dry the ether over sodium sulfate and slowly run in 50 ml of 5N hydrogen chloride solution in ether, at the boil. Cool in ice. Filter, wash with ether and dry in a vacuum oven. 33.6 g of crude product are obtained. Recrystallize from 200 ml of isopropanol in the presence of 3 SA carbon black. Filter. Wash and dry in a vacuum oven. 26.9 g of a white, crystalline water-soluble powder are obtained. Yield: 39.2%. Instantaneous melting point: 192°-193°C. References Merck Index 1443 Kleeman and Engel p.121 DOT 11 (9) 339 (1975) I.N. p. 161 Lafon, L: US Patent 3,895,030; July 15, 1975; assigned to Orsymonde

714

Buformin hydrochloride

BUFORMIN HYDROCHLORIDE Therapeutic Function: Antidiabetic Chemical Name: N-Butylimidodicarbonimidic diamide hydrochloride Common Name: Butyldiguanide Structural Formula:

Chemical Abstracts Registry No.: 692-13-7 (Base) Trade Name

Manufacturer

Country

Year Introduced

Silubin

Protochemie

Switz.

-

Sindiatil

Bayer

Italy

1979

Adebit

Chinoin

Hungary

-

Andere

Toyama

Japan

-

Biforon

Meiji

Japan

-

Bigunal

Nikken

Japan

-

Bufonamin

Kaken

Japan

-

Bulbonin

Sankyo

Japan

-

Dibetos

Kodama

Japan

-

Gliporai

Grossmann

Mexico

-

Insulamin

Iwaki

Japan

-

Panformin

Shionogi

Japan

-

Ziavetine

Teikoku Kagaku

Japan

-

Raw Materials n-Butylamine HCl Dicyandiamide Manufacturing Process 105.6 g of n-butylamine hydrochloride and 79.3 g of dicyandiamide were ground intimately and mixed. The mixture was heated by means of an oil bath, gradually with stirring, and after thirty minutes when the internal temperature had reached 150°C, an exothermic reaction ensued with internal pressure rising to 178°C. The reaction mixture was removed from the oil bath until the internal temperature had fallen to 150°C and then heating was resumed at 150°C for one hour. The cooled fusion mixture was dissolved in 3 liters of acetonitrile and on cooling n-butyl-biguanide hydrochloride

Bufuralol hydrochloride

715

precipitated. References Merck index 1445 OCDS Vol.1 p.221 (1977); 2, 21 (1980) I.N. p. 162 Shapiro, S.L.; US Patent 2,961,377; November 22, 1960; assigned to US Vitamin and Pharmaceutical Corp.

BUFURALOL HYDROCHLORIDE Therapeutic Function: Beta-adrenergic blocker Chemical Name: α-[[(1,1-Dimethylethyl)amino]methyl]-7-ethyl-2benzofuranmethanol hydrochloride Common Name: Bufuralol hydrochloride; Angium Structural Formula:

Chemical Abstracts Registry No.: 54340-62-4 (Base); 59652-29-8 Trade Name

Manufacturer

Country

Year Introduced

Bururalol hydrochloride

Onbio Inc.

-

-

Raw Materials Trimethyl-phenyl-ammonium perbromide 5-Bromo-2-acetyl-7-ethylbenzofuran 2-Propanamine, 2-methylPalladium on carbon

Sodium borohydride Hydrochloric acid Sodium hydroxide Hydrogen

Manufacturing Process 68.3 g (0.182 mol) of trimethyl-phenyl-ammonium perbromide were added in a single portion at 20°C to a stirred solution of 48.5 g (0.182 mol) of 5bromo-2-acetyl-7-ethylbenzofuran in 400 ml of dry tetrahydro-furan. The

716

Bumadizon

resulting mixture was stirred at 20°C for 3 h, during which time trimethylphenyl-ammonium bromide precipitated out. The mixture was then poured into water and extracted 3 times with ether. The combined ether extracts were washed successively with water, saturated sodium bicarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The solid residue was recrystallized from ethanol to yield 43.1 g of 5-bromo-2-bromoacetyl-7-ethylbenzofuran as yellow crystals, melting point 101-102°C. 1.35 g of sodium borohydride were added portion-wise at room temperature over a period of 20 min to a stirred solution of 17.3 g (0.05 mol) of 5-bromo2-bromoacetyl-7-ethylbenzofuran in 100 ml of dioxane and 25 ml of water. The mixture was stirred at room temperature for 3 h, then dioxane was removed by evaporation at 40°C under reduced pressure and the residue was diluted with water and extracted 3 times with ether. The combined ether extracts were worked up in the usual manner to yield 16.0 g of crude 5bromo-2-(2-bromo-1-hydroxyethyl)-7-ethyl-benzofuran as a viscous oil. 16.0 g of crude 5-bromo-2-(2-bromo-1-hydroxyethyl)-7-ethylbenzofuran and 37.0 g of t-butylamine were heated at 100°C in a sealed autoclave for 24 h. After cooling, excess t-butylamine was evaporated off and the residue was taken up in dilute aqueous hydrochloric acid. The aqueous solution was washed twice with ether, basified with dilute aqueous sodium hydroxide solution and extracted twice with ether. The combined ether extracts were washed with water and with brine, dried over anhydrous sodium sulfate, filtered and evaporated. The solid residue was crystallized from petroleum ether (boiling point 60-80°C) to yield 4.7 g of 5-bromo-2-(2-t-butylamino-1hydroxyethyl)-7-ethylbenzofuran as buff crystals, melting point 101-103°C. 4.8 g of 5-bromo-2-(2-t-butylamino-1-hydroxyethyl)-7-ethylbenzofuran in 50 ml of ethanol were hydrogenated at room temperature and atmospheric pressure in the presence of 0.3 g of 5% palladium-on-carbon catalyst. After the uptake of one equivalent of hydrogen, the hydrogenation was terminated, catalyst was filtered off and the filtrate was evaporated to dryness. The residue was basified and extracted twice with ether. The combined ether extracts were worked up in the usual manner to give 2-(2-t-butylamino-1hydroxyethyl)-7-ethylbenzofuran in the form of an oil. In practice it is usually used as hydrochloride. References Fothergill G.A. et al.; US Patent No. 3,929,836; December 30, 1975; Assigned: Hoffmann-La Roche Inc., Nutley, N.J.

BUMADIZON Therapeutic Function: Analgesic, Antipyretic, Antirheumatic Chemical Name: Butylpropanedioic acid mono-(1,2-diphenylhydrazide)

Bumadizon

717

Common Name: Butylmalonic acid diphenylhydrazide Structural Formula:

Chemical Abstracts Registry No.: 3583-64-0 Trade Name

Manufacturer

Country

Year Introduced

Eumotol

Byk Gulden

W. Germany

1972

Eumotol

Iromedica

Switz.

1972

Eumotol

Valpan

France

1976

Eumotol

Byk Gulden

Italy

1976

Dibilan

Byk Gulden

-

-

Rheumatol

Tosse

W. Germany

-

Raw Materials Dicyclohexylcarbodiimide n-Butylmalonic acid ethyl ester Hydrazobenzene Manufacturing Process (a) A solution of 22.4 grams of dicyclohexylcarbodiimide in 120 ml of absolute tetrahydrofuran is added dropwise at 5°-10°C in an atmosphere of nitrogen to a solution of 20 grams of n-butylmalonic acid monoethyl ester and 19.6 grams of freshly recrystallized hydrazobenzene in 320 ml of anhydrous tetrahydrofuran. The mixture is then stirred for 15 hr at 25°C in an atmosphere of nitrogen, then the precipitated dicyclohexyl urea is filtered off and the filtrate, after the addition of 3 drops of glacial acetic acid, is evaporated to dryness in vacuo. The residue is dissolved in 1 liter of ether, the ethereal solution is extracted twice with 2 N potassium bicarbonate solution and twice with 2 N hydrochloric acid, whereupon it is washed with water until the washing water is neutral. The ethereal solution is dried over sodium sulfate and concentrated in vacuo. The residue is fractionally distilled under high vacuum whereupon the ester is obtained as a yellow oil. BP 170°C at 0.05 torr vacuum. Crystals which melt at 63°-65°C are obtained from cyclohexane. (b) A suspension of 7.1 grams of the ester obtained according to (a) in 40 ml of aqueous 0.5 N sodium hydroxide solution is refluxed for 24 hours in an atmosphere of nitrogen. The solution is filtered and traces of hydrazobenzene are removed by extraction with ether. The aqueous solution is made acid to

718

Bumetanide

Congo paper at 10°C with concentrated hydrochloric acid, the oil which separates is dissolved in 40 ml of ethyl acetate, the ethyl acetate solution is isolated, and washed neutral with water. The solution is then extracted twice with 36 ml of 0.5 N sodium bicarbonate solution each time. The separate extracts are made acid to Congo paper with concentrated HCl, extracted with ethyl acetate, the extracts are washed neutral with a little water, dried and concentrated under vacuum. The colorless oil which remains is recrystallized twice from ether/petroleum ether, whereupon n-butylmalonic acid-N,N'-diphenylhydrazide is obtained in the form of short needles which melt at 116°-118°C. References Merck Index 1451 Kleeman and Engel p.121 DOT 9 (1) 14 (1973) I.N. p.162 Pfister, R., Sallmann, A. and Hammerschmidt, W.; US Patent 3,455,999; July 16,1969; assigned to Geigy Chemical Corporation

BUMETANIDE Therapeutic Function: Diuretic Chemical Name: 3-(Aminosulfonyl)-5-(butylamino)-4-phenoxybenzoic acid Common Name: Structural Formula:

Chemical Abstracts Registry No.: 28395-03-1 Raw Materials Sodium bicarbonate Hydrogen Phenol

4-Chloro-3-nitro-5-sulfamyl benzoic acid n-Butanol

Bumetanide

719

Trade Name

Manufacturer

Country

Year Introduced

Burinex

Leo

UK

1973

Fordiuran

Thomae

W. Germany

1976

Lunetoron

Sankyo

Japan

1976

Burinex

Sigma Tau

Italy

1977

Lixil

Leo

France

1978

Fontego

Polifarma

Italy

1979

Bumex

Hoffmann - La Roche Inc.

US

1983

Aquazone

Prodes

Spain

-

Butinat

Gerardo Ramon

Argentina

-

Cambiex

Bernabo

Argentina

-

Farmadiuril

Alter

Spain

-

Poliurene

Lepetit

-

-

Primex

Medica

Finland

-

Salurex

Byk Gulden

-

-

Salurin

Yurtoglu

Turkey

-

Segurex

Ricar

Argentina

-

Yurinex

Hemofarm

Yugoslavia

-

Manufacturing Process Preparation of 3-Nitro-4-Phenoxy-5-Sulfamylbenzoic Acid: A mixture of 4chloro-3-nitro-5-sulfamylbenzoic acid (140 grams), phenol (100 grams), sodium hydrogencarbonate (170 grams), and water (1.000 ml) was heated to 85°C while stirring and kept at this temperature for 16 hours. After cooling to 4°C, the precipitated sodium salt of 3-nitro-4-phenoxy-5-sulfamylbenzoic acid was filtered off and washed with ice water. The sodium salt was dissolved in boiling water (3,000 ml), and the 3-nitro-4-phenoxy-5-sulfamylbenzoic acid was precipitated by addition of 4N hydrochloric acid. After cooling, the acid was isolated by suction and dried. The melting point was 255°-256°C. Preparation of 3-Amino-4-Phenoxy-5-Sulfamylbenzoic Acid: A suspension of 3nitro-4-phenoxy-5-sulfamylbenzoic acid (20 grams) in water (100 ml) was adjusted to pH 8 by addition of 1N lithium hydroxide. The resulting solution was hydrogenated at room temperature and 1.1 atmospheres hydrogen pressure after addition of Pd on carbon catalyst (0.6 grams catalyst containing 10% Pd). After the hydrogen uptake had become negligible, the catalyst was removed by filtration, and the 3-amino-4-phenoxy-5-sulfamylbenzoic acid was precipitated from the filtrate by addition of 4N hydrochloric acid to pH 2.5. After recrystallization from aqueous ethanol and drying, the melting point was 255°-256°C. Preparation of 3-n-Butylamino-4-Phenoxy-5-Sulfamylbenzoic Acid: To a suspension of 3-amino-4-phenoxy-5-sulfamyibenzoic acid (10 grams) in nbutanol (200 ml), concentrated sulfuric acid (2 ml) was added while stirring. The reaction mixture was heated under reflux under conditions in which the water formed during the reaction could be removed. When, after dilution with

720

Bumetrizole

n-butanol, the NMR-spectrum of a sample of the reaction mixture showed at the two doublets of the aromatic protons in ring A that the butyl-3-amino-4phenoxy-5-sulfamylbenzoate formed as an intermediate was more than 90% converted to the corresponding 3-n-butylaminobenzoate, 2 N sodium hydroxide (200 ml) was added and the boiling was continued for 45 minutes. After the saponification, the reaction mixture was neutralized to pH 8 by addition of concentrated hydrochloric acid. By cooling, the sodium salt of 3-n-butylamino-4-phenoxy-5-sulfamylbenzoic acid precipitated. It was filtered off and recrystallized from water (100 ml). The sodium salt, crystallizing with 3 molecules of water, was then dissolved in boiling water (200 ml), 1N hydrochloric acid was added to pH 2.5, and after cooling the precipitated 3-n-butylamino-4-phenoxy-5-sulfamylbenzoic acid was collected by filtration. After recrystallization from aqueous ethanol and drying, the pure compounds were obtained with melting point 230°-231°C. References Merck Index 1452 Kleeman and Engel p.121 PDR p.1479 OCDS Vol.2 p.87 (1980) DOT 8 (6) 238 (1972) and 9 (11) 449 (1973) I.N. p.162 Felt, P.W.; US Patent 3,634,583; January 11, 1972; assigned to Lovens Kemiske Fabrik Produktionsaktieselskab. Denmark

BUMETRIZOLE Therapeutic Function: Sunscreen agent Chemical Name: Phenol, 2-(5-chloro-2H-benzotriazol-2-yl)-6-(1,1dimethylethyl)-4-methylCommon Name: Bumetrizole Structural Formula:

Chemical Abstracts Registry No.: 3896-11-5 Trade Name

Manufacturer

Country

Year Introduced

Bumetrizole

Onbio Inc.

-

-

Bunaftine

721

Raw Materials 2'-Hydroxy-3'-t-butyl-5'-methyl-5-chloro-2-nitroazobenzene Sodium hydroxide Zinc Hydrochloric acid Manufacturing Process To a 2000 ml 3-necked, round-bottomed flask equipped with an agitator, reflux condenser, nitrogen inlet and thermometer were charged 140.5 g of 2'hydroxy-3'-t-butyl-5'-methyl-5-chloro-2-nitroazobenzene, 119 g of isopropanol and 80 g of Amsco mineral spirits. A stream of nitrogen was introduced over the surface of the contents of the flask and the nitrogen atmosphere was then maintained throughout the remainder of the reduction process. 13.7 g of 50% aqueous sodium hydroxide solution and 222 g of water were added and the temperature of the contents of the flask were adjusted to 55°C. The ratio of the moles of alkali to moles of o-nitroazobenzene intermediate used was is 0.848/1. 104 g of zinc dust was added in 5 portions over a 2 hours period with the temperature of the flask being held at 55-60°C with some slight external cooling. The total concentration of iron impurities from all reactants less than 150 ppm based on zinc used. After all the zinc was added, the temperature was raised to 60°C and held at this temperature until a spot test indicated no more o-nitroazobenzene intermediate was present. The temperature was then raised to 65°C and held there for 4 to 5 hours or until TLC analysis indicated that no more of the N-oxy-intermediate was present. 62.6 g of anhydrous sodium sulfate and 35.6 g of water were then added, the batch was heated to 70°C and stirred for 15 min. The material was then allowed to stand and separate into three liquid phases plus unreacted zinc dust. The top two layers containing the desired product were transferred to another flask. The remaining aqueous zinc slurry was washed at 65-70°C with three successive 16 g portions of Amsco mineral spirits: isopropanol 50:50. The combined product layers and wash liquids were then washed once at 70°C with an aqueous hydrochloric acid solution made from 130 g of water and 40 g of 32% hydrochloric acid to remove cleavage amine by-products. A second and third wash followed at 70°C with aqueous hydrochloric acid solutions made each from 65 g of water and 20 g of 32% hydrochloric acid. The last wash was essentially colorless. 14 g of 32% hydrochloric acid and 220 g of isopropanol were added to the solution of the product. The batch was allowed to crystallize slowly. The solid product form was filtered and washed with isopropanol at 0°C to give 110 g of 5-chloro-2-(2-hydroxy-3-t-butyl-5methylphenyl)-2H-benzotriazole with a melting point of 140-141°C. References White Howard L.; US Patent No. 4,041,044; August 9, 1977; Assigned to Ciba-Geig Corporation (Ardsley, NY)

BUNAFTINE Therapeutic Function: Antiarrhythmic

722

Bunaprolast

Chemical Name: N-Butyl-N-[2-(diethylamino)ethyl]-1-naphthalenecarboxamide Common Name: Bunaftine; Bunaphtide; Meregon Structural Formula:

Chemical Abstracts Registry No.: 32421-46-8 Trade Name

Manufacturer

Country

Year Introduced

Bunaftine

Malesci

-

-

Raw Materials 1-Naphthoic acid chloride N,N-2-Diethylamine-ethyl-N'(n-butyl)amine

Hydrochloric acid Potassium carbonate

Manufacturing Process Into a solution containing α-naphthoic acid chloride in benzene with agitation and cooling for 0.5 h a benzene solution of N,N-diethylamine-ethyl-N'-(nbutyl)amine is dropped. As the dropping is ended, the solution is kept under agitation in a water bath for 3 h. After cooling the benzene solution is extracted with 10% hydrochloric acid; then the aqueous solution is saturated with potassium carbonate. The separated oil is extracted with ether and, after drying on sodium sulfate, the solvent is removed and the residue is vacuum distilled. So the N-(2diethylamino-ethyl)-N-(n-butyl)-1-naphthalenecarboxamide, boiling point 178°C/0.1 mm/Hg. References Giannini M.; US Patent No. 3,704,322; November 28, 1972; Assigned: Malesci S.A.S. Istituto Farmacobiologico, Florence, Italy

BUNAPROLAST Therapeutic Function: Anti-asthmatic Chemical Name: 1-Naphthalenol, 2-butyl-4-methoxy-, acetate

Bunaprolast

723

Common Name: Bunaprolast Structural Formula:

Chemical Abstracts Registry No.: 99107-52-5 Trade Name

Manufacturer

Country

Year Introduced

Bunaprolast

ZYF Pharm Chemical

-

-

Raw Materials Chromium hexacarbonyl Phenyl lithium Acetic anhydride Triethylamine

Trimethyloxonium tetrafluoroborate(1-) 1-Hexyne Acetylene

Manufacturing Process Preparation of pentacarbonyl[phenyl(methoxy)carbene]chromium: To a suspension of 22 g (0.1 mole) of chromium hexacarbonyl in ether is slowly added phenyllithium (51 ml, 0.1 mole, cyclohexane/ether solution) via syringe over a period of 15-20 minutes under argon at room temperature, and the resulting deep red solution is stirred at room temperature for 1 hour. The solvent is removed under reduced pressure (bath temperature should be below 40°C), and the black residue is dissolved in 200 ml water. (CH3)3O·BF4 (about 15 g) is added portionwise to the solution until it becomes slightly acidic (pH 5.5). The aqueous layer is extracted three times with 200 ml of ether, and the combined etheral extracts are washed once with 300 ml of saturated brine solution, once with 300 ml of saturated sodium carbonate solution, and three times with 300 ml of saturated brine solution, dried over anhydrous sodium sulfate and filtered. The solvent is removed using a rotary evaporator. The deep red tarry residue is purified using flash chromatography by a silica gel column (200 g). Elution by 10% ether in n-hexane gives a deep red syrup, which is solidified upon cooling. Recrystallization from pet-ether at -70°C gives 25.12 g (80.5%) of pentacarbonyl[phenyl(methoxy)carbene] chromium as deep red crystalline. The physical properties of the product are consistent with those described in the literature. 2-Butyl-4-methoxy-1-naphthalenol, acetate:

724

Bunazosin hydrochloride

Reaction of pentacarbonyl[phenyl(methoxy)carbene ]chromium with 1hexyne: Part A. A mixture of the carbene complex (1.0 g, 3.2 mmole), 1-hexyne (2.6 equivalents), acetic anhydride (1.0 eq.) and triethylamine (1.0 eq.) in tetrahydrofuran (90 ml) is heated at 65°C under an argon atmosphere for 1 hour. The solution is cooled and concentrated to give a black residue, which is chromatographed through a silica gel (200 g) column using a flash chromatography. Elution by10% ether in n-hexane gives 71 5 mg (82.2%) of the title product, which solidified. Recrystallization from pet-ether gave white crystals of 2-butyl-4-methoxy-1-naphthalenol acetate; MP: 49°C. Part B. Alternatively, a mixture of 2.0 g (6.4 mmole) of the carbene complex, acetylene (2.6 eq.) and acetic acid in tetrahydrofuran is heated at 65°C for 2 hours under argon atmosphere. After cooling the reaction solution is concentrated and the black residue is loaded on a silica gel (200 g) column for a flash chromatography. Elution by 10% ether in n-hexane gives 895 mg (51.4%) of the title product. References Yamashita A.; European Patent No. 0,146,348; December 13, 1984; The Upjohn Company, Michigan, USA

BUNAZOSIN HYDROCHLORIDE Therapeutic Function: Antihypertensive Chemical Name: 1-(4-Amino-6,7-dimethoxy-2-quinazolinyl)hexahydro-4-(1oxobutyl)-1H-1,4-diazepine monohydrochloride Common Name: Bunazosin hydrochloride; Andante; Bunatenon Structural Formula:

Bunitrolol

725

Chemical Abstracts Registry No.: 52712-76-2 Trade Name

Manufacturer

Country

Year Introduced

Andante

Boehringer-Ingelh.

-

-

Bunazosin hydrochloride

Eisai

-

-

Raw Materials 2-Chloro-4-amino-6,7-dimethoxyquinazoline N-Formylhomopiperazine 2-Butylcarboxylic acid chloride Manufacturing Process 17.0 g of 2-chloro-4-amino-6,7-dimethoxyquinazoline and 18.2 g of Nformylhomopiperazine are added to 170 ml of butanol and the whole is refluxed with stirring for 3 h. After completion of the reaction, the mixture is cooled, and the crystals thus precipitated are filtered out, washed with a small quantity of ethanol and air-dried. 25.0 g of crude 2-homopiperazino-4-amino6,7-dimethoxyquinazoline are obtained. A solution of 2-homopiperazino-4-amino-6,7-dimethoxyquinazoline in 60 ml of acetone is added dropwise to a solution of 2-butylcarboxylic acid chloride in acetone under stirring and ice-cooling. After completion of the addition, the stirring is continued for additional 1 h to complete the reaction. The crystals thus precipitated are filtered out and the 1-(4-amino-6,7-dimethoxy-2quinazolinyl)hexahydro-4-(1-oxobutyl)-1H-1,4-diazepine, melting point 280282°C (recrystallized from a mixture of methanol-ethanol) is obtained. References Takahashy T., Sugimoto H.; US Patent No. 3,920,636; November 18, 1975; Assigned: Eisai Co., Ltd., Tokyo, Japan

BUNITROLOL Therapeutic Function: Antianginal Chemical Name: 2-[3-[(1,1-Dimethylethyl)amino]-2-hydroxypropoxy]benzonitrile Common Name: Chemical Abstracts Registry No.: 34915-68-9

726

Bunitrolol

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

St resson

Boehringer Ingelheim

W. Germany

1976

Betriol

Boehringer Ingelheim

Italy

1981

Betrilol

Boehringer Ingelheim

Japan

1983

Betrilol

TANABE SEIYAKU

Japan

1983

Raw Materials Epichlorohydrin 2-Cyanophenol t-Butylamine Manufacturing Process Epichlorohydrin and 2-cyanophenol are first reacted to give 1-(2cyanophenoxy)-2,3-epoxypropane. 15 g (0.085 mol) of 1-(2-cyanophenoxy)-2,3-epoxy propane were dissolved in 100 ml of ethanol and 18.6 g (0.255 mol) of t-butylamine were added thereto. After standing for 1 hour at room temperature, the solution was heated at 60°-70°C for 2 hours after which the volatile constituents were distilled off in vacuo. The residue was digested with dilute HCl, and the insoluble constituents were vacuum filtered off. Then the filtrate was made alkaline with NaOH and the precipitating base was taken up in ether. After the ether solution had been dried over MgSO4, the ether was distilled off and the residue was dissolved in ethanol and by addition of ethereal HCl, the hydrochloride was precipitated there from in crystalline form which after recrystallization from ethanol with an addition of ether gave9.8 g of 1-(2cyanophenoxy)-2-hydroxy-3-t-butylamino propane hydrochloride having a melting point of 163°-165°C. References Merck Index 1457 DFU 1 (5) 210 (1976) Kleeman and Engel p.123 OCDS Vol. 2 pp.106, 110 (1980) DOT 13 (1) 15 (1977) I.N. p.163 Koppe, H., Engelhardt, A. and Zelle, K.; US Patents 3,541,130; November 17, 1970; 3,940,489; February 24, 1976; and 3,961,071 ; June 1, 1976; all assigned to Boehringer Ingelheim GmbH

Buphenine hydrochloride

727

BUPHENINE HYDROCHLORIDE Therapeutic Function: Vasodilator Chemical Name: 4-Hydroxy-α-[1-[(1-methyl-3-phenylpropyl)amino]ethyl] benzenemethanol hydrochloride Common Name: Buphenine hydrochloride; Nylidrine hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 849-55-8 Trade Name

Manufacturer

Country

Year Introduced

Buphenine hydrochloride

Troponwerke

-

-

Opino

Bayropharm

-

-

Pervadil

Empire

-

-

Verina

Daiichi

-

-

Raw Materials 1-Phenyl-3-aminobutane Hydrogen Acetic acid

p-Benzoxy-α-bromopropiophenone Palladium hydroxide on barium sulfate

Manufacturing Process The p-benzoxy-α-bromopropiophenone and 1-phenyl-3-amino-butane were heating for an hour on the water bath in the absence of solvents. A solid crystalline cake was obtained. After being extracted with boiling acetic acid, the hydrobromide of 1-(p-hydroxyphenyl)-2-(β-phenylbutylamino)propanone-1 was obtained. The hydrobromide of 1-(p-hydroxyphenyl)-2-(β-phenylbutylamino)propanone1 was suspended in very pure methanol and shaken with a 10% palladium hydroxide barium sulfate catalyst in contact with, hydrogen. After rather more than 2 mols of hydrogen had been taken-up the hydrogenation stopped. The 1-(p-hydroxyphenyl)-2-(3-phenylbutylamino)propanol-1, was filtered, washed with methanol and evaporated, melting point 110-111°C.

728

Bupicomide

References Kulz F. et al.; US Patent No. 2,661,373; December 1, 1953; Assigned: Fritz Kulz, and Clemens Schopf, Darmstadt, Germany

BUPICOMIDE Therapeutic Function: Antihypertensive Chemical Name: 5-Butyl-2-pyridinecarboxamide Common Name: Bupicomide Structural Formula:

Chemical Abstracts Registry No.: 22632-06-0 Trade Name

Manufacturer

Country

Year Introduced

Bupicomide

ZYF Pharm Chemical

-

-

Raw Materials Methyl vinylketone Hydroxylamine Thionyl chloride Potassium carbonate

Acetic acid Selenium dioxide Ammonia

Manufacturing Process 3-n-Butyl-6-methyl-3,4-dihydro-1,2-pyran was obtained and isolated from the reaction mixture by fractional distillation in vacuum to separate a by-product formed by cyclodimerisation of methyl vinylketone. The yield of the3-n-butyl6-methyl-3,4-dihydro-1,2-pyran was 47% (boiling point 106-107°C. The saponification of the 3-n-butyl-6-methyl-3,4-dihydro-1,2-pyran was accomplished by heating for 0.5 h in a mixture with acetic acid. The 1-methyl4-n-butyl-1,5-dicarbonyl acid formed not isolated from the reaction mixture was added to hydroxylamine. The reaction with hydroxylamine was carried out by gradual addition of acetic acid solution of 1,5-dicarbonyl compound to the stirring refluxing suspension of hydroxylamine in glacial acetic acid. By usual treatment was fractionned in vacuum to yield 37.5% of 2-methyl-5-nbutylpyridine, boiling point 105°C.

Bupivacaine

729

The 2-methyl-5-n-butylpyridine was oxidated by selenium dioxide in pyridine to 5-n-butyl-2-pyridine carboxylic (fusarinic) acid, melting point 100-101°C. 25.0 g of the 5-n-butyl-2-pyridine carboxylic (fusarinic) acid and 25 ml of thionyl chloride were mixed; after all of the acid is dissolved, concentrate (in vacuo) the mixture and take up the mixture in 500 ml of anhydrous benzene; with cooling add the mixture to a solution of excess ammonia in 1 l of benzene, concentrate (in vacuo) the resulting mixture; add water and potassium carbonate and extract the amide with ether; dry and concentrate the ether extract and 5-n-butyl-2-pyridine carboxamide was obtained (recrystallize from acetonitrile). References Symchowicz S., Sherlock M.H.; US Patent No. 3,519,717; July 7, 1970; Assigned: Schering Corporation, Bloomfield, N.J.., a corporation of a New Jersey Chumakov Yu.I., Sherstyuk V.P.; Tetrahedron Letters N 2, pp.129-135, 1965

BUPIVACAINE Therapeutic Function: Local anesthetic Chemical Name: dl-1-Butyl-2',6'-pipecoloxylidide Common Name: Structural Formula:

Chemical Abstracts Registry No.: 2180-92-9; 18010-40-7 (Hydrochloride salt) Raw Materials 2,6-Dimethylaniline Formic acid Zinc

Nitrosyl chloride Diethyl malonate n-Butyl bromide

730

Bupivacaine

Trade Name

Manufacturer

Country

Year Introduced

Carbostesin

Astra

W. Germany

1967

Carbostesin

Giobopharm

Switz.

1967

Marcain

Duncan Flockhart

UK

1968

Marcain

Yoshitomi

Japan

1969

Marcaina

Pierrel

Italy

1971

Marcaine

Winthrop-Breon

US

1973

Marcaine

Cook-Waite

US

-

Sensorcaine

Astra

US

1981

Bupivan

Abbott

US

-

Meaverin

Woelm Pharma

W. Germany

-

Manufacturing Process 121 parts by weight of 2.6-xylidine are heated with 400 parts of diethylmalonate at 160°C for 1 hour, and the alcohol formed by the reaction is allowed to distill off. Thereafter the reaction mass is cooled to 80°C, and 500 parts of alcohol are added. After cooling the dixylidide is sucked off, and the alcohol solution with malonic ester monoxylidide is poured into 2,000 parts of water. The monoxylidide precipitates, is filtered off and washed with water, and recrystallized in diluted alcohol. Nitrosation thereafter takes place by dissolving the dried monoxylidide in chloroform and by introducing nitrosyl chloride at 0°C until the nitrosation is completed. The isonitrosomalonic ester xylidide is filtered off and dried. Thereafter the reduction takes place with zinc powder and formic acid at 90°-100°C. The formic acid is distilled off, and the remainder dissolved in warm benzene and washed with a bicarbonate solution to a neutral reaction. After the benzene has been distilled off, the aminomalonic ester xylidide is obtained. This is treated with an equal quantity of sodium ethylate and boiled with twice the theoretical quantity of tetramethylene bromide in absolute alcohol. After 6 hours of boiling, the sodium bromide formed is separated, and the mixture is steamdistilled in order to remove the excess of tetramethylene bromide. The remaining oil, which mainly consists of deltabromobutylaminomalonic ester xylidide is separated from the water and boiled with 3 parts of concentrated hydrochloric acid for 3 hours. Thereafter carbonfiltering and evaporation to dryness under vacuum takes place. The residue is dissolved in water, and the pH adjusted with sodium hydroxide to 5.5. The solution is extracted twice with ether, and the water is made strongly alkaline with sodium hydroxide. The oil precipitates and is crystallized after a time. The crystals are separated and dried under vacuum. The pipecolyl-2,6-xylidide produced is alkylated by boiling for 10-20 hours with 0.6 part n-butylbromide in an n-butanol solution in the presence of 0.5 part potassium carbonate. The potassium carbonate is filtered off and the butanol is distilled off in vacuum. The residue is dissolved in diluted hydrochloric acid and carbon treated, after which the base is precipitated with sodium hydroxide in the form of white crystals, which are filtered off and washed with water. The base obtained, which consists of N-n-

Bupranolol

731

butyl-pipecolyl-2,6-xylidide is sufficiently pure for the production of salts. References Merck Index 1462 Kleeman and Engel p.124 PDR pp.596, 825, 1915 OCDS Vol.1 p.17 (1977) DOT 3 (3) 88 (1967) I.N. p.164 REM p.1050 Thuresson, B. and Egner, B.P.H.; US Patent 2,792,399; May 14, 1957; assigned to AB Bofors, Sweden Thuresson, B. and Pettersson, B.G.; US Patent 2,955,111; October 4, 1960; assigned to AB Bofors, Sweden

BUPRANOLOL Therapeutic Function: Antiarrhythmic Chemical Name: 1-(tert-Butylamino)-3-[(6-chloro-m-tolyl)oxy]-2-propanol Common Name: Bupranol Structural Formula:

Chemical Abstracts Registry No.: 14556-46-8; 15146-80-8 (Hydrochloride salt) Trade Name

Manufacturer

Country

Year Introduced

Betadrenol

Pharma-Schwarz

W. Germany

1969

Betadrenol

Adrosanol

Switz.

1969

Betadran

Logeais

France

1972

Looser (Lucer)

Kaken

Japan

1974

Panimit

Nattermann

W. Germany

-

Ophtorenin

Dr. Winzer

W. Germany

-

Raw Materials Epichlorohydrin 2-Chloro-5-methylphenol t-Butylamine

732

Bupropion hydrochloride

Manufacturing Process A mixture of 16.3 g of (2-chloro-5-methylphenyl)glycidic ether (from epichlorohydrin and 2-chloro-5-methylphenol) and 6.2 g of t-butylamine in 50 ml of ethanol is heated at reflux for 6 hours. The solvent is removed, the residue is washed with water and then extracted with benzene. The dried extract is evaporated to give 1-t-butylamino-3-(2-chloro-5-methylphenoxy)-2propanol. Treatment of the free base in benzene solution with dry hydrogen chloride yields the hydrochloride salt. References Merck Index 1463 Kleeman and Engel p.125 I.N. p.164 Kunz, W., Jacobi, H., Koch, C. and Geus, R.J.; US Patent 3,309,406; March 14, 1967

BUPROPION HYDROCHLORIDE Therapeutic Function: Antidepressant; Smoking cessation aid Chemical Name: 1-Propanone, 1-(3-chlorophenyl)-2-((1,1-dimethylethyl) amino)-, (+/-)-, hydrochloride Common Name: Amfebutamone hydrochloride; Bupropion hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 34911-55-2 (Base); 31677-93-7 Trade Name

Manufacturer

Country

Year Introduced

Bupropion hydrochloride

AroKor Holdings Inc.

-

-

Wellbutrin

Glaxo-Wellcome

-

-

Zyban

Glaxo-Wellcome

-

-

Bupropion hydrochloride

Shanghai BR Chemical Co., Ltd.

-

Bupropion hydrochloride

733

Raw Materials Ethyl magnesium bromide Hydrochloric acid t-Butylamine

m-Chlorobenzonitrile Bromine Sodium hydroxide

Manufacturing Process To ethyl magnesium bromide (2 L, 3 M) was added over 45 min with stirring and cooling m-chlorobenzonitrile (688.0 g, 5 mole) in ether (2.5 L). The resultant solution was heated under gentle reflux for 5 h. The reaction mixture was hydrolyzed with cold dilute hydrochloric acid, the ether was distilled off, and the aqueous solution was heated at 90°C for 1 h. The flask was then cooled. The solid ketone that separated was washed with cold water and recrystallized from methanol. The recrystallized m-chloropropiophenone, melting point 39°-40°C, weighed 750.0 g. In methylene chloride (3 L) was dissolved m-chloropropiophenone (698.0 g; 4.15 mole). The solution was stirred with charcoal (Darco) and magnesium sulfate for 2 h and filtered. To it was added with stirring (662.0 g) of bromine in methylene chloride (1 L). When the bromine color had faded completely, the solvent was evaporated in vacuum and m-chloro-α-bromopropiophenone was obtained as oil. The m-chloro-α-bromopropiophenone was dissolved in acetonitrile (1300 ml). To this, t-butylamine (733.0 g) in acetonitrile (1300 ml) was added while keeping the temperature below 32°C. The reaction mixture was allowed to stand over night. It was then partitioned between water (4200 ml) and ether (2700 ml). The aqueous layer was extracted with a further portion of ether (1300 ml). The combined ethereal layers were then washed with water (4200 ml) to which hydrochloric acid was added until the pH of the aqueous layer was 9. The aqueous layer was separated and washed with ether (500 ml) and then discarded. The combined ethereal layers were then stirred with ice (560.0 g) and concentrated hydrochloric acid (324 ml). The ethereal layer was separated and again washed with water (200 ml) and concentrated hydrochloric acid (50 ml). These last two acid layers were combined and concentrated in vacuum until crystals appeared. The solution was then chilled to 5°C and filtered. The product was sucked dry, washed with acetone and recrystallized from a mixture of isopropanol (3 L) and absolute ethanol (800 ml). The DL-m-chloro-α-t-butylaminopropiophenone hydrochloride so was obtained, melting point 233°-234°C. The DL-m-chloro-α-t-butylaminopropiophenone was obtained by treatment of DL-m-chloro-α-t-butylaminopropiophenone hydrochloride with sodium hydroxide. References Nariman B.M.; US Patent No. 3,819,706; June 25, 1974; Assigned: Burroughs Wellcome Co., Research Triangle Park, N.C.

734

Buquineran

BUQUINERAN Therapeutic Function: Coronary vasodilator Chemical Name: N-Butyl-N'-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl] urea Common Name: Buquineran; BDPU Structural Formula:

Chemical Abstracts Registry No.: 59184-78-0 Trade Name

Manufacturer

Country

Year Introduced

Buquineran

Pfizer Central Research

-

-

Raw Materials Triethylamine 4-Chloro-6,7-dimethoxyquinazoline Sodium hydroxide 4-(3-n-Butylureido)piperidine hydrochloride Manufacturing Process 4-Chloro-6,7-dimethoxyquinazoline (45.0 g), 4-(3-n-butylureido)piperidine monhydrochloride (80.0 g) and triethylamine (140 ml) were refluxed in ethanol (450 ml) for 1.25 h. The mixture was then concentrated in vacuo and the resultant solid was stirred in water which was then basified to pH 11 with 5 N NaOH solution. The suspension was shaken with chloroform and the organic layer was separated, dried (Na2CO3) and evaporated to dryness in vacuo to give a yellow oily solid. Trituration with ether followed by recrystallization from ethanol gave the product (37.0 g) with small traces of impurities, wich were removed by running a chloroform solution of it down a glass column packed with "Florisil" and eluting with 10% isopropanol in chloroform. After evaporation, appropriate fractions were bulked to give a pure 4-(4-[3-nbutylureido]piperidino)-6,7-dimethoxyquinazoline, melting point 204-205°C (21.0 g; recrystallized from ethanol).

Buquiterine

735

References Danilewicz J.C. et al.; US Patent No. 4,001,422; January 4, 1977; Assigned: Pfizer Inc., New York, N.Y.

BUQUITERINE Therapeutic Function: Bronchodilator Chemical Name: 2-[(1,1-Dimethylethyl)amino]-6,7-dihydro-9,10-dimethoxy4H-pyrimido[6,1-a]isoquinolin-4-one Common Name: Buquiterine Structural Formula:

Chemical Abstracts Registry No.: 76536-74-8 Trade Name

Manufacturer

Country

Year Introduced

Buquiterine

ZYF Pharm Chemical

-

-

Raw Materials Sodium hydroxide t-Butylamine 9,10-Dimethoxy-2-chloro-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-4one Manufacturing Process A solution of 9,10-dimethoxy-2-chloro-6,7-dihydro-4H-pyrimido[6,1a]isoquinolin-4-one (3.0 g) and t-butylamine (10 ml) in chloroform (75 ml) is heated under reflux for 16 h. The solvent is evaporated under reduced pressure and the residue triturated with a dilute solution of sodium hydroxide to give a white precipitate of 9,10-dimethoxy-2-t-butylamino-6,7-dihydro-4Hpyrimido[6,1-a]isoquinolin-4-one. References Lal B., et al.; US Patent No. 4,482,556; November 13, 1984; Assigned: Hoechst Aktiengesellschaft, Frankfurt am Main, Fed. Rep. of Germany

736

Buspirone hydrochloride

BURAMATE Therapeutic Function: Anticonvulsant, Tranquilizer Chemical Name: (Phenylmethyl)carbamic acid 2-hydroxyethyl ester Common Name: Buramate; Hyamate Structural Formula:

Chemical Abstracts Registry No.: 4663-83-6 Trade Name

Manufacturer

Country

Year Introduced

Buramate

Chauny and Cirey

-

-

Raw Materials Cyclic carbonate of glycol Benzylamine Manufacturing Process Into a vessel provided with efficient stirring means there are gradually introduced, while maintaining the temperature at 40°C, 535.0 g of benzylamine and 440.0 g of cyclic carbonate of glycol. The mass obtained is maintained at a temperature 40-50°C for about 12 h. Upon cooling, there is obtained a glycol benzylcarbamate as a white crystalline, melting point at 40°C, yield 92%. References GB Patent No. 689,705; April 1, 1953; Assigned: Societe Anonyme des Manufactures des Glaces et Produits Chimiques de Saint-Gobain, Chauny et Cirey, a Company organized under the laws of the French Republic, of 1 bis Place des saussaies, Paris VIIIe, Franc

BUSPIRONE HYDROCHLORIDE Therapeutic Function: Anxiolytic Chemical Name: 8-Azaspiro[4.5]decane-7,9-dione, 8-(4-(4-(2-pyrimidinyl)1-piperazinyl)butyl), monohydrochloride

Buspirone hydrochloride

737

Common Name: Buspirone hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 33386-08-2 Trade Name Ansial Anxiolan Bespar Buspar Buspirone hydrochloride

Manufacturer Bristol-Myers Squibb Medochemie Ltd. Bristol-Myers Squibb Bristol-Myers Squibb Alexis Biochemicals

Country -

Year Introduced -

Busirone

Bristol-Myers Squibb

-

-

Raw Materials 3-Chloropropionitrile Cyclohexane Nickel Raney

3,3-Tetramethyleneglutaric anhydride 1-(2-Pyrimidinyl)piperazine Hydrazine hydrate

Manufacturing Process There is the 3 methods for preparing of 8-azaspiro(4.5)decane-7,9-dione, 8(4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl) monohydrochloride (U.S. Patent 3,717,634). One of them is follows: a mixture of 0.1 mole of the substituted glutaric anhydride, 0.1 mole of l-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine (U.S. Pat. 3,398151), and 300 ml of pyridine was refluxed until imide formation was completed. The degree of reaction was readily followed by taking an aliquot portion of the reaction mixture, removing the solvent, and obtaining the infrared absorption spectrum of the residue. When reaction is complete, the spectrum exhibited typical infrared imide bands at 1701 and 1710 cm-1 whereas if incomplete, the infrared spectrum contains amide and carboxyl absorption bands at 1680, 1760 and 3300 cm-1. 1-(3-Cyanopropyl)-4-(2-pyrimidinyl)-piperazine. A mixture of 1-(2pyrimidinyl)piperazine (6.0 g, 0.04 mole), 4.6 g (0.044 mole) of 3chloropropionitrile and sodium carbonate (4.24 g, 0.04 mole) in 50 ml of nbutanol was gently refluxed for 16 hours. The reaction mixture was concentrated in vacuo and the residual oil dissolved in about 100 ml of cyclohexane. On standing a white crystalline material separated which was crystallized from cyclohexane to provide 6.5 g (yield 70%) of the cyano

738

Busulfan

intermediate, m.p. 56.6-58°C. A solution of 11.5 g (0.05 mole) of 1-(3cyanopropyl)-4-(2-pyrimidinyl)piperazine in 150 ml of absolute ethanol was saturated with ammonia. W-6 Raney nickel catalyst was added and the mixture hydrogenated under 1200 p.s.i. When the hydrogenation was completed the mixture was filtered and the residual oil distilled under reduced pressure to provide 8.2 g (70% ) of 1-(4-aminobutyl)-4-(2pyrimidinyl)piperazine, b.p. 143-146°C at 0.1 mm. (nD26 = 1.5582). The azospiroalkenedione 8-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-8azaspiro[4.5]decane-7,9-dione was purified as free base by stripping off the pyridine solvent and crystallizing the residue from a suitable solvent or by vacuum distillation thereof hydrochloric salt of it was prepared by treating of an ethanol solution of free base with equimolar amount of HCl. References Yao Hua Wu et al.; US Patent No. 3,717,634; Feb. 20, 1973; Assigned: Mead Johnson and Company (Evansville, IN) Yao Hua Wu et al.; US Patent No. 3,976,776; Aug. 24, 1976; Assigned: Mead Johnson and Company (Evansville, IN)

BUSULFAN Therapeutic Function: Antineoplastic Chemical Name: 1,4-Butanediol dimethanesulfonate Common Name: Structural Formula:

Chemical Abstracts Registry No.: 55-98-1 Trade Name

Manufacturer

Country

Year Introduced

Myleran

US

1954

Misulban

BurroughsWellcome Techni-Pharma

France

1955

Myleran

Wellcome

Switz.

1955

Myleran

Wellcome

W. Germany

1955

Mablin

Takeda

Japan

-

Mielucin

Farmasimes

Spain

-

Myeleukon

Arzneimittelwerk Dresden Spofa

E. Germany

-

Czechoslovakia

-

Mylecytan

Butabarbital sodium

739

Raw Materials 1,4-Butanediol Methanesulfonyl chloride Manufacturing Process 3.6 grams of redistilled 1,4-butanediol were dissolved in 10 ml of pyridine and the solution was cooled in ice and water. 9.6 grams of redistilled methanesulfonyl-chloride were added dropwise at such a rate that the temperature did not rise above 20°C. The solution was then allowed to stand at room temperature to; 30 minutes, during which time the temperature rose to 60°C. A thick precipitate of pyridine hydrochloride was formed. The mass was cooled in ice water and was treated with 30 ml of ice cold water. On agitation, a white crystalline precipitate was formed. This was filtered off and washed well with ice cold water and allowed to drain on the pump. It weighed 7.8 grams and had a melting point of 100°C. 3.5 grams of the material were recrystallized from acetone and ether to give small white needles, having a melting point of 106°-107°C, unchanged by further recrystallization. References Merck Index 1470 Kleeman and Engel p.125 PDR p.754 I.N. p.165 REM p.1144 Timmis, G.M.; US Patent 2,917,432; December 15, 1959; assigned to Burroughs Wellcome and Co., Inc.

BUTABARBITAL SODIUM Therapeutic Function: Hypnotic Chemical Name: Barbituric acid, 5-sec-butyl-5-ethyl-, sodium salt Common Name: Butabarbital sodium; Butabarbitone sodium; Secbutabarbital sodium; Secbutobarbitone sodium Structural Formula:

Chemical Abstracts Registry No.: 143-81-7

740

Butacaine

Trade Name Butisol sodium Butisol sodium

Manufacturer Wallace Labs Acura Pharmaceuticals, Inc.

Country USA -

Year Introduced -

Raw Materials Diethyl ester of malonic acid Sodium ethylate Urea

Ethyl bromide 2-Butyl bromide

Manufacturing Process 5-sec-Butyl-5-ethylbarbituric acid was prepared from diethyl ester of malonic acid in 3 steps. At the above malonic ester was reacted with C2H5Br and sodium ethylate producing the diethyl ester of ethylmalonic acid, which after a reaction with sodium ethylate and 2-butylbromide gave the ethyl-(2-butyl)malonic acid diethyl ester. The last one produced the 5-sec-butyl-5-ethylbarbituric acid after a reaction with urea and sodium ethylate. 23 g sodium (1 mol) was dissolved in 300 ml alcohol. To this solution was added a solution of 5-sec-butyl-5-ethyl-barbituric acid (1 mol) in 800 ml alcohol. To a mixture was added 1000 ml benzene, which precipitated the sodium salt of the barbituric acid (butabarbital sodium). The product was filtered and dried. References Whitmore F.C. et al.; US Patent No. 2,161,212; June 6, 1939 Shonle H.A. et al.; US Patent No. 1,856,792; May 3, 1932 Pharmazeitishe Wirkstoffe, A. Kleeman und J. Engel, N.I. 1982

BUTACAINE Therapeutic Function: Local anesthetic Chemical Name: 1-Propanol, 3-(dibutylamino)-, p-aminobenzoate (ester) Common Name: Butacaine; Butaprobenz; Butocaina Chemical Abstracts Registry No.: 149-16-6 Trade Name Butelline Butyn Dental

Manufacturer ALK-Abello Abbott

Country -

Year Introduced -

Raw Materials p-Nitro-gamma-bromo-propylbenzoate Hydrochloric acid

Dibutylamine Iron filings

Butadiazamide

741

Structural Formula:

Manufacturing Process 40 g p-nitro-gamma-bromo-propylbenzoate and 40 g dibutylamine are heated together at 60°C, for four hours. The excess dibutyl amine is removed by washing the product with water and then steam distilling the residue. The material remaining in the flask is taken up in benzene and treated with aqueous hydrochloric acid. Part of the p-nitrobenzoyl-gamma-di-nbutylamminopropanol hydrochloride thus formed goes into the water layer, while most of it separates as a heavy oily layer. This, together with the water layer, is separated from the benzene layer, made alkaline, and the resulting base taken up in benzene. Upon removal of the solvent, the desired pnitrobenzoyl-gamma-di-n-butylamminopropanol is obtained. The p-nitrobenzoyl-gamma-di-n-butylamminopropanol is reduced by warming to about 60°C with an excess of iron filings and a small amount of hydrochloric acid for four hours. The material is then allowed to cool, neutralized with dilute sodium hydroxide solution, and extracted with ether. Upon the removal of the ether, the free base, para-aminobenzoyl-gamma-din-butylaminopropanol, remains behind as an oil. It is exactly neutralized with aqueous hydrochloric acid and the resulting solid salt purified by recrystallization from water or a suitable organic solvent. It melts at 151°152°C (corr.) after drying at 100°C. References Merck Index, Monograph number: 1531, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. Adams R., Volwiler E.H.; US Patent No. 1,358,751; Nov. 16, 1920 Adams R., Volwiler E.H.; US Patent No. 1,676,470; July 10, 1928

BUTADIAZAMIDE Therapeutic Function: Oral hypoglycemic Chemical Name: N-(5-Butyl-1,3,4-thiadiazol-2-yl)-4-chlorobenzenesulfonamide

742

Butalamine hydrochloride

Common Name: Butadiazamide Structural Formula:

Chemical Abstracts Registry No.: 7007-88-7 Trade Name

Manufacturer

Country

Year Introduced

Butadiazamide

Onbio Inc.

-

-

Raw Materials 5-Amino-2-n-butyl-1:3:4-thiadiazole p-Chlorobenzene sulfonyl chloride Hydrochloric acid Manufacturing Process 15.7 g of 5-amino-2-n-butyl-1:3:4-thiadiazole (0.1 mol) was dissolved in 150 ml dry pyridine and treated with 21.1 g of ρ-chlorobenzene sulfonyl chloride (0.1 mol). The mixture was heated on a steam bath for 4 h and the pyridine removed by distillation under reduced pressure. The residue was treated with 50 ml 2 N hydrochloric acid, and after filtration the 2-n-butyl-5-ρchlorobenzenesulfonamido-1:3:4-thiadiazole as colourless prisms, melting point 129-130°C (recrystallised from benzene) was obtained. References Macrae F.J., Drain D.J.; GB Patent No. 824,978; December 9, 1959; Assigned: T.J. Smith and Nephew Limited, a British Company, of Neptune Street, Kingston-upon-Hull, Yorkshire

BUTALAMINE HYDROCHLORIDE Therapeutic Function: Vasodilator Chemical Name: N,N-Dibutyl-N'-(3-phenyl-1,2,4-oxadiazol-5-yl)-1,2ethanediamine hydrochloride Common Name: -

Butalamine hydrochloride

743

Structural Formula:

Chemical Abstracts Registry No.: 22131-35-7 (Base); 28875-47-0 (Hydrochloride salt) Trade Name

Manufacturer

Country

Year Introduced

Surheme

Aron

France

1969

Surheme

Spemsa

Italy

1974

Adrevil

Zyma-Blaes

W. Germany

1975

Oxadilene

Leurquin

France

-

Surem

Cepa

Spain

-

Raw Materials Benzaldehyde Dibutylaminoethyl chloride Cyanamide

Chlorine Hydroxylamine Sodium amide

Manufacturing Process Benzaldehyde and hydroxylamine may be reacted, the product chlorinated and then reacted with cyanamide to give 5-amino-3-phenyl-1,2,4-oxadiazole. 32 grams of 3-phenyl-5-amino-1,2,4-oxadiazole dissolved in about 150 ml of anhydrous benzene, 7.8 grams of sodium amide are added and the reaction mixture heated at the boiling point with stirring for 2 hours. A solution of 38.3 grams of dibutylaminoethyl chloride in benzene is then added and the mixture heated to boiling under reflux for four hours. The sodium chloride is separated as previously described, the benzene removed by vacuum distillation and 56 grams of 3-phenyl-5-(dibutylaminoethylamino)-1,2,4-oxadiazole is obtained in the form of an oil which is then converted directly to the crystalline hydrochloride. This is accomplished by dissolving the oil in ethanol and adding the stoichiometric equivalent of anhydrous ethyl ether saturated with gaseous hydrogen chloride. The recrystallized salt is found to have a melting point of 145°C. References Merck Index 1477 Kleeman and Engel p.126 I.N. p.166 Aron-Samuel, J.M.D. and Sterne, J.J.; US. Patent 3,338,899; August 29, 1967

744

Butalbital

BUTALBITAL Therapeutic Function: Hypnotic, Sedative Chemical Name: 2,4,6(1H,3H,5H)-Pyrimidinetrione, 5-(2-methylpropyl)-5-(2propenyl)Common Name: Alisobumalum; Allylbarbital; Butalbital; Itobarbital; Tetrallobarbital Structural Formula:

Chemical Abstracts Registry No.: 77-26-9 Trade Name Axocet Esgic-Esgic Plus Zyban Fiorinal Floricet Sandoptal Medigesic Pacaps Phrenilin Repan Sedacap Tenake Tencon

Manufacturer Savage Labs Forest Glaxo-Wellcome Sandoz Sandoz Sandoz US Pharmaceutical Corporation Lunsco Canrick Labs Everett Lab Merz Pharmaceuticals

Country -

Year Introduced -

-

-

Seatrace Pharmaceuticals Intarnational Ethical Labs

-

-

-

-

Raw Materials Sodium Ethyl malonic acid ester Urea Allyl bromide

Alcohol 2-Isobutyl bromide Potassium hydroxide

Manufacturing Process 1 mole of sodium is dissolved in 10 to 12 times its weight of absolute alcohol

Butamirate citrate

745

under a reflux condenser. To this are added 1 mole of ethyl malonic acid ester, and then gradually about 1.1 moles of 2-isobutyl bromide. The mixture is gently refluxed for some hours, or until it no longer shows alkaline reaction to moist litmus paper. Most of the alcohol is removed by vacuum distillation, leaving an oily residue. Water is added to this residue to dissolve the sodium bromide; and the oily layer, which is ethyl isopropyl-carbinyl malonic acid ester, is separated and dried. It is purified by fractional distillation in vacuum. When thus purified, ethyl isopropyl-carbinyl malonic acid ester is a colorless or pale yellow liquid, having a boiling point of 103°-105°C at about 4 mm pressure, and a refractive index at 25°C. 3 moles of sodium are dissolved in 10 to 12 times its weight of absolute alcohol under a reflux condenser. To this are added 1.6 moles of urea and 1 mole of ethyl isopropyl-carbinyl malonic acid ester. The mixture is gently refluxed for 2-4 h, after which most of the alcohol is removed by vacuum distillation. The residue is dissolved in water, and a sufficient amount of dilute acid is added to completely precipitate the isopropyl-carbinyl barbituric acid. The precipitate is filtered off, dried, and recrystallized from dilute alcohol. 1 mole of isopropyl-carbinyl barbituric acid is dissolved in a suitable vessel in a 10%-35% aqueous solution of 1 mole of potassium hydroxide. To this are added somewhat in excess of 1 mole of allyl bromide, and alcohol equal to about 10% of the total volume of the solution. The vessel is agitated for 5075 h. At the end of this time, the solution, which may still exhibit two layers, is concentrated to about one-half its volume, to remove the excess allyl bromide and the alcohol. On cooling, an oily layer, which is isopropyl-carbinyl allyl barbituric acid, separates out as a sticky viscous mass. It is dried, washed with petroleum ether, and dissolved in the minimum amount of benzene. Any unreacted isopropyl-carbinyl barbituric acid, which does not dissolve, is filtered off. The addition of petroleum ether to the clear filtrate causes the isopropyl-carbinyl allyl barbituric acid to precipitate as an oily mass. This is separated, washed with petroleum ether, and dried in vacuum. References Shonle H.A.; US Patent No. 1,954,429; April 10, 1934; Assigned: Eli Lilly and Company, Indianapolis, Ind., a Corporation of Indiana

BUTAMIRATE CITRATE Therapeutic Function: Antitussive Chemical Name: α-Ethylbenzeneacetic acid 2-[2-(diethylamino)ethoxy]ethyl ester citrate Common Name: Butamyrate Chemical Abstracts Registry No.: 18109-81-4; 18109-80-3 (Base)

746

Butamirate citrate

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Sinecod

Hommel

Switz.

1967

Sinecod

Karlspharma

W. Germany

1967

Sinecod

Bonomelli

Italy

1969

Acodeen

Hommel

Switz.

-

Acodfen

Klimitschek

Austria

-

Codesin-F

Hommel

Switz.

-

Intussin

Spofa

Czechoslovakia

-

Sincoden

Hommel

Switz.

-

Sincodix

Beta

Argentina

-

Sinecod

Abello

Spain

-

Pertix-Hommel

Hommel

W. Germany

-

Raw Materials α-Phenylbutyric acid chloride Diethylaminoethoxyethanol Citric acid Manufacturing Process 18.2 grams of α-phenylbutyric acid chloride are dissolved in 25 ml of toluene. To this solution, there is slowly added a solution of 16.1 grams of diethylaminoethoxyethanol in 25 ml of toluene, the reaction mixture thereby becoming hot. It is then heated for 8 hr under reflux. The reaction mixture, after cooling, is carefully poured onto 75 grams of ice and made alkaline with dilute ammonia. After thorough shaking of the solution, the toluene layer is removed and washed until neutral with water. The toluene solution is treated with carbon and dried over sodium sulfate. The toluene is distilled off from the filtered solution. The residue is α-phenylbutyric acid diethylaminoethoxyethyl ester. The basic ester is purified by distillation in a high vacuum. 10 grams of ester are added to a solution of 7 grams of citric acid in 30 ml of warm acetone. After standing for some time, the citrate of the ester crystallizes out. After suction filtration

Butamisole hydrochloride

747

and washing with acetone the ester citrate is recrystallized from acetone. The melting point of the citrate is 75°C. References Merck Index 1481 Kleeman and Engel p.127 OCDS Vol.2 p.76 (1980) DOT 9 (7) 280 (1973) I.N. p. 166 Heusser, J.; US Patent 3,349,114; October 24, 1967; Assigned to Hommel AG, Switzerland

BUTAMISOLE HYDROCHLORIDE Therapeutic Function: Anthelmintic Chemical Name: (S)-2-Methyl-N-[3-(2,3,5,6-tetrahydroimidazo[2,1b]thiazol-6-yl)phenyl]propanamide monohydrochloride Common Name: Butamisole hydrochloride; Styquin Structural Formula:

Chemical Abstracts Registry No.: 54400-62-3 Trade Name

Manufacturer

Country

Year Introduced

Butamisole hydrochloride

American Cyanamid (AHP)

-

-

Raw Materials 3'-Acetylacetanilide 2-Amino-2-thiazoline Isobutyric anhydride Sodium hydroxide Ammonium hydroxide

Bromine Sodium borohydride Sulfuric acid Hydrochloric acid

Manufacturing Process To a stirred solution of 110.0 g (0.62 mole) of 3'-acetylacetanilide in 2400 ml of chloroform is added dropwise a solution of 33.0 ml (102.9 g; 0.644 mole)

748

Butamisole hydrochloride

of bromine in 240 ml of chloroform. The solution is stirred 1 h and the resultant precipitate is then filtered, washed with ether and dried. The solid is stirred in a large volume of water to give an oily precipitate which crystallizes on further stirring. The solid is filtered, washed with water and then 2propanol, dried to give 148.34 g of the 3'-bromacetylacetanilide, melting point 108.5-110°C (recrystallized from 2-propanol). A solution of 5.12 g (0.020 mole) of 3'-bromoacetylacetanilide in 70 ml of acetone is added to a stirred solution of 2.04 g (0.020 mole) of 2-amino-2thiazoline in 30 ml of acetone. The mixture is stirred 1.5 h and the precipitate then filtered, washed with acetone and dried to give 6.00 g of 3'-[(2-imino-3thiazolidinyl)acetyl]acetaniIide hydrobromide, meltng point 275-277°C (recrystallization from water). To a stirred slurry of 63.47 g (0.177 mole) of 3'-[(2-imino-3-thiazolidinyl) acetyl]acetanilide hydrobromide in 1 L of 95% ethanol, maintained at 5°C, is added 5.70 g (0.15 mole) of sodium borohyride. After stirring 40 min an additional 4.10 g of sodium borohydride is added and the mixture is acidified with hydrochloric acid and evaporated under reduced pressure. The residue is partitioned between chloroform and dilute aqueous ammonium hydroxide. Two further chloroform extracts are combined with the original, washed with brine, dried (sodium sulfate) and evaporated to give an oil. Treatment with acetone gives 6.77 g (48%) of 3'-[l-hydroxy-2-(2-imino-3thiazolidinyl)ethyl]acetanilide hydrochloride as white crystalline, melting point 235-237°C. Addition of 5.00 g (0.0158 mole) of 3'-[1-hydroxy-2-(2-imino-3thiazolidinyl)ethyl]acetanilide hydrochloride to 15 ml of concentrated sulfuric icid is carried out in small increments over 0.5 h. The orange solution is stirred an additional 1 h, poured onto ice and made basic with concentrated ammonium hydroxide. The aqueous base is extracted twice with chloroform and the combined organic layers washed with water, brine, dried (sodium sulfate) and evaporated at reduced pressure to give 3.32 g (80% crude yield) of the 3'-(2,3,5,6-tetrahydroimidazo[2,1-b]thiazol-6-yl)acetanilide, melting point 164-166°C (recrystallization from 2-propanol). A solution of 1.00 g (0.0038 mole) of 3'-(2,3,5,6-tetrahydroimidazo[2,1b]thiazol-6-yl)acetanilide in 17 ml of 6 N hydrochloric acid is heated at reflux for 2.5 h and then allowed to stand overnight at room temperature. The solution is concentrated at reduced pressure, made basic with concentrated aqueous sodium hydroxide while cooling and then extracted with 3 portions of chloroform. The combined organic layers are washed with brine, dried (sodium sulfate) and evaporated to give 0.84 g of an oil, i.e., 6-(m-aminophenyl)2,3,5,6-tetrahydroimidazo[2,1-b]thiazole free base. The oil is dissolved in hot methanol and strongly acidified with hydrogen chloride in 2-propanol. Evaporation of the solution give the 6-(m-aminophenyl)-2,3,5,6tetrahydroimidazo[2,1-b]thiazole dihydrochloride, melting point 198-201°C (crystallization from 2-propanol). 2.2 g (0.010 mole) of 6-(m-aminophenyl)-2,3,5,6-tetrahydroimidazo[2,1b]thiazole dihydrochloride is disolved in a mixture of 15 ml methanol and 15 ml water and the pH is adjusted to about 6 with an aqueous hydrochloric acid solution. This solution is then added to 3.2 g (0.020 mole) of isobutyric anhydride. The mixture is allowed to stand at room temperature for 12 h. The

Butanilicaine

749

reaction mixture is then added to a mixture of 100 ml methylene chloride and 50 ml water and then made basic (pH 10) with an aqueous sodium hydroxide. The methylene chloride layer is removed and the water layer is washed twice with 75 ml of fresh methylene chloride. The methylene chloride extract are then combined, dried over magnesium sulfate, and the methylene chloride evaporated leaving a tacky solid. The free base of the product is recrystallized from a chloroformethyl ether mixture. The yield of the 3'-(2,3,5,6tetrahydroimidazo[2,1-b]thiazol-6-yl)isobutyranilide is 1.6 g (55%). References Spicer L.D., Hand J.J.; US Patent No. 3,899,583; August,1975; Assigned: American Cyanamid Company, Stamford, Conn.

BUTANILICAINE Therapeutic Function: Local anesthetic Chemical Name: 2-(Butylamino)-6'-chloro-o-acetoluidide Common Name: Butacetoluide; Butanilicaine Structural Formula:

Chemical Abstracts Registry No.: 3785-21-5 Trade Name

Manufacturer

Country

Year Introduced

Butanilicaine

Enreco, INC

-

-

Raw Materials 4-Bromo-2-methylaniline n-Butylamine

Chloroacetyl chloride Hydrochloric acid

Manufacturing Process To a solution of 4-bromo-2-methylaniline is added 13 g of chloroacetyl chloride. After the reaction is finished to the mixture id added a solution of 33 g sodium acetate in 138 ml of water. Chloroacetic acid 4-bromo-2methylanilide is filtered; yield 24 g, M.P. 135°C (crystallization from ethanol). 20 g of chloroacetic acid 4-bromo-2-methylanilide is dissolved in 200 ml of

750

Butanixin

butylamine. After about 15 hours to the solution is added 2 N hydrochloric acid. Butylaminoacetic acid 4-bromo-2-methylanilide hydrochloride is removed by suction and washed with water; yield 90%, M.P. 252-253°C (from methanol). References Merck Index, Monograph number: 1542, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. Walter A. et al., DE Patent No. 1,009,633; 1957.06.06; Assigned to Hoechst AG

BUTANIXIN Therapeutic Function: Analgesic, Antiinflammatory Chemical Name: 2-(p-Butanilino)nicotinic acid Common Name: Butanixin Structural Formula:

Chemical Abstracts Registry No.: 55285-35-3 Trade Name

Manufacturer

Country

Year Introduced

Butanixin

ZYF Pharm Chemical

-

-

Raw Materials 2-Chloronicotinic acid p-n-Butyl aniline Manufacturing Process 5 g 2-chloronicotinic acid and 9.4 g p-n-butyl aniline were heated for 1 hour at 160°C by vigorous stirring under a nitrogen atmosphere. Then the mixture was dissolved in 2 N sodium hydroxide and extracted with benzene. The water layer was acidified and a precipitate obtained was filtered off, washed with water and dried. 5 g 2-[(4-butylphenyl)amino]-3-pyridinecarboxylic acid yielded. MP: 171°-173°C (deg.).

Butantrone

751

References Stampa A.; D.E. Patent No. 2,409,260; January 30, 1975; Laboratorios Hermes S.A. Barcelona (Spain)

BUTANTRONE Therapeutic Function: Antipsoriatic Chemical Name: 1,8-Dihydroxy-10-(1-oxobutyl)-9(10H)-anthracenone Common Name: Butantrone Structural Formula:

Chemical Abstracts Registry No.: 75464-11-8 Trade Name

Manufacturer

Country

Year Introduced

Butantrone

Onbio Inc.

-

-

Raw Materials Anthralin Pyridine Butyryl chloride Manufacturing Process To a solution of 56.6 g (0.25 mol) of anthralin in 1750 ml of absolute toluene and 27.3 ml of pyridine, 31.5 ml (0.3 mol) of butyryl chloride was added with stirring over 30 min at room temperature. The reaction mixture was then heated to 85°C for 1 hour. After this mixture had recooled to room temperature, 27.3 ml of pyridine and 31.5 ml of butyryl chloride were again added. The suspension obtained was then heated to 85-90°C for 1 hour. The precipitated pyridinium hydrochloride was eliminated by filtration then washed with toluene. The toluene filtrates were concentrated to around 500 ml under reduced pressure, washed several times with water then dried over magnesium sulfate. The product was then fractionated by chromatography on

752

Butaperazine

silica gel, using toluene and then a mixture of toluene and ethyl acetate as the mobile phase. The different fractions containing the 1,8-dihydroxy-10-(1oxobutyl)-9(10H)-anthracenone were then concentrated and recrystallized from a toluene-hexane mixture. In this way 25 g of yellow crystals of 1,8dihydroxy-10-(1-oxobutyl)-9(10H)-anthracenone having a melting point of 138°C was obtained. References Shroot Braham, Lang Gerard, Maignan Jean; US Patent No. 4,696,941; September 29, 1987; Assigned to Groupement d'Interet Economique dit: Centre International 'de Recherches (Valbonne, FR)

BUTAPERAZINE Therapeutic Function: Neuroleptic, Antiemetic Chemical Name: 1-Butanone, 1-(10-(3-(4-methyl-1-piperazinyl)propyl)-10Hphenothiazin-2-yl)Common Name: Butaperazine; Butyrylperazine Structural Formula:

Chemical Abstracts Registry No.: 653-03-2 Trade Name

Manufacturer

Country

Year Introduced

Bayer 1362

Bayer

-

-

Repoise

Robins

-

-

Butyrylperazine

Robins

-

-

Randolectil

Bayer

-

-

AHR 712

Robins

-

-

Raw Materials Sodium amide 2-Buterylphenothiazine Sodium hydroxide

Butedronic acid

753

Manufacturing Process To a suspension of sodamide in liquid ammonia is added of 2buterylphenothiazine. After stirring for one hour, there is added 1-bromo-3chloropropane. The ammonia is allowed to evaporate and the residue is diluted with the water. The mixture is extracted with ether and the ether solution is dried over anhydrous sodium sulfate, filtered and concentrated. The residue consists of crude 10-(3-chloropropyl)-2-buterylphenothiazine as viscous oil and is used in the next step without further purification. A mixture of 1-methylpiperazine and crude 10-(3-chloropropyl)-2buterylphenothiazine is heated on a steam bath for 18 hours. The mixture is diluted with the water and extracted with ether. The ether solution is extracted with dilute hydrochloric acid. The aqueous acid solution is made alkaline with sodium hydroxide and the product is extracted with ether. The ether extracts are dried and concentrated to a residue consisting of the free base 2-butyryl-10-(3-(4-methyl-1-piperazinyl)propyl)phenothiazine. References Merck Index, Monograph number: 1543, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. Sheriock M.H. et al.; US Patent No. 2,985,654; May 23, 1961; Assigned to Schering Corporation, Bloomfield, N.Y., a corporation of New Jersey

BUTEDRONIC ACID Therapeutic Function: Diagnostic aid Chemical Name: (Diphosphonomethyl)butanedioic acid Common Name: Butedronic acid Structural Formula:

Chemical Abstracts Registry No.: 51395-42-7 Trade Name

Manufacturer

Country

Year Introduced

Butedronic acid

Bayer A.G.

-

-

754

Butenafine hydrochloride

Raw Materials Methylene diphosphonic acid tetraethyl ester Maleic acid diethyl ester Sodium ethylate Acetic acid Hydrochloric acid Manufacturing Process 0.5 mole of methylene diphosphonic acid tetraethyl ester is heated for 6 h to 110°C with 0.5 mole of maleic acid diethyl ester in the presence of 25 ml of a saturated sodium ethylate solution. The sodium ethylate is then neutralized with acetic acid and the reaction mixture is quickly distilled invacuo in order to avoid decomposition. The crude distillate is redistillated, the main fraction accumulating in the range from 190-213°C at a pressure of 0.05 Torr, yield 50%. The ester is hydrolyzed by boiling with concentrated hydrochloric acid. 1,1Diphosphonopropane-2,3-dicarboxylic acid crystallizes out after purification with active carbon and concentration of the hydrolysis product, yield 100%. References Heins A. et al.; US Patent No. 3,923,876; December 2, 1975; Assigned: Bayer Aktiengesellschaft, Leverkusen, Germany

BUTENAFINE HYDROCHLORIDE Therapeutic Function: Antifungal Chemical Name: 1-Naphthalenemethanamine, N-((4-(1,1-dimethylethyl) phenyl)methyl)-N-methyl-, hydrochloride Common Name: Butenafine hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 101827-46-7

Buterizine

755

Trade Name

Manufacturer

Country

Year Introduced

Butenafine Hydrochloride

Shenzhen Fangye Industries Co., Ltd.

China

-

KP-363

Shenzhen Fangye Industries Co., Ltd.

China

-

Lotrimin Ultra

Schering-Plough HealthCare Products, Inc.

-

Mentax-TC

Bertek

-

-

Raw Materials N-Methyl-1-naphtylmethylamine hydrochloride p-tret-Butylbenzyl bromide Manufacturing Process N-Methyl-1-naphtylmethylamine hydrochloride (2.1 g, 0.01 mole) was dissolved in 50 ml of dry dimethylformamide, and 3.71 g (0.035 mole) of anhydrous sodium carbonate was added, then 2.49 g (0.011 mole) of p-tbutylbenzyl bromide was added by stirring and the mixture was reacted at 30° to 40°C for 5 hours. Ice water was added, and the mixture was extracted with toluene. The organic layer was washed with water, and toluene was evaporated. The residue was chromatographed on silica gel column, and eluated with 5% ethyl acetate/n-hexane. The eluate was concentrated to give 2.98 g (yield 94%) of an oily substance. Hydrochloric acid/ethanol was added to 1 g of this oily product, and the mixture was concentrated. The residue was recrystallized from methanol/acetic acid to give 0.95 g of desired 1naphthalenemethanamine, N-((4-(1,1-dimethylethyl)phenyl)methyl)-Nmethyl-, hydrochloride having melting point 200° to 202°C. References Arita et al.; US Patent No. 4,822,822; Apr. 18, 1989; Assigned Mitsui Toatsu Chemicals, Inc., Tokyo, Japan

BUTERIZINE Therapeutic Function: Vasodilator Chemical Name: 2-Butyl-5-[[4-(diphenylmethyl)-1-piperazinyl]methyl]-1ethyl-1H-benzimidazole Common Name: Buterizine Chemical Abstracts Registry No.: 68741-18-4

756

Buterizine

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Buterizine

Shanghai Chemfrom Chemical Co., Ltd.

-

-

Raw Materials 1-Chloro-4-(chloromethyl)-2nitrobenzene Nickel Raney Sodium hydroxide Pentyl ethanimidate hydrochloride

1-(Diphenylmethyl)piperazine Ethanamine Hydrogen Acetic acid

Manufacturing Process A mixture of 10.3 parts of 1-chloro-4-(chloromethyl)-2-nitrobenzene, 25.2 parts of 1-(diphenylmethyl)piperazine and 120 parts of ethanol is stirred and refluxed for 4 h. The reaction mixture is cooled and evaporated. The residue is taken up in about 100 parts of water and the product is extracted with methylbenzene. The extract is washed with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using trichloromethane as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of 2,2'oxybispropane and hexane (1:2 by volume). The product is filtered off, washed with hexane and dried, yielding 19.6 parts of 1-(4-chloro-3nitrophenylmethyl)-4-(diphenylmethyl)piperazine; melting point 101.6°C. During 20 h, gaseous ethanamine is bubbled through a stirred and hot (6070°C) mixture of 1-(4-chloro-3-nitrophenylmethyl)-4(diphenylmethyl)piperazine and dimethylsulfoxide. The reaction mixture is cooled and poured onto ice-water. The precipitated product is filtered off, washed with water and taken up in methylbenzene. The latter is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol as eluent. The pure fractions are collected and the eluent is evaporated, yielding 4-[4(diphenylmethyl)-1-piperazinylmethyl]-N-ethyl-2-nitrobenzenamine; melting point 128.2°C (crystallized from 2,2'-oxybispropane). A solution of 4-[4-(diphenylmethyl)-1-piperazinylmethyl]-N-ethyl-2nitrobenzenamine in methanol is hydrogenated at normal pressure and at room temperature with Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated,

Butetamate citrate

757

yielding 4-[4-(diphenylmethyl)-1-piperazinylmethyl]-N1-ethyl-1,2benzenediamine. A mixture of 4-[4-(diphenylmethyl)-1-piperazinylmethyl]-N1-ethyl-1,2benzenediamine and acetic acid is stirred at room temperature till all solid enters solution. Then there are added pentyl ethanimidate hydrochloride and stirring is continued first for 1 h at room temperature and further for 1 h at reflux. The reaction mixture is evaporated and the residue is stirred in water. The whole is alkalized with a sodium hydroxide solution and the product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol as eluent. The pure fractions are collected and the eluent is evaporated. The product is filtered off and dried, yielding 5-[4-(diphenylmethyl)-1-piperazinylmethyl]-1-ethyl-2-butyl-1Hbenzimidazole; melting point 124.8°C (crystallized from 4-methyl-2pentanone). References Raeymaekers A.H.M. et al.; US Patent No. 4,179,505; December 18, 1979; Assigned: Janssen Pharmaceutica N.V. Beers, Belgium

BUTETAMATE CITRATE Therapeutic Function: Anticholinergic, Spasmolytic, Antitussive Chemical Name: 2-(Diethylamino)ethyl-2-phenylbutyrate, citrate salt Common Name: Butetamate citrate; Phenethylamincitrat; Butethamate citrate Structural Formula:

Chemical Abstracts Registry No.: 14007-64-8

758

Butethamine

Trade Name

Manufacturer

Country

Year Introduced

Butetamatdihydrogencitrat

-

-

Convenil

Chemische Werke Hommel GmbH and Co.KG Hommel

-

-

Convenal

Hommel

-

-

Hicoseen

Klimitschek

-

-

Phenetin

Alpinapharm

-

-

Aspectonetten

Krewel Meuselbach -

-

CAM

Rybar-Ireland

-

-

Raw Materials alpha-Phenylbutiric acid beta-Diethylaminoethylchloride hydrochloride Potassium carbonate Manufacturing Process 16.4 parts of alpha-phenylbutiric acid, 17.5 parts of betadiethylaminoethylchloride hydrochloride and 35 parts of dry potassium carbonate in 60 parts diisopropyl ether was stirred for 18 hours under reflux. To the reaction mixture at 40°C was added 120 parts of the water. Organic layer was washed with the water. The solvent was removed and the 2(diethylamino)ethyl-2-phenylbutyrate was distilled at 167-168°C/10 mm; melting point of hydrochloride 167-169°C. In practice it is usually used as citrate. References Schweizerische Patent No. 291,375; Sept. 16, 1953; Assigned to Aktiengesellschaft Hommels Haematogen, Zurich

BUTETHAMINE Therapeutic Function: Local anesthetic Chemical Name: 2-[(2-Methylpropyl)amino]ethanol 4-aminobenzoate Common Name: Ibylcaine Structural Formula:

Butethamine

759

Chemical Abstracts Registry No.: 2090-89-3; 553-68-4 (Hydrochloride salt) Trade Name

Manufacturer

Country

Year Introduced

Monoceine

Novocol

US

1941

Dentocaine

Amer. Chem.

US

-

Raw Materials Isobutylaminoethanol Tin

4-Nitrobenzoyl chloride Hydrochloric acid

Manufacturing Process The preparation of the normal butyl analog is as follows: 10 g of isobutylaminoethanol, 16 g of p-nitrobenzoyl chloride and 5 g of sodium hydroxide in 175 cc of water were allowed to react. The temperature was maintained between 30°-40°C during reaction. The reaction mixture was extracted with ether, the ether evaporated, and the resultant oil washed with water to remove any unreacted secondary amino alcohol and then dried. The yield was 21 g or 91% of theory. The compound responded positively when tested for the presence of the amine configuration and also the nitro group. The yellow viscous oil which was formed was isobutylaminoethyl pnitrobenzoate. 20 g of this latter material was directly reduced with 15 g of tin and 50 cc of concentrated hydrochloric acid. The temperature of the reduction was controlled by addition from time to time of small quantities of cold water to maintain the temperature at or near 70°C. When the reaction was completed 150 cc of sodium hydroxide was added and the solution then cooled to 15°C. The oil which gradually formed combined with undissolved tin to form a pasty mass which soon settled. The supernatant liquid was decanted and the residue washed two or three times with water to remove all traces of alkali. The oily mass, freed from most of its water, was then extracted with ether and filtered. The filtrate was evaporated to dryness and the yield of the base obtained was 13 g or 73.5% of theory. In order to get the melting point of the base, the monohydrochloride was first formed and purified, then the hydrochloride was dissolved in water and just neutralized with ammonia water. The colorless oil formed soon crystallized into a white solid, which after filtration and air drying, had a melting point of 74°-74.5°C. The hydrochloride was made when the oily base was dissolved in propyl alcohol and the calculated quantity of aqueous hydrochloric acid added to form the monohydrochloride of this compound. After repeated recrystallizations, a white needle crystal was formed which had a melting point at 146°C. References Merck Index 1492 Kleeman and Engel p.128 DOT 15 (7) 368 (1979) I.N. p.168 Goldberg, S.D.; US Patent 2,139,818; December 13, 1938; assigned to Novocol Chemical Mfg. Co., Inc.

760

Buthiazide

BUTHIAZIDE Therapeutic Function: Diuretic, Antihypertensive Chemical Name: 6-Chloro-3,4-dihydro-3-(2-methylpropyl)-2H-1,2,4benzothiadiazine-7-sulfonamide-1,1-dioxide Common Name: Thiabutazide; Butizide; Isobutylhydrochlorothiazide Structural Formula:

Chemical Abstracts Registry No.: 2043-38-1 Trade Name

Manufacturer

Country

Year Introduced

Saltucin

Boehringer Mannheim

W. Germany

1961

Eunephran

Servier

France

-

Intensain

Boehringer Mannheim

W. Germany

-

Modenol

Boehringer Mannheim

W. Germany

-

Sembrina

Boehringer Mannheim

W. Germany

-

Raw Materials 3-Chloraniline Ammonia

Chlorosulfonic acid Isovaleraldehyde

Manufacturing Process Chlorsulfonic acid and 3-chloroaniline react to give an intermediate which when treated with ammonia yields 5-chloro-2,4-disulfamylaniline. 20 g of 5-chloro-2,4-disulfamylaniline in 15 cc of diethyleneglycol-dimethyl ether with 0.9 g of isovaleraldehyde are reacted in the presence of 0.5 cc of a saturated solution of hydrochloric acid in ethyl acetate at 80°-90°C. The reaction mixture is concentrated under reduced pressure, an oily product precipitates on the addition of water, the latter is decanted and ethanol added to the remaining oil. 3-Isobutyl-6-chloro-7-sulfamyl-3,4-dihydro-1,2,4benzothiadiazine-1,1-dioxide crystallizes and, after recrystallization from dimethylformamide and water, melts at 241°-245°C. References

Butibufen

761

Merck Index 1494 Kleeman and Engel p.129 DOT 14 (3) 119 (1978) I.N. p.169 Ciba, Ltd.; British Patents 861,367; February 22, 1961 and 885,078; December 20, 1961

BUTIBUFEN Therapeutic Function: Antiinflammatory, Analgesic Chemical Name: 2-(p-Isobutylphenyl)butyric acid Common Name: Butilopan Structural Formula:

Chemical Abstracts Registry No.: 55837-18-8 Raw Materials Trade Name Butibufen Butilopan Butilopan

Manufacturer Onbio Inc. Juste Merck

Paraformaldehyde Hydrogen chloride Sodium amide Sodium hydroxide Hydrochloric acid

Country -

Year Introduced -

Zinc chloride Sodium cyanide Ethyl iodide Sodium

Manufacturing Process 1st method: 4-Isobutylphenylbenzyl chloride was prepared by passing a stream of hydrogen chloride into a suspension of p-bromoaldehyde and anhydrous zinc chloride in isobutylbenzene. A mixture of 137 g (0.75 mol) of 4-isobutylbenzyl chloride thus prepared, 44.1 g (0.90 mol) of sodium cyanide, 216 g of 99% ethanol, and 81.3 g of water was heated refluxed for 6 hours. The mixture became reddish-black in color. From this mixture, 215 ml of ethanol and water

762

Butibufen

was then distilled and the residue was filtered. The solids that were separated by filtration were washed with 100 ml of diethyl ether and the ether washings were combined with the original filtrate, to which 800 ml of water was then added. The organic phase was then separated from the aqueous phase, washed with five 400 ml portions of water and dried over anhydrous sodium sulfate. The ether was evaporated from the dried organic phase by vacuum distillation and the residue which distilled between 130°C and 132°C at a pressure of 7 mm of mercury was collected. The yields of 4-isobutylbenzene cyanide 100-113 g. To a solution of 6.7 g of sodium amide in 100 ml of anhydrous diethyl ether was added dropwise 26 g of 4-isobutylbenzene cyanide while the mixture was stirred and heated under gentle reflux. After all of the 4-isobutylbenzene cyanide had been added, the mixture was heated under gentle reflux for 15 min, after which 23.4 g of ethyl iodide was slowly added dropwise thereto from the dropping funnel. After completion of the addition of the ethyl iodide, the mixture was heated under gentle reflux for an initial period of 15 min, after which it was diluted with an equal volume of water and shaken. The two layers that formed were separated and the aqueous layer was then extracted with two 50 ml portions of diethyl ether. The ether extracts were combined and then washed with two 80 ml portions of water and dried over anhydrous magnesium sulfate. The dried ether extract was then distilled at a subatmospheric pressure. In this manner, 25 g of a clear transparent uncolored liquid having a boiling point of 118-122°C at a pressure of 1mm of mercury, which consisted of 2-(4-isobutylphenyl)butyronitrile, was collected. This yield was equivalent to 83% of the theoretical. A mixture of 40 g (0.2 mol) of 2-(4-isobutylphenyl)butyronitrile and 78 ml of a freshly prepared solution of sodium hydroxide that was prepared by dissolving 28 g of sodium hydroxide in 25 ml of distilled water and the volume of which was brought to 100 ml by addition thereto of methanol, was heated under gentle reflux in a flask provided with a stirrer and reflux condenser while the mixture was stirred during a period of 9 hours. From the mixture the methanol and a portion of the water were distilled and the mixture was then cooled, the crystals began to separate. The mixture was then diluted with 150 ml of water and extracted with two 25 ml portions of diethyl ether. The remaining aqueous solution containing the sodium salt of 2-(4isobutylphenyl)butyric acid was then saturated with sodium chloride until the salt started to precipitate. The solution was then cooled to 5°C and the precipitated salt was separated by filtration, recrystallized from isopropanol, and dried in a vacuum desiccator at a pressure of 1 mm of mercury until it had attained a constant weight. In this manner, 32 g of sodium 2-(4isobutylphenyl)butyrate having a melting point of 188-191°C, which is equivalent to a yield of 67% of the theoretical, was obtained. Dilute hydrochloric acid (19% by weight of hydrogen chloride) was slowly added to a cold solution of 25 g of the sodium 2-(4-isobutylphenyl)butyrate thus prepared in 100 ml of water until the solution corresponded to pH of 1.0. The oil which precipitated was then allowed to solidify to a white solid by standing in a refrigerator. The white solid was then separated by filtration, dried, and recrystallized from petroleum ether. It had a melting point of 5052°C, and its elementary analysis corresponded to the 2-(4isobutylphenyl)butyric acid.

Butibufen

763

2nd method: 5.0 g of small pellets of sodium metal were added slowly with stirring to 150 ml of absolute ethanol, while a current of nitrogen gas was passed there through so as to blanket the solution from the atmosphere. After all of the sodium metal had been dissolved and while the solution was maintained at a temperature of 50°C, a solution of 52 g of ethyl 2-(4isobutylphenyl)cyanoacetate in 50 ml of absolute ethanol was added dropwise while the mixture was stirred. Subsequently, 81 g of ethyl iodide was gradually added to the mixture with stirring, after which the introduction of nitrogen gas into the mixture was discontinued and the mixture was heated for a period of 2.5 hours under gentle reflux. Thereafter, the ethanol and excess ethyl iodide were distilled from the mixture and the residue was then diluted with three times its volume of water and shaken therewith. The 2-(4isobutylphenyl)-2-(ethoxycarbonyl)butyronitrile was then extracted from the mixture with three 50 ml portions of diethyl ether, the extracts were combined, washed with a 20% aqueous solution of sodium bisulfate and dried over anhydrous magnesium sulfate. The ether was then expelled from the extract by distillation and the residue was distilled at a subatmospheric pressure, yielding 45 g of a fraction containing 2-(4-isobutylphenyl)-2(ethoxycarbonyl)butyronitrile having a boiling point of 150-155°C/3 mm of mercury (78% of the theoretical yield). In a 2-liter flask provided with a stirrer and reflux condenser a solution of 129 g of 2-(4-isobutylphenyl)-2-(ethyoxycarbonyl)butyronitrile in 980 ml of a 20% solution of potassium hydroxide in methanol was heated with stirring at 40°C for a period of 1 hour. The mixture was then heated under gentle reflux with stirring for an additional period of 3 hours, during which a white solid precipitated. This mixture was then poured into 1.5 liters of water and acidified with an aqueous solution of hydrochloric acid (concentrated hydrochloric acid diluted with an equal volume of water) to a hydrogen ion concentration corresponding to a pH of 2.5, while carbon dioxide was evolved therefrom. The aqueous mixture was then extracted with diethyl ether. The extracts were washed successively with a saturated solution of sodium bicarbonate and water, dried over anhydrous magnesium sulfate, and distilled at a subatmospheric pressure, to yield 86.5 g of a fraction consisting of 2-(4isobutylphenyl)butyronitrile having a boiling point of 124-128°C at a pressure of 1.5 mm of mercury, which is equivalent to approximately 0.43 mol and a yield of 91% of the theoretical based on the original 2-(4-isobutylphenyl)-2(ethoxycarbonyl)butyronitrile. The 2-(4-isobutylphenyl)butyronitrile was converted to sodium 2-(4isobutylphenyl)butyrate and subsequently to 2-(4-isobutylphenyl)butyric acid in the same manner as described in Method 1 hereinbefore. References Aparicio Luis, Gayo Nenesio, Carretero Jose, Martin Jose Luis, Ron Armando; US Patent No. 4,031,243; June 21, 1977; Assigned to Juste, S.A. Quimico-Farmaceutica (Madrid, ES)

764

Butinazocine

BUTINAZOCINE Therapeutic Function: Analgesic Chemical Name: (-)-3-(3-Butynyl)-1,2,3,4,5,6-hexahydro-11,11-dimethyl2,6-methano-3-benzazocine-6,8-diol Common Name: Butinazocine Structural Formula:

Chemical Abstracts Registry No.: 93821-75-1 Trade Name

Manufacturer

Country

Year Introduced

Butinazocine

ZYF Pharm Chemical

-

-

Raw Materials 2-(4-Methoxybenzyl)-1,3,3-trimethyl4-piperidone hydrochloride Sodium hydroxide Ammonia Lithium aluminum hydride Toluene-4-sulfonic acid but-3-ynyl ester Methyliodide

Nitrobenzene Aluminum trichloride Hydrochloric acid Cyanogen bromide Sodium hydride Calcium carbonate Ethanethiol

Manufacturing Process A mixture of 59.5 g (0.2 mol) 2-(4-methoxybenzyl)-1,3,3-trimethyl-4piperidone hydrochloride and 53.8 g (0.4 mol) of aluminum trichloride and 54.0 g of nitrobenzene in 1500 ml of dry benzene are boiled under reflux for 1 h. After cooling the reaction mixture is extracted with 750 ml 4 N sodium hydroxide solution, the temperature being maintained below 35°C. The organic phase is separated and extracted with 750 ml 1 N hydrochloric acid. The acid aequeous phase is rendered alkali by the addition of 100 ml 25% ammonia and extracted three times with 250 ml chloroform. The collected chloroformic phases are dried with sodium sulfate and evaporated under reduced pressure. The residue, 46.7 g, is converted into the hydrochloride by reaction with iso-propanol/HCl and crystallized from a mixture of methanol and ethylacetate. 44.6 g of the 5-hydroxy-2’-methoxy-2,9,9-trimethyl-6,7benzomorphan hydrochloride are obtained, melting point 233-236° C (dec.).

Butinazocine

765

21.8 g (0.5 mol) of a 55% dispersion of sodium hydride in oil are added to 52.2 g (0.2 mol) of 5-hydroxy-2’-methoxy-2,9,9-trimethyl-6,7-benzomorphan in 500 ml of dry peroxide-free tetrahydrofuran, followed by the drop-wise addition over 45 min of 142.0 g (1.0 mol) of methyliodide, and the mixture is stirred for 4 h at room temperature, 9 ml of water are added carefully to the obtained reaction mixture and the tetrahydrofuran is evaporated off under reduced pressure. After addition of 250 ml of water the residue is extracted 3 times with 250 ml of chloroform. The combined chloroformic phases are dried over sodium sulfate and concentrated under reduced pressure. The residue is converted into the hydrochloride, washed with toluene to remove paraffin oil and crystallized form methanol/ethylacetate. There are obtained 53.5 g of the 2’,5-dimethoxy-2,9,9-trimethoxy-6,7-benzomorphan hydrochloride, melting point 212-214°C (dec.). A solution of 4.68 g (44 mmol) cyanogenbromide in 28 ml chloroform are added drop-wise within 5 min to a solution of 8.25 g (30 mmol) 2’,5dimethoxy-2,9,9-trimethyl-6,7-benzomorphan in 20 ml dry ethanol free chloroform. After boiling for 4 h under reflux the solution is concentrated under reduced pressure, the residue dissolved in 150 ml toluene, washed twice with 50 ml 2 N hydrochloric acid and once with water, dried over sodium sulfate and evaporated to dryness under reduced pressure to yield 7.82 g 2cyano-2’,5-dimethoxy-2,9,9-trimethyl-6,7-benzomorphan. The obtained residue is dissolved in 40 ml of dry peroxide-free tetrahydrofuran and the solution added drop-wise under a nitrogen atmosphere over a period of 20 min to a suspension of 2.10 g (61.7 mmol) of lithium aluminum hydride in 85 ml tetrahydrofuran. After boiling for 3 h under reflux and cooling, 2.1 ml water, 1.6 ml 4 N sodium hydroxide solution, 7.3 ml water and 85 ml chloroform are added sequentially. After stirring for 30 min the obtained hydroxide is filtered off over hyflo. The precipitate is stirred 3 times with 50 ml chloroform/butanol (9:1). The filtrate washed with water, dried over sodium sulfate and concentrated under reduced pressure. The residue is converted into the hydrochloride and crystallized from methanol/ethylacetate to yield 4.9 g of the 2’,5-dimethoxy-9,9-dimethyl-6,7-benzomorphan hydrochloride, melting point 220-222°C (dec.). A solution of ethanethiol in dimethylformamide (DMF) are added dropwise to a suspension of sodium hydride (55% suspension in oil) in dry DMF. The obtained suspension is stirred for a further 45 min and a solution of 2’,5dimethoxy-9,9-dimethyl-6,7-benzomorphan in 190 ml of dry DMF are added dropwise over 20 min. The initially formed volatile components are distilled off and the reaction mixture heated until the DMF boils. After boiling for 6 h under reflux the reaction mixture is concentrated under reduced pressure and the residue taken up in toluene and 2 N hydrochloric acid. The acid aqueous phase is made alkaline with 25% ammonia and extracted 3 times with chloroform/butanol (8:2). After evaporation of the organic phase, the residue is converted into the 9,9-dimethyl-2’,5-dihydroxy-6,7-benzomorphan hydrochloride, (crystallized from isopropanol). A mixture of 9,9-dimethyl-2’,5-dihydroxy-6,7-benzomorphan hydrochloride, calcium carbonate and toluene-4-sulfonic acid but-3-ynyl ester in dimethylformamide is heated and subsequently concentrated under reduced pressure. The residue is taken up in a mixture of water and chloroform (1:1) and the aequeous phase extracted twice with chloroform/butanol (9:1). The combined organic phases are concentrated under reduced pressure to give the

766

Butirosin

2-butynyl-9,9-dimethyl-2’,5-dihydroxy-6,7-benzomorphan (crystallized from methanol/ethylacetate). References Akkerman A.M. et al.; US Patent No. 4,425,353; January 10, 1984; Assigned: ACF Chemiefarma NV, Maarssen, Netherlands

BUTIROSIN Therapeutic Function: Chemical Name: N1-(4-Amino-2-hydroxybutyryl)-4-O-2,6-diamino-2,6didexy-D-glucopyranosyl)-5-O-D-xelofuranosyl-2-deoxystreptamine (mixture of A- and B-form) Common Name: Ambutyrosin; Butirosin Structural Formula:

Chemical Abstracts Registry No.: 12772-35-9 Trade Name

Manufacturer

Country

Year Introduced

Butirosin

SigmaAldrich

-

-

Butirosin

767

Raw Materials Amberlite Carbobenzoxy chloride N-Hydroxysuccinimide Palladium on charcoal

5-β-D-Xylofuranosylneamine L-(-)-γ-Amino-α-hydroxybutyric acid Dicyclohexylcarbodiimide

Manufacturing Process Ambutyrosin is the another name of butirosin. Ambutyrosin obtained from fermentation broths of Bacillus circulans contains a major proportion of N1-(4amino-2-hydroxybutyryl)-4-O-2,6-diamino-2,6-didexy-D-glucopyranosyl)-5-OD-xelofuranosyl-2-deoxystreptamine (ambutyrosin A) and a minor proportion (up to 10-15%) of N1-(4-amino-2-hydroxybutyryl)-4-O-2,6-diamino-2,6didexy-D-glucopyranosyl)-5-O-D-ribofuranosyl-2-deoxystreptamine (ambutyrosine B). A process for preparation of ambutyrosin by semisynthetic procedure of acylating of 5-β-D-xylofuranosylneamine or 5-βribofuranosylneamine is described below. Preparation of 5-β-D-pentofuranosyIneamine: ambutyrosin A (1.0 g) in 30 ml of 0.5 N sodium hydroxide solution was refluxed for one hour, then neutralized with 6 N hydrochloric acid and applied on a column of Amberlite CG-50 (NH4+ form, 30 ml). The column was washed with water (ca. 100 ml) until the ninhydrin test became negative, and then eluted with 0.2 N ammonium hydroxide. Biologically active fractions were collected, concentrated in vacuum to 5 ml and treated with 5 ml of methanol to induce precipitation. It was further purified by re-precipitation from aqueous methanol to yield 607 mg (65%) of deacylated ambutyrosin A hereafter referred to as DA1. The wash water of the above CG-50 column was adjusted to pH 7.0 and applied on a column of Amberlite IR-120 (H+ form, 30 ml). The column was washed with water and then eluted with 1 N ammonium hydroxide. Ninhydrinpositive fractions were combined, treated with active carbon and neutralized with IRC-50 resin (H+ form). The solution was concentrated to a small volume, treated with ethanol, and kept in the cold overnight to yield 160 mg (75%) of γ-amino-α-hydroxybutyric acid as colorless needles which melted at 217°C-218°C. [α]D23= -30.3° (c=1.0%, H2O). The above experiments were also carried out on 1.0 g of ambutyrosin B yielding 579 mg (62%) of deacylated ambutyrosin B, hereafter called DA2. L-(-)-γ-benzyloxycarbonylamino-α-ydroxybutyric acid: L-(-)-γ-amino-αhydroxybutyric acid (7.4 g, 0.062 mole) was added to 50 ml of aqueous sodium 3 hydroxide solution (5.2 g, 0.13 mole). To the solution was added dropwise 11.7 g (0.068 mole) of carbobenzoxy chloride with stirring at 0°C to 5°C for one hour. The reaction mixture was washed with 50 ml of ether, adjusted to pH 2 with dilute hydrochloric acid, and extracted with four 80-ml portions of ether. The extracts were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated in vacuum, and the residue was crystallized from benzene to give 11.6 g (74%) of 4 colorless plates. M.P: 78.5°-79.5°C. N-Hydroxysuccinimide ester of L-(-)-γ-benzyloxycarbonylamino-α-

768

Butirosin

hydroxybutyric acid: a solution of L-(-)-γ-benzyloxycarbonylamino-αhydroxybutyric acid (10.6 s g, 0.042 mole) and N-hydroxysuccinimide (4.8 g, 0.042 mole) in 200 ml of ethyl acetate was cooled to 0°C and added to 8.6 g (0.042 mole) of dicyclohexylearbodiimide. The mixture was stirred overnight at 5°C. The dicyclohexylurea which separated was removed by filtration, and the filtrate was concentrated in vacuum. The product was obtained as colorless plates. Yield: 13.4 g (92%). M.P: 117°-118°C [α]D23= +1.5° (c= 2.0%, CHCl3). N-(Benzyloxycarbonyloxy)succinimide: N-hydroxysuccinimide (23 g, 0.2 mole) was dissolved in 200 ml of aqueous NaOH solution (9 g, 0.22 mole). To the stirred solution was added dropwise 34 g (0.2 mole) of carbobenzoxy chloride with water-cooling. The mixture was stirred overnight at room temperature, and the precipitate which separated was collected by filtration, washed with water, and air dried. Yield: 41.1 g (82%). Recrystallization from benzene-nhexane (10:1) gave colorless prisms melting at 78°-79°C. 6'-Carbobenzoxy-DA1 and 1,6'-dicarbobenzoxy-DA1: To a solution of 9.1 g (20 mmoles) of above prepared DA1 in 150 ml of water and 60 ml of tetrahydrofuran (THF) was slowly added, under vigorous stirring and cooling (5°C), a solution of 5.17 g (20.8 mmoles) of N(benzyloxycarbonyloxy)succinimide in 60 ml of THF. The mixture was stirred for 24 hours at 5°C and for an additional 16 hours at room temperature and then concentrated in vacuum to dryness. The crude product thus obtained was roughly separated into two fractions by a preparative counter-current distributor (52 tubes, 100 ml/tube) using a solvent system of n-BuOHCHCl3·H2O (4:1:5). Tube No. 1-15 were combined and evaporated in vacuum to give 9.75 g of solid. The solid was dissolved in 20 ml of water and applied on a column of amberlite CG-50 (NH4+ form, 120 ml). The column was washed with water and then eluted with aqueous 0.1 N ammonium hydroxide collecting each 20-ml fraction. Fractions No 62-93 were combined and concentrated in vacuum to give 5.75 g (49%) of 6'-carbobenzoxy-DA1 as a white solid. NMR in D2O and elememtal analysis confirmed its structure. Tubes No. 36-49 from the above current distribution were combined and evaporated in vacuum to give 2.91 g of solid. The solid was further purified by silica gel column chromatography developed with methanol-ethyl acetate (4:1) to yield 1.11 g (7.5%) of 1,6'-dicarbobenzoxy-DA1. TLC [silica gel plate, MeOAc-n-PrOH-28% NH4OH (45:105:60)]. Rf=0.44. 1-[L-(-)-γ-Amino-α-hydroxybutyryl]-DA1: a solution of 6'-carbobenzoxy-DA1 (588 mg, 1 mmole) in 10 ml of water and 5 ml of THF was added dropwise to a solution of N-hydroxysuccinimide ester of L-(-)-γ-benzyloxycarbonylamino-αhydroxybutyric acid (350 mg, 1 mmole) in 5 ml of THF with stirring and cooling (5°C). The mixture was stirred overnight at room temperature and then concentrated in vacuum to dryness. The residue was shaken with a mixture of n-butanol-ethyl acetate-water (4:1:5). The upper layer of the solvent mixture was separated and evaporated in vacuum to dryness. The solid thus obtained was dissolved in 30% aqueous ethanol and hydrogenated over 250 mg of 10% palladium-on-charcoal at room temperature. The reaction mixture was filtered to remove the palladium catalyst, and the filtrate

Butixocort

769

was concentrated in vacuum to dryness. The residual solid was dissolved in 10 ml of water and chromatographed on a column of CG-50 (NH4+ form, 40 ml). The column was washed by water and then eluted fractionally with aqueous 0.5 N NH4OH. Biologically active fractions which showed Rf=0.20 by TLC were collected, concentrated in vacuum and lyophilized to give 94 mg (14%) of product as a white solid, which was identified with ambutyrosin A in every respect. It melts with decomposition over a wide range beginning at about 149°C. [α]D25= +26°C (1.4%, water). Ambutyrosin B was prepared in a similar manner. It melts with decomposition at about 146°C [α]D25=+33° (1.5%, water). References Kawaguchi H. et al.; US Pataent No. 3,792,037; February 12, 1974; Assigned to Bristol-Myers Company, New York, N.Y. Woo P.W.K. et al.; US Patent No. 3,541,078; November 17, 1970; Assigned to Parke, Davis and Company, Detroit, Mich., a corporation of Michigan

BUTIXOCORT Therapeutic Function: Glucocorticoid Chemical Name: 11β,17-Dihydroxy-21-mercaptopregn-4-ene-3,20-dione 17butyrate Common Name: Butixocort; Tixocortol butyrate Structural Formula:

Chemical Abstracts Registry No.: 120815-74-9 Trade Name

Manufacturer

Country

Year Introduced

Butixocort

Jouveinal

-

-

Butixocort

Onbio Inc.

-

-

Raw Materials S-Thioacetic acid Hexametapol

Sodium methylate methanolic solution Cortisol-21-mesylate-17-butyrate

770

Butoconazole nitrate

Manufacturing Process 3,20-Dione-11β-hydroxypregn-4-ene-21-thioacetate-17-butyrate (or hydrocortisone): 10.0 g (0.129 mole) of S-thioacetic acid and 220 ml of hexametapol are introduced into a reactor 27.7 ml of a 4.65 N sodium methylate methanolic solution (0.129 mole) are introduced, accompanied by stirring, at a temperature close to 20°C and then the beige solution is stirred for 1 hour at ambient temperature. Within 10 minutes, a solution of 44.0 g (0.086 mole) of cortisol-21-mesylate-17-butyrate is introduced into 440 ml of hexametapol. The solution is stirred for 2.5 hours at ambient temperature. The orange solution is precipitated in 8 liters of ice water. The insoluble substances formed are filtered and then taken up in methyl ether. The ethereal solution is extracted twice with 250 ml of 1 N sodium hydroxide solution and then three times with 500 ml of saturated sodium chloride solution. After drying the ethereal phase, the solvent is eliminated by distillation. The residue (39 g) is purified by column chromatography with the aid of 1 kg of "Florisil''. Elution by a mixture of dichloromethane and acetone 95:5 (v/v) makes it possible to collect 21 g of purified product. This product is finally recrystallized in 170 ml of a mixture of methanol and water 8:2 (v/v). Weight=19 g. Yield=44.3%. Melting point: 130°C; the structure of prepared compound is confirmed by NMR spectrum. References Aubard et al; US Patent No. 4,933,331; June 12, 1990; Assigned to Jouveinal, S.A., Paris, France

BUTOCONAZOLE NITRATE Therapeutic Function: Antifungal Chemical Name: 1H-Imidazole, 1-(4-(4-chlorophenyl)-2-((2,6dichlorophenyl)thio)butyl)-, mononitrate Common Name: Butoconazole nitrate Structural Formula:

Chemical Abstracts Registry No.: 64872-77-1 Trade Name

Manufacturer

Country

Year Introduced

Butoconazole nitrate

Cipla Limited

India

-

Butoconazole nitrate

771

Trade Name

Manufacturer

Country

Year Introduced

Femstat

Hoffmann - LaRoche Inc.

-

-

Femstat 3

Procter and Gamble

-

-

Femstat 3

Roche

-

-

Gynazole-1

KV Pharmaceutical Co.

USA

-

Gynomyk

Will-Pharma B.V.

Netherlands

-

Raw Materials Imidazole Glycidyl tosylate, (+/-)Triethylamine Methanesulfonyl chloride

4-Chloromagnesium chloride Sodium hydride Dilithium tetrachlorocuprate(II) 2,6-Dichlorobenzenethiol

Manufacturing Process 1H-Imidazole, 1-(4-(4-chlorophenyl)-2-((2,6-dichlorophenyl)thio)butyl)-, (+/)-, mononitrate may be prepared by the same way as described below for enantiomers. To a solution of Li2CuCl4 (0.10 M, 8.8 ml, 0.88 mmol) in dry THF (75 ml) was added dropwise a solution of 4-chloromagnesium chloride (17.5 mmol) in ether (15 ml) at -35°C. After stirring for 45 min, a pre-cooled (-35°C) solution of (S)-(+)-glycydil tosylate (2.0 g, 8.8 mmol) in THF (5 ml) was added via syringe. After 2 h at -35°C, the mixture was quenched with saturated NH4Cl and extracted with ether. The organic layer was dried (Na2SO4), evaporated to dryness and purificated by flash chromatography affording (2S)-1-(ptoluenesulphonyloxy)-4-(4-chlorophenyl)butan-2-ol, as a white solid (1.9 g, 77%), m.p. 72.7-74°C. (2S)-1-[2-Hydroxy-4-(4-chlorophenyl)butyl]-1H-imidazole was prepared as follows: to a solution of imidasole (0.52 g, 7.61 mmol) in dry DMF (5 ml) at 0°C under N2 was added NaH (60% dispersion in oil, 0.3 g, 7.61 mmol). The reaction mixture was warmed to room temperature and stirred for 30 min. A solution of (2S)-1-(p-toluenesulphonyloxy)-4-(4chlorophenyl)butan-2-ol in DMF (15 ml) was then added dropwise over 15 min. The reaction mixture was heated at 75°C for 24 h, cooled poured into water and extracted with ethyl acetate. The organic phase was dried and evaporated and was the residue purified by flash chromatography. Gradient elution (1-5% MeOH/CH2Cl2) afforded (2S)-1-[2-hydroxy-4-(4-chlorophenyl)butyl]-1H-imidazole which was recrystallized from EtOAc/Et2O (236 mg, 67%), m.p. 128°-131°C; [α]D2523.23 (c 0.4, CHCl3). (2S)-1-[2-Hydroxy-4-(4-chlorophenyl)butyl]-1H-imidazole nitrate was prepared as follows. To a solution of (2S)-1-(p-toluenesulphonyloxy)-4-(4chlorophenyl)butan-2-ol (250 mg, 1 mmol) in THF (5 ml) at 0°C was added triethylamine (0.28 ml, 2.0 mmol), followed by methanesulfonyl chloride (0,15 ml, 2.0 mmol). The reaction mixture was was warmed to room temperature and stirred for 1 h. The mixture was poured into aq. NaHCO3, extracted with EtOAC, and the organic phase dried and evaporated to dryness. The resulting mesylate was dissolved in acetone (50 ml), then 2,6-dichlorobenzenethiol

772

Butofilolol

(464 mg, 2.6 mmol) and K2CO3 (568 mg, 4.1 mmol) were added. The mixture was heated at reflux under N2, cooled to room temperature, evaporated to dryness and partionated between water and EtOAc. The organic phase was dried (Na2SO4), evaporated, and residue purified by flash chromatography (12% MeOH/CH2Cl2 gradient elution) to give an oil which was converted to nitrate salt. Recrystallization from EtOAc/Et2O gave 260 mg (55%) (2S)-1-[2hydroxy-4-(4-chlorophenyl)butyl]-1H-imidazole nitrate, m.p. 120°-124°C; [α]D25+22.68 (c 0.4, EtOH). The R enantiomer was prepared the same way from (-)-glycidyl tosylate. References Walker K.A.M. et al.; US Patent No. 4,036,970; July 19, 1977; Assigned: Syntex (U.S.A.) Inc. (Palo Alto, CA) Tetrahedron, v.4, No 7, pp. 1521-1526, 1993, D.M. Rotstein, K.A.M. Walker

BUTOFILOLOL Therapeutic Function: Beta-adrenergic blocker Chemical Name: 1-[2-[3-[(1,1-Dimethylethyl)amino]-2-hydroxypropoxy]-5fluorophenyl]-1-butanone Common Name: Structural Formula:

Chemical Abstracts Registry No.: 64552-17-6 Trade Name

Manufacturer

Country

Year Introduced

Cafide

Clin Midy

France

1982

Raw Materials 5-Fluorosalicylaldehyde Propyl Magnesium Bromide Hydrogen chloride

1-Chloro-2-hydroxy-3-t-butylaminopropane Sodium hydride

Butofilolol

773

Manufacturing Process (a) 5-Chloromethyl-3-tert-butyl-2-(2-hydroxy-5-fluorophenyl)oxazolidine: 5Fluorosalicylaldehyde (1.4 g, 0.01 mol) is dissolved in anhydrous benzene (20 ml) in the presence of a crystal of p-toluenesulfonic acid in a Dean-Stark apparatus. 1-Chloro-2-hydroxy-3-tert-butylaminopropane (2.08 g, approximately 1 equivalent, purity 75%) is then added within a period of 10 hours in portions of 250 mg at a time at the reflux temperature of benzene and the mixture is allowed to stand overnight. An insoluble substance is precipitated on addition of ether after which the solution is filtered, concentrated and distilled. A fraction is obtained having a boiling point of 118°-123°C/10-3 mm of mercury. A mixture of 1.03 g (yield 43%) of isomeric oxazolidines is obtained which solidifies. This is crystallized once from hexane. Melting point 75°-78°C. (b) 8-Aza-4,9-dioxa-11l-fluoro-8-tert-butyl-2,3-benzobicyclo[4.2.1]octane: The product of the previous stage (620 mg) is dissolved in anhydrous dimethylformamide (10 ml) and two quantities each of 300 mg of 50% sodium hydride is added within 2 hours. The mixture is then left for 24 hours at 25°C while being stirred mechanically and is then heated for 2 minutes on a water bath (80°-90°C). The mixture is poured into water, the product extracted with ether, the ethereal extract dried over anhydrous sodium sulfate and the organic phase then concentrated and filtered through a short column of activated alumina. A mixture of light petroleum and diethyl ether (75:25) is used to elute 186 mg of pure product from the column. Melting point 85°86°C (after recrystallization from diisopropyl ether). (c) 1-(2-Formyl-4-fluorophenoxy)-2-hydroxy-3-tert-butylaminopropane: The compound obtained as described above (50 mg) is dissolved in a solution of 1N hydrochloric acid (0.5 ml). The mixture is then heated on a water bath (80°-90°C) for several hours. After complete hydrolysis, which requires approximately 8 hours, the mixture is poured into an excess of water which has been basified, the solid base thus formed is extracted with ether, dried and recrystallized from diisopropyl ether. Melting point 103°-105°C. (d)1-[2(1-Hydroxybutyl)-4-fluorophenoxy]-2-hydroxy-3-tertbutylaminopropane: To a solution of propylmagnesium bromide prepared from 195 mg (8.1 X 10-3 mol) of magnesium, 1.08 g (8.1 X 10-3 mol) of bromopropane and a crystal of iodine in 10 ml of anhydrous diethyl ether under nitrogen is added a solution of the previously prepared aldehyde (197 mg, 0.73 x 10-3 mol) in 4 ml of an ether/tetrahydrofuran mixture (1:3 by volume) and the mixture is heated to reflux for 70 minutes. The mixture is poured into water, extracted with diethyl ether, dried over anhydrous sodium sulfate and 208 mg of an oil which is homogeneous, as shown by thin-layer chromatography, is isolated. (e) CM 6805 (Butofilolol): The previously prepared base (200 mg, 0.66 X mol) is dissolved in purified acetone (8 ml). A drop of sulfuric acid solution (prepared from 35 ml of concentrated sulfuric acid and 65 ml of water) is added and the mixture heated on a water bath for 1 minute. When the solution has cooled to 5° to 10°C a solution of chromic acid (66 mg, 1 equivalent) dissolved in 2 ml of the same acid solution is quickly added and the resulting mixture is stirred while cold. The mixture is then poured into a saturated solution of sodium carbonate, the acetone is evaporated under

774

Butopamine

reduced pressure on a water bath, and the organic phase is extracted with diethyl ether. After drying and evaporating the solvent an oil is obtained (172 mg) all of which solidifies. Recrystallization is carried out from diisopropyl ether. 122 mg of CM 6805 is obtained (yield 61%). Melting point 88°-89°C. References Merck Index 1500 DFU 7 (2) 96 (1982) DOT 18 (10) 551 (1982) and 19 (2)112 (1983) I.N. p.169 Demame, H.; US Patent 4,252,825; February 24, 1981; assigned to C.M. Industries.

BUTOPAMINE Therapeutic Function: Cardiotonic Chemical Name: 4-Hydroxy-α-[[[3-(4-hydroxyphenyl)-1-methylpropyl] amino]methyl]benzenemethanol Common Name: Butopamine Structural Formula:

Chemical Abstracts Registry No.: 66734-12-1 Trade Name

Manufacturer

Country

Year Introduced

Butopamine

ZYF Pharm Chemical

-

-

Butopamine

Lilly

-

-

Raw Materials Ammonia Hydrochloric acid Palladium on carbon Sodium hydroxide

Methyl 2-(4-benzyloxyphenyl)ethyl ketone Hydrogen 1-(4-Hydroxyphenyl)-2-aminoethanol

Manufacturing Process A solution of 32.8 g (0.2 m) of methyl 2-(4-hydroxyphenyl)ethyl ketone and 42.6 g (0.2 m) of 1-(4-hydroxyphenyl)-2-aminoethanol in 380 ml of ethanol

Butorphanol

775

containing 3.8 g of 5% palladium on carbon was stirred for 16 h at 60°C under hydrogen at 55 psi. The reaction mixture was then filtered, and the filtrate was diluted by addition of 350 ml of water. The aqueous mixture was concentrated to a volume of about 400 ml, and then washed with dichloromethane. The aqueous mixture was acidified by addition of 50 ml of conc. hydrochloric acid. After standing at room temperature for 2 h, the aqueous acid mixture was filtered and the filter cake was washed with 40 ml of ice water and dried at 50°C in vacuum to provide 47.0 g of 1-(4-hydroxyphenyl-2propylamino]ethanol hydrochloride, melting point 124-129°C. The 1-(4-hydroxyphenyl)-2-[1-methyl-3-(4-hydroxyphenyl)propylamino] ethanol was obtained by treatment of 1-(4-hydroxyphenyl-2propylamino]ethanol hydrochloride with sodium hydroxide. References Anderson D.B. et al.; US Patent No. 4,690,951; September 1, 1987; Assigned: Eli Lilly and Company, Indianapolis, Ind.

BUTORPHANOL Therapeutic Function: Analgesic, Antitussive Chemical Name: N-Cyclobutylmethyl-3,14-dihydroxymorphinan Common Name: Structural Formula:

Chemical Abstracts Registry No.: 42408-82-2 Trade Name

Manufacturer

Country

Year Introduced

Stadol

Bristol-Myers

US

1978

Stadol

Bristol-Myers

UK

1980

Moradol

Galenika

Yugoslavia

-

Raw Materials N-Cyclobutylmethyl-14-hydroxy-3-methoxymorphinan Hydrogen bromide

776

Butoxamine hydrochloride

Manufacturing Process A mixture of 1.0 g (2.58 mmols) of N-cyclobutylmethyl-14-hydroxy-9methoxymorphinan and 10 ml of 48% HBr was refluxed, under a nitrogen atmosphere, during five minutes. After cooling, the reaction mixture was diluted with water and made basic with aqueous ammonium hydroxide. The aquous basic mixture was extracted with chloroform and the combined chloroform extracts were dried over anhyrous sodium sulfate. After evaporation of the solvent, the residual oil (730 mg) was taken up in dry ether and the resulting solution filtered through celite-charcoal. The filtrate was treated with a saturated solution of hydrogen chloride in dry ether. The hydrochloride salt thus obtained was collected by filtration and recrystallized from a methanol-acetone mixture to yield 565 mg (56.5%)of Butorphanol hydrochloride crystals melting at 272°-274°C (decomposition). References Merck Index 1503 DFU 2 (4) 231 (1977) and 3 (5) 330 (1978) Kleeman and Engel p.129 PDR p.713 OCDS Vol.2 p.325 (1980) DOT 14 (5)197 (1978) I.N. p.170 REM p.1107 Monkovic, I. and Conway, T.T.; US Patent 3,775,414; November 27, 1973; Monkovic, I., Wong, H. and Lim, G.; US Patent 3,980,641; September 14, 1976; Pachter, I.J., Belleau, B.R. and Monkovic, I.; US Patent 3,819,635; June 25, 1974; and Lim, G. and Hooper,

BUTOXAMINE HYDROCHLORIDE Therapeutic Function: Oral hypoglycemic, Antihyperlipidemic Chemical Name: Benzenemethanol, α-(1-((1,1-dimethylethyl)amino)ethyl)2,5-dimethoxy-, (R*,S*)-(+-)-, hydrochloride Common Name: Butaxamine hydrochloride; Butoxamine hydrochloride Structural Formula:

Butriptyline

777

Chemical Abstracts Registry No.: 5696-15-1 Trade Name

Manufacturer

Country

Year Introduced

Butoxamine hydrochloride

SigmaAldrich

-

-

Raw Materials Butylamine Platinum Hydrochloric acid

2,5-Dimethoxy-α-bromopropiophenone Hydrogen Sodium hydroxide

Manufacturing Process 548.0 g (2 mol) of 2,5-dimethoxy-α-bromopropiophenone was dissolved in 500 ml of acetanitrile and 365.0 g (5 mol) of t-butylamine was added. The solution was allowed to stand at room temperature for 64 h and was then diluted with 2 L of anhydrous ether. The precipitated t-butylamine hydrobromide was filtered off and washed with ether. The filtrate and washings were concentrated in vacuo using a water-bath kept at 40°C. When most of the solvent had been removed, the residual material was dissolve in cold methanol and acidified with hydrochloric acid. The solution was then taken down to dryness in vacuo on the steam bath and the 1-(2,5dimethoxyphenyl)-2-(t-butylamino)propiophenone was obtained, melting point 175-176°C (recrystallised from an ethanol ether mixture). The bulk of the 1-(2,5-dimethoxyphenyl)-2-(t-butylamino)propiophenone was dissolved in methanol and hydrogenated over platinum (Adams' catalyst). After removal of the catalyst, the solvent was removed in vacuo and the residual solid was dissolved in water and the solution was washed with ether. The aqueous layer was basified (dilute sodium hydroxide solution) and the base was taken into ether. After drying over anhydrous potassium carbonate, the ether was evaporated and the base was distille at 0.3 mm pressure. So the DL-erythro 1-(2,5-dimethoxyphenyl)-2-(t-butylamino)propanol, boiling point 127-128°C was obtained. References GB Patent No. 1,104,292; February 21, 1968; Assigned: The Wellcome Foundation Limited, of 183-193 Euston Road, London

BUTRIPTYLINE Therapeutic Function: Antidepressant Chemical Name: (+-)-10,11-Dihydro-N,N,β-trimethyl-5H-dibenzo[a,d] cycloheptene-5-propanamine

778

Butriptyline

Common Name: Structural Formula:

Chemical Abstracts Registry No.: 35941-65-2; 5585-73-9 (Hydrochloride salt) Trade Name Evadyne Evadene Centrolyse Evasidol

Manufacturer Ayerst Ayerst Ayerst Arcana

Country UK Italy Austria

Year Introduced 1975 1976 -

Raw Materials Dibenzo[a,e]cycloheptadiene Sodium hydride 2-Methyl-3-dimethylaminopropyl chloride Manufacturing Process A solution of dibenzo[a,e]cycloheptadiene in anhydrous xylene is added in a dropwise fashion with stirring to a suspension of sodium hydride in refluxing anhydrous xylene. The mixture is heated at reflux for two hours with continual agitation and there is then added dropwise a solution of 2-methyl-3dimethylaminopropyl chloride in an equal volume of xylene. The mixture is then heated for fifteen hours, after which time it is cooled and decomposed by the cautious addition of ice water. The layers are separated and the aqueous layer extracted with ether. The combined organic layers are next extracted with 10% hydrochloric acid and the acidic extracts then rendered alkaline by the addition of ammonium hydroxide. The precipitated oil is extracted three times with chloroform. The chloroform extracts are dried and concentrated in vacuo, the residue being distiiled to yield the product. References Merck Index 1506 Kleeman and Engel p.131 OCDS Vol.1 p.151 (1977) DOT 9 (6) 219 (1973) and 10 (7) 235 (1974) I.N. p.170 Villani, F.J.; US Patent 3,409,640; November 5, 1968; assigned to Schering Corporation

Butropium bromide

779

BUTROPIUM BROMIDE Therapeutic Function: Spasmolytic Chemical Name: [3(S)-endo]-8-[(4-Butoxyphenyl)methyl]-3-(3-hydroxy-1oxo-2-phenylpropoxy)-8-methyl-8-azoniabicyclo[3.2.1]octane bromide Common Name: Structural Formula:

Chemical Abstracts Registry No.: 29025-14-7 Trade Name

Manufacturer

Country

Year Introduced

Coliopan

Eisai

Japan

1974

Raw Materials Hyoscyamin Butoxybenzyl bromide Manufacturing Process To 100 ml of an isopropanol solution containing 11.8 grams of hyoscyamine base were added drop by drop with stirring 10 ml of an isopropanol solution containing 11 grams of p-n-butoxybenzyl bromide. After a while, the reaction mixture had a turbid appearance followed by separation of white crystals. After stirring for 5 hours at room temperature, the crystals were recovered by filtration, which were then recrystallized from 120 ml of isopropanol. There was obtained 15.8 grams of white needles having the melting point of 158°160°C. References Merck Index 1507

780

Butylscopolamine bromide

Kleeman and Engel p.131 OCDS Vol.2 p.308 (1980) DOT 10 (11) 292 (1974) I.N. p.170 Tanaka, S.and Hasimoto, K.; US Patent 3,696,110; October 3, 1972; assigned to Eisai, KK, Japan

BUTYLSCOPOLAMINE BROMIDE Therapeutic Function: Anticholinergic, Spasmolytic Chemical Name: 1-alpha-H,5-alpha-H-Tropanium, 8-butyl-6-beta,7-betaepoxy-3-alpha-hydroxy-, bromide, (-)-tropate Common Name: Butylscopolamin(e) bromide; Butylscopolamini bromidum; Butylscopolammonium bromide; Hyoscine butyl bromide; Scopolamine butyl bromide; Scopolaminium butylbromatum Structural Formula:

Chemical Abstracts Registry No.: 149-64-4; 7182-53-8 (Base) Trade Name

Manufacturer

Country

Year Introduced

Butylscopolamine bromide

China Pharm Chemical Co., Ltd.

-

Scopolamine Nbutyl bromide

Andard-Mount Company Limited

-

-

Butylscopolamine bromide

Shchem Corporation

-

-

Scopolamine Butylbromide BP98

Shanghai Lancheng Corporation

-

-

Buscopan

-

-

Antispasmin

Boehringer Ingelheim Vetmedica, Inc. Green Cross

-

-

BS-ratiopharm

Ratiopharm

-

-

Butylscopolamine bromide

781

Trade Name

Manufacturer

Country

Year Introduced

Buscol

Pliva

-

-

Buscolysin

-

-

Buscolysin

PharmachimHolding AD Sopharma

-

-

Buscolysin

Pharmachim S.A

-

-

Buscopan

Boehringer Ingelheim Pharma

-

-

Buscovital

Vitalia K SA

-

-

Buscovital

Omega Pharma

-

-

Buspin

Intas

-

-

Buspon

Toyo Pharmar

-

-

Butilescopolamina Duncan

Duncan

-

-

Butipolan

Tobishi

-

-

Butopan

-

-

-

-

-

-

Cifespasmo

Biofarma Ilac San. ve Tic. A.S. Hokuriku Seiyaku Co. Ltd. Kobayashi Kako Co. Ltd. Northia

-

-

Colobolina

Fabra

-

-

Cryopina

Highnoon Laboratories Limited

-

-

Dhacopan

-

-

Dividol Remedica

Haw Par Healthcare Ltd. Remedica Ltd.

-

-

Espa-butyl

Innopharm

-

-

Hioscina

Veinfar

-

-

Hioscina, butilbromuro Hioscina

Fabra

-

-

Zimaia

-

-

Hioscina Fada

Fada Pharma

-

-

Hioscina N-butyl bromuro N-Butylbromuro de hioscina

Bussie S.A.

-

-

Laboratorios Synthesis -

-

Hioscina N-Butil

Richmond

-

-

Hybropan

Binex

-

-

Hyospan

Howards/LCPW

-

-

Hyospasmol

Pharmacare Limited

-

-

Hyospasmol

Lennon

-

-

Hyospasmol

Aspen Pharmacare

-

-

Hyscopan

M/s. Indus, Karachi.

-

-

Butylpan Butysco

782

Butylscopolamine bromide

Trade Name

Manufacturer

Country

Year Introduced

Hyscopan

Armoxindo Farma

-

-

Hysopan

Rephco Laboratories Ltd.

-

-

Hysopan

Lahore Chemical and Pharmaceutical Works (LCPW) (PVT.) Ltd.

-

-

Luar G

Klonal

-

-

Pasmodina

Drawer

-

-

Rupe N

Bioquim

-

-

Scobut

Laboratoarele Magistra

-

-

Scobutil

Sicomed S.A.

-

-

Scopex

Propan

-

-

Scopinal

Julphar

-

-

Scopolan

Herbapol Wroclaw

-

-

Selpiran-S

Laboratorios Diba, S. A.

-

-

Sparicon

Masung and Co., Ltd.

-

-

Spasman scop.

Merckle

-

-

Spasmopan

APM

-

-

Spasmopan

LEX LECIVA a.s

-

-

Spasmowern

Pharma Wernigerode

-

-

Raw Materials Scopolamine n-Butyl bromide Manufacturing Process 1300 g of scopolamine base and 350 g of n-butylbromide in 600 ml acetonitrile is heated at 65°C for 160 hours. The oil obtained is dissolved in methanol. The solution is cooled and crystalline scopolamine N-n-butylbromide is filtered. After recrystallization from methanol was obtained scopolamine Nn-butylbromide with melting point 142-144°C and [α]d20 = -20.5° (3% solution in water); yield 65%. References Merck Index, Monograph number: 1624, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. Adickes F., DE Patent No. 856,890; 1952.11.24; Assigned to Boenhringer Sohn Ingelheim

C

CABERGOLINE Therapeutic Function: Prolactin inhibitor Chemical Name: 1-((6-Allylergolin-8β-yl)carbonyl)-1-(3-(dimethylamino) propyl)-3-ethylurea Common Name: Cabergoline Structural Formula:

Chemical Abstracts Registry No.: 81409-90-7 Trade Name

Manufacturer

Country

Year Introduced

Destinex

Farmitalia Carlo Erba

Italy

-

Cabergoline

Pharmacia and Upjohn

-

-

Raw Materials 6-Methyl-8β-carboxy-ergoline N-(3-Dimethylaminopropyl)-N-ethyl carbodiimide Sodium hydroxide Manufacturing Process A mixture of 6-(2-propenyl)-8β-carboxy-ergoline and N-(3dimethylaminopropyl)-N-ethyl carbodiimide in tetrahydrofuran were refluxed, with stirring and under nitrogen, for 24 h. The resultant solution was evaporated in vacuo to dryness and the residue taken up with chloroform and

783

784

Cafaminol

5% sodium hydroxide solution. The organic phase was separated, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica (eluant chloroform with 1% methanol) to give the title compound N-(3-(dimethylamino)propyl)-N-((ethylamino)carbonyl)-8βcarboxamide-6-(2-propenyl)ergoline. References Salvati P. et al; US Patent No. 4,526,892; July 2, 1985; Assigned: Farmitalia Carlo Erba, S.p.A., Milan, Italy

CAFAMINOL Therapeutic Function: Nasal decongestant Chemical Name: 3,7-Dihydro-8-[(2-hydroxyethyl)methylamino]-1,3,7trimethyl-1H-purine-2,6-dione Common Name: Methylcoffanolamine Structural Formula:

Chemical Abstracts Registry No.: 30924-31-3 Trade Name

Manufacturer

Country

Year Introduced

Rhinoptil

Promonta

W. Germany

1974

Rhinetten

Arzneimittelwerk Dresden

E. Germany

-

Raw Materials 8-Chlorocaffeine beta-N-Methylaminoethanol Manufacturing Process 21 g 8-chlorocaffeine and 15 g beta-N-methylaminoethanol are heated to 140°-160°C for 30 minutes. Then the temperature is increased for 15-20 minutes to 165°-170°C. On cooling a colorless mass of crystals results. This is boiled with 50-60 ml ethanol and crystallized. Colorless crystals result which

Cafedrine

785

are soluble in water up to about 6%; pH of the aqueous solution is 6.9. The yield is 19 g while the MP is 162°-164°C. References Merck Index 1603 I.N. p. 173 Klosa, J.; US Patent 3,094,531; June 18,1963; assigned to Delmar Chemicals Ltd. (Canada)

CAFEDRINE Therapeutic Function: Analeptic Chemical Name: Theophylline, 7-(2-(beta-hydroxy-alpha-methylphenethylamino)ethyl)Common Name: Cafedrine; Kafedrin; Norephedrinoethyltheophylline Structural Formula:

Chemical Abstracts Registry No.: 78396-34-6 Trade Name

Manufacturer

Country

Year Introduced

Praxinor

Merck Lipha Sante

-

-

Cafedrine

Merck

-

-

Cafedrine

Shanghai Lancheng Corporation

-

-

Cafedrine

Gennapharm, Inc.

-

-

Akrinor

Adcock Ingram Ltd.

-

-

Akrinor

AWD Pharma GmbH and Co. KG

-

-

Bifort

Finadiet

-

-

786

Caffeine

Raw Materials 7-(2-Bromethyl)theophylline 1-Norphedrine Manufacturing Process 7.5 g 7-(2-bromethyl)theophylline, 11.3 g 1-norphedrine and 12.5 ml isopropanol were refluxed with stirring for 6 hours. Then 30 ml ethanol and HCl in ethanol to pH 5-6 were added. The mixture stood for 2 days. 9.6 g of 7-(2-(beta-hydroxy-alpha-methylphenethylamino)ethyl)theophylline hydrochloride was filtered off and dried. MP 243°-244°C. In practice it is usually used as free base. References Kohlstaedt E. et al.; D. B. Patent No. 1,095,285; 25 Sept. 1956; Assigned to Chemiewerk Homburg Zweigniedererlassung der Deutschen Gold- und Silber-Scheideanstalt vormals Roessler Franffurt/Main

CAFFEINE Therapeutic Function: Neurotropic, Central stimulant Chemical Name: 3,7-Dihydro-1,3,7-trimethyl-1H-purine-2,6-dione Common Name: Cafeina; Caféine; Caffeine; Coffein; Guaranine; Kafeiyin; Kaffein; Koffein; Mateina; Methyltheobromine; Thein Structural Formula:

Chemical Abstracts Registry No.: 58-08-2 Trade Name Caffedrine Caffeine Koffein Vivarin

Manufacturer Thompson Med. Prolab Prolab GlaxoSmithKline Consumer Healthcare, L.P.

Country USA

Year Introduced -

Calcifediol

787

Raw Materials Theophylline Dimethyl sulfoxide Dimethyl sulfate Manufacturing Process Caffeine was synthesized by the reaction N-chloromethylation of theophylline by action dimethylsulphate in dimethylsulfoxide. References DBP 834105 (Boehringer Ing.; Anm. 1949)

CALCIFEDIOL Therapeutic Function: Calcium regulator Chemical Name: 9,10-Secocholesta-5,7,10(19)-triene-3,25-diol Common Name: 25-Hydroxyvitamin D3; 25-Hydroxycholecalciferol Structural Formula:

Chemical Abstracts Registry No.: 19356-17-3 Trade Name

Manufacturer

Country

Year Introduced

Dedrogyl

Roussel

France

1976

Delakmin

Roussel

W. Germany

1978

Calderol

Upjohn

US

1980

Didrogyl

Roussel Maestretti Italy

1980

Dedrogyl

Hoechst

Switz.

1982

Hidroferol

Juventus

Spain

-

Calderol

Organon

US

-

788

Calcifediol

Raw Materials Cholesta-5,7-diene-3β,25-diol Manufacturing Process A solution of 125 mg of cholesta-5,7-diene-3β,25-diol in 125 ml of benzene and 10 ml of absolute ethanol is placed in a photo reactor equipped with a quartz lamp well cooled with water and a nitrogen inlet. The reaction mixture is cooled to about 16°C, and purged with N2. A Hanovia 8A36, 100-watt lamp, centered in the lampwell 2.5 cm from the internal surface of the reaction mixture, is turned on for 15 minutes, including the 5-6 minutes required for the lamp to reach full brilliance. The lamp is a typical actinic energy source suitable for the irradiation step in the known synthesis of Vitamin D, and can be replaced by any such available lamp. The specific lamp used is a 100-watt high-pressure quartz mercury-vapor lamp, producing approximately 11.5 watts total radiated energy distributed over the range of 220-1400 nm. A fast stream of water is necessary to keep the outlet water temperature below 20°C. The reaction mixture is concentrated to dryness in a rotary evaporator below room temperature. The semisolid residue is triturated with 5 ml of 35% ethyl acetate-65% Skellysolve B hexanes mixture and filtered and another 5 ml of the same solvent is used for wash. The solid contains unreacted starting material and the liquor contains the product. The liquor is poured onto a 40 g column containing TLC grade Florisil, 150-200 mesh packed wet with 35% ethyl acetate-Skellysolve B hexanes, and the products are eluted with the same solvent mixture collecting 10 ml fractions. The fractions containing the product, located by spotting on a TLC plate, are combined and evaporated to dryness below room temperature to give an oily residue. A few drops of absolute ether are added and removed under vacuum to give 25hydroxyprecholecalciferol as a fluffy foam; yield 60 mg. A solution of about 300 mg of 25-hydroxyprecholecalciferol prepared as described above in 5 ml of chloroform is heated for 3.5 hours at 70°-75°C under N2 in a sealed flask. The solvent is evaporated and the residue is chromatographed through a 60 g column containing TLC grade Florisil, 150200 mesh packed wet with 35% ethyl acetate in Skellysolve B hexanes. The column is eluted with the same solvent mixture, collecting 10 ml fractions. The fractions which crystallize on trituration with aqueous methanol are combined and recrystallized twice from aqueous methanol to give 25hydroxycholecalciferol hydrate; yield 120 mg, MP 81°-83°C (sinters 75°C). A solution of 20 mg of 25-hydroxycholecalciferol hydrate, prepared as described above, in 20 ml of methylene chloride is dried with 200 mg of anhydrous sodium sulfate. The solution is filtered and the filtrate is evaporated to yield 25-hydroxycholecalciferol essentially anhydrous as an amorphous oil. References Merck Index 1610 Kleeman and Engel p. 133 PDR p. 1285 OCDS Vol. 3 p. 101 (1984)

Calcipotriol

789

DOT 13 (6) 225 (1977) I.N. p. 174 Babcock, J.C. and Campbell, J.A.; US Patent 3,833,622; September 3, 1974; assigned to The Upjohn Company Saimond, W.G.; US Patent 4,001,096; January 4, 1977; assigned to The Upjohn Company

CALCIPOTRIOL Therapeutic Function: Antipsoriatic Chemical Name: 9,10-Secochola-5,7,10(19),22-tetraene-1,3,24-triol, 24cyclopropyl-, (1α,3β,5Z,7E,22E,24S)Common Name: Calcipotriene; Calcipotriol; Dovonex; MC 903 Structural Formula:

Chemical Abstracts Registry No.: 112965-21-6 Trade Name

Manufacturer

Country

Year Introduced

Psorcutan

KOHLPHARMA

-

-

Raw Materials (1S,3R)-Bis-(tert-butyldimethylsilyloxy)-(20S)-formyl-9.10-secopregna(5E,7E,10(19))triene (Cyclopropyl)(triphenylphosphoranylidene)ketone Cerium (III) chloride Cyclopropyl magnesium bromide Anthracene Sodium borohydride Triethylamine Tetrabutylammonium fluoride

790

Calcitonin

Manufacturing Process (1S,3R)-Bis-(t-butyldimethylsilyloxy)-(20S)-formyl-9,10-secopregna(5E,7E,10 (19))triene (Calverley Tetrahedron 43.4609 (1967) and (cyclopropyl)(triphenylphoshoranylidene)ketone are stirred in dimethyl sulfoxide under nitrogen. The reaction mixture is then diluted at room temperature with ethyl acetate and washed with common salt solution. The organic phase is dried on sodium sulfate and filtered. After removal of the solvent, the residue is filtered with toluene through silica gel. Evaporation of the solvent and gradient chromatography (toluene/hexane (1:1)-toluene) of the residue on silica gel yield (5E,7E,22E),(1S,3R)-1,3-bis-(t-butyldimethylsilyloxy)-24-cyclopropyl9,10-secochola-5,7,10(19),22-tetraene-24-one. (5E,7E,22E),(1S,3R)-1,3-Bis-(t-butyldimethylsilyloxy)-24-cyclopropyl-9,10secochola-5,7,10(19),22-tetraene-24-one in tetrahydrofuran and methanol are mixed with a 0.4 M methanol CeCl3·7H2O solution. Sodium borohydride is added by portions under nitrogen with ice cooling. The suspension is stirred with ice cooling and then put into ice/common salt solution. The aqueous phase is extracted with ethyl acetate, the organic phase is washed neutral with water and dried on sodium sulfate. Filtration and removal of the solvent yield oil. By chromatography on silica gel with ethyl acetate/hexane (1:9). The (5E,7E,22E),(1S,3R,24S)-1,3-bis-(t-butyldimethylsilyloxy)-24-cyclopropyl9,10-secochola-5,7,10(19),22-tetraene-24-ol is obtained. (5E,7E,22E),(1S,3R,24S)-1,3-Bis-(t-butyldimethylsilyloxy)-24-cyclopropyl9,10-secochola-5,7,10(19),22-tetraene-24-ol is dissolved in toluene and after addition of anthracene and 1 drop of triethylamine it is radiated at room temperature with a high pressure mercury vapor lamp (Heraeus TQ 150) through Pyrex glass. The reaction mixture is concentrated by evaporation and the residue a mixture of (5Z,7E,22E),(1S,3R,24S)-1,3-bis-(tbutyldimethylsilyloxy)-24-cyclopropyl-9,10-secochola-5,7,10(19),22-tetraene24-ol and anthracene - is directly reacted with tetrabutylammonium fluoride. (5Z,7E,22E),(1S,3R,24S)-1,3-Bis-(t-butyldimethylsilyloxy)-24-cyclopropyl9,10-secochola-5,7,10(19),22-tetraene-24-ol in tetrahydrofuran is kept with a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran under nitrogen. For working up, the cooled reaction mixture is poured into cold sodium bicarbonate solution and then extracted with ethyl acetate. After drying of the organic phase on sodium sulfate, filtration and evaporation of the solvent yields a resin-like residue. Chromatography on silica gel with ethyl acetate/hexane (2:1) yields (5Z,7E,22E),(1S,3R,24S)-24-cyclopropyl-9,10secochola-5,7,10(19),22-tetraene-1,3,24-triol. References Kircsch G. et al.; US Patent No. 5,665,716; Sept. 9, 1997; Assigned to Schering Aktiengesellscaft, Berlin, Germany

CALCITONIN Therapeutic Function: Calcium regulator

Calcitonin

791

Chemical Name: Complex hormone of molecular weight about 4,500 Common Name: Thyrocalcitonin Structural Formula: H-L-Cys-L-Ser-L-Asp(NH2)-L-Leu-L-Ser-L-Thr-L-Cys-LVal-L-Leu-Gly-L-Lys-L-Leu-L-Ser-L-Glu(NH2)-L-Glu-L-Leu-L-His-L-Lys-L-Leu-LGlu(NH2)-L-Thr-L-Tyr-L-Pro-L-Arg-L-Thr-L-Asp(NH2)-L-Thr-Gly-L-Ser-Gly-L-ThrL-Pro-NH2 (Disulfide bridge: 1-7) Chemical Abstracts Registry No.: 9007-12-9 Trade Name

Manufacturer

Country

Year Introduced

Calcitar

Yamanouchi

Japan

1978

Cibacalcin

Ciba Geigy

Switz.

1978

Elcitonin

Toyo Jozo

Japan

1981

Calcimar

Armour

US

-

Calcitonin-Sandoz

Sandoz

Switz.

-

Calsyn

Armour

UK

-

Calsynar

Armour

UK

-

Miacalcic

Sandoz

Switz.

-

Staporos

Roussel

France

-

Raw Materials C-cell-rich thyroid gland carcinoma Manufacturing Process The process for the manufacture of human calcitonin in pure form from C-cell rich medulla carcinoma of the thyroid gland or from C-cell metastasis material is one wherein medullar carcinoma of the thyroid gland or C-cell metastasis material, which has been defatted, for example with acetone or ether, and which may have been first purified with alcohol or with aqueous trichloroacetic acid, is extracted one or more times with a solvent system containing water and an alkanol having at most 5 carbon atoms, at a pH of from about 1 to 6, and the extracted product subjected to gel chromatography using aqueous formic acid as eluant. The calcitonin may be separated into its constituents by countercurrent distribution, for example by Craig distribution using a solvent system advantageously containing n-butanol and acetic acid. References Merck Index 1611 DFU 8 (2) 105 (1983) PDR p. 1809 DOT 14 (4) 139 (1978) I.N. p. 174 REM p. 979 Ciba-Geigy A.G.; British Patent 1,270,595; April 12, 1972

792

Calcitriol

CALCITRIOL Therapeutic Function: Calcium regulator Chemical Name: 9,10-Secocholesta-5,7,10(19)-triene-1,3,25-triol Common Name: 1α,25-Dihydroxycholecalciferol; 1α,25-Dihydroxyvitamin D3 Structural Formula:

Chemical Abstracts Registry No.: 32222-06-3 Trade Name

Manufacturer

Country

Year Introduced

Rocaltrol

Roche

US

1978

Rocaltrol

Roche

W. Germany

1980

Rocaltrol

Roche

UK

1980

Rocaltrol

Roche

Switz.

1980

Rocaltrol

Roche

Italy

1981

Raw Materials 1α,25-Diacetoxyprecholecalciferol Potassium hydroxide Manufacturing Process 1α,25-Dihydroxyprecholecalciferol: A solution of 1α,25diacetoxyprecholecalciferol (0.712 g, 1.42 mmols), potassium hydroxide (2.0 g, 35.6 mmols) and methanol (40 ml) was stirred at room temperature under argon for 30 hours. The reaction mixture was concentrated under reduced pressure. Water (50 ml) was added to the residue and the mixture was extracted with methylene chloride (3 x 100 ml). The combined organic extracts were washed with saturated sodium chloride solution (3 x 50 ml), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 0.619 g of 1alpha,25-dihydroxyprecholecalciferol as a thick oil. 1α,25-Dihydroxycholecalciferol: A solution of 1α,25-dihydroxyprecholecalciferol [0.619 g in dioxane (30 ml)] was heated under reflux for 30 minutes under an atmosphere of argon. The reaction mixture was concentrated under reduced

Calcium pantothenate

793

pressure and the residue was purified with a Waters Associates liquid chromatograph model 202 using a 8 foot * 3/8 inch Porasil A column and a 5:1 mixture of ethyl acetate-n-hexane as the eluent to give 0.474 g (80% yield based on 1α,25-diacetoxyprecholecalciferol) of pure 1α,25dihydroxycholecalciferol. Recrystallization from methyl formate afforded 0.340 g of 1α,25-dihydroxcholecalciferol as colorless crystals, MP 113°-114°C. References Merck Index 1612 Kleeman and Engel p. 134 PDR p. 1498 OCDS Vol. 3 p. 103 (1984) DOT 16 (5) 149 (1980) I.N. p. 175 REM p. 1012 Uskokovic, M.R., Narwid, T.A., Iacobelli, J.A. and Baggiolini, E.; US Patent 3,993,675; November 23, 1976; assigned to Hoffmann-La Roche, Inc.

CALCIUM PANTOTHENATE Therapeutic Function: Vitamin Chemical Name: β-Alanine, N-(2,4-dihydroxy-3,3-dimethyl-1-oxobutyl)-, calcium salt (2:1), (R)Common Name: Calcium D-panthothenate; Calcium pantothenate Structural Formula:

Chemical Abstracts Registry No.: 137-08-6 Trade Name Calcium D-Pantothenate Calcium pantothenate

Manufacturer Country Arocor Holdings Inc. Mallinckrodt Baker, Inc.

Year Introduced -

Calcium pantothenate Detro Calcium Pantothenate

Epochem Co., Ltd. Shandong Xinfa Parmaceutical Co., Ltd.

-

-

Calcium pantothenate Calcium pantothenate

ICN Natura Sanat BV

-

-

794

Calcium pantothenate

Trade Name

Manufacturer

Country

Year Introduced

Calcium pantothenate

Pharmeta BV

-

-

Calcipan T

Spencer Pharma

-

-

Calcipan

M/s. Fisons, Karachi

-

-

Calcipan

Tabros Pharma

-

-

Calpan

Pharm Chemical

-

-

Calpan

Metagenics, Inc.

-

-

Cal Pan

Fertrell Company products

-

-

Calpanate

Hangzhou Minsheng Bio-Tech Co., Ltd.

-

Kerato Biciron (N) S and K PHARMA

-

-

Pantogen

Pantogen

-

-

Pantonate

Oasis

-

-

Eagle Pantonate

-

-

Pantothen

Eagle Pharmaceuticals Linz

-

-

Pantothen-Streuli

Streuli

-

-

Raw Materials Isobutyraldehyde Sodium cyanide β-Alanine Brucine

Formaldehyde Sodium methoxide Diethylamine

Manufacturing Process A mixture of 288 g (4 mols) of isobutyraldehyde, 288 g of methanol was cooled to 10°C and 170 g (2 mols) of 36.6% formalin containing 8.5 g (3% based on isobutyraldehyde) of sodium hydroxide was added dropwise over a 55 minute period to produce alpha,alpha-dimethyl-beta-hydroxypropionaldehyde. The mixture was stirred for an additional 2 hours at 10-15°C and then contacted with acetic acid to neutralize the catalyst. The excess isobutyraldehyde and methanol were stripped off at a kettle temperature of 50°C at 25 mm. To the residual α,α-dimethyl-beta-hydroxypropionaldehyde a mixture of 260 ml of methanol and 2 g (0.75%) sodium cyanide was added and the solution cooled to 10°C before adding 59.4 g (2.2 mols) of hydrogen cyanide dropwise over a 35 minute period to produce α,γ-dihydroxy-β,βdimethylbutyronitrile. The mixture was stirred at 10°C for one hour period and then contacted with acetic acid to neutralize the catalyst before stripping off the excess methanol to a kettle temperature of 45°C at 18 mm. The crude cyanohydrin was then hydrolysed by heating with 4 mols of concentrated hydrochloric acid at 80°C for 2 hours, then diluting with an equal volume of water and heating at 100°C for an additional 8 hours. The aqueous mixture was extracted continuously with ethylene dichloride. The solvent was

Calfactant

795

removed, and pantolactone (B. P. 131°C/19 mm, M.P. 61-77°C, 96.5% purity by saponification) was obtained by distillation in 71.5% yield based on formaldehyde and 55% efficiency based on isobutyraldehyde. 26 grams of racemic pantolactone (0.2 mol) and 1.1 grams of sodium methoxide (0.02 mol) contained in 30 ml of methanol, were added to 78.8 grams of 1-brucine (0.2 mol) contained in 156 ml of methanol. The resulting mixture was refluxed for 1.5 hours and allowed to stand at room temperature overnight. After centrifuging, washing with methanol and drying, 65.4 grams of D-(-)-pantolactone 1-brucine (62% of theory based upon all of the racemic pantolactone) melting at 203° to 206°C were obtained. Upon chilling the mother liquor, 13.46 grams of additional complex melting at 175° to 177°C were obtained. D-(-)-Pantolactone was obtained from the complex in the following manner. The 65.4 grams of complex obtained above were treated with 65 ml of chloroform and 5.35 grams of sodium hydroxide contained in 35 ml of water for one hour at room temperature. The aqueous layer was extracted 6 times with 20 ml portions of chloroform in order to remove the brucine. The sodium pantoate contained in the aqueous layer was relactonized by treatment with 11 ml of concentrated hydrochloric acid. Extraction of the crude D-(-)pantolactone yielded 15.29 grams. This material was then recrystallized from 7 ml of methyl isobutyl ketone and 7 ml hexane thereby yielding 9.77 grams of D-(-)-pantolactone (37% of theory). The αD25 was -44.8°. Into a vessel equipped with an agitator and reflux condenser are placed approximately 52 parts by weight of α-hydroxy-β,β-di-methyl-γ-butyrolactone, approximately 36 parts by weight of β-alanine, about 40 parts by weight of diethylamine and about 100 parts by weight of anhydrous methanol. The mixture is stirred and refluxed for about 12 hours until the reaction is complete as evidenced by the dissolution of the β-alanine. To this resulting mass is gradually added 8 parts by weight of calcium metal nodules or pellets and refluxing continued until the metal is dissolved. The diethylamine and alcohol are distilled off until the residue becomes viscous. The viscous residue is dried under vacuum at 100°C. The solid residue recovered, as biologically assayed, indicated a 91% yield of calcium pantothenate. References Lynn J.W.; US Patent No. 2,863,878; Dec. 9, 1958; Assigned to Unione Carbide Corporation, a corporation of New York Bckmann C.O. et al.; US Patent No. 2,967,869; Jan. 10, 1961; Assigned to Nopco Chemical Company Harrison, N.J., a corporation of New Jersey Lekberg R.D. et al.; US Patent No. 2,809,213; Oct. 8, 1957; Assigned to Chemik Laboratorics Inc., a corporation of Illinois

CALFACTANT Therapeutic Function: Lung surfactant Chemical Name: Calfactant

796

Calusterone

Common Name: Infasurf Structural Formula: Mixture of phospholipids Chemical Abstracts Registry No.: 183325-78-2 Trade Name

Manufacturer

Country

Year Introduced

Infasurf

Forest Pharmaceuticals, Inc.

USA

-

Raw Materials Calf lungs Aqueous solution NaCl (0.15 M) Manufacturing Process Calfactant is purified surfactant phospholipids extracted from calf lungs and purified by gel permeation chromatography. Calfactant include phospholipids, neutral lipides, and hydrophobic surfactant - three biophysically active proteins SP-A, SP-B, and SP-C. It contained no preservatives. References Egan E.A. et al.; US Patent No. 6,458,759; Oct. 1, 2002; Assigned: Ony, Inc. (Amherst, NY) http://www.fda.gov/cder/foi/label/1998/20521lbl.pdf http://www.infasurf.com/Infasurf_pi.pdf

CALUSTERONE Therapeutic Function: Antineoplastic Chemical Name: 17β-Hydroxy-7β,17-dimethylandrost-4-en-3-one Common Name: 7,17-Dimethyltestosterone Structural Formula:

Calusterone

797

Chemical Abstracts Registry No.: 17021-26-0 Trade Name

Manufacturer

Country

Year Introduced

Methosarb

Upjohn

US

1973

Riedemil

Upjohn

US

-

Raw Materials 6-Dehydro-17-methyltestosterone Methyl magnesium bromide Manufacturing Process As described in US Patent 3,029,263, one possibility is a multistep synthesis starting from 3β,17β-dihydroxy-17α-methyl-5-androstene. Alternatively, as described in US Patent 3,341,557, 6-dehydro-17methyltestosterone may be used as the starting material. A mixture of 0.4 g of cuprous chloride, 20 ml of 4M methylmagnesium bromide in ether and 60 ml of redistilled tetrahydrofuran was stirred and cooled in an ice bath during the addition of a mixture of 2.0 g of 6-dehydro-17-methyltestosterone, 60 ml of redistilled tetrahydrofuran and 0.2 g of cuprous chloride. The ice bath was removed and stirring was continued for four hours. Ice and water were then carefully added, the solution acidified with 3 N hydrochloric acid and extracted several times with ether. The combined ether extracts were washed with a brine-sodium carbonate solution, brine and then dried over anhydrous magnesium sulfate, filtered and then poured over a 75-g column of magnesium silicate (Florisil) packed wet with hexanes (Skellysolve B). The column was eluted with 250 ml of hexanes, 0.5 liter of 2% acetone, two liters of 4% acetone and 3.5 liters of 6% acetone in hexanes. Four 250-ml fractions were collected followed by 150 ml fractions. The residues from fractions 8 to 16 were combined and rechromatographed over a 125-g column of magnesium silicate. The solumn was eluted with 6% acetone in hexanes which was collected in 150 ml portions. Fractions 18 to 29 were combined and dissolved in acetone, decolorized with charcoal, and recrystallized from acetone. One gram of a crystalline mixture of the 7epimers of 7,17-dimethyltestosterone was obtained melting at 120° to 140°C. References Merck Index 1701 Kleeman and Engel p. 138 OCDS Vol. 2 p. 154 (1980) DOT 10 (3) 85 (1974) I.N.p. 177 REM p. 1001 Campbell, J.A. and Babcock, J.C.; US, Patents 3,029,263; April 10, 1962 and 3,341,557; September 12, 1967; both assigned to The Upjohn Company

798

Camazepam

CAMAZEPAM Therapeutic Function: Anxiolytic Chemical Name: 3-N,N-Dimethylcarbamoyloxy-1-methyl-7-chloro-5-phenyl1,3-dihydro-2H-1,4-benzodiazepin-2-one Common Name: Structural Formula:

Chemical Abstracts Registry No.: 36104-80-0 Trade Name

Manufacturer

Country

Year Introduced

Albego

Simes

Italy

1977

Albego

W. Germany

1978

Albego

Boehringer Ingelheim Inpharzam

Switz.

1978

Albego

Farmasimes

Spain

-

Limpidon

Crinos

Italy

-

Raw Materials 7-Chloro-5-phenyl-1-methyl-3-hydroxy-1,3-dihydro-2H-1,4benzodiazepine-2-one Phenyl chlorocarbonate Dimethylamine Manufacturing Process A suspension of 100 g of 7-chloro-5-phenyl-1-methyl-3-hydroxy-1,3-dihydro2H-1,4-benzodiazepin-2-one in 700 ml of anhydrous pyridine, kept stirred between 0°C and +5°C, is slowly treated, during 20 to 30 minutes, with 54.5 ml phenyl chlorocarbonate. The temperature is gradually allowed to rise to 20°-25°C and stirring is maintained at this temperature during 24 hours. 2 l of water are then slowly added (during about 30 minutes) and stirring is maintained during 1 hour. The precipitate which has been formed is collected on a filter, washed thoroughly with water, dried in a vacuo at 50°C and recrystallized by dissolving it at 60°C in 1,400 ml dioxane, the solution thus

Candesartan cilexetil

799

obtained being evaporated under reduced pressures to one-half of its volume, and 1,700 ml of ligroin (BP 80°C to 120°C) being added thereto. 7-chloro-5-phenyl-1-methyl-3-phenoxycarbonyloxy-1,3-dihydro-2H-1,4benzodiazepin-2-one is thus obtained, with a melting point of 162°C to 164°C. A suspension of 45 g 3-phenoxycarbonyloxy-1-methyl-7-chloro-5-phenyl-1,3dihydro-2H-1,4benzodiazepin-2-one in 450 ml methanol is treated with stirring, with 43 ml of a solution of dimethylamine in methanol (containing 31 g dimethylamine in 100 ml). Stirring is maintained at 20°C to 25°C during 5 hours. The reaction mixture is filtered, and the filtrate is diluted with 450 ml water. The precipitate thus formed, is 3-(N,N-dimethylcarbamoyloxy)-1methyl-7-chloro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one, which is collected on a filter, dried and recrystallized from ethyl acetate, and has a melting point of 173°C to 174°C. References Merck Index 1703 DFU 1 (10) 458 (1976) Kleeman and Engel p. 139 DOT 11 (5) 182 (1975); 13 (12) 521 (1977) I.N. p. 177 Ferrari, G. and Casagrande, C.; US Patent 3,799,920; March 26, 1974; assigned to Siphar SA

CANDESARTAN CILEXETIL Therapeutic Function: Antihypertensive Chemical Name: 1H-Benzimidazole-7-carboxylic acid, 2-ethoxy-1-((2'-(1Htetrazol-5-yl)(1,1'-biphenyl)-4-yl)methyl)-, 1-(((cyclohexyloxy)carbonyl) oxy)ethyl ester Common Name: Candesartan cilexetil Structural Formula:

Chemical Abstracts Registry No.: 145040-37-5

800

Candesartan cilexetil

Trade Name

Manufacturer

Country

Year Introduced

Amias

Microlab

-

-

Amias

AstraZeneca

-

-

Amias

Takeda

USA

-

Atacand

Astra Merck, Inc.

-

-

Atacand

AstraZeneca

-

-

Raw Materials 3-Nitrophthalic acid Sulfuric acid Potassium carbonate Sodium azide Sodium hydroxide

Trimethyltin azide Trityl chloride 4-(2-Cyanophenyl)benzyl bromide Cyclohexyl 1-iodoethyl carbonate Stannous dichloride dihydrate

Manufacturing Process 3-Nitrophthalic acid (35 g) in 300 ml ethanol and 20 ml concentrated sulfuric acid was heated under reflux for 24 hours. The solvent was evaporated in vacuo and the residue was poured into 700 ml cold water. The mixture was extracted with ethyl acetate. The aqueous layer was made acidic with hydrochloric acid and the mixture was extracted with methylene chloride. After evaporation of methylene chloride was obtained 29 g (74%) ethyl 2carboxy-3-nitrobenzoate. A mixture of 23.9 g ethyl 2-carboxy-3-nitrobenzoate and 12 ml thionyl chloride in 150 ml benzene were heated under reflux for 3 hours. The reaction mixture was concentrated to dryness. The resultant acid chloride (26 g) was dissolved in 20 ml. The solution was added to a mixture of sodium azide (9.75 g) in 20 ml DMF with stirring. The reaction mixture was poured into 200 ml a mixture of ether-hexane (3:1). The organic layer was washed with water and evaporated. The residue was dissolved in 200 ml tert-butanol and the solution was heated gradually with stirring, followed by heating under reflux for 2 hours. The reaction mixture was concentrated to give an oily ethyl 2butoxycarbonylamino-3-nitrobenzoate (30 g). To a solution of ethyl 2-butoxycarbonylamino-3-nitrobenzoate (29 g) in 50 ml THF was added, while stirring under ice-cooling, sodium hydride (60% dispersion in mineral oil, 2.8 g). After 20 min to the mixture were added 18 g 4-(2-cyanophenyl)benzyl bromide and 0.36 g potassium iodide. After heating for 10 hours under reflux the solvent was evaporated and the residue was partitioned between 250 ml water and 200 ml ether. The organic layer was washed with water, dried and concentrated to give yellow syrup. The syrup was dissolved in a mixture of 60 ml trifluoroacetic acid and 40 ml methylene chloride and the solution was stirred for 2 hour at room temperature. The reaction mixture was concentrated to dryness and to residue was added 200 ml ethyl ether to give crystals of ethyl 2-[(2'-cyanobiphenyl-4yl)methylamino]nitrobenzoate (22.1 g, 85%), M.P. 118-119°C. To a solution of 10.4 g ethyl 2-[(2'-cyanobiphenyl-4-yl)methylamino] nitrobenzoate in 50 ml ethanol was added 28.1 g stannous dichloride dihydrate and the mixture was stirred for 2 hours at 80°C. The solvent was

Candesartan cilexetil

801

evaporated. To the ice-cooling mixture of the residue in 300 ml ethyl acetate was added dropwise 2 N NaOH (500 ml). The aqueous layer was extracted with ethyl acetate (200 ml x 2). The organic layers were combined and evaporated to dryness. Product was purified by column chromatography on silica gel. Recrystallization from ethyl acetate-hexane gave colorless crystals ethyl-3-amino-2-[[(2'-cyanobiphenyl-4-yl)methyl]amino]benzoate (7.3 g, 79%), M.P. 104-105°C. Acetic acid (0.2 g) was added to a solution of ethyl-3-amino-2-[[(2'cyanobiphenyl-4-yl)methyl]amino]benzoate (1 g) in ethylorthocarbonate (5 ml). The mixture was stirred at 80°C for 1 hours. The reaction mixture was concentrated. The solution was washed with an aqueous solution of NaHCO3 and water. The solvent was evaporeted to give crystals. Recrystallization from ethyl acetate-benzene afforded colorless crystals 1-[(2'-cyanobiphenyl-4yl)methyl]-2-ethoxybenzimidazole-7-carboxylate (0.79 g, 69%), M.P. 131132°C. A mixture of 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethoxybenzimidazole-7carboxylate (0.7 g) and trimethyltin azide (0.7 g) in toluene (15 ml) was heated under reflux for 4 days. The reaction mixture was concentrated, and to the residue were added methanol (20 ml) and 1 N HCl (10 ml). The solution was stirred at room temperature for 30 minutes and adjusted to pH 3-4 with 1 N NaOH. After removal of the solvent, the residue was partitioned between chloroform and water. The organic layer was evaporated to dryness to dive a syrup. The syrup was purified by column chromatography on silica gel to give crystals. Recrystallization from ethyl acetate-benzene afforded colorless crystals ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (0.35 g, 45%), M.P. 158-159°C. Ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]-methyl]benzimidazole7-carboxylate (0.24 g) was stirred with 1 N NaOH (1.5 ml) in ethanol (4 ml) for 1 hours at 80°C. The reaction mixture was concentrated, and the concentrate was exrtacted with water and ethyl acetate. The aqueous layer was adjusted to pH 3-4 with 1 N HCl to give crystals. Recrystallization from ethyl acetate-benzene afforded colorless crystals of 2-ethoxy-1-[[2'-(1Htetrazol-5-yl)biphenyl-4-yl]-methyl]benzimidazole-7-carboxylic acid (0.15 g, 67%), M.P. 183-185°C. To a solution of 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (2.07 g) in methylene chloride (10 ml) were added trityl chloride (1.59 g) and triethylamine (0.8 ml). The mixture was stirred at room temperature for 1 hour. The mixture was washed with water and concentrated to dryness. The residue was purified by column chromatography on silica gel to give crystals. Recrystallization from ethyl acetate-benzene afforded colorless crystals 2-ethoxy-1-[[2'-(Ntriphenylmethyltetrazol-5-yl)biphenyl-4-yl]-methyl]benzimidazole-7-carboxylic acid (2.12 g, 66%), M.P. 168-170°C. To a solution 2-ethoxy-1-[[2'-(N-triphenylmethyltetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (0.5 g) in DMF (5 ml) were added potassium carbonate (0.12 g) and cyclohexyl 1-iodoethyl carbonate (0.26 g). The mixture was stirred at room temperature for 1 hour. To the mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried. After removal of the solvent, the

802

Candicidin

residue was dissolved in methanol (10 ml) and to solution was added 1 N HCl (2 ml). The mixture was stirred at room temperature for 1 hour. After removal of the solvent, the residue was purified by column chromatography on silica gel to give colorless powder (0.21 g), M.P. 103-106°C. The mixture was stirred for 3 hours at room temperature. To the powder (1 g) obtained as above was added ethanol (6 ml). The mixture was stirred for 3 hours at room temperature and allowed to stand under ice-cooling. The mixture was then stirred for 1 hour at temperature not higher than 10°C. Resultant crystals were collected and washed with cold ethanol. The crystals were dried at 25°C for 9 hours under reduced pressure, then at 35°C for further 18 hours to obtain white powdery crystal 1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-benzimidazole-7-carboxylate (0.94 g, M.P. 158-166°C). References Naka T., Nishikawa K., Kato T.; US Patent No. 5,196,444; 03.23.1993; Assigned to Takeda Chemical Industries, Ltd.

CANDICIDIN Therapeutic Function: Topical antifungal Chemical Name: Heptaene macrolide antibiotic Common Name: Structural Formula:

Chemical Abstracts Registry No.: 1403-17-4 Trade Name

Manufacturer

Country

Year Introduced

Candeptin

Schmidt

US

1964

Candimon

Averst

US

-

Prostatin

Schmidt

US

-

Vanobid

Merrell Dow

US

-

Candicidin

803

Raw Materials Yeast-glucose medium Streptomyces Griseus No. 3570 bacterium Manufacturing Process Hubert Lechevalier et al were the first to describe "Candicidin, a New Antifungal Antibiotic," in Mycologia XLV, No. 2, 155-171, March-April 1953. They produced candicidin by growing a culture of the organism streptomyces griseus No. 3570 on a yeast-glucose medium, isolating a "crude candicidin" from the resulting broth and purifying it. An improved extraction and purification method is described in US Patent 2,872,373 and is shown in the flow diagram below.

804

Canrenoate potassium

Another extraction and separation process is described in US Patent 2,992,162. References I.N. p. 178 REM p. 1226 Siminoff, P.; US Patent 2,872,373; February 3, 1959; assigned to S.B. Penick and Company, Inc. Waksman, S.A. and Lechevalier, H.A.; US Patent 2,992,162; July 11, 1961; assigned to Rutgers Research and Educational Foundation

CANRENOATE POTASSIUM Therapeutic Function: Aldosterone antagonist, Diuretic Chemical Name: 17-Hydroxy-3-oxo-17α-pregna-4,6-diene-21 carboxylic acid potassium salt Common Name: Structural Formula:

Chemical Abstracts Registry No.: 2181-04-6; 976-71-6 (Canrenone base) Trade Name

Manufacturer

Country

Year Introduced

Spiroctan

Switz.

1968

Soldactone

Boehringer Mannheim Diethelm

Switz.

1968

Osyrol

Hoechst

W. Germany

1968

Soludactone

Searle

France

1971

Venactone

Lepetit

Italy

1978

Spiroctan-M

MCP Pharm.

UK

1981

Soldacton

Dainippon

Japan

1981

Capecitabine

805

Trade Name

Manufacturer

Country

Year Introduced

Aldactone

W. Germany

-

Aldatense

Boehringer Mannheim Searle

France

-

Aldatense

SPA

Italy

-

Phanurane

Specia

France

-

Sincomen

Schering

W. Germany

-

Soldactone

Searle

US

-

Raw Materials 17α-Carboxyethyl-17β-hydroxyandrost 4-en-3-one lactone Chloranil Manufacturing Process The lactone is prepared as follows: A solution of 5 parts of 17α-carboxyethyl17β-hydroxyandrost-4-en-3-one lactone and 5 parts of chloranil in 400 parts of xylene containing a trace of p-toluenesulfonic acid is heated at the boiling point of the solvent under reflux overnight. The solution is then cooled and filtered through approximately 200 parts of silica gel. The gel is successively washed with 5%, 10%, and 15% ethyl acetate-benzene solutions, and the washings comprising 15% ethyl acetate are thereupon purified by chromatography on a further quantity of silica gel, using benzene and ethyl acetate as developing solvents. From the 15% ethyl acetate eluate there is obtained pure 17α-carboxyethyl-17β-hydroxyandrost-4,6-dien-3-one lactone, melting at 148° to 151°C. The product solidifies above this melting point and melts again at 165°C. References Merck Index 1726 Kleeman and Engel p. 507 OCDS Vol. 2 p. 174 (1980) DOT 12 (2)45 (1976) I.N. p. 178 Cella, J.A.; US Patent 2,900,383; August 18, 1959; assigned to G.D. Searle and Co.

CAPECITABINE Therapeutic Function: Antitumor Chemical Name: 5'-Deoxy-5-fluoro-N4-(4-(n-pentyloxy)carbonyl)cytidine Common Name: Capecitabine Chemical Abstracts Registry No.: 154361-50-9; 158798-73-3

806

Capreomycin

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Xeloda

Hoffmann - La Roche Inc.

USA

-

Raw Materials 2',3'-Bis-O-(tert-butyldimethylsilyl)-5'-deoxy-5-fluorocytidine n-Pentylchloroformate Tetrabutylammonium fluoride Manufacturing Process 5-Deoxy-5-fluoro-N4-((n-pentyloxy)carbonyl)cytidine may be prepared according to US Patent No. 6,114,520. From 2',3'-bis-O-(tert-butyldimethylsilyl)-5'-deoxy-5-fluorocytidine and npentylchloroformate in dichloromethane and pyridine may be obtained 2',3'bis-O-(tert-butyldimethylsilyl)-5'-deoxy-5-fluoro-N4-((pentyloxy)carbonyl) cytidine.From 2',3'-bis-O-(tert-butyldimethylsilyl)-5'-deoxy-5-fluoro-N4((pentyloxy)carbonyl)cytidineand tetrabutylammonium fluoride in tetrahydrofuran at room temperature for 2 hours may be prepared the product which by hydrolyses may be converted to 5-deoxy-5-fluoro-N4((pentyloxy)carbonyl)cytidine. Purification of the product may be carried out by silica gel chromatography (using dichloromethane:methanol = 20:1 as an eluent). References Hattory K. et al.; US Patent No. 6,114,520; Sep. 5, 2000; Assigned to Hoffmann-La, RocHe Inc. Fujii M. et al.; US Patent No. 4,966,891, Oct. 30, 1990; Assigned to Hoffmann-La, RocHe Inc.

CAPREOMYCIN Therapeutic Function: Antibacterial, Antitubercular

Capreomycin

807

Chemical Name: Mixture of Capreomycin I A with Capreomycin I B and small quantities of Capreomycin II A and II B Common Name: Capreomicina, Capreomycin, Capromycin Structural Formula:

Chemical Abstracts Registry No.: 11003-38-6 Trade Name

Manufacturer

Country

Year Introduced

Capastat

Dista

-

-

Capastat

Eli Lilly

-

-

Raw Materials Culture of NRRL 2773 Vegetative culture medium (Soluble starch, Peptones, Beef extract, Sodium chloride, Yeast extract, water) Manufacturing Process Preparation of Capreomycin

808

Capreomycin

A culture of NRRL 2773 is produced by growing the organism on a nutrient agar slant having the following composition: Tomato paste 20 g, Pre-cooked oatmeal 20 g, Agar 15 g and tap water up to 1 L. The slant is inoculated for 10 days at about 30°C. The culture growth on the slant is covered with 6 ml of nutrient broth, and the slant is scraped gently to remove the organisms to provide an aqueous suspension. Employing aseptic techniques, the inocolum obtained is used to inoculate a 2 L Erlenmeyer flask containing a 500 ml portion of a sterilized vegetative culture medium having the following composition: Soluble starch 10 g, Peptones 5 g, Beef extract 5 g, Sodium chloride 5 g, Yeast extract 2.5 g and tap water 1100 ml. The incubation is carried out at 28°C for 48 hours; during which time the flasks are shaken at the rate of 250 cycles per minute on a rotary shaker having a 1-inch stroke. To produce a larger quantity of vegetative inocolum, 500 ml of the vegetative inocolum is added aseptically to a stainless steel 350-gallon fermentation tank containing 250 gallons of sterile medium having following composition (weight/volume): Glucose 1.5%, Yeast 1.5%, Antifoam ("Polyglycol No 2000" sold by Dow Chemical Co) 0.02%. The inoculum is allowed to grow for 22 hours at 30°C. Throughout the growth period, the medium is aerated with sterile air at the rate of 17 cubic feet per minute and is agitated with 16-inch impeller rotating at 160 revolution per minute. To a 1700-gallon stainless steel fermentor are added 1100 gallons of a medium having following composition (weight/volume): Glucose 2.5%, Molasses 1.0%, Peptones 4.0%, Calcium carbonate 0.2%, Hydrolyzed casein 0.6%, Antifoam ("Polyglycol No 2000" sold by Dow Chemical Co) 0.005%. The medium after sterilization is inoculated with 100 gallons of the inoculum grown in the fermentation tank. The fermentation is carried on at 30°C for 5 days. The foam is controlled by the addition, when needed, of "Larex No 1" (an antifoam product sold by Swift and Co.). Throughout the fermentation, the medium is aerated with sterile air at the rate of 17 cubic feet per minute and is agitated with 22-inch impeller rotating at 140 revolution per minute. At the end of the fermentation, 240 pounds of "Dicalite 476" (a perlite filler product sold by Great Lakes Carbon Corporation) are added 1000 gallons or the antibiotic broth, and the mixture is stirred and filtered. The filter cake is washed with tap water and the filtrates are combined to provide a total volume of 1000 gallons. To 500 gallons of the combined liquids are added 132 pounds of "Darco G-60". The mixture is filtered, and the filtrate is discarded. The carbon filter cake is washed with 200 L of tap water, the wash water being discarded. The washed carbon cake on which the capreomycin is adsorbed is washed with 200 L of 0.05 N aqueous hydrochloric acid. The acid wash is discarded. The washed carbon cake is eluted during a one-hour period with 400 L of an aqueous acetone containing 1.65 L of 11.7 N hydrochloric acid and 80 L of acetone. The filter cake is further eluted by washing the cake with 200 L of an aqueous acetone containing 825 ml of 11.7 N hydrochloric acid and 40 L of acetone during a 15-minute period. The combined eluates, having a total volume 575 L, are concentrated in vacuo to 52.5 L. The concentrate is added

Capreomycin sulfate

809

with stirring to 525 L of acetone and the acetone mixture is permitted to stand overnight at room temperature, during which time an oily precipitate of capreomycin separates. The supernatant is decanted and discarded, and the oily precipitate which remains is dissolved in 20 L of distilled water. The aqueous solution is filtered. The filtrate is added to 240 L of methanol. The methanolic solution is acidified by the addition of 1 L of 10 N sulfuric acid, whereupon the precipitation of the capreomycin disulfate commences. The mixture is permitted to stand overnight. The supernant is removed by decantation and filtering. The precipitate is washed with 10 L of methanol, yield Capreomycin 2510 g. References Herr E.B. et al.; US Patent No. 3,143,468; 04.08.1964; Assigned to Eli Lilly and Company; W.S. Marsh et al.; US Patent No. 2,633,445; 31.03.1953; Assigned to Ciba Pharm. Products

CAPREOMYCIN SULFATE Therapeutic Function: Antitubercular Chemical Name: Cyclic polypeptide antibiotic Common Name: Caprolin Structural Formula:

Chemical Abstracts Registry No.: 1405-37-4 Trade Name

Manufacturer

Country

Year Introduced

Capastat

Lilly

UK

1966

810

Capreomycin sulfate

Trade Name

Manufacturer

Country

Year Introduced

Capastat

Serum Impfinst.

Switz.

1967

Ogostac

Lilly

W. Germany

1967

Capastat

Lilly

US

1971

Capastat

Lilly

Italy

1973

Capastat

Shionogi

Japan

-

Raw Materials Glucose Culture of NRRL 2773 Manufacturing Process A culture of NRRL 2773 is produced by growing the organism on a nutrient agar slant having the following composition: Oatmeal-Tomato Paste Agar

Tomato paste Precooked oatmeal Agar

Grams 20 20 15

Tap water, added to make a final volume of 1 liter. The slant is inoculated with spores of NRRL 2773 and is incubated for 10 days at about 30°C. The culture growth on the slant is covered with 6 ml of nutrient broth, and the slant is scraped gently to remove the organisms to provide an aqueous suspension. Employing aseptic techniques, the inoculum obtained from one 1-inch agar slant is used to inoculate a 2-liter Erlenmeyer flask containing a 500-ml portion of a sterilized vegetative culture medium having the following composition: soluble starch, 10 g; peptones, 5 g; beef extract, 5 g; sodium chloride, 5 g; yeast extract, 2.5 g; and tap water, 1,100 ml. The incubation is carried on at 28°C for 48 hours with shaking at 250 cycles per minute on a rotary shaker having a 1-inch stroke. To produce a larger quantity of vegetative inoculum, 500 ml of the vegetative inoculum is added aseptically to a stainless steel 350-gallon fermentation tank containing 250 gallons of sterile medium having the following composition (weight/volume): glucose, 1.5%; yeast, 1.5%; and antifoam (Polyglycol No. 2000, Dow Chemical Co.), 0.02%. The inoculum is allowed to grow for about 22 hours at a temperature of 30°C. Throughout the growth period, the medium is aerated with sterile air at the rate of 17 cfm and is agitated with two 16-inch impellers rotating at 160 revolutions per minute. To a 1,700gallon stainless steel fermentor are added 1,100 gallons of a medium having the following composition (weight/volume): Peptone No. 159 Medium

Capreomycin sulfate

Glucose Molasses Peptones Calcium carbonate Hydrolyzed casein

811

Percent 2.5 1.0 4.0 0.2 0.6

Antifoam (Polyglycol No. 2000, Dow Chemical Co.) 0.005 The medium after sterilization is inoculated with 100 gallons of the inoculum grown in the fermentation tank. The fermentation is carried on at 30°C for about five days. The foam is controlled by the addition, when needed, of Larex No. 1 (an antifoam product, Swift and Co.). Throughout the fermentation, the medium is aerated by the addition of sterile air at the rate of 96 cfm and is agitated with two 22-inch impellers operated at 140 revolutions per minute. At the end of the fermentation, 240 lb of Dicalite 476 (a perlite filter product, Great Lakes Carbon Corporation) are added to 1,000 gallons of the antibiotic broth, and the mixture is stirred and filtered. The filter cake is washed with tap water and the wash water and the filtrate are combined to provide a total volume of 1,000 gallons. To 500 gallons of the combined liquids are added 132 lb of Darco G-60. The mixture is stirred thoroughly and filtered, and the filtrate is discarded, The carbon filter cake is washed with 200 liters of tap water, the wash water being discarded. The washed carbon cake on which the capreomycin is adsorbed is further washed with 200 liters of 0.05 N aqueous hydrochloric acid. The acid wash is discarded. The washed carbon cake is eluted during a one-hour period with 400 liters of an aqueous acetone mixture containing 1.65 liters of 11.7 N hydrochloric acid and 80 liters of acetone. The filter cake is further eluted by washing the cake with 200 liters of an aqueous acetone mixture containing 825 ml of 11.7 N hydrochloric acid and 40 liters of acetone during a 15minute period. The combined eluates, having a total volume of 575 liters, are concentrated in vacuo to 52.5 liters. The concentrate is added with stirring to 525 liters of acetone and the acetone mixture is permitted to stand overnight at room temperature, during which time an oily precipitate of capreomycin separates. The supernatant is decanted and discarded, and the oily precipitate which remains is dissolved in 20 liters of distilled water. The aqueous solution is concentrated in vacuo to 12 liters to remove any residual acetone. The aqueous concentrate containing capreomycin is filtered to remove a small amount of a precipitate, which is discarded. The filtrate containing the capreomycin is added to 240 liters of methanol with stirring. The methanolic solution of capreomycin is acidified by the addition of one liter of 10 N sulfuric acid, whereupon the precipitation of the sulfuric acid addition salt of capreomycin commences. The mixture is permitted to stand overnight for more complete precipitation. The supernatant is removed by decanting and filtering. The precipitate, consisting of the capreomycin disulfate, is washed with 10 liters of methanol and is dried in vacuo. Yield: 2,510 grams.

812

Captodiamine

References Merck Index 1732 Kleeman and Engel p. 141 PDR p. 1039 DOT 1 (1) 33 (1965) I.N. p. 179 REM p. 1202 Herr, E.B., Jr., Hamill, R.L. and McGuire, J.M.; US Patent 3,143,468; August 4, 1964; assigned to Eli Lilly and Company

CAPTODIAMINE Therapeutic Function: Sedative Chemical Name: 2-[[[4-(Butylthio)phenyl]phenylmethyl]thio]-N,Ndimethylethanamine Common Name: Captodiam; Captodramine Structural Formula:

Chemical Abstracts Registry No.: 486-17-9; 904-04-1 (Hydrochloride salt) Trade Name Covatine Suvren Covatix

Manufacturer Bailly Ayerst Lundbeck

Country France US Denmark

Year Introduced 1958 1958 -

Raw Materials Thiourea Sodium hydroxide Diethylaminoethyl chloride

4-Butylmercaptobenzhydryl chloride Sodium

Manufacturing Process p-Butylmercaptobenzhydryl chloride was boiled with thiourea in alcohol

Captopril

813

thereby yielding p-butylmercaptobenzhydrylisothiouronium chloride which was then subjected to hydrolysis with dilute aqueous sodium hydroxide solution whereupon p-butylmercaptobenzhydryl mercaptan was formed. p-Butylmercaptobenzhydryl mercaptan (28.5 g) was added to a solution of sodium (2.3 g) in absolute alcohol (75 ml), followed by the addition of a solution of diethylaminoethyl chloride (13.6 g) in toluene (50 ml). The mixture was boiled on a steam bath for 3 hours and the sodium chloride which separated out was removed by filtration. The filtrate was concentrated to onethird of its volume and dissolved in ether. The ether solution was shaken with 2N hydrochloric acid (100 ml), and the resulting middle oily layer was separated, dissolved in water and the resulting aqueous solution was washed with ether, then treated with aqueous sodium hydroxide solution to precipitate an oil. The latter was dissolved in ether, dried with anhydrous potassium carbonate, filtered and then treated with anhydrous hydrogen chloride whereupon the desired p-butylmercaptobenzhydryl 2-diethylaminoethyl sulfide hydrochloride precipitated as a white, crystalline substance which was filtered and dried in a desiccator. The melting point of the product was 124°C. References Merck Index 1746 Kleeman and Engel p. 141 OCDS Vol. 1 p. 44 (1977) I.N. p. 179 Hubner, O.F. and Petersen, P.V.; US Patent 2,830,088; April 8, 1958

CAPTOPRIL Therapeutic Function: Antihypertensive Chemical Name: 1-(3-Mercapto-2-D-methylpropanoyl)-L-proline Common Name: Structural Formula:

Chemical Abstracts Registry No.: 62571-86-2 Trade Name

Manufacturer

Country

Year Introduced

Lopirin

Von Heyden

W. Germany

1980

814

Captopril

Trade Name

Manufacturer

Country

Year Introduced

Capoten

Squibb

US

1981

Lopirin

Squibb

Switz.

1981

Capoten

Squibb

UK

1981

Capoten

Squibb

Italy

1981

Lopril

Squibb

France

1982

Captoril

Sankyo

Japan

1983

Dilabar

Vita

Spain

-

Isopresol

Elea

Argentina

-

Raw Materials L-Proline Benzyloxycarbonyl chloride Ammonia Trifluoroacetic acid

Isobutylene Hydrogen 3-Acetylthiomethyl propanoic acid

Manufacturing Process The first step is the manufacture of L-proline tert-butyl ester. L-proline (230 g) is dissolved in a mixture of water (1 l) and 5 N sodium hydroxide (400 ml). The solution is chilled in an ice bath, and under vigorous stirring, 5 N sodium hydroxide (460 ml) and benzyloxycarbonyl chloride (340 ml) are added in five equal aliquots during a half-hour period. After one hour stirring at room temperature, the mixture is extracted twice with ether and acidified with concentrated hydrochloric acid. The precipitate is filtered and dried. Yield is 442 g; MP 78°C to 80°C. The benzyloxycarbonyl-L-proline thus obtained (180 g) is dissolved in a mixture of dichloromethane (300 ml), liquid isobutylene (800 ml) and concentrated sulfuric acid (7.2 ml). The solution is shaken in a pressure bottle for 72 hours. The pressure is released, the isobutylene is allowed to evaporate and the solution is washed with 5% sodium carbonate, water, dried over magnesium sulfate and concentrated to dryness in vacuo, to obtain benzyloxycarbonyl-L-proline tert-butyl ester, yield 205 g. Benzyloxycarbonyl-L-proline tert-butyl ester (205 g) is dissolved in absolute ethanol (1.2 l) and hydrogenated at normal pressure with 10% Pd on carbon (10 g) until only a trace of carbon dioxide is observed in the hydrogen exit gas (24 hours). The catalyst is filtered off and the filtrate is concentrated in vacuo at 30 mm Hg. The residue is distilled in vacuo, to obtain L-proline tertbutyl ester, BP1mm 50°C to 51°C. The next step yields 1-(3-acetylthio-2-methylpropanoyl)-L-proline tert-butyl ester. L-proline tert-butyl ester (5.1 g) is dissolved in dichloromethane (40 ml) and the solution stirred and chilled in an ice bath. Dicyclohexylcarbodiimide (15 ml) is added followed immediately by a solution of 3-acetylthio-2methylpropanoic acid (4.9 g) in dichloromethane (5 ml). After 15 minutes stirring in the ice bath and 16 hours at room temperature, the precipitate is filtered off and the filtrate is concentrated to dryness in vacuo. The residue is dissolved in ethyl acetate and washed neutral. The organic phase is dried over

Caramiphen edisylate

815

magnesium sulfate and concentrated to dryness in vacuo. The residue 1-(3acetylthio-2-methylpropanoyl)-L-proline tert-butyl ester is purified by column chromatography (silica gel-chloroform), yield 7.9 g. Then, 1-(3-acetylthio-2-methylpropanoyl)-L-proline is produced. The 1-(3acetylthio-3-methylpropanoyl)-L-proline tert-butyl ester (7.8 g) is dissolved in a mixture of anisole (55 ml) and trifluoroacetic acid (110 ml). After one hour storage at room temperature the solvent is removed in vacuo and the residue is precipitated several times from ether-hexane. The residue (6.8 g) is dissolved in acetonitrile (40 ml) and dicyclohexylamine (4.5 ml) is added. The crystalline salt is boiled with fresh acetonitrile (100 ml), chilled to room temperature and filtered, yield 3.8 g, MP 187°C to 188°C. This material is recrystallized from isopropanol [α]D-67° (C 1.4, EtOH). The crystalline dicyclohexylamine salt is suspended in a mixture of 5% aqueous potassium bisulfate and ethyl acetate. The organic phase is washed with water and concentrated to dryness. The residue is crystallized from ethyl acetate-hexane to yield the 1-(3-acetylthio-2-D-methylpropanoyl)-L-proline, MP 83°C to 85°C. Finally, Captopril is produced. The thioester (0.85 g) is dissolved in 5.5 N methanolic ammonia and the solution is kept at room temperature for 2 hours. The solvent is removed in vacuo and the residue is dissolved in water, applied to an ion exchange column on the H+ Cycle (Dowex 50, analytical grade) and eluted with water. The fractions that give positive thiol reaction are pooled and freeze dried. The residue is crystallized from ethyl acetate-hexane, yield 0.3 g. The 1-(3-mercapto-2-D-methylpropanoyl)-L-proline has a melting point of 103°C to 104°C. References Merck Index 1747 DFU 3 (11) 795 (1978) Kleeman and Engel p. 142 PDR p. 1736 OCDS Vo1.3 p. 128 (1984) DOT 17 (6) 233 (1981); 18 (10) 554 (1982) I.N. p. 180 REM p. 850 Ondetti, M.A. and Cushman, D.W.; US Patent 4,046,889; September 6, 1977; assigned to E.R. Squibb and Sons, Inc. Ondetti, M.A. and Cushman, D.W.; US Patent 4,105,776; August 8, 1978; assigned to E.R. Squibb and Sons, Inc. Ondetti, M.A. and Cushman, D.W.; US Patent 4,154,840; May 15,1979; assigned to E.R. Squibb and Sons, Inc.

CARAMIPHEN EDISYLATE Therapeutic Function: Antitussive Chemical Name: 1-Phenylcyclopentanecarboxylic acid 2-(diethylamino)-ethyl ester 1,2-ethanedisulfonate

816

Caramiphen edisylate

Common Name: Structural Formula:

Chemical Abstracts Registry No.: 125-86-0 Trade Name

Manufacturer

Country

Year Introduced

Panparnit

Geigy

US

1949

Toryn

Smith Kline

US

1953

Tuss-Ade

Schein

US

-

Tuss-Ornade

Smith Kline

US

-

Raw Materials 1-Phenylcyclopentyl-1-carboxylic acid chloride Diethylaminoethanol Ethanedisulfonic acid Manufacturing Process 20.8 parts of 1-phenylcyclopentyl-1-carboxylic acid chloride, obtained from the acid (cf. Am. Soc. 1934, 56, 715) by means of thionyl chloride, are dissolved in 250 parts by volume of absolute ether, then, while stirring and cooling with a mixture of common salt and ice a solution of 12 parts of diethylaminoethanol in 50 parts by volume of absolute ether is allowed to drop there into, the temperature being maintained below 0°C, whereupon stirring is continued during 2 hours at room temperature. The whole is then twice shaken out with water and once with diluted hydrochloric acid, the combined aqueous solutions are made alkaline with a potassium carbonate solution and shaken out with ether. The ethereal solution is washed with water, dried over potassium carbonate and the solvent is distilled off. The base boils at a pressure of 0.07 mm at 112°C to 115°C.

Carazolol

817

The base may then be converted to the hydrochloride or to the ethanedisulfonic acid salt (edisylate). References Merck Index 1750 PDR pp. 1606,1730 OCDS Vol. 1 pg. 90 (1977) I.N. p. 180 Martin, H. and Hafliger, F.; US Patent 2,404,588; July 23, 1946; assigned to J.R. Geigy A.G. (Switzerland)

CARAZOLOL Therapeutic Function: Beta-adrenergic blocker Chemical Name: 4-(3-Isopropylamino-2-hydroxypropoxy)carbazole Common Name: Structural Formula:

Chemical Abstracts Registry No.: 57775-29-8 Trade Name

Manufacturer

Country

Year Introduced

Conducton

Klinge

W. Germany

1980

Raw Materials Hydroxycarbazole Epichlorohydrin Isopropylamine Manufacturing Process The 4-(2,3-epoxypropoxy)carbazole used as starting material is prepared as follows. A solution of 16.3 g 4-hydroxycarbazole in a mixture of 190 ml dioxan and 98 ml 1 N sodium hydroxide is, after the addition of 66 ml epichlorohydrin, stirred for 2 hours at 40°C to 45°C. The reaction mixture is

818

Carbachol

then diluted with water and shaken out with methylene chloride. The methylene chloride phase is washed with water, dried over anhydrous sodium sulfate and evaporated. There are obtained 16.8 g 4-(2,3epoxypropoxy)carbazole. A solution of 3.5 g 4-(2,3-epoxypropoxy)carbazole in 50 ml absolute alcohol is mixed with 30 ml isopropylamine and heated for 3 hours under reflux. When the reaction is finished, the reaction mixture is evaporated to dryness. The residue obtained is taken up in methylene chloride and chromatographed over an aluminum oxide column (300 g basic aluminum oxide, activity stage IV; eluent methylene chloride). The eluted fractions are evaporated and the residue is dissolved in methanol and acidified with 2 N ethereal hydrochloric acid. The precipitate obtained is filtered off and recrystallized from methanol. There are obtained 3.1 g (62% of theory) 4-(3-isopropylamino-2-hydroxypropoxy) carbazole hydrochloride; MP 234°C to 235°C. References Merck Index 1753 DFU 2 (11) 715 (1977) Kleeman and Engel p. 143 DOT 17 (2) 53 (1981) and 18 (10) 551 (1982) I.N. p. 180 Boehringer Mannheim GmbH; British Patent 1,369,580; October 9, 1974

CARBACHOL Therapeutic Function: Cholinergic Chemical Name: 2-[(Aminocarbonyl)oxy]-N,N,N-trimethyl-ethanaminium chloride Common Name: Carbocholine Structural Formula:

Chemical Abstracts Registry No.: 51-83-2 Trade Name Miostat Atonyl

Manufacturer Alcon Ferrosan

Country US Denmark

Year Introduced 1979 -

Carbachol

819

Trade Name

Manufacturer

Country

Year Introduced

Cacholitin

Vaise

Denmark

-

Carbacel

Warner Lambert

US

-

Carbamiotin

Tilden Yates

US

-

Carbyl

Tubi Lux Pharma

Italy

-

Carcholin

Merck Sharp and Dohme

US

-

Doryl

Merck

W. Germany

-

Iricoline

Lematte/Boinot

France

-

Isopto-Carbachol

Alcon

US

-

Jestryl

Ankerwerk

E. Germany

-

Lentin

Merck

W. Germany

-

Lentivasan

Kwizda

Austria

-

Mistura

Lederle

US

-

Moryl

Savory and Moore UK

-

Oftan-Karbakol

Star

Finland

-

P.V. Carbachol

Allergan

US

-

Rilentol

Richter

Austria

-

Secretin

Streuli

Switz.

-

Spersacarbachol

Dispersa

Switz.

-

Tonocholin

A.F.I.

Norway

-

Raw Materials Choline chloride Phosgene Manufacturing Process About 14 g of choline chloride are stirred with a solution of about 20 g of phosgene in 100 g of chloroform for about two hours at room temperature. The mixture becomes a two-phase liquid mixture. Hydrochloric acid and excess phosgene are removed by distillation in vacuo. Chloroform is added to the syrup, and the mixture is then added to a solution of excess ammonia in chloroform which was cooled with solid carbon dioxide-acetone. The mixture is filtered, and the solid is extracted with hot absolute alcohol. The solid in the alcoholic solution is precipitated with ether, and filtered. It is recrystallized from a methyl alcohol-ether mixture; the carbaminoyl-choline chloride obtained has a melting point of about 208°-210°C. References Merck Index 1754 Kleeman and Engel p. 144 I.N. p. 180 REM p. 896

820

Carbadox

Major, R.T. and Bonnett, H.T.; US Patent 2,374,367; April 24, 1945; assigned to Merck and Co., Inc.

CARBADOX Therapeutic Function: Antibacterial Chemical Name: Hydrazinecarboxylic acid, (2-quinoxalinylmethylene)-, methyl ester, N,N'-dioxide Common Name: Carbadox; Enterodox; Getroxel Structural Formula:

Chemical Abstracts Registry No.: 6804-07-5 Trade Name

Manufacturer

Country

Year Introduced

Carbadox

Agrimex

-

-

Carbadox

Intraco LTD

-

-

Carbadox

Impextraco

-

-

Carbamix

Zineb

-

-

Enterodox

Orffa

-

-

Enterodox

Dox-Al Australia PTY Ltd.

-

-

Addi-dox

Addi-tech BVBA

-

-

Mecadox

Orffa

-

-

Mecadox

Pfizer Inc.

-

-

Raw Materials Methylcarbazate 2-Formylquinoxaline-1,4-dioxide Manufacturing Process A solution of methylcarbazate (48.0 mg) in methanol (250 ml) is added all at once at room temperature to a well stirred solution of 2-formylquinoxaline1,4-dioxide (100 g) in methanol (2.5 liters). Two drops of concentrated hydrochloric acid are added. The mixture is stirred for 3 hours then filtered to

Carbamazepine

821

remove the yellow crystalline product. The crystals of (2quinoxalinylmethylene)hydrazinecarboxylic acid methyl ester are washed with methanol then air dried; M.P. 234.5-236°C (dec.). Yield=121.8 g. The product is purified by refluxing in chloroform for 2 hours, followed by filtration and air drying; M.P. 239.5-240°C (dec.). The ultraviolet absorption spectrum (water) exhibits maxima at 236, 251, 303, 366 and 373 nm with extinction coefficients of 11,000, 10,900, 36,400, 16,100 and 16,200, respectively. References James David Johnston, Old Saybrook; US Patent No. 3,433,871; Mar. 18, 1962; Assigned to Chas. Pfizer and Co., Inc., New York, N.Y., a corporation of Delaware

CARBAMAZEPINE Therapeutic Function: Analgesic, Anticonvulsant Chemical Name: 5H-Dibenz[b,f]azepine-5-carboxamide Common Name: 5-Carbamyl iminostilbene Structural Formula:

Chemical Abstracts Registry No.: 298-46-4 Trade Name

Manufacturer

Country

Year Introduced

Tegretol

Geigy

W. Germany

1964

Tegretol

Geigy

UK

1964

Tegretol

Geigy

France

1964

Tegretol

Geigy

US

1968

Tegretol

Geigy

Italy

1972

Biston

Spofa

Czechoslovakia

-

Convuline

Protea

Australia

-

Finlepsin

Arzneimittelwerk Dresden

E. Germany

-

822

Carbamazepine

Trade Name

Manufacturer

Country

Year Introduced

Hermolepsin

Laake

Finland

-

Lexin

Fujinaga

Japan

-

Mazepine

ICN

Canada

-

Neuritol

Eczacibasi

Turkey

-

Neurotol

Farmos

Finland

-

Nordotol

Farmos

Finland

-

Servimazepine

Servipharm

Switz.

-

Stazepine

Polfa

Poland

-

Telesmin

Yoshitomi

Japan

-

Temporol

Orion

Finland

-

Teril

Taro

Israel

-

Timonil

Desitin

W. Germany

-

Raw Materials Iminostilbene Phosgene Ammonia Manufacturing Process 19.3 parts of iminostilbene are dispersed in 100 parts by volume of toluene. Phosgene is then introduced whereupon the temperature of the reaction mixture rises to 70°C. While boiling under reflux, further phosgene is introduced until all the iminostilbene has dissolved and the hydrogen chloride development is complete. The reaction mixture is then cooled and the 5chlorocarbonyl iminostilbene which has crystallized out is filtered off under suction. It melts at 168° to 169°C. 12.8 parts of 5-chlorocarbonyl iminostilbene are dispersed in 128 parts by volume of absolute ethanol and ammonia gas is introduced for three hours into this mixture while stirring at boiling temperature. The reaction is complete after this time; the reaction mixture is cooled and the crystals which precipitate are filtered off under suction. The ammonium chloride is washed from the crystals with water and the residue is recrystallized first from absolute ethanol and then from benzene. 5-carbamyl iminostilbene is obtained which melts at 204° to 206°C. References Merck Index 1758 Kleeman and Engel p. 144 PDR p. 900 OCDS Vol. 1 p. 403 (1977) DOT 1 (3) 82 (1965) I.N. p. 181 REM p. 1077 Schindier, W.; US Patent 2,948,718; August 9, 1960; assigned to Geigy Chemical Corporation

Carbaspirin calcium

823

CARBASPIRIN CALCIUM Therapeutic Function: Analgesic, Antipyretic, Antirheumatic Chemical Name: 2-(Acetyloxy)benzoic acid calcium salt Common Name: Calcium aspirin; Calcium acetylsalicylate Structural Formula:

Chemical Abstracts Registry No.: 69-46-3 Trade Name

Manufacturer

Country

Year Introduced

Calurin

Dorsey

US

1959

Iromin

Iromedica

Switz.

-

Soluspan

UPSA

France

1983

Iromin

Omegin

W. Germany

-

Fiogesic

Sandoz

US

-

Ursinus

Dorsey

US

-

Raw Materials Acetylsalicylic acid Calcium carbonate Manufacturing Process 500 g of finely powdered acetylsalicylic acid and 160 g of calcium carbonate (precipitated chalk), are intimately mixed and 3,000 cc of water are added. The mixture is stirred for 15 minutes or until the reaction is completed, which is indicated by the cessation of the liberation of carbon dioxide. The temperature is desirably maintained below 20°C by any suitable means. The mass is allowed to settle until the supernatant liquor is almost clear; this usually takes about 5 minutes, and the mixture is then filtered to remove unreacted material. This part of the process is carried out as quickly as possible so as to minimize any tendency of the calcium aspirin to hydrolyze in the solution. The filtrate is cooled to about 10°C and 1 to 1.5 volumes of 97%

824

Carbazochrome

methanol, or pure wood alcohol is added. This causes the calcium aspirin to precipitate and the mass is then filtered to remove as thoroughly as possible the mother liquor. The residue of calcium aspirin is then suspended in a quantity of methanol equivalent to the volume previously used as a precipitant, and it is allowed to stand there for one hour or more with occasional or continuous agitation. The mass is again filtered, the filtrate being employed for the precipitation of calcium aspirin in a later batch. After the filtering of the first wash liquor, the calcium aspirin is again suspended in another quantity of methanol of an equivalent volume. This constitutes the second wash and it is carried out in the same way as the first wash. The filtrate is employed as a first wash in a later batch and this filtrate in turn is used, as is the filtrate of the first wash, for the precipitation of more calcium aspirin. Fresh alcohol is used as a new wash in a later batch and the washes are carried out in series. After the second wash the calcium aspirin is dried in a suitable manner, as by passing dry warm air over it, the temperature not being allowed to rise to such an extent as to decompose the aspirin; preferably the temperature is not permitted to rise above 50°C, but should be high enough to avoid deposition of water vapor, and the drying is completed when there is no longer an odor of methanol. References Merck Index 1615 Kleeman and Engel p. 145 PDR p. 1583 Lawrence, W.H., Jr.; US Patent 2,003,374; June 4, 1935; assigned to Lee Laboratories, Inc.

CARBAZOCHROME Therapeutic Function: Hemostatic Chemical Name: 3-Hydroxy-1-methyl-5,6-indolinedione semicarbazone Common Name: Adrenochrome Structural Formula:

Chemical Abstracts Registry No.: 69-81-8; 13051-01-9 (Salicylate)

Carbenicillin disodium

825

Trade Name

Manufacturer

Country

Year Introduced

Adrenosem

Beecham

US

1953

Adrestat

Organon

US

1957

Adrenoxyl

Labaz

France

1957

Adrenoxyl

Nordmark

W. Germany

-

Anaroxyl

Organon

US

-

Cromosil

Zambeletti

Italy

-

Cromoxin

R. Rius

Spain

-

Meronyl

Santen

Japan

-

Raw Materials Adrenalin Silver oxide Semicarbazide hydrochloride Manufacturing Process A suspension containing 1 part by weight of adrenalin and 2 to 6 parts by weight of silver oxide in 150 to 250 parts by weight of methanol or ethanol is stirred for about 10 minutes. The alcoholic adrenochrome solution obtained is separated by draining and the filtrate is quickly evaporated to dryness at low temperature and in vacuo. The red crystals of adrenochrome obtained are dissolved in 45 to 55 parts by weight of water. To this solution, 2 parts of sodium acetate dissolved in 2 to 3 parts of water and 2 parts of semicarbazide hydrochloride dissolved in 2 to 3 parts of water are added. The formed precipitate consisting of red-orange prismatic needles is separated by filtration and recrystallized from diluted ethanol. There is obtained 0.30 to 0.40 part by weight of adrenochrome monosemicarbazone dihydrate, melting at 203°C with decomposition. References Merck Index 1767, 1768 Kleeman and Engel p. 146 I.N. p. 182 REM p. 832 Dechamps, G., Le Bihan, H. and Baudet, C.; US Patent 2,506,794; May 2, 1950; assigned to Societe Belge de l'azote et des Produits Chimiques du Marly (Belgium)

CARBENICILLIN DISODIUM Therapeutic Function: Antibacterial Chemical Name: N-(2-Carboxy-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0]hept-6-yl)-2-phenylmalonamic acid sodium salt

826

Carbenicillin disodium

Common Name: Carboxybenzylpenicillin sodium salt Structural Formula:

Chemical Abstracts Registry No.: 4800-94-6; 4697-36-3 (Base) Trade Name

Manufacturer

Country

Year Introduced

Pyopen

Beecham

Switz.

1968

Pyopen

Beecham

UK

1968

Carindapen

Pfizer

W. Germany

1968

Pyopen

Beecham

US

1970

Geopen

Roerig

US

1970

Gripenin

Fujisawa

Japan

1970

Geopen

Pfizer Taito

Japan

1971

Pyocianil

Farmitalia

Italy

1972

Anabactyl

Beecham

W. Germany

-

Carbapen

C.S.L.

Australia

-

Carbecin

Beecham

-

-

Fugacillin

Astra

Sweden

-

Microcillin

Bayer

W. Germany

-

Rexcilina

Wolner

Spain

-

Raw Materials Phenylmalonic acid Benzyl alcohol Thionyl chloride 6-Amino penicillanic acid Hydrogen Sodium bicarbonate Manufacturing Process The required monobenzyl phenylmalonate, MP 68°C, was prepared by treating a mixture of phenylmalonic acid (18 g) and benzyl alcohol (13 g) in carbon tetrachloride (80 ml) with dry hydrogen chloride. Monobenzyl phenylmalonate (13.3 g) in dry benzene (100 ml) was refluxed

Carbenicillin indanyl sodium

827

with thionyl chloride (6.45 g) for 90 minutes, then concentrated in vacuo. The residual oil was dissolved in dry acetone (50 ml) and added to a stirred, icecooled solution of 6-aminopenicillanic acid (9.7 g) in N sodium bicarbonate solution (135 ml), water (150 ml), and acetone (300 ml). The mixture was stirred for 30 minutes at 0°C and then for 90 minutes at room temperature, then concentrated under reduced pressure to remove acetone. The aqueous solution was brought to pH 2 with dilute hydrochloric acid and extracted with ether (3 x 100 ml). The ether solution was washed with water and then itself extracted with sufficient N sodium bicarbonate solution to give an aqueous phase of pH 7.5. The aqueous layer was separated and evaporated at low temperature and pressure to leave the impure sodium salt of alpha(benzyloxycarbonyl) benzylpenicillin. This crude product (15.8 g) in water (360 ml) was added to a prehydrogenated suspension of 10% palladium on charcoal (4 g) in water (400 ml), and hydrogenation was continued for 30 minutes. The catalyst was removed and the filtrate was adjusted to pH 7.5 with sodium bicarbonate, then evaporated at low temperature and pressure. The residue was purified by chromatography on a column of cellulose powder, eluting first with butanol/ethanol/water mixture and then with acetone/isopropanol/water. The main fraction was evaporated at low temperature and pressure to give a 32% yield of the sodium salt of alpha-carboxybenzylpenicillin as a white powder. The product was estimated by monometric assay with penicillinase to be 58% pure. References Merck Index 1773 Kleeman and Engel p. 147 PDR p. 1404 OCDS Vol. 1 p. 414 (1977) and 2 p. 437 (1980) DOT 4 (3) 96 (1968) I.N. p. 183 REM p. 1194 Brain, E.G. and Nayler, J.H.C.; US Patents 3,282,926; November 1, 1966 and 3,492,291; January 27, 1970; both assigned to Beecham Group Limited, England

CARBENICILLIN INDANYL SODIUM Therapeutic Function: Antibacterial Chemical Name: N-(2-Carboxy-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0]hept-6-yl)-2-phenylmalonamic acid, 1-(5-indanyl ester), monosodium salt Common Name: Carindacillin; Indanylcarbenicillin Chemical Abstracts Registry No.: 26605-69-6; 35531-88-5 (Base)

828

Carbenicillin indanyl sodium

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Geocillin

Roerig

US

1972

Carindapen

Pfizer

W. Germany

1973

Geopen

Pfizer

Switz.

1973

Geopen-U

Pfizer Taito

Japan

1976

Unipen

Pfizer-Roerig

US

-

Urobac

Pfizer-Roerig

-

-

Raw Materials Phenylmalonic acid 6-Aminopenicillanic acid Triethylamine

5-Indanyl alcohol Phosphorus pentachloride

Manufacturing Process (A) Preparation of Phenylchlorocarbonyl Ketene: To phenylmalonic acid (20 g) in ethyl ether (100 ml) there is added phosphorus pentachloride (46 g). A vigorous reaction occurs. The reaction mixture is refluxed for 4 hours then the ether partially removed by heating on a steam bath. The reaction mixture becomes black when about half the ether is removed and the remaining ether is removed under reduced pressure (at 100 mm). The residue is distilled under vacuum and the fraction boiling at 75° to 90°C at 1.5 to 4 mm collected. The product, a yellow liquid, is redistilled at 74°C and 1.5 mm. It shows a strong peak in the infrared region of the spectrum at 4.69 mu. Repetition of this procedure but using 10 g of phenylmalonic acid instead of 20 g produces a less vigorous reaction on addition of the phosphorus pentachloride. The same product is obtained. (B) Acylation of 6-Aminopenicillanic Acid: To a solution of the aryl halocarbonyl ketene (0.1 mol) in methylene chloride (sufficient to provide a clear solution and generally from about 5 to 10 ml per gram of ketene) there is added the proper alcohol R2OH (0.1 mol), in this case 5-indanyl alcohol. The reaction mixture is maintained under an atmosphere of nitrogen and stirred for a period of from 20 minutes to 3 hours, care being taken to

Carbenoxolone

829

exclude moisture. The temperature may range from about -70° to about 20°C. The infrared spectrum of the mixture is then taken to determine and confirm the presence of the ketene ester. A solution of 6-aminopenicillanic acid-triethylamine salt (0.1 mol) in methylene chloride (50 ml) is added and the mixture stirred at -70° to -20°C for 10 minutes. The cooling bath is then removed and the reaction mixture stirred continuously and allowed to warm to room temperature. Various isolation methods are then spelled out in US Patent 3,679,801. References Merck Index 1823 Kleeman and Engel p. 155 PDR p. 1524 DOT 8 (8) 310 (1972 and 9 (4)128 (1973) I.N. p. 189 REM p. 1195 Butler,K.; US Patents 3,557,090; January 19, 1971; 3,574,189; April 6, 1971; and 3,679,801; July 25, 1962; all assigned to Chas. Pfizer and Co., Inc.

CARBENOXOLONE Therapeutic Function: Antiinflammatory (gastric) Chemical Name: 3β-Hydroxy-11-oxo-20β-olean-12-en-29-oic acid hydrogen butanedioate Common Name: Glycyrrhetinic acid hydrogen succinate Structural Formula:

Chemical Abstracts Registry No.: 5697-56-3; 7421-40-1 (Sodium salt)

830

Carbenoxolone

Trade Name

Manufacturer

Country

Year Introduced

Biogastrone

Winthrop

UK

1963

Biogastrone

Homburg

W. Germany

1970

Gastrausil

Italseber

Italy

1971

Biogastrone

Richardson-Merrell Switz.

1978

Biogastron

Shionogi

Japan

1979

Biogastrone

Abic

Israel

-

Bioral

Biorex, Berk

UK

-

Duogastrone

Merrell

France

-

Duogastrone

Abic

Israel

-

Karbenol

Yurtoglu

Turkey

-

Neogel

Homburg

W. Germany

-

Neutrogastrol Ulcus Pyrogastone

Septa

Spain

-

Winthrop

UK

-

Sanodin

Leo

Spain

-

Sustac

Sintyal

Argentina

-

Terulcon

ISF

Italy

-

Ulcofer

Mulda

Turkey

-

Ulcus-Tablinen

Sanorania

W. Germany

-

Ulkon

Eczacibasi

Turkey

-

Ventroxol

Medica

Finland

-

Raw Materials Glycyrrhetinic acid Succinic anhydride Manufacturing Process 23.5 g of glycyrrhetinic acid were dissolved in 50 cc of dry pyridine. A solution of 6.0 g of succinic anhydride in 30 cc of dry pyridine was added, followed by 30 cc of dry triethylamine and then, for washing purposes, 5 cc of dry pyridine. The solution was heated on a boiling water bath for ten hours and then poured into excess of dilute hydrochloric acid and ice. The fine gray precipitate formed was filtered off, washed with water, dissolved in chloroform, and the solution repeatedly extracted with dilute hydrochloric acid and later with water. It was dried over sodium sulfate and evaporated to dryness. Crystallization from methanol, using charcoal to effect decolorization, gave the hydrogen succinate as cream-colored crystals, MP 291° to 294°C, with previous softening. One molecular proportion of glycyrrhetinic acid hydrogen succinate was ground with a dilute (5%) aqueous solution containing two molecular proportions of sodium hydroxide. The solution was filtered and evaporated in vacuum over concentrated sulfuric acid. The sodium salt is then obtained as a creamy white water-soluble solid. Glycyrrhetinic acid is obtainable from licorice root.

Carbidopa

831

References Merck Index 1774 Kleeman and Engel p. 147 I.N. p. 183 Gottfried,S. and Baxendale, L.; US Patent 3,070,623; December 25, 1962; assigned to Biorex Laboratories Limited, England

CARBIDOPA Therapeutic Function: Muscle relaxant, Antiparkinsonian Chemical Name: S-α-Hydrazino-3,4-dihydroxy-α-methylbenzenepropanoic acid monohydrate Common Name: Methyldopahydrazine Structural Formula:

Chemical Abstracts Registry No.: 38821-49-7; 28860-95-9 (Anhydrous) Trade Name

Manufacturer

Country

Year Introduced

Sinemet

Merck Sharp and Dohme

Italy

1974

Sinemet

Merck Sharp and Dohme

UK

1974

Nacom

Sharp and Dohme W. Germany

1975

Sinemet

Chibret

France

1975

Lodosyn

Merck Sharp and Dohme

US

1977

Menesit

Merck-Banyu

Japan

1980

Neo-Dopaston

Sankyo

Japan

1980

Raw Materials Vanillin Potassium cyanide

Nitroethane Hydrazine hydrate

832

Carbidopa Butylamine Iron Hydrobromic acid

Acetic acid Hydrogen chloride Hydrochloric acid

Manufacturing Process To a solution of vanillin in toluene is added nitroethane, butylamine and glacial acetic acid. The mixture is refluxed and the water of reaction is steadily azeotropically removed by distillation. After the theoretical amount of water is distilled out, distillation is continued to remove excess reactants. The last trace of excess reactants is then removed at room temperature under a vacuum. The product is then triturated with a hydrocarbon solvent such as Skellysolve B and is thus obtained in a crystalline state. In general, however, it is preferred to dissolve the residue directly in toluene for use in the next step, without isolating the 1-(2-nitropropen-1-yl)-4-hydroxy-3methoxybenzene. A mixture of iron, ferric chloride and water is added to the toluene solution. The mixture is heated to reflux and concentrated hydrochloric acid is added dropwise at a rate calculated to keep the mixture refluxing vigorously. After the hydrochloric acid is all added, the refluxing is continued by the application of heat for several hours. A siliceous filter aid is then added to the cooled reaction mixture and the material is removed by filtration. The filter cake is washed four times, each time with 90 ml of benzene. The organic layer is then separated from the filtrate. The water layer is acidified to a pH of 2 and extracted three times with 90 ml portions of benzene. These extracts are then combined with the organic solvent layer and the combined organic phase is extracted four times with 100 ml portions of water. It is then stirred for an hour with 230 ml of 10% sodium bisulfite solution. The organic solvent phase is then separated, washed seven times with 100 ml portions of water and dried over magnesium sulfate. Evaporation of the solvent gives 1-(4-hydroxy-3-methoxyphenyl)-2-propanone in the form of an oil. A mixture of 59.5 g of that oily product, 1.85 liters of benzene and 1 kg of potassium bisulfite in 200 liters of water is stirred at room temperature for two hours. The precipitated bisulfite addition product of the ketone is isolated by filtration and washed with isopropanol and then with ether. Five hundred grams of the adduct is mixed with 119.5 g of potassium cyanide, 292 ml of 85% hydrazine hydrate and 910 ml of water. The mixture is stirred overnight at room temperature after which the product is isolated by filtration. The product is washed 3 times with 250 ml portions of water and then 3 times with 230 ml portions of ether. It is then air dried and vacuum dried at room temperature. Fifty cubic centimeters of concentrated hydrochloric acid is saturated with hydrogen chloride gas at -10°C. To the solution is then added 2.5 g of the intermediate product, of the formula shown above, slowly with vigorous stirring. The mixture is allowed to stir overnight while warming at room temperature gradually. It is then concentrated in vacuo to a syrup. To the residual syrup is added 100 ml of 48% hydrobromic acid. The reaction vessel is purged with nitrogen and the reaction mixture is then refluxed for 3 hours after which it is concentrated in vacuo to a mixture of a syrup and a solid. The

Carbimazole

833

residue is taken up in sufficient water to form a clear solution. Activated charcoal is added and the mixture is heated to boiling and filtered. The filtrate is concentrated to dryness in vacuo and the residue is taken up in 25 cc of ethanol. The residual ammonium bromide is removed by filtration and to the filtrate there is added sufficient diethylamine to change the pH to 6.4. The mixture is warmed to 60°C and then cooled to room temperature. It is then allowed to stand overnight to effect complete crystallization. It is then cooled to 0°C and the product is isolated by filtration, washed with methanol and air dried. The product (α-hydrazino-α-methyl-β-(3,4-dihydroxyphenyl)propionic acid) is recrystallized once from water using a proportion of 15 cc water per gram of product. References Merck Index 1778 Kleeman and Engel p. 148 PDR p. 1210 OCDS Vol. 2p. 119 (1980) DOT 10 (9) 322 (1974) I.N. p. 184 REM p. 929 Chemerda, J.M., Sletzinger, M. and Bollinger, F.W.; US Patent 3,462,536; August 19, 1969; assigned to Merck and Co., Inc.

CARBIMAZOLE Therapeutic Function: Thyroid inhibitor Chemical Name: Ethyl 3-methyl-2-thioimidazoline-1-carboxylate Common Name: Athyromazole; Carbimazole; Kabimazuo Structural Formula:

Chemical Abstracts Registry No.: 22232-54-8 Trade Name Carbimazol Carbimazol Carbimazol

Manufacturer Cid Co. Henning Berlin Slovakofarma

Country -

Year Introduced -

834

Carbimazole

Trade Name

Manufacturer

Country

Year Introduced

Carbimazol

Genfarma

-

-

Carbimazol

Pharbita

-

-

Carbimazol

Pharmachemie

-

-

Carbist AD

Stada

-

-

Neo-Carbimazole

Landerlan

-

-

Neo-mercazole

Roche

-

-

Neo-mercazole

-

-

Neo-mercazole

Pharmacare Limited Nicholas Piramal

-

-

Neo-mercazole

Macleods

-

-

Neo-mercazole

Lagamed

-

-

Neo-mercazole

Nicholas

-

-

Neo-mercazole

Ferraz, Lynce

-

-

Neo-mercazole

Nicholas/Meda

-

-

Neo-Thyreostat

Herbrand

-

-

Neo-Tomizol

Robert

-

-

Thyrostat

NI-THE

-

-

Tyrazol

Orion Oy

-

-

Tyrazol

Algol Pharma Oy

-

-

Raw Materials 1-Methyl-2-mercaptoglyoxaline Ethyl chloroformate Pyridine Manufacturing Process 0.1 mol of 1-methyl-2-mercaptoglyoxaline is dissolved in the minimum quantity of pyridine at 0°C 0.1 mol of ethyl chloroformate is added drop wise with stirring. More pyridine is added, if necessary, to keep the mixture semifluid. The sludge is then placed in an ice bath for 30 minutes. The crystals are filtered off and washed firstly with a little ethanol and secondly with ethanol and water. The non-basic desired ethyl 3-methyl-2-thioimidazoline-1carboxylate is the colourless needles having a melting point of 122°-123°C. References Rimington C. et al.; US Patent No. 2,815,349; Dec. 3, 1957; Assigned to National Research Development Corporation, London, England, a British corporation Rimington C. et al.; US Patent No. 2,671,088; Mar. 2, 1954; Assigned to National Research Development Corporation, London, England, a British corporation Baker J.A., J. Chem. Soc. 1958, p. 2387

Carbinoxamine maleate

835

CARBINOXAMINE MALEATE Therapeutic Function: Antihistaminic Chemical Name: 2-[(4-Chlorophenyl)-2-pyridinyl-methoxy]-N,Ndimethylethanamine maleate Common Name: Structural Formula:

Chemical Abstracts Registry No.: 3505-38-2; 486-16-8 (Base) Trade Name Clistin Allergefon Polistin Cardec Cibelon Hislosine Histex Histine Lergefin Polistine Rondec Ziriton

Manufacturer McNeil Lafon Trommsdorff Schein Taisho Toho Sigma Pharbil Larma Pharbil Boss Importex

Country US France W. Germany US Japan Japan Australia Belgium Spain Netherlands US Italy

Year Introduced 1953 1962 1963 -

Raw Materials p-Bromochlorobenzene 2-Pyridine aldehyde 2-Dimethylaminoethyl chloride

Magnesium Sodium metal

Manufacturing Process As described in US Patent 2,800,485 a solution of p-chlorophenylmagnesium bromide is prepared by adding dropwise a solution of 230 g (1.2 mols) of pbromochlorobenzene in 900 cc of anhydrous ether to 26.7 g (1.1 g-atoms) of

836

Carbocysteine

magnesium suspended in 100 cc of anhydrous ether containing a small crystal of iodine. To this solution, 107 g (1 mol) of 2-pyridinealdehyde are added slowly with stripping at a rate to maintain refluxing. The reaction mixture is then stirred for one hour at room temperature. The mixture is then poured onto an equal volume of crushed ice and water and acidified with concentrated hydrochloric acid. The ether layer is removed. The aqueous layer is made basic with ammonia and extracted with ether. The ether solution is evaporated and the residue dried by addition of benzene and removal by distillation to give 208 g (95%) of solid alpha-(p-chlorophenyl)-2-pyridinemethanol melting at 78° to 80°C. The p-chlorophenyl pyridinemethanol may alternatively be prepared from 4-chloroacetophenone, pyridine and granular aluminum as described in US Patent 2,606,195. In either case, the synthesis then proceeds as described in US Patent 2,800,485. A solution of 219 g (1 mol) of α-(p-chlorophenyl)-2-pyridinemethanol in one liter of dry toluene is heated to 100°C with stirring. Twenty-three grams (1 gatom) of sodium are then added in portions. After all the sodium has reacted, a dried solution of 2-dimethylaminoethyl chloride in benzene is added. This benzene solution is prepared by dissolving 173 g (1.2 mols) of 2dimethylaminoethyl chloride hydrochloride in the minimum amount of water, adding 500 cc of benzene followed by 300 g of sodium carbonate decahydrate, stirring, separating the benzene layer and drying. The mixture is refluxed with stirring for ten hours, cooled and filtered. The filtrate is extracted three times with 200 cc portions of 6 N acetic acid. The aqueous acetic acid solution is then made strongly basic with 10% sodium hydroxide solution, and extracted three times with 200 cc portions of ether. The ether extract is dried with anhydrous sodium sulfate, stirred with 5 g of activated carbon and filtered to provide 2-[p-chloro-α(2-dimethylaminoethoxy) benzyl]pyridine in solution. Addition of a solution of 116 g (1 mol) of maleic acid in 1,500 cc of ether gives 323 g (79%) of solid which, on recrystallization from ethyl acetate, gives white solid 2-[p-chloro-α(2-dimethylaminoethoxy) benzyl]pyridine maleate melting at 117° to 119°C. References Merck Index 1780 Kleeman and Engel p. 150 PDR pp.1561, 1606 OCDS Vol. 1 p.43 (1977) and 2 p. 32 (1980) I.N.p. 184 REM p. 1126 Tilford. C.H. and Shelton, R.S.; US Patent 2,606,195; August 5, 1952; assigned to The Wm. S. Merrell Company Swain, A.P.; US Patent 2,800,485; July 23, 1957; assigned to McNeil Laboratories, Inc.

CARBOCYSTEINE Therapeutic Function: Mucolytic, Expectorant, Nasal antiinfective

Carbocysteine

837

Chemical Name: S-(Carboxymethyl)-L-cysteine Common Name: Structural Formula:

Chemical Abstracts Registry No.: 638-23-3 Trade Name

Manufacturer

Country

Year Introduced

Rhinathiol

Kramer

Switz.

-

Rhinathiol

Joullie

France

1961

Mucodyne

Berk

UK

1963

Transbronchin

Homburg

W. Germany

1975

Lisomucil

Lirca

Italy

1975

Mucodyne

Kyorin

Japan

1981

Actithiol

Funk

Spain

-

Bronchette

S. Africa

-

Bronchipect

Continental Ethicals Mepros

Netherlands

-

Bronchokod

Genekod

France

-

Broncodeterge

Valderrama

Spain

-

Carbocit

C.T.

Italy

-

Flemex

Parke Davis

US

-

Fluifort

Lampugnani

Italy

-

Loviscol

Robins

US

-

Muciclar

Parke Davis

US

-

Mucocaps

Berk

UK

-

Mucocis

Crosara

Italy

-

Mucolex

Warner Lambert

US

-

Mucopront

Mack

W. Germany

-

Mucosirop

Berk

UK

-

Mucospect

Lennon

S. Africa

-

Mucoliz

Yurtoglu

Turkey

-

Pectox

Infar-Nattermann

Spain

-

Pulmoclase

UCB

Belgium

-

Reodyn

Remeda

Finland

-

Reomucil

Tosi

Italy

-

Siroxyl

Sopar

Belgium

-

Solvopact

Mepros

Netherlands

-

838

Carbomycin

Raw Materials L-Cysteine Sodium metal Chloroacetic acid Manufacturing Process There were placed 120g of L-cysteine (0.5 mol) in a 2 liter three-necked flask equipped with a stirrer thermometer and methanol/dry ice cooling and 1.5 liters of liquid ammonia were allowed to enter at -40°C. Then there were added under continuous cooling 50 g (2.17 mols) of sodium metal in portions of 1 to 2 g during the course of one hour. The end of the reaction was recognized by the continuation of the blue color. After the end of the reaction the excess sodium was destroyed by the addition of ammonium chloride and the ammonia vaporized at normal pressure. The residue was taken up in 500 ml of water and concentrated in a vacuum to 200 ml in order to remove residual ammonia, and again treated with 300 ml of water. The entire operations were carried out under a nitrogen atmosphere. The aqueous solution of the disodium salt of L-cysteine obtained is then reacted at 20°C to 30°C under a nitrogen atmosphere in the course of 30 minutes with stirring with a solution of 104 g of chloroacetic acid (1.1 mols) and 4 g of sodium pyrosulfite in 200 ml of water. It is also allowed to post react for 15 minutes at 20°C, the solution clarified over activated carbon and the filtrate treated with 90 ml of concentrated hydrochloric acid to a pH of 2.5. Thereby the S-carboxymethyl-L-cysteine precipitates out in crystalline form. The product is filtered off with suction, well stirred in 500 ml of water, again filtered with suction and dried in a vacuum at 70°C. The yield is 92% based on L-cysteine. References Merck Index 1785 Kleeman and Engel p. 151 I.N. p. 185 Maierhofer, A. and Wagner. H.; US Patent 4,129,593; December 12, 1978: assigned to Deutsche Gold und Silber-Scheideanstalt vormals Roessler (Germany)

CARBOMYCIN Therapeutic Function: Antibiotic Chemical Name: 9-Deoxy-12,13-epoxy-9-oxo-leucomycin V-3-acetate-4B-(3methylbutanoate) Common Name: -

Carbomycin

839

Structural Formula:

Chemical Abstracts Registry No.: 4564-87-8 Trade Name

Manufacturer

Country

Year Introduced

Magnamycin

Pfizer

US

1953

Raw Materials Nutrient broth Streptomyces halsredii bacterium Manufacturing Process A selected strain of Streptomyces halstedii was cultivated in an aqueous nutrient medium under aerobic conditions and the resulting broth containing carbomycin antibiotics was filtered. The solutions was extracted twice at pH 6.5 with one-quarter volume of methyl isobutyl ketone. The combined extracts were concentrated to one-tenth volume under vacuum, and the antibiotics were extracted into water adjusted to a pH of about 2 with sulfuric acid. After adjusting the separated aqueous solution to pH 6.5, the antibiotic was extracted into benzene and the solution was concentrated to a small volume. Addition of hexane resulted in the separation of a solid product containing the benzene complexes of carbomycin A and carbomycin B, present in the fermentation broth. References Merck Index 1790 I.N.p. 186 Tanner, F.W. Jr., Lees, T.M. and Routien, J.B.; US Patent 2,771,392; November 20, 1956; assigned to Chas. Pfizer and Co., Inc.

840

Carboplatin

Friedman, I.J., Martin, E.G., Taylor, R.J. and Wagner, R.L. Jr.; US Patent 2,960,438; November 15, 1960; assigned to Chas. Pfizer and Co., Inc.

CARBOPLATIN Therapeutic Function: Antitumor Chemical Name: Platinum, diammine(1,1-cyclobutanedicarboxylato(2-)O,O')-, (SP-4-2)Common Name: Carboplatin Structural Formula:

Chemical Abstracts Registry No.: 41575-94-4 Trade Name

Manufacturer

Country

Year Introduced

Blastocarb

Lemery

Mexico

-

Carboplatin

Teva

Israel

-

Carboplatin

Yunnan Gejiu Biochemical Pharmaceutical Factory

China

-

Carboplatin

Pharmacia and Upjohn

Australia

-

Carboplatin-Ebewe Ebewe

Australia

-

Carboplatin-Teva

Pharmachemie

Netherlands

-

Cycloplatin

Pliva-Lachema

Czech Republic

-

Paraplatin

Bristol-Myers Squibb

Italy

-

Raw Materials cis-Diammine platinum diiodide Silver sulfate Barium salt of 1,1-cyclobutanedicarboxylic acid Manufacturing Process cis-Diammine platinum diiodide was reacted with silver sulfate to give cis-

Carboprost tromethamine

841

diaquodiammine platinum sulfate. This was reacted with the barium salt of 1,1-cyclobutanedicarboxylic acid to yield Carboplatin. References Harrison R.C. et al.; Inorg. Chem. Acta, 46, L15 (1980)

CARBOPROST TROMETHAMINE Therapeutic Function: Oxytocic Chemical Name: Prosta-5,13-dien-1-oic acid, 9,11,15-trihydroxy-15-methyl-, (5Z,9α,11α,13E,15S)-, compd. with 2-amino-2-(hydroxymethyl)-1,3propanediol (1:1) Common Name: Carboprost Trometamol; Carboprost Tromethamine; Prostodin Structural Formula:

Chemical Abstracts Registry No.: 58551-69-2 Trade Name

Manufacturer

Country

Year Introduced

Hemabate

Pharmacia and Upjohn Company

-

-

Prostinfenem

Pfizer

-

-

Prostin 15M

Pharmacia and Upjohn Company

-

-

Prostodin

AstraZeneca

-

-

Deviprost

Dr. Reddy`s Laboratories Ltd.

-

-

842

Carboprost tromethamine

Raw Materials (+)-2β,4β-Dihydroxy-3α-iodo-5α(methoxymetyl)cyclopentane-1βacetic acid γ-lactone Lithium aluminum hydride (2-Oxoheptyl)phosphonate Methyl magnesium bromide Diisobutylaluminum hydride Carboxybutyltriphenylphosphonium bromide

Benzoyl chloride Tributyltin chloride Boron trifluoride Sodium hydride Sodium hydroxide Sodium bisulfate Diazomethane 2-Amino-2-(hydroxymethyl)1,3-propanediol

Manufacturing Process (+)-2β4β-Dihydroxy-3α-iodo-5α-(methoxymetyl)cyclopentane-1β-acetic acid γlactone 4-benzoate: To a stirred solution at 20°C of 75 g of (+)-2β,4β-dihydroxy-3α-iodo-5α (methoxymetyl)cyclopentane-1β-acetic acid γ-lactone (M.P. 101-102°C, [α]D = -50° (c 0.98, CHCl3) in 135 ml of dry pyridine was added 30.4 ml of benzoyl chloride. After 30 min, 250 ml of toluene was added and the resulting solution evaporated to dryness under reduced pressure. The residue was dissolved in 1000 ml of ethyl acetate. The organic solution was washed with 200 ml 20% of aqueous sulfuric acid and 200 ml of brine. The aqueous solution was washed with 200 ml of ethyl acetate. The ethyl acetate solution was dried and evaporated under reduced pressure to give 95 g of oil which crystallized. The crude product was recrystallized to give 90 g of the white solid, M.P. 84-86°C, [α]D = +5° (c 1.03, CHCl3). (-)-3α,5α-Dihydroxy-2β-(methoxymethyl)cyclopentane-1-α-acetic acid γlactone 3-benzoate: To a solution of 4.2 g of lithium aluminum hydride in 420 ml of ether under a nitrogen atmosphere and cooled in a ice bath was added dropwise a solution of 99 g of tributyltin chloride in 210 ml of ether. The cooling bath was removed and stirring continued at ambient temperature for 1.5 hours. To the cooled solution was added 260 ml of water. The organic layer was washed with water and dried. This solution was added slowly at 15°C to a solution of (+)-2β,4β-dihydroxy-3α-iodo-5α-(methoxymethyl)cyclopentane-1β-acetic acid γ-lactone 4-benzoate in 240 ml of benzene. Then the solution was evaporated and the product was stirred with water. Yield of (-)-3α,5α-dihydroxy-2β(hydroxymethyl)cyclopentane-1α-acetic acid γ-lactone 3-benzoate 93%. (-)-3α,5α-Dihydroxy-2β-(methoxymethyl)cyclopentane-1α-acetic acid γ-lactone 3-benzoate: To a solution of 20 g of (-)-3α,5α-dihydroxy-2β-(hydroxymethyl)cyclopentane1α-acetic acid γ-lactone 3-benzoate in 320 ml of methylene chloride under nitrogen atmosphere and cooled in an ice bath was added dropwise 24.8 ml of boron trifluoride in 320 ml of methylene chloride. After 1 hour to the solution was added 78 g of sodium carbonate in 200 ml of water and then 66 g of solid sodium chloride. The aqueous phase was extracted with ethyl acetate. Yield of (-)-3α,5α-dihydroxy-2β-(methoxymethyl)cyclopentane-1α-acetic acid

Carboprost tromethamine

843

γ-lactone 3-benzoate 95%, M.P. 116-118°C. (-)-3α,5α-Dihydroxy-2β-(3-oxo-trans-1-octenyl)cyclopentane-1α-acetic acid γlactone 3-benzoate: To a mixture of 1.75 g of sodium hydride and 2509 ml of tetrahydrofuran at 5°C was added 8.0 g of (2-oxoheptyl)phosphonate. After 2.5 hours a thick white precipitate formed (ilide mixture). To a stirred mixture of 11 g of anhydrous cromium trioxide and 150 ml of methylene chloride under nitrogene atmosphere and cooled in an ice bath was added 17 g of anhydrous pyridine. The mixture was stirred for 15 min at 0°C for 2 hours at room temperature, then at 0°C again. A solution of 5.0 g of (-)-3α,5α-dihydroxy-2β(methoxymethyl)cyclopentane-1α-acetic acid γ-lactone 3-benzoate in 150 ml methylene chloride was added to at 0°C to a to the cold Collins oxidant solution. The resulting black mixture was stirred 5 min. After addition of 100 ml of benzene, the mixture was filtered through Celite, washing with benzene. The filtrate was concentrated to 50 ml under reduced pressure and then diluted with 100 ml of benzene. This solution was added to the cold ilide mixture. The resulting dark mixture was stirred for 1.5 hours at room temperature. After dropwise addition of 3 ml of acetic acid the mixture was concentrated to dryness. The residue was dissolved in 400 ml of ethyl acetate. The solution was washed with water and then with brine. Organic phase was dried and evaporated to give dark oil. This oil was purified on silica gel, yield of (-)-3α,5α-dihydroxy-2β-(3-oxo-trans-1-octenyl)cyclopentane-1α-acetic acid γ-lactone 3-benzoate 48%, M.P. 63-63.8°C, [α]D = -113° (c 1.18, CHCl3). (-)-3α,5α-Dihydroxy-2β-[(3RS)-3-hydroxy-3-methyl-trans-octenyl] cyclopentane-1α-acetic acid γ-lactone 3-benzoate: To a solution of 0.20 g of (-)-3α,5α-dihydroxy-2β-(3-oxo-trans-1-octenyl) cyclopentane-1α-acetic acid γ-lactone 3-benzoate in 15 ml of tetrahydrofuran at -78°C under nitrogen was added dropwise 3 ml etheral solution 3 M methylmagnesium bromide. The solution became heterogeneous after 2 hours, to the mixture was added 10 ml of saturated aqueous ammonium chloride and then ether and water. Organic extract was washed with brine, dried over sodium sulfate, and evaporated to give 0.21 g of (-)-3α,5αdihydroxy-2β-[(3RS)-3-hydroxy-3-methyl-trans-octenyl]cyclopentane-1α-acetic acid γ-lactone 3-benzoate as a colorless oil; [α]D = -80° (c 1.0, CHCl3). (-)-3α,5α-Dihydroxy-2β-[3-(RS)-3-hydroxy-3-methyl-trans-octenyl] cyclopentane-1α-acetaldehyde γ-lactol 3-benzoate: To a solution of 0.50 g of (-)-3α,5α-dihydroxy-2β-[(3RS)-3-hydroxy-3-methyltrans-octenyl]cyclopentane-1α-acetic acid γ-lactone 3-benzoate in 15 ml of tetrahydrofuran at -78°C under nitrogen was added 10 ml of 10% diisobutylaluminum hydride in toluene. After a gas evolution was ceased, the reaction was quenched by addition of 10 ml of saturated aqueous ammonium chloride. The resulting mixture was stirred at room temperature, filtered through Celite, and extracted with ethyl acetate. Extract was evaporated to give 0.48 g of (-)-3α,5α-dihydroxy-2β-[3-(RS)-3-hydroxy-3-methyl-transoctenyl]cyclopentane-1-α-acetaldehyde γ-lactol 3-benzoate as an oil. (15R)- and (15S)-15-methyl-PGF2α methyl esthers:

844

Carboquone

A mixture of 0.23 g sodium hydride (50% dispersion in mineral oil) and 10 ml of dimethyl sulfoxide stirred under nitrogene at 70-75°C. After 1 hours, gas evolution had ceased. After 0.5 hour, the mixture was cooled to room temperature. To the mixture was added 1.06 g 4carboxybutyltriphenylphosphonium bromide and the resulting dark red solution stirred 0.5 hour. To this solution was added a solution of 0.48 g of (-)-3α,5α-dihydroxy-2β-[3-(RS)-3-hydroxy-3-methyl-trans-octenyl] cyclopentane-1α-acetaldehyde γ-lactol 3-benzoate in 15 ml of dimethyl sulfoxide. The resulting dark orange mixture was stirred at room temperature for 12 hours. Another 1.2 mmol of freshly prepared ilide in 3.6 ml of solution (prepared as above) was added. After 24 hours, the reaction was quenched by addition to 15 ml of 2 M sodium bisulfate (diluted with ice water) and 25 ml of ether. The organic extract was washed with 5 ml of 1 N sodium hydroxide, and twice with water. The aqueous washings were combined (pH £ 11) and acidified with sodium bisulfate to pH about 1 in the presence of ether. The aqueous phase was extracted with ether. The extract was evaporated to give 0.45 g of dark oily solid. The crude product was dissolved in a mixture of methylene chloride, ether and methanol and treated with excess etheral diazomethane. Evaporation gave 0.40 g of dark oil. The crude product was chromatographed on 10 g of silica gel. Fraction 9-12 contained a mixture of epimers (15R)- and (15S)-15-methyl-PGF2α-methyl esthers, yield 160 mg (35%) as an oil. The structure of product was confirmed by 1H-NMR spectrum. (15S)-15-methyl-PGF2α methyl esthers: 1 g of the mixture of epimers was chromatographed on 100 g (eluent acetone-methylene chloride). It was obtained 150 mg of pure (15S)-15methyl-PGF2α methyl esthers; M.P. 55-56°C, [α]D = +24° (c 0.81, ethanol). Carboprost tromethamine: The drug was prepared by mixing of (15S)-15-methyl-PGF2α methyl esthers with 2-amino-2-(hydroxymethyl)-1,3-propanediol (1:1). References Yankee E.W. et al.; J. Amer. Chem. Soc.; 1974, 96, 5865 US Patent No. 6,211,233; Apr. 3, 2001; Assigned to Nixon S.A., Paris (FR)

CARBOQUONE Therapeutic Function: Antineoplastic Chemical Name: 2,5-Bis(1-aziridinyl)-3-(1-methoxy-2-carbamoyloxyethyl)-6methyl-1,4-benzoquinone Common Name: Carbazilquinone Chemical Abstracts Registry No.: 24279-91-2

Carbromal

845

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Esquinon

Sankyo

Japan

1974

Raw Materials 2-Methyl-5-(1-methoxy-2-carbamoyloxyethyl)-1,4-benzoquinone Aziridine Manufacturing Process In 10 ml of ethanol was dissolved with heating 200 mg of 2-methyl-5-(1methoxy-2-carbamoyloxyethyl)-1,4-benzoquinone and the resulting solution was cooled. To the cooled solution was added 0.5 ml of aziridine and then the resulting mixture was allowed to stand in a refrigerator at 5°C to 8°C for 4 days. Thereafter, the crystalline substance which precipitated in situ was recovered by filtration and washed with ethanol to give 50 mg of the desired product as red crystals melting at 200°C (with decomposition). References Merck Index 1806 Kleeman and Engel p. 151 DOT 11 (9) 344 (1975) I.N. p. 186 Nakao, H., Arakawa, M. and Nakamura, T.; US Patent 3,631,026; December 28, 1971; assigned to Sankyo Co., Ltd.

CARBROMAL Therapeutic Function: Hypnotic, Sedative Chemical Name: Urea, (2-bromo-2-ethylbutyryl)Common Name: Bromacetocarbamidum; Bromdiaethylacetylcarbamidum; Bromadal; Carbromal Chemical Abstracts Registry No.: 77-65-6

846

Carbutamide

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Antineuralgiae

Jelfa

-

-

Seduan

Pharmed

-

-

Adalin

Bayer

-

-

Diacid

Daro

-

-

Addisomnol

Synochem

-

-

CARBRITAL

WARNER-LAMBERT CO.

-

-

CARBROMAL

-

-

Adabrom

Shanghai Lancheng Corporation Hosco

-

-

Carbalin

Arochem Industries

-

-

Dulcipan

Cl Ocana

-

-

P.R.

Boots

-

-

Sedadorm

Pharma Funcke

-

-

Sedamon

Sapic

-

-

Raw Materials Urea 2-Bromo-2-ethyl-butyrylbromide Manufacturing Process 120 parts urea and 258 parts 2-bromo-2-ethylbutyrylbromide was mixed and stood at room temperature for 12 hours; then the mixture was heated about 3 hours on water bath and adjusted to alkaline pH with sodium bicarbonate after cooling. The unreacted products was dissolved in brine, the insoluble part was filtered off. The recrystallization from ethanol gave the title product (2-bromo-2-ethyl-butyryl)urea as the colorless, odorless crystals. MP 114°118°C. References Bayer F.; D.R. Patent No. 225,710; 10 July 1909; Assigned to Farbenfabriken F. Bayer and Co. in Elberfeld

CARBUTAMIDE Therapeutic Function: Oral hypoglycemic

Carbutamide

847

Chemical Name: Benzenesulfonamide, 4-amino-N-((butylamino)carbonyl)Common Name: Aminophenurobutane; Butylcarbamide; Carbutamide; Glybutamide; Sulfabutylharnstoff Structural Formula:

Chemical Abstracts Registry No.: 339-43-5 Trade Name Carbutamide Carbutamide

Manufacturer Servier Shanghai Lancheng Corporation

Country -

Year Introduced -

Bucarban Glucidoral Oranil Glucofren Invenol Nadisan Bucarban Bucarban Diabetin Diabeton Diabex Diabex Diaboral Diabutan Dibefanil Glucidoral Insoral Insoral Norboral Orabetic Orabetic Orabetic Orabetic Oranil Oranil

Chinoin Servier Berlin-Chemie Cophar Hoechst Boehringer, Mann Chinoin Sanofi Diasan Servier Dambergis Alphapharm PHARMEX G. Streuli and Co. AG Mepha Pharma AG Servier Valeas Elvetium S.A. Silanes Lilly Biotech Cathay Mibe GmbH Arzneimittel AGRINDUSTRIAL, S.A. A.Menarini Pharmaceutical Industre's Group Ltd.

-

-

848

Carbuterol

Raw Materials Sodium salt of acetylsulfaniamide N-Butyl isothiocyanate Sodium nitrite Manufacturing Process 223 g of the sodium salt of acetylsulfaniamide are stirred with 223 ml of triethylene glycol. 118 g of n-butyl isothiocyanate are added to the resulting homogeneous mixture. The resulting syrup is heated to 85°C for 4 hours. The mixture is then stirred with 1000 ml of chloroform and 1000 ml of water. The chloroform layer is twice shaken with water, each time with 250 ml. The aqueous extracts are combined and rendered weakly alkaline to phenolphthalein by addition of hydrochloric acid. Unreacted acetyl sulfanilamide precipitates and filtered off. The filtrate is acidified to a pH of 6.5 by the addition of HCl. An oily precipitate settles from the reaction solution and is separated therefrom. N-Butyl acetyl sulfanilylthiourea is precipitated from mother liquors obtained thereby by addition of HCl until Congo paper changes its color to blue. 210 g N-butyl acetyl sulfanilylthiourea are dissolved in 1400 ml of acetone while heating. The solution is mixed with 500 ml of water. A solution of 63 g of sodium nitrite in 120 ml of water is added thereto within about 45 minutes while stirring and cooling to 15°-20°C. A suspension of crystals is obtained. 240 ml of 25% glacial acid are added thereto within 30 minutes. Stirring of the mixture is continued for 6 hours. NButyl acetyl sulfanilylurea mixed with sulfur is precipitated and filtered off. The crude reaction product is suspended in 1000 ml of water and is rendered weakly alkaline to phenolphthalein. Undissolved sulfur is filtered off. The filtrate is acidified by the addition of HCl. 250 g of N-butyl acetyl sulfanilylthiourea having a melting point of 186°-189°C are obtained. It is heated with 500 ml of 5 N potassium hydroxide solution to a temperature of 92°C for 2 hours while stirring. The solid reaction product is dissolved by heating with 750 ml of water and is purified by means of activated charcoal. The resulting solution is heated to 60°C and acidified by addition of HCl. 187 g of N-butyl acetyl sulfanilylthiourea melting at 139°-141°C obtained thereby. References Haak E. et al.; US Patent No. 2,907,692; Oct.6, 1959; Assigned to C.F. Boehringer and Soehne G.m.b.H., Mannheim-Waldhof, Germany, a corporation of Germany

CARBUTEROL Therapeutic Function: Bronchodilator Chemical Name: [5-[2-[(1,1-Dimethylethyl)amino]-1-hydroxyethyl]-2hydroxyphenyl]urea Common Name: -

Carbuterol

849

Structural Formula:

Chemical Abstracts Registry No.: 34866-47-2 Trade Name Bronsecur Bronsecur Pirem Dilabron Rispan

Manufacturer SK and F SK and F Sasse Warner Lambert SK and F

Country W. Germany Italy W. Germany -

Year Introduced 1980 1980 1982 -

Raw Materials 3-Amino-4-benzyloxyacetophenone Ammonia N-Benzyl-N-t-butylamine

Phosgene Bromine Hydrogen

Manufacturing Process A stirred solution of 40 g (0.41 m) of phosgene in 150 ml of toluene is held at 25°C with a cooling bath while a mixture of 252 g (0.105 m) of 3-amino-4benzyloxyacetophenone and 220 ml of toluene are added slowly. The mixture is heated to reflux and continued for 30 minutes. Nitrogen is passed through the mixture and then concentrated in vacuo to give a crystalline isocyanate, MP 105°-106°C. A stirred solution of the isocyanate (28.0 g) in 500 ml of dry benzene is saturated with ammonia. After one hour, the mixture is cooled to give the crystalline 4-benzyloxy-3-ureidoacetophenone, MP 184°-186°C. To a stirred solution of 5.7 g (0.02 m) of 4-benzyloxy-2-ureidoacetophenone in 100 ml of chloroform is added 32 g (0.02 m) of bromine. The mixture is stirred at room temperature for about 45 minutes and the solution is concentrated in vacuo at 25°-30°C. The amorphous residue (hydrobromide salt of 4-benzyloxy-α-bromo-3-ureidoacetophenone) is dissolved in 80 ml of acetonitrile and 98 g (0.06 m) of N-benzyl-N-t-butylamine is added. The mixture is stirred and refluxed for 1.5 hours, then it is cooled to 0°C in an ice bath. Crystalline N-benzyl-N-t-butylamine hydrobromide is filtered. The filtrate is acidified with ethereal hydrogen chloride. The semicrystalline product is filtered after diluting the mixture with a large excess of ether. Trituration of the product with 60 ml of cold ethanol gives 4-benzyloxy-α-(N-benzyl-N-tbutylamino)-3-ureidoacetophenone hydrochloride, MP 200°-221°C (decomposition). A solution of 10.5 g (0.0218 m) of 4-benzyloxy-α-(N-benzyl-N-t-butylamino)-

850

Carfecillin sodium

3-ureidoacetophenone hydrochloride in 65 ml of methanol and 25 ml of water is added to a suspension of 1.5 g of 10% palladium-on-carbon in 10 ml of water. The mixture is hydrogenated on the Parr apparatus at room temperature, using an initial pressure of 60 psi of hydrogen. After 4 hours about 80% of the theoretical volume of hydrogen has been absorbed. The mixture is filtered, an additional 1.5 g of 10% palladium-on-carbon is added and the mixture is again hydrogenated on the Parr apparatus under the same conditions. After hydrogenating for an additional 3 hours, the mixture is filtered and the filtrate is concentrated in vacuo. The residue is stripped twice with toluene and crystallized with ether-ethanol to give α-(tbutylaminomethyl)-4-hydroxy-3-ureidobenzyl alcohol hydrochloride, MP 214°215°C. References Merck Index 1817 DFU 1 (9) 412 (1976) Kleeman and Engel p. 153 OCDS Vol. 2 p. 41 (1980) DOT 12 (2) 483 (1976) I.N. p. 187 Kaiser, C. and Ross, S.T.; US Patent 3,763,232; October 2, 1973; assigned to Smith Kline and French Laboratories Kaiser, C. and Ross, S.T.; US Patent 3,917,847; November 4, 1975; assigned to Smith Kline Corp.

CARFECILLIN SODIUM Therapeutic Function: Antibiotic Chemical Name: Malonamic acid, N-(2-carboxy-3,3-dimethyl-7-oxo-4-thia-1azabicyclo(3.2.0)hept-6-yl)-2-phenyl-, 1-phenyl ester monosodium salt Common Name: Carbenicillin phenyl sodium; Carfecillin sodium Structural Formula:

Chemical Abstracts Registry No.: 21649-57-0

Carfecillin sodium

851

Trade Name

Manufacturer

Country

Year Introduced

Carfecillin sodium

Beecham (GSK)

-

-

Raw Materials Phenylmalonic acid Thionyl chloride Phenol 6-Aminopenicillanic acid Manufacturing Process Phenylmalonic acid (27 g) was mixed with dry ether (80 ml) and treated with thionyl chloride (17.85 g, 10.9 ml) and dimethylformamide (4 drops). The mixture was refluxed for 3 hours on a hot water bath. The solvent was evaporated under reduced pressure and the residue dissolved in fresh dry ether (80 ml). Phenol (14.1 g) was added all at once and the mixture refluxed for 2 hours. The reaction was cooled to room temperature, washed with water (25 ml) and extracted with saturated sodium bicarbonate solution until the extracts were alkaline. The combined aqueous extracts were washed with ether (100 ml) and acidified with 5 N HCl. The precipitated oil was extracted with methylene chloride. The combined organic extracts were washed thoroughly with water (6x120 ml) dried over anhydrous magnesium sulphate and evaporated. The solid residue was crystallised from benzene to give monophenyl phenylmalonate, a colourless crystalline solid 30.2 g (78.7 %) MP 115-117°C. This product (5.12 g, 0.02 m) was mixed with thionyl chloride (20 ml) and heated in a water bath at 75°C for 1 hour. The excess thionyl chloride was evaporated under reduced pressure. The residue was mixed with dry benzene (10 ml) and again evaporated to dryness to remove residual thionyl chloride. The final residue was dissolved in dry acetone (100 ml) and added, with stirring, to a solution of 6-aminophenicillanic acid (4.32) in water (100 ml), 1 N sodium hydroxide (20 ml), 1 N sodium bicarbonate solution (30 ml) and acetone (50 ml) cooled to 12°C. The reaction mixture was stirred for 2 hours. The resulting mixture was stirred at room temperature for 2 hours. The resulting solution was extracted with ether (3x60 ml) and the extracts discarded. The aqueous layer was covered with ether (60 ml) and acidified with 1 N HCl to pH 2. The ether layer was separated and the aqueous layer extracted with ether (2x60 ml). The combine ether extracts were washed with water (20 ml) and extracted with 1 N sodium bicarbonate solution to pH 7. The neutral aqueous extract was evaporated under reduced temperature and pressure. The residue was dried over phosphorous pentoxide in vacuo to give 6.7 (70.4%) of penicillin salt as an amorphous solid. The solid, when dissolved in ethanol (50 ml) at room temperature gave on standing 30 min the penicillin salt as a colorless crystalline solid 5.23 g (78.1 %). References Hardy K. et al.; US Patent No. 3,853,849; Dec. 10, 1974; Assigned to Beecham Group Limited, Brentford Middlesex, England

852

Cargutocin

CARGUTOCIN Therapeutic Function: Oxytocic Chemical Name: 1-Butanoic acid-7-glycine-1,6-dicarbaoxytocin Common Name: Structural Formula:

Chemical Abstracts Registry No.: 33065-67-3 Trade Name

Manufacturer

Country

Year Introduced

Statocin

Yoshitomi

Japan

1982

Raw Materials Cyclic polypeptide Hydrogen Manufacturing Process To a suspension of Z-Tyr(Bz)-Ile-Gln-Asn-Asu(OTCP)-Gly-Leu-Gly-NH2 (1,310 mg) in DMF (350 ml) is added a suitable amount of palladium black. Hydrogen gas is introduced with stirring at room temperature (25°C) for about 40 hours. After stirring the mixture at 30°-35°C for several hours, the catalyst is filtered off and the filtrate is concentrated under reduced pressure. A large amount of ether is added to the residue, and the white coagulum is collected

Carisoprodol

853

by filtration, washed with ether and dried. This is dissolved in water (30 ml), and the solution is filtered. The filtrate is passed through a column (3 x 11.5 cm) of Amerlite IR-45 (OH-form). The fractions which show a UV-absorption maximum at 280 nm are combined and passed through a column (3 x 125 cm) of CM-Sephadex C-25 to remove the noncyclic compound and obtain neutral parts. The detection of the objective compound is made by UVabsorption at 280 nm. The aqueous solution of the neutral parts is concentrated below 35°C, under reduced pressure, and the concentrate is lyophilized to give 504 mg of the crude title compound in the form of 5 hydrate. References Merck Index 1822 DFU 8 (3) 188 (1983) DOT 19 (3) 130 (1983) Sakakibara, S. and Yamanaka, T.; US Patent 3,749,705; July 31, 1973; as signed to Yoshitomi Pharmaceutical Industries Ltd. (Japan)

CARISOPRODOL Therapeutic Function: Muscle relaxant Chemical Name: (1-Methylethyl)carbamic acid 2-([(aminocarbonyl)oxy] methyl)-2-methylpentyl ester Common Name: Isopropyl meprobamate Structural Formula:

Chemical Abstracts Registry No.: 78-44-4 Trade Name Soma Rela Sanoma Flexartal

Manufacturer Wallace Schering Heilit Clin Midy

Country US US W. Germany France

Year Introduced 1959 1959 1961

854

Carisoprodol

Trade Name

Manufacturer

Country

Year Introduced

Caprodat

Ferrosan

Denmark

-

Carisol

AFI

Norway

-

Carisoma

Wallace

US

-

Diolene

Italy

-

Erbasoma

Pharma. Farm. Spec. Erba

Italy

-

Meprodat

Star

Finland

-

Mioril

Rossini

Italy

-

Mioxom

Dessy

Italy

-

Myobutazolidin

Fujisawa

Japan

-

Relasom

Rafa

Israel

-

Relaxo-Powel

Erba

Italy

-

Soma

Horner

Canada

-

Soma

Guidotti

Italy

-

Somadril

Dumex

Denmark

-

Somalgit

Wallace

US

-

Somalgit Simple

Inibsa

Spain

-

Somanil

Banyu

Japan

-

Soprodol

Schein

US

-

Raw Materials Isopropylamine Phosgene

2-Methyl-2-propyl-1,3-propanediol Sodium cyanate

Manufacturing Process A cooled 10% solution of 1 mol of phosgene in toluene was added with stirring to a cooled solution of 1 mol of 2-methyl-2-propyl-1,3-propanediol and 2 mols of dimethylaniline also dissolved in toluene, at such a rate that the temperature of the mixture was maintained at about 25°C. The mixture was allowed to remain at this temperature for several hours, then cooled and extracted with cold 5% hydrochloric acid solution to remove the dimethylaniline. The toluene layer was dried using a suitable drying agent and the 2-methyl-2-propyl-3-hydroxypropyl chlorocarbonate used in subsequent reactions in the form of its solution in anhydrous toluene. A quantity of solution obtained as described containing 0.1 mol of the chlorocarbonate was treated with 0.2 mol of anhydrous isopropylamine and allowed to react at ordinary room temperature. The solution was cooled, extracted with dilute hydrochloric acid and the organic layer concentrated by evaporation of the solvent. The crude monocarbamate was purified by distilling at 86° to 88°C at about 0.01 mm. It was a clear, viscous liquid. 21.7 g (0.1 mol) of N-isopropyl-2-methyl-2-propyl-3-hydroxypropylcarbamate and 7.5 g (0.11 mol) of anhydrous sodium cyanate are stirred in 200 ml anhydrous chloroform in a suitable vessel equipped with a gas inlet tube,

Carmofur

855

stirrer and thermometer. While cooling the vessel, anhydrous hydrogen chloride is passed into the stirred mixture slowly for 5 hours maintaining the temperature between 0° and 5°C. Alternatively ethyl urethane in the presence of aluminum isopropylate as a catalyst may be used in place of the sodium cyanates and HCl. The mixture is then allowed to stand at room temperature overnight. The solid material is separated by filtration and the chloroform solution concentrated to an oil under reduced pressure. The oil is dissolved in 50 ml of trichloroethylene, the solution treated with charcoal, filtered and the filtrate added to 125 ml of hexane. The crystalline material which forms on standing at refrigerator temperature is removed by filtration, washed with light petroleum ether and dried at about 50°C. Approximately 20 g of product are obtained. On recrystallizing from trichloroethylene-hexane, 17.8 g of purified compound are obtained, MP 89° to 91°C. References Merck Index 1824 Kleeman and Engel p. 155 PDR pp. 830, 1606,1883 OCDS Vol. 1 p. 219 (1977) I.N.p. 189 REM p. 926 Berger, F.M. and Ludwig, B.J.; US Patent 2,937,119; May 17, 1960; assigned to Carter Products, Inc.

CARMOFUR Therapeutic Function: Antineoplastic Chemical Name: 5-Fluoro-N-hexyl-3,4-d-dihydro-2,4-dioxo-1(2H)pyrimidinecarboxamide Common Name: HCFU Structural Formula:

Chemical Abstracts Registry No.: 61422-45-5

856

Carmustine

Trade Name Mifurol Yamafur

Manufacturer Mitsui Yamanouchi

Country Japan Japan

Year Introduced 1981 1981

Raw Materials 5-Fluorouracil n-Hexyl isocyanate Manufacturing Process 13.0 g (0.10 mol) of 5-fluorouracil was suspended in 60 ml of dimethyl acetamide, then 14.0 g (0.11 mol) of n-hexyl isocyanate was added thereto at room temperature and stirred at 50°C for 8 hours. After the reaction mixture was concentrated under reduced pressure, the residue was poured into 400 ml of water and resultant precipitate was filtered off. The precipitate was washed and dried and 19.3 g (75.0% yield) of 5-fluoro-1-(n-hexylcarbamoyl)uracil was obtained. The product was recrystallized from ether and there were obtained white crystals melting at 283°C (decomposition). References Merck Index 1828 DFU 1 (4) 235 (1982) DOT 18 (9) 424 (1982) I.N. p. 190 Ozaki, S. and Mori, H.; US Patent 4,071,519; January 31, 1978; assigned to Mitsu Toatsu Chemicals, Inc.

CARMUSTINE Therapeutic Function: Antitumor Chemical Name: Urea, 1,3-bis(2-chloroethyl)-1-nitrosoCommon Name: Carmustine Structural Formula:

Chemical Abstracts Registry No.: 154-93-8

Carnitine

857

Trade Name

Manufacturer

Country

Year Introduced

BCNU

Gencorp Aerojet

US

-

BCNU

Bristol-Myers Squibb

-

-

BiCNU

Bristol-Myers Squibb

-

-

Gliadel Wafer

Rhone-Poulenc Rorer

-

-

Raw Materials N,N'-Bis-(2-chloroether)-urea Sodium nitrite Formic acid Manufacturing Process A solution of sodium nitrite (6.9 g, 0.10 mole) in water (60 ml) was added dropwise to a cold (0-5°C), stirred solution of 1,3-bis(2-chloroethyl)urea (8.0 g, 0.044 mole) in formic acid (50 ml). The reaction mixture was stirred further at 0°C until the pale yellow oil that had formed solidified. The nitrosourea was collected and washed quickly with cold water (2 x 10 ml), and dried in vacuum; yield 6.7 g. (71%). References Johnston T.P. et.al.; J. Med. Chem. 6, 669, (1963) Bastian H., Justus Liebigs, Ann. Chem., 566, 210 (1950)

CARNITINE Therapeutic Function: Gastric stimulator, Pancreatic stimulator Chemical Name: 3-Carboxy-2-hydroxy-N,N,N-trimethyl-1-propanaminium hydroxide, inner salt Common Name: Structural Formula:

Chemical Abstracts Registry No.: 461-06-3; 5842-94-8 (Hydrochloride salt)

858

Carnitine

Trade Name Flatistine Carnetina Nefrocarnit Carnitene Abedine Bicarnesine Carn Carnitan Carnitine Carnitolo Entomin Metina Monocamin Polycartin

Manufacturer Sauba Sigma Tau Nefro Pharma Refarmed SA Nippon Zoki Labaz Benvegna Kakenyaku Kako Tyson Sirt-B.B.P. Maruko Francia Tanabe Daigo Eiyo

Country France Italy W. Germany Switz. Japan France Italy Japan US Italy Japan Italy Japan Japan

Year Introduced 1978 1981 1983 1983 -

Raw Materials Trimethylamine Epichlorohydrin

Sodium cyanide Hydrogen chloride

Manufacturing Process 9.3 g of epichlorohydrin was added at a temperature of 40°-50°C under stirring to 9.6 g of trimethylamine hydrochloride dissolved in 10 cc of water. Continuing the reaction for an hour at the above temperature, the reaction product was concentrated under reduced pressure to obtain the crystals of 3chloro-2-oxypropyl trimethyl ammonium chloride which were recrystallized with 25 cc of ethanol. The crystals obtained by concentrating the mother liquor were also recrystallized. The yield was 17.4 g (MP 190°C, yield 91.5%). This substance occurs as white, somewhat hygroscopic crystals and is readily soluble in water or alcohol, but insoluble in benzene, toluene, ether, acetone or chloroform. The result of analysis assuming (C6H15C10N)+Cl--calculated value: N, 7.45%; total Cl, 37.7%; Cl-, 18.88%. Observed value: N, 7.36%; total Cl, 37.54%; Cl-, 18.98%. 18.8 g of 3-chloro-2-oxypropyl trimethyl ammonium chloride was dissolved in a mixed solvent composed of 19 cc of methanol and 1 cc of water. 5.1 g of sodium cyanide dissolved in 8 cc of water was dropped into the solution at 50°C under stirring. After dropping, the mixture was held at this temperature for 30 minutes under stirring. The reaction product was then neutralized with 6 N hydrochloric acid toward pH 5, and, after cooling, sodium chloride separated out and was filtered. The filtrate was concentrated to dryness under reduced pressure, and the residue was washed with small quantity of ethanol. Drying the residue, dissolving in hot methanol, filtering off insoluble matters, and cooling mother liquor, the crystals of 3-cyano-2-axypropyl trimethyl ammonium chloride which deposited out were filtered and dried. Yield 16.7 g [MP (decomposition) 220°-223°C, yield 93.4%].

β-Carotene

859

12.5 cc of concentrated hydrochloric acid was added to 17.9 g of 3-cyano-2oxypropyl trimethyl ammonium chloride. Gradually heating the mixture on a water bath under stirring, so bringing the temperature up to 98°C at the end of about 3 hours, 9 cc of water was added. After cooling, free hydrochloric acid was neutralized with 3 cc of 6 N sodium hydroxide, and then by adding 1 g of active charcoal, the reaction product was decolorized and filtered. The filtrate was concentrated to almost dryness under reduced pressure. Then, this concentrate was, after washing with 10 cc of ethanol, dried. Yield 24.7 g. The dried product was dissolved in 46.5 cc of glacial acetic acid by heating on a boiling water bath. The insoluble matter is removed by filtering hot, and on cooling the mother liquor, crystals of carnitine hydrochloride separated out. The crystals were filtered, washed with 10 cc of ethanol, and dried. Recrystallizing 19.7 g of the crude carnitine with methanol, 17 g of the refined carnitine was obtained [MP 195°-198°C (decomposing point), yield 86%], The overall yield of the refined carnitine through whole steps was about 74%. Carnitine thus prepared was an odorless, white, crystalline powder, having a strong acid taste. References Merck Index 1833 Kleeman and Engel p. 156 PDR p. 1807 DOT 19 (4) 185 (1983) I.N. p. 190 Noguchi, J. and Sakota, N.; US Patent 3,135,788; June 2, 1964; assigned to Nihon Zoki Seiyaku Kabushikikaisha (Japan)

β-CAROTENE Therapeutic Function: Vitamin A precursor, Sunscreen agent Chemical Name: β-Carotene Common Name: Structural Formula:

Chemical Abstracts Registry No.: 7235-40-7

860

β-Carotene

Trade Name Carotaben Solatene Vitacarotene Beta-carotene

Manufacturer Hermal Roche Pellestier Solgar

Country W. Germany US Spain US

Year Introduced 1975 1975 -

Raw Materials 3,8-Dimethyl-3,5,7-decatrien-1,9-diyne Phenyl lithium 4-(2,6,6-Trimethyl-1-cyclohexen-1-yl)-2-methyl-2-buten-1-al Hydrogen Manufacturing Process 3.6 g (0.023 mol) of 3,8-dimethyl-3,5,7-decatrien-1,9-diyne were dissolved in 50 ml of absolute ether, and to the solution was added 0.05 mol of ethereal phenyl-lithium solution. The mixture was refluxed for 30 minutes. Then a solution of 11 g (0.05 mol) of 4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-methyl2-buten-1-al in 100 ml of ether was added dropwise, and the reaction mixture was boiled for 2 hours. The reaction mixture was then hydrolyzed with aqueous ammonium acetate solution, and the ethereal layer was separated, dried and concentrated. The residue, i.e., 1,18-di(2,6,6-trimethyl-1cyclohexen-1-yl)-3,7,12,16-tetramethyl-4,15-dihydroxy-2,7,9,11,16octadecapentaen-5,13-diyne, was a resinous product (having 1.9 active hydrogen atoms and absorption maxima in the ultraviolet spectrum at 326 and 341 nm) which was used for the next step without any further purification. The resin was dissolved in 200 ml of methylene chloride, 10 ml of glacial acetic acid were added to the solution, and the mixture was cooled to 40°C in a carbon dioxide atmosphere, while stirring. Then, 9 ml of aqueous hydrobromic acid (60%) were added in one portion, the mixture was stirred at -35°C for 1.5 minutes, and subsequently 200 ml of ice water were run into the mixture. After further stirring the mixture for 2 hours at 0°C, the methylene chloride layer was separated, washed with water and sodium bicarbonate solution, dried with Na2SO4 andconcentrated in vacuo. The residue, i.e., 11,12-11',12'-bisdehydro-betta-carotene, was a tough resin or a foamy solid (having no active hydrogen atoms and possessing absorption maxima in the ultraviolet spectrum at 334 and 408 nm). This product can be purified by chromatography. The crude product can also be used for the next step without any preliminary purification. 11.4 g of 11,12-11',12'-bisdehydro-β-carotene were dissolved in 100 ml of petroleum ether (boiling range 80° to100°C), and the solution was hydrogenated under normal conditions after the addition of 0.5 ml of quinoline and 5 g of a lead-poisoned palladium catalyst. After the calculated amount of hydrogen had been absorbed, the catalyst was removed by filtration and the filtrate was extracted with dilute sulfuric acid to remove the quinoline. By concentrating the solution in the usual manner there was obtained 11,1211',12'-di-cis-carotene. The product was purified by recrystallization from benzene-alcohol. The purified product melts at 154°C; absorption maxima in the ultraviolet spectrum at 276, 334, 338, 401 and 405 nm. The isomerization was effected by heating the product for 10 hours at 90 to 100°C in highboiling petroleum ether in a carbon dioxide atmosphere. The resulting and

Caroxazone

861

carotene melted at 180°C; ultraviolet absorption maxima at 452 and 480 nm. Preparation of the intermediates for the above chemical synthesis are also described in US. Patent 2,917,539. The other patents cited below describe a fermentation route. US Patent 2,848,508 describes preparation from carrots. References Merck Index 1837 PDR pp. 1501, 1734 I.N.P. 136 REM p. 1005 Barnett, H.M., Hartmann, M.L., Mosher, R.C. and Espoy, H.M.; US Patent 2,848,508; August 19, 1958; assigned to Barnett Isler, O., Montavon, M., Ruegg, R. and Zeller, P.; US Patent 2,917,539; December 15, 1959; assigned to Hoffmann - La Roche Inc. Zajic, J.E.; US Patents 2,959,521 and 2,959,522; November 8, 1960; both assigned to Grain Processing Corp. Miescher, G.M., US Patent 3,001,912; September 26, 1961; assigned to Commercial Solvents Cow. Zajic, J.E.; US Patent 3,128,236; April 7, 1964; assigned to Grain Processing Corp.

CAROXAZONE Therapeutic Function: Antidepressant Chemical Name: 2-Oxo-2H-1,3-benzoxazine-3(4H)-acetamide Common Name: Structural Formula:

Chemical Abstracts Registry No.: 18464-39-6 Trade Name

Manufacturer

Country

Year Introduced

Timostenil

Farmitalia

Italy

1975

Raw Materials Ethyl glycinate HCl Salicylic aldehyde Ammonia

Hydrogen Phosgene

862

Carphenazine maleate

Manufacturing Process 37.9 g of ethyl glycinate hydrochloride were dissolved in 400 cc of ethanol and 33.5 g of salicylic aldehyde were added. It is refluxed for half an hour and cooled. 38 cc of triethylamine and 25 g of Raney nickel are then added where after hydrogenation is carried out at room temperature and under atmospheric pressure. After hydrogen adsorption was complete, the mixture was filtered and the alcohol evaporated off. The residue was taken up with acidified water, extracted with ether to eliminate part of the by-products, consisting mainly of o-cresol, then made alkaline with ammonia and extracted with ethyl acetate. The solvent was removed in vacuo and the residue crystallized from ether/petroleum ether. 36.7 g of o-hydroxybenzylaminoacetic acid ethyl ester melting at 47°C are obtained. 20 g of this compound were dissolved in 100 cc of tetrahydrofuran and 100 cc of a 30% solution of phosgene in tetrahydrofuran solution were added. After one night at room temperature, the reaction mixture was dried, taken up with 150 cc of anhydrous pyridine and allowed to stand overnight. The pyridine was then removed in vacuo and the residue dissolved in benzol was washed several times with water and chromatographed over 250 g of alumina. Elution with benzene/petroleum ether yielded 16 g of 4H-3-carboethoxymethyl-1,3benzoxazine-2-one, melting at 90°-91°C. 5 g of this last compound were dissolved in 120 cc of absolute ethanol and saturated with NH3 at 0°C. It was allowed to stand overnight where after 1.5 g of 4H-3-carboxamidomethyl-1,3-andenzoxazine-2-one, melting at 205°C, were obtained. By evaporation from the mother liquors further quantities of the same product were obtained. References Merck Index 1842 Kleeman and Engel p. 157 OCDS Vol. 3 p. 191 (1984) DOT 12 (6) 236 (1976) I.N. p. 190 Bernardi, L., Coda, S., Pegrassi, L. and Suchowsky, G.K.; US Patent 3,427,313; February 11, 1969; assigned to Societa Farmaceutici Italia (Italy)

CARPHENAZINE MALEATE Therapeutic Function: Tranquilizer Chemical Name: 1-[10-[3-[4-(2-Hydroxyethyl)-1-piperazinyl]propyl]-10Hphenothiazin-2-yl]-1-propanone dimaleate Common Name: Carfenazine maleate Chemical Abstracts Registry No.: 2975-34-0; 2622-30-2 (Base)

Carphenazine maleate

863

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Proketazine

Wyeth

US

1962

Raw Materials 2-Propionylphenothiazine N-(2-Hydroxyethyl)piperazine

Sodium hydride Trimethylene chlorobromide

Manufacturing Process As described in US Patent 3,023,146, in a round-bottomed flask were placed 35 g of 2-propionyl phenothiazine (0.14 mol) 7 g of 50% sodium hydride in mineral oil (0.14 mol), and 240 cc of dimethyl formamide dried over sodium hydride. The resultant solution was stirred at room temperature for 2 hours, and then 88 g (0.56 mol) of trimethylene chlorobromide was added at once. The mixture was stirred for 2 hours, heated at 60 to 70°C for 1 hour and poured into 2 liters of H2O. The resulting suspension was extracted with ether, the ether layer separated and the ether removed under vacuum. A gummy mass remained which was dissolved in decalin and the solution was partly distilled to remove excess chlorobromide. After removal of most of the decalin under vacuum, the residue was treated with a large excess of N-(βhydroxyethyl)-piperazine and heated on a steam bath for 2 hours. This material was extracted with dilute aqueous HCl, this acid layer neutralized with aqueous base and the resulting oil extracted into ether. The ether layer was washed with water until the washings were neutral and dried over anhydrous potassium carbonate. On treatment with maleic acid in ether a yellow solid separated which was recrystallized from isopropanol. This yellow solid had MP 175° to 177°C. References Merck Index 1844 Kleeman and Engel p. 154

864

Carprofen

OCDS Vol. 1 p.383 (1977) I.N. p. 188 REM p. 1086 Tislow, R.F., Bruce, W.F. and Page, J.A.; US Patent 3,023,146; February 27, 1962; assigned to American Home Products Corporation Sherlock, M.H. and Sperber, N.; US Patent 2,985,654; May 23, 1961; assigned to Schering Corporation

CARPROFEN Therapeutic Function: Antiinflammatory Chemical Name: 6-Chloro-α-methylcarbazole-2-acetic acid Common Name: Structural Formula:

Chemical Abstracts Registry No.: 53716-49-7 Trade Name Imadyl Imadyl Imafen Rimadyt

Manufacturer Roche Roche Roche Roche

Country Switz. W. Germany -

Year Introduced 1981 1982 -

Raw Materials 6-Chloro-α-methyl-1,2,3,4-tetrahydrocarbazole-2-acetic acid ethyl ester p-Chloranil Sodium hydroxide Hydrogen chloride Manufacturing Process A mixture of 34.9 g of 6-chloro-α-methyl-1,2,3,4-tetrahydrocarbazole-2-acetic acid ethyl ester (mixture of diastereomers), 350 ml CP xylene and 56.0 g of p-chloranil was stirred and heated under an atmosphere of dry nitrogen. The reaction flask was wrapped in aluminum foil in order to keep out any extraneous light. After the reaction mixture had stirred at reflux temperature for 6 hours, heating and stirring were stopped and the reaction mixture was left overnight at room temperature. The supernatant liquid was decanted

Carteolol

865

through a filter. The residue was triturated with 100 ml of warm benzene and the supernatant liquid was decanted through a filter. This process was repeated three more times. Ether (300 ml) was added to the combined filtrates. The solution was extracted with cold 2 N sodium hydroxide (3 x 100 ml), washed by extraction with water until neutral and dried over anhydrous magnesium sulfate. Following filtration of the desiccant and evaporation of the solvent, a residue of 35.5 g remained. Crystallization from 50 ml of methanol gave 14.8 g of 6-chloro-α-methylcarbazole-2-acetic acid ethyl ester, MP 106°107.5°C (43.2%). A stirred mixture of 11 g of 6-chloro-α-methylcarbazole-2-acetic acid ethyl ester, 100 ml ethanol and 100 ml of 3 N sodium hydroxide was heated (N2 atmosphere). After 2 hours at reflux, the reaction mixture was concentrated to dryness under reduced pressure. Water (300 ml) and ice (200 g) were added to the residue and concentrated hydrochloric acid was added until the mixture was strongly acid. The acidic mixture was extracted with ether (3 x 200 ml). The ether extracts were combined, washed by extraction with water (3 x 100 ml) and dried over anhydrous magnesium sulfate. Following filtration of the desiccant and evaporation of the solvent, a yield of 9.89 (98.2%) was obtained. Crystallization from CHCl3 yielded 6.2 g (62.0%) of 6-chloro-αmethylcarbazole-2-acetic acid, MP 197°-198°C. A second crop of 1.6 g, MP 195°-199°C was obtained from the mother liquors. References Merck Index 1846 DFU 2 (1) 15 (1977) OCDS Vol. 3 p. 169 (1984) DOT 18 (4) 172 (1982) I.N. p. 191 Berger, L. and Corraz, A.J.; US Patent 3,896,145; July 22, 1975; assigned to Hoffmann-LaRoche, Inc.

CARTEOLOL Therapeutic Function: Beta-adrenergic blocker Chemical Name: 5-(3-tert-Butylamino-2-hydroxypropoxy)-3,4dihydrocarbostyril Common Name: Structural Formula:

866

Carticaine

Chemical Abstracts Registry No.: 51781-06-7 Trade Name Mikelan Endak

Manufacturer Otsuka Madaus

Country Japan W. Germany

Year Introduced 1981 1982

Raw Materials 5-Hydroxy-3,4-dihydrocarbostyril Epibromohydrin t-Butylamine Manufacturing Process A mixture of 1.63 g of 5-hydroxy-3,4-dihydrocarbostyril, 2.5 g of epibromohydrin and 2 drops of piperidine was heated at a temperature of 95°C to 100°C for a period of 4 hours with stirring. The reaction mixture was then concentrated to dryness under reduced pressure and the residue was recrystallized from acetone to obtain 1.2 g of 5-(2,3-epoxy)propoxy-3,4dihydrocarbostyril as a colorless powder having a melting point of 172°C to 173°C. A mixture of 0.75 g of 5-(2,3-epoxy)propoxy-3,4-dihydrocarbostyril, 1.0 g of tert-butylamine and 25 ml of ethanol was stirred at a temperature of from 50°C to 55°C for a period of 4 hours. Ethanol and unreacted tert-butylamine were distilled off under reduced pressure and the resulting residue was dissolved in acetone. References Merck Index 1850 DFU 2 (5) 288 (1977) Kleeman and Engel p. 158 OCDS Vol. 3 p. 183 (1984) DOT 18 (10) 551 (1982) and 19 (7) 413 (1983) I.N. p. 191 Tamura, Y., Nakagawa, K., Yoshizaki, S. and Murakami, N.; US Patent 3,910,924; October 7, 1975; assigned to Otsuka Pharmaceutical Co., Ltd.

CARTICAINE Therapeutic Function: Local anesthetic Chemical Name: 4-Methyl-3-[[1-oxo-2-(propylamino)propyl]amino]-2thiophene carboxylic acid methyl ester Common Name: Chemical Abstracts Registry No.: 23964-58-1; 23964-57-0 (Hydrochloride salt)

Carvedilol

867

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Ultracain

Hoechst

W. Germany

1976

Ultracain

Hoechst

France

1981

Raw Materials 3-Amino-2-carbomethoxy-4-methyl thiophene Chloropropionyl chloride n-Propylamine Manufacturing Process 3-α-Chloropropionylamino-2-carbomethoxy-4-methylthiophene (prepared from 3-amino-2-carbomethoxy-4-methylthiophene and chloropropionyl chloride) was dissolved in toluene and n-propylamine added. The whole mixture was heated to boiling for 6 to 7 hours. After cooling, the propylamine hydrochloride that had formed was removed by washing with water, The toluene phase was dried with sodium sulfate, and then the solvent and excess propylamine were removed by distillation. The oily residue was taken up in ether. The hydrochloride of 3-n-propylamino-α-propionylamino-2carbomethoxy-4-methylthiophene was obtained by introducing hydrogen chloride gas or by means of methanolic hydrogen chloride. The base boils at 162°C to 167°C under 0.3 mm of mercury pressure and the hydrochloride melts at 177°C to 178°C. References Merck Index 1853 Kleeman and Engel p. 158 DOT 12 (4) 132 (1976) Ruschig, H., Schorr, M., Muschaweck, R. and Rippel, R .; U.S. Patent 3,855,243; December 17, 1974; assigned to Farbwerke Hoechst AG (Germany)

CARVEDILOL Therapeutic Function: Beta-adrenergic blocker Chemical Name: 2-Propanol, 1-(9H-carbazol-4-yloxy)-3-((2-(2methoxyphenoxy)ethyl)amino)-

868

Carvedilol

Common Name: Carvedilol; Karvedilol Structural Formula:

Chemical Abstracts Registry No.: 72956-09-3 Trade Name

Manufacturer

Country

Year Introduced

Coreg

Roche

-

-

Coreg

GlaxoSmithKline

UK

-

Coropres

Roche

-

-

Dimitone

Roche

-

-

Eucardic

Roche

-

-

Raw Materials Epichlorohydrin 4-Hydroxycarbazole o-Methoxyphenoxyethylamine Manufacturing Process 1-(9H-Carbazol-4-yloxy)-3-((2-(2-methoxyphenoxy)ethyl)amino)-2-propanol may be synthesized by the method of preparation of S-(-)-(1-carbazol-4yloxy)-3-[2-(2-methoxyphenoxy)]ethylaminopropan-2-ol (Patent US 4,697,022 and 4,824,963). 27.5 g 4-hydroxycarbazole are dissolved in a mixture of 150 ml 1 N aqueous sodium hydroxide solution and 70 ml dimethylsulfoxide. To this is added at ambient temperature 13.9 g epichlorohydrin, followed by stirring for 18 hours at ambient temperature. 280 ml water are then added thereto, followed by stirring for 15 min and filtering off with suction. The filter residue is washed with 0.1 N aqueous sodium hydroxide solution and water and subsequently dissolved in methylene chloride. The methylene chloride solution is dried over anhydrous sodium sulfate, treated with active charcoal and floridin and evaporated. 4-(2,3-Epoxypropoxy)-carbazole is purified by recrystallising twice from ethyl acetate. From the mother liquors there are isolated a further 4(2,3-epoxypropoxy)-carbazole. 10 g 4-(2,3-epoxypropoxy)-carbazole are, together with 13.97 g omethoxyphenoxyethylamine, heated under reflux in 70 ml isopropanol for 2 hours. The solvent is evaporated off and the residue is stirred for 2 hours with a mixture of 115 ml toluene, 35 ml cyclohexane and 40 ml ethyl acetate. After filtering off with suction, the (1-carbazol-4-yloxy)-3-[2-(2-

Cefaclor

869

methoxyphenoxy)]-ethylaminopropan-2-ol is recrystallised from 150 ml ethyl acetate. References Leinert H., US Patent No. 4,697,022; Sep. 29, 1987; Assigned to Boehringer Mannheim GmbH Leinert H., US Patent No. 4,824,963; Apr. 25, 1989; Assigned to Boehringer Mannheim GmbH

CEFACLOR Therapeutic Function: Antibiotic Chemical Name: 7-(D-α-Phenylglycylamido)-3-chloro-3-cephem-4-carboxlic acid Common Name: Structural Formula:

Chemical Abstracts Registry No.: 53994-73-3 Trade Name Ceclor Panoral Distaclor Ceclor Alfatil Panacef Kefral Kefolor

Manufacturer Lilly Lilly Dista Lilly Lilly Lilly Shionogi Lilly

Country US W. Germany UK Switz. France Italy Japan -

Year Introduced 1979 1979 1979 1980 1980 1981 1982 -

870

Cefaclor

Raw Materials p-Nitrobenzyl-7-amino-3-chloro3-cephem-4-carboxylate HCl Methyl chloroformate

Hydrogen N,O-Bis-(trimethylsilyl)acetamide Methyl-3α-carboxybenzylaminocrotonate sodium salt

Manufacturing Process Preparation of 7-amino-3-chloro-3-cephem-4-carboxylic acid: To a solution of 750 mg (185 mmol) of p-nitrobenzyl 7amino-3-chloro-3cephem-4-carboxylate hydrochloride in 20 ml of tetrahydrofuran and 40 ml of methanol was added a suspension of 750 mg of prereduced 5% palladium on carbon catalyst in 20 ml of ethanol and the suspension was hydrogenated under 50 psi of hydrogen at room temperature for 45 minutes. The catalyst was filtered and washed with THF and water. The filtrate and catalyst washes were combined and evaporated to dryness, The residue was dissolved in a water-ethyl acetate mixture and the pH adjusted to pH 3. The insoluble product was filtered and triturated with acetone. The product was then dried to yield 115 mg of 7amino-3-chloro-3-cephem-4-carboxylic acid. Preparation of 7-(D-α-phenylglycylamido)-3-chloro-3-cephem-4-carboxylic acid: To a suspension of 280 mg (1.2 mmol) of 7-amino-3-chloro-3-cephem4-carboxylic acid in 14 ml of acetonitrile was added with stirring at room temperature 0.5 ml of N,O-bis-(trimethylsilyl)acetamide to form the soluble disilylmethyl derivative thereof. The solution was cooled to 0 C and was slowly added to a solution of the mixed anhydride formed by reacting 408 mg (1.5 mmol) of methyl-3-α-carboxybenzylaminocrotonate sodium salt with 161 mg (1.7 mmol) of methyl chloroformate in the presence to 2 drops of N,Ndimethylbenzyl amine in 7 ml of acetonitrile. The mixture was stirred at ice bath temperature for 2 hours, 1 ml of methanol was added and the mixture was filtered to remove insoluble impurities. Two milliliters of water were added to the filtrate and the pH was adjusted momentarily to pH 1.5, to effect removal of the enamine block, and then to pH 4.5 with triethylamine. After stirring for an additional hour at ice bath temperature the reaction product, 7-(D-α-phenylglycylamido)-3-chloro-3cephem-4-carboxylic acid (zwitterion) precipitated from the reaction mixture as a crystalline solid. The product was filtered, washed with acetonitrile and dried in vacuo to yield 200 mg. References Merck Index 1896 DFU 2 (6) 368 (1977) Kleeman and Engel p. 160 OCDS Vol. 3 p. 209 (1984) DOT 15 (7) 311 (1979) I.N. p. 193 REM p. 1184 Chauvette, R R.; British Patent 1,461,323; January 13, 1977; assigned to Eli Lilly and Co. Chauvette, R.R.; US Patent 3,925,372; December 9, 1975; assigned to Eli Lilly and Co.

Cefadroxil

871

CEFADROXIL Therapeutic Function: Antibacterial Chemical Name: 7-[[Amino-(4-hydroxyphenyl)acetyl]amino]-3-methyl-8oxo-5-thia-1-aza-bicyclo[4.2.0]- act-2-ene-2-carboxylic acid monohydrate Common Name: p-Hydroxycephalexine monohydrate Structural Formula:

Chemical Abstracts Registry No.: 50370-12-2 Trade Name

Manufacturer

Country

Year Introduced

Oracefal

Bristol

France

1977

Duricef

Mead Johnson

US

1978

Ultracef

Bristol

US

1980

Duracef

Ciba Geigy

Switz.

1980

Cephamox

Bristol

W. Germany

1980

Duracef

Bristol

Italy

1980

Sedral

Banyu

Japan

1982

Baxan

Bristol

UK

1982

Bidocef

Bristol-Myers

-

-

Cefos

C.T.

Italy

-

Droxicef

Alfa Farm.

Italy

-

Raw Materials Sodium N-(1-methoxycarbonyl-1-propen-2-yl)-D(-)-α-amino-(4hydroxyphenyl)acetate Ethyl chlorocarbonate 7-Amino-3-methyl-3-cephem-4-carboxylic acid Manufacturing Process 1.8 g of sodium N-(1-methoxycarbonyl-1-propen-2-yl)-D(-)-α-amino-(4hydroxyphenyl)acetate was suspended in 10 ml of acetone, and one droplet of N-methylmorpholine was added thereto, and the mixture was cooled to -15°C.

872

Cefamandole nafate sodium salt

There was added 0.85 g of ethyl chlorocarbonate thereto, and the mixture was reacted at -13°C to -10°C for 30 minutes, and then the reaction solution was cooled to -20°C. On the other hand, 1 g of 7-amino-3-methyl-3-cephem-4-carboxylic acid was suspended in 20 ml of methanol, and 1.4 g of triethylamine was added thereto to be dissolved, and 0.4 ml of acetic acid was further added thereto. This solution was cooled to -20°C and the mixed acid anhydride prepared previously was added thereto. After the mixture was reacted at -20°C for 1 hour, the temperature of the reaction mixture was raised to 0°C over a period of 1 hour, and the mixture was reacted for 3 hours at the same temperature. After the reaction, 1 ml of water was added to the reaction mixture, and the mixture was adjusted to a pH of 1.0 with concentrated hydrochloric acid while being cooled, and then stirred for 30 minutes, The insoluble matters were filtered off, and the filtrate was adjusted to a pH of 5.5 with triethylamine. This solution was concentrated under reduced pressure, and the residue was diluted with 20 ml of acetone to precipitate white crystals. The crystals were collected by filtration and washed with ethanol to obtain 1.46 g of white crystals of 7-[D(-)-α-amino-(4-hydroxyphenyl)acetamido]-3-methyl-3cephem-4-carboxylic acid having a decomposition point of 197°C. References Merck Index 1897 Kleeman and Engel p. 161 PDR pp.716, 1124 OCDS Vo1. 2 p. 440 (1980) DOT 13 (3) 126 (1977) and 13 (11) 471 (1977) I.N. p. 194 REM p. 1185 Ishimaru, T. and Kodama. Y.: US Patent 3,864,340; February 4, 1975; assigned to Toyama Chemical Co. Ltd. (Japan) Crast, L.B. Jr. and Gottstein, W.J.; US Patent 3,985,741; October 12, 1976; assigned to Bristol-Myers Co.

CEFAMANDOLE NAFATE SODIUM SALT Therapeutic Function: Antibiotic Chemical Name: Sodium 7-(D-2-formyloxy-2-phenylacetamido)-3-(1-methyl1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylate Common Name: Chemical Abstracts Registry No.: 42540-40-9; 34444-01-4 (Base) Trade Name Mandokef Kefadol

Manufacturer Lilly Lilly

Country W. Germany UK

Year Introduced 1977 1978

Cefamandole nafate sodium salt

873

Trade Name

Manufacturer

Country

Year Introduced

Mandol

Lilly

US

1978

Kefandol

Lilly

France

1978

Mandokef

Lilly

Italy

1981

Cedol

Tiber

Italy

-

Cefam

Magis

Italy

-

Cefman

I.B.P.

Italy

-

Cemado

Farmochimica

Italy

-

Cemandil

S.I.T.

Italy

-

Fado

Errekappa

Italy

-

Lampomandol

A.G.I.P.S.

Italy

-

Mandolsan

San Carlo

Italy

-

Neocefal

Gibipharma

Italy

-

Structural Formula:

Raw Materials Mandelic acid, DFormic acid Thionyl chloride Monotrimethyl silyl acetamide Sodium 2-ethylhexanoate 7-Amino-3-(1-methyl-1H-tetrazol-5-yl-thiomethyl)-3-cephem-4-carboxylic acid Manufacturing Process To 21.6 kg (17.8 l) of 98% formic acid was added 1.14 kg (7.5 mols) of D-(-)mandelic acid and the reaction mixture was heated for 4 hours at 70°C with stirring. The excess formic acid was evaporated off in vacuo and the residual syrup was dissolved in 6 l of benzene. The solution was washed twice with 6 l portions of water and was dried over magnesium sulfate. The drying agent was filtered and washed with 1.5 l of benzene, the washes being added to the filtrate. The dried filtrate was evaporated in vacuo to obtain the D-(-)mandelic acid formate ether as a syrup. The product can be crystallized from cyclohexane to yield material melting at about 55°C to 58°C.

874

Cefatrizine

The mandelic acid formate ester obtained as a syrup as described above is stirred for 2 hours with 2.9 kg (~1.75 l) of thionyl chloride at a temperature of about 70°C. The excess thionyl chloride is removed by evaporation and the residual green solution is vacuum distilled. The product, O-formyl mandeloyl chloride, distills over at 127°C to 130°C (15 mm) or at 108°C to 112°C (7 mm). To 13 l of ethyl acetate were added 85.1 g (2.59 mols) of 7-amino-3-(1methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid and 1,361 g (10.37 mols) of monotrimethylsilyl acetamide, and the mixture was stirred at 50°C until a clear solution was obtained. The solution was cooled to 20°C and 514 g (2.59 mold of O-formyl mandeloyl chloride was added at a rate such that the temperature of the reaction solution was maintained between about 20°C to 25% with ice-cooling. The reaction mixture was stirred for 1.5 hours at about room temperature after the addition of the mandeloyl chloride was completed. Five liters of water were then added to the reaction mixture and the diluted mixture was stirred for about 10 minutes. The organic layer was separated and was washed twice with water. The combined washes are extracted with 1.5 l of ethyl acetate and the extract is combined with the washed organic layer. The whole was dried over magnesium sulfate, filtered and evaporated in vacuo on a 25°C water bath to yield 1,460 g of product, 7-(D-2-formyloxy-2phenylacetamido)-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4carboxylic acid, as a yellow foam. The product was dissolved in 5 l of acetone and the solution was mixed with a solution of 430 g (2.59 mols) of sodium 2-ethylhexanoate in 5.4 l of acetone. The combined solutions were seeded and stirred in an ice bath for 1.5 hours. The crystalline precipitate of sodium 7-(D-2-formyloxy-2-phenylacetamido)-3(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylate was filtered and washed with 5 l of acetone. The crystalline salt was dried overnight in a vacuum oven at 40°C to yield 1,060 g (80%)of product, melting at 182°C to 184°C. References Merck Index 1898 DFU 2 (10) 646 (1977) Kleeman and Engel p. 166 PDR p. 1059 OCDS Vol. 2 p. 441 (1980) and 14 (4) 151 (1978) DOT 12 (5) 177 (1976) I.N.p. 196 REM p. 1185 Greene, J.M. and Indelicato, J.M.; US Patent 3,928,592; December 23, 1975; assigned to Eli Lilly and Co.

CEFATRIZINE Therapeutic Function: Antibiotic

Cefatrizine

875

Chemical Name: 7-[D-α-Amino-α-(p-hydroxyphenyl)acetamido]-3-(1,2,3triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid Common Name: Structural Formula:

Chemical Abstracts Registry No.: 51627-14-6 Trade Name

Manufacturer

Country

Year Introduced

Bricef

Bristol Banyu

Japan

1980

Cepticol

Banyu

Japan

1980

Cefatrix

Ausonia

Italy

1982

Latocef

Dukron

Italy

1982

Raw Materials 7-[D-α-t-Butoxycarbonylamino-α-(p-hydroxyphenyl)acetamido]-3-(1,2,3triazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid Formic acid Manufacturing Process A total 6.5 g (1 1.55 mmol) of 7-[D-α-t-butoxycarbonylamino-α-(phydroxyphenyl)acetamido]-3-(1,2,3-triazol-5-ylthiomethyl)-3-cephem-4carboxylic acid was dissolved in 175 ml (98 to 100% formic acid under anhydrous conditions. The mixture was stirred at room temperature for 2.5 hours. Part of the solution, 125 ml, was evaporated under reduced pressure to an amber oil. The oil was then azeotroped 3 times with 70 ml of toluene under reduced pressure. The residue was suspended in an 80:20 H2O-CH3OH solution (700 ml) and stirred for 0.5 hour until most of the solid dissolved, then filtered. The filtration was treated with 1.59 of (Darko) charcoal for about 20 minutes. The charcoal was filtered off through a Celite pad. The solution was then freeze-dried in 9 separate 100 ml round bottom flasks. The freezedried material weighed 2.415 g. It was recrystallized in batches of 0.200 g as described above to yield a total of 0.923 g 7-[D-α-amino-α-(p-hydroxyphenyl) acetamidol-3-(1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid. NMR was consistent, indicating the presence of 0.33 mol of CH3OH.

876

Cefazedone sodium

References Merck Index 1899 DFU 2 (10) 653 (1977) OCDS Vol. 3 p. 211 (1984) DOT 12 (5)183 (1976) I.N. p. 197 Kaplan, M.A. and Granatek, A.P.; US Patent 3,970,651; July 20, 1976; assigned to Bristol-Myers Co.

CEFAZEDONE SODIUM Therapeutic Function: Antibiotic Chemical Name: 5-Thia-1-azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid, 7(((3,5-dichloro-4-oxo-1(4H)-pyridinyl)acetyl)amino)-3-(((5-methyl-1,3,4thiadiazol-2-yl)thio)methyl)-8-oxo-, (6R-trans)-, sodium salt Common Name: Cefazedone sodium Structural Formula:

Chemical Abstracts Registry No.: 63521-15-3; 56187-47-4 (Base) Trade Name Cefazedone Sodium Cefazedone Sodium Cefazedone Sodium

Manufacturer Arocor Holdings Inc.

Country -

Yick-Vic Chemicals and Pharmaceuticals (HK) Ltd. CKD Pharm -

-

Refosporen

Teva Pharmaceuticals

-

-

Raw Materials tert-Butyl ester of 7-aminocephalosporanic acid Dicyclohexylcarbodiimide 3,5-Dichloro-4-pyridone-1-acetic acid Trifluoroacetic acid 5-Methyl-1,3,4-thiadiazole-2-thiol

Year Introduced -

-

Cefazolin sodium

877

Manufacturing Process A solution of 1 eq. of the tert-butyl ester of 7-aminocephalosporanic acid and 1 eq. of dicyclohexylcarbodiimide in 100 ml of methylene chloride/DMF (1:1) is cooled to 0°C. The mixture is combined with 1 eq. of 3,5-dichloro-4pyridone-1-acetic acid; after 5 min the ice bath is removed and the mixture agitated for another 30 min at 25°C. The thus-formed urea is filtered off and the filtrate filtered over silica gel (eluent: ethyl acetate/1% methanol). The solvent is concentrated by evaporation, and the thus-obtained tert-butyl ester of 7-(3,5-dichloro-1,4-dihydro-4-oxo-1-pyridylacetamido)cephalosporanic acid is crystallized from ether. 1 eq. of the tert-butyl ester is dissolved in 30 ml of trifluoroacetic acid. After 30 minutes, the solution is evaporated and the thus-produced 7-(3,5-dichloro1,4-dihydro-4-oxo-1-pyridylacetamido)cephalosporanic acid crystallized from ether. 1 eq. of the obtained 7-(3,5-dichloro-1,4-dihydro-4-oxo-1-pyridylacetamido) cephalosporanic acid is dissolved in 60 ml of saturated aqueous sodium bicarbonate solution at a pH of below 7 and combined with 1 eq. of 5-methyl1,3,4-thiadiazole-2-thiol in 20 ml of acetone. The reaction solution is agitated for 2 hours at 80°C and at a pH of 6.3 under a nitrogen atmosphere. The acetone is thereupon removed, the solution is washed with ether and acidified to pH 2. The thus-obtained 3-(1-methyltetrazolyl-5-mercaptomethyl)-7-(3,5dichloro-1,4-dihydro-4-oxo-1-pyridylacetamido)-3-cephem-4-carboxylic acid is filtered off and dried. IR spectrum confirmed the structure of cefazedone. In practice it is usually used as sodium salt. References Gericke R.; US Patent No. 4,153,693; May 8, 1979; Assigned to Merck Patent Gesellschaft mit beschrankter Haftung, Darmstadt, Fed. Rep. of Germany

CEFAZOLIN SODIUM Therapeutic Function: Antibacterial Chemical Name: (6R-trans)-3-([(5-Methyl-1,3,4-thiadiazol-2-yl)thio]methyl)8-oxo-7-([(1-H-tetrazol-1-yl)acetyl]amino)-5-thia-1-azabicyclo[4.2.0]oct2-ene-2-carboxylic acid sodium salt Common Name: Chemical Abstracts Registry No.: 27164-46-1; 25953-19-9 (Base)

878

Cefazolin sodium

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Cefamedin

Fujisawa

Japan

1971

Kefzol

Lilly

US

1973

Ancef

SKF

US

1973

Totacef

Bristol

Italy

1973

Grammaxin

W. Germany

1974

Kefzol

Boehringer Mannheim Lilly

UK

1974

Kefzol

Serum Impfinst.

Switz.

1974

Cefacidal

Allard

France

1976

Kefzol

Lilly

France

1976

Acef

Tiber

Italy

-

Areuzolin

Areu

Spain

-

Atirin

Intersint

Italy

-

Biazolina

Panthox and Burck Italy

-

Bor-Cefazol

Proter

Italy

-

Brizolina

Bristol-Myers

-

-

Caricef

Antibioticos

Spain

-

Cefacene

Centrum

Spain

-

Cefalomicina

Marxer

Argentina

-

Cefamezin

Fujisawa

Japan

-

Cefazina

Chemil

Italy

-

Celmetin

A.L.

Norway

-

Cromezin

Crosara

Italy

-

Elzogram

Lilly

W. Germany

-

Fidesporin

Fides

Spain

-

Firmacel

Firma

Italy

-

Kurgan

Normon

Spain

-

Legemzolina

Legem

Spain

-

Lifezolina

Lifepharma

Spain

-

Liviclina

Sierochimica

Italy

-

Maksipor

Fako

Turkey

-

Neofazol

Rubio

Spain

-

Vifazolin

Vianex

Greece

-

Zolicef

Bristol-Myers

W. Germany

-

Cefdinir

879

Raw Materials 7-Aminocephalosporanic acid 5-Methyl-1,3,4-thiadiazole-2-thiol Sodium bicarbonate

1H-Tetrazole-1-acetyl chloride Sodium hydroxide

Manufacturing Process 7-Aminocephalosporanic acid is converted to its sodium salt and acylated with 1H-tetrazole-1-acetyl chloride. The acetoxy group is then displaced by reaction with 5-methyl-1,3,4-thiadiazole-2-thiol in buffer solution. The product acid is converted to the sodium salt by NaHCO3. References Merck Index 1901 Kleeman and Engel p. 168 PDR pp. 1058, 1701 OCDS Vol. 3 p. 442 (1984) DOT 7 (5) 146, 167, 181 (1971) I.N. p. 197 REM p. 1185 Takano, T., Kurita, M., Nikaido, H., Mera, M., Konishi, N. and Nakagawa, R.; US Patent 3,516,997; June 23, 1970; assigned to Fujisawa Pharmaceutical Co., Ltd., Japan

CEFDINIR Therapeutic Function: Antibiotic Chemical Name: 5-Thia-1-azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid, 7(((2Z)-(2-amino-4-thiazolyl)(hydroxyimino)acetyl)amino)-3-ethenyl-8oxo-, (6R,7R)Common Name: Cefdinir; Cefdinyl Structural Formula:

Chemical Abstracts Registry No.: 91832-40-5

880

Cefdinir

Trade Name Manufacturer

Country

Year Introduced

Adcef

Torrent Pharmaceuticals Ltd. Sarabhai Piramal Pharmaceuticals Ltd.

India

-

India

-

Cefdiel

Ranbaxy Laboratories Limited

India

-

Cefzon

Fujisawa Pharmaceutical Co., Ltd.

-

-

Oceph Cap

Emcure Pharmaceuticals Ltd.

India

-

Omnicef

Hikma

-

-

Omnicef

Abbott Laboratories

-

-

Sefdin

Unichem Laboratories Ltd.

India

-

Zefdinir

German Remedies Limited

Germany

-

Cednir

Raw Materials 7-Amino-8-oxo-3-vinyl-5-thia-1-azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid 4-methoxyphenyl ester 4-Bromoacetyl bromide Sodium nitrite Trifluoroacetic acid Manufacturing Process By interaction of 7-amino-8-oxo-3-vinyl-5-thia-1-azabicyclo(4.2.0)oct-2-ene2-carboxylic acid 4-methoxyphenyl ester with 4-bromoacetyl bromide was prepared 7-(4-bromo-3-oxo-butyrylamino)-8-oxo-3-vinyl-5-thia-1-azabicyclo (4.2.0)oct-2-ene-2-carboxylic acid 4-methoxyphenyl ester. The active methylene group in that product was then nitrosated with sodium nitrite. The initial product spontaneously tautomerizes to afford 7-(4-bromo-2hydroxyimino-3-oxo-butyrylamino)-8-oxo-3-vinyl-5-thia-1-azabicyclo(4.2.0) oct-2-ene-2-carboxylic acid 4-methoxyphenyl ester. By the reaction of that compound with thiourea and then with trifluoroacetic acid was obtained (6R,7R)-7-(2-(2-amino-4-thiazolyl)glyoxylamido)-8-oxo-3-vinyl-5-thia-1azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid sodium nitrite, (Z)-oxime (Cefdinir sodium nitrile). In practice it is usually used as free acid. Synthesis of 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(trytiloxyimino)acetamido]-3vinyl-3-cephem-4-carboxylic acid x p-toluenesulfonic acid x 2 N,Ndimethylacetamide (the precursor of Cefdinir) was described in Patent US 6,093,814. References Inamoto Y. et al., J. Antibiotics, 1988, V. 41, P. 828 Org. Chem. Drug. Synth., V.6, P.170

Cefditoren pivoxil

881

Gwan S.L. et al.; US Patent No. 6,093,814; Jul 25, 2000; Assigned to Hanmi Pharmaceutical Co, Ltd., Rep. Korea

CEFDITOREN PIVOXIL Therapeutic Function: Antibiotic Chemical Name: 5-Thia-1-azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid, 7(((2Z)-(2-amino-4-thiazolyl)(methoxyimino)acetyl)amino)-3-((1Z)-2-(4methyl-5-thiazolyl)ethenyl)-8-oxo-, (2,2-dimethyl-1-oxopropoxy)methyl ester, (6R,7R)Common Name: Cefditoren pivoxil; Cefoviten pivoxil Structural Formula:

Chemical Abstracts Registry No.: 117467-28-4 Trade Name Meiact Spectracef Spectracef

Manufacturer Meiji Seika TAP Pharmaceuticals Abbott Laboratories

Country Japan -

Year Introduced -

Raw Materials (Z)-(2-Aminothiazol-4-yl)methoxyimino acetic acid Bis-(2-oxo-oxazolidinyl)phosphinic chloride 2-Mercapto-5-phenyl-1,3,4-oxadiazole 7-Amino-3-[(Z)-2-(methyl-5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid Triethylamine Manufacturing Process A mixture of THF (250 ml) and water (150 ml) was stirred under inert atmosphere. At 0°-1°C, 7-amino-3-[(Z)-2-(methyl-5-thiazolyl)vinyl]-3-

882

Cefepime

cephem-4-carboxylic acid (25.0 g) and 2-mercapto-5-phenyl-1,3,4oxadiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2-methoxyimino acetate (33.3 g) were added. Triethylamine (10.5 g) was slowly added to reaction by maintaining the pH between 7.5 to 8.5. The reaction was monitored by HPLC. After 4-5 hrs., the reaction mixture was extracted by methylene chloride. The aqueous layer is subjected for charcoal (0.125 g) treatment. Ethylacetate was added to the filtrate and the solution was acidified with diluted HCl at 10°C to pH 3.0. The solid separated was filtered, washed with water and ethylacetate and then dried under vacuum at 40-45°C to get 3-[(Z)-2-(4-methyl-5-thiazolyl)vinyl]-7[(Z)-(2-aminothiazolyl-4-yl)-2-(methoxyimino)acetamido]-3-cephem-4carboxylic acid (Cefditoren acid), 35.0 g (yield 90%), HPLC (purity)=96-98%. In practice it is often used as Cefditoren pivoxil. References Deshpande P. B., Luthra P. K.; US Patent No. 6,713,625; August 27, 2002; Assigned to Orchid Chemicals and Pharmaceuticals Ltd. Yasui K. et al.; US Patent No. 6,441,162; August 27, 2002; Assigned to Meiji Seika Kaisha, Ltd. (Tokyo, JP)

CEFEPIME Therapeutic Function: Antibiotic Chemical Name: Pyrrolidinium, 1-(((6R,7R)-7-(((2Z)-(2-amino-4-thiazolyl) (methoxyimino)acetyl)amino)-2-carboxy-8-oxo-5-thia-1-azabicyclo(4.2.0) oct-2-en-3-yl)methyl)-1-methyl-, inner salt Common Name: Cefepime Structural Formula:

Chemical Abstracts Registry No.: 88040-23-7 Trade Name Ceficad Forpar

Manufacturer Cadila Pharmaceuticals Ltd. Cipla Limited

Country India India

Year Introduced -

Cefepime

883

Trade Name

Manufacturer

Country

Year Introduced

Ivipime

VHB Life Sciences

India

-

Maxicef

Aristo Pharmaceutical Ltd.

India

-

Maxipime

Bristol-Myers Squibb

USA

-

Maxipime

EPI

USA

-

Ultipime

Recon Healthcare Ltd.

India

-

Zwiter

Lyka Hetro Labs. Ltd.

India

-

Raw Materials Ethyl (Z)-2-hydroxyimino-2-(2-tritylaminothiazol-4-yl) acetate Methyliodide 7-Phenylacetimidocephalosporanic acid sodium salt Diphenyldiazomethane Bis(trimethylsilyl)acetamide Potassium carbonate Phosphorus pentachloride Manufacturing Process A mixture of ethyl (Z)-2-hydroxyimino-2-(2-tritylaminothiazol-4-yl) acetate (5 g, 10.9 mmoles), methyliodide (2.04 ml, 32.8 mmoles) and K2CO3 (4.54 g, 32.8 mmoles) in dry DMSO (100 ml) was stirred at room temperature overnight and then poured into water (250 ml). The precipitate was collected, washed with water and dried to give 2-methoxyimino-2-(2-tritylaminothiazol4-yl) acetate (1.15 g, melting point 115°C (dec.)) Ethyl (Z)-2-hydroxyimino-2-(2-tritylaminothiazol-4-yl) acetate (6 g, 12.7 mmol) in ethanol was treated with 2 N NaOH (12.7 ml) at room temperature overnight. The mixture was adjusted to pH 8 by the addition of powdered dry ice and the solvent evaporated. The residue was dissolved in water (100 ml) and was added to the solution which was acidified with 1 N HCl to pH 2 and then extracted with ethyl acetate. Extract was evaporated, the residue was crystallized from ethyl acetate-hexane to afford ethyl (Z)-2-hydroxyimino-2(2-tritylaminothiazol-4-yl)acetic acid (5.56 g, melting point 138-143°C (dec.)). To a suspension of phosphate buffer (pH 7, 162.5 ml) and wheat bran (20 g, dry) at room temperature was added 7-phenylacetimidocephalosporanic acid sodium salt (5 g). After 5 hours the suspension was filtered to remove wheat bran and the filtrate was cooled to 5-10°C, then was added methylene chloride (32 ml) and 0.5 M solution of diphenyldiazomethane in methylene chloride (24 ml). The pH was then adjusted to 3.0 with 28% phosphoric acid. After 1 hour the mixture was allowed to rise to 20°C. Heptane was slowly added (56 ml) and was recovered benzhydryl 3-hydroxymethyl-7phenylacetamido-3-cephem-4-carboxylate (3.0 g, 50%). The mixture of PCl5(8.3 g) and pyridine (3.2 g) in CH2Cl2 was added to benzhydryl 3-hydroxymethyl-7-phenylacetamido-3-cephem-4-carboxylate (5.1 g) at -40°C. The mixture was stirred at -10°C for 15 minutes and allowed to stand at -15-10°C for 7 hours. To the solution at -20°C was added propane1,3-diol (10 ml) and the mixture was allowed to stand at -20°C for 16 hours

884

Cefepime

and then at room temperature for 20 minutes. The resulting solution was washed with ice-water and saturated aqueous NaCl (10 ml), dried and concentrated. The gummy residue (12 g) was dissolved in CHCl3-hexane (2:1), and subjected to chromatography using silica gel column and the same solvent as eluant. After evaporation of the solvents was obtained benzhydryl7-amino-3-chloromethyl-3-cephem-4-carboxylate (2.1 g, 51%, melting point >110°C(dec.)). Benzhydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylate (2.29 g) was treated with bis(trimethylsilyl)acetamide (4.06 ml) at room temperature for 50 min to give a clear solution. Top the solution was added an acid chloride solution, which was prepared from (Z)-2-hydroxyimino-2-(2tritylaminothiazol-4-yl)acetic acid (2.04 g) and PCl5 (1.15 g) in methylene chloride (20 ml). The mixture was stirred at room temperature for 30 min, poured in cold water (200 ml) and extracted with ethyl acetate (100 ml x 3). After evaporation of the solution was obtained the syrup (4 g) which was chromatographed on a silica gel column by eluting with 10:1 and 3:1 mixture of toluene and ethyl acetate successively. After evaporation of the solvents was obtained benzhydryl 3-chloromethyl-7-[(Z)-2-methoxyimino-2-(2tritylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (2.62 g, 68%). A mixture of the benzhydryl 3-chloromethyl-7-[(Z)-2-methoxyimino-2-(2tritylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (1.50 g, 1.79 mmoles) and NaI (1.34 g, 8.93 mmoles) in methyl ethyl ketone (30 ml) was stirred at room temperature for 1 hour. After evaporation of the solvent the residue was dissolved in ethyl acetate (100 ml) and washed with water, aqueous Na2S2O3 and aqueous NaCl, dried and evaporated to give 7-[(Z)-2ethoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-iodomethyl-3-cephem4-carboxilate (1.47 g, 89%) as an amorphous powder. A mixture of 7-[(Z)-2-ethoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3iodomethyl-3-cephem-4-carboxilate (4.5 g, 4.83 mmoles) and Nmethylpyrrolidine (0.65 ml, 6.28 mmoles) in CH2Cl2 (45 ml) was stirred at room temperature for 20 min. Ether (300 ml) was added to the mixture to separate the quaternary salt of the blocked cephalosporin, which was collected by filtration and treated with 90% trifluoroacetic acid (TFA) (40 ml) at room temperature for 1 hour. The mixture was then evaporated under reduced pressure below 20°C. The residue was triturated with ether to give the TFA salt of 7-[(Z)-2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[(1methyl-1-pyrrolidinium)methyl]-3-cephem-4-carboxylate (2.40 g), which was dissolved in methanol (5 ml) and treated with 1 M solution of sodium-2ethylhexoate in ethyl acetate (8 ml) at room temperature for 30 min. After the addition of ethyl acetate (100 ml), the precipitate (1.94 g) formed was collected by filtration. HPLC analysis showed that the crude product was 7% pure with a 1:8 ratio of the δ3 isomer to the δ2 isomer. Purification of the product by HPLC was repeated three times (Lichrosorb RP-18, eluted with 5% aqueous methanol or 0.01 M ammonium phosphate buffer (pH 7.2 containing 5% of methanol) to give 35 mg (1.5%) of the title product as a colorless powder of 7-[(Z)-2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[(1methyl-1-pyrrolidinium)methyl]-3-cephem-4-carboxylate. Estimated purity (by HPLC) 90%. M.p. 150°C (dec.).

Cefixime

885

References Aburaki Sh. et al.; US Patent No. 4,406,899; 09.27.1983; Assigned to BristolMyers Company

CEFIXIME Therapeutic Function: Antibiotic Chemical Name: 5-Thia-1-azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid, 7(((2Z)-(2-amino-4-thiazolyl)(carboxymethoxy)imino)acetylamino)-3ethenyl-8-oxo-, (6R,7R)Common Name: Cefixime; Cefvixime Structural Formula:

Chemical Abstracts Registry No.: 79350-37-1 Trade Name

Manufacturer

Country

Year Introduced

Acrotex

Acron Pharmaceuticals

India

-

Biotax-O

Biochem Pharma Industries

-

-

Cebay D. Syp.

Leben Laboratories Pvt. Ltd.

India

-

Cefaden-O

Eden Healthcare

India

-

Cefex

Talent Laboratories

India

-

Cefixime

Rhone-Poulenc Rorer

-

-

Cefnax

Andromaco

-

-

Cefspan

Hikma Pharmaceuticals

Iordania

-

Cefspan

Glaxo Smithkline

-

-

Ceftiwin

Parenteral Drugs (India) Ltd. India

-

Defender

Skymax Laboratories Pvt. Ltd.

India

-

Evacef O

Neon Laboratories Ltd.

India

-

Excef-DT

Ind-Swift Ltd.

India

-

886

Cefmenoxime

Trade Name Exime Fixx Lyceft-O Ocef Omnatax-O O-Powercef Pancef-O Pedixim Suprax Suprax

Manufacturer J.K. Drugs and Pharmaceuticals Ltd. Unichem Laboratories Ltd. Lyka Hetro Labs. Ltd. Osper Pharmanautics Pvt. Ltd.

Country India

Year Introduced -

India India India

-

Nicholas Piramal India Ltd. (Npil) Wockhardt Ltd. Aglowmed Limited Biological E. Limited Hikma Pharmaceuticals Aventis Pharma

India

-

India India India Iordania -

-

Raw Materials 7-Amino-3-vinyl-3-cephem-4-carboxylic acid 2-(Aminothiazol-4-yl)-2-(tert-butoxycarbonylmethoxyimino)acetic acid Smercaptobenzothiazole ester Triethylamine Manufacturing Process To a suspension of 7-amino-3-vinyl-3-cephem-4-carboxylic acid (11.25 g), 2(aminothiazol-4-yl)-2-(tert-butoxycarbonylmethoxyimino)acetic acid Smercaptobenzothiazole ester (23.88 g) in ethylacetate (266 ml) and water (9 ml) at 2°C is added triethylamine. After completion of the reaction, water is added and pH is adjusted to 2.1 with diluted sulfuric acid. The phases are separated and the aqueous phase is extracted with ethylacetate. The organic extracts are combined and concentrated to a volume of 120 ml, then acetonitrile (100 ml) and formic acid (22 ml) are added. The mixture is stirred at 30-35°C for 1 hour. The mixture is cooled to 2°C, the precipitate is filtered, washed with acetonitrile and dried to obtain 20.86 g of 5-thia-1azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid, 7-(((2Z)-(2-amino-4thiazolyl)(carboxymethoxy)imino)acetylamino)-3-ethenyl-8-oxo-, (6R,7R)(Cefixime). References Carbi W. et al.; WO03040148, Nov. 9, 2001

CEFMENOXIME Therapeutic Function: Antibacterial Chemical Name: 7β-[α-Methoxyimino-α-(2-aminothiazol-4-yl)acetamido]-3(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid

Cefmenoxime

887

Common Name: Structural Formula:

Chemical Abstracts Registry No.: 65085-01-0 Trade Name Tacef Bestcall

Manufacturer Takeda Takeda

Country W. Germany Japan

Year Introduced 1983 1983

Raw Materials 7β-[α-Methoxyimino-α-(2-aminothiazol-4-yl)acetamido] cephalosporanicacid trifluoroacetic acid salt 1-Methyl-5-mercapto-1H-tetrazole Manufacturing Process 7β-[α-Methoxyimino-α-(2-aminothiazol-4-yl)acetamido]cephalosporanicacid trifluoroacetic acid salt is dissolved in a solution of 272 mg of 1-methyl-5mercapto-1H-tetrazole, 555 mg of sodium bicarbonate and 68 mg of triethylbenzylammonium bromide in 10 ml of water. The solution is heated at 60°C in nitrogen atmosphere for 6 hours. After cooling, the reaction solution is passed through a column of Amberlite XAD-2 and eluted with water and then with 2.5% ethanol. The procedure yields sodium 7β-[α-methoxyimino-α(2-aminothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3cephem-4-carboxylate, MP 174°C to 175°C (decomposition). References Merck Index 1902 DFU 5 (3) 146 and (12) 635 (1980) (as SCE-1365) DOT 19 (6) 335 and (8) 429 (1983) I.N. p. 198 REM p. 1189 Ochiai, M., Okada, T., Aki, O., Morimoto, A., Kawakita, K. and Matsushita, Y.; US Patent 4,098,888; July 4, 1978; assigned to Takeda Chemical Industries, Ltd.

888

Cefoperazone

CEFOPERAZONE Therapeutic Function: Antibiotic Chemical Name: 7-[D-(-)-α-(4-Ethyl-2,3-dioxo-1-piperazinecarboxamido)-α(4-hydroxyphenyl)acetamido]-3-[(1-methyl-1H-tetrazol-5-yl)thiomethyl]3-cephem-4-carboxylic acid Common Name: Structural Formula:

Chemical Abstracts Registry No.: 62893-19-0; 62893-20-3 (Sodium Salt) Trade Name

Manufacturer

Country

Year Introduced

Cefobid

Pfizer

W. Germany

1981

Cefobine

Pfizer

France

1981

Cefobis

Pfizer

Switz.

1981

Cefoperazin

Pfizer Taito

Japan

1982

Cefobid

Roerig

US

1982

Raw Materials 7-[D-(-)-α-Amino-p-hydroxyphenylacetamido]-3-[5-(1-methyl-1,2,3,4tetrazolyl)-thiomethyl]-δ(3)-cephem-4-carboxylic acid 4-Ethyl-2,3-dioxo-1-piperazinocarbonyl chloride Manufacturing Process To a suspension of 3.0 g of 7-[D-(-)-α-amino-p-hydroxyphenylacetamido]-3[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-∆3-cephem-4-carboxylic acid in 29 ml of water was added 0.95 g of anhydrous potassium carbonate. After the solution was formed, 15 ml of ethyl acetate was added to the solution, and 1.35 g of 4-ethyl-2,3-dioxo-1-piperazinocarbonyl chloride was added to the resulting solution at 0°C to 5°C over a period of 15 minutes, and then the mixture was reacted at 0°C to 5°C for 30 minutes. After the reaction, an aqueous layer was separated off, 40 ml of ethyl acetate and 10 ml of acetone

Cefotaxime sodium

889

were added to the aqueous layer, and then the resulting solution was adjusted to a pH of 2.0 by addition of dilute hydrochloric acid. Thereafter, an organic layer was separated off, the organic layer was washed two times with 10 ml of water, dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was dissolved in 10 ml of acetone, and 60 ml of 2-propanol was added to the solution to deposit crystals. The deposited crystals were collected by filtration, washed with 2propanol, and then dried to obtain 3.27 g of 7-[D-(-)-α-(4-ethyl-2,3-dioxo)-1piperazinocarbonylamino)-p-hydroxyphenylacetamido]-3-[5-(1-methyl1,2,3,4-tetrazolyl)thiomethyl]-∆3-cephem-4-carboxylicacid, yield 80.7%. The product forms crystals, MP 188°C to 190°C (with decomposition). References Merck Index 1905 DFU 4 (9) (675) and (12) 911 (1979) (as T-1551) Kleeman and Engel p. 169 PDR p. 1521 DOT 17 (12) 535 (1981) I.N. p. 198 REM p. 1185 Saikawa, I., Takano, S., Yoshida, C., Takashima, O., Momonoi, K., Kuroda, S., Komatsu, M., Yasuda, T. and Kodama, Y.; British Patent 1,508,071; April 19, 1978;assigned to Toyama Chemical Co., Ltd. and US Patent 4,110,327; August 29, 1978; also assigned to

CEFOTAXIME SODIUM Therapeutic Function: Antibiotic Chemical Name: Sodium 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2methoxyimino]-acetamido-3-cephem-4-carboxylate Common Name: Structural Formula:

890

Cefotaxime sodium

Chemical Abstracts Registry No.: 64485-93-4; 63527-52-6 (Base) Trade Name Claforan Claforan Claforan Zariviz Claforan Claforan Cefotax Claforan Pretor Primafen Ralopar Tolvcar

Manufacturer Hoechst-Roussel Roussel Maestretti Roussel Hoechst Roussel-Hoechst Roussel Roussel Hoechst Hoechst Hoechst Hoechst Hoechst

Country W. Germany Italy France Italy Switz. UK Japan US -

Year Introduced 1980 1980 1980 1980 1981 1981 1981 1981 -

Raw Materials Sodium bicarbonate 3-Acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylic acid (Cefotaxime) Manufacturing Process A solution of 8 g of sodium bicarbonate in about 20 ml of ethanol was progressively added to 45.55 g of pure 3-acetoxymethyl-7-[2-(2-amino-4thiazolyl)-2-methoxyiminoacetamido]-ceph-3-eme-4-carboxylic acid in 100 ml of distilled water and another 80 ml of ethanol and 4.5 g of activated carbon were added thereto. The mixture was stirred for 5 minutes and was filtered. The filter was rinsed with ethanol and the filtrate was evaporated to dryness under reduced pressure. The residue was taken up in 100 ml of ethanol and evaporated to dryness again. The residue was dissolved in 100 ml of methanol and the solution was poured into 2 l of acetone. The mixture was vigorously stirred and was vacuum filtered. The recovered product was rinsed with acetone and then ether and dried under reduced pressure to obtain 43.7 g of a white product which rehydrated in air to obtain a final weight of 45.2 g of sodium 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2methoxyiminoacetamido]-ceph-3-eme-4-carboxylate. References Merck Index 1907 DFU 3 (12) 905 (1978) Kleeman and Engel p. 171 PDR p. 935 OCDS Vol. 3 p. 216 (1984) DOT 17 (1) 16 (1981) I.N.p. 198 REM p. 1186 Heymes, R. and Lutz, A.; US Patent 4,152,432; May 1, 1979; assigned to Roussel Uclaf

Cefotiam

891

CEFOTIAM Therapeutic Function: Antibiotic Chemical Name: 5-Thia-1-azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid, 7(((2-amino-4-thiazolyl)acetyl)amino)-3-(((1-(2-(dimethylamino)ethyl)1H-tetrazol-5-yl)thio)methyl)-8-oxo-, (6R-trans)Common Name: Cefotiam; Ceftiazole Structural Formula:

Chemical Abstracts Registry No.: 61622-34-2 Trade Name

Manufacturer

Country

Year Introduced

Cefotiam

Qingdao Ftz United International Inc.

-

-

Cefotiam

Terio Corporation

-

-

Cefotiam

Arocor Holdings Inc.

-

-

Ceradolan

Takeda

-

-

Halospor

Novartis

-

-

Halospor

Ciba-Geigy

-

-

Sporidyn

Zoja

-

-

Spizef

Grunenthal

-

-

Pansporin

Takeda

-

-

Taketiam

Takeda

-

-

Texodil

Cassenne

-

-

Raw Materials 7-Acetamindocephalosporinic acid 1-(2-Dimethylaminoethyl-1Htetrazol-5-thiol 2-(2-Aminothiazol-4-yl)acetic acid

Hydroxylamine hydrochloride N-Hydroxysuccinimide Triethylamine Amberlite

892

Cefoxitin sodium

Manufacturing Process 2 mmol of 7-acetamindocephalosporinic acid in phosphate buffer (pH 7), 2 mmol of 1-(2-dimethylaminoethyl-1H-tetrazol-5-thiol and 2.2 mmol of sodium hydrogen carbonate are mixed and resulting solution was stirred at 60°-65°C for 16 hours. After cooling the mixture was adjusted pH 3.6 and hydrochloride of NH2OH was added to give 7-amino-3-[2-(2-dimethylaminoethyl)-2Htetrazol-5-ylsulfanylmethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2carboxylic acid. 0.4 g (2 mmol) of 2-(2-aminothiazol-4-yl)acetic acid hydrochloride in 10 ml of dimethylformamide are dissolved, 0.25 g (2.2 mmol) of N-hydroxysuccinimide and 0.412 g (2 mmol) of dicyclohexylcarbodiimide and the solution is allowed to stand at room temperature for 3 hours. The reaction mixture is subjected to filtration under suction to remove the precipitate of N,N'-dicyclohexylurea. The filtrate is added at a stroke to a solution of 2 mmol of above prepared 7amino-3-[2-(2-dimethylaminoethyl)-2H-tetrazol-5-ylsulfanylmethyl]-8-oxo-5thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 0.404 g (4 mmol) of triethylamine in 20 ml of dichloromethane and the mixed solution is stirred for 24 hours at room temperature. The solvent is distilled off under reduced pressure and the residue is adjusted pH from to 6 to 7 by adding a 10% aqueous solution of sodium hydrogen carbonate. The resultant solution is chromatographed on column of polystyrene resin (Amberlite XAD-2) and developed with water. The fractions containing the desired product are pooled and freeze-dried to obtain the title product. References Numata M. et al.; US Patent No. 4,517,361; May 14, 1985; Assigned to Takeda Chemical Industries, Ltd., Osaka, Japan Tsushima S. et al.; US Patent No. 4,245,088; Jan. 13, 1981; Assigned to Takeda Chemical Industries, Ltd., Osaka, Japan

CEFOXITIN SODIUM Therapeutic Function: Antibiotic Chemical Name: 3-Carbamoyloxymethyl-7-α-methoxy-7β-(2thienylacetamido)decephalosporanic acid sodium salt Common Name: Structural Formula:

Cefoxitin sodium

893

Chemical Abstracts Registry No.: 33654-30-6; 35607-66-0 (Base) Trade Name

Manufacturer

Country

Year Introduced

Mefoxin

Merck Sharp and Dohme

US

1978

Mefoxitin

Sharp and Dohme

W. Germany

1978

Mefoxin

MSD

UK

1978

Mefoxitin

MSD

Switz.

1979

Mefoxin

MSD

Italy

1979

Cenomicin

Daiichi Seiyaku

Japan

1980

Mefoxin

MSD

France

1980

Merkicin

Merck-Banyu

Japan

1980

Betacel

Firma

Italy

-

Boncefin

MSD

-

-

Cefaxicina

Cefa

Spain

-

Cefoctin

Teva

Israel

-

Farmoxin

Farm. Carlo Erba

Italy

-

Raw Materials Benzhydryl 3-carbamyloxymethyl-7α-hydroxy-7β-(2-thienylacetamino)decephalosporanate Sodium hydride Dimethyl sulfate Trifluoroacetic acid Manufacturing Process Benzhydryl 3-carbamoyloxymethyl-7α-hydroxy-7β-(2-thienylacetamido) decephalosporanate, 543 mg, is stirred in 15 ml dry DMSO. Sodium hydride, 24 mg (48 mg of a 50% suspension of NaH in mineral oi1, which has been washed with hexane to remove the oil), is added. When hydrogen evolution has ceased, 126 mg dimethyl sulfate is added. The solution is stirred for one hour at room temperature, diluted with 100 ml benzene and washed six times with water; the last wash is made to pH 8, if necessary, by adding sodium bicarbonate. The solution is dried over MgSO4, filtered and evaporated, leaving benzhydryl 3-carbamoyloxymethyl-7β-(2-thienylacetamido)-7αmethoxydecephalosporanate, which may be purified if desired by chromatography on silica gel, eluting with 25:1 chloroformethyl acetate. Other methylating agents may be used in place of methyl sulfate, e.g., an equimolar amount of methyl iodide, bromide or chloride, using the same conditions, or methyl trifluoromethylsulfonate or trimethyloxonium trinitrobenzenesulfonate. The solvent in the latter two reagents is dimethyl ether-HMPA 1:1, using a reaction temperature of -20°C warming later to 25°C. In each instance, the benzhydryl 3-carbamoyloxymethyl-7β-(2thienylacetamido)-7α-methoxydecephalosporanate is obtained. Benzhydryl 3-carbamoyloxymethyl-7β-(2-thienylacetamido)-7αmethoxydecephalosporanate (300 mg) in 0.5 ml in anisole and 2.5 ml of trifluoroacetic acid is reacted for 15 minutes at 10°C. The resulting mixture is

894

Cefpodoxime proxetil

evaporated at reduced pressure and flushed twice with anisole. The residue is dissolved in methylene chloride and extracted with 5% sodium bicarbonate solution. The aqueous solution is adjusted to pH 1.8 with 5% phosphoric acid and extracted with ethyl acetate. The organic solution is dried and evaporated to yield the pure 3-carbamoyloxymethyl-7α-methoxy-7β-(2thienylacetamido)decephalosporanic acid, MP 165°C to 167°C. This may then be converted to the sodium salt. References Merck Index 1910 DFU 3 (6) 434 (1978) Kleeman and Engel p. 173 PDR p. 1194 OCDS Vol. 2 pp. 435, 443 (1980) DOT 14 (2) 545 (1978) I.N. p. 199 REM p. 1186 Christiansen, B.G. and Firestone, R.A.; US Patent 3,775,410; November 27, 1973; assigned to Merck and Company, Inc. Hazen, G.C.; US Patent 3,780,033; December 18, 1973; assigned to Merck and Company, Inc.

CEFPODOXIME PROXETIL Therapeutic Function: Antibiotic Chemical Name: 5-Thia-1-azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid, 7(((2Z)-(2-amino-4-thiazolyl)(methoxyimino)acetyl)amino)-3(methoxymethyl)-8-oxo-, 1-(((1-methylethoxy)carbonyl)oxy)ethyl ester, (6R,7R)Common Name: Cefpodoxime proxetil Structural Formula:

Chemical Abstracts Registry No.: 87239-81-4

Cefpodoxime proxetil

895

Trade Name

Manufacturer

Country

Year Introduced

Cefpodoxime proxetil

Ranbaxy Laboratories Limited Hoechst Marion Roussel Pharmacia and Upjohn

India

-

-

-

-

-

Orelox Vantin

Raw Materials 7-Amino-3-methoxymethyl-3-cephem-4-carboxylic acid 1,8-Diazabicyclo[5.4.0]undec-7-ene Z-(2-Formamidothiazol-4-yl)-methoxy-acetyl chloride hydrochloride Manufacturing Process A suspension of 30 g of 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid in 300 ml acetone is mixed with 18.6 g 1,8-diazabicyclo[5.4.0]undec-7ene. The solution obtained mixed at ca. 0°C with 261 g of a 14% toluene solution of 1-iodoethylisopropyl carbonate. After 4 hours the solution is poured onto a mixture of 600 ml of water and 21 ml conc. HCl. The pH of mixture is adjusted to ca. 1.0. The aqueous phase is extracted with 200 ml of hexane, mixed with 700 ml ethyl acetate and pH is adjusted to ca. 8.2. A solution of 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid 1(isopropoxycarbonyloxy)ethyl ester is obtained. Diastereoisomeric ratio B/(A+B)=0.49 (B is more apolar of the two diastereoisomers). To a solution of 37.4 g of 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid 1-(isopropoxycarbonyloxy)ethyl ester in 689 ml ethyl acetate at 2-3°C is added for 25 min 0.105 moles Z-(2-formamidothiazol-4-yl)-methoxy-acetyl chloride hydrochloride. After 25 min pH is adjusted to ca. 6.5-7.3. After 1 hour the organic layer is washed with water and concentrated. It was obtained a crude 5-thia-1-azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid, 7-(((2Z)-(2amino-4-thiazolyl)(methoxyimino)acetyl)amino)-3-(methoxymethyl)-8-oxo-, 1-(((1-methylethoxy)carbonyl)oxy)ethyl ester, (6R,7R)- (Cefpodoxime proxetil). Diastereoisomeric ratio 0.49. For purification 5 g of cefpodoxime proxetil are added to a mixture of 35 ml of methanol and 0.6 ml conc. H2SO4. The mixture is stirred for 90 min and slowly added during 25 min to a mixture of 2.1 g sodium bicarbonate and 400 ml water. The suspension obtained is stirred for 1 hour and the precipitate is isolated through a suction filter, washed with water and dried over phosphorus pentoxide at 35°C in a vacuum. 5-Thia-1-azabicyclo(4.2.0)oct-2-ene-2carboxylic acid, 7-(((2Z)-(2-amino-4-thiazolyl)(methoxyimino)acetyl)amino)3-(methoxymethyl)-8-oxo-, 1-(((1-methylethoxy)carbonyl)oxy)ethyl ester, (6R,7R)-; (Cefpodoxime proxetil) is obtained in a diastereoisomeric ratio 0.528. References Takaya T. et al.; US Patent No. 4,409,215; 10.11.1983; Assignee to Fujisawa Pharmaceutical Co., Ltd, Japan.

896

Cefprozil

Nakao H. et al.; US Patent No. 4,486,425; Dec. 4, 1984; Assigned to Sankyo Co., Ltd. (Tokyo) Grell Ju. et al.; US Patent No. 6,489,470; 12.03.2002; Assigned to Biochemie Gesellschaft Lee G.-S. et al.; US Patent No. 6,620,930; Assigned to Hanml Pharm. Co., Ltd.

CEFPROZIL Therapeutic Function: Antibiotic Chemical Name: 5-Thia-1-azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid, 7(((2R)-amino(4-hydroxyphenyl)acetyl)amino)-8-oxo-3-(1-propenyl)-, (6R,7R)Common Name: Cefprozil; Cephprozyl Structural Formula:

Chemical Abstracts Registry No.: 92665-29-7 Trade Name

Manufacturer

Country

Year Introduced

Cefprozil

Bristol-Myers Squibb

USA

-

Cefzil

Bristol-Myers Squibb

USA

-

Raw Materials Ammonium hydroxide Sulfuric acid Ethylene glycol

Recombinant penicillin G amidase 4-Hydroxy-D-phenylglycine Immobilized recombinant penicillin G amidase

Manufacturing Process A mixture of 4-hydroxy-D-phenylglycine (10 g), ethylene glycol (15 ml) and concentrated sulfuric acid (5 ml) was stirred for 18 hours at 55°C under anhydrous conditions. The solution was cooled, and then ice (10 g) was added to it, and the pH was adjusted to 1.0 with 10 N NH4OH (4.5 ml) giving 40 ml of solution of hydroxyethyl ester of 4-hydroxy-D-phenylglycine.

Cefroxadine

897

The enzyme mixture of 20 ml containing immobilized recombinant penicillin G amidase as the enzyme, 10% hydroxyethyl ester of 4-hydroxy-Dphenylglycine, 4% cefprozil (amine source), and 8% enzyme (immobilized recombinant penicillin G amidase, equivalent to 32 IU/ml of enzyme) was made up without buffer. The above prepared ester solution (6.9 ml) was mixed with water (2 ml) and adjusted to pH 7.5 with 10 N NH4OH. Then the amine source (0.8 g) was added to it and the pH adjusted to 7.5 with 1 N NH4OH and the volume to 18.4 ml. Then the mixture was cooled to 5-15°C and solid enzyme (1.6 g; 640 IU) was added to it. The pH was not maintained at 7.5 and fell about 0.6 units during the reaction. The reaction mixture was analyzed by HPLC on a C18 Reverse Phase column. The mobile phase was 10% acetonitrile/0.3% H3PO4. The isomers of cefprozil appeared at 2.9 minutes (cis) and at 5.1 minutes (trans). The final product was obtained with a maximum yield of 92-96%. The whole experiment was completed in 25-50 min. Synthesis of cefprozil may be carried out at 15°C using Boehringer penicillin G amidase as the enzyme and hydroxyethyl ester of 4-hydroxy-D-phenylglycine. A maximum yield of about 95%. The experiment was completed in 35 minutes. References Usher J.J., Romancik G.; US Patent No. 6,156,534; 12.05.2000; Assigned to Bristol-Myers Squib Company Van Dooren Th.J.G.M., Smeets J.Ch.M., Moody H.M.; US Patent No. 6,287,799; 09.11.2001; Assigned to DSM N.V.

CEFROXADINE Therapeutic Function: Antibacterial Chemical Name: 7-[(Amino-1,4-cyclohexadien-1-yl-acetyl)amino]-3methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid Common Name: Structural Formula:

Chemical Abstracts Registry No.: 51762-05-1

898

Cefroxadine

Trade Name Oraspor Oraspor Oraspor Oraspor

Manufacturer Ciba Geigy Ciba Geigy Ciba Geigy Ciba Geigy

Country Switz. Japan W. Germany Italy

Year Introduced 1981 1982 1983 1983

Raw Materials D-α-Amino-α-(1,4-cyclohexadienyl)acetic acid Phosphorus pentachloride 7β-Amino-3-methoxy-3-cephem-4-carboxylic acid hydrochloride dioxanate Bis(trimethylsilyl)acetamide Propylene oxide Sodium hydroxide Manufacturing Process A suspension of 30.64 g (0.2 mol) of D-α-amino-α-(1,4-cyclohexadienyl)acetic acid in 600 ml of methylene chloride is cooled under a stream of argon to 6°C, whereupon hydrogen chloride is passed in for about 30 minutes until the mixture is saturated. Phosphorpentachloride (62.4 g, 0.3 mol) is added in two portions. The mixture is stirred for 2 hours at 6°C to 8°C. The colorless precipitate is filtered off under nitrogen and exclusion of moisture, washed with methylene chloride and dried for 18 hours at 0.05 mm Hg at room temperature to give D-α-amino-α-(1,4-cyclohexadienyl)-acetylchloride hydrochloride in form of colorless crystals. A suspension of 37.3 g (0.1 mol) of 7β-amino-3-methoxy-3-cephem-4carboxylic acid hydrochloride dioxanate in 500 ml methylene chloride is stirred for 15 minutes at room temparature under an argon atmosphere and treated with 57.2 ml (0.23 mol) of bis-(trimethylsilyl)acetamide. After 45 minutes the faintly yellow slightly turbid solution is cooled to 0°C and treated within 10 minutes with 31.29 (0.15 mol) of D-α-amino-α-(1,4-cyclohexadienyl)-acetyl chloride hydrochloride. Thirty minutes thereafter 15 ml (about 0.21 mol) of propylene oxide is added and the mixture is further stirred for 1 hour at 0°C: A cooled mixture of 20 ml of absolute methanol in 200 ml of methylene chloride is added within 30 minutes, after another 30 minutes the precipitate is filtered off under exclusion of moisture, washed with methylene chloride and dried under reduced pressure at room temperature. The obtained hygroscopic crystals of the hydrochloride of 7β-[D-α-(1,4-cyclohexadienyl)acetylamino]-3-methoxy-3-cephem-4-carboxylic acid are stirred into 200 ml of ice water and the milky solution treated with about 66 ml of cold 2 N sodium hydroxide solution until pH 3.5 is reached. The solution is clarified by filtration through diatomaceous earth, washed with ice water, cooled to 0°C and treated with 20 ml of 2 N sodium hydroxide solution until pH 5.7 is reached. A second filtration through a glass filter frit results in a clear solution which is treated with acetone (800 ml) at 0°C. The crystals are filtered washed with acetone:water (2:1), acetone and diethyl ether and dried for 20 hours at room temperature and 0.05 mm Hg to give the 7β-[D-α-amino-α-(1,4cyclohexadienyl)-acetylamino]-3-methoxy-3-cephem-4-carboxylic acid dihydrate.

Cefsulodin

899

References Merck Index 1911 DFU 4 (12) 911 (1979) OCDS Vol. 3 p. 210 (1984) DOT 19 (4) 190 (1983) I.N. p. 200 Scartazzini, R. and Bickel, H.; US Patent 4,073,902; February 14, 1978; assigned to Ciba-Geigy Corp.

CEFSULODIN Therapeutic Function: Antibiotic Chemical Name: 7-(α-Sulfophenylacetamido)-3-(4'-carbamoylpyridinium) methyl-3-cephem-4-carboxylate Common Name: Sulcephalosporin Structural Formula:

Chemical Abstracts Registry No.: 52152-93-9 (Sodium salt) Trade Name Pseudomonil Monaspor Pyocefalin Takesulin Tilmapor Monaspor Pseudocef

Manufacturer Ciba Geigy Ciba Geigy Cassenne Takeda Ciba Geigy Ciba Geigy Gruenenthal

Country W. Germany Switz. France Japan Japan UK W. Germany

Raw Materials 7-(α-Sulfophenylacetamido)cephalosporanic acid Isonicotinamide Potassium thiocyanate

Year Introduced 1980 1980 1981 1981 1981 1982 -

900

Ceftazidime

Manufacturing Process 0.514 g (4 x 10-3 mol) of 7-(α-sulfophenylacetamido)cephalosporanic acid, 0.466 g (3 x 10-3 mol) of isonicotinamide and 2.0 g (2.06 x 10-3 mol) of potassium thiocyanate were dissolved in 2.5 ml of water. The resulting solution was allowed to stand and heated for 20 hours in a thermostat kept at 50°C and then directly purified by chromatography on an Amberlite XAD-2 column (16 x 880 mm). Subsequently, the fractions containing the cephalosporins were collected and subjected to freeze-drying to obtain 270 g of the title product in the form of a pale yellowish white powder. The product is usually used as the sodium salt. References Merck Index 1912 DFU 5 (2) 67 (1980) OCDS Vol. 3 p. 214 (1984) DOT 17 (12) 542 (1981) I.N. p. 200 REM p. 1188 British Patent 1,387,656; March 19, 1975; assigned to Takeda Chemicals Industries, Ltd.

CEFTAZIDIME Therapeutic Function: Antibiotic Chemical Name: (6R,7R)-1-[(Z)-2-(2-Aminothiazol-4-yl)-2-(2-carboxyprop2-oxyimino)-acetamido]-3-(1-pyridiniummethyl)-ceph-3-em-4-carboxylic acid inner salt Common Name: Structural Formula:

Chemical Abstracts Registry No.: 72558-82-8

Ceftazidime

901

Trade Name

Manufacturer

Country

Year Introduced

Fortum

Glaxo

UK

1983

Raw Materials (Z)-2-(2-t-Butoxycarbonylprop-2-oxyimino)-2-(2-tritylaminothiazol-4yl)acetic acid t-Butyl-(6R,7R)-3-acetoxymethyl-7-aminoceph-3-em-4-carboxylate Pyridine Manufacturing Process (a) t-Butyl(6R,7R)-3-acetoxymethyl-7-[(Z)-2-(2-t-butoxycarbonylprop-2oxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]ceph-3-em-4-carboxylate: A stirred solution of (Z)-2-(2-t-butoxycarbonylprop-2-oxyimino)-2-(2tritylaminothiazol-4-yl)acetic acid (572 mg) and t-butyl(6R,7R)-3acetoxymethyl-7-aminoceph-3-em-4-carboxylate (328 mg) in dimethylformamide (10 ml) was cooled to 0°C, and 1-hydroxybenzotriazole (150 mg) was added, followed by dicyclohexylcarbodiimide (225 mg). The mixture was warmed to room temperature, stirred for 5 hours and allowed to stand overnight. The mixture was filtered, and the white solid washed with a little ether. The filtrate and washings were diluted with water (50 ml) and extracted with ethyl acetate. The organic extracts were combined, washed successively with water, 2 N hydrochloric acid, water, sodium bicarbonate solution, and saturated brine, dried and evaporated. The residue was eluted through a silica column with ether. The product-containing eluate was collected and concentrated to give the title compound (533 mg). A portion was recrystallized from diisopropyl ether, MP 103°C to 113°C (decomp.); [α]D20 +8.5 (conc. 1.0, DMSO). (b) (6R,7R)-3-Acetoxymethyl-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2carboxyprop-2-oxyimino)acetamido]ceph-3-em-4-carboxylic acid: Trifluoroacetic acid (18 ml) was added to a solution of the product of (a) (2.4 g) in anisole (18 ml) at 0°C. The mixture was stirred at room temperature for 2 hours and concentrated. The residue was dissolved in ethyl acetate and extracted with saturated sodium bicarbonate solution. The pH of the aqueous extracts was adjusted to 6, and the solution washed with ethyl acetate. The aqueous phase was acidified to pH 1.5 under ethyl acetate, saturated with sodium chloride, and extracted with ethyl acetate. The combined organic extracts were washed with saturated brine, dried and evaporated. The residue was dissolved in warm 50% aqueous formic acid (20 ml) and allowed to stand for 2 hours. The mixture was diluted with water (50 ml) and filtered. The filtrate was concentrated. The residue was taken up in water (50 ml), refiltered, and lyophilized to give the title compound (920 mg). (c) (6R,7R)-7-[(Z)-(2-Aminothiazol-4-yl)-2-(2-carboxyprop-2oxyimino)acetamido]-3-(1-pyridiniummethyl)-ceph-3-em-4-carboxylate, monosodium salt: Pyridine (2 ml) and the product of (b) (1.8 g) were added to a stirred solution of sodium iodide (7.12 g) in water (2.2 ml) at 80°C. The solution was stirred at 80 C for 1 hour, cooled, and diluted to 100 ml with water. The pH of the solution was adjusted to 6.0 with 2N sodium hydroxide solution, and this solution was concentrated to remove pyridine. The aqueous residue was diluted to 100 ml with water, methyl isobutyl ketone (2 drops)

902

Ceftezole

was added, and the solution was acidified to pH 1 with 2 N hydrochloric acid. The mixture was filtered, and the solid was washed with a little water. The filtrate and washings were collected and washed with ethyl acetate, and the pH adjusted to 6.0 with 2 N sodium hydroxide solution. The solution was concentrated to 50 ml and applied to a column of 500 g Amberlite XAD-2 resin, using first water and then 20% aqueous ethanol as eluting solvent. The product-containing fractions were concentrated and lyophilized to give the title compound (0.56 g). References Merck Index 1913 DFU 6 (10) 612 (1981) PDR p. 909 OCDS Vol. 3 p. 216 (1984) DOT 19 (6) 336 (1983) REM p. 1188 O'Callaghan, C.H., Livermore, D.G.H. and Newall, C.E.; British Patent 2,025,398; January 23, 1980; assigned to Glaxo Group Ltd.

CEFTEZOLE Therapeutic Function: Antibiotic Chemical Name: (6R,7R)-8-Oxo-7-(2-(1H-tetrazol-1-yl)acetamido)-3((1,3,4-thiadiazol-2-ylthio)methyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2carboxylic acid Common Name: Ceftezole; Demethylcefazolin Structural Formula:

Chemical Abstracts Registry No.: 26973-24-0 Trade Name

Manufacturer

Country

Year Introduced

Ceftezole

Arocor Holdings Inc.

-

-

Ceftezole

-

-

Alomen

DAE HAN NEW PHARM CO., LTD. Benedetti

-

-

Falomesin

Chugai

-

-

Ceftibuten

903

Raw Materials 1H-Tetrazole-1-acetic acid Triethylamine Pivaloyl chloride 1,3,4-Thiadiazole-2-thiol Manufacturing Process To a solution of 1 equivalent (eq.) of 1H-tetrazole-1-acetic acid and 1 eq. of triethylamine in 20 ml of tetrahydrofuran cooled to -20°C was added 1 eq. of pivaloyl chloride. After thirty-minute stirring of the mixture 20 ml of a chloroform solution containing 1 eq. of and 1 eq. of triethylamine was poured into the solution cooled at -10°C during a period of 30 minutes. The resulting mixed solution was stirred for 30 minutes at the same temperature, for 1 hour in an ice-water mixture and for 3 hours at room temperature. Removal of a solvent from the reaction mixture afforded an oily residue, which was dissolved into 15 ml of 10% sodium bicarbonate aqueous solution. The resulting aqueous layer was adjusted to pH 1.0-2.0 with 10% hydrochloric acid, washed with ether and extracted with ethyl acetate. The extract was washed with water, dried over sodium sulfate and concentrated under reduced pressure leaving a residue which was triturated with ethyl acetate to obtain 3acetoxymethyl-8-oxo-7-(2-tetrazol-1-acetylamino)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. A solution of 1 eq. of sodium salt of 3-acetoxymethyl-8-oxo-7-(2-tetrazol-1acetylamino)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid (it may be prepared with equivalent of sodium bicarbonate and above named acid) and 1 eq. of [1.3.4]-thiadiazole-2-thiol in 20 ml of phosphate buffer (pH 6.4) was stirred for 5.5 hours at 60°C. The reaction mixture was adjusted to pH 2.0 with 5% hydrochloric acid and treated with ethyl acetate to form a title compound - ceftezole. References Takano T. et al.; US Patent No. 3,516,997; June 23, 1970; Assigned to Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan

CEFTIBUTEN Therapeutic Function: Antibiotic Chemical Name: 5-Thia-1-azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid, 7(((2Z)-2-(2-amino-4-thiazolyl)-4-carboxy-1-oxo-2-butenyl)amino)-8-oxo-, (6R,7R)Common Name: Ceftibuten Chemical Abstracts Registry No.: 97519-39-6

904

Ceftibuten

Structural Formula:

Trade Name Cedax Keimax

Manufacturer Schering-Plough Essex Pharma GmbH

Country Germany

Year Introduced -

Procef

Bristol-Myers Squibb

USA

-

Raw Materials 8-Oxo-7-phenylacetylamino-5-thia-1-aza-bicyclo[4.2.0]oct-1-ene-2carboxylic acid benzhydryl ester Phosphorus pentachloride/pyridine reagent 4-(3-Aminothiophen-2-yl)-5-oxohex-3-enoic acid 3-methylbut-2-enyl ester Diphenylmethyl thiazoleacetate Ethyl formate Aluminum chloride Phosphorane from benzyl 2-triphenylphosphonium acetate Trifluoroacetic acid Desmethyl cephalosporin Manufacturing Process The 1st method of synthesis The 8-oxo-7-phenylacetylamino-5-thia-1-aza-bicyclo[4.2.0]oct-1-ene-2carboxylic acid benzhydryl ester is reacted with phosphorus pentachloride/pyridine reagent in methylene dichloride, and the reaction mixture is thereafter cooled to -35°C and treated with methanol to produce hydrochloride of 7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2carboxylic acid benzhydryl ester. This hydrochloride is reacted with 4-(3aminothiophen-2-yl)-5-oxohex-3-enoic acid 3-methylbut-2-enyl ester. Then 7[2-(2-benzoylamino-thiazol-5-yl)(3-tert-butyl-4,4-dimethylpent-2enoxycarbonyl)-pent-2-enoylamino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2ene-2-carboxylic acid synthesized is reacted with aluminum chloride in anisole and diluted hydrochloric acid and then with dimethylmalonate to give 5-thia1-azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid, 7-(((2Z)-2-(2-amino-4thiazolyl)-4-carboxy-1-oxo-2-butenyl)amino)-8-oxo-, (6R,7R)- (Ceftibuten). The 2st method of synthesis

Ceftizoxime

905

Formulation of the diphenylmethyl thiazoleacetate with ethyl formate leads to 2-(2-aminothiazol-5-yl)-3-hydroxyacrylic acid benzhydryl ester. Condensation of 2-(2-aminothiazol-5-yl)-3-hydroxyacrylic acid benzhydryl ester with the phosphorane from benzyl 2-triphenylphosphonium acetate leads to the 2-(2aminothiazol-5-ylmethylene)succinic acid 1-benzhydryl ester 4-benzyl ester. Exposure of this ester to trifluoroacetic acid selectively cleaves the diphenylmethyl group over the benzyl ester to give 2-(2-aminothiazol-5ylmethylene)succinic acid 4-benzyl ester. Condensation of the acid with free amino group in the desmethyl cephalosporin affords the amide of 7-[3-(2aminothiazol-5-yl)-2-benzoylcarbonylmethylacryloylamino)-8-oxo-5-thia-1azabicyclo[4.2.1]oct-2-ene-2-carboxylic acid benzyl ester. The remaining benzyl ester protecting groups are removed by means of aluminum chloride to afford 7-[3-(2-aminothiazol-5-yl)-2-benzoylcarbonylmethylacryloylamino)-8oxo-5-thia-1-azabicyclo[4.2.1]oct-2-ene-2-carboxylic acid or ceftibuten References Torii S. et al.; US Patent No. 6,576,761; Nov. 21, 2000; Assignee to Otsuka Kagaku Kabushiki Kaisha (Osaka, JP) Hamashima Y. et al.// J. Antibiot., 1987, 40, 1468

CEFTIZOXIME Therapeutic Function: Antibacterial Chemical Name: 7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]cephalosporanic acid Common Name: Structural Formula:

Chemical Abstracts Registry No.: 68401-81-0; 68401-82-1 (Sodium salt) Trade Name Eposelin Cefizox Ceftix Cefizox

Manufacturer Fujisawa SKF Boehringer Mannheim Eurroughs Wellcome

Country Japan US W. Germany

Year Introduced 1982 1983 1983

UK

-

906

Ceftriaxone sodium

Raw Materials Phosphorus oxychloride 2-Methoxyimino-2-(2-amino1,3-thiazol-4-yl)acetic acid

Bis(trimethylsilyl)acetamide 7-Aminocephalosporanic acid

Manufacturing Process Phosphorus oxychloride (2.0 g) was added at one time at 5°C to 10°C to a suspension of 2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetic acid (syn isomer) (2 g) in dry ethyl acetate (20 ml). After stirring for 20 minutes at 7°C to 10°C, bis(trimethylsilyl)acetamide (0.4 g) was added thereto at the same temperature. After stirring for 10 minutes at 7°C to 10°C, phosphorus oxychloride (2.0 g) was dropwise added thereto at the same temperature. The resulting mixture was stirred for 10 minutes at 7°C to 10°C, and dry dimethylformamide (0.8 g) was dropwise added thereto at the same temperature. The mixture was stirred for 30 minutes at 7°C to 10°C to give a clear solution. On the other hand, trimethylsilylacetamide (7.35 g) was added to a suspension of 7-aminocephalosporanic acid (2.45 g) in dry ethyl acetate (8 ml), after which the mixture was stirred at 40°C to give a clear solution. To this solution was added at one time the above-obtained ethyl acetate solution at -15°C, and the resulting mixture was stirred for 1 hour at -10°C to -15°C. The reaction mixture was cooled to -30°C, and water (80 ml) was added thereto. The aqueous layer was separated, adjusted to pH 4.5 with sodium bicarbonate and subjected to column chromatography on Diaion HP-20 resin (Mitsubishi Chemical Industries Ltd.) using 25% aqueous solution of isopropyl alcohol as an eluent. The eluate was lyophilized to give 7-[2methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]cephalosporanic acid (syn isomer) (1.8 g), MP 227°C (decomp.). References Merck Index 1915 DFU 5 (5) 226 (1980) PDR p. 1704 OCDS Vol. 3 p. 218 (1984) DOT 19 (3) 133 (1983) I.N. p. 200 REM p. 1189 Takaya, T., Masugi, T., Takasugi, H. and Kochi, H.; US Patent 4,166,115; assigned to Fujisawa Pharmaceutical Co., Ltd.

CEFTRIAXONE SODIUM Therapeutic Function: Antibacterial Chemical Name: Sodium salt of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2(methoxyimino)acetamido]-8-oxo-3-[[(1,4,5,6-tetrahydro-4-methyl-5,6dioxo-as-triazin-3-yl)thio]methyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2carboxylic acid

Ceftriaxone sodium

907

Common Name: Structural Formula:

Chemical Abstracts Registry No.: 75478-69-1; 73384-59-5 (Base) Trade Name Rocephin Rocephin Acantex

Manufacturer Roche Roche Roche

Country Switz. W. Germany -

Year Introduced 1982 1983 -

Raw Materials (6R,7R)-7-[2-[2-(2-Chloroacetamido)-4-thiazolyl]-2-(methoxyimino) acetamido]-8-oxo-3-[[(1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-astriazin-3-yl)thio]methyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2carboxylic acid Formic acid Manufacturing Process 19 g of (6R,7R)-7-[2-[2-(2-chloroacetamido)-4-thiazolyl]-2-(methoxyimino) acetamido]-8-oxo-3-[[(1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as-triazin-3yl)thio]methyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid are suspended in 150 ml of water together with 9.5 g of thiourea. The pH is adjusted to 6.8 with 5% sodium hydrogen carbonate solution while gassing with nitrogen and stirring, there being obtained a yellow-orange solution. The pH of the solution is held constant at 6.8-7.0 for 6 hours by adding sodium hydrogen carbonate solution by means of an autotitrator. 100% formic acid is added to the orange colored solution until the pH is 3.5. The precipitated material is filtered off under suction and washed with 100 ml of 10% formic acid. This material is denoted as (1). The filtrate is adjusted to pH 2.5 by adding 100% formic acid, whereby additional substance precipitates out. The mixture is held in an ice-bath for 1 hour, the precipitated substance is then filtered off and washed with a small amount of ice-water. This material is denoted as fraction I. The aforementioned orange-brown material (1) is suspended in 250 ml of water. The suspension is adjusted to pH 7 with 2 N sodium hydroxide, there being obtained an orange-brown solution. Additional 100% formic acid is added to this solution until the pH is 3.5. The material

908

Cefuroxime

which thereby precipitates out is filtered off under suction and discarded. The filtrate is adjusted to pH 2.5 with 100% formic acid, whereby additional substance precipitates out. The mixture is held in an ice-bath for 1 hour, the precipitated substance is then filtered off under suction and washed with a small amount of ice-water. This material is denoted as fraction II. Fractions I and II are suspended together in 500 ml of ethanol and evaporated in a rotary evaporator in order to remove water. After adding ether, the mixture is filtered under suction and the precipitate is washed successively with ether and low-boiling petroleum ether. There is thus obtained the title substance in the form of a yellowish solid material which is denoted as A. The mother liquors and washings of fractions I and II are concentrated from a volume of about 1.7 liters to 250 ml, the pH is adjusted to 2.5 with 100% formic acid and the solution is stored overnight in a refrigerator, whereby further substance crystallizes. This is filtered off under suction and washed with a small amount of water. The residue on the suction filter is azeotropically distilled with ethanol. There is obtained solid, almost colorless title substance which is denoted as B. B is purer than A according to thin-layer chromatography. In order to obtain pure title substance, the acid B is suspended in 150 ml of methanol and treated while stirring with 10 ml of a 2 N solution of the sodium salt of 2-ethylcaproic acid in ethyl acetate. After about 10 minutes, there results a solution which is treated with 100 ml of ethanol. The mixture is extensively concentrated at 40°C in vacuo. The sodium salt precipitates out in amorphous form after adding ethanol. This salt is filtered off under suction, washed successively with ethanol and low-boiling petroleum ether and dried at 40°C in a high vacuum. There is obtained the title substance in the form of an almost colorless amorphous powder. References Merck Index 1916 PDR D. 1499 DOT 19 (12) 653 (1983) I.N. p. 200 REM p. 1189 Montavon, M. and Reiner, R.; British Patent 2,022,090; December 12, 1979; assigned to F. Hoffman - La Roche and Co. A.G. (Switz.)

CEFUROXIME Therapeutic Function: Antibiotic Chemical Name: (6R,7R)-3-Carbamoyloxymethyl-7-[2-(2-furyl)-2(methoxyimino)acetamido]-ceph-3-em-4-carboxylic acid Common Name: Chemical Abstracts Registry No.: 55268-75-2; 56238-63-2 (Sodium salt)

Cefuroxime

909

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Ultroxim

Duncan

Italy

1978

Curoxime

Glaxo

Italy

1978

Zinacef

Hoechst

W. Germany

1978

Zinacef

Glaxo

UK

1978

Zinacef

Glaxo

Switz.

1978

Ceroxime

Glaxo

France

1980

Zinacef

Glaxo

Japan

1982

Zinacef

TANABE SEIYAKU

Japan

1982

Zinacef

Glaxo

US

1983

Altacel

Pulitzer

Italy

-

Biociclin

Italy

-

Bioxima

Del Saz and Filippini Italsuisse

Italy

-

Cefamar

Firma

Italy

-

Cefoprim

Esseti

Italy

-

Cefumax

Locatelli

Italy

-

Cefur

Tiber

Italy

-

Cefurex

Sarm

Italy

-

Cefurin

Magis

Italy

-

Cefurox

Glaxo

-

-

Colifossim

Coli

Italy

-

Curisef

Glaxo

Italy

-

Duxima

Dukron

Italy

-

Furex

Lafare

Italy

-

Gibicef

Gibipharma

Italy

-

Itorex

Ausonia

Italy

-

Kefox

C.T.

Italy

-

Kesint

Proter

Italy

-

Ketocef

Glaxo

-

-

Lamposporin

Von Boch

Italy

-

Medoxin

Medici

Italy

-

Polixima

Sierochimica

Italy

-

Supero

Farmochimica

Italy

-

Ultroxim

Sigma Tau

Italy

-

910

Celecoxib

Raw Materials (6R,7R)-7-Amino-3-carbamoyloxymethylceph-3-em-4-carboxylic acid Phosphorus pentachloride 2-(Fur-2-yl)-2-methoxyiminoacetic acid Hydrogen chloride Manufacturing Process A stirred mixture of N,N-dimethylacetamide (75 ml), acetonitrile (75 ml), triethylamine (42 ml, 0.3 mol) and (6R,7R)-7-amino-3-carbamoyloxymethylceph-3-em-4-carboxylic acid was immersed in an ice-bath and water (10 ml) was added. The mixture was stirred at 0°C to 2°C for 45 minutes, the solid slowly dissolving to give a yellow solution. Meanwhile a stirred suspension of phosphorus pentachloride (14.99 g, 0.072 mol) in dry dichloromethane (150 ml) was cooled to 0°C, and N,Ndimethylacetamide (27.5 ml) was added. The resulting solution was recooled to -10°C and 2-(fur-2-yl)-2-methoxyiminoacetic acid (synisomer) (12.17 g, 0.072 mol) was added. The mixture was stirred at -10°C for 15 minutes and crushed ice (35 g) was added. The mixture was stirred at 0°C for 10minutes, where after the lower dichloromethane phase was added over 10 minutes to the cephalosporin solution prepared above, cooled to -10°C so that the reaction temperature rose steadily to 0°C. The mixture was stirred at 0°C to 2°C for 1 hour, where after the cooling bath was removed and the reaction temperature allowed to rise to 20°C over 1 hour. The reaction mixture was then added slowly to 2 N hydrochloric acid (100 ml) diluted with cold water (1.15 l) at 5°C. The pH of the two phase mixture was adjusted to below 2 with 2 N hydrochloric acid (10 ml), and the mixture was stirred and recooled to 5°C. The solid which precipitated was filtered, washed with dichloromethane (100 ml) and water (250 ml), and dried in vacuo at 40°C overnight to give the title compound (22.04 g, 86.6%). References Merck Index 191 DFU 3 (4) 266 (1978) Kleeman and Engel p. 177 PDR p. 922 OCDS Vol. 3 p. 216 (1984) DOT 12 (5) 189 (1976) and 15 (1) 10 (1979) I.N. p. 200 REM p. 1187 Cook, M.C., Gregory, G.I. and Bradshaw, J.; US Patent 3,966,717; June 29, 1976; assigned to Glaxo Laboratories, Ltd. Cook, M.C., Gregory, G.I. and Bradshaw, J.; US Patent 3,974,153; August 10, 1976; assigned to Glaxo Laboratories, Ltd.

CELECOXIB Therapeutic Function: Antiinflammatory

Celecoxib

911

Chemical Name: Benzenesulfonamide, 4-(5-(4-methylphenyl)-3(trifluoromethyl)-1H-pyrazol-1-yl)Common Name: Celecoxib Structural Formula:

Chemical Abstracts Registry No.: 169590-42-5; 184007-95-2 Trade Name Celact

Manufacturer Sun Pharmaceuticals Industries Ltd.

Country India

Year Introduced -

Celcib

Khandelwal Laboratories Ltd.

India

-

Celebrex Celebrex Celebrex Celecap

Searle Ltd. Pfizer Bayer Centaur Laboratories (P) Ltd.

India

-

Celecoxib Colcibra

Pharmacia Crosland Research Laboratories

India

-

Celedol Celetop

IPCA laboratories Ltd. Sarabhai Piramal Pharmaceuticals Ltd.

India India

-

Celib

Unichem Laboratories Ltd.

India

-

Cobix Cobix

Cipla Limited Brown and Burk Pharmaceuticals Ltd. Emcure Pharmaceuticals Ltd.

India India

-

India

-

Orthocel

Biochem Pharma Industries

-

-

Revibra

Dr. Reddy's Laboratories Ltd.

India

-

Eloxib

912

Celiprolol

Trade Name

Manufacturer

Country

Year Introduced

Sionara

Alembic Ltd.

India

-

Zecoxib

Win Medicare

India

-

Zycel

Zydus Cadila

India

-

Raw Materials Ethyl trifluoroacetate Sodium methoxide 4-Chloroaceteophenone 4-Sulphonamidophenylhydrazine hydrochloride Hydrochloric acid Manufacturing Process 4-(5-(4-Methylphenyl)-3-trifluoromethyl-N-pyrazol-1-yl)benzenesulfonamide To a solution of ethyl trifluoroacetate (1.90 ml, 16.0 mmol) in 7 ml of methyl tert-butyl ether was added 25% NaOMe (3.62 ml, 16.8 mmol). Next 4chloroaceteophenone (2.08 ml, 16.0 mmol) in 2 ml of methyl tert-butyl ether was added. The mixture was stirred at room temperature overnight. To above solution was added 100 ml of 90% EtOH, followed by 4 N HCl (4.0 ml, 16 mmol) and 4-sulphonamidophenylhydrazine hydrochloride (3.58 g, 16 mmol). The mixture was heated to reflux for 3 hours. The mixture was concentrated. When 30 ml of water was added, a solid formed. The solid was filtered and washed with 20 ml of 60% EtOH to give 4.50 g of white solid. The filtrate was evaporated and taken up in ethyl acetate (100 ml), washed with saturated NaHCO3, and brine, dried over MgSO4, and concentrated. Heptane was added at boiling point of the mixture. After cooling down to 0°C, 1.01 g more product was obtained. The combined yield of the 4-(5-(4-methylphenyl)-3trifluoromethyl-N-pyrazol-1-yl)benzenesulfonamide (Celecoxib) was 86%. References Zhi Benxin et al.; WO 96/37476, Nov. 28, 1996; Applicante Searle and Co. (US)

CELIPROLOL Therapeutic Function: Beta-adrenergic blocker Chemical Name: N'-[3-Acetyl-4-[3-[(1,1-dimethylethyl)amino]-2hydroxypropoxy]phenyl]-N,N-dimethylurea Common Name: Chemical Abstracts Registry No.: 56980-93-9

Cephacetrile sodium

913

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Selectol

Chemie Linz

Austria

1983

Selectol

Chemie Linz

W. Germany

1983

Raw Materials 3-Acetyl-4-hydroxyaniline Dimethylcarbamoyl chloride

Epichlorohydrin t-Butylamine

Manufacturing Process 3-Acetyl-4-hydroxyaniline, in solution in pyridine, is reacted with dimethylcarbamoyl chloride at room temperature to give N-(3-acetyl-4hydroxy)phenyl-N'-dimethylurea, which after evaporating the pyridine, taking up the residue in chloroform and evaporating the latter, is obtained in a crystalline form. Melting point: 160°-162°C. After reaction of the product in alkaline aqueous solution, with epichlorohydrin, N-[3-acetyl-4-(2',3'-epoxy)propoxy]-phenyl-N'-dimethylurea (melting point: 98°-102°C) is obtained, and this, in turn, is reacted with excess tert-butylamine in aqueous solution at room temperature to give N-[3-acetyl-4-(3'-tert-butylamino-2'-hydroxy)propoxy)-phenyl-N'-dimethylurea of melting point: 120°-122°C. References Merck Index 1921 DFU 4 (3) 181 (1979) DOT 18 (12) 632 (1982) I.N. p. 201 Zolss, G., Pittner, H., Stormann-Menninger-Lerchenthal, H. and Lindner, I.; US Patent 3,983,169; September 28, 1976; assigned to Chemie Linz AG (Austria)

CEPHACETRILE SODIUM Therapeutic Function: Antibiotic Chemical Name: 7-(2-Cyanoacetamido)-3-(hydroxymethyl)-8-oxo-5-thia-1azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid acetate monosodium salt

914

Cephacetrile sodium

Common Name: Sodium 7-(2-cyanoacetamido)-cephalosporanic acid Structural Formula:

Chemical Abstracts Registry No.: 23239-41-0; 10206-21-0 (Base) Trade Name Celospor Celospor Clospor Celospor Celospor Celtol Celospor Flunicef

Manufacturer Ciba Geigy Ciba Gruenenthal Ciba Ciba Takeda Ciba Geigy Alfa Farm.

Country Switz. France W. Germany Italy W. Germany Japan Japan Italy

Year Introduced 1969 1973 1974 1974 1974 1978 1978 -

Raw Materials 7-Aminocephalosporanic acid Cyanoacetyl chloride Sodium hydroxide Manufacturing Process 13.6 g (0.05 mol) of 7-aminocephalosporanic acid are taken up in a mixture of 150 ml of methylene chloride and 19.5 ml of tributylamine (0.12 mol) and at 0°C a solution of 8.4 g of cyanoacetylchloride (0.07 mol) in 100 ml of methylene chloride is stirred in. The bath is then stirred for ½ hour at 0°C and for ½ hour at 20°C, the reaction solution is evaporated under vacuum and the residue taken up in 10% aqueous dipotassium hydrogenphosphate solution. This aqueous phase is washed with ethyl acetate, acidified to pH 2.0 with concentrated hydrochloric acid and extracted with ethyl acetate. After having been dried over sodium sulfate and evaporated under vacuum, this extract gives as a solid residue 14.7 g of crude 7-cyanoacetylaminocephalosporanic acid which is purified by chromatography on 30 times its own weight of silica gel. The fractions eluted with chloroform plus acetone (7:3) furnish a product which crystallizes from acetone plus ether in the form of needles melting at 168° to 170°C with decomposition. 5.10 g (15 mmol) of 7-cyanoacetyl-aminocephalosporanic acid are suspended

Cephalexin

915

in 102 ml of distilled water and converted into the sodium salt by stirring in dropwise 15 ml of N sodium hydroxide solution. References Merck Index 1934 Kleeman and Engel p. 159 DOT 7 (5) 181 (1971) 9 (2) 50 (1973) and 10 (7) 239 (1974) I.N. p. 193 Bickel, H., Bosshardt, R., Fechtig, B., Schenker, K. and Urech, J.; US Patent 3,483,197; December 9, 1969; assigned to Ciba Corporation

CEPHALEXIN Therapeutic Function: Antibiotic Chemical Name: 7-[(Aminophenylacetyl)amino]-3-methyl-8-oxo-5-thia-1azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid Common Name: Structural Formula:

Chemical Abstracts Registry No.: 15686-71-2; 23325-78-2 (Monohydrate) Trade Name

Manufacturer

Country

Year Introduced

Ceporex

Glaxo

UK

1970

Ceprorexine

Glaxo

France

1970

Cepol

Torii

Japan

1970

Keflex

Shionogi

Japan

1970

Keflex

Lilly

UK

1970

Keflex

Lilly

US

1971

Ceporex

Glaxo

Italy

1971

Keforal

Lilly

France

1971

Keforal

Lilly

Italy

1971

Oracef

Lilly

W. Germany

1971

916

Cephalexin

Trade Name

Manufacturer

Country

Year Introduced

Keflex

Serum Impfinst.

Switz.

1974

Acaxina

Martin Santos

Spain

-

Acinipan

Aldon

Spain

-

Ambal

Medical

Spain

-

Amplicefal

Miluy

Spain

-

Ampligram

Hermes

Spain

-

Ausocef

Ausonia

Italy

-

Basporin

Basileos

Spain

-

Bilatox

Biopharma

Spain

-

Bioporina

Biologia Marina

Spain

-

Brisoral

Bristol-Myers

-

-

Cefabiot Oral

Galepharma Iberica

Spain

-

Cefadina

Antibioticos

Spain

-

Cefadros

Proter

Italy

-

Cefa-Iskia

Iskia

Spain

-

Cefaleh Ina

Alvarez-Gomez

Spain

-

Cefalekey

Pereira

Spain

-

Cefalex-Gobens

Normon

Spain

-

Cefalival

Valles Mestre

Spain

-

Cefaloto

Lifepharma

Spain

-

Cefa-Reder

Reder

Spain

-

Cefaxin

Bristol

Italy

-

Cefibacter

Rubio

Spain

-

Ceflon

Mulda

Turkey

-

Ceflor

Coli

Italy

-

Ceforal

Teva

Israel

-

Cepexin

Glaxo

-

-

Cephalomax

Daisan

Japan

-

Cephazal

Hokuriku

Japan

-

Cepol

Torii

Japan

-

Cepoven

Glaxo

Italy

-

CEX

Glaxo

Japan

-

Chemosporal

Erba

Italy

-

Cilicef Oral

Hortel

Spain

-

Ciponium

Nippon Kayaku, Co.

Japan

-

Derantel

Nippon Chemiphar

Japan

-

Devaleksin

Deva

Turkey

-

Diabeton

Teknofarma

Italy

-

Erifalecin

Dreikehl

Spain

-

Cephalexin

917

Trade Name

Manufacturer

Country

Year Introduced

Erocetin

Roemmers

Argentina

-

Esmezin

Sawai

Japan

-

Falecina

Italquimica

Spain

-

Farexin

Lafare

Italy

-

Fergon

Alfar

Spain

-

Garasin

Wakamoto

Japan

-

Grafalex

Graino

Spain

-

Huberlexina

Hubber

Spain

-

Ibilex

I.B.I.

Italy

-

Iwalexin

Iwaki

Japan

-

Janocilin

Janovich

Spain

-

Keflex

Shionogi

Japan

-

Kelfison

Davur

Spain

-

Larixin

Toyama

Japan

-

Latoral

Dukron

Italy

-

Lefosporina

Bicsa

Spain

-

Lexibiotico

Llano

Spain

-

Libesporal

Liberman

Spain

-

Llenas Biotic

Llenas

Spain

-

Lorexina

Crosara

Italy

-

Madlexin

Meiji

Japan

-

Maksipor

Fako

Turkey

-

Mamalexin

Showa

Japan

-

Mepilacin

Kanto

Japan

-

Neolexina

Asia

Spain

-

Nilexina

Pental

Spain

-

Ohlexin

Ohta

Japan

-

Oracocin

Tobishi

Japan

-

Oralexine

Novo

Denmark

-

Oroxin

Otsuka

Japan

-

Ortisporina

Turro

Spain

-

Ospexin

Biochemie

Austria

-

Palitrex

Galenika

Yugoslavia

-

Porinabis

Santos

Spain

-

Pracefal

Pradel

Spain

-

Prindex

Hosbon

Spain

-

Pyassan

Chinoin

Hungary

-

Rinesal

Kissei Pharmaceutical Co., Ltd. Roger

Japan

-

Spain

-

Rogeridina

918

Cephalexin

Trade Name

Manufacturer

Country

Year Introduced

Salitex

Banyu

Japan

-

Sargetina

Sarget

France

-

Sartosona

Sanomed

Spain

-

Sasperos

Schiapparelli

Italy

-

Sayra

Legem

Spain

-

Sefaleksin

Ilsan

Turkey

-

Segoramin

Takata

Japan

-

Sencephalin

Takeda

Japan

-

Septilisin

Bago

Argentina

-

Syncel

Toyo Jozo

Japan

-

Taicelexin

Taiyo

Japan

-

Talinsul

Ester

Spain

-

Testaxina

Bryan

Spain

-

Tokilexin

Isei

Japan

-

Torlasporin

Torlan

Spain

-

Wasserporina

Wassermann

Spain

-

Xahl

S.S. Seiyaku

Japan

-

Raw Materials Soidum-D-α-phenylglycine Zinc Methyl acetoacetate Hydrogen chloride p-Nitrobenzyl-7-aminodesacetoxycephalosporanate Manufacturing Process To a 1 liter flask containing dimethylformamide at 0°C, was added 24.8 g sodium N-(2-methoxycarbonyl-1-methylvinyl)-D-α-phenylglycine (prepared from sodium D-α-phenylglycine and methyl acetoacetate). The mixture was cooled to -40°C and methyl chloroformate (7.5 ml) and dimethylbenzylamine (0.26 ml) added. After stirring for 25 minutes, p-nitrobenzyl 7aminodesacetoxycephalosporanate (32.8 g) in the form of its hydrochloride salt was added, followed by triethylamine (12.1 ml) and dimethylformamide (140 ml) over a period of 20 minutes. The reaction mixture was stirred for 2 hours at -25°C to -35°C, then warmed to 0°C and water (32 ml) added. To the resultant solution, hydrochloric acid (54 ml) was added followed by zinc (21.8 g) in portions over a period of 5 minutes, the temperature being maintained at 5°C to 10°C. Further hydrochloric acid (35 ml) was added and the solution stirred at 15°C to 20°C for 7 hours. The pH was adjusted to 3.3 with triethylamine and semicarbazidehydrochloride (9.5 g) added. The mixture was brought back to pH 3 with further triethylamine, then stirred for 30 minutes at pH 3. The resultant mixture was adjusted slowly over 4 hours to pH 6.8 by addition of triethylamine, seeding being carried out when pH 4.5 was reached. The

Cephaloglycin

919

precipitated cephalexin was filtered off, washed with dimethylformamide (200 ml) and the cephalexin recovered, yield 75%. References Merck Index 1936 Kleeman and Engel p. 161 PDR p. 841 OCDS Vol. 1 p.417 (1977) and 2 p. 439 (1980) DOT 5 (1) 29 (1969) and 6 (5) 165 (1970) I.N. p. 194 REM p. 1189 Davison, M., Frankham, D.B., Spence, T.W.M.; US Patent 3,946,002; March 23, 1976; assigned to Lilly Industries Ltd.

CEPHALOGLYCIN Therapeutic Function: Antibacterial Chemical Name: 3-[(Acetyloxy)methyl]-7-[(aminophenylacetyl)amino]-8oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Common Name: 7-(D-α-Aminophenylacetylamido)-caphalosporanic acid Structural Formula:

Chemical Abstracts Registry No.: 3577-01-3 Trade Name

Manufacturer

Country

Year Introduced

Kefglycin

Shionogi

Japan

1969

Kafocin

Lilly

US

1970

Raw Materials D-Phenylglycine 7-Aminocephalosporanic acid Isobutyl chloroformate

Carbobenzoxy chloride Hydrogen

920

Cephaloglycin

Manufacturing Process dl-Phenylglycine is resolved in a conventional manner by reaction with cinchonine, fractional crystallization of the resulting diastereoisomers, and acidification to release the phenylglycine enantiomorphs. D-phenylglycine, thus prepared, is reacted with carbobenzoxy chloride in a conventional manner to produce N-carbobenzoxy-D-phenylglycine. A 0.60 g portion of N-carbobenzoxy-D-phenylglycine is dissolved in 10 ml of dry tetrahydrofuran. The solution is cooled in an ice-salt bath, and to it is added 0.29 ml of triethylamine with stirring over a period of 10 minutes, followed by 0.29 ml of isobutyl chloroformate, after which stirring is continued for 10 minutes at -5°C. During this time, 0.57 g of 7-aminocephalosporanic acid and 0.29 ml of triethylamine are dissolved in 5 ml of tetrahydrofuran and 5 ml of water, and the solution is centrifuged to remove a dark sludge. The clarified solution is cooled in ice and slowly added to the reaction mixture, and stirring is continued in the ice bath for 0.5 hour, followed by one hour at room temperature. The reaction product mixture is a homogenous solution having a pH of about 6. It is evaporated under vacuum to a semisolid residue. To the residue are added 35 ml of water and a few drops of triethylamine to raise the pH to 8. The aqueous solution obtained thereby is extracted successively with 50 ml and 35 ml portions of ethyl acetate, the pH being adjusted to 2 at each extraction with hydrochloric acid. The extracts are combined, filtered, dried over sodium sulfate, stripped of solvent, and evaporated under vacuum. The product is 7-(N-carbobenzoxy-D-α-aminophenylacetamido)cephalosporanic acid in the form of a yellow-white amorphous solid weighing 1.10 g. Of this material 1.0 g is dissolved in 150 ml of warm 95% ethyl alcohol. To the solution is added 1.0 g of 5% palladium on carbon catalyst, and the mixture is hydrogenated at room temperature and atmospheric pressure by bubbling hydrogen into it for 3 hours with stirring. The hydrogenation product is filtered. The solid phase, comprising the catalyst and the desired product, is suspended in ethyl acetate and water and adjusted to pH 2 with hydrochloric acid. The suspension is filtered to remove the catalyst. The aqueous phase is separated from the filtrate, and is evaporated under vacuum to recover the desired product, 7-(D-α-aminophenylacetamido)cephalosporanicacid. References Merck Index 1938 Kleeman and Engel p. 163 OCDS Vol. 1 p.417 (1977) DOT 6 (5) 169 (1970) I.N. p. 195 British Patent 1,017,624; January 19,1966; assigned to Merck and Co., Inc. British Patent 985,747; March 10, 1965; assigned to Eli Lilly and Company Wall, W.F., Fatherey, M. and Boothroyd, B.; US Patent 3,422,103; January 14, 1969; assigned to Glaxo Laboratories, Ltd. Pfeiffer, R.R. and Bottorff, E.M.; US Patent 3,497,505; February 24, 1970; assigned to Eli Lilly and Co. Jackson, B.G.; US Patent 3,671,449; June 20, 1972; assigned to Eli Lilly and Co.

Cephaloridine

921

CEPHALORIDINE Therapeutic Function: Antibacterial Chemical Name: (6R-trans)-1-[[2-Carboxy-8-oxo-7-[(2-thienylacetyl)amino]5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]pyridinium hydroxide inner salt Common Name: Cefaloridin Structural Formula:

Chemical Abstracts Registry No.: 50-59-9 Trade Name

Manufacturer

Country

Year Introduced

Ceporin

Glaxo

UK

1964

Ceporin

Glaxo

Switz.

1965

Cepaloridin

Glaxo

W. Germany

1965

Kefiodin

Lilly

France

1967

Loridine

Lilly

US

1968

Ceporin

Glaxo

Italy

1976

Acaporina

Martin Santos

Spain

-

Aliporina

Asla

Spain

-

Amplicerina

Miluy

Spain

-

Ampligram

Hermes

Spain

-

Basporidina

Basileos

Spain

-

Bioporina

Biologia Marina

Spain

-

Cefabena

Jebena

Spain

-

Cefabiot

Galepharma Iberica

Spain

-

Cefaclox

Sigma Tau

Italy

-

Cefalescord

Callol

Spain

-

Cefalisan

Lifepharma

Spain

-

Cefalobiotic

Wolner

Spain

-

Cefalogobens

Normon

Spain

-

Cefalomiso

Oftalmiso

Spain

-

Cefamusel

De La Cruz

Spain

-

922

Cephaloridine

Trade Name

Manufacturer

Country

Year Introduced

Cefaresan

Alacan

Spain

-

Ceflorin

Glaxo

-

-

Cepalorin

Glaxo

-

-

Ceporan

Glaxo

-

-

Ceporan

Torii

Japan

-

Ceproduc

Glaxo

Italy

-

CER

Glaxo

Japan

-

Cidan-Cef

Cidan

Spain

-

Cilicef

Hortel

Spain

-

Cobalcina

Pradel

Spain

-

Cusisporina

Norte De Espana

Spain

-

Diclocef

Medici

Italy

-

Dinasint

Proter

Italy

-

Eldia

Legem

Spain

-

Endosporol

Cantabria

Spain

-

Enebiotico

Llano

Spain

-

Faredina

Lefare

Italy

-

Filoklin

Lifasa

Spain

-

Floridin

Coli

Italy

-

Gencefal

Morgens

Spain

-

Glaxoridin

Glaxo

-

-

Huberlexina

Hubber

Spain

-

Intrasporin

Torlan

Spain

-

Janosina

Janovich

Spain

-

Keflodin

Shionogi

Japan

-

Kefspor

Lilly

-

-

Kelfison

Davur

Spain

-

Latorex

Durron

Italy

-

Lauridin

Crosara

Italy

-

Lexibiotico

Llano

Spain

-

Libesporina

Liberman

Spain

-

Liexina

ICN

-

-

Llenas Biotic

Llenas

Spain

-

Lloncefal

Castillon

Spain

-

Poricefal

Santos

Spain

-

Prinderin

Hosbon

Spain

-

Rogeridina

Roger

Spain

-

Rolex ins

Fedal

Spain

-

Sargefal

Sarget

France

-

Cephaloridine

923

Trade Name

Manufacturer

Country

Year Introduced

Sintoridyn

I.S.F.

Italy

-

Sporanicum

Incasa-Wolff

Spain

-

Talinsul

Ester

Spain

-

Tapiola

Guadalupe

Spain

-

Testadina

Bryan

Spain

-

Totalmicina

Emyfar

Spain

-

Wasser idina

Wassermann

Spain

-

Raw Materials 7-Aminocephalosporanic acid 2-Thienylacetyl chloride Pyridine Manufacturing Process 7-Aminocephalosporanic acid (5.00 g) which passed through a 100-mesh sieve was suspended in boiling ethyl acetate (200 ml), and 2-thienylacetyl chloride (Cagniant, Bull. Soc. Chim. France, 1949, 847) (4.42 g, 1.5 equiv.) was added in ethyl acetate (20 ml). The mixture was boiled under reflux for 40 minutes, cooled, and filtered. Aniline (5.03 ml) was added, and after 1 hour the mixture was extracted with 3% sodium hydrogen carbonate solution (1 x 150 ml, 2 x 100 ml, 1 x 50 ml) and the alkaline extracts washed with ethyl acetate (3 x 100 ml). The aqueous solution was acidified to pH 1.2, and extracted with ethyl acetate (2 x 150 ml). The ethyl acetate extract was washed with water (4 x 40 ml), dried (MgSO4), and concentrated in vacuo to low volume. The crude 7-2'-thienylacetamidocephalosporanic acid (2.5 g) which separated was collected by filtration. Evaporation of the filtrate gave a further 2.68 g (71%) of the product, which was purified by crystallization from ethyl acetate, then aqueous acetone, MP 150°C to 157°C (decomp.). 7-2'-Thienylacetamidocephalosporanic acid (7.0 g) was suspended in water (60 ml) and stirred with pyridine (7 ml) until the acid dissolved. The resulting solution (pH 5.9) was kept at 35°C for 3 days, then filtered and extracted with methylene chloride (4 x 60 ml). The methylene chloride extract was backextracted with a little water and the total aqueous solutions were then percolated through a column of Dowex 1 x 8 resin, (100 to 200 mesh, 150 g) in the acetate form at pH 4.3. The column was washed with water until the optical rotation of the eluate fell to zero and the eluate (500 ml) was freezedried. The residual white solid was dissolved in the minimum volume of methanol and after a few minutes the pyridine derivative crystallized; this is the cephaloridine product. References Merck Index 1940 Kleeman and Engel p. 164 OCDS Vol. 1 p. 417 (1977) DOT 1 (3) 88 (1965) I.N. p. 195

924

Cephalothin sodium

Arkley, V., Eardley, S. and Long, A.G.; British Patent 1,030,630; May 25, 1966; assigned to Glaxo Laboratories, Ltd. Higgins, H.M. Jr.; US Patent 3,270,012; August 30, 1966; assigned to Eli Lilly and Co.

CEPHALOTHIN SODIUM Therapeutic Function: Antibacterial Chemical Name: 6R-trans-3-[(Acetyloxy)methyl]-8-oxo-7-[(2-thienylacetyl) amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-carboxylic acid sodium salt Common Name: 7-(2-Thienyiacetamido)cephalosporanic acid Structural Formula:

Chemical Abstracts Registry No.: 58-71-9; 153-61-7 (Base) Trade Name

Manufacturer

Country

Year Introduced

Keflin

Lilly

US

1964

Cepovenin

Hoechst/Glaxo

W. Germany

1965

Keflin

Lilly

France

1965

Keflin

Serum Impfinst.

Switz.

1965

Kefiin

Shionogi

Japan

1966

Keflin

Lilly

Italy

1967

Keflin

Lilly

UK

1969

Seffin

Glaxo

US

1983

Averon

Alfar

Spain

-

Averon-I

Alfa Farm.

Italy

-

Cephalotin

Lilly

W. Germany

-

Cephation

Meiji

Japan

-

Ceporacin

Glaxo

W. Germany

-

Cepovenin

Hoechst

-

-

CET

Glaxo

Japan

-

Coaxin

Tobishi

Japan

-

Loccalline

Showa

Japan

-

Cephapirin sodium Trade Name Lospoven Restin Sodium Cephalotin Sucira N Synclotin Toricelosin

Manufacturer Hoechst Ono Green Cross Mohan Toyo Jozo Torii

Country Japan Japan Japan Japan Japan Japan

925

Year Introduced -

Raw Materials 2-Thienylacetic acid Sodium hydroxide

Thionyl chloride 7-Aminocephalosporanic acid

Manufacturing Process 7-(2'-Thienylacetamido)cephalosporanic acid sodium salt may be produced from 2-thienylacetyl chloride, obtainable by treatment of 2-thienylacetic acid [Ernst, Berichte, 19 (1886) 3281] with thionyl chloride in a conventional manner. The 2-thienylacetyl chloride is then reacted with 7aminocephalosporanic acid and then converted to the sodium salt using sodium hydroxide. References Merck Index 1943 Kleeman and Engel p. 165 PDR pp. 911, 1056 OCDS Vol. 1 pp. 417, 420 (1977) DOT 2 (2) 44 (1966) I.N. p. 196 REM p. 1187 British Patent 982,252; February 3, 1965; assigned to Eli Lilly and Company

CEPHAPIRIN SODIUM Therapeutic Function: Antibacterial Chemical Name: 3-[(Acetyloxy)methyl]-8-oxo-7-([(4-pyridinylthio)acetyl] amino)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid monosodium salt Common Name: Sodium 7-(pyrid-4-ylthioacetamido)cephalosporanate Chemical Abstracts Registry No.: 24356-60-3; 21593-23-7 (Acid)

926

Cephapirin sodium

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Cefadyl

Bristol

US

1974

Bristocef

Bristol

W. Germany

1974

Cephaloject

Bristol

France

1974

Cefatrexyl

Essex

Switz.

1974

Brisporin

Bristol

Italy

1976

Cefatrexyl

Bristol

Japan

1977

Brisfirina

Bristol-Myers

-

-

Cefa-Lak

Bristol

-

-

Cefatrex

Bristol-Myers

-

-

Cefatrexil

Mead Johnson

-

-

Cefatrexyl

Galenika

Yugoslavia

-

Piricef

C.T.

Italy

-

Today

Bristol-Myers

-

-

Raw Materials Aminocephalosporanic acid Sodium-2-ethylhexanoate 2-Mercaptopyrimidine

Sodium bicarbonate Bromoacetyl bromide

Manufacturing Process One route is that described in US Patent 3,422,100 as follows, starting with aminocephalosporanic acid (ACA): 27.2 g (0.1 mol) of 7-ACA, 33.2 g (0.3 mol) of NaHCO3, 200 ml of water and 100 ml of acetone were mixed together, cooled to 0°C and stirred rapidly while 20.1 g (0.1 mol) of bromoacetyl bromide dissolved in 100 ml of acetone was added in one fast addition. The temperature was kept at 0 to 5°C for ten minutes, then the ice-salt bath was removed and stirring continued for one hour as the temperature approached 25°C. The mixture was concentrated in vacuo at 20°C to one-half volume and 200 ml of water added. Two 400 ml ether extracts were made and discarded. The aqueous solution was covered with 200 ml of ethyl acetate and vigorously stirred and cooled while being acidified to pH 2 with 40% phosphoric acid. The mixture was filtered, the ethyl acetate layer separated and washed with three 100 ml portions of water, dried over Na2SO4, filtered and treated with 30 ml of sodium 2-ethylhexanoate in n-butanol (34 ml = 0.1 mol). The oil which settled out was scratched to induce crystallization. After stirring for 20

Cephapirin sodium

927

minutes the product, sodium 7-(α-bromoacetamido)cephalosporanate, was scraped from the sides of the flask and collected. The filter cake was washed with several portions of acetone, air dried, and dried in vacuo over P2O5.The yield was 22.5 g and decomposed at 193°C. A solution of 1.13 g (0.01 mol) of 2-mercaptopyrimidine and 1.06 g (0.01 mol) of sodium carbonate dissolved in 25 ml of water was added dropwise over a period of an hour at room temperature, to a stirred solution of 4.15 g (0.01 mol) of sodium 7-(α-bromoacetamido)cephalosporanate in 25 ml of water. Stirring was continued an additional 90 minutes and then 50 ml of ethyl acetate was added, Forty percent H3PO4 was added dropwise with vigorous stirring until pH 2.5 to 3 was obtained. The product crystallized immediately and was filtered off, washed several times with water and then three times with 25 ml portions of ethyl acetate, following which it was air dried. The yield was 2.9 g of crystals that decomposed at 167 to 168°C. The IR and NMR spectra were consistent with the desired product, 7-[α-(2-pyrimidinylthio) acetamido]-cephalosporanic acid monohydrate. An alternate route is that described in US Patent 3,503,967 which uses ACA in the last step. Another alternative route is that described in US Patent 3,578,661 uses bromomethylcephalosporin as one raw material. However the acid is prepared, the sodium salt may be prepared as described in US Patent 3,503,967: Five liters of methylene chloride were added to a clean dry vessel equipped with stirrer. 7-[α(4-pyridylthio)acetamido] cephalosporanic acid (1,000 g) was added to the vessel, followed by 350 ml of triethylamine. The resultant solution was treated with decolorizing charcoal for 15 minutes and filtered. A solution of sodium-3-ethyl-hexanoate (27.3%) in butanol-methylene chloride was added to the filtrate with stirring. Seven thousand five hundred milliliters of acetone was added. Crystallization occurred while stirring was continued several hours under dry conditions. The crystals were collected by filtration, washed with large volumes of acetone, and then dried in vacuo at 50°C to yield about 950 g of the title compound. References Merck Index 1945 Kleeman and Engel p. 167 PDR p. 695 OCDS Vol. 2 p. 441 (1980) DOT9 (2) 56 (1973) and 10 (11) 299 (1974) I.N. p. 197 REM p. 1187 Crast, L.B. Jr.; US Patent 3,422,100; January 14, 1969; assigned to BristolMyers Company Silvestri, H.H. and Johnson, D.A.; US Patent 3,503,967; March 31, 1970; assigned to Bristol-Myers Company Havranek, R.E. and Crast, L.B. Jr.; US Patent 3,578,661; May 11, 1971; assigned to Bristol-Myers Company

928

Cephradine

CEPHRADINE Therapeutic Function: Antibiotic Chemical Name: 7-[D-2-Amino-2-(1,4-cyclohexadien-1-yl)acetamido]-3methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Common Name: Structural Formula:

Chemical Abstracts Registry No.: 38821-53-3 Trade Name Sefril Eskacef Velosef Sefril Velocef Velosef Anspor Velosef Eskacef Dicefalin Cefro Lisacef Askacef Cefamid Cefosan Cefradex Cefrag Cefro Cefrum Celex Cesporan Citicel Dimacef Ecosporina

Manufacturer Squibb SKF Squibb Von Heyden Squibb Squibb SKF Squibb SKF Nippon Squibb Sankyo Lisapharma SKF Gibipharma San Carlo Ausonia Magis Sankyo San Carlo Aristochimica Errekappa C.T. Dima Ecobi

Country Switz. UK UK W. Germany Italy US US France France Japan Japan Italy Italy Italy Italy Italy Japan Italy Italy Italy Italy Italy Italy

Year Introduced 1972 1972 1973 1973 1974 1974 1975 1975 1978 1980 1980 -

Cephradine

929

Trade Name

Manufacturer

Country

Year Introduced

Eskacef

SKF

Italy

-

Eskacef

SK Dauelsberg

W. Germany

-

Forticef

Godecke

W. Germany

-

Lisacef

Lisapharma

Italy

-

Medicef

Medici

Italy

-

Megacef

Beytout

France

-

Noblitina

Juste

Spain

-

Protocef

Ripari-Gero

Italy

-

Samedrin

Savoma

Italy

-

Raw Materials D-Phenylglycine Methyl acetoacetate Lithium

3-Deacetoxy-7-aminocephalosporanic acid Ammonia

Manufacturing Process In a first step, D-2-amino-2-(1,4-cyclohexadienyl)acetic acid is obtained as follows. A solution of 11.0 g (72.7 mmol) of D-phenylglycine in 900 ml distilled ammonia (which has been treated with 45 mg lithium after distillation to destroy traces of moisture) is slowly diluted with 370 ml dry ten-butyl alcohol. Over a period of hours, 1.65 g lithium (3.27 eq) is added in small portions until a permanent blue color is obtained. The blue reaction mixture is then treated with 38 g of triethylamine hydrochloride. The ammonia is allowed to evaporate at room temperature overnight and the residual solvent is evaporated at reduced pressure. The white residue is taken up in a small amount of methanol-water and added to 4 liters of cold 1:1 chloroformacetone to precipitate the crude product. After 20 minutes stirring the suspension is filtered and the white filter cake dried in vacuo; the filter cake is then pulverized and submitted once more to the precipitation process from 1:1 chloroform-acetone. The white, crystalline product, 11.8 g, MP 297°C (dec), [α]D -89.7 (2 N NaOH) is quantitatively obtained but is slightly contaminated with lithium chloride, 0.6% ionic chlorine being found by analysis. The product of a second step is the methyl acetoacetic ester enamine of N-2amino-2-(1,4-cyclohexadienyl)acetic acid sodium salt. 306 mg D-2-amino-2(1,4-cyclohexadienyl)acetic acid (2.00 mmol) are dissolved by warming in a solution of 108 mg of NaOCH3 (2.00 mmol) in 4.3 ml reagent grade MeOH. 255 mg (0.24 ml, 2.20 mmol) methyl acetoacetate are added and the mixture refluxed for 45 minutes. The MeOH is almost totally stripped off in vacuo. Five milliliters benzene are added and distilled off to a small residual volume. The addition and distillation of benzene is repeated to insure complete removal of the MeOH and water. The product crystallizes out overnight from a small residual volume of benzene. It is filtered off, washed with benzene, and dried

930

Ceruletide

in vacuo. Yield 463 mg. Then 3-deacetoxy-7-aminocephalosporanic acid is condensed with the above described sodium salt in the presence of triethylamine to give cephradine. References Merck Index 1947 Kleeman and Engel p. 175 PDR pp. 1703, 1771 OCDS Vol. 2 p. 440 (1980) DOT 9 (3) 89 (1973) I.N. p. 199 REM p. 1188 Weisenborn, F.L., Dolfini, J.E., Bach, G.G. and Bernstein, J.; US Patent 3,485,819; December 23, 1969; assigned to E.R. Squibb and Sons, Inc.

CERULETIDE Therapeutic Function: Stimulant (gastric secretory) Chemical Name: Decapeptide of empirical formula C58H73N13O21S2 Common Name: Cerulein; Caerulein Structural Formula:

Cetalkonium chloride

931

Chemical Abstracts Registry No.: 17650-98-5 Trade Name Ceosunin Takas Takus Tymtran Cerulex

Manufacturer Kyowa Hakko Carlo Erba Essex Adria Farmitalia

Country Japan W. Germany Switz. US France

Year Introduced 1976 1978 1981 1982 1983

Raw Materials L-Pyroglutamyl-L-glutaminyl-L-aspartyl-L-tyrosine azide L-Threonyl-glycyl-L-tryptophanyl-L-methionyl-L-aspartyl-Lphenylalaninamide Pyridine sulfuric anhydride Sodium carbonate Manufacturing Process The tetrapeptide, L-pyroglutamyl-L-glutaminyl-L-aspartyl-L-tyrosine-azide (I), is condensed with the hexapeptide, L-threonyl-glycyl-L-tryptophanyl-Lmethionyl-L-aspartyl-L-phenylalaninamide (II), having the hydroxyl of the threonyl radical blocked by an acyl radical in a suitable solvent, such as dimethylformamide, to obtain the decapeptide, L-pyroglutamyl-L-glutaminyl-Laspartyl-L-tyrosyl-L-threonylglycyl-L-tryptophanyl-L-methionyl-L-aspartylLphenylaninamide (III) having the hydroxy group of the threonyl radical blocked by an acyl radical. The decapeptide (III) is treated, at low temperature, with the complex anhydrous pyridine sulfuric anhydride finally to obtain the decapeptide, L-pyroglutamyl-L-glutaminyl-L-aspartyl-L-tyrosyl-Lthreonyl-glycyl-L-tryptophanyl-L-methionyl-L-aspartyl-L-phenylalaninamide (IV) having the phenolic group of the tyrosyl radical protected by a sulfate radical and the hydroxyl of the threonyl radical protected by an acyl radical. Finally, by mild alkaline hydrolysis of the decapeptide (IV) one obtains the decapeptide product. References Merck Index 1963 DFU 1 (8) 359 (1976) Kleeman and Engel p. 178 DOT 15 (11) 13 (1979) I.N. p. 203 REM p. 1274 Bernardi, L., Bosisio, G., De Castiglione, R. and Goffredo, O.; US Patent 3,472,832; Oct. 14, 1969; assigned to Societa Farmaceutici Italia (Italy)

CETALKONIUM CHLORIDE Therapeutic Function: Antiseptic

932

Cetalkonium chloride

Chemical Name: Ammonium, benzyldimethylhexadecyl-, chloride Common Name: Cetalkonium chloride; Cetol Structural Formula:

Chemical Abstracts Registry No.: 122-18-9; 10328-34-4 (Base) Trade Name

Manufacturer

Country

Year Introduced

Cetalkonium Chloride

Chemische Fabrik Berg

-

-

Baktonium

BODE CHEMIE GMBH and CO.

-

-

Ceetolan

Lannett Company, Inc.

-

-

Raw Materials Hexadecylamine Benzyl chloride Methyl chloride Manufacturing Process 185 parts of hexadecylamine and 126.5 parts of benzylchloride was stirred at 100°C for 8 hours. After cooling to the crystalline product was added methyl chloride. N-Hexadecyl-N,N-dimethylbenzenemethanaminium chloride was obtained. References Merck Index, Monograph number: 2059, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. Fr. Patent No. 771,746; Oct. 15, 1934; Assigned to I.G. Farbenindustrie Aktiengesellschaft

Cetiedil

933

CETIEDIL Therapeutic Function: Vasodilator Chemical Name: α-Cyclohexyl-3-thiopheneacetic acid 2-(hexahydro-1Hazepin-1-yl)ethyl ester Common Name: Structural Formula:

Chemical Abstracts Registry No.: 14176-10-4; 16286-69-4 (Citrate) Trade Name

Manufacturer

Country

Year Introduced

Stratene

Innothera

France

1973

Stratene

Sigma Tau

Italy

1976

Fusten

Galenika

Greece

-

Huberdilat

Hubber

Spain

-

Vasocet

Winthrop

-

-

Raw Materials Sodium (3-Thienyl)acetonitrile 1-(2-Chloroethyl)-hexahydro-1H-azepine Cyclohexyl bromide Manufacturing Process In a 100 ml flask fitted with a mechanical stirrer, a vertical condensor protected by a calcium chloride stopper, a dropping-funnel and a source of nitrogen were introduced 30 ml of hexamethylenephosphotriamide and 2.3 g (0.1 mol) of finely cut sodium wire. A mixture of 12.3 g (0.1 mol) of (3thienyl)-acetonitrile and 16.3 g (0.1 mol) of cyclohexyl bromide was then quickly added at a temperature of 20 C. The reaction mixture was then maintained under nitrogen atmosphere and stirred for 12 hours at room temperature. The excess of sodium was destroyed by adding 5 ml of ethanol and the organic solution was slowly poured into 100 ml of a 1 N iced solution of hydrochloric acid. The solution was extracted twice with 100 ml ether. The ethereal phases were collected, washed with water, dried and concentrated under reduced pressure. The crude product was then purified by

934

Cetirizine dihydrochloride

chromatography on a silica column (150 g of silica) using a 1/1 benzene/cyclohexane mixture as elution agent. The product obtained was rectified by distillation. In this manner, 3.4 g of alpha(3-thienyl)-alpha-cyclohexylacetonitrile were obtained, which represents a yield of 16%. The nitrile may then be hydrolyzed to cyclohexyl-(3-thienyl)acetic acid which is reacted with 1-(2-chloroethyl)-hexahydro-1H-azepine to give cetiedil. It is commonly used as the citrate. References Merck Index 1976 Kleeman and Engel p. 179 OCDS Vol. 3 p. 42 (1984) DOT 10 (4) 126 (1974) I.N.p. 204 Pigerol, C., De Cointet De Fillain, P., Grain, C. and Le Blat, J.; US Patent 4,108,865; August 22, 1978; assigned to Labaz (France)

CETIRIZINE DIHYDROCHLORIDE Therapeutic Function: Antihistaminic; Antiallergic Chemical Name: Acetic acid, (2-(4-((4-chlorophenyl)phenylmethyl)-1piperazinyl)ethoxy)-, dihydrochloride Common Name: Cetirizine hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 83881-52-1 Trade Name Cesil Citizen

Manufacturer Silva Pharmaceticals Ltd. Zenith Pharmaceuticals Ltd.

Country India India

Year Introduced -

Cetirizine dihydrochloride

935

Trade Name

Manufacturer

Country

Year Introduced

Cetizin

Acme Laboratories Ltd.

India

-

Cetra

India

-

Nosemin

Cosmo Pharma Laboratories Ltd. Ibn Sina Pharmaceuticals

India

-

Rinitrin

Sigma Laboratories Ltd.

-

-

Riz

Orion Laboratories Ltd.

India

-

Zyrtec

UCB

Belgium

-

Zyrtec

Pfizer

-

-

Zyrtec

Sun Pharma

-

-

Raw Materials 2-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]-ethanol tert-BuOK Sodium chloracetate Manufacturing Process Preparation of 2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetic acid (cetirizine). To a mixture of 50 g 2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethanol and 225 ml of tert-butanol at 45°C under a nitrogen was added 21 g tert-BuOK. The temperature was raised to 75-80°C and the mixture was kept at this temperature. After 45 min was added 11 g sodium chloracetate; after 1.5 hour was added 5.2 g tert-BuOK; after 2 hours was added 5.64 g sodium chloracetate; after 2.5 hours was added 1.9 g tert-BuOK; after 3 hours was added 1.9 g sodium chloracetate; after 3.5 hours was added 0.8 g tert-BuOK; and after 4 hours was added 1.13 g sodium chloracetate. Then about 150 ml tert-butanol was distilled of, 190 ml of water was added and the distillation of tert-butanol was continued until the temperature of the vapour reaches 100°C. To the reaction mixture was added 60 ml of water and 8 ml concentrated hydrochloric acid to pH 8. Unreacted 2-[4-[(4-chlorophenyl) phenylmethyl]-1-piperazinyl]-ethanol was extracted with diethyl ether. The aqueous phase was acidified to pH 5 by addition of hydrochloric acid and extracted with dichloromethane (200 ml x 3). The extract was dried over MgSO4, filtered and concentrated in a rotary evaporator. An obtained oil was allowed to crystallize by addition of 150 ml of 2-butanone, yields of 2-[4-[(4chlorophenyl)phenylmethyl]-1-piperazinyl]-ethoxy]acetic acid 55.5%, M.P. 146-148°C. 32.7 g 2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]-ethoxy]acetic acid was suspended in a mixture of 125 ml of water and 13.8 ml 37% aqueous hydrochloric acid. The mixture was concentrated in a rotary evaporator. An obtained oil was allowed to crystallize by addition of 245 ml of 2-butanone, yields of 2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]-ethoxy]acetic acid dihydrochloride 88%, M.P. 228.22°C.

936

Cetobemidone

References Taj Yong, Kariman Rhoshayar, Tam Tim Fat; US Patent No. 6,046,332; April 4, 2000; Bodson G. et al.; Canadian Patent 1,320,732

CETOBEMIDONE Therapeutic Function: Narcotic analgesic Chemical Name: 1-[4-(3-Hydroxyphenyl)-1-methyl-piperidin-4-yl]-propan-1one Common Name: Cetobemidone; Chetobemidone; Ketobemidone Structural Formula:

Chemical Abstracts Registry No.: 469-79-4 Trade Name Ketobemidone

Cliradon Ketogan Ketogin Ketodur Ketogan novum Ketorax Ketorax

Manufacturer Shanghai Lancheng Corporation Ciba Lundbeck Lundbeck Pfizer Pharmacia Pharmacia Pfizer

Country -

Year Introduced -

-

-

Raw Materials Sodium amide 3-Methoxybenzyl cyanide Magnesium Ethyl bromide N,N-Bis(2-chloroethyl)-N-methylamine

Cetyl alcohol

937

Manufacturing Process The process includes the following steps: 1. 80 weight parts (w.p.) powder of sodium amide was added to 147 w.p. 3methoxy-benzylcyanide, 156 w.p. N,N-bis(2-chloroethyl)-N-methylamine and 350 w.p. toluene in 6-8 portions by stirring at 40°-45°C. The mixture was slowly heated to 100°-105°C with stirring for 1 hour at this temperature. Some water was added after cooling, the toluene layer was treated with diluted HCl and it therefrom was adjusted to a alkaline pH by addition of sodium hydroxide, extracted with ether and the ether layer dried over Na2CO3. The solvent was removed; the distillation of the residue gave 4-cyan4-(3-metoxyphenyl)-1-methylpiperidine as a colorless oil; BP 150°C at 2 mm/Hg, hardened by standing; MP 44°C. The yield was 65-68%. 2. The solution of ethyl magnesium bromide from 36 w.p. magnesium and 165 w.p. ethyl bromide in 700 w.p. ether was added to 230 w.p. above cyanide in 330 w.p toluene. The mixture was refluxed for 1 hour. Then the ether was slowly distilled and the residue was stood for 1 hour at water bath temperature. After cooling with an ice the mixture was acidified by addition of HCl to adjust the congo acid pH. 4-(3-Methoxyphenyl-1-methyl-4propipnylpiperidine was prepared by a saturation of above solution with NH3 and it therefrom was dried over K2CO3 and distilled to give a colorless product BP 184°-185°C at 6 mm/Hg. 3. The mixture 261 w.p 4-(3-methoxyphenyl)-1-methyl-4-propipnylpiperidine and 750 w.p. HBr (BP 126°C) was refluxed for 1 hour. Then 2/3 of acid was distilled on an oil bath and the hot water was added to the rest. The title product was precipitated by NH3 as the oil that became hard and after recrystallisation from ethylacetate had MP 156°-157°C. References Eisleb O.E.; D.R. Patent No. 752,755; 10 Nov. 1952; Assigned to I.G. Farbenindustrie A.G., Frankfurt/Main

CETYL ALCOHOL Therapeutic Function: Pharmaceutic aid Chemical Name: n-Hexadecanol Common Name: 1-Hexadecanol; Ethal; Ethol; Palmityl alcohol Structural Formula:

938

Cetyl alcohol

Chemical Abstracts Registry No.: 36653-82-4 Trade Name

Manufacturer

Country

Year Introduced

Hexadecyl alcohol

Esso Res. And Eng. Co.

-

-

Ego Skin Cream

Ego

-

-

Raw Materials Sodium bicarbonate Hydrochloric acid Palmitoyl chloride

Hexadecyl bromide Calcium oxide Sodium borohydride

Manufacturing Process 1). A slurry of sodium bicarbonate comprising 39.8 g sodium bicarbonate and 254 ml water was placed in an autoclave. 96.3 g hexadecyl bromide and 635 ml acetone were then added. The autoclave was sealed and while stirring (590 r.p.m.) it was heated to a temperature of 218°C over a period of 1 hour 15 min. The temperature was maintained at 218-220°C for an additional hour. At the end of the reaction the autoclave was cooled to about 50°C, that is, to a temperature at which the alcohol remains molten. The autoclave was then rinsed with acetone and 1 N hydrochloric acid add to neutralize the sodium bicarbonate. The reaction mixture was diluted with an equivalent volume of water and then extracted with n-pentane. (Other suitable water insoluble solvents such as benzene, carbon tetrachloride, chloroform, petroleum ether and the like can be used for extraction). The pentane extract was washed with water and then dried over magnesium sulfate. The dried solution was filtered and evaporated. The residue was melted and a vacuum applied to remove the last traces of pentane. On distillation a yield of 94.8% of the theoretical yield white crystals of hexadecanol was recovered; M.P. 49°C, B.P. 344°C, nD79 = 1.4283. 2). 5.80 g of hexadecyl bromide, 36 ml of 60% aqueous dioxane and 0.73 g of calcium oxide were placed in an ampoule. The ampoule was then heated, while shaking, to a temperature of 220°C over a period of 0.5 hours, and maintained at this temperature for 1 hour. After the reaction the ampoule was cooled and the products worked up as in method 1. Analysis for alcohol content by Zerewitinoff active hydrogen determination showed the yield to be 92.5%; M.P. 49°C, B.P. 344°C, nD79 = 1.4283. 3). A solution of palmitoyl chloride in dioxane was added dropwise to a cooled dispersion of sodium borohydride.The mixture was heated on the steam bath for a short time and then, after cooling, water was added. On distillation a yield of hexadecanol 87%, M.P. 49°C, B.P. 344°C. References Levine I. E., Uppinger E. C.; US Patent No. 3,018,308; Jan.23, 1962; Assigned to California Research Corporation, San Francisco, Calif., a corporation of Delaware Caikin, Brown; J. Am. Chem. Soc.; 1949, 71, 122

Cevimeline hydrochloride

939

CEVIMELINE HYDROCHLORIDE Therapeutic Function: Salivation stimulant Chemical Name: Spiro(1-azabicyclo(2.2.2)octane-3,5'-(1,3)oxathiolane), 2'methyl-, hydrochloride, hemihydrate, cisCommon Name: Cevimeline hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 153504-70-2 Trade Name Evoxac Evoxac

Manufacturer SnowBrand Pharmaceuticals Daiichi

Country -

Year Introduced -

-

-

Raw Materials 3-Hydroxy-3-mercaptomethylquinuclidine Acetaldehyde Sodium sulfate Hydrogen chloride Stannic chloride Sodium hydroxide Manufacturing Process (1) Into a 500 ml four-necked flask equipped with a stirrer, a thermometer and a calcium chloride tube, 10.6 g of 3-hydroxy-3mercaptomethylquinuclidine (purity: 98.3%), 222.8 g of chloroform, 31.7 g of toluene and 2.2 g of dimethylsulfoxide were charged, and 17.3 g of acetaldehyde was added thereto at 10-15°C. While maintaining the temperature at the same level, 12.2 g of anhydrous sodium sulfate was added thereto. Then, 9.8 g of hydrogen chloride gas was blown thereinto over a period of two hours, and then the mixture was maintained at room temperature for 6 hours with stirring. To the reaction mixture, 125.7 g of a 15% sodium hydroxide aqueous solution was dropwise added to make the reaction mixture strongly alkaline. Then, undissolved inorganic salts were separated by filtration, and the inorganic

940

Cevimeline hydrochloride

salts were washed with 18.9 g of chloroform. The filtrate was subjected to liquid separation, and the aqueous layer was re-extracted with chloroform. These chloroform layers were put together, and 100.5 g of 5% sulfuric acid was added thereto to obtain desired 2-methylspiro(1,3-oxathiolane5,3')quinuclidine sulfate. Then, it was again made alkaline with 54.6 g of a 10% sodium hydroxide aqueous solution to free the desired 2methylspiro(1,3-oxathiolane-5,3')quinuclidine, which was then extracted four times with 33 g of n-hexane. The n-hexane layer was dried over anhydrous sodium sulfate, and then, sodium sulfate was filtered off to obtain a n-hexane solution of 2-methylspiro(1,3-oxathiolane-5,3')quinuclidine. To this n-hexane solution, 18.0 g of an iso-propyl alcohol solution containing 20% of hydrochloric acid was dropwise added to obtain 2-methylspiro(1,3oxathiolane-5,3')quinuclidine hydrochloride. After stirring for 3 hours, precipitated white crystals were collected by filtration to obtain 10.1 g of a mixture of hydrochlorides of trans- and cis-2-methylspiro(1,3-oxathiolane5,3')quinuclidine (purity: 95.8%, yield of pure product 68.5%). (2) Into a 500 ml four-necked flask equipped with a stirrer and a thermometer, 4.9 g (0.02 mol) of the mixture of hydrochlorides of trans- and cis-2-methylspiro(1,3-oxathiolane-5,3')quinuclidine obtained in the above step (1) (the weight ratio of cis-and trans-isomers was 50.5/49.5) and 34 ml of chloroform (this chloroform contained 0.5 wt % of ethyl alcohol) were charged, and 17 ml of a chloroform solution containing 0.2 g of hydrogen chloride (this chloroform also contained 0.5 wt % of ethyl alcohol) was added thereto with stirring. Then, 7.8 g of stannic chloride was dropwise added thereto over a period of 30 min, and an isomerization reaction was carried out with stirring at room temperature for 24 hours. To the reaction product, 50 ml of water was added, and a 48% sodium hydroxide aqueous solution was added thereto with stirring to make the reaction mixture strongly alkaline. Then, the chloroform layer was separated. To the aqueous solution, 10 ml of chloroform was added for re-extraction. These chloroform layers were put together, and 24.0 g of 5% sulfuric acid was added thereto to convert 2methylspiro(1,3-oxathiolane-5,3')quinuclidine in the reaction mixture to a sulfate, which was then dissolved in water. To this aqueous layer, a 10% sodium hydroxide aqueous solution was again added to make it strongly alkaline and to free 2-methylspiro(1,3-oxathiolane-5,3')quinuclidine in the reaction mixture. Then, it was extracted four times with 15 ml of n-hexane. The extracted n-hexane layer was dried over anhydrous sodium sulfate. Then, an iso-propyl alcohol solution containing 20% of hydrochloric acid was dropwise added thereto to convert 2-methylspiro(1,3-oxathiolane5,3')quinuclidine in the reaction mixture to a hydrochloride, and precipitated white crystals were collected by filtration and dried to obtain 4.4 g of a mixture containing hydrochlorides of cis- and trans-2-methylspiro(1,3oxathiolane-5,3')quinuclidine (yield hydrochlorides: 92.1%). The ratio of cisand trans-2-methylspiro(1,3-oxathiolane-5,3')quinuclidine was 98.6/1.4 (was analyzed by liquid chromatography). References Hayashi K. et al.; US Patent No. 5571918; Nov. 5, 1996; Assigned to Ishihara Sangyo Kaisha Ltd. (Osaka, JP)

Chenodiol

941

CHENODIOL Therapeutic Function: Gallostone dissolving agent Chemical Name: 3,7-Dihydroxycholan-24-oic acid Common Name: Chenodeoxycholic acid; Chenic acid Structural Formula:

Chemical Abstracts Registry No.: 474-25-9 Trade Name Chenofalk Chenofalk Chenossil Chenodex Chendol Regalen Chenocol Chenix Aholit Bilo Calcolise Carbilcolina Chelobil Chemicolina Chenar Chendal Chendix Chendol Chenoacid Chenodecil Chenodex Chenomas Chenotar Cholonorm

Manufacturer Fa1k Pharmacolor Giuliani I.S.H. Weddell Eisai Yamanouchi Reid-Rowell Vetprom Iltas Prodes Ralay Oftalmiso Ern Armour-Montagu Tika Weddell Weddell Falk Aldon Houde Guadalupe Armour Gruenenthal

Country W. Germany Switz. Italy France UK Japan Japan US Yugoslavia Turkey Spain Spain Spain Spain Sweden UK UK W. Germany Spain France Spain W. Germany

Year Introduced 1974 1974 1975 1977 1978 1982 1982 1983 -

942

Chenodiol

Trade Name

Manufacturer

Country

Year Introduced

Cholasa

Tokyo Tanabe

Japan

-

Cholestex

Ikapharm

Israel

-

Duanox

Roche

-

-

Fluibil

Zambon

Italy

-

Gamiquenol

Gamir

Spain

-

Hekbilin

Hek

W. Germany

-

Henohol

Galenika

Yugoslavia

-

Kebilis

Hoechst-Roussel

-

-

Kenolite

Leurquin

France

-

Quenobilan

Estedi

Spain

-

Soluston

Rafa

Israel

-

Ulmenid

Roche

-

-

Raw Materials 7-Acetyl-12-ketochenodeoxycholic acid Hydrazine hydrate Potassium hydroxide Manufacturing Process To 1,400 ml of an approximately 50% water/triglycol solution of the potassium salt of chenodeoxycholic acid, obtained by the Wolff-Kishner reduction (using hydrazine hydrate and potassium hydroxide) from 50 g of 7acetyl-12-ketochenodeoxycholic acid, 220 ml of dilute hydrochloric acid is added to bring the pH to 2. The solution is stirred and the crude chenodeoxycholic acid precipitates. The precipitate is recovered and dried to constant weight at about 60°C. About 36 g of the crude chenodeoxycholic acid, melting in the range of 126°-129°C, is obtained. 25 g of crude chenodeoxycholic acid so obtained is dissolved in 750 ml of acetonitrile while stirring and heating. 3 g of activated charcoal is added and then removed by suction filtering. The resulting liquid filtrate is cooled, the pure chenodeoxycholic acid crystallizing out. The crystals are recovered by suction filtering and the recovered crystals dried under vacuum. The yield is 19 g of pure chenodeoxycholic acid with a melting range of 168°-171°C. References Merck Index 2007 Kleeman and Engel p. 181 PDR p. 1446 DOT 8 (7) 273 (1972) and 12 (2) 52 (1976) I.N. p. 17 REM p. 812 Maeke, S. and Rambacher, P.; US Patent 4,163,017; July 31, 1979; assigned to Diamalt A.G. (Germany)

Chlophedianol

943

CHLOPHEDIANOL Therapeutic Function: Antitussive Chemical Name: 2-Chloro-α-[2-(dimethylamino)ethyl]-αphenylbenzenemethanol Common Name: Clofedanol Structural Formula:

Chemical Abstracts Registry No.: 791-35-5 Trade Name Detigon Detigon Ulo Tussiplegyl Colorin Abehol Anayok Baltix Demax Dencyl Eletuss Eutus Farmatox Fugatox Gen-Tos Gutabex Pectolitan Prontosed Refugal Tigonal Tuxidin Tuxinil Ulone

Manufacturer Bayer Bayer Riker Bayer Nippon Shinyaku Pliva Chibi Kobanyai Orma Bencard Serpero Eupharma Cifa Ifisa Morgens Russi Kettelhack Riker Francia Bayer I.B.P. Gazzini Bieffe Riker

Country W. Germany Italy US France Japan Yugoslavia Italy Hungary Italy UK Italy Italy Italy Italy Spain Italy W. Germany Italy Italy Italy Italy -

Year Introduced 1958 1959 1960 1969 1981 -

944

Chloral betaine

Raw Materials o-Chlorobenzophenone Acetonitrile Sodium amide

Hydrogen Methyl sulfate

Manufacturing Process This compound may be produced by reacting o-chlorobenzophenone with acetonitrile in the presence of sodium amide or another strongly basic condensing agent, to form the nitrile of beta-phenyl-beta-o-chlorophenylhydracrylic acid, which is then hydrogenated to yield 1-phenyl-1-ochlorophenyl-3-aminopropanol-1. The latter intermediate compound is subsequently dimethylated with an agent such as methyl sulfate to provide the desired end product 1-o-chlorophenyl-1-phenyl-3-dimethylaminopropanol. References Merck Index 2018 Kleeman and Engel p. 226 I.N. p. 244 REM p. 871 Lorenz, R., Gosswald, R. and Henecka, H.; US Patent 3,031,377; April 24, 1962; assigned to Farbenfabriken Bayer AG, Germany

CHLORAL BETAINE Therapeutic Function: Sedative Chemical Name: Adduct of chloral hydrate with betaine Common Name: Structural Formula:

Chemical Abstracts Registry No.: 2218-68-0 Trade Name

Manufacturer

Country

Year Introduced

Beta-Chlor

Mead Johnson

US

1963

Chloralodol

945

Raw Materials Betaine hydrate Chloral hydrate Manufacturing Process An intimate mixture of betaine hydrate (67.5 g) and chloral hydrate (100 g) was warmed to ca. 60°C when an exothermic reaction occurred and the mixture became pasty. It was then stirred at 60°C for 30 minutes. The residue solidified on cooling and was crystallized from a small amount of water. The product separated in hard, colorless prisms of MP 122.5 to 124.5°C (corr). References Merck Index 2026 Kieeman and Engel p. 184 Petrow, V., Thomas, A.J. and Stephenson, O.; US Patent 3,028,420; April 3, 1962; assigned to The British Drug Houses Limited, England

CHLORALODOL Therapeutic Function: Hypnotic Chemical Name: 2-Methyl-4-(2,2,2-trichloro-1-hydroxyethoxy)-2-pentanol Common Name: Chloralodol; Chlorhexadol Structural Formula:

Chemical Abstracts Registry No.: 3563-58-4 Trade Name Chloralodol

Manufacturer Shanghai Lancheng Corporation

Country -

Year Introduced -

Lora (formerly) Medodorm

Wallace Labs Medo

-

-

946

Chlorambucil

Raw Materials 2-Methyl-2,4-pentanediol Chloral hydrate Manufacturing Process 472 g of 2-methyl-2,4-pentanediol (4 moles) are heated to 70°-80°C in a bowl, and 660 g of chloral hydrate (4 moles) are added under stirring until all of chloral hydrate is dissolved. The temperature, which decreases during the addition, then increased to 60° to 70°C. When reaction mixture has become a nearly dry crystal powder, the powder is subjected to further drying by slight heating. Yield of raw product is about 1060 g. Recrystallization is carried out from tetrachloromethane, and the yield is 980 g (about 92 %). References Christensen J.E.T.; US Patent No. 2,931,838; Apr. 5, 1960; Assigned to Det Danske Medicinal and Keminkalle-Kompagni A-S, Copenhagen, Denmark

CHLORAMBUCIL Therapeutic Function: Antineoplastic Chemical Name: 4-[Bis(2-chloroethyl)amino]benzenebutanoic acid Common Name: Structural Formula:

Chemical Abstracts Registry No.: 305-03-3 Trade Name

Manufacturer

Country

Year Introduced

Leukeran

BurroughsWellcome

US

1957

Leukeran

Wellcome

W. Germany

-

Leukeran

Wellcome

Switz.

-

Amboclorin

Simes

Italy

-

Chloraminophene

Techni-Pharma

France

-

Linfolysin

I.S.M.

Italy

-

Chloramphenicol

947

Raw Materials Acetanilide Maleic acid Phosphorus oxychloride

Hydrogen Ethylene oxide

Manufacturing Process Acetanilide and maleic acid are condensed to give beta-(p-acetaminobenzoyl) acrilic acid which is hydrogenated to give methyl-gamma-(p-aminophenyl) butyrate. That is reacted with ethylene oxide and then with phosphorus oxychloride to give the methyl ester which is finally hydrolyzed to give chlorambucil. References Merck Index 2031 Kleeman and Engel p. 184 PDR p. 752 DOT 16 (5) 70 (1980) I.N. p. 208 REM p. 1145 Phillips, A.P. and Mentha, J.W.; US Patent 3,046,301; July 24, 1962; assigned to Burroughs Wellcome and Co. (USA.) Inc.

CHLORAMPHENICOL Therapeutic Function: Antimicrobial Chemical Name: D(-)-threo-2,2-Dichloro-N-[β-hydroxy-α-(hydroxymethyl)-pnitrophenethyl]acetamide Common Name: Structural Formula:

Chemical Abstracts Registry No.: 56-75-7

948

Chloramphenicol

Trade Name

Manufacturer

Country

Year Introduced

Leukomycin

Bayer

W. Germany

-

Chloromycetin

Warner Lambert

Switz.

-

Chloromycetin

Parke Davis

US

1949

Chloramphenicol

MSD-Chibret

France

1954

Econochlor Sol

Alcon

US

1975

Amboken

Gedeon Richter

Mexico

-

Amphicol

McKesson

US

-

Antacin

Sumitomo

Japan

-

Aquamycin

Winzer

W. Germany

-

Bemacol

Int'l. Multifoods

US

-

Berlicetin

Ankerwerk

E. Germany

-

Biocetin

Tasman Vaccine

UK

-

Biophenicol

Biochemie

Austria

-

Cafenolo

Benvegna

Italy

-

Catilan

Hoechst

W. Germany

-

Cebenicol

Chauvin-Blache

France

-

Chemicetina

Erba

Italy

-

Chemyzin

S.I.T.

Italy

-

Chlomin

Knoll

W. Germany

-

Chloramex

Dumex

Denmark

-

Chloramol

Protea

Australia

-

ChloramphenicolPOS

Ursapharm

W. Germany

-

Chlorasol

Evsco

US

-

Chlora-Tabs

Evsco

US

-

Chloricol

Evsco

US

-

Chlornitromycin

Farmakhim

Bulgaria

-

Chlorocid

EGYT

Hungary

-

Chloromycetin

Sankyo

Japan

-

Chloronitrin

Jenapharm

E. Germany

-

Chloroptic

Allergan

US

-

Chlorsig

Sigma

Australia

-

Chloramidina

Arco

Switz.

-

Clorbiotina

Wassermann

Spain

-

Clorofenicina

Antibioticos

Spain

-

Clorosintex

Angelini

Italy

-

Cylphenicol

Trent

US

-

Desphen

Despopharm

Switz.

-

Detreomine

Polfa

Poland

-

Devamycetin

Deva

Turkey

-

Chloramphenicol

949

Trade Name

Manufacturer

Country

Year Introduced

Dextromycin

V.N.I.Kh.F.J.

USSR

-

Doctamicina

Docta

Switz.

-

Farmicetina

Erba

Italy

-

Globenicol

Gist Brocades

-

-

Glorous

Sanwa

Japan

-

Halomycetin

Kwizda

Austria

-

Hortfenicol

Hortel

Spain

-

Ismicetina

I.S.M.

Italy

-

Isophenicol

Bouchara

France

-

Kamaver

Engelhard

W. Germany

-

Kemicetin

Aesca

Austria

-

Kernicetine

Fujisawa

Japan

-

Kernicetine

Erba

Italy

-

Kemicetine

Vifor

Switz.

-

Kemicetine

I.C.N.

Canada

-

Kemicotine

Erba

UK

-

Kloromisin

Biofarma

Turkey

-

Labamicol

Labatec

Switz.

-

Levomycetin

Provita

Austria

-

Lomecitina

Locatelli

Italy

-

Loromisin

Atabay

Turkey

-

Medichol

Copanos

US

-

Micochlorine

Continental Pharma

Belgium

-

Misetin

Dif-Dogu

Turkey

-

Mycetin

Farmigea

Italy

-

Mychel

Rachelle

US

-

Mycinol

Horner

Canada

-

Neocetin

Uranium

Turkey

-

Novochlorcap

Novopharm

Canada

-

Novaphenicol

Nova

Canada

-

Novophenicol

Solac

France

-

Oftakloram

Tan

Turkey

-

Oftalent

Weifa

Norway

-

Oleomycetin

Winzer

W. Germany

-

Ophtaphenicol

Faure

France

-

Oralmisetin

Mulda

Turkey

-

Otachron

Alpine

Austria

-

Otomycin

Pliva

Yugoslavia

-

Pantovernil

Heyden

W. Germany

-

950

Chloramphenicol

Trade Name Paraxin

Manufacturer Boehringer Mannheim

Country W. Germany

Year Introduced -

Paraxin Pedimycetin Pentamycetin Pentocetine Rivomycin Romphenil Septicol Serviclofen Sificetina Sno-Paenicol Sopamycetin Spersanicol Suismycetin Synthomycetin Tevocin Thilocanfol Tifomycine Veticol Viceton Viklorin Vitaklorinlltas

Yamanouchi T.E.M.S. Pentagone Ibsa Rivopharm Zeria Streuli Servipharm Sifi Smith and Nephew Pharbec Dispersa Lagap Abic Tevcon Thilo Roussel Copanos Int'l. Multifoods Ilsan Iltas

Japan Turkey Canada Switz. Switz. Japan Switz. Switz. Italy UK Canada Switz. Switz. Israel US W. Germany France US US Turkey Turkey

-

Raw Materials Sodium Methyl dichloroacetate Benzaldehyde Hydrogen

beta-Nitroethanol Acetic anhydride Nitric acid

Manufacturing Process Chloramphenicol may be prepared by fermentation or by chemical synthesis. The fermentation route to chloramphenicol is described in US Patents 2,483,871 and 2,483,892. To quote from US Patent 2,483,892: The cultivation of Streptomyces venezuelae may be carried out in a number of different ways. For example, the microorganism may be cultivated under aerobic conditions on the surface of the medium, or it may be cultivated beneath the surface of the medium, i.e., in the submerged condition, if oxygen is simultaneously supplied. Briefly stated, the production of chloramphenicol by the surface culture method involves inoculating a shallow layer, usually less than about 2 cm, of a sterile, aqueous nutrient medium with Streptomyces venezuelae and incubating the mixture under aerobic conditions at a temperature between about 20° and 40°C, preferably at room temperature (about 25°C), for a period of about 10 to 15 days. The mycelium is then removed from the liquid and the culture liquid is then treated by methods described for isolating there

Chloramphenicol

951

from the desired chloramphenicol. The synthetic route to chloramphenicol is described in US Patent 2,483,884 as follows: 1.1 g of sodium is dissolved in 20 cc of methanol and the resulting solution added to a solution of 5 g of benzaldehyde and 4.5 g of betanitroethanol in 20 cc of methanol. After standing at room temperature for a short time the gel which forms on the mixing of the reactants changes to a white insoluble powder. The precipitate is collected, washed with methanol and ether and then dried. The product thus produced is the sodium salt of 1phenyl-2-nitropropane-1,3-diol. Eighteen grams of the sodium salt of 1-phenyl-2-nitropropane-1,3-diolis dissolved in 200 cc of glacial acetic acid. 0.75 g of palladium oxide hydrogenation catalyst is added and the mixture shaken at room temperature under three atmospheres pressure of hydrogen overnight. The reaction vessel is opened, 2.5 g of 10% palladium on carbon hydrogenation catalyst added and the mixture shaken under three atmospheres pressure of hydrogen for 3 hours. The catalyst is removed from the reaction mixture by filtration and the filtrate concentrated under reduced pressure. Fifty cubic centimeters of npropanol is added to the residue and the insoluble inorganic salt removed by filtration. The filtrate is treated with excess hydrochloric acid and evaporated to obtain a pale yellow oil. Five grams of the oil thus obtained is treated with 15 cc of saturated potassium carbonate solution and the mixture extracted with 50 cc of ether, then with 30 cc of ethyl acetate and finally with two 30 cc portions of ethanol. Evaporation of the solvent from the extract gives the following quantities of the desired 1-phenyl-2-aminopropane-1,3-diol: 0.5 g, 1.0 g and 3.1 g. 1.7 g of 1-phenyl-2-aminopropane-1,3-diol is treated with 1.6 g of methyl dichloroacetate and the mixture heated at 100°C for 1.25 hours. The residue is washed with two 20 cc portions of petroleum ether and the insoluble product collected. Recrystallization from ethyl acetate yields the desired (dl)reg.-1-phenyl-2-dichloroacetamidopropane-1,3-diol in pure form; MP 154° to 156°C. Five hundred milligrams of (dl)-reg.-1-phenyl-2-dichloroacetamidopropane1,3-diolis added to a solution consisting of 1 cc of pyridine and 1 cc of acetic anhydride and the resulting reaction mixture heated at 100°C for 1/2 hour. The reaction mixture is evaporated to dryness under reduced pressure and the residue taken up in and crystallized from methanol. Recrystallization from methanol produces the pure diacetate of (dl)-reg.-1-phenyl-2-dichloroacetamidopropane-1,3-diol (MP 94°C). Two hundred milligrams of the diacetate of (dl)-reg.-1-phenyl-2dichloroacetamidopropane1,3-diol is added to a mixture consisting of 0.25 cc of concentrated nitric acid and 0.25 cc of concentrated sulfuric acid at 0°C. The reaction mixture is stirred until solution is complete, poured onto 25 g of ice and the mixture extracted with ethyl acetate. The ethyl acetate extracts are evaporated under reduced pressure and the diacetate of (dl)-reg.-1pnitrophenyl-2-dichloroacetamidopropane-1,3-diol so produced purified by recristallization from ethanol; MP 134°C.

952

Chloramphenicol palmitate

Five hundred milligrams of the diacetate of (dl)-reg.-1-p-nitrophenyl-2dichloroacetamidopropane-1,3-diol is dissolved in a mixture consisting of 25 cc of acetone and an equal volume of 0.2 N sodium hydroxide solution at 0°C and the mixture allowed to stand for one hour. The reaction mixture is neutralized with hydrochloric acid and evaporated under reduced pressure to dryness. The residue is extracted with several portions of hot ethylene dichloride, the extracts concentrated and then cooled to obtain the crystalline (dl)-reg.-1- p-nitrophenyl-2-dichloroacetamidopropane-1,3-diol; MP 171°C. References Merck Index 2035 Kleeman and Engel p. 185 PDR PP. 1321, 1379, 1606, 1999 OCDS Vol. 1 p. 75 (1977) and 2 pp. 28, 45 (1980) I.N. p. 209 REM p. 1208 Bartz, Q.R.; US Patent 2,483,871; October 4, 1949; assigned to Parke, Davis and Company Crooks, H.M., Jr., Rebstock, M.C., Controulis, J. and Bartz, Q.R.; US Patent 2,483,884; October 4, 1949; assigned to Parke, Davis and Company Ehrlich, J., Smith, R.M. and Penner, M.A.; US Patent 2,483,892; October 4, 1949; assigned to Parke, Davis and Company Carrara, G.; US Patent 2,776,312; January 1, 1957 Slack, R.; US Patent 2,786,870; March 26, 1957; assigned to Parke, Davis and Company

CHLORAMPHENICOL PALMITATE Therapeutic Function: Antibacterial; Antirickettsial Chemical Name: D(-)-threo-1-p-Nitrophenyl-2-dichloroacetamido-3palmitoyloxypropane-1-ol Common Name: Structural Formula:

Chemical Abstracts Registry No.: 530-43-8

Chlorazanil hydrochloride

Trade Name Chloromycetin B-CP Berlicetin Chlorambon Chloromisol Colimycin Detreopal Hortfenicol Levomicetina Paidomicetina Protophenicol Sintomicetina

Manufacturer Parke Davis Biokema Ankerwerk Biokema Maipe Biofarma Polfa Hortel Lepetit Lafare Arco Lepetit

Country US Switz. E. Germany Switz. Spain Turkey Poland Spain Italy Italy Switz. -

953

Year Introduced 1951 -

Raw Materials Palmitoyl chloride Chloramphenicol Manufacturing Process 1,674 g of palmitoyl chloride is added to 1,870 g of D(-)-threo-1-pnitrophenyl-2-dichloroacetamidopropane-1,3-diol (chloramphenicol) in 2,700 cc of pyridine and the solution stirred for 1 hour. The mixture is poured into 16 liters of water and the solid collected. Recrystallization of the crude product from benzene yields the desired D(+)-threo-1-p-nitrophenyl1dichloroacetamido-3-palmitoyloxypropane-1-ol in pure form: MP 90°C. References Merck Index 2036 PDR p. 1324 I.N. p. 210 REM p. 1209 Edgerton, W.H.; US Patent 2,662,906; December 15, 1953; assigned to Parke, Davis and Co.

CHLORAZANIL HYDROCHLORIDE Therapeutic Function: Diuretic Chemical Name: 1,3,5-Triazine-2,4-diamine, N-(4-chlorophenyl)-, hydrochloride Common Name: Chloramanozinum; Chlorazanil hydrochloride Chemical Abstracts Registry No.: 2019-25-2; 500-42-5 (Base)

954

Chlorbenzoxamine

Structural Formula:

Trade Name Chlorazanil hydrochloride

Manufacturer Shanghai Lancheng Corporation

Country -

Year Introduced -

Diuretico Orpidan

Sol Heumann

-

-

Raw Materials (4-Chlorophenyl)biguanidine hydrochloride Formic acid Manufacturing Process 31.2 g (4-chlorophenyl)biguanidine hydrochloride and 35 ml of concentrated formic acid were refluxed for 4 hours. The hot solution was cooled and mixed with 200 ml of diluted hydrochloric acid. The falling crystals were filtered off. The yield of chlorazanil was 24 g (74%). MP 258°C. In practice it is usually used as hydrochloride. References Bauereis R.; D.B.Patent No. 1,008,303; 31 August 1955; Assigned to Heumann and Co Chem. pharm. Fabrik, Nürnberg

CHLORBENZOXAMINE Therapeutic Function: Anticholinergic, Antiulcer Chemical Name: 1-[2-[(2-Chlorophenyl)phenylmethoxy]ethyl]-4-[(2methylphenyl)methyl]piperazine Common Name: Chlorbenzoxamine; Chlorbenzoxyethamine

Chlorcyclizine

955

Structural Formula:

Chemical Abstracts Registry No.: 522-18-9 Trade Name

Manufacturer

Chlorbenzoxamine Shanghai Lansheng Corporation

Country

Year Introduced

-

-

Raw Materials 1-m-Methylbenzyl-4-(2-hydroxyethyl)-piperazine o-Chlorobenzhydrile chloride Manufacturing Process A mixture of 0.1 mol of 1-m-methylbenzyl-4-(2-hydroxyethyl)-piperazine and 0.1 mol of o-chlorobenzhydrile chloride was heated at 160°C for 3 hours. After cooling the product obtained was dissolved in benzene. The solution was washed with 20% aqueous solution of sodium carbonate and then with water. Chlorbenzoxamine was distilled in vacuo, B.P. 240°C/0.1 mm Hg. Yield 50%. References Merck Index, Monograph number: 2125, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. Morren H.; Belg. Patent No. 549,420; July 10, 1956

CHLORCYCLIZINE Therapeutic Function: Antihistaminic Chemical Name: 1-[(4-Chlorophenyl)phenylmethyl]-4-methylpiperazine Common Name: Histachlorazine Chemical Abstracts Registry No.: 82-93-9; 1620-21-9 (Hydrochloride salt)

956

Chlorcyclizine

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Perazil

Burroughs-Wellcome

US

1949

Di-Paralene

Abbott

US

1950

Histantin

Burroughs-Wellcome

-

-

Histofax

Burroughs-Wellcome

UK

-

Mantadil

Burroughs-Wellcome

US

-

Prurisedine

Couvreur

Belgium

-

Trihistan

Revit

Switz.

-

Trihistan

Gea

Denmark

-

Trihistan

Weifa

Norway

-

Raw Materials 4-Chlorobenzhydryl chloride Methyl piperazine Manufacturing Process 0.08 mol (19 9) of 4-chlorobenzhydryl chloride and 0.16 mol (16 g) of methylpiperazine were mixed in about 20 cc of dry benzene. The flask containing the reaction mixture was covered by a watch glass and set in a steam bath, and heating was continued for 6 hours. The contents of the flask were partitioned between ether and water and the ethereal layer was washed with water until the washings were neutral. The ethereal layer was extracted successively with 30 and 10 cc portions of 3 N hydrochloric acid. On evaporation of the ether layer there remained a residue of 2.5 9. The aqueous extracts were united and basified with concentrated alkali. The oily base was taken into ether and dried over potassium carbonate. On evaporation of the ether, N-methyl-N'-(4-chlorobenzhydryl) piperazine was recovered in the form of a viscous oil in 75% yield. The N-methyl-N'-(4-chlorobenzhydryl) piperazine was dissolved in absolute alcohol and ethanolic hydrogen chloride added in excess. The dihydrochloride crystallized on addition of absolute ether and was recrystallized from the same solvent mixture in the form of longish prisms melting at about 216°C.

Chlordantoin

957

References Merck Index 2045 Kleeman and Engel p. 188 PDR p. 754 OCDS Vol. 1 p. 58 (1977) I.N. p. 211 REM p.1132 Baltzly, R. and Castillo, J.C.; US Patent 2,630,435; March 3, 1953; assigned to Burroughs-Wellcome and Co. (USA.) Inc.

CHLORDANTOIN Therapeutic Function: Topical antifungal Chemical Name: 5-(1-Ethylpentyl)-3-[(trichloromethyl)thio]-2,4imidazolidinedione Common Name: Clodantoin Structural Formula:

Chemical Abstracts Registry No.: 5588-20-5 Trade Name Sporostacin Sporostacin Gynelan

Manufacturer Ortho Ortho Eisai

Country US UK Japan

Year Introduced 1960 -

Raw Materials Perchloromethyl mercaptan 5-(1-Ethylpentyl)hydantoin sodium salt Manufacturing Process Perchloromethylmercaptan is reacted with the sodium salt of 5-(1ethylpentyl)hydantoin.

958

Chlordiazepoxide hydrochloride

References Merck Index 2047 Kleeman and Enael P. 225 I.N. p. 243 Kittleson, A.R.; US Patent 2,553,770; May 22, 1951; assigned to Standard Oil Development Company Hawley, R.S., Kittleson, A.R. and Smith, P.V. Jr.; US Patent 2,553,775; May 22, 1951; assigned to Standard Oil Development Company

CHLORDIAZEPOXIDE HYDROCHLORIDE Therapeutic Function: Tranquilizer Chemical Name: 7-Chloro-N-methyl-5-phenyl-3H-1,4-benzodiazepin-2amino-4-oxide hydrochloride Common Name: Metaminodiazepoxide hydrochloride; Methaminodiazepoxide hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 438-41-5; 58-25-3 (Base) Trade Name Librium Librium Librium Librium Librium Librium SK-Lygen Diazachel A-Poxide Zetran Balance Bent

Manufacturer Roche Roche Roche Sauter Roche Roche SKF Rachelle Abbott Hauck Yamanouchi Pharma. Farm. Spec.

Country W. Germany US Switz. UK France Italy US US US US Japan Italy

Year Introduced 1960 1960 1960 1960 1961 1961 1976 1976 1977 1978 -

Chlordiazepoxide hydrochloride

959

Trade Name

Manufacturer

Country

Year Introduced

Benzodiapin

Lisapharma

Italy

-

Binomil

Uriach

Spain

-

Cebrum

Cifa

Italy

-

Chemdipoxide

Chemo-Drug

Canada

-

Chlordiazachel

Rachelle

US

-

Contol

Takeda

Japan

-

Diapax

Therapex

Canada

-

Dolibrax

Roche

France

-

Elenium

Polfa

Poland

-

Endequil

Panther-Osfa

Italy

-

Equibral

Ravizza

Italy

-

Gene-Poxide

Franca

Canada

-

Huberplex

Hubber

Spain

-

I-Liberty

I-Pharmacal

US

-

Labican

BoniscontroGazzone

Italy

-

Lentotran

Farm Patria

Portugal

-

Lixin

I.S.M.

Italy

-

Medilium

Medic

Canada

-

Murcil

Reid-Provident

US

-

Napoton

Chemimportexport Rumania

-

Normide

Inibsa

Spain

-

Novopoxide

Novopharm

Canada

-

Omnalio

Estedi

Spain

-

Peast C

Sawai

Japan

-

Protensin

Elliott-Marion

Canada

-

Psicofar

Terapeutico

Italy

-

Psicoterina

Francia

Italy

-

Radepur

Arzneimittelwerk Dresden

E. Germany

-

Reliberan

Geymonat Sud

Italy

-

Relium

Riva

Canada

-

Risolid

Dumex

Denmark

-

Sakina

Causyth

Italy

-

Sereen

Foy

US

-

Smail

Saita

Italy

-

Solium

Horner

Canada

-

Sophiamin

Santen

Japan

-

Trakipearl

Hishiyama

Japan

-

Tropium

D.D.S.A.

UK

-

Untensin

Pharmador

S. Africa

-

Via-Quil

Denver

Canada

-

960

Chlordiazepoxide hydrochloride

Raw Materials 2-Amino-5-chlorobenzophenone Hydrogen chloride Methylamine

Chloroacetyl chloride Hydroxylamine

Manufacturing Process A mixture of 202 g 2-amino-5-chlorobenzophenone, 190 g hydroxylamine hydrochloride, 500 cc pyridine and 1,200 cc alcohol was refluxed for 16 hours, then concentrated in vacuo to dryness. The residue was treated with a mixture of ether and water. The water was separated, the ether layer containing a considerable amount of precipitated reaction product was washed with some water and diluted with petroleum ether. The crystalline reaction product, 2-amino-5-chlorobenzophenone-alpha-oxime, was filtered off. The product was recrystallized from a mixture of ether and petroleum ether forming colorless prisms, MP 164 to 167°C. To a warm solution (50°C) of 172.5 g (0.7 mol) of 2-amino-5chlorobenzophenone-alpha-oxime in one liter glacial acetic acid were added 110 cc (1.47 mols) chloroacetyl chloride. The mixture was heated for 10 minutes at 50°C and then stirred at room temperature for 15 hours. The precipitated yellow prisms, 2-chloromethyl-4-phenyl-6-chloroquinazoline 3oxide hydrochloride, were filtered off, melting range 128° to 150°C with dec. The acetic acid mother liquor, containing the rest of the reaction product, was concentrated in vacuo. The residue was dissolved in methylene chloride and washed with ice cold sodium carbonate solution. The organic solution was dried, concentrated in vacuo to a small volume and diluted with ether and petroleum ether. Fine yellow needles of 2-chloromethyl-4-phenyl-6chloroquinazoline 3-oxide precipitated. The pure base was recrystallized from a mixture of methylene chloride, ether and petroleum ether, MP 133° to 134°C. Ninety-eight grams of 6-chloro-2-chloromethyl-4-phenylquinazoline 3-oxide hydrochloride were introduced into 600 cc of ice cold 25% methanolic methylamine. The mixture was initially cooled to about 30°C and then stirred at room temperature. After 15 hours the reaction product which precipitated was filtered off. The mother liquor was concentrated in vacuo to dryness. The residue was dissolved in methylene chloride, washed with water and dried with sodium sulfate. The methylene chloride solution was concentrated in vacuo and the crystalline residue was boiled with a small amount of acetone to dissolve the more soluble impurities. The mixture was then cooled at 5°C for 10 hours and filtered. The crystalline product, 7-chloro-2-methylamino-5phenyl-3H-1,4-benzodiazepine 4-oxide, was recrystallized from ethanol forming light yellow plates, MP 236° to 236.5°C. A solution of 7-chloro-2-methylamino-5-phenyl-3H-1,4-benzodiazepine 4-oxide in an equivalent amount of methanolic hydrochloric acid was diluted with ether and petroleum ether. The precipitated hydrochloride was filtered off and recrystallized from methanol, MP 213°C.

Chlorhexidine

961

References Merck Index 2049 Kleeman and Engel p. 188 PDR pp. 993, 1510, 1606, 1723, 1999 OCDS Vol. 1 p. 365 (1977) and 2 p. 401 (1980) DOT 9 (6) 236 (1973) REM p. 1061 Sternbach, L.H.; US Patent 2,893,992; July 7, 1959; assigned to Hoffmann-La Roche, Inc.

CHLORHEXIDINE Therapeutic Function: Antimicrobial Chemical Name: N,N''-Bis(4-chlorophenyl)-3,12-diimino-2,4,11,13tetraazatetradecanediimidamide Common Name: 1,6-di(4'-Chlorophenyldiguanido)hexane Structural Formula:

Chemical Abstracts Registry No.: 55-56-1 Trade Name

Manufacturer

Country

Year Introduced

Hibiclens

Stuart

US

1976

Hibitane

I.C.I.

France

1976

Corsodyl

I.C.I.

UK

1977

Souplens

Chauvin-Blache

France

1978

Hibitane

Stuart

US

1979

Hibistat

ICI

US

1980

Abacil

Polfa

Poland

-

Aseptigel

Medicornea

France

-

962

Chlorhexidine

Trade Name

Manufacturer

Bactigras

Smith and Nephew UK

Country

Year Introduced -

Biotensid

Arcana

Austria

-

Cetal

Orapharm

Australia

-

Chlorhexamed

Blendax

W. Germany

-

Chlorohex

Geistlich

Switz.

-

Dacrine

Chibret

France

-

Dentosmin

VEB Leipziger Arz. E. Germany

-

Desmanol

Schulke and Mayr

W. Germany

-

Desocort

Chauvin-Blache

France

-

Dialens

Chauvin-Blache

France

-

Eludril

Inava

France

-

Hexadol

Green Cross

Japan

-

Hibiscrub

ICI Pharma

France

-

Hibiscrub

ICI

Japan

-

Hibitane

Sumitomo

Japan

-

Larylin

Beiersdorf

W. Germany

-

Lisium

Brunton Chemists

UK

-

Manusan

Polfa

Poland

-

Maskin

Maruishi

Japan

-

Nolvasan

Fort Dodge Labs

US

-

Oronine

Otsuka

Japan

-

Pabron

Taisho

Japan

-

Plac Out

Bernabo

Argentina

-

Plak-Out

Hawe-Neos

Switz.

-

Plurexid

Sythemedica

France

-

Rhino-Blache

Chauvin-Blache

France

-

Rotersept

Roter

Netherlands

-

Scarlene

Chauvin-Blache

France

-

Secalan

Zyma

Switz.

-

Septalone

Abic

Israel

-

Sterilone

Roter

Netherlands

-

Trachitol

Engelhard

W. Germany

-

Vitacontact

Faure

France

-

Raw Materials Hexamethylene bis-dicyandiamide p-Chloroaniline hydrochloride Manufacturing Process 25 parts of hexamethylene bis-dicyandiamide, 35 parts of p-chloroaniline hydrochloride and 250 parts of beta-ethoxyethanol are stirred together at

Chlorhexidine digluconate

963

130°C to 140°C for 2 hours under reflux. The mixture is then cooled and filtered and the solid is washed with water and crystallized from 50% aqueous acetic acid. 1,6-di(N1,N1'-p-chlorophenyldiguanido-N5,N5')hexane dihydrochloride is obtained as colorless plates of MP 258°C to 260°C. The following is an alternative route: 19.4 parts of pchlorophenyldicyandiamide, 9.4 parts of hexamethylene diaminedihydrochloride and 100 parts of nitrobenzene are stirred together and heated at 150 C to 160°C for 6 hours. The mixture is cooled, diluted with 200 parts of benzene and filtered. The solid residue is washed with benzene and crystallized from 50% acetic acid. 1,6-di(N1,N1'-p-chlorophenyldiguanidoN5,N5')hexane dihydrochloride is obtained. References Merck Index 2057 Kleeman and Engel p. 189 PDR p. 1781 I.N. p. 212 REM p. 1159 Rose, F.L. and Swain, G.; US Patent 2,684,924; July 27, 1954; assigned to Imperial Chemical Industries, Ltd.

CHLORHEXIDINE DIGLUCONATE Therapeutic Function: Antiseptic Chemical Name: D-Gluconic acid, compd. with N,N''-bis(4-chlorophenyl)3,12-diimino-2,4,11,13-tetraazatetradecane diimidamide (2:1) Common Name: Chlorhexidine gluconate; Clorexidina gluconato Structural Formula:

964

Chlorhexidine digluconate

Chemical Abstracts Registry No.: 18472-51-0 Trade Name

Manufacturer

Country

Year Introduced

Abacil

Polfa-Lodz SA

Poland

-

Aseptinol S

PFC SNC

France

-

Betasept

The Purdue Frederick Company

-

-

Chlorhexidine gluconate

Xttrium Laboratories

USA

-

Corsodyl

GlaxoSmithKline Consumer Healthcare

USA

-

Elugel

Pierre Fabre Medicament

France

-

Hibiclens

Medical Supply, Inc.

-

-

Hibiclens

Zeneca

-

-

Peridex

Zila Pharmaceuticals

Canada

-

Periochip

Dexcel Pharma Ltd.

-

-

Periochip

Dexcel Pharma Ltd.

-

-

Periogard Oral Rinse

Colgate Oral Care

-

-

Plivasept

Pliva

Horvatia

-

Sensisept

Diversey Lever

France

-

Raw Materials Hexamethylene bis-dicyandiamide p-Chloroaniline hydrochloride Manufacturing Process 35 parts of hexamethylene bis-dicyandiamide, 35 parts of p-chloroaniline hydrochloride and 250 parts of β-etoxyethanol are stirred together at 130140°C for 2 hours under reflux. The mixture is then cooled and filtered. The solid is washed with water and crystallised from 50% aqueous acetic acid. 1,1'-Hexamethylene bis(5-(p-chlorophenyl)biguanide) is obtained as colorless plates, melting point 258-260°C. By addition of D-gluconic acid to aqueous solution of chlorhexidine base is prepared 1,1'-hexamethylenebis(5-(pchlorophenyl)biguanide)digluconate (1:2). References Leslie F. et al.; US Patent No. 2,684,924; July 27, 1954; Assigneed to Imperial Chemical Industries Limited Werie P. et al.; US Patent No. 6,500,466; Dec.31, 2002; Assigneed to Degussa AG, Dusseldorf (DE)

Chlorisondamine chloride

965

CHLORISONDAMINE CHLORIDE Therapeutic Function: Antihypertensive Chemical Name: 4,5,6,7-Tetrachloro-1,3-dihydro-2-methyl-2-[2(trimethylammonio)ethyl]-2H-isoindolium dichloride Common Name: Chlorisondamine dimethochloride Structural Formula:

Chemical Abstracts Registry No.: 69-27-2 Trade Name

Manufacturer

Country

Year Introduced

Ecolid Chloride

Ciba

US

1956

Raw Materials 3,4,5,6-Tetrachlorophthalic anhydride 2-Dimethylaminoethyl amine Lithium aluminum hydride

Methyl iodide Silver chloride

Manufacturing Process 50 parts by weight of 3,4,5,6-tetrachlorophthalic anhydride is added with stirring and cooling to 30 parts by volume of 2-dimethylaminoethyl amine. The mixture is heated at 170°C for 4 minutes and the oily residue then dissolved in 200 parts by volume of hot ethanol. On cooling, N-(2'dimethylaminoethyl)-3,4,5,6-tetrachlorophthalimide separates. It crystallizes from ethanol and melts at 184°-186°C. 6 parts by weight of N-(2'-dimethylaminoethyl)-3,4,5,6-tetrachlorophthalimide is extracted continuously with 300 parts by volume of dry ether in which have been dissolved 3.1 parts by weight of lithium aluminum hydride. After 48 hours the excess lithium aluminum hydride is destroyed by cautious addition of 9 parts by volume of ethyl acetate while stirring. There is then added in succession with stirring 3 parts by volume of water, 6 parts by volume of 15% aqueous sodium hydroxide and 9 parts by volume of water. The granular precipitate of lithium and aluminum salts are filtered and washed with ether. The ether is distilled off, yielding the crude, oily 4,5,6,7-tetrachloro-2-(2'dimethylaminoethyl)-isoindoline. The above base is dissolved in 25 parts by volume of 90% ethanol and refluxed 2 hours with 6 parts by volume of methyl iodide. 4,5,6,7-tetrachloro-2-(2'-dimethylaminoethyl)-isoindoline dimethiodide separates during the reaction. It is collected by filtration and recrystallized

966

Chlormadinone acetate

from a mixture of ethanol and water; MP 244°-246°C. 4,5,6,7-tetrachloro-2-(2'-dimethylaminoethyl)-isoindoline dimethochloride is prepared by shaking an aqueous solution of the dimethiodide with an excess of freshly prepared silver chloride and evaporating to dryness the aqueous solution after removal of the silver salts. 4,5,6,7-tetrachloro-2-(2'dimethylaminoethyl)-isoindoline dimethochloride is recrystallized from ethanolethylacetate; MP 276°-280°C. References Merck Index 2068 I.N. p. 213 Huebner, C.F.; US Patent 3,025,294; March 13, 1962;assigned to Ciba Pharmaceutical Products, Inc.

CHLORMADINONE ACETATE Therapeutic Function: Progestin Chemical Name: Pregna-4,6-diene-3,20-dione, 6-chloro-17-hydroxy-, acetate Common Name: Chlormadinone acetate; Clormadinone aceteto Structural Formula:

Chemical Abstracts Registry No.: 302-22-7 Trade Name

Manufacturer

Country

Year Introduced

Chlormadinone Acetate Chlormadinone Acetate

Teikoku Hormone Mfg. Co., Ltd. Taizhou Baida Pharmaceutical Co., Ltd.

-

Chlormadinone Acetate

Lansheng Crop. Pharm Chemical

-

-

Hypostat

Kyowa

-

-

Lutoral

Shionogi

-

-

-

Chlormerodrin

967

Trade Name

Manufacturer

Country

Year Introduced

Lutoral

Syntex

-

-

Prostal

Teikoku Hormone Mfg. Co., Ltd.

-

-

Raw Materials 6-Dehydro-17α-acetoxy-progesterone Succinimide, N-chloroPerchloric acid Aluminum oxide Manufacturing Process 10 g 6-dehydro-17α-acetoxy-progesterone was dissolved in 400 ml dioxane and 40 ml water. The solution was added to 4 g N-chlorosuccinimide and 2.4 ml 70% perchloric acid. The mixture was left at ambient temperature for 24 hours, whereupon it was poured in water, a dropping precipitate was filtered off, washed with water and dried. It was filtered through aluminum oxide and recrystallized from ether to give 6-chloro-6-dehydro-17α-acetoxyprogesterone (chlormadinone acetate). MP: 204°-206°C. [α]D= +54.6° (chloroform). References Merck Index, Monograph number: 3876, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. Brueckner K. et al.; D.B. Patent No. 1,075,114; April, 29, 1958

CHLORMERODRIN Therapeutic Function: Diuretic Chemical Name: 1-[3-(Chloromercuri)-2-methoxypropyl]urea Common Name: Chlormeroprin Structural Formula:

Chemical Abstracts Registry No.: 62-37-3

968

Chlormezanone

Trade Name Neohydrin Asahydrin Bucohydral Mercloran Merilid Oricur Orimercur Ormerdan

Manufacturer Lakeside Pharmacia Vifor Parke Davis Pharmacia Medix Reder Parke Davis

Country US Sweden Switz. US Sweden Denmark Spain US

Year Introduced 1952 -

Raw Materials Allyl urea Mercury acetate Sodium chloride Manufacturing Process To a refluxing solution of 100 g of allyl urea and 600 ml of absolute methanol there was added with stirring a suspension of 319 g of mercuric acetate and 600 ml of absolute methanol and 60 ml of glacial acetate acid; complete solution resulted. After 6 hours of refluxing, the solution was cooled and clarified by filtration. To this solution there were added 50 g of sodium chloride and 240 ml of water. After a short time a heavy white precipitate settled out. This precipitate, which was 3-chloromercuri-2-methoxypropylurea, was filtered, washed and dried. References Merck Index 2071 Kleeman 81 Engel p. 191 I.N. p.213 REM p. 489 Foreman, E.L; US Patent 2,635,983; April 21, 1953; assigned to Lakeside Laboratories, Inc.

CHLORMEZANONE Therapeutic Function: Tranquilizer Chemical Name: 2-(4-Chlorophenyl)tetrahydro-3-methyl-4H-1,3-thiazin-4one-1,1-dioxide Common Name: Chloromethazanone Chemical Abstracts Registry No.: 80-77-3

Chlormezanone

969

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Trancopal

Winthrop-Breon

US

1958

Supotran

Winthrop

France

1965

Alinam

Lucien

France

-

Chlomedinon

Taiyo

Japan

-

Lumbaxol

Aldo Union

Spain

-

Metsapal

Leiras

Turkey

-

Muxotal

Farmos

Finland

-

Muskel

Winthrop

W. Germany

-

Myolespen

Dojin

Japan

-

Relizon

Mochida

Japan

-

Rexan

Labif

Italy

-

Rilaquil

Guidotti

Italy

-

Tanafol

A.M.S.A.

Italy

-

Trancote

Sawai

Japan

-

Transanate

Teikoku

Japan

-

Raw Materials 4-Chlorobenzaldehyde β-Mercaptopropionic acid

Methylamine Potassium permanganate

Manufacturing Process A solution of 4-chlorobenzaldehyde is reacted with beta-mercaptopropionic acid and with methylamine. The mixture is refluxed in benzene and water is removed from an overhead separator. The reaction mixture was cooled, washed with dilute ammonium hydroxide and water, and the benzene was removed by distillation in vacuo. The oily residue was taken up in ether from which it crystallized. The precipitate was recrystallized twice from ether to yield 2-(4-chlorophenyl)-3-methyl-4-metathiazanone. A solution of 11.2 g of potassium permanganate in 100 ml of warm water was added dropwise to a well stirred solution of 10 g of 2-(4-chlorophenyl)-3methyl-4-metathiazanone in 50 ml of glacial acetic acid. The temperature was kept below 30°C with external cooling. An aqueous sodium bisulfite solution was then added to remove the manganese dioxide. The thick whitish oil which separated was taken up in chloroform and the extract was washed with water. Removal of the chloroform by distillation in vacuo yielded an oily residue which solidified. The solid was recrystallized from isopropyl alcohol to give 5 g

970

Chlormidazole

of the product, 2-(4-chlorophenyl)-3-methyl-4-metathiazanone-1,1-dioxide, MP 116.2° to 118.6°C (corr.). References Merck Index 2072 Kleeman and Engel p. 191 PDR p. 1934 DOT 9 (6) 243 (1973) I.N. p. 214 REM p. 1074 British Patent 815,203; June 17, 1959; assigned to Sterling Drug, Inc.

CHLORMIDAZOLE Therapeutic Function: Antifungal Chemical Name: 1-p-Chlorobenzyl-2-methylbenzimidazole Common Name: Chlormidazole; Clomidazolum Structural Formula:

Chemical Abstracts Registry No.: 3689-76-7 Trade Name Diamyceline Polfungicid zasypka Futrican Myco-Polycid Unifungicid Polfungicid plyn

Manufacturer Diamant ICN Astra Zdr Unia ICN

Raw Materials 2-Methylbenzimidazole Sodium amide p-Chlorobenzylbromide p-Chlorobenzyl-o-phenylene diamine Acetic acid

Country -

Year Introduced -

Chlorobutanol

971

Manufacturing Process The first method synthesis of 1-p-chlorobenzyl-2-methylbenzimidazole: 26.4 g of 2-methylbenzimidazole are dissolved in 350 ml of dioxane, 10 g of sodium amide are added there to. After about 5 min 41,2 g of pchlorobenzylbromide are added to the resulting mixture which is then boiled under reflux for 6 hours. Dioxane is removed by distillation. The residue is triturated with dilute hydrochloric acid. The resulting crystalline mass representing the crude hydrochloride of 1-p-chlorobenzyl-2methylbenzimidazole is filtered off by suction and recrystallized from water. On cooling, colorless crystals are obtained which are dissolved in hot water. Dilute ammonia solution is added to the resulting aqueous solution to render it weakly alkaline. The base of 1-p-chloro-benzyl-2-methylbenzimidazole precipitates, first in liquid form, and gradually solidifies to a white mass of its hydrate. After recyrstallization from aqueous ethanol, the product has a melting point of 67-68°C. The base of 1-p-chlorobenzyl-2methylbenzimidazole distills in the form of a colorless oil at 240-242°C/12 mm. Its hydrate of the melting point 67-68°C is obtained by trituration with water. The second method of synthesis of 1-p-chlorobenzyl-2-methylbenzimidazole: 23.3 g of p-chlorobenzyl-o-phenylenediamine are boiled under reflux with 75 ml of glacial acetic acid for 3 hours. Most of the acetic acid is then removed by distillation. Dilute sodium hydroxide solution is added to the residue to render it weakly alkaline. The resulting base of 1-p-chlorobenzyl-2methylbenzunidazole is purified as such by recrystallization from aqueous ethanol. It may also be converted into its hydrochloride which is then worked up as described hereinabove in the first method of synthesis. References Merck Index, Monograph number: 2156, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. Herrling S. et al.; US Patent No. 2,876,233; Mar. 3, 1959; Assigned to Chemie Gruenenthal G.m.b.H., Rhineeland, Germany, Stolberg, a corporation of Germany

CHLOROBUTANOL Therapeutic Function: Hypnotic, Anesthetic, Antiseptic, Pharmaceutic aid, Ophthalmologic Chemical Name: 2-Propanol, 1,1,1-trichloro-2-methylCommon Name: Acetone chloroform; Alcohol trichlorisobutylicus; Chlorbutanol; Chlorbutol(un); Trichlorbutanolum Chemical Abstracts Registry No.: 57-15-8

972

Chloroprednisone acetate

Structural Formula:

Trade Name Chlorobutanol Lacri-Lube Coliquifilm Chloretone

Manufacturer Narchem Corporation Allergan Allergan Parke Davis

Country -

Year Introduced -

-

-

Raw Materials Acetone Chloroform Potassium hydroxide Manufacturing Process 33 g (0.59 mol) of powdered potassium hydroxide was added in small amounts to a solution of 50 g (0.86 mol) of acetone in 100 g (0.84 mol) of chloroform to form a reaction mixture containing approximately 0.7 mol of KOH per mol of chloroform. The mixture was chilled to a temperature below 0°C, thoroughly agitated, and than allowed to stand at temperature of about 0°C for 24 hours. The mixture was then filtered and the filtrate was distilled. The fraction boiling within the range of 165-175°C was poured into an equal amount of water to precipitate the 1,1,1-trichloro-tert-butyl alcohol. The precipitated 1,1,1-trichloro-tert-butyl alcohol was filtered and recrystallized from an ethanol-water mixture and air dried. The yield of 1,1,1-trichloro-tertbutyl alcohol was 6 g, that is, somewhat less than 4% of the theoretical yield based on chloroform charged. When calculated on the basis of chloroform consumed the yield was about 15%. References Merck Index, Monograph number: 2180, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. Harrington G.A.; US Patent No. 2,462,389; Feb. 22, 1949; Assigned to Socony-Vacuum Oil Company, Incorporated. New York, N.Y., a corporation of New York

CHLOROPREDNISONE ACETATE Therapeutic Function: Glucocorticoid Chemical Name: 6α-Chloro-17,21-dihydroxypregna-1,4-diene-3,11,20-trione 21-acetate

Chloroprednisone acetate

973

Common Name: Chloroprednisone acetate; Chlorprednisoni acetas Structural Formula:

Chemical Abstracts Registry No.: 140066-79-6 Trade Name Topilan Localyn

Manufacturer Country Syntex Recordati Industria Chimica e Farmaceutica S.p.A.

Year Introduced -

Raw Materials 6-α-Chlorocortisone Selenium oxide Aluminum oxide Manufacturing Process A suspension of 500 mg 6-α-chlorocortisone (or 6-α-chloro-17-α-hydroxy 21 acetoxy-δ4-pregnene-3,11,20-trione) 25 ml dry tert-butanol, 150 mg selenium oxide and 0.05 ml pyridine were heated to reflux for 70 hours in a nitrogen atmosphere. On cooling the mixture was diluted with 50 ml ethyl acetate, filtered through Cilite and thoroughly washed with ethyl acetate. Ethyl acetate was distilled to a dryness, the dry residue was adsorbed on 25 g of aluminum oxide and eluated with mixture of benzene, ethyl acetate and ether. The obtained fractions were distilled to dryness and recrystallized from acetonehexane. 105 mg of 6α-chloro-17,21-dihydroxypregna-1,4-diene-3,11,20-trione 21-acetate (or 6-α-chloro 17,21-α-hydroxy 21-acetoxy-δ1,4-pregnadiene3,11,20-trione) was obtained. MP: 217°-219°C. λmax 238 mµ. References Djerassi C. et al.; DB Patent No. 1,079,042; March 4, 1958; Mexico

974

Chloroprocaine hydrochloride

CHLOROPROCAINE HYDROCHLORIDE Therapeutic Function: Local anesthetic Chemical Name: 4-Amino-2-chlorobenzoic acid 2-diethylaminoethyl ester hydrochloride Common Name: Structural Formula:

Chemical Abstracts Registry No.: 3858-89-7; 133-16-4 (Base) Trade Name Nesacaine Nesacaine Nesacaine Piocaine

Manufacturer Astra Pennwalt Strasenburgh Teikoku-Nagase

Country US US US Japan

Year Introduced 1956 -

Raw Materials 2-Chloro-4-amino benzoic acid beta-Diethyl amino ethanol

Thionyl chloride Hydrogen chloride

Manufacturing Process In the first step, 2-chloro-4-aminobenzoyl chloride hydrochloride is prepared by refluxing a mixture of 25 cc of purified thionyl chloride and 10 g of 2chloro-4-aminobenzoic acid until all of the solid has gone into solution. To the cooled solution is added 150 cc of dry ethyl ether. A brisk stream of dry hydrogen chloride is passed into the solution until the precipitation of 2chloro-4-aminobenzoylchloride hydrochloride is complete. The acyl halide is removed by filtration and dried in a vacuum desiccator. In the second step, the diethylaminoethyl 2-chloro-4-aminobenzoate hydrochloride is prepared by refluxing equimolar proportions of the hydrochloride of beta-diethylaminoethanol in a suitable inert solvent such as a mixture of dry toluene and tetrachloroethane and the hydrochloride of 2chloro-4-aminobenzoyl chloride until the reaction as indicated by the cessation of hydrogen chloride evolution is complete. The supernatant solvents are decanted from the reaction product which can be conveniently purified by crystallization from absolute ethanol.

Chloropyramine hydrochloride

975

An alternative purification can be effected by dissolving the reaction product in water. The ester base is liberated by rendering the clarified aqueous solution alkaline. Removal of the base from the alkaline solution is achieved by extraction with a suitable solvent such as benzene or ether. The pure hydrochloride of diethylaminoethyl 2-chloro-4-aminobenzoate is then precipitated from the dried extract by the addition of dry hydrogen chloride. After removal by filtration and recrystallization from ethanol it is found to have a melting point of 173° to 174°C. References Merck Index 2131 Kleeman and Engel p. 193 PDR p. 594 OCDS Vol. 1 p. 11 (1977) I.N. p. 220 REM p. 1050 Marks, H.C. and Rubin, M.I.; US Patent 2,460,139; January 25, 1949; assigned to Wallace and Tiernan Products, Inc.

CHLOROPYRAMINE HYDROCHLORIDE Therapeutic Function: Antihistaminic Chemical Name: 1,2-Ethanediamine, N-((4-chlorophenyl)methyl)-N',N'dimethyl-N-2-pyridinyl-, hydrochloride Common Name: Chlortripelennamine hydrochloride; Halopyramine hydrochloride; Chloropyramine hydrochloride; Chlorpyraminum hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 6170-42-9; 59-32-5 (Base) Trade Name

Manufacturer

Country

Year Introduced

Chloropyramine hydrochloride

Vramed

-

-

Chloropyramine hydrochloride

Sopharma

-

-

976

Chloropyramine hydrochloride

Trade Name Allergosan Antiapin Antiapin

Manufacturer Sopharma Pharmachim Balkanpharma Troyapharm

Country -

Avapena

Novartis Farmaceutica, S. A. de C. V.

-

Suprastin

Egis Pharmaceuticals Ltd. -

-

Synopen

Pliva

-

-

Year Introduced -

Raw Materials 2-Bromopyridine Quinoline Sodium hydroxide Ammonia

N,N-Dimethyl-N'-(4-chlorobenzyl) ethylenediamine Potassium

Manufacturing Process A solution comprising 40 parts of 2-bromopyridine, 100 parts of N,N-dimethylN'-(4-chlorobenzyl)ethylenediamine and 100 parts of quinoline is heated at 140-145°C for 5 hours. The oil layer after washing with 30% sodium hydroxide solution is distilled, and the fraction which distills at 142-170°C/1 mm is collected. This oil is converted to the monohydrochloride and recrystallized from a mixture of amyl alcohol and ether. The monohydrochloride salt of N,N-dimethyl-N'-(4-chlorobenzyl)-N'-(2-pyridyl) ethylenediamine is obtained which melts at 167-168.4°C. N,N-Dimethyl-N'-(4-chlorobenzyl)-N'-(2-pyridyl)ethylenediamine may be prepared by another method: To a mixture of 100 ml of liquid ammonia and about 80 mg of black iron oxide was added 0.78 g (0.02 atom) of potassium. When all of the potassium had reacted, 3.3 g of N,N-dimethyl-N'-(2-pyridyl)ethylenediamine was added. After the addition of 75 ml of dry toluene the ammonia was removed on the steam bath. To the cooled and stirred mixture was added 4.26 g of p-chlorobenzyl chloride, and the reaction mixture was stirred on the steam bath for 11 hours. It was then filtered and concentrated to an oil. This concentrate was taken up in ether, and the ethereal solution was washed with water, dried over sodium sulfate, and concentrated. Distillation gave 2.96 g of yellow liquid. Treatment of this distillate with an equivalent quantity of hydrogen chloride in absolute alcohol and precipitation by the addition of anhydrous ether gave 2.33 g of the N,N-dimethyl-N'-(4-chlorobenzyl)-N'-(2-pyridyl)ethylenediamine hydrochloride. References Merck Index, Monograph number: 2214, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. Howard K.L.; US Patent No. 2,569,314; Sept. 25, 1951; Assigned to American Cyanamid Company, New York, N.Y., a corporation of Maine

Chloroquine phosphate

977

CHLOROQUINE PHOSPHATE Therapeutic Function: Antimalarial Chemical Name: N4-(7-Chloro-4-quinolinyl)-N',N'-diethyl-1,4pentanediamine phosphate Common Name: Structural Formula:

Chemical Abstracts Registry No.: 50-63-5; 54-05-7 (Base) Trade Name

Manufacturer

Country

Year Introduced

Nivaquine

Specia

France

1949

Aralen

Winthrop

US

-

Arthrochin

Arcana

Austria

-

Artri

Badrial

France

-

Aspiquinol

Bayer

France

-

Avloclor

I.C.I.

UK

-

Chemochin

Pliva

Yugoslavia

-

Clorochina

Bayer

Italy

-

Cidanchin

Cidan

Spain

-

Delagil

EGYT

Hungary

-

Dichinalex

Savoma

Italy

-

Elestol

Bayer

France

-

Heliopar

Farmos

Finland

-

Imagon

Astra

-

-

Lagaquin

Legap

Switz.

-

Letaquine

Letap

Switz.

-

Malarex

Dumex

Denmark

-

Quinachlor

Cophar

Switz.

-

Quinercil

France

-

Quinilon

Robert and Carriere Sumitomo

Japan

-

Resochin

Bayer

Japan

-

Rivoquine

Rivopharm

Switz.

-

978

Chlorothiazide

Trade Name

Manufacturer

Country

Year Introduced

Serviquin

Servipharm

Switz.

-

Silbesan

Atmos

W. Germany

-

Siragon

Biochemie

Austria

-

Tresochin

Bayer

-

-

Raw Materials 4,7-Dichloroquinoline 1-Diethylamino-4-aminopentane Phosphoric acid Manufacturing Process 105 g of 4,7-dichloroquinoline (MP 93 to 94°C) are heated with 200 g of 1diethylamino-4-aminopentane for 7 hours in an oil bath to 180°C while stirring, until a test portion dissolved in diluted nitric acid does not show a precipitation with sodium acetate solution. The mixture is dissolved in diluted acetic acid and made alkaline by adding sodium lye. The base is extracted with ether, dried with potassium carbonate, the ether removed by distillation and the residue fractionated. The 4-(5'diethylaminopentyl-2'-amino)-7-chloroquinoline (BP 212 to 214C/0.2 mm) is obtained. On cooling the compound solidifies crystalline. It melts, recrystallized from benzene, at 88°C. The base combines with phosphoric acid to yield a diphosphate salt. References Merck Index 2136 Kleeman and Engel p. 194 PDR p. 1902 OCDS Vol. 1 p. 341 (1977) I.N. p. 220 REM p. 1218 Andersag, H., Breitner, S. and Jung, H.; US Patent 2,233,970; March 4, 1941; assigned to Winthrop Chemical Company, Inc.

CHLOROTHIAZIDE Therapeutic Function: Diuretic; Antihypertensive Chemical Name: 6-Chloro-2H-1,2,4-benzothiadiazine-7-sulfonamide-1,1dioxide Common Name: Chemical Abstracts Registry No.: 58-94-6

Chlorothiazide

979

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Diuril

Merck Sharp and Dohme

US

1957

Diurilix

Theraplix

France

1959

Aldoclor

MSD

US

-

Azide

Fawns and McAllan Australia

-

Chlorosal

Teva

Israel

-

Chloroserpine

Schein

US

-

Chlotride

Sharp and Dohme W. Germany

-

Clotride

MSD

Italy

-

Diubram

Bramble

Australia

-

Diupres

MSD

US

-

Diuret

Protea

Australia

-

Diurone

Knoll

Australia

-

Fenuril

Pharmacia

Sweden

-

Lyovac

MSD

US

-

Niagar

Cimes

Belgium

-

Ro-Chlorozide

Robinson

US

-

Salisan

Ferrosan

Denmark

-

Saluren

Croce Bianca

Italy

-

Saluretil

Gayoso Wellcome

Spain

-

Saluric

MSD

UK

-

Salutrid

Leiras

Finland

-

SK-Chlorothiazide

SK and F

US

-

Urinex

Orion

Finland

-

Raw Materials m-Chloroaniline Ammonia

Chlorosulfonic acid Formic acid

Manufacturing Process (A) m-Chloroaniline (64 g, 0.5 mol) was added dropwise with stirring to 375 ml of chlorosulfonic acid in a 3-liter round bottom, 3-necked flask cooled in an ice bath. Sodium chloride (350 g) was added portionwise over a period of 1 to

980

Chlorotrianisene

2 hours and the mixture then heated gradually in an oil bath to 150°C. After 3 hours at 150° to 160°C, the flask was cooled thoroughly in an ice bath and the contents treated with a liter of cold water. The product was extracted with ether and the extract washed with water and dried over sodium sulfate. After removal of ether on the steam bath, the residual 5-chloroaniline-2,4disulfonyl chloride, which may be crystallized from benzene-hexane MP 130° to 132°C, was cooled in an ice bath and treated with 150 ml of 28% ammonium hydroxide in a 2-liter Erlenmeyer flask. The mixture was heated on the steam bath for 1 hour, cooled and the product collected on the filter, washed with water and dried. Upon crystallization from dilute alcohol 5chloro-2,4-disulfamylaniline was obtained as colorless needles, MP 251° to 252°C. (B) A solution of 88 g of 5-chloro-2,4-disulfamylaniline in 1.1 liters of 88% formic acid was heated under reflux for 2 hours. After removal of 200 ml of solvent by distillation, one liter of water was added and the product collected, washed with water and dried. Crystallization from dilute alcohol afforded 6chloro-7-sulfamyl-1,2,4-benzothiadiazine-1,1-dioxide as colorless needles, MP 342.5° to 343°C, as described in US Patent 2,809,194. References Merck Index 2143 Kleeman and Engel p. 194 PDR pp. 830, 993, 1133, 1168, 1606, 1723 OCDS Vol. 1 pp. 321, 355 (1977) and 2 p. 395 (1980) I.N. p. 221 REM p.938 Novello, F.C.; US Patent 2,809,194; October 8, 1957; assigned to Merck and Co., Inc. Hinkley, D.F.; US Patent 2,937,169; May 17, 1960; assigned to Merck and Co., Inc.

CHLOROTRIANISENE Therapeutic Function: Estrogen Chemical Name: 1,1',1''-(1-Chloro-1-ethenyl-2-ylidene)tris[4methoxybenzene] Common Name: Tri-p-anisylchloroethylene Chemical Abstracts Registry No.: 569-57-3 Raw Materials Tris-p-methoxyphenyl ethylene Chlorine

4-chloro-3,5-xylenol

981

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

TACE

Merrell

US

1952

TACE FN

Merrell

France

1959

Anisene

Farmila

Italy

-

Clorotrisin

Courtois

Italy

-

Merbentul

Merrell

W. Germany

-

Triagen

Gentili

Italy

-

Manufacturing Process The following method is described in US Patent 2,430,891. To a solution of 10 parts of tris-p-methoxyphenyl ethylene in 35 to 40 parts of carbon tetrachloride is added a solution of 2.0 parts of chlorine in 50 parts of carbon tetrachloride, with stirring, and over a period of ½ hour. The carbon tetrachloride is then removed by distillation on a steam bath and the residual oil is recrystallized from 250 to 400 parts of methanol, decolorizing with charcoal or the like if necessary. Tris-p-methoxyphenyl chloroethylene is obtained in a yield of 65 to 75%. It melts at 113° to 114°C. References Merck Index 2149 Kleeman and Engel p. 195 PDR p. 1239 OCDS Vol. 1 p. 104 (1977) I.N.p. 221 REM p. 988 Shelton, R.S. and Van Campen, M.G. Jr.; US Patent 2,430,891; November 18, 1947; assigned to the Wm. S. Merrell Company

4-CHLORO-3,5-XYLENOL Therapeutic Function: Topical antiseptic; Disinfectant Chemical Name: 4-Chloro-3,5-dimethylphenol

982

4-chloro-3,5-xylenol

Common Name: Structural Formula:

Chemical Abstracts Registry No.: 88-04-0 Trade Name Septiderm Anti-Sept Bacillotox Baktol Cruex Dettol Fungoid Ice-O-Derm Metasep Micro-Guard Orlex Otall Pedi-Pro Foot Powder Rezamid Rocapyol Roxenol Satinasept Sween-Soft Valvanol Zetar

Manufacturer Fougera Seamless Bode Bode Pharmacraft Reckitt and Coleman Pedinol Wampole Marion Sween Baylor Saron Pharmacal Pedinol

Country US US W. Germany W. Germany US UK

Year Introduced 1960 -

US US US US US US US

-

Dermik Plurosan Saunders Mack Sween Asid Dermik

US Austria Canada W. Germany US W. Germany US

-

Raw Materials Sulfuryl chloride m-5-Xylenol Manufacturing Process 546 g of intermediate xylenol fraction having a crystallizing point of 45°C mixed with an equal weight of m-5-xylenol are placed in a suitable vessel, equipped with stirring gear, and 273 g of sulfuryl chloride are added slowly. The temperature rises in the course of the reaction to about 40°C. When all the sulfuryl chloride is added the reaction mixture is heated to 80°C and the

Chlorphenesin carbamate

983

acid gases removed as far as possible by air-blowing or any other suitable means. On cooling a quantity of the required chlor-xylenol separates out and is removed from the mother liquor. Further quantities of the material required can be isolated by vacuum distillation of the mother liquors and further crystallization. In all, 200 to 208 g of material substantially 2-chlor-m-5xylenol can be obtained having a melting point of 112°C to 115°C. The material can be purified if desired by crystallization from a solvent such as a hydrocarbon. References Merck Index 2152 Kleeman and Engel p. 196 PDR pp. 1397, 1662, 1790 I.N. p. 222 REM p. 1168 Gladden, G.W.; US Patent 2,350,677; June 6, 1944: assigned to W.W. Cocker

CHLORPHENESIN CARBAMATE Therapeutic Function: Muscle relaxant Chemical Name: 3-(4-Chlorophenoxy)-1,2-propanediol-1-carbamate Common Name: 3-p-Chlorophenoxy-2-hydroxypropyl carbamate Structural Formula:

Chemical Abstracts Registry No.: 886-74-8 Trade Name Maolate Kolpicortin Rinlaxer

Manufacturer Upjohn Doetsch Grether Taisho

Raw Materials p-Chlorophenol Glyceryl monochlorohydrin Phosgene Ammonia

Country US Switz. Japan

Year Introduced 1967 -

984

Chlorpheniramine maleate

Manufacturing Process 1.0 mol of 3-p-chlorophenoxy-1,2-propanediol (chlorphenesin) is suspended in 1,000 ml of benzene in a 5-liter flask equipped with a dropping funnel, thermometer and stirrer. 1.0 mol of phosgene in 500 ml of cold, dry benzene is then added dropwise over a period of 45 minutes, the resulting mixture being maintained at 30°C until all solid material is dissolved. 1.0 mol of triethylamine is added dropwise and the resulting reaction mixture stirred for 45 minutes at 30°C following the addition. The reaction mixture is then cooled to 5°C and extracted repeatedly with 600 ml portions of cold water to remove the triethylamine hydrochloride. The benzene fraction, containing the intermediate 3-p-chlorophenoxy-3hydroxypropyl chlorocarbonate, is added to 600 ml of cold concentrated ammonium hydroxide and the resulting reaction mixture agitated vigorously at 5°C for 7 hours. The crude 3-p-chlorophenoxy-2-hydroxypropylcarbamate solid is then filtered off, dissolved in hot benzene, dried to remove all traces of water, and permitted to crystallize out. Several recrystallirations from solvent mixtures of benzene and toluene, with small amounts of acetone, produced a crystalline white solid in about 65% yield. The product is 3-p-chlorophenoxy2-hydroxypropyl carbamate, melting at 89° to 91°C. The chlorphenesin starting material is made by reacting p-chlorophenol with glyceryl monochlorohydrin as noted in US Patent 3,214,336. References Merck Index 2156 Kleeman and Engel p. 198 PDR p. 1850 OCDS Vol. 1 p. 118 (1977) DOT 2 (4) 138 (1966) I.N. p. 223 REM p. 927 Collins, R.J. and Matthews, R.J.; US Patent 3,161,567; December 15, 1964; assigned to The Upjohn Company Parker, H.E.; US Patent 3,214,336; October 26, 1965; assigned to The Upjohn Company

CHLORPHENIRAMINE MALEATE Therapeutic Function: Antihistaminic Chemical Name: γ-(4-Chlorophenyl)-N,N-dimethyl-2-pyridinepropanamine maleate Common Name: Chlorophenyl pyridyl propyldimethylamine maleate; Chlorphenamine maleate; Chlorprophen-pyridamine maleate Chemical Abstracts Registry No.: 113-92-8; 132-22-9 (Base)

Chlorpheniramine maleate

985

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Chlor-Trimeton

Schering

US

1949

Teldrin

SKF

US

1954

Drize

Ascher

US

1967

Histaspan

U.S.V.

US

1968

Allerbid

Amfre-Grant

US

1971

Antagonate

Dome

US

1973

Animing

Nisshin Seiyaku

Japan

1981

Ahiston

Ikapharm

Israel

-

Alaspan

Almay

US

-

Alermine

Reid-Provident

US

-

Allerdor

Fellows-Testagar

US

-

Allergex

Protea

Australia

-

Allergin

Dellsberger

Switz.

-

Allergin

Sankyo

Japan

-

Allergisan

Pharmacia

Sweden

-

Allersan

Pharmacia

Sweden

-

Allertab

Tri-State

Italy

-

Allerton

Scalari

Italy

-

Anaphyl

Sam-On

Israel

-

AnthistaminSigletten Atalis-D

Rohm Pharma

W. Germany

-

Kanto

Japan

-

Bismilla

Fuso

Japan

-

Chlo-Amine

Hollister-Stier

US

-

Chlodamine

Maruko

Japan

-

Chloramate

Reid-Provident

US

-

Chloramin

Langley

Australia

-

Chlor-Hab

Danbury

US

-

Chlor-Mal

Rugby

US

-

Chlormene

Robinson

US

-

Chloroton

Cenci

US

-

Chlorphen

Pro Doc

Canada

-

Chlor-Tel

Garden

US

-

986

Chlorpheniramine maleate

Trade Name Chlortrone Clorten C-Meton Cotuxinf Dallergy Decongestant Elixir

Manufacturer Barlow Cote Panthox and Burck S.S. Pharm Sauba Laser Schein

Country Canada Italy Japan France US US

Year Introduced -

Demazin Donatussin DowChlorpheniramine

Schering Laser Dow

US US US

-

Hexapneumine Histachlor Histadur Histaids Histalen Histamic Histapen Histol Isoclor Kloromin Lekrica Lorphen Neoallermin Neorestamin Niratron Novahistine Novopheniram Piriton Pneumopan Polaronic Poracemin Probahist Propofan Pyridamal Pyrroxate Quadrahist Rachelamine Rumicine Singlet Synistamine Trimeton Trymegen U.R.I. Vitac

Doms Vitamix Wynn Ohio Medical Len-Tag Metro Med Douglas Blaine Arnar-Stone Halsey Yoshitomi Geneva Taiyo Kowa Progress Dow Novopharm Allen and Hanburys Sauba Byk-Essex Horita Legere Lepetit Bel Mar Upjohn Schein Rachelle Cetrane Dow Sigmapharm Essex Medco ICN Egnaro

France US US US US US New Zealand US US US Japan US Japan Japan US US Canada UK France W. Germany Japan US France US US US US France US Austria Italy US US France

-

Chlorphenoxamine hydrochloride

987

Raw Materials 4-Chlorobenzyl cyanide Dimethylaminoethyl chloride Sulfuric acid

2-Chloropyridine Sodium amide

Manufacturing Process See "Brompheniramine Maleate." The starting material is simply a chlorophenyl compound. References Merck Index 2157 Kleeman and Engel p. 196 PDR pp. 992, 1033, 1246, 1606 OCDS Vol. 1 p. 77 (1977) I.N. p. 222 Sperber, N., Papa, D. and Schwenk, E.; US Patents 2,567,245; September 11, 1951; and 2,676,964; April 27, 1954; both assigned to Schering Corporation

CHLORPHENOXAMINE HYDROCHLORIDE Therapeutic Function: Muscle relaxant; Antiparkinsonian Chemical Name: 2-[1-(4-Chlorophenyl)-1-phenylethoxy]-N,Ndimethylethanamine hydrochloride Common Name: Structural Formula:

Chemical Abstracts Registry No.: 562-09-4: 77-38-3 (Base) Trade Name Phenoxene Systral

Manufacturer Dow Lucien

Country US France

Year Introduced 1959 1963

988

Chlorphenoxamine hydrochloride

Trade Name Clorevan Contristamine Rodavan Systral Svstral

Manufacturer Evans Noristan Asta Asta Kyorin

Country UK S. Africa W. Germany W. Germany Japan

Year Introduced -

Raw Materials Methyl chloride 4-Chlorobenzophenone Sodium amide

Magnesium Dimethylaminoethyl chloride Hydrogen chloride

Manufacturing Process A Grignard solution is prepared by introducing methyl chloride into a boiling suspension of 36 g of magnesium in 1,000 cc of absolute ether until all the magnesium has reacted. 216 grams of 4-chloro-benzophenone are slowly added to the Grignard solution with ice cooling and stirring; after 15 hours, the thus-obtained product is poured into a mixture of 200 g of ammonium chloride and ice, whereupon it is separated with ether. The separated ether layer is dried with sodium sulfate, and the ether is distilled. The residual carbinol is added to a suspension of 45 g of sodium amide in 500 cc of toluene. To the thus-obtained mixture there are added 125 g of dimethylaminoethyl chloride, and the mixture is heated at boiling temperature for 3 hours with stirring. The mixture is taken up with water and the base is extracted from the toluene with dilute hydrochloric acid. The hydrochloric solution is rendered alkaline with caustic soda, the base is separated with ether, dried, and after distillation of the ether fractionated in vacuo, BP at 0.05 mm Hg, 150° to 153°C. The basic ether is then dissolved in dry ether, and ether saturated with dry hydrogen chloride is added dropwise with stirring. An excess of hydrogen chloride must be avoided as it may produce decomposition to the corresponding diphenyl ethylene. The ether-moist hydrochloride is preferably dried at once in vacuo and subsequently reprecipitated from acetone-ether and then again dried in vacuo over phosphorus pentoxide. Hydrochloride, MP 128°C. References Merck index 2159 Kleeman and Engel p. 198 OCDS Vol. 1 p. 44 (1977) I.N. p. 223 REM p.931 Arnold, H., Brock, N. and Kuhas, E.; US Patent 2,785,202; March 12, 1957; assigned to Asta-Werke A.G. Chemische Fabrik, Germany

Chlorproethazine hydrochloride

989

CHLORPROETHAZINE HYDROCHLORIDE Therapeutic Function: Muscle relaxant; Tranquilizer Chemical Name: 2-Chloro-N,N-diethyl-10H-phenothiazine-10-propanamine hydrochloride Common Name: Structural Formula:

Chemical Abstracts Registry No.: 84-01-5 (Base) Trade Name

Manufacturer

Country

Year Introduced

Neuriplege

Genevrier

France

1961

Raw Materials 2-Bromo-2'-(3''-dimethylaminopropyl)-amino-4'-chlorodiphenyl sulfide Copper Potassium carbonate Hydrogen chloride Manufacturing Process 2-Bromo-2'-(3''-dimethylaminopropyl)-amino-4'-chlorodiphenylsulfide (10 g) is dissolved in dimethylformamide (80 cc). To this solution is added potassium carbonate (5 g) and copper powder (0.4 g). It is then heated under reflux for 48 hours, cooled, and the insoluble matter filtered off. After washing with dimethylformamide (20 cc), the filtrate is taken up in distilled water (200cc). The base formed is extracted with ether (3 times with 50 cc), the ethereal solution is dried over sodium sulfate, the ether driven off on a water-bath and the residue distilled. In this way there is obtained 3-chloro-10-(3'dimethylaminopropyl)-phenothiazine (6.4 g) which boils at 210 C to 225°C under 0.7 mm of mercury. The hydrochloride is made by the action of ethereal hydrogen chloride on the base dissolved in acetone; this hydrochloride melts at 180°C.

990

Chlorpromazine hydrochloride

References Merck Index 2161 OCDS Vol. 1 p. 379 (1977) I.N. p. 224 Buisson, P.J.C., Gaillot, P. and Gaudechon, J.; US Patent 2,769,002; October 30, 1956; assigned to Societe des Usines Chimiques Rhone-Poulenc (France)

CHLORPROMAZINE HYDROCHLORIDE Therapeutic Function: Tranquilizer Chemical Name: 2-Chloro-N,N-dimethyl-10H-phenothiazine-10-propanamine hydrochloride Common Name: N-(3-Dimethylaminopropyl)-3-chlorophenothiazine Structural Formula:

Chemical Abstracts Registry No.: 69-09-0; 50-53-3 (Base) Trade Name

Manufacturer

Country

Year Introduced

Thorazine

SKF

US

1954

Chlor-PZ

U.S.V

US

1973

Promapar

Parke Davis

US

1973

Prochel

Rachelle

US

1975

Acemin

Sankyo

Japan

-

Chloractil

D.D.S.A.

UK

-

Chlorazin

Streuli

Switz.

-

Chlorpromados

Holz

W. Germany

-

Chlor-Promanyl

Paul Maney

Canada

-

Chlorprom-Ez-Ets

Barlow Cote

Canada

-

Contomin

Yoshitomi

Japan

-

Copormin

Kaken

Japan

-

Chlorpromazine hydrochloride

991

Trade Name

Manufacturer

Country

Year Introduced

Cromedazine

Fellows-Testagar

US

-

Doimazin

Nippon Shinyaku

Japan

-

Elmarine

Elliott-Marion

Canada

-

Epokuhl

Kyowa

Japan

-

Esmind

Otsuka

Japan

-

Fenactil

Polfa

Poland

-

Hibanil

Mekos

Sweden

-

Hibernal

Leo

Sweden

-

Ishitomin

Kanto

Japan

-

Klorazin

Star

Finland

-

Klorproman

Orion

Finland

-

Klorpromex

Dumex

Denmark

-

Largactil

Specia

France

-

Megaphen

Bayer

W. Germany

-

Neurazine

Misr. Co-Pharm.

Egypt

-

Norcozine

Iwaki

Japan

-

Procalm

Bramble

Australia

-

Promachlor

Geneva

US

-

Promacid

Knoll

Australia

-

Promactil

Wassermann

Spain

-

Promexin

Meiji

Japan

-

Promosol

Horner

Canada

-

Propafenin

Deutsches Hydrierwerk

E. Germany

-

Protran

Protea

Australia

-

Prozil

Dumex

Denmark

-

Prozin

Lusofarmaco

Italy

-

Psychozine

O'Neal, Jones and Feldman

US

-

Psylkatil

Farmos

Finland

-

Repazine

Lennon

S. Africa

-

Taroctyl

Taro

Israel

-

Wintermin

Shionogi

Japan

-

Raw Materials Sodium amide Chlorophenothiazine

Hydrogen chloride 3-Dimethylamino-1-chloropropane

Manufacturing Process To a boiling suspension of 11.6 g of chlorophenothiazine (consisting of a mixture of two isomers melting at 196° to 198°C and 116° to 117°C, respectively, the latter in minor proportion) and 2.4 g of sodium amide (80%) in 60 cc of xylene, there are added over a period of one hour 7.5 g of 3-

992

Chlorpropamide

dimethylamino-1-chloropropane in solution in its own weight of xylene. At the end of the addition, heating is continued for one hour under reflux. After cooling, the contents are taken up in acidified water and the xylene separated. The aqueous layer is made strongly alkaline by means of sodium hydroxide in order to liberate the base and this is extracted with ether. On distillation of the ethereal extract there is obtained 10-(3'-dimethylamino-propyl)chlorophenothiazine which distills at 200° to 205°C under a pressure of 0.8 mm Hg. Its hydrochloride, recrystallized from chlorobenzene, melts at 177° to 178°C. The chlorophenothiazine may be prepared by reacting mchlorodiphenylamine with sulfur in the presence of an iodine catalyst. References Merck Index 2163 Kleeman and Engel p. 199 PDR p. 1728 OCDS Vol. 1 pp. 319, 378 (1977), 2 p. 409 (1980) and 3p. 72 (1984) I.N.p. 224 REM p. 1086 Charpentier, P.; US Patent 2,645,640; July 14, 1953; assigned to Societe des Usines Chimiques Rhone-Poulenc, France

CHLORPROPAMIDE Therapeutic Function: Oral hypoglycemic Chemical Name: 4-Chloro-N-[(propylamino)carbonyl]benzenesulfonamide Common Name: 1-(p-Chlorobenzenesulfonyl)-3-propylurea Structural Formula:

Chemical Abstracts Registry No.: 94-20-2 Trade Name Diabinese Diabinese Dynalase Insulase Abemide Adiaben Arodoc-C

Manufacturer Pfizer Pfizer Pharmadyne Premo Kabayashi Belupo Ltd. Sawai

Country US France US US Japan Yugoslavia Japan

Year Introduced 1958 1960 1980 1980 -

Chlorpropamide Trade Name Biadibe Bioglumin Catanil Chloronase Chloronase Clordiabet Clordiasan Cloro-Hipoglucina Diabemide Diabet Diabetabs Diabetasi Diabetoral Diabexan Diabitex Diamel-Ex Diamide Gliconorm Glucamide Glucosulfina Meldian Melisar Melitase Mellitos Melormin Normoglic Novopropamide Orabet Orabines Orbin Prodiaben Promide Shuabate Stabinol Toyomelin

Manufacturer Guidotti Uriach De Angeli Hoechst Hoechst Carulla-Vekar Santos Lefa Guidotti Pages Maruny Wolfs Biagini Boehringer Mannheim Crosara Irapharm Ibsa Kanto Gentili Lemmon Infale Pliva Beolet Berk Ono Farmos Salfa Novopharm Deva Biofarma Biles Labif Protea Toyama Horner Toyo Jozo

993

Country Italy Spain Italy W. Germany Japan Spain Spain Spain Italy Spain Belgium Italy W. Germany

Year Introduced -

Italy Israel Switz. Japan Italy US Spain Yugoslavia Italy UK Japan Finland Italy Canada Turkey Turkey Turkey Italy Australia Japan Canada Japan

-

Raw Materials Propyl isocyanate p-Chlorobenzene sulfonamide Triethylamine Manufacturing Process A solution of 54 g (0.64 mol) of propyl isocyanate in 60 ml of anhydrous

994

Chlorprothixene

dimethylformamide was added to a cold, well-stirred suspension of 81 g (0.42 mol) of dry p-chlorobenzenesulfonamide in 210 ml of anhydrous triethylamine during the course of 20 to 30 minutes. The mildly exothermic reaction was completed by allowing it to stand at room temperature for about 5 hours. The reaction mixture was then slowly added to 3 liters of cold 20% acetic acid during the course of about one hour, constant agitation being maintained throughout the addition. After the addition was complete, the desired product, which had crystallized out, was filtered and washed well with about 2 liters of cold water. The crude material was then dissolved in 1 liter of cold 5% sodium carbonate and the resulting solution was immediately filtered from an insoluble gum. The product was then reprecipitated, by slowly adding the filtrate to 3 liters of 20% acetic acid. The precipitate, which is very nearly pure N-(p-chlorobenzenesulfonyl)N'-propylurea, was then dried and subsequently recrystallized from about 800 ml of benzene to give a 59% yield of pure product, MP 129.2 to 129.8°C. References Merck Index 2164 Kleeman and Engel p. 200 PDR pp. 830, 993, 1034, 1417, 1999 OCDS Vol. 1 p. 137 (1977) I.N.p. 225 REM p. 976 McLamore, W.M.; US Patent 3,349,124; October 24, 1967; assigned to Chas. Pfizer Co., Inc.

CHLORPROTHIXENE Therapeutic Function: Tranquilizer Chemical Name: 3-(2-Chloro-9H-thioxanthen-9-ylidene)-N,N-dimethyl-1propanamine Common Name: Structural Formula:

Chlorprothixene

995

Chemical Abstracts Registry No.: 113-59-7; 6469-93-8 (Hydrochloride salt) Trade Name Taractan Taractan Clothixen Cloxan Minithixen Paxyl Tra-Quilan Truxal Truxal Truxaletten

Manufacturer Roche Roche Yoshitomi Orion Spofa Ikapharm Eisai Tropon Toyama Tropon

Country France US Japan Finland Czechoslovakia Israel Japan W. Germany Japan W. Germany

Year Introduced 1960 1962 -

Raw Materials 3-Dimethylaminopropyl chloride 2-Chlorothiaxanthone Acetyl chloride Magnesium Ethyl bromide Manufacturing Process Chlorprothixene may be prepared as described in US Patent 2,951,082. Magnesium turnings, 4.86 g (0.2 g-atom) was placed in a 500 ml reaction flask fitted with a mercury sealed stirrer, reflux condenser and a dropping funnel. Tetrahydrofuran, 50 ml and calcium hydride, 500 mg, were added. Ethyl bromide, 2.18 g and a crystal of iodine then were added. A vigorous reaction set in that evolved sufficient heat to induce refluxing. After 5 minutes, a solution of 3-dimethylaminopropyl chloride (dried over calcium hydride) in 50 ml of tetrahydrofuran was added to the refluxing solution at such a rate that gentle refluxing was maintained. The addition required 25 minutes. The reaction mixture was stirred at reflux for an additional 30 minutes when nearly all of the magnesium had dissolved and determination of magnesium in an aliquot of the solution showed that an 82% yield of Grignard reagent had been obtained. The reaction mixture was cooled in an ice bath and stirred while 24.67 g (0.1 mol) of 2-chlorothiaxanthone was added over a period of 10 minutes. The reaction was stirred at room temperature for 30 minutes then allowed to stand overnight in the refrigerator. The tetrahydrofuran was evaporated at 50°C under reduced pressure. Benzene, 150 ml, was added to the residue. The mixture was hydrolyzed in the cold by the dropwise addition of 50 ml of water. The benzene layer was separated by decantation and the gelatinous precipitate washed with two 100 ml portions of benzene. The precipitate was then mixed with diatomaceous earth, collected on a filter, and washed with water and extracted with two 100 ml portions of boiling

996

Chlorquinaldol

benzene. The aqueous filtrate was extracted with 50 ml of benzene, the combined benzene extracts washed with water and evaporated to dryness under reduced pressure. The crystalline residue, MP 140° to 147°C, weighed 30.8 g. Recrystallization from a mixture of benzene and hexane gave 27.6 g (83%) of 2-chloro-10-(3-dimethylaminopropyl)-10-hydroxythiaxanthene, MP 152° to 154°C. Analytically pure material from another experiment melted at 153° to 154°C. 2-Chloro-10-(3-dimethylaminopropyl)-10-hydroxythiaxanthene, 3.34 g (0.01 mol) obtained as described was dissolved in 15 ml of dry, alcohol-free chloroform. Acetyl chloride, 2.36 g (0.03 mol) was added and the clear yellow solution was refluxed for one hour in a system protected by a drying tube. The solvent then was evaporated on the steam bath under reduced pressure and the residue dissolved in absolute alcohol. The hydrochloride of 2-chloro10-(3-dimethylaminopropylidene)-thiaxanthene was precipitated by the cautious addition of absolute ether. After drying at 70°C the yield of white crystalline 2-chloro10-(3-dimethylaminopropylidene)-thiaxanthene hydrochloride, MP 189 to 190°C (to a cloudy melt), was 3.20 g (90%). This material is a mixture of geometric isomers. Trans-2-chloro-9-(ω-dimethylamino-propylidene)-thioxanthene [MP 98°C, MP of the hydrochloride 225°C (corr.)], is a valuable medicinal agent, being used as a tranquilizer and antiemetic agent, whereas the corresponding cis isomer (MP 44°C, MP of the hydrochloride 209°C) is not useful for these indications, as described in US Patent 3,115,502, which describes procedures for conversion of the cis to the trans form. References Merck Index 2166 Kleeman and Engel p. 200 PDR p. 1503 OCDS Vol. 1 p. 389 (1977) DOT 9 (6) 229 (1973) I.N.p. 225 REM p. 1087 Sprague, J.M. and Engelhardt, E.L.; US Patent 2,951,082; August 30, 1960; assigned to Merck and Co., Inc. Schlapfer, R. and Spiegelberg, H.; US Patent 3,115,502; December 24, 1963;assigned to Hoffmann-LaRoche Inc.

CHLORQUINALDOL Therapeutic Function: Antibacterial Chemical Name: 5,7-Dichloro-2-methyl-8-quinolinol Common Name: Hydroxydichloroquinaldine; Chloroquinaidol Chemical Abstracts Registry No.: 72-80-0

Chlorquinaldol

997

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Sterosan

Geigy

US

1954

Gynotherax

Bouchard

France

1967

Afungyl

EGYT

Hungary

-

Chinosicc

Schering

W. Germany

-

Chinotiol

Bouty

Italy

-

Gyno-Sterosan

Geigy

W. Germany

-

Intensol

Anasco

W. Germany

-

Lonjee

Sampo

Japan

-

Phyletten

Muller Rorer

W. Germany

-

Quesil

EGYT

Hungary

-

Rub-All T

Toyama

Japan

-

Saprosan

C.I.F.

Rumania

-

Serviderm

Servipharm

Switz.

-

Siogeno

Geigy

W. Germany

-

Siogene

Geigy

France

-

Siosteran

Fujisawa

Japan

-

Steroxin

Geigy

UK

-

Raw Materials 8-Hydroxyquinaldine Chlorine Manufacturing Process 11.1 parts of 8-hydroxy-quinaldine are dissolved in 140 parts of formic acid. Chlorine is introduced into this solution under cooling, until the increase in weight corresponds to the required quantity of chlorine and a test of the chlorination mixtures gives no more dyestuff formation with diazo-benzene in an acetic acid solution. When the chlorination is complete, the reaction mixture is poured into 1,000 parts of water and treated with a dilute sodium bisulfite solution, until no more reaction may be observed with starch potassium iodide paper. Thereby the 5,7-dichloro-8-hydroxy-quinaldine separates out in form of a weakly yellowish colored precipitate. The same is filtered off and thoroughly washed with water.

998

Chlortetracycline

After drying, 15 parts of 5,7-dichloro-8-hydroxy-quinaldine melting at 111°C to 112°C are obtained. When recrystallized from alcohol, the product is obtained in voluminous, slightly yellowish needles having the melting point of 111.5°C to 112°C. References Merck Index 2168 Kleeman and Engel p. 201 I.N. p. 225 Senn, E.; US Patent 2,411,670; November 26, 1946; assigned to J.R. Geigy AG

CHLORTETRACYCLINE Therapeutic Function: Antibacterial Chemical Name: 7-Chloro-4-dimethylamino-1,4,4a,5,5a,6,11,12a-octahydro3,6,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2naphthacenecarboxamide Common Name: Structural Formula:

Chemical Abstracts Registry No.: 57-62-5 Trade Name

Manufacturer

Country

Year Introduced

Aureomycin

Lederle

US

1948

Aureomycine

Specia

France

1951

Aureum

Farmigea

Italy

-

Aufofac

American Cyanamid (AHP)

US

-

B-Aureo

Biokema

Switz.

-

Chevita C-10

Chevita

W. Germany

-

Chlortet

Langley

Australia

-

Chrysomycin

Dispersa

Switz.

-

Ciorteta

Pierrel

Italy

-

Chlortetracycline

999

Trade Name

Manufacturer

Country

Year Introduced

Colircusi Aureomicina

Cusi

Spain

-

CTC Soluble

Diamond Shamrock

US

-

Vi-Mvcin

Vineland Chemical US

-

Raw Materials Sucrose Corn steep liquor S. aureofaciens bacterium Manufacturing Process The following process description is taken from US Patent 2,987,449. An appropriate S. aureofaciens strain such as mutant S1308 (ATCC No. 12,748) is grown aerobically in a suitable inoculum medium. A typical medium used to grow the primary inoculum is prepared according to the following formula: sucrose, 20.0 g; corn steep liquor, 16.5 ml, ammonium sulfate, 2.0 g; calcium carbonate, 7.0 g; and water to 1,000 ml. A 100 ml aliquot of this medium is placed in a 500 mi Erlenmeyer flask and sterilized by autoclaving for 20 minutes under 15 psi pressure. Spores of mutant strain S. aureofaciens S1308 (ATCC No. 12,748) are washed from an agar slant into the flask with sterile distilled water to form a suspension containing approximately 108 spores per milliliter. A 1.0 ml portion of this suspension is used to inoculate the fermentation media in the example which follows. A fermentation medium consisting of the following ingredients was prepared.

(NH4)2SO4 CaCO3 NH4Cl MgCl2·6H2O FeSO4·7H2O MnSO4·4H2O CoCl2·6H2O ZnSO4·7H2O Corn steep liquor Cornstarch Water to

Grams 5.0 9.0 1.5 2.0 0.06 0.05 0.005 0.1 25.0 55.0 1,000 ml

25 ml aliquots of this fermentation medium were placed in each of two 250 ml Erlenmeyer flasks and 0.5 ml of lard oil was added to each flask. Then 0.002 mg/ml of riboflavin was added to one flask, the other flask being retained as a control. The flasks were sterilized in an autoclave for 20 minutes under 15 psi pressure, then cooled to room temperature (25°±5°C). At this point, a 1.0 ml portion of inoculum of mutant strain S. aureofaciens S1308 (ATCC No. 12,748) was added to each of the two flasks. The flasks were incubated at

1000

Chlorthalidone

25°C for 120 hours on a rotary shaker operating at 180 rpm. Upon completion of the fermentation period the mashes were assayed for 7-chlorotetracycline content. The increase in production due to the addition of riboflavin was very noticeable in the above example. A similar effect was reported for cupric sulfate pentahydrate addition according to US Patent 3,050,446. References Merck Index 2170 Kleeman and Engel p. 203 PDR p. 1007 OCDS Vol. 1 p. 212 (1977) I.N. p. 226 REM p. 1208 Duggar, B.M.; US Patent 2,482,055; September 13, 1949; assigned to American Cyanamid Company Niedercorn, J.G.; US Patent 2,609,329; September 2, 1952; assigned to American Cyanamid Company Winterbottom, R., Mendelsohn, H., Muller, S.A., and McCormick, J.R.D.; US Patent 2,899,422; August 11, 1959; assigned to American Cyanamid Company Miller, P.A., Goodman, J.J., Sjolander, N.O. and McCormick, J.R.D.; US Patent 2,987,449; June 6, 1961; assigned to American Cyanamid Company Goodman, J.J.; US Patent 3,050,446; August 21, 1962; assigned to American Cyanamid Company

CHLORTHALIDONE Therapeutic Function: Diuretic, Antihypertensive Chemical Name: 2-Chloro-5-(1-hydroxy-3-oxo-1-isoindolinyl) benzenesulfonamide Common Name: Chlortalidone Structural Formula:

Chemical Abstracts Registry No.: 77-36-1

Chlorthalidone

1001

Trade Name

Manufacturer

Country

Year Introduced

Hygroton

Geigy

US

1960

Hygroton

Ciba Geigy

France

1960

Hygroton

Ciba Geigy

Switz.

1960

Hygroton

Ciba Geigy

W. Germany

1960

Hygroton

Ciba Geigy

UK

1960

Igroton

Geigy

Italy

1961

Thalitone

Boehringer Ingelheim

US

1982

Aquadon

Ikapharm

Israel

-

Hybasedock

Sawai

Japan

-

Hydoban

Medica

Finland

-

Hydro-Long

Sanorama

W. Germany

-

Hygroton

Pliva

Yugoslavia

-

Hygroton

Geigy

Japan

-

Hypertol

Farmos

Finland

-

Igrolina

Benedetti

Italy

-

Novothalidone

Novopharm

Canada

-

Regretron

U.S.V.

US

-

Renon

Medal

Italy

-

Servidone

Servipharm

Switz.

-

Urid

Protea

Australia

-

Uridon

I.C.N.

Canada

-

Urolin

Sidus

Italy

-

Zambesil

Spemsa

Italy

-

Raw Materials 4-Chloro-3-amino-benzophenone-2'-carboxylic acid Sodium nitrate Hydrogen chloride Sulfur dioxide Thionyl chloride Ammonia Manufacturing Process 15 parts of aqueous 46% sodium nitrite solution are gradually added to a mixture of 27.5 parts of 4-chloro-3-amino-benzophenone-2'-carboxylic acid, 200 parts of glacial acetic acid and 20 parts of 37% hydrochloric acid at 0° to 10°C. The solution of the diazonium salt is poured into an ice-cooled mixture of 200 parts of 30% sulfur dioxide solution in glacial acetic acid and 3 parts of crystallized cupric chloride in 15 parts of water. Nitrogen is developed and, after a short time, the 4-chloro-2'-carboxy-benzophenone-3-sulfochloride crystallizes out. After 1 hour it is filtered off and washed with water. MP 178° to 182°C.

1002

Chlorthenoxazine

35.9 parts of 4-chloro-2'-carboxy-benzophenone-3-sulfochloride and 50 parts of thionyl chloride are heated first for 3 hours at 30° to 35°C and then for 1 hour at 45°C. The excess thionyl chloride is distilled off in the vacuum, the dichloride, 3-chloro-3-(3'-chlorosulfonyl-4'-chlorophenyl)phthalide, which remains as a crystallized mass is dissolved in 150 parts of chloroform and a mixture of 200 parts of 25% aqueous ammonia solution and 200 parts of ethanol is added dropwise at about 10°C while stirring and cooling. After stirring for 1 hour at 40°C, the solvent is distilled off in the vacuum and diluted hydro chloric acid is added to the residue whereupon the 1-oxo-3-(3'sulfamyl-4'-chloro-phenyl)3-hydroxy-isoindoline which is tautomeric to the 4chloro-2'-carbamyl-benzophenone-3-sulfonamide, separates out. On recrystallizing from diluted ethanol, the isoindoline derivative melts at 215°C on decomposition. Instead of reacting the dichloride in aqueous solution with ammonia, it can also be reacted at -50° to -40°C with a great excess of liquid ammonia. After removal of the ammonia, the crude product obtained is recrystallized as described above. References Merck Index 2171 Kleeman and Engel p. 202 PDR pp. 509, 676, 682, 830, 993, 1326, 1606, 1786, 1813, 1820, 1999 OCDS Vol. 1 p. 322 (1977) DOT 16 (1) 32 (1980) I.N. p. 226 REM p. 938 Graf, W., Schmid, E. and Stoll, W.G.; US Patent 3,055,904; September 25, 1962; assigned to Geigy Chemical Corporation

CHLORTHENOXAZINE Therapeutic Function: Antipyretic, Analgesic Chemical Name: 2-(2-Chloroethyl)-2,3-dihydro-4H-1,3-benzoxazin-4-one Common Name: Structural Formula:

Chemical Abstracts Registry No.: 132-89-8

Chlorthenoxazine Trade Name Reugaril Apirogen Betix Fiobrol Ossazin Ossazone Ossipirina Oxal Reulin Reumital Valtorin

Manufacturer Farber Dessy Saba Geigy Scalari Brocchieri Radiumpharma Saita Isola-Ibi Farge Boehringer Ingelheim

Country Italy Italy Italy W. Germany Italy Italy Italy Italy Italy Italy -

1003

Year Introduced 1966 -

Raw Materials Acrolein Hydrogen chloride Salicylamide Manufacturing Process A mixture of 4 liters chloroform and 1,050 cc ethanol was saturated with dry hydrogen chloride gas at -5°C to +5°C in a vessel having a net volume of 15 liters and provided with a stirring device, reflux cooler, gas feed line, thermometer and dropping funnel. 455 g acrolein which had been precooled to 0°C were added dropwise to the solution over a period of 1 to 2 hours while maintaining the temperature below +5°C and vigorously stirring. 1,070 g salicylamide and 1,080 g glacial acetic acid were added to the resulting solution of beta-chloropropionaldehyde acetal, thereby forming a suspension which was heated to 60°C while stirring. A clear solution was formed which was maintained at 60°C for an additional hour. The solution was allowed to cool to about 40°C and was then washed with water by passing a strong stream of water under the surface of the chloroform and continuously withdrawing the upper phase. When the water had reached a pH of 3-4, the precipitated reaction product was separated by vacuum filtration. The chloroform phase of the filtrate was evaporated under a weak vacuum and the residue was combined with the precipitate first obtained. The combined products were stirred with 2 liters of a 5% sodium hydroxide solution. The raw reaction product was then washed with water, dried and recrystallized from ethanol. The product had the melting point of 146°C to 147°C (decomposition). The yield was 1,260 g, corresponding to 76% of the theoretical yield. References Merck Index 2172 Kleeman and Engel p. 203 I.N. p. 226 Ohnacker, G. and Scheffler, H.; US Patent 2,943,087; June 28, 1960; assigned to Dr. Karl Thomae G.m.b.H. (Germany)

1004

Chlorzoxazone

CHLORZOXAZONE Therapeutic Function: Muscle relaxant Chemical Name: 5-Chloro-2(3H)-benzoxazolone Common Name: 5-Chloro-2-hydroxybenzoxazole Structural Formula:

Chemical Abstracts Registry No.: 95-25-0 Trade Name Paraflex Benzoflex Biomioran Chroxin Chlozoxine Deltapyrin Escoflex Framenco Kiricoron Mesin Myoflex Myoflexin Oxyren Paraflex Pathorysin Remoflex Solaxin Sorazin Trancrol

Manufacturer McNeil Benzon Bioindustria Kanyo Sanko Kodama Streuli Fuso Sampo Yamanouchi Pliva Chinoin Astra Cilag Kowa Belupo Ltd. Eisai Toho Mohan

Country US Denmark Italy Japan Japan Japan Switz. Japan Japan Japan Yugoslavia Hungary W. Germany Japan Yugoslavia Japan Japan Japan

Year Introduced 1958 -

Raw Materials 2-Amino-5-chlorobenzoxazole Hydrogen chloride Sodium hydroxide Manufacturing Process A solution of 16.9 g (0.1 mol) of 2-amino-5-chlorobenzoxazole in 200 ml of 1 N HCl is refluxed until precipitation is complete. The resulting solid is collected

Cholecalciferol

1005

by filtration, dissolved in 200 ml of 1 N NaOH and the solution extracted with 50 ml of ether. Acidification of the alkaline solution gives a precipitate which is purified by crystallization from acetone to give 2-hydroxy-5-chlorobenzoxazole melting at 191° to 191.5°C. References Merck Index 2174 Kleeman and Engel p. 204 PDR pp. 830, 993, 1093, 1441, 1606, 1999 OCDS Vol. 1 p. 323 (1977) I.N. p. 227 REM p. 926 Marsh, D.F.; US Patent 2,895,877; July 21, 1959; assigned to McNeil Laboratories, Inc.

CHOLECALCIFEROL Therapeutic Function: Vitamin, Antirachitic Chemical Name: 9,10-Secocholesta-5,7,10(19)-trien-3-ol, (3β,5Z,7E) Common Name: Cholecalciferol; Colecalciferol; Dehydrocholesterolum activatum; Oleovitamin D3; Vitamin D; Vitamin D3 Structural Formula:

Chemical Abstracts Registry No.: 67-97-0 Trade Name Vitamin D Vitamin D Vitamin D

Manufacturer Country Life Nature's Way Solgar

Country -

Year Introduced -

1006

Cholestyramine

Trade Name Vitamin D Vitamin D

Manufacturer Vitamin Power Carlson Laboratories

Country -

Year Introduced -

Vitamin D Vitamin D3

Solaray Solgar

Netherlands

-

Raw Materials 7-Dehydrocholesteryl acetate Acetic acid n-Hexane Manufacturing Process 5 g of 7-dehydrocholesteryl acetate (prepared by W.R. Ness, R. S. Kostic and Mosetting, J. Am. Chem. Soc. 78, 436, 1956) were dissolved in 500 ml of nhexane. This solution was irradiated with ultraviolet ray by recyclicly passing it through a quartz apparatus surrounding 450 w high pressure mercury vapor lamps for 80 minutes. After irradiation and then the distillating off of nhexane the solution was added with 50 ml of ethanol and the ethanolic solution was left to stand overnight at the temperature of -20°C. The formed crystals were filtered off from ethanolic solution and filtrate was heated at the temperature 78°C for 4 hours. After cooling of filtrate, the cooled filtrate was added with 4 ml of ethanolic solution containing 0.7 g of potassium hydroxide to effect a reaction at the temperature of 20°C and under nitrogen for 60 minutes. The reaction product was added with 0.7 ml glacial acetic acid and then ethanol was distilled off under reduced pressure from the reaction product. The obtained residue was extracted with 50 ml of n-hexane and extract was washed with water and n-hexane was distilled off from extract to obtain 2.5 g of yellow oily matter containing vitamin D3. The content of vitamin D3 in yellow oily matter was 40.2% by weight. References Toyoda M. et al.; US Patent No. 3,661,939; May 9, 1972; Assigned to Nisshin Flour Milling Co., Ltd., Tokyo, Japan Hunziker H., Mullner F.X.; Helv. Chim. Acta 41, 70, 1958

CHOLESTYRAMINE Therapeutic Function: Anticholesteremic Chemical Name: Cholestyramine Common Name: Cholestyramine (Resin); Colestyramine; Divistyramine; Filicol; Resin-colestiramina Chemical Abstracts Registry No.: 11041-12-6

Cholestyramine

1007

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

LoCholest

Warner-Chilcott

USA

-

Prevalite

Upsher-Smith Laboratories, Inc.

USA

-

Questran

Bristol-Myers Squibb

USA

-

Manufacturing Process For reducing cholesterol blood levels were used the polymeric compounds which can to bind bile acids such as 1) "Acryloid CQ" and "Acrysol CQ", a linear acrylic type quaternary ammonium salt having a molecular weight of the order of about 2,000,000, made by Rohm and Haas Company, Philadelphia. This polymers, structurally a straight carbon skeleton with ester side chains, the esters being from quaternary ammonium substituted alcohols, are soluble in water, and the water solution has a viscosity of 2500 to 5000 centipoises in 5% aqueous solution at room temperature. Equivalent weight of the polymers based on the ammonium groups, are about 350-360; 2) "Acrysol CA", a soluble tertiary amine salt available from Rohm and Haas Company. Equivalent weight of the polymer is of the order 325; 3) Linear polyethyleneimine with a molecular weight is about 30,000 and equivalent weight of the order of about 43. This polymer is available from the Borden and Yaas Cj, New York; 4) "Separan CR70", made bt the Dow Chemical Co., Midland, Michigan. This material is a copolymer acrylamide and vinyl benzyl trimethylammonium chloride in weight ratio of about 30:70, having equivalent weight of about 302 and a average molecular weight about 100,000; 5) Chlormethylated polystyrene which was modified with by tertiary amines such as trimethylamine and dimethylaminoethanol. The examined polymeric compounds are used as per os. References Wolf F.J. et al., US Patent No. 3,308,020; 07.05.1967; Assigned: Merck and Co., Inc. Todd R.S. et al.; US Patent No. 4,172,120; Oct. 23, 1979; Assigned: Reckitt and Colman Products Limited (London, GB2)

1008

Choline dihydrogen citrate

CHOLINE DIHYDROGEN CITRATE Therapeutic Function: Lipotropic Chemical Name: (2-Hydroxyethyl)trimethylammonium citrate Common Name: Structural Formula:

Chemical Abstracts Registry No.: 77-91-8 Trade Name Chothyn Citrocholine

Manufacturer Flint United

Country US US

Year Introduced 1945 1949

Raw Materials Trimethyl amine Ethylene oxide Citric acid Manufacturing Process 30 lb of trimethylamine were added to 70.4 lb of methyl alcohol to which 9.2 lb of water had previously been added. To the resulting solution in a closed vessel 23 lb of ethylene oxide gas were introduced and the resulting mixture then maintained at a temperature of 16 C to 30 C and agitated for 6 hours. During the reaction the pressure in the reaction vessel varied from about 17.5 psi at the start of the reaction to 0 psi at the end of the reaction. The resulting solution was then added with agitation to a refluxing solution of 40 liters of isopropyl alcohol containing 95 lb of citric acid dissolved therein. This mixture was then cooled to 0°C and held at that temperature overnight. The white crystalline choline dihydrogen citrate which formed was separated from the solvent mixture by filtration and dried in vacuo. 117 lb of anhydrous, crystalline choline dihydrogen citrate having a purity of 99.6% were obtained. This was a yield of 78% based on the amount of trimethylamine employed. References Merck Index 2187 I .N. p. 227

Choline salicylate

1009

REM p. 1026 Klein, H.C., DiSalvo, W.A. and Kapp, R.; US Patent 2,870,198; January 20, 1959; assigned to Nopco Chemical Co.

CHOLINE SALICYLATE Therapeutic Function: Analgesic; Antipyretic Chemical Name: 2-Hydroxy-N,N,N-trimethyl-ethanaminium salt with 2hydroxy benzoic acid Common Name: Choline salicylic acid salt Structural Formula:

Chemical Abstracts Registry No.: 2016-36-6 Trade Name

Manufacturer

Country

Year Introduced

Arthropan

Purdue Frederick

US

1959

Actasal

Purdue Frederick

US

1959

Atilen

Spofa

Czechoslovakia

-

Audax

Napp

UK

-

Audax

Ethimed

S. Africa

-

Audax

Mundipharma

W. Germany

-

Bonjela

Lloyds

UK

-

Mundisal

Mundipharma

Switz.

-

Mundisal

Erco

Denmark

-

Otho

Purdue Frederick

US

-

Sachol

Polfa

Poland

-

Rheumavincin

Owege

W. Germany

-

Salicol

Sais

Italy

-

Satibon

Grelan

Japan

-

Syrap

Carrion

France

-

Teejel

Napp

UK

-

Tegunor

Mundipharma

W. Germany

-

Trilisate

Purdue Frederick

US

-

1010

Choline theophyllinate

Raw Materials Choline chloride Sodium salicylate Manufacturing Process A method of preparation is to react an acid salt of choline (such as choline chloride or choline bromide) with an alkaline salt of salicylic acid (such as sodium salicylate, potassium salicylate, or magnesium salicylate) in an alcoholic media. References Merck Index 2189 Kleeman and Engel p. 205 I.N. p. 228 Broh-Kahn, E.H. and Sasmor, E.J.; US Patent 3,069,321; December 18, 1962; assigned to Laboratories for Pharmaceutical Development, Inc.

CHOLINE THEOPHYLLINATE Therapeutic Function: Smooth muscle relaxant Chemical Name: Theophylline cholinate Common Name: Oxotriphylline; Oxytrimethylline Structural Formula:

Chemical Abstracts Registry No.: 4499-40-5 Trade Name Sabidal S.R. Brondaxin Cholecyl Choledyl Cholegyl

Manufacturer Zyma Ferrosan Substancia Nepera Substantia

Country UK Denmark Spain US Netherlands

Year Introduced 1983 -

Chromonar hydrochloride

1011

Trade Name Chophyllin Euspirax Glomax

Manufacturer Ferraton Ascher Midlands Int. Chem.

Country Denmark W. Germany UK

Year Introduced -

Isoperin Monofillina Novotriphyl Rouphylline Sclerofillina Teocolina Teofilcolina Teovent

Spofa Manetti-Roberts Novopharm Rougier Medici Domus Nessa Salfa Ferrosan

Yugoslavia Italy Canada Canada Italy Spain Italy Denmark

-

Raw Materials Theophylline Choline bicarbonate Manufacturing Process 18 parts by weight of theophylline are added to 37.8 parts by weight of aqueous choline bicarbonate (47% assay) and the mixture stirred and heated at 80°C to 90°C until the evolution of carbon dioxide has ceased and complete solution effected. Water is separated from the reaction mixture by distillation under a vacuum sufficient to keep the still temperature between 50°C and 55 C. After about 95 parts by weight of water have been separated, about 80 parts by weight of isopropyl alcohol are added and the mixture subjected to further distillation under a vacuum sufficient to keep the mixture boiling at about 40°C. The distillation removes some of the water as an azeotrope with the isopropyl alcohol. During the removal of the water-isopropyl alcohol azeotrope a crystalline precipitate forms. The mixture is further cooled slowly to 5°C and the crystalline precipitate filtered off. The choline theophyllinate crystals are then washed with isopropyl alcohol and dried under vacuum at about 70°C. A second crop of the product may be obtained from the mother liquor by further reduction in volume and cooling. A yield of 90.5% of theory of choline theophyllinate is obtained completely free of inorganic salts. References Merck Index 2190 I.N. p. 228 REM p. 872 Ladenburg, K., Duesel, B.F. and Fand, T.I.; US Patent 2,776,287; January 1, 1957; assigned to Nepera Chemical Co., Inc.

CHROMONAR HYDROCHLORIDE Therapeutic Function: Coronary vasodilator

1012

Chromonar hydrochloride

Chemical Name: [[3-[2-(Diethylamino)ethyl]-4-methyl-2-oxo-2H-1benzopyran-7-yl]oxy]acetic acid ethyl ester hydrochloride Common Name: Carbocromene Structural Formula:

Chemical Abstracts Registry No.: 655-35-6; 804-10-4 (Base) Trade Name

Manufacturer

Country

Year Introduced

Intensain

Hoechst

Switz.

1963

Intensain

Cassella

W. Germany

1963

Intensain

Diamant

France

1966

Intensain

Pierrel

Italy

1971

Antiagor

I.S.M.

Italy

-

Beta-Intensain

Cassella

W. Germany

-

Cardiocap

Fidia

Italy

-

Cromene

Scharper

Italy

-

Intensain

Takeda

Japan

-

Intensacrom

Albert Pharma

Spain

-

Sedo-Intensain

Diamant

France

-

Intenkordin

Polfa

Poland

-

Raw Materials Resorcinol 2-(2-Diethylaminoethyl)acetic acid ethyl ester Bromoacetic acid ethyl ester Manufacturing Process 18.7 g of 3β-diethylaminoethyl-4-methyl-7-hydroxy-coumarin chlorhydrate are dissolved in 200 cc methyl ethyl ketone and 18 g anhydrous potassium carbonate are added. The mixture is stirred for 1 hour at 70°C and then 12 g bromoacetic acid ethyl ester are allowed to drop in. The reaction mixture is stirred under reflux for 9 hours and then it is filtered off with suction in the heat. The filtrate is concentrated in the vacuum to dryness and the resultant

Chymopapain

1013

residue is dissolved in ether. The etheric solution is washed with diluted caustic soda solution for several times and, subsequently, dried with Glauber's salt. By introduction of hydrochloric acid gas into the etheric solution the reaction product is precipitated in the form of chlorhydrate. Yield: 15 g of 3βdiethylaminoethyl-4-methylcoumarin-7-ethyl oxyacetate chlorhydrate having a melting point of 154° to 156°C (= 63% of the theory). The starting material is produced by reacting resorcinol with 2-(2diethylaminoethyl)acetic acid ethyl ester. References Merck Index 2217 Kleeman and Engel p. 150 OCDS Vol. 1 p. 331 (1977) I.N. p. 185 Ritter, H., Hanau, K., Beyerle, R. and Nitz, R.-E.; US Patent 3,282,938; November 1, 1966; assigned to Cassella Fabrwerke Mainkur AG, Germany

CHYMOPAPAIN Therapeutic Function: Proteolytic enzyme Chemical Name: See structure Common Name: Structural Formula: Chymopapain is a sulfhydryl enzyme similar to papain. Has components of molecular weight about 35,000 Chemical Abstracts Registry No.: 9001-09-06 Trade Name

Manufacturer

Country

Year Introduced

Chymodiactin

Smith

US

1982

Chemolase

Ortho-Tex

US

-

Discase

Travenol

US

-

Raw Materials Papaya latex Hydrochloric acid Manufacturing Process The undried latex of papaya is mixed with about three times its weight of hundredth normal hydrochloric acid. To this mixture is then added dilute hydrochloric acid (about normal) until a pH of substantially 2 has been

1014

Ciclonicate

attained. The acidified latex is next allowed to stand over night or longer in a cold place (0°C to 10°C). The material still in solution is then separated out, by any convenient means, such as filtration through paper. From the soluble portion, a small amount of inert protein is precipitated, by half saturation with sodium chloride at about 10°C. The desired enzyme is next precipitated as a nearly pure protein by raising the concentration of salt to full saturation, while the pH is kept at a level of substantially 2, by the addition of normal alkali, if necessary. The precipitate of protein is removed by any suitable means, and may be kept as a thick paste out of contact with the air, and in the cold, The keeping properties at higher temperatures are enhanced by addition of enough alkali to the protein to bring its pH to 4.5-6.0. This protein may be further purified, if desired, and eventually may be crystallized, by redissolving the paste in saturated sodium chloride solution by adjusting the pH to 4.5-6.0, and reprecipitating the enzyme protein by the gradual addition of acid in the cold, until a pH of approximately 2.0 is obtained; or, the purification may be accomplished by dissolving the protein in acid at a pH of 2, and then precipitating the enzyme, by increasing the concentration of salt. When the activity and other properties of the several times recrystallized new enzyme protein are compared with those of the uncrystallized precipitate obtained in the first stages of the process, it is found that even in the first stages, the enzyme is present in sufficiently pure form for most purposes. References Merck Index 2244 PDR p. 1732 DOT 19 (7) 413 (1983) and (8) 454 (1983) I.N. p. 229 REM p. 1036 Jansen, E.F. and Balls, A.K.; US Patent 2,313,875; March 16, 1943; assigned to Government of the USA. Stern, I.J.; US Patent 3,558,433; January 26, 1971; assigned to Baxter Laboratories, Inc.

CICLONICATE Therapeutic Function: Vasodilator Chemical Name: 3-Pyridinecarboxylic acid 3,3,5-trimethylcyclohexyl ester Common Name: Cyclonicate Chemical Abstracts Registry No.: 53449-58-4

Ciclopirox

1015

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Bled

Poli

Italy

1978

Bled

Poli

Switz.

1981

Cortofludan

Knoll

W. Germany

-

Elastan 200

Byk Liprandi

Argentina

-

Raw Materials trans-3,3,5-Trimethylcyclohexanol Niacin chloride hydrochloride Sodium hydroxide Manufacturing Process To a solution of 142 g (1 mol) of trans-3,3,5-trimethylcyclohexanol in 400 cc of anhydrous benzene heated to 70 C is added gradually 178 g (1 mol) of niacin chloride hydrochloride. Heating is carried out under reflux conditions for 3 hours, the solution is cooled, the ester hydrochloride is filtered off and then recrystallized in an ethanol-ethyl ether mixture to obtain 227 g (80% yield) of product melting at 155°C to 157°C. By treating the hydrochloride with an aqueous solution of NaOH at 0°C, the free base is obtained in the form of a viscous white liquid which boils at 115°C under 0.05 mm. References Merck Index 2249 DOT 19 (1) 12 (1983) I.N. p.231 British Patent 1,409,990; October 15, 1975; assigned to Poli Industria Chimica S.p.A. (Italy)

CICLOPIROX Therapeutic Function: Antifungal

1016

Ciclopirox

Chemical Name: 2(1H)-Pyridinone, 6-cyclohexyl-1-hydroxy-4-methylCommon Name: Cicloprox Structural Formula:

Chemical Abstracts Registry No.: 29342-05-0 Trade Name

Manufacturer

Country

Year Introduced

Fungirox Esmalte

UCI-Farma

-

-

Loprox Laca

Aventis Pharma, S. A. de C. V.

-

Mycoster 8%

Sinbio

-

-

Mycoster 8%

Pierre Fabre

-

-

Nagel Batrafen

Aventis Pharma D

-

-

-

-

Penlac Nail Laquer Dermik Laboratories Inc. Raw Materials

Hexahydrobenzoyl chloride β,β-Dimethylacrylic acid methyl ester Hydroxylamine hydrochloride Sodium hydroxide Manufacturing Process A mixture of 5-oxo-3-methyl-5-cyclohexylpentene-2 acid 1-methyl ester and 5-oxo-3-methyl-5-cyclohexylpentene-3 acid 1-methyl ester was obtained by condensation of hexahydrobenzoyl chloride with β,β-dimethylacrylic acid methyl ester. 11.2 g of this mixture and a solution of 4.6 g of sodium acetate and 4 g of hydroxylamine hydrochloride were shaken for 20 hours at 25°C with a mixture of 8 ml of water and 15 ml methanol. Subsequently, a solution of 4 g of sodium hydroxide in 8 ml of water was then added, while cooling, shaken for 1 hour at room temperature. The mixture was extracted by means of benzene and the aqueous phase was acidified to reach a pH of 6. 3.5 g of 1-hydroxy-4-methyl-6-cyclohexyl-2-pyridone were obtained; melting point 144°C. For preparation of cyclopirox from 1-hydroxy-4-methyl-6-cyclohexyl-2pyridone was added 2-aminoethanol (1:1).

Ciclopiroxolamine

1017

References Merck Index, Monograph number: 2325, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. Greene L.A.; US Patent No. 5,846,984; Dec. 8, 1998; Assigned to The Trustees of Columbia University in the City of New York (New York, NY) Lohaus G. et al.; US Patent No. 3,883,545; May 13, 1975; Assigned to Hoechst Aktiengesellschaft, Frankfurt am Main, Germany

CICLOPIROXOLAMINE Therapeutic Function: Antifungal Chemical Name: 6-Cyclohexyl-1-hydroxy-4-methyl-2(1H )-pyridone ethanolamine salt Common Name: Structural Formula:

Chemical Abstracts Registry No.: 41621-49-2 Trade Name

Manufacturer

Country

Year Introduced

Batrafen

Cassella-Riedel

W. Germany

1980

Batrafen

Hoechst

Japan

1981

Loprox

Hoechst

Canada

1983

Loprox

Hoechst

US

1983

Raw Materials 4-Methyl-6-cyclohexyl-2-pyrone Hydroxylamine hydrochloride Ethanolamine Manufacturing Process Ciclopirox may be produced as follows: 2 g of 4-methyl-6-cyclohexyl-2-pyrone were heated with 1 g of hydroxylamine hydrochloride and 5 g of 2-

1018

Cicloxilic acid

aminopyridine to 80 C for 8 hours. The reaction mixture was then dissolved in methylene chloride, the amine was removed by shaking with dilute hydrochloric acid, the reaction product was extracted from the organic phase by means of dilute sodium hydroxide solution and the alkaline solution was acidified with acetic acid to a pH value of 6. The 1-hydroxy-4-cnethyl-6-cyclohexyl-2-pyridone precipitated in crystalline form. It was filtered off with suction, washed with water and dried. The yield was 1.05 g (49% of theory); melting point 143 C. Reaction of ciclopirox with ethanolamine gives the desired product. References Merck Index 2250 DFU 4 (11) 795 (1979) Kleeman and Engel p. 206 PDR p. 940 OCDS Vol. 2 p. 282 (1980) DOT 17 (9) 364 (1981) I.N. p. 231 REM p. 1230 Lohaus, G. and Dittmar, W.; US Patents 3,972,888; August 3, 1976; and 3,883,545; May 13, 1975; both assigned to Hoechst A.G.

CICLOXILIC ACID Therapeutic Function: Choleretic Chemical Name: cis-2-Hydroxy-2-phenylcyclohexanecarboxylic acid Common Name: Structural Formula:

Chemical Abstracts Registry No.: 57808-63-6

Cicloxilic acid

1019

Trade Name

Manufacturer

Country

Year Introduced

Plecton

Guidotti

Italy

1975

Sintiabil

Sintyal

Argentina

-

Raw Materials 2-Hydroxymethyl cyclohexanone Bromobenzene Potassium permanganate Magnesium Manufacturing Process 25 g of 2-hydroxy-methyl-cyclohexanone, diluted in 20 cc of ether, were dropped into a vessel containing an ether suspension of phenyl-magnesiumbromide (prepared from 19.6 g of magnesium and 128 g of bromobenzene in 300 cc of ether according to usual techniques by stirring and external icecooling). The mixture was stirred for some time, then the magnesium compound was decomposed by pouring it carefully into water and ice; the magnesium hydroxide was dissolved in 50 cc of a saturated solution of ammonium chloride, the ether portion was separated and the aqueous portion extracted with further ether. Collected and dried ether extracts were evaporated and the residue vacuum distilled yielded 15 g of a thick oil of boiling point at 0.1 to 0.2 mm Hg 127°C to 135°C. This product crystallized by dissolving in ether and reprecipitation with petroleum ether yielded 7 g of 1-phenyl-2-hydroxy-ethylene-cyclohexan-1-ol, melting point (Kofler) 81°C to 83°C. The thus obtained product was dried and finely powdered, and then suspended in 1.4 liters of an aqueous solution of 14 g of KMnO4 and 7 g of N2CO3, and the suspension was thoroughly stirred for one day. After filtering off the MnO2, thus formed, a small amount of Na2SO3 was added until the violet coloration disappeared; MnO2 was filtered again and the alkaline solution was acidified with concentrated HCl. After one day standing in a refrigerator, the product was filtered and washed with water, thus yielding 5 g of 2-phenyl-2-hydroxy-cyclohexane-carboxylic acid, melting point (Kofler) 143°C to 145°C. References Kleeman and Engel p. 207 DOT 15 (4) 185 (1979) I.N. p. 18 Turbanti, L.; US Patent 3,700,775; October 24, 1972

1020

Cidofovir

CIDOFOVIR Therapeutic Function: Antiviral Chemical Name: Phosphonic acid, ((2-(4-amino-2-oxo-1(2H)-pyrimidinyl)-1(hydroxymethyl)ethoxy)methyl)-, (1S)Common Name: Cidofovir Structural Formula:

Chemical Abstracts Registry No.: 113852-37-2 Trade Name

Manufacturer

Country

Year Introduced

Cidofovir

Pharmacia and Upjohn

-

-

Forvade

Gilead Sciences Inc.

-

-

Vistide

Pharmacia and Upjohn

-

-

Vistide

Gilead Sciences Inc.

-

-

Raw Materials N-Benzoyl uracil 2-Trityloxy-oxirane Toluene-(4-sulfomethyl)phosphonic acid diethyl ester Hydrogen chloride Trimethylsilyl bromide Ammonium hydroxide Manufacturing Process By the alkylation of N-benzoyl uracil with the chiral 2-trityloxy-oxirane was obtained glycoside-like derivative N-[1-(2-hydroxy-3-trityloxy-propyl)-2-oxo1,2-dihydroxypyrimidin-4-yl]-N-methylbenzamide as a single isomer. From N[1-(2-hydroxy-3-trityloxy-propyl)-2-oxo-1,2-dihydroxypyrimidin-4-yl]-Nmethylbenzamide and toluene-(4-sulfomethyl)phosphonic acid diethyl ester was prepared [2-[(benzoylmethylamino)-2-oxo-2H-pyrimidin-1-yl]-1trityloxymethylethoxymethyl]phosphonic acid diethyl ester. As a result of

Cimetidine

1021

treatment of the product with hydrogen chloride was synthesized [2[(benzoylmethylamino)-2-oxo-2H-pyrimidin-1-yl]-1-hydroxymethylethoxymethyl]phosphonic acid diethyl ester. Sequential reaction with trimethylsilyl bromide and ammonium hydroxide cleaves the phosphite ethyl groups and saponifies the benzamide function to afford (1S)-1-(3-hydroxy-2phosphonylmethoxypropyl)cytosine (Cidofovir). References Brodfuehrer H. et al., Tetrahedron Lett., 1994, 35, 3243

CIMETIDINE Therapeutic Function: Antiulcer Chemical Name: N-Cyano-N'-methyl, N''-[2-[[(5-methyl-1H-imidazol-4yl)methyl]thio]ethyl]guanidine Common Name: Structural Formula:

Chemical Abstracts Registry No.: 51481-61-9 Trade Name

Manufacturer

Country

Year Introduced

Tagamet

SKF

UK

1977

Tagamet

SKF

US

1977

Tagamet

SKF

France

1977

Tagamet

SKF

W. Germany

1977

Tagamet

SKF

Switz.

1977

Euroceptor

Zambon

Italy

1978

Tagamet

Fujisawa

Japan

1982

Cimetag

Cehasol

Austria

1983

Acibilin

Exa

Argentina

-

Aciloc

Orion

Finland

-

Altramet

Lek

Yugoslavia

-

Belomet

Belupo Ltd.

Yugoslavia

-

Biomag

Pulitzer

Italy

-

1022

Cimetidine

Trade Name

Manufacturer

Country

Year Introduced

Brumetidina

Bruschettini

Italy

-

Cimetum

Sintyal

Argentina

-

Cinamet

Isis

Yugoslavia

-

Cinulcus

Wassermann

Spain

-

Citius

Prodes

Spain

-

Civent

Medica

Finland

-

Fremet

Antibioticos

Spain

-

Gastromet

Sigurta

Italy

-

Itacem

Italchemie

Italy

-

Mansal

Vita

Spain

-

Peptol

Horner

Canada

-

Stomakon

Andromaco

Brazil

-

Tametin

Giuliani

Italy

-

Tratul

Ricar

Argentina

-

Ulcedin

Agips

Italy

-

Ulcedine

I.C.N.-Usafarma

Brazil

-

Ulcerfen

Finadiet

Argentina

-

Ulcestop

Gibipharma

Italy

-

Ulcimet

Farmasa

Brazil

-

Ulcodina

Locatelli

Italy

-

Ulcomet

Italfarmaco

Italy

-

Ulhys

Farnex

Italy

-

Raw Materials 2-Chloroacetic acid ethyl ester Cysteamine Dimethyl sulfate Ammonia sodium Methylamine

Potassium hydroxide Carbon disulfide Formamide Cyanamide

Manufacturing Process In an initial step, 2-chloroacetic acid ethyl ester is reacted with formamide to give 5-methylimidazole-4-carboxylic acid ethyl ester. Then sodium in ammonia is used to convert that to 4-hydroxymethyl-5-methylimidazole-hydrochloride. Cysteamine HCl (HSCH2CH2NH2·HCl) is then reacted to give 4-(2aminomethyl)-thiomethyl-5-methyl-imidazole dihydrochloride. Then Ncyanamido-5,5-dimethyl-dithio-carbonate (from cyanamid, KOH, CS2 and ((CH3)2SO4) is reacted to give a further intermediate which is finally reacted with methylamine to give cimetidine. The preparation of the pyridyl analogs of the imidazolyl compounds of the type of cimetidine are discussed in the patent cited below. Further references are given by Kleeman and Engel in the reference below.

Cinchocaine hydrochloride

1023

References Merck Index 2254 DFU 1 (1) 13 (1976) Kleeman and Engel p. 208 PDR p. 1725 OCDS Vol. 2 p. 353 (1980) DOT 13 (5) 187 (1977) and 16 (11) 393 (1980) I .N p. 232 REM p.797 Durant, G.J., Emmett, J.C. and Ganellin, C.R.; US Patent 3,876,647; April 8, 1975; assigned to Smith Kline and French Laboratories Limited

CINCHOCAINE HYDROCHLORIDE Therapeutic Function: Local anesthetic Chemical Name: 4-Quinolinecarboxamide, 2-butoxy-N-(2(diethylamino)ethyl)-, hydrochloride Common Name: Cincaini chloridum; Cinchocaine hydrochloride; Cinchocainium chloride; Cinkain; Sovcain(um); Zinchokainhydrochloride Structural Formula:

Chemical Abstracts Registry No.: 85-79-0 Trade Name Cincain Dibucaine hydrochloride

Manufacturer Ophtha Nacalai Tesque

Country -

Year Introduced -

Dibucaine hydrochloride

Sigma-Aldrich

-

-

DoloPosterine N

Dr. Kade Pharmazeutische Fabrik

-

-

Raw Materials α-Chloro-γ-quinoline-carboxylic acid chloride

1024

Cinepazet maleate

Diethylethylenediamine Sodium Butanol Manufacturing Process A benzene solution of 2.2 parts of α-chloro-γ-quinoline-carboxylic acid chloride is gradually mixed, while cooling, with 2.3 parts of unsymmetrical diethylethylenediamine. When the reaction is at an end the solution is washed with water and the new base extracted by means of hydrochloric acid. The base is precipitated by means of sodium carbonate and extracted with benzene. The solvent is distilled and the base recrystallized from petroleum ether. The α-chloro-γ-quinoline-carboxylic acid diethyl-amino-ethylene amide forms colorless lamina crystals of melting point 74°C. With acids the base forms neutral salts soluble in water. A solution of 2.5 parts of sodium in n-butylalcohol is boiled with 30 parts of αchloro-γ-quinoline-carboxylic acid diethyl-amino-ethylene-amide in a reflux apparatus, and when the reaction is over the excess of butylalcohol is distilled. The remaining base is taken up with ether; the solution is washed with water and dried. The solvent is then distilled. The α-n-butoxy-γ-quinolinecarboxylic acid diethyl-amino-ethylene-amide forms as colorless crystals, after recrystallization from petroleum ether melting point of it 64°C. In practice it is usually used as hydrochloride. References Miescher K.; US Patent No. 1,825,623; Sep. 29, 1931; Assigned: Ferm society of chemical industry in Basle, of Basel, Switzerland

CINEPAZET MALEATE Therapeutic Function: Antianginal Chemical Name: 4-[1-Oxo-3-(3,4,5-trimethoxyphenyl)-2-propenyl)-1piperazineacetic acid ethyl ester (Z)-2-butenedioate (1:1) Common Name: Ethyl cinepazate maleate Chemical Abstracts Registry No.: 50679-07-7; 23887-41-4 (Base) Trade Name

Manufacturer

Country

Year Introduced

Vascoril

Delalande

France

1971

Vascoril

Delalande

Italy

1974

Raw Materials 1-Piperazine ethyl acetate

Cinmetacin

1025

Sodium bicarbonate 3,4,5-Trimethoxy cinnamoyl chloride Maleic acid Structural Formula:

Manufacturing Process A solution of 1-piperazino ethyl acetate (0.2 mol) in benzene (300 ml) is treated with 3,4,5-trimethoxy cinnamoyl chloride (0.2 mol) in the presence of sodium bicarbonate (0.3 mol). After contacting for one hour at room temperature, the mixture is refluxed for a further hour. The benzene solution is then treated with an aqueous solution of sodium bicarbonate. After evaporation of the solvent, a solid product is obtained which is recrystallized from isopropyl ether. Melting point = 96°C. This base, when treated with hydrochloric acid, gives a hydrochloride having a melting point of 200°C with decomposition. By the action of maleic acid the acid maleate is obtained, having a melting point of 130°C. References Merck Index 2266 Kleeman and Engel p. 210 OCDS Vol. 3 p. 157 (1984) DOT 10 (12) 336 (1974) I.N. p. 233 Fauran, C., Huguet, G., Raynaud,G., Pourrias, B. and Turin, M.; US Patent 3,590,034; June 29, 1971; assigned to Delalande S.A. (France)

CINMETACIN Therapeutic Function: Antiinflammatory Chemical Name: 1H-Indole-3-acetic acid, 5-methoxy-2-methyl-1-(1-oxo-3phenyl-2-propenyl)-

1026

Cinmetacin

Common Name: Cinmetacin; Tsinmetatsin Structural Formula:

Chemical Abstracts Registry No.: 20168-99-4 Trade Name

Manufacturer

Country

Year Introduced

Cindomet

Chiesi

-

-

Indolacin

Sumitomo

-

-

Indolacin

Jian An Pharmaceutical Ltd.

-

-

Indolacin

Yinduolaxin Changrong Jiaonang

-

-

Cinmetacin

Yick-Vic Chemicals and Pharmaceuticals (HK) Ltd.

-

-

Cinmetacin

North China Pharmaceutical Group Corp. (NCPC)

-

-

Raw Materials Cinnamoyl chloride Triethylamine Acetonylmalonic acid

p-Methoxyphenylhydrazine hydrochloride Hydrogen chloride

Manufacturing Process 6.0 g of cinnamoyl chloride was dropwise added to a mixture of 8.7 g of pmethoxyphenylhydrazine hydrochloride, 10.1 g of triethylamine and 200 ml of toluene under cooling at -5° to 0°C. The reaction mixture was stirred at 20°25°C for 1 h. The separated precipitates were filtered off and dry gaseous hydrogen chloride was introduced into the filtrate. As a result a large amount of crystals of N1-cinnamoyl-N1-(p-methoxyphenyl)hydrazine hydrochloride were produced. These crystals were collected by filtration and washed with 20 ml of ether and dried to yield N1-cinnamoyl-N1-(p-methoxyphenyl)hydrazine hydrochloride of melting point 183°-185°C. A mixture of N1-cinnamoyl-N1-(p-methoxyphenyl)hydrazine hydrochloride and

Cinnamedrine hydrochloride

1027

acetonylmalonic acid was heated in acetic acid at heating with stirring. Thereafter, the reaction mixture was allowed to cool, and was poured into cold water, and then crystals were produced. They were collected by filtration, and dried to give crude product. The recrystallization from acetone-water gave fine white needle crystals of 1-cinnamoyl-2-methyl-5-methoxy-3-indolylacetic acid, melting point 164°-165°C. References Yamamoto H. et al.; US Patent No. 3,576,800; April 27, 1971; Assigned: Sumitomo Chemical Company, Ltd., Osaka, Japan

CINNAMEDRINE HYDROCHLORIDE Therapeutic Function: Smooth muscle relaxant Chemical Name: Benzenemethanol, α-(1-(methyl(3-phenyl-2-propenyl) amino)ethyl)-, hydrochloride Common Name: Cinnamedrine hydrochloride; Cinnamylephedrine hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 90-86-8 (Base) Trade Name

Manufacturer

Country

Year Introduced

Midol Tab

Sterling Winthrop

-

-

Midol - Caplet

Bayer Inc., Consumer Care Division

-

-

Raw Materials 1-Phenyl-2-methylaminopropanol-1 Hydrochloric acid

Cinnamylbromide Ammonia

Manufacturing Process 8.0 g of 1-phenyl-2-methylaminopropanol-1 are dissolved in 30 ml of warm benzene and the solution is mixed with 5.0 g of cinnamylbromide. It is

1028

Cinnarizine

allowed to stand for 2 h at room temperature; the whole is then filtered with suction to eliminate the phenylmethylaminopropanol hydrobromide formed and the filtrate is shaken out with dilute hydrochloric acid, while adding such a quantity of water that the thick oil drops which separate are dissolved. The aqueous extract is filtered until it is clear, rendered alkaline by means of ammonia, shaken with ether, the ether is distilled off, the residue is recrystalized, so 1-phenyl-2-methyl-cinnamylaminopropanol-1 was obtained. In practice it is usually used as hydrochloride. References Stolz F., Flaecher F.; US Patent No. 1,959,392; May 22, 1934; Assigned: Winthrop Chemica Company, Inc., New York, N.Y., a corporation of New York

CINNARIZINE Therapeutic Function: Antihistaminic Chemical Name: 1-(Diphenylmethyl)-4-(3-phenyl-2-propenyl)piperazine Common Name: Structural Formula:

Chemical Abstracts Registry No.: 298-57-7 Trade Name

Manufacturer

Country

Year Introduced

Stugeron

Janssen

UK

1961

Stutgeron

Janssen

W. Germany

1961

Midronal

Delalande

France

1962

Sturgeron

Janssen

Italy

1970

Aplactan

Janssen

Belgium

1970

Stugeron

Cilag Chemie

Switz.

1980

Amynoral

Delalande

France

-

Cinnarizine

1029

Trade Name

Manufacturer

Country

Year Introduced

Annarizine

Sioe

Japan

-

Antigeron

Farmasa

Brazil

-

Aplactan

Eisai

Japan

-

Aplexal

Taiyo

Japan

-

Apomiterl

Teizo

Japan

-

Apotomin

Kowa

Japan

-

Apsatan

Wakamoto

Japan

-

Artate

Nippon Chemiphar Japan

-

Carecin

Zensei

Japan

-

Cerebolan

Tobishi

Japan

-

Cerepar

Merckle

W. Germany

-

Cero-Aterin

Chassot

Switz.

-

Cinaperazine

Kinki

Japan

-

Cinazin

Siegfried

Switz.

-

Cinazyn

Italchimici

Italy

-

Cinnabene

Merckle

W. Germany

-

Cinnacet

Schwarzhaupt

W. Germany

-

Cinnageron

Streuli

Switz.

-

Cinnarizine

Green Cross

Japan

-

Cinnipirine

A.C.F.

Netherlands

-

Coldrin

JandJ

US

-

Corathiem

Ohta

Japan

-

Cysten

Tsuruhara

Japan

-

Denapol

Teikoku

Japan

-

Dismaren

Gerardo Ramon

Argentina

-

Ederal

Esteve

Spain

-

Eglen

Tatsumi

Japan

-

Folcodal

Syncro

Argentina

-

Giganten

Tropon

W. Germany

-

Glanil

Leo

Sweden

-

Hilactan

Kyoritsu

Japan

-

Hirdsyn

Fuso

Japan

-

Izaberizin

Tohu

Japan

-

Katoseran

Hishiyama

Japan

-

Midronal

Delalande

France

-

Milactan

Miwa

Japan

-

Myodel

Delalande

France

-

Olamin

Siegfried

Switz.

-

Pericephal

Hofmann

Austria

-

Plegitux

Carrion

France

-

1030

Cinnarizine

Trade Name

Manufacturer

Country

Year Introduced

Processine

Sankyo

Japan

-

Purazine

Lennon

S. Africa

-

Razlin

S.S. Pharm

Japan

-

Ribrain

Endopharm

W. Germany

-

Roin

Maruishi

Japan

-

Salarizine

Iwaki

Japan

-

Sapratol

Takeda

Japan

-

Sedatromin

Takata

Japan

-

Sefal

Nobel

Turkey

-

Sigmal

Fuji Zoki

Japan

-

Siptazin

Isei

Japan

-

Spaderizine

Kotobuki

Japan

-

Stunarone

Abic

Israel

-

Toliman

Corvi

Italy

-

Tolesmin

Sato

Japan

-

Torizin

Towa

Japan

-

Raw Materials Cinnamoyl chloride Benzhydryl piperazine Lithium aluminum hydride Manufacturing Process This compound can be prepared by the reaction of cinnamoyl chloride with benzhydryl piperazine. The reaction is carried out in dry benzene under reflux. The benzene is then evaporated, the residue taken up in chloroform, washed with dilute HCl and then made alkaline. The chloroform layer is washed with a dilute aqueous sodium hydroxide solution, thereafter with water, and is finally dried over potassium carbonate. The residue, which is obtained after evaporation of the chloroform, is dissolved by heating in a mixture of 25% of toluene and 75% of heptane. On cooling this solution to about 20°C the product precipitates. That compound is reduced with LiAlH4, to give cinnarizine. References Merck Index 2281 DFU 3 (8) 572 (1978) Kleeman and Engel p. 272 OCDS Vol. 1 p. 58 (1977) DOT 16 (10) 360 (1974) and 18 (1) 27 (1982) I.N. p. 234 Janssen, P.A.J.; US Patent 2,882,271; April 14, 1959; assigned to Laboratoria Pharmaceutica Dr. C. Janssen, Belgium

Cinoxacin

1031

CINOXACIN Therapeutic Function: Antibacterial Chemical Name: 1-Ethyl-6,7-methylenedioxy-4(1H)-oxocinnoline-3carboxylic acid Common Name: Structural Formula:

Chemical Abstracts Registry No.: 28657-80-9 Trade Name Cinobac Cinobac Cinobactin Cinobac Cinobact Cinobactin

Manufacturer Lilly Lilly Lilly Lilly Shionogi Lilly

Country UK Switz. W. Germany US Japan Sweden

Year Introduced 1979 1979 1980 1981 1983 1983

Raw Materials 1-Ethyl-6,7-methylenedioxy-4(1H)-oxocinnoline-3-carbonitrile Hydrogen chloride Manufacturing Process About 23 g (0.095 mol) of 1-ethyl-6,7-methylenedioxy-4(1H)-oxocinnoline-3carbonitrile were added to a mixture of 200 ml of concentrated hydrochloric acid and 200 ml of acetic acid. The resultant reaction mixture was heated under reflux for 18 hours, The excess acids were removed under vacuum, and the residue was taken up in 150 ml of a 5% sodium bicarbonate solution. The resultant solution was treated with 5 g of charcoal and filtered. The filtrate was made acidic by the addition of hydrochloric acid and the resulting precipitate was removed by filtration. 23 g, representing a yield of 91.6% of 1-ethyl-6,7-methylenedioxy-4(1H)-oxocinnoline-3-carboxylic acid as light tan crystals which melted at 261°C to 262°C with decomposition were recovered. References Merck Index 2284 DFU 3 (1) 22 (1978)

1032

Cinromide

Kleeman and Engel p. 213 PDR p. 836 OCDS Vol. 2 p. 388 (1980) DOT 11 (10) 402 (1975) and 16 (2) 45 (1980) I.N. p. 235 REM p. 1216 White, W.A.; US Patent 3,669,965; June 13, 1972; assigned to Eli Lilly and Company

CINROMIDE Therapeutic Function: Anticonvulsant, Antiepileptic Chemical Name: (E)-3-(3-Bromophenyl)-N-ethyl-2-propenamide Common Name: Cinromide; Vumide Structural Formula:

Chemical Abstracts Registry No.: 58473-74-8 Trade Name

Manufacturer

Country

Year Introduced

Cinromide

ZYF Pharm Chemical

-

-

Raw Materials trans-3-Bromocinnamoyl chloride Sulfuric acid Sodium methylate

Ethylamine Sodium hydroxide Molecular sieves

Manufacturing Process 3-Bromo-N-ethylcinnamamide: I). A solution of trans-3-bromocinnamoyl chloride (12.3 g) in anhydrous toluene (150 ml) was added slowly with stirring to a solution of ethylamine (10 g) in dry ether (100 ml) at room temperature. The reaction mixture was heated at reflux for 1 hour, and the solvent and excess amine were then removed under reduced pressure. The residue was triturated with water, filtered, and recrystallized from ethanol-water to give trans-3-bromo-Nethylcinnamamide, m.p. 89-90°C, as a white crystalline material. NMR and IR spectra as well as elemental analysis were consistent with the assigned

Cioteronel

1033

structure. II). trans-m-Bromocinnamic acid (14.8 g), ethanol (173 ml) and concentrated sulfuric acid (0.4 ml) were combined and heated at reflux for 15 hours. About 150 ml of the ethanol was distilled off, and the remaining solution was poured into ice/water (140 ml). The cold mixture was made strongly alkaline with 40% sodium hydroxide and extracted with methylene chloride (4x60 ml). The combined methylene chloride extract was dried over anhydrous potassium carbonate. The potassium carbonate was removed by filtration and the solvent stripped off under reduced pressure. trans-ethyl-3-Bromocinnamate, was obtained as a partially solidified oil. (IR spectrum was consistent with this compound). trans-Ethyl-3-bromocinnamate (8.4 g), ethylamine (6.7 g), methanol (18 ml) and 4A molecular sieves (1 g) were combined and heated at reflux for ½ hour. The mixture was cooled to about 45°C and sodium methylate (0.6 g) added. The mixture was then heated at reflux 1½ hour and then cooled. It was acidified with concentrated hydrochloric acid (12 ml). The sieves were removed by filtration. Ice water was added to the filtrate to precipitate trans 3-bromo-N-ethylcinnamamide, m.p. 89-90°C (after recrystallization from ethanol/water). References Grivsky Eugene M.; US Patent No. 4,041,071; August 9, 1977; Assignee to Burroughs Wellcome Co. (Research Triangle Park, NC)

CIOTERONEL Therapeutic Function: Antiandrogen Chemical Name: Hexahydro-4-(5-methoxyheptyl)-2(1H)-pentalenone Common Name: Cioteronel; Cyoctol Structural Formula:

Chemical Abstracts Registry No.: 89672-11-7 Trade Name Cyoctol Ethocyn

Manufacturer Squibb Chantal Pharmaceutical Corporation

Country -

Year Introduced -

1034

Cioteronel

Raw Materials Magnesium 3-Chlorocyclopentene Triethylamine Potassium hydroxide Acetic acid

1-Chloro-5-methoxyheptane Dichloroacetyl chloride Diazomethane N-Methyl-N-nitroso-p-toluene sulfonamide Zinc

Manufacturing Process 3-(5-Methoxyhept-1-yl)cyclopentene: A three-neck, round-bottomed flask containing magnesium metal turnings (7.2 g, 0.299 moles), is equipped with a Friedrich condenser and kept under a nitrogen atmosphere. Tetrahydrofuran (300 ml) is added and the contents are allowed to stir. A solution of 1-chloro-5-methoxyheptane (48.1 g, 0.292 moles) is added in small portions and refluxed. The mixture is allowed to stir for 3 hours. The resultant dark yellow solution is cooled to -25°C, and the condenser is removed and replaced with a dry ice addition funnel. A solution of 3-chlorocyclopentene (29.9 g, 0.292 moles) is added over a period of one hour. The viscous solution is poured into two liters of saturated ammonium chloride, extracted with ether, and dried over anhydrous sodium sulfate. Distillation yields 3-(5-methoxyhept-1-yl)cyclopentene (51.5 g, 0.262 moles) as clear, colorless oil boiling at about 90°C/0.3 mm and 54°C/0.1 mm. 6,6-Dichloro-2-(5-methoxyhept-1-yl)bicyclo[3.2.0]heptan-7-one: A 1,000 ml three-neck, round-bottomed flask, containing 3-(5-methoxyhept1-yl)cyclopentene (15.0 g, 0.076 moles) in 300 ml of hexane, is equipped with a reflux condenser. Freshly distilled dichloroacetyl chloride (35.1 g, 0.240 moles) is added and the solution stirred and heated to reflux. Triethylamine (25.2 g, 0.249 moles) in 200 ml hexane, is added dropwise to the refluxing solution and the solution allowed to stir for 4 hours. The solvent is removed and the residue distilled and chromatographically purified with silica gel, leaving the 6,6-dichloro-2-(5-methoxyhept-1-yl)bicyclo[3.2.0]heptan-7-one (17 g). 6,6-Dichloro-2-(5-methoxyhept-1-yl)bicyclo[3.3.0]octan-7-one: 6,6-Dichloro-2-(5-methoxyhept-1-yl)bicyclo[3.2.0]heptan-7-one (5 g), is dissolved in 100 ml of ether and transferred to a 500 ml, round-bottomed flask. An excess of diazomethane is generated in situ by reacting N-methyl-Nnitroso-p-toluene sulfonamide (60 g) with potassium hydroxide in ethanol. The diazomethane is allowed to react for 50 min, after which time acetic acid is added to destroy any remaining diazomethane. The solution is extracted with ether and dried over anhydrous sodium sulfate and yields the crude 6,6dichloro-2-(5-methoxyhept-1-yl)bicyclo[3.3.0]octan-7-one as an orange oil. 2-(5-Methoxyhept-1-yl)bicyclo[3.3.0]octan-7-one: 6,6-Dichloro-2-(5-methoxyhept-1-yl)bicyclo[3.3.0]octan-7-one (45.9 g) is added to a 100 ml, round-bottomed flask fitted with a condenser. Powdered zinc metal (92 g) and glacial acetic acid (312 ml) are added to the flask and

Ciprofibrate

1035

the solution allowed to reflux for an hour. The solution is filtered to remove the zinc and zinc chloride, formed in the reaction. The product is washed with an aqueous sodium bicarbonate solution and extracted three times with ether. The ether extracts are combined and dried over anhydrous sodium sulfate. The resulting yellow oil is chromatographed on silica gel and eluted with 4:1 hexane:ether. The fractions are combined, and gave 2-(5-methoxyhept-1yl)bicyclo[3.3.0]octan-7-one as a clear, colorless oil. References Kasha Walter J., Burnison; Chantal S.; US Patent No. 4,689,345; August 25, 1987; Assigned to CBD Corporation (Los Angeles, CA)

CIPROFIBRATE Therapeutic Function: Antihyperlipidemic Chemical Name: 2-[4-[2',2'-Dichlorocyclopropyl)phenoxy]-2-methylpropionic acid Common Name: Structural Formula:

Chemical Abstracts Registry No.: 52214-83-3 Trade Name

Manufacturer

Country

Year Introduced

Lipanor

Winthrop

France

1983

Raw Materials p-(2,2-Dichlorocyclopropyl)phenol Acetone

Sodium hydroxide Chloroform

Manufacturing Process A mixture of 8 g (0.0356 mol) of p-(2,2-dichlorocyclopropyl)phenol, 11.2 g (0.28 mol) of sodium hydroxide pellets, 11 g of chloroform and 350 ml of acetone was prepared at 0°C. The cooling bath was removed, the mixture stirred for a minute and then heated on a steam bath to reflux temperature. The reaction mixture was stirred at reflux for three hours and then concentrated in vacuo. The residual gum was partitioned between dilute

1036

Ciprofloxacin

hydrochloric acid and ether, and the ether layer was separated, dried and concentrated in vacuo. The residual oil (14 g) was partitioned between dilute aqueous sodium bicarbonate and ether. The sodium bicarbonate solution was acidified with concentrated hydrochloric acid and extracted with ether. The ether solution was dried over anhydrous sodium sulfate and concentrated. The residue (9.5 g of yellow oil) was crystallized twice from hexane to give 6.0 g of 2-[p-(2,2-dichlorocyclopropyl)phenoxy]-2-methyl propionic acid in the form of a pale cream-colored solid, MP 114°C to 116°C. References Merck Index 2286 DFU 2 (5) 297 (1977) OCDS Vol. 3 p. 44 (1984) I.N. p. 235 Phillips, D.K.; US Patent 3,948,973; April 6, 1976; assigned to Sterling Drug, Inc.

CIPROFLOXACIN Therapeutic Function: Antibiotic Chemical Name: 1-Cyclopropyl-6-fluoro-4-oxo-7-(1-piperazinyl)-1,4-dihydro3-quinolinecarboxylic acid Common Name: Ciprofloxacin Structural Formula:

Chemical Abstracts Registry No.: 85721-33-1 Trade Name

Manufacturer

Country

Year Introduced

Alcipro

Alkem Laboratories Ltd.

India

-

Aquacipro

Aquarius Enterprises

India

-

Cipro

Bayer Pharma

-

-

Ciprobay

Bayer Pharma

Germany

-

Ciramadol

1037

Trade Name

Manufacturer

Country

Year Introduced

Ciprofloxacin

Natur Produkt Europe B.V.

Netherlands

-

Ciprofloxacin

BalkanpharmaDupnitza AD

Bulgaria

-

Ciflocin

Deva Holding

Turkey

-

Cifloxinal

Pro. Med. CS Praha a.s.

Czech Republic

-

Citeral

Alkaloid

Macedonia

-

Ificipro

Unique

India

-

Lyproquin

Lyka Labs

India

-

Microflox

Micronova Pharmaceuticals Torrent

India

-

India

-

Japan

-

Quintor

Vero-Ciprofloxacin Okasa Pharma Raw Materials

Cyclopropyl-6-fluoro-4-oxo-7-(1-piperazinyl)-1,4-dihydro-3quinolinecarboxylic acid Piperazine Manufacturing Process Cyclopropyl-6-fluoro-4-oxo-7-(1-piperazinyl)-1,4-dihydro-3-quinolinecarboxylic acid was synthesized by heating of a mixture of 7-chloro-1-cyclopropyl-6fluoro-1,4-dihydro-4-oxo-quinolin-3-carboxylic acid and 30.1 g dry piperazine in 100 ml DMSO for 2 hours at 135-140°C. DMSO was evaporated in high vacuum. The residue was heated with 100 ml of water, and was dried over CaCl2 in vacuum. Cyclopropyl-6-fluoro-4-oxo-7-(1-piperazinyl)-1,4-dihydro-3quinolinecarboxylic acid obtained has a temperature of decomposition 255257°C. References Grohe K. et al.; EP 0078362; 29.10.82; Assigned to BAYER AG European Patent Application 49,355 and German Patent Application 3,142,854

CIRAMADOL Therapeutic Function: Analgesic Chemical Name: [1R-[1α-(R*),2α]]-3-[(Dimethylamino)(2hydroxycyclohexyl)methyl]phenol Common Name: Ciradol; Ciramadol

1038

Ciramadol

Structural Formula:

Chemical Abstracts Registry No.: 63269-31-8 Trade Name

Manufacturer

Country

Year Introduced

Ciramadol

American Home Products (AHP)

-

-

Ciramadol

Wyeth

-

-

Raw Materials m-Methoxymethoxybenzaldehyde Potassium hydroxide Lithium aluminum hydride Hydrochloric acid

Cyclohexanone Dimethylamine Sodium hydroxide

Manufacturing Process m-Methoxymethoxybenzaldehyde (167 g, 1.0 mole) and cyclohexanone (318 ml, 3.0 moles) were refluxed for 4 hours under nitrogen with a solution of potassium hydroxide (50 g, 0.89 moles) in water (1 liter). After cooling the oily layer was extracted with ether (twice). The ether solution was washed with water (thrice), brine, dried (sodium sulfate), and evaporated. The residue was distilled and the product obtained as a yellow oil (132 g.), boiling point of m-methoxymethoxybenzalcyclohexanone 173-176°C at 0.3 mm, λmax 287 nm (ethanol, ε 13,000). A solution of m-methoxybenzalcyclohexanone (50 g ) in ether (50 ml) was cooled to -5°C in a pressure bottle and treated with 20 ml dimethylamine. The bottle was stoppered and left at room temperature during 60 hours. The above reaction was performed in duplicate (IR monitoring indicates the mixture attains an equilibrium concentration in which the β-dimethylamino ketone addition product is favored over the m-methoxybenzalcyclohexanone by a ratio of ca. 2:1). the combined total reaction mixtures were added dropwise under nitrogen to a stirred suspension of LiAlH4 (20 g) in ether (1.2 liters) and the mixture was refluxed during 4 hours. The ice cooled reaction mixture was treated with 3% aqueous sodium hydroxide solution (100 ml) and filtered. The precipitated solids were washed with boiling ether and the combined filtrates evaporated to approximately 1 liter. The ether layer was extracted (twice) with an excess of dilute hydrochloric acid followed by a water extraction. The combined aqueous extracts were back extracted with ether, basified with 50% sodium hydroxide solution and extracted with ether (twice). The ether layers were washed with brine and evaporated to an oil (50 g) to give a mixture containing predominantly (96%) of two components. 32 g of the residue were chromatographed on a Woelm alumina column (900 g

Cisapride monohydrate

1039

neutral activity Grade III), built in benzene-hexane (1:1). Benzene-hexane fractions (1:1 and 2:1) eluted the major component trans-2-(αdimethylamino-m-methoxybenzyl)cyclohexanol (20 g). Cis-2-[α-dimethylamino-m-(methoxymethoxy)benzyl] cyclohexanol (10 g) in ether was treated with a slight excess of isopropanolic hydrogen chloride. The gummy solid which crystallized on trituration with boiling ether-acetone was recrystallized first from ethanol-ether and finally from methanol-acetone to give the cis-2-(α-dimethylamino-m-hydroxybenzyl)cyclohexanol, hydrochloride, melting point 263-265°C; [α]D25 = -15.3° (methanol). References Yardley John P., Russel; Peter B.; US Patent No. 4,017,637; April 12, 1977; Assigned to American Home Products Corporation (New York, NY)

CISAPRIDE MONOHYDRATE Therapeutic Function: Gastrointestinal drug Chemical Name: Benzamide, 4-amino-5-chloro-N-(1-(3-(4-fluorophenoxy) propyl)-3-methoxy-4-piperidinyl)-2-methoxy-, monohydrate, cisCommon Name: Cisapride Structural Formula:

Chemical Abstracts Registry No.: 81098-60-4 Trade Name

Manufacturer

Country

Year Introduced

Cisapride

Janssen-Cilag

-

-

Cisapride

Manav Drugs Pvt. Ltd. India

-

Peristal

Mustafa Nevzat

Turkey

-

Prepulsid

Janssen-Ortho Inc.

Canada

-

Propulsid

Janssen

-

-

Propulsid Quicksolv

Jansssen

-

-

1040

Cisapride monohydrate

Raw Materials 1-[3-(4-Fluorophenoxy)-propyl]3-methoxy-4-piperidinone Hydrogen 4-Amino-5-chloro-2-methoxybenzoic acid

Benzylamine Palladium on charcoal Nitric acid Ethyl chloroformate

Manufacturing Process A mixture of 1-[3-(4-fluorophenoxy)-propyl]-3-methoxy-4-piperidinone (140 mg), benzylamine (61 mg), Pd 10% on charcoal (100 mg) and a 0.02% solution of thiophene in THF was reacted under hydrogen gas for 3 hours at 50°C. The catalyst was filtered off and fresh palladium 10% on charcoal (100 mg) was added. Debenzylation of the formed intermediate took place under hydrogen atmosphere for 18 hours at 50°C. The reaction mixture was filtered and evaporated under a stream of nitrogen to yield 1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinamine having a cis/trans ratio of about 93/7. 1-[3-(4-Fluorophenoxy)-propyl]-3-methoxy-4-piperidinamine (50 g) was dissolved in methyl isobutylketone (250 ml) and a nitric acid solution (65%, 12.8 ml) was carefully added so that the temperature of the solution did not exceed 45°C. The reaction mixture was stirred at a temperature of 30°C and seeded. When crystallisation started, the reaction mixture was cooled to 0°C and stirred for another 2 hours. The product was filtered off, washed with a small amount of toluene and dried, yielding 1-[3-(4-fluorophenoxy)-propyl]-3methoxy-4-piperidinamine nitrate (m.p. 60°C). 1-[3-(4-Fluorophenoxy)-propyl]-3-methoxy-4-piperidinamine nitrate was dissolved in water (95 ml). The reaction mixture was stirred and toluene (95 ml) was added. A NaOH solution (50%, 10.3 ml) was slowly added and the temperature of the reaction mixture was raised to 75°C. After 30 min, the aqueous layer was discarded and the organic layer was evaporated, yielding 1-[3-(4-fluorophenoxy)-propyl]-3-methoxy-4-piperidinamine having a cis/trans ratio equal to or higher than 98/2. To a solution of 4-amino-5-chloro-2-methoxybenzoic acid (20.2 g) in methyl isobutylketone (250 ml) and triethyl amine (15.3 ml) was slowly dropped ethyl chloroformate (9.6 ml). The reaction mixture was stirred for 30 min at room temperature. To the formed mixed anhydride was then added 1-[3-(4fluorophenoxy)-propyl]-3-methoxy-4-piperidinamine (28.2 g) and the reaction mixture was stirred for 2 hours at room temperature. Subsequently, the reaction mixture was washed with water (80 ml) and a NaOH solution (6.5% w/v, 50 ml). The organic layer was warmed to 65°C and methanol (50 ml) and water (8.5 ml) were added. The solution was cooled slowly and stirred for 2 days during which crystallisation occurred, yielding benzamide, 4-amino-5chloro-N-(1-(3-(4-fluorophenoxy)propyl)-3-methoxy-4-piperidinyl)-2-methoxy, monohydrate, cis- (Cisapride) having a cis/trans ratio higher than 99/1. References Lu Y.-F. et al.; US Patent No. 5,585,387; 12.17.1996; Assigned: Torcan Chemical Ltd. De Knaep A.G.M.,Moens L.J.R.; US Patent No. 6,218,542; 04.17.2001; Assigned: Jenssen Pharmaceutica

Cisatracurium besylate

1041

CISATRACURIUM BESYLATE Therapeutic Function: Neuromuscular blocker Chemical Name: Isoquinolinium, 2,2'-(1,5-pentanediylbis(oxy(3-oxo-3,1propanediyl)))bis(1-((3,4-dimethoxyphenyl)methyl)-1,2,3,4-tetrahydro6,7-dimethoxy-2-methyl-, (1R,1'R,2R,2'R)-, dibenzenesulfonate Common Name: Cistracurium besylate Structural Formula:

Chemical Abstracts Registry No.: 96946-42-8 Trade Name Nimbex Nimbex Nimbex

Manufacturer GlaxoWellcome GlaxoSmithKline DSM Catalytica Pharmaceuticals, Inc.

Country UK US

Year Introduced -

Raw Materials Acryloyl chloride Pentane-1,5-diol Oxalic acid

Tetrahydropapaverine Pyrogallol Triethylamine

Manufacturing Process Acryloyl chloride (0.2 mole) in dry benzene (60 ml) was added over 0.5 hour to pentane-1,5-diol (0.1 mole), triehylamine (0.2 mole) and pyrogallol (0.1 g) in dry benzene (100 ml). Further dry benzene (100 ml) was added followed by triehylamine (10 ml), and the mixture stirred at 50°C for 0.5 hour. The triehylamine hydrochloride was filtered off and the solvent removed in vacuo to leave yellow oil which was distilled in the presence of a trace of pmethoxyphenol, excluding light, to give 1,5-pentamethylene diacrylate (12.9

1042

Cisplatin

g, 61%, b.p. 90-95°C/0.01 mm Hg). A solution of tetrahydropapaverine (4.43 g) and 1,5-pentamethylene diacrylate (1.30 g) in dry benzene (15 ml) was stirred under reflux for 48 hours, excluding light. The solvent was removed in vacuo and the residual pale red oil dissolved in chloroform (10 ml). Addition of ether (ca. 400 ml), followed by saturated ethereal oxalic acid solution (ca. 500 ml) gave a flocculent white precipitate, which was filtered off, washed with ether and dried. Crystallization (twice) from ethanol gave N,N'-4,10-dioxa-3,11dioxodecylene-1,13-bis-tetrahydropapaverine dioxalate as a white powder (3.5 g, 51%, m.p. 117-121°C). The free base N,N'-4,10-dioxa-3,11-dioxodecylene-1,13-bistetrahydropapaverine was obtained by basifying an aqueous solution of the dioxalate with sodium bicarbonate solution, followed by extraction with toluene and evaporation of the solvent, to give a colorless viscous oil. Scrupulously dried base in spectroscopically pure acetonitrile was treated with benzenesulfonic acid at room temperature for 22 hours. The filtered reaction mixture was added dropwise to dry ether (ca. 450 ml). The flocculent white precipitate was filtered off, washed with dry ether, and dried in vacuo over P2O5 at 50°C to yield N,N'-4,10-dioxa-3,11-dioxodecylene-1,13-bistetrahydropapaverine dimesylate, a white powder with m.p. 104-112°C. References Stenlake J.B. et al., US Patent No. 4,179,507; 12.18.1979; Assigned to Burroughs Wellcome Co. Chamberlin St.A. et al.; US Patent No. 5,684,154; 11.04.1977; Assigned to Abbot Laboratories

CISPLATIN Therapeutic Function: Antitumor Chemical Name: Platinum, diamminedichloro-, (SP-4-2)Common Name: Cisplatin Structural Formula:

Chemical Abstracts Registry No.: 15663-27-1

Cisplatin

1043

Trade Name

Manufacturer

Country

Year Introduced

Blastolem

Lemery

Mexico

-

Cisplatin

Teva

Israel

-

Cisplatin

Laboratoires Thissen

Belgium

-

Cisplatin

Yunnan Gejiu Biochemical Pharmaceutical Factory

China

-

Cisplatin

Choongwae Pharma Corporation

Korea

-

Cisplatin

Pharmacia and Upjohn

Australia

-

Cisplatin

Serum Institute of India

India

-

Cisplatin-Ebewe

Ebewe

Austria

-

Cisplatin-Teva

Pharmachemie

Netherlands

-

Cisplatyl

Rhone-Poulenc Rorer

France

-

Citoplatin

Cipla Limited

India

-

Kemoplat

Dabur Pharmaceuticals Ltd.

India

-

Platamine

Pharmacia and Upjohn Lachema

Italy

-

Czech Republic

-

Bristol-Myers Squibb Okasa Pharma

Italy

-

Japan

-

Platidiam Platinol Vero-Cisplatin Raw Materials

Potassium hexachlorplatinate Potassium iodide

Hydrazine Ammonium hydroxide

Manufacturing Process The synthesis proceeds dy reduction of potassium hexachlorplatinate with hydrazine to give potassium tetrachloroplatinate. This is converted to potassium tetraiodoplatinate by treatment with potassium iodide and then reacted with 6 M ammonium hydroxide to give crystals of cisplatin. References Kauffman G.B., Cowan D.O., Inorg. Synth., 7, 239 (1969) Kaplan M.A., Granatek A.P.; US Patent No. 4,322,391; Mar. 30, 1982; Assigned to Bristol-Myers Company, N.Y.

1044

Citalopram hydrobromide

CITALOPRAM HYDROBROMIDE Therapeutic Function: Antidepressant Chemical Name: 5-Isobenzofurancarbonitrile, 1-(3-(dimethylamino)propyl)1-(4-fluorophenyl)-1,3-dihydro-, monohydrobromide Common Name: Citalopram hydrobromide; Nitalapram hydrobromide Structural Formula:

Chemical Abstracts Registry No.: 59729-32-7 Trade Name

Manufacturer

Country

Year Introduced

Celexa

Lundbeck, Forest Laboratories Inc.

-

-

Celica

Solus

India

-

Cipramil

Lundbeck

Denmark

-

Seropram

Lundbeck

Switz.

-

Raw Materials 5-Bromo-1-(4-fluorophenyl)-1-(3-dimethylaminopropyl)-1,3dihydroisobenzofuran Magnesium Butyl lithium tert-Butyl methyl ether Isopropylmagnesium chloride Thionyl chloride Sulfamide Dry ice Manufacturing Process 5-Carboxy-1-(4-fluorophenyl)-1-(3-dimethylaminopropyl)-1,3dihydroisobenzofuranwas synthesized by three methods: 1. A solution of 1-(4-fluorophenyl)-1-(3-dimethylaminopropyl)-1,3-dihydroisobenzofuran-5-yl magnesium bromide in dry THF (90 mL) (prepared by ordinary methods from 5-bromo-1-(4-fluorophenyl)-1-(3-

Citalopram hydrobromide

1045

dimethylaminopropyl)-1,3-dihydro-isobenzofuran (9 g, 0.024 mole) and magnesium (0.73 g, 0.03 mole)) was added to dry solid CO2 (50 g). After addition, the mixture was left at room temperature for 16 hours. The volatile materials were removed in vacuo and the residue was taken up in water (100 mL). pH was adjusted to 5.5 by adding HCl (aqueous, 4 N). The aqueous phase was extracted with toluene (100 mL). The toluene was removed in vacuo and the 5-carboxy-1-(4-fluorophenyl)-1-(3-dimethylaminopropyl)-1,3dihydroisobenzofuran was obtained as oil. Yield 6 g. 2. To a solution of 5-bromo-1-(4-fluorophenyl)-1-(3-dimethylaminopropyl)1,3-dihydroisobenzofuran (9 g, 0.024 mole) in tertbutyl methyl ether (150 mL) was added n-BuLi (1.6 M in hexanes, 40 mL) at -78 to -65°C. The temperature of the solution was allowed to raise to -30°C over a period of 2 hours. The reaction mixture was added to dry solid CO2 (50 g). After addition, the mixture was left at room temperature for 16 hours. The volatile materials were removed in vacuo and the residue was taken up in water (100 mL). pH was adjusted to 5.5 by adding HCl (aqueous, 4 N). The aqueous phase was extracted with toluene (100 mL). The toluene was removed in vacuo and the 5-carboxy-1-(4-fluorophenyl)-1-(3-dimethylaminopropyl)-1,3dihydroisobenzofuran was obtained as an oil. Yield 7.5 g. 3. n-BuLi (20 mL, 1.6 M in hexane) was added to a solution of isopropylmagnesium chloride (8.0 mL, 2 M in diethyl ether) in THF (25 mL) at 0°C. The resulting mixture was stirred at 0°C for 1 h, then cooled to -78°C and a solution of 5-bromo-1-(4-fluorophenyl)-1-(3-dimethylaminopropyl)-1,3dihydro-isobenzofuran (5.0 g, 13.0 mmol) in THF (25 mL) was added. The mixture was allowed to warm to -10°C during 1 h, then cooled again to -78°C and CO2 (5.7 g, 130 mmol) was added. The mixture was allowed to warm to room temperature, and then evaporated. Ion exchange chromatography of the residue (Dowex RTM-50, acidic form) eluting with 1 M NH3 afforded the 5carboxy-1-(4-fluorophenyl)-1-(3-dimethylaminopropyl)-1,3dihydroisobenzofuran as a thick oil. 5-Carboxy-1-(4-fluorophenyl)-1-(3-dimethylaminopropyl)-1,3dihydroisobenzofuran (5 g, 0.015 mole) and sulfamide (1.65 g, 0.017 mole) were dissolved in sulfolane (15 mL). Thionyl chloride (2.25 g, 0.019 mole) was added at room temperature and the temperature of the reaction mixture was raised to 130°C for 2 hours. The reaction mixture was allowed to cool to 75°C and water (25 mL) was added. The temperature was held at 75°C for 15 min, and then the reaction mixture was cooled to room temperature. pH was ajusted to 9 with ammonium hydroxide and then n-heptane (75 mL) was added. The temperature was raised to 70°C and the hot n-heptane layer was isolated from which the 5-cyano-1-(4-fluorophenyl)-1-(3dimethylaminopropyl)-1,3-dihydroisobenzofuran (Citalopram, free base) crystallised on cooling. Yield 3.77 g. Purity (HPLC peak area) >97%. The hydrobromide was prepared in conventional manner and crystallized from isopropanol; melting point 148-150°C. References Bogese K.,Toft A.S.; US Patent No. 4,136,193; 01.23.1979; Assigned to Kefalas A/S, Denmark

1046

Citicoline

Petersen H.,Ahmadian H.; US Patent No. 6,426,422; 07.30.2002; Assigned to H. Lundbeck A/S, Denmark

CITICOLINE Therapeutic Function: Cerebral circulation stimulant Chemical Name: Cytidine 5'-(trihydrogen diphosphate)mono[2(trimethylammonio)ethyl]ester hydroxide inner salt Common Name: Citidoline; Cytidine diphosphate choline Structural Formula:

Chemical Abstracts Registry No.: 987-78-0 Trade Name Nicholin Rexort Alaton Andes Brassel CDP-Choline Cereb Ceregut Cidifos Colite Corenalin Cyscholin Daicoline Difosfocin Emicholine Emilian Ensign Erholen

Manufacturer Cyanamid Cassenne Zambon Nippon Kayaku, Co. Alfa Farm. Kowa Ohta Kodama Neopharmed Nippon Chemiphar Kaken Kanto Daisan Magis Dojin Beppu Yamanouchi Nichiiko

Country Italy France Italy Japan Italy Japan Japan Japan Italy Japan Japan Japan Japan Italy Japan Japan Japan Japan

Year Introduced 1971 1977 -

Citicoline

1047

Trade Name

Manufacturer

Country

Year Introduced

Haibrain

Ono

Japan

-

Haocolin

Fuso

Japan

-

Hornbest

Hoei

Japan

-

Intelon

Takata

Japan

-

Meibis

Sanken

Japan

-

Neucolis

Nippon Shinyaku

Japan

-

Nicholin

Takeda

Japan

-

Niticolin

Morishita

Japan

-

Plube

Mochida

Japan

-

Recognan

Toyo Jozo

Japan

-

Rupis

Vitacain

Japan

-

Sauran

Abello

Spain

-

Sinkron

Ripari-Gero

Italy

-

Sintoclar

Pulitzer

Italy

-

Somazina

Ferrer

Spain

-

Startonyl

Cyanamid

-

-

Suncholin

Mohan

Japan

-

Raw Materials Cytidine-5'-monophosphate Choline Brevibacterium ammoniagenes Manufacturing Process A 250 ml conical flask containing 30 ml of a reaction liquor (pH 7.0) having a composition of 7.38 mg/ml of disodium salt of CMP (cytidine-5'monophosphate), 24 mg/ml of choline, 10 mg/ml of glucose, 100 mg/ml of acetone-dried cells of Brevibacterium ammoniagenes ATCC 6872, 11.6 mg/ml of monopotassium phosphate, 20 mg/ml of dipotassium phosphate and 2.96 mg/ml of magnesium sulfate, (MgSO4·7H2O), was subjected to culturing at 30°C for 4 hours. Cytidine diphosphate choline was formed and accumulated at a concentration of 3.8 mg/ml in the culture liquor. The pH of 1.2 liters of filtrate containing 3.8 mg/ml of cytidine diphosphate choline, obtained by removing solid matters from the culturing liquor, was adjusted to a pH of 8.5 with a 0.5 N KOH solution. The filtrate was passed through a column of strongly basic anion exchange resin, Dowex 1 x 2 (formic acid type). After washing the resin with water, a formic acid solution was passed through the column with gradual increase in the concentration of formic acid (until 0.04 N max.). A fraction of cytidine diphosphate choline was collected by elution according to the so-called gradient elution method and absorbed onto carbon powders. Then, elution was effected with acetone, and the eluate was concentrated and dried. 1.3 g of cytidine diphosphate choline powders were obtained.

1048

Citiolone

References Merck Index 2290 Kleeman and Engel p. 214 DOT 4 (2) 68 (1968) I.N. p. 237 Nakayama, K. and Hagino, H.; US Patent 3,684,652; August 15, 1972; assigned to Kyowa Hakko Kogyo Co., Ltd. (Japan) Nakamachi, H., Kamiya, K. and Nishikawa, M.; US Patent 3,687,932; August 29, 1972; assigned to Takeda Chemical Industries, Ltd. (Japan)

CITIOLONE Therapeutic Function: Hepatoprotectant Chemical Name: 2-Acetamido-4-mercaptobutyric acid γ-lactone Common Name: Acetylhomocystein thiolactone; Acetamido thiobutyrolactone Structural Formula:

Chemical Abstracts Registry No.: 1195-16-0 Trade Name

Manufacturer

Citiolase

Roussel Maestretti France

Country

1970

Thioxidrene

Bottu

1972

Citiolase

Roussel Maestretti Italy

1976

Mucorex

Spain

-

Reducdyn

BerenguerBeneyto Nordmark

W. Germany

-

Sitilon

Roussel

-

-

Thioncycline

Merrell

France

-

France

Year Introduced

Raw Materials Acetyl methionine Ammonia sodium Hydrogen chloride Manufacturing Process 12.73 kg of acetyl methionine are gradually introduced into a brine-cooled

Citrulline malate

1049

pressure-tight apparatus provided with a stirrer and containing 140 liters of liquid ammonia at -50°C. The amino acid is dissolved after a short time; 6.5 kg of sodium metal are then introduced over a period of from 4 to 5 hours at a temperature of from -40°C to 60°C. Eventually, a persistent blue coloration of the ammoniacal solution indicates the end of the reaction. The ammonia is distilled off and the residue is taken up in 70 liters of methanol. In order to remove ammonia which has been formed from sodium amide, 30 to 40 liters of methanol are distilled off and the residue is made up with methanol to 80 liters. The strongly alkaline solution is neutralized with 22 liters of concentrated aqueous hydrochloric acid. The solution is filtered off from the precipitated sodium chloride and evaporated to dryness in vacuo. The closing of the thiolactone ring takes place as a result of the evaporation of the solution to dryness in the acid pH range and the N-acetyl homocystein originally present is converted into N-acetyl homocystein thiolactone. In order to isolate this compound, the residue is recrystallized from 25% aqueous alcohol. 9 kg of N-acetyl homocystein thiolactone are obtained, this corresponding to a yield of 85% of the theoretical. References Merck Index 2291 Kleeman and Engel p. 215 DOT 7 (1) 14 (1971) I.N. p. 237 British Patent 955,231; April 15, 1964; assigned to Deutsche Gold-und SilberScheideanstalt Vormals Roessler (Germany)

CITRULLINE MALATE Therapeutic Function: Stimulant, Detoxicant Chemical Name: L-Ornithine, N5-(aminocarbonyl)-, mono(+-)hydroxybutanedioate Common Name: Citrulline malate Structural Formula:

Chemical Abstracts Registry No.: 70796-17-7; 372-75-8 (Base)

1050

Cladribine

Trade Name

Manufacturer

Country

Year Introduced

StaminO2

ErgoPharm

-

-

Citrulline malate

Sinochem Qingdao

-

-

Dynergum

Sanobia

-

-

Dynergum

Laboratoires Biocodex Biodiphar N.V.

-

-

Stimol

Biocodex

-

-

Stimufor

Vifor SA

-

-

Raw Materials L-Arginine hydrochloride Copper oxide

Sodium hydroxide Hydrogen sulfide

Manufacturing Process Citrulline is obtained as a result of a reaction of L-arginine hydrochloride with sodium hydroxide, copper oxide and hydrogen sulfide. In practice it is usually used as malate salt. References Kleemann A., Engel J.; Pharmazeutische Wirkstoffe, GeorgThieme Verlag Stuttgart. New York, 1982

CLADRIBINE Therapeutic Function: Cytostatic Chemical Name: Adenosine, 2-chloro-2'-deoxyCommon Name: 2-Chlorodeoxyadenosine; Cladaribine; Cladribine Structural Formula:

Cladribine

1051

Chemical Abstracts Registry No.: 4291-63-8; 24757-90-2 Trade Name Cladribine Leukeran Leustatin

Manufacturer Janssen-Cilag GlaxoSmithKline Ortho Biotech. Inc.

Country -

Year Introduced -

Raw Materials Guanosine Pyridine N,N-Dimethylaniline n-Pentyl nitrite Phenyl chlorothionoformate 4-Dimethylaminopyridine Tri-n-butyltin hydride

Acetic anhydride Tetraethylammonium chloride Phosphorous oxychloride Triphenylmethyl chloride 1,3-Dichloro-1,1,3,3tetraisopropyldisiloxane Azobisisobutyronitrile

Manufacturing Process Preparation of 2',3',5'-O-triacetyl guanosine A mixture of guanosine (355 g, 1.25 M), acetic anhydride (0.750 L), pyridine (0.375 L) and dimethylformamide (1 L) is stirred at room temperature for 2 hours and then heated at 75°C for 4 hours. After the heating, the mixture is cooled to room temperature and stirred overnight. Most of the solvent is then removed by vacuum distillation at 45°C to yield a white precipitate. The solid is isolated by filtration and washed with isopropanol. The solid is suspended in isopropanol, and heated to reflux whereupon most of the solid dissolves. The isopropanol is then allowed to cool to room temperature, and filtered to yield a white solid that is dried overnight in a vacuum oven at 60°C to yield the title compound (358 g, 69.8%). Preparation of 9-(2',3',5'-O-triacetyl-β-D-ribofuranosyl)-2-amino-6chloropurine A mixture of 2',3',5'-O-triacetyl guanosine (480 g, 1.17 M), N,Ndimethylaniline (150 mL), tetraethylammonium chloride (386.4 g) and acetonitrile (0.70 L) is prepared, and then phosphorous oxychloride (400 mL) is added slowly (dropwise) over 3 hours at room temperature under a N2 atmosphere. After the addition, the mixture is heated at 100°C for 14 minutes, and then cooled to room temperature. Most of the solvent is removed in vacuo to yield a red oil. The oil is treated with methylene chloride (2 L), and then poured into ice water (1.5 L). The organic layer is separated and the aqueous layer extracted with CH2Cl2 (3x500 mL). The separated organic layer and the organic extracts are combined, washed with a saturated sodium bicarbonate solution until a pH of 6 to 7 is reached, and then washed with ice-water (2 times 1 L). The organic layer is dried over sodium sulfate, and the solvent removed in vacuo to yield a thick oil. The oil is treated with isopropanol (200 mL), stirred at 45°C for 1 hour, allowed to cool to room temperature, and left overnight whereupon a precipitate is formed. The precipitate is isolated by filtering and then the precipitate is washed with cold isopropanol to yield the title compound (235 g, 47%).

1052

Cladribine

Preparation of 9-(2',3',5'-O-triacetyl-β-D-ribofuranosyl)-2,6-dichloropurine n-Pentyl nitrite (98 g, 838 mM) is added over one hour at room temperature under nitrogen to a mixture of the above purine compound (350 g, 819 mM), triphenylmethyl chloride (500 g, 1.79 M) and potassium carbonate (65 g) in CH2Cl2 (3 L). The resulting mixture is heated at reflux for 20 minutes, cooled to room temperature and filtered. The filtrate is concentrated in vacuo, and the resulting residue is purified by column chromatography on silica gel (2.5 kg, ethyl acetate/hexane 1:4-3:7) to yield the title compound as a pale yellow solid (272 g, 74%). Preparation of 2-chloroadenosine A mixture of 9-(2',3',5'-O-triacetyl-β-D-ribofuranosyl)-2,6-dichloropurine (271 g, 0.606 M), concentrated ammonium hydroxide (4 L) and tetrahydrofuran (0.5 L) is stirred at room temperature under nitrogen for 4 days. The solvent volume is reduced in vacuo and the resulting residue is triturated with absolute ethanol. The title compound is precipitated out of the ethanolic solvent to yield a light brown solid, (159 g, 87%). Preparation of 2-chloro-(3',5'-O-tetraisopropyldisiloxyl)adenosine A mixture of 2-chloroadenosine (13 g, 43 mM), 1,3-dichloro-1,1,3,3tetraisopropyldisiloxane (15 g, 47.6 mM) and pyridine (150 mL) is stirred at room temperature under nitrogen for 3 hours. The solvent volume is reduced in vacuo and the resulting residue is dissolved in CH2Cl2 (250 mL), washed with a saturated copper sulfate solution (2x150 mL) and dried with sodium sulfate. The organic layer is concentrated in vacuo and purified by column chromatography on silica gel (200 g) with ethyl acetate/hexane (1:1) to yield the title compound as a white powder (14.7 g, 63%, MP 198-200°C). NMR, IR and elemental analysis are confirmed the structure of the title compound. Preparation of 2-chloro-2'-O-phenoxythiocarbonyl-(3',5'-O-tetraisopropyldisiloxyl)adenosine Phenyl chlorothionoformate (4.66 g, 27 mM) is added to a mixture of 2chloro-(3',5'-O-tetraisopropyldisiloxyl)adenosine (14 g, 25.8 mM), 4dimethylaminopyridine (DMAP) (6.88 g, 56.4 mM) and acetonitrile (400 mL) at room temperature under nitrogen, and stirred overnight. The solvent is removed in vacuo and the residue is purified by column chromatography on silica gel (200 g) with ethyl acetate/hexane (4:6) to yield the title compound as a pale yellow powder (9.8 g, 56%, MP 153-155°C). NMR, IR and elemental analysis are confirmed the structure of the title compound. Preparation of 2-chloro-2'-deoxy-(3',5'-O-tetraisopropyldisiloxyl)adenosine A mixture of the compound of 2-chloro-2'-O-phenoxythiocarbonyl-(3',5'-Otetraisopropyldisiloxyl)adenosine (5.8 g, 8.54 mM), tri-n-butyltin hydride (3 mL, 11 mM) and azobisisobutyronitrile (320 mg) in benzene (100 mL) is heated to reflux for 3 hours under nitrogen. After cooling, the solvent is removed in vacuo and the residue is purified by column chromatography on silica gel (200 g) with ethyl acetate/hexane (4.5:5.5) to yield the title compound as a white powder (3.78 g, 84%, MP 171°-173°C). NMR, IR and

Clarithromycin

1053

elemental analysis are confirmed the structure of the title compound. Preparation of 2-chloro-2'-deoxy-adenosine A mixture of 2-chloro-2'-deoxy-(3',5'-O-tetraisopropyldisiloxyl)adenosine (2.5 g, 4.74 mM), and tetra-n-butylammonium fluoride (1.1 M, 8.6 mL, 9.46 mM) in tetrahydrofuran (10 mL) is stirred at room temperature under nitrogen for 2 hours. The solvent volume is reduced in vacuo and the resulting residue is treated with water (200 mL) and extracted with ether (3x20 mL). The aqueous layer is purified by preparative HPLC (C-18 reverse phase column, methanol/water 15:85 to 20:80) to yield the title compound (600 mg, 44%); MP >230°C. References Chen R.; US Patent No. 5,208,327; May 4, 1993; Assigned to Ortho Pharmaceutical Corporation, Raritan, N.J.

CLARITHROMYCIN Therapeutic Function: Antibiotic Chemical Name: Erythromycin, 6-O-methylCommon Name: Clarithromycin Structural Formula:

Chemical Abstracts Registry No.: 81103-11-9

1054

Clarithromycin

Trade Name

Manufacturer

Country

Year Introduced

Biaxin

Neo Quimica

-

-

Biaxin

EMS/Sigma

-

-

Binoclar

Novartis Limited

Bangladesh

-

Claricin

Brown and Burk Pharmaceuticals Ltd.

India

-

Clarith

Taisho Pharmaceutical Co., Ltd.

-

-

Clarithromycin

Alembic Ltd.

India

-

Fromilid

Krka

Slovenia

-

Klabax

Ranbaxy

India

-

Klacid

Abbott

France

-

Klaricid

Cipla Limited

India

-

Klaricid

Abbott

-

-

Klaricid

Dainabot Co., Ltd. -

-

Klacid SR

Abbott

UK

-

Klerimed

Medochemie Ltd.

Cyprus

-

Raw Materials O,N-Dibenzyloxycarbonyl-desN-methylerythromycin A Triethylamine Formaldehyde

Methyl iodide Sodium hydride Palladium

Manufacturing Process In a mixture of 50 ml of dry dimethylsulfoxide and 100 ml of dry tetrahydrofuran were dissolved 30 g of O,N-dibenzyloxycarbonyl-des-Nmethylerythromycin A and 18 ml of methyl iodide. The solution was stirred under cooling at -12-10°C in a nitrogen stream and 2.4 g of 55-65% sodium hydride oily dispersion were added thereto in small portions. The mixture was stirred for a further one hour. After completion of the reaction, 50 ml of triethylamine were poured into the reaction mixture with stirring under icecooling, and the precipitates were filtered off. The obtained solid product was washed thoroughly with ethyl acetate, and the washings and the mother liquor were combined. The combined liquor was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo and the crude product was applied onto a silica gel dry column (E. Merck Darmstadt; silica gel 60 for column chromatography, 70-230 mesh). The mixture was eluted with of ethyl acetate/n-hexane (1:1). 15 ml each of fraction was collected and analyzed by silica gel thin layer chromatography, developing in a mixture of ethyl acetate and n-hexane (1:1). The fractions having Rf value 0.16 were combined (c.f., Rf value of starting compound 0.07) and the solvent was evaporated in vacuo, affording 12.2 g of

Clavulanate potassium

1055

a colorless froth. In a mixture of 1.32 g of sodium acetate, 0.8 ml of sodium acetate, 40 ml of water and 200 ml of ethanol were dissolved 10 g of the colorless froth obtained, and 1.0 g of palladium black was added to the above solution. Catalytic reduction was performed for 5 hours at room temperature under atmospheric pressure in a gentle hydrogen stream. 32 ml of 37% aqueous formaldehyde solution were poured into the reaction mixture and the catalytic reduction was continued for a further 7 hours. After completion of the reaction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure approximately to a quarter volume. To the concentrate were added 100 ml of water, and the mixture was adjusted to about pH 10 with an aqueous sodium carbonate solution. The mixture was extracted thoroughly with chloroform and the extract was washed with water and dried. After evaporation of the solvent in vacuo, the residue was recrystallized from a mixture of chloroform and diethyl ether, giving 6 g of crystals. The crystals were stirred for 5 hours in 500 ml of diethyl ether and filtered off. The filtrate was concentrated to dryness and the residual substance was recrystallized from a mixture of chloroform and diethyl ether, giving 4.5 g of 6-O-methylerythromycin A (Clarithromycin) in the form of colorless needles; m.p. 217-220°C (with decomposition). References Dominguez A. et al.; US Patent No. 6,642,364; Nov. 4, 2003; Assigned to Ercros Industrial, S.A. (Barcelona, ES) Watanabe Y., et al.; US Patent No. 4,331,803, May 25, 1982; Assigned to Taisho Pharmaceutical Co., Ltd. (JP)

CLAVULANATE POTASSIUM Therapeutic Function: Beta-lactamase inhibitor Chemical Name: 4-Oxa-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, 3-(2hydroxyethylidene)-7-oxo-, monopotassium salt, (2R-(2α,3Z,5α))Common Name: Clavulanate potassium; Potassium clavulanate Structural Formula:

1056

Clavulanate potassium

Chemical Abstracts Registry No.: 61177-45-5 Trade Name Clavulanate potassium

Manufacturer Lek

Country -

Year Introduced -

Potassium clavulanate Potassium clavulanate

Paganfarma

-

-

Yick-Vic Chemicals and Pharmaceuticals (HK) Ltd.

-

-

Raw Materials Streptomyces clavuligerus Glucose Oxoid Malt Extract Peptone Potassium hydrocarbonate

Yeatex Oxoid agar No. 3 Glycerol Water Sodium hydroxide

Manufacturing Process Clavulanic acid may be obtained by aerobic cultivation of Streptomyces clavuligerus in conventional nutrient media at, for example, about 25°-30°C under roughly neutral conditions. Cultivation of Streptomyces clavuligeru: Streptomyces clavuligerus was cultivated at 26°C on agar slopes containing 1% Yeatex (yeast extract) ("Yeatex" is a Registered Trade mark), 1% glucose and 2% Oxoid agar No. 3, pH 6.8. A sterile loop was used to transfer mycelium and spores from the slope into 100 ml of a liquid medium in a 500 ml Ehrlenmeyer flask. The liquid medium had the following composition: Oxoid Malt Extract 10g/L, Oxoid Bacteriological Peptone 10g/L, Glycerol 20 g/L, Tap water 1 L. The medium was adjusted to pH 7.0 with sodium hydroxide solution and 100 ml volumes dispensed into flasks which were closed with foam plugs prior to autoclaving at 15 lb/sq.in. for 20 min. An inoculated seed flask was shaken for 3 days at 26°C on a rotary shaker with a 2 inch throw and a speed of 240 r.p.m. Production stage flasks containing the liquid medium described above were inoculated with 5% vegetative inoculum and grown under the same conditions as the seed flask. Clavulanic acid may be extracted from the culture medium. Normally the cells of the Streptomyces clavuligerus are first removed from culture medium by filtration or centrifugation. Then clavulanic acid is extracted into an organic solvent, for example, n-butanol or ethyl acetate, or n-butyl acetate, or methyl isobutyl ketone. Then n-butanol fraction are treated with new aqueous phase using potassium hydrogen carbonate and then this aqueous phase is washed with n-butanol. This aqueous extract, after separation of the phases, is concentrated under reduced pressure. Freeze-drying at -20°C may also be

Clavulanic acid

1057

employed to provide a solid crude preparation of the potassium Z-(2R,5R)-3(β-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3,2,0]heptane-2-carboxylate (clavulanate potassium). References Cole M. et al.; GB Patent No. 1,508,977; April 26, 1978; Assigned: Beecham Group Limited, a British Company of Beecham House, Great West Road, Brentford, Middlesex, England

CLAVULANIC ACID Therapeutic Function: Antibacterial Chemical Name: 3-(2-Hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0] heptane-2-carboxylic acid Common Name: Structural Formula:

Chemical Abstracts Registry No.: 58001-44-8 Trade Name Augmentin Augmentin Augmentan Synulox

Manufacturer Beecham Beecham Beecham Beecham

Country UK Switz. W. Germany -

Year Introduced 1981 1982 1982 -

Raw Materials Dextrin Soybean flour Bacterium Streptomyces Clavuligerus Manufacturing Process 100 ml of sterile water was added to a sporing culture which had been grown on Bennetts agar in a Roux bottle for 10 days at 26°C. A mycelium/spore

1058

Clemastine fumarate

suspension was produced and used to inoculate 75 liters of steam sterilized medium of the following composition in tap water. Dextrin Arkasoy '50'* 10% Pluronic L81 in soybean oil

2% W/V 1% W/V 0.03% V/V

*Arkasoy is soybean flour supplied by British Arkady Co., Old Trafford, Manchester, UK The pH of the medium was adjusted to 7.0 The medium was contained in a 100 liter stainless steel baffled fermenter, agitated by a 7.5 inch vaned disc impeller at 140 rpm. Sterile air was supplied at 75 liters per minute and the tank incubated for 72 hours at 26°C. The contents of the seed fermenter were used to inoculate 1,500 liters of steam sterilized medium of the following composition in tap water. Arkasoy '50' Glycerol KH2PO4

1.5% W/V 1.0% W/V 0.1% W/V

10% Pluronic L81 in soybean oil 0.2% V/V The pH of the medium was adjusted to 7.0 The medium was contained in a 2,000 liter stainless steel fully baffled fermenter agitated by two 19 inch vaned disc impellers at 106 rpm. Sterile air was supplied at 1,200 liters per minute. Antifoam was added in 25 ml amounts as required. (10% Pluronic L81 in soybean oil). The fermentation was controlled at 26°C until a maximum yield of clavulanic acid was obtained between 3-5 days when 200-300 µg/ml of clavulanic acid were produced. References Merck Index 2311 DFU 2 (6) 372 (1977) PDR p. 659 DOT 19 (3) 169 (1983) I.N. p. 18 REM p. 1200 Cole, M., Howarth, T.T. and Reading, C.; US Patent 4,110,165; August 29, 1978; assigned to Beecham Group, Ltd. (UK)

CLEMASTINE FUMARATE Therapeutic Function: Antihistaminic

Clemastine fumarate

1059

Chemical Name: 2-[2-[1-(4-Chlorophenyl)-1-phenylethoxy]ethyl]-1methylpyrrolidine hydrogen fumarate Common Name: Meclastin Structural Formula:

Chemical Abstracts Registry No.: 14976-57-9; 15686-51-8 (Base) Trade Name

Manufacturer

Country

Year Introduced

Tavegyl

Sandoz

France

1967

Tavegyl

Sandoz

Switz.

1967

Tavegil

Sandoz

W. Germany

1967

Tavegyl

Sandoz

Italy

1968

Tavegyl

Sankyo

Japan

1970

Tavegil

Sandoz

UK

1971

Tavist

Dorsey

US

1978

Agasten

Sandoz

-

-

Alagyl

Sawai

Japan

-

Aloginan

Tobishi

Japan

-

Alphamin

S.S. Pharm

Japan

-

Anhistan

Nippon Zoki

Japan

-

Antriptin

Nippon Yakuhin

Japan

-

Arrest

Taisho

Japan

-

Batomu

Zensei

Japan

-

Benanzyl

Isei

Japan

-

Chlonaryl

Ohta

Japan

-

Clemanil

Kyoritsu

Japan

-

Fuluminol

Tatsumi

Japan

-

Fumalestine

Hishiyama

Japan

-

Fumaresutin

Hishiyama

Japan

-

Inbestan

Maruko

Japan

-

Kinotomin

Toa Eiyo

Japan

-

Lacretin

Toyo Tanabe

Japan

-

1060

Clemizole

Trade Name

Manufacturer

Country

Year Introduced

Lecasol

Kaken

Japan

-

Maikohis

Nichiiko

Japan

-

Mallermin-F

Taiyo Yakuko

Japan

-

Marsthine

Towa

Japan

-

Masletine

Shioe

Japan

-

Piloral

Nippon Kayaku, Co.

Japan

-

Raseltin

Maruishi

Japan

-

Reconin

Toyama

Japan

-

Romien

Fuji Zoki

Japan

-

Telgin G

Taiyo

Japan

-

Trabest

Hoei

Japan

-

Xolamin

Sanko

Japan

-

Raw Materials Sodium amide Fumaric acid

α-Methyl-p-chlorobenzhydrol N-Methylpyrrolidyl-(2)-ethyl chloride

Manufacturing Process 9.9 g of α-methyl-p-chlorobenzhydrol are added to a suspension of 2.3 g of powdered sodamide in 30 cc of benzene. Subsequently 7.4 g of Nmethylpyrrolidyl-(2)-ethyl chloride are added and the solution is heated to the boil at reflux for 20 hours. Then shaking is first effected with water and then 4 times each time with 25 cc of 2 N hydrochloric acid. The acid extracts are made alkaline with potassium hydroxide solution while cooling strongly, and the precipitated oil is extracted with ether. After drying of the ethereal solution over potassium carbonate, the solvent is evaporated and the residue is fractionally distilled in a high vacuum, whereby N-methyl-2-[2'-(α-methyl-pchlorobenzhydryloxy)-ethyl]-pyrrolidine boils over at 154°C/0.02 mm Hg. The base is converted to the fumarate by reaction with fumaric acid. References Merck Index 2314 Kleeman 81 Engel p. 216 PDR p. 1597 OCDS Vol. 2 p. 32 (1980) I.N. p. 239 REM p. 1127 British Patent 942,152; November 20, 1963; assigned to Sandoz Ltd.

CLEMIZOLE Therapeutic Function: Antihistaminic

Clemizole

1061

Chemical Name: 1-[(4-Chlorophenyl)methyl]-2-(1-pyrrolidinylmethyl)]-1Hbenzimidazole Common Name: Structural Formula:

Chemical Abstracts Registry No.: 442-52-4; 1163-36-6 (Hydrochloride salt) Trade Name

Manufacturer

Country

Year Introduced

Allercur

Roerig

US

1960

Reactrol

Purdue Frederick

US

1961

Allercur

Schering

Switz.

-

Allerpant

Panther-Osfa

Italy

-

Deliproct

S.E.P.S.S.

France

-

Penargyl

Morgan

Italy

-

Ultralan

S.E.P.S.S.

France

-

Ultraproct

S.E.P.S.S.

France

-

Raw Materials o-Nitrochlorobenzene Chloroacetyl chloride Pyrrolidine

p-Chlorobenzylamine Hydrogen

Manufacturing Process From 13.1 g of N-p-chlorobenzyl-2-nitroaniline (MP 110°C, obtained in the form of orange-red needles, from o-nitrochlorobenzene and pchlorobenzylamine by reaction for 3 hours at 150°C) by reduction with Raneynickel and hydrogen, in which reaction the substance may be suspended in methanol or dissolved in methanol-ethyl acetate at normal pressure and at about 40°C with combination of the theoretical quantity of hydrogen, 12.2 g are obtained of o-amino-N-p-chlorobenzylaniline, which after recrystallization from aqueous methanol has a MP of 90°C.

1062

Clenbuterol

8 g of o-amino-N-p-chlorobenzylaniline and 2.8 g of pyridine are dissolved in dry ether and reacted with an ethereal solution of 3.9 g of chloracetyl chloride with cooling in a mixture of ice and common salt. 8 g of N-p-chlorobenzyl-N'chloracetyl-o-phenylene diamine are obtained which can be worked up in the form of the crude product and, in the slightly colored form, has a MP of 130°C. 7.6 g of this compound are boiled with 3.9 g of pyrrolidine in 70 cc of toluene for some hours under reflux. After extraction by shaking with water and treatment with hydrochloric acid the hydrochloride is produced of N-pchlorobenzyl-N'-pyrrolidylacetyl-o-phenylene diamine together with some 1-pchlorobenzyl-2-N-pyrrolidylmethyl-benzimidazole. The former, after recrystallization from butanol, melts with foaming at 205°C, the latter, after recrystallization from butanol melts at 239°C to 241°C, and is in the form of white microscopic rods. Boiling in nitrobenzene converts the former compound into the latter. References Merck Index 2315 Kleeman and Engel p.217 OCDS Vol. 1 p. 324 (1977) I.N. p. 239 Schenck, M. and Heinz, W.; US Patent 2,689,853; September 21, 1954; assigned to Schering A.G. (Germany)

CLENBUTEROL Therapeutic Function: Anti-asthmatic Chemical Name: 4-Amino-3,5-dichloro-[[(1,1-dimethylethyl)amino]methyl] benzenemethanol Common Name: Structural Formula:

Chemical Abstracts Registry No.: 37148-27-9 Trade Name Spiropent Monores

Manufacturer Thomae Valeas

Country W. Germany Italy

Year Introduced 1977 1981

Clidanac

1063

Raw Materials 1-(4'-Aminophenyl)-2-t-butylaminoethanol-(1) HCl Chlorine hydrogen chloride Manufacturing Process 127 g of 1-(4'-aminophenyl)-2-t-butylaminoethanol-(1) hydrochloride were dissolved in a mixture of 250 cc of glacial acetic acid and 50 cc of water, and chlorine added while stirring the solution and maintaining the temperature of the reaction mixture below 30°C by cooling with ice water. After all of the chlorine had been added, the reaction mixture was stirred for thirty minutes more, then diluted with 200 cc of water, and made alkaline with concentrated ammonia while cooling with ice, taking care that the temperature of the reaction mixture did not rise above 40°C. The alkaline mixture was extracted three times with 200 cc portions of chloroform, and the chloroform extract solutions were combined, dried with sodium sulfate and evaporated. The residue, the free base 1-(4'-amino-3',5'-dichlorophenyl)-2-tbutylaminoethanol-(1), was dissolved in absolute ethanol, gaseous hydrogen chloride was passed through the solution, and the precipitate formed thereby was collected. It was identified to be 1-(4'-amino-3',5'-dichlorophenyl)-2-tbutylaminoethanol-(1) hydrochloride, melting point 174.0°C to 175.5°C (decamp.). References Merck Index 2316 DFU 1 (5) 221 (1976) Kleeman and Engel p. 218 DOT 14 (2) 59 (1978) and 17 (8) 339 (1981) I.N. p.240 Keck, J., Kruger, G., Machleidt, H., Noll, K., Engelhardt, G. and Eckenfels, A.; US Patent 3,536,712; October 27, 1970: assigned to Boehringer Ingelheim G.m.b.H. (Germany)

CLIDANAC Therapeutic Function: Antiinflammatory, Antipyretic Chemical Name: 6-Chloro-5-cyclohexyl-2,3-dihydro-1H-indene-1-carboxylic acid Common Name: Structural Formula:

1064

Clidinium bromide

Chemical Abstracts Registry No.: 34148-01-1 Trade Name

Manufacturer

Country

Year Introduced

Indanal

Takeda

Japan

1981

Britai

Bristol Banyu

Japan

1981

Raw Materials N-Chlorosuccinimide 5-Cyclohexyl-1-indancarboxylic acid Manufacturing Process N-chlorosuccinimide (8.2 g.0.0614 mol) was added to a stirred, cooled (icewater) solution of (±)-5-cyclohexyl-1-indancarboxylic acid (10.0 g, 0.0409 mol) in dimethylformamide (82 ml). The solution was stirred for fifteen minutes at 0°C. thirty minutes at 25°C. nine hours at 50°C, followed by eight hours at 25°C. The solution was diluted with cold water (400 ml) and stirred until the precipitated product turned granular (fifteen minutes). The crude product was collected, washed with cold water, and dried. Crystallization from Skellysolve B with charcoal treatment gave colorless crystals (6.65 g, 58%), MP 149°C to 150°C. The product was recrystallized twice from Skellysolve B to give (±)-6-chloro-5-cyclohexyl-1-indancarboxylic acid as colorless crystals, MP 150.5°C to 152.5°C. References Merck Index 2319 DFU 4 (3) 229 (1979) DOT 17 (8) 319 (1981) I.N. p. 240 Juby, P.F., DeWitt, R.A.P. and Hudyma,T.W.; US Patent 3,565,943; February 23, 1971; assigned to Bristol-Myers Co.

CLIDINIUM BROMIDE Therapeutic Function: Anticholinergic Chemical Name: 3-[(Hydroxydiphenylacetyl)oxy]-1-methyl-1-azoniabicyclo [2.2.2]octane bromide Common Name: Structural Formula:

Clidinium bromide

1065

Chemical Abstracts Registry No.: 3485-62-9 Trade Name

Manufacturer

Country

Year Introduced

Librax

Roche

US

1961

Quarzan

Roche

US

1976

Dolibrax

Roche

France

-

Raw Materials 1-Azabicyclo[2.2 2]-3-octanol Sodium

Diphenylchloroacetyl chloride Methyl bromide

Manufacturing Process 5.12 g of 1-azabicyclo[2.2.2]-3-octanol were refluxed with a suspension of 0.92 g of finely divided sodium in 50 cc of toluene, until most of the sodium had reacted (about 4 hours). The thus obtained suspension of the white amorphous alcoholate was cooled with ice, and reacted with 10.16 g of diphenylchloroacetyl chloride, which was added in form of a solution in approximately 40 cc of toluene. The mixture was stirred for 1 hour at room temperature. Small amounts of unreacted sodium were destroyed with isopropanol, and 120 cc of 1 N hydrochloric acid were then added, The mixture was refluxed for 1/2 hour, in order to convert the first formed product, diphenylchloroacetic acid ester of 1-azabicyclo[2.2.2]-3-octanol, into the corresponding benzilic acid ester. The toluene phase was separated and discarded. The aqueous phase, together with a precipitated water- and toluene-insoluble oil, was made alkaline and extracted repeatedly with chloroform. The chloroform solution was concentrated in vacuo. The residue was recrystallized from a mixture of acetone and ether (alternatively, from chloroform and ether), and formed needles melting at 164° to 165°C. It was identified as 3-benziloyloxy-1azabicyclo[2.2.2]octane. 3-Benziloyloxy-1-azabicyclo[2.2.2]octane methobromide was prepared by adding 20 cc of a 30% solution of methyl bromide in ether to a solution of 2.5 g of 3-benziloyloxy-1-azabicyclo[2.2.2]octane in 20 cc of chloroform. After standing for 3 hours at room temperature and 15 hours at +5°C, a crystalline precipitate had formed. This was filtered off and recrystallized from a mixture of methanol, acetone, and ether; prisms melting at 240° to 241°C. References Merck Index 2320 Kleeman and Engel p. 219 PDR pp. 1510, 1606, 1999 I.N. p. 240 REM p. 914 Sternbach, L.H.; US Patent 2,648,667; August 11, 1953; assigned to Hoffmann-LaRoche, Inc.

1066

Clindamycin hydrochloride

CLINDAMYCIN HYDROCHLORIDE Therapeutic Function: Antibacterial Chemical Name: 7(S)-Chloro-7-deoxylincomycin hydrochloride Common Name: Structural Formula:

Chemical Abstracts Registry No.: 21462-39-5; 18323-44-9 (Base) Trade Name Dalacin-C Sobelin Cleocin Dalacin-C Dalacin Dalacin C Dalacin

Manufacturer Diethelm Upjohn Upjohn Upjohn Sumitomo Upjohn Alter

Country Switz. W. Germany US UK Japan Italy Spain

Year Introduced 1968 1968 1970 1970 1971 1975 -

Raw Materials Lincomycin hydrochloride Triphenylphosphine

Acetonitrile Hydrogen chloride

Manufacturing Process The following procedure is described in US Patent 3,475,407. A solution of 50 g of lincomycin hydrochloride, 120 g of triphenylphosphine, and 500 ml of acetonitrile in a 3 liter flask equipped with a stirrer was cooled in an ice bath and 500 ml of carbon tetrachloride was added in one portion. The reaction mixture was then stirred for 18 hours without addition of ice to the cooling

Clindamycin hydrochloride

1067

bath. The reaction was evaporated to dryness under vacuum on a 50° to 60°C water bath, yielding a clear, pale yellow viscous oil. An equal volume of water was added and the mixture shaken until all of the oil was dissolved. The resulting suspension of white solid (Ph3PO) was filtered through a sintered glass mat and discarded. The filtrate was adjusted to pH 11 by addition of 6 N aqueous sodium hydroxide. A solid precipitated. The resulting slurry was extracted with four 300 ml portions of chloroform. The aqueous phase was discarded. The combined chloroform extract was washed once with 100 ml of saturated aqueous sodium chloride solution and the sodium chloride phase was discarded. The chloroform phase was evaporated to dryness under vacuum on a 50° to 60°C water bath and an equal volume of methanol was added to the residue and the resulting solution heated at reflux for 1 hour. The methanol solution was evaporated to dryness under vacuum on a 50° to 60°C water bath. The residue was a clear pale yellow viscous oil. An equal volume of water and 10 ml of 37% aqueous HCl was added and the resultant was shaken until the oil dissolved and a white solid (more Ph3PO) remained in suspension. The suspension was filtered through a sintered glass mat at pH 1 to 2 and the solid discarded. The filtrate was extracted twice with 100 ml of carbon tetrachloride. The carbon tetrachloride phase was discarded. The aqueous phase was adjusted to pH 11 by addition of 6 N aqueous sodium hydroxide and extracted four times with 300 ml portions of chloroform. The combined chloroform extract was washed three times with 100 ml of saturated aqueous sodium chloride solution and the sodium chloride phase was discarded. The chloroform extract was dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated to dryness under vacuum on a 50° to 60 °C water bath. The residue was a clear, colorless glass weighing 45 g analyzing about 95% 7(S)chloro-7-deoxylincomycin. To the crude product there was added 100 ml of ethanol with warming until a clear solution was obtained. Then 150 ml ethyl acetate was added and the resultant filtered through a glass mat and the filtrate adjusted to pH 1 by the addition of saturated ethanolic HCl. Crystallization soon occurred. The resultant was allowed to stand at 0°C for 18 hours and then filtered through a sintered glass mat. The solid was dried under vacuum at 60°C for 18 hours yielding 35 g, a 67% yield of 7(S)-chloro7-deoxylincomycin hydrochloride as an ethanol solvate. References Merck Index 2321 Kleeman and Engel p. 220 PDR p. 1827 DOT 5 (1) 32 (1969) and 7 (5) 188 (1972) I.N. p. 240 REM p. 1209 Birkenmeyer, R.D.; US Patent 3,475,407; October 28, 1969; assigned to The Upjohn Company Kagan, F. and Magerlein, B.J.; US Patent 3,509,127; April 28, 1970; assigned to The Upjohn Company

1068

Clinofibrate

CLINOFIBRATE Therapeutic Function: Antihyperlipoproteinemic Chemical Name: 2,2'-[Cyclohexylidene-bis(4,1-phenyleneoxy)]bis[2methylbutanoic acid] Common Name: Structural Formula:

Chemical Abstracts Registry No.: 30299-08-2 Trade Name

Manufacturer

Country

Year Introduced

Lipocrin

Sumitomo

Japan

1981

Lipocyclin

Sumitomo

Japan

-

Raw Materials Bis-(phenyleneoxy)cyclohexane Methylethyl ketone Manufacturing Process Into a mixture of 6.0 g of a bishydroxyphenyl derivative, and 44.0 g of methyl ethyl ketone was added 16.2 g of crushed potassium hydroxide or sodium hydroxide. Chloroform was added dropwise into the above mixture with stirring at 20°C to 80°C, and the resultant mixture was heated for 20 hours under reflux to complete the reaction. Thereafter the reaction mixture was concentrated to give a residue. Into the residue was added water. After cooling, the resultant mixture was treated with activated charcoal and acidified by diluted hydrochloric acid or sulfuric acid to give an oily substance. The oily substance was extracted by ether and the ether solution was contacted with aqueous diluted Na2CO3 solution. The separated aqueous layer was washed with ether, acidified and again extracted with ether. The obtained ester layer was dried over anhydrous sodium sulfate and concentrated to give 1.0 g of a crude product which was purified by recrystallization or chromatography, to give crystals MP 143°C to 146°C (decomp.).

Clioquinol

1069

References Merck Index 2322 DFU 3 (12) 905 (1978) DOT 18 (5) 221 (1982) I.N.p.241 Nakamura, Y., Agatsuma, K., Tanaka, Y. and Aono, S.; US Patent 3,716,583; February 13, 1973; assigned to Sumitomo Chemical Co., Ltd. (Japan)

CLIOQUINOL Therapeutic Function: Antibacterial Chemical Name: 8-Quinolinol, 5-chloro-7-iodoCommon Name: Chinoform(um); Chlorjodhydroxycginolinum; Chloroiodoquine; Chlorojodochin; Cliochinolum; Clioquinol; Iodochlorhydroxyquin; Iodochloroxychinoline; Quiniodochlor Structural Formula:

Chemical Abstracts Registry No.: 130-26-7 Trade Name

Manufacturer

Country

Year Introduced

Clioquinol

CIBA-GEIGY Corp.

-

-

Clioquinol

Napp Chemicals Inc.

-

-

Clioquinol

Polychemical Laboratories Inc.

-

-

Clioquinol

Geneva Generics Inc. -

-

Clioquinol

-

-

Clioquinol

C and M Pharmaceutical Inc. UAD Laboratories Inc

-

-

Budoform

Dolder

-

-

Entero-Vioform

Ciba

-

-

Vioform

Ciba

-

-

Vioformio

Ciba-Geigy

-

-

Enterex

Mepha

-

-

Stanquinate

Smith Stanistreet

-

-

1070

Clobazam

Trade Name Enterol Iodochlorhydroxy quinolin Clioquinol

Manufacturer Vita CFM Oskar Tropitzsch Tianjin Mid-Chem Co., Ltd.

Country -

Year Introduced -

-

-

Raw Materials Chlor-5-oxy-8-chinoline Potassium iodide Sodium thiosulfate

Potassium hydroxide Chloride of lime Hydrochloric acid

Manufacturing Process Chlor-5-oxy-8-chinoline (18 kg) was mixed with potassium hydroxide (6.0 kg), water (400 kg) and heated. To this solution 50 L saturated aqueous solution of potassium iodide (16.6 kg) was added, mixed and continued to heat. Solution was filtered at room temperature. Then to this yellow solution the solution of chloride of lime and 50 kg 5% solution of were added then all this was mixed and allowed to stand for 24 h. After eliminating of free iodine by addition of sodium thiosulfate the obtained precipitate was washed with water. To residue 1% solution of acidum hydrochloricum (50.0 kg) and rapidly was heated to 50°C. Then it was washed with water and dried, so 5-chloro-7-iodo-quinolinol-8 was obtained, melting point 170°-175°C. References DR Patent No. 117,767; September 12, 1899; Assigned: Basler Chemische Fabrik in Basel

CLOBAZAM Therapeutic Function: Tranquilizer Chemical Name: 7-Chloro-1-methyl-5-phenyl-1H-1,5-benzodiazepine2,4(3H,5H)-dione Common Name: Structural Formula:

Clobazam

1071

Chemical Abstracts Registry No.: 22316-47-8 Trade Name Urbanyl Frisium Frisium Urbanul Frisium Castilium Clarmyl Clopax Karidium Noiafren Sentil Urbadan Urbanil Urbanol

Manufacturer Diamant Albert Pharma Hoechst Hoechst Hoechst Hoechst Roussel-Iberica Prodes Hoechst Hoechst Hoechst Roussel Sarsa Roussel

Country France Italy W. Germany Switz. UK Spain Spain Brazil -

Year Introduced 1975 1977 1978 1979 1979 -

Raw Materials N-Phenyl-N-(2-amino-5-chlorophenyl)malonic acid ethyl ester amide Sodium Ethanol Methyl iodide Manufacturing Process 1.65 g of N-phenyl-N-(2-amino-5-chlorophenyl)-malonic acid ethyl ester amide of MP 108° to 109°C are added to a sodium ethoxide solution, prepared from 20 ml of absolute alcohol and 150 mg of sodium. The solution is allowed to rest for 5 hours at room temperature. Then 1 ml of methyl iodide is added and the reaction mixture is refluxed for 7 hours. After evaporation of the solution in vacuo it is mixed with water and the solution is shaken with methylene chloride. The methylene chloride phase is dried and evaporated. By treatment of the residue with ethyl acetate/charcoal are isolated 500 mg of 7chloro-1-methyl-5-phenyl-1H-1,5-benzodiazepine-2,4-(3H,5H)-dione of MP 180° to 182°C. The yield amounts to 34% of theory. References Merck Index 2325 Kleeman and Engel p. 221 OCDS Vol. 2 p. 406 (1980) DOT9 (6) 240 (1973), 11 (1) 39 (1975) and 16 (1) 9 (1980) I.N. p. 241 REM p. 1083 Hauptmann, K.H., Weber, K.-H., Zeile, K., Danneberg, P. and Giesemann, R.; South African Patent 68/0803; February 7, 1968; assigned to Boehringer Ingelheim GmbH, Germany

1072

Clobenzorex hydrochloride

CLOBENZOREX HYDROCHLORIDE Therapeutic Function: Anorexic Chemical Name: Benzeneethanamine, N-((2-chlorophenyl)methyl)-α-methyl-, (+)-, hydrochloride Common Name: Clobenzorex hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 5843-53-8; 13364-32-4 (Base) Trade Name Asenlix Dinintel Finedal Rexigen

Manufacturer Aventis Roussel Diamant Llorente Bago

Country -

Year Introduced -

Raw Materials 2-Chlorobenzaldehyde Sodium borohydride Sodium hydroxide

D-1-Phenyl-2-amino-propane Hydrochloric acid

Manufacturing Process A solution of 21.0 g (0.15 mol) of 2-chlorobenzaldehyde in 100 ml of ethanol (95%) was added to a solution of 20.5 g (0.152 mol) of D-1-phenyl-2-aminopropane in 100 ml of ethanol (95%). After standing for 15 h at room temperature, the ethanol was driven off, and the oily residue was then distilled to yield 36.2 g (94%) of D-N-(2-chlorobenzylidene)-2-amino-1phenylpropane, boiling point 142°-146°C/0.1 mm Hg. To the solution of 36.0 g (0.14 mol) of D-N-(2-chlorobenzylidene)-2-amino-1phenylpropane in 200 ml of dry methanol were added, in portions, 5.3 g (0.14 mol) of sodium borohydride. The mixture was stirred for 1 h at room temperature, and refluxed for 1 h water (100 ml) was then added and the methanol was removed in vacuo. After acidifying carefully with dilute hydrochloric acid, the solution was made alkaline by dilute sodium hydroxide, and extracted with ether. 33.0 g (90%) of D-N-(1-phenyl-2-propyl)-2chlorobenzylamine, boiling point 132°-134°C/0.1 mm Hg, were obtained by distillation.

Clobenztropine hydrochloride

1073

References GB Patent No. 1,123,565; Nov. 23, 1965; Assigned: Societe Industrielle Pour la Fabrication, des Antibiotiques (S.I.F.A.), Paris, France

CLOBENZTROPINE HYDROCHLORIDE Therapeutic Function: Antihistaminic Chemical Name: 3-((p-Chloro-α-phenylbenzyl)oxy)tropane hydrochloride Common Name: Chlorobenztropine hydrochloride; Clobenztropine hydrochloride; Teprin Structural Formula:

Chemical Abstracts Registry No.: 5627-46-3 (Base); 14008-79-8 Trade Name

Manufacturer

Country

Year Introduced

Clobenztropine hydrochloride

Onbio Inc.

-

-

Raw Materials 3-Tropanol Potassium carbonate Potassium hydroxide

4-Chlorobenzhydryl chloride Hydrochloric acid Isopropanoic acid hydrogen chloride

Manufacturing Process A solution of 28.2 g (0.2 mol) of 3-tropanol is prepared in 50 ml of xylol, and to this solution is added 23.8 g (0.1 mol) of 4-chlorobenzhydryl chloride. The resultant solution is heated for 7 h at 145°-155°C, following which the mixture is cooled and filtered. The clear filtrate thus obtained is washed with 50 ml of 5% aqueous potassium carbonate solution and then with three successive 25 ml portion of water. The xylol solution is then extracted with three successive 50 ml portions of 2 N hydrochloric acid. The xylol layer is discarded and the acid extracts are combined and rendered strongly basic by the addition of 22.5% aqueous potassium hydroxide, resulting in the formation of an oily base which separates and which is then extracted with

1074

Clobetasol

benzol, from which the benzol is evaporated to yield crude 3-(4'chlorobenzhydryloxy)tropane as a brown oil. 2.0 g of 3-(4'-chlorobenzhydryloxy)tropane is treated with 10 ml of 4.5 N isopropanoic acid hydrogen chloride solution, and the pasty mixture which results is diluted with approximately 30 ml of absolute ether. A solid product is formed which is separated by filtration and then washed with absolute ether. The product is then purified by dissolving it in hot isopropanol, followed by clarification with activated charcoal. Upon cooling the filtrate, the 3-(4'chlorophenylbenzyloxy)tropane separates as a crystalline powder, melting point 215°-217°C. In practice it is usually used as hydrochloride. References Nield C.H., Bosch W.F.X.; US Patent No. 2,782,200; Feb. 19, 1957; Assigned: Schenley Laboratories, Inc., New York, N.Y., a corporation of Delaware

CLOBETASOL Therapeutic Function: Corticosteroid, Antiinflammatory Chemical Name: 21-Chloro-9-fluoro-11β,17-dihydroxy-16β-methylpregna1,4-diene-3,20-dione Common Name: Structural Formula:

Chemical Abstracts Registry No.: 25122-41-2; 25122-46-7 (Propionate) Trade Name Dermovate Dermoxin Clobesol Dermoval Dermovate Dermadex

Manufacturer Glaxo Glaxo Glaxo Glaxo Glaxo Glaxo

Country UK W. Germany Italy France Japan -

Year Introduced 1973 1976 1977 1978 1979 -

Clobutinol

1075

Raw Materials Betamethasone-21-methanesulfonate Lithium chloride Propionic anhydride Manufacturing Process A solution of betamethasone 21-methanesulfonate (4 g) in dimethylformamide (25 ml) was treated with lithium chloride (4 g) and the mixture heated on the steam bath for 30 minutes. Dilution with water gave the crude product which was recrystallized to afford the title compound, MP 226°C. Clobetasol is usually converted to the propionate as the useful form by reaction with propionic anhydride. References Merck Index 2330 Kleeman and Engel p. 222 DOT 9 (8) 339 (1973) I.N. p. 242 Elks, J., Phillipps, G.H. and May, P.J.; US Patent 3,721,687; March 20, 1973; assigned to Glaxo Laboratories Limited, England

CLOBUTINOL Therapeutic Function: Antitussive Chemical Name: 4-Chloro-α-[2-(dimethylamino)-1-methylethyl]-a-methyl benzeneethanol Common Name: Structural Formula:

Chemical Abstracts Registry No.: 14860-49-2; 1215-83-4 (Hydrochloride salt) Trade Name Silomat Silomat

Manufacturer Boehringer Ingelheim Thomae

Country Switz. W. Germany

Year Introduced 1960 1960

1076

Clobutinol

Trade Name

Manufacturer

Country

Year Introduced

Camaldin

Italy

1962

Silomat

Boehringer Ingelheim Badrial

France

1969

Silomat

Morishita

Japan

1975

Biotertussin

Bioter

-

-

Lomisat

Boehringer Ingelheim Violani-Farmavigor Italy

Pertoxil

-

Raw Materials 3-Methyl-4-dimethylamino-butanone-(2) Magnesium p-Chlorobenzyl chloride Hydrogen chloride Manufacturing Process A solution of 0.2 mol (33 g) of 3-methyl-4-dimethylamino-butanone-(2) [produced according to Mannich, Arch. Pharm., vol. 265, page 589 (1927)] in 50 cc absolute ether was added dropwise, while stirring and cooling with ice, to a Grignard solution of 0.4 mol p-chlorobenzylmagnesium-chloride which was produced from 64.5 g p-chlorobenzyl-chloride and 9.8 g magnesium in 200 cc absolute ether. The reaction product was heated for an additional onehalf hour under reflux to bring the reaction to completion, and thereafter the reaction mixture was decomposed into an ether phase and an aqueous phase with about 50 cc concentrated hydrochloric acid and about 200 g ice. The ether phase was discarded and the aqueous phase was adjusted to an alkaline pH with ammonia and then thoroughly extracted with ether. After concentrating the united, dried ether extract solutions, the oily residue was fractionally distilled. The reaction product was obtained in the form of a colorless oil having a boiling point of 179° to 181°C. The yield was 48.5 g corresponding to 95% of theory. The hydrochloride addition salt of the above reaction product was prepared in customary fashion, that is, by reaction with hydrochloric acid, followed by fractional crystallization from a mixture of alcohol and ether. The two possible racemic forms were obtained thereby. The difficultly soluble racemate had a melting point of 169° to 170°C and the more readily soluble racemate had a boiling point of 145° to 148°C. References Merck Index 2332 Kleeman and Engel p. 224 OCDS Vol. 2 p. 121 (1980) I.N.p. 242 Berg, A.; US Patent 3,121,087; February 11, 1964; assigned to Dr. Karl Thomae GmbH, Germany

Clocapramine

1077

CLOCAPRAMINE Therapeutic Function: Neuroleptic Chemical Name: 1'-[3-(3-Chloro-10,11-dihydro-5H-dibenz[b,f]azepin-5yl)propyl][1,4-bipiperidine]-4]carboxamide Common Name: Clocarpramine Structural Formula:

Chemical Abstracts Registry No.: 47739-98-4 Trade Name

Manufacturer

Country

Year Introduced

Clofekton

Yoshitomi

Japan

1974

Raw Materials 3-Chloro-5-(3-chloropropyl)-10,11-dihydro-5H-dibenz[b,f]azepine 4-Carbamoyl-4-piperidinopiperidine Manufacturing Process A mixture of 5.0 g of 3-chloro-5-(3-chloropropyl)-10,11-dihydro-5Hdibenz[b,f]azepine, 5.0 g of 4-carbamoyl-4-piperidinopiperidine and 50 ml of dimethylformamide is heated at 100°C for 10 hours. The solvent is distilled off. After the addition of a 2% sodium carbonate solution to the flask, the content is scratched to yield a semisolid, which is dissolved in 50 ml of isopropanol. A solution of 5 g of maleic acid in 50 ml of isopropanol is added, and the precipitate is collected by filtration and recrystallized from isopropanol to give 5.6 g of crystalline 3-chloro-5-[3-(4-carbamoyl-4-piperidinopiperidino) propyl]-10,11-dihydro-5H-dibenz[b,f]azepine di(hydrogen maleate) with 1/2 molecule of water of crystallization melting at 181°C to 183°C. References Merck Index 2334 Kleeman and Engel p. 224 OCDS Vol. 2 p. 416 (1980) DOT 10 (5) 161 (1974) I.N. p. 243 Nakanishi, M. and Tashiro, C.; US Patent 3,668,210; June 6, 1972; assigned to Yoshitomi Pharmaceutical Industries, Ltd. (Japan)

1078

Clocortolone

CLOCORTOLONE Therapeutic Function: Glucocorticoid Chemical Name: 9-Chloro-6α-11β21-dihydroxy-16α-methylpregna-1,4-diene3,20-dione Common Name: Clocortolone Structural Formula:

Chemical Abstracts Registry No.: 4828-27-7 Trade Name Clocortolone Clocortolone CLODERM

Manufacturer Schering AG Germapharm DFB Pharmaceuticals, Inc.

Country -

Year Introduced -

Raw Materials 6α-Fluoro-16α-methyl-21-hydroxy-1,4,9(11)-pregnatriene-3,20-dione Nitroethane Perchloric acid t-Butyl hypochlorite Sodium sulfite Manufacturing Process 6α-Fluoro-16α-methyl-21-hydroxy-1,4,9(11)-pregnatriene-3,20-dione is suspended in nitroethane at heating. To this suspension 1 N perchloric acid is added and then t-butyl hypochlorite is added dropwise. The reaction mixture is agitated at heating, then cooled to room temperature, mixed with methanol, stirred and then poured with water containing ice. The mixture is then stirred, thus precipitated product is filtered, washed neutral with water, dried; The crude product is treated with hot methanol, and recrystallized from ethanol, thus 9α-chloro-6α-fluoro-11β,21-dihydroxy-16α-methyl-1,4pregnadiene-3,20-dione was obtained.

Clofedanol hydrochloride

1079

References Kaspar E. et al.; US Patent No. 3,729,495; April 24, 1973; Schering A.G., Berlin, Germany

CLOFEDANOL HYDROCHLORIDE Therapeutic Function: Antitussive Chemical Name: Benzenemethanol, 2-chloro-α-(2-(dimethylamino)ethyl)-αphenyl-, hydrochloride Common Name: Chlophedianol hydrochloride; Clofendanol hydrochloride; Tigonal Structural Formula:

Chemical Abstracts Registry No.: 511-13-7 Trade Name Abehol Alivin Antitussin Antitussin

Manufacturer Pliva Grossmann Sopharma Yick-Vic Chemicals and Pharmaceuticals (HK) Ltd

Country -

Year Introduced -

Chlophedianol hydrochloride Coldrin Coldrin Detigon linctus Tussigon

Shanghai Lancheng Corporation Janssen Cilag Nippon Shinyaku Bayer (India) Limited King Pharmaceuticals, Inc.

-

-

-

-

Tussistop

Atral

-

-

Raw Materials Sodium amide o-Chlorobenzophenone

1080

Clofexamide

Cobalt Raney Formaldehyde Nickel Raney Acetonitrile Hydrogen Manufacturing Process To a suspension of 330.0 g of sodamide (moistened with toluene) in 1500 ml of absolute ether, a solution of 1080.0 g of o-chlorobenzophenone and 350.0 g of acetonitrile in 3500 ml of absolute ether was gradually added dropwise, with stirring, such that the reaction temperature adjusted itself to 28°-30°C. The reaction mixture was stirred for 12 to 15 h at room temperature and was then added carefully to some ice water. The resulting solution was extracted 3 times with ether. The ether solution was washed with water, dried over Na2SO4, filtered, and finally concentrated. When 1 L of petroleum ether was added, 1240.0 g (96% of theoretical) of β-phenyl-β-o-chlorophenylhydroacrylonitrile (melting point 90°-92°C) precipitated. 500.0 g of the β-phenyl-β-o-chlorophenyl-hydroacrylonitrile were dissolved in 3 L of methanol and hydrogenated in the presence of 50.0 g of Raney cobalt at a temperature of 60°-70°C and a pressure of 80-85 ATM. Two moles of hydrogen were absorbed, and after separation of the methanolic solution from the catalyst, 450.0 g of 1-o-chlorophenyl-1-phenyl-3-aminopropanol-1 of melting point 117°C were obtained. Catalytic methylation of 1-o-chlorophenyl-1-phenyl-3-aminopropanol-1 (hydrogenation in the presence of 2.2 mol of formaldehyde in aqueous methanol with Raney nickel catalyst) yielded 450.0 g of l-o-chlorophenyl-1phenyl-3 dimethylaminopropanol-1 of melting point 120°C. In practice it is usually used as hydrochloride. References Lorenz R. et al.; US Patent No. 3,031,377; April 24, 1962; Assigned: Farbenfabriken Bayer Aktiengesellschaft, a corporation of Germany

CLOFEXAMIDE Therapeutic Function: Antidepressant, Analgesic, Antiinflammatory, Local anesthetic Chemical Name: Acetamide, 2-(4-chlorophenoxy)-N-(2-(diethylamino)ethyl)Common Name: Clofexamide; Amichlophen Chemical Abstracts Registry No.: 1223-36-5

Clofezone

1081

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Clofexamide

CNRS

-

-

Raw Materials N,N-Diethylethylenediamine Chloride of p-chlorophenoxyacetic acid Soda lye Manufacturing Process In 1 L of water there is dissolved 116.0 g (1 mole) of N,Ndiethylethylenediamine and, under vigorous stirring at a temperature maintained below 50°C, there is added 205.0 g (1 mole) of the chloride of pchlorphenoxyacetic acid. The solution becomes rapidly homogeneous; the formation of the basic amide hydrochloride is rapidly completed by further stirring the reaction mixture for 2 h at about 20°C. Then an excess of soda lye is added and the basic amide formed is extracted by ether. The ethereal solution is dried on anhydrous sodium sulfate and ether is distilled after that the residue is dried. So 2-(p-chlorophenoxy)-N-(2-(diethylamino)ethyl) acetamide is obtained. References GB Patent No. 942,761; November 27, 1963; Assigned: Centre National De La Recherche Scientifique, Paris, France

CLOFEZONE Therapeutic Function: Analgesic, Antiinflammatory Chemical Name: Equimolar mixture of clofexamide which is 2-(pchlorophenoxy)-N-[2-(diethylamino)ethyl]acetamide with phenylbutazone Common Name: Chemical Abstracts Registry No.: 17449-96-6; 60104-29-2 (Dihydrate)

1082

Clofezone

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Perclusone

Anphar-Rolland

France

1967

Perclusone

Heinrich Mack

W. Germany

1974

Panas

Grelan

Japan

1976

Perclusone

Pierrel

Italy

1976

Perclusone

Abic

Israel

-

Perclustop

Uquifa

Spain

-

Raw Materials Phenylbutazone p-Chlorophenoxyacetic acid diethylamino ethylamide (Clofexamid) Manufacturing Process 935 g of phenylbutazone are dissolved, with heating to a lukewarm state, in 2.7 liters of acetone containing 20% water, and the mixture is filtered if necessary. 853.5 g of p-chlorophenoxyacetic acid diethylamino ethylamide are dissolved in 300 cc of acetone containing 20% water, and the solution is poured into the phenylbutazone solution. There is slight heating, and the solution clarifies. The salt crystallizes rapidly. Drying is effected on a Buchner funnel and the mixture is washed in 450 cc of acetone containing 20% of water. The 1,702 g of product obtained is recrystallized in 2,450 cc of acetone containing 20% of water and, after drying in an oven at 37°C, 1,585 g (86%) of product are obtained. The product is in the form of a white crystalline powder having a melting point of from 87° to 89°C in the Maquenne block. References Kleeman and Engel p. 227 I.N.p. 245 Rumpf, P. and Thuillier, J.E.; US Patent 3,491,190; January 20, 1970

Clofibrate

1083

CLOFIBRATE Therapeutic Function: Antihyperlipidemic Chemical Name: 2-(4-Chlorophenoxy)-2-methylpropanoic acid ethyl ester Common Name: Ethyl p-chlorophenoxyisobutyrate Structural Formula:

Chemical Abstracts Registry No.: 637-07-0 Trade Name

Manufacturer

Country

Year Introduced

Atromid-S

I.C.I.

UK

1963

Skleromexe

Merckle

W. Germany

1964

Atromid-S

Ayerst

US

1967

Atromidin

I.C. Pharma

Italy

1969

Liposid

Ohta

Japan

1970

Amotril

Sumitomo

Japan

-

Apoterin A

Seiko

Japan

-

Arterioflexin

Arcana

Austria

-

Arterioflexin

Protea

Australia

-

Artes

Farmos

Finland

-

Artevil

N.C.S.N.

Italy

-

Ateculon

Nippon Chemiphar Japan

-

Ateles

Tokyo Hosei

Japan

-

Atemarol

Kowa

Japan

-

Ateriosan

Finadiet

Argentina

-

Aterosol

Ferrosol

Denmark

-

Athebrate

Karenyaku

Japan

-

Atherolate

Fuji Zoki

Japan

-

Atheromide

Ono

Japan

-

Atherolip

Solac

France

-

Atheropront

Mack

W. Germany

-

Atmol

Taisho

Japan

-

Atosterine

Kanto

Japan

-

Atrofort

Dif-Dogu

Turkey

-

1084

Clofibrate

Trade Name

Manufacturer

Country

Year Introduced

Atrolen

Firma

Italy

-

Atromidin

I.C. Pharma

Italy

-

Atrovis

Novis

Israel

-

Auparton

Samya

Japan

-

Binograc

Zeria

Japan

-

Bioscleran

Pfleger

W. Germany

-

Bresit

Toyo Jozo

Japan

-

Cartagyl

Sopar

Belgium

-

Cholenal

Yamanouchi

Japan

-

Cholestol

Toho

Japan

-

Cholesrun

Hokuriku

Japan

-

Citiflus

C.T.

Italy

-

Claresan

Sarbach

France

-

Claripex

I.C.N.-Usafarma

Brazil

-

Clarol

Toyama

Japan

-

Climinon

Meiji

Japan

-

Cloberat

Negroni

Italy

-

Clobrat

Weifa

Norway

-

Clobrate

Chugai

Japan

-

Clobren

Morishita

Japan

-

Clof

Siegfried

Switz.

-

Clofbate

Mohan

Japan

-

Clofibral

Farmochimica

Italy

-

Clofinit

Gentili

Italy

-

Clofipront

Mack

W. Germany

-

Clofirem

Roland-Marie

France

-

Deliva

Nippon Kayaku, Co.

Japan

-

Geromid

Zoja

Italy

-

Healthstyle

Sawai

Japan

-

Hyclorate

Funai

Japan

-

Hypocerol

Fuso

Japan

-

Ipolipid

Isnardi

Italy

-

Klofiran

Remeda

Finland

-

Levatrom

Abic

Israel

-

Lipavil

Farmades

Italy

-

Lipavlon

Avlon

France

-

Lipidicon

Aristochimica

Italy

-

Liprinal

Bristol

UK

-

Liprinal

Banyu

Japan

-

Clofibrate

1085

Trade Name

Manufacturer

Country

Year Introduced

Miscleron

Chinoin

Hungary

-

Normolipol

Delagrange

France

-

Novofibrate

Novopharm

Canada

-

Recolip

Benzon

Denmark

-

Sclerovasal

I.T.I.

Italy

-

Scrobin

Nikken

Japan

-

Sklero-Tablinen

Sanorania

W. Germany

-

Ticlobran

Siegfried

Switz.

-

Xyduril

Dorsh

W. Germany

-

Yoclo

Shinshin

Japan

-

Raw Materials p-Chlorophenoxyisobutyric acid Ethanol Manufacturing Process The ethyl p-chlorophenoxyisobutyrate may be obtained by heating a mixture of 206 parts of dry p-chlorophenoxyisobutyric acid, 1,000 parts of ethanol and 40 parts of concentrated sulfuric acid under reflux during 5 hours. The alcohol is then distilled off and the residue is diluted with water and extracted with chloroform. The chloroform extract is washed with sodium hydrogen carbonate solution, dried over sodium sulfate and the chloroform removed by distillation. The residue is distilled under reduced pressure and there is obtained ethyl pchlorophenoxyisobutyrate, BP 148° to 150°C/20 mm. The p-chlorophenoxyisobutyric acid used as starting material may be obtained as follows. A mixture of 200 parts of p-chlorophenol, 1,000 parts of acetone and 360 parts of sodium hydroxide pellets is heated under reflux and 240 parts of chloroform are gradually added at such a rate that the mixture continues to reflux without further application of heat. When addition is complete the mixture is heated under reflux during 5 hours and then the acetone is removed by distillation. The residue is dissolved in water, acidified with hydrochloric acid and the mixture extracted with chloroform. The chloroform extract is stirred with sodium hydrogen carbonate solution and the aqueous layer is separated. The alkaline extract is acidified with hydrochloric acid and filtered. The solid product is drained free from oil on a filter pump, then washed with petroleum ether (BP 40° to 60°C), and dried at 50°C. The solid residue, MP 114° to 116°C, may be crystallized from methanol (with the addition of charcoal) to give p-chlorophenoxyisobutyric acid, MP 118° to 119°C. References Merck Index 2340 Kleeman and Engel p. 227

1086

Clofibride

PDR p. 613 OCDS Vol. 1 p. 119 (1977) and 2 pp. 79, 101, 432 (1980) DOT 11 (4) 141 (1975) I.N. p. 245 REM p. 863 Jones, W.G.M., Thorp, J.M. and Waring, W.S.; US Patent 3,262,850; July 26, 1966; assigned to Imperial Chemical Industries Limited, England

CLOFIBRIDE Therapeutic Function: Antihyperlipidemic Chemical Name: 3-(Dimethylaminocarbonyl)-propyl-4'chlorophenoxyisobutyrate Common Name: Structural Formula:

Chemical Abstracts Registry No.: 26717-47-5 Trade Name

Manufacturer

Country

Year Introduced

Lipenan

Charpentier

France

1974

Evimot

Muller Rorer

W. Germany

1978

Raw Materials Ethyl 4'-chlorophenoxyisobutyrate 4-Hydroxy-N,N-dimethylbutyramide Manufacturing Process 48.5 parts of ethyl 4'-chlorophenoxyisobutyrate are dissolved in 200 parts by volume of dry toluene in the presence of 262 parts of 4-hydroxy-N,Ndimethylbutyramide and 2 parts of aluminum isopropylate. The solution is heated for 8 hours, while collecting the toluene-ethanol azeotrope, in an apparatus provided with a distillation column at a controllable rate of reflux. After this it is filtered ,the solvent is evaporated in vacuo and the residue is distilled. An almost colorless, slightly yellow oil is obtained, the purity of which by chromatographic examination in the gaseous phase is of the order of 99.5%. Its boiling point is 175°C under 0.1 torr.

Clofoctol

1087

This oil is kept supercooled at the ambient temperature. Crystallization may be obtained by cooling or by seeding with crystals of the product. The melting point is 34°C (instantaneous on the Maquenne block). The product can be recrystallized. For this, it is dissolved, for example, at the ambient temperature in petrol ether, ethyl ether or isopropyl ether, and this solution is cooled at about -50°C while stirring. After drying over sulfuric acid under vacuum, white needles of very great purity are thus obtained. References DOT 9 (5) 169 (1973) I.N. p. 246 Nordmann, J., Mattioda, G.D. and Loiseau, G.P.M.H.; US Patent 3,792,082; February 12, 1974; assigned to Ugine Kuhlmann

CLOFOCTOL Therapeutic Function: Antiinfective, Bacteriostatic Chemical Name: 2-(2,4-Dichlorobenzyl)-4-(1,1,3,3-tetramethylbutyl)phenol Common Name: Structural Formula:

Chemical Abstracts Registry No.: 37693-01-9 Trade Name

Manufacturer

Country

Year Introduced

Octofene

Debat

France

1978

Raw Materials p-(1,1,3,3-Tetramethylbutyl)phenol 2,4-Dichlorobenzyl chloride Zinc chloride

1088

Clometacin

Manufacturing Process The following were introduced into a 1 liter flask provided with a reflux condenser: 206 g (1 mol) of p-(1,1,3,3-tetramethylbutyl)-phenol, 147 g (0.75 mol) of 2,4-dichlorobenzyl chloride, 27 g (0.2 mol) of pure melted zinc chloride, and 750 ml of anhydrous chloroform. The mixture was heated to reflux for 24 hours. The chloroformic reaction mixture was washed with water, and then dried over anhydrous sodium sulfate. The chloroform was evaporated off and the oil obtained was fractionally distilled under a pressure of 0.2 mm Hg. The fraction distilling at 140°C to 160°C, being the desired product indicated above, was collected and crystallized. Yield: 94 g (32% of theory); MP 78°C (after recrystallization in petroleum ether). References Kleeman and Engel p. 228 DOT 15 (4) 171 (1979) I.N. p. 246 Debat, J.; US Patent 3,830,852; August 20, 1974; assigned to Institute de Recherches Chimiques et Biologiques Appliquees (I.R.C.E.B.A.) (France)

CLOMETACIN Therapeutic Function: Analgesic, Antiinflammatory Chemical Name: 1H-Indole-1-acetic acid, 3-(4-chlorobenzoyl)-6-methoxy-2methylCommon Name: Clometacin; Mindolic acid Structural Formula:

Chemical Abstracts Registry No.: 25803-14-9 Trade Name

Manufacturer

Country

Year Introduced

Clometacin

Roussel-Uclaf (Aventis)

-

-

Clometacin

1089

Raw Materials 2-Nitro-4-methoxybenzaldehyde Nitroethane Palladium on charcoal N,N-Dimethyl-p-chlorobenzamide Sodium hydride Potassium hydroxide

Acetic acid Ammonium acetate Hydrogen Phosphorus oxychloride Methyl monochloroacetate

Manufacturing Process Preparation of 1-carboxymethyl-2-methyl-3-p-chlorobenzoyl-6-methoxy-indole STEP A: 1-(2'-Nitro-4'-methoxyphenyl)-2-methyl-2-nitroethylene 15.0 g of 2-nitro-4-methoxybenzaldehyde (Boon, Soc., 1949 Suppl., p. 230) were introduced into a mixture of 75 ml of acetic acid, 9.5 ml of nitroethane and 6.5 gm of ammonium acetate and the resulting mixture was heated to reflux and held there for 2 h. After cooling the mixture to room temperature, the mixture was added to ice water and the precipitate formed was recovered by vacuum filtration. The precipitate was washed with water and twice crystallized from ethanol and treated with carbon black to obtain 9.6 gm of 1(2'-nitro-4'-methoxyphenyl)-2-methyl-2-nitroethylene having a melting point of 111°C. STEP B: 2-Methyl-6-rnethoxyindole 32 g of 1-(2'-nitro-4'-methoxyphenyl)-2-methyl-2-nitroethylene and 3.2 g of palladized charcoal con training 18% palladium were introduced into a mixture of 320 ml of ethyl acetate, 48 ml of ethanol and 240 ml of acetic acid and after a purge with nitrogen then with hydrogen, the mixture was agitated under a hydrogen atmosphere. The reaction temperature was allowed to rise to 50°C and was held at that temperature by cooling. 18.2 L of hydrogen were absorbed in 3 h after which the reaction mixture was purged with nitrogen and the catalyst was removed by filtration. The reaction mixture was concentrated to dryness under reduced pressure and the residue was dissolved in methylene chloride. The methylene chloride solution was washed with an aqueous solution of sodium bicarbonate, with water, was dried and concentrated to dryness under reduced pressure. The residue was crystallized from petroleum ether (boiling point 65-75°C) and the resulting product was dissolved in ether. The ether solution was filtered over alumina and 6.4 g of 2methyl-6-methoxy-indole having a melting point of 104°C were obtained there from. STEP C: 2-Methyl-3-p-chlorobenzoyl-6-methoxyindole 9 g of 2-methyl-6-methoxy-indole were added to a suspension of 20.6 g of N, N-dimethyl-p-chlorobenzamide and 6.4 ml of phosphorus oxychloride. The interior reaction temperature obtained was brought to 60°C and rapidly rose to 115°C, the temperature was reduced and held for 2 h at 85°C. The temperature was then reduced to 50°C and the reaction mixture was added to water and then 400 ml of ethanol were added thereto. The reaction mixture was adjusted to a pH of 10 by the addition of sodium hydroxide solution and

1090

Clomethiazole

was stirred at room temperature overnight. The precipitate was recovered by filtration and washed with water until the wash-waters were neutral. The precipitate was impasted with 20 ml of ethanol at 20°C, vacuum filtered and dried at 60°C to obtain 16.5 g of 2-methyl-3-p-chlorobenzoyl-6-methoxyindole having a melting point of 208°C. Step D: Methyl ester of 1-carboxymethyl-2-methyl-3-p-chlorobenzoyl-6methoxyindole 20 ml of dimethylformamide were added to 0.32 g of a 50% suspension of sodium hydride in oil and then a solution of 2 g of 2-methyl-3-pchlorobenzoyl-6-methoxy-indole in 20 ml of dimethylformamide was added thereto. After hydrogen evolution ceased, a solution of 1 g of methyl monochloroacetate in 5 ml of dimethylformamide was added and the reaction mixture was stirred overnight at room temperature. The mixture was evaporated to dryness and the residue was taken up in water and vacuum filtered. The crystals were washed with water and dried in vacuum at 60°C to obtain 2.5 g of product which was purified by recrystallization from hot and cold methanol to give 1.9 g of the methyl ester of 1-carboxymethyl-2-methyl3-p-chloro-benzoyl-6-methoxy-indole having a melting point of 148-149°C as yellow crystals. STEP E: 1-Carboxymethyl-2-methyl-3-p-chlorobenzoyl-6-methoxy-indole 2.25 g of potassium hydroxide were dissolved in 100 ml of methanol and 5 ml of water and then 7.45 g of the methylester of 1-carboxymethyl-2methylchlorobenzoyl-6-methoxy-indole were added thereto. The mixture was heated at reflux for 1 h and then was concentrated to dryness. The residue was taken up in 70 ml of boiling water and the solution was filtered while hot. The filtrate was cooled to 20°C and acidified to a pH of 1 by the addition of 30 ml of 2 N hydrochloric acid. The precipitate was recovered by vacuum filtration and was washed with water, then methanol and finally ether and was dried at 70°C. The resulting 6.3 g of product was purified by recrystallization from ethanol to obtain 3.7 g of 1-carboxymethyl-2-methyl-3-p-chloro-benzoyl6-methoxyindole having a melting point of 242°C. References Allais A., Nomine G.; US Patent No. 3,856,967; Dec. 24, 1974; Assigned: Roussel Uclaf, Paris, France

CLOMETHIAZOLE Therapeutic Function: Anticonvulsant, Hypnotic, Sedative Chemical Name: 5-(2-Chloroethyl)-4-methylthiazole Common Name: Chlormethiazol; Clomethiazole Chemical Abstracts Registry No.: 533-45-9

Clometocillin potassium

1091

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Clomethiazole

Hoffmann La Roche (Roche)

-

-

Raw Materials 1,3-Dichlorpentanon-4 Hydrogen chloride

Ammonium dithiocarbamate Hydrogen peroxide

Manufacturing Process 2-Mercapto-4-methyl-5-(2-chlorethyl)-1,3-thyazol is produced as a result of reaction of 1,3-dichlorpentanon-4 with ammoniumdithiocarbamat (melting point 128°C). To 193,5 g 2-mercapto-4-methyl-5-(2-chlorethyl)-1,3-thyazol 600.0 g 35% HCl is added and heated to 60°C, after this 30.0 g hydrogen peroxide is added. After oxidation the mixture is treated by BaCl2 filtered, washed by ether and dried. So 4-methyl-5-(2-chlorethyl)-1,3-thyazol is obtained. References CH Patent No. 200,248; March 12, 1937; Assigned: F. Hoffmann-La Roche and Co Aktiengesellschaft, Basel (Schweiz).

CLOMETOCILLIN POTASSIUM Therapeutic Function: Antibiotic Chemical Name: (3,4-Dichloro-alpha-methoxybenzyl)penicillin potassium Common Name: Chlomethocillin potassium; Clometocillin potassium; Penicillin 356 Chemical Abstracts Registry No.: 15433-28-0; 1926-49-4 (Base) Trade Name

Manufacturer

Country

Year Introduced

Clometocillin potassium

Ribbon

-

-

Rixapen

Menarini

-

-

1092

Clometocillin potassium

Structural Formula:

Raw Materials 6-Aminopenicillanic acid Phosphoric acid Triethylamine Ethylchloroformate Potassium hydroxide

Potassium bicarbonate α-Methoxy-3,4-dichloro-phenylacetyl chloride α-Methoxy-4-chlorophenyl acetic acid

Manufacturing Process 2 Methods of producing of clometocillin: 1. 6-Aminopenicillanic acid (2.16 g) is dissolved in 20 ml of a one molar aqueous solution of potassium bicarbonate and 10 ml of acetone. The resultant solution is cooled in an ice-water bath and to it is added with stirring a solution of 2.7 g of alpha-methoxy-3,4-dichloro-phenylacetyl chloride in 10 ml of acetone. The pH is adjusted to 7-8 and upon completion of the addition the reaction medium is stirred for 15 min at ice bath temperature and then for 2.5 h at room temperature, maintaining the pH range between 7 and 8. The solution is extracted once with ether and then adjusted to pH 2.5 with 20% phosphoric acid. The acidic solution is extracted once with 30 ml of butyl acetate and again with 10 ml of butyl acetate. These combined butyl acetate extracts are thereafter successively washed twice with water and reextracted at pH 7 with 0.5 N aqueous potassium hydroxide solution. The aqueous layer is washed twice with ether and the remaining organic solvent is then removed by evaporation under reduced pressure. The washed aqueous layer is then lyophilized and the residue thus obtained taken up in acetone. The crystal line product is collected by filtration and dried to yield the potassium salt of 6-(αmethoxy-3,4-dichlorophenylacetamido)penicillanic acid. Upon treatment with mineral acid of an aqueous solution of the compound so prepared, there is obtained the free acid, 6-(α-methoxy-3,4-dichlorophenylacetamido)penicillanic acid. 2. A solution of 19.2 g (0.096 mole) of α-methoxy-4-chlorophenyl acetic acid in 200 ml of acetone is cooled in an ice bath to 0°C. To the cooled solution is added 10.2 g (0.1 mole) of triethylamine in 100 ml of acetone. The temperature of the reaction mixture is maintained at 10°C and a solution of 11.0 g (0.1 mole) of ethylchloroformate in 45 ml of acetone is added dropwise with agitation so as to maintain a final reaction temperature of -5°C. To this mixture is then slowly added with stirring a solution of 23.8 g (0.11 mole) of 6-aminopenicillanic acid in 40 ml of water and 15 ml of triethylamine. Upon completion of the addition, the mixture is stirred while attaining room

Clomiphene dihydrogen citrate

1093

temperature and then stirred for an additional 1.5 h. The mixture is extracted with three portions of 300 ml, of ether and the resulting aqueous solution adjusted to pH 2.0 with 6 N sulfuric acid, maintaining a temperature of less than 10°C. At pH 2, the solution is extracted with 250 ml, of butyl acetate and then extracted twice with 75 ml each of butyl acetate. To the combined butyl acetate extracts are added 250 ml of water and the pH adjusted to 8.0 by the addition of sodium bicarbonate. The layers are separated and the aqueous layer adjusted to 2.0 by the addition of 6 N sulfuric acid at less than 10°C. This acid aqueous mixture is next extracted with 200 ml of butyl acetate and the organic extract extracted once with water and dried over sodium sulfate. To the butyl acetate solution is added with vigorous stirring a solution of potassium hydroxide in n-butanol (40 g/l) until the pH of the reaction mixture is 8.4. The mixture is then cooled until crystallization occurs. The crystals are collected by centrifugation, washed with a small amount of acetone and dried. These dried crystals are recrystallized from butanol and retried to yield 6-(αmethoxy-4-chlorophenylacetamido)penicillanic acid as the potassium salt. Treatment with acid yields the corresponding free acid 6-(α-methoxy-4-chlorophenylacetamido)penicillanic acid. References Vanderhaeghe H., et al.; US Patent No. 3,007,920; Nov. 7, 1961; Assigned: Recherche et Industrie Therapeutiques, en abrege R.I.T., Genval, Belgium, a corporation of Belgium

CLOMIPHENE DIHYDROGEN CITRATE Therapeutic Function: Antiestrogen Chemical Name: 2-[4-(2-Chloro-1,2-diphenylethenyl)phenoxy]-N,Ndiethylethanamine dihydrogen citrate Common Name: Clomifen citrate Structural Formula:

Chemical Abstracts Registry No.: 50-41-9; 911-45-5 (Base)

1094

Clomiphene dihydrogen citrate

Trade Name

Manufacturer

Country

Year Introduced

Clomid

Lepetit

Italy

1966

Clomid

Merrell Dow

UK

1966

Clomid

Doetsch Grether

Switz.

1967

Clomid

Merrell National

US

1967

Dyneric

Merrell

W. Germany

1967

Clomid

Merrell

France

1968

Serophene

Serono

US

1982

Clomivid

Draco

Sweden

-

Clostilbegyt

EGYT

Hungary

-

Gravosan

Spofa

Czechoslovakia

-

Ikaclomine

Ika

Israel

-

Omifin

Inibsa

Spain

-

Prolifen

Chiesi

Italy

-

Raw Materials 4-(β-Diethylaminoethoxy)benzophenone Benzyl magnesium chloride N-Chlorosuccinimide Hydrogen chloride Citric acid Manufacturing Process A mixture of 20 g of 1-[p-(β-diethylaminoethoxy)phenyl]-1,2-diphenylethanol in 200 cc of ethanol containing an excess of hydrogen chloride was refluxed 3 hours. The solvent and excess hydrogen chloride were removed under vacuum, and the residue was dissolved in a mixture of ethyl acetate and methylene chloride. 1-[p-(β-diethylaminoethoxy)phenyl]-1,2-diphenylethylene hydrochloride was obtained, melting at 148° to 157°C. This hydrochloride salt was treated with N-chlorosuccinimide in dry chloroform under reflux. The product then obtained was converted to the free base and treated with citric acid. The dihydrogen citrate salt of 1-[p-(β-diethylaminoethoxy)phenyl]-1,2diphenylchloroethylene was obtained, melting at 116.5° to 118°C. The intermediate 1-[p-(β-diethylaminoethoxy)phenyl]-1,2-diphenylethanol was obtained by treating 4-(β-diethylaminoethoxy)benzophenone with benzylmagnesium chloride. It melted at 95° to 96°C. References Merck Index 2349 DFU 3 (11) 850 (1978) Kleeman and Engel p. 230 PDR pp. 1225, 1699 OCDS Vol. 1 pp. 105, 148 (1977) and 2 p. 127 (1980) I.N.p.247

Clomipramine

1095

REM p. 990 Allen, R .E., Palopoli, F .P., Schumann, E.L. and Van Campen, M.G. Jr.; US Patent 2,914,563; November 24, 1959; assigned to The Wm. S. Merrell Company

CLOMIPRAMINE Therapeutic Function: Antidepressant Chemical Name: 3-Chloro-10,11-dihydro-N,N-dimethyl-5H-dibenz[bf] azepine-5-propanamine Common Name: Chlorimipramine Structural Formula:

Chemical Abstracts Registry No.: 303-49-1; 17321-77-6 (Hydrochloride salt) Trade Name Anafranil Anafranil Anafranil Anafranil Anafranil Anafranil Marunil Hydiphen

Manufacturer Ciba Geigy Ciba Geigy Fujisawa Ciba Geigy Ciba Geigy Ciba Geigy Unipharm Arzneimittelwerk Dresden

Country Switz. W. Germany Japan Italy UK Australia Israel E. Germany

Year Introduced 1968 1968 1970 1970 1970 1983 -

Raw Materials 3-Chloroiminodibenzyl Sodium amide γ-Dimethylaminopropyl chloride Manufacturing Process 22.9 parts of 3-chloroiminodibenzyl are dissolved in 300 parts by volume of xylene, and 4 parts of sodium amide, pulverized and suspended in toluene,

1096

Clonazepam

are added thereto while stirring and maintaining the whole under a nitrogen atmosphere. The xylene solution immediately turns dark colored, but upon crystallization of the sodium salt therefrom it becomes again light-colored. The reaction mixture is stirred for about 2 hours at 80°C until the development of ammonia has terminated. A solution of γ-dimethylaminopropyl chloride in toluene, prepared by setting free a corresponding amount of the free base from 17.4 parts of its hydrochloride salt by addition of aqueous sodium hydroxide solution in about 10% excess, extraction with toluene and drying for 2 hours over anhydrous sodium sulfate is added to the xylene solution containing the sodium salt mentioned above and the whole is stirred under reflux for 15 hours. Precipitated sodium chloride is filtered off and the filtrate is concentrated. The residue is diluted with ether, and the hydrochloride of 3chloro-5-(γ-dimethylaminopropyl)-iminodibenzyl is precipitated by introducing dry, gaseous hydrogen chloride. It is filtered off under suction and purified by repeated recrystallization from acetone; the pure substance melts at 191.5°C to 192°C. References Merck Index 2350 Kleeman and Engel p. 231 DOT 4 (4) 143 (1968) and 9 (6) 218 (1973) I.N. p.248 Schindler, W. and Dietrich, H.; US Patent 3,515,785; June 2, 1970; assigned to Geigy Chemical Corp.

CLONAZEPAM Therapeutic Function: Anticonvulsant Chemical Name: 5-(o-Chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4benzodiazepin-2-one Common Name: Structural Formula:

Chemical Abstracts Registry No.: 1622-61-3

Clonazepam

1097

Trade Name

Manufacturer

Country

Year Introduced

Rivotril

Roche

France

1973

Rivotril

Roche

UK

1974

Clonopin

Roche

US

1975

Rivotril

Roche

Italy

1975

Rivotril

Roche

W. Germany

1976

Rivotril

Roche

Switz.

1976

Rivotril

Roche

Japan

1980

Rancedon

Sumitomo

Japan

1981

Antelepsin

Arzneimittelwerk Dresden

E. Germany

-

Clonex

Teva

Israel

-

Iktorivil

Roche

-

-

Landsen

Sumitomo

Japan

-

Raw Materials Sodium nitrite Ammonia Hydrogen chloride Pyridine Potassium nitrate

Hydrogen 2-Amino-2'-nitrobenzophenone Bromoacetyl bromide Sulfuric acid

Manufacturing Process The following description is taken from US Patent 3,116,203. A stirred solution of 75 g of 2-amino-2'-nitrobenzophenone in 700 ml of hot concentrated hydrochloric acid was cooled to 0°C and a solution of 21.5 g of sodium nitrite in 50 ml of water was added in the course of 3 hours. The temperature of the suspension was kept at 2° to 7°C during the addition. The resulting clear solution was poured into a stirred solution of 37 g of cuprous chloride in 350 ml of hydrochloric acid 1:1. The solid which had formed after a few minutes was filtered off, washed with water and recrystallized from ethanol. Crystals of 2-chloro-2'-nitrobenzophenone melting at 76° to 79°C were obtained. A solution of 20 g of 2-chloro-2'-nitrobenzophenone in 450 ml of ethanol was hydrogenated at normal pressure and room temperature with Raney nickel. After uptake of about 6 liters of hydrogen the catalyst was filtered off, and the alcohol then removed in vacuo. The residue was distilled in a bulb tube at 0.4 mm and a bath temperature of 150° to 165°C giving a yellow oil. The oil was dissolved in alcohol, and on addition of water, needles of 2-amino-2'chlorobenzophenone melting at 58° to 60°C were obtained. To a solution of 42 g of 2-amino-2'-chlorobenzophenone in 500 ml of benzene, 19 ml of bromoacetyl bromide was added dropwise. After refluxing for 2 hours, the solution was cooled, washed with 2 N sodium hydroxide and evaporated. The residue was recrystallized from methanol giving crystals of 2bromo-2'-(2-chlorobenzoyl)acetanilide melting at 119° to 121°C.

1098

Clonidine hydrochloride

To a solution of 14.5 g of 2-bromo-2'-(2-chlorobenzoyl)acetanilide in 100 ml of tetrahydrofuran, an excess of liquid ammonia (ca 150 ml) was added. The ammonia was kept refluxing with a dry-ice condenser for 3 hours after which time the ammonia was allowed to evaporate and the solution was poured into water. Crystals of 2-amino-2'-(2-chlorobenzoyl)acetanilide were collected, which after recrystallization from ethanol melted at 162° to 164°C. A solution of 3 g of 2-amino-2'-(2-chlorobenzoyl)acetanilide in 50 ml of pyridine was refluxed for 24 hours after which time the pyridine was removed in vacuo. The residue was recrystallized from methanol and a mixture of dichloromethane and ether giving crystals of 5-(2-chlorophenyl)-3H-1,4benzodiazepin-2(1H)-one melting at 212° to 213°C. To a solution of 13.5 g of 5-(2-chlorophenyl)-3H-1,4-benzodiazepin-2(1H)-one in 60 ml of concentrated sulfuric acid, a solution of 5.5 g of potassium nitrate in 20 ml concentrated sulfuric acid was added dropwise. The solution then was heated in a bath at 45° to 50°C for 2.5 hours, cooled and poured on ice. After neutralizing with ammonia, the formed precipitate was filtered off and boiled with ethanol. A small amount of white insoluble material was then filtered off. The alcoholic solution on concentration yielded crystals of 7-nitro-5-(2chlorophenyl)-3H-1,4-benzodiazepin-2(1H)-one which, after recrystallization from dichloromethane, melted at 238° to 240°C. References Merck Index 2352 Kleeman and Engel p. 232 PDR p. 1481 DOT 9 (6) 237 (1973) and 9 (12) 487 (1973) I.N.p. 248 REM p. 1077 Kariss, J. and Newmark, H.L.; US Patents 3,116,203; December 31, 1963; and 3,123,529; March 3, 1964; both assigned to Hoffmann-LaRoche, Inc. Keller, O., Steiger, N. and Sternbach, L.H.; US Patents 3,121,114; February 11, 1964; and 3,203,990; August 31, 1965; both assigned to HoffmannLaRoche, Inc. Focella, A. and Rachlin, A.I.; US Patent 3,335,181; August 8, 1967; assigned to Hoffmann-LaRoche. Inc.

CLONIDINE HYDROCHLORIDE Therapeutic Function: Antihypertensive Chemical Name: 2-(2,6-Dichloroanilino)-2-imidazoline hydrochloride Common Name: Chemical Abstracts Registry No.: 4205-91-8; 4205-90-7 (Base)

Clonidine hydrochloride

1099

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Catapresan

Boehringer Ingelheim

W. Germany

1966

Catapresan

Boehringer Ingelheim Boehringer Ingelheim Tanabe

Switz.

1966

Italy

1970

Japan

1970

Catapres

Boehringer Ingelheim

UK

1971

Catapresan

France

1971

US

1974

Bapresan

Boehringer Ingelheim Boehringer Ingelheim Chemie Linz

Austria

-

Caprysin

Star

Finland

-

Clonilou

Hermes

Spain

-

Clonisin

Leiras

Finland

-

Clonnirit

Rafa

Israel

-

Dixarit

W.B. Pharm.

UK

-

Haemiton

Arzneimittelwerk Dresden

E. Germany

-

Ipotensium

Pierrel

Italy

-

Isoglaucon

Boehringer Ingelheim

W. Germany

-

Normopresan

Rafa

Israel

-

Tensinova

Cheminova

Spain

-

Catapresan Catapres

Catapres

Raw Materials 2,6-Dichloroaniline Hydrogen chloride Ethylenediamine

Methyl iodide Ammonium thiocyanate

Manufacturing Process N-(2,6-dichlorophenyl)thiourea (MP 149°C) was prepared in customary manner from 2,6-dichloroaniline (Organic Synthesis III, 262-263) and ammonium thiocyanate. 16.0 g of this thiourea derivative were refluxed for

1100

Clopamide

2.5 hours together with 16 g of methyl iodide in 150 cc of methanol. Thereafter, the methanol was evaporated out of the reaction mixture in vacuo, leaving as a residue 22 g of N-(2,6-dichlorophenyl)-S-methyl-isothiouronium hydroiodide of the formula having a melting point of 170°C. The entire residue was then admixed with an excess (120%) above the molar equivalent of ethylenediamine, and the mixture was heated for about one hour at 130° to 150°C. Methyl mercaptan was given off. Thereafter, the reaction mixture comprising 2-(2',6'-dichloroanilino)-1,3-diazacyclopentene-(2) hydroiodide was taken up in hot dilute acetic acid, and the resulting solution was made alkaline with 2 N NaOH. A precipitate formed which was separated by vacuum filtration, washed with water and dried. 4.0 g of 2-(2',6'-dichloroanilino)-1,3diazacyclopentene-(2) were obtained. The product had a melting point of 130°C. The free base was then dissolved in absolute methanol, and the resulting solution was then adjusted to an acid pH value with an ethereal hydrochloric acid solution. The acidified solution was purified with charcoal and then dry ether was added thereto until crystallization took place. The hydrochloride, prepared in this customary manner, had a melting point of 305°C according to US Patent 3,202,660. References Merck Index 2353 Kleeman and Engel p. 232 PDR p. 675 OCDS Vol. 1 p. 241 (1977) DOT 9 (3) 97 (1973) I.N. p. 249 REM p. 845 Zeile, K., Hauptmann, K.-H. and Stahle, H.; US Patents 3,202,660; August 24, 1965; and 3,236,857; February 22, 1966; both assigned to Boehringer Ingelheim GmbH, Germany

CLOPAMIDE Therapeutic Function: Diuretic, Antihypertensive Chemical Name: Benzamide, 3-(aminosulfonyl)-4-chloro-N-(2,6-dimethyl-1piperidinyl)-, cisCommon Name: Chlosudimeprimylum; Clopamide Chemical Abstracts Registry No.: 636-54-4 Raw Materials 3-Chlorsulfonyl-4-chlorobenzoylchloride 1-Amino-cis-2,6-dimethylpiperidin-hydrochloride Ammonium

Clopenthixol

1101

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Brinaldix

Novartis

-

-

Brinaldix

Egis

-

-

Viskaldix

Novartis (ex.Sandoz)

-

-

Adurix

Benzon

-

-

Adurix

-

Aquex

Nycomed Danmark A/S Sandoz -

Brinaldix

Sandoz

-

-

Clopamide

Interpharma Praha, a.s.

-

-

Clopamide

Polfa

-

-

-

Manufacturing Process To a solution of 5.5 g of 3-chlorsulfonyl-4-chlorobenzoylchloride in 20 ml chlorobenzole 3.3 g of 1-amino-cis-2,6-dimethylpiperidin-hydrochloride slowly was added at room temperature. Reaction mixture was heated to 100°-105°C during 8 h, then it was cooled to room temperature. The precipitated crystals of N-[cis-2,6-dimethyl-piperidyl-(1)]-3-chlorsulfonyl-4-chlorobenzoylamide were filtered and dried at 100°C under vacuo, then was treated by ammonium at room temperature. The obtained product was chromatographed (aluminum oxide; eluent: chloroform-methanol 9:1 and methanol-ether) to give N-[cis2,6-dimethylpiperidyl-(1)]-3-sulfamyl-4-chlorbenzoylamide, melting point 235°-237°C. References Lindenmann A.J., Bruschweiler C.; CH Patent No. 436,288; May 31, 1967; Assigned: Sandoz, AG, Basel

CLOPENTHIXOL Therapeutic Function: Antipsychotic

1102

Clopenthixol

Chemical Name: 4-[3-(2-Chloro-9H-thioxanthen-9-ylidene)propyl]-1piperazineethanol Common Name: Structural Formula:

Chemical Abstracts Registry No.: 982-24-1 Trade Name Ciatyl Sordinol Clopixol Cisordinol Sordenac Thiapax

Manufacturer Tropon Bracco Lundbeck Lundbeck Lundbeck Ikapharm

Country W. Germany Italy UK Israel

Year Introduced 1961 1967 1978 -

Raw Materials 2-Chloro-9-(3'-dimethylaminopropylidene)-thiaxanthene N-(β-Hydroxyethyl)-piperazine Manufacturing Process A mixture of 31 5 g (0.1 mol) of 2-chloro-9-(3'-dimethylaminopropylidene)thiaxanthene (MP 97°C) and 100 g of N-(β-hydroxyethyl)piperazine is heated to 130°C and boiled under reflux at this temperature for 48 hours. After cooling,the excess of N-(β-hydroxyethyl)piperazine is evaporated in vacuo, and the residue is dissolved in ether. The ether phase is washed with water and extracted with dilute acetic acid, and 2-chloro-9-[3'-N-(N'-βhydroxyethyl)piperazinylpropylidene]-thiaxanthene separated from the aqueous acetic acid solution by addition of dilute sodium hydroxide solution to basic reaction. The free base is extracted with ether, the ether phase dried over potassium carbonate, the ether evaporated and the residue dissolved in absolute ethanol. By complete neutralization of the ethanolic solution with a solution of dry hydrogen chloride in absolute ethanol, the dihydrochloride of 2chloro-9-[3'-N-(N'-β-hydroxyethyl)piperazinylpropylidene]-thiaxanthene is produced and crystallizes out as a white substance melting at about 250°C to 260°C with decomposition. The yield is 32 g.

Cloperastine

1103

References Merck Index 2357 Kleeman and Engel p. 234 OCDS Vol. 1 p. 399 (1977) DOT 9 (6) 229 (1973) I.N. p. 249 Petersen, P.V., Lassen, N.O. and Holm, T.O.; US Patent 3,149,103; September 15, 1964; assigned to Kefalas A/S (Denmark)

CLOPERASTINE Therapeutic Function: Antitussive Chemical Name: 1-[2-[(p-Chloro-α-phenylbenzyl)oxy]ethyl]piperidine Common Name: Structural Formula:

Chemical Abstracts Registry No.: 3703-76-2 Trade Name Hustazol Seki

Manufacturer Yoshitomi Symes

Country Japan Italy

Year Introduced 1972 1981

Raw Materials p-Chlorobenzhydryl bromide Ethylene chlorohydrin Piperidine Manufacturing Process The manufacture of a related compound is first described. 28.1 parts of pchloro-benzhydryl bromide are heated to boiling, under reflux and with stirring, with 50 parts of ethylene chlorohydrin and 5.3 parts of calcined sodium carbonate. The reaction product is extracted with ether and the ethereal solution washed with water and dilute hydrochloric acid. The residue

1104

Clopidogrel sulfate

from the solution in ether boils at 134° to 137°C under 0.2 mm pressure and is p-chloro-benzhydryl-(β-chloroethyl)ether. 28.1 parts of this ether are heated with 12 parts of methylethylamine (100%) in a sealed tube for 4 hours at 110°C. The product of the reaction is extracted several times with dilute hydrochloric acid, the acid solution made alkaline, in the cold, with concentrated caustic soda solution and the base which separates taken up in ether. The ether extract is washed with concentrated potassium carbonate solution, evaporated down, and the residue distilled in vacuo. The product is β-methylethyl aminoethyl p-chlorobenzhydryl ether, BP 152° to 153°C/0.1 mm. Reaction with dimethylethylamine instead of methylethylamine leads directly to a quaternary compound, which type of compound can also be obtained by reacting the tertiary aminoethyl ether with reactive esters. If 18 parts of piperidine are used instead of 12 parts of methylethylamine then the same procedure results in the formation of p-chloro-benzyhydril-(βpiperidino-ethyl)ether, boiling at 178° to 180°C under 0.15 mm pressure. References Merck Index 2358 Kleeman and Engel p. 234 I.N. p. 250 British Patent 670,622; April 23, 1952; assigned to Parke, Davis and Company

CLOPIDOGREL SULFATE Therapeutic Function: Platelet aggregation inhibitor Chemical Name: Thieno(3,2-c)pyridine-5(4H)-acetic acid, α-(2chlorophenyl)-6,7-dihydro-, methyl ester, (αS)-, sulfate (1:1) Common Name: Clopidogrel sulfate Structural Formula:

Chemical Abstracts Registry No.: 120202-66-6

Clopidogrel sulfate

1105

Trade Name

Manufacturer

Country

Year Introduced

Iscover

Bristol-Myers Squibb

-

-

Plavix

Sanofi-Synthelabo -

-

Plavix

Bristol-Myers Squibb

-

-

Raw Materials Racemic methyl-α-5-(4,5,6,7-tetrahydro-thieno(3,2-c)pyridyl)(2chlorophenyl)-acetate Ammonium camphor-10-sulfonate, LSaturated aqueous solution of sodium hydrogen carbonate Sulfuric acid Manufacturing Process Levo-rotatory ammonium camphor-10-sulfonate is dissolved in a minimum of water and applied to the column of Amberlite IRN-77 resin. Elution is carried out with water. The eluted fractions containing the levo-rotatory camphor-10sulfonic acid are lyophilized, melting point 198°C. 32 g (0.0994 mole) of racemic methyl-α-5-(4,5,6,7-tetrahydro-thieno(3,2c)pyridyl)(2-chlorophenyl)-acetate are dissolved in 150 ml of acetone. 9.95 g (0.0397 mole) of levo-rotatory camphor-10-sulfonic acid monohydrate are added. The clear solution is left to stand at room temperature. After 48 hours the reaction mixture is concentrated to 50 ml and left to stand at room temperature for 24 hours. The obtained camphor-10-sulfonic acid salt of methyl-α-5-(4,5,6,7-tetrahydro-thieno(3,2-c)pyridyl)(2-chlorophenyl)-acetate (SR 25990) are filtered off, washed with acetone and dried (yield: 55% on the basis of the starting racemate), melting point 165°C, [α]D20=+24.67 (c=1.58 g/100 ml; methanol). The crystals obtained above are redissolved in the minimum of boiling acetone (50 ml). The crystals obtained after cooling are filtered off, washed with acetone and dried (yield: 88%), m.p. 165°C, [α]D20=+24.75 (c=1.68 g/100 ml; methanol). 12 g (0.022 mole) of the pure camphor-10-sulfonic acid salt of methyl-α-5(4,5,6,7-tetrahydro-thieno(3,2-c)pyridyl)(2-chlorophenyl)-acetate are dissolved in a minimum of water. After cooling to 5°C, the aqueous solution obtained is made alkaline with a saturated aqueous solution of sodium hydrogen carbonate. The alkaline aqueous phase is extracted with dichloromethane. The organic extracts are dried over anhydrous sodium sulfate. On evaporation of the solvent a colorless oil of dextro-rotatory methyl-α-5-(4,5,6,7-tetrahydro-thieno(3,2-c)pyridyl)(2-chlorophenyl)-acetate is obtained (quantitative yield). Oil, [α]D20=+51.52 (c=1.61 g/100 ml; methanol). 800 ml of a saturated aqueous solution of sodium bicarbonate are added to a suspension of 200 g of SR 25990 in 800 ml of dichloromethane. After vigorous shaking, the organic phase is separated, dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is dissolved in 500 ml of ice-cold acetone and 20.7 ml of concentrated sulfuric acid (93.64%) are

1106

Clopirac

added drop-wise. The precipitate formed is isolated by filtration and washed with 1 L of acetone, then dried in a vacuum oven at 50°C. 139 g of pure white crystals of hydrogen sulfate of dextro-rotatory methyl-α-5-(4,5,6,7tetrahydro-thieno(3,2-c)pyridyl)(2-chlorophenyl)-acetate (SR 25990 C) are thus obtained, m.p. 184°C, [α]D20=+55.10 (c=1.891 g/100 ml; methanol). References Badore A., Frehel D., US Patent No. 4,847,265; 07.11.1989; Assigned to Sanofi, France Pandey B. et al., US Patent No. 6,635,763 B2; 10.21.2003; Assigned to Cadila Health Care Ltd.

CLOPIRAC Therapeutic Function: Antiinflammatory Chemical Name: 1H-Pyrrole-3-acetic acid, 1-(4-chlorophenyl)-2,5-dimethylCommon Name: Clopirac Structural Formula:

Chemical Abstracts Registry No.: 42779-82-8 Trade Name Nidran Nidran

Manufacturer Cont. Pharma Sankyo

Country -

Year Introduced -

Raw Materials Dimethylamine Acetic acid Sodium hydroxide Sodium cyanide p-Chloroaniline Morpholine Sodium bicarbonate

1-p-Chlorophenyl-2,5-dimethylpyrrole Formaldehyde Methyl iodide Potassium hydroxide 3-Acetyl-2,5-hexanedione Hydrogen chloride

Clopirac

1107

Manufacturing Process 2 Methods of producing of 1-p-chlorophenyl-2,5-dimethyl-3-pyrroleacetic acid 1. To 47.0 g (0.23 mol) of finely ground 1-p-chlorophenyl-2,5-dimethylpyrrole, a solution of 47.5 ml of an aqueous solution of 40% dimethylamine, 57.5 ml of acetic acid and 27.5 ml of 35% formaldehyde is slowly added while stirring. The mixture is stirred overnight at room temperature and extraction is made with 2 x 100 ml of ether. To the aqueous phase, 700 ml of 20% NaOH are added and extraction is made with ether. The organic phase is dried on MgSO4, filtered and evaporated. To the residue obtained, 60 ml of absolute ethanol are added, then dropwise while stirring 34.1 g of methyl iodide. The mixture is stirred for 1 h, then the precipitate obtained is filtered; 85.9 g (yield: 92.5%) of methiodide of 1-p-chlorophenyl-2,5-dimethyl-3dimethylaminomethylpyrrole are thus obtained, melting point 197°-201°C (dec). To 166.0 g (0.41 mol) of the methiodide of 1-p-chlorophenyl-2,5-dimethyl-3dimethylaminomethylpyrrole in 600 ml of dimethylsulfoxide, 66.6 g of sodium cyanide are added and the mixture is heated to 100°C with stirring and under a nitrogen stream for 3.5 h. After cooling, the mixture is poured into 1500 ml of water and extracted with ether. The ethereal phase is washed with water, dried on MgSO4 and evaporated. The residue is vacuum stripped; 62.1 g of a yellow oil are thus obtained, which rapidly solidifies and which is recrystallized from aqueous methanol, 57.4 g (yield: 56%) of 1-p-chlorophenyl-2,5dimethyl-3-pyrrole acetonitrile are obtained, melting point 86°-88°C, boiling point 158°-161°C (0.4 mm). To 64.0 g of 1-p-chlorophenyl-2,5-dimethyl-3-pyrrole acetonitrile, 64.0 g of KOH and 300 ml of ethanol are added and the mixture is refluxed for 15 h. The alcohol is evaporated and one dilutes with 300 ml of water. The aqueous phase is washed with ether, and then acidified with 20% HCl. The precipitated obtained is filtered and one washes with petroleum ether and a minimum of ether. 58.5 g (yield: 85%) of 1-p-chlorophenyl-2,5-dimethyl-3-pyrroleacetic acid are thus obtained, melting point 99.5°-101°C. 2. To 9.5 g of 3-acetyl-2,5-hexanedione in 50 ml of benzene, 7.7 g of pchloroaniline are added and the mixture is refluxed for 5 h with azeotropic removal of the water formed. The excess solvent is evaporated and residue is vacuum stripped: 12.0 g (yield: 80%) of 1-p-chlorophenyl-2,5-dimethyl-3acetylpyrrole as an orange oil which rapidly crystallizes are thus obtained, boiling point 144°-146°C. Melting point of it 80°-81°C (recrystallization from hexane). To 5.0 g of the 1-p-chlorophenyl-2,5-dimethyl-3-acetylpyrrole, 0.7 g of sulfur and 2.7 ml of morpholine are added and the mixture is refluxed for 5 h. Then, 20 ml of an aqueous solution of 20% are added and the mixture is refluxed for 4 h. The mixture is washed with ether, acidified with 20% HCl, and then extracted with ether. The organic phase is extracted with a 10% sodium bicarbonate solution which is acidified with 5% HCl. The solid obtained is filtered and recrystallized several times from a diethyl ether-pentane mixture. 1.1 g (yield: 20%) of 1-p-chlorophenyl-2,5-dimethyl-3-pyrroleacetic acid are thus obtained, melting point 100°-103°C.

1108

Cloprednol

References GB Patent No. 1,406,330; Dec. 20, 1972; Assigned: Continental Pharma, a Belgian Body Corporate, Brussels, Begium

CLOPREDNOL Therapeutic Function: Glucocorticoid Chemical Name: 6-Chloro-11,17,21-trihydroxypregna-1,4,6-triene-3,20dione Common Name: Structural Formula:

Chemical Abstracts Registry No.: 5251-34-3 Trade Name Syntestan Novacort Synclopred

Manufacturer Syntex Syntex Syntex

Country W. Germany Switz. -

Year Introduced 1980 1983 -

Raw Materials 6α-Chlorohydrocortisone 21-acetate Chloranil Manufacturing Process A mixture of 5 g of the 21-acetate of 6α-chlorohydrocortisone, 7 g of chloranil and 100 cc of n-amyl alcohol was refluxed for 16 hours, cooled and diluted with ether. The solution was successively washed with water, 5% sodium carbonate solution and water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. Chromatographic purification of the residue yielded the 21-acetate of 6-chloro-δ1,4,6pregnatriene-11β,17α,21-triol-3,20-dione.

Clorazepate dipotassium

1109

References Merck Index 2361 DFU 2 (1) 18 (1977) OCDS Vol. 2 p. 182 (1980) DOT 17 (10) 393 (1981) I.N.p.250 Ringold, H.J. and Rosenkranz, G.; US Patent 3,232,965; February 1, 1966; assigned to Syntex Corp.

CLORAZEPATE DIPOTASSIUM Therapeutic Function: Tranquilizer Chemical Name: 7-Chloro-2,3-dihydro-2,2-dihydroxy-5-phenyl-1H-1,4benzodiazepine-3-carboxylic acid dipotassium salt Common Name: Structural Formula:

Chemical Abstracts Registry No.: 15585-90-7; 20432-69-3 (Base) Trade Name Tranxene Tranxilium Tranxilium Transene Tranxene Tranxene

Manufacturer Clin-Comar-Byla Mack Cun Midy Zambeletti Abbott Boehringer Ingelheim

Country France W. Germany Switz. Italy US UK

Year Introduced 1968 1969 1969 1970 1972 1973

Mendon Anxidin Azene Belseren Enadine Nansius

Dainippon Orion Endo Mead Johnson York Prodes

Japan Finland US Argentina Spain

1980 -

1110

Clorazepate dipotassium

Trade Name Noctran Tranex Tranxilen

Manufacturer Clin-Comar-Byla Idravlje Leo

Country France Yugoslavia Sweden

Year Introduced -

Raw Materials 2-Amino-5-chlorobenzonitrile Potassium hydroxide Magnesium

Methyl aminomalonate Bromobenzene

Manufacturing Process (A) Preparation of (2-Amino-5-Chlorophenyl)Phenylmethaneimine (4356 CB): A solution of 228.7 g (1.5 mold of 2-amino-5-chlorobenzonitrilein 1,800 ml of dry ether is added slowly in the course of about 3.5 hours to a solution of phenyl magnesium bromide prepared from 109 g (4.5 g-atoms) of magnesium turnings and 848 g (5.4 mols) of bromobenzene in 3,600 ml of anhydrous ether, and the mixture then heated under reflux for 15 hours. The complex is decomposed by stirring the reaction mixture into a solution prepared from 500 g of ammonium chloride in 2,000 mi of water to which 3 kg of crushed ice have been added. After extraction and washing, the ether is evaporated in vacuo at 40°C. The oily residue is taken up in 500 ml of petroleum ether and left to crystallize by cooling at -20°C. The yellowish crystals formed are dried (309 g); MPk (Kofler block): 74°C; yield: 92%. (B) Preparation of 7-Chloro-3-Methoxycarbonyl-5-Phenyl-2-Oxo-2,3-Dihydro1H-Benzo[f]-1,4-Diazepine (4347 CB): A solution of 9.2 g (0.04 mol) of compound 4356 CB in 20 ml of methanol is added dropwise, in the course of one hour and 30 minutes, to a boiling solution of 9.2 g (0.05 mol) of the hydrochloride of methyl aminomalonate in 30 ml of methanol. When this is completed, heating under reflux is continued for 30 minutes and the product then concentrated to dryness under reduced pressure. The residue is taken up in water and ether, the ethereal layer separated, the product washed with water and dried over sodium sulfate. The solvent is evaporated under reduced pressure. The residue, which consists of the methyl ester, could not be obtained in the crystalline state. It is dissolved in 25 ml of acetic acid, heated under reflux for 15 minutes, the product evaporated to dryness and the residual oil taken up in ether. A colorless solid separates which is filtered by suction and recrystallized from methanol. Colorless crystals are obtained (4.7 9); MPk (Kofler block): 226°C. A second crop (1.5 g) is obtained on concentration of the mother liquor; MPk (Kofler block): 222°C; total quantity 6.2 g, corresponding to a yield of 47%. (C) Preparation of Dipotassium Salt of [2-Phenyl-2-(2-Amino-5-Chlorophenyl)1-Azavinyl] Malonic Acid (4306 CB): 50 g of caustic potash are dissolved in 1,350 ml of 96% ethyl alcohol, and 82 g (0.25 mol) of compound 4347 CB are then added all at once at a temperature of about 70°C. The solid dissolves rapidly to form a yellow solution which then loses color while simultaneously an abundant colorless precipitate appears.

Clorexolone

1111

After cooling, the solid is filtered by suction and washed with alcohol at 96°C. The product is dried at ordinary temperature in a high vacuum. A colorless solid is obtained (quantitative yield), which is completely soluble in water. The aqueous solution is strongly alkaline in reaction; when acidified with acetic acid and heated on a water bath, it yields a precipitate of 7-chloro-5-phenyl2-oxo-2,3-dihydro-1H-benzo[f]-1,4-diazepine. References Merck Index 2364 Kleeman and Engel p. 311 PDR p. 553 DOT 4 (4) 137 (1968) and 9 (6) 238 (1973) I.N. p. 251 REM p. 1061 Schmitt, J.; US Patent 3,516,988; June 23, 1970

CLOREXOLONE Therapeutic Function: Diuretic Chemical Name: 6-Chloro-2-cyclohexyl-2,3-dihydro-3-oxo-1H-isoindole-5sulfonamide Common Name: Structural Formula:

Chemical Abstracts Registry No.: 2127-01-7 Trade Name

Manufacturer

Country

Year Introduced

Speciatensol

Specia

France

1966

Flonatril

Specia

France

-

Nefrolan

May and Baker

UK

-

Nefrolan

Teikoku Zoki

Japan

-

1112

Clorexolone

Raw Materials 4-Chlorophthalimide Cyclohexylamine Tin Hydrogen chloride Potassium nitrate

Sulfuric acid Stannous chloride Sodium nitrite Sulfur dioxide Ammonia

Manufacturing Process 4-Chlorophthalimide (263 g) was reacted in amyl alcohol (2.6 l) with cyclohexylamine (143.5 g, 1 mol) at reflux temperature for 16 hours to give N-cyclohexyl-4-chlorophthalimide (250 g, 66%) as a solid, MP 134°C to 136°C. N-Cyclohexyl-1-chlorophthalimide (250 g) was dissolved in glacial acetic acid (2.5 l), concentrated hydrochloric acid (555 ml) and tin (278 g) were added and the suspension was heated on a steam bath for 16 hours. The cooled solution was filtered and concentrated to dryness in vacuo to give a white solid. This solid was dissolved in water and the precipitated oil extracted with chloroform. The chloroform solution was dried and concentrated in vacuo to give a solid which, after recrystallization, yielded 5-chloro-2cyclohexylisoindolin-1-one (43%), MP 140°C to 142°C. 5-Chloro-2-cyclohexylisoindolin-1-one (102.9 g) was dissolved in concentrated sulfuric acid (665 ml); potassium nitrate (723 g) in concentrated sulfuric acid (166 ml) was added at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred at 25°C for 12 hours. The reaction mixture was poured onto ice to give a cream solid which, after recrystallization from benzene, gave 5-chloro-2-cyclohexyl-6-nitroisoindolin-1-one (46.7 g, 44%) as a white solid, MP 164°C to 168°C. 5-Chloro-2-cyclohexyl-6-nitroisoindolin-1-one (93.9 g) was reduced in concentrated hydrochloric acid (1,970 ml) with stannous chloride (376 g). The reaction temperature rose to 70°C. The resulting solution was cooled in ice and filtered. The product was washed well with water, filtered and dried to give 6-amino-5-chloro-2-cyclohexylisoindolin-1-one (74.1 g, 87.6%) which, after recrystallization from benzene, had a MP of 216°C to 218°C. 6-Amino-5-chloro-2-cyclohexylisoindolin-1-one (42.5 g) was dissolved in concentrated hydrochloric acid (425 ml) and the solution diazotized by the addition of sodium nitrite (21.25 g) in water (125 ml). The resulting diazonium salt solution was added to a solution of liquid sulfur dioxide (93 ml) in glacial acetic acid (243 ml) containing cuprous chloride (2.25 g). A yellow solid was precipitated; this was filtered off, washed, dried and recrystallized from benzene to give 5-chloro-2-cyclohexylisoindolin-1-one-6-sulfonyl chloride (45 g, 80%) as a cream solid, MP 171°C to 174°C. This sulfonyl chloride (23.7 g) was reacted with liquid ammonia (237 ml) to give 5-chloro-2-cyclohexyl-6-sulfamoylisoindolin-1-one (14.2 g, 53%). MP 259°C to 261°C.

Clorprenaline

1113

References Merck Index 2365 Kleeman and Engel p. 235 DOT 2 (4) 128 (1966) I.N. p.251 Lee, G.E. and Wragg, W.R.; US Patent 3,183,243; May 11, 1965; assigned to May and Baker, Ltd.

CLORPRENALINE Therapeutic Function: Bronchodilator Chemical Name: 2-Chloro-α-[(1-methylethyl)amino]methyl]benzenemethanol Common Name: Structural Formula:

Chemical Abstracts Registry No.: 3811-25-4; 5588-22-7 (Hydrochloride monohydrate) Trade Name Asthone Aremans Asnormal Bronocon Clopinerin Clorprenaline Conselt Cosmoline Fusca Kalutein Pentadoll Propran Restanolon Troberin

Manufacturer Eisai Zensei Sawai Wakamoto Nippon Shoji Kongo Sana Chemiphar Hoei Tatsumi Showa Kobayashi Kako Isei Nippon Zoki

Country Japan Japan Japan Japan Japan Japan Japan Japan Japan Japan Japan Japan Japan Japan

Raw Materials o-Chloroacetophenone Bromine

Sodium borohydride Isopropylamine

Year Introduced 1970 -

1114

Clorprenaline

Manufacturing Process To a solution of 279 g of o-chloroacetophenone in 2 liters of anhydrous diethyl ether were added about 3 g of dibenzoyl peroxide. 5 g of bromine were added to the resulting solution, and after 3 minutes, the color of bromine had been discharged, indicating that the formation of ω-bromo-o-chloroacetophenone had been initiated. A further amount of 288 g of bromine was added dropwise to the reaction mixture over a 1.5 hour interval. After the addition of the bromine had been completed, the reaction mixture was stirred for one-half hour and poured over about 1 kg of crushed ice. After the ice had melted, the resulting aqueous and ethereal layers were separated. The ethereal layer containing ω-bromo-o-chloroacetophenone was washed with successive 500 ml quantities of water, 5% sodium carbonate solution and again with water to remove the hydrogen bromide formed as a by-product in the reaction. The ethereal layer was dehydrated by contacting with anhydrous magnesium sulfate. The drying agent was removed by filtration and the ether was evaporated from the filtrate. The residue remaining after the evaporation consisted of about 400 g of ω-bromo-ochloroacetophenone. A solution of 400 g of ω-bromo-o-chloroacetophenone in one liter of methanol was cooled to about 25°C. A cold solution of 92.5 g of sodium borohydride in one liter of methanol was added as rapidly as possible to this cooled solution while maintaining the temperature below about 25°C. After the addition had been completed, the reaction mixture was allowed to stand for 4 hours at ambient room temperature, to complete the reduction of the keto group of the ω-bromo-o-chloroacetophenone. The reaction mixture containing a mixture of o-chlorophenyl ethylene-β-bromohydrin and o-chlorophenyl ethylene oxide was then evaporated in vacuo at room temperature to a syrup which was poured into about one liter of 5% hydrochloric acid to decompose any boratealcohol complexes. The two compounds were dissolved in diethyl ether by extracting the acidic layer three times with successive 500 ml portions of diethyl ether. The combined ether extracts were dried over anhydrous magnesium sulfate and filtered, and the ether was removed by evaporation in vacuo. A residue consisting of 400 g of a mixture of o-chlorophenyl ethylene-β-bromohydrin and o-chlorophenyl ethylene oxide was obtained. 400 g of a mixture of o-clilorophenyl ethylene-β-bromohydrin and ochlorophenyl ethylene oxide were dissolved in one liter of anhydrous ethanol. To this solution was added a solution of 306 g of isopropylamine in one liter of anhydrous ethanol. The reaction mixture was heated at refluxing temperature for about 16 hours, thus forming N-[β-(o-chlorophenyl)-β-hydroxyethyl]isopropylamine. The solvent was removed in vacuo, and to the residue was added a solution containing 200 ml of 12 N HCl in 2,500 ml of water. The acidic solution was washed twice with 500 ml portions of ether which were discarded. The acidic layer was then made basic by the addition of 250 ml of 5% (w/v) sodium hydroxide, thus liberating the free base of N-[β-(ochlorophenyl)-β-hydroxyethyl]-isopropylamine. The free base was extracted with two successive one liter portions of diethyl ether. The combined ether extracts were dried over anhydrous magnesium sulfate, filtered and

Clortermine hydrochloride

1115

concentrated in vacuo to remove all of the solvents. N-[β-(o-chlorophenyl)-βhydroxyethyl]-isopropylamine was thus obtained, according to US Patent 2,887,509. The N-[β-(o-chlorophenyl)-β-hydroxyethyl]-isopropylamine obtained by the foregoing procedure was dissolved in about 3 liters of ether and dry hydrogen chloride gas was bubbled into the solution until it was saturated, whereupon the hydrochloride salt of N-[β-(o-chlorophenyl)-β-(hydroxy)ethyl]isopropylamine precipitated. The salt was separated from the ether by filtration, and was dissolved in two liters of anhydrous ethanol. The alcoholic solution was decolorized with charcoal and filtered. Three liters of anhydrous ether were added thereto and the N-[β-(ochlorophenyl)-β-hydroxyethyl]-isopropylamine hydrochloride precipitated in crystalline form as the monohydrate. The mixture was maintained at about 0°C for 40 hours and then filtered. The filter cake was washed with ether and dried. About 209 g of N-[β-(o-chlorophenyl)-β-(hydroxy)-ethyl]isopropylamine hydrochloride monohydrate, melting at about 163° to 164°C, were obtained according to US Patent 2,816,059. References Merck Index 2368 Kleeman and Engel p. 236 OCDS Vol. 2 p. 39 (1980) I.N . p. 252 Mills, J.; US Patent 2,816,059; December 10, 1957; assigned to Eli Lilly and Company Nash, J.F.; US Patent 2,887,509; May 19, 1959; assigned to Eli Lilly and Company

CLORTERMINE HYDROCHLORIDE Therapeutic Function: Antiobesity Chemical Name: 2-Chloro-α-α-dimethylbenzeneethanamine hydrochloride Common Name: 1-(o-Chlorophenyl)-2-methyl-2-aminopropane hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 10389-72-7; 10389-73-8 (Base)

1116

Clortermine hydrochloride

Trade Name

Manufacturer

Country

Year Introduced

Voranil

U.S.V.

US

1973

Raw Materials o,α-Dichlorotoluene Sodium cyanide Sulfuric acid

Acetone Magnesium Hydrogen chloride

Manufacturing Process To a Grignard reagent (prepared from 50.0 g of o,α-dichloro-toluene and 7.45 g of magnesium in diethyl ether) is added 18.0 g of acetone at such rate that constant reflux is maintained. The reaction mixture is allowed to stand overnight at room temperature, and is then poured onto a mixture of 20% sulfuric acid and ice. The organic layer is separated, washed with water, an aqueous solution of sodium hydrogen carbonate and again with water, dried over magnesium sulfate and evaporated to dryness. The residue is distilled under reduced pressure to yield 42.6 g of 1-(o-chlorophenyl)-2-methyl-2propanol, BP 120° to 122°C/12.5 mm. To 29.0 ml of glacial acetic acid, cooled to 15°C, is added 11.5 g of sodium cyanide (98%) while stirring, and then dropwise 32.4 ml of concentrated sulfuric acid, dissolved in 29 ml of glacial acetic acid, while maintaining a temperature of 20°C. The 1-(o-chlorophenyl)-2-methyl-2-propanol is added moderately fast, allowing the temperature to rise spontaneously. After completing the addition, the reaction mixture is heated to 70°C and stirred, and is then poured onto a mixture of water and ice. The aqueous mixture is neutralized with sodium carbonate and extracted with diethyl ether. The organic solution is washed with water, dried over magnesium sulfate and evaporated to dryness. The oily residue is taken up in 100 ml of 6 N aqueous hydrochloric acid and refluxed until a clear solution is obtained. The latter is made basic with aqueous ammonia and extracted with diethyl ether; the organic solution is separated, washed, dried and evaporated. The residue is distilled under reduced pressure to yield 26.3 g of 1-(o-chlorophenyl)-2-methyl-2propylamine, BP 116° to 118°C/16 mm. The 1-(o-chlorophenyl)-2-methyl-2-propylamine hydrochloride is prepared by adding ethanolic hydrogen chloride to an ice-cold solution of the free base in ethanol; the desired salt precipitates and is recrystallized from ethanol, MP 245° to 246°C. References Merck Index 2369 Kleeman and Engel p. 236 I.N. p. 253 REM p.891 Finocchio, D.V. and Heubner, C.F.; US Patent 3,415,937; December 10, 1968; assigned to Ciba Corporation

Clostebol acetate

1117

CLOSTEBOL ACETATE Therapeutic Function: Anabolic Chemical Name: Androst-4-en-3-one, 17-(acetyloxy)-4-chloro-, (17-β)Common Name: Chlortestesterone acetate; Clostebol acetate Structural Formula:

Chemical Abstracts Registry No.: 855-19-6 Trade Name

Manufacturer

Country

Year Introduced

Clostebol acetate

Hunan Steroid Chemicals Co., Ltd.

-

-

Clostebol acetate

UCC Pharm Co., Ltd.

-

-

Alfa-Trofodermin

Pharmacia

-

-

Alfa-Trofodermin

Farmitalia

-

-

Steranabol

Farmitalia

-

-

Megagrisevit-Mono

Pharmacia

-

-

Turinabol

British Dragon

-

-

Raw Materials Hydrogen chloride Sodium bicarbonate Acetic anhydride

4β,5-Epoxy-etiocholane-17β-ol-3-one 4α,5-Epoxy-androstane-17β-ol-3-one Pyridine

Manufacturing Process 15 g of a mixture of 4β,5-epoxy-etiocholane-17β-ol-3-one and 4β,5-epoxyandrostane-17β-ol-3-one, dissolved in 375 ml chloroform, are treated with a stream of gaseous HCl at room temperature for about 2 h. The chloroform solution is neutralized with a sodium bicarbonate solution, washed with water and dried. The residue is crystallized from benzene or aqueous methanol and 9 g of needle-shaped crystals of 4-chloro-testosterone, melting point 186°188°C, are obtained. Upon concentrating the mother-liquor, 3.2 g of this

1118

Clotiazepam

product, melting point 180°-184°C, are covered. 1 g 4-chloro-testosterone are acetylated with 1 ml acetic anhydride and 5 ml pyridine at room temperature for 16 h. Ice is added to the solution, and the precipitate is filtered off and recrystallized from chloroform-ethanol; 1 g 4chloro-testosterone-acetate, melting point 228°-230°C, is obtained. References Camerino B.; US Patent No. 2,953,582; Sep. 20, 1960; Assigned: Societa Farmaceutici Italia, a corporation of Italy

CLOTIAZEPAM Therapeutic Function: Tranquilizer Chemical Name: 5-(o-Chlorophenyl)-7-ethyl-1,3-dihydro-1-methyl-1Hthieno[2,3-e]-1,4-diazepin-2-one Common Name: Structural Formula:

Chemical Abstracts Registry No.: 33671-46-4 Trade Name

Manufacturer

Country

Year Introduced

Rize

Yoshitomi

Japan

1979

Trecalmo

Tropon

W. Germany

1979

Raw Materials 2-N-Methyiaminoacetamido-3-o-chlorobenzyl-5-ethylthiophene Acetic acid Manufacturing Process To a solution of 10 g of 2-N-methylaminoacetamido-3-o-chlorobenzoyl-5-

Clotrimazole

1119

ethylthiophene in 50 ml of pyridine are added 20 ml of benzene and 1.9 g of acetic acid. The resulting mixture is refluxed with stirring for 10 hours in a flask provided with a water-removing adaptor. The reaction mixture is concentrated, and the residue is extracted with chloroform. The chloroform layer is washed with water and then with a sodium hydrogen carbonate solution, then dried over magnesium sulfate. The chloroform is distilled off under reduced pressure, and toluene is added to the residue. Thus is precipitated white crystalline-5-o-chlorophenyl-7-ethyl-1-methyl-1,2-dihydro3H-thieno-[2,3-e][1,4]diazepin-2-one, MP 105°C to 106°C. References Merck Index 2373 DFU 1 (8) 363 (1976) Kleeman and Engel p. 237 DOT 16 (1) 13 (1980) I.N. p. 254 Nakanishi, M., Araki, K.,Tahara, T. and Shiroki, M.; US Patent 3,849,405; November 19, 1974; assigned to Yoshitomi Pharmaceutical Industries, Ltd.

CLOTRIMAZOLE Therapeutic Function: Antifungal Chemical Name: 1-[(2-Chlorophenyl)diphenylmethyl]-1H-imidazole Common Name: 1-(o-Chlorotrityl)imidazole Structural Formula:

Chemical Abstracts Registry No.: 23593-75-1 Trade Name Canesten Canesten Canesten Lotrimin

Manufacturer Bayer Bayer Bayer Schering

Country UK Italy W. Germany US

Year Introduced 1973 1973 1973 1975

1120

Cloxacillin

Trade Name Empecid Trimysten Mycelex Baycuten Gyne-Lotrimin Micoter Myclo Mycosporin

Manufacturer Bayer Bellon Miles Bayropharm Debay Cusi Boehringer Ingelheim Bayer

Country Japan France US W. Germany US Spain -

Year Introduced 1976 1978 1979 -

-

-

Raw Materials o-Chlorophenyldiphenylmethyl chloride Imidazole Manufacturing Process 156.5 g (0.5 mol) o-chlorophenyldiphenylmethyl chloride and 34 g (0.5 mol) imidazole are dissolved in 500 ml acetonitrile, with stirring, and 51 g (0.5 mol) triethylamine are added, whereupon separation of triethylamine hydrochloride occurs even at room temperature. In order to complete the reaction, heating at 50°C is carried out for 3 hours. After cooling, one liter of benzene is added and the reaction mixture is stirred, then washed salt-free with water. The benzene solution is dried over anhydrous sodium sulfate, filtered and concentrated by evaporation; giving 167 g crude 1-(ochlorophenylbisphenylmethyl)-imidazole. By recrystallization from acetone, 115 g (= 71% of the theory) of pure 1-(o-chlorophenylbisphenylmethyl)imidazole of MP 154° to 156°C are obtained. References Merck Index 2374 Kleeman and Engel p. 238 PDR pp. 1257, 1631 DOT 10 (1) 32 (1974) I.N. p. 254 REM p. 1227 Buechel, K.H., et al; South African Patent 69/0039; January 3, 1969; assigned to Farbenfabriken Bayer AG, Germany Buechel, K.H., Regel, E. and Plempel, M.; US Patent 3,660,577; May 2, 1972; and US Patent 3,705,172; Dec. 5, 1972; both assigned to Farbenfabriken Bayer A.G. (Germany)

CLOXACILLIN Therapeutic Function: Antibacterial

Cloxacillin

1121

Chemical Name: 6-[[[[3-(2-Chlorophenyl)-5-methyl-4-isoxazolyl]carbonyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2carboxylic acid Common Name: [3-(o-Chlorophenyl)-5-methyl-4-isoxazolyl]penicillin Structural Formula:

Chemical Abstracts Registry No.: 61-72-3; 642-78-4 (Sodium Salt) Trade Name

Manufacturer

Country

Year Introduced

Orbenin

Beecham

UK

1962

Cloxypen

Allard

France

1964

Orbenin

Beecham

W. Germany

1964

Tegopen

Bristol

US

1965

Cloxapen

Beecham

US

1976

Acucillin

Fuji

Japan

-

Ampiclox

Beecham

W. Germany

-

Austrastaph

C.S.L.

Australia

-

Benicil

Ibsa

Switz.

-

Ellecid

Pharmax

Italy

-

Ekvacilline

Astra

-

-

Gelstaph

Beecham

-

-

Kloxerate

Duphar

UK

-

Methocillin-S

Meiji

Japan

-

Novocloxin

Novopharm

Canada

-

Orbenil

Teva

Israel

-

Orbenine

Beecham-Sevigne

France

-

Penstapho-N

Bristol

-

-

Prostaphlin

Galenika

Yugoslavia

-

Prostaphlin

Banyu

Japan

-

Rivoclox

Rivopharm

Switz.

-

SolcilIin-C

Takeda

Japan

-

Staphybiotic

Delagrange

France

-

Syntarpen

Polfa

Poland

-

Totaclox

Beecham

Japan

-

1122

Cloxazolam

Raw Materials Ethyl acetoacetate o-Chlorobenzohydroxamic acid chloride 6-Aminopenicillanic acid Manufacturing Process The reaction between 6-aminopenicillanic acid (6.5 g) and 3-o-chlorophenyl-5methylisoxazole4-carbonyl chloride (7.66 g) gave the sodium salt of 3-ochlorophenyl-5-methyl-4-isoxazolylpenicillin (9.98 g) as a pale yellow solid. Colorimetric assay with hydroxylamine against a benzylpenicillin standard indicated a purity of 68%. The 3-o-chlorophenyl-5-methylisoxazole-4-carboxylic acid, from which the acid chloride was prepared, was obtained by hydrolysis of the ester product of the reaction between o-chlorobenzohydroxamic chloride and ethyl acetoacetate in methanolic sodium methoxide. Reaction with thionyl chloride gave the starting material. References Merck Index 2376 Kleeman and Engel p. 239 PDR pp. 673, 1606 OCDS Vol. 1 p. 413 (1977) I.N.p.254 REM p. 1195 Doyle, F.P. and Nayler, J.H.C.; British Patent 905,778; September 12, 1962; assigned to Beecham Research Laboratories, Ltd. Doyle, F.P. and Nayler, J.H.C.; US Patent 2,996,501; August 15, 1961

CLOXAZOLAM Therapeutic Function: Tranquilizer Chemical Name: 10-Chloro-11b-(2-chlorophenyl)-2,3,7,11btetrahydrooxazolo[3,2-d][1,4]benzodiazepin-6(5H)-one Common Name: Structural Formula:

Clozapine

1123

Chemical Abstracts Registry No.: 24166-13-0 Trade Name

Manufacturer

Country

Year Introduced

Sepazon

Sankyo

Japan

1974

Enadel

Pfizer Taito

Japan

1974

Lubalix

Lubapharm

Switz.

1983

Betavel

Pharm. Investi

Spain

-

Olcadil

Sankyo

Japan

-

Tolestan

Roemmers

Argentina

-

Raw Materials 5-Chloro-2-bromoacetylamino-o-chlorobenzophenone Ethanolamine Manufacturing Process As described in US Patent 3,772,371: To a solution of 5.8 g of 5-chloro-2bromoacetylamino-o-chlorobenzophenone in 120 ml of ethanol were added 0.95 g of ethanolamine and 1.3 g of sodium acetate. The resulting mixture was heated under reflux for 16 hours. After completion of the reaction, the solvent was distilled off and the residue was extracted with dichloromethane. The extract was washed with water, dried over anhydrous sodium sulfate and the solvent was distilled off to give 3.25 g of the desired product melting at 202° to 204°C with decomposition. References Merck Index 2377 Kleeman and Engel p. 240 DOT 11 (1) 35 (1975) I.N. p. 254 Tachikawa, R., Takagi, H., Kamioka, T., Fukunaga, M., Kawano, Y. and Miyadera, T.; US Patents 3,696,094; October 3, 1972; and 3,772,371; November 13, 1973; both assigned to Sankyo Company Limited, Japan

CLOZAPINE Therapeutic Function: Tranquilizer Chemical Name: 8-Chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e][1,4] diazepine Common Name: Chemical Abstracts Registry No.: 5786-21-0

1124

Cobamamide

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Leponex

Wander

W. Germany

1974

Leponex

Wander

Switz.

1975

Clozaril

Sandoz

-

-

Raw Materials 2-Amino-4-chlorodiphenylamine-2'-carboxylic(4"-methyl)piperazide Phosphoroxychloride Manufacturing Process 7.4 g of 2-amino-4-chlorodiphenylamine-2'-carboxylic acid (4"-methyl) piperazide and 35 ml of phosphoroxychloride are heated for 3 hours under reflux in the presence of 1.4 ml of N,N-dimethylaniline. Upon concentration of the reaction mixture in vacuo as far as possible, the residue is distributed between benzene and ammonia/ice water. The benzene solution is extracted with dilute acetic acid. The acid extract is clarified with charcoal and treated with concentrated ammonia water to precipitate the alkaline substance, which is dissolved in ether. The ethereal solution is washed with water and dried over sodium sulfate. The residue obtained yields, after recrystallization from ether/petroleum ether 2.9 g (41% of the theoretical yield) of 8-chloro-11-(4methyl-1-piperazinyl)-5H-dibenzo[b,e][1,4]diazepine in the form of yellow grains of melting point 182° to 184°C (from acetone/petroleum ether). References Merck Index 2378 Kleeman and Engel p. 240 OCDS Vol. 2 p. 425 (1980) DOT 9 (1) 17 and (6) 232 (1973) I.N. p.255 Schmutz, J. and Hunziker, F.;US Patent 3,539,573; November 10, 1970

COBAMAMIDE Therapeutic Function: Anabolic, Analgesic

Cobamamide

1125

Chemical Name: Cobinamide, O-(5'-deoxyadenosine-5') deriv., hydroxide, dihydrogen phosphate (ester), inner salt, 3'-ester with 5,6-dimethyl-1alpha-D-ribofuranosylbenzimidazole Common Name: Adenosylcobalamin; Cobamamide; Coenzima B12; Coenzym B12; Dibencozide; Dibenzcozamide; Dimebenzcozamide Structural Formula:

Chemical Abstracts Registry No.: 13870-90-1 Trade Name Actimide Ademide Betarin Calomide Cobamamide

Manufacturer Tobishi Toyo Jozo Beta Yamanouchi Hebei Huarong Pharmaceutical Co., Ltd.

Country -

Year Introduced -

Cobamamide

Shijiazhuang Pharmaceutical Group Co., Ltd.

-

-

Cobamamide Cobamamide Mecobal OD

Thorne Research Recordati SpA Rapross Pharmaceuticals Pvt. Ltd.

-

1126

Cobamamide

Trade Name

Manufacturer

Country

Year Introduced

Vitamin B12 Depot

Siegfried

-

-

Cobalin

Laboratorios Finlay, S.A.

-

-

Raw Materials Isopropylidine adenosine Hydroxocobalamin Hydrochloric acid

Tosyl chlorine Sodium borohydride

Manufacturing Process Isopropylidine adenosine was converted to the p-toluene sulphonyl (tosyl) ester by reaction with tosyl chlorine solution, following the method of Clark et al. (1951) [J. Chem. Soc. 2952]. Because of its tendency to cyclization, the reagent was used directly it was ready. A reaction flask with separating funnels was set up in such a way that the whole system could be evacuated and filled with pure nitrogen two or three times, to eliminate all oxygen, and reagents could then be added when desired, in the closed system. The flask contained 700.0 mg hydroxocobalamin in 20 ml of water, one funnel 200.0 mg sodium borohydride in 10 ml of water, and another the crude isopropylidine adenosine tosyl ester made from 500 mg isopropylidine adenosine dissolved in 10 ml of 50% aqueous methanol. On adding the borohydride to the vitamin, the color changed instantly from red to brown, then slowly to a greenish black. After 15 min the isopropylidine adenosine tosyl ester was added, and the colour slowly changed to a red-brown. After 45 min at room temperature air was admitted and the mixture was shaken to reoxidise any remaining reduced vitamin B12. The alkaline solution was neutralized with dilute hydrochloric acid and extracted with phenol carbon tetrachloride 3:1 in small portions till the aqueous layer was nearly colorless. The combined extracts were washed with water, mixed with about ten parts of carbon tetrachloride-acetone 10:1 and shaken with small portions of water till all red color was removed. The product was purified by chromatography on columns of DEAE (diethyl aminoethyl) cellulose (3 x 1) followed by CM (carboxymethyl) cellulose (6 x 1), developed with water. Nearly all the color washed quickly through DEAE cellulose. The effluent and washes were applied to the CM cellulose column, which was further developed with water. Elution was continued as long as this fraction continued to emerge, in a total of 850 ml. One half of this fraction (425 ml) was concentrated to a few ml under reduced pressure; it crystallized slowly after adding acetone to slight turbidity. So cobamamide was obtained. References Smith E.L. et al.; US Patent No. 3,213,082; Oct. 19, 1965; Assigned: Glaxo Group Limited, Middlesex, England, a British company

Cocarboxylase chloride

1127

COCARBOXYLASE CHLORIDE Therapeutic Function: Coenzyme, Metabolic Chemical Name: Thiazolium, 3-((4-amino-2-methyl-5-pyrimidinyl)methyl)-4methyl-5-(4,6,6-trihydroxy-3,5-dioxa-4,6-diphosphahex-1-yl)-, chloride, P,P'-dioxide Common Name: Cocarbossilasi; Cocarboxylase; Diphosphothiamine; Pyruvodehydrase; Thiamine pyrophosphate Structural Formula:

Chemical Abstracts Registry No.: 154-87-0 Trade Name

Manufacturer

Country

Year Introduced

Actimide

Tobishi

-

-

Ademide

Toyo Jozo

-

-

Betarin

Beta

-

-

Calomide

Yamanouchi

-

-

Cobamamide

Hebei Huarong Pharmaceutical Co., Ltd.

-

-

Cobamamide

Shijiazhuang Pharmaceutical Group Co., Ltd.

-

-

Cobamamide

Thorne Research

-

-

Cobamamide

Recordati SpA

-

-

Mecobal OD

Rapross Pharmaceuticals Pvt. Ltd.

-

-

Vitamin B12 Depot Siegfried

-

-

Cobalin

-

-

Laboratorios Finlay, S.A.

Raw Materials Phosphoric acid Hydrochloric acid

Phosphorous pentoxide Thiamine chloride hydrochloride

1128

Codeine phosphate

Manufacturing Process 4.5 kg of aqueous 89% orthophosphoric acid are heated to 135°C, and kept at this temperature for about 3 h while being actively stirred. Then, the heating is discontinued and 3.5 kg of phosphorouspentoxide are added during a period of 2.5 to 3 h, while being actively stirred. During this period, the interior temperature rises to 165°-175°C. After completion of the addition of phosphorouspentoxide, the stirring is continued until all phosphorouspentoxide is dissolved. The phosphoric acid mixture thus produced is subsequently cooled down to 130°C. At this temperature 2.0 kg of thiamine chloride hydrochloride (vitamin B1) were added during 2 to 3 h while being well stirred. The stirring is continued at 130°C until the phosphorylated mixture no longer contains chlorine ions. A phosphorylated melt is thus obtained. The thus obtained phosphorylation melt is dissolved in 6-8 L of water (with ice) at a temperature below 10°C, while being vigorously stirred. The aqueous solution is stirred into 100 L of 96% alcohol and left standing overnight. The supernatant solvent is decanted from the separated syrup; the latter is taken up in 4 L of water. The solution thus obtained is fed, depending upon the volume of phosphoric acid contained therein, to an exchanger column filled with anion exchanger (weak basic, for instance Amberlite IRA 45, 20-30 L) (a polystyrene resin with primary, secondary and quaternary amino groups). The solution is caused to seep into the column from the top thereof and is then washed with water until the runoff at the bottom no longer shows any thiamine reaction. About 25 L of the solution are obtained, which are concentrated to 6 L at 30°C and 12 Torr. The concentrated residue is added to 20 to 30 L of a cationic exchanger (Amberlite IRC 50) in order to separate the thiamine-orthophosphoric acid ester from the thiamine-pyrophosphoric acid ester, and subsequently washed with water until the eluate is free of thiamine. 70-80 L of a solution are obtained which are concentrated to 1.5 L in a circulation evaporator at 30°C and 12 Torr. 7.5 L of 96% ethanol are slowly added to a concentrate while being stirred. The cocarboxylase-tetrahydrate separates in the form of fine needles. The yield is 530.0 g with a melting point of 220°-225°C (dec.). 10.0 g of cocarboxylase-tetrahydrate are dissolved in 25 ml of 5% aqueous hydrochloric acid, and 75 ml acetone are added dropwise while being stirred. The precipitated hydrochloride of the cocarboxylase, melting point 240°C is sucked off. The yield is 9.5 g. References Wenz A. et al.; US Patent No. 2,991,284; July 4, 1961; Assigned: E. Merck, Aktiengesellschaft, Darmstadt, Darmstadt, Germany, a corporation of Germany

CODEINE PHOSPHATE Therapeutic Function: Narcotic analgesic, Antitussive

Colestipol

1129

Chemical Name: Morphinan-6-ol, 7,8-didehydro-4,5-epoxy-3-methoxy-17methyl-, (5α,6α)-, phosphate (1:1) (salt) Common Name: Codeinum phosphoridum Structural Formula:

Chemical Abstracts Registry No.: 52-28-8 Trade Name

Manufacturer

Country

Year Introduced

Actacode Linctus

Sigma Pharmaceuticals

-

-

Bronchodine

Pharmethic

Belgium

-

Bronchosedal codeine

Janssen-Cilag

-

-

Galcodine

Galena a.s.

Czech Republic

-

Raw Materials Morphine Trimethylphenylammonium chloride Sodium hydroxide Manufacturing Process Interaction of morphin, trimethylphenylammonium chloride and sodium hydroxide in methanol give the morphinan-6-α-ol, 7,8-didehydro-4,5-α-epoxy3-methoxy-17-methyl. Then the free base was converted into phosphate. References Boheringer H., DE 247,180, 1912 Ullmann 3, Aufl., Bd.3, 232

COLESTIPOL Therapeutic Function: Antihyperlipoproteinemic

1130

Colestipol

Chemical Name: N-(2-Aminoethyl)-1,2-ethanediamine polymer with (chloromethyl) oxirane Common Name: Structural Formula: See Chemical Name Chemical Abstracts Registry No.: 26658-42-4 Trade Name Colestid Colestid Colestid Colestid Lestid

Manufacturer Upjohn Upjohn Upjohn Upjohn Upjohn

Country US UK W. Germany Switz. -

Year Introduced 1977 1978 1978 1978 -

Raw Materials Epichlorohydrin Tetraethylene pentamine Manufacturing Process Into a 1,000 gallon, jacketed, glass-lined reactor equipped with baffles and a two-speed (67 and 135 rpm) reversed impeller is introduced 200 g of Richonate 60B (a 60% aqueous slurry of sodium salts of alkylbenzenesulfonic acids) and 364 liters of deionized water, followed by 90.5 kg of tetraethylenepentamine rinsed in with 5 gallons of toluene. The solution is stirred at the low speed and then 500 gallons of toluene are added to form a dispersion. To the stirred dispersion is added 109 kg of epichlorohydrin, rinsed in with 5 gallons of toluene, and the resulting mixture is heated at reflux for two hours. The reaction mixture is cooled to about 20°C and then treated with 58.5 kg of a filtered 50% aqueous solution of sodium hydroxide. The mixture is removed from the reactor and filtered, and the copolymer is collected and dried by treating it first with hot (75°C to 80°C) filtered nitrogen and then with an 80°C air stream. The resulting crude product is returned to the reactor, washed extensively with filtered deionized water (at the low speed), dried with an 80°C air stream and blended until homogeneous to give about 155 kg of a dry tetraethylenepentamine-epichlorohydrin copolymer hydrochloride, particle diameter 0.002-0.02 inch. References Merck Index 2440 PDR p. 1832 DOT 14 (2) 69 (1978) I.N. p. 259 REM p.864 Lednicer, D. and Peery, C.Y.; US Patent 3,803,237; April 9, 1974; assigned to The Upjohn Co.

Convallatoxin

1131

CONVALLATOXIN Therapeutic Function: Cardiotonic Chemical Name: Card-20(22)-enolide, 3-((6-deoxy-α-L-mannopyranosyl) oxy)-5,14-dihydroxy-19-oxo-, (3β,5β)Common Name: Convallatoxin; Corglykon Structural Formula:

Chemical Abstracts Registry No.: 508-75-8 Trade Name

Manufacturer

Convallatoxin

C-Strong Co., Ltd. -

Country

Year Introduced -

Raw Materials Flowers Convallaria majalis, lily of valley Lead(II) acetate Manufacturing Process 1 part of grinded flowers Convallaria majalis and 12 parts of water was stirred for 15 hours at ambient temperature. After a filtration and washing with water, a clear brown filtrate was mixed with a concentrate solution of lead acetate. A lead consisted precipitate was filtered off and sodium phosphate was added to filtrate for removing the remaining lead. The solution was filtered again and 0.5 - 0.6 parts of a coal was added and the mixture was stirred for 3 hours at ambient temperature. The coal was filtered off, washed with a little water and dried at 30°-40°C. A hot CHCl3 was added to dry coal adsorbent. CHCl3 was distilled off to dryness in vacuum. The residue was dissolved in a little methanol and the obtained solution was shook 3 times with 2 volumes of petrol ether and then distilled to dryness in vacuum. This product was dissolved in minimum absolute ethanol and added to 10 volumes of dry ether. The formed precipitate was filtered and washed with ether to

1132

Cortisone acetate

give the glycoside as a gray powder. It was crystallized from diluted ethanol as colorless needles. References DR Patent No. 490,648; Jan. 31, 1930; F. Hoffmann-la Roche and Co. Akt.Ges. in Basel, Schweiz.

CORTISONE ACETATE Therapeutic Function: Glucocorticoid Chemical Name: 17α,21-Dihydroxy-4-pregnene-3,11,20-trione-21-acetate Common Name: Structural Formula:

Chemical Abstracts Registry No.: 50-04-4; 53-06-5 (Base) Trade Name

Manufacturer

Country

Year Introduced

Cortone Acetate

MSD

US

1950

Acetisone

Farmigea

Italy

-

Raw Materials Potassium cyanide Acetic acid Chromic acid

3(α)-Hydroxy-21-acetoxy-11,20-diketopregnane Phosphorus oxychloride Osmium tetroxide

Manufacturing Process The following technique is described in US Patent 2,541,104. A solution of 2.0 g of 3(α)-hydroxy-21-acetoxy-11,20-diketo-pregnane, which can be prepared as described in Helv. Chim. Acta 27, 1287 (1944), is treated in a mixture of 25 cc of alcohol and 6.4 cc of acetic acid at 0°C with 6.0 g of potassium

Cortisone acetate

1133

cyanide. The solution is allowed to warm to room temperature and after 3 hours is diluted with water. The addition of a large volume of water to the alcohol-hydrogen cyanide mixture precipitates a gum which is extracted with chloroform or ethyl acetate. The extract is washed with water, and evaporated to small volume under reduced pressure. The crystalline precipitate (1.3 g) consists of 3(α),20-dihydroxy-20-cyano-21-acetoxy-11-keto-pregnane; dec. 175° to 185°C. A solution of 0.60 g of chromic acid in 1.2 cc of water and 11 cc of acetic acid is added to a solution containing about 1.2 g of 3(α),20-dihydroxy-20-cyano21-acetoxy-11-ketopregnane at room temperature. After 1 hour, water is added and the product, which precipitates, is filtered and recrystallized from ethyl acetate to produce 3,11-diketo-20-hydroxy-20-cyano-21-acetoxypregnane; dec. 214° to 217°C. 0.40 cc of phosphorus oxychloride is added to a solution containing about 950 mg of 3,11-diketo-20-hydroxy-20-cyano-21-acetoxy-pregnane dissolved in 3 cc of pyridine. After standing at room temperature for 24 hours, the solution is poured into water and dilute hydrochloric acid, extracted with benzene and concentrated to dryness. The crude product, after chromatography gives one main constituent, namely δ17-3,11-diketo-20-cyano-21-acetoxy-pregnene; MP 189° to 190°C. A solution of 1.0 g of δ17-3,11-diketo-20-cyano-21-acetoxy-pregnene in 10 cc of benzene is treated with 1.0 g of osmium tetroxide and 0.43 g of pyridine. After standing at room temperature for 18 hours, the resulting solution is treated successively with 50 cc of alcohol, and with 50 cc of water containing 2.5 g of sodium sulfite. The mixture is stirred for 30 hours, filtered, and the filtrate acidified with 0.5 cc of acetic acid and concentrated to small volume in vacuo. The aqueous suspension is then extracted four times with chloroform, the chloroform extracts are combined, washed with water and concentrated to dryness in vacuo. Recrystallization of the residue from acetone gives 9°C. This compound is then treated with acetic anhydride and pyridine for 15 minutes at room temperature to produce 3,11,20-triketo-17(α)-hydroxy-21-acetoxypregnane or cortisone acetate. References Merck Index 2510 Kleeman and Engel p. 246 OCDS Vol. 1 pp. 188, 190 (1977) I.N . p. 265 REM p.964 Reichstein, T.; US Patent 2,403,683; July 9, 1946 Gallagher, T.F.; US Patent 2,447,325; August 17, 1948; assigned to Research Corporation Sarett, L.H.; US Patent 2,541,104; February 13, 1951; assigned to Merck and Co., Inc

1134

Cortivazol

CORTIVAZOL Therapeutic Function: Glucocorticoid Chemical Name: 11β,17,21-Trihydroxy-6,16α-dimethyl-2'-phenyl-2'H-pregna2,4,6-trieno-[3,2-c]pyrazol-20-one-21-acetate Common Name: Structural Formula:

Chemical Abstracts Registry No.: 1110-40-3 Trade Name

Manufacturer

Country

Year Introduced

Diaster

Diamant

France

1972

Altim

Roussel

France

-

Idaitim

Roussel

-

-

Dilaster

Roussel

-

-

Raw Materials 11β,17α,21-Trihydroxy-6,16αdimethyl-4,6-pregnadiene3,20-dione Phenyl hydrazine Acetic anhydride

Formaldehyde Hydrogen chloride Ethyl formate Formic acid

Manufacturing Process To a suspension of 25.0 g of 11β,17α,21-trihydroxy-6,16α-dimethyl-4,6pregnadiene-3,20-dione in 1.5 liters of alcohol-free chloroform cooled to about 5°C in an ice bath is added with constant stirring 750 ml of cold, concentrated hydrochloric acid and then 750 ml of formalin (low in methanol). The mixture is removed from the ice bath and stirred at room temperature for 7 hours.

Cortivazol

1135

The layers are separated and the aqueous phase is back-extracted twice with chloroform. The combined organic layers are washed twice with a 5% solution of sodium bicarbonate, and twice with a saturated salt solution. The solution is dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue is triturated with methanol to afford a crystalline solid. This material contains no detectable amount of starting material by paperstrip chromatography but shows two UV absorbing spots near the solvent front (methanol-formamide 2:1 vs benzene-n-hexane 1:1). An aliquot is recrystallized three times from a mixture of benzene and n-hexane to give 17α,20,20,21-bis(methylenedioxy)-11β-hydroxy-6,16α-dimethyl-4,6pregnadiene-3-one which is used in the subsequent step of the synthesis without further purification. 17α,20,20,21-bis(methylenedioxy)-11β-hydroxy-6,16α-dimethyl-4,6pregnadiene-3-one (500 mg) is dissolved in 25 cc of benzene and then about 5 cc of benzene is removed by distillation at normal pressure. The resulting solution is cooled to room temperature. Then 0.75 cc of freshly distilled ethyl formate is added. The air in the system is replaced with nitrogen and 150 mg of sodium hydride (as a 57% dispersion in mineral oil) is added. The mixture is stirred under nitrogen at room temperature for three hours. Then 15 cc of a saturated aqueous solution of sodium dihydrogen phosphate is added and the product is extracted into ether. The ether extracts are extracted with 2 N sodium hydroxide and the sodium hydroxide extracts are acidified with sodium dihydrogen phosphate and extracted again into ether. The ether extract is evaporated to dryness to give about 500 mg of a crude product. From the ether solution there is obtained about 290 mg of yellow crystals, MP 220° to 236°C which is 17α,20,20,21bis(methylenedioxy)-11β-formyloxy-2-hydroxy-methylene-6,16α-dimethyl-4,6pregnadiene-3-one. The analytical sample is recrystallized from ethyl acetate and has a melting point of 249° to 255°C, [α]D27 -217°, I R 5.81 and 8.37 µm. From the mother liquor is obtained about 127 mg of 17α,20,20-21bis(methylenedioxy)-11β-hydroxy-2-hydroxymethylene-6,16α-dimethyl-4,6pregnadiene-3-one. The analytical sample is recrystallized from ether and has a melting point of 200° to 204°C, [α]D27 -197°, IR 6.05 to 6.2 and 6.4 µ. The 17α,20,20,21-bis(methylenedioxy)-11β-hydroxy-2-hydroxymethylene6,16α-dimethyl-4,6-pregnadiene-3-one (1.19 g) is dissolved in 25 cc of ethanol. 300 mg of phenyl hydrazine is added and the mixture is refluxed under nitrogen for one hour. About 25 cc of water is added. The product is then extracted into 150 cc of ether. The extracts are washed with 2N HCl, with saturated sodium bicarbonate, water and saturated sodium chloride solution, and then dried over sodium sulfate and evaporated to dryness to give about 1.2 g of crude product. On crystallization from ether there is obtained as a major component the 17α,20,20,21-bis(methylenedioxy)-11β-hydroxy-6,16αdimethyl-2'-phenyl-4,6-pregnadieno-[3,2-c] pyrazole. 17α,20,20,21-bis(methylenedioxy)-11β-hydroxy-6,16α-dimethyl-2'-phenyl4,6-pregnadieno[3,2-c] pyrazole (430 mg), is heated on a steam bath under nitrogen with 40 cc of a 60% aqueous solution of formic acid for about 30 minutes. About 40 cc of water is added and the mixture is then extracted into 200 cc of chloroform. The chloroform solution is washed with water, saturated

1136

Creatinolfosfate

sodium bicarbonate solution and water, then dried over sodium sulfate and evaporated under vacuum to give 430 mg of crude product. This is dissolved in 60 cc of absolute methanol, and 0.1 equivalent of sodium methoxide in methanol is added. The mixture is stirred under nitrogen at room temperature for 15 minutes. It is then acidified with acetic acid and the solvent is removed under vacuum at room temperature. About 20 cc of water is added and the product is extracted into 150 cc of ethyl acetate. The ethyl acetate solution is washed with saturated sodium bicarbonate and then with water. It is then dried over sodium sulfate and taken to dryness to give an amorphous solid. The crude product obtained above is dried in high vacuum and then dissolved in 4 cc of pyridine. About 3 cc of acetic anhydride is added. The mixture is then heated on the steam bath for about 15 minutes and then evaporated to dryness in vacuo. About 20 cc of water is added. The product is then extracted into 150 cc of ethyl acetate, washed with saturated sodium bicarbonate solution and water, and dried over sodium sulfate. The solvent is removed in vacuo to give a residue which is crystallized from ethyl acetatebenzene to yield about 250 mg of 11β,17α,21-trihydroxy-6,16α-dimethyl-20oxo-2'-phenyl-4,6-pregnadieno-[3,2-c]pyrazole 21-acetate, as described in US Patent 3,300,483. References Merck Index 2513 Kleeman and Engel p. 248 OCDS Vol. 2 p. 191 (1980) DOT 8 (10) 374 (1972) I.N. p. 265 Tishler, M., Steinberg, N.G. and Hirschmann, R.F.; US Patents 3,067,194; December 4, 1962; and 3,300,483; January 24, 1967; both assigned to Merck and Co., Inc.

CREATINOLFOSFATE Therapeutic Function: Cardiotonic Chemical Name: 1-(2-Hydroxyethyl)-1-methylguanidine dihydrogen phosphate Common Name: Structural Formula:

Cromolyn sodium

1137

Chemical Abstracts Registry No.: 6903-79-3 Trade Name Aplodan Dragosil Nergize

Manufacturer Simes Farmasimes Byk Liprandi

Country Italy Spain Argentina

Year Introduced 1968 -

Raw Materials Creatinol phosphate Polyphosphoric acid Manufacturing Process In a reactor put 80 kg of polyphosphoric acid having the following composition: H5P3O10 - 60%; (HPO3)6 - 10%; H4P2O7 - 15%; (HPO3)x - 10%; total content in P2O5 about 83%; this is heated to about 160°C. Then 360 kg of creatinol phosphate are added to the polyphosphoric acid; continue to heat for about two hours under vacuum until the reaction water is eliminated. The molten mass is then poured into ethanol at 95°C, the solution cooled down to 10°C and the precipitated product separated by centrifugation. The resulting product is dissolved in the minimum quantity of warm water and the solution poured into ethanol. Thus 297 kg of the phosphoric ester of the creatinol are obtained having these characteristics: MP 240°C to 243°C. References Kleeman and Engel p. 249 I.N. p. 268 Allievi, E.; US Patent 4,012,467; March 15, 1977

CROMOLYN SODIUM Therapeutic Function: Bronchodilator Chemical Name: 5,5'-[(2-Hydroxy-1,3-propanediyl)bis-(oxy)]bis[4-oxo-4H-1benzopyran-2-carboxylic acid] disodium salt Common Name: Cromogycinic acid sodium salt; Disodium cromogycate Chemical Abstracts Registry No.: 15826-37-6; 16110-51-3 (Base)

1138

Cromolyn sodium

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Intal

Fisons

UK

1969

Intal

Fisons

W. Germany

1970

Lomudal

Fisons

Switz.

1970

Intal

Fujisawa

Japan

1971

Frenasma

Italseber

Italy

1971

Lomudal

Fisons

France

1972

Intal

Fisons

US

1973

Aarane

Fisons

US

1973

Nalcrom

Fisons

Italy

1983

Aarane

Syntex

US

-

Alercrom

Osiris

Argentina

-

Colimone

Fisons

W. Germany

-

Cromo-Asma

Aldo Union

Spain

-

Cusicrom

Cusi

Spain

-

Frenal

I.S.F.

Italy

-

Gastrofrenal

I.S.F.

Italy

-

Kromolin

Iltas

Turkey

-

Lomupren

Fisons

W. Germany

-

Nalcrom

Fisons

UK

-

Nasmil

Lusofarmaco

Spain

-

Nebulasma

Septa

Spain

-

Opticron

Fisons

France

-

Rynacrom

Fisons

UK

-

Raw Materials 2,6-Dihydroxyacetophenone Epichlorohydrin

Diethyl oxalate Sodium hydroxide

Manufacturing Process To a solution of 970 parts of 2,6-dihydroxyacetophenone and 325 parts of epichlorohydrin in 1,500 parts of hot isopropanol was added, with stirring

Cropropamide

1139

under reflux, a solution of 233 parts of 85% KOH in 2,500 parts of isopropanol and sufficient water (ca 100 parts) to dissolve the solid. The mixture was heated, with stirring, under reflux for 48 hours. Half the solvent was then distilled off and 5,000 parts of water were added. The mixture was cooled and the solid filtered off and washed with isopropanol and ether. It was then recrystallized from 12,500 parts of isopropanol to obtain a first crop of 380 parts and a second crop, after concentration, of 300 parts of 1,3-bis(2acetyl-3-hydroxyphenoxy)-2hydroxypropane. 4.6 parts of 1,3-bis(2-acetyl-3-hydroxyphenoxy)-2-hydroxypropane were reacted with diethyl oxalate and the product cyclized to obtain 4.4 parts of pure diethyl ester of 1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane as pale yellow crystals melting between 180° and 182°C from a mixture of benzene and petrol, 4 parts of the diethyl ester of 1,3-bis(2-carboxychromon5-yloxy)-2-hydroxypropane were saponified with sodium hydroxide to obtain 3.2 parts of the disodium salt tetrahydrate as colorless crystals from aqueous alcohol. References Merck Index 2580 Kleeman and Engel p. 250 PDR p. 876 OCDS Vol. 3 pp. 66, 235 (1984) DOT 10 (7) 246 (1974) and 14 (7) 283 (1978) I.N. p. 19 REM p. 1131 Fitzmaurice, C. and Lee, T.B.; US Patent 3,419,578; December 31, 1968; assigned to Fisons Pharmaceuticals Limited, England

CROPROPAMIDE Therapeutic Function: Respiratory stimulant Chemical Name: 2-Butenamide, N-(1-((dimethylamino)carbonyl)propyl)-NpropylCommon Name: Cropropamide; Propylbutamidum Structural Formula:

Chemical Abstracts Registry No.: 633-47-6

1140

Crotamiton

Trade Name

Manufacturer

Country

Year Introduced

Cropropamide

Geigy (Novartis)

-

-

Raw Materials 2-Chlorbutyric acid dimethyl amide Propylamine Crotonic acid chloride Manufacturing Process 2-Chlorbutiric acid dimethyl amide are dissolved in absolute benzene and heated to 110°C with propylamine in the autoclave. After cooling the propylamine hydrochloride is filtered off, then the benzene solution is treated with water and freed from any dissolved propylamine hydrochloride by means of potassium lye. After distillation of the benzene the 2-propylaminobutyric acid dimethyl amide is rectified in vacuum. 2-Propylaminobutyric acid dimethyl amide is dissolved in benzene and while cooling, crotonic acid chloride is added and mixed. Then, reaction mixture is filtered and freed from benzene to give 2-(N-propyl-crotonylamido)butyric acid dimethyl amide, melting point 128°-130°C. References Martin H., Gysin H.; US Patent No. 2,447,587; August 24, 1948; Assigned: J. R. Geigy A.G., Basel, Switzerland

CROTAMITON Therapeutic Function: Scabicide Chemical Name: N-Ethyl-N-(2-methylphenyl)-2-butenamide Common Name: Crotonyl-N-ethyl-o-toluidine Structural Formula:

Chemical Abstracts Registry No.: 483-63-6

Crotethamide

1141

Trade Name

Manufacturer

Country

Year Introduced

Eurax

Ciba Geigy

France

1949

Eurax

Ciba Geigy

US

1949

Crotan

Owen

US

1982

Crotamitex

Tropon

W. Germany

-

Euraxil

Geigy

W. Germany

-

Servitamitone

Servipharm

Switz.

-

Veteusan

Veterinaria

Switz.

-

Raw Materials Crotonyl chloride N-Ethyl-o-toluidine Manufacturing Process 10.5 parts of crotonyl chloride are dropped in such a manner into 27 parts of N-ethyl-o-toluidine, white stirring, that the temperature rises to 130° to 140°C. After cooling, the reaction product is dissolved in ether or other solvent that is immiscible with water, and the solution is washed successively with hydrochloric acid, alkali solution and water. After distilling off the solvent, the residue is distilled in vacuo. The crotonic acid N-ethyl-o-toluidide boils at 153° to 155°C at a pressure of 13 mm and is a slightly yellowish oil. Instead of carrying the reaction out in the presence of an excess of N-ethyl-otoluidine, it may be carried out in the presence of an acid-combining agent, for example, potash, advantageously in a solvent (e.g., acetone). References Merck Index 2583 Kleeman and Engel p. 251 I.N. p. 269 REM p. 1239 British Patent 615,137; January 3, 1949; assigned to J.R. Geigy AG, Switzerland

CROTETHAMIDE Therapeutic Function: Respiratory stimulant Chemical Name: N-(1-(Dimethylcarbamoyl)propyl)-N-ethylcrotonamide Common Name: Crotetamide; Crotethamide Chemical Abstracts Registry No.: 6168-76-9

1142

Cryptenamine tannates

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Micorene

Geisy

-

-

Micoren

Novartis Consumer -

-

Raw Materials 2-Clorobutiric acid dimethyl amide Ethylamine Crotonic acid chloride Manufacturing Process 2-Clorobutiric acid dimethyl amide is dissolved in absolute benzene and heated to 110°-120°C with ethylamine in the autoclave. After cooling the ethylamine hydrochloride is filtered off, then the benzene solution is treated with water and freed from any dissolved ethylamine hydrochloride by means of potassium lye. After distillation of the benzene the 2-ethylaminobutyric acid dimethyl amide is rectified in vacuum. 2-Ethylaminobutyric acid dimethyl amide is dissolved in absolute ether, then the mixture is well cooled and treated drowsy under stirring with crotonic acid chloride. After a stirring reaction mixture is filtered and residue obtained is dissolved in water and treated by potassium hydroxide. The remaining product is finally rectified in high vacuum to give 2-(N-ethyl-crotonylamido)butyric acid dimethyl amide. References Martin H., Gysin H.; US Patent No. 2,447,587; August 24, 1948; Assigned: J. R. Geigy A.G., Basel, Switzerland

CRYPTENAMINE TANNATES Therapeutic Function: Antihypertensive Chemical Name: Complex alkaloid mixture Common Name:

Cryptenamine tannates

1143

Structural Formula: C32H49O6N-tannate Chemical Abstracts Registry No.: 1405-40-9 Trade Name

Manufacturer

Country

Year Introduced

Unitensen

Neisler

US

1954

Raw Materials Veratrum viride Tannic acid Hydrogen chloride

Triethylamine Benzene

Manufacturing Process Initial Extraction Technique: Continuous extraction apparatus was employed, including an extractor designed to contain the starting plant materials, a distillation flask to hold the solvent mixture, the flask being equipped with a reflux condenser, a drip device to facilitate the removal of the volatilized mixture from the condenser and to percolate it through the continuous extractor, and a Soxhlet type return. Means for heating the continuous extraction system were provided. 1,000 g of Veratrum viride powder was placed in a continuous plant extractor and a mixture of 2,000 ml of benzene and 20 ml of triethylamine was poured over a Veratrum powder in the reactor and permitted to siphon into the distillation flask. Approximately 50 g of an inert desiccant (Drierite) was added to the distillation flask, heat applied to initiate the distillation of the reaction mixture in the flask, and the continuous extraction procedure continued for 8 hours, during which time constant, gentle heat was applied to insure refluxing of the mixture (about 80° to 90°C). The extraction procedure was discontinued and the contents of the distillation flask filtered. The resulting filtrate was concentrated by distilling off and recovering a large portion of the benzene solvent together with virtually all of the triethylamine base. 50 ml of the concentrated benzene solution was thus obtained. Preparation of Alkaloid Mixture: 50 ml of the concentrated benzene solution, obtained as described was rapidly stirred, and a saturated solution of hydrogen chloride in ether added to the concentrated benzene solution until no more precipitate was obtained. The resulting precipitate was recovered by filtration and comprised the crude hydrochlorides of the extracted alkaloids and the hydrochloride of any unrecovered triethylamine. This material was dried by heating at a temperature of about 75°C for 6 hours, the crude, dried precipitate ground with 50 ml of isopropanol and to this slurry was added 1,000 ml of water. The resulting mixture was filtered. To the clear filtrate, cooled to 5°C, there was slowly added with rapid stirring, a 10% aqueous solution of ammonium hydroxide, until complete precipitation was accomplished. The precipitate was filtered off, washed with water and dried by heating at about 75°C for 6 hours. There was thus obtained a mixture of Veratrum viride alkaloids having substantial utility as a hypertension reducing agent, without the concomitant

1144

Cyamemazine

marked side-actions normally associated with the clinical use of Veratrum viride extracts. This material may be clinically administered in this form, or further purification may be performed as described hereinafter. Preparation of Alkaloid III : 100 g of the alkaloid mixture was dissolved in a liter of benzene and the resulting mixture filtered. The filtrate was diluted with approximately 4 liters of an aliphatic hydrocarbon solvent (Skellysolve B) and the resulting mixture filtered. The filtrate was cooled with Dry Ice to cause precipitation, and the alkaloid removed by filtration. There was thus obtained an alkaloid, which, for convenience, is called Alkaloid III, having analytical values consistent with a molecular formula C32H49O6N, apparently an ester of a tertiary alkamine. This material sinters at a temperature above about 125°C and melts at 130° to 135°C; UV absorption; lambda maximum 255 nm, lamda minimum 240 nm. It contains one ester group and no N-methyl groups. Preparation of Alkaloid III Tannate: 20 g of Alkaloid III was dissolved in 200 ml of isopropyl alcohol at room temperature and a mixture of 30 g of tannic acid dissolved in 300 ml of isopropyl alcohol, maintained at 40° to 50°C was added thereto with rapid stirring. The mixture was cooled to 20°C, filtered and the precipitate dried at about 80°C. There was thus obtained 33.5 g of the tannate salt of Alkaloid III, as a pale yellow amorphous powder, relatively insoluble in water, and having an indefinite melting point. References Merck Index 2596 PDR p. 1875 I.N. p. 270 REM p. 850 Cavallito, C.J.; USPatent 2,789,977; April 23, 1957; assigned to Irwrin, Neisler and Company

CYAMEMAZINE Therapeutic Function: Tranquilizer Chemical Name: 10-[3-(Dimethylamino)-2-methylpropyl]-10Hphenothiazine-2-carbonitrile Common Name: Cyamepromazine Chemical Abstracts Registry No.: 3546-03-0 Trade Name

Manufacturer

Country

Year Introduced

Terckian

Theraplix

France

1972

Cyanocobalamin

1145

Structural Formula:

Raw Materials 3-Chlorophenthiazine Copper cyanide Sodium amide 1-Dimethylamino-2-methyl-3-chloropropane Manufacturing Process The 3-cyanophenthiazine used as starting material can be prepared by the action of cupric cyanide on 3-chlorophenthiazine in boiling quinoline. It has a first melting point of about 185°C and a second of about 203° to 205°C. A solution of 3-cyanophenthiazine (10 g) in anhydrous xylene (75 cc) is heated under reflux and treated with 95% sodium amide (2.15 g). The heating is continued for 1 hour and then a solution of 1-dimethylamino-2methyl-3-chloropropane (7.05 g) in xylene (70 cc) is added over 15 minutes. The mixture is heated under reflux for 20 hours and then cooled. The reaction mixture is treated with water (40 cc) and N methane-sulfonic acid (75 cc). The xylene phase is removed and the aqueous phase is made alkaline with sodium hydroxide. The free base obtained is extracted with ether and the ethereal extracts are dried over anhydrous potassium carbonate and concentrated to dryness. The residue is distilled in vacuo. 3-Cyano-10-(3dimethylamino-2-methylpropyl)phenthiazine (8.5 g), BP 180° to 205°C/0.9 mm Hg, is thus obtained. The acid maleate prepared in and recrystallized from ethanol melts at 204° to 205°C. References Merck Index 2678 Kleeman and Engel p. 252 DOT 8 (6) 216 (1972) I.N. p. 271 Jacob, R.M. and Robert, J.G.; US Patent 2,877,224; March 10, 1959; assigned to Societe des Usines Chimiques Rhone-Poulenc, France

CYANOCOBALAMIN Therapeutic Function: Hematinic

1146

Cyanocobalamin

Chemical Name: 5,6-Dimethylbenzimidazocyl cyanocobamide Common Name: Vitamin B12 Structural Formula:

Chemical Abstracts Registry No.: 68-19-9 Trade Name

Manufacturer

Country

Year Introduced

Berubigen

Upjohn

US

1949

Rubramin

Squibb

US

1949

Bevidox

Abbott

US

1949

Betalin

Lilly

US

1949

Cobione

MSD

US

1949

Docibin

National

US

1950

Ducobee

Breon

US

1950

Dodex

Organon

US

1950

Be-Dodec

Schieffelin

US

1950

B-Twelvora

Sherman

US

1950

Crystamin

Armour

US

1951

Bexil

Conal

US

1951

Redisol

MSD

US

1951

Bevatine

Dorsey

US

1953

Vibalt

Roerig

US

1954

Bedoce

Lincoln

US

1957

Cyanocobalamin

1147

Trade Name

Manufacturer

Country

Year Introduced

Vi-Twel

Cooper

US

1960

Cyano-Gel

Maurry

US

1961

Clarex

Minn. Pharm.

US

1962

Cyredin

Merrell National

US

1967

Feryl

Central

US

1968

Dicopac

Kaken

Japan

1969

Anacobin

Allen and Hanburys

UK

-

Actamin

Yashima

Japan

-

Apavit B12

Locatelli

Italy

-

Antipernicin

Galenika

Yugoslavia

-

Arcavit B12

Arcana

Austria

-

Arcored

Arco

Switz.

-

Arphos

Fournier

France

-

Bedocefarm

Wolner

Spain

-

Bedodeka

Teva

Israel

-

Beduzin

Dincel

Turkey

-

Behepan

Kabi Vitrum

Sweden

-

Berubi

Redel

W. Germany

-

Betolvex

Dumex

Denmark

-

Bexibee

N. American

US

-

Bidocit

Ausonia

Italy

-

B12 Mille

Delagrange

France

-

B12 Vicotrat

Heyl

W. Germany

-

Cabadon M

Raid-Provident

US

-

Cincomil Bedoce

Andromaco

Spain

-

Cobalomin

S. Pacific

Australia

-

Cobalparen

Saarstickstoff-Fatol W. Germany

-

Cobavite

Lemmon

US

-

Cocavitan

Coca

Spain

-

Copharvit

Cophar

Switz.

-

Cyanabin

Stickley

Canada

-

Cyanovit

Adrian-Marinier

France

-

Cykobemin

Kabi Vitrum

Sweden

-

Cytakon

Glaxo

UK

-

Cytamen

Glaxo

UK

-

Cytobion

Merck

W. Germany

-

Dobetin

Angelini

Italy

-

Docetasan

Santos

Spain

-

Docivit

Robisch

W. Germany

-

Dodecabee

Miller

US

-

Dodecavite

U.S.V.

US

-

1148

Cyanocobalamin

Trade Name

Manufacturer

Country

Year Introduced

Dodevitina

C.T.

Italy

-

Eocill B12

Nessa

Spain

-

Erftamin

Erfto-Chemie

W. Germany

-

Eritron

Manetti-Roberts

Italy

-

Eritrovit B12

Lisapharma

Italy

-

Erycytol

Sanabo

Austria

-

Fiviton B12

Alfar

Spain

-

Hemomin

Kirk

US

-

Hemosalus

Totalpharm

Italy

-

Hepacon B12

Consolidated

UK

-

Hepcovite

Endo

US

-

Juvabe

Dolder

Switz.

-

Lifaton B12

Lifasa

Spain

-

Lophakornb B12

Lornapharm

W. Germany

-

Milbedoc

Andromaco

Spain

-

Millevit

Nordmark

W. Germany

-

Neo-Cytamen

Bilim

Turkey

-

Neurobaltina

Sidus

Italy

-

Neuro Liser B12

Perga

Spain

-

Nova-Rubi

Novo

Canada

-

Noventabedoce

Andromaco

Spain

-

Omeogen

UCB-Smit

Italy

-

Optovite B 12

Normon

Spain

-

Permicipur

Mulli

W. Germany

-

Plentasal

Lopez-Brea

Spain

-

Primabalt

Primedics

US

-

Rectocenga

Biotherax

France

-

Redamin

Washington

Italy

-

Reedvit

Celtia

Argentina

-

Retidec B12

Dexter

Spain

-

Rubesol

Central

US

-

Rubraluy

Miluy

Spain

-

Ruvite

Savage

US

-

Sancoba

Santen

Japan

-

Sorbevit B12

Casen

Spain

-

Sorbigen B12

Gentili

Italy

-

Surgevit

Maipe

Spain

-

Twel-Be

Pitman-Moore

US

-

Vicapanbiz

Merckle

W. Germany

-

Viemin 12

Valeas

Italy

-

Vitarubin

Streuli

Switz.

-

Cyanocobalamin

1149

Raw Materials Potassium cyanide Sodium nitrite

Milorganite (activated sewage sludge) Hydrochloric acid

Manufacturing Process The following is taken from US Patent 3,057,851. Milorganite was extracted with water to obtain an aqueous extract containing vitamin B12 active substances. This aqueous extract was purified by treatment with an ion exchange resin according to the following method. An aqueous extract of milorganite, 100 ml containing 300 µg of vitamin B12 active substances and 4.5 grams of total solids, was combined with 0.5 gram of sodium nitrite and 0.4 gram of potassium cyanide. The resulting solution was adjusted to pH 4.0 with hydrochloric acid and heated to boiling. The boiled solution was filtered through a Super-Cel filter surface, and the filter was then washed with water. The filtrate was obtained in a total volume of 130 ml including the washings. Amerlite XE-97, an ion exchange resin of the carboxyl type (Rohm and Haas), was classified to an average wet particle size of 100 to 150 mesh. The classified resin was utilized in the hydrogen form, and was not buffered during the ion exchange fractionation. The classified resin, in the amount of 35 ml, was packed into a glass column having a diameter of 25 mm and a height of 250 mm. The cyanide-treated aqueous extract of milorganite was infused gravitationally into the ion exchange bed at a rate of 3 ml per minute. The effluent was discarded and the resin bed was then washed with the following solutions in the specified sequence: (1) 120 ml of an aqueous 0.1 N hydrochloric acid solution; (2) 75 ml of an aqueous 85% acetone solution; and (3) 70 ml of an aqueous 0.1 N hydrochloric acid solution. After washing, the resin bed was eluted with an aqueous 60% dioxane solution containing 0.1 N of hydrochloric acid. In this elution, 8 ml of colored eluate was collected. This portion of the eluate was found to contain 295 µg of cyanocobalamin and 9 mg of total solids. References Merck Index 9822 Kleeman and Engel p. 252 PDR pp. 655, 785, 872, 905, 916, 966, 1083, 1603, 1989 I.N. p. 272 REM pp. 1020, 1022 Rickes, E.L. and Wood, T.R.; US Patents 2,703,302 and 2,703,303; both dated March 1, 1955; both assigned to Merck and Co., Inc. Speedie, J.D. and Hull, G.W.; US Patent 2,951,017; August 30, 1960; assigned to The Distillers Company Limited, Scotland McDaniel, L.E.; US Patent 3,000,793; September 19, 1961; assigned to Merck and Co., Inc. Long, R.A.; US Patent 3,018,225; January 23, 1962; assigned to Merck and Co., Inc. Van Melle, P.J.; US Patent 3,057,851; October 9, 1962; assigned to ArmourPharmaceutical Bernhauer, K., Friedrich, W. and Zeller, P.; US Patent 3,120,509; February 4, 1964; assigned to Hoffmann-La Roche Inc.

1150

Cyclacillin

CYCLACILLIN Therapeutic Function: Antibacterial Chemical Name: 6-(1-Aminocyclohexanecarboxamido)-3,3-dimethyl-7-oxo-4thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Common Name: 6-(1-Aminocyclohexanecarboxamido)penicillanic acid; 1Aminocyclohexylpenicillin; Ciclacillin Structural Formula:

Chemical Abstracts Registry No.: 3485-14-1 Trade Name

Manufacturer

Country

Year Introduced

UItracillin

Gruenenthal

W. Germany

1972

Wybital

Wyeth

Japan

1972

Vastollin

Takeda

Japan

1972

Ultracillin

Gruenenthal

Switz.

1973

Cyclapen

Wyeth

US

1979

Calthor

Ayerst

UK

1980

Bionacillin-C

Takata

Japan

-

Citocilina

Medinsa

Spain

-

Citosarin

Toyo Jozo

Japan

-

Orfilina

Orfi

Spain

-

Peamezin

Sawai

Japan

-

Syngacillin

Wyeth

-

-

Vasticillin

Takeda

Japan

-

Vipicil

Wyeth

-

-

Raw Materials 6-Aminopenicillanic acid 1-Amino-1-cyclohexane carboxylic acid chloride

Cyclamate calcium

1151

Manufacturing Process To 21.6 g (0.10 mol) of 6-aminopenicillanic acid (6-APA) and 213 ml of methylene chloride in a dry 500 ml 3-neck flask fitted with stirrer, thermometer, nitrogen inlet and reflux condenser with drying tube, 25.3 g (0.25 mol) of triethylamine and 13.4 g (0.11 mol) of N,N-dimethylaniline were added. After stirring at reflux for one hour, the mixture was cooled and 21.7 g (0.20 mol) of trimethylchlorosilane was added dropwise at 12° to 15°C The mixture was refluxed for 45 minutes, cooled under nitrogen, and 19.8 g (0.10 mol) of 1-amino-1-cyclohexane-carboxylic acid chloride HCl was added portionwise at -10°C over 20 minutes. The mixture was stirred for an additional hour while the temperature rose to 20°C. The reaction mixture was poured into 200 ml of cold water with stirring and the two-phase mixture clarified by filtration. Dilute sodium hydroxide solution was added to the filtrate at 5° to 10°C to pH 5.4. After stirring overnight at room temperature, the crystalline product was collected by filtration, washed with water and finally with acetone, and then dried at 45°C; yield of dihydrate, 29.9 g or 79% of theory based on 6-APA; iodometric assay, 922 mcg per mg; bioassay, 921 mcg per mg, as described in US Patent 3,478,018. References Merck Index 2693 Kleeman and Engel p. 205 PDR p. 1945 OCDS Vol. 2 p. 439 (1980) DOT 8 (5) 168 (1972) I.N. p.230 REM p. 1200 Alburn, H.E., Grant, N.H. and Fletcher, H. III; US Patent 3,194,802; assigned to American Home Products Corporation Robinson, C.A. and Nescio, J.J.; US Patent 3,478,018; November 11, 1969; assigned to American Home Products Corporation

CYCLAMATE CALCIUM Therapeutic Function: Pharmaceutic aid Chemical Name: Cyclohexylsulfamic acid calcium salt Common Name: Chemical Abstracts Registry No.: 139-06-0 Trade Name Sucaryl Calcium Sucaryl Calcium

Manufacturer Abbott Abbott

Country US France

Year Introduced 1953 1966

1152

Cyclamate calcium

Structural Formula:

Raw Materials Cyclohexylamine Ammonium sulfamate Calcium hydroxide Manufacturing Process 220 parts by weight, 2.22 mols, of cyclohexylamine and 57 parts by weight, 0,50 mol, of ammonium sulfamate were mixed at room temperature and heated with agitation. At the end of one-half hour of heating the temperature had reached 110°C and approximately one-half mol of ammonia had been evolved. Heating was continued under reflux at 133°C for 22 additional hours. A second half-mol of ammonia was liberated. The ammonia yield was 100%. The reaction mixture was cooled to 100°C. To the mixture was added a water slurry containing 20.3 parts by weight, 0.55 equivalent, of calcium hydroxide and 700 parts by weight of water. Cyclohexylamine was then removed by azeotropic distillation with water. The amine which was recovered can be reused after drying. The residue from the distillation was evaporated to dryness in a vacuum oven at 50°C and the resulting product analyzed. The product weighing 105.5 parts by weight, 0.488 equivalent, was obtained which is a 98% yield of the technical calcium cyclohexylsulfamate dihydrate. References Merck Index 1636 I.N.p.273 Cummins, E.W. and Johnson, R.S.; US Patent 2,799,700; July 16, 1957; assigned to E.I. du Pont de Nemours and Co. McQuaid, H.S.; US Patent 2,804,477; August 27, 1957; assigned to E.I. du Pont de Nemours and Co. Freifelder, M.; US Patent 3,082,247; March 19, 1963; assigned to Abbott Laboratories Birsten, O.G. and Rosin, J.; US Patents 3,361,798; January 2, 1968; and 3,366,670; January 30, 1968; both assigned to Baldwin-Montrose Chemical Co., Inc.

Cyclandelate

1153

CYCLANDELATE Therapeutic Function: Spasmolytic Chemical Name: α-Hydroxybenzeneacetic acid 3,3,5-trimethylcyclohexyl ester Common Name: 3,3,5-Trimethylcyclohexyl mandelate Structural Formula:

Chemical Abstracts Registry No.: 456-59-7 Trade Name

Manufacturer

Country

Year Introduced

Cyclospasmol

Ives

US

1958

Cyclospasmol

Beytout

France

1972

Acyclin

Arcana

Austria

-

Anaspat

I.C.I.

Italy

-

Anticen

Nippon Kayaku, Co.

Japan

-

Aposelebin

Hokuriku

Japan

-

Capilan

Takeda

Japan

-

Capistar

Kowa

Japan

-

Ceaclan

Mohan

Japan

-

Cepidan

Meiji

Japan

-

Circle-one

Funai

Japan

-

Circulat

Kozani

Japan

-

Cyclan

Ohta

Japan

-

Cyclan-Cap

Nichiiko

Japan

-

Cyclansato

S.S. Pharm

Japan

-

Cycleat Cap

Hishiyama

Japan

-

Cyclobral

Norgine

UK

-

Cyclolyt

Taro

Israel

-

Hacosan

Sankyo

Japan

-

Hi-Cyclane Cap

Tyama

Japan

-

Lisospasm

Chibi

Italy

-

Mandelic

Seiko

Japan

-

Marucyclan

Maruko

Japan

-

Mitalon

Toyo

Japan

-

Newcellan

Kowa

Japan

-

1154

Cyclandelate

Trade Name

Manufacturer

Country

Year Introduced

Perebral

Biopharma

France

-

Saiclate

Morishita

Japan

-

Sancyclan

Santen

Japan

-

Sepyron

Sankyo

Japan

-

Spadelate

Zeria

Japan

-

Spasmione

Ravizza

Italy

-

Spasmocyclon

Kettelhack Riker

W. Germany

-

Syklandal

Orion

Finland

-

Vasodyl

Morrith

Spain

-

Vasosyklan

Farmos

Finland

-

Venala

Mochida

Japan

-

Zirkulat

Nippon Shoji

Japan

-

Raw Materials dl-Mandelic acid 3,3,5-Trimethylcyclohexanol Manufacturing Process 50 g of dl-mandelic acid are heated for 6 hours at approximately 100°C with 50 g of 3,3,5-trimethylcyclohexanol (mixture of cis and trans isomers), while passing dry hydrochloric acid gas as a catalyst through the mixture. The reaction product is subsequently poured out into water. After neutralization with potassium bicarbonate the ester is extracted with ether. The ether extract is dried with sodium sulfate, the ether is distilled off and the residue is distilled in vacuo. The fraction, which has a boiling point of 192° to 194°C at 14 mm, consists of the 3,3,5-trimethylcyclohexyl ester of mandelic acid, which is obtained in a yield of about 70%. The liquid solidifies to a colorless solid substance having a melting point of 50° to 53°C, according to US Patent 2,707,193. It has been found that crude cyclandelate may be purified by the following procedure. Crude cyclandelate is dissolved in a solvent chosen for convenience from the class of saturated hydrocarbons. The crude cyclandelate solution is stirred for a suitable interval, typically 1 to 5 hours, with an aqueous solution of sodium borohydride (NaBH4) at temperatures ranging from 25° to 65°C. The preferred temperature range is 40° to 50°C. The pH of the solution may be adjusted to any desired level in the range between 2.5 to 11.5. The preferred pH range is 8.0 to 11.0 because at lower pH levels borohydride is unstable and decomposes rapidly. The amount of sodium borohydride used ranges from about 0.5 to 2.0 wt % of the amount of cyclandelate present. At the end of the stirring period cyclandelate is recovered by well-known procedures. For instance, the aqueous organic layers may be separated gravimetrically and the product organic layer washed with an appropriate solvent and then distilled, according to US Patent 3,663,597.

Cyclarbamate

1155

References Merck Index 2695 Kleeman and Engel p. 254 PDR pp. 1606, 1947, 1999 OCDS Vol. 1 p. 94 (1977) I.N. p. 273 REM p.852 Flitter, D.; US Patent 3,663,597; May 16, 1972; assigned to American Home Products Corporation Nauta, W.T.; US Patent 2,707,193; April 26, 1955; assigned to N.V. Koninklijke Pharmaceutische Fabrieken Voorbeen Brocades-Stheeman and Pharmacia, Netherlands

CYCLARBAMATE Therapeutic Function: Spasmolytic Chemical Name: 1,1-Dimethylolcyclopentane N,N'-diphenyl-dicarbamate Common Name: Cyclopentaphene Structural Formula:

Chemical Abstracts Registry No.: 5779-54-4 Trade Name

Manufacturer

Country

Year Introduced

Casmalon

Cassenne

France

1961

Raw Materials 1,1-Dimethylol cyclopentane Phenyl isocyanate

1156

Cyclizine

Manufacturing Process This compound is obtained by heating a mixture of 1,1-dimethylol cyclopentane and phenyl isocyanate at a temperature of 85°C to 90°C for one-half hour. The resultant product is washed with petroleum ether, recrystallized from methanol, dissolved in acetone (impurities are filtered off) and recrystallized from acetone. The compound appears in the form of a white powder or of needle-shaped crystals (MP = 147°C to 149°C), which are tasteless and odorless. References Merck Index 2696 I.N. p.274 Rosenberg, E.E.; US Patent 3,067,240; December 4, 1962; assigned to Laboratoires Cassenne (France)

CYCLIZINE Therapeutic Function: Antinauseant Chemical Name: 1-Diphenylmethyl-4-methylpiperazine Common Name: Structural Formula:

Chemical Abstracts Registry No.: 82-92-8; 303-25-3 (Hydrochloride salt) Trade Name Marezine Marzine Bon Voyage Cleamine Echnatol

Manufacturer BurroughsWellcome Wellcome Cupal Kodama Gerot

Country US

Year Introduced 1953

France UK Japan Austria

1965 -

Cyclobarbital Trade Name Fortravel Happy Trip Maremal Migwell Motozina Reis-Fit Valoid

Manufacturer Chemofux Mepros Gayoso Wellcome Wellcome Biomedica Foscama A.P.F. BurroughsWellcome

1157

Country Austria Netherlands Spain France Italy

Year Introduced -

Netherlands UK

-

Raw Materials Benzhydryl chloride N-Methylpiperazine Manufacturing Process One-tenth mol (20 g) of benzhydryl chloride was mixed with 0.19 mol (19 g) of N-methylpiperazine and about 10 cc of benzene and the whole was heated on the steam bath four hours. The contents of the flask was partitioned between ether and water, and the ethereal layer was washed with water until the washings were neutral. The base was then extracted from the ethereal layer by N hydrochloric acid and the extract, made acid to Congo red paper, was evaporated under vacuum. 29.5 g of the pure dihydrochloride of Nmethyl-N'-benzhydryl piperazine was recovered from the residue by recrystallization from 95% alcohol melting above 250°C with decomposition. The addition of alkali to an aqueous solution of the dihydrochloride liberated the base which was recovered by recrystallization from petroleum ether melting at 105.5° to 107.5°C. References Merck Index 2703 Kleeman and Engel p. 254 PDR p. 754 OCDS Vol. 1 p. 58 (1977) I .N. p. 274 REM p. 807 Baltzly, R. and Castillo, J.C.; US Patent 2,630,435; March 3, 1953; assigned to Burroughs Wellcome and Co. (U.S.A.) Inc.

CYCLOBARBITAL Therapeutic Function: Hypnotic Chemical Name: 2,4,6-(1H,3H,5H)-Pyrimidinetrione, 5-(1-cyclohexen-1-yl)5-ethyl-

1158

Cyclobarbital

Common Name: Ciclobarbital; Cyclobarbital; Cyclobarbitone; Tetrahydrophenobarbital Structural Formula:

Chemical Abstracts Registry No.: 52-31-3 Trade Name

Manufacturer

Country

Year Introduced

Cyclobarbital

Bayer

-

-

Cyklonal

Leo

-

-

Dorminal

Star

-

-

Prodorm

Nyco

-

-

Raw Materials δ-1,2-Cyclohexenylcyanacetic acid ethyl ester Ethyl iodide Sulfuric acid

Sodium Alcohol Quanidine sulfate

Manufacturing Process 772.0 g of δ-1,2-cyclohexenylcyanacetic acid ethyl ester are introduced into a stirred and ice cooled solution of 92.0 g of sodium in 1500 ml of absolute alcohol. The sodium δ-1,2-cyclohexenylcyanacetic acid ester formed is then gradually treated without ice cooling with 750.0 g of ethyl iodide. The reaction mixture become warm, sodium iodide separates out and the whole is neutral after a short time. The sodium iodide is filtered off, the filtrate freed from alcohol by distillation, the residues taken up in water, siphoned off, dried over calcium chloride and distilled in vacuum, yields δ-1,2cyclohexenylethylcyanacetic acid ethyl ester, boil point 125°C. 72.0 g of sodium are dissolved in 1086.0 g of absolute alcohol and boiled for 3.75 h with 285.0 g of guanidine sulfate, then 221.0 g of δ-1,2cyclohexenylethylcyanacetic acid ester are added and boiling is continued for a further 12 h. The residue remaining after distilling off the alcohol is boiled with 10 times its weight of dilute sulfuric acid and then δ-1,2cyclohexenylethylbarbituric acid which separates out is recrystallized from hot water, melting point 170°C. References DB Patent No. 231,150; March 21,1924; Assigned: Farbeenfabriken vorm. Friedr. Bayer and Co., Germany

Cyclobenzaprine

1159

CYCLOBENZAPRINE Therapeutic Function: Muscle relaxant Chemical Name: 5-(3-Dimethylaminopropylidene)-dibenzo[a,e] cycloheptatriene Common Name: Structural Formula:

Chemical Abstracts Registry No.: 303-53-7; 6202-23-9 (Hydrochloride salt) Trade Name

Manufacturer

Country

Year Introduced

Flexeril

Merck Sharp and Dohme

US

1977

Raw Materials Dibenzo[a,d]cycloheptene-5-one Magnesium

3-Dimethylaminopropyl chloride Hydrogen chloride

Manufacturing Process In an initial step, dibenzo [a,d]cyclohepten-5-one is reacted with the Grignard reagent of 3-dimethylaminopropyl chloride and hydrolyzed to give 5-(3dimethylaminopropyl)-dibenzo[a,d][1,4]cycloheptatriene-5-ol. Then 13 g of that material, 40 ml of hydrochloric acid, and 135 ml of glacial acetic acid is refluxed for 3½ hours. The solution is then evaporated to dryness in vacuo and added to ice water which is then rendered basic by addition of ammonium hydroxide solution. Extraction of the basic solution with chloroform and removal of the solvent from the dried chloroform extracts yields the crude product which when distilled in vacuo yields essentially pure 5-(3dimethylaminopropylidene)-dibenzo[a,d][1,4]cycloheptatriene, BP 173°C to 177°C at 1.0 mm. References Merck Index 2706 DFU 2 (5) 299 (1977) Kleeman and Engel p. 255 PDR p. 1178

1160

Cyclobutyrol

OCDS Vol. 3 p. 77 (1984) DOT 14 (12) 467 (1978) I.N. p. 275 REM p. 926 Villani, F.J.; US Patent 3,409,640; November 5, 1968; assigned to Schering Corporation

CYCLOBUTYROL Therapeutic Function: Choleretic Chemical Name: α-(Hydroxy-1-cyclohexyl)butyric acid Common Name: Structural Formula:

Chemical Abstracts Registry No.: 512-16-3 Trade Name

Manufacturer

Country

Year Introduced

Hebucol

Logeais

France

1957

Bas-Bil

Isola-Ibi

Italy

-

Citoliver

Bayropharm

Italy

-

Cytinium

Roques

France

-

Dibilene

Logeais

France

-

Epo-Bon

Sierochimica

Italy

-

Juvallax

Pierrel

Italy

-

Lipotrin

Eisai

Japan

-

Riphole N

Nichiiko

Japan

-

Secrobil

Medital

Italy

-

Tribil

Biol. Italia

Italy

-

Tribilina

Farge

Italy

-

Trommogallol

Trommsdorff

W. Germany

-

Raw Materials Cyclohexanone Barium hydroxide Sulfuric acid

Ethyl α-bromobutyrate Zinc

Cyclofenil

1161

Manufacturing Process Into a balloon flask with two lateral necks furnished with an efficient mechanical agitator and protected from moisture by a calcium chloride guard, there are introduced 12 g (0.185 mol) of pure powdered zinc and 20 ml of a solution of 16.6 g (0.17 mol) of anhydrous cyclohexanone and 31.5 g (0.16 mol) of ethyl α-bromobutyrate in 25 ml of anhydrous benzene. With vigorous stirring in a manner to put the zinc into suspension, the balloon flask is gradually heated in an oil bath to 100°C to 105°C. After a few minutes, a reaction starts, causing violent boiling which is maintained while adding the balance of the reactants. Boiling is then continued for one hour. After cooling, the reaction mixture is turned into a beaker containing 30 ml of sulfuric acid to half (by volume) with ice. After agitation, the mixture is decanted into a container for separation. The aqueous phase is reextracted with benzene. The pooled benzene solutions are washed with dilute (10%) cold sulfuric acid, then with cold sodium carbonate (5%) and then with ice water, and dried over anhydrous sodium sulfate. The benzene is evaporated and the ester, which is ethyl α(hydroxy-1-cyclohexyl) butyrate, is distilled off under reduced pressure. The yield obtained was 17 to 19 g or 49% to 55%. The ester was saponified with baryta in aqueous methanol as follows: 21.5 g (0.1 mol) of the above ethyl ester is saponified by boiling under reflux for 4 hours, while agitating, with 30 g (0.095 mol) of barium oxide hydrated to 8H2O in 250 ml of a mixture of equal volumes of methanol and water. After concentration to one-half its volume under reduced pressure and filtration, the aqueous solution is washed with ether and then acidified at 0°C with 10% hydrochloric acid. The acid liberated in oily form is extracted with ether. The ether is washed with water, dried and evaporated. The yield is 75-80% (14-15 g of crude acid) which crystallizes spontaneously little by little. It can be crystallized in a mixture of ether and petroleum ether (1:10) or, with better yield, in light gasoline or oil (solubility of the pure acid ranges from 0.3% at 0°C to 100% at the boiling point). The yield of crystals is 75-80%. The α(hydroxy-1-cyclohexyl) butyric acid thus obtained is a colorless crystalline product with a melting point of 81°C to 82°C. References Merck Index 2709 Kleeman and Engel p. 256 I.N.p.275 Maillard, J.G.A.E., Morin, R.M. and Benard, M.M.M.; US Patent 3,065,134; November 20, 1962; assigned to Societe d'Exploitation des Laboratoires Jacques Logeals (S.A.R.L.) (France)

CYCLOFENIL Therapeutic Function: Ovulation stimulant Chemical Name: 4-[[4-(Acetyloxy)phenyl]cyclohexylidenemethyl]phenol acetate

1162

Cyclofenil

Common Name: p,p'-Diacetoxybenzhydrilidenecyclohexane Structural Formula:

Chemical Abstracts Registry No.: 2624-43-3 Trade Name

Manufacturer

Country

Year Introduced

Ondogyne

Roussel

France

1970

Sexovid

Teikoku Hormon

Japan

1972

Fertodur

Schering

W. Germany

1972

Ondonvid

Roussel

UK

1972

Fertodur

Schering

Italy

1974

Klofenil

Yurtoglu

Turkey

-

Neoclym

Poli

Italy

-

Sexovid

Ferrosan

Sweden

-

Raw Materials p-Bromoanisole Potassium hydroxide Magnesium

p-Hydroxyphenyl cyclohexyl ketone Ammonium chloride Acetic anhydride

Manufacturing Process (A) Preparation of p-Hydroxy-p'-Methoxybenzhydrylidenecyclohexane: To a Grignard solution prepared from 110 g of magnesium (4.5 mols) and 840 g of p-bromoanisole (4.5 mols) in one liter of anhydrous ether, there was added dropwise with vigorous agitation 307 g of p-hydroxyphenyl cyclohexyl ketone (1.5 mols) dissolved in one liter of anhydrous ether. Upon completion of the addition the reaction mixture was refluxed for 2.5 hours with agitation, and was then cooled. Thereupon 15 mols of ammonium chloride dissolved in 3 liters of water were added. The ethereal layer was separated, washed with water, dried over anhydrous sodium sulfate and distilled. Yield: 370 g. BP 180° to 190°C at 0.1 mm. The substance was recrystallized from a mixture of carbon tetrachloride and petroleum ether. MP 145° to 146°C. (B)Preparation of p,p'-Dihydroxybenzhydrylidenecyclohexane: A mixture of 118 g of p-hydroxy-p'-methoxybenzhydrylidenecyclohexane (0.4 mol), 120 g of potassium hydroxide pellets and 500 ml of triethylene glycol was stirred 4 hours at 220°C. When the reaction mixture was poured into water the substance crystallized, and the crystals were filtered off and washed with

Cyclomethycaine

1163

water. The substance was then recrystallized from a mixture of ethanol and petroleum ether. Yield: 104 g. MP 235° to 236°C. (C) Preparation of p,p'-Diacetoxybenzhydrylidenecyclohexane: 56 g of p,p'dihydroxybenzhydrylidenecyclohexane (0.2 mol) was mixed with 250 ml of acetic anhydride and 500 ml of pyridine. The mixture was refluxed for 2 hours and was then poured into water, the substance crystallizing out. The crystals were filtered off and washed with water. Finally the substance was recrystallized from ethanol. Yield: 62 g. MP 135° to 136°C. References Merck Index 2714 Kleeman and Engel p. 256 DOT 7 (1) 11 (1971) I.N. p. 275 Olsson, K.G., Wahlstam, H.E.A., Sundbeck, B., Barany, E.H. and Miquel, J.F.; US Patent 3,287,397; November 22, 1966

CYCLOMETHYCAINE Therapeutic Function: Local anesthetic Chemical Name: 4-(Cyclohexyloxy)benzoic acid 3-(2-methyl-1-piperidinyl) propyl ester Common Name: Structural Formula:

Chemical Abstracts Registry No.: 139-62-8 Trade Name Surfacaine Topocaine

Manufacturer Lilly Lilly

Country US -

Year Introduced 1948 -

Raw Materials Ethyl-p-hydroxybenzoate Sodium Sodium hydroxide

Cyclohexyl bromide 3-(2'-Methylpiperidino)propyl chloride

1164

Cyclopentamine hydrochloride

Manufacturing Process 7.4 g of sodium are dissolved in 250 cc of isoamyl alcohol, 53 g of ethyl phydroxybenzoate are added and the mixture is heated to refluxing temperature for about 15 minutes. To the cooled mixture, 65 g of cyclohexyl bromide are added and the mixture is refluxed for about 3 hours. The isoamyl alcohol is removed by evaporation in vacuo and the residue is extracted with 10% aqueous sodium hydroxide solution to remove the unreacted ethyl phydroxybenzoate. The alkali-insoluble residue comprising ethyl p-cyclohexyloxybenzoate is hydrolyzed by refluxing with 10% sodium hydroxide solution for about 3 hours. The alkaline reaction mixture is acidified with hydrochloric acid whereupon p-cyclohexyloxybenzoic acid precipitates. The precipitate is separated by filtration, washed with water and dried. It melts at about 178° to 180°C. Yield: about 7%. 62 g of p-cyclohexyloxybenozic acid and 49.5g of 3-(2'-methylpiperidino)propyl chloride are dissolved in 300 cc of dry isopropanol and the mixture refluxed for about 12 hours. About half of the isopropanol is then distilled off and the residual solution cooled to about 0°C. 3(2'-methylpiperidino)-propyl p-cyclohexyloxybenzoate hydrochloride precipitates as a white crystalline compound. It is filtered off, washed once with ether and recrystallized from isopropanol. 3(2'-Methylpiperidino)-propyl p-cyclohexyloxybenzoate hydrochloride thus prepared melted at about 178° to 180°C. Analysis showed the presence of 8.88% chlorine as compared with the calculated value of 8.96%. References Merck Index 2729 Kleeman and Engel p. 257 OCDS Vol. 1 p. 14 (1977) I.N. p.276 REM p. 1055 McElvain, S.M. and Carney,T.P.; US Patent 2,439,818; April 20, 1948

CYCLOPENTAMINE HYDROCHLORIDE Therapeutic Function: Vasoconstrictor Chemical Name: N-α-Dimethylcyclopentaneethaneamine hydrochloride Common Name: Cyclopentadrine Structural Formula:

Cyclopentamine hydrochloride

1165

Chemical Abstracts Registry No.: 102-45-4 (Base) Trade Name Clopane Cyclonaranol Nazett

Manufacturer Lilly Hepatrol A.L.

Country US France Norway

Year Introduced 1951 -

Raw Materials Cyclopentanone Cyanoacetic acid Ammonium acetate Hydrogen Magnesium Methyl iodide Methylamine Hydrogen chloride Manufacturing Process A mixture of 126 g (1.5 mols) of cyclopentanone, 128 g (1.5 mols) cyanoacetic acid, 31 g (0.5 mol) of ammonium acetate and 200 cc of dry benzene is heated under a refluxing condenser and a water trap. The mixture is refluxed for about 12 hours after which time no more water collects in the trap, and the formation of cyclopentylideneacetonitrile is complete. The reaction mixture comprising a mixture of cyclopentylideneacetonitrile and cyclopentylideneacetic acid is washed with about one liter of 2% hydrochloric acid and the benzene layer is separated and the mixture is distilled to cause decarboxylation of the cyclopentylideneacetic acid present. The distillate comprising cyclopentylideneacetonitrile which boils at 172° to 175°C is purified by distillation. A mixture of 53.5 g (0.5 mol) of cyclopentylideneacetonitrile dissolved in 50 cc of absolute ethanol and 0.5 g of a palladium-carbon catalyst is hydrogenated with hydrogen at a pressure of about 40 lb for about 3 hours. An additional amount of 0.8 g of palladium-carbon catalyst is then added and the hydrogenation continued for about 4 hours during which time the reduction is substantially completed and the cyclopentylideneacetonitrile is converted to cyclopentylacetonitrile. The reaction mixture is filtered to remove the catalyst and the alcohol is evaporated in vacuo. The residue comprising chiefly cyclopentylacetonitrile is washed with dilute hydrochloric acid to remove any amine which may have been formed during the hydrogenation process, and the organic residue comprising cyclopentylacetonitrile is dissolved in ether, the ether solution dried over anhydrous magnesium sulfate and distilled. The cyclopentylacetonitrile boils at 185° to 187°C and has a refractive index of nD25 = 1.4456. To an ethereal solution of methyl magnesium iodide prepared from 26.7 g (1.1 mols) of magnesium and 160 g (1.13 mols) of methyl iodide in 200 cc of dry ether, is added a solution of 79 g (0.72 mol) of cyclopentylacetonitrile in 100 cc of dry ether. The reaction mixture is refluxed for 4 hours. The reaction mixture is then decomposed with ice in the usual way, and the ether layer

1166

Cyclopentolate hydrochloride

containing the cyclopentylacetone is separated, is dried over anhydrous magnesium sulfate and the ether removed by evaporation. The residue comprising cyclopentylacetone is purified by distillation in vacuo. The cyclopentylacetone boils at 82° to 84°C at about 32 mm pressure. A mixture of 75 g (0.6 mol) of cyclopentylacetone, 75 g (2.4 mols) of methylamine, and 10 g of Raney nickel catalyst is placed in a high pressure bomb previously cooled to a temperature below -6°C, and hydrogen is admitted under an initial pressure of about 2,000 psi. The bomb is then heated to about 135° to 150°C for about 2 hours, during which time reductive amination takes place and 1-cyclopentyl-2-methylaminopropane is produced. During the period of heating the reaction mixture is agitated by rocking the bomb. The bomb is then cooled and opened thus permitting the escape of hydrogen and most of the excess methylamine. The reaction mixture is filtered to remove the nickel catalyst and the filtrate comprising 1-cyclopentyl2-methylaminopropane is purified by distillation under reduced pressure. 1Cyclopentyl-2-methylaminopropane boils at 83° to 86°C at about 30 mm pressure. 1-Cyclopentyl-2-methylaminopropane thus produced is a colorless liquid of slightly ammoniacal odor. It has a refractive of nD25 = 1.4500. Analysis showed the presence of 9.79% N as compared with a calculated value of 9.99% N. 141 g (1 mol) of 1-cyclopentyl-2-methylaminopropane are dissolved in 500 cc of dry ether, and dry hydrogen chloride is passed into the solution until the weight of the mixture and container has increased by 36 g. During the addition of the hydrogen chloride, the hydrochloric acid addition salt of 1cyclopentyl-2-methylaminopropane precipitates as a white powder. The salt is filtered off and washed with dry ether. 1-Cyclopentyl-2-methylaminopropane hydrochloride thus prepared melts at about 113° to 115°C. The yield is practically quantitative. References Merck Index 2733 Kleeman and Engel p. 258 I.N.p.277 Rohrmann, E.; US Patent 2,520,015; August 22, 1950; assigned to Eli Lilly and Company

CYCLOPENTOLATE HYDROCHLORIDE Therapeutic Function: Anticholinergic (ophthalmic) Chemical Name: α-(1-Hydroxycyclopentyl)benzene-acetic acid 2(dimethylamino)ethyl ester hydrochloride Common Name: -

Cyclopentolate hydrochloride

1167

Structural Formula:

Chemical Abstracts Registry No.: 5870-29-1; 512-15-2 (Base) Trade Name Cyclogyl Cyplegin Skiacol Pentolair Ciclolux Cicloplegic Colircusi Ciclopejico

Manufacturer Schieffelin Santen P.O.S. Pharmafair Tubi Lux Pharma Frumtost Cusi

Country US Japan France US Italy Spain Spain

Year Introduced 1953 1972 1976 1983 -

Cyclomydrin Cyclopen Cyclopentol Mydplegic Mydrilate Oftan-Syklo Zykolate

Alcon Irving Cusi Cooper Vision W.B. Pharm. Star Mann

US Australia Belgium Puerto Rico UK Finland W. Germany

-

Raw Materials Sodium phenyl acetate β-Chloroethyl dimethylamine Cyclopentanone

Isopropyl bromide Magnesium

Manufacturing Process To a well stirred suspension of 9 g of sodium phenyl acetate and 2.4 g of magnesium turnings in 25 cc of anhydrous ether, a solution of 9.4 cc of isopropyl bromide in 50 cc of anhydrous ether are added. The mixture is refluxed for one hour (during which time propane is evolved) and then 5 cc of cyclopentanone in 25 cc of anhydrous ether are added dropwise. The mixture is then refluxed for one hour and poured over ice water containing some hydrochloric acid. The ether solution is separated and extracted with 200 cc of 5% sodium hydroxide. The alkaline solution on acidification gives the free acid

1168

Cyclophosphamide

which is filtered off, dried in a desiccator and recrystallized from a mixture of ethylene dichloride and petroleum ether. The product is 2-phenyl-2-(1-hydroxycyclopentyl)ethanoic acid, melting at 95° to 97°C. Of this product, 4.5 g in 30 cc of dry isopropyl alcohol are refluxed for 16 hours with 2.5 g of β-chloroethyl dimethyl amine. The solution is cooled and filtered clear from the solid by-product. The solvent is removed under reduced pressure on the steam bath and the residue is washed with anhydrous ether. It is dissolved in ethyl acetate from which it crystallizes. It is the hydrochloride of β-(dimethylamino)ethyl ester of 2-phenyl-2-(1hydroxycyclopentyl) ethanoic acid, melting at 134° to 136°C. References Merck Index 2740 Kleeman and Engel p. 259 OCDS Vol. 1 p.92 (1977) I.N. p. 277 REM p.914 Treves, G.R.; US Patent 2,554,511; May 29, 1951; assigned to Schieffelin and Co.

CYCLOPHOSPHAMIDE Therapeutic Function: Antineoplastic Chemical Name: N,N-Bis(2-chloroethyl)tetrahydro-2H-1,3,2oxazaphosphorin-2-amine-2-oxide Common Name: Cyclophosphane; Cytophosphane Structural Formula:

Chemical Abstracts Registry No.: 50-18-0 Trade Name

Manufacturer

Country

Year Introduced

Cytoxan

Mead Johnson

US

1959

Endoxan

Lucien

France

1960

Neosar

Adria

US

1982

Carloxan

Laake

Finland

-

Cicloblastina

Montedison

W. Germany

-

Cycloserine

1169

Trade Name

Manufacturer

Country

Year Introduced

Cyclostin

Farm. Carlo Erba

Italy

-

Cytophosphan

Taro

Israel

-

Edoxana

Asta

W. Germany

-

Edoxana

W.B. Pharm.

UK

-

Genoxal

Funk

Spain

-

Procytox

Horner

Canada

-

Sendoxan

Pharmacia

Sweden

-

Raw Materials N,N-Bis(β-chloroethyl)phosphoric acid amide dichloride Triethylamine 1.3-Propanolamine Manufacturing Process A solution of 7.5 g (0.1 mol) of 1,3-propanolamine and 20.2 g of triethylamine in 100 cc of absolute dioxane is added dropwise at 25°C to 30°C while stirring well to a solution of 25.9 g (0.1 mol) of N,N-bis-(β-chloroethyl)phosphoric acid amide dichloride in 100 cc of absolute dioxane. After the reaction is complete, the product is separated from the precipitated triethylamine hydrochloride and the filtrate is concentrated by evaporation in waterjet vacuum at 35°C. The residue is dissolved in a large amount of ether and mixed to saturation with water. The N,N-bis-(β-chloroethyl)-N,O-propylene phosphoric acid diamide crystallizes out of the ethereal solution, after it has stood for some time in a refrigerator, in the form of colorless water-soluble crystals. MP 48°C to 49°C. Yield: 65% to 70% of the theoretical. References Merck Index 2741 Kleeman and Engel p. 259 PDR pp.569, 719 OCDS Vol. 3 p. 161 (1984) DOT 16 (5) 169 (1980) I.N. p.278 REM p. 1146 Arnold, H., Brock, N. and Bourseaux, F.; US Patent 3,018,302; January 23, 1962;assigned to Asta-Werke A.G. Chemische Fabrik (W. Germany)

CYCLOSERINE Therapeutic Function: Antitubercular Chemical Name: D-4-Amino-3-isoxazolidinone Common Name: Orientomycin

1170

Cycloserine

Structural Formula:

Chemical Abstracts Registry No.: 68-41-7 Trade Name Oxamycin Seromycin Aristoserina Ciclovalidin Cyclomycin Cycloserine D-Cycloserin Farmiserina Micoserina Miroseryn Orientmycin Setavax Tisomycin

Manufacturer Merck Sharp and Dohme Lilly Aristochimica Bracco Shionogi Lilly Roche Farm. Carlo Erba Beolet Morgan Kayaru-Kaken Yaku I.C.N. Lilly

Country US

Year Introduced 1956

US Italy Italy Japan US W. Germany Italy Italy Italy Japan

1956 -

-

-

Raw Materials β-Aminoxyalanine ethyl ester Bacterium Streptomyces lavendulae

Soybean meal Potassium hydroxide

Manufacturing Process Cycloserine may be made by a fermentation process or by direct synthesis. The fermentation process is described in US Patent 2,773,878. A fermentation medium containing the following proportions of ingredients was prepared:

Soybean meal Cornstarch Corn steep liquor Sodium nitrate

Parts by Weight 30.0 5.0 3.0 3.0

This material was made up with distilled water to provide 41 g per liter, and the mixture was adjusted to pH 7.0 with potassium hydroxide solution. To the mixture were added per liter 5.0 g of calcium carbonate and 7.5 ml of soybean oil. 2,000 ml portions of this medium were then added to fermentation vessels, equipped with stirrers and aeration spargers, and sterilized at 121°C for 60 minutes. After cooling the flasks were inoculated with a suspension of strain No. ATCC 11924 of Streptomyces lavendulae,

Cyclosporin

1171

obtained from the surface of agar slants. The flasks were stirred for 4 days at 28°C at approximately 1,700 rpm. At the end of this period the broth was found to contain cycloserine in the amount of about 250 C.D.U./ml of broth. The mycelium was separated from the broth by filtration. The broth had a pH of about 7.5. Tests showed it to be highly active against a variety of microorganisms. The direct synthetic process is described in US Patent 2,772,280. A solution of 73.3 g (0.332 mol) of β-aminoxyalanine ethyl ester dihydrochloride in 100 ml of water was stirred in a 500 ml 3-necked round-bottomed flask cooled in an ice-bath. To the above solution was added over a 30-minute period 65.6 g (1.17 mols) of potassium hydroxide dissolved in 100 ml of water, While the pH of the reaction mixture was 7 to 10.5, a red color appeared which disappeared when the pH reached 11 to 11.5. The light yellow solution was allowed to stand at room temperature for ½ hour and then added to 1,800 ml of 1:1 ethanol-isopropanol. The reaction flask was washed twice with 10 ml portions of water and the washings added to the alcohol solution. The precipitated salts were filtered out of the alcohol solution and the filtrate cooled to 5°C in a 5 liter 3-necked round-bottomed flask. To the cold, well-stirred solution was added dropwise over a 35-minute period sufficient glacial acetic acid to bring the pH of the alcohol solution to 6.0. When the pH of the solution had reached 7 to 7.5, the solution was seeded and no further acetic acid added until crystallization of the oil already precipitated had definitely begun. The crystalline precipitate was collected on a filter, washed twice with 1:1 ethanolisopropanol and twice with ether. The yield of 4-amino-3-isoxazolidone was 22.7 g. References Merck Index 2747 Kleeman and Engel p. 260 PDR p. 1069 OCDS Vol. 3 p. 14 (1984) I.N.p.278 REM p. 1210 Fermentation Process: Shull, G.M., Routien, J.B. and Finlay, A.C.; US Patent 2,773,878; December 11, 1956; assigned to Chas. Pfizer and Co., Inc. Harned, R.L.; US Patents 2,789,983; April 23, 1957; and 3,124,590; March 10, 1964; both assigned to Commercial Solvents Corporation Howe, E.E.; US Patent 2,845,433; July 29, 1958; assigned to Merck and Co.,Inc. Synthetic Process: Peck, R.L.; US Patent 2,772,280; November 27, 1956; assigned to Merck and Co., Inc. Holly, F.W. and Stammer, C.H.; US Patent 2,840,565; June 24, 1958; assigned to Merck and o., Inc.

CYCLOSPORIN Therapeutic Function: Immunosuppressive

1172

Cyclosporin

Chemical Name: Cyclic oligopeptide Common Name: Ciclosporin Structural Formula:

Chemical Abstracts Registry No.: 59865-13-3 Trade Name Sandimmune Sandimmun Sandimmun Sandimmune

Manufacturer Sandoz Sandoz Sandoz Sandoz

Country US UK W. Germany Switz.

Year Introduced 1983 1983 1983 1983

Raw Materials Sucrose Corn steep liquor Fungus Cylindrocarpon Lucidum (NRRL 5760) Manufacturing Process 10 liters of a nutrient solution (of which each liter contains 30 g of sucrose, 10 g of corn steep, 3 g of NaNO3, 1 g of K2HPO4, 0.5 g of MgSO4·7H2O, 0.5 g of KCl and 0.01 g of FeSO4·7H2O) are inoculated with 100 cc of a conidia and

Cyclothiazide

1173

mycelium suspension of the strain NRRL 5760, and incubation is effected in 700 cc penicillin flasks at 27°C for 11 days. The mycelium, which has been separated from the culture liquid, is extracted in a Turrax apparatus by crushing and stirring with 3.5 liters of 90% methanol, and the crushed mycelium, which is separated from the solvent by filtering with suction, is again treated twice in the same manner with 90% methanol. The combined filtrates are concentrated by evaporation in a vacuum at a bath temperature of 40°C to such an extent that the vapor mainly consists of water alone. The resulting mixture is extracted six times with the same volume of ethylene chloride by shaking, whereupon the combined ethylene chloride solutions are purified by extraction with water and are concentrated by evaporation in a vacuum at a bath temperature of 40°C. The resulting residue is chromatographed on 250 g of silica gel (silica gel 60 Merck, grain size 0.063-0.200 mm), using chloroform containing 2% of methanol as eluant, and is collected in 200 cc fractions. The fractions which are antibiotically active against Aspergillus niger in the plate diffusion test are combined, evaporated to dryness as described above, and after dissolving in methanol are chromatographed on 110 g of Sephadex LH20 with the same solvent, whereupon those 20 cc fractions showing an antibiotic effect against Aspergillus niger in the test indicated above, are combined. A test in the thin layer chromatogram, e.g., with silica gel on Polygram foils and hexane/acetone (1:1) as eluant, indicates that the residue of the methanol solution evaporated as described above mainly consists of the two new antibiotics S 7481/F-1 and S 7481/F-2. These are separated and simultaneously purified by a further chromatography of the mixture thereof, using a 1,000-fold amount of silica gel on the above indicated quality and chloroform contains 2% of methanol. A testing of the eluate fractions having a volume in milliliters which is half as large as the weight of the silica gel in grams, in the thin layer chromatogram, indicates that the antibiotic S 7481/F1 appears first in the eluate, followed by a mixture of the two antibiotics and finally by homogeneous S748l/F-2. Further amounts of the two antibiotics may be obtained from the mixture by repeating chromatography under the same conditions. References Merck Index 2748 DFU 4 (8) 567 (1979) PDR p. 1592 DOT 19 (7) 413 and (12) 665 (1983) I.N. p. 231 REM p. 1147 Harri, E. and Ruegger, A.; US Patent 4,117,118; September 26, 1978; assigned to Sandoz, Ltd. (Switz.)

CYCLOTHIAZIDE Therapeutic Function: Diuretic, Antihypertensive

1174

Cyclothiazide

Chemical Name: 3-Bicyclo[2.2.1]hept-5-en-2-yl-6-chloro-3,4-dihydro-2H1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide Common Name: Structural Formula:

Chemical Abstracts Registry No.: 2259-96-3 Trade Name

Manufacturer

Country

Year Introduced

Anhydron

Lilly

US

1963

Fluidil

Adria

US

1980

Baronorm

Roussel

France

-

Cycloteriam

Roussel

France

-

Dimapres

Dieckmann

W. Germany

-

Doburil

Pharmacia

Sweden

-

Doburil

Boehringer Ingelheim

-

-

Tensodiural

Rafa

Israel

-

Valmiran

Boehringer Tanabe Japan

-

Raw Materials 6-Chloro-4-aminobenzene-1,3-disulfonamide 2,5-Endomethylene-δ(3)-tetrahydrobenzaldehyde Manufacturing Process A mixture of 8.5 g (0.03 mol) of 6-chloro-4-amino-benzene-1,3disulfonamide, 4.0 g (0.033 mol) of 2,5-endomethylene-δ3tetrahydrobenzaldehyde and 25 cc of diethyleneglycol-dimethyl ether was heated for 2 hours at 100°C. During this time the major portion of the initially undissolved crystals went into solution; thereafter, the reaction mixture was allowed to stand for 14 hours at room temperature, during which the remaining undissolved crystals also went into solution. The reddish, clear solution thus obtained was admixed with 50 cc of chloroform. The greyishwhite precipitate formed thereby was separated by vacuum filtration, washed with a small amount of chloroform, dried and recrystallized from aqueous methanol. 7.5 g of white crystalline needles having a melting point of 229° to 230°C were obtained.

Cycrimine hydrochloride

1175

References Merck Index 2749 Kleeman and Engel p. 261 OCDS Vol. 1 p. 358 (1977) I.N .p. 278 REM p. 939 Muller, E. and Hasspacher, K.; US Patent 3,275,625; September 27, 1966; assigned to Boehringer Ingelheim GmbH, Germany

CYCRIMINE HYDROCHLORIDE Therapeutic Function: Muscle relaxant, Antiparkinsonian Chemical Name: α-Cyclopentyl-α-phenyl-1-piperidinepropanol hydrochloride Common Name: Structural Formula:

Chemical Abstracts Registry No.: 126-02-3; 77-39-4 (Base) Trade Name Pagitane Pagitane

Manufacturer Lilly Lilly

Country US Italy

Year Introduced 1953 -

Raw Materials Bromobenzene Magnesium

Cyclopentyl-β-(N-piperidyl)ethyl ketone Hydrogen chloride

Manufacturing Process The manufacture of the cyclohexyl analog is as follows. Phenyl magnesium bromide was prepared from 48.5 g (0.308 mol) of bromobenzene, 7 g (0.29 mol) of magnesium, and 125 ml of dry ether. To it was added at 5°C over a period of ½ hour 40 g (0.18 mol) of cyclohexyl β-(N-piperidyl)-ethyl ketone (BP 115° to 117°C/1 mm) in 125 ml of dry ether. The mixture was allowed slowly to come to room temperature, refluxed for one hour, and then poured into ice containing 80 ml of concentrated hydrochloric acid. Ammonium

1176

Cymarin

chloride (100 g) and 200 ml of concentrated ammonium hydroxide were added and the organic layer was separated. After drying and removing the solvent, the residue was distilled under reduced pressure. The base distilled at 158° to 170°C (1 mm) and solidified. Upon recrystallization from methanol it melted at 112° to 113°C. References Merck index 2752 Kleeman and Engel p. 262 OCDS Vol. 1 p. 47 (1977) I.N. p.279 REM p.932 Ruddy, A.W. and Becker, T.J.; US Patent 2,680,115; June 1, 1954; assigned to Winthrop-Stearns Inc.

CYMARIN Therapeutic Function: Cardiotonic Chemical Name: 5β-Card-20(22)-enolide, 3β-3-((2,6-dideoxy-3-O-methyl-βD-ribo-hexopyranosyl)oxy)-5,14-dihydroxy-19-oxoCommon Name: Cimarinum; Cymarin; h-Strophanthin; k-Strophanthin-β; Tsimarin Structural Formula:

Chemical Abstracts Registry No.: 508-77-0 Trade Name

Manufacturer

Country

Year Introduced

Alvonal

Goumldecke

-

-

Raw Materials Seeds of Castilloa elastica Column of alumina

Cymarin

1177

Manufacturing Process Finely ground seeds of Castilloa elastica (3550 g) are percolated with sufficient light petroleum (boiling point 60°-80°C) to ensure removal of all the fat. The mart is dried with a current of air and percolated with chloroform until no further color is obtained with alkaline m-dinitrobenzene. The percolate is evaporated under reduced pressure, the residue triturated with dry ether (750 ml) and filtered. The residue (69.75 g) is washed with dry ether, dried, and some of the washed residue (20 g) is dissolved in a benzene-chloroform mixture (50 ml), comprising one part benzene to two parts chloroform by volume, and is absorbed on to a column of alumina (7x32 cm), previously deactivated with 10% acetic acid [hereinafter referred to as Column (l)] and eluted with the same solvent mixture. The compositions of the following fractions (collected from Column (I)) are identified by paper chromatography using Whatman No. 1 paper [Registered Trade Mark] and the aforementioned benzene-chloroform mixture. Column (I). Fraction: (a) a pigment; (b) a substance of Rf 0.66; (c) a small quantity of a substance of Rf 0.66 and a substance of Rf 0.45; (d) a substance of Rf 0.45. Fraction (c) is obtained from the column and concentrated. The solid residue is dissolved in the aforementioned benzene-chloroform mixture (15 ml) and fractionated further on a second deactivated alumina column (4x30cm). From this column [hereinafter referred to as Column (II)] the following fractions are collected and identified using the same chromatographic system as was used for identifying the fractions of Column (I). Column (II). Fraction: (a) a substance of Rf 0.66; (b) a trace of a substance of Rf 0.66; (c) a substance of Rf 0.45. The fractions (d) of Column (I) and (c) of Column (II) are combined and evaporated and the residue (80 g) crystallized from methanol and ether followed by further re-crystallization from dilute alcohol. On heating to 120°C under a pressure of 0.01 mm/Hg, the crystals Iost water to give a compound, cymarin, which has an [α]d22 =+39.0°. The [α]d20 of cymarin (obtained from another source) in methanol is + 39.3°. Alternatively, fractional crystallization may be used in place of adsorption chromatography. Cumarin may be also prepared from seeds of Strophantus Kombe. References Wilinson S.; G.B. Patent No. 972,917; April 21, 1961; Assigned to Wellcome Foundation Limited a company incorporated in England, London Stoll A., Renz J.; D.R. Patent No. 721,001; May 21, 1942; Assigned to Sandoz A.G. in Basel, Schweiz.

1178

Cynarine

CYNARINE Therapeutic Function: Choleretic, Antihyperlipidemic Chemical Name: Cyclohexanecarboxylic acid, 1,3-bis((3-(3,4dihydroxyphenyl)-1-oxo-2-propenyl)oxy)-4,5-dihydroxy-, (1R(1α,3α,4α,5β))Common Name: Cinarina; Cynarex; Cynarine Structural Formula:

Chemical Abstracts Registry No.: 30964-13-7 Trade Name

Manufacturer

Country

Year Introduced

Anghirol

Biofarm

-

-

Angirol

BiofarmRomferchim

-

-

Listrocol

Farmitalia

-

-

Plemocil

Farmitalia

-

-

Hepar SL 50

Serturner Arzneimittel

-

-

Raw Materials Caffeic acid Sodium bicarbonate Phosphorus pentachloride Hydrochloric acid Quinide Ligroin Manufacturing Process 18.0 g of caffeic acid, suspended in 500 ml of water, are dissolved by adding

Cyproheptadine

1179

sodium bicarbonate and stirring. The solution is cooled to 2°-3°C and then, while stirring continuously, 20.0 g of phosgene dissolved in 200 ml of chloroform are added in 4 to 5 portions. After acidifying by cautiously adding iced hydrochloric acid (1:1), the solution is filtered and the collected precipitate is washed with water. Upon crystallization from glacial acetic acid, the carbonylcaffeic acid thus obtained melts at 238°-240°C (dec.). 5.0 g of carbonylcaffeic acid are suspended in 70 ml of ligroin (b. p. 120°140°C). After adding 6.0 g of phosphorus pentachloride and avoiding access of moisture while frequently stirring, the suspension is refluxed by boiling slowly and gently until everything is dissolved except a small amount of reddish, resinous materials that adhere to the bottom. Then solution is rapidly decanted into another flask containing 1.0 g of phosphorus pentachloride and the whole is refluxed gently for about 15-30 min, after which time evolution of hydrochloric acid ceases. This solution is left to cool on air for 1-2 h, and then, the obtained carbonylcaffeic acid chloride rapidly is filtered, washed with low-boiling ligroin and dried under vacuum at room temperature for about 11.5 h. Melting point 118°-120°C. 5.0 g of carbonylcaffeic acid chloride are thoroughly mixed with 12.8 g of dry, powdered quinide in a flask immersed in an oil bath. The flask is put under vacuum and is heated to 120°C and then, slowly, to about 160°C, maintaining this temperature for about 20-30 min. The molten mass is left to cool under vacuum and then it is crushed in a mortar in the presence of water. This material is washed with water several times. The residue is dissolved in dioxin. 400 ml of cold, 3% barium hydroxide solution are added and cooled with ice water and stirring vigorously in nitrogen atmosphere. The solution is left standing insulated from contact with air for 20 h, whereupon the content is rapidly acidified and concentrated in vacuum, on a water bath, to a volume of about 80-100 ml. After cooling and standing, well protected from contact with air, the brown material is filtered off and purified by crystallization from 50% acetic acid. 1,4-Dicaffeylquinic acid is obtained, melting point 226°228°C. References Rome L. P., Vercellone A.; US Patent No. 3,100,224; August 6, 1963; Assigned: Societa Farmaceutici Italia, Milan, Italy

CYPROHEPTADINE Therapeutic Function: Antipruritic, Antihistaminic, Appetite stimulant Chemical Name: 4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1methylpiperidine Common Name: Chemical Abstracts Registry No.: 129-03-3; 969-33-5 (Hydrochloride salt)

1180

Cyproheptadine

Structural Formula:

Trade Name Periactin

Manufacturer Merck Sharp and Dohme

Country US

Year Introduced 1961

Nuran

Merck Sharp and Dohme

W. Germany

1961

Periactin Periactin Periactin Periactine Anarexol Antegan Cipractin Cipro Cypromin Ifrasarl Oractine Periactol Peritol Sigloton Sipraktin Siprodin Vimicon

Chibret MSD MSD MSD-Chibret MSD Frosst Andromaco Beta Sawai Showa Teva Sharp and Dohme EGYT Miluy Kimya Evi Saba Merck-Frosst

Switz. UK Italy France Australia Spain Argentina Japan Japan Israel W. Germany Hungary Spain Turkey Turkey Canada

1961 1961 1961 1962 -

Raw Materials Ethyl bromide Hydrogen chloride Magnesium Sodium hydroxide

4-Chloro-1-methylpiperidine Dibenzo[a,e]cycloheptatrien-5-one Acetic anhydride

Manufacturing Process (A) Preparation of 1-Methyl-4-Piperidyl-Magnesium Chloride: Magnesium turnings (5.45 g, 0.22 g-atom) were placed in a 500 ml 3-necked flask provided with a condenser, Hershberg stirrer and dropping funnel and protected with a drying tube. An atmosphere of dry nitrogen was maintained in the apparatus throughout the reaction. The magnesium was covered with

Cyproheptadine

1181

20 ml of dry tetrahydrofuran. A crystal of iodine and 1.2 g of ethyl bromide were added and after the reaction had subsided (formation of ethylmagnesium bromide) a solution of 29.4 g (0.22 mol) of 4-chloro-1-methyl-piperidine in dry tetrahydrofuran (total volume, 103 ml) was added dropwise at such a rate that gentle reflux was maintained. The solution of 4-chloro-1-methylpiperidine in tetrahydrofuran was dried over calcium hydride at ice-bath temperature prior to use. When the addition of the halide was complete the reaction mixture was refluxed with stirring for one hour. In some subsequent experiments this period of refluxing was omitted with no deleterious result. (B) Preparation of 1-Methyl-4-(5-Hydroxy-5-Dibenzo[a,e]Cycloheptatrienyl)Piperidine: The solution of the Grignard reagent prepared in (A) was cooled to 5° to 10°C and stirred while 22.7 g (0.11 mol) of dibenzo[a,e] cycloheptatrien-5-one was added in portions. After stirring for 1 hour during which time the reaction mixture was allowed to warm up to room temperature, the bulk of the tetrahydrofuran was distilled at 40° to 50°C under reduced pressure. Benzene, 150 ml, was added and the reaction mixture stirred and cooled in an ice-bath while water, 100 ml, was added gradually. The benzene layer was separated by decantation and the gelatinous residue extracted three times with 75 ml portions of boiling benzene. The solvent was evaporated from the combined benzene extracts to give 33.4 g of a clear light brown resin. Crystallization from an alcohol-water mixture gave 19.5 g of 1-methyl-4-(5-hydroxy-5-dibenzo[a,e]cycloheptatrienyl)piperidine, MP 156° to 157°C. Two recrystallizations from alcohol-water mixtures followed by two recrystallizations from benzene-hexane mixtures gave analytically pure product, MP 166.7° to 167.7°C. (C) Preparation of 1-Methyl-4-(5-Dibenzo[a,e]Cycloheptatrienylidene)Piperidine Hydrochloride: 1-Methyl-4-(5-hydroxy-5-dibenzo[a,e] cycloheptatrienyl)-piperidine (3.05 g, 0.01 mol) was dissolved in glacial acetic acid, 15 ml. The solution was saturated with dry hydrogen chloride with external cooling. A white solid separated. Acetic anhydride (3.07 g, 0.03 mol) was added and the mixture heated on the steam bath for one hour. The solid dissolved in the first 5 minutes of the heating period. The reaction mixture was poured into 25 ml of water and the mixture made strongly basic with 10N sodium hydroxide solution. The mixture was extracted 3 times with 50 ml portions of benzene, the combined extracts washed with water and concentrated to a volume of approximately 50 ml. The solution was saturated with dry hydrogen chloride and the white crystalline product collected and dried. The yield of product, MP 251.6° to 252.6°C (dec.) was 2.5 g. Recrystallization from a mixture of absolute alcohol and absolute ether gave a product, MP 252.6° to 253.6°C. A sample was analyzed after drying for 7 hours at 110°C over phosphorus pentoxide in vacuo. (D) Preparation of 1-Methyl-4-(5-Dibenzo[a,e]Cycloheptatrienylidene)Piperidine: The hydrochloride salt, 4.3 g, was suspended in 100 ml of warm water and the mixture made strongly alkaline by the addition of 15 ml of 5% sodium hydroxide. The mixture was extracted with four 50 ml portions of benzene and the extracts dried over sodium sulfate. Evaporation of the benzene on the steam-bath at reduced pressure left 3.7 g (97%) of the base,

1182

Cyproterone acetate

MP 110.3° to 111.3°C. Recrystallization from a mixture of alcohol and water gave product, MP 112.3° to 113.3°C. References Merck Index 2766 Kleeman and Engel p. 263 PDR pp.830, 1208, 1606, 1999 OCDS Vol. 1 p. 151 (1977) I.N. p. 280 REM p. 1132 Engelhardt, E.L.; US Patent 3,014,911; December 26, 1961; assigned to Merck and Co., Inc.

CYPROTERONE ACETATE Therapeutic Function: Antiandrogen Chemical Name: 6-Chloro-1β,2β-dihydro-17-hydroxy-3'H-cyclopropa[1,2] pregna-1,4,6-triene-3,20-dione acetate Common Name: Structural Formula:

Chemical Abstracts Registry No.: 2098-66-01 Trade Name

Manufacturer

Country

Year Introduced

Androcur

Schering

W. Germany

1973

Androcur

Schering

Switz.

1973

Androcur

Schering

UK

1974

Androcur

Schering

Italy

1975

Androcur

Schering

Japan

1982

Cyprostat

Schering

-

-

Diane

Schering

W. Germany

-

Cytarabine hydrochloride

1183

Raw Materials 1,2α-Methylene-δ(4,6)-pregnadiene-17α-ol-3,20-dione-17-acetate Perbenzoic acid Acetic acid Manufacturing Process 2.34 g of 1,2α-methylene-δ4,6-pregnadiene-17α-ol-3,20-dione-17-acetate are dissolved in 18.25 cc of ethylene chloride which contains 844 rng of perbenzoic acid. The solution is stored for 16 hours at +5°C and 7 hours at room temperature. It is then diluted with methylene chloride and, with aqueous ferrous sulfate solution, sodium bicarbonate solution and with water washed until neutral. The organic phase is dried over sodium sulfate and then concentrated to dryness. 1.62 g of the thus obtained crude 1,2α-methylene-6,7α-oxido-δ4pregnene-17α-ol-3,20-dione-17-acetate are dissolved in 109 cc of glacial acetic acid. This solution is then saturated at room temperature with hydrogen chloride gas and stored for 20 hours, It is then diluted with methylene chloride and washed with water until neutral. The organic phase is dried over sodium sulfate and then concentrated to dryness. The thus obtained crude 6-chloro-1α-chloromethyl-δ4,6-pregnadiene17α-ol-3,20-dione-17-acetate is heated to boiling in 20 cc of collidine for 20 minutes under nitrogen. After dilution with ether it is washed with 4 N hydrochloric acid and washed with water until neutral. After drying over sodium sulfate and concentration to vacuum the remaining residue is subjected to chromatography over silica gel. Using a benzene-ethyl acetate mixture (19:1) there is eluated 900 mg of 6-chloro-1,2α-methyleneδ4,6-pregnadiene-17α-ol-3,20-dione-17-acetate, which upon recrystallization from isopropyl ether melts at 200° to 201°C. References Merck Index 2769 Kleeman and Engel p. 263 OCDS Vol. 2 p. 166 (1980) DOT 10 (1) 12 (1974) I.N.p.280 Wiechert, R.; US Patent 3,234,093; February 8, 1966; assigned to Schering AG, Germany

CYTARABINE HYDROCHLORIDE Therapeutic Function: Cancer chemotherapy Chemical Name: 4-Amino-1β-D-arabinofuranosyl-2(1H)-pyrimidinone hydrochloride

1184

Cytarabine hydrochloride

Common Name: β-Cytosine arabinoside Structural Formula:

Chemical Abstracts Registry No.: 69-74-9; 147-94-4 (Base) Trade Name Cytosar Cytosar Alexan Kilocyde Cytosar Aracytine Aracytin Arabitin Cyclocide Erpalfa Iretin Udicil

Manufacturer Upjohn Upjohn Mack Nippon Shinyaku Diethelm Upjohn Upjohn Sankyo Nippon Kayaku, Co. Intes Torii Upjohn

Country US UK W. Germany Japan Switz. France Italy Japan Japan Italy Japan W. Germany

Year Introduced 1969 1970 1971 1971 1971 1972 1972 -

Raw Materials 1-(2,3,5-Tri-O-acetyl-β-arabinofuranosyl)uracil Phosphorus pentasulfide Ammonia Manufacturing Process (A) Preparation of 1- (2,3,5-Tri-O-Acetyl-β-D-Arabinofuranosyl)-4-Thiouracil: A mixture of 1.85 g (5.0 mmol) of 1-(2,3,5-tri-O-acetyl-β-arabinofuranosyl) uracil, 1.23 g (5.55 mmol) of phosphorus pentasulfide, and 30 ml of pyridine was heated under gentle reflux for 2.5 hours with exclusion of moisture. The reaction mixture was cooled, and the supernatant solution was transferred by means of a pipette into a mixture of crushed ice and water. The reaction flask was washed twice with pyridine, and these washings were added to the icewater mixture. This mixture was kept at about 25°C until the ice had melted, and was then stored at 0°C for one hour. A pale yellow precipitate that formed was collected on a filter, washed with ice-water, and dried in air. This material was triturated with chloroform, and the chloroform mixture was filtered. A small amount of undissolved material collected on the filter and it

Cytarabine hydrochloride

1185

was washed with chloroform. The chloroform solution (filtrate plus washings) was washed three times with ice-water, twice with ice-cold 3 N sulfuric acid, twice with ice-cold saturated aqueous sodium bicarbonate solution, twice with ice-water, and then dried over anhydrous sodium sulfate. The chloroform was removed under reduced pressure at a bath temperature of about 40°C, leaving a yellow, somewhat gummy residue. This yellow residue was dissolved in absolute methanol which was then evaporated at reduced pressure at about 40°C, and the residue was then held for 2 hours at 0.5 to 2.0 mm pressure and a bath temperature of about 50°C. There was thus obtained 1.69 g of 1(2,3,5-tri-O-acetyl-β-D-arabinofuranosyl)-4-thiouracil. (B) Preparation of 1-β-D-Arabinofuranosylcytosine: In a glass liner, a mixture of 1.16 g (3.0 mmol) of 1-(2,3,5-tri-O-acetyl-β-D-arabinofuranosyl)-4thiouracil prepared in (A) and about 60 ml of absolute methanol which had been saturated with anhydrous ammonia at 0°C was heated in a steel bomb at 98° to 105°C for 35 hours. After cooling to about 25°C and venting the bomb, the dark solution was filtered into a round-bottom flask. The methanol and excess ammonia were then removed under reduced pressure at about 25°C. The residual syrup was dissolved in absolute methanol, and the methanol was removed under reduced pressure at a bath temperature of about 40°C. This procedure of dissolving in absolute methanol and removing the solvent was repeated, and the residue was held under reduced pressure at a bath temperature of 45°C for 12 hours. The resulting semisolid was triturated thoroughly with absolute methanol, and the resulting suspension was chilled at 0°C. A pale tan solid that separated was collected on a filter and washed repeatedly with methanol. After washing with anhydrous ether, there was obtained 430 mg of 1-β-Darabinofuranosylcytosine. (C) Preparation of 1-β-D-Arabinofuranosylcytosine Hydrochloride: The absolute methanolic filtrate obtained after triturating and filtering the 1-β-Darabinofuranosylcytosine in (B) above was warmed and stirred with decolorizing charcoal. The mixture was filtered through a bed of filter aid, and the filter bed was washed repeatedly with absolute methanol. The combined filtrate and washings were pale yellow. The solution was diluted to faint cloudiness with anhydrous ether, and an excess of anhydrous hydrogen chloride was introduced. Crystallization began at about 25°C and further crystallization was induced by chilling at 0°C for 14 hours. The crystalline product was collected on a filter, washed with anhydrous ether, and dried in air. There was thus obtained 180 mg of pale yellow 1-β-Darabinofuranosylcytosine hydrochloride melting at 186° to 189°C. The pale yellow product was dissolved in warm, absolute methanol, and the solution after mixing with decolorizing charcoal was filtered through a bed of filter aid. The filter bed was washed with warm absolute methanol, and the combined methanolic filtrate and washings were warmed and diluted with anhydrous ether to incipient crystallization. The methanol-ether mixture was kept at about 25°C for about 1 hour and then chilled, first at 0°C, and then at -20°C. The resulting colorless needles were collected on a filter, washed with anhydrous ether, and dried at 85°C, yielding 100 mg of 1-β-Darabinofuranosylcytosine hydrochloride having a melting point of 186° to 188°C.

1186

Cytarabine hydrochloride

References Merck Index 2778 Kleeman and. Engel p. 264 PDR p. 1833 DOT 13 (11) 477 (1977) I.N. p.281 REM p. 1147 Hunter, J.H.; US Patent 3,116,282; December 31, 1963; assigned to The Upjohn Company

D

DACTINOMYCIN Therapeutic Function: Cancer chemotherapy Chemical Name: Actinomycin D Common Name: Meractinomycin; Actinomycin D; Actinomycin AIV Structural Formula:

Chemical Abstracts Registry No.: 50-76-0 Trade Name Cosmegen

Manufacturer Merck Sharp and Dohme

Country US

Year Introduced 1965

Lyovac

Merck Sharp and Dohme Merck-Banyu Merck Sharp and Dohme

W. Germany

1966

Japan Italy

1969 1973

Cosmegen Cosmegen

1187

1188

Dactinomycin

Raw Materials Bacterium Actinomyces antibioticus Nutrient medium Manufacturing Process An incubated culture of Actinomyces antibioticus was prepared using a medium consisting of 1% tryptone-peptone, 0.5% starch, 0.2% K2HPO4, 0.2% NaCl and 0.25% agar in distilled water, grown at a temperature of approximately 25° to 35°C, the incubation being complete after 6 to 10 days. 50 liters of this incubated culture are extracted approximately six times with ether, using 20 liters of ether for each extraction. The final extract is faintly pale yellow in color, whereas the previous extracts are orange. The combined ether extracts are concentrated to dryness and about 3 grams of a reddish-brown residue is obtained. The residue is stirred with approximately 400 cc of petroleum ether for two to three hours, the solvent decanted and the residue treated again with approximately 400 cc of petroleum ether. A pale yellow oil constituting crude actinomycin B is recovered by evaporation from the petroleum ether. The dark petroleum ether insoluble residue is dissolved in 1 liter of benzene with gentle heating. Usually a small amount of black amorphous material remains undissolved and is filtered off. The benzene solution is permitted to drop through a chromatographic tower (60 x 5 cm) packed with aluminum oxide (according to Brockman). The pigment is readily adsorbed. The column is washed with about 1 liter of benzene during which operation very little migration of the color bands occurs. The column is then washed with benzene-acetone solution (15:85) whereby a chromatogram develops. By continued washing, light yellow colored pigments pass out of the column. When the main band (orange-red) reaches the lower end of the column, a solution of 30:70 acetone-benzene is passed through the column. The latter solvent elutes the pigment and when the eluate is very pale in color, washing is discontinued. The eluate is concentrated to dryness under reduced pressure, taken up in 25 cc of hot acetone, filtered, and diluted with ether. The pigment which crystallizes as red-brick colored platelets is essentially pure but may be recrystallized if desired from hot ethyl acetate. An analysis of the product showed C = 59.01; H = 6.81; N = 13.38. References Merck Index 2792 Kleeman and Engel p. 265 PDR p. 1151 I.N. p. 282 REM p. 1148 Waksman, S.A. and Woodruff, H.B.; US Patent 2,378,876; June 19, 1945; assigned to Merck and Co., Inc.

Dalteparin sodium

1189

DALTEPARIN SODIUM Therapeutic Function: Anticoagulant, Antithrombotic Chemical Name: Heparin, compounds, sodium salt Common Name: Dalteparin sodium; Tedelparin 4-6 Structural Formula: Heparin, compounds, sodium salt Chemical Abstracts Registry No.: 9041-08-1 Trade Name Fragmin Fragmin LigoFragmin

Manufacturer Vetter PharmaFertigung GmbH Pharmacia and Upjohn

Country Germany

Year Introduced -

Belgium

-

Pfizer

Argentina

-

Raw Materials Heparin Starch-iodine paper

Sodium nitrate Caustic soda

Manufacturing Process Heparinic acid a highly acidic mucopolysaccharide formed of equal parts of sulfated D-glucosamine and D-glucuronic acid with sulfaminic bridges. The molecular weight ranges from six to twenty thousand. Heparin occurs in and is obtained from liver, lung, mast cells, etc., of vertebrates. Its function is unknown, but it is used to prevent blood clotting in vivo and vitro, in the form of many different salts. In a self-regulated process for depolymerizing a heparin in an aqueous solution by providing about 0.02 to 0.1 M nitrous acid and a pH of about 2 to 3 in said solution, so that process occurs when all the nitrous acid has been consumed and mucopolysaccharides are produced from the heparin having an average molecular weight of less than 6,000. Heparin has molecular weight from 2000 to 50000. The products obtained by a below described method are constituted by a major part of species of molecular weight of about 2,000 to 8,000, which corresponds to structures having from about 8 to 40 saccharide entities (the molecular weights are measured by the HPLC method, by means, for example, of a 0.5 M sodium sulphate buffer). Self-Regulated Depolymerization of Heparin and Production of MPS of Low Molecular Weight. Into 15 liters of distilled water at +20°C, 1,500 grams of commercial heparin having a YW/USP ratio in the vicinity of 1 and a USP titer of 160 iu, are dissolved. 51.8 g of sodium nitrate dissolved in 300 ml of distilled water are added, and immediately the pH is lowered to 2.5 by pure hydrochloric acid.

1190

Danaparoid sodium

The reaction then takes place and its progress is checked until the absence of nitrous ions. After 40 minutes, the presence or absence of nitrous ions is checked at regular intervals in the reaction medium. Starch-iodine paper, for example, is used, checking every 5 minutes. After about 60 minutes of reaction, the nitrous acid had been entirely consumed and no more NO2- ions remained in the reaction medium. The pH was then adjusted to 7 with pure caustic soda, and the products of the reaction were recovered by the addition of 31 liters of pure ethanol (2 volumes). The precipitate formed was collected by centrifugation, washed with ethanol and dried at 60°C under vacuum. 1,200 g of products having the following characteristics were collected: USP titer: 19 µ/mg; APTT titer: 13 µ/mg; Yin and Wessler titer: 202 µ/mg. In 10 liters of distilled water, at room temperature (15°-20°C) 1,000 grams of commercial injectable heparin having a USP titer of 170 µ/mg and a YW titer of 160 µ/mg, are dissolved. 38 g of sodium nitrite (final molarity 0.055 M) dissolved in 200 ml of water, is added. The pH is immediately lowered to 2.5 by pure hydrochloric acid. The reaction is checked as above at regular intervals of time (5-10 minutes). After 30 minutes, NO2- ions are no longer detected in the reaction medium. The pH is then adjusted to 7 with 5 N soda; the products of the reaction are recovered by the addition of 21 liters of pure ethanol (2 volumes). The precipitate formed is collected by centrifugation, washed with ethanol and dried at 60°C under vacuum. Finally there are obtained 780 grams of white coloured powder having the following characteristics: USP Titer: 22 µ/mg; Yin and Wessler Titer: 260 µ/mg; APTT Titer: 10 µ/mg. Content of nitrites-nitrates: 5 ppm: 1.5 g/cc), soluble in methanol and formamide, slightly soluble in ethanol and isopropanol, insoluble in ether, benzene and chloroform; MP 162° to 163°C with decomposition (uncorrected). References Merck Index 7325 I.N. p. 775 Gradnik, B., Pedrazzoli, A. and Cipelletti, G.; US Patent 3,149,114; September 15, 1964; assigned to Societe d'Etudes de Recherches et d'Applications Scientifiques et Medicales, France

Mepindolol

2167

MEPINDOLOL Therapeutic Function: Beta-adrenergic blocker Chemical Name: 4-(2-Hydroxy-3-isopropylaminopropoxyl)-2-methylindole Common Name: Structural Formula:

Chemical Abstracts Registry No.: 56396-94-2 (Sulfate salt) Trade Name Corindolan

Manufacturer Schering

Country W. Germany

Year Introduced 1980

Raw Materials 4-Benzyloxy-2-dimethylamino-methylindole Hydrogen Epichlorohydrin Isopropylamine Manufacturing Process The 4-hydroxy-2-methylindole (MP 112°C to 115°C from benzene/ethyl acetate), used as starting material, may be obtained by hydrogenation of 4benzyloxy-2-dimethylamino-methylindole (MP 117°C to 120°C from benzene) in the presence of a palladium catalyst (5% on aluminum oxide). 11.6 g of 4-hydroxy-2-methylindole are added to a solution of 3.1 g of sodium hydroxide in 150 cc of water, and then 12.4 cc of epichlorhydrin are added while stirring and in an atmosphere of nitrogen. The reaction mixture is further stirred at room temperature for 24 hours, is extracted 4 times with methylene chloride, and the combined organic layers which have been dried over magnesium sulfate are concentrated by evaporation at reduced pressure. The resulting residue is taken up in 150 cc of dioxane and 50 cc of isopropylamine, and the mixture is heated to the boil for 6 hours. The reaction mixture is evaporated to dryness at reduced pressure, the residue is shaken 4 times between ethyl acetate and a 1 N aqueous tartaric acid solution, and a 5 N caustic soda solution is then added to the combined tartaric acid phases until an alkaline reaction is obtained. The alkaline solution is then shaken out 6 times with methylene chloride, the combined extracts are dried over magnesium sulfate, and the solvent is evaporated in a vacuum. The oily viscous residue may be crystallized from ethyl acetate. The title compound

2168

Mepitiostane

has a MP of 95°C to 97°C. References Merck Index 5684 DFU 3 (5) 381 (1978) DOT 17 (10) 426 (1981) and 18 (10) 551 (1982) I.N. p. 594 Troxler, F. and Hofmann, A.; British Patent 1,260,907; January 19, 1972; assigned to Sandoz, Ltd.

MEPITIOSTANE Therapeutic Function: Antiestrogen Chemical Name: 17β-(1-Ethoxycyclopentyl)oxy-2α,3α-epithio-5α-androstane Common Name: Structural Formula:

Chemical Abstracts Registry No.: 21362-69-6 Trade Name Thioderon

Manufacturer Shionogi

Country Japan

Year Introduced 1979

Raw Materials 2α,3α-Epithio-5α-androstan-17β-ol Methoxycyclopentene Manufacturing Process A mixture of 1.759 g of 2α,3α-epithio-5α-androstan-17β-ol, 2.3 ml of 1methoxycyclopentene, 20 mg of pyridine salt of p-toluenesulfonic acid and 20 ml of t-butanol is stirred for 4 hours at room temperature. The reaction

Mepivacaine

2169

mixture is poured into an aqueous solution of sodium carbonate and the whole extracted with dichloromethane. The extract is dried over anhydrous sodium sulfate and evaporated to remove solvent. Purification of the residue by chromatography over alumina gives 1.487 g of 17β-(1-methoxycyclopentyl) oxy-2α,3α-epithio-5α-androstane. Yield 68.2%. MP 98°C to 101°C. References Merck Index 5687 DFU 3 (4) 311 (1978) Kleeman and Engel p. 557 I.N. p. 594 Komeno, T.; US Patent 3,567,713; March 2, 1971; assigned to Shionogi and Co.

MEPIVACAINE Therapeutic Function: Local anesthetic Chemical Name: N-(2,6-Dimethylphenyl)-1-methyl-2-piperidinecarboxamide Common Name: N-Methylpipecolic acid 2,6-dimethylanilide Structural Formula:

Chemical Abstracts Registry No.: 96-88-8; 16452-56-5 (Hydrochloride salt) Trade Name Carboraine Chlorocain Isocaine Meaverin Mepivastesin Scandicain Tevacaine Raw Materials Ethyl bromide

Manufacturer Winthrop Pharmac. Mfg. Novocol Woelm Pharma Espe Astra Teva

Country US UK US W. Germany W. Germany Sweden Israel

Year Introduced 1960 -

2170

Meprednisone

Magnesium N-Methylpipecolic acid ethyl ester 2,6-Dimethylaniline Manufacturing Process Ethyl magnesium bromide is prepared in the usual way by reacting 185 parts by weight of ethyl bromide in 800 parts of anhydrous ether with 37 parts by weight of magnesium turnings. Under vigorous stirring 121 parts of 2,6dimethyl aniline are added at a rate depending on the vigor of the gas evaporation. When the evolution of gas has ceased, 85 parts by weight of Nmethylpipecolic acid ethyl ester are added to the 2,6-dimethyl aniline magnesium bromide slurry. The mixture is refluxed for ½ hour with continued stirring, after which it is cooled down. Dilute hydrochloric acid is added carefully in order to dissolve and hydrolyze the magnesium compound formed. The pH is adjusted to 5.5 and the water phase separated and extracted with additional ether in order to remove the surplus dimethyl aniline. After addition of an excess of ammonia to the solution, the reaction product, Nmethylpipecolic acid 2,6-dimethyl anilide, is recovered by extraction with isoamyl alcohol. The isoamyl alcohol solution is evaporated to dryness, the product dissolved in dilute hydrochloric acid, treated with charcoal and reprecipitated with NaOH. N-methylpipecolic acid 2,6-dimethyl anilide is obtained in crystalline form. References Merck Index 5688 Kleeman and Engel p. 558 PDR pp. 824, 1906 OCDS Vol. 1 p. 17 (1977) I.N. p. 594 REM p. 1052 af Ekenstam, B.T. and Egner, B.P.H.; US Patent 2,799,679; July 16, 1957; assigned to AB Bofors, Sweden Pettersson, B.G.; US Patent 4,110,331; August 29, 1978; assigned to AB Bofors

MEPREDNISONE Therapeutic Function: Glucocorticoid Chemical Name: 17,21-Dihydroxy-16β-methylpregna-1,4-diene-3,11,20trione Common Name: 16β-Methylprednisone Chemical Abstracts Registry No.: 1247-42-3

Meprednisone

2171

Structural Formula:

Trade Name Betapar Betalone Betapred Corti-Bi

Manufacturer Parke Davis Lepetit Schering Sidus

Country US France US Italy

Year Introduced 1970 -

Raw Materials 16β-Methylprednisone-21-acetate Potassium bicarbonate Bacterium Bacillus sphaericus var. fusifermis Nutrient broth Manufacturing Process 16β-Methylprednisone 21-acetate (0.5 g), when hydrolyzed by means of aqueous alcoholic potassium bicarbonate yields 16β-ethylprednisone. An alternative method of the preparation of the compound of this example is as follows. Bacillus sphaericus var. fusifermis (A.T.C.C. 7055) is incubated on a nutrient agar (composed of Bacto-beef extract, 3 g; Bacto-peptone, 5 9; sodium chloride, 8 9; agar, 15 g; and tap water, 1 liter) for 24 hours at 28°C. To 100 ml of a sterile nutrient broth (composed of Bacto-beef extract, 3 9; Bacto-peptone, 5 9; per liter of tap water) in a 300 ml flask is added one loopful of the incubated culture and the broth mixture is further incubated for 24 hours at 28°C on a shaking machine. The broth culture so obtained is employed as an inoculum (1%). Into each of ten flasks containing 100 ml of sterile nutrient broth is added 1 ml of the inoculum. The flasks are agitated on a rotary shaker for 8 hours at 28°C at 240 strokes per minute. After this growth period, a solution of 25 mg of 16β-methylcortisonein 0.5 ml of methanol is aseptically added to each flask which in turn is reshaken and incubated for an additional 24 hours. The final pH is 7.8. The contents of the flasks are then combined and extracted 3 times with two liters of chloroform per extraction. The combined chloroform extracts are evaporated to dryness yielding 310 mg of crude product. The crude steroid is purified by chromatography on a chromatographic system described by G.M. Shull, Abstracts of Papers of the 126th Meeting of the American Chemical Society, December 12-17, 1954, page 9a, paper No. 24. Chromatographic evaluation shows a quantitative conversion of the starting material to the

2172

Meprobamatex

diene when an authentic sample of the 16β-methylprednisone is used as a control. Alternatively, the crude product is recrystallized from acetone affording 225 mg of 16β-methylprednisone. References Merck Index 5689 Kleeman and Engel p. 558 I.N. p. 595 Rausser, R. and Oliveto, E.P.; US Patent 3,164,618; January 5, 1965; assigned to Schering Corporation

MEPROBAMATE Therapeutic Function: Tranquilizer Chemical Name: 2-Methyl-2-propyl-1,3-propanediol dicarbamate Common Name: Procalmadiol; Procalmidol Structural Formula:

Chemical Abstracts Registry No.: 57-53-4 Trade Name Equanil Miltown Meprotabs Meprospan Viobamate Meprocon Canquil Klort Equanil SK-Bamate Amepromamat Amosene

Manufacturer Wyeth Wallace Wallace Wallace Rowell Consol. Midland Canfield Lemmon Clin Midy SKF Arcana Ferndale

Country US US US US US US US US France US Austria US

Year Introduced 1955 1955 1957 1958 1963 1964 1964 1964 1967 1971 -

Meprobamate Trade Name Aneural Ansietan Ansiowas Artolon Atraxin Carb-A-Med Coprobate Cyrpon Dabrobamat Dapaz Deprol Dormabrol Dystoid Ecuanil Edenal Epikur Equagesic Erina Gene-Bamate Harmonin Kesso-Bamate Lan-Dol Marbate Meditran Mepavlon Meprate Mepriam Mepro Meproban Meprocon CMC Meprodil Meprodiol Meprol Mepron Mepron Mepronel Meprosa Meprotil Meriprobate Microbamat Midixin Miltaun Misedant M.P. Trantabs My-Trans Neo-Tran Nervonus

Manufacturer Wyeth Italfarmaco Wassermann Roter Daiichi Chemieprodukte Coastal Tropon Dabrowski Alter Wallace Kwizda Makara Orfi Wassermann Agepha Wyeth Sumitomo Franca Yoshitomi McKesson Bio-Chimique Mardale Medic I.C.I. DDSA Lennon Rekah Draco Consol. Midland Streuli Pirri Lokman Choseido Hamilton Heather Drug Chemipharma Brunner-Tillman Meriot Werfft Reid-Provident Mack Lemmon Martin-Phillips Heather Drug Neo Orion

Country W. Germany Italy Spain Netherlands Japan Austria US W. Germany W. Germany Spain US Austria W. Germany Spain Italy Austria US Japan Canada Japan US Canada US Canada UK UK US Israel Sweden US Switz. Italy Turkey Japan Australia US W. Germany US Canada Austria US W. Germany US US US Canada Finland

2173

Year Introduced -

2174

Meprobamate

Trade Name Neuramate Novamato Novomepro Oasil Paxin Pensive Perequil PMB Ayerst Probasan Quietidon Relaksin Restanil Sedanyl Selene Sopanil Sowell Stensolo TCM Trankilin Tranlisant Trelmar Urbilat Wescomep Xalogen

Manufacturer Halsey Torlan Novopharm Simes Pierrel Norbrook Lepetit Ayerst I.C.N. Pharma. Farm. Spec. Deva Kabi Washington Biomedica Foscama Sopar Cophar Salfa Zenith Biofarma Vita Elliott-Marion Hor-Fer-Vit Saunders Ono

Country US Spain Canada Italy Italy UK Italy US Canada Italy Turkey W. Germany Italy Italy Belgium Switz. Italy US Turkey Canada Canada W. Germany Canada Japan

Year Introduced -

Raw Materials 2-Methyl-2-propyl-1,3-propanediol Phosgene Ammonia Manufacturing Process A solution containing 52.8 parts of 2-methyl-2-n-propyl-1,3-propanediol and 128 parts of acetone is added with stirring to 112 parts of liquid phosgene at such a rate that the temperature of the reaction is maintained at -5° to 0°C. The reaction is stirred one hour at about 0°C then cooled to -15°C. A cooled 30% solution of 32 parts of sodium hydroxide is added with stirring to the reaction at such a rate that the temperature is maintained at -15° to -5°C. The mixture is stirred for an additional ½ hour at about 0°C then cooled to 20°C. 180 parts of cooled ammonium hydroxide solution (28.6% NH3) are added while cooling and with stirring at such a rate that the temperature rises slowly to 20°C and stirring is continued for an additional ½ hour. The mixture is poured with agitation into 1,700 parts of ice water. The solid which separates is removed by filtration and dried. Recrystallization from water gives 55 parts (63% of theoretical yield) of 2-methyl-2-n-propyl-1,3-propanediol dicarbamate, MP 104° to 105°C.

Meproscillarin

2175

References Merck Index 5690 Kleeman and Engel p. 559 PDR pp. 634, 830, 1024, 1606, 1723, 1874, 1880, 1947, 1949 OCDS Vol. 1 p. 218 (1977) and 2, 21 (1980) I.N. p. 595 REM p. 1072 Berger, F.M. and Ludwig, B.J.; US Patent 2,724,720; November 22, 1955; assigned to Carter Products, Inc.

MEPROSCILLARIN Therapeutic Function: Cardiotonic Chemical Name: 14-β-Bufa-4,20,22-trienolide, 3-β-((6-deoxy-4-O-methyl-αL-mannopyranosyl)oxy)-14-hydroxyCommon Name: Meproscillarin; Methylproscilleridin; Rambufaside Structural Formula:

Chemical Abstracts Registry No.: 33396-37-1 Trade Name Clift Clift Talusin Raw Materials Proscillaridin

Manufacturer Knoll Abbott Laboratories Lek D.D.

Country -

Year Introduced -

2176

Meprylcaine hydrochloride

Triethyl orto-formiate 4-Toluenesulfonic acid Methyl iodide Sodium hydride Manufacturing Process 100 g proscillaridin (from Scilla maritima L., enzymatic hydrolysis) was dissolved in 500 ml dry tetrahydrofuran, mixed with 100 ml of triethyl ortoformiate and 50 mg p-tholuene sulfonic acid and stirred for 15 minutes at 20°C. It was put into a separating funnel and shook with 1 L ethyl acetate and 200 ml of 5% sodium hydroxide. The an organic layer was separated, with 2-3 L water washed (portions 400-500 ml), dried over sodium sulfate and distilled in vacuum to dryness at about 60°C. 121.2 g crude proscillaridin-2,3-ethyl ortoformiate yielded. It was dissolved in 1 L dimethylformamide, mixed with 200 ml methyl iodide and stirred with 20 g 55-60% suspension of sodium hydride at 20°C for 1 hour. 14 L ethyl acetate was added, 5 times with 1-2 L water shook and the organic layer was distilled to 1/4 of volume. The solution of proscillaridin-2,3-ethyl ortho-formiate-4-methyl ester obtained (about 1 L) was mixed with 2 L 0.002 N HCl and stood for 2 hours at 20°C. Then it was neutralized with 0.1 N sodium hydroxide and distilled in vacuum to about 1 L. The solution was shook with 2 L chloroform and 1 L water, organic layer was separated, water layer was 2 times was extracted with still 1 L chloroform and the pooled organic phase dried over sodium sulfate. Then the solvent was removed and 147 g of obtained product was purified by chromatography on silica gel in system chloroform/acetone 4:1. 63 g of crude amorphic 4-O-methylproscillaridin was isolated and recrystallized from methylene chloride/ethyl acetate to give 49.3 g (53% yield) the desired product; MP: 213°-217°C. References Kubinyi H.; D.B. Patent No. 2,301,382; Jan. 12, 1973; Assigned to Knoll AG, Chemische Fabriken, 6700 Ludwigshafen

MEPRYLCAINE HYDROCHLORIDE Therapeutic Function: Local anesthetic Chemical Name: 1-Propanol, 2-methyl-2-(propylamino)-, benzoate, hydrochloride Common Name: Meprylcaine hydrochloride

Meprylcaine hydrochloride

2177

Structural Formula:

Chemical Abstracts Registry No.: 956-03-6; 495-70-5 (Base) Trade Name Oracaine Meprylcaine hydrochloride

Manufacturer ALK-Abello Shanghai Lansheng Corporation

Country -

Year Introduced -

Raw Materials N-(1,1-Dimethyl-2-hydroxyethyl)propylamine Benzoyl chloride Manufacturing Process 78 g of N-(1,1-dimethyl-2-hydroxy-ethyl)propylamine is added to a solution of 30 g of sodium hydroxide in 700 ml of water. To this is added 300 ml of ether and this is followed by the dropwise addition of 70 ml of benzoyl chloride benzoyl chloride while stirring and cooling. The benzoyl chloride is added at such a rate that the temperature does no rise above 30°C. When the addition is complete, the stirring is continued for another 30 minutes. The aqueous layer is removed and the ether layer is washed with water, dried and evaporated to leave an yellow oil 1-propanol, 2-methyl-2-(propylamino)-, benzoate. This is treated slowly with 45 ml of concentrated hydrochloric acid, during which addition a vigorous exothermic reaction ensues. When the reaction mixture is cooled, it solidifies to a pasty solid which is allowed to dry. This is dissolved in boiling isopropanol and allowed to cool when white crystals of the hydrochloride are formed. The resultant slurry is filtered and the hydrochloride of 1-propanol, 2-methyl-2-(propylamino)-, benzoate recrystallized from isopropanol to give white crystals; MP: 150°-151°C. It is useful in base and salt forms as such as a topical local anesthetic being administrable in oil or alcohol solution. In practice it is usually used as hydrochloride. References Reasenberg J.R.; US Patent No. 2,767,207; Oct. 16, 1956; Assigned to Mizzy Inc., a corporation of New York

2178

Meptazinol

MEPTAZINOL Therapeutic Function: Analgesic Chemical Name: 3-Ethyl-3-(m-hydroxyphenyl)-1-methylhexahydro-1Hazepine Common Name: Structural Formula:

Chemical Abstracts Registry No.: 54340-58-8 Trade Name Meptid

Manufacturer Wyeth

Country UK

Year Introduced 1983

Raw Materials Formaldehyde Sodium amide Hydrogen Hydrogen bromide

2-(m-Methoxyphenyl)butyronitrile Ethyl-4-iodobutyrate Lithium aluminum hydride

Manufacturing Process 2-(m-Methoxyphenyl)butyronitrile in dry ether was added to a stirred suspension of sodium amide in liquid ammonia. The mixture was stirred for 30 minutes then ethyl-4-iodobutyrate (99.25 g, 0.4 mol) in dry ether (200 ml) was added dropwise. The mixture was stirred at the temperature of refluxing liquid ammonia for 5 hours. Ammonium chloride (10 g) was added and the mixture allowed to warm to room temperature. Water (300 ml) was added, the organic layer separated, washed with water, 2 N sulfuric acid and water. After drying over magnesium sulfate and removing the ether, the product was distilled yielding ethyl 5-cyano-5-(mmethoxyphenyl)heptanoate. That material was hydrogenated in cyclohexane using a Raney nickel catalyst. The product after distillation was recrystallized from ethyl acetate affording 10.0 g of 6-ethyl-(m-methoxyphenyl)hexahydro-2H-azepin-2one, MP 87°C to 88°C. The azepinone (9.1 g) in dry tetrahydrofuran (50 ml) and ether (50 ml) was added dropwise to a stirred suspension of aluminum lithium hydride (7.5 g) in dry ether (50 ml). After heating under reflux for 3 hours the reaction mixture was worked up and distilled yielding 7.66 g of a compound which was a

Mequitazine

2179

colorless oil, BP 108°C to 110°C/0.01 mm. That product was then heated under reflux with 50% hydrobromic acid for 1.5 hours. The reaction mixture was evaporated to dryness and reevaporated with three portions of propan-2-ol. The oil obtained was dissolved in propan-2-ol and diluted with ether. 3-Ethyl-3-(m-hydroxyphenyl)hexahydro-1H-azepine was obtained. That material in turn was reductively methylated by hydrogenation in the presence of formaldehyde in absolute ethanol solution to give 3-ethyl-3-(m-methoxyphenyl)-1-methylhexahydro-1H-azepine. The methoxy group was converted to a hydroxy group by refluxing with 80% HBr giving meptazinol hydrobromide. References Merck Index A-8 DFU 1 (2) 68 (1976) DOT 19 (7) 415 (1983) I.N. p. 597 Cavalla, J.F. and White, A.C.; British Patent 1,285,025; August 9, 1972; assigned to John Wyeth & Brother Ltd. Cavalla, J.F. and White, A.C.; US Patent 3,729,465; April 24, 1973; assigned to John Wyeth & Brother Ltd. Cavalla, J.F. and White, A.C.; US Patent 4,197,241; April 8, 1980; assigned to John Wyeth & Brother Ltd.

MEQUITAZINE Therapeutic Function: Antihistaminic Chemical Name: 10-(1-Azabicyclo[2.2.2]oct-3-yl-methyl)-10H-phenothiazine Common Name: Structural Formula:

Chemical Abstracts Registry No.: 29216-28-2

2180

Mequitazine

Trade Name Primalan Primalan Metaplexan Nipolazin Zesulan Instotal Mircol Vigigan

Manufacturer Berk Spret-Mauchant Bad. Arzneimittel Nippon Shoji Toyo Jozo IMA Pharmuka Spret-Mauchant

Country UK France W. Germany Japan Japan Argentina Belgium France

Year Introduced 1976 1976 1977 1983 1983 -

Raw Materials Phenothiazine Sodium amide 3-Chloromethyl quinuclidine HCl Manufacturing Process 30 g of phenothiazine were added, all at once, to a suspension of 6 g of sodium amide in 240 ml of anhydrous xylene. The mixture was agitated and heated to reflux. When evolution of ammonia ceased (5 hours), 15 g of 3chloromethyl-quinuclidine hydrochloride were added portionwise over a period of 50 minutes and reflux was then maintained for 22 hours. After cooling to room temperature, 250 ml of distilled water and 250 ml of ethyl acetate were added to the reaction mixture. The aqueous phase was decanted and extracted twice with a total of 250 ml of methyl acetate. The combined organic extracts were extracted three times with a total of 750 ml of a 10% aqueous solution of tartaric acid. The combined acid solutions were treated with 5 g of animal charcoal, filtered and rendered alkaline on an ice bath with 96 ml of 10 N aqueous caustic soda. The oil which separated was extracted three times with a total of 1.500 ml of ethyl acetate. The combined organic extracts were washed to neutrality by washing twice with a total of 1 liter of distilled water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure on a water bath at 45°C. 17 g of oil were obtained which was purified by chromatography on an inert alumina column. 13.3 g of crystallized product were obtained. 10-(3-Quinuclidinyl-methyl)-phenothiazine having a MP of 130°C to 131°C was obtained by recrystallization in boiling acetonitrile. The 3-chloromethyl-quinuclidine hydrochloride used as starting material in this process can be obtained as described by Grob and coll., Helv. Chim. Acta, 37 (1954),1689. References Merck Index 5694 Kleeman and Engel p. 562 DOT 15 (4)199 (1979) I.N. p. 597 Gueremy, C., Labey, R., Wirth, D. and Auclair, M.; US Patent 3,987,042; October 19, 1976

Meralluride

2181

MERALLURIDE Therapeutic Function: Diuretic Chemical Name: [3-[[[(3-Carboxy-1-oxopropyl)amino]carbonyl]amino]-2methoxypropyl]-hydroxymercury mixture with 3,7-dihydro-1,3-dimethyl1H-purine-2,6-dione Common Name: [3-[3-(3-Carboxypropionyl)ureido]-2-methoxypropyl] hydroxymercury mixture with theophylline Structural Formula:

Chemical Abstracts Registry No.: 8069-64-5 Trade Name Mercuhydrin Mercardac Mercadon

Manufacturer Merrell National Parke Davis Parke Davis

Country US US US

Year Introduced 1943 -

Raw Materials Allyl carbamide Succinic anhydride Mercury acetate Theophylline Manufacturing Process First, to produce the mercury component, a pulverized mixture of 50 g of allylcarbamide and 50 g of succinic anhydride is heated for 30 minutes at 110°C. After cooling the fused mass is ground with 50 cc of cold water and the crystalline mass after quick filtering from the liquid is recrystallized from hot water. The white crystalline needles having a MP of 142° to 144°C are allyl-succinyl-carbamide. In order to produce a mercury compound thereof a mixture of 20 g of the allyl-succinyl-carbamide and 30 g of mercury acetate is

2182

Merbromin

shaken for 3 hours with methanol. The scarcely soluble precipitate of the mercury compound after filtration is washed with methanol and with water and dried in vacuum. The white powder melts at 185° to 186°C under decomposition. Then, condensation with an equimolar proportion of theophylline yields meralluride. References Merck Index 5696 OCDS Vol. 1 p, 224 (1977) I.N. p. 598 Geiger, E., Vargha, L. and Richter, L.; US Patent 2,208,941; July 23, 1940; assigned to Chemical Works of Gedeon Richter Ltd., Hungary

MERBROMIN Therapeutic Function: Antiseptic Chemical Name: Mercury, (2',7'-dibromo-3',6'-dihydroxy-3-oxospiro (isobenzofuran-1(3H),9'-(9H)xanthen)-4'-yl)hydroxy-, disodium salt Common Name: Merbromin; Merbromine sodique; Mercuresceine; Mercurobromfluorescein; Mercurochrome; Mercurocromo Structural Formula:

Chemical Abstracts Registry No.: 129-16-8 Trade Name Mercurin Mersol Pharmadose mercuresceine

Raw Materials 2,7-Dibromofluorescein Mercury (II) oxide

Manufacturer Monik Merkez Gilbert

Country -

Year Introduced -

Mercaptomerin sodium

2183

Manufacturing Process 49 g 2,7-dibromofluorescein are dissolved in a solution of 8 g of sodium hydroxide in 50 ml of water, and diluted to 200 ml 12.5 ml of glacial acetic acid are added to this solution with stirring. A homogeneous pasty precipitate results with vigorously stirring. A filtered solution of about 22.5 g of mercuric oxide in 25 ml of glacial acid and 50 ml water, diluted after solution to 100 ml, is then added to the suspended precipitate, and the whole diluted to about 500 ml. The mixture is boiled until a small portion of filtered solution gives no test for mercury when treated with ammonium sulfide, the approximate time required for this operation being about 4.5-6 hours. As the boiling continues the precipitate become darker in color and more granular. It is washed, preferably by centrifuging, to remove acetic acid and sodium acetate, and dried at about 110°C. By close adherence to above conditions an almost quantitative yield may be secured. The product may be regarded as consisting essentially of 2,7-dibromo-4-hydroxymercuryfluorescein, resulting from substantially complete hydrolysis of an acetoxy-mercury compound, which probably formed as an intermediate. It is red powder, which is insoluble in the usual solvents but dissolves in two equivalents of sodium hydroxide yielding a deep cherry-red solution. The solution has the tendency to decomposition on long standing. References White E. C.; US Patent No. 1,535,003; April 21, 1925

MERCAPTOMERIN SODIUM Therapeutic Function: Diuretic Chemical Name: [3-[[(3-Carboxy-2,2,3-trimethylcyclopentyl)carbonyl] amino]-2-methoxypropyl](mercaptoacetato-S)mercury disodium salt Common Name: Structural Formula:

Chemical Abstracts Registry No.: 21259-76-7

2184

Mercaptomerin sodium

Trade Name Thiomerin Diucardyn Thio-Novurit

Manufacturer Wyeth Ayerst Chinoin

Country US Hungary

Year Introduced 1949 -

Raw Materials dl-N-Allylcamphoramic acid Mercury acetate Sodium methylate Thioglycolic acid Manufacturing Process (A) Preparation of dl-N-(γ-Chloromercuri-β-Methoxy)-Propylcamphoramic Acid: A suspension of 31.9 g (= 0.10 M) of mercuric acetate in 25 ml of methanol is stirred for 30 minutes at room temperature in a 4-necked flask equipped with stirrer, dropping funnel, drying tube and thermometer. To this suspension is added dropwise and with stirring, a solution of 23.9 g (= 0.10M) of dl-Nallylcamphoramic acid in 65 ml of methanol over a period of 30 minutes. The temperature of the reaction mixture should not rise over 30°C. The stirring is continued for one hour. The reaction mixture is allowed to stand at room temperature overnight in the dark to complete the reaction. A solution of 5.9 g (= 0.10M) of sodium chloride in 25 ml of water is added and the stirring is continued for four hours. The small amount of gray precipitate produced is removed by centrifuging. The colorless, clear supernatant is concentrated to about half of its original volume and then dropped into 300 ml of water with stirring. The white precipitate which forms is filtered and dried at 80°C, yielding 45 g of chloromercuri acid (= 89% of the theory), MP 106° to 109°C (decomp.). This compound is finally obtained in analytically pure form and with a constant melting point by two recrystallizations from acetone-water giving a MP of 131° to 132°C with decomposition. (B) Preparation of the Chloromercuri Acid Sodium Salt Solution: 50.6 g (= 0.100 M) of the chloromercuri acid (dried over CaCl2, at 0.1 mm and room temperature overnight) is dissolved in 100 ml of warm methanol. To this solution 6.0 g (= 0.111 M) of sodium methylate is added in small portions with constant stirring, so that the temperature of the solution does not rise over 30°C. The solution is centrifuged, and the glass is rinsed with 10 ml of methanol. The final pH of the combined solutions is 8.5. (C) Preparation of the Disodium Thioglycolate Solution: The following steps are carried out under nitrogen. To 9.2 g (= 0.100 M) of freshly distilled thioglycolic acid (BP at 2 mm, 84° to 85°C) in 100 ml of methanol in a flask is added 12.0 g (= 0.222 M) of sodium methylate in small portions with stirring. The turbid solution is poured into a dropping funnel and the flask is rinsed with 20 ml of methanol. The final pH of the combined methanolic solutions is 11, according to US Patent 2,834,795. To 50 cc of a carefully purified aqueous solution of the sodium salt of N(γchloromercuri-β-methoxy-propyl)-d-α-camphoramic acid containing 40 mg of

Mercaptopurine

2185

mercury per cc is added 10 cc of a solution containing 1.14 g (1 mol equivalent) of sodium thioglycolate and the mixture is then evaporated to dryness at room temperature and reduced pressure in the presence of a desiccant. The product is an amorphous white powder which decomposes at 156° to 158°C (uncorr.), and which was found on analysis to have a mercury content of 33.0%, according to US Patent 2,576,349. References Merck Index 5701 OCDS Vol. 1 p. 224 (1977) I.N. p. 599 Lehman, R.A.; US Patent 2,576,349; November 27, 1951; assigned to Wyeth Incorporated Wendt, G.R.; US Patent 2,834,795; May 13,1958; assigned to American Home Products Corporation

MERCAPTOPURINE Therapeutic Function: Cancer chemotherapy Chemical Name: 6-Purinethiol Common Name: Structural Formula:

Chemical Abstracts Registry No.: 50-44-2 Trade Name Purinethol Purinethol Classen Ismipur Leukerin Mercaleukin

Manufacturer Sandoz Burroughs-Wellcome Nippon Shoji I.S.M. Takeda Arzneimittelwerk Dresden

Country France US Japan Italy Japan E. Germany

Year Introduced 1950 1953 -

Mern 6-MP Oncomercaptopurina Puri-Nethol Thioinosie

Tanabe Dojin Simes Burroughs-Wellcome Morishita

Japan Japan Belgium UK Japan

-

2186

Meropenem

Raw Materials 4-Amino-6-chloro-5-nitropyrimidine Hydrogen sulfide Formic acid Sodium hydroxide Manufacturing Process 7.5 g of 4-amino-6-chloro-5-nitropyrimidine was suspended in 200 ml of 1 N potassium hydrosulfide and heated on the steam bath for 2 hours while passing hydrogen sulfide through the reaction mixture. The reaction mixture was allowed to cool slowly, acidified with 10 N sulfuric acid and chilled. The precipitate consisted of 4,5-diamino-6-mercaptopyrimidine and sulfur. It was boiled with 300 ml of water, filtered hot and then chilled. The product precipitated as pale yellow needles (4.2 g); an additional 0.95 g was obtained by concentration of the mother liquors to 100 ml. A mixture of 2 g of 4,5-diamino-6-mercaptopyrimidine and 10 ml of 98% formic acid was heated at 70°C for two hours and then evaporated to dryness on the steam bath to give as a residue, 7-amino-thiazolo (5,4-d) pyrimidine. To 820 mg of 7-amino-thiazolo[5,4-d]pyrimidine was added 2.5 cc of 2 N sodium hydroxide. The water was removed under reduced pressure. The sodium salt was then heated at 240°C for one hour, during which time it melted, gave off water and resolidified. The sodium salt of 6-mercaptopurine was dissolved in 15 ml of water and acidified to pH 5 with acetic acid. Yellow crystals of 6-mercaptopurine hydrate precipitated, according to US Patent 2,933,498. References Merck Index 5702 Kleeman & Engel p. 563 PDR p. 759 I.N. p. 599 REM p. 1151 Hitchings, G.H. and Elion, G.B.; US Patent 2,721,866; October 25, 1955; assigned to Burroughs Wellcome & Co. (USA.) Inc. Hitchings, G.H. and Elion, G.B.; US Patent 2,724,711; November 22, 1955; assigned to Burroughs Wellcome & Co. (USA.) Inc. Hitchings, G.H. and Elion, G.B.; US Patent 2,933,498; April 19, 1960; assigned to Burroughs Wellcome & Co. (USA.) Inc.

MEROPENEM Therapeutic Function: Antibiotic Chemical Name: 1-Azabicyclo(3.2.0)hept-2-ene-2-carboxylic acid, 3-((5-(2dimethylamino)carbonyl)-3-pyrrolidinyl)thio)-6-(1-hydroxyethyl)-4methyl-7-oxo-, trihydrate, (4R- (3(3S*,5S*),4alpha,5beta,6beta(R*)))-

Meropenem

2187

Common Name: Meropenem Structural Formula:

Chemical Abstracts Registry No.: 96036-03-2 Trade Name Merrem Meronem Meropenem Merozen Zeropenem

Manufacturer AstraZeneca AstraZeneca AstraZeneca AstraZeneca Hoechst Marion Roussel

Country -

Year Introduced -

Raw Materials Ethyl chloroformate Triethylamine Thioacetic acid Palladium on carbon Zinc Diphenyl chlorophosphate Hydrogen Diisopropylethylamine (3R,4R)-4-Acetoxy-3-[(R)-1-(tbutyldimethylsilyloxy)ethyl]-2azetidinone

Methanesulfonyl chloride Diethylaluminium chloride Orpholinopropanesulfonic acid buffer Benzyl-α-bromopropionate trans-1-(p-Nitrobenzyloxycarbonyl)-4hydroxy-L-proline Methanesulfonyl chloride t-Butyldimethylsilyl chloride

Manufacturing Process 3.10 g of trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline and 1.10 g of triethylamine were dissolved in 40 ml of dried tetrahydrofuran, and a solution of 1.20 g of ethyl chloroformate in 10 ml of dried tetrahydrofuran was added dropwise thereto at -25-35°C. After stirring at the same temperature for 50 min, 10 ml of concentrated aqueous ammonia was added dropwise to the mixture at -25-40°C. The temperature was then gradually elevated to room temperature, and the reaction mixture was stirred for 1 hour, followed by concentration under reduced pressure. To the residue were added 20 ml of water and 50 ml of diethyl ether. After ice-cooling, the thus formed white crystals were separated by filtration, washed successively with cool water and cool diethyl ether, and dried under reduced pressure to yield trans-1-(pnitrobenzyloxycarbonyl)-4-hydroxy-L-prolineamide. Melting point: 163.3-

2188

Meropenem

164.0°C. A solution of 1.89 g of methanesulfonyl chloride in 10 ml of dried tetrahydrofuran was added dropwise to a suspension of 2.32 g of trans-1-(pnitrobenzyloxycarbonyl)-4-hydroxy-L-prolineamide and 1.67 g of triethylamine in 40 ml of dried tetrahydrofuran at room temperature. After stirring for 1 hour, the reaction mixture was concentrated under reduced pressure, and to the residue were added 30 ml of water and 30 ml of diethyl ether. After cooling, the resulting white crystals were separated by filtration, washed successively with cool water and cool diethyl ether and dried under reduced pressure to obtain trans-1-(p-nitrobenzyloxycarbonyl)-4-methanesulfonyloxyL-prolineamide. Melting point: 149.5-151°C. A solution of 642 mg of thioacetic acid in 14 ml of dried dimethylformamide was added to a suspension of 374 mg of 50% sodium hydride in 13 ml of dried dimethylformamide in a nitrogen stream, followed by stirring at room temperature for 25 minutes. To the mixture were added 975 mg of sodium iodide and then a solution of 2.52 g of trans-1-(p-nitrobenzyloxycarbonyl)-4methanesulfonyloxy-L-prolineamide in 12 ml of dried dimethylformamide, and the resulting mixture was heated to 70°C for 6 hours while stirring. The reaction mixture was poured into a cool aqueous solution of sodium chloride and extracted with benzene. The extract was washed successively with a 10% aqueous solution of sodium sulfate and a sodium chloride aqueous solution, dried over sodium sulfate and distilled off to remove the solvent. The resulting crude crystals were washed with a warm mixed solvent of tetrahydrofuran and benzene to obtain (2S,4S)-1-(p-nitrobenzyloxycarbonyl)- 2-carbamoyl-4acetylthio-L-prolineamide. Melting point: 168.5-169.5°C. 950 mg of (2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-carbamoyl-4acetylthiopyrrolidine was dissolved in 95 ml of methanol, and 2.59 ml of a 1 N aqueous solution of sodium hydroxide was added thereto at room temperature in an argon stream, followed by stirring at that temperature for 15 min. The reaction mixture was neutralized with 2.59 ml of a 1 N aqueous solution of hydrochloric acid and distilled off under reduced pressure to remove the methanol. The thus precipitated crystals were filtered and washed with water to obtain (2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-carbamoyl-4mercaptopyrrolidine. Melting point: 158-162°C. To 1.33 g (20 mM) of activated zinc was added 20 ml of dried tetrahydrofuran, and 8.8 ml of a 15% n-hexane solution of diethylaluminium chloride was added thereto in a nitrogen stream under ice-cooling. A solution prepared by dissolving 1.49 g (5.2 mM) of (3R,4R)-4-acetoxy-3-[(R)-1-(tbutyldimethylsilyloxy)ethyl]-2-azetidinone and 3.73 g (15.3 mM) of benzyl-αbromopropionate in 13.3 ml of dried tetrahydrofuran was added dropwise to the mixture over a period of 30 to 40 min, followed by stirring for 1 hours. Under ice-cooling, 2.8 ml of pyridine, 13.2 ml of water, 26.5 ml of ethyl acetate and 13.2 ml of a 1 N hydrochloric acid aqueous solution were successively added thereto, and the resulting mixture was filtered using Celite. The filtrate was washed with water, and the organic layer was dried over sodium sulfate and distilled off to remove the solvent. The resulting oily residue was subjected to silica gel column chromatography to obtain an isomeric mixture of 4-(1-benzyloxycarbonyl)ethyl-3-[(R)-1-(tbutyldimethylsilyloxy)ethyl]-2-azetidinone.

Meropenem

2189

The isomeric mixture was separated into each compound by Lober column chromatography using silica gel and 1.5% isopropanol/n-hexane as an eluent to obtain the compound (1a) and the compound (1b) as oily substances. 200 mg of 4-(1-benzyloxycarbonyl)ethyl-3-[(R)-1-(t-butyl-dimethylsilyloxy) ethyl]-2-azetidinone (1a) was dissolved in 2 ml of dried dimethylformamide. 126 mg of triethylamine was added to the resulting solution, and then 151 mg of t-butyldimethylsilyl chloride was added thereto, followed by stirring at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water, dried over sodium sulfate and purified by silica gel chromatography to obtain 4-(1-benzyloxycarbonyl)ethyl-3-[(R)-1-(tbutyldimethylsilyloxy)ethyl]-1-(t-butyldimethylsilyl)-2-azetidinone (2a). 184 mg of (2a) was dissolved in 4 ml of methanol, and the resulting solution was stirred together with 20 mg of 10% palladium-on-carbon at an atmospheric pressure of hydrogen for 2 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain 4-(1-carboxy)ethyl-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-1-(tbutyldimethylsilyl)-2-azetidinone (3a). (4R,5R,6S,8R)-p-Nitrobenzyl-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo [3.2.0]-hept-3,7-dione-2-carboxylate was obtained from 170 mg of 4-(1carboxy)ethyl-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-1-(t-butyldimethylsilyl)2-azetidinone (3a) according to the method described in Japanese Patent Application OPI No. 26887/83, pages 64-65. (a) 53 mg of (4R,5R,6S,8R)-p-nitrobenzyl-4-methyl-6-(1-hydroxyethyl)-1azabicyclo[3,2,0 ]-hept-3,7-dione-2-carboxylate was dissolved in 5 ml of dry acetonitrile, and 57 mg of diisopropylethylamine and then 43 mg of diphenyl chlorophosphate were added thereto. After stirring for 2.5 hours, 57 mg of [2S,4S]-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4mercaptopyrrolidine was added to the mixture, followed by stirring for 1 hour. The reaction solution was diluted with ethyl acetate, washed with water, dried over magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel thin layer chromatography to obtain 35 mg of (4R,5S,6S,8R,2'S,4'S)-p-nitrobenzyl-3-[4-(1-p-nitrobenzyloxycarbonyl-2dimethylaminecarbonyl)pyrrolidinylthio]-4-methyl-6-(1-hydroxyethyl)-1azabicyclo[3,2,0]-hept-2-ene-7-one-2-carboxylate. (b) 25 mg of (4R,5S,6S,8R,2'S,4'S)-p-nitrobenzyl-3-[4-(1-pnitrobenzyloxycarbonyl-2-dimethylaminecarbonyl)pyrrolidinylthio]-4-methyl-6(1-hydroxyethyl)-1-azabicyclo[3,2,0]hept-2-ene-7-one-2-carboxylate was dissolved in a mixture of 1.9 ml of tetrahydrofuran and 0.3 ml of ethanol, and the mixture was hydrogenated in a morpholinopropanesulfonic acid buffer solution (pH = 7.0, 1.9 ml) under atmospheric pressure of hydrogen for 3 hours at room temperature in the presence of 30 mg of 10% palladiumcarbon, which had been activated in hydrogen atmosphere for 1 hour followed by washing with water. After filtering off the catalyst, tetrahydrofuran and ethanol were distilled off under reduced pressure, and the residual solution was washed with ethyl acetate. The aqueous layer was again distilled under reduced pressure to remove organic solvents, and the residual solution was subjected to polymer chromatography (CHP-20P) to obtain (4R,5S,6S,8R,2'S,4'S)-3-[4-(2-dimethylaminecarbonyl)pyrrolidinylthio]-4methyl-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0]hept-2-ene-7-one-2-carboxylic

2190

Mesalamine

acid from the fraction eluted with water. References Merck Index, Monograph number: 5960, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. Nishitani Y., Irie T.; US Patent No. 5,122,604; May 31, 1994; Assigned to: Shionogi Seiyaku Kabushiki Kaisha (Osaka, JP) Sunagawa M.; US Patent No. 4,943,569; July 24, 1990; Assigned to Sumitomo Pharmaceuticals Co., Ltd. (Osaka, JP) Sunagawa M. et al.; J. Antibiotics; 1990, 43, 519

MESALAMINE Therapeutic Function: Antibacterial Chemical Name: Salicylic acid, 5-aminoCommon Name: Acidum metaminosalicylicum; Fisalamine; Mesalamine; Mesalazine Structural Formula:

Chemical Abstracts Registry No.: 89-57-6 Trade Name Asacol Asacol Asalit Mesacol Mesalamine Mesasal Pentasa Salofalk Walsa

Manufacturer Proctor and Gamble Tillots Pharma AG Ziefen Merck Sun Pharma Novopharm Glaxol/Wellcome Ferring Minipharm Wallace Pharmaceuticals Ltd.

Raw Materials 5-Nitrosalicylic acid potassium salt Hydrazine hydrate

Country India

Year Introduced -

Mesna

2191

Nickel Raney Hydrogen Manufacturing Process Procedure A: To 5-nitrosalicylic acid potassium salt (55 g, 246 mmol) dissolved in water (200 mL) was added potassium hydroxide pellets to reach pH 11.5. To this solution 2 g of Raney nickel were added. The mixture was heated-up to reflux and hydrazine hydrate (40 mL, 80% in water, 64 mmol) was added dropwise during 3-4 hrs. The reflux was maintened until HPLC showed the disappearance of the starting material and the complete reduction of 5-nitrosalicylic acid (3-4 hrs). The hot mixture was filtered under nitrogen and the solution was collected. The solution was cooled to 40°C and the pH was adjusted to 2.3 by addition of 35% HCl aqueous solution. The precipitation of 5-aminosalicylic acid occurred. The solution was cooled at 0°C, and after standing at this temperature for 2 hr, the precipitate was filtered, washed with water, and dried at 60-70°C. 5-Aminosalicylic acid was obtained in 89% yield. Procedure B: To 5-nitrosalicylic acid potassium salt (55 g, 246 mmol) dissolved in water (200 mL) was added potassium hydroxide pellets to reach pH 11.5. The solution was charged in a stainless steel autoclave and 2 g of Raney nickel are added. Hydrogen was introduced into the autoclave reaching a pressure of 8 atm. The mixture was heated-up to 100°C. The temperature was maintained until HPLC-test 5-aminosalicylic acid showed the disappearance of the starting material and the complete reduction of 5aminosalicylic acid (6-8 hrs). Hydrogen was purged and replaced by nitrogen. The hot mixture was filtered under nitrogen, the filtrate was cooled to 40°C, and the pH was adjusted to 2.3 by addition of 35% HCl aqueous solution. The precipitation of the 5-aminosalicylic acid occurred. The solution was cooled at 0°C, and after standing at this temperature for 2 hr, the precipitate was filtered, washed with ion depleted water, and dried at 60-70°C. References Breviglieri G., Giacomo B., Contrini Sergio, Assanelli Cinzia, Eileen Campanab, Mauro Panunzio, Molecules 2001, 6, M260 Martelli, G., Spunta, G., Panunzio, M.; Tetrahedron Lett. 1998, 39, 6257-6260 Kennedy, J.F., Barker, S.A., Epton, J., Kennedy, G.R.; J. Chem. Soc. Perkin 1, 1973, 488-490

MESNA Therapeutic Function: Mucolytic Chemical Name: 2-Mercaptoethane sulfonic acid sodium salt Common Name: -

2192

Mesna

Structural Formula:

Chemical Abstracts Registry No.: 19767-45-4; 3375-50-6 (Base) Trade Name

Manufacturer

Country

Year Introduced

Mistabronco

UCB

W. Germany

1973

Mistabron

Diethelm

Switz.

1978

Mucofluid

UCB Fraysse

France

1978

Mucofluid

UCB

Italy

1981

Uromitexan

W.B. Pharm.

UK

1983

Uromitexan

Asta

W. Germany

-

Raw Materials β-S-Thiuronium ethanesulfonate Ammonia Manufacturing Process 2,100 g of β-S-thiuronium ethanesulfonate were placed in a solution of 2,100 cc of concentrated aqueous ammonia and 400 cc of water. The mixture was carefully warmed on a steam bath and an exothermic reaction ensured, at which point the β-S-thiuronium ethanesulfonate passed into solution. After standing for two hours at room temperature, the solution was concentrated until all of the excess ammonia had been removed. The resultant clear solution from the ammonolysis reaction was processed through "Amberlite IR-120" ion exchange resin and converted into β-Smercaptoethanesulfonic acid in 93.7% yield (based on β-S-thiuronium ethanesulfonate). It is expedient not to heat the reaction mixture rapidly since this increases the loss of ammonia and effects an incomplete reaction. Heating the mixture too rapidly may retard the ammonolysis reaction entirely. The amount of ammonia used is considered to be a satisfactory minimum and larger quantities of ammonia are not found to have any beneficial effect on the reaction. It is also expedient to remove the excess ammonia before processing the guanidinium β-mercaptoethanesulfonate solution through the ion exchange resin since the resin will also remove the ammonia with the result that the capacity of the resin for the exchange of guanidinium ions will be reduced. Although the preparation of β-mercaptoethanesulfonic acid through the ammonolysis reaction is the preferred method, it is also possible to prepare the sulfonic acid by the sodium hydroxide hydrolysis of β-S-thiuronium

Mesoridazine besylate

2193

ethanesulfonate followed by the ion exchange treatment. The resulting acid, however, is generally not as satisfactory as that prepared by the ammonolysis reaction. References Merck Index 5754 Kleeman & Engel p. 563 DOT 8 (5) 180 (1972); 19 (10) 585 and (11) 608 (1983) I.N. p. 601 Schramm, C.H. and Karlson, R.H.; US Patent 2,695,310; November 23, 1954; assigned to Lever Brothers Co.

MESORIDAZINE BESYLATE Therapeutic Function: Tranquilizer Chemical Name: 10-[2-(1-Methyl-2-piperidinyl)ethyl]-2-methylsulfinyl-10Hphenothiazine benzene sulfonate Common Name: Structural Formula:

Chemical Abstracts Registry No.: 32672-69-8; 5588-33-0 (Base) Trade Name Serentil Calodal Lidanil

Manufacturer Sandoz Heyden Salvoxyl-Wander

Country US Switz. France

Year Introduced 1970 1980 -

Raw Materials Acetic anhydride Hydrogen peroxide Sodium hydroxide

3-Methylmercaptophenothiazine Potassium carbonate 2-(N-Methylpiperidyl-2')-1-chloroethane

2194

Mesoridazine besylate

Manufacturing Process 10.0 g of 3-methylmercapto phenothiazine and 17.5 cc of acetic acid anhydride are refluxed for 8 hours from an oil bath maintained at a temperature of 180°C. After concentration of the solution the residue is crystallized from ethanol. The pure 3-methylmercapto-10-acetyl phenothiazine melts at 89° to 91°C. For the purpose of oxidation 5.0 g of 3methylmercapto-10-acetyl phenothiazine are dissolved in 50 cc of ethanol, refluxed from an oil bath maintained at 120°C and 1.6 cc of a 40% hydrogen peroxide solution are then added dropwise in the course of 30 minutes. Heating is continued for another 5 hours and the reaction mixture is concentrated after 50 cc of water have been added. The residue is taken up in 40 cc of benzene and the benzene layer washed with 10 cc of water. After having been concentrated, the residue, crude 3-methylsulfinyl-10-acetyl phenothiazine, is dissolved in 55 cc of a 90% methanol solution for splitting off the acetyl group and, after 2.9 g of potassium carbonate have been added, it is boiled for 2 hours under reflux on an oil bath kept at a temperature of 120°C. After concentration, the residue is taken up in 50 cc of chloroform, the chloroform layer is washed with a total of 25 cc of water, dried over potassium carbonate, filtered and concentrated. After twice crystallizing the residue, each time from 50 cc of ethanol, analytically pure 3-methylsulfinyl phenothiazine (MP 193° to 195°C) is obtained. A mixture of 10.0 g of 3-methylsulfinyl phenothiazine (MP 193° to 195°C), 6.1 g of finely powdered sodium hydroxide and 125 cc of toluene is boiled for 1 hour under reflux with a water separator on an oil bath kept at a temperature of 150°C, while the mixture is stirred. Without interrupting the boil a solution of 7.0 g of 2-(N-methyl-piperidyl-2')-1-chloroethane (BP 84°C/10 mm Hg) in 10 cc of toluene is added dropwise in the course of 1 hour, after which boiling is continued for another 3 hours. When the reaction mixture has cooled it is first washed with 25 cc of water three times and then extracted with 75 cc of a 15% aqueous tartaric acid solution. The tartaric acid extract is shaken out with 25 cc of benzene, 20 cc of concentrated caustic soda are added until the phenolphthalein reaction is alkaline, and the separated oily base is taken up in a total of 150 cc of benzene. After having been washed with 50 cc of water the benzene layer is dried over potassium carbonate, filtered, allowed to stand over 10 g of alumina for about 1½ hours for partial decolorization, filtered again and concentrated under reduced pressure. The oily base which remains as a residue is directly converted into the tartrate. A solution cooled to 0°C, of 6.50 g of the free base in 100 cc of acetic acid ethyl ester is thoroughly shaken and poured into an ice cold solution of 2.66 g of tartaric acid in 410 cc of acetic acid ethyl ester. The precipitated, analytically pure, tartrate of 3-methylsulfinyl-10-[2'-Nmethyl-piperidyl-2')-ethyl-l']-phenothiazine melts at 115° to 120°C (foam formation) and sinters above 80°C. The base is reacted with benzene sulfonic acid in a suitable solvent to give the besylate. References Merck Index 5755 Kleeman & Engel p. 564 PDR p. 681

Mesterolone

2195

OCDS Vol. 1 p. 389 (1977) DOT 6 (6) 211 (1970) and 9 (6) 227 (1973) I.N. p.601 REM p. 1089 Renz, J., Bourquin, J.-P. and Schwarb, G.; US Patent 3,084,161; April 2, 1963; assigned to Sandoz Ltd., Switzerland

MESTEROLONE Therapeutic Function: Androgen Chemical Name: 17β-Hydroxy-1α-methyl-5α-androstan-3-one Common Name: Structural Formula:

Chemical Abstracts Registry No.: 1424-00-6 Trade Name

Manufacturer

Country

Year Introduced

Proviron

Schering

W. Germany

1967

Proviron

Schering

Italy

1971

Pro-Viron

Schering

UK

1971

Proviron

S.E.P.P.S.

France

1975

Mestoran

Schering

W. Germany

-

Vistimon

Jenapharm

E. Germany

-

Raw Materials 1α-Methyl-androstan-17β-ol-3-one-17-acetate Sodium hydroxide Manufacturing Process 500 mg of 1α-methyl-androstan-17β-ol-3-one-17-acetate are heated under reflux for 90 minutes in a nitrogen atmosphere in 5 ml of 4% methanolic sodium hydroxide solution. The reaction mixture is then stirred into ice water,

2196

Mestranol

the precipitated product filtered with suction and recrystallized from isopropyl ether. 1α-Methyl-androstan-17β-ol-3-one melts at 203.5° to 205°C. References Merck Index 5760 Kleeman & Engel p. 565 OCDS Vol. 1 p. 174 (1977) I.N. p. 602 Schering AG, Germany; British Patent 977,082; December 2, 1964 Schering AG, Germany; British Patent 977,083; December 2, 1964 Wiechert, R.; US Patent 3,361,773; January 2, 1968; assigned to Schering A.G.

MESTRANOL Therapeutic Function: Estrogen Chemical Name: 3-Methoxy-19-nor-17α-pregna-1,3,5(10)-trien-20-yn-17-ol Common Name: 17α-Ethynylestradiol 3-methyl ether Structural Formula:

Chemical Abstracts Registry No.: 72-33-3 Trade Name Enovid Ortho-Novum Enovid-E Norinyl C-Quens Ovulen Conceplan Conovid Enavid Estalor Gestamestrol

Manufacturer Searle Ortho Searle Syntex Lilly Searle Gruenenthal Searle Dainippon Lilly Hermal

Country US US US US US US W. Germany UK Japan US W. Germany

Year Introduced 1957 1963 1964 1964 1965 1966 -

Mesulfen Trade Name Lutedione Lyndiol Metrulen Noracycline Noriday Norinyl Norluten Norquen Nuriphasic Orgaluton O.V. 28 Ovanon Ovastol

Manufacturer Teikoku Zoki Organon-Sankyo Searle Ciba Geigy Syntex Syntex Shionogi Syntex Noury Pharma Organon Biosedra Organon Rendell

Country Japan Japan UK France US US Japan US W. Germany UK France UK UK

2197

Year Introduced -

Raw Materials 3-Methoxy-δ(1,3,5)-estratrien-17-one Acetylene Manufacturing Process A stirred solution of 120 parts of 3-methoxy-δ1,3,5-estratrien-17-one in 2,600 parts of anhydrous toluene and 4,300 parts of anhydrous ether is saturated with a slow stream of acetylene. In the course of 30 minutes there is added a solution of 120 parts of potassium tert-amylate in 2,800 parts of anhydrous tert-pentanol. The passage of acetylene and stirring are continued for an additional 5 hours after which the reaction mixture is washed 5 times with 3,000-part portions of saturated ammonium chloride solution and then with water. It is then dried over anhydrous sodium sulfate and concentrated to dryness under vacuum. The residue is recrystallized from methanol. The 3methoxy-17-ethynyl-δ1,3,5 estratrien-17-ol thus obtained melts at about 143° to 146°C. A further recrystallization from acetone yields crystals melting at about 150° to 151°C. References Merck Index 5762 Kleeman & Engel p. 566 PDR pp. 1297,1680,1793 OCDS Vol. 1 p. 162 (1977) I.N. p. 602 REM p.989 Colton, F.B.; US Patent 2,666,769; January 19, 1954; assigned to G.D. Searle & Co.

MESULFEN Therapeutic Function: Scabicide

2198

Mesulfen

Chemical Name: 2,7-Dimethylthianthrene Common Name: Mesulfen; Mesulphen; Thianthol Structural Formula:

Chemical Abstracts Registry No.: 135-58-0 Trade Name Mesulfen

Manufacturer Synopharm GMBH and CO.KG

Country -

Year Introduced -

Odylen Anacar Schwefelol Sulfor Thiotal Citemul S

Winthrop Teknofarma Solco Takeda Linz Medopharm Arzneim

-

-

Raw Materials Toluene Sulfur Aluminum chloride Manufacturing Process 100 parts by weight of toluene, 330 parts of sulfur and 80 parts of aluminum chloride were heated to reflux on the oil bath before the formation of hydrogen sulfide and hydrogen chloride ended. The mixture was poured into water for removing the excess of aluminum chloride. A toluene layer was separated, dried and distilled in vacuum. When toluene was distilled off, about 500 parts by weight the residual yellow oil boiled at 150°-230°C/3 mm Hg was yielded. An objectionable odor was removed by shaking with sodium hydroxide. The residual sulfur (23-25%) was removed by washing with hydrogen peroxide. The residue (mesulfen) looked like fragile asphalt mass after distillation. References Weyland H. et al.; D.R. Patent No. 365,169; Sept. 4, 1919; Assigned to Farbenfabriken vorm. Friedr. Bayer and Co. in Leverkusen b. Koin a. Rh.

Metahexamide

2199

METAHEXAMIDE Therapeutic Function: Oral hypoglycemic Chemical Name: Benzenesulfonamide, 3-amino-N-((cyclohexylamino) carbonyl)-4-methylCommon Name: Metahexamide; Metahexanamide Structural Formula:

Chemical Abstracts Registry No.: 565-33-3 Trade Name Metahexamide Melanex

Manufacturer Shanghai Lansheng Corporation Upjohn

Country -

Year Introduced -

-

-

Raw Materials Ethyl chloroformate 3-Acetylamino-p-toluene sulphonic acid amide Cyclohexylamine Manufacturing Process 39 g ethyl chloroformate are added dropwise to a mixture of 68.4 g 3acetylamino-p-toluene sulphonic acid amide, 123 g potassium carbonate and 450 ml acetone for one hour while boiling under reflux. Refluxing is then continued for a further nine hours. The reaction mixture is cooled and mixed, while stirring, with a mixture of 450 ml water and 50 ml 2 N potassium hydroxide solution. Thereby two layers are formed. The upper layer, which consists of aqueous acetone, is separated. Acetone is distilled off in a vacuum. The pH-value of the resulting aqueous solution is adjusted to a pH of 8.8 by passing in gaseous carbon dioxide. Precipitated unchanged starting material is filtered off. The filtrate is rendered congo acid by the addition of dilute hydrochloric acid. The precipitated 3-acetylamino-p-toluene sulfnyl ethyl urethane is filtered off by suction, washed with water, and dried in a vacuum. The yield is 77%. The resulting compound melts at 183°-194°C. 54.3 g above prepared 3-acetylamino-p-toluene sulphonyl ethyl urethane are mixed with 37 ml dimethylformamide and 18 g cyclohexylamine. The resulting

2200

Metampicillin sodium

clear solution is heated at 70°C for 1.5 hours and at 110°C for 1.5 more hours. After cooling, the reaction mixture is poured into 500 ml water while stirring. The precipitated oily product crystallizes shortly. The crystals are filtered off by suction, washed with water and dried in a vacuum. Yield of 3acetylamino-p-toluene sulphonyl cyclohexyl urea is 84%. MP: 174°C. The urea is saponified without further purification by heating it in 90 ml 5 N potassium hydroxide solution at 90°C for one hour. After dilution with 500 ml water the resulting reaction mixture is rendered acid (pH 6.5) by the addition of dilute hydrochloric acid. Thereby, 1-(3-amino-p-tolylsulfonyl)-3-cyclohexylurea separates in crystals, which are collected, washed with water, and dried. The yield is 86%. After recrystallization from ethanol the compound has MP: 151°152°C. References Boehringer C.F., Soehne G.m.b.H., Germany; G.B. Patent No. 831,043; Feb. 26, 1957

METAMPICILLIN SODIUM Therapeutic Function: Antibacterial Chemical Name: 3,3-Dimethyl-6-[[(methyleneamino)phenylacetyl]amino]-7oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid sodium salt Common Name: Structural Formula:

Chemical Abstracts Registry No.: 6489-61-8; 6489-97-0 (Base) Trade Name Magnipen Magnipen Actuapen Ampilprats Apliopenil Co-Metampicil Daniven

Manufacturer Clin-Comar-Byla Clin Midy Larma Prats Miluy Sanchez-Covisa Aldon

Country Italy France Spain Spain Spain Spain Spain

Year Introduced 1969 1970 -

Metampicillin sodium Trade Name Fedacilina Janopen Madecilina Maipen Mempil Metabacter Metacidan Meta-Ferran Metakes Metambac Metampicef Metamplimedix Metiskia Ocelina Pluriespec Ruticina Tisquibron Venzoquimpe Vigocina

Manufacturer Fedal Janovich Made Maipe Kairon Rubio Cidan Ferran Kessler Wolner Cecef Medix Iskia Roux-Ocefa Vir Bernabo Bryan Quimpe Europa

Country Spain Spain Spain Spain Spain Spain Spain Spain Spain Spain Spain Spain Spain Argentina Spain Argentina Spain Spain Spain

2201

Year Introduced -

Raw Materials 6-[D-(-)α-Aminophenylacetamido]penicillanic acid Sodium bicarbonate Formaldehyde Manufacturing Process 0.01 mol of 6-[D(-)α-(aminophenylacetamido)]-penicillanic acid was suspended in 150 cc of water cooled to +5°C and treated with 0.01 mol of sodium bicarbonate. The solution was treated with 0.01 mol of formaldehyde in aqueous solution, with agitation. The solution was then filtered to eliminate traces of insoluble product and the filtrate was lyophilized. Sodium 6-[D(-)-alpha-(methyleneamino-phenylacetamido)]-penicillanate was obtained. References Merck Index 5775 Kleeman & Engel p. 569 OCDS Vol. 1 p. 414 (1977) DOT 6 (3) 85 (1970) I.N. p. 604 Gradnick, B.; British Patent 1,081,093; August 31, 1967; assigned to Societe d'Etudes de Recherches et d'Applications Scientifiques et Medicales (E.R.A.S.M.E.) (France)

2202

Metapramine

METAPRAMINE Therapeutic Function: Antidepressant Chemical Name: 10,11-Dihydro-5-methyl-10(methylamino)-5Hdibenz[b,f]azepine Common Name: Structural Formula:

Chemical Abstracts Registry No.: 21730-16-5; 21737-55-3 (Hydrochloride salt) Trade Name Timaxel Rodostene

Manufacturer Specia Rhone Poulenc

Country France France

Year Introduced 1983 -

Raw Materials 5-Methyl-dibenzo[b,f]azepine Methylamine Sodium hypochlorite Manufacturing Process 5-Methyl-dibenzo[b,f]azepine (4.1 g), N-diethylaminoborane (1.7 g) and freshly distilled toluene (150 cc) are introduced into a 500 cc three-neck flask equipped with a dropping funnel and a condenser, and protected against moisture by a calcium chloride guard tube. The solution is heated under reflux (110°C) for 22 hours under a nitrogen atmosphere and then cooled. A 2 N aqueous sodium hydroxide solution (33 cc) is then run in followed by an 0.316 N aqueous methylchloramine solution (190 cc), the addition of which takes 9 minutes. The mixture is stirred for 1 hour and then decanted. The organic layer is washed with water until it has a pH of 6 and is then extracted with 2 N hydrochloric acid (5 times 50 cc), dried over sodium sulfate, filtered and evaporated. Recrystallization of the residue from petroleum ether yields some unconverted 5-methyl-dibenzo[b,f]azepine (2.17 g). The aqueous acid solution is rendered alkaline by adding 2 N sodium hydroxide solution. After extracting with diethyl ether (3 times 100 cc), drying the extracts over potassium carbonate, treating them with decolorizing charcoal, filtering and evaporating the ether, a yellowish oil (0.9 g), identified

Metaproterenol sulfate

2203

as 5-methyl-10-methylamino-10,11-dihydrodibenzo[b,f]azepine, is obtained in a yield of 37.5%. Methylchloramine can be prepared by adding an aqueous solution of sodium hypochlorite to an aqueous solution of methylamine in accordance with the process described by W.S. Metcalf, J. Chem. Soc.1942,148. References Merck Index 5781 DFU 6 (8) 479 (1981) Kleeman& Engel p. 569 I.N. p. 605 Linares, H.; British Patent 1,323,219; July 11, 1973; assigned to RhonePoulenc SA Fouche, J.C.L. and Gueremy, C.G.A.; US Patent 3,622,565; November 23, 1971; assigned to Rhone-Poulenc S.A.

METAPROTERENOL SULFATE Therapeutic Function: Bronchodilator Chemical Name: 5-[1-Hydroxy-2-[(1-methylethyl)amino]ethyl]-1,3benzenediol sulfate Common Name: Orciprenaline sulfate Structural Formula:

Chemical Abstracts Registry No.: 5874-97-5; 586-06-1 (Base) Trade Name Alupent Dosalupent Alupent Alupent Metaprel Alotec Astmopent

Manufacturer Boehringer Ingelheim Boehringer Ingelheim Badrial Boehringer Ingelheim Dorsey Tanabe Polfa

Country W. Germany Italy France US US Japan Poland

Year Introduced 1961 1963 1966 1973 1973 -

2204

Metaraminol

Trade Name Astop Lenasma Novasmasol

Manufacturer Rafa Ravasini Zambeletti

Country Israel Italy Italy

Year Introduced -

Raw Materials 3,5-Diacetoxyacetophenone Isopropylamine Bromine Hydrogen Manufacturing Process In an initial operation, 3,5-diacetoxyacetophenone was reacted first with bromine and then with isopropylamine to give 1-(3,5-dihydroxyphenyl)-2isopropylaminoethanone. 59 g of 1-(3,5-dihydroxy-phenyl)-2-isopropylaminoethanone (free base) were dissolved in 590 cc of methanol, and the solution was hydrogenated in the presence of about 80 g Raney nickel at room temperature and under a pressure of 5 atm. Hydrogen absorption was terminated after a few minutes. The catalyst was separated by vacuum filtration, and the filtrate, an ethanolic solution of 1-(3,5-dihydroxyphenyl)-1-hydroxy-2-isopropylaminoethane, was admixed with the calculated amount of an alcoholic 20% sulfuric acid solution. A crystalline precipitate formed which was filtered off and washed with alcohol. For purification, the product was dissolved in water and the solution was filtered through iron-free charcoal. Thereafter, the filtrate was evaporated to dryness in vacuo and the residue was taken up in alcohol. The crystalline precipitate which separated out after some standing was separated by vacuum filtration and washed with alcohol. After recrystallization from 90% alcohol, 61 g (83.2% of theory) of 1-(3,5dihydroxyphenyl)-1-hydroxy-2-isopropylamino-ethane sulfate, MP 202° to 203°C, was obtained. References Merck Index 5782 Kleeman & Engel p. 658 PDR pp. 674, 848 OCDSVol. 1 p.64 (1977) I.N. p. 705 REM p. 887 Thoma, O. and Zeile, K.; US Patent 3,341,594; September 12, 1967; assigned to Boehringer Ingelheim G.m.b.H., Germany

METARAMINOL Therapeutic Function: Hypertensive

Metaraminol

2205

Chemical Name: α-(1-Aminoethyl)-3-hydroxybenzenemethanol Common Name: m-Hydroxynorephedrine; m-Hydroxypropadrine; Metaradrine Structural Formula:

Chemical Abstracts Registry No.: 54-49-9 Trade Name

Manufacturer

Country

Year Introduced

Aramine

MSD

US

1952

Pressoral

Travenol

US

1963

Pressonex

Winthrop

US

1963

Aramine

MSD-Chibret

France

1963

Araminiurn

Sharp and Dohme W. Germany

-

Ararninon

Merck-Banyu

Japan

-

Icopal B

Bayer

-

-

Levicor

Bioindustria

Italy

-

Metaraminol

Bristol

US

-

Raw Materials m-Hydroxyphenylethyl ketone Butyl nitrite Hydrogen Manufacturing Process The hydrochloride of the m-hydroxyphenylpropanolamine may be prepared by dissolving or suspending 90 parts of m-hydroxyphenylethyl ketone, O = C(C6H4-OH)-C2H5, in about 400 parts of ether. Hydrogen chloride is slowly bubbled through the solution or suspension while agitating it and 61.8 g of butyl nitrite is added during the course of 60 to 90 minutes. During the addition of the butyl nitrite the suspended m-hydroxyphenylethyl ketone gradually dissolves. The mixture or solution is allowed to stand for at least an hour, but preferably overnight. It is then repeatedly extracted with dilute alkali until all alkali-soluble material is removed. The alkaline extract is slowly acidified and the precipitate which forms is crude m-hydroxyphenyl-αoximinoethyl ketone. After recrystallization from water this melts at 138°C. 10.8 parts of the meta ketone is dissolved in about 125 parts of absolute alcohol containing 5.6 parts of hydrogen chloride. The solution is agitated with a catalyst such as the palladium catalyst above described in an atmsophere of

2206

Metaxalone

hydrogen until no more hydrogen is absorbed. This requires from 60 to 90 minutes or more. When reduction is complete the catalyst is filtered off and the filtrate evaporated to dryness by being placed in a desiccator at ordinary temperature. The residue is the hydrochloride of m-hydroxyphenyl-α-aminoethyl ketone. This is purified by recrystallization from absolute alcohol. It is then dissolved in 200 parts of water and agitated with a further quantity of the palladium catalyst in an atmosphere of hydrogen until saturated. The product thus recovered from the solution is the hydrochloride of m-hydroxyphenylpropanol amine. After recrystallization from absolute alcohol this melts at 177°C. The corresponding free base can be prepared from the hydrochloride by treatment with ammonia, according to US Patent 1,995,709. Metaraminol is often used in the form of the bitartrate. References Merck Index 5783 Kleeman & Engel p. 570 PDR pp. 695, 1140 I.N. p. 605 REM p. 888 Bockmuhl, M., Ehrhart, G. and Stein, L.; US Patent 1,948,162; February 20, 1934; assigned to Winthrop Chemical Company, Inc. Bockmuhl, M., Ehrhart, G. and Stein, L.; US Patent 1,951,302; March 13,1934; assigned to Winthrop Chemical Company, Inc. Hartung, W.H.; US Patent 1,995,709; March 26,1935; assigned to Sharp & Dohme, Inc.

METAXALONE Therapeutic Function: Muscle relaxant Chemical Name: 5-(3,5-Dimethylphenoxymethyl)-2-oxazolidnone Common Name: Structural Formula:

Chemical Abstracts Registry No.: 1665-48-1

Metergoline Trade Name Skelaxin

Manufacturer Robins

Country US

2207

Year Introduced 1962

Raw Materials Urea 3-(3',5'-Dimethylphenoxy)-1,2-propanediol Manufacturing Process Urea (118 g, 1.96 mols) was added to 192 g (0.98 mol) of 3-(3',5'dimethylphenoxy)-1,2-propane-diol which had previously been heated to 150°C. The reaction mixture was then heated rapidly to 195° to 200°C and maintained at this temperature for 5 hours with constant stirring. The resulting mixture was partitioned between water and ethyl acetate and the ethyl acetate layer was dried over sodium sulfate and concentrated. The residue was distilled in vacuo and the fraction boiling at 220° to 225°C/1.5 mm was collected. Yield, 172 g (79%). The distillate was crystallized from dry ethyl acetate; MP, 121.5° to 123°C. References Merck Index 5785 Kleeman & Engel. p.571 PDR p. 783 OCDS Vol. 1 p. 119 (1977) I.N.p. 606 REMp. 927 Lunsford, C.D.; US Patent 3,062,827; November 6, 1962; assigned to A.H. Robins Company, Inc.

METERGOLINE Therapeutic Function: Analgesic Chemical Name: [[(8β)-1,6-Dimethylergolin-8-yl]methyl]carbamic acid phenylmethyl ester Common Name: Methyl-N-carbobenzoxy-dihydro-lysergamine Chemical Abstracts Registry No.: 17692-51-2 Trade Name Liserdol

Manufacturer Farmitalia

Raw Materials 1-Methyl-dihydro-lysergamine Carbobenzoxy chloride

Country Italy

Year Introduced 1970

2208

Metformin hydrochloride

Structural Formula:

Manufacturing Process 16 g of 1-methyl-dihydro-lysergamine (the 10-position hydrogen has the αconfiguration) are dissolved in 80 cc of anhydrous pyridine by mildly heating. To the solution, cooled to -10°C and stirred, 18 cc of 85% carbobenzoxychloride (in toluene) diluted in 36 cc of chloroform are added dropwise, rather rapidly. The mixture is kept at -10°C during the addition, and for 10 minutes afterwards. The cooling means is removed and the temperature is allowed to rise to room level in 10 minutes. The reaction mixture is diluted with 240 cc of chloroform and rapidly washed with 80 cc of 5% aqueous sodium hydroxide solution, with saturated aqueous sodium bicarbonate solution, and finally with water. The chloroform solution is briefly dried over anhydrous sodium sulfate and evaporated to dryness in vacuo at 40°C. The oily residue is taken up in 160 cc of benzene and passed through a column containing 48 g of alumina. The column is then eluted with further 160 cc of benzene. The collected eluates are evaporated in vacuo at 40°C. The thick oily residue is mixed with a small amount of anhydrous diethyl ether. After some time a crystalline mass is obtained, which is collected and washed with a small amount of benzene and diethyl ether. 12 g of white crystals are obtained, melting at 146° to 148°C. References Merck Index 5790 I.N. p. 606 Camerino, B., Patelli, B. and Glaesser, A.; US Patent 3,238311; March 1, 1966; assigned to Societa Farmaceutici Italia, Italy

METFORMIN HYDROCHLORIDE Therapeutic Function: Oral hypoglycemic

Methacycline

2209

Chemical Name: Biguanide, 1,1-dimethyl-, hydrochloride Common Name: Dimethylguanilguanidini chloridum; Metformin Structural Formula:

Chemical Abstracts Registry No.: 1115-70-4; 15537-72-1; 657-24-9 (Base) Trade Name Diabetex Diabetex Diaformin Diaphage D.B.I. Glucomet Glucophage Glucophage Metforal

Manufacturer Germania Terrapharm Alphapharm UPM Montpellier USV Laboratoires Aron Bristol-Meyers Squibb Menarini

Country India France USA Italy

Year Introduced -

Raw Materials Dimethylamine Dicyanamide Hydrogen chloride Manufacturing Process The boiling mixture of 1,000 L xylene, 450 kg dimethylamine and 840 kg dicyanamide was added 365 kg hydrogene chloride. Yield of biguanide, 1,1dimethyl-, hydrochloride 1,588 kg (96%). Biguanide, 1,1-dimethyl-, hydrochloride may be recrystallysed from methanol. References Patent DE 1023757 Patent FR 2,322,860; Sep. 1975; Assigned to ARON S.A.R.L.

METHACYCLINE Therapeutic Function: Antibiotic

2210

Methacycline

Chemical Name: 4-Dimethylamino-1,4,4a,5,5a,6,11,12a-octahydro3,5,10,12,12a-pentahydroxy-6-methylene-1,11-dioxo-2naphthacenecarboxamide Common Name: 6-Methylene-5-hydroxytetracycline Structural Formula:

Chemical Abstracts Registry No.: 914-00-1; 3963-95-9 (Hydrochloride salt) Trade Name Rondomycin Megamycine Rondomycin Adramycin Apriclina Benciclina Boscillina Brevicillina Ciclobiotic Ciclum Duecap Duplaciclina Duramicina Dynamicin Esarondil Esquilin Fitociclina Franciclina Francomicina Gammaciclina Globociclina Idrossimicina Isometa Largomicina Medomycin Megamycine Metabiotic Metabioticon BG

Manufacturer Pfizer Creat Wallace Janko Lancet Benvegna Molteni Neopharmed Beta Italsuisse Sam Locatelli Bergamon Medal Terapeutico Saita Ifisa Francia N.C.S.N. Sthol Importex San Carlo Isom Jamco Medosan C.R.E.A.T. Panther-Osfa Boniscontro-Gazzone

Country UK France US Japan Italy Italy Italy Italy Italy Italy Italy Italy Italy Italy Italy Italy Italy Italy Italy Italy Italy Italy Italy Italy Italy Italy Italy Italy

Year Introduced 1963 1966 1966 -

Methacycline Trade Name Metac Metacil Metaclin Metaclor Metadomus Metagram Metilenbiotic Microcilina Mit-Ciclina Molciclina Optimicine Ossirondil Paveciclina Physiomycine Piziacina Plurigram Prontomicina Quickmcina Radiomicin Rindex Rotilen Sernamicina Stafilon Tachiciclina Tetrabios Tetranovo Tiberciclina Ticomicina Treis-Ciclina Valcin Vitabiotic Wassermicina Yatrociclina Zermicina

Manufacturer Dima Ibirn Medici Esset Medici Domus Zanardi Coli Biotrading Von Boch Molteni Biochemie Gazzini I.B.P. Roland-Marie Farmochimica Lafare Tosi-Novara Panthox and Burck Radiopharma Sidus Arnelix Pharma Williams A.G.I.P.S. C.T. Ausonia Totalpharm Tiber Benedetti Ecobi Chemil PHARMEX Wassermann Italfarmaco Pulitzer

Country Italy Italy Italy Italy Italy Italy Italy Italy Italy Italy Austria Italy Italy France Italy Italy Italy Italy Italy Italy Italy Italy Italy Italy Italy Italy Italy Italy Italy Italy Italy Italy Italy Italy

2211

Year Introduced -

Raw Materials Oxytetracycline Sulfur trioxide Hydrogen fluoride Manufacturing Process To a stirred solution of 4.6 g (0.01 mol) of anhydrous oxytetracycline in 40 ml of dry tetrahydrofuran is added 3.5 g (0.021 mol) of pyridine-sulfur trioxide complex. After 16 hours of stirring at room temperature, the resulting suspension is filtered, and the solid is slurried with 25 ml of 2% hydrochloric acid for 10 minutes, filtered and thoroughly washed with methanol followed by ether. The pale yellow crystalline 5-oxytetracycline-6,12-hemiketal-12-sulfuric

2212

Methadone hydrlchloride

acid ester melts at 210°C. 500 mg 5-oxytetracycline-6,12-hemiketal-12-sulfuric acid ester, prepared as described, is added to 4 ml dry liquid hydrogen fluoride, and the mixture is stirred for 1.5 hours at ice bath temperature. The hydrogen fluoride is then evaporated in a stream of nitrogen and the resulting gummy solids are triturated with about 15 ml ether and filtered. The resulting solid hydrofluoride salt is further purified by suspending in water, adjusting the pH to about 4, and extracting the 6-methylene-5-oxytetracycline free base from the aqueous phase with ethyl acetate. The extract is separated and evaporated to dryness under reduced pressure. The resulting residue is triturated with ether and filtered, and the solid is recrystallized from methanol-acetone-etherconcentrated hydrochloric acid to obtain the product as a purified hydrochloride, according to US Patent 3,026,354. References Merck Index 5798 Kleeman & Engel p. 567 PDR p. 1881 OCDS Vol. 2 p. 227 (1980) DOT 1 (1) 10 (1965) I.N. p. 603 REM p. 1205 Blackwood, R.K., Rennhard, H.H., Beereboom, J.J. and Stephens, C.R., Jr.; US Patent 2,984,686; May 16, 1961; assigned to Chas. Pfizer & Co., Inc. Biackwood, R.K.; US Patent 3,026,354; March20, 1962; assigned to Chas. Pfizer & Co., Inc.

METHADONE HYDROCHLORIDE Therapeutic Function: Narcotic analgesic Chemical Name: 6-Dimethylamino-4,4-diphenyl-3-heptanone hydrochloride Common Name: Amidone hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 1095-90-5; 76-99-3 (Base)

Methallenestril Trade Name Dolophine Adanon Westadone Adolan Eptadone Heptadon Heptanal Heptanon Ketalgin Mephenon Optalgin Physeptone

Manufacturer Lilly Winthrop Vitarine Abic Tosi E.B.E.W.E. Treupha Pliva Amino Spemsa Dr. Wust Burroughs-Wellcome

Country US US US Israel Italy Austria Switz. Yugoslavia Switz. Italy Switz. UK

2213

Year Introduced 1947 1947 1973 -

Raw Materials Ethyl bromide Diphenylacetonitrile Hydrogen chloride

Magnesium 2-Chloro-1-dimethylaminopropane

Manufacturing Process Diphenylacetonitrile is condensed with 2-chloro-1-dimethylaminopropane to give 4-(dimethylamino)-2,2-diphenyl valeronitrile. It is then reacted with ethyl magnesium bromide and then hydrolyzed using HCl to give methadone hydrochloride. References Merck Index 5799 Kleeman & Engel p. 573 PDR pp. 1048, 1061, 1571 OCDS Vol.1 pp.79, 289, 298 (1977) and 2, 328 (1980) I.N. p. 607 REM p. 1109 Resolution of Optical Isomers: Howe, E.E. and Tishler, M.; US Patent 2,644,010; June 30, 1953; assigned to Merck & Co., Inc. Zaugg, H.E.; US Patent 2,983,757; May 9, 1961; assigned to Abbott Laboratories

METHALLENESTRIL Therapeutic Function: Estrogen Chemical Name: β-Ethyl-6-methoxy-α,α-dimethyl-2-naphthalenepropionic acid Common Name: -

2214

Methallenestril

Structural Formula:

Chemical Abstracts Registry No.: 517-18-0 Trade Name Vallestril Cur-Men Ercostrol Ercostrol

Manufacturer Searle Novapharma Erco Green Cross

Country US Italy Denmark Japan

Year Introduced 1952 -

Raw Materials Copper cyanide Ethyl bromide Magnesium Hydrogen

2-Bromo-6-methoxynaphthalene Ethyl bromoisobutyrate Potassium bisulfate Sodium hydroxide

Manufacturing Process A first step involves the preparation of 2-cyano-6-methoxynaphthalene (cyanonerolin). 90 g of 2-bromo-6-methoxynaphthalene are heated with 60 g of cuprous cyanide in a metal bath at 240° to 250°C stirring for one hour. At the instant when the cuprous cyanide begins to react and dissolves, the mass turns brown, liquefies and heats up strongly. The molten mass is poured onto a cold surface, is pulverized and sifted. This powder is treated with dilute ammonia (1 liter of water to 300 cc of commercial ammonia solution). The solution is filtered on a Buchner filter and the precipitate that remains on the filter is washed with dilute ammonia and then with water. After drying, the residue is treated in a Kumagawa extracting apparatus with boiling benzene. The benzene is evaporated and the residue is distilled in vacuo. About 50 g of cyanonerolin (BP = 205° to 208°C/14 mm) are obtained with a yield of about 70%. By recrystallization in 200 cc of methyl alcohol, 40 g of the product are obtained in absolutely pure state, in the shape of beautiful colorless needles (MP = 103°C with the Maquene block). By concentrating the mother liquor to half its original volume, a further 3.6 g of pure product are obtained. The 2-cyano-6-methoxy-naphthaleneis in turn converted by successive reactions into: (a) β-ketonic ester, (b) ester-alcohol, (c) β-ethylene ester by dehydration, (d) saturated ester, and (e) [3-(6-methoxy-2-naphthyl)]2,2dimethyl pentanoic acid which is the required product. (A) Obtaining a β-Ketonic Ester by Reacting Ethyl Bromoisobutyrate with Cyanonerolin: 9 g of cyanonerolin are heated in a reflux apparatus for 40 minutes with 7 g of zinc and 19 g of ethyl bromoisobutyrate in the presence

Methallenestril

2215

of 150 cc of anhydrous benzene. After cooling, the mixture is filtered to eliminate unreacted zinc and is hydrolyzed by stirring for one hour with dilute sulfuric acid (10 cc of sulfuric acid to 200 cc of water). The benzene layer is washed, dried and the solvent is eliminated. It is purified by recrystallization in methyl alcohol. 12.5 g of ketonic ester (MP = 72.5° to 73.5°C) are thus obtained in the form of large prismatic crystals. (B) Obtaining an Ester-Alcohol by Reacting Magnesium Ethyl Bromide with the Previous Ketonic Ester: 10 g of the previous ester dissolved in 40 cc of anhydrous benzene are gradually poured while stirring into an iced solution of magnesium ethyl bromide prepared from 1.035 g of magnesium, 4.15 cc of ethyl bromide and 40 cc of anhydrous ether. After heating in a reflux apparatus for one-half hour, the mixture is poured into ice in the presence of ammonium chloride. After washing the ether-benzene layer, the solvents are eliminated in vacuo and an ester-alcohol is thus obtained with a yield of 98%, in the form of a transparent resin. This resin, if treated with petroleum ether, yields 6.35 g of ester-alcohol in the form of fine needles (MP = 66.68°C) which are very soluble in the chief organic solvents and in petroleum ether. (C) Conversion into Ethyl [3(6-Methoxy-2-Naphthyl)] 2,2-Dimethyl-3Pentanoate by Dehydrating the Previous Ester-Alcohol: The semi-oily raw product of the previous reaction is dehydrated by heating with its own weight of potassium bisulfate to 180°C until boiling stops. After cooling, the magma is removed from the anhydrous ether in small portions. The ether is then evaporated and an ethylene ester is obtained in the form of an oil which slowly solidifies, with a yield of 98%. The product, after being purified by chromatography, melts at 48° to 51°C. (D) Obtaining Ethyl [3-(6-Methoxy-2-Naphthyl)] 2,2-Dimethyl Pentanoate by Hydrogenation of the Previous Ethylene Ester: 3.5 g of the previous ethylene ester, purified by chromatography, are hydrogenated in the presence of 3.6 g of platinum in 30 cc of ether. The quantity of hydrogen fixed corresponds to the theoretical quantity calculated. After filtering, the ether is evaporated, 3.45 g of ester are thus obtained in the form of an oil which quickly solidifies. Purification is effected by chromatography. (E) Obtaining [3-(6-Methoxy-2-Naphthyl)] 2,2-Dimethyl Pentanoic Acid: 2.5 g of the previous ester are saponified by means of 15 cc of soda lye and 25 cc of methyl glycol. The mixture is boiled for one hour, diluted with water and, after cooling, is treated twice with ether in order to eliminate the remaining neutral fractions. The aqueous layer is precipitated by means of 15 cc of acetic acid. 2.1 g of raw acid are obtained. After effecting two crystallizations in 10 parts of acetic acid mixed with 3 parts of water, fine needles are obtained which are grouped in rosettes and melt at 131.5° to 132.5°C. References Merck Index 5803 Kleeman & Engel p. 574 OCDS Vol. 1 p. 87 (1977) I.N. p. 608 Horeau, A. and Jacques, J.; US Patent 2,547,123; April 3, 1951

2216

Methaphetamine hydrochloride

METHAMPHETAMINE HYDROCHLORIDE Therapeutic Function: Sympathomimetic, Central stimulant Chemical Name: Benzeneethanamine, N,alpha-dimethyl-, hydrochloride, (S)Common Name: Desoxyephedrine hydrochloride; Metamfetamine hydrochloride; Metamphetamine hydrochloride; Methaphetamine hydrochloride; Methylamphetamine hydrochloride; Phenylmethylaminopropane hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 51-57-0 ; 537-46-2 (Base) Trade Name Desoxyn Amphedroxyn Destim Drinalfa Gerobit Isophen Madrine Methampex Methampex Methedrine Pervitin Soxysympamine Syndrox Tonedron

Manufacturer Abbott Laboratories Lilly Central Pharm. Squibb Gerot Knoll Langley Lemmon Teva Burroughs-Wellcome Temmler Ferndale McNeil Grimault

Country -

Year Introduced -

Raw Materials Ephedrine, (-)Phenylisopropylamine

Platinum on carbon Hydrochloric acid

Manufacturing Process 2 Methods of prepearing of methamphetamine: 1. (-)-Ephedrin was reduced by hydrogenesation with hydrogen in the presence of Pt-C catalyst to give the (+)-N-α-dimethylphenethylamine (methamphetamine), melting point 172°-174°C.

Methandrostenolone

2217

2. Methamphetamine was obtained by the methylation of phenylisopropylamine. To give methamphetamine hydrochloride the base methamphetamine was treated by eqimolar quantity of hydrochloric acid. References Haletsky A.M.; Pharmaceutical Chemistry, Medicina. L., 1966, 761p. Emde H.; Helv. Chim. Acta 1929, v. 12, p. 365

METHANDROSTENOLONE Therapeutic Function: Androgen, Anabolic Chemical Name: 17β-Hydroxy-17-methylandrosta-1,4-dien-3-one Common Name: Methandienone Structural Formula:

Chemical Abstracts Registry No.: 72-63-9 Trade Name Dianabol Abirol Anabolin Anoredan Encephan Lanabolin Metabolina Metanabol Metastenol Naposim Nerobol Perbolin Vanabol

Manufacturer Ciba Takeda Medica Kodama Sato/Shinshin Labatec Guidi Polfa Farber-R.E.F. Terapia Galenika Ion Vitrum

Country US Japan Finland Japan Switz. Italy Poland Italy Rumania Yugoslavia Italy Sweden

Year Introduced 1960 -

2218

Methandrostenolone

Raw Materials Bacterium Didymella lycopersici 17β-Methyl testosterone Selenium dioxide Manufacturing Process As described in US Patent 2,929,763, methandrostenolone may be made by a fermentation route. 2 g of sodium nitrate, 1 g of primary potassium orthophosphate, 0.5 g of magnesium sulfate heptahydrate, 0.5 g of potassium chloride, 50 g of glucose and 1 g of Difco yeast extract are dissolved in one liter of tap water, brought to pH 5 by addition of a sodium hydroxide solution and sterilized. The resulting nutrient solution is inoculated with 50 cc of a 4day-old shaking culture of Didymella lycopersici and shaken for 48 hours at 27°C, whereby the culture becomes well developed. To two liters of a culture so prepared there is added under sterile conditions a solution of 500 mg of 17α-methyl-testosterone in 15 cc of acetone. Shaking is carried out for 3 days at 27°C, the mycellium then filtered off with suction, washed with water and ethyl acetate and the combined filtrates extracted with ethyl acetate. The extraction residue obtained after evaporation of the solvent is dissolved in a little acetone. On addition of ether, the 1-dehydro-17αmethyl-testosterone is obtained in compact crystals. MP 163° to 164°C. An alternative synthetic route is described in US Patent 2,900,398 as follows. A suspension of 30 g of 17α-methyl-testosterone and 10 g of selenium dioxide in 600 cc of tertiary amyl alcohol is treated with 60 g of magnesium powder and 6 cc of glacial acetic acid. The mixture is refluxed for 24 hours with good stirring in an atmosphere of nitrogen, another 10 g of selenium dioxide being added after 10 hours. After some cooling, the suspension is filtered through some Hyflo and washed thoroughly with ethyl acetate. The resulting brown solution is evaporated in vacuo and the residue dissolved in ethyl acetate. The ethyl acetate solution is then washed with water, dried and evaporated. To remove any selenium still present, the residue is dissolved in 200 cc of methanol and mixed with 100 g of iron powder and 2 g of active carbon. The mixture is heated for 30 minutes with stirring under reflux, then filtered with suction, washed with methanol and the solution evaporated in vacuo. The residue is then chromatographed on 900 g of aluminum oxide. The residues of the evaporated benzene and ether fractions are treated with active carbon in methanol or acetone, evaporated again, and the residue recrystallized from a mixture of acetone and ether. There are obtained 17.5 g of pure 1-dehydro17α-methyl-testosterone which melts at 163° to 164°C. References Merck Index 5810 Kleeman & Engel p. 570 OCDS Vol. 1 p. 173 (1977) I.N. p. 605

Methapyrilene hydrochloride

2219

REM p.998 Wettstein, A., Hunger, A., Meystre, C. and Ehmann, L.; US Patent 2,900,398; August 18, 1959; assigned to Ciba Pharmaceutical Products, Inc. Wettstein, A., Vischer, E. and Meystre, C.; US Patent 2,929,763; March 22, 1960; assigned to Ciba Pharmaceutical Products, Inc.

METHAPYRILENE HYDROCHLORIDE Therapeutic Function: Antihistaminic Chemical Name: N,N-Dimethyl-N'-2-pyridinyl-N'-(2-thienylmethyl)-1,2ethanediamine hydrochloride Common Name: Thenylpyramine hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 135-23-9; 91-80-5 (Base) Trade Name Thenylene Pyrathyn Histadyl Semikon Lullamin Dozar Allergin Allerest Brexin Citra Ephed-Organidin Excedrin P.M. Histadyl M.P. Sedanoct Contac Co-Pyronil

Manufacturer Abbott Davis Sly Lilly Beecham Reed Carnrick Tutag Myers-Carter Pharmacraft Savage Boyle Wallace Bristol-Myers Lilly Dymond Woalm-Pharma Vonora Lilly

Country US US US US US US US US US US US US US Canada W. Germany W. Germany Italy

Year Introduced 1947 1947 1948 1949 1954 1956 -

2220

Methaqualone

Raw Materials 2-Aminopyridine 2-Thenyl chloride Hydrogen chloride

N,N-Dimethyl-β-chloroethylamine Sodium amide

Manufacturing Process To a slurry of sodamide in 200 cc of toluene representing 6.7 g of sodium was added at 30° to 40°C, 32.3 g (0.31 mol) of 2-aminopyridine. The mixture was heated to reflux temperature and was refluxed for 1½ hours. To the resulting mixture was added over a period of approximately one hour a solution of 32 g of freshly distilled N,N-dimethyl-β-chloroethylamine in 40 to 50 cc of dry toluene, The reaction mixture was then heated for 2 hours at reflux temperature. Thereafter, 200 cc of water was added and the toluene layer was separated and washed with water. The toluene was stripped from the mixture by distillation and the residue was distilled under reduced pressure. The distillate was refractionated and the portion distilled at 93° to 103°C/1 mm was recovered. Yield of N-(2-pyridyl)-N',N'-dimethyl-ethylenediamine, 60%. A solution of 20 g (0.121 mol) of N-(2-pyridyl)-N',N'-dimethylethylenediamine in 25 cc of toluene was added to a slurry of sodamide in 100 cc of toluene representing 2.8 g of sodium. The mixture was refluxed for one hour. To this mixture was added over a period of ½ hour a solution of 16 g (0.121 mol) of 2-thenyl chloride in 25 cc of toluene. The resulting reaction mixture was refluxed for 3 hours. Thereafter, water was added and the toluene layer was separated and washed with water. The toluene was then stripped off by distillation and the residue was distilled under reduced pressure. The main fraction was redistilled. Yield of N-(2pyridyl)-N-(2-thenyl)-N',N'-dimethyl-ethylenediamine was 69%; BP 130° to 140°C/0.4 mm. A portion of the product was dissolved in ether and an ether solution of hydrogen chloride was added. The monohydrochloride of N-(2pyridyl)-N-(2-thenyl)-N',N'-dimethyl-ethylenediamine which separated was washed with ether and dried. References Merck Index 5819 Kleeman & Engel p. 575 OCDS Vol. 1 p. 54 (1977) I.N. p. 609 Kyrides, L.P.; US Patent 2,581,868; January 8, 1952; assigned to Monsanto Chemical Company

METHAQUALONE Therapeutic Function: Hypnotic Chemical Name: 2-Methyl-3-o-tolyl-4(3H)-quinazolinone

Methaqualone

2221

Common Name: Metolquizolone; Ortonal Structural Formula:

Chemical Abstracts Registry No.: 72-44-6; 340-56-7 (Hydrochloride salt) Trade Name Quaalude Sopor Somnafac Parest Quaalude Optimil Aqualon Cateudyl Citexal Divinoctal Dormigoa Dormir Dormutil Hyptor Hyminal Mandrax Mequelon Meroctan Methadorm Metasedil Mollinox Motolon Nene Nobadorm Normi-Nox Normorest Noxybel Oblioser Optinoxan Parmilene Paxidorm Pexaqualone Pro-Dorm Revonal Rouqualone

Manufacturer Lemmon Amer. Crit. Care Cooper Lemmon Rorer Wallace Arcana Cavor Draco I.S.H. Scheurich Langley Isis-Chemie Bio-Chimique Eisai I.S.H. Merck-Frosst Sanwa Eri Cooper Asperal Chinoin Sankyo Streuli Herbrand Doitsu-Aoi Probel Gamaprod. Robisch Chiesi Wallace Therapex Schurholz Merck Rougier

Country US US US US Italy US Austria Belgium Sweden France W. Germany Australia E. Germany Canada Japan France Canada Japan Canada Switz. Belgium Hungary Japan Switz. W. Germany Japan Belgium Australia W. Germany Italy US Canada W. Germany UK Canada

Year Introduced 1965 1967 1968 1969 1969 1972 -

2222

Methazolamide

Trade Name Sedalone Sleepinal Somnium Sovelin Sovinal Spasmipront Tiqualone Tualone

Manufacturer Pharbec Medichem Fargal Weifa N.D. and K. Mack Barlow Cote I.C.N.

Country Canada Australia Italy Norway Denmark W. Germany Canada Canada

Year Introduced -

Raw Materials Anthranilic acid o-Toluidine Acetic anhydride Hydrogen chloride Manufacturing Process Anthranilic acid (1 part) is dissolved in acetic anhydride (2 parts) and the temperature raised progressively to 190° to 200°C while distillation takes place. The last traces of acetic acid are removed under vacuum and, after cooling to about 50° to 60°C, o-toluidine (1 part) is added in portions. The temperature is then raised to 170° to 200°C when the excess water and o-toluidine is gradually distilled off, finally maintaining the temperature at 180° to 200°C for 2 hours. After cooling to about 100°C dilute hydrochloric acid (3 parts) is added and the mixture boiled and stirred. The solution is then neutralized with NaOH with stirring and the product which separates is recrystallized twice from alcohol after decolorizing with carbon. Yield: 70% of theoretical, LIP 114° to 115°C. References Merck Index 5820 Kleeman & Engel p. 576 OCDS Vol. 1 p.353 (1977) DOT 9 (6) 245 (1973) I.N. p.610 REM p. 1072 Laboratoires Toraude, France; British Patent 843,073; August 4, 1960

METHAZOLAMIDE Therapeutic Function: Carbonic anhydrase inhibitor Chemical Name: N-[5-(Aminosulfonyl)-3-methyl-1,3,4-thiadiazol-2(3H)ylidene]acetamide

Methazolamide

2223

Common Name: Structural Formula:

Chemical Abstracts Registry No.: 554-57-4 Trade Name Neptazane Neptazane

Manufacturer Lederle Theraplix

Country US France

Year Introduced 1959 1961

Raw Materials 5-Acetylimino-4-methyl-2-benzylmercapto-δ2-1,3,4-thiadiazoline Chlorine Ammonia Manufacturing Process A suspension of 6 parts by weight of 5-acetylimino-4-methyl-2benzylmercapto-δ2-1,3,4-thiadiazoline in 180 parts by volume of 33% aqueous acetic acid was chlorinated at 5°C for 30 minutes. The solid was filtered off, dried, and added portion-wise to 100 parts by volume of liquid ammonia. The ammonia was removed under a stream of dry nitrogen. The residual solid was partially dissolved in 10 parts by volume of water, filtered, and acidified to give 5-acetylimino-4-methyl-δ2-1,3,4-thiadiazoline-2sulfonamide. The product was purified by two recrystallizations from hot water. References Merck Index 5824 Kleeman & Engel p. 576 PDR p. 1021 OCDS Vol. 1 p. 250 (1977) I.N. p. 610 REM p.936 Young, R.W., Wood, K.H. and Vaughan, J.R., Jr.; US Patent 2,783,241; February 26, 1957; assigned to American Cyanamid Company

2224

Methdilazine hydrochloride

METHDILAZINE HYDROCHLORIDE Therapeutic Function: Antipruritic Chemical Name: 10-[(1-Methyl-3-pyrrolidinyl)methyl]phenothiazine hydrochloride Common Name: Structural Formula:

Chemical Abstracts Registry No.: 1229-35-2; 1982-37-2 (Base) Trade Name Tacaryl Dilosyn Disyncran Tacryl

Manufacturer Westwood Duncan Flockhart Allard Pharmacia

Country US UK France Sweden

Year Introduced 1960 -

Raw Materials 1-Methyl-3-pyrrolidylmethyl chloride Phenothiazine Hydrogen chloride Manufacturing Process 10.8 parts of 10-(1-methyl-3-pyrrolidylmethyl) phenothiazine (prepared from 1-methyl-3-pyrrolidylmethyl chloride by reaction with phenothiazine) in 80 parts of 99% isopropyl alcohol were treated with a solution of 1.33 parts of hydrogen chloride in 30 parts of the same solvent. The clear light yellow solution soon deposited white crystals of the acid addition salt. After cooling overnight at 0°C, the crystalline product was collected on a filter, washed with 99% isopropyl alcohol and anhydrous ether and then dried in a vacuum oven at 95°C. Yield 10.4 parts, MP 187.5° to 189°C. References Merck Index 5826 Kleeman & Engel p. 577 PDR p. 1895

Methenamine hippurate

2225

OCDS Vol. 1 p. 387 (1977) I.N. p. 611 REM p. 1129 Feldkamp, R.F. and Wu, Y.H.; US Patent 2,945,855; July 19, 1960; assigned to Mead Johnson & Company

METHENAMINE HIPPURATE Therapeutic Function: Antibacterial (urinary) Chemical Name: Hexamethylenetetramine hippurate Common Name: Structural Formula:

Chemical Abstracts Registry No.: 5714-73-8 Trade Name Hiprex Hiprex Hiprex Hipeksal Hippuran Lisogerm Urotractan

Manufacturer Merrell National Riker Kettelhack Riker Leiras Orion Labofarma Klinge

Country US UK W. Germany Finland Finland Brazil W. Germany

Year Introduced 1967 1971 1975 -

Raw Materials Hexamethylenetetramine Hippuric acid Manufacturing Process 179 g (1 mol) hippuric acid (benzoyl glycine) and 140 g (1 mol) hexamethylenetetramine were heated under reflux in 500 ml methanol. The small amount of water necessary to give a clear, homogeneous solution was

2226

Methenolone acetate

added to the resulting reaction mixture which was then evaporated to dryness. The residue soon crystallized, a procedure that could be greatly accelerated by seeding with crystals of hexamethylenetetramine hippurate from a previous preparation. The resulting solid product was broken up and pulverized. Hexamethylenetetramine hippurate is stable on exposure to air and is soluble in water and alcohol. It melts at 105° to 110°C. References Merck Index 5832 PDR pp. 1227, 1453 DOT 4 (3) 108 (1968) I.N. p. 611 REM p. 1167 Galat, A.; US Patent 3,004,026; October 10, 1961

METHENOLONE ACETATE Therapeutic Function: Anabolic Chemical Name: 17β-Hydroxy-1β-methyl-5α-androst-l-ene-3-one acetate Common Name: Structural Formula:

Chemical Abstracts Registry No.: 434-05-9; 153-00-4 (Base) Trade Name Primobolan Dacomid Fortabol Neuro-Fortabol

Manufacturer Schering Schering Schering Schering

Country W. Germany W. Germany W. Germany W. Germany

Year Introduced 1961 -

Raw Materials Methyl iodide Magnesium

∆(1,4,6)-Androstatrien-17β-ol-3-one-17-acetate Hydrogen

Methicillin sodium

2227

Manufacturing Process 8.42 ml of methyl iodide are slowly added dropwise at room temperature with stirring in a nitrogen atmosphere to 3.067 g of magnesium turnings and 107 ml of absolute ether. After about 30 minutes, 185 ml of absolute tetrahydrofuran are slowly introduced and then liquid is distilled off until a boiling point of 62°C is reached. After cooling to room temperature, 613 mg of cuprous chloride are added and then 10 g of ∆1,4,6-androstatrien-17β-ol-3one-17-acetate in 110 ml of tetrahydrofuran slowly introduced. After 30 minutes reaction time, the whole is cooled to 0C, the excess of Grignard reagent decomposed with saturated ammonium chloride solution, the product diluted with ether and the aqueous phase separated. The ethereal phase is washed consecutively with aqueous sodium thiosulfate solution, saturated ammonium chloride solution and water. It is dried over sodium sulfate and evaporated to dryness under vacuum. The residue is dissolved in 40 ml of pyridine and 20 ml of acetic anhydride and the solution kept for 16 hours at room temperature. It is then stirred into ice water and the precipitate filtered with suction, dried and recrystallized from isopropyl ether. 1α-Methyl-∆4,6androstadien-17β-ol-3-one-17-acetate is obtained. MP 156°C to 157°C; [α]D25 = -33.8° (in CHCl3; c = 0.9). Yield 65-70% of the theoretical. 4.67 g of 1α-methyl-∆4,6-androstadien-17β-ol-3-one-17-acetate are dissolved in 273 ml of methanol and, after the addition of 350 mg of 10% palladium on calcium carbonate catalyst, hydrogenated until 1 mol equivalent of hydrogen has been taken up. After filtering off the catalyst, the solution is treated with 150 ml of 2N-hydrochloric acid and evaporated under vacuum to about 1/3 of the volume. The whole is then diluted with water and extracted with ether. The ethereal solution is washed with water until neutral, dried over sodium sulfate and evaporated. The crude product is heated on a steam bath for 90 minutes in 10 ml of pyridine and 10 ml of acetic anhydride. Extraction with ether is then carried out and the ethereal phase washed until neutral with water. The crude crystalline 1α-methyl-∆4-androsten-17β-ol-3-one-17acetateobtained after drying and evaporation of the solution, melts at 122°C to 129°C. Yield 98% of the theoretical. 1α-Methyl-∆4-androsten-17β-ol-3-one-17-acetate when purified by recrystallization from isopropyl ether melts at 138°C to 139°C. References Merck Index 5839 Kleeman and Engel p. 571 OCDS Vol. 1 p. 175 (1977) I.N. p. 606 Schering A.G.; British Patent 977,082; December 2, 1944

METHICILLIN SODIUM Therapeutic Function: Antimicrobial

2228

Methicillin sodium

Chemical Name: 6-(2,6-Dimethoxybenzamido)-3,3-dimethyl-7-oxo-4-thia-1azabicyclo[3.2.0]heptane-2-carboxylic acid sodium salt Common Name: 2,6-Dimethoxyphenylpenicillin sodium salt Structural Formula:

Chemical Abstracts Registry No.: 7246-14-2 Trade Name Celbenin Staphcillin Dimocillin Flabelline Celbenin Azapen Baclyn Celpillina Ellecillina Esapenil B.G. Metin Methocillin Penysol Sintespen Staficyn

Manufacturer Beecham Bristol Squibb Delagrange Beecham Pfizer Sifrochimica Farmitalia Ellea Boniscontro-Gazzone C.S.L. Meiji Saita Coli Firma

Country UK US US France US US Italy Italy Italy Italy Australia Japan Italy Italy Italy

Year Introduced 1960 1960 1961 1961 1973 1975 -

Raw Materials 6-Aminopenicillanic acid 2,6-Dimethoxybenzoyl chloride Manufacturing Process To a stirred suspension of 6-aminopenicillanic acid (540 g) in dry alcohol-free chloroform (3.75 liters) was added dry triethylamine (697 ml), and the mixture stirred for 10 minutes at room temperature. It was then cooled in a bath of crushed ice while a solution of 2,6-dimethoxybenzoyl chloride (500 g) in dry alcohol-free chloroform (3.75 liters) was added in a steady stream over 20 minutes. When all the acid chloride had been added the cooling bath was removed and the mixture stirred for 1 hour at room temperature. The mixture

Methimazole

2229

was stirred vigorously and sufficient dilute hydrochloride acid (2.3 liters of 0.87 N) was added to give an aqueous layer of pH 2.5. The mixture was filtered, the layers separated, and only the chloroform layer was retained. This was stirred vigorously while further dilute hydrochloric acid (0.69 liter of 0.87 N) was added to give an aqueous layer of pH 1. The layers were separated and again only the chloroform layer was retained. Then the chloroform layer was stirred vigorously while sufficient sodium bicarbonate solution (3.2 liters of 0.97 N) was added to give an aqueous layer of pH 6.7 to 7.0. The layers were separated and both were retained. The chloroform layer was stirred vigorously while sufficient sodium bicarbonate solution (50 ml of 0.97 N) was added to give an aqueous layer of pH 7.7, and again the layers were separated. The two bicarbonate extracts were combined, washed with ether (1 liter), and then concentrated at low temperature and pressure until the concentrate weighed 1,415 g. The concentrate was treated with dry acetone (22 liters), the mixture well mixed, and then filtered to remove precipitated solid impurities. Further dry acetone (4 liters) was added to the filtrate, then the product started to crystallize slowly. Crystallization was allowed to proceed at a temperature between 0° and 3°C for 16 hours and then the product (563 g) was collected by filtration. Dry ether (7.5 liters) was added to the filtrate, and after several hours a second crop (203 g) of solid was collected. The two crops were combined to give sodium 2,6-dimethoxyphenylpenicillin monohydrate (766 g, 73%) as a white crystalline solid. References Merck Index 5842 Kleeman and Engel p. 591 PDR p. 713 OCDS Vol. 1 p.412 (1977) I.N. p. 626 REM p. 1200 Doyle, F.P., Nayler, J.H.C. and Rolinson, G.N.; US Patent 2,951,839; September 6,1960

METHIMAZOLE Therapeutic Function: Thyroid inhibitor Chemical Name: 2H-Imidazole-2-thione, 1,3-dihydro-1-methylCommon Name: Mercazolyl(um); Methimazole; Methymazole; Thiamazole; Tiamazol Chemical Abstracts Registry No.: 60-56-0

2230

Methimazole

Structural Formula:

Trade Name Favistan Favistan Tapazole Thiamazole Metisol Thyrozol

Manufacturer Asta Temmler Pharma Lilly Marion Merrel Dow Polfa Merck

Country -

Year Introduced -

Raw Materials Sulfuric acid Bromine Methylamine Hydrochloric acid

3,3-Diethoxypropylamine Potassium thiocyanate Methylisothiocyanate 1,1-Diethoxyethane

Manufacturing Process 2 Methods of preparation of thiamazole: 1. To 2,2-diethoxyethylamine methylisothiocyanate was added and mixed after then 1-(2,2-diethoxy-ethyl)-3-methylthiourea was obtained. The reaction of the 1-(2,2-diethoxyethyl)-3-methylthiourea with sulfuric acid yield thiamazole. 2. 1,1-Diethoxyethane was treated by bromine in the presence CaCO3 and 2bromo-1,1-diethoxyethane was obtained. Then to the 2-bromo-1,1-diethoxyethane methylamine was added, mixed and reaction mixture was heated to 120°-130°C in autoclave. As the result (2,2diethoxyethyl)methylamine was obtained. (2,2-Diethoxyethyl)methylamine reacted with potassium thiocyanate in the presence of hydrochloric acid and give the thiamazole, yellow crystallic precipitate, melting point 144°-147°C. References Kleemann A., Engel J.; Pharmazeutische Wirkstoffe, GeorgThieme Verlag Stuttgart. New York, 1982 Chaletsky A.M. Pharmaceutical chemistry, Medicina, L., 1966, 761p.

Methionine

2231

METHIONINE Therapeutic Function: Lipotropic Chemical Name: 2-Amino-4-(methylthio)butyric acid Common Name: Structural Formula:

Chemical Abstracts Registry No.: 63-68-3 Trade Name Meonine Lobamine Oradash Ammonil Dyprin Acimetion Amino-Serv AminoPlex Antamon P.E.D. Methnine Monile Ninol Uracid Unanap Urimeth

Manufacturer Ives Opodex Lambda Philips Roxane Lincoln Continental Pharma Milex Tyson Protea Medical Research Cortunon Horner Wesley N. Amer. Pharm. N. Amer. Pharm.

Country US France US US US Belgium US US S. Africa Australia Canada Canada US US US

Year Introduced 1944 1948 1955 1957 1958 -

Raw Materials Methyl mercaptan Sodium cyanide Sodium hydroxide Acrolein Ammonium chloride Manufacturing Process A 3-necked flask fitted with a stirrer, thermometer, gas inlet, dropping funnel, and brine-cooled reflux condenser was charged with 53 g (1.1 mol) methyl mercaptan and 0.35 g mercuric methyl mercaptide. After admitting 56 g (1.0

2232

Methitural

mol) of acrolein during the course of 15 minutes with an inside temperature of about 10°C, the temperature was allowed to rise spontaneously to 75°C, at which point an ice bath was applied. There was no indication of further reaction one hour after the addition of the acrolein. Distillation of the product gave 71 g (yield 68%) of β-methylmercaptopropionaldehyde, as described in US Patent 2,584,496. Then as described in US Patent 2,732,400, β-methylmercaptopropionaldehyde (0.60 M) (56.5 g) is added to a stirred solution of sodium cyanide (0.66 M) (32.4 g) and ammonium chloride (0.63 M) (33.7 g) in water (140 ml). The temperature of the mixture rises to 49°C and is maintained at this point by heat evolution for about 5 minutes when it slowly begins to fall. Methanol (50 ml) is added and the mixture is stirred for 4 hours as the temperature falls to 28°C (room temperature). After chilling to +12°C, additional methanol (35 ml) and a concentrated aqueous ammoniun hydroxide solution (1.4 M) (100 ml) are added and stirring is continued for 2 hours at a temperature maintained at from +5° to +15°C. The organic layer is separated and solvent is stripped from the aqueous layer at water aspirator pressure at a temperature below 40°C. The residue is extracted several times with chloroform and the chloroform extracts are combined with the separated oil. Chloroform is removed at water aspirator pressure at a temperature below 35°C to leave crude α-amino-γmethylmercaptobutyronitrile (methionine nitrile) in 88% yield (68 g) as a clear, somewhat viscous oil. The methionine nitrile (20 g) is dissolved in a solution prepared from 50 ml of aqueous 5 N sodium hydroxide solution and 65 ml of ethanol. The solution is then refluxed for 24 hours; ammonia is evolved. The solution is treated with activated carbon, filtered, acidified with glacial acetic acid (17 ml), chilled to 10°C and filtered to give crude product. This crude product is then slurried with a solution made up of 20 ml of water and 20 ml of methanol, filtered at 5° to +10°C and dried to give dl-methionine as white platelets. References Merck Index 5849 PDR pp. 1263,1807 I.N. p. 612 Pierson, E. and Tishler, M; US Patent 2,584,496; February 5, 1952; assigned to Merck and Co., Inc. Weiss, M.J.; US Patent 2,732,400; January 24, 1956; assigned to American Cyanamid Company

METHITURAL Therapeutic Function: Hypnotic, Sedative Chemical Name: Dihydro-5-(1-methylbutyl)-5-[2-(methylthio)ethyl]-2thioxo-4,6-(1H,5H)pyrimidinedione monosodium salt

Methitural

2233

Common Name: Methioturiate Structural Formula:

Chemical Abstracts Registry No.: 730-68-7 Trade Name Neraval Diogenal Thiogenal

Manufacturer Schering Merck Merck

Country US -

Year Introduced 1956 -

Raw Materials Thiourea Sodium Sulfuric acid

Ethanol Sodium hydroxide β-Methyl-thioethyl-(1-methyl)-n-butyl-cyanoacetic acid ethyl ester

Manufacturing Process A solution of 69 g of sodium in 1,380 cc of absolute alcohol is mixed with 257.4 g of β-methylthioethyl-(1-methyl)-n-butyl-cyano-acetic acid ethyl ester and 114 g of thiourea and the whole mass boiled under reflux with stirring for six hours. After concentration under vacuum the residue is taken up in 1.5 liters of water and shaken up thrice, each time with 300 cc of ether. The aqueous alcoholic layer is stripped, under vacuum, of the dissolved ether and mixed with 300 cc of 30% acetic acid under stirring and ice cooling. The precipitated material is sucked off, washed with water, dried and recrystallized from isopropyl alcohol. The thus obtained β-methyl-thioethyl-(1-methyl)-nbutyl-cyano-acetyl thiourea forms yellowish green crystals having a melting point of 229°C to 230C. 100 g of this product are boiled under reflux for three hours with 1 liter of 20% sulfuric acid. After cooling the mixture is taken up in ether, the ether solution washed with water, dried, filtered, concentrated and drawn off under vacuum. The residue is caused to crystallize by treatment with a mixture of 60 volume parts of methanol and 40 volume parts of petroleum benzene. The isolated crystals are recrystallized from the mentioned solvent mixture and yield thereby 5-β-methyl-thioethyl-5-(1-methyl)-n-butyl-2-thiobarbituric acid having a melting point of 79°C to 81°C. 20 g of the free acid are shaken up (in a machine) for one hour with 69.5 cc

2234

Methixene hydrochloride

n/l (normal) caustic soda. The filtered solution is concentrated under vacuum, the residue is taken up in absolute alcohol and again with drawn under vacuum. After two recrystallizations of the residue from isopropyl alcohol one obtains the readily water-soluble, analytically pure, sodium salt of the 5-βmethyl-thioethyl-5-(1 -methyl)-n-butyl-2-thiobarbituric acid. References Merck Index 5854 OCDS Vol. 1 p.275 (1977) I.N. p. 612 Zima, O. and Von Werder, F.; US Patent 2,802,827; August 13,1957; assigned to Emanuel Merck (Germany)

METHIXENE HYDROCHLORIDE Therapeutic Function: Spasmolytic Chemical Name: 1-Methyl-3-(9H-thioxanthen-9-yl-methyl)piperidine hydrochloride Common Name: Structural Formula:

Chemical Abstracts Registry No.: 1553-34-0; 4969-02-2 (Base) Trade Name

Manufacturer

Country

Year Introduced

Tremarit

Wander

W. Germany

1960

Tremaril

Wander

Italy

1962

Tremonil

Wander

UK

1963

Trest

Dorsey

US

1965

Atosil

Teikoku

Japan

-

Cholinfall

Tokyo Tanabe

Japan

-

Dalpan

Grelan

Japan

-

Inoball

Sawai

Japan

-

Methixart

Fuso

Japan

-

Methyloxan

Nippon Shoji

Japan

-

Methocarbamol Trade Name Raunans Spasmenzyme Thioperkin

Manufacturer Kowa Salvoxyl-Wander Hokuriku

Country Japan France Japan

2235

Year Introduced -

Raw Materials Thioxanthene Chlorobenzene Sodium

N-Methyl-3-chloromethyl-piperidine Hydrogen chloride

Manufacturing Process To 4.9 g of finely pulverized sodium in 50 ml of absolute benzene add dropwise with stirring 12 g of chlorobenzene in 50 ml of absolute benzene. As soon as the exothermic reaction begins, maintain the temperature by cooling between 30° and 35°C, and continue stirring for 2 to 3 hours. To the resulting phenyl sodium add dropwise 19.8 g of thioxanthene in 120 ml of absolute benzene. The slightly exothermic reaction ceases after about 1 to 1½ hours. To this newly formed 9-thioxanthyl sodium add dropwise, with stirring and cooling, 13.1 g of N-methyl-3-chloromethyl-piperidine in 30 to 40 ml of absolute benzene, then continue stirring at about 25°C for 1½ hours, and heat subsequently to 40°C for 1 hour. Decompose the resulting mixture by adding carefully a small amount of water, and then extract the newly formed base from the benzene solution by means of dilute hydrochloric acid. The aqueous hydrochloric solution is made alkaline by adding dilute sodium hydroxide, and the thioxanthene base is isolated by extraction with ether. This results in 22 g of a slightly yellow, viscous base of BP 171° to 175°C/0.07 mm. The base is acidified with alcoholic hydrochloric acid. Alcohol-ether (1:2) is then added and the hydrochloride salt is crystallized as colorless flakes melting at 211° to 213°C. References Merck Index 5855 Kleeman and Engel p. 592 OCDS Vol. 1 p.400 (1977) and 2,413 (1980) I.N. p. 628 REM p.919 Schmutz, J.; US Patent 2,905,590; September 22,1959; assigned to The Wander Company

METHOCARBAMOL Therapeutic Function: Muscle relaxant

2236

Methocarbamol

Chemical Name: 3-(o-Methoxyphenoxy)-1,2-propanediol-1-carbamate Common Name: Guaiacol glyceryl ether carbamate Structural Formula:

Chemical Abstracts Registry No.: 532-03-6 Trade Name Robaxin Lumirelax Robaxin Carbametin Carxin Delaxin Methocabal Methocal Miowas Myomethol Parabaxin Relax Robamol Robaxisal Romethocarb Traumacut Tresortil

Manufacturer Robins Sarbach Brenner Uji Kanto Ferndale Zeria Daiko Wassermann Abic Parmed Ion Cenci Robins Robinson Brenner Gea

Country US France W. Germany Japan Japan US Japan Japan Italy Israel US Italy Italy US US W. Germany Denmark

Year Introduced 1957 1968 1976 -

Raw Materials Guaiacol glyceryl ether Phosgene Ammonia Manufacturing Process The starting material for methocarbamol is 3-o-methoxyphenoxy-1,2propanediol (guaiacol glyceryl ether) (see entry under Guaifenesin for its preparation). To a stirred suspension of 198.2 g (1.0 mol) of 3-omethoxyphenoxy-1,2-propanediol in 1,000 ml of dry benzene contained in a 5-liter, 3-neck, round bottom flask equipped with a thermometer, dropping funnel and blade stirrer, was added dropwise (in 30 minutes) a solution of 98.9 g (1.0 mol) of phosgene in 400 ml of cold dry benzene. The mixture was stirred at 30°C until all solid material dissolved (about 3 hours was required)

Methohexital sodium

2237

and stirring was continued for 30 minutes longer. To this mixture was added dropwise 79.1 g (1.0 mol) of dry pyridine, the temperature being held below 30°C by cooling. After addition of the pyridine, stirring at 30°C was continued for 30 minutes. The mixture was cooled to 7°C, extracted with two 500-cc portions of ice water to remove pyridine hydrochloride, and the benzene solution of 3-omethoxyphenoxy-2-hydroxypropyl chlorocarbonate was added to 500 ml of cold concentrated ammonium hydroxide. The mixture was vigorously stirred at 5°C for 6 hours, then the crude white precipitate of 3-o-methoxyphenoxy-2hydroxypropyl carbamate was filtered off, dissolved in 1,500 ml of hot benzene and completely dried by codistillation of last traces of water with benzene, treated with decolorizing carbon and filtered while hot. On cooling 160 g of product crystallized as white needles melting at 88° to 90°C. References Merck Index 5856 Kleeman and Engel p. 578 PDR pp.830, 993, 1466, 1569, 1606, 1999 OCDS Vol. 1 p. 118 (1977) I.N. p. 613 REM p. 927 Murphey, R.S.; US Patent 2,770,649; November 13,1956; assigned to A.H. Robins Company, Inc.

METHOHEXITAL SODIUM Therapeutic Function: Anesthetic Chemical Name: (+/-)-1-Methyl-5-(1-methyl-2-pentynyl)-5-(2-propenyl)2,4,6-(1H,3H,5H)-pyrimidinetrione sodium salt Common Name: Methohexitone Structural Formula:

Chemical Abstracts Registry No.: 309-36-4

2238

Methohexital sodium

Trade Name Brevital Brietal Brevimytal Brietal

Manufacturer Lilly Lilly Lilly Lilly

Country US UK W. Germany Italy

Year Introduced 1960 1961 1963 1963

Raw Materials Magnesium Sodium Allyl bromide Acetaldehyde Ethanol

Ethyl acetylene (1-butyne) Phosphorus tribromide Ethyl bromide Diethyl malonate Methyl urea

Manufacturing Process Preparation of 3-Hexyne-2-ol: A solution of ethyl magnesium bromide was prepared by the reaction of 229 g of ethyl bromide and 48.6 g of magnesium in 750 ml of anhydrous ether. To the ether solution was then added with stirring a solution of 108 g of ethyl acetylene in 250 ml of cold anhydrous ether. The addition required approximately 3 hours, and the mixture was stirred and refluxed for a further period of 3½ hours. Thereafter there was added to the reaction mixture a solution of 88 g of freshly distilled acetaldehyde in 170 ml of anhydrous ether, over a period of about 45 minutes and at a temperature in the range of about -10° to 0°C. The resulting reaction mixture was poured over about 1 kg of crushed ice, and neutralized with 10% aqueous hydrochloric acid. The organic phase of the resulting mixture was separated, and the aqueous phase was extracted 3 times with 250 ml portions of ether. The combined organic phase and ether washings were washed twice with water and dried over anhydrous potassium carbonate. The dried ether solution was fractionally distilled, and the 3hexyne-2-ol formed in the reaction was collected as a fraction boiling at about 79° to 80°C at the pressure of 60 mm of mercury. Preparation of 2-Bromo-3-Hexyne: A solution of 138 g of 3-hexyne-2-ol and 9 g of pyridine in 138 ml of anhydrous ether was treated with 175 g of phosphorus tribromide, added dropwise over a period of about 20 minutes at a temperature of about -10°C. The reaction mixture was permitted to come to room temperature while stirring for about 3 hours, and was then heated to refluxing for about 1 hour. After cooling, the reaction mixture was poured over about 50 g of crushed ice. A two-phase system formed, and the ether layer was separated, washed with dilute sodium bicarbonate solution, dried over anhydrous potassium carbonate and fractionally distilled. The 2-bromo-3hexyne formed in the reaction was collected at 75°C at the pressure of 50 mm of mercury. Preparation of Diethyl (1-Methyl-2-Pentynyl) Malonate: To a solution of 28.6 g of sodium in 430 ml of absolute ethanol were added 200 g of diethyl malonate. About half of the alcohol was removed by distillation in vacuo, and thereafter a solution of 200 g of 2bromo-3-hexyne in 100 ml of anhydrous ether was added slowly to the reaction mixture.

Methohexital sodium

2239

The heat of reaction brought about refluxing during the addition of the 2bromo-3-hexyne, and when the addition was complete the reaction mixture was heated to refluxing for a further period of 30 minutes. A sufficient amount of water was then added to the reaction mixture to dissolve the sodium bromide which had formed, and the only organic layer was separated, washed with water and dried over anhydrous magnesium sulfate. The dried organic layer was then fractionally distilled under reduced pressure, and the diethyl (1-methyl-2-pentynyl) malonate formed in the reaction was collected at about 117° to 120°C at the pressure of 2 mm of mercury. Preparation of Diethyl Allyl (1-Methyl-2-Pentynyl) Malonate: A solution of 12.1 g of sodium in 182 ml of absolute ethanol was prepared, and thereto were added 126.6 g of diethyl (1-methyl-2-pentynyl) malonate. Most of the ethanol was then distilled off under reduced pressure, and the residue was cooled and 63.5 g of allyl bromide were slowly added thereto. After completion of the addition, the mixture was refluxed for about 1 hour. The reaction mixture was cooled, treated with about 100 ml of water, and the oily organic layer which formed was removed, washed with water and dried over anhydrous magnesium sulfate. The dried oily organic material was fractionally distilled in vacuo, and diethyl allyl (1-methyl-2-pentynyl) malonate boiling at 105° to 107°C at the pressure of 1 mm of mercury was recovered. Preparation of 1-Methyl-5-Allyl-5-(1-Methyl-2-Pentynyl) Barbituric Acid: A solution of 23.8 g of sodium in 360 ml of absolute alcohol was prepared and thereto were added 38.3 g of methyl urea and 96.8 g of diethyl allyl (1methyl-2-pentynyl) malonate. The mixture was refluxed for about 20 hours, cooled, and the ethanol was removed by distillation in vacuo. The residue was dissolved in about 300 ml of water and the aqueous solution was washed with ether, and the washings were discarded. The aqueous solution was then acidified with acetic acid, and extracted with three 150 ml of portions of ether. The combined ether extracts were washed with 5% aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and fractionally distilled in vacuo. The fraction boiling at about 145 to 150°C at the pressure of 0.5 mm of mercury, weighing 61 g and consisting of 1-methyl-5-allyl-5-(1methyl-2-pentynyl) barbituric acid, was collected. The only distillate was substantially pure, and could be used as such in pharmaceutical preparation or a salt could be prepared therefrom according to the procedures disclosed hereinafter. On standing, the oil crystallized. The crystalline 1-methyl-5-allyl5-(1-methyl-2-pentynyl) barbituric acid melted at about 60° to 64°C after recrystallization from dilute ethanol. Preparation of Sodium 1-Methyl-5-Allyl-5-(1-Methyl-2-Pentynyl) Barbiturate: A solution of 61 g of 1-methyl-5-allyl-5-(1-methyl-2-pentynyl) barbituric acid in 100 ml of ether was extracted with 465 ml of 2% aqueous sodium hydroxide solution. The aqueous extract was washed with successive 75 ml and 50 ml portions of ether. The pH of the aqueous solution was adjusted to 11.7, using 5% aqueous sodium hydroxide solution. 5 g of decolorizing carbon were added to the solution with stirring; the mixture was permitted to stand for 20 minutes at room temperature, and the carbon was removed by filtration. A solution containing 4 g of sodium carbonate in 25 ml of water was added to the aqueous solution, and the mixture was filtered sterile through a porcelain filter candle of 02 porosity into sterile bottles. The aqueous solution was then dried from the frozen state, whereupon a sterile residue of sodium 1-methyl-

2240

Methotrexate

5-allyl-5-(1-methyl-2-pentynyl) barbiturate, weighing about 62 g was obtained. References Merck Index 5857 Kleeman and Engel p. 578 PDR p.1038 OCDS Vol. 1 p. 269 (1977) I.N. p. 613 REM p.1046 Doran, W.J.; US Patent 2,872,448; February 3,1959; assigned to Eli Lilly and Company

METHOTREXATE Therapeutic Function: Antineoplastic Chemical Name: N-[4-[[(2,4-Diamino-6-pteridinyl)methyl]methylamino]benzoyl]-L-glutamic acid Common Name: Amethopterin Structural Formula:

Chemical Abstracts Registry No.: 59-05-2 Trade Name Methotrexate Mexate Emtexate Folex Abitrexate Emthexate Ledertrexate

Manufacturer Lederle Bristol Nordic Adria Abic Pharmachemie Lederle

Country US US UK US Israel Netherlands France

Raw Materials Diethyl-p-methylaminobenzoyl-L-glutamate

Year Introduced 1955 1979 1981 1983 -

Methotrexate

2241

Aminomalononitrile tosylate β-Bromopyruvaldoxime Guanidine acetate Manufacturing Process 5 g (15 mmol) of diethyl-p-methylaminobenzoyl-L-glutamate and 8.0 g of aminomalononitrile tosylate (65% by NMR assay, 20 mmol) were dissolved in warm ethanol (65 ml, with 15% water by volume). To this solution, cooled to 0°C, was added all at once and with vigorous stirring, 3.6 g of βbromopyruvaldoxime (89% by NMR assay, 19 mmol). After 30 minutes the stirred mixture, which was allowed to warm slowly to room temperature, was neutralized with powdered NaHCO3 to pH 6, stirring continued for four additional hours, and the resulting mixture filtered through Celite. The filtrate was evaporated under reduced pressure to a glasslike substance, which was taken up in 500 ml of chloroform. The resulting suspension was then filtered using Celite, and the filtrate was washed with water, dried with anhydrous MgSO4, and evaporated to give an orange glasslike substance which was used directly in the next step. To a 20% solution of titanium trichloride in water (39 mmol), stirred under nitrogen, was added a solution of 18 g (230 mmol) of ammonium acetate in 55 ml of water. Then, to this mixture, cooled to 10°C and stirred with an airdriven stirrer, was added over a period of 5 minutes a solution of the orange glassy substance above distilled in 60 ml of tetrahydrofuran. The mixture was vigorously stirred for 15 minutes while a rapid stream of nitrogen was passed through. After this time, 15 g of powdered sodium sulfite (120 mmol) was added to the mixture, which after several minutes turned from green to yellowish white. This mixture was stirred into 1 liter of chloroform, and the heavy yellow layer separated by use of a separatory funnel. This chloroform layer was washed with water, dried using anhydrous MgSO4, and evaporated under reduced pressure to give a light orange glass, which was then chromatographed rapidly on a column made from 80 g of Baker silica gel, using 5% ethyl acetate in chloroform as the eluent. The product obtained by evaporation of the eluate was recrystallized from ethanol-ether (1:10) to give a light yellow powder, MP 85 to 88°C. The yield was 4.4 g (63%). A solution containing 4.8 g (10.2 mmol) of diethyl-N-[p-[[(2-amino-3-cyano5-pyrazinyl)methyl] methylamino]benzoyl]glutamate and 5 g (42 mmol) of guanidine acetate in 40 ml of dimethylformamide was stirred under nitrogen at 120°C for six hours. The resulting solution was cooled to room temperature, filtered and evaporated to a glassy product using a rotary evaporator and a mechanical vacuum pump to insure a better vacuum. The residual glass was taken up in 500 ml of chloroform, the resulting suspension filtered using Celite, and the filtrate washed with water, dried using anhydrous MgSO4, and evaporated to dryness. (The residual material was chromatographed rapidly on a column prepared from 250 g of Baker silica gel using, initially, 2% ethanol in chloroform, and then 5% ethanol in chloroform as eluents.) The material obtained by evaporation of the eluates was crystallized from ethanol-chloroform (4:1) to give small, pale yellow lustrous platelets, MP 142°C to 154°C; yield, 3.8 g (73%). Further crystallization of

2242

Methotrimeprazine

this material from ethanol-chloroform (4:1) raised the MP to 153°C to 155°C. The compound is completely racemic. A sample of this product was hydrolyzed in a mixture of water and methanol in the presence of potassium hydroxide. Essentially pure methotrexate was thus obtained. References Merck Index 5861 Kleeman and Engel p. 579 PDR p. 1016 DOT 8 (11) 426 (1972) and 16 (5) 170 (1980) I.N. p. 614 REM p. 1152 Wiecko, J.; US Patent 4,057,548; November 8,1977 Ellard, J.A.; US Patent 4,080,325; March 21,1978; assigned to US Dept. of Health, Education and Welfare

METHOTRIMEPRAZINE Therapeutic Function: Analgesic Chemical Name: 2-Methoxy-N,N,β-trimethyl-10H-phenothiazine-10propanamine Common Name: Levomepromazine Structural Formula:

Chemical Abstracts Registry No.: 60-99-1; 1236-99-3 (Hydrochloride salt) Trade Name Levoprome Hirnamin Levaru Levomezine Levotomin Nozinan Ronexine

Manufacturer Lederle Shionogi Mohan Toho Shionogi Farmalabor Ikapharm

Country US Japan Japan Japan Japan Italy Israel

Year Introduced 1966 -

Methoxamine hydrochloride Trade Name Sinogan Sofmin Veractil

Manufacturer Rhodia Iberica Dainippon May and Baker

Country Spain Japan US

2243

Year Introduced -

Raw Materials 3-Methoxyphenthiazine Sodium amide 1-Dimethylamino-2-methyl-3-chloropropane Manufacturing Process 95% sodamide (2.33 g) is added to a boiling solution of 3methoxyphenthiazine (12 g) in anhydrous xylene (150 cc) and the mixture is heated with agitation under reflux for 1½ hours. A solution of 1dimethylamino-2-methyl-3-chloropropane (8.2 g) in anhydrous xylene (90 cc) is then run in over a period of 45 minutes while the reaction temperature is maintained and heating under reflux is continued for 18 hours. After cooling, the reaction mixture is agitated with a mixture of water (40 cc) and a normal solution of methanesulfonic acid (70 cc), the xylene layer is removed and the acid liquors are washed with ether (200 cc). The aqueous phase is then made alkaline with sodium hydroxide (d = 1.33; 10 cc) and the liberated base is extracted with ether. The ethereal solution is dried over anhydrous potassium carbonate and concentrated at normal pressure. On distillation of the residue under reduced pressure 3-(3-methoxy-10phenthiazinyl)-2-methyl-1-dimethylaminopropane (11.3 g) is obtained, MP 103°C, BP 182° to 191°C/0.15 mm Hg. The hydrochloride prepared in isopropanol melts at about 90°C. References Merck Index 5862 Kleeman and Engel p. 522 DOT 3 (2) 62 (1967) and 9 (7) 227 (1971) I.N. p. 556 REM p. 1113 Jacob, R.M. and Robert, J.G.; US Patent 2,837,518; June 3,1958; assigned to Societe des Usines Chimiques Rhone-Poulenc, France

METHOXAMINE HYDROCHLORIDE Therapeutic Function: Hypertensive Chemical Name: α-(1-Aminoethyl)-2,5-dimethoxybenzenemethanol hydrochloride Common Name: -

2244

Methoxamine hydrochloride

Structural Formula:

Chemical Abstracts Registry No.: 61-16-5; 390-28-3 (Base) Trade Name Vasoxyl Idasal Mexan Vasylox

Manufacturer Burroughs-Wellcome Gayoso Wellcome Nippon Shinyaku Burroughs-Wellcome

Country US Spain Japan -

Year Introduced 1949 -

Raw Materials 2,5-Dimethoxypropiophenone Methyl nitrite Hydrogen Manufacturing Process 2,5-Dimethoxypropiophenone is treated in absolute ether with methyl nitrite and hydrogen chloride. The hydrochloride of 2,5-dimethoxy-αisonitrosopropiophenone crystallizes out of the solution. It is removed, the base is liberated and crystallized from benzene-heptane forming yellow leaflets that melt at about 97° to 98°C. This isonitrosoketone is dissolved in absolute alcohol containing an excess of hydrogen chloride and is hydrogenated with palladized charcoal, yielding β-(2,5-dimethoxyphenyl)-βketoisopropylamine hydrochloride, a salt that melts at about 176°C with decomposition. 12.3 g (1/20 mol) of β-(2,5-dimethoxyphenyl)-β-ketoisopropylamine hydrochloride (MP 176°C) is dissolved in 50 cc of water and hydrogenated with platinum oxide platinum black in the customary Adams-Burgess Parr apparatus. About 1/20 mol of hydrogen is absorbed, after which the solution is filtered off from the catalyst, evaporated to dryness in vacuo and recrystallized from absolute alcohol, absolute ether being added to decrease solubility. The hydrochloride is thus obtained in substantially theoretical yield. It crystallizes in plates and melts at 215°C. References Merck Index 5863 Kleeman and Engel p. 580 PDR p. 768 I.N. p. 614

Methoxsalen

2245

REM p. 888 Baltzly, R., de Beer, E.J. and Buck, J.S.; US Patent 2,359,707; October 3,1944; assigned to Burroughs Wellcome and Co. (USA.) Inc.

METHOXSALEN Therapeutic Function: Dermal pigmentation enhancer Chemical Name: 9-Methoxy-7H-furo[3,2-g][1]benzopyran-7-one Common Name: 8-Methoxypsoralen; Ammoidin; Xanthotoxin Structural Formula:

Chemical Abstracts Registry No.: 298-81-7 Trade Name Oxsoracen Meloxine Meladinine Oxoralen Psoritin Puvalen Soloxsalen

Manufacturer Eider Upjohn Basotherm Farmochimica Yurtoglu Star I.C.N.

Country US US W. Germany Italy Turkey Finland Canada

Year Introduced 1955 1958 -

Raw Materials 8-Geranoxy psoralen Sulfuric acid Diazomethane Manufacturing Process It has been found that the compound 8-geranoxy psoralen is present in citrus oils, particularly lemon and lime oils. This compound can be isolated from the oil by a process which involves primarily absorption on an adsorbent material followed by elution with a suitable solvent. (A) Cleavage of 8-Geranoxypsoralen: 275 mg of 8-geranoxypsoralen was dissolved with mechanical stirring in 4 ml glacial acetic acid. After 10 minutes,

2246

Methoxyflurane

one drop of concentrated sulfuric acid was added to the solution. In 4 minutes thereafter a light tan precipitate began to form. Stirring was continued for 35 minutes and the reaction mixture was refrigerated for one hour and 20 minutes. The precipitate was then removed by suction filtration and washed on the filter with glacial acetic acid followed by ice-cold ethyl ether. The product, 8-hydroxypsoralen, weighed 115 mg, that is, 74% of theory. (B) Methylation of 8-Hydroxypsoralen: 115 mg of 8-hydroxypsoralen was dissolved in 10 ml absolute methanol, an excess of diazomethane dissolved in ether was added and the mixture allowed to stand at room temperature with occasional stirring for 3 hours. The next day the reaction mixture was reduced in volume to 3 ml by evaporation on the steam bath and the concentrate was held in a refrigerator overnight. The next day, fine needles (80 mg) of 8methoxypsoralen were filtered from the solution. The compound had a MP of 145 to 146°C and was obtained in a yield of 65% of theory. There is also a wholly synthetic route to Methoxsalen as outlined by Kleeman and Engel. References Merck Index 5864 Kleeman and Engel p. 580 PDR p. 867 OCDS Vol. 1 p. 333 (1977) I.N. p. 614 REM p. 788 Stanley, W.L. and Vannier, S.H.; US Patent 2,889,337; June 2,1959; assigned to the US Secretary of Agriculture Glunz, L.J. and Dickson, D.E.; US Patent 4,129,575; December 12, 1978; assigned to Thomas C. Elder, Inc. Liebman, A.A. and Liu, Y.-Y.; US Patent 4,147,703; April 3,1979; assigned to Hoffmann-LaRoche, Inc.

METHOXYFLURANE Therapeutic Function: Inhalation anesthetic Chemical Name: 2,2-Dichloro-1,1-difluoro-1-methoxyethane Common Name: 1,1-Difluoro-2,2-dichloroethyl methyl ether Structural Formula:

Chemical Abstracts Registry No.: 76-38-0

Methoxyflurane

2247

Trade Name

Manufacturer

Country

Year Introduced

Penthrane

Abbott

US

1962

Penthrane

Abbott

W. Germany

1962

Penthrane

Abbott

UK

1963

Anecotan

Spofa

Czechoslovakia

-

Methofane

Pitman-Moore

US

-

Raw Materials 1,1-Dichloro-2,2-difluoroethylene Methanol Manufacturing Process Into a reactor equipped with agitator and temperature control jacket is charged approximately 100 lb (about 3 lb mols) of methanol, technical. This methanol is used in excess, and so it is both a reactant and a solvent in the synthesis. Approximately 1 US gallon of ion exchange resin beads wet with methanol is then added to the methanol. This is in the hydroxide form with at least 0.7 milliequivalent OH- per milliliter of wet beads. Approximately 190 lb of 1,1dichloro-2,2-difluoroethylene (about 1.44 lb mols) is then added to the reactor and, within it, to the 100 lb of methanol through a sparge pipe while the beads are kept in suspension by agitation. Coolant is run through the jacket of the reactor during this addition because the reaction is exothermic. The temperature in the reaction medium is kept at 10° to 20°C, to prevent side reactions and to minimize losses of the dichlorodifluoroethylene, which boils at 17°C. Reaction time is affected by the rate of heat removal and the reaction normally takes from 4 to 8 hours, using the stated quantities and conditions. After the dichlorodifluoroethylene is added, the resin is checked for residual alkalinity. If the resin is alkaline to phenolphthalein, it is assumed to have been of sufficient capacity and is removed from the CH3OCF2CHCI2-methanol mixture. If it is not alkaline to phenolphthalein, additional resin is added to insure complete reaction. Essentially the same procedure can be carried out, employing as alkali any strongly alkaline substance, such as caustic soda in methanol solution. Control of the reaction rate may be accomplished by the rate of the addition of reactants and the amount of cooling applied to the reaction mixture. Agitation is employed to insure efficient contact of the reactants. After removal of the resin catalyst, the excess methanol is extracted out of the mixture using three separate water washes, suitably of 25 gallons each. The water layer is decanted off, leaving product as an immiscible organic layer, after each wash. The 2,2-dichloro-1,1-difluoroethyl methyl ether containing intolerable unsaturated impurities may be purified and stabilized by a treatment with oxidizing agents such as air, oxygen, ozone, peroxy compounds, or other similar oxidizing agents, with subsequent removal of the decomposition or oxidation products and distilling if desired.

2248

Methscopolamine bromide

References Merck Index 5869 Kleeman and Engel p. 581 PDR p. 547 I.N. p. 615 REM p. 1043 Larsen, E.R.; US Patent 3,264,356; August 2,1966; assigned to The Dow Chemical Company

METHSCOPOLAMINE BROMIDE Therapeutic Function: Spasmolytic Chemical Name: 7-(3-Hydroxy-1-oxo-2-phenylpropoxy)-9,9-dimethyl-3-oxa9-azoniatricyclo-[3.3.1.02,4]nonane bromide Common Name: Hyoscine methyl bromide Structural Formula:

Chemical Abstracts Registry No.: 155-41-9 Trade Name

Manufacturer

Country

Year Introduced

Pamine

Upjohn

US

1953

Daipin

Daiichi Seiyaku

Japan

1972

Ace

Ono

Japan

-

Blocan

Estedi

Spain

-

Lescopine

Lincoln

US

-

Meporamin

Taiyo

Japan

-

Neo Avagal

Andrews

Australia

-

Parantin

Teva

Israel

-

Proscomide

Miller

US

-

Scopolate

Strasenburgh

US

-

Scordin

Ono

Japan

-

Skopyl

Farillon

UK

-

Methsuximide

2249

Raw Materials Scopolamine hydrobromide trihydrate Methyl bromide Manufacturing Process In a one-liter separatory funnel, 94 g (0.215 mol) of scopolamine hydrobromide trihydrate was dissolved in 250 ml of water, made alkaline by shaking with 40 g (1 mol) of sodium hydroxide in 150 ml of water, and the free base immediately extracted with ether. As scopolamine is somewhat soluble in water, the aqueous layer was saturated with potassium carbonate and again extracted with ether. The combined ether extracts were dried over anhydrous magnesium sulfate and the ether removed by distillation, leaving 65 g (0.214 mol; 100% yield) of nearly colorless oil. Then 100 g (1.05 mols) of cold methyl bromide was added to a chilled, 500-ml pressure flask containing the 65 g of scopolamine, the flask stoppered tightly with a clamp, and allowed to stand at room temperature for 96 hours. The flask was cooled before opening, excess methyl bromide removed by filtration, and the white solid washed thoroughly with dry ether. The yield of crude scopolamine methyl bromide was 80g (94% yield; 93.5% over-all yield). The salt was recrystallized from 550 ml of alcohol; first crop, 70 g, MP 212° to 214°C; second crop, 6 g, MP 195° to 200°C. The combined crops were again recrystallized from 500 ml of 3-A alcohol; MP 210° to 212°C. The third recrystallization from 600 ml of alcohol yielded 64 g, MP 214° to 216°C, a 75% yield based on scopolamine hydrobromide trihydrate starting material. References Merck Index 5881 Kleeman and Engel p. 582 PDR p. 1857 I.N. p. 508 REM p. 917 Visscher, F.E.; US Patent 2,753,288; July 3,1956; assigned to The Upjohn Company

METHSUXIMIDE Therapeutic Function: Anticonvulsant Chemical Name: 1,3-Dimethyl-3-phenyl-2,5-pyrrolidinedione Common Name: Mesuximid

2250

Methyldopa

Structural Formula:

Chemical Abstracts Registry No.: 77-41-8 Trade Name Celontin Petinutin

Manufacturer Parke Davis Parke Davis

Country US W. Germany

Year Introduced 1957 -

Raw Materials α-Phenyl-α-methylsuccinic acid Methylamine Manufacturing Process 100 g of α-phenyl-α-methylsuccinic acid and 110 g of 40% aqueous methyl amine are heated together at 200 to 250°C until no more distillate is obtained. Upon vacuum distillation of the residue, the N-methyl-α-phenyl-αmethylsuccinimide, of BP 121° to 122°C at 0.1 mm is obtained. After recrystallization from aqueous ethanol, this compound melts at 52° to 53°C. References Merck Index 5882 Kleeman and Engel p. 567 PDR p. 1320 OCDS Vol. 1 p. 228 (1977) I.N. p. 602 REM p. 1079 Miller, C.A. and Long, L.M.; US Patent 2,643,257; June 23, 1953; assigned to Parke, Davis and Company

METHYLDOPA Therapeutic Function: Antihypertensive Chemical Name: 3-Hydroxy-α-methyl-L-tyrosine Common Name: L-α-Methyl-3,4-dihydroxyphenylalanine

Methyldopa

2251

Structural Formula:

Chemical Abstracts Registry No.: 555-30-6 Trade Name Aldometil Aldomet Aldomet Aldomet Aldomet Adopal Aldomin Aldoril Alphamex Becanta Caprinol Dansul Desens Dimal Domecin Dopamet Dopamin Dopatec Dopegyt Equibar Grospisk Hydromet Hyperten Hypolag Hy-Po-Tone Medimet Medomet Medopa Medopal Medopren Metholes Methoplain Nichidopa Novomedopa Polinal Sembrina

Manufacturer MSD MSD MSD MSD MSD-Chibret Pharmacal Teva MSD Protea Kissei Pharmaceutical Co., Ltd. Bayer Nippon Yakko Nissin Protea Sankyo Berk Hokuriku Labatec Gedeon Richter Genekod Toho Iyaku MSD Toho Lagap Lennon Medic D.D.S.A. Kaigai A.L. Dietopharma Taisho Kowa Nichiiko Novopharm Boehringer Yamanouchi Boehringer Mannheim

Country W. Germany UK Italy US France Finland Israel US S. Africa Japan

Year Introduced 1962 1962 1962 1963 1964 -

W. Germany Japan Japan Australia Japan US Japan Switz. Hungary France Japan France Japan Switz. S. Africa Canada UK Japan Norway Italy Japan Japan Japan Canada Japan Italy

-

2252

Methylergonovine maleate

Raw Materials 3-Hydroxy-4-methoxyphenylalanine Hydrogen chloride Manufacturing Process The dl-α-methyl-3,4-dihydroxyphenylalanine may be made as described in US Patent 2,868,818. Five-tenths of a gram of 3-hydroxy-4methoxyphenylalaninewas dissolved in 20 ml of concentrated hydrochloric acid, the solution saturated with hydrogen chloride and heated in a sealed tube at 150°C for 2 hours. The dark reaction mixture was concentrated to dryness in vacuo, excess acid removed by flushing several times with ethanol. On dissolving the dark residue in a minimum amount of water and adjusting the clarified solution to pH 6.5 with ammonium hydroxide the compound separated in fine crystals which were filtered, washed with alcohol and ether. The crystalline product had a MP of 299.5 to 300°C with decomposition. Then, as described in US Patent 3,158,648, the optical isomers may be resolved as follows. 37 g of racemic α-methyl-3,4-dihydroxyphenylalanine are slurried at 35°C in 100 cc of 1.0 N hydrochloric acid. The excess solids are filtered leaving a saturated solution containing 34.6 g of racemic amino acid of which about 61% is present as the hydrochloride. The solution is then seeded at 35°C with 7 g of hydrated L-α-methyl-3,4-dihydroxyphenylalanine (6.2 g of anhydrous material). The mixture is then cooled to 20°C in 30 minutes and aged one hour at 20°C. The separated material is isolated by filtration, washed twice with 10 cc of cold water and dried in vacuo. The yield of product is 14.1 g of L-α-methyl-3,4-dihydroxyphenylalanine in the form of a sesquihydrate of 100% purity as determined by the rotation of the copper complex. References Merck Index 5928 Kleeman and Engel p. 583 PDR pp. 993, 1133 OCDS Vol. 1 p. 95 (1977) DOT 10 (9) 323 (1974) and 19 (3) 170 (1983) I.N. p. 618 REM p.846 Pfister, K., Ill and Stein, G.A.; US Patent 2,868,818; January 13, 1959; assigned to Merck and Co., Inc. Jones, R.T., Krieger, K.H. and Lago, J.; US Patent 3,158,648; November 24,1964; assigned to Merck and Co., Inc.

METHYLERGONOVINE MALEATE Therapeutic Function: Oxytocic Chemical Name: 9,10-Didehydro-N-[1-(hydroxymethyl)propyl]-6methylergoline-8-carboxamide maleate

Methylergonovine maleate

2253

Common Name: d-Lysergic acid dl-hydroxybutylamide-2; Methylergometrin maleate Structural Formula:

Chemical Abstracts Registry No.: 7054-07-1; 113-42-8 (Base) Trade Name Methergine Methergin Ergotrate Levospan Metenarin Methylergobrevin Metiler Myomergin Ryegonovin Spametrin M Takimetrin M Uterin

Manufacturer Sandoz Sandoz Lilly Isei Teikoku Zoki Arzneimittelwerk Dresden Adika Leiras Morishita Sanzen Nakataki Biofarma

Country US France US Japan Japan E. Germany

Year Introduced 1948 1953 -

Turkey Finland Japan Japan Japan Turkey

-

Raw Materials d-lsolysergic acid azide d-2-Aminobutanol-1 Manufacturing Process To a freshly prepared solution of 2 parts of d-isolysergic acid azide in 300 parts of either is added an ethereal solution of 2 parts of d-2-aminobutanol-1 and the mixture is left to stand at room temperature during 12 hours. The yellowish clear solution is then washed several times with some water, dried over sodium sulfate and the ether evaporated in vacuo. The crystallized residue is treated with a small quantity of acetone and filtered. Yield: 2.2

2254

Methylhexaneamine carbonate

parts of d-isolysergic acid-d-1-hydroxybutylamide-2. On recrystallization from some hot methanol the new compound is obtained in form of beautiful polygonal crystals that melt with some decomposition at 192° to 194°C (corr.). 1 part of the iso-compound is then dissolved in 10 parts of absolute ethanol and an alcoholic potassium hydroxide solution is added thereto. The mixture is left to stand at room temperature during 45 minutes. After this time equilibrium is reached between lysergic acid and the isolysergic acid forms, which can be checked by determination of the constancy of the optical rotation of the solution. When this point is reached, potassium hydroxide is transformed into potassium carbonate by bubbling through the solution a stream of carbon dioxide; the thick crystal paste of potassium carbonate is then diluted with 50 parts of ether, filtered and washed again with 50 parts of ether. The alcoholic ethereal filtrate is then dried over calcined potassium carbonate and the solution evaporated, whereby 0.9 to 1 part of a mixture of d-lysergic acid-d-1-hydroxybutylamide-2 and of d-isolysergic acid-d-1hydroxybutylamide-2 is obtained. In order to separate the isomers, the residue is dissolved in 15 parts of hot chloroform and filtered from the small quantity of inorganic salt, whereby on cooling down, the difficultly soluble chloroform compound of d-lysergic acid-d-1-hydroxybutylamide-2 crystallizes out. Yield: 0.4 part. This compound can be recrystallized from hot benzene, whereby crystals melting with some decomposition at 172°C (corr.) are obtained. It may then be reacted with maleic acid to give the maleate. References Merck Index 5943 Kleeman and Engel p. 584 PDR p. 1587 I.N. p. 619 REM p. 948 Stoll, A. and Hofmann, A.; US Patent 2,265,207; December 9,1941; assigned to Sandoz AG, Switzerland

METHYLHEXANEAMINE CARBONATE Therapeutic Function: Nasal decongestant Chemical Name: 4-Methyl-2-hexylamine carbonate Common Name: Chemical Abstracts Registry No.: 105-41-9 (Base) Trade Name

Manufacturer

Country

Year Introduced

Forthane

Lilly

US

1948

Methylhexaneamine carbonate

2255

Structural Formula:

Raw Materials 4-Methylhexanone-2 Hydroxylamine

Hydrogen Carbon dioxide

Manufacturing Process One molecular equivalent of 4-methylhexanone-2 is reacted with slightly more than one molecular equivalent of hydroxylamine. Desirably, the hydroxylamine is prepared in the presence of the 4-methylhexanone-2 by reacting the hydrochloride or sulfate or other salt of the hydroxylamine with a suitable base, such as sodium carbonate or sodium hydroxide. Desirably, the reaction mixture is agitated for a few hours to insure the conversion of the 4methylhexanone-2 to 4-methylhexanone-2 oxime. The resulting 4-methylhexanone-2 oxime separates and is dried by any suitable means, such as with a dehydrating agent, for example, sodium sulfate or magnesium sulfate. After drying, 4-methylhexanone-2 oxime is reduced with hydrogen by means of a catalyst, such as Raney nickel, or by reaction of sodium and a primary alcohol, such as ethanol. The resulting 2amino-4-methylhexane may be purified by distillation, as described in US Patent 2,350,318. 115 g (1 mol) of 2-amino-4-methylhexane and 9 g (0.5 mol) of water are placed in a tared 500 cc 3-necked flask which is equipped with a mechanical stirrer, a thermometer, and a gas delivery tube. The flask is surrounded by a cooling bath of ice and water. Dry carbon dioxide gas is introduced into the solution through the gas delivery tube, with constant stirring, until the increase in weight is approximately 22 g (0.5 mol). The temperature during this addition is maintained between 20° and 30°C. A viscous liquid results, and consists essentially of 2-amino-4-methylhexane carbonate. This also dissociates very slowly at room temperature to the free amine, carbon dioxide, and water; and is effective as an inhalant, according to US Patent 2,386,273. References Merck Index 5955 I.N. p. 620 Shonle, H.A. and Rohrmann, E.; US Patent 2,350,318; May 30,1944; assigned to Eli Lilly and Company Shonle, H.A. and Rohrmann, E.; US Patent 2,386,273; October 9,1945; assigned to Eli Lilly and Company

2256

Methylmethioninsulfonium chloride

METHYLMETHIONINSULFONIUM CHLORIDE Therapeutic Function: Hepatoprotectant Chemical Name: (3-Amino-3-carboxypropyl)dimethylsulphonium chloride Common Name: Methiosulfonii chloridum; Methylmethioninesulfonium chloride; U-Vitamin; Vitamin U Structural Formula:

Chemical Abstracts Registry No.: 1115-84-0 Trade Name Cabagin-U Vitamin U

Manufacturer Kowa Medexport

Country -

Year Introduced -

Raw Materials dl-Methionine Methyl chloride Manufacturing Process 298 g dl-methionine, 2000 ml water and 151.1 methyl chloride were put into autoclave (volume 3 L) made from V4-a steel. The mixture was heated at temperature 50°-55°C for 8 hours and pressure 12-13 atmospheres. On cooling an excess of methyl chloride was evaporated, the slightly yellow residue was mixed with 0.2% activated coal and filtered. Water was evaporated in vacuum at 45°-55°C. 2 L methanol was poured into an almost colorless syrup obtained, cooled to -5°-(-10°)C. The methylmethioninesulfonium chloride crystallized. It was filtered off to give 340 g (85.3%) of desired product 99.5 % purity (data of thin-layer chromatography). References Wagner H.; D.B. Patent No. 1,239,697; Feb. 20, 1963; Deutsche Gold- und Silber- Scheideanstalt vormals Roessler, Frankfurt/M.

Methylol riboflavin

2257

METHYLOL RIBOFLAVIN Therapeutic Function: Enzyme cofactor vitamin source Chemical Name: Riboflavin monomethylol Common Name: Structural Formula:

Chemical Abstracts Registry No.: 83-88-5 (Base) Trade Name

Manufacturer

Country

Year Introduced

Hyflavin

Endo

US

1948

Raw Materials Riboflavin Formaldehyde Manufacturing Process 100 g of riboflavin and 3 of potassium carbonate are suspended in 500 cc of the aqueous formaldehyde solution and the mixture is stirred at 30°C for 8 hours. At the end of this period, 5 cc of glacial acetic acid and 1 liter of methanol are added, with stirring. The solution is freed from undissolved material by filtration and the clear solution is poured slowly at about 20°C to 22°C with vigorous stirring into 8 liters of anhydrous acetone. The resultant precipitate is filtered off, washed repeatedly with anhydrous acetone and with ether, and then dried at room temperature and with vacuum. The resultant dried powder is dissolved in hot water at 95°C to give an aqueous solution of 20% by weight. This solution is kept in the dark at room temperature for 3 to 4 weeks, after which time a large amount of material crystallizes out of the solution. This crystallized material is removed by filtration and recrystallized from hot water. A small amount of dark red insoluble material is filtered from the hot solution. This recrystallization step is repeated four times. The

2258

Methylpentynol

resultant end product is monomethylol riboflavin, which crystallized in small orange clusters. It has a melting point of 232°C to 234°C with decomposition, and it becomes dark when heated above 225°C. References Merck Index 5974 I.N. p. 621 Schoen, K. and Gordon, S.M.; US Patent 2,587,533; February 26,1952; assigned to Endo Products, Inc.

METHYLPENTYNOL Therapeutic Function: Sedative Chemical Name: 1-Pentyn-3-ol, 3-methylCommon Name: Meparfynol; Methylparafynol; Methylpentynol Structural Formula:

Chemical Abstracts Registry No.: 77-75-8 Trade Name Citodorm Dormiphen

Manufacturer Haury Darck

Country -

Year Introduced -

Raw Materials Sodium acetylene Methyl ethyl ketone Manufacturing Process To 5 parts of sodium acetylene in absolute ether 6 parts of dry methyl ethyl ketone was slowly dropwise added with ice cooling and stirring. Than the reaction mixture was poured into excess of acetic acid by ice cooling and extracted with ether. The ether extract was washed with solution of potash for removing the diluted acetic acid and dried over potassium carbonate. The ether was distilled off and residual colorless oil methylpentynol had BP at 120°-121°C. Instead of sodium acetylene the solution of sodium acetylene in liquid ammonia may be successfully used.

Methylphenidate hydrochloride

2259

References Farbenfabriken vorm. Friedr. Bayer and CO. in Leverkusen b. Coln a. Rh.; D.R. Patent No. 285,770; Nov. 22, 1913

METHYLPHENIDATE HYDROCHLORIDE Therapeutic Function: Psychostimulant Chemical Name: α-Phenyl-2-piperidineacetic acid methyl ester hydrochloride Common Name: Structural Formula:

Chemical Abstracts Registry No.: 298-59-9; 113-45-1 (Base) Trade Name Ritalin Rubifen

Manufacturer Ciba Rubio

Country US Spain

Year Introduced 1958 -

Raw Materials Phenylacetonitrile Methanol Sodium amide Hydrogen chloride

2-Chloropyridine Hydrogen Sulfuric acid

Manufacturing Process As described in US Patent 2,507,631, 80 g of pulverized sodium amide are gradually added, while stirring and cooling, to a solution of 117 g of phenylacetonitrile and 113 g of 2-chloropyridine in 400 cc of absolute toluene. The mixture is then slowly heated to 110° to 120°C and maintained at this temperature for 1 hour. Water is added thereto after cooling, the toluene solution is shaken with dilute hydrochloric acid and the hydrochloric acid extracts are made alkaline with concentrated caustic soda solution. A solid mass is separated thereby which is taken up in acetic ester and distilled, αphenyl-α-pyridyl-(2)-acetonitrile passing over at 150° to 155°C under 0.5 mm

2260

Methylphenobarbital

pressure. When recrystallized from ethyl acetate it melts at 88° to 89°C, the yield amounting to 135 g. 100 g of α-phenyl-α-pyridyl-(2)-acetonitrile are introduced into 400 cc of concentrated sulfuric acid, allowed to stand overnight at room temperature, poured into ice and rendered alkaline with sodium carbonate. α-Phenyl-αpyridyl-(2)-acetamide is precipitated thereby which melts at 134°C after recrystallization from ethyl acetate. 100g of the resulting α-phenyl-α-pyridyl-(2)-acetamide, when dissolved in one liter of methyl alcohol and treated for 6 hours at water-bath temperature with hydrogen chloride, and after concentrating, diluting with water and rendering alkaline with sodium carbonate, yield 90 g of the α-phenyl-α-pyridyl-(2)-acetic acid methylester of MP 74° to 75°C (from alcohol of 50% strength). The α-phenyl-α-piperidyl-(2)-acetic acid methylester of BP 135° to 137°C under 0.6 mm pressure is obtained in theoretical yield by hydrogenation of 50 g of α-phenyl-α-pyridyl(2)-acetic acid methylester in glacial acetic acid in the presence of 1 g of platinum catalyst at room temperature, while taking up 6 hydrogen atoms. Reaction with HCl gives the hydrochloride. Resolution of stereoisomers is described in US Patent 2,957,880. References Merck Index 5981 Kleeman and Engel p. 586 PDR p. 811 OCDS Vol. 1 p. 88 (1977) I.N. p. 622 REM p. 1136 Hartmann, M. and Panizzon, L.; US Patent 2,507,631;May 16,1950; assigned to Ciba Pharmaceutical Products Inc. Rornetsch, R.; US Patent 2,957,880; October 25,1960; assigned to Ciba Pharmaceutical Products Inc.

METHYLPHENOBARBITAL Therapeutic Function: Anticonvulsant Chemical Name: Barbituric acid, 5-ethyl-1-methyl-5-phenylCommon Name: Acidum methyl-phenyl-aethyl-barbiuricum; Enfenemal; Enphenemal; Mefoberbital; Mephobarbital; Methylfenobarbital; Methylphenobarbital; Methylphenobarbitone; Metilfenobarbitale Chemical Abstracts Registry No.: 115-38-8 Trade Name

Manufacturer

Country

Year Introduced

Isonal

Roussel

-

-

Methylprednisolone

2261

Structural Formula:

Raw Materials Sodium Phenyl ethyl malonic acid diethyl ester Methylurea Manufacturing Process 46 parts metallic sodium was dissolved in 1000 parts absolute alcohol. The obtained solution was mixed with 264 parts of phenyl ethyl malonic acid diethyl ester and 80 parts of monomethyl urea and heated for 8 hours at reflux. Alcohol was distilled off, the residue was dissolved in water and neutralized with diluted sulfuric acid. N-Methylethylphenylbarbituric acid precipitated as a powder. It was filtered off, washed to neutral and dissolved in 50 parts of boiling alcohol. On cooling the obtained methylphenobarbital precipitated as the colorless prisms. MP: 176.5°C. This compound may be also prepared by condensation of equivalents of phenyl malonic ester and monomethyl urea, which was dissolved in above described solution of sodium ethylate. References Taub L., Kropp W.; D.R. Patent No. 537,366; Oct. 15, 1931; I. G. Farbenindustrie Akt.-Ges. in Frankfurt a. M.

METHYLPREDNISOLONE Therapeutic Function: Glucocorticoid Chemical Name: 11β,17α,21-Trihydroxy-6α-methyl-l,4-pregnadiene-3,20dione Common Name: 1-Dehydro-6α-methylhydrocortisone

2262

Methylprednisolone

Structural Formula:

Chemical Abstracts Registry No.: 83-43-2 Trade Name

Manufacturer

Country

Year Introduced

Medrol

Upjohn

US

1957

Medrol

Upjohn

France

1959

A-Methapred

Abbott

US

1978

Solu-Medrol

Upjohn

Japan

1980

Caberdelta

Caber

Italy

-

Cortalfa

S.A.M.

Italy

-

Depo-Medrate

Upjohn

W. Germany

-

Emmetip

Magis

Italy

-

Esametone

Lisapharma

Italy

-

Eutisone

Eufarma

Italy

-

Firmacort

Firma

Italy

-

Horusona

Horus

Spain

-

Medesone

Fargal

Italy

-

Mega-Star

Ausonia

Italy

-

Metilbetasone

Coli

Italy

-

Metilcort

Gazzini

Italy

-

Metilprednilone

Guidi

Italy

-

Metilstendiolo

Panther-Osfa

Italy

-

Moderin

Alter

Spain

-

Nirypan

Jugoremedija

Yugoslavia

-

Nixolan

S.I.T.

Italy

-

Prednilen

Lenza

Italy

-

Prednol

Mustafa Nevzat

Turkey

-

Radiosone

Radiumpharma

Italy

-

Reactenol

Lafare

Italy

-

Sieropresol

Sierochimica

Italy

-

Summicort

Benvegna

Italy

-

Suprametil

Geistlich

Switz.

-

Urbason

Hoehst

Italy

-

Methylprednisolone

2263

Raw Materials Bacterium Septomyxa affinis Corn steep liquor Glucose 64-α-Methylhydrocortisone Manufacturing Process The following process description is taken from US Patent 2,897,218. Six 100ml portions of a medium in 250-ml Erlenmeyer flasks containing 1% glucose, 2% corn steep liquor (60% solids) and tap water was adjusted to a pH of 4.9. This medium was sterilized for 45 minutes at 15 psi pressure and inoculated with a one to two day growth of Septomyxa affinis ATCC 6737. The Erlenmeyer flasks were shaken at room temperature at about 24°C for a period of 3 days. At the end of this period, this 600-ml volume was used as an inoculum for ten liters of the same glucose-corn steep liquor medium which in addition contained 10 ml of an antifoam (a mixture of lard oil and octadecanol). The fermentor was placed into the water bath, adjusted to 28°C, and the contents stirred (300 rpm) and aerated (0.5 liter air/10 liters beer). After 17 hours of incubation, when a good growth developed and the acidity rose to pH 6.7, 2 g of 6α-methylhydrocortisone plus 1 g of 3-ketobisnor-4-cholen-22-al, dissolved in 115 ml of dimethylformamide, was added and the incubation (conversion) carried out at the same temperature and aeration for 24 hours (final pH 7.9). The mycelium (56 g dry weight) was filtered off and the steroidal material was extracted with methylene chloride, the methylene extracts evaporated to dryness, and the resulting residue chromatographed over a Florisil column. The column was packed with 200 g of Florisil and was developed with five 400-ml fractions each of methylene chloride, Skellysolve B-acetone mixtures of 9:1, 8:2, 7:3, 1:1, and methanol. The fraction eluted with Skellysolve Bacetone (7:3) weighed 1.545 g and on recrystallization from acetone gave, in three crops, 928 mg of product of MP 210° to 235°C. The sample prepared for analysis melted at 245° to 247°C. References Merck Index 5984 Kleeman and Engel p. 587 PDR pp. 1286,1606,1850 OCDS Vol. 1 p. 196 (1977) I.N. p. 623 REM p.968 Sebek, O.K. and Spero, G.B.; US Patent 2,897,218; July 28, 1959; assigned to The Upjohn Company Gould, D.H.; US Patent 3,053,832; September 11, 1962; assigned to Schering Corporation

2264

Methylscopolamine nitrate

METHYLSCOPOLAMINE NITRATE Therapeutic Function: Anticholinergic, Spasmolytic Chemical Name: 1αH,5αH-Tropanium, 6β,7β-epoxy-3α-hydroxy-8-methyl-, nitrate, (-)Common Name: Hyocsine methonitrate; Methylscopolamine nitrate; Scopolamine methylnitrate Structural Formula:

Chemical Abstracts Registry No.: 6106-46-3 Trade Name

Manufacturer

Country

Year Introduced

Transderm Scop

Novartis Consumer Health Inc.

-

-

Raw Materials Scopolamine hydrobromide trihydrate Methyl bromide Silver nitrate Manufacturing Process In a one-liter separatory funnel, 94 g (0.215 mol) of scopolamine hydrobromide trihydrate was dissolved in 250 ml of water, made alkaline by shaking with 40 g (1 mol) of sodium hydroxide in 150 ml of water, and the free base immediately extracted with ether. As scopolamine is somewhat soluble in water, the aqueous layer was saturated with potassium carbonate and again extracted with ether. The combined ether extracts were dried over anhydrous magnesium sulfate and the ether removed by distillation, leaving 65 g (0.214 mol; 100% yield) of nearly colorless oil. Then 100 g (1.05 mol) of

Methyltestosterone

2265

cold methyl bromide was added to a chilled, 500-ml pressure flask containing the 65 g of scopolamine, the flask stoppered tightly with a clamp, and allowed to stand at room temperature for 96 hours. The flask was cooled before opening, excess methyl bromide removed by distilling, and the white solid washed thoroughly with dry ether. The yield of crude Nmethylscopolammonium bromide was 80 g (94 %t yield). The salt was recrystallized from 550 ml of alcohol; first crop, 70 g, MP: 212-214°C; second crop, 6 g, melting point 195-200°C. The combined crops were again recrystallized from 500 ml of alcohol; melting point 210-212°C. The third recrystallization from 600 ml of alcohol yielded 64 g, melting point 214216°C, a 75 % yield based on scopolamine hydro-bromide trihydrate starting material. N-Methylscopolammonium bromide may be dissolved in water. An equivalent of solution AgNO3 was added, a precipitated AgBr was filtered off. The filtrate was evaporated to dryness to give the desired Nmethylscopolammonium nitrate. References Visscher F. E.; US Patent No. 2,753,288; July 3, 1956; Assigned to The Upjohn Company, Kalamazoo, Mich., a corporation of Michigan

METHYLTESTOSTERONE Therapeutic Function: Androgen Chemical Name: 17β-Hydroxy-17-methyl-androst-4-ene-3-one Common Name: Structural Formula:

Chemical Abstracts Registry No.: 58-18-4 Trade Name Metandren Oreton-M Neo-Hombreol Hormale Android-S Arcosterone Climaterine

Manufacturer Ciba Schering Organon Key Brown Arcum Lucien

Country US US US US US US France

Year Introduced 1941 1941 1941 1958 -

2266

Methyltestosterone

Trade Name Climatone Dumone Estan Gynosterone Hormobin Malogen Orchisterone Seksfort Steronyl Synandrets Testipron Testomet Testora Testostelets Testonic B Testovis Testred Virilon

Manufacturer Paines and Byrne Squibb Schering Sam-On Munir Sahin Fellows-Testagar Negroni Uranium Kay Pfizer Kwizda Protea Alcon Barlow Cote Sam-On Vister I.C.N. Star

Country UK US US Israel Turkey US Italy Turkey US US Austria Australia US Canada Israel Italy US US

Year Introduced -

Raw Materials 17-Methyl-∆(5,6)-androstenediol-(3,17) Magnesium Acetone Methyl chloride Manufacturing Process 0.6 g of 17-Methyl-∆5,6-androstenediol-(3,17) is heated under reflux cooling during 20 hours in 50 cm3 of benzene and 12 cm3 of acetone with 3 g of tertiary chloromagnesium butylate, which may be prepared by conversion of acetone with methyl magnesium chloride. The magnesium is then removed by shaking out with dilute H2SO4; the benzene layer is washed with water, dried with sodium sulfate and then evaporated to dryness. Methyltestosterone (MP 160° to 162°C) is obtained in a yield of more than 75% of the theory, according to US Patent 2,384,335. References Merck Index 6000 Kleeman and Engel p. 588 PDR pp.645, 729, 802, 949, 1447, 1643, 1778 OCDS Vol. 1 p. 172 (1977) I.N. p.625 REM p. 998 Miescher, K. and Wettstein, A.; US Patent 2,374,369; April 24, 1945; assigned to Ciba Pharmaceutical Products, Incorporated Miescher, K. and Wettstein, A.; US Patent 2,374,370; April 24, 1945; assigned to Ciba Pharmaceutical Products, Incorporated

Methyprylon

2267

Oppenauer, R.; US Patent 2,384,335; September 4, 1946 Miescher, K.; US Patent 2,386,331; October 9, 1945; assigned to Ciba Pharmaceutical Products, Incorporated Miescher, K.; US Patent 2,435,013; January 27,1948; assigned to Ciba Pharmaceutical Products, Incorporated

METHYPRYLON Therapeutic Function: Sedative, Hypnotic Chemical Name: 3,3-Diethyl-5-methyl-2,4-piperidinedione Common Name: 2,4-Dioxo-3,3-diethyl-5-methylpiperidine Structural Formula:

Chemical Abstracts Registry No.: 125-64-4 Trade Name Noludar Noctan Nolurate

Manufacturer Roche Yamanouchi Roche

Country US Japan -

Year Introduced 1955 -

Raw Materials 2,4-Dioxo-3,3-diethyl-piperidine Hydrogen Sodium Methyl formate Manufacturing Process 24 parts by weight of powdered sodium are suspended in 100 parts by volume of absolute benzene and to this suspension is added a freshly prepared solution of 150 parts by weight of methyl formate and 165 parts by weight of 2,4-dioxo-3,3-diethyl-piperidine in 900 parts by volume of absolute benzene. By cooling with cold water, the temperature is maintained at 25° to 28°C. After being stirred for 12 hours 200 parts by volume of 0.6 N sodium hydroxide are added while cooling. The aqueous layer is separated and acidified to Congo red by means of 35% hydrochloric acid. The 2,4-dioxo-3,3diethyl-5-oxymethylenepiperidine is precipitated in good yield as a solid. After having been recrystallized in chloroform/petroleum ether it melts at 140° to

2268

Methysergide maleate

141°C. 5 parts by weight of 2,4-dioxo-3,3-diethyl-5-oxymethylene-piperidine are hydrogenated in 25 parts by volume of methanol in the presence of about 2 parts by weight of Raney nickel at 120°C and under an elevated pressure of 100 atm. Once 2 mols of hydrogen are absorbed, the hydrogenation is interrupted, the solution is separated from the catalyst and concentrated and the residue is distilled in vacuo. The distillate, boiling between 178° and 185°C under a pressure of 16 mm, consists of 2,4-dioxo-3,3-diethyl-5-methylpiperidine, which melts at 74° to 75°C. The same compound is obtained when proceeding according to the following alternative procedure. A mixture of 39.4 parts by weight of 2,4-dioxo-3,3diethyl-5-oxymethylenepiperidine and 27 parts by weight of dibutylamine are heated to 150°C in a closed vessel. The 2,4-dioxo-3,3-diethyl-5-dibutylaminomethylene-piperidine formed melts at 77°C after having been recrystallized in petroleum ether. 31 parts by weight of the latter compound are hydrogenated in 150 parts by volume of alcohol, containing 6 parts by weight of acetic acid, in the presence of 10 parts by weight of Raney nickel, at 120°C and under an elevated pressure of 100 atm. The catalyst is separated and the solution is distilled in vacuo. The 2,4-dioxo-3,3-diethyl-5-methyl-piperidine boils between 178° and 185°C under a pressure of 16 mm and melts at 74° to 75°C. References Merck Index 6010 Kleeman and Engel p. 590 PDR p. 1495 DOT 9 (6) 245 (1973) I.N. p. 626 REM p. 1072 Frick, H.and Lutz, A.H.; US Patent 2,680,116; June 1, 1954; assigned to Hoffmann-LaRoche Inc.

METHYSERGIDE MALEATE Therapeutic Function: Migraine therapy Chemical Name: 9,10-Didehydro-N-[1-(hydroxymethyl)propyl]-1,6dimethylergoline-8-carboxamide maleate Common Name: 1-Methyl-d-lysergic acid butanolamide maleate Chemical Abstracts Registry No.: 129-49-7; 361-37-5 (Base)

Methysergide maleate

2269

Structural Formula:

Trade Name Sansert Desernil Deseril

Manufacturer Sandoz Sandoz Sandoz

Country US France UK

Year Introduced 1962 1962 1963

Raw Materials Potassium Ammonia Methyl iodide Maleic acid Lysergic acid-1'hydroxy-butylamide-2' Manufacturing Process As described in US Patent 3,218,324, 0.9 part of potassium are dissolved in 500 parts by volume of liquid ammonia, then oxidized with ferric nitrate to potassium amide, after which 4.85 parts of lysergic acid-1'-hydroxybutylamide-2' are dissolved in the obtained mixture. After 15 minutes there are added to the obtained yellow solution 4.1 parts of methyl iodide in 5 parts by volume of ether, the mixture being allowed to stand for 30 more minutes at -60°C. The liquid ammonia is thereupon evaporated and the dry residue is shaken out between water and chloroform. The mixture of bases which remains after the evaporation of the chloroform is chromatographed on a column of 250 parts of aluminum oxide, the desired 1-methyl-lysergic acid-1'hydroxy-butylamide-2' being washed into the filtrate with chloroform and chloroform-0.2% ethanol. The 1-methyl-lysergic acid-1'hydroxy-butylamide-2' crystallizes from chloroform in the form of plates which melt at 194° to 196°C. Reaction with maleic acid gives the dimaleate, melting at 187° to 188°C. References Merck Index 6011 Kleeman and Engel p. 590

2270

Metiazinic acid

PDR p. 1596 OCDS Vol. 2 p. 477 (1980) I.N. p. 626 REM pp. 949, 1113 Hofmann, A. and Troxler, F.; US Patent 3,113,133; December 3,1963; assigned to Sandoz Ltd., Switzerland Hofmann, A. and Troxler, F.; US Patent 3,218,324; November 16,1965; assigned to Sandoz Ltd., Switzerland

METIAZINIC ACID Therapeutic Function: Antiinflammatory Chemical Name: 10-Methylphenothiazine-2-acetic acid Common Name: Structural Formula:

Chemical Abstracts Registry No.: 13993-65-2 Trade Name Soripan Soripal Soripal Ambrunate Metian Novartril Roimal Soridermal

Manufacturer Specia Torii Farmalabor Rhodia Horus Andromaco Nippon Rhodia Specia

Country France Japan Italy Argentina Spain Spain Japan France

Year Introduced 1970 1977 1978 -

Raw Materials 10-Methyl-3-acetylphenthiazine Morpholine Sulfur Potassium hydroxide Manufacturing Process 10-Methyl-3-acetylphenthiazine is prepared in accordance with G. Cauquil and A. Casadevall, Bull. Soc.Chim., p 768 (1955). (10-Methyl-3-

Meticrane

2271

phenthiazinyl)acetic acid (MP 146°C; 21.4 g) is prepared by Willgerodt's reaction (action of sulfur and morpholine, followed by hydrolysis) employing 10-methyl-3-acetylphenthiazine as starting material. References Merck Index 6013 Kleeman and Engel p. 591 I.N. p. 32 Farge, D., Jeanmart, C. and Messer, M.N.; US Patent 3,424,748; January 28, 1969; assigned to Rhone-Poulenc S.A., France

METICRANE Therapeutic Function: Diuretic Chemical Name: 2H-1-Benzothiopyran-7-sulfonamide, 3,4-dihydro-6methyl-, 1,1-dioxide Common Name: Meticrane Structural Formula:

Chemical Abstracts Registry No.: 1084-65-7 Trade Name

Manufacturer

Country

Year Introduced

Fontilix

Diamant

-

-

Raw Materials 6-Methylthiachromane Hydrogen peroxide Chlorosulfonic acid Ammonia Manufacturing Process 64.5 g of 6-methylthiachromane were dissolved in 500 ml of acetic acid and 250 ml of 110-volume hydrogen peroxide were added. The solution was placed on a water bath for 1.5 hour; it was then diluted with iced water, the precipitate obtained was recovered, and this was washed and dried. There were obtained 59.6 g of 6-methylthiachromane-1,1-dioxide (yield: 77.5%; melting point 79°-81°C).

2272

Metoclopramide hydrochloride

52 g of this product were added to 250 ml of chlorosulfonic acid and the mixture was placed on a water bath at a temperature of 70°-75°C for 2 hours. It was allowed to cool and poured onto crushed ice; the product was extracted by means of chloroform, the extracted solutions were washed and the chloroform was evaporated. There were obtained 67 g of crude 6-methyl7-chloro-sulfonyl-thiachromane-1,1-dioxide (yield: 86%; melting point 158°161°C). 47 g of this sulfochloride were introduced into 200 ml of liquid ammonia. The mixture was left to stand at ambient temperature until the ammonia evaporated. The residue was taken up in water and the solution was acidified. The precipitate formed was centrifuged, washed with water and dried. There were obtained 30.8 g of 6-methyl-7-sulfamido-thiachromane-1,1-dioxide, recrystallized from 2-methoxy ethanol (yield: 49%; MP: 236°-237°C). References Boissier J.R. et al.; US Patent No. 3,488,424; Jan. 6, 1970; Assigned to Societe Industrielle pour la Fabrication des Antibiotiques (S.I.F.A.), Paris, France, a French company

METOCLOPRAMIDE HYDROCHLORIDE Therapeutic Function: Antiemetic Chemical Name: 4-Amino-5-chloro-N-[(2-diethylamino)ethyl]-2methoxybenzamide hydrochloride Common Name: Structural Formula:

Chemical Abstracts Registry No.: 7232-21-5; 364-62-5 (Base) Trade Name Primperan Paspertin Maxolon Plasil Reglan

Manufacturer Delagrange Kali-Chemie Beecham Richter Robins

Country France W. Germany UK Italy US

Year Introduced 1964 1965 1967 1967 1979

Metoclopramide hydrochloride

2273

Trade Name

Manufacturer

Country

Year Introduced

Metox

Steinhard

UK

1983

Ananda

Bonomelli-Hommel

Italy

-

Cerucal

Arzneimittelwerk Dresden

E. Germany

-

Clodil-Ion

Ion

Italy

-

Clopamon

Petersen

S. Africa

-

Clopan

Firma

Italy

-

Contromet

Script Intal

S. Africa

-

Digetres

Scalari

Italy

-

Donopon-GP

Sana

Japan

-

Elietin

Nippon Kayaku, Co.

Japan

-

Emesa

Mulda

Turkey

-

Emetisan

Phoenix

Argentina

-

Emperal

Neofarma

Finland

-

Gastronertron

Dolorgiet

W. Germany

-

Imperan

Bender

Austria

-

Kilozim

A.G.I.P.S.

Italy

-

Maxrean

Nordic

Canada

-

MCP-Ratiopharm

Ratiopharm

W. Germany

-

Meclopran

Lagap

Switz.

-

Metamide

Protea

Australia

-

Metoclol

Toyama

Japan

-

Metocobil

Beta

Italy

-

Metopram

Leiras

Finland

-

Metpamid

Sifar

Turkey

-

Moriperan

Morishita

Japan

-

Nadir

Oti

Italy

-

Netaf

Sintyal

Japan

-

Peraprin

Taiyo

Japan

-

Placitril

Sigurta

Italy

-

Pramiel

Nagase

Japan

-

Pramin

Rafa

Israel

-

Primperil

Lacefa

Argentina

-

Prindarl

Sawai

Japan

-

Prometin

Yamanouchi

Japan

-

Putoprin

Mohan

Japan

-

Quanto

Mediolanum

Italy

-

Randum

Scharper

Italy

-

Regastrol

Sarm

Italy

-

Reliveran

Finadiet

Argentina

-

Rimetin

Farmakhim

Bulgaria

-

Terperan

Teikoku Zoki

Japan

-

Viscal

Zoja

Italy

-

2274

Metoclopramide hydrochloride

Raw Materials o-Toluidine Nitrous acid Acetic anhydride Nitric acid Thionyl chloride Chlorine

Potassium permanganate N,N-Diethylene diamine Hydrogen chloride Dimethyl sulfate Hydrogen

Manufacturing Process The N-(diethylaminoethyl)-2-methoxy-4-aminobenzamide used as the starting material may be prepared from o-toluidine. The o-toluidine is initially nitrated with nitric acid to produce 4-nitro-o-toluidine. The 4-nitro-o-toluidine is then converted to 2-hydroxy-4-nitrotoluene by heating with nitrous acid. By reacting the resulting 2-hydroxy-4-nitrotoluene with dimethyl sulfate, 2methoxy-4-nitrotoluene is formed. The 2-methoxy-4-nitrotoluene is oxidized with potassium permanganate to produce 2-methoxy-4-nitrobenzoic acid. The latter substituted benzoic acid is treated with thionyl chloride to form 2methoxy-4-nitrobenzoyl chloride. A methyl ethyl ketone solution of the 2methoxy-4-nitrobenzoyl chloride is added over a period of about 1½ hours to a methyl ethyl ketone solution containing an equal molecular quantity of N,Ndiethylethylene diamine while stirring and maintaining the temperature between 0°C and 5°C. The N-(diethylaminoethyl)-2-methoxy-4nitrobenzamide hydrochloride formed precipitates. It is filtered, washed twice with methyl ethyl ketone, dissolved in alcohol, and reduced catalytically in an absolute isopropyl alcohol solution to form N-(diethylaminoethyl)-2-methoxy4-aminobenzamide. The base is obtained by precipitating with sodium hydroxide. 80 g (0.3mol) of N-(2-diethylaminoethyl)-2-methoxy-4-aminobenzamide are dissolved in small portions in 150 cc of acetic acid. The mixture is cooled and 45 g (0.45 mol) of acetic anhydride are added, and the solution obtained is heated for two hours on a water bath. After cooling, the solution is decanted into a round-bottomed flask with a stirrer, a thermometer and a tube for introducing the chlorine. It is stirred and the current of chlorine is passed through, the temperature being maintained between 20°C and 25°C. The stirring is continued for one hour after the completion of the absorption of the chlorine. The mixture obtained is poured into 2 liters of water and the base is precipitated with 30% soda. The precipitated base is extracted with 400 cc of methylene chloride. After evaporation of the solvent, the N-(2diethylaminoethyl)-2-methoxy-4-acetamino-5-chlorobenzamide formed crystallizes. The melting point is 86°C to 87°C and the yield is 95%. To obtain the corresponding amino derivative, 109 g of base are heated under agitation in a round-bottomed flask with 300 cc of 35-36% concentrated hydrochloric acid and 600 cc of water. It is heated on a water bath until dissolution is complete, then maintained at boiling point for 90 minutes, cooled, diluted with 1 liter of water, and neutralized with about 350 cc of 30% soda. The N-(2-diethylaminoethyl)-2-methoxy-4-amino-5-chlorobenzamide formed crystallizes, is centrifuged and washed in water. Its melting point is 122°C and the yield is 74%.

Metolazone

2275

To obtain the corresponding dihydrochloride, the base is dissolved in absolute alcohol (3 volumes) and to that solution is added 5 N alcoholic hydrochloric acid. The dihydrochloride precipitates, is centrifuged and washed with alcohol. It is a solid white material, having a melting point of 134°C to 135°C. References Merck Index 6019 Kleeman and Engel p. 593 PDR p. 1463 DOT 1 (2) 66 (1965); 16 (5) 159 (1980) and 19 (8) 476 (1983) I.N. p. 629 REM p. 809 Thominet, M.L.; US Patent 3,177,252; April 6,1965; assigned to Soc. d'Etudes Scientifiques et lndustrielles de l'Ile de France (France)

METOLAZONE Therapeutic Function: Diuretic Chemical Name: 7-Chloro-l,2,3,4-tetrahydro-2-methyl-3-(2-methylphenyl)-4oxo-6-quinolinesulfonamide Common Name: Structural Formula:

Chemical Abstracts Registry No.: 17560-51-9 Trade Name

Manufacturer

Country

Year Introduced

Zaroxolyn

Pennwalt

UK

1973

Zaroxolyn

Pennwalt

US

1974

Diulo

Searle

US

1978

Zaroxolyn

Searle

W. Germany

1978

Zaroxolyn

Sandoz

Switz.

1978

Zaroxolyn

I.S.F.

Italy

1981

Normeran

Sankyo

Japan

1982

Metenix

Hoechst

UK

-

Oldren

Roemmers

Argentina

-

2276

Metolazone

Raw Materials 5-Chloro-2-methylaniline o-Toluidine Acetic anhydride Phosphorus trichloride

Chlorosulfonic acid Sodium borohydride Ammonia

Manufacturing Process Preparation of Intermediate Compound N-Acetyl-5-Chloro-2-Methylaniline: To a well-stirred mixture of 1,270 g (9 mols) of 5-chloro-2-methylaniline in 7.5 liters of water at 34°C was added all at once 1,710 ml (18 mols) of acetic anhydride. A solution was obtained and then almost immediately the product started to crystallize. The temperature rose to 60°C. The mixture was stirred until the temperature dropped to 30°C. The product was filtered and washed well with water. Yield 97% (1,640 g), MP 134° to 138°C. Product was air dried and then in vacuum over P2O5. Preparation of Intermediate Compound 5-Chloro-2-Methyl-4Sulfamylacetanilide: Into a 3-necked 3-liter flask fitted with stirrer and thermometer 540 ml of chlorosulfonic acid were placed and cooled in an ice bath to 20°C. 300 g of the acetanilide were added portionwise while stirring and maintaining temperature at 20°C. This addition takes approximately 20 minutes. Remove the ice bath and add 88 g of sodium chloride portionwise (approximately 1 tsp every 10 minutes), This addition takes approximately 1 hour. Some foaming takes place. Using heating mantle bring temperature up slowly (approximately ½ hour) to 75°C. Considerable foaming takes place and heating is continued another ½ hour until 92°C is reached. Foaming can be controlled by shutting off heat and with good stirring. Once the temperature of 92°C has been reached and foaming has subsided reaction can be left unattended. Keep reaction at 92°C for a total of 2½ hours. Pour the hot reaction mixture onto 4 liters of crushed ice. Pour slowly and stir the ice mixture. What remains in the flask can be worked up by adding ice to it and swirling the contents. After approximately 3/4 of an hour, the solid is filtered and washed with approximately 600 ml water. Break up cake into small pieces and add to 2.5 liters concentrated NH4OH in 4 liter beaker. Stir. Solid goes into solution and then the sulfonamide precipitates out. Heat to 50°C and then turn off heat. After ½ hour cool in ice bath and filter. Wash cake with 600 ml water. Add cake to 2 liters 5% NaOH (130 ml 50% NaOH to 2 liters water). Filter and discard insolubles. While cooling filtrate add concentrated HCl until mixture is acid. Filter and wash cake until filtrate is neutral. Suck cake as dry as possible then air dry. Yield approximately 200 g (45%), MP 255° to 260°C. Preparation of Intermediate Compound 4-Chloro-5-Sulfamyl-NAcetylanthranilic Acid: To a hot solution (80°C) of 366 g (1.482 mols) of magnesium sulfate (Epsom salts) in 2.8 liters of water was added 130 g (0.495 mol) of powdered 5-chloro-2-methyl-4-sulfamylacetanilide. With stirring and maintaining the temperature at 83°C, 234 g (1.482 mols) of potassium permanganate was added portionwise over a period of 2 hours. The mixture was then kept at 85°C with stirring for an additional 3 hours. By this

Metolazone

2277

time the pink color of the permanganate had been discharged. The mixture was cooled to 65°C and 250 g (2.0 mols) of sodium carbonate monohydrate was added. The warm reaction mixture was filtered and the cake washed with water. The filtrate was then slowly treated with concentrated hydrochloric acid until mixture tested acid. Product was then filtered, washed with water and dried. Yield 103 g (71.0%), MP 245° to 249°C (dec.). Preparation of Intermediate Compound 2-Methyl-3-o-Tolyl-6-Sulfamyl-7Chloro-4(3H)-Quinazolinone: Set up a 5-liter 3-necked flask fitted with a stirrer, condenser and a drying tube. To a stirred mixture of 100 g (0.342 mol) of powdered 4-chloro-5-sulfamyl-N-acetylanthranilic acid, 40.2 g (0.376 mol) of o-toluidine and 2.0 liters of dry toluene was added dropwise, over a period of 15 minutes, 21.7 ml (34.1 g) (0.248 mol) of phosphorus trichloride. The mixture was then refluxed for 10 hours. The solid turned somewhat gummy towards the latter part of the first hour. The mixture then became more free flowing as heating was continued. Let stand overnight. The yellow solid was filtered, washed with toluene and dried. The toluene filtrate was discarded. The dried solid was triturated with 1.5 liters of 10% sodium bicarbonate, filtered and the cake washed with water. The filtrate on acidification yielded 11.5 g of the starting acid. The damp product was dissolved in 4.5 liters of 95% ethanol and the solution treated with charcoal and filtered. On cooling filtrate yielded 69.5 g (55.5%) of the title compound, MP 271.5° to 274°C. Preparation of the Final Compound 2-Methyl-3-o-Tolyl-6-Sulfamyl-7-Chloro1,2,3,4-Tetrahydro-4(3H)-Quinazolinone: To 4 liters of dry diglyme in a 12liter 3-necked flask fitted with a stirrer, thermometer and drying tube was added 5.34 g (0.04 mol) of aluminum chloride, while stirring. To the resulting solution was added 43.6 g (0.12 mol) of 2-methyl-3-o-tolyl-6-sulfamyl-7chloro-4(3H)-quinazoline. A solution of 4.56 g (0.12 mol) of sodium borohydride in 1 liter of dry diglyme was added portionwise over a period of 1 hour while stirring the mixture. The mixture was then heated at 85°C, with stirring, for 1 hour. After cooling the reaction mixture to 25°C in an ice bath 600 ml of water was added and then enough dilute hydrochloric acid (approximately 100 ml) to make the solution acid. The solvent was then removed under reduced pressure at 60° to 70°C. The very viscid residue solidified when triturated with water. The solid was filtered and washed with water. The solid was dissolved in approximately 400 ml 95% ethanol and the solution filtered through Celite. On cooling the solution yielded 30 g of colorless solid, MP 253° to 259°C. The filtrate was concentrated to 200 ml to yield another 4.6 g, MP 253° to 259°C. The above product was then recrystallized from 900 ml of 95% ethanol after filtering the hot solution through Celite. Crystallization was initiated and the mixture agitated occasionally while being cooled in the refrigerator. Yield of product 29 g, MP 253° to 259°C. Concentration of the filtrate to 125 ml yielded another 7.5 g of product, MP 253° to 259°C. The product was recrystallized another time in the manner described above. Total yield, first and second crops, 28.8 g (66%), MP 250° to 255°C. Product was dried at 80°C in a vacuum, according to US Patent 3,360,518.

2278

Metopimazine

References Merck Index 6024 Kleeman and Engel p. 594 PDR pp. 1401, 1668 OCDS Vol. 2 p. 384 (1980) DOT 9 (12) 498 (1973) I.N. p. 629 REM p. 940 Shetty, B.V.; US Patent 3,360,518; December 26, 1967; assigned to Wallace and Tiernan Inc. Shetty, B.V.; US Patent 3,557,111; January 19, 1971

METOPIMAZINE Therapeutic Function: Antiemetic Chemical Name: 4-Piperidinecarboxamide, 1-(3-(2-(methylsulfonyl)-10Hphenothiazin-10-yl)propyl)Common Name: Metopimazine Structural Formula:

Chemical Abstracts Registry No.: 14008-44-7 Trade Name

Manufacturer

Country

Year Introduced

Nortrip

Rhodia

-

-

Raw Materials 2-Methylsulfonylphenothiazine 1-Bromo-3-chloropropane Piperidine-4-carboxylic acid amide Sodium Ammonia

Metoprolol tartrate

2279

Manufacturing Process 2-Methylsulfonyl-10-(3-chloropropyl)phenothiazine was prepared by condensation of 1-bromo-3-chloropropane and 2-methylsulfonyl phenothiazine in liquid ammonia in presence of obtained in situ sodium amide. 10 g 2-methylsulfonyl-10-(3-chloropropyl)-phenothiazine, 4 g piperidine-4carboxylic acid amide, 3.5 g dry sodium carbonate in 200 ml of ethanol was heated to reflux for 24 hours. Than 1.75 g sodium carbonate was added and the mixture was heated another 8 hours. After that the new 1.75 g portion of sodium carbonate was added and heated for 16 hours. The solvent was removed in vacuum (20 mm Hg). The residue was stirred with 50 ml water and 150 ml ethyl acetate. The organic layer was separated and extracted with 200 ml 1 N hydrochloric acid. The water layer was made alkaline with 4 N sodium hydroxide, extracted with ethyl acetate and dried over sodium sulfate. The solvent was removed in vacuum (20 mm Hg) to dryness. The obtained residue 2-methylsulfonyl-10-(3-(4-carbamoylpiperidino)propyl)phenothiazine was recrystallized from ethyl acetate. Yield 6 g; MP: 170°-171°C. References Jacob R. et al.; D.B. Patent No. 1,092,476; April 14, 1959; Societe des Usines Chimiques Rhone-Poulenc, Paris

METOPROLOL TARTRATE Therapeutic Function: Beta-adrenergic blocker Chemical Name: 1-[4-(2-Methoxyethyl)phenoxy]-3-[(1-methylethyl)amino]2-propanol tartrate Common Name: Structural Formula:

Chemical Abstracts Registry No.: 56392-17-7; 37350-58-6 (Base)

2280

Metoprolol tartrate

Trade Name Betaloc Lopressor Beloc Lopressor Lopressor Selomen Lopressor Seloken Seloken Lopresol Lati 2 Neobloc Prelis

Manufacturer Astra Geigy Astra Ciba Geigy Ciba Geigy Bracco Ciba Geigy Searle Fujisawa Takeda Unifa Unipharm Brunnengraber

Country UK UK W. Germany W. Germany Italy Italy US France Japan Japan Argentina Israel W. Germany

Year Introduced 1975 1975 1976 1976 1978 1978 1978 1980 1983 1983 -

Raw Materials Isopropylamine Tartaric acid Epichlorohydrin

Sodium bicarbonate p-(β-Methoxyethyl)phenol

Manufacturing Process The starting material 1,2-epoxy-3-[p-(β-methoxyethyl)phenoxy]-propane was obtained from p-(β-methoxyethyl)-phenol which was reacted with epichlorohydrin whereafter the reaction product was distilled at 118°C to 128°C at a pressure of 0.35mm Hg. 1,2-Epoxy-3-[p-(β-methoxyethyl)-phenoxy]-propane (16.7g) was dissolved in 50 ml isopropanol and mixed with 20 ml isopropylamine. The mixture was heated in an autoclave on boiling water-bath overnight, whereafter it was evaporated and the remainder dissolved in 2 N HCI. The solution was extracted first with ether and thereafter with methylene chloride. After evaporating the methylene chloride phase, the hydrochloride of 1isopropylamino-3-[p(β-methoxyethyl)-phenoxy] -propanol-2 was obtained which, after recrystallization from ethyl acetate, weighed 10.4 g. Melting point 83°C. Equivalent weight: found 304.0, calculated 303.8. The hydrochloride is then converted to the tartrate. References Merck Index 6027 Kleeman and Engel p. 595 PDR p. 894 OCDS Vol. 2 p. 109 (1980) DOT 11 (9) 360 (1975) and 17 (2) 65 (1981) I.N. p. 630 REM p. 905 Brandstrom, A.E., Carlsson, P.A.E., Carlsson, S.A.I., Corrodi, H.R., Ek, L.and Ablad, B.A.H.; US Patent 3,873,600; March 25, 1975

Metrizamide

2281

METRIZAMIDE Therapeutic Function: Diagnostic aid Chemical Name: D-Glucose, 2-((3-(acetylamino)-5-(acetylmethylamino)2,4,6-triiodobenzoyl)amino)-2-deoxyCommon Name: Metrizamide Structural Formula:

Chemical Abstracts Registry No.: 31112-62-6 Trade Name

Manufacturer

Country

Year Introduced

Amipaque

Winthrop laboratories

-

-

Raw Materials 3-(Acetylmethylamino)-2,4,6-triiodo-5-methylamino-benzoic acid Thionyl chloride Glucosamine Manufacturing Process 1 mole 3-(acetyl-methyl-amino)-2,4,6-triiodo-5-methylamino-benzoic acid was suspended in thionyl chloride and reacted by stirring at 70°C for 16 hours. Excess thionyl chloride was distilled off in vacuum, the residue dissolved in chloroform, cooled in the ice bath, washed with iced water (3x100 ml), saturated sodium bicarbonate solution (3 x 100 ml), 2 N sodium carbonate solution (2 x 100 ml) and finally with water (3 x 100 ml). After drying with CaCl2 the chloroform distilled off and residue dried in vacuum. Yield of 3acetylamino-5-(acetyl-methyl-amino)-2,4,6-triiodo-benzoyl chloride: 66%; MP: 238°-240°C (the re-crystallization from tetrahydrofuran). It (0.02 mole) was dissolved in dioxan (120 ml). To the solution was added (25 ml) and NaHCO3 (0.0022 mol). Glucosamine (0.022 mol) was added in portions and reaction mixture left by stirring at room temperature for 24 hours. The solution was evaporated to dryness in vacuum, the residue dissolved in water (500 ml), filtered clear and run through an Amberlite IR

2282

Metrizoic acid

120 H+ ion exchange column. The effluent was evaporated to dryness in vacuum resulting in a white crystalline residue. The crude 3-acetylamino-5-Nmethyl-acetylamino-2,4,6-triiodobenzoyl glucosamine was crystallised from isopropanol (charcoal-treated when in solution), dissolved in water and charcoal-treated at 100°C for 20 min. The water was distilled off in vacuum and the white residue dried in vacuum at 70°C. MP: 190°-195°C. References Almen T.H.O.; US Patent No. 3,701,771; Oct. 31, 1972; Assigned to Nyegaard and Co. A/S; Norway

METRIZOIC ACID Therapeutic Function: Diagnostic aid (radiopaque medium) Chemical Name: 3-(Acetylamino)-5-(acetylmethylamino)-2,4,6-triiodobenzoic acid Common Name: Structural Formula:

Chemical Abstracts Registry No.: 1949-45-7 Trade Name Isopaque Isopaque Isopaque Ronpacon

Manufacturer Winthrop Sterling Winthrop Cilag Chemie

Country France US Italy W. Germany

Year Introduced 1973 1975 1978 -

Raw Materials Diatrizoic acid (diatrizoate) Dimethyl sulfate Manufacturing Process 3,5-Diacetamido-2,4,6-triiodobenzoic acid (diatrizoic acid) (see Diatrizoate

Metronidazole

2283

entry for synthesis) (10 g) is suspended in water (10 ml), 5 N potassium hydroxide (4.3 equivalent) is added and the mixture cooled to about 15°C. Dimethyl sulfate (0.5 equivalent) dissolved in an equal volume of acetone is added drop by drop while stirring. After the reaction mixture has been stirred for about 1 hour hydrochloric acid (1:1) is added, with stirring to pH about 0.5. The precipitate is filtered, washed and suspended moist in 4 parts of water, concentrated ammonia is added to pH about 7 and the ammonium salt solution is isomerized at 90°C to 100°C for about one-half hour whereafter additional ammonia is added to pH about 9 followed by solid ammonium chloride (about 10% weight/volume) and the solution stirred overnight and the excess of 3,5-diacetamide-2,4,6-triiodobenzoic acid recovered as ammonium salt on the filter. The filtrate is precipitated by means of hydrochloric acid (1:1 ) at pH about 0.5 and the N-methyl-3,5-diacetamido2,4,6-triiodobenzoic acid collected on a filter, washed and dried. References Merck Index 6032 Kleeman and Engel p. 597 I.N. p. 631 REM p. 1270 Holtermann, H., Haugen, L.G., Nordal, V. and Haavaldsen, J.L.; US Patent 3,178,473; April 13, 1965; assigned to Nyegaard and Co. A/S (Norway)

METRONIDAZOLE Therapeutic Function: Antiprotozoal Chemical Name: 2-Methyl-5-nitroimidazole-1-ethanol Common Name: Structural Formula:

Chemical Abstracts Registry No.: 443-48-1 Trade Name Flagyl Flagyl Flagyl Flagyl Flagyl

Manufacturer Specia May and Baker Rhone Poulenc Farmitalia Searle

Country France UK W. Germany Italy US

Year Introduced 1960 1960 1961 1962 1963

2284

Metronidazole

Trade Name

Manufacturer

Country

Year Introduced

Satric

Savage

US

1982

Metryl

Lemmon

US

1982

Metro IV

McGaw

US

1982

Protostat

Ortho

US

1983

Anaerobex

Gerot

Austria

-

Arilin

Wolff

W. Germany

-

Asuzol

Fuji

Japan

-

Clont

Bayer

W. Germany

-

Deflamon

SPA

Italy

-

Efloran

Krka

Yugoslavia

-

Elyzol

Dumex

Denmark

-

Entizol

Polfa

Poland

-

Flagemona

Phoenix

Argentina

-

Fossyol

Merckle

W. Germany

-

Gineflavir

Crosara

Italy

-

Klion

Kobanyai

Hungary

-

Kreucosan

Kreussler

W. Germany

-

Medazol

Belupo Ltd.

Yugoslavia

-

Meronidal

Kissei Pharmaceutical Co., Ltd.

Japan

-

Metrajil

Mulda

Turkey

-

Matrogil

Lkapharm

Israel

-

Metrolag

Lagap

Switz.

-

Monasin

Helvepharm

Switz.

-

Nalox

Omega

Argentina

-

Neo-Tric

Neo

Canada

-

Nida

Toyo Pharm.

Japan

-

Novonidazol

Novopharm

Canada

-

Orvagil

Galenika

Yugoslavia

-

Rathimed N

Pfleger

W. Germany

-

Rivozol

Rivopharm

Switz.

-

Rodogyl

Specia

France

-

Salandol

Sato

Japan

-

Sanatrichom

Godecke

W. Germany

-

Sawagyl

Sawai

Japan

-

Servizol

Servipharm

Switz.

-

Surimol

Labatec

Switz.

-

Takimetol

Nakataki

Japan

-

Tarozole

Taro

Israel

-

Tranoxa

Exa

Argentina

-

Trichazol

Will

Canada

-

Trichex

Gerot

Austria

-

Trichocide

Green Cross

Japan

-

Metyrapone Trade Name Tricho Cordes TrichoGynaedron Trichomol Trichostop Trichozole Tricowas B Trikamon Trikozol Trivazol Vagilen Vagimid Vaginyl Wagitran

Manufacturer Icthyol Artesan Gea Sigmapharm Protea Wassermann Elliott-Marion Farmos Vister Farmigea Apogepha D.D.S.A. Ono

Country W. Germany W. Germany Denmark Austria Australia Spain Canada Finland Italy Italy E. Germany UK Japan

2285

Year Introduced -

Raw Materials 2-Methyl-5-nitroimidazole Ethylene chlorohydrin Manufacturing Process 2-Methyl-4(or 5)-nitroimidazole (127 g) is heated with ethylene chlorohydrin (795 g) for 18 hours at 128° to 130°C and the chlorohydrin (660 g) is then distilled under reduced pressure (30mm Hg). The residue is treated with water (300 cc) and filtered, and the filtrate is made alkaline by the addition of sodium hydroxide solution (d = 1.33, 100 cc). It is then extracted with chloroform (1,000 cc) and, after evaporation of the chloroform in vacuo, there is obtained a pasty mass (77 g) which is recrystallized from ethyl acetate (450 cc) in the presence of animal charcoal. There is thus obtained 1-(2hydroxyethyl)-2-methyl-5-nitroimidazole (24 g) as a creamy white crystalline powder melting at 158° to 160°C. References Merck Index 6033 Kleeman and Engel p. 597 PDR pp. 830, 872, 876, 993, 1034, 1305, 1605, 1670, 1723, 1999 OCDS Vol. 1 p. 240 (1977) DOT 13 (4) 147 (1977) 8117 (1) 34 (1981) I.N. p. 632 REM p. 1222 Jacob, R.M., Regnier, G.L. and Crisan, C.; US Patent 2,944,061; July 5,1960; assigned to Societe des Usines Chimiques Rhone-Poulenc, France

METYRAPONE Therapeutic Function: Diagnostic aid (pituitary function)

2286

Metyrapone

Chemical Name: 2-Methyl-1,2-di-3-pyridyl-1-propanone Common Name: Structural Formula:

Chemical Abstracts Registry No.: 54-36-4 Trade Name Metopirone Metopirone Metyrapone Metopiron

Manufacturer Ciba Ciba Ciba Ciba

Country US UK Switz. W. Germany

Year Introduced 1961 1961 1964 1966

Raw Materials 3-Acetylpyridine Sulfuric acid Hydrogen Hydroxylamine sulfate Manufacturing Process According to US Patent 2,966,493, the 2,3-bis-(3-pyridyl)-2,3-butanediol used as the starting material may be prepared as follows. A solution of 1,430 g of 3-acetyl-pyridine in 7,042 ml of a 1 N aqueous solution of potassium hydroxide is placed into a cathode chamber containing a mercury cathode with a surface of 353 cm2 and is separated from an anode chamber by an Alundum membrane. As anode a platinum wire is used and the anolyte consists of a 1 N solution of aqueous potassium hydroxide which is replenished from time to time. The electrolysis is carried out at a reference potential of -2.4 volts vs a standard calomel electrode. An initial current density of 0.0403 amp/cm2 is obtained which drops to 0.0195 amp/cm2 at the end of the reduction, which is carried on over a period of 1,682 minutes at 15° to 20°C. The catholyte is filtered, the solid material is washed with water and dried. 430 g of the 2,3bis-(3-pyridyl)-butane-2,3-diol is recrystallized from water, MP 244° to 245°C. A mixture of 3.43 g of 2,3-bis-(3-pyridyl)-2,3-butane-diol and 25 ml of concentrated sulfuric acid is heated to 76°C and kept at that temperature for 7½ hours. It is then poured on ice, neutralized with 50% aqueous solution of sodium hydroxide and the pH is adjusted to 8 with solid sodium carbonate. The aqueous solution is three times extracted with ethyl acetate, the separated organic layer dried over sodium sulfate and evaporated to dryness.

Metyrosine

2287

The residue is distilled and 1.86 g of viscous, colorless oil is obtained which is purified by distillation. BP 140° to 160°C/0.07 mm. The infrared spectrum shows the presence of a mixture of two compounds, one containing a conjugated, the other one an unconjugated carbonyl group, without the presence of a compound containing a hydroxyl group; thus the rearrangement has taken place. The resulting mixture does not crystalize and is converted into a mixture of oximes by treatment of a solution of the mixture in 20 ml of ethanol with a solution of 1.8 g of hydroxylamine sulfate in 3 ml of water. 1.8 g of sodium acetate in 5 ml of water is added, and the mixture is refluxed for 5 hours, then extracted with ethyl acetate, and the ethyl acetate solution is washed with a saturated aqueous sodium chloride solution and dried over sodium sulfate. After evaporating the solvent, the residue is triturated with warm ether and 1.1 g of a crystalline oxime is obtained, MP 168° to 171°C. 0.1 g of the resulting oxime is dissolved in 5 ml of 2 N aqueous sulfuric acid and the mixture is refluxed for 3 hours and allowed to stand overnight. After being rendered basic by adding a concentrated aqueous solution of sodium hydroxide and adjusted to a pH of 8 with sodium carbonate, the mixture is extracted 3 times with ethyl acetate; the organic layer is washed with water, dried and evaporated. Upon distillation of the residue an oily product is obtained, BP 130° to 160°C/0.3 mm. Infrared analysis shows the presence of a uniform compound, containing a conjugated carbonyl group. The 2-methyl1,2-bis-(3-pyridyl)-propane-1-one crystallizes upon standing at room temperature or by covering the oily distillate with pentane and cooling to 80°C and filtering the oily crystals. It melts after recrystallization from a mixture of ether, hexane and petroleum ether at 48° to 50°C. References Merck Index 6036 Kleernan and Engel p. 598 PDR p. 803 I.N. p. 633 REM p. 1276 Bencze, W.L. and Allen, M.J.; US Patent 2,923,710; February 2, 1960; assigned to Ciba Pharmaceutical Products, Inc. Allen, M.J. and Bencze, W.L.; US Patent 2,966,493; December 27, 1960; assigned to Ciba Pharmaceutical Products, Inc.

METYROSINE Therapeutic Function: Tyrosine hydroxylase inhibitor Chemical Name: α-Methyl-L-tyrosine Common Name: Metirosine

2288

Metyrosine

Structural Formula:

Chemical Abstracts Registry No.: 672-87-7 Trade Name

Manufacturer

Country

Year Introduced

Demser

MSD

US

1979

Raw Materials Hydrogen Sulfuric acid α-Methyl-N-dichloroacetyl-pnitrophenylalanine

Sodium nitrite Hydrogen chloride

Manufacturing Process 50 g of α-methyl-N-dichloroacetyl-p-nitrophenylalanine was dissolved in 500 ml methanol, 300 mg of platinum oxide were added and the mixture reduced at 41 pounds of pressure; within an hour 14.5 pounds were used up (theory 12.4 pounds). After filtration of the catalyst, the red clear filtrate was concentrated in vacuo and the residual syrup flushed several times with ether. The crystalline residue thus obtained, after air drying, weighed 45.3 g (99.5%), MP unsharp at about 104°C to 108°C with decomposition. After two precipitations with ether from an alcoholic solution, the somewhat hygroscopic amine was dried over sulfuric acid for analysis. 10 g of the amine prepared above was dissolved in 5 ml of 50% sulfuric acid at room temperature; the viscous solution was then cooled in ice and a solution of sodium nitrite (2.4 g) in 10 ml water gradually added with agitation. A flocculent precipitate formed. After all the nitrite had been added, the mixture was aged in ice for an hour, after which it was allowed to warm up to room temperature. Nitrogen came off and the precipitate changed to a sticky oil. After heating on the steam bath until evolution of nitrogen ceased, the oil was extracted with ethyl acetate. After removal of the solvent in vacuo, 9.4 g of colored solid residue was obtained, which was refluxed with 150 ml hydrochloric acid (1:1) for 17 hours. The resulting dark solution; after Norite treatment and extraction with ethyl acetate, was concentrated in vacuo to dryness and the tan colored residue (7.4 g) sweetened with ethanol. Dissolution of the residue in minimum amount of ethanol and neutralization with diethylamine of the clarified solution, precipitated the α-methyl tyrosine, which was filtered, washed with ethanol (until free of chlorides) and ether. The crude amino acid melted at 309°C with decomposition. For further purification, it was dissolved in 250 ml of a saturated sulfur dioxide-water solution, and the solution, after Noriting, concentrated to about 80 ml, the tan colored solid filtered washed with ethanol and ether. Obtained 1.5 g of α-methyl tyrosine, MP 320°C dec.

Mexenone

2289

References Merck Index 6038 PDR p. 1167 DOT 16 (10) 346 (1980) I.N. p. 628 REM p. 909 Pfister, K. Ill and Stein, G.A.; US Patent 2,868,818; January 13, 1959;assigned to Merck and Co., Inc.

MEXENONE Therapeutic Function: Sunscreen agent Chemical Name: (2-Hydroxy-4-methoxyphenyl)(4-methylphenyl)methanone Common Name: 2-Hydroxy-4-methoxy-4'-methylbenzophenone Structural Formula:

Chemical Abstracts Registry No.: 1641-17-4 Trade Name

Manufacturer

Country

Year Introduced

Uvistat-L

Ward Blenkinsop

UK

1960

Raw Materials p-Toluoyl chloride 1,3-Dimethoxybenzene Hydrogen chloride Sodium hydroxide Manufacturing Process p-Toluoyl chloride is the starting material. To this is added chlorobenzene and 1,3-dimethoxybenzene. The reaction mixture is cooled to 12°C in an ice bath and aluminum chloride is added gradually, keeping the reaction below 30°C. The reaction is then gradually heated to 115°C with the evolution of hydrogen chloride gas. As the temperature increases, the reaction mixture becomes thicker. At 105°C, dimethyl formamide is added slowly. The reaction is heated at 115°C for a short time and is then poured into concentrated hydrochloric

2290

Mexiletine hydrochloride

acid. The reaction mixture pours very easily and very cleanly. The acid mixture is heated with steam to dissolve all the material which had not hydrolyzed and the mixture is filtered. The red chlorobenzene layer is separated and washed twice with hot water. To the chlorobenzene solution is then added sodium hydroxide dissolved in water and the chlorobenzene is removed by a steam distillation. After all of the chlorobenzene is removed, the precipitate which forms during the distillation is removed by filtration and discarded. The solution is cooled and acidified with hydrochloric acid, precipitating a tan solid. This is removed by filtration and washed acid-free. It is then treated with sodium bicarbonate solution to remove any acid present and is then washed with water to remove all traces of bicarbonate. After drying approximately a 75% yield of mexenone is obtained. References Merck Index 6045 Kleeman and Engel p. 598 OCDS Vol. 2 p. 175 (1980) I.N. p. 633 Hardy. W.B. and Forster, W.S.; US Patent 2,773,903; December 11, 1956; assigned to American Cyanamid Company

MEXILETINE HYDROCHLORIDE Therapeutic Function: Antiarrhythmic Chemical Name: 1-(2,6-Dimethylphenoxy)-2-propanamine hydrochloride Common Name: Structural Formula:

Chemical Abstracts Registry No.: 5370-01-4; 31828-71-4 (Base) Trade Name Mexitil Mexitil Mexitil Mexitil Mexitil

Manufacturer Boehringer Ingelheim Boehringer Ingelheim Boehringer Ingelheim Boehringer Ingelheim Boehringer Ingelheim

Country US Switz. W. Germany France Italy

Year Introduced 1976 1978 1979 1981 1982

Mezlocillin

2291

Raw Materials Dimethyl phenol Hydrogen Hydroxylamine

Chloroacetone Sodium hydroxide

Manufacturing Process The sodium salt of dimethyl phenol was reacted with chloroacetone and this product with hydroxylamine to give the starting material. 245 g of this 1-(2',6'-dimethyl-phenoxy)-propanone-(2)-oxime were dissolved in 1,300 cc of methanol, and the solution was hydrogenated at 5 atmospheres gauge and 60°C in the presence of Raney nickel. After the calculated amount of hydrogen had been absorbed, the catalyst was filtered off, the methanol was distilled out of the filtrate,and the residue, raw 1-(2',6'-dimethylphenoxy)-2-amino-propane, was dissolved in ethanol. The resulting solution was acidified with ethereal hydrochloric acid, the acidic solution was allowed to cool, and the precipitate formed thereby was collected by vacuum filtration. The filter cake was dissolved in ethanol and recystallized therefrom by addition of ether. 140.5 g (51.5% of theory) of a substance having a melting point of 203°C to 205°C were obtained, which was identified to be 1-(2',6'dimethyl-phenoxy)-2-anino-propane hydrochloride. References Merck Index 6047 DFU 1 (4) 180 (1976) Kleeman and Engel p. 598 DOT 12 (9) 361 (1976) I.N. p.633 REM p.861 Koppe, H., Zeile, K., Kummer, W., Stahle, H. and Dannenberg, P.; US Patent 3,659,019; April 25,1972; assigned to Boehringer Ingelheim G.m.b.H. (W. Germany)

MEZLOCILLIN Therapeutic Function: Antibiotic Chemical Name: Sodium D(-)-α-[(3-methylsulfonyl-imidazolidin-2-on-1-yl)carbonylamino]benzylpenicillin Common Name: Chemical Abstracts Registry No.: 51481-65-3

2292

Mezlocillin

Structural Formula:

Trade Name Baypen Baypen Baypen Baypen Mezlin Baypen Baypen Baypen Baycipen Optocillin

Manufacturer Bayer Bayer Bayer Bayer Miles Bayer Yakuhin Bayer Bayer Bayer Bayer

Country W. Germany UK Switz. Italy US Japan France Sweden W. Germany

Year Introduced 1977 1980 1980 1981 1981 1982 1983 1983 -

Raw Materials Ampicillin Methanesulfonyl chloride 2-Imidazolidone Phosgene Manufacturing Process 9.3 parts by weight of ampicillin were suspended in 80% strength aqueous tetrahydrofuran (140 parts by volume) and sufficient triethylamine (approximately 6.3 parts by volume) was added dropwise while stirring at 20°C, just to produce a clear solution and to give a pH value of between 7.5 and 8.2 (glass electrode). The mixture was cooled to 0°C and 5.1 parts by weight of 3-methylsulfonyl-imidazolidin-2-one-1-carbonyl chloride were added gradually in portions over the course of 30 minutes, while the mixture was stirred and kept at a pH value of between 7 and 8 by simultaneous addition of triethylamine. The carbonyl chloride reactant was prepared by reacting 2-imidazolidone with methanesulfonyl chloride then that product with phosgene. The mixture was stirred for 10 minutes at 0°C and subsequently further stirred at room temperature until no further addition of triethylamine was necessary to maintain a pH value of 7 to 8. 150 parts by volume of water were added and

Mianserin

2293

the tetrahydrofuran was largely removed in a rotary evaporator at room temperature. The residual aqueous solution was extracted once by shaking with ethyl acetate, covered with 250 parts by volume of fresh ethyl acetate and acidified to pH 1.5 to 2.0 with dilute hydrochloric acid while being cooled with ice. The organic phase was separated off, washed twice with 50 parts by volume of water at a time and dried for 1 hour over anhydrous MgSO4 in a refrigerator. After filtration, about 45 parts by volume of a 1 molar solution of sodium 2ethylhexanoate in ether containing methanol were added to the solution of the penicillin. The mixture was concentrated on a rotary evaporator until it had an oily consistency and was dissolved in a sufficient amount of methanol by vigorous shaking, and the solution was rapidly added dropwise, with vigorous stirring, to 500 parts by volume of ether which contained 10% of methanol. The precipitate was allowed to settle for 30 minutes, the solution was decanted from the precipitate, and the latter was again suspended in ether, filtered off and washed with anhydrous ether. After drying over P2O5 in a vacuum desiccator, the sodium salt of the mezlocillin was obtained in the form of a white solid substance. References Merck Index 6049 DFU 2 (9) 200 (1977) Kleeman and Engel p. 599 PDR p. 1254 OCDS Vol. 3 p. 206 (1984) DOT 11 (11) 444 (1975) and 15 (2) 54 (1979) I.N. p. 633 REM p. 1196 Konig, H.B., Schrock, W. and Metzger, K.G.; US Patents 3,972,869; August 3, 1976; 3,972,870; August 3, 1976; 3,974,141; August 10, 1976; 3,974,142; August 10, 1976; 3,975,375; August 17, 1976; 3,978,056; August 31, 1976; 3,983,105; September 28,1976; and

MIANSERIN Therapeutic Function: Serotonin antagonist, Antihistaminic Chemical Name: 1,2,3,4,10,14b-Hexahydro-2-methyldibenzo[c]pyrazino[1,2a]azepine Common Name: 2-Methyl-1,2,3,4,10,14b-hexahydro-2H-pyrazino-[1,2f]morphanthridine Chemical Abstracts Registry No.: 24219-97-4; 21535-47-7 (Hydrochloride salt)

2294

Mianserin

Structural Formula:

Trade Name Tolvin Bolvidon Norval Lantanon Athymil Athmyl Tetramide

Manufacturer Organon Organon Bencard Ravasini Organon Organon Sankyo

Country W. Germany UK UK Italy France Switz. Japan

Year Introduced 1975 1976 1976 1976 1979 1980 1983

Raw Materials 2-Benzylaniline Diethyloxalate Chloroacetyl chloride Lithium aluminum hydride

Polyphosphoric acid Diborane Methylamine

Manufacturing Process (A) 25 g of 2-benzylaniline dissolved in 150 ml of benzene are cooled down in an ice bath to 8°C. To this solution are added 15 ml of pyridine and after that a solution of 15 ml of chloroacetyl chloride in 25 ml of benzene, maintaining the temperature of the reaction mixture at 10° to 15°C. After stirring for 1 hour at room temperature 25 ml of water are added and the mixture is shaken for 30 minutes. Next the mixture is sucked off and the benzene layer separated. Then the benzene layer is washed successively with 2 N HCl, a sodium carbonate solution and water. The extract dried on sodium sulfate is evaporated and the residue crystallized together with the crystals obtained already from benzene. Yield 18 g; MP 130° to 133°C. (B) 40 g of N-chloroacetyl-2-benzylaniline are heated for 2 hours at 120°C together with 50 ml of phosphorus oxychloride and 320 g of polyphosphoric acid. Next the reaction mixture is poured on ice and extracted with benzene. The extract is washed and dried on sodium sulfate and the benzene distilled off. The product obtained (31g) yields after recrystallization 24 g of 6chloromethyl-morphanthridine of MP 136° to 137°C. (C) 10 g of 6-chloromethyl-morphanthridine are passed into 150 ml of a solution of methylamine in benzene (10%). After storage of the solution for 20 hours at 0° to 5°C the methylamine hydrochloride formed is sucked off and the filtrate evaporated to dryness. There remains as residue 11 g of crude

Mibefradil hydrochloride

2295

6-methylaminomethyl-morphanthridine. (D) 11 g of crude 6-methylaminomethyl-morphanthridine are dissolved in 50 ml of absolute ether. While cooling in ice 2.7 g of lithium aluminumhydride, dissolved in 100 ml of absolute ether, are added. After boiling for 1 hour and cooling down in ice 11 ml of water are added slowly dropwise while stirring. After stirring for another 30 minutes at room temperature the mixture is sucked off and the filtrate evaporated to obtain 11 g of crude 5,6-dihydro-6methylaminomethyl-morphanthridine in the form of a light yellow oil. (E) 10 g of 5,6-dihydro-6-methylaminomethyl-morphanthridine are heated slowly, in 30 minutes, from 100° to 160°C with 7 g of pure diethyloxalate and after that from 160° to 180°C in 45 minutes. After cooling down the reaction mixture is stirred with benzene. The crystals are sucked off and yield after crystallization from dimethylformamide 9 g of 1,2-diketo-3(N)-methyl2,3,4,4a-tetrahydro-1H-pyrazino-[1,2-f]-morphanthridine of MP 245° to 247°C. (F) 9 g of the diketo-pyrazino-morphanthridine compound obtained above are reduced with diborane to give mianserin. References Merck Index 6050 Kleeman and Engel p. 599 OCDS Vol. 2 p. 451 (1980) DOT 12 (1) 31 (1976) I.N. p. 634 van der Burg,W.J. and Delobelle, J.; US Patent 3,534,041; October 13,1970; assigned to Organon Inc.

MIBEFRADIL HYDROCHLORIDE Therapeutic Function: Coronary vasodilator Chemical Name: Acetic acid, methoxy-, 2-(2-((3-(1H-benzimidazol-2yl)propyl)methylamino)ethyl)-6-fluoro-1,2,3,4-tetrahydro-1-(1methylethyl)-2-naphthalenyl ester, dihydrochloride, (1S-cis)Common Name: Mibefradil hydrochloride Chemical Abstracts Registry No.: 116666-63-8; 116644-53-2 (Base) Trade Name

Manufacturer

Country

Year Introduced

Posicor

Roche Pharmaceuticals

USA

-

2296

Mibefradil hydrochloride

Structural Formula:

Raw Materials Butyl lithium [3-(1H-Benzimidazol-2-yl)propyl]methylamine Diisopropylamine Isopropenyl acetate Lithium chloride Potassium hydroxide Methoxyacetyl chloride Sodium bis(2-methoxyethoxy)aluminum hydride (S)-6-Fluoro-1-isopropyl-3,4-dihydro-1H-naphthalen-2-one Manufacturing Process To the solution of 5.35 g (28 mmol) [3-(1H-benzimidazol-2yl)propyl]methylamine in 12.5 mL toluene was added by syringe 12.5 mL (11.42 g, 114 mmol) isopropenyl acetate. The reaction mixture was heated to reflux temperature, and stirred at that temperature for 1.75 hours, with reaction completion monitored by thin-layer chromatography (silica gel, eluting with 70% ethyl acetate/30% methanol). The product, N-[3-(1Hbenzimidazol-2-yl)propyl]-N-methylacetamide, was obtained in quantitative yield. Under a dry nitrogen atmosphere, a 2.5 molar solution of butyl lithium in hexane, 8.4 mL (21 mmol) was added by syringe to 20 mL pentane. The solution was cooled to 0°C and 2.75 mL (2.13 g, 21 mmol) diisopropylamine was added by syringe over six min. The solution was warmed to 25°C and stirred for three hours, then volatiles were removed in vacuo. THF, 20 mL, was added via syringe to the residue, and the resulting yellow solution cooled to 0°C. A solution of 2.42 g (10.5 mmol) N-[3-(1H-benzimidazol-2-yl)propyl]N-methylacetamide in 10 mL THF was added by syringe over 9 min. The yellow solution was stirred for 15 min, then cooled to -78°C. (S)-6-Fluoro-1isopropyl-3,4-dihydro-1H-naphthalen-2-one, 2.166 g, 87.2% pure (97.6:2.4 S:R), in 2 mL toluene was added by syringe over 12 min, and a further 2 mL toluene was used to complete the transfer. After stirring for two hours, the viscous yellow mixture was added to 50 mL water at less than 10°C. The suspension that formed was extracted with diethyl ether; and the extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 3.74 g of impure (1S,2S)-N-[3-(1H-benzimidazol-2-yl)propyl]2-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl)-N-

Mibefradil hydrochloride

2297

methylacetamide as a yellow foam. The foam was recrystallized from toluene, yield of a colorless solid 2.69 g, melting point 132-138°C. This material may be recrystallized a second time from toluene to remove residual (S)-6-fluoro1-isopropyl-3,4-dihydro-1H-naphthalen-2-one if necessary. (1S,2S)-N-[3-(1H-Benzimidazol-2-yl)propyl]-2-(6-fluoro-2-hydroxy-1isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl)-N-methylacetamidemay be synthesized by another method: To the mixture 22.7 g (0.54 mol) dry lithium chloride and 100 mL THF at 15°C was added 160 mL 2 molar lithium diisopropylamide (0.32 mol) in heptane/THF/ethylbenzene was added. Then a solution of 36.6 g (0.16 mol) N-[3-(1H-benzimidazol-2-yl)-propyl]-N-methylacetamide in 140 mL toluene was added, the solution was stirred for 2 hours, and a further 155 mL toluene was added. (S)-6-Fluoro-1-isopropyl-3,4-dihydro-1H-naphthalen-2-one (29.9 g, 0.15 mol), in 15 mL toluene was added. After stirring at -10°C for 4 hours, the resulting solution was added to 200 mL ice water. The pH of the resulting mixture was adjusted to 7-8 by addition of a 71 g concentrated hydrochloric acid. The organic layer washed with water, then the solvents removed under reduced pressure to give 96 g of (1S,2S)-N-[3-(1H-benzimidazol-2-yl)propyl]2-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl)-Nmethylacetamide as a brown oil. The product was crystallysed from toluene, yield 45.3 g. (1S,2S)-N-[3-(1H-Benzimidazol-2-yl)propyl]-2-(6-fluoro-2-hydroxy-1isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl)-N-methylacetamide,20.22 g (45.7 mmol), dissolved in 200 mL toluene at 40°C, was added by cannula over 40 min at 0°C to a suspension of sodium bis(2-methoxyethoxy)aluminum hydride in toluene, 40 mL (41.44 g suspension, 26.94 g sodium bis(2methoxyethoxy)aluminum hydride, 133 mmol). The mixture was stirred at 0°C for 15 min, then at 35-40°C for 3 hours. The mixture was cooled to 25°C then added carefully to 70 g sodium hydroxide in 140 g ice. The resulting suspension was warmed to 25°C over 30 min, and the phases were separated. The aqueous phase was extracted with toluene; and the organic phase was washed twice with 10% aqueous sodium hydroxide, once with water, then once with saturated brine. The toluene phase was dried and concentrated in vacuo to afford 20.61 g of (1S,2S)-2-[2-{[3-(1H-benzimidazol-2yl)propyl]methylmethylamino}ethyl]-6-fluoro-1-isopropyl-1,2,3,4tetrahydronaphthalen-2-ol as a colorless foam. To the mixture of 41.0 g (1S,2S)-2-[2-{[3-(1H-benzimidazol-2yl)propyl]methylmethylamino}ethyl]-6-fluoro-1-isopropyl-1,2,3,4tetrahydronaphthalen-2-ol, 240 mL water, and 240 mL toluene were added 22.4 g potassium hydroxide, and the mixture heated to 45-50°C for one hour. The resulting two-phase mixture was separated. To the organic phase was added 39.4 g (4.0 eq.) potassium carbonate sesquihydrate; then a solution of 21.0 g (17.7 mL, 3.25 eq.) methoxyacetyl chloride in 33 mL toluene was added over two hours at 25-30°C, and the resulting mixture stirred for an additional 30 min. Water, 200 mL, was added to quench the reaction. The organic phase, containing mibefradil as the free base was added an ethanol. To the stirred mixture of mibefradil and ethanol was added at 20°C a solution of 4.4 g of hydrogen chloride in 44.6 mL (35.0 g) ethanol. The mixture was heated to 50°C and 1.0 mL water was added, followed by a solution of 3.4 mL water in 332 mL methyl tert-butyl ether over one hour. The mixture was

2298

Miconazole nitrate

stirred for 3 hours. Mibefradil dihydrochloride crystals was seeded. A solution of 0.6 mL water in 65 mL methyl tert-butyl ether was added over one hour, and the mixture aged for a further 1.5 hours. The mixture was then cooled, and the resulting slurry of mibefradil dihydrochloride was filtered; yield 95%. References Harrington P. J.; US Patent No. 5,892,055; April 6, 1999; Assigned to Roche Colorado Corporation (Boulder, CO)

MICONAZOLE NITRATE Therapeutic Function: Antifungal Chemical Name: 1-[2,4-Dichloro-β-[(2,4-dichlorobenzyl)oxy]phenethyl] imidazole mononitrate Common Name: Structural Formula:

Chemical Abstracts Registry No.: 22832-87-7; 22916-47-8 (Base) Trade Name Daktarin Daktarin Daktar Dermonistat Monistat Daktarin Micatin Minostate Andergin Frolid P Aflorix Conofite Dektarin Deralbine

Manufacturer Janssen Janssen Janssen Ortho Ortho Le Brun Johnson and Johnson Janssen Isom Mochida Gerardo Ramon Pitman-Moore Janssen Andromaco

Country Italy UK W. Germany UK US France US US Italy Japan Argentina US Italy Argentina

Year Introduced 1974 1974 1974 1974 1974 1975 1976 1978 1980 1981 -

Miconazole nitrate Trade Name Epi-Monistat Florid Fungisdin Gyno-Daktarin Gyno-Monistat Micatin Miconal Micotef Vodol

Manufacturer Cilag Mochida Esteve Le Brun Cilag McNeil Ecobi Italfarmaco Andromaco

Country W. Germany Japan Spain France W. Germany US Italy Italy Brazil

2299

Year Introduced -

Raw Materials Imidazole Sodium hydride Nitric acid

ω-Bromo-2,4-dichloroacetophenone 2,4-Dichlorobenzyl chloride Sodium borohydride

Manufacturing Process Imidazole is reacted with ω-bromo-2,4-dichloroacetophenone and that product reduced with sodium borohydride. A suspension of 10.3 parts of the α-(2,4-dichlorophenyl)imidazole-1-ethanol thus obtained and 2.1 parts of sodium hydride in 50 parts of dry tetrahydrofuran is stirred and refluxed for 2 hours. After this reaction time, the evolution of hydrogen is ceased. Then there are added successively 60 parts dimethylformamide and 8 parts of 2,4-dichlorobenzyl chloride and stirring and refluxing are continued for another 2 hours. The tetrahydrofuran is removed at atmospheric pressure. The dimethylformamide solution is poured onto water. The product, 1-[2,4-dichloro-β-(2,4 -dichlorobenzyloxy)phenethyl]imidazole, is extracted with benzene. The extract is washed with water, dried, filtered and evaporated in vacuo. From the residual oily free base, the nitrate salt is prepared in the usual manner in 2-propanol by treatment with concentrated nitric acid, yielding, after recrystallization of the crude solid salt from a mixture of 2-propanol, methanol and diisopropyl ether, 1-[2,4-dichloro-βdichlorobenzyloxy)phenethyl]imidazole nitrate; melting point 170.5°C. References Merck Index 6053 Kleeman and Engel p. 601 PDR pp.956, 1293 OCDS Vol. 2 p. 249 (1980) DOT 7 ( ) 192 (1971) and 8 (6) 229 (1972) I.N. p. 634 REM p. 1229 Godefroi, E.F. and Heeres, J.; US Patent 3,717,655; February 20,1973; assigned to Janssen Pharmaceutica NV Godefroi, E.F. and Heeres, J.; US Patent 3,839,574; October 1,1974; assigned to Janssen Pharmaceutica NV

2300

Micronomicin

MICRONOMICIN Therapeutic Function: Antibiotic Chemical Name: O-2-Amino-2,3,4,6-tetradeoxy-6-(methylamino)-α-Derythrohexopyranosyl(1-->4)-O-[3-deoxy-4-C-methyl-3-(methylamino)-βL-arabinopyranosyl-(1-->6)-2-deoxy-D-streptamine Common Name: 6'-N-Methylgentamicin C1a; Sagamicin Structural Formula:

Chemical Abstracts Registry No.: 52093-21-7 Trade Name

Manufacturer

Country

Year Introduced

Sagamicin

Kyowa Hakko

Japan

1982

Raw Materials Bacterium Micromonospora sagamiensis Dextrin Soybean meal Manufacturing Process A. Culturing of MK-65: In this example, Micromonospora sagamiensis MK-65 ATCC 21826 (FERM-P No. 1530) is used as the seed strain. One loopful of the seed strain is inoculated into 30 ml of a first seed medium in a 250 mlErlenmeyer flask. The first seed medium has the following composition:

Dextrin Glucose Peptone Yeast extract CaCO3(pH: 7.2 before sterilization)

Percent 1 1 0.5 0.5 0.1

Culturing is carried out with shaking at 30°C for 5 days. 30 ml of the seed culture is then inoculated into 300 ml of a second seed medium, of the same composition as the first seed medium, in a 2 liter-Erlenmeyer flask provided with baffles. The second seed culturing is carried out with shaking at 30°C for

Micronomicin

2301

2 days. Then 1.5 liters of the second seed culture (corresponding to the content of 5 flasks) is inoculated into 15 liters of a third seed medium of the same composition as set forth above, in a 30 liter-glass jar fermenter. Culturing in the jar fermenter is carried out with aeration (15 liters/minute) and stirring (350 rpm) at 30°C for 2 days. Then, 15 liters of the third seed culture is inoculated into 60 liters of a fourth seed medium of the same composition as set forth above, in a 300 liter-fermenter. Culturing in the fermenter is carried out with aeration (60 liters/minute) and stirring (150 rpm) at 30°C for 2 days. Finally, 60 liters of the fourth seed culture is inoculated into 600 liters of a fermentation medium having the following composition in a 1,000 liter-fermenter.

Dextrin Soybean meal CaCO3 (pH: 7.2 before sterilization)

Percent 5 4 0.7

Culturing in the fermenter is carried out with aeration (600 liters/minute) and stirring 150 rpm) at 35°C for 5 days. B. Isolation of crude antibiotic: After the completion of fermentation, the culture liquor is adjusted to a pH of 2.0 with 12 N sulfuric acid and stirred for 30 minutes. Then, about 10 kg of a filter aid, Radiolite No. 600 (product of Showa Kagaku Kogyo Co., Ltd., Japan) is added thereto and the microbial cells are removed by filtration. The filtrate is adjusted to a pH of 8.0 with 6N sodium hydroxide and passed through a column packed with about 50 liters of a cation exchange resin, Amberlite IRC-50 (ammonia form). The active substance is adsorbed on the resin and the eluate is discarded. After washing the resin with water, the active substance is eluted out with 1N aqueous ammonia. The eluate is obtained in fractions and the activity of each of the fractions is determined against Bacillus subtilis No. 10707 by a paper disk method using an agar plate. Active fractions are combined and concentrated in vacuo to about 5 liters. The concentrate is then adjusted to a pH of 8.0 with 6N sulfuric acid and passed through a column packed with 1 liter of an anion exchange resin, Dowex 1X2 (OH-form). The column is washed with about 5 liters of water and the effluent and the washings containing active substance are combined and are concentrated to 1/15 by volume. The concentrate is adjusted to a pH of 10.5 with 6 N sodium hydroxide and 5 volumes of acetone is added thereto. The resultant precipitate is removed by filtration and the filtrate is concentrated to 500 ml. The concentrate is adjusted to a pH of 4.5 with 6 N sulfuric acid and 2.5 liters of methanol is added thereto. After cooling, a white precipitate is obtained. The precipitate is separated by filtration and washed with methanol. After drying in vacuo, about 300 g of white powder is obtained. The white powder is a mixture of the sulfate of gentamicin C1a, and the sulfate of XK-62-2, and exhibits an activity of 620 units/mg (the activity of 1 mg of pure product corresponds to 1,000 units). C. Isolation and purification of XK-62-2: 100 g of the white powder obtained in the above step B are placed to form a thin, uniform layer on the upper part of a 5 cm x 150 cm column packed with about 3 kg of silica gel advancely suspended in a solvent of chloroform, isopropanol and 17% aqueous ammonia

2302

Midazolam maleate

(2:1:1 by volume). Thereafter, elution is carried out with the same solvent at a flow rate of about 250 ml/hour. The eluate is separated in 100 ml portions. The active fraction is subjected to paper chromatography to examine the components eluted. XK-62-2 is eluted in fraction Nos. 53-75 and gentamicin C1ais eluted in fraction Nos. 85-120. The fraction Nos. 53-75 are combined and concentrated under reduced pressure to sufficiently remove the solvent. The concentrate is then dissolved in a small amount of water. After freezedrying the solution, about 38 g of a purified preparate of XK-62-2 (free base) is obtained. The preparate has an activity of 950 units/mg. Likewise, fraction Nos. 85-120 are combined and concentrated under reduced pressure to sufficiently remove the solvent. The concentrate is then dissolved in a small amount of water. After freeze-drying the solution, about 50 g of a purified preparate of gentamicin C1a (free base) is obtained. The activity of the preparate is about 980 units/mg. References Merck Index A-9 DFU 4 (5) 360 (1979) (as sagamicin) and 6 (5) 332 (1980) DOT 19 (4) 211 (1983) I.N. p. 635 Nara, T., Takasawa, S.,Okachi, R., Kawamoto, I., Yamamoto, M., Sato, S., Sato, T. and Morikawa, A.; US Patent 4,045,298; August 30,1977; assigned to Abbott Laboratories

MIDAZOLAM MALEATE Therapeutic Function: Anesthetic Chemical Name: 8-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo-[1,5a][1,4]benzodiazepine maleate Common Name: Structural Formula:

Chemical Abstracts Registry No.: 59467-70-8 (Base)

Midazolam maleate Trade Name Dormicum Dormonid Hypnovel Sorenor

Manufacturer Roche Roche Roche Roche

Country Switz. UK -

2303

Year Introduced 1982 -

Raw Materials Acetic anhydride Polyphosphoric acid Manganese dioxide Maleic acid 2-Aminomethyl-7-chloro-2,3-dihydro5-(2-fluorophenyl)-1H-1,4-benzodiazepine Manufacturing Process Acetic anhydride (7 ml) was added to a solution of 6.16 g of crude 2aminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepine in 200 ml of methylene chloride. The solution was added to 200 ml of saturated aqueous sodium bicarbonate and the mixture was stirred for 20 minutes. The organic layer was separated, washed with sodium bicarbonate, dried over sodium sulfate and evaporated to leave resinous 2acetylaminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-lH -l,4benzodiazepine. This material was heated with 40 g of polyphosphoric acid at 150°C for 10 minutes. The cooled reaction mixture was dissolved in water, made alkaline with ammonia and ice and extracted with methylene chloride. The extracts were dried and evaporated and the residue was chromatographed over 120 g of silica gel using 20% methanol in methylene chloride. The clean fractions were combined and evaporated to yield resinous 8-chloro-3a,4-dihydro-6-(2-fluorophenyl)-1- methyl-4H-imidazo[1,5-a][1,4] benzodiazepine. A mixture of this material with 500 ml of toluene and 30 g of manganese dioxide was heated to reflux for 1½ hours. The manganese dioxide was separated by filtration over Celite. The filtrate was evaporated and the residue was crystallized from ether to yield 8-chloro-6-(2-fluorophenyl)-1-methyl-4Himidazo[1,5-a][1,4]benzodiazepine, melting point 152°C to 154°C. The analytical sample was recrystallized from methylene chloride/hexane. A warm solution of 6.5 g (0.02 mol) of 8-chloro-6-(2-fluorophenyl)-1-methyl4H-imidazo[1,5-a] [1,4]-benzodiazepine in 30 ml of ethanol was combined with a warm solution of 2.6 g (0.022 mol) of maleic acid in 20 ml of ethanol. The mixture was diluted with 150 ml of ether and heated on the steam bath for 3 minutes. After cooling, the crystals were collected, washed with ether and dried in vacuo to yield 8-chloro-6-(2-fluorophenyl)-1-methyl-4Himidazo[1.5-a] [1,4]-benzodiazepine maleate, melting point 148°C to 151°C. References Merck Index 6056 DFU 3 (11) 822 (1978) OCDS Vol. 3 p. 197 (1984) DOT 19 (2) 113; (4) 221 and (7) 378 (1983) I.N.p. 635

2304

Midecamycin

F. Hoffmann-La Roche and Co.; British Patent 1,527,131; October 4,1978

MIDECAMYCIN Therapeutic Function: Antibacterial Chemical Name: Leucomycin V, 3,4B-dipropanoate Common Name: Espinomycin Structural Formula:

Chemical Abstracts Registry No.: 35457-80-8 Trade Name Medemycin Midecacine Midecacine Midicacin Aboren Macro-Dil

Manufacturer Meiji Seika Clin Midy Clin Midy Midy Promeco Roussel

Country Japan France Switz. Italy Argentina -

Year Introduced 1974 1978 1980 1981 -

Raw Materials Bacterium Streptomyces mycsrofaciens Starch Vegetable protein Manufacturing Process The SF-837 strain, namely Streptomyces mycarofaciens identified as ATCC No. 21454 was inoculated to 60 liters of a liquid culture medium containing 2.5% saccharified starch, 4% soluble vegetable protein, 0.3% potassium chloride and 0.3% calcium carbonate at pH 7.0, and then stir-cultured in a jar-

Midecamycin

2305

fermenter at 28°C for 35 hours under aeration. The resulting culture was filtered directly and the filter cake comprising the mycelium cake was washed with dilute hydrochloric acid. The culture filtrate combined with the washing liquid was obtained at a total volume of 50 liters (potency 150 mcg/ml). The filtrate (pH 8) was then extracted with 25 liters of ethyl acetate and 22 liters of the ethyl acetate phase was concentrated to approximately 3 liters under reduced pressure. The concentrate was diluted with 1.5 liters of water, adjusted to pH 2.0 by addition of 5N hydrochloric acid and then shaken thoroughly. The aqueous phase was separated from the organic phase and this aqueous solution was adjusted to pH 8 by addition of 3N sodium hydroxide and then extracted with 800 rnl of ethyl acetate. The resulting ethyl acetate extract was then shaken similarly together with 500 ml of aqueous hydrochloric acid to transfer the active substances into the latter which was again extracted with 400 ml of ethyl ether at pH 8.The ether extract was dried with anhydrous sodium sulfate and concentrated under reduced pressure to give 16.5 g of light yellow colored powder. 12 g of this crude powder were dissolved in 200 ml of ethyl acetate and the solution was passed through a column of 600 ml of pulverized carbon which had been impregnated with ethyl acetate. The development was carried out using ethyl acetate as the solvent and the active fractions of eluate were collected to a total volume of 2,500 ml, which was then evaporated to dryness under reduced pressure to yield 5 g of a white colored powder. This powder was dissolved in 10 ml of benzene and the insoluble matters were filtered out. The filtered solution in benzene was then subjected to chromatographic isolation by passing through a column of 700 ml of silica gel which had been impregnated with benzene. The development of the active substances adsorbed on the silica gel was effected using a solvent system consisting of benzene-acetone (4:1), and the eluate was collected in fractions of each 20 ml. The active fractions No. 90-380 which gave a single spot in alumina thin layer chromatography and which could be recognized as containing the SF837 substance purely in view of the Rf-value of the single spot were combined together to a total volume of 4,000 ml, and then concentrated under reduced pressure to yield 1.5 g of white colored powder of a melting point of 122°C to 124°C which was found by analysis to be the pure SF-837 substance free base. References Merck Index 6057 Kleeman and Engel p. 601 DOT 10 (2) 62 (1974) I.N. p. 635 Tsuruoka,T., Shomura.T., Ezaki, N., Akita, E., Inoue, S., Fukatsu, S., Amano,S., Watanabe, H. and Niida, T.; US Patent 3,761,588; September 25,1973; assigned to Meiji Seika Kaisha, Ltd. (Japan)

2306

Midodrine

MIDODRINE Therapeutic Function: Peripheral vasotonic, Antihypotensive Chemical Name: 2-Amino-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]acetamide Common Name: Structural Formula:

Chemical Abstracts Registry No.: 42794-76-3; 3092-17-9 (Hydrochloride salt) Trade Name Gutron Gutron Alphamine

Manufacturer Hormonchemie Chemie Linz Centerchem

Country W. Germany Italy US

Year Introduced 1977 1981 -

Raw Materials Carbobenzoxyglycine Isovaleric acid chloride 1-(2',5'-Dimethoxyphenyl)-2-aminoethanol-(1) Hydrogen Manufacturing Process 19.5 parts of carbobenzoxyglycine, 7.1 parts of triethylamine and 162 parts of dry toluene are mixed with 11.2 parts of isovaleric acid chloride at 0°C to form the mixed anhydride and the mixture is agitated for two hours at 0°C. 32.4 parts of 1-(2',5'-dimethoxyphenyl)-2-aminoethanol-(1) are then added, the mixture is agitated for four hours at a temperature between 0°C and +10°C and then left to stand overnight at that temperature. A thick crystal paste forms. The reaction product is dissolved in 450 parts of ethyl acetate and 200 parts of water. The ethyl acetate solution is separated, washed with hydrochloric acid, sodium bicarbonate solution and water, dried over sodium sulfate and inspissated. The inspissation residue is digested with 342 parts of xylene, the required product crystallizing out. 34.9 parts of 1-(2',5'dimethoxyphenyl)-2-(N-carbobenzoxyglycineamido)-ethanol-(1) are obtained.

Mifepristone

2307

66.2 parts of 1-(2',5'-dimethoxyphenyl)-2-(N-carbobenzoxyglycineamido)ethanol-(1) are hydrogenated in the presence of 6.6 parts of palladium carbon (10%) in 2,000 parts of glacial acetic acid. When no more hydrogen is absorbed (3 mols of hydrogen are used), hydrogenation stops. The catalyst is removed by suction and the equivalent quantity of hydrochloric acid in ethanol is added to the filtrate with agitation. During further agitation at room temperature 28.6 parts of crude 1-(2',5'-dimethoxyphenyl)-2glycineamidoethanol-(1)hydrochloride crystallize, and are isolated and recrystallized from water-methanol for purification. 22.1 parts of pure product are obtained with a melting point of 192°C to 193°C. An alternative synthesis route is described by Kleeman and Engel. References Merck Index 6058 Kleeman and Engel p. 602 DOT 18 (10 530 (1982) I.N. p. 636 Wismayr, K., Schmid, O., Kilches, R. and Zolss, G.; US Patent 3,340,298; September 5, 1967; assigned to Oesterreichische Stickstoffwerke A.G. (Austria)

MIFEPRISTONE Therapeutic Function: Antiprogesterone Chemical Name: Estra-4,9-dien-3-one, 11-(4-(dimethylamino)phenyl)-17hydroxy-17-(1-propynyl)-, (11β,17β)Common Name: Mifepristone Structural Formula:

Chemical Abstracts Registry No.: 84371-65-3

2308

Mifepristone

Trade Name Mifegyne Mifegyne

Manufacturer HMR Exelgyn

Country -

Year Introduced -

Raw Materials 4-(N,N-Dimethylaminoethoxy)bromobenzene 1,2-Dibromoethane Dimethylsulfide-cuprous bromide complex 3,3-[1,2-(Ethanediyl-bisoxy)]-5α,10α-epoxy-17α-prop-1-ynyl-δ(9(11))estrene-17β-ol Manufacturing Process 1st method of synthesis of mifepristone: A solution of 24 g of 4-(N,N-dimethylaminoethoxy)bromobenzene was added dropwise over 45 min to magnesium in 90 ml of anhydrous tetrahydrofuran. 2 ml of 1,2-dibromoethane were added as catalyst. After the addition, the mixture was stirred at 25°C for one hour to obtain a solution of 0.7 M of 4(N,N-dimethylaminoethoxy)-benzene magnesium bromide which was then added to a solution of 6.16 g of dimethylsulfide-cuprous bromide complex in 20 ml of tetrahydrofuran. The mixture was stirred at room temperature for 20 min and a solution of 3.7 g of 3,3-[1,2-(ethanediyl-bisoxy)]-5α,10α-epoxy17α-prop-1-ynyl-δ(9(11))-estrene-17β-ol in 50 ml of tetrahydrofuran was added thereto dropwise over a few minutes. The mixture was stirred under an inert atmosphere for one hour and was then poured into a solution of 15 g of ammonium chloride in 20 ml of iced water. The mixture was extracted with ether and the organic phase was washed with aqueous saturated sodium chloride solution, was dried and evaporated to dryness under reduced pressure. The 18.3 g of oil were chromatographed over silica gel and eluted with chloroform to obtain 4.5 g of 3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,Ndimethylaminoethoxy)phenyl]-17α-(prop-1-ynyl)-δ9-estrene-5α,17β-diol with a specific rotation of [α]D20 =-44(+/-)1.5° (c = 1% in chloroform). 9.5 ml of 2 N hydrochloric acid were added to a solution of 4.5 g of 3,3-[1,2ethanediyl-bisoxy]-11β-[4-(N,N-dimethylaminoethoxy)phenyl]-17α-(prop-1ynyl)-δ9-estrene-5α,17β-diol in 20 ml of methanol and the solution was stirred at room temperature for 2 hours. 260 ml of ether and 110 ml of an aqueous saturated sodium bicarbonate solution were added to the mixture which was stirred at room temperature for 15 min. The decanted aqueous phase was extracted with ether and the organic phase was dried and evaporated to dryness under reduced pressure. The 3.3 g of residue were chromatographed over silica gel and eluted with a 92.5/7.5 methylene chloride-methanol mixture to obtain 1.8 g of amorphous 11β-[4-(N,N-dimethylaminoethoxy) phenyl]-17α-(prop-1-ynyl)-δ4,9-estradiene-17β-ol-3-one with a specific rotation of [α]D20 =+71° (c = 1% in chloroform). 2th method of synthesis of mifepristone (see scheme):

Mifepristone

2309

The oxidation of the diene I, which constitutes an intermediate for total synthesis of 19-nor steroids, with a reagent prepared from trifluoroacetic anhydride/hydrogen peroxide was obtained exclusively α-epoxide II. The condensation of II with the Grignard reagent from 4-bromo-N,Ndimethylaniline results in addition of the reagent at the 11β-position. This results in rearragement of the olefin to 9,10 and opening of the epoxide. The stereochemistry of the product obtained III is consistent with trans-opening of the oxirane, albeit at a remove of two carbon atoms. Mild hydrolysis removes the silyl cyanohydrin protecting group at the 17-position to give a ketone IV. Reaction of the ketone with propargyl lithium leads to V. Hydrolysis of that product under more strenuous condition results in removal of the acetal at 3; the resulting β-hydroxyketone then dehydrates to afford the 4,10(9)-dienone VI. Another name of VI is estra-4,9-dien-3-one, 11-(4-(dimethylamino) phenyl)-17-hydroxy-17-(1-propynyl)-, (11β,17β)- or mifepristone. References Merck Index, Monograph number: 6273, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc.

2310

Miglitol

Teutsch J.G. et al.; US Patent No. 4,386,085; May 31, 1983; Assigned to Roussell Uclaf, Paris, France Velluz L. et al.; Compt. Rend., 257, 569 (1963) Lednicer D.; Ed 'Chronicles of Drug Discovery', Vol. 3, p.1., ACS Books, Washington, DC, 1993, p.1

MIGLITOL Therapeutic Function: Glucosidase inhibitor Chemical Name: 3,4,5-Piperidinetriol, 1-(2-hydroxyethyl)-2(hydroxymethyl)-, (2R-(2α,3β,4α,5β))Common Name: Glycet; Miglitol Structural Formula:

Chemical Abstracts Registry No.: 72432-03-2 Trade Name Miglitol Miglitol Diastabol Diastabol Diastabol Glyset

Manufacturer SMS Pharmaceuticals Limited ZYF Pharm Chemical Sanofi-Synthelabo Sanofi Aventis Bayer Pharma Pharmacia and Upjohn

Country -

Year Introduced -

-

-

Raw Materials Triethylamine Sodium borohydride Lewatit

6-Amino-6-desoxy-L-sorbose hydrochloride Dimethylaminoborane 1,5-Didesoxy-1,5-imino-D-glucitol of 6amino-6-desoxy-L-sorbose hydrochloride

Manufacturing Process 50 g (0.23 mole) of 6-amino-6-desoxy-L-sorbose hydrochloride were dissolved

Milrinone lactate

2311

in 500 ml of distilled water, and the solution was added in the course of one hour to a solution of 11.2 g of dimethylaminoborane in 500 ml of distilled water, whilst stirring at a temperature of 50°C. The mixture was stirred for one hour at room temperature and one hour at 50°C, 5 ml of triethylamine were added to it, and it was then poured over a column containing 800 ml of strongly basic ion exchanger ("Lewatit" MP 500 OH--form). The exchanger was washed with distilled water, and the runnings collected were concentrated to a syrup on a rotary evaporator. The concentrated syrup was crystallised at 50°C on addition of a large amount of ethanol. The suspension of crystals was cooled and filtered off under suction, and the crystalline product was dried in a vacuum drying cabinet. Yield: 30 g, 80% of theory. MP: 192°-193°C. 25 g (0.115 mole) 1,5-didesoxy-1,5-imino-D-glucitol of 6-amino-6-desoxy-Lsorbose hydrochloride were dissolved in 200 ml of distilled water, and the solution was added at 5°C to a mixture of 4.8 g of NaBH4, 250 ml of ethanol/water 1:1 and 16.2 ml of triethylamine, whilst stirring. The mixture was further stirred for one hour at room temperature and one hour at 50°C., and the reaction mixture was poured over a column containing 400 ml of strongly basic ion exchanger ("Lewatit" MP 500 OH-form). The exchanger was washed with distilled water, and the eluate collected was concentrated to a syrup in a rotary evaporator. Th syrup was taken up with 200 ml of distilled water, and the mixture was poured over a column containing 400 ml of acid ion exchanger ("Lewatit" S 100 H+-form). The column was rinsed with distilled water, and the product was eluted with 10% strength ammonia water. The runnings, rendered alkaline with ammonia, were collected and were concentrated to a syrup in a rotary evaporator. The syrup was crystallized, whilst warm, with a large amount of ethanol, and the suspension of crystals was cooled and is filtered off under suction, and the crystalline product was dried in a vacuum drying cabinet. Yield of 1,5-dideoxy-1,5-((2hydroxyethyl)imino)-D-glucitol 14 g, 74% of theory. MP: 192°-193°C. References Koebernick W.; US Patent No. 4,611,058; September 9, 1986; Assigned to Bayer Aktiengesellschaft (Leverkusen, DE)

MILRINONE LACTATE Therapeutic Function: Cardiotonic Chemical Name: Propanoic acid, 2-hydroxy-, compd. with 1,6-dihydro-2methyl-6-oxo(3,4'-bipyridine)-5-carbonitrile Common Name: Milrinone lactate Chemical Abstracts Registry No.: 100286-97-3; 78415-72-2 (Base) Trade Name

Manufacturer

Country

Year Introduced

Primacor

Baxter Healthcare Corporation

-

-

2312

Milrinone lactate

Structural Formula:

Raw Materials α-Cyanoacetamide Sodium methoxide Malononitrile

1-(4-Pyridinyl)-2-propanone Dimethylformamide dimethyl acetal

Manufacturing Process A mixture containing 20 g of 1-(4-pyridinyl)-2-propanone and 30 ml of hexamethylphosphoramide was diluted with 65 ml of dimethylformamide dimethyl acetal and the resulting mixture was refluxed for 30 min. TLC analysis showed a single spot, thereby indicating completion of the reaction (in another run, the reaction appeared to be complete after 30 min at room temperature). The mixture was evaporated under reduced pressure and a pressure, thereby resulting in a crystalline residue weighing 24 g. The residue was purified by continuous chromatographic extraction on alumina (about 150 g) using refluxing chloroform as eluant. After 90 min, the extract was heated in vacuo to remove the chloroform, thereby leaving, as a light yellow crystalline material, 23.2 g of 1-(4-pyridinyl)-2-(dimethylamino)ethenyl methyl ketone, alternatively named 4-dimethylamino-2-(4-pyridinyl)-3-buten2-one. To a mixture containing 23 g of 1-(4-pyridinyl)-2-(dimethylamino)ethenyl methyl ketone and 11 g of α-cyanoacetamide dissolved in 400 ml of dimethylformamide was added with stirring 14 g of sodium methoxide and the resulting reaction mixture was heated in an oil bath under gentle reflux for one hour. TLC analysis showed no starting material in the reaction mixture which was then concentrated in vacuo on a rotary evaporator to a volume of about 80 ml. The concentrate was treated with about 160 ml of acetonitrile and the resulting mixture was stirred on a rotary evaporator with warming until homogenous and then cooled. The crystalline product was collected, rinsed successively with acetonitrile and ether, and dried overnight at 55°C to yield 28 g of crystalline product, namely, sodium salt of 1,2-dihydro-6-methyl2-oxo-5-(4-pyridinyl)nicotinonitrile, the presence of cyano being confirmed by IR analysis. An 8 g portion of said sodium salt was dissolved in 75 ml of hot water, the aqueous solution treated with decolorizing charcoal, filtered, the filtrate again treated with decolorizing charcoal and filtered, and the filtrate acidified with 6 N hydrochloric acid by dropwise addition to a pH of 3. The acidic mixture was diluted with ethanol and cooled. The crystalline product was collected, dried, recrystallized from dimethylformamide-water and dried to produce 3.75 g of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile, m.p. >300°C. Another method of preparation of 1,2-dihydro-6-methyl-2-oxo-5-(4-

Minaprine

2313

pyridinyl)nicotinonitrile (Patent US 4,413,127) A 69.5 g portion of 1-ethoxy-2-(4-pyridinyl)ethenyl methyl ketone was dissolved in 300 ml of ethanol and to the solution was added 13.2 g of malononitrile. The resulting mixture was refluxed for 5 hours, crystals starting to separate after about 30 min of refluxing. The reaction mixture was allowed to cool to room temperature and, the precipitate of fine needles was filtered, washed with ethanol and dried in a vacuum at 90°C to yield 25.4 g of 1,2dihydro-6-methyl-2-oxo-5-(4-pyridinyl)-nicotinonitrile, m.p. >300°C. Concentration of the mother liquor provided another 2.1 g of product, m.p. >300°C. To a aqueous solution of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl) nicotinonitrile was added one molar equivalent of lactic acid to prepare the monolactate of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile. References Lesher G. Y. et al.; US Patent No. 4,413,127; Feb. 2, 1982; Assigned to Sterling Drug Inc. (New York, NY) Lesher G.Y. et al.; US Patent No. 4,313,951; Feb. 2, 1982; Assigneed to Sterling Drug Inc. (New York, NY)

MINAPRINE Therapeutic Function: Antidepressant Chemical Name: 3-(2-Morpholinoethylamino)-4-methyl-6-phenylpyridazine dihydrochloride Common Name: Structural Formula:

Chemical Abstracts Registry No.: 25905-77-5; 25953-17-7 (Dihydrochloride salt)

2314

Minocycline

Trade Name Cantor Kantor

Manufacturer Clin Midy Gador

Country France Argentina

Year Introduced 1979 1983

Raw Materials 3-Chloro-4-methyl-6-phenylpyridazine N-(2-Aminoethyl)morpholine Hydrogen chloride Manufacturing Process (a) Preparation of the free base: A mixture comprising 0.1 mol (20.4 g) of 3chloro-4-methyl-6-phenylpyridazine and 0.2 mol (26.2 g) of N-(2-aminoethyl)morpholine in 100 ml of n-butanol, with a pinch of copper powder, was heated under reflux for 12 hours. At the end of this time, the hot solution was poured into 200 ml of cold water. The resulting mixture was filtered through a sintered glass filter and the precipitate washed with ether. The filtrate and the ether washings were placed in a separating funnel and extracted with two 150 ml portions of ether. The ethereal layer was then extracted with about 250 ml of N sulfuric acid. The acid solution was made alkaline with a 10% aqueous solution of sodium carbonate, and left to crystallize overnight. The solution was filtered, yielding the colorless needles which were recrystallized from isopropanol. The yield was 15 g (53%). (b) Preparation of the hydrochloride: The base was dissolved in the smallest amount possible of anhydrous acetone. Double that volume of anhydrous ether was added, and a stream of hydrogen chloride gas was passed through the solution. The hydrochloride salt obtained was recrystallized from absolute alcohol. The yield after recrystallization was 17 g (90%). References Merck Index 6066 DFU 2 (12) 811 (1977) Kleeman and Engel p. 602 I.N. p. 637 Laborit, H.; British Patent 1,345,880; Feb. 6, 1974; and US Patent 4,169,158; Sept. 25, 1979; both assigned to Centre D'Etudes Experimentales et Cliniques de Physiobiologie de Pharmacologie et D'Eutonologie (C.E.P.B.E.P.E.)

MINOCYCLINE Therapeutic Function: Antibiotic

Minocycline

2315

Chemical Name: 4,7-Bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide Common Name: 7-Dimethylamino-6-demethyl-6-deoxytetracycline Structural Formula:

Chemical Abstracts Registry No.: 10118-90 8; 13614-98-7 (Hydrochloride salt) Trade Name Minocin Minomycin Klinomycin Minocin Minomycin Vectrin Minocin Mynocine Ultramycin

Manufacturer Lederle Lederle Lederle Lederle Takeda Parke Davis Lederle Lederle Parke Davis

Country US Japan W. Germany Italy Japan US UK France -

Year Introduced 1971 1971 1972 1972 1972 1973 1973 1973 -

Raw Materials 6-Demethyltetracycline Dibenzyl azodicarboxylate Hydrogen Manufacturing Process Preparation of 7-(N,N'-Dicarbobenzyloxyhydrazino)-6-Demethyltetracycline: A 1.0 g portion of 6-demethyltetracycline was dissolved in a mixture of 9.6 ml of tetrahydrofuran and 10.4 ml of methanesulfonic acid at -10°C. The mixture was allowed to warm to 0°C. A solution of 0.86 g of dibenzyl azodicarboxylate in 0.5 ml of tetrahydrofuran was added dropwise and the mixture was stirred for 2 hours while the temperature was maintained at 0°C. The reaction mixture was added to ether. The product was filtered off, washed with ether and then dried. The 7-(N,N'-dicarbobenzyloxyhydrazino)-6demethyltetracycline was identified by paper chromatography. Reductive Methylation of 7-(N,N'-Dicarbobenzyloxyhydrazino)-6-Demethyl-6Deoxytetracycline to 7-Dimethylamino-6-Demethyl-6-Deoxytetracycline: A solution of 100 mg of 7(N,N'-dicarbobenzyloxyhydrazino)-6-demethyl-6deoxytetracycline in 2.6 ml of methanol, 0.4 ml of 40% aqueous

2316

Minoxidil

formaldehyde solution and 50 mg of 5% palladium on carbon catalyst was hydrogenated at room temperature and two atmospheres pressure. Uptake of the hydrogen was complete in 3 hours. The catalyst was filtered off and the solution was taken to dryness under reduced pressure. The residue was triturated with ether and then identified as 7-dimethylamino-6-demethyl-6deoxytetracycline by comparison with an authentic sample, according to US Patent 3,483,251. References Merck Index 6068 Kleeman and Engel p. 603 PDR p. 1018 OCDS Vol. 1 p. 214 (1977) and 2,288 (1980) DOT 5 (2) 75 (1969); 7 (5) 188 (1971) and 8 (3) 93 (1972) I.N. p.637 REM p. 1206 Boothe, J.H. and Petisi, J.; US Patent 3,148,212; September 8,1964; assigned to American Cyanamid Company Petisi, J. and Boothe, J.H.; US Patent 3,226,436; December 28,1965; assigned to American Cyanamid Company Winterbottom, R., Bitha, P. and Kissman, H.M.; US Patent 3,345,410; October 3,1967; assigned to American Cyanamid Company Zambrano, R.T.; US Patent 3,403,179; September 24,1968; assigned to American Cyanamid Company Zambrano, R.T.; US Patent 3,483,251 ;December 9,1969; assigned to American Cyanamid Company

MINOXIDIL Therapeutic Function: Antihypertensive Chemical Name: 6-Amino-1,2-dihydro-1-hydroxy-2-imino-4piperidinopyrimidine Common Name: Structural Formula:

Chemical Abstracts Registry No.: 38304-91-5 Raw Materials Barbituric acid Ammonia Piperidine

2,4,6-Trichloropyrimidine m-Chloroperbenzoic acid Phosphorus oxychloride

Mirtazapine Trade Name Loniten Loniten Loniten Loniten Loniten Prexidil

Manufacturer Upjohn Upjohn Upjohn Upjohn Upjohn Bioindustria

Country US UK Switz. W. Germany Italy Italy

2317

Year Introduced 1979 1980 1981 1982 1983 1983

Manufacturing Process Barbituric acid is reacted with phosphorus oxychloride then with 2,4,6trichloropyrimidine and that product with ammonia to give 4-chloro-2,6diaminopyritnidine. A 30 g (0.15 mol) quantity of 4-chloro-2,6-diaminopyrimidine is dissolved in 600 ml of hot 3A alcohol, the solution cooled to 0°C to 10°C and 41.8 g (0.24 mol) of m-chloroperbenzoic acid is added. The mixture is held at 0°C to 10°C for 4 hours and filtered. The solid is shaken for 2 hours in 0.24 mol of 10% sodium hydroxide and filtered. The solid is washed with water and dried to yield 193 g of crude product. This product is extracted for 1 hour with 900 ml of boiling acetonitrile to yield 14.8 g (44.7% yield) of 6-amino-4-chloro-1,2dihydro-1-hydroxy-2-iminopyrimidine, melting point 193°C. A mixture of 3.0 g (0.019 mol) of 6-amino-4-chloro-1,2-dihydro-1-hydroxy-2iminopyrimidine and 35 ml of piperidine is refluxed for 1.5 hours, cooled and filtered. The solid is shaken for 20 minutes in a solution of 0.8 g of sodium hydroxide in 30 ml of water and filtered. The solid is washed with water and extracted with 800 ml of boiling acetonitrile and filtered to yield 3.5 g (89%) yield of 6-amino-4-chloro-1,2-dihydro-1-hydroxy-2-iminopyrimidine, melting point 248°C, decomposition at 259°C to 261°C. References Merck Index 6069 DFU 2 (6) 383 (1977) Kleeman and Engel p. 604 PDR p. 1848 OCDS Vol. 1 p. 262 (1977) DOT8 (7) 277 (1972) and 16 (9) 298 (1980) I.N.p. 638 REM p. 848 Anthony, W.C. and Ursprung, J.J.; US Patents 3,382,247; May 7,1968 and 3,382,248; May 7,1968; both assigned to The Upjohn Co. Anthony, W.C.; US Patent 3,644,364; February 22,1972; assigned to The Upjohn Co.

MIRTAZAPINE Therapeutic Function: Antidepressant, Antihistaminic, Antidiuretic

2318

Mirtazapine

Chemical Name: Pyrazino[2,1-a]pyrido[2,3-c](2)benzazepine, 1,2,3,4,10,14b-hexahydro-2-methylCommon Name: Azamiaserin; Mepirzapin; Mirtazapine Structural Formula:

Chemical Abstracts Registry No.: 61337-67-5 Trade Name Mirazep Mirt Mirtaz

Manufacturer Syncro (A Div. of Microlabs) Panacea Biotec Ltd. Sun Pharmaceuticals Industries Ltd.

Country India India India

Year Introduced -

Remeron Zispin

Organon Triton

Netherlands -

-

Raw Materials Potassium fluoride 2-Chloronicotinonitrile Sulfuric acid 1-Methyl-3-phenylpiperazine Lithium aluminum hydride Manufacturing Process 1) 1-(3-Cyanopyridyl-2)-2-phenyl-4-methylpiperazine 17.43 g (0.3 mol) potassium fluoride is added to a solution of 13.85 g (0.1 mol) 2-chloronicotinonitrile and 17.62 g (0.1 mol) 1-methyl-3phenylpiperazine in 250 ml dry DMF and the suspension is heated at 140°C under a nitrogen atmosphere for 20 hours. After cooling, the reaction mixture is poured into 1,250 ml water. The aqueous phase is extracted four times with ethyl acetate the combined organic extracts are washed with 100 ml water. After drying, the extracts are evaporated. The crude oil may be used as such for the following step. The nitrile obtained may however also be purified by column chromatography on SiO2, with hexane-acetone (95:5). In this way, 21.9 g (79%) pure 1-(3-cyanopyridyl-2)-4-methyl-2-phenylpiperazine is obtained; the substance crystallizes from petroleum ether; melting point 66.567.5°C.

Misoprostol

2319

2) 1-(3-Carboxypyridyl-2)-2-phenyl-4-methylpiperazine The solution of 19.5 g (0.07 mol) 1-(3-cyanopyridyl-2)-4-methyl-2phenylpiperazine in 390 ml of a solution of 25 g KOH/ 100 ml ethanol is heated at 100°C for 24 hours. After cooling, water (390 ml) is added. The alcohol is evaporated under vacuum and the cloudy solution remaining is extracted twice with 100 ml methylene chloride. The residual aqueous phase is cooled and the pH is adjusted to 7 with 2 N HCl, after which it is extracted with chloroform. After drying the chloroform extract, it is evaporated and 16.2 g 1-(3-carboxypyridyl-2)-4-methyl-2-phenylpiperazine is obtained as a colourless oil. Crystallization from ethanol gives a crystalline substance with a melting point of 161-162°C. 3) 1-(3-Hydroxymethylpyridyl-2)-2-phenyl-4-methylpiperazine 20.4 g (0.07 mol) 1-(3-carboxypyridyl-2)-2-phenyl-4-methylpiperazine is dissolved in 300 ml dry THF and gradually added to a boiling suspension of 20.4 g LiAlH4in 600 ml dry THF under a nitrogen atmosphere. The mixture is boiled for 4 hours, after which it is cooled in an ice-bath and decomposed by adding 81.6 ml water. The inorganic salts are filtered off. The filtrate is dried and solvent is removed by evaporation, giving a yield of 18.39 g (93%) 1-(3hydroxymethylpyridyl-2)-2-phenyl-4-methylpiperazine. Recrystallization from ether gives a crystalline product (white needles) of melting point 124-126°C. 4)2-Methyl-1,2,3,4,10,14b-hexahydro-benzo[c]pyrazino-[1,2-a]-pyrido[2,3c]azepine(Mirtazapine) 6.5 ml concentrated sulfuric acid is added dropwise at room temperature to 3.25 g of 1-(3-hydroxymethylpyridyl-2)-2-phenyl-4-methylpiperazine. During the addition, the temperature rises to 35°C. The whole is subsequently stirred for a few hours, after which 60 g ice is added and the mixture is made alkaline with concentrated ammonia (22 ml). The reaction mixture is then extracted with chloroform. The chloroform extracts are dried and concentrated. The crude reaction product crystallizes when ether is added, and the solid obtained is recrystallized from petroleum ether. Yield of 2methyl-1,2,3,4,10,14b-hexahydro-benzo[c]pyrazino-[1,2-a]-pyrido[2,3c]azepine 2.43 g; melting point: 114-116°C. References Maeda, et al.; US Patent No. 6,660,730; Dec. 9, 2003; Assigned to Sumika Fine Chemicals Co., Ltd.

MISOPROSTOL Therapeutic Function: Antiulcer Chemical Name: Prost-13-en-1-oic acid, 11,16-dihydroxy-16-methyl-9-oxo-, methyl ester, (11α,13E)-(+-)-

2320

Misoprostol

Common Name: Misoprostol Structural Formula:

Chemical Abstracts Registry No.: 59122-46-2; 62015-39-8 Trade Name Cytotec Misoprost Misoprostol Misoprostol

Manufacturer Searle, division of Monsanto plc. Cipla Limited IVAX G.D. Searle and Co.

Country UK

Year Introduced -

India USA

-

Raw Materials (E)-Trimethyl[[1-methyl-1-[3-(tributylstannyl)-2propenyl]pentyl]oxy]silane Copper (I) iodide Methyllithium Methyl-5-oxo-3-[(triethylsilyl)oxy]-1-cyclopentene-1-heptanoate Manufacturing Process 1 method of synthesis To a 1000 ml dried flask under a nitrogen atmosphere was added 74.6 g of (E)-trimethyl-[[1-methyl-1-[3-(tributylstannyl)-2-propenyl]pentyl]oxy]silane, 125 ml anhydrous THF and 24.2 g of copper (I) iodide. The mixture was stirred at room temperature for 30 minutes and then it was cooled to -25 to 30°C. 98.8 ml of methyllithium (2.86 M) in DEM was added dropwise and the resultant solution was stirred at -15°C for 2 hours. Then the reaction mixture was cooled to -78°C and 25 g of methyl-5-oxo-3-[(triethylsilyl)oxy]-1cyclopentene-1-heptanoate in 100 ml of THF was added rapidly. After stirring the mixture for 5 min at -78°C, it was quenched into a mixture of 750 ml of aqueous ammonium chloride solution and 200 ml of ammonium hydroxide. The resulting mixture was warmed to room temperature and stirred until a deep blue aqueous layer was obtained. Ethyl acetate (250 ml) was used for extraction. Then the combined organic layers were washed with brine and subsequently dried over magnesium sulfate. After a filtration and concentration under reduced pressure, an oil (105 g) was obtained. This oil containing the protected prostaglandin was subjected to acidic deprotection (cat. PPTS, acetone and water) and purification (chromatography on silica gel) to provide 15.8 g (60%) of misoprostol was identical.

Mitobronitol

2321

2 method of synthesis To a 300 ml dried flask under a nitrogen atmosphere was added 4.45 g of copper (I) iodide and 60 ml of anhydrous THF. The mixture was cooled to 0°C 35 ml of 1.4 M methyllithium in diethyl ether was added dropwise and the resultant solution was stirred at 0°C for 30 min. 13.7 g of (E)-trimethyl-[[1methyl-1-[3-(tributylstannyl)-2-propenyl]pentyl]oxy]silane in 5 ml of THF was added and then the mixture was stirred at 0°C for 30 min. Then an additional 1.5 ml of 1.4 M methyllithium in diethyl ether was added and the mixture was stirred for another 30 min. The reaction mixture was cooled to -78°C and 10 g of methyl 5-oxo-3-[(triethylsilyl)oxy]-1-cyclopentene-1-heptanoate in 10 ml of THF was added rapidly. After stirring the mixture for 5 min at -78°C, it was quenched into 210 ml of basic aqueous ammonium chloride solution. The resulting mixture was warmed to room temperature and stirred until a deep blue aqueous layer was obtained. Ethyl acetate was used for extraction. Then the combined organic layers were washed with water (10 ml), then with brine (25 ml) and subsequently dried over magnesium sulfate. After a filtration and concentration under reduced pressure, an oil (21 g) was obtained. This oil containing the protected prostaglandin was subjected to acidic deprotection (cat. PPTS, acetone and water) and purification (chromatography on silica gel) to provide 4.2 g (40%) misoprostol. References Li Y.-F. et al.; US Patent No. 5,684,177; Nov. 4, 1997; Assigned to Torcan Chemical Ltd. "Organometallics in Synthesis: A Manual", Chapter 4, page 283-382; B. H. Lipshutz, Edited by M Schlosser, John Wiley and Sons, 1994 Lipshutz B.H., Synthesis, 325 (1987)

MITOBRONITOL Therapeutic Function: Cancer chemotherapy Chemical Name: 1,6-Dibromo-1,6-dideoxy-D-mannitol Common Name: Structural Formula:

Chemical Abstracts Registry No.: 488-41-5

2322

Mitomycin

Trade Name Myelobromol Myelobromol Myebrol

Manufacturer Hormonchemie Berk Kyorin

Country W. Germany UK Japan

Year Introduced 1967 1970 1978

Raw Materials D-Mannitol Hydrogen bromide Manufacturing Process 750 g D-mannitol are dissolved in 4,000 ml of a 48% aqueous hydrogen bromide solution, whereupon the solution thus obtained is saturated at 0°C with gaseous hydrogen bromide until a HBr content of 69 to 70% is achieved. The reaction mixture is heated for 6 hours at 60°C in an autoclave, is then decolorized with charcoal, extracted with 1 liter chloroform twice and diluted with 7 liters of water. The pH value of the solution is adjusted by means of sodium bicarbonate to1 to 2. The crystals precipitated after cooling for a day are filtered and washed with water until free from acid. 250 g crude 1,6dibromo-1,6-didesoxy-D-mannitol are obtained. MP 176° to 178°C. Analysis: Br % = 52 (calc.: 51.9). 250 g of the crude DBM are dissolved in 2.5 liters of hot methanol and on decolorizing and filtration 2.5 liters of dichloroethane are added. 220 g of crystalline DBM are obtained. MP 178°C. Br % = 51.9. References Merck Index 6076 Kleeman and Engel p. 604 I.N. p. 639 REM p. 1156 Chinoin Gyogyszeres Vegyeszeti Termekek Gyarart; British Patent 959,407; June 3,1964

MITOMYCIN Therapeutic Function: Cancer chemotherapy Chemical Name: Azirino(2',3':3,4)pyrrolo(1,2-a)indole-4,7-dione, 6-amino-8(((aminocarbonyl)oxy)methyl)-1,1a,2,8,8a,8b-hexahydro-8a-methoxy-5methyl-, (1aS,8S,8aR,8bS)Common Name: Chemical Abstracts Registry No.: 50-07-7

Mitomycin

2323

Structural Formula:

Trade Name Mitomycin Mitomycin C Ametycine Mitamycin Mitomycin C Mitamycin Mitomycin C

Manufacturer Medac Kyowa Choay Bristol Kyowa Bristol Syntex

Country W. Germany Italy France US Japan Sweden Switz.

Year Introduced 1960 1961 1970 1974 1980 1983 1983

Raw Materials Bacterium Streptomyces caespitosus Nutrient broth Manufacturing Process The commercial production of mitomycin involves the preparation of mitomycin-containing broths by culturing a mitomycin-producing organism, e.g. Streptomyces caespitosus, in suitable media as described at length in the literature. At the end of the fermentation cycle the whole broth is usually centrifuged, filtered or otherwise treated to separate the solids (mycelia) from the supernatant which contains substantially all of the antibiotic activity. In commercial processes there is usually a period of time intervening between the end of the fermentation cycle and the time at which the mycelia is actually removed from the broth; such a period may range from several minutes to several hours in length and may be due to a number of factors, e.g., the time necessary to conduct the actual centrifugation or filtration of large quantities of broth, or the time involved in waiting for equipment to become available for use. In the commercial preparation of mitomycin, the mitomycin-containing whole broths decrease rapidly in potency during the time following the completion of the fermentation cycle and prior to the removal of the mycelia. It has been observed that a whole broth will lose substantially all of its mitomycin activity within about 6 hours at room temperature and within about 24 hours at 10°C. It has, however, been discovered, as described in US Patent 3,042,582, that in the process for the recovery of mitomycin C from mitomycin C-containing whole broth, the step of adding about 0.1 wt % with whole broth of sodium lauryl sulfate to the whole broth at the completion of the fermentation cycle substantially eliminates such destruction of mitomycin C by mitase.

2324

Mitopodozide

References Merck Index 6079 Kleeman and Engel p. 604 PDR p. 724 I.N. p.640 REM p. 1156 Gourevitch, A., Chertow, B. and Lein, J.; US Patent 3,042,582; July 3,1962; assigned to Bristol-Myers Company

MITOPODOZIDE Therapeutic Function: Antineoplastic Chemical Name: 5,6,7,8-Tetrahydro-8-hydroxy-7-(hydroxymethyl)-5-(3,4,5trimethoxyphenyl)naphtho[2,3d]-1,3-dioxole-6-carboxylic acid-2ethylhydrazide Common Name: Podophyllinic acid 2-ethylhydrazide Structural Formula:

Chemical Abstracts Registry No.: 1508-45-8 Trade Name Proresid Proresid

Manufacturer Sandoz Sankyo

Raw Materials Podophyllinic acid hydrazide Acetaldehyde Hydrogen

Country W. Germany Japan

Year Introduced 1966 1969

Mitotane

2325

Manufacturing Process 500 g of podophyllinic acid hydrazide are heated together with 150 cc of acetaldehyde with 2,200 cc of methanol to 40°C. The solution obtained is filtered and then cooled. The product which crystallizes out is filtered off with suction and washed with methanol. Together with a second fraction obtained after concentration of the mother liquors there are produced 450 g of podophyllinic acid ethylidene hydrazide, having a melting point of 222°C to 224°C and a specific rotation of [α]D = -285° (c. = 0.5 in ethanol). The product is hydrogenated in 4,000 cc of ethanol at room temperature and under normal atmospheric pressure with a catalyst prepared in the usual manner from 400 g of Raney nickel alloy. The calculated amount of hydrogen is taken up in approximately 75 hours. After filtration and evaporation to a small volume, the residue is distributed between 1,000 cc of chloroform and water each. The chloroform solution is then dried over sodium sulfate and evaporated toa small volume. Precipitation of the hydrogenation product with petroleum ether yields an amorphous white powder which is filtered by suction, washed with petroleum ether and dried at 50°C in a high vacuum. 1ethyl-2-podophyllinic acid hydrazide is obtained in a practically quantitative yield. References Merck Index 7414 Kleeman and Engel p. 605 I.N. p. 640 Rutschmann, J.; US Patent 3,054,802; September 18, 1962; assigned to Sandoz Ltd. (Switzerland)

MITOTANE Therapeutic Function: Antineoplastic Chemical Name: Ethane, 2-(o-chlorophenyl)-2-(p-chlorophenyl)-1,1-dichloroCommon Name: Mitotane Structural Formula:

Chemical Abstracts Registry No.: 53-19-0

2326

Mitoxantrone dihydrochloride

Trade Name

Manufacturer

Country

Lysodren

Bristol Labs, Division of Bristol- Canada Myers Squibb Canada Inc.

Year Introduced -

Raw Materials Dichloroacetaldehyde 2-Chlorphenylmagnesiumbromide Manufacturing Process From dichloroacetaldehyde and 2-chlorphenylmagnesiumbromide was prepared 1-(2-chlorphenyl-2,2-dichloroethanol. By action of H2SO4 on 1-(2chlorphenyl)-2,2-dichloroethanol in chlorobenzene was prepared 1,1-dichloro2,2-bis(2,4'-dichlorophenyl)ethane. References Haller B.L. et al.; JACS 1945, 67, 1591

MITOXANTRONE DIHYDROCHLORIDE Therapeutic Function: Antineoplastic Chemical Name: 9,10-Anthraquinone, 5,8-bis((2-((2-hydroxyethyl)amino) ethyl)amino)-1,4-dihydroxy-, dihydrochloride Common Name: Mitoxantrone hydrochloride; Mitozantrone hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 70476-82-3; 65271-80-9 (Base) Trade Name

Manufacturer

Country

Year Introduced

Novantrone

Immunex Corporation

-

-

Oncotrone

Baxter Oncology GmbH

Germany

-

Mivacurium chloride

2327

Raw Materials 2-(2-Aminoethylamino)ethanol N,N,N',N'-Tetramethylethylenediamine Leuco-1,4,5,8-tetrahydroxyanthraquinone Chloranil Manufacturing Process A suspension of 12.5 g of 2-(2-aminoethylamino)ethanol in 40 ml of N,N,N',N'-tetramethylethylenediamine is stirred and de-aerated by bubbling nitrogen in for 15 min. A 10.97 g of leuco-1,4,5,8-tetrahydroxyanthraquinone is gradually added with stirring. The suspension is heated and stirred under nitrogen at 50-52°C for 5 hours. The mixture is allowed to stand and cool under nitrogen for 12 hours. The solid is collected by decantation, macerated in ethanol, collected and washed with ethanol giving 15.06 g of the desired product leuco-1,4-bis[2-(2-hydroxyethylamino)ethylamino]-5,8dihydroxyanthraquinone as a green-gray solid, melting point 129-131°C. Chloranil oxidation. To 17.86 g of a suspension of the leuco-1,4-bis[2-(2hydroxyethylamino)ethylamino]-5,8-dihydroxyanthraquinone (0.03 mole) in 2methoxyethanol was added gradually with stirring 15 ml of 8 N ethanolic hydrogen chloride. The system was chilled with an ice bath and stirred as 7.50 g (0.0305 mole) of chloranil powder was gradually added. The mixture was stirred overnight at room temperature and diluted with 600 ml of ether. The solid was collected and washed with tetrahydrofuran. Yield of 1,4-bis[2-(2hydroxyethylamino)ethylamino]-5,8-dihydroxyanthraquinone dihydrochloride 21.34 g, melting point 203-205°C (without recrystallisation). References Murdock K.C., Durr F.E.; US Patent No. 4,197,249; April 8, 1980; Assigned: American Cyanamid Company

MIVACURIUM CHLORIDE Therapeutic Function: Muscle relaxant Chemical Name: Isoquinolinium, 2,2'-((1,8-dioxo-4-octene-1,8-diyl)bis(oxy3,1-propanediyl))bis(1,2,3,4-tetrahydro-6,7-dimethoxy-2-methyl-1((3,4,5-trimethoxyphenyl)methyl)-, dichloride, (R-(R*,R*-(E)))Common Name: Mivacurium chloride Chemical Abstracts Registry No.: 106861-44-3; 133814-19-4 (Base) Trade Name Mivacron Mivacron

Manufacturer GlaxoSmithKline S.p.A. Abbott Laboratories

Country Italy -

Year Introduced -

2328

Mivacurium chloride

Structural Formula:

Raw Materials 3-Chloropropanol Sodium iodide Tartaric acid, dibenzoate, (-)-, monohydrate (E)-4-Octene-1,8-dioic acid chloride

(+/-)-5'-Methoxylaudanosine Sodium carbonate Tartaric acid, dibenzoate, (+)-, monohydrate

Manufacturing Process To ()-5'-methoxylaudanosine (46.4 g) in methanol (240 mL) was added (-)dibenzoyltartaric acid monohydrate (45.2 g). The mixture was heated to boiling, cooled at 5°C for 16 h and the (S)-(-)-5'-methoxylaudanosinium dibenzoyltartrate salt (35.6 g, 80%) was filtered and discarded. The mother liquors were made basic with concentrated aqueous NaOH and evaporated under vacuum. The solid residue was partitioned between H2O and diethyl ether. The ether phase was dried and evaporated to an oil (24.9 g). To the oil in methanol (128 mL) was added (+)-dibenzoyltartaric acid monohydrate (26.6 g). The mixture was heated to boiling and cooled at 5°C for 16 h. Crystals were collected and recrystallized from methanol until a constant specific rotation of [α]D20=+17.7° (1% EtOH) had been achieved. The yield of (R)-(+)-5'-methoxylaudanosinium dibenzoyltartrate as white crystals was 29.4 g (66%). A portion of the salt (15.0 g) in methanol (200 mL) was made basic with concentrated aqueous NaOH. The mixture was evaporated under vacuum and the residue was partitioned between H2O and diethyl ether. The combined ether layers were dried and evaporated under vacuum to yield 7.2 g (92%) of (R)-(-)-5'-methoxylaudanosine as an oil. (R)-(-)-5'-Methoxylaudanosine (7.2 g), 3-chloropropanol (3.5 g), sodium iodide (5.6 g) and sodium carbonate (0.5 g) were refluxed in 2-butanone (125 mL) for 16 h. The white suspension was filtered hot and solvent removed from the filtrate under vacuum. The residual gum was trituated with hot ethyl acetate to remove excess 3-iodopropanol, dissolved in 200 mL methanol and passed through a column packed with Dowex RTM.1-X8 ion exchange resin (60 g chloride form). The eluant was stripped of solvent under vacuum to give N-3-hydroxypropyl-1-(R)-5'-methoxylaudanosinium chloride (8.4 g) as an amophous solid. The material was assayed by HPLC as a 2.3/1 mixture of the

Modafinil

2329

trans/cis diastereomers. N-3-Hydroxypropyl-1-(R)-5'-methoxylaudanosinium chloride (2.3/1, trans/cis by HPLC, 2.5 g) was dissolved in 60 mL 1,2-dichloroethane at about 70°C. (E)-4-Octene-1,8-dioic acid chloride (0.5 g) (K. Sisido, K. Sei, and H. Nozaki, J. Org. Chem., 1962, 27, 2681) was added and the mixture was stirred at ambient temperature for 19 h. Solvent was removed under vacuum to give an amorphous solid which was dissolved in chloroform (25 mL) and washed with 5% aqueous sodium chloride solution to remove unreacted quaternary salts. The chloroform layer was dried and evaporated under vacuum to give an amorphous solid. The acid ester impurities were substantially removed by washing with hot 2-butanone. Residual solvent was evaporated under vacuum and the resulting amorphous solid was dissolved in methanol, filtered and lyophilized to give 1.9 g of (E)-(1R,1'R)-2,2'-[4-octenedioylbis (oxytrimethylene)]bis[1,2,4,3-tetrahydro-6,7-dimethoxy-2-methyl-1-(3,4,5trimethoxybenzyl)isoquinolinium] dichloride, which was assayed by HPLC as 44.6% RS-RS (trans-trans) diester, 42.4% RR-RS (cis-trans) diester, 7.5% RRRR(cis-cis) diester, 4.0% RS (trans) acid ester and 1.5% RR (cis) (E)(1R,1'R)-2,2'-[4-Octenedioylbis(oxytrimethylene)]bis[1,2,3,4-tetrahydro-6,7dimethoxy-2-methyl-1-(3,4,5-trimethoxybenzyl)isoquinolinium]dichloride acid ester, [α]D20=-62.7° (1.9% in water). References Swaririgen R.A. et al.; US Patent No. 4,761,418; Aug. 2; Assigned to Burroughs Weiicome Co., Research Triangle Park, N.C.; Boston, Mass.

MODAFINIL Therapeutic Function: Psychostimulant Chemical Name: Acetamide, 2-((diphenylmethyl)sulfinyl)Common Name: Modafinil Structural Formula:

Chemical Abstracts Registry No.: 68693-11-8 Trade Name Modafinil Modafinil

Manufacturer Cephalon, Inc. Merckle GmbH

Country USA Germany

Year Introduced -

2330

Modafinil

Trade Name Modavigil Provigil Provigil

Manufacturer CSL LTD Aetna Inc. Cephalon, Inc.

Country -

Year Introduced -

Raw Materials Thionyl chloride Ammonia Thiourea Benzhydrol Hydrogen peroxide

Benzhydrylthioacetic acid Acetic acid Hydrobromic acid Chloroacetic acid Dimethyl sulfate

Manufacturing Process To 19.5 g (0.076 mol) of benzhydrylthioacetic acid in 110 ml of benzene was added drop by drop 19 ml of thionyl chloride. The mixture was refluxed 1 hour, benzene and the excess thionyl chloride was evaporated. A clear orange oil of benzhydrylthioacetyl chloride is obtained. The benzhydrylthioacetyl chloride in 100 ml of methylene chloride was added drop by drop to 35 ml of ammonia in 40 ml of water. Once the addition is complete, the organic phase is washed with a dilute solution of soda and dried over Na2SO4, the solvent is evaporated and the residue is taken up in diisopropyl ether, the benzhydrylthioacetamide is crystallised. 16.8 g of product (yield 86%) are obtained. Melting point 110°C. 14.39 g (0.056) of benzhydrylthioacetamide are placed in a balloon flask and 60 ml of acetic acid and 5.6 ml of H2O2 are added. The mixture is left for one night at 40°C and about 200 ml of water are then added; the CRL 40476 crystallises. By recrystallisation from methanol 11.2 g of benzhydrylsulphinylacetamide are obtained. Yield: 73%, melting point 164166°C. The synthesis of benzhydrylsulphinylacetamide (CRL 40476) on an industrial scale. 1.003 kg of thiourea is dissolved in 5.72 L of 48% hydrobromic acid and 0.880 L of water in a 20 L reaction vessel. The mixture is heated to 60°C and 2.024 kg of benzhydrol are introduced. The temperature is increased to 95°C and the contents of the vessel are allowed to cool to room temperature. The crystals are filtered off and washed with water. They are made into a paste again in 5.5 L of water and this is introduced into a 20 L reaction vessel with 3.5 L of soda lye (d = 1.33). The mixture is heated to 70°C and 1144 g of chloroacetic acid dissolved in 2.2 L of water are passed in slowly. After cooling the benzhydrylthioacetic acid is obtained, but is not isolated. 1.430 L of hydrogen peroxide are passed in over 3 hours at 30°C into the above reaction mixture. 22 L of water are then passed in, the insoluble material is filtered off and acidification is carried out with hydrochloric acid (d = 1.18). Filtration, washing with water to reform a paste and drying without heat are carried out. In this way, the benzhydrylsulphinylacetic acid is obtained.

Moexipril hydrochloride

2331

The above acid is placed in a 20 L reaction vessel with 6 L of water. 1.1 liters of soda lye (d = 1.33) and 1.848 kg of sodium bicarbonate are added. 2.1 L of dimethyl sulfate are added. After one hour, crystallisation is induced. Filtration, drying without heat and washing are carried out. Methyl benzhydrylsulphinylacetate is obtained. 1 kg of methyl benzhydrylsulphinylacetate is dissolved in 3.5 liters of anhydrous methanol in a 10-liter balloon flask. NH3 is bubbled in at a high rate of flow for 1 hour, and then left in contact for 4 hours. Filtration, drying without heat and washing with water are then carried out. By recrystallisation from a mixture of water and methanol (4:1) and then from a mixture of water and methanol (9:1) and drying under reduced pressure, CRL 40476 is obtained in the form of a white crystalline powder; melting point 164-166°C. Total yield (calculated from the benzhydrol): 41%. References Lafon L.; US Patent No. 4,177,290; Dec. 4, 1989; Assigned to Laboratoire L. Lafon

MOEXIPRIL HYDROCHLORIDE Therapeutic Function: Antihypertensive Chemical Name: 3-Isoquinolinecarboxylic acid, 1,2,3,4-tetrahydro-6,7dimethoxy-2-(2-((1-(ethoxycarbonyl)-3-phenylpropyl)amino)-1oxopropyl)-, monohydrochloride, (3S-(2(R*(R*)),3R*))Common Name: Moexipril hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 82586-52-5; 103775-10-6 (Base)

2332

Moexipril hydrochloride

Trade Name Moexipril Hydrochloride Perdix Primox Tablets Univasc Univasc

Manufacturer Schwarz Pharma

Country Germany

Year Introduced -

Schwarz Pharma Minipharm Teva Pharmaceuticals Schwarz Pharma

Germany USA USA

-

Raw Materials t-Butyl alanine Triethylamine 1-Hydroxybenzotriazole Diclohexylcarbodiimide

Ethyl 2-bromo-4-phenylbutanoate 1,2,3,4-Tetrahydro-3-isoquinolinecarboxylic acid (S-form)

Manufacturing Process 1) A solution of 2.0 g of t-butyl alanine (S-form) and 3.78 g of ethyl 2-bromo4-phenylbutanoate in 25 ml of DMF was treated with 1.8 ml of triethylamine and the solution was heated at 70°C for 18 hours. The solvent was removed at reduced pressure and the residue was mixed with water and extracted with ethyl ether. The organic layer was washed with water and dried over magnesium sulfate. Concentration of the solvent at reduced pressure gave the oily ethyl-α-[(1-carboxyethyl)amino]benzene-t-butanoate. A solution of 143.7 g of this t-butyl ester in 630 ml of trifluoroacetic acid was stirred at room temperature for one hour. The solvent was removed at reduced pressure and the residue was dissolved in ethyl ether and again evaporated. This operation was repeated. Then the ether solution was treated dropwise with a solution of hydrogen chloride gas in ethyl ether until precipitation ceased. The solid, collected by filtration, was a mixture of diastereoisomers of ethyl-α-[(1-carboxyethyl)amino]benzenebutanoate hydrochloride, melting point 153-165°C; [α]D23 = +3.6° (1% MeOH). The free amino acid (S,S-form) was prepared by treatment of an aqueous solution of the hydrochloride with saturated sodium acetate. The product was filtered, washed efficiently with cold water and recrystallized from ethyl acetate; melting point 149-151°C; [α]D23 = +29.7°. 2) A stirred solution of 0.0158 mole of ethyl-α-[(1-carboxyethyl)amino] benzenebutanoate hydrochloride in 200 ml of methylene chloride was treated successively with 1.60 g (0.0158 mole) of triethylamine, 0.0158 mole of 1hydroxybenzotriazole, 0.0158 mole of 1,2,3,4-tetrahydro-6,7-dimethoxy-3isoquinolinecarboxylic acid and then with 0.0158 mole of dicyclohexylcarbodiimide in 10 ml of methylene dichloride. Dicyclohexylurea gradually separated. The mixture was allowed to stand at room temperature overnight. Hexane (300 ml) was added and the urea was filtered. The filtrate was washed with 250 ml of saturated sodium bicarbonate, dried over sodium sulfate and concentrated to remove solvent. The viscous residue was triturated with 50 ml of ether and filtered to remove insolubles. The filtrate was concentrated to give 2-[2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]-1oxopropyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylic acid.

Mofebutazone

2333

After addition of hydrochloric acid was obtained 2-[2-[[1-(ethoxycarbonyl)-3phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-3isoquinolinecarboxylic acid, hydrochloride. References Hoefle M.L., Klutchko S.; US Patent No. 4,344,949; August 17, 1982; Assigned: Warner-Lambert Company O'Reilly N. J., Lin H. C.; US Patent No. 4,912,221; March 27, 1990; Assigned: Occidental Chemical Corporation Wang Z.-X., Horne S.E.; US Patent No. 6,642,384; Nov. 4, 2003; Assigned: Brantford Chemicals Inc.

MOFEBUTAZONE Therapeutic Function: Antirheumatic, Analgesic, Antiinflammatory Chemical Name: 3,5-Pyrazolidinedione, 4-butyl-1-phenylCommon Name: Mofebutazone; Monophenylbutazone; Mophebutazonum Structural Formula:

Chemical Abstracts Registry No.: 2210-63-1 Trade Name

Manufacturer

Country

Year Introduced

Butaphen

Wiedenmann

-

-

Ecasil

Laquifa

-

-

Metrogyl

Benzon

-

-

Monofen

Star

-

-

Raw Materials Phenyl hydrazine n-Butylmalonic acid

2334

Molindone

Manufacturing Process A mixture comprising 108 g of phenyl hydrazine and 216 g of the diethyl ester of n-butylmalonic acid is heated on an oil bath at 170°-180°C for 12 hours. The residue is taken up with water in which an alkaline compound has been dissolved and acetic acid is added to precipitate 4-n-butyl-2-phenylpyrazolidine-3,5-dione. The product is a white crystalline solid having a MP: 103°C. It is soluble in acetone and benzene, soluble in hot condition in methanol and ethanol and insoluble in water. References Commissionara Farmaceutica Milaneze, an Italian Company, Milan Italy; G.B. Patent No. 839,057; Nov. 28, 1956

MOLINDONE Therapeutic Function: Antipsychotic Chemical Name: 3-Ethyl-1,5,6,7-tetrahydro-2-methyl-5-(4morpholinylmethyl)-4H-indol-4-one Common Name: Structural Formula:

Chemical Abstracts Registry No.: 7416-34-4; 15622-65-8 (Hydrochloride salt) Trade Name Moban Lidone

Manufacturer Endo Abbott

Country US US

Year Introduced 1974 1977

Raw Materials Diethyl ketone Paraformaldehyde Morpholine hydrochloride

Cyclohexan-1,3-dione Methyl nitrite

Manufacturing Process Diethyl ketone may be reacted with methyl nitrite and that product in turn

Molsidomine

2335

reacted with cyclohexan-1,3-dione to give 3-ethyl-4,5,6,7-tetrahydro-2methyl-4-oxoindole. 3-ethyl-4,5,6,7-tetrahydro-2-methyl-4-oxoindole 14.1 g (0.08 mol), 14.8 g morpholine hydrochloride (0.12 mol), and 3.6 g paraformaldehyde (0.12 mol) were refluxed in 200 ml ethanol for 40 hours. The solution was evaporated to dryness in vacuo on a steam bath and the residue digested with a mixture of 150 ml water and 10 ml 2N HCl. An insoluble residue of unreacted starting material was filtered off. To the acid solution, ammonia water was added dropwise with stirring and the amine crystallized out. It was purified by dissolving in 1N HCl and addition of ammonia, then by 2 crystallizations from benzene followed by 2 crystallizations from isopropanol, to yield 3-ethyl4,5,6,7-tetrahydro-2-methyl-4-oxoindole, melting point 180°C to 181°C. References Merck Index 6086 Kleeman and Engel p. 606 PDR p. 856 OCDS Vol. 2 p.455 (1980) DOT 5 (1) 34 (1969); 9 (6) 233 (1973) and 11 (2) 60 (1975) I.N. p. 642 REM p. 1092 Pachter, I.J. and Schoen, K.; US Patent 3,491,093; January 20, 1970; assigned to Endo Laboratories, Inc.

MOLSIDOMINE Therapeutic Function: Coronary vasodilator Chemical Name: Sydnone imine, N-carboxy-3-morpholino-, ethyl ester Common Name: Molsidomine; Morsydomine Structural Formula:

Chemical Abstracts Registry No.: 25717-80-0 Trade Name

Manufacturer

Country

Year Introduced

Corvasal

Hoechst

-

-

2336

Mometasone furoate

Raw Materials 3-Morpholinosydnonimine hydrochloride Ethyl chloroformate Pyridine Manufacturing Process 1.6 parts by volume of ethyl chloroformate is stirred dropwise into a suspension of 1.0 part by weight of 3-morpholinosydnonimine hydrochloride in 5 parts by volume of pyridine, and the mixture is agitated for a while to allow reaction to take place. Pyridine is removed from the reaction mixture by evaporation, and the residue is dissolved in a small amount of water and extracted with chloroform several times. The extract is dehydrated by adding anhydrous magnesium sulfate and subjected to filtration. Chloroform is removed from the filtrate by distillation, crude crystals being obtained. Recrystallization of the crude crystals from toluene gives 0.6 part by weight of 3-morpholino-N-carboethoxysydnonimine having a melting point of 140°141°C. Yield 51%. References Masuda K. et al.; US Patent No. 3,812,128; May 21, 1974; Assigned to Takeda Chemical Industries, Ltd., Osaka, Japan

MOMETASONE FUROATE Therapeutic Function: Glucocorticoid Chemical Name: Pregna-1,4-diene-3,20-dione, 9,21-dichloro-17-((2furanylcarbonyl)oxy)-11-hydroxy-16-methyl-, (11β,16α)Common Name: Mometasone furoate Structural Formula:

Chemical Abstracts Registry No.: 83919-23-7

Mometasone furoate Trade Name Asmanex Asmanex Twisthaler Cutizone-T Elocon Elocon Nasonex

2337

Manufacturer Novartis Communications Schering-Plough

Country Switz. Belgium

Year Introduced -

Crosland Research Laboratories Fulford GALT (India) Ltd. Schering-Plough Schering-Plough

India

-

India Belgium Belgium

-

Raw Materials 9β,11β-Epoxy-17α,21-dihydroxy-16α-methyl-1,4-pregnadiene-3,20-dione Mesyl chloride 4-Dimethylaminopyridine 2-Furoyl chloride 1,3-Dichloro-5,5-dimethylhydantoinyl Manufacturing Process METHOD I (Patent U.S. 4,472,393) A. 21-Chloro-9β,11β-epoxy-17α-hydroxy-16α-methyl-1,4-pregnadiene-3,20dione Prepare a solution of 5.0 g. of 9β,11β-epoxy-17α,21-dihydroxy-16α-methyl1,4-pregnadiene-3,20-dione in 20 ml of dry pyridine. Cool on an ice bath; to the stirred solution under nitrogen, add dropwise 1.1 ml of mesyl chloride. Remove the ice bath and continue stirring at room temperature for 30 min. Add 2.0 g of lithium chloride and continue stirring for a further 150 min. Add to a mixture of 150 ml ethyl acetate and 100 ml distilled water. Wash the organic phase with dilute 3% aqueous hydrochloric acid, then saturated aqueous sodium chloride solution and finally saturated sodium bicarbonate solution. Dry the organic phase over magnesium sulfate, filter and remove the solvent to give 4.62 g of 21-chloro-9β,11β-epoxy-17α-hydroxy-16α-methyl1,4-pregnadiene-3,20-dione. B. 21-Chloro-9β,11β-epoxy-17α-hydroxy-16α-methyl-1,4-pregnadiene-3,20dione 17-(2'-furoate) Prepare under argon a solution of 8 g of 4-dimethylaminopyridine in 250 ml of dry methylene chloride. Cool on an ice bath and add to the stirred solution 6.0 ml of 2-furoyl chloride. Remove from the ice bath, allow the temperature to rise to room temperature and then add 11.5 g of the 21-chloro-9β,11β-epoxy17α-hydroxy-16α-methyl-1,4-pregnadiene-3,20-dione. After 24 hours add 500 ml of ethyl acetate saturated with water. Filter off the precipitate and then evaporate off the solvent to give the crude 21-chloro-9β,11β-epoxy-17αhydroxy-16α-methyl-1,4-pregnadiene-3,20-dione 17-(2'-furoate). C. 9α,21-Dichloro-11β,17α-hydroxy-16α-methyl-1,4-pregnadiene-3,20-dione 17-(2'-furoate) To the crude 21-chloro-9β,11β-epoxy-17α-hydroxy-16α-methyl-1,4pregnadiene-3,20-dione 17-(2'-furoate) add 50 ml of glacial acetic acid, then

2338

Mometasone furoate

add a solution of 3.5 g of anhydrous hydrogen chloride in 125 ml of glacial acetic acid. Stir for 15 minutes and then quench with 500 ml of distilled water. Filter off the solids, recrystallise from methanol:water, dry for 24 hours under vacuum to give 12.6 g 9α,21-dichloro-11β,17α-hydroxy-16α-methyl-1,4pregnadiene-3,20-dione 17-(2'-furoate) (yield 83% of theory). Prepare under nitrogen a solution of 1.80 g of 21-chloro-17α-hydroxy-16αmethyl-1,4,9(11)-pregnatriene-3,20-dione 17-(2'-furoate). Add, with stirring, a solution of 1.15 ml of 70% perchloric acid in 2.53 ml of distilled water, and immediately thereafter 604 mg of 1,3-dichloro-5,5-dimethylhydantoin. Stir the reaction mixture for twenty minutes and then raise the temperature to ambient temperature. Monitor the consumption of starting material by thin layer chromatography of aliquots using chloroform:1,3-dichloro-5,5dimethylhydantoinyl acetate (9:1) and hexane:ethyl acetate (1:1). When the starting material is consumed, pour the reaction mixture into 500 ml of distilled water containing the 1,3-dichloro-5,5-dimethylhydantoin and 7 g of sodium bisulphite. Add sodium chloride until the solution is saturated. Filter the precipitated solid, wash and dry at 50°C under vacuum. Purify the resulting crude product by preparative chromatography on 1000 micron silica gel plates using chloroform: ethyl acetate (19:1). Elute the desired band with ethyl acetate, filter the eluate and evaporate at room temperature to give crude product (1.3 g). Recrystallize the product by dissolving in refluxing methylene chloride, filtering and then replacing the methylene chloride at reflux with methanol and then the methanol with distilled water. Cool the suspension to room temperature, filter and dry under vacuum at 50°C to give the pure pregna-1,4-diene-3,20-dione, 9,21-dichloro-17-((2furanylcarbonyl)oxy)-11-hydroxy-16-methyl-, (11β-,16α)-. METHOD II The present invention (Patent U.S. 6,177,560) refers to a new process for the preparation of mometasone furoate carried out by esterifiication of the 17 hydroxy group of mometasone without prior protection of the 11 hydroxy group. Mometasone (30 g) was suspended in methylene chloride (300 ml) and the resulting suspension was cooled to 0-5°C. At this temperature triethylamine (57 ml) was added. 2-Furoyl chloride (24 ml) was then added slowly. The mixture was then stirred at 8-12°C until the level of mometasone present was lower than 0.2% by HPLC. The reaction solution was then cooled to between -5-5°C and water (120 ml) was added with stirring. After stirring for 1 hour at 10-15°C the mixture was cooled to between 0-5°C and concentrated hydrochloric acid was added to adjust the pH of the aqueous layer between 1 and 2. The phases were separated and the aqueous layer was extracted with methylene chloride (60 ml). To the combined organic layers concentrated hydrochloric acid (90 ml) and acetic acid (30 ml) was added at a temperature 15-25°C. Then the two phase reaction mixture was stirred until less than 0.1% of the side products remained as monitored by HPLC. The reaction mixture was cooled to 0-5°C and water (120 ml) was added. The lower organic layer was separated, water (120 ml) and 8 N aqueous sodium hydroxide solution (about 30 ml) were added to adjust the pH to between 5 and 6. After stirring for 2 hours the organic layer was separated and washed with water (120 ml). The organic solution [containing the mometasone 17-(2furoate)] was concentrated by distillation to a volume of 120 ml. Further

Montelukast sodium

2339

methanol (120 ml) was added and the mixture was concentrated to 120 ml. This procedure was repeated twice more. The reaction mixture was slowly cooled to 0-5°C and stirred for 2 hours. The crude mometasone 17-(2furoate) was then filtered off and washed with cold methanol. Purification of mometasone 17-(2-furoate) The wet cake was dissolved in acetone (395 ml) and charcoal (3 g) was added. After 24 hours, the charcoal was filtered off and washed with acetone (90 ml). Charcoal (3 g) was added to the solution and the solution stirred for at least 24 hours at between 15-25°C. The charcoal was then filtered off and washed with acetone (75 ml). The solution was concentrated by distillation to a volume of 120 ml. During this concentration the mometasone 17-(2-furoate) started to crystallise. Methanol (120 ml) was added and the solution was again concentrated to 120 ml. This procedure was repeated twice. The suspension was cooled slowly to 0-5°C and stirred for about 2 hours at this temperature. The pure mometasone 17-(2-furoate) was then filtered off and washed with cold methanol. The product was dried at 60-70°C. A yield of 29.92 g was obtained. References Shapiro E.L.; US Patent No. 4,472,393; Sep. 18, 1984; Assigned: Schering Corporation (Kenilworth, NJ) Heggie W., Bandarra J.; US Patent No. 6,177,560; Jan. 23, 2001; Assigned to Hovione Inter Ltd.

MONTELUKAST SODIUM Therapeutic Function: Anti-asthmatic Chemical Name: Cyclopropaneacetic acid, 1-((((1R)-1-(3-((1E)-2-(7-chloro2-quinolinyl)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl) propyl)thio)methyl)-, monosodium salt Common Name: Montelukast sodium Structural Formula:

2340

Montelukast sodium

Chemical Abstracts Registry No.: 151767-02-1; 158966-92-8 (Base) Trade Name

Manufacturer

Country

Year Introduced

Singulair

Merck Pharmaceutical Corporation

Canada

-

Raw Materials Crotonaldehyde 4-Chloroaniline Chloranil Palladium (II) acetate Cerium (III) chloride Thionyl chloride Sodium cyanide Triethylamine Potassium t-butoxide

Methyl 2-(2-iodophenyl)propanoate Tetrabutylammonium chloride Diethyl 1,1-cyclopropanedicarboxylate Vinyl magnesium bromide Methyl magnesium chloride Borane-tetrahydrofuran complex Diisopropylethylamine Methanesulfonyl chloride

Manufacturing Process Crotonaldehyde (3.23 mol) in 100 mL of 2-butanol was added dropwise to a refluxing solution of 4-chloroaniline (3.23 mol), p-chloranil (3.23 mol) and HCl conc. (808 mL) in 5.4 L of 2-butanol. After 2 hours of heating 2.7 L of solvent was removed under vacuum at 60°C. Then 2 L of toluene was added to the reaction mixture followed by removal of 2.5-3 L of solvent until a very pasty solid formed. THF (2 L) was added and the mixture heated 30 min after which it was cooled to 0°C. The solid was collected and washed with THF until pure by tlc. The solid was then dissolved in aq. K2CO3/EtOAc and the organic phase separated. The aqueous phase was extracted with EtOAc and the organic phases combined, dried over MgSO4 and the solvent removed. The product was crystallized in the minimum amount of EtOAc to give 328.08 g (57%) of 4-chloro-2-methylquinolin. 4-Chloro-2-methylquinalin was converted into 3-(2-(7-chloro)-2quinolinyl)ethenyl)benzaldehyde. Reaction was carried out according to a method described in U.S. Pat. No. 4,851,409 To a degassed suspension of 3-(2-(7-chloro-2-quinolinyl)ethenyl)benzaldehyde (0.34 mol) in toluene (700 mL) at 0°C was added 1.0 M vinylmagnesium bromide in toluene/THF (370 mL). After stirring for 1 hour at 0°C, the reaction was quenched by the addition of saturated NH4Cl solution (150 ml), followed by H2O (500 mL) and HOAc (50 mL). The product was extracted with EtOAc and the two-phase system was filtered through celite to remove an insoluble precipitate. The aqueous phase was then re-extracted with EtOAc (100 mL) and the combined organic layer was washed with H2O, followed by brine. The solution was dried (MgSO4), and evaporated to give a dark yellow residue which was purified by flash chromatography (EtOAc:hexane 1:5, then 1:3). The product was filtered from the column fractions to give a solid of 1(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-2-propen-1-ol (melting point = 110-112°C). The filtrate was concentrated and the resulting residue was recrystallized from EtOAc/hexane 1:4 to give a second crop of 15.1 g. A degassed suspension of 1-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-2-

Montelukast sodium

2341

propen-1-ol (46.6 mmol), n-Bu4NCl (93 mmol), LiOAcH2O (115 mmol), LiCl (93 mmol), Pd(OAc)2 (1.4 mmol) and methyl 2-(2-iodophenyl)propanoate in DMF (90 mL) was stirred for 2 hours at 100°C. The dark red solution was then cooled to 0°C and poured into saturated NaHCO3 solution (500 mL). The product was extracted with EtOAc and the organic layer was washed with H2O followed by brine. The solvent was removed under vacuum and the residue was purified by flash chromatography (EtOAc:hexane 1:10, 1:5 and 3:10) to give a pale yellow foam of ethyl 2-(3(S)-(3-(2-(7-chloro-2-quinolinyl)ethenyl) phenyl)-3-hydroxy-propyl)benzoate (18.9 g). A mixture of anhydrous CeCl3 (164 mmol) in THF (500 mL) was refluxed overnight using a Dean Stark trap filled with activated molecular sieves. Methyl magnesium chloride (3.0 Molar solution in THF, 790 mmol) was added dropwise over 30 min to the CeCl3 slurry at 0°C. After stirring 2 hours, the mixture was cooled to -5°C and a toluene (600 mL) solution of the ethyl 2(3(S)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-hydroxy-propyl)benzoate (152 mmol) was added dropwise over 1 hour. The reaction mixture was stirred another hour before the addition of 2 M HOAc (600 mL) and toluene (600 mL). The organic layer was washed with saturated aq. NaHCO3 and with brine. Concentration in vacuo and purification of the residue by flash chromatography (30% EtOAc in toluene) gave 63.48 g (91%) of the 2-(2(3(S)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-hydroxypropyl)phenyl)-2propanol. To a solution of BH3THF complex (1 M in THF, 262 mL) was added diethyl 1,1cyclopropanedicarboxylate (134 mmol) at 25°C under N2. The solution was heated at reflux for 6 hours, cooled to r.t., and MeOH (300 mL) was cautiously added. The solution was stirred for 1 hour and then concentrated to an oil. The crude 2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3hydroxypropyl)phenyl)-2-propanol was dissolved in CH2Cl2 (234 mL) and SOCl2 (15.9 g, 134 mmol) was added dropwise over a period of 15 min at 25°C. After stirring for another 15 min, the mixture was washed with aqueous NaHCO3. The organic extract was dried over Na2SO4, filtered and concentrated to give quantitatively the 1,1-cyclopropanedimethanol cyclic sulfite. To a solution of the 1,1-cyclopropanedimethanol cyclic sulfite (99 mmol) in DMF (83 mL) was added NaCN (199 mmol). The mixture was heated to 90°C for 20 hours. Upon cooling, EtOAc (400 mL) was added and the solution was washed with saturated NaHCO3 solution (55 mL), H2O (4 times 55 mL), saturated NaCl solution and dried over Na2SO4. The solution was concentrated to give 7.1 g (65%) of 1-(hydroxymethyl)cyclopropaneacetonitrile. To a solution of 1-(hydroxymethyl)cyclopropaneacetonitrile (42 g, 378 mmol) in dry CH2Cl2 (450 mL) at -30°C was added Et3N (741 mmol) followed by CH3SO2Cl (562 mmol) dropwise. The mixture was warmed to 25°C, washed with NaHCO3, dried over Na2SO4 and concentrated in vacuo to give the corresponding mesylate. The mesylate was then dissolved in DMF (450 mL) and cooled to 0°C. Potassium thioacetate (55.4 g, 485 mmol) was added, and the mixture was stirred at 25°C for 18 hours. EtOAc (1.5 L) was added, the solution was washed with NaHCO3, dried over Na2SO4 and concentrated in vacuo to give 45 g (70%) of 1-(acetythiomethyl)cyclopropaneacetonitrile.

2342

Moperone hydrochloride

To a solution of the 1-(acetythiomethyl)cyclopropaneacetonitrile (266 mmol) in MeOH (1.36 L) was added H2O (84 mL) and conc. H2SO4(168 mL). The mixture was heated to reflux for 20 hours, cooled to 25°C, H2O (1 L) was added and the product was extracted with CH2Cl2. The organic extract was washed with H2O and dried over Na2SO4. Concentration of the organic solution gave 36 g (93%) of the methyl 1-(thiomethyl)cyclopropaneacetate. To a solution of 2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3hydroxypropyl)phenyl)-2-propanol in THF was dissolved in THF (1 mL) and DMF (1 mL) at -40°C was added diisopropylethylamine (2.2 mmol) and then methanesulfonyl chloride (2.2 mmol). The mixture was stirred 2 hours with slow warming to -30°C. The methyl 1-(thiomethyl)cyclopropaneacetate (2.3 mmol) was added to the cloudy reaction mixture followed by dropwise addition of potassium tert-butoxide/THF solution (4.4 mmol). The reaction mixture was stirred at -30°C for 3.5 hours before quenching it with 25% aq NH4OAc. Extraction with EtOAc, washing the organic layer with brine and evaporation of the solvents left a residue that was purified by flash chromatography (5%-10% EtOAc in toluene) giving 658 mg (53%) of methyl 1-((((R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2propyl)phenyl)propyl)thio)methyl)cyclopropaneacetate. Following the hydrolysis the methyl 1-((((R)-(3-(2-(7-chloro-2-quinolinyl) ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)propyl)thio)methyl) cyclopropaneacetate with NaOH was obtained the free acid: 4-((1(R)-(3-(2-(7chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)-phenyl)propyl) thio)methyl)cyclopropaneacetic acid or sodium 1-(((1(R)-(3-(2-(7-chloro-2quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)propyl)thio) methyl) cyclopropaneacetate. References Zamboni R. et al.; US Patent No. 5,270,324; Dec. 14, 1993; Assigned to Merck Frosst Canada, Inc.

MOPERONE HYDROCHLORIDE Therapeutic Function: Neuroleptic Chemical Name: 4'-Fluoro-4-(4-hydroxy-4-p-tolylpiperidino)butyrophenone hydrochloride Common Name: Moperone hydrochloride; Methylperidol Chemical Abstracts Registry No.: 3871-82-7 Trade Name

Manufacturer

Country

Year Introduced

Luvatren

Cilag

-

-

Moperone hydrochloride

Janssen Pharmaceutica

-

-

Moperone hydrochloride

2343

Structural Formula:

Raw Materials Methyl bromide Magnesium Manufacturing Process A solution of 95 parts of methyl bromide in 356 parts of ether was added portionwise to a refluxing suspension of 24 parts of magnesium in 214 parts of ether. The mixture was refluxed for 2 hours, and 92 parts of 4methylacetophenone were added in the course of 90 minutes. The refluxing was continued for 3 hours, and the mixture was stirred for 24 hours at room temperature. The Grignard complex was destroyed by the addition of ammonium chloride and 10% hydrochloric acid. The mixture was extracted with ether and the ether extracts were washed with 10% sulfuric acid and then with water. Then extracts were dried over anhydrous calcium chloride, filtered, and concentrated in vacuum to remove the solvent. About 0.5 part of hydroquinone was added to the residue, which was then heated to a temperature of 100-110°C at 50 mm. The distillate was extracted with ether and the ether extracts were dried over anhydrous calcium chloride and filtered. A small quantity of hydroquinone was added to the ether. The solution was fractionated by distillation to yield 4-methyl-α-methylstyrene boiling at about 72-74°C at 80 mm. A mixture of 856 parts of ammonium chloride and 3000 parts of 36% formaldehyde was stirred and heated to about 60°C. With cooling to maintain this temperature, 944 parts of 4-methyl-α-methylstyrene were added slowly. After the addition was completed, the mixture was stirred at room temperature until the temperature of the reaction mixture dropped to about 40°C. After 2000 parts of methanol were added, the stirring was continued for 20 hours. The methanol was removed in vacuum and the residue was diluted with 3000 parts of concentrated hydrochloric acid. For 4 hours, the mixture was heated with stirring at a temperature of 100°C. The mixture was cooled, diluted with 2000 parts of water, and made alkaline with 15 N sodium hydroxide solution. The reaction mixture was extracted with benzene, and the benzene extracts were dried over anhydrous potassium carbonate and filtered. The benzene was removed from the filtrate. The remaining residue was distilled in vacuum to yield 4-(p-tolyl)-1,2,3,6-tetrahydropyridine. This base was dissolved in benzene. Dry, gaseous hydrogen chloride was passed through the solution, whereupon there precipitated the hydrochloride, which was collected on a filter. The 4-(p-tolyl)-1,2,3,6-tetrahydropyridine hydrochloride boiling at about 162-170°C/10 mm Hg.

2344

Mopidamol

While the temperature was being maintained at about 10-20°C, anhydrous hydrogen bromide gas was passed for 7 hours through a solution of 160 parts of 4-(p-tolyl)-1,2,3,6-tetrahydropyridine in 500 parts of acetic acid. The mixture was stirred during the addition of the hydrogen bromide gas. The mixture was then allowed to stand at room temperature of 16 hours. The acetic acid and the excess hydrogen bromide were removed in vacuum at a bath temperature of less than 40°C. The residue was treated with ether. This solution was cooled, and the product was collected on a filter to give the 4-(ptolyl)-4-bromopiperidine hydrobromide. A solution of 160 parts of above prepared hydrobromide in 3000 parts of water was treated with 100 parts of 20% sodium hydroxide solution. The resulting precipitate was recovered by filtration and washed with water. The precipitate was then dissolved in toluene, and the solution was dried over anhydrous potassium carbonate and filtered. The filtrate was cooled to 0°C. The crystalline product thus obtained was collected on a filter to yield 4-(p-tolyl)-piperidin-4-ol; MP: 136-137°C. To a suspension of 341 parts of aluminium chloride in 1740 parts of carbon disulphide were added 96 parts of fluorobenzene with stirring and cooling. While the temperature was maintained at about 10°C, 141 parts of γchlorobutyryl chloride were added. After the addition was completed, the cooling bath was removed and the stirring was continued for 2 hours. The reaction mixture was poured into ice water. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the residue was distilled to yield γ-chloro-p-fluorobutyrophenone. BP: at about 136-142°C/6 mm Hg. 3.7 parts by weight of it, 14.16 parts of 4-(p-tolyl)-piperidin-4-ol, 0.1 parts KI and 150 parts by volume of toluene was treated in the pressure vessel at 140-150°C for 72 hours. On cooling to room temperature the reaction mixture was filtered. The solid residue was treated with mixture of water and ether and ethereal layer added to filtrate from original with water and pressed as dry as possible on the filter. It was then dissolved in 1500 parts by volume of boiling toluene to which anhydrous potassium carbonate was added to remove the remaining water. The mixture was filtered and the filtrate cooled to 0°C. The was p-fluoro-4-(4-hydroxy-4-p-tolyl-piperidino)butyrophenone. MP of chlorohydrate: 216-218°C. References PAUL ADRIAAN JAN JANSSEN; GB Patent No. 881,893; Nov. 8, 1961; N.V. Research Laboratorim Dr.C. Janssen, a Belgium Limited Liability Company, Belgium

MOPIDAMOL Therapeutic Function: Platelet aggregation inhibitor Chemical Name: 2,6-Bis(diethanolamino)-8-(N-piperidino)pyrimido[5,4-d] pyrimidine Common Name: -

Mopidamol

2345

Structural Formula:

Chemical Abstracts Registry No.: 13665-88-8 Trade Name Rapenton

Manufacturer Thomae

Country W. Germany

Year Introduced 1980

Raw Materials Dipyridamole Iodine Zinc Formic acid Manufacturing Process 3.9 g (0.06 mol) of zinc powder were introduced into a solution of 5.0 g (0.01 mol) of 2,6-bis-(diethanolamino)-4,8-dipiperidino-pyrimido-[5,4-d]-pyrimidine (dipyridamole; see entry under that name for its synthesis) in 120 cc of aqueous 10% formic acid. The resulting mixture was heated on a water bath, while occasionally stirring, until the intense yellow color of the starting compound disappeared, which occurred after about 30 to 40 minutes. Thereafter, the unconsumed zinc powder was separated by vacuum filtration, the virtually colorless filtrate was essentially an aqueous solution of 2,6-bis(diethanolamino)-8-piperidino-1,2,3,4-tetrahydropyrimido-[5,4-d]pyrimidine. The filtrate was adjusted to a pH of 9 by adding concentrated ammonia, and then a 1 N aqueous iodine-potassium iodide solution was added dropwise, whereby the tetrahydropyrimido[5,4-d]pyrimidine obtained by hydrogenation with zinc in formic acid was converted by oxidation into 2,6-bis(diethanolamino)-8-piperidino-pyrimido-[5,4-d]-pyrimidine. The completion of the oxidation was checked by means of a starch solution. The major amount of the oxidation product already separated out as a deep yellow crystalline precipitate during the addition of the iodine solution. After the oxidation reaction was complete, the reaction mixture was allowed to stand for a short period of time, and then the precipitate was separated by vacuum filtration,

2346

Morclofone

washed with water and dried. It had a melting point of 157°C to 158°C. The yield was 8.0 g, which corresponds to 95% theory. References Merck Index 6115 DFU 5 (11) 550 (1980) Kleeman and Engel p. 608 DOT 17 (3) 89 (1981) I.N. p. 644 Roch, J. and Scheffler, H.; US Patent 3,322,755; May 30,1967;assigned to Boehringer Ingelheim GmbH

MORCLOFONE Therapeutic Function: Antitussive Chemical Name: (4-Chlorophenyl)[3,6-dimethoxy-4-[2-(4-morpholinyl)ethoxy]phenyl]methanone Common Name: Dimeclophenone Structural Formula:

Chemical Abstracts Registry No.: 31848-01-8; 31848-02-9 (Hydrochloride salt) Trade Name Plausitin Nitux Medicil NovotussiI

Manufacturer Carlo Erba Inpharzam Medici Inpharzam

Country Italy Switz. Italy Belgium

Raw Materials 3,5-Dimethoxy-4'-chloro-4-hydroxybenzophenone Sodium methoxide β-Morpholinoethyl chloride

Year Introduced 1975 1981 -

Moricizine hydrochloride

2347

Manufacturing Process Sodium methoxide (1.2 g) in dimethylformamide (150 ml) was stirred with 3,5-dimethoxy-4'-chloro-4-hydroxybenzophenone (6 g) in dimethylformamide (50 ml), for 2 hours at 120°C. The reaction mixture was then treated with βmorpholinoethyl chloride (3.4 g) and heated for 1 hour at 140C, then evaporated to dryness, and treated with water to give a solid material. The mixture was filtered, washed and crystallized from cyclohexane to give 3,5dimethoxy-4'-chloro-4-(β-morpholinoethoxy)-benzophenone (6.5 g), MP 91°C to 92°C. The product was then reacted at about 0°C with gaseous hydrogen chloride in ether to give, after crystallization from isopropanol, the corresponding hydrochloride which had a MP of 187.9°C. References Merck Index 6120 Kleeman and Engel p. 609 DOT 12 (7) 269 (1976) I.N. p. 645 Lauria, F., Vecchietti, V. and Logemann, W.; US Patent 3,708,482; January 2, 1973; assigned to Carlo Erba SpA (Italy)

MORICIZINE HYDROCHLORIDE Therapeutic Function: Antiarrhythmic Chemical Name: Carbamic acid, (10-(3-(4-morpholinyl)-1-oxopropyl)-10Hphenothiazin-2-yl)-, ethyl ester, hydrochloride Common Name: Moracizine hydrochloride; Moricizine hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 29560-58-5 ; 31883-05-3 (Base) Trade Name

Manufacturer

Country

Year Introduced

Ethmozine

Bristol-Myers Squibb

-

-

2348

Morinamide

Raw Materials Ethyl phenthiazine-2-carbamate 3-Chloropropionyl chloride Morpholine hydrochloride Manufacturing Process To a solution of 10 g (0.035 mole) of ethyl phenthiazine-2-carbamate in 30 ml of anhydrous toluene is added dropwise 5.3 g (0.042 mole) of 3chloropropionyl chloride, and the mixture is refluxed at 110-120°C for 4 hours, followed by clarifying the mixture with activated carbon and cooling it to room temperature. A precipitate of ethyl 10-(3-chloropropionyl)phenthiazine-2-carbamate is removed by filtration. The yield is 10.2 g (77.5% of the theoretical amount), M.P. 169-170°C. 10.2 g of ethyl 10-(3-chloropropionyl)-phenthiazine-2-carbamate ester is dissolved in 50 ml of toluene, 4.72 g of morpholine is added thereto, and the mixture is refluxed at 110-120°C for a period of 3 hours. A precipitate of morpholine hydrochloride is removed by filtration, and the filtrate is washed with water in order to remove excess morpholine, followed by acidulating with dilute hydrochloric acid to adjust the pH of the filtrate is adjusted at 3. The acidic aqueous layer is separated, clarified by treatment with activated carbon and made alkaline until the pH equals 8-9. This procedure yields the free base of ethyl 10-(β-morpholylpropionyl)-phenthiazine-2-carbamate, M.P. 156157°C. The free base thus obtained is extracted with toluene, the extract is dried over magnesium sulphate and to the anhydrous toluene solution is added an anhydrous ethereal solution of hydrogen chloride until the precipitation of the target compound is complete. This procedure yields 9.53 g (76.2% of the theoretical amount) of ethyl 10-(β-morpholylpropionyl)-phenthiazine-2carbamate hydrochloride. After recrystallization from dichloroethane, the target compound melts at 189°C. (decomp.). References Merck Index, Monograph number: 6351, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. Page G.O.; US Patent No. 5,202,435; April 13, 1993; Assigned to Du Pont Merck Pharmaceutical Company (Wilmington, DE) Gritsenko A. et al.; US Patent No. 3,864,487; Feb. 4, 1975

MORINAMIDE Therapeutic Function: Antitubercular Chemical Name: Pyrazinecarboxamide, N-(morpholinomethyl)Common Name: Morfazinamida; Morinamide; Morinammide; Morphazinamide

Morinamide

2349

Structural Formula:

Chemical Abstracts Registry No.: 952-54-5 Trade Name

Manufacturer

Country

Year Introduced

Morinamide

Bracco Industria Chimica S.p.A.

-

-

Raw Materials 2-Pyrazinecarboxamide Diethylamine Formaldehyde Morpholine Manufacturing Process 98.5 parts by weight 2-pyrazinecarboxamide was mixed with 260 parts by volume of diethylamine. 91 parts by weight of 37% formaldehyde was added to above mixture by stirring for 30 minutes. The reaction mixture was spontaneously heated to 50°C. Then it heated to reflux for 5 hours on water bath. After that it was distilled to dryness at temperature between 40°-50°C. The residue was dissolved with about 200 parts by volume of ligroin (B.P. 60°C) by heating. The solution was filtered hot for removing the not reacted 2-pyrazinecarboxamide. Then it was cooled to -10°C and desired N(diethylaminomethyl)-pyrazinecarboxylic acid amide discharged. It was filtered off and recrystallized from light petrol ester. Yield about 90%, MP: 47°-50°C. 500 parts by weight of N-(diethylaminomethyl)pyrazinecarboxylic acid amide and 2500 parts by volume of was mixed and heated by stirring to temperature 140°-150°C. At 60°-100°C a distillation begun and ended at 127°C (a boiling point of morpholine). The distillate consisted from diethylamine and morpholine. After 30-60 minutes the mixture was cooled to 50°C and distilled in vacuum to dryness. The residue was recrystallized from 400 parts by volume of benzene to give N-(morpholinomethyl)pyrazinecarboxamide, yield 92%, MP: 114°-117°C. References Felder E., Tiepolo U.; D.B. Patent No. 1,129,492; June 23, 1960; Bracco Industria Chimica S.p.A., Mailand (Italien)

2350

Moroxydine hydrochloride

MOROXYDINE HYDROCHLORIDE Therapeutic Function: Antiviral Chemical Name: 4-Morpholinecarboximidoylguanidine, hydrochloride Common Name: Abitilguanide; Moroxydine hydrochloride; Morpholinobiguanide hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 3160-91-6; 3731-59-7 (Base) Trade Name Grippe Tamaxin Virobis Virustat

Manufacturer Nissin Sawai S.C.S. Delagrange

Country -

Year Introduced -

Raw Materials Morpholine Dicyandiamide Manufacturing Process 43.5 g morpholine, 41.7 ml concentrated hydrochloric acid, 40 ml of water, and 42 g dicyandiamide are refluxed for 48 hours, whereupon the reaction mixture is cooled to +5°C and filtered. The filtrate is evaporated to dryness and extracted and extracted with boiling ethanol. Yield: 50 g. The formed 4morpholinecarboximidoylguanidine hydrochloride is purified by recrystallization from methanol. The salt may be converted into the base by adding equivalent of any basic compound (triethylamine, sodium bicarbonate and so on). In practice it is usually used as hydrochloride. References Aktiebolaget Kabi, a Swedish Body corporate, of Stockholm 30, Sweden; G.B. Patent No. 776,176; Sept. 15, 1953

Morphine sulfate

2351

MORPHINE SULFATE Therapeutic Function: Narcotic analgesic, Sedative Chemical Name: Morphinan-3,6-α-diol, 7,8-didehydro-4, 5-α-epoxy-17methyl-, sulfate (2:1) (salt) Common Name: Morphine sulfate Structural Formula:

Chemical Abstracts Registry No.: 64-31-3; 57-27-2 (Base) Trade Name Avinza Continus Dolcontin Dolcontin Duramor Doloral Duralgin Kadian Kapanol M-Eslon Morcontin Morphine Sulfate SR MST Continus Oblioser Oramorph SR RMS Skenan Substitol

Manufacturer Aetna Inc. Napp Kabipharmacia Norsk Ph. Biological E. Limited Atlas Ethypharm Alpharma USHP GlaxoSmithKline Grunenthal Modi-Mundi Pharma Limited Pharmascience

Country India Australia Germany India

Year Introduced -

USA

-

Mundipharma Serono Roxane Laboratories Upsher-Smith UPSA Mundipharma

Austria France -

-

Raw Materials Plant vegetable Methanol or the aqueous solution of potassium pyrosulfate

2352

Motretinide

Manufacturing Process Morphin was extracted from the plant vegetable (the poppy) by the mixture of water and methanol or the aqueous solution of potassium pyrosulfate. The precipitation of the morphin was carried out by addition to the extract the aqueous solution of sodium carbonate. Morphin can be obtained from the extract by using the cation exchanger. Free base of morphin was transformated to the sulfate salt. References Pharmazeutische Wirkstoffe, 610-611, p.610 Heropolitanski R. et al.; DE Patent No. 2,905,468, 13.02.1979 DE Patent No. 2,726,925, 13.02.1979

MOTRETINIDE Therapeutic Function: Antipsoriatic Chemical Name: N-Ethyl-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl2,4,6,8-nonatetraenamide Common Name: Structural Formula:

Chemical Abstracts Registry No.: 56281-36-8 Trade Name

Manufacturer

Country

Year Introduced

Tasmaderm

Roche

Switz.

1981

Motretinide

2353

Raw Materials Sodium hydride Sodium hydroxide Ethylamine

3-Formylcrotonic acid butyl ester Phosphorus trichloride 5-(4-Methoxy-2,3,6-trimethylphenyl)-3methylpenta-2,4-diene-1triphenylphosphonium bromide

Manufacturing Process 228 g of 5-(4-methoxy-2,3,6-trimethyl-phenyl)-3-methyl-penta-2,4-diene-1triphenylphosphonium bromide are introduced under nitrogen gassing into 910 ml of dimethylformamide and treated with cooling at 5°C to 10°C within 20 minutes with 17.5 g of a suspension of sodium hydride (about 50% by weight) in mineral oil. The mixture is stirred for 1 hour at about 10°C, then treated at 5°C to 8°C dropwise with 61.8 g of 3-formylcrotonic acid butyl ester, heated for 2 hours at 65°C, subsequently introduced into 8 liters of icewater and, after the addition of 300 g of sodium chloride, thoroughly extracted with a total of 18 liters of hexane. The extract is washed 5 times with 1 liter of methanol/water (6:4 parts by volume) each time and 2 times with 1.5 liters of water each time, dried over sodium sulfate and evaporated under reduced pressure to leave 9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7dimethyl-nona-2,4,6,8-tetraen-1-oic acid butyl ester, MP 80°C to 81°C as the residue. 125.8 g of 9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8tetraen-1-oic acid butyl ester are introduced into 2,000 ml of absolute ethanol and treated with a solution of 125.8 g of potassium hydroxide in 195 ml of water. The mixture is heated to boiling under nitrogen gassing for 30 minutes, then cooled, introduced into 10 liters of ice-water and, after the addition of about 240 ml of concentrated hydrochloric acid (pH 2-4), thoroughly extracted with a total of 9 liters of methylene chloride. The extract is washed with about 6 liters of water to neutrality, dried over calcium chloride and evaporated under reduced pressure. The residue is taken up in 700 ml of hexane. The precipitated 9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8tetraen-1-oic acid melts at 228°C to 230°C. 28.6 g of 9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8tetraen-1-oic acid are introduced into 300 ml of benzene and treated under nitrogen gassing with 12 g of phosphorus trichloride. The benzene is subsequently distilled off under reduced pressure. The remaining 9-(4methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid chloride is dissolved in 1,200 ml of diethyl ether. The solution is added dropwise at -33°C into 500 ml of ethylamine and stirred for 3 hours. The reaction mixture is then diluted with 500 ml of diethyl ether and stirred without cooling for a further 12 hours, the ammonia evaporating. The residue is dissolved in 10 liters of methylene chloride. The solution is washed 2 times with 3 liters of water, dried over sodium sulfate and evaporated under reduced pressure. The remaining N-ethyl-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7dimethylnona-2,4,6,8-tetraen-1-oic acid amide melts, after recrystallization from ethanol, at 179°C to 180°C.

2354

Moxalactam disodium

References Merck Index 6142 DFU 3 (2) 126 (1978) OCDS Vol. 3 p. 12 (1984) DOT 18 (12) 653 (1982) I.N. p. 647 Bollag, W., Ruegg, R.and Ryser, G.; US Patents 4,105,681; August 8,1978; and 4,215,215; July 29,1980; both assigned to Hoffmann-LaRoche, Inc.

MOXALACTAM DISODIUM Therapeutic Function: Antiinfective Chemical Name: 7-[[Carboxy(4-hydroxyphenyl)acetyl]amino]-7-methoxy-3[[(1-methyl-1H-tetrazole-5-yl)thio]-methyl]-8-oxo-5-oxa-1azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid disodium salt Common Name: Lamoxactam; Latamoxef Structural Formula:

Chemical Abstracts Registry No.: 64952-97-2 (Base) Trade Name

Manufacturer

Country

Year Introduced

Moxam

Lilly

US

1981

Moxalactam

Lilly

W. Germany

1981

Festamoxin

Shionogi

W. Germany

1981

Moxalactam

Lilly

France

1981

Moxalactam

Lilly

UK

1982

Shiomalin

Shionogi

Japan

1982

Moxalactam disodium

2355

Raw Materials p-(p-Methoxybenzyloxy)-phenylmalonic acid Diphenylmethyl 7β-amino-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxa-dethia-3-cephem-4-carboxylate Aluminum chloride Sodium-2-ethylhexanoate Manufacturing Process To a stirred suspension of p-(p-methoxybenzyloxy)-phenylmalonic acid (125 mg) in methylene chloride (3 ml) are added triethylamine (55 l) and oxalyl chloride (26 l) at -15°C, and the suspension is stirred for 40 minutes at 0°C. The mixture is added to a solution of diphenylmethyl 7β-amino-7α-methoxy-3(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylate (100 mg) in methylene chloride (3 ml) and pyridine (63 l), and the mixture is stirred for 30 minutes at 0°C. The reaction mixture is diluted with ethyl acetate, washed with aqueous 2N-hydrochloric acid and water, dried over sodium sulfate, and concentrated to give crude product (212 mg), which is chromatographed on silica gel (20 g) and eluted with a mixture of ethyl acetate and acetic acid (99:1) to give diphenylmethyl-7β-[α-p-(pmethoxybenzyloxy)phenyl-α-carboxyacetamido]-7α-methoxy-3-(1methyltetrazol-5yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylate as foam (71 mg). Yield: 45%. To a solution of diphenylmethyl-7β-[α-p-(p-methoxybenzyl)-oxy-phenyl-α-pmethoxybenzyl-oxycarbonil-acetamido]-7α-methoxy-3-(1-methyltetrazol-5yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylate (1.20 g) in methylene chloride (24 ml) are added anisole (2.4 ml) and a solution of aluminum chloride (2.58 g) in nitromethane (12 ml) at 0°C under nitrogen. After stirring for 15 minutes at 0°C, the mixture is poured into cold 5% sodium hydrogen carbonate aqueous solution (100 ml) and filtered to remove the formed precipitate. The filtate is washed twice with methylene chloride (2 x 100 ml), acidified with 2N-hydrochloric acid to pH 2.60, and poured in a column of high porous polymer HP-20 (60 ml) sold by Mitsubishi Chemical Industries Ltd. The column is washed with water (300 ml) and eluted with methanol. The eluate is concentrated under reduced pressure at room temperature. The residue is dissolved in methanol, treated with active carbon, and concentrated under reduced pressure to give 7β(α-p-hydroxyphenyl-α-carboxyacetamido)-7βmethoxy-3-(1-methyl-tetrazol-5-yl)thiomethyl1-oxadethia-3-cephem-4carboxylic acid as powder (595 mg) decomposing at 125°C to 132°C. Yield: 88.5%. To a solution of 7β(α-p-hydroxyphenyl-α-carboxyacetamido)-7α-methoxy-3-(1methyl-tetrazol-5-yl)thiomethyl1-oxadethia-3-cephem-4-carboxylic acid (359 mg) in methanol (7 ml) is added a solution of sodium 2-ethylhexanoate in methanol (2 mols/liter; 1.73 ml) at room temperature. After stirring for 10 minutes, the reaction mixture is diluted with ethyl acetate, stirred for 5 minutes, and filtered to collect separated solid, which is washed with ethyl acetate, and dried to give disodium salt of 7β(α-p-hydroxyphenyl-αcarboxyacetamido)-7α-methoxy-3-(1-methyl-tetrazol-5-yl)thiomethyl1oxadethia-3-cephem-4-carboxylic acid (342 mg). Yield: 888%. Colorless powder. MP decomposition from 170°C.

2356

Moxaverine hydrochloride

References Merck Index 6143 DFU 5 (9) 467 (1980) PDR p. 1064 OCDS Vol. 3 p. 218 (1984) DOT 18 (3) 132 (1982) I.N. p. 550 Narisada, M. and Nagata, W.; US Patent 4,138,486; February 6,1979; assigned to Shionogi and Co., Ltd. (Japan)

MOXAVERINE HYDROCHLORIDE Therapeutic Function: Spasmolytic Chemical Name: 1-Benzyl-3-ethyl-6,7-dimethoxyisoquinoline hydrochloride Common Name: Moxaverine hydrochloride; Meteverine hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 1163-37-7 Trade Name

Manufacturer

Country

Year Introduced

Paverin

Bracco

-

-

Raw Materials 1-Nitropropane 3,4-Dimethoxybenzaldehyde Sodium Formic acid Zinc Phenylacetic acid chloride Phosphorous oxychloride Manufacturing Process 166 g (1 mol) of 3,4-dimethoxybenzaldehyde were stirred for several hours (8 to 10 hours) with 180 g (2.02 mols.) of 1-nitropropane in 300 ml of methanol, in which 12 g of metallic sodium had previously been dissolved, the stirring taking place while heating to 45-50°C. After usual working up of the reaction

Moxestrol

2357

mixture, there were obtained 155 g of a white, crystalline product, which constituted the 1-(3,4-dimethoxyphenyl)-2-nitro-1-butanol and melted after recrystallization from isopropanol at 93-94°C (uncorrected). The composition was confirmed by elementary analysis and an infra-red spectrogram. 204 g (0.8 mol) of the above nitro alcohol were reduced at 30-35°C in 1250 g of 44% formic acid with 320 g of powdered zinc (about 4.9 at.). After working up, the base 1-(3,4-dimethoxyphenyl)-2-amino-1-butanol was obtained as a white crystalline product. After recrystallization from ethyl acetate, it melted at 91-93°C and the yield was 168 g, i.e. 93.3% of the theoretical. 90 g (0.4 mol) of the above amino alcohol are reacted at 45-50°C in 400 ml of chloroform in the presence of 95 g (1.2 mols) of pyridine by means of 139 g (0.9 mol) of phenylacetic acid chloride. After working up the reaction mixture, a yellowish-crystalline product was isolated (183.5 g, theoretical: 184.6 g), which melted at 123-125°C. After recrystallization from ethyl acetate, it yielded minute, white crystals, which melted at 129 -131°C (uncorrected). The composition of the product was confirmed by elementary analysis. 217 g of the above 1-(3,4-dimethoxyphenyl)-2-(phenylacetamido)-butanol-1phenyl acetate (0.47 mol) were stirred in 80 1300 ml of xylene with 145 g of phosphorous oxychloride at 100-105°C. After some hours, when the evolution of hydrochloric acid gas had ceased, the reaction mixture was poured on to ice and stirred while cold until the crystallization was completed. After filtering, 144 g (89%) of the formed 1-benzyl-6,7-dimethoxy-3-ethyl isoquinoline hydrochloride were obtained in the form of yellowish crystals, which melted at 198-202°C with decomposition. From the separated aqueous mother liquors, the remainder of the formed isoquinoline base was obtained after treatment with ammonia and extraction with ether, the said base being isolated by way of the sparingly soluble and readily crystallisable acid sulfate. The salt represented a yellowish crystal powder, which melted at 239-243°C and weighed 21 g (11%). Thus, the yield of crude isoquinoline salt was almost the theoretical yield. The crude hydrochloride acid salt yielded white, lustrous prisms after recrystallisation from 96% ethanol, the said prisms melting at 208-210°C with decomposition. 1-Benzyl-6,7 -dimethoxy-3-ethyl isoquinoline may be prepared as a base from its salt by adding of equivalent of triethyl amine or any other base. References Orgamol S. A., a Swiss Body Corporate of Postfach, Switzerland; G.B. Patent No. 1,030,022; June 16, 1966

MOXESTROL Therapeutic Function: Estrogen Chemical Name: 11β-Methoxy-19-nor-17α-pregna-1,3,5(10)-trien-20-yne3,17-diol

2358

Moxestrol

Common Name: 11β-Methoxy-17a-ethynylestradiol Structural Formula:

Chemical Abstracts Registry No.: 34816-55-2 Trade Name

Manufacturer

Country

Year Introduced

Surestryl

Roussel

France

1974

Raw Materials Methanol Acetylene Potassium

∆4,9-Estradiene-11β-ol-3,17-dione Palladium hydroxide

Manufacturing Process (A) Preparation of 11β-Methoxy-∆4,9-Estradiene-3,17-Dione: 0.5 g of ∆4,9estradiene-11β-ol-3,17-dione were dissolved at room temperature in 25 cc of methylene chloride containing 2% of methanol and after 5 mg of p-toluenesulfonic acid were added, the reaction mixture was agitated for several minutes. Then the reaction mixture was poured into ice water, washed with water until the wash waters were neutral, and distilled to dryness under vacuum. The resulting residue was crystallized from ethyl ether to obtain 0.46 g of 11β-methoxy-∆4,9-estradiene-3,17-dione having a MP of 140°C. (B) Preparation of 11β-Methoxy-∆1,3,5(10)-Estradiene-3-ol-17-one: 12.3 g of 11β-methoxy-∆4,9-estradiene-3,17-dionewere dissolved in 1,230 cc of methanol and then, under an atmosphere of nitrogen, 7.38 g of palladium hydroxide were added and the mixture was held at reflux for one hour under agitation and a nitrogen atmosphere. Then the reaction mixture was cooled to 30°C, filtered, vacuum filtered and washed with methanol. The methanolic solutions were concentrated to about 50 cc, allowed to stand overnight at room temperature and filtered. The precipitate formed was triturated in methanol and dried at 80°C to obtain 10.74 g (yield = 87.5%) of 11βmethoxy-∆1,3,5(10)-estradiene-3-ol-17-one having a MP of 264°C. (C)Preparation of 11β-Methoxy-17α-Ethynyl-∆1,3,5(10)-Estradiene-3,17β-Diol: Under agitation and an atmosphere of nitrogen, 12 g of potassium were heated at 80°C in 180 cc of tertiary-amyl alcohol. The mixture was agitated for 30 minutes, cooled to 20°C and after 60 cc of dioxane were added thereto, a stream of acetylene was allowed to bubble through the mixture for one hour

Moxifloxacin hydrochloride

2359

and fifteen minutes. Then a solution of 3 g of 11β-methoxy-∆1,3,5(10)estradiene-3-ol-17-one in 50 cc of dioxane was added and the mixture was agitated for 4 hours while continuing the passage of acetylene at room temperature. Thereafter, 50 cc of a 50% aqueous acetic acid solution was added and the mixture was poured into water and extracted with ether. The organic phases were washed first with an aqueous solution containing 10% of neutral sodium carbonate, then with water until the wash waters were neutral, dried over sodium sulfate and concentrated under vacuum until crystallization started. The reaction mixture was iced for one hour, vacuum filtered and the precipitate dried under vacuum to obtain 3.8 g of the raw 17α-ethynyl derivative, which was purified by dissolution in ethyl acetate at reflux and by icing to obtain 2.33 g (yield = 77%) of 11β-methoxy-17α-ethynyl-∆1,3,5(10)estradiene-3,17β-diol, having a MP of 280°C. References Merck Index 6145 Kleeman and Engel p. 611 DOT 11 (4) 149 (1975) I.N. p. 647 Bertin, D. and Pierdet, A.; US Patent 3,579,545; May 18, 1971; assigned to Roussel- UCLAF, France

MOXIFLOXACIN HYDROCHLORIDE Therapeutic Function: Antibacterial Chemical Name: 3-Quinolinecarboxylic acid, 1-cyclopropyl-6-fluoro-1,4dihydro-8-methoxy-7-((4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridin-6yl)-4-oxo-, monohydrochloride Common Name: Moxifloxacin hydrochloride; Proflox Structural Formula:

Chemical Abstracts Registry No.: 151096-09-2 (Base); 186826-86-8

2360

Moxifloxacin hydrochloride

Trade Name Avelox Actira Octegra Octegra Proflox

Manufacturer Bayer Bayer Lilly Bayer Div. Sigma

Country -

Year Introduced -

Raw Materials Hydrogen Potassium hydroxide Copper cyanide Hydrochloric acid Sulfuric acid Thionyl chloride Diethyl malonate Acetic anhydride Sodium fluoride Ethyl orthoformate Acetic acid Pyridine-2,3-dicarboxylic acid

N-Methyl-2-pyrrolidone Ferric chloride hexahydrate Glycol monomethyl ether Lithium aluminum hydride Ruthenium on charcoal Magnesium ethoxide 4-Toluenesulfonic acid Sodium bicarbonate 1,2,3,4-Tetrafluorobenzene Palladium on charcoal Cyclopropylamine N-benzylimide

Manufacturing Process Synthesis of intermidate octahydropyrrolo[3,4-b]pyridine (2,8diazabicyclo[4.3.0]nonane): 47.6 g (0.2 mol) of pyridine-2,3-dicarboxylic acid N-benzylimide (British Patent No. 1,086,637; Chem. Abstr. 68, 95695w) are hydrogenated in 400 ml of glycol monomethyl ether over 15 g of ruthenium-on-active charcoal (5% strength) at 90°C under 100 bar until the calculated amount of hydrogen has been taken up. The catalyst is then filtered off and the filtrate is concentrated on a rotary evaporator 44 g of an oily crude product are obtained. The corresponding hydrogenation with palladium-on-active charcoal (5% strength) gives a quantitative yield of a pure 6-benzyl-5,7-dioxooctahydropyrrolo[3,4-b]pyridine of melting point 67°-69°C. 1.52 g (40 mmol) of lithium aluminium hydride are initially introduced into 30 ml of anhydrous tetrahydrofuran, and 44 g (about 0.18 mol) of crude or pure 6-benzyl-5,7-dioxo-octahydropyrrolo[3,4-b]pyridine are added dropwise as a solution in 15 ml of anhydrous tetrahydrofuran. The mixture is then subsequently stirred at the boiling point for 10 h. 1.5 ml of water, 1.5 ml of 15% strength potassium hydroxide solution and 4.5 ml of water are added dropwise in succession to the batch and the precipitate is then filtered off with suction and washed with tetrahydrofuran. The filtrate is concentrated on a rotary evaporator and the residue is distilled. 24.4 g of a colorless oil of 6benzyl-octahydropyrrolo[3,4-b]pyridine having a boiling point of 93°95°C/0.06 mbar are obtained on distillation. 69 g (0.32 mol) of 6-benzyl-octahydropyrrolo[3,4-b]pyridine are hydrogenated in 450 ml of methanol over 7 g of palladium-on-active charcoal (5% strength)

Moxifloxacin hydrochloride

2361

at 90°C/90 bar in the course of 3 h. The catalyst is then filtered off, the filtrate is concentrated and the residue is distilled. 33.8 g (84% of theory) of a colorless solid of octahydropyrrolo[3,4-b]pyridine (2,8-diazabicyclo[4.3.0] nonane) having a melting point of 65°-67° C and a boiling point of 78°C/9 mbar are obtained. Synthesis of intermidate 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4oxo-3-quinolinecarboxylic acid: According to the method by Bardon et al. (Tetrahedron, 22, 2541 (1966)), 1,2,3,4-tetrafluorobenzene (50 g) was brominated and methoxylated to give 1-bromo-3-methoxy-2,4,5-trifluorobenzene (22.2 g) as colorless oil. A mixture of the oily product (22 g), cuprous cyanide (10 g) and N-methyl-2pyrrolidone (37 ml) in sealed tube was heated for 4.5 h at 140° to 150°C. After cooling, a solution of ferric chloride hexahydrate (44 g) and concentrated hydrochloric acid (11 ml) in water (60 ml) was added to the reaction mixture and then stirred at 50° to 60°C for 20 min. The reaction mixture was extracted with ether and the organic layer was washed with dilute aqueous hydrochloric acid, with water and with saturated saline solution successively, and dried over anhydrous sodium sulfate and then concentrated. The residue was purified by distillation under reduced pressure to give 3-methoxy-2,4,5trifluorobenzonitrile (14.25 g) as colorless oil, boiling point 94°C/8 mm Hg. To oily product thus obtained (14.2 g) were added concentrated sulfuric acid (8.5 ml) and water (40 ml) and the mixture was stirred for 1 h at 110°C. After cooling, the reaction mixture was poured into ice water (50 ml) and the resulting precipitate was collected by filtration, washed with water, and recrystallized from a solution of dichloromethane-n-hexane to give 3methoxy-2,4,5-trifluorobenzamide (11.59 g) as white needle, melting point 130°-133°C. Then, to these crystals were added 18 N sulfuric acid (150 ml) and the mixture was heated for 3.5 h at 100°C. After cooling, water (400 ml) was added to the mixture and the resulting crystals were recrystallized from nhexane to give the 3-methoxy-2,4,5-trifluorobenzoic acid (9.61 g) as colorless needle, melting point 98°-101°C. To 3-methoxy-2,4,5-trifluorobenzoic acid (9.4 g) was added thionyl chloride (50 ml), the mixture was refluxed for 3 h and then concentrated. The residue was purified by distillation under reduced pressure to give 3-methoxy-2,4,5trifluorobenzoyl chloride (8.86 g) as yellow oil, boiling point 108°-112°C/20 mm Hg. To magnesium ethoxide (5.9 g) was added diethyl malonate (7 g) in anhydrous toluene (35 ml) dropwise and the mixture was warmed for 2 h at 50° to 60°C and then cooled to -10°C. To the mixture was added a solution of the acid chloride (8.86 g) in anhydrous toluene (10 ml) dropwise over 15 min. After stirring for 1 h at -5° to 0°C, ice water (30 ml) containing concentrated sulfuric acid (8 ml) was added to the mixture and the organic layer was separated. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate and then concentrated to give diethyl 3methoxy-2,4,5-trifluorobenzoylmalonate (13.64 g) as brown oil.

2362

Moxifloxacin hydrochloride

To oily product, the diethyl 3-methoxy-2,4,5-trifluorobenzoylmalonate (13.55 g) were added water (20 ml) and p-toluenesulfonic acid (14 mg), and the mixture was refluxed for 9 h. After cooling, the reaction mixture was extracted with dichloromethane and the organic layer was washed with 7% aqueous sodium bicarbonate solution and with saturated saline solution successively, dried over anhydrous sodium sulfate and then concentrated to give ethyl 3methoxy-2,4,5-trifluorobenzoylacetate (10.29 g). To the ethyl 3-methoxy-2,4,5-trifluorobenzoylacetate (9.79 g) were added acetic anhydride (9.6 g) and ethyl orthoformate added cyclopropylamine (8.4 g), and the mixture was refluxed for 3 h. After supplemented further acetic anhydride (3.2 g) and ethyl orthoformate (8.8 g), the mixture was refluxed for 8 h, and then concentrated to give ethyl 2-(3-methoxy-2,4,5trifluorobenzoyl)-3-ethoxyacrylate (9.73 g) as brown oil. To a solution of the ethyl 2-(3-methoxy-2,4,5-trifluorobenzoyl)-3ethoxyacrylate (9.73 g) in ethanol (20 ml) cyclopropylamine (2.0 g) was added dropwise under cooling. After stirring for 2 h at room temperature, the reaction mixture was concentrated and the residue was purified by silica gel column chromatography eluting with n-hexane-ethyl acetate (5:1) to give ethyl 2-(3-methoxy-2,4,5-trifluorobenzoyl)-3-cyclopropylaminoacrylate (7.52 g) as yellowish white crystals, melting point 56°-58°C. The mixture of the ethyl 2-(3-methoxy-2,4,5-trifluorobenzoyl)-3cyclopropylaminoacrylate (6.68 g), sodium fluoride (1.31 g) and anhydrous dimethylformamide (26 ml) was refluxed for 5 h. After cooling, the reaction mixture was poured into ice water (100 ml) and the resulting precipitate was collected by filtration, washed with water and recrystallized from ethyl acetate to give ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3quinolinecarboxylate (4.53 g) as colorless needle, melting point 178°-180°C. To the ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3quinolinecarboxylate (4.5 g) was added a mixed solution of acetic acid (30 ml), concentrated sulfuric acid (4 ml) and water (22 ml), and the mixture was refluxed for 1 h. After cooling, ice water (100 ml) was added and the resulting precipitate was collected by filtration, washed with water and then dried to give 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3quinolinecarboxylic acid (4 g) as colorless powder, melting point 185°-186°C. Syntesis of 1-cyclopropyl-7-(2,8-diazabicyclo[4.3.0]non-8-yl)-6-fluoro-1,4dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid hydrochloride (moxifloxacin hydrochloride): A mixture of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3quinolinecarboxylic acid, 2,8-diazabicyclo[4.3.0]nonane, DBU (1,8diazobicyclo[5.4.-0]undec-7-ene and anhydrous acetonitrile was refluxed. After cooling, the resulting precipitate was collected by filtration and recrystallized from methanol to give the 1-cyclopropyl-7-(2,8diazabicyclo[4.3.0]non-8-yl)-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3quinolinecarboxylic acid. The 1-cyclopropyl-7-(2,8-diazabicyclo[4.3.0]non-8-yl)-6-fluoro-1,4-dihydro-8methoxy-4-oxo-3-quinolinecarboxylic acid are dissolved in half-concentrated hydrochloric acid by heating, the solution is concentrated and the residue is

Moxisylyte

2363

stirred with ethanol. The undissolved precipitate of 1-cyclopropyl-7-(2,8diazabicyclo[4.3.0]non-8-yl)-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3quinolinecarboxylic acid hydrochloride is filtered off with suction, washed with ethanol and dried at 100°C in vacuo. References Masuzawa K. et al.; US Patent No. 5,043,450; August 27, 1991; Assigned: Kyorin Pharmaceutical Co., Ltd., Tokuo, Japan Petersen U. et al.; US Patent No. 4,990,517; February 5, 1991; Assigned: Bayer Aktiengesellschaft, Leverkusen, Fed. Rep. of Germany

MOXISYLYTE Therapeutic Function: Vasodilator Chemical Name: 4-[2-(Dimethylamino)ethoxy]-2-methyl-5-(1-methylethyl)phenol acetate (ester) Common Name: Thymoxamine Structural Formula:

Chemical Abstracts Registry No.: 54-32-0 Trade Name

Manufacturer

Country

Year Introduced

Carlytene

Dedieu

France

1962

Vasoklin

Godecke

W. Germany

1973

Opilon

Parke Davis

Italy

1975

Apifor

Substancia

Spain

-

Arlitene

Chinoin

Italy

-

Sympal

VEB Berlin Chemie

E. Germany

-

Valyten

Landerlan

Spain

-

2364

Moxisylyte

Raw Materials Thymol Sodium Sulfuric acid Acetic anhydride Hydrogen chloride

Hydrogen sulfide Dimethylaminoethyl chloride Sodium nitrite Ethanol

Manufacturing Process A hydrochloric acid solution of 100 g of thymol in alcohol is reacted with 72 g of sodium nitrite, the nitrosothymol (Organic Syntheses 6, New York, 1926, p. 92) thus obtained is introduced into ammonia, and is reduced by the introduction of hydrogen sulfide to 4-aminothymol (Organic Syntheses Coll. Vol. 1, New York, 1932, p. 458). 133.3 g of this 4-aminothymol are mixed with 67 g of sodium acetate, 107 g of glacial acetic acid and 80 g of acetic acid anhydride to form 4-acetaminothymol (Plancher, Gazzetta Chimica Italiana 25, II, p. 388). 156 parts by weight of this last formed substance dissolved in 600 cc of alcohol are added to a solution of 17.6 parts by weight of sodium in 600cc of alcohol, the mixture being boiled under reflux for some time with 82 g of dimethylaminoethyl chloride. The reaction product is treated with water, and neutralized with hydrochloric acid using acid Congo reagent indicator, and the alcohol is distilled off in vacuo. The base liberated by alkali is dissolved in ether. By evaporating the ether solution the dimethylaminoethyl ether of the 4-acetaminothymol is obtained as a brownish-yellow oil. After some time this oil solidifies in a crystalline state. 100 g of this base are dissolved in a mixture of 300 cc of concentrated hydrochloric acid (density 1.19) and 400 cc of water, and the solution is boiled for one hour under a reflux condenser. Thereupon it is made alkaline, extracted with ether, and the ether is distilled off. 23.6 g of the 4aminothymoxyethyldimethylamine thus obtained are diazotized in the presence of sulfuric acid at a temperature not exceeding 0°C using a solution of 7.2 g of sodium nitrite in 70 cc of water, and the diazo compound is heated to boiling point after the addition of 1 g of copper sulfate, until no further gas is evolved. It is then made alkaline, and carbon dioxide is introduced. The base is precipitated first in an oily state, and soon becomes crystalline. The 4oxythymoxyethyldimethylamine forms a neutral hydrochloride which is readily soluble in water, and has a melting point of 174°C to 175.5°C. 36.8 g of 4-oxythymoxyethyldimethylamine are boiled for one hour on a water bath with 160 cc of acetic anhydride and 17.5 cc of pyridine. After this period, the solution is diluted with water, made alkaline, and the base is extracted with ether and the ether distilled off. With acids, the base obtained forms crystalline salts which are readily soluble in water. The hydrochloride melts between 208°C and 210°C. References Merck Index 6146 Kleeman and Engel p. 612 OCDS Vol. 1 p. 116 (1977) I.N. p. 647 Veritas Drug Co., Ltd; British Patent 745,070; February 22,1956

Mupirocin

2365

MUPIROCIN Therapeutic Function: Antibiotic Chemical Name: Nonanoic acid, 9-((3-methyl-1-oxo-4-(tetrahydro-3,4dihydroxy-5-((3-(2-hydroxy-1-methylpropyl)oxiranyl)methyl)-2H-pyran-2yl)-2-butenyl)oxy)-, (2S-(2-α(E),3-β,4-β,5-α(2R*,3R*(1R*,2R*))))Common Name: Acidum pseudomonicum; Mupirocin; Pseudomonic acid A Structural Formula:

Chemical Abstracts Registry No.: 12650-69-0 Trade Name Bactroban Bactroban Bactroban Nasal Bactoderm Bactoderm Eismycin

Manufacturer GlaxoSmithKline SmithKline Beecham Beecham Pharmco Puerto Rico, Inc. Beecham GlaxoSmithKline

Country UK Germany

Year Introduced -

Raw Materials Pseudomonas fluorescens, strain NCIB 10586 Manufacturing Process Production and recovery of Antibacterially active pseudomonic acid and Pseudomonic acid A Pseudomonas fluorescens, strain NCIB 10586 was grown in submerged culture at 30°C in a medium containing 1% corn steep liquor and 0.5% glucose in a basic salts solution. The maximum yield of the antibiotic occurred after 24 hours and all of the detectable activity was in the culture fluid. After the addition of barium chloride (0.5%) the cells and precipitated non-active contaminant material were removed by centrifugation. The activity was progressively concentrated by partitioning into isobutylmethyl ketone (IBMK) (0.2 vol) at pH 4.5 water (0.8 vol) at pH 8.5, and then IBMK (0.25 vol) at pH 4.5 followed by evaporation to a small volume under reduced pressure. After a further partition into water at pH 8.5 and then adjustment to pH 7-8 the aqueous solution was freeze dried to give the sodium salt which could be stored at 0°C for several months, without loss of activity. The antibiotic extract was stable within the range pH 4-9 at 37°C for 24 hours. Outside these limits rapid loss of activity occurred. The sodium salt showed a broad

2366

Muzolimine

antibacterial spectrum against Gram positive and Gram negative bacteria, showed low toxicity and was bacteriostatic against S. aureus (N.C.T.C. 6571) and E. coli (M.R.E. 600). Further purification of the crude acid was effected by chromatography on Amberlite XAD-2 polystyrene resin with a linear gradient produced by adding 0.1 N methanolic ammonia, to 0.01 N aqueous ammonia. A series of low molecular weight acids was eluted first, followed by a fraction (30-60% elution) that possessed the major part of the antibacterial (biological) activity. Purification of Pseudomonic acid and Pseudomonic Acid A The produced biologically active material upon methylation with diazomethane in ether showed two spots by thin layer chromatography corresponding to methyl pseudomonate as the major component and a minor amount of component methyl pseudomonate-A (ratio ca 9:1 by wt.). Methyl pseudomonate was separated from methyl pseudomonate-A by preparative layer silica gel (GF245) chromatography on development with chloroform/isopropanol (9:1). 50% of methyl pseudomonate was recovered from the impure residue by crystallization from benzene/petroleum ether to give colorless needles of m.p. 76.5-78°C. Acetylation of the methyl ester with pyridine/acetic anhydride affords a triacetate. Reduction of the methyl ester with LiAlH4 in THF afforded 1,9dihydroxynonanoate, m.p. 46°C. References Barrow K. D., Mellows G.; US Patent No. 4,289,703; Sep. 15, 1981; Assigned: Beecham Group Limited O'Hanlon P. J. et al.; US Patent No. 4,222,942; Sep. 16, 1980; Assigned: Beecham Group Limited

MUZOLIMINE Therapeutic Function: Diuretic Chemical Name: 3-Amino-1-(α-methyl-3,4-dichlorobenzyl)pyrazol-5-one Common Name: Structural Formula:

Mycophenolate mofetil hydrochloride

2367

Chemical Abstracts Registry No.: 55294-15-0 Trade Name

Manufacturer

Country

Year Introduced

Edrul

Bayer

Italy

1982

Raw Materials α-Methyl-3,4-dichlorobenzylhydrazine β-Amino-β-ethoxyacrylic acid ethyl ester Manufacturing Process 41 g of α-methyl-3,4-dichlorobenzylhydrazine, dissolved in absolute ethanol, were added dropwise to a solution of 31.8 g of β-amino-β-ethoxyacrylic acid ethyl ester and 1.5 g of p-toluenesulfonic acid in 150 ml of ethanol at room temperature under nitrogen gas. After stirring for 2 hours and standing overnight, the reaction solution was concentrated as far as possible on a rotary evaporator. The residue which remained was dissolved in 2 N sodium hydroxide solution. Any unconverted starting products or by-products were extracted with ether. The aqueous phase was then brought to pH 5 with acetic acid. The oil thereby produced was taken up in methylene chloride and the organic phase was dried over Na2SO4. After evaporating off the solvent, the reaction product crystallized out. It was recrystallized from methanol; melting point 127°C to 129°C; yield 21 g (38.5% of theory). References Merck Index 6165 DFU 2 (6) 387 (1977) OCDS Vol. 3 p. 137 (1984) DOT 18 (10) 555 (1982) and 19 (5) 267 (1983) I.N. p. 649 Moller, E., Meng, K., Wehinger, E. and Horstmann, H.; British Patent 1,429,141; March 24, 1976; assigned to Bayer AG Moller, E., Meng, K., Wehinger, E. and Horstmann, H.; US Patent 4,018,890; April 19, 1977; assigned to Bayer AG

MYCOPHENOLATE MOFETIL HYDROCHLORIDE Therapeutic Function: Antiarthritic, Immunosuppressive Chemical Name: 4-Hexenoic acid, 6-(1,3-dihydro-4-hydroxy-6-methoxy-7methyl-3-oxo-5-isobenzofuranyl)-4-methyl-, 2-(4-morpholinyl)ethyl ester, (4E)-, hydrochloride Common Name: Mycophenolate mofetil hydrochloride

2368

Mycophenolate mofetil hydrochloride

Structural Formula:

Chemical Abstracts Registry No.: 116680-01-4; 128794-94-5 (Base) Trade Name CellCept CellCept CellCept

Manufacturer Pharmacia Roche Syntex

Country Italy Italy -

Year Introduced -

Raw Materials Sodium diethylmalonate Diazomethane t-Butylhypochlorite Phosphorus Thionyl chloride

3-Methylpent-3-en-2-on Ammonium hydroxide Hydroiodic acid Silver oxide Morpholinoethanol

Manufacturing Process The synthesis of Mycophenolic acid (Canonica L. Et al., Tetrahedron Letters, 1971, N 28, p.2691-2692) By condensation of sodium diethylmalonate and 3-methylpent-3-en-2-on in ethanol was obtained 2,3-dimethyl-4,6-dioxocyclohexanecarboxilic acid ethyl ester, which was aromatised to 4,6-dihydroxy-2,3-dimethylbenzoic acid ethyl ester (melting point 115-116°C). By treatment with diazomethane or with CH3I and K2CO3 this compound was transformed into 2,4-dimethoxy-5,6dimethylbenzoic acid ethyl ester (melting point 62-63°C). The hydrolysis of the ester group furnished the 2,4-dimethoxy-5,6-dimethylbenzoic acid (melting point 208-210°C), which was converted into the amide: carbamic acid 3-methoxy-4,5,6-trimethylphenyl ester (melting point 225-229°C). Treatment of the amide with t-butylhypochlorite in methylene dichloride yielded the corresponding N-chloroamide which was photolysed to the intermediate iminolactone and was immediately hydrolized to 5,7-dimethoxy4-methyl-3H-isobenzofuran-1-one. This compound with hydriodic acid in acetic acid in the presence of red phosphorous at reflux yielded 5,7-dihydroxy-4-methyl-3H-isobenzofuran-1one. Condensation of 6-bromo-4-methylhex-4-enoic acid methyl ester and 5,7-dihydroxy-4-methyl-3H-isobenzofuran-1-one with silver oxide in dioxane at room temperature yielded 6-(4,6-dihydroxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoic acid methyl ester (36% yield). At last, monomethylation with diazomethane yield 6-(4-hydroxy-6-methoxy-7methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methylhex-4-enoic acid

Myrtecaine

2369

methyl ester, which was hydrolysed with aqueous sodium hydroxide to 6-(4hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4methylhex-4-enoic acid (Mycophenolic acid). Mycophenolic acid may be obtained by the fermentation broth of Pennicillium brevicompactum. The synthesis of Mycophenolate mofetil (Patent U.S. 4,753,935). The mixture of Mycophenolic acid (32.0 g), thionyl chloride (25.0 ml) and DMF (0.3 ml) in dichloromethane (250 ml) was stirred at room temperature for 3 hours, after which the volatile components were removed under vacuum to afford mycophenolic acid chloride as an oil. The mycophenolic acid chloride oil was dissolved in dichloromethane (50.0 ml) and added to the chilled solution of morpholinoethanol (30.5 ml) in dichloromethane (250 ml). After stirring for 90 min at 4°C, the reaction mixture was washed with water and then with aqueous sodium bicarbonate. The organic solution was dried with sodium sulfate and evaporated to yield Mycophenolate mofetil: morpholinoethyl E-6-(1,3-dihydro-4-hydroxy-6methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoate (melting point 93-94°C). The product (38.0 g) was dissolved in isopropanol (200 ml) and the solution was added to a solution of hydrogen chloride (10.0 g) in isopropanol (150 ml). The hydrochloride of Mycophenolate mofetil was collected by filtration and dried under vacuum (melting point 154-155°C). References Nelson P. et al.; US Patent No. 4,753,935; Jun. 28, 1988; Assigned to Syntex (USA) Inc. Pharmazeutische Wirkstoffe, S. 613 Kida T. et al.; US Patent No. 4,452,891; June 5, 1984; Assigned: Ajinomoto Company Incorporated (Tokyo, JP) Queener S.W. et al.; US Patent No. 4,115,197; Sep. 19, 1978; Assigned: Eli Lilly and Company (Indianapolis, IN) Canonica L. et al.; Tetrahedron Letters, 1971, N 28, p.2691-2692

MYRTECAINE Therapeutic Function: Local anesthetic, Spasmolytic Chemical Name: Ethanamine, 2-(2-(6,6-dimethylbicyclo(3.1.1)hept-2-en-2yl)ethoxy)-N,N-diethylCommon Name: Myrtecaine; Nopoxamine Chemical Abstracts Registry No.: 7712-50-7 Trade Name Myrtecaine Nopoxamine Nopoxamine

Manufacturer Chemical Land21 Desynth Bio Sidus

Country -

Year Introduced -

2370

Myrtecaine

Structural Formula:

Raw Materials Homomyrtenol Sodium amide Diethylaminochloroethane Manufacturing Process 60 g (1.5 mol) of powdered sodium amide are put in suspension in 800 ml of toluene. The mixture is heated to 60°C and 166 g of homomyrtenol (1 mol) are added little by little. The reaction is continued for several hours until the homomyrtenol is entirely converted into sodium derivative. It is allowed to stand and the excess amide is filtered. The reaction is followed by titration on a sample of the decanted liquid after having removed the ammonia. Added to the solution of the sodium derivative of the terpenic alcohol (1 mol) is a toluenic solution of 138 g (1.02 mol) diethylaminochloroethane in toluene. This mixture is refluxed in a nitrogen atmosphere for 12 hours. A precipitate of sodium chloride is formed which is dissolved in water. Two modes of extraction of the base myrtecaine are possible: A) The toluenic solution is extracted with two times 200 ml of concentrated hydrochloric acid diluted to 20%. ln this way there is obtained an aqueous solution of the hydrochloride, when the required amino base is salted out by addition of potassium carbonate. The amino ether-oxide is finally rectified under a vacuum. The fraction boiling between 135° and 140°C under 2 to 3 mm is collected; nD20 = 1.477. B) The toluenic solution is dried on potassium carbonate and then rectified. There is collected the toluene, then between 120° and 130°C under 2 mm the homomyrtenol which has not reacted, and then between 130° and 145°C a fraction which is again fractionated. The pure product is collected at 135°140°C/2-3mm Hg. References Gaudin O.P.; G.B. Patent No. 861,900; Aug. 6, 1959

N

NABILONE Therapeutic Function: Antianxiety Chemical Name: 1-Hydroxy-3-(1',1'-dimethylheptyl)-6,6-dimethyl6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-one Common Name: Structural Formula:

Chemical Abstracts Registry No.: 51022-71-0 Trade Name Cesamet Cesametic Cesamet

Manufacturer Lilly Lilly Lilly

Country Canada W. Germany UK

Year Introduced 1982 1983 1983

Raw Materials dl-3-(1',1'-Dimethylheptyl)-6,6a,7,8-tetrahydro-1-hydroxy-6,6-dimethyl9H-dibenzo[b,d]pyran-9-one Lithium Ammonia Manufacturing Process A solution of 1.5 g of dl-3-(1',1'-dimethylheptyl)-6,6a,7,8-tetrahydro-1hydroxy-6,6-dimethyl-9H-dibenzo[b,d]pyran-9-one in 50 ml of anhydrous

2371

2372

Nabumetone

tetrahydrofuran (THF) was added dropwise to a solution of lithium metal in liquid ammonia at -80°C. Excess lithium metal was added in chunks to the solution as the blue color, indicating free dissolved lithium, disappeared. After the addition was complete, ammonium chloride was added to react with any excess lithium metal still present. The mixture was then allowed to warm to room temperature in a nitrogen atmosphere during which process the ammonia evaporated. The reaction mixture was then acidified with 1 N aqueous hydrochloric acid, and the organic constituents extracted with ethyl acetate. The ethyl acetate extracts were combined, washed with water and dried. Evaporation of the ethyl acetate under reduced pressure yielded 1.4 g of crude dl-trans-3-(1',1'dimethylheptyl)-6,6aβ,7,8,10,10aβ-hexahydro-1-hydroxy-6,6-dimethyl-9Hdibenzo[b,d]pyran-9-one. The crude product was chromatographed over 50 g of silica gel from benzene solution and the desired product was eluted in 20 ml fractions with a benzene eluant containing 2% ethyl acetate. Fractions 200 to 240 contained 808 mg of a white crystalline solid comprising purified dltrans-3-(1',1'-dimethylheptyl)-6,6aβ,7,8,10,10aβ-hexahydro-1-hydroxy-6,6dimethyl-9H-dibenzo[b,d]pyran-9-one. The purified compound melted at 159°C to 160°C after recrystallization from an ethyl acetate-hexane solvent mixture. References Merck Index 6193 DFU 3 (3) 207 (1978) OCDS Vol. 3, p 189 (1984) DOT 19 (7) 415 & (8) 436 (1983) I.N. p. 652 Archer, R.A.; US Patents 3,928,598; December 23, 1975; 3,944,673; March 16,1976; and 3,953,603; April 27, 1976; all assigned to Eli Lilly & Co.

NABUMETONE Therapeutic Function: Antiinflammatory Chemical Name: 2-Butanone, 4-(6-methoxy-2-naphthalenyl)Common Name: Nabumetone Structural Formula:

Chemical Abstracts Registry No.: 42924-53-8

Nabumetone Trade Name Artaxan Arthaxan Balmox Dolsinal Listran Mebutan Mebutan Nabuflam Nabumetone Nabumetone Nabumetone Nabumetone Nabumetone Relafen Relafen Relifex Rodanol S

Manufacturer Malesci SpA Ist. Farmacobiol Pharm Chemical Shanghai Lansheng Corporation Alloga AG Ferrer Internacional Uriach Bencard Glaxo SmithKline Beecham Micro Labs Copley Pharmaceutical Teva IVAX Pharmaceuticals, Inc. Eon Labs, Inc. Genpharm Inc. SmithKline Beecham Eon Labs, Inc. GlaxoSmithKline Lek

2373

Country Italy China

Year Introduced -

Switz. Spain Spain India USA USA USA USA Canada USA Slovenia

-

Raw Materials Sodium methoxide Palladium on carbon Sodium bisulfite Sodium acetate 2-Acetyl-5-bromo-6-methoxynaphthalene Manufacturing Process 4-(5-Bromo-6-methoxy-2-naphthyl)-4-hydroxybut-3-en-2-one 50 grams (0.179 moles) of 2-acetyl-5-bromo-6-methoxynaphthalene and 200 ml of n-butyl acetate are placed in a flask equipped with refrigerator and stirrer and, under stirring and at the temperature of 15°C, 14.5 g (0.268 moles) of sodium methoxide are added. The temperature of the reaction mixture goes up to 25°C and is kept at this value for 30 minutes, then the mixture is warmed at 65°C for one hour, is added with 100 ml of water and is brought to pH 4 by adding a concentrated aqueous solution of hydrochloric acid. The reaction mixture is then cooled to 0°-5°C and kept at this temperature for one hour. The solid is filtered, abundantly washed with water on the filter, then washed with butyl acetate and dried in oven under vacuum obtaining 53 g of product with a yield equal to 92%. Example 1. 4-(6-Methoxy-2-naphthyl)butan-2-one 48 grams (0.150 moles) of 4-(5-bromo-6-methoxy-2-naphthyl)-4-hydroxybut3-en-2-one, 6.1 g of sodium acetate hydrate containing 32.4% of water, equivalent to 0.050 moles of sodium acetate, 4 g of a 50% suspension in water of 10% palladium on carbon, equivalent to 0.0019 moles of palladium, and 500 ml of methanol are put in a hydrogenator. The hydrogenator is washed with nitrogen in order to eliminate the oxygen and then hydrogen is introduced at the pressure of 2 atmospheres. The temperature of reaction is

2374

Nadolol

kept at 40°C for a period of time of 6 hours, then the hydrogen is let off, the hydrogenator is washed with nitrogen and the reaction mixture is filtered to eliminate the catalyst. The solution is brought to pH 6 with a 5% aqueous solution of sodium hydroxide and concentrated under vacuum. The oily residue is dissolved into 130 ml of isopropanol and 30 ml of N,Ndimethylformamide and the solution is added with 45 ml of water and 17.6 g of sodium bisulfite obtaining a suspension that is stirred for one hour at 60°C, then is cooled to 5°C and is filtered. The obtained solid is washed with 75 ml of methanol, suspended in 200 ml of a 5% aqueous solution of sodium hydroxide and kept under stirring at room temperature for three hours. The suspension is then filtered, the solid is washed with water until neutrality and dried in oven under vacuum obtaining 18 g of product with a yield equal to 52.8%. Example 2. 4-(6-Methoxy-2-naphthy)butan-2-one The reaction described above is repeated with the sole changes of doubling the amount of sodium acetate hydrate containing 32.4% of water, 12.22 g equivalent to 0.100 moles of sodium acetate, and of lowering the hydrogenation time to five hours. In this way 22.5 g of product are obtained with a yield equal to 66%. Example 3. 4-(6-Methoxy-2-naphthyl)butan-2-one The reaction described in example 3 is repeated with the sole changes of nearly triplicating the amount of sodium acetate hydrate containing 32.4% of water, 17.60 g equivalent to 0.145 moles of sodium acetate, and of lowering the hydrogenation time to five hours. The oil obtained by evaporating the solvent at the end of the reaction is treated with 300 ml of toluene and 100 ml of water and after 15 minutes of stirring the two layers are separated. The aqueous phase is discarded while the organic phase is evaporated under vacuum at 70°C obtaining an oil that is dissolved into 100 ml of methanol. The solution is kept at 0°C for two hours and the precipitated solid is filtered, washed with 15 ml of methanol cooled to 0°C and dried in oven under vacuum. In this way 21.7 g of product are obtained. The methanolic filtrates from crystallization and washing are concentrated under vacuum to half volume so obtaining, after cooling to 0°C, the crystallization of other 4 g of product with an overall yield equal to 75.3%. References Cannata V. et al.; US Reissued Patent No. RE37,813; Aug. 6, 2002; Assigned to Honeywell International Inc., Morristown, NJ (US)

NADOLOL Therapeutic Function: Antiarrhythmic Chemical Name: 2,3-cis-1,2,3,4-Tetrahydro-5-[2-hydroxy-3-(tertbutylamino)propoxy]-2,3-naphthalenediol

Nadolol

2375

Common Name: Structural Formula:

Chemical Abstracts Registry No.: 42200-33-9 Trade Name Solgol Corgard Corgard Corgard Corgard Corgard Betadol Corzide

Manufacturer Heyden Squibb Squibb Squibb Squibb Squibb Fako Squibb

Country W. Germany Switz. UK US Italy France Turkey US

Year Introduced 1978 1978 1979 1979 1980 1982 -

Raw Materials 5,8-Dihydro-1-naphthol Sodium hydroxide Acetic anhydride Sodium methoxide

Silver acetate Epichlorohydrin Iodine t-Butylamine

Manufacturing Process (a) cis-5,6,7,8-Tetrahydro-1,6,7-naphthalenetriol: A solution of 29.2 g (0.2 mol) of 5,8-dihydro-1-naphthol and 40 ml of acetic anhydride in 100 ml of pyridine is prepared. After 16 hours the solvent is removed in vacuo and the residue dissolved in ether and washed with 200 ml of 5% hydrochloric acid, water, 200 ml of 10% sodium hydroxide, saturated salt solution and dried. Solvent removal gives 34.2 g (90.5%) of crude acetate which is dissolved in 900 ml of acetic acid and 36 ml of water. 53.3 g (0.32 mol) of silver acetate is added followed by 40.6 g (0.16 g-atom) of iodine. The slurry is heated with good stirring at 85°10°C for 3 hours under nitrogen, cooled and filtered. The filtrate is evaporated in vacuo and the residue dissolved in 250 ml of methanol and cooled to 0°C. A solution of 40 g of sodium hydroxide in 200 ml of water is added under nitrogen and the mixture stirred overnight. The bulk of the methanol is removed in vacuo whereupon a solid forms. The solid is separated by filtration, dissolved in 150 ml of water and acidified with 20 ml of concentrated hydrochloric acid. Cooling gives a solid which is filtered and dried to give 16.5 g cis-5,6,7,8-tetrahydro-1,6,7-naphthalenetriol, melting point

2376

Nafarelin acetate

184.5°C to 187°C. Three recrystallizations from absolute ethanol give the analytical sample, melting point 188°C to 188.5°C. (b) 2,3-cis-1,2,3,4-Tetrahydro-5-[2,3-(epoxy)-propoxy]-2,3-naphthalenediol: A solution of 1.20 g (0.03 mol) of sodium methoxide and 5.4 g (0.03 mol) of cis-5,6,7,8-tetrahydro-1,6,7-naphthalenetriol in 200 ml of methanol is prepared under nitrogen. The residue obtained upon solvent removal is stirred overnight with 200 ml of dimethylsulfoxide and 4.65 g (0.05 mol) of epichlorohydrin under nitrogen. The bulk of the solvent is removed at 50°C at 0.1 mm and the residue dissolved in 100 ml of water. Extraction with chloroform (10 x 200 ml) gives a solid which is recrystallized from 150 ml of hexane-ethyl acetate to give epoxy diol of the above title. (c)2,3-cis-1,2,3,4-Tetrahydro-5-[2-hydroxy-3-(tert-butylamino)propoxy]-2,3naphthalenediol: A mixture of 2,3-cis-1,2,3,4-tetrahydro-5-[2,3(epoxy)propoxy]-2,3-naphthalenediol (melting point 104°C to 107°C, one spot on TLC-alumina, 5% methanol in chloroform, iodine visualization) and 22 ml of tert-butylamine is heated at 85°C to 95°C for 15 hours in a Parr bomb and the excess amine removed in vacuo. The solid obtained by trituration of the residue with ether is filtered and recrystallized from benzene to give 3.4 g, melting point 124°C to 136°C. References Merck Index 6195 DFU 1 (9) 434 (1976) Kleeman & Engel p. 614 PDR pp. 1739, 1741 OCDS Vol. 2 p. 110 (1980) DOT 15 (9) 411 (1979) I.N. p. 652 REM p. 905 Hauck, F.P., Cimarusti, C.M. and Narayanan, V.L.; US Patent 3,935,267; January 27, 1976; assigned to E.R. Squibb & Sons, Inc.

NAFARELIN ACETATE Therapeutic Function: Gonadotropic Chemical Name: 6-(3-(2-Naphthalenyl)-D-alanine)luteinizing hormonereleasing factor (pig), monoacetate (salt) Common Name: Nafarelin acetate Chemical Abstracts Registry No.: 76932-60-0; 76932-56-4 (Base)

Nafarelin acetate

2377

Structural Formula:

Trade Name Nafarelin Acetate Nasanyl Synarel Synarel Synarel Nasal Spray Synrelina Synrelina

Manufacturer Bachem AG Yamanouchi Pharmaceutical Co., Ltd. Searle Pfizer Canada Inc. Syntex

Country Japan

Year Introduced -

France Canada USA

-

Pharmacia AG Pfizer AG

Switz.

-

Raw Materials Boc-Gly-OH Cobalt(III) fluoride Boc-Pro-OH Boc-3-(2-naphthyl)-D-alanine Boc-Leu-OH Boc-Arg(Tosyl)-OH Boc-Trp-OH 1-Hydroxybenzotriazole Pyroglutamic acid Boc-Ser(Benzyl)-OH Boc-His(Tosyl)-OH Hydrofluoric acid N,N'-Dicyclohexylcarbodiimide N-Boc, O-2-bromobenzoyloxycarbonyl-L-tyrosine Benzhydrylamino-polystyrene-divinylbenzene resin Manufacturing Process In the reaction vessel of a Beckman 990 Peptide Synthesizer was placed 0.8 g (0.8 mmol) of benzhydrylamino-polystyrene-divinylbenzene resin (Lab Systems, Inc.) as described by Rivaille, supra. Amino acids were added sequentially to this resin by means of the usual methods of Boc-strategy of peptide synthesis on above copolymer. The resin was coupled sequentially with a 2.5 molar excess of each protected

2378

Nafcillin sodium

amino acid and DCC. Thus, the resin was treated during successive coupling cycles with 0.433 g Boc-Gly-OH, 0.432 g Boc-Pro-OH, 0.857 g Boc-Arg(Tosyl)OH, 0.462 g Boc-Leu-OH, 0,504 g Boc-3-(2-naphthyl)-D-alanine and 0.272 g 1-hydroxybenzotriazole, 0.724 g N-Boc, O-2-bromobenzoyloxycarbonyl-Ltyrosine, 0.59 g Boc-Ser(Benzyl)-OH, 0.608 g Boc-Trp-OH, 0.654 g BocHis(Tosyl)-OH and 0.524 g pyroglutamic acid. A coupling cycle for one amino acid and completeness of the reaction is checked by the ninhydrin method of E. Kaiser, et al., Anal. Biochem., 34, 595 (1970). The resin was removed from the reaction vessel, washed with CH2Cl2, and dried in vacuo to yield 2.0 g of protected polypeptide resin. The polypeptide product was simultaneously removed from the resin and completely deprotected by treatment with anhydrous liquid HF. A mixture of 2.0 g of protected polypeptide resin and 2 mL of anisole (scavenger) in a KelF reaction vessel was treated with 20 mL of redistilled (from CoF3) anhydrous liquid HF at 0°C for 30 minutes. The HF was evaporated under vacuum and the residue of (pyro)-Glu-His-Trp-Ser-Tyr-3-(2-naphthyl)-D-alanyl-Leu-ArgPro-Gly-NH2,as its HF salt, was washed with ether. The residue was then extracted with glacial acetic acid. The acetic acid extract was lyophilized to yield 0.8 g of crude material. The crude polypeptide was loaded on a 4x40 cm. Amberlite XAD-4 column (polystyrene-4% divinylbenzene copolymer) and eluted with a concave gradient from water (0.5 L) to ethanol (1 L). The tubes containing fractions from effluent volume 690 mL to 1,470 mL were pooled and stripped to dryness to yield 490 mg of partially purified polypeptide. A 150 mg sample of the partially purified product was subjected to partition chromatography on a 3 times 50 cm. column of Sephadex G-25 using the solvent system 1-butanol/toluene/acetic acid/water containing 1.5% pyridine in the ratios 10:15:12:18. The pure fractions were pooled on the basis of thin layer chromatography (silica gel; BuOH/H2O/HOAc/EtOAc; 1:1:1:1) and HPLC (5 micron, reverse phase, octadecylsilyl packing; 40% 0.03 M NH4OAc/60% acetonitrile). The desired product came off the column in fractions from effluent volume 1,000 mL to 1,400 mL (Rf 0.1). The pure fractions were pooled, stripped to dryness, taken up in H2O, and lyophilized to yield 57 mg of pure pyro-glutamyl-histidyl-tryptophylseryl-tyrosyl-3-(2-naphthyl)-D-alanylleucyl-arginylprolyl-glycinamide, as its acetic acid addition salt, [α]D25-27.4° (c 0.9, HOAc), m.p. 185°-193°C (dec.). References Nestor et al.; US Patent No. 4,234,571; Nov. 18, 1980; Assinged to Syntex (U. S. A.) Inc., Polo Alto, Calif.

NAFCILLIN SODIUM Therapeutic Function: Antibacterial Chemical Name: 6-(2-Ethoxy-1-naphthamido)-3,3-dimethyl-7-oxo-4-thia-1azabicyclo[3.2.0]heptane-2-carboxylic acid sodium salt

Nafcillin sodium

2379

Common Name: 6-(2-Ethoxy-1-naphthamido)penicillin sodium salt Structural Formula:

Chemical Abstracts Registry No.: 985-16-0; 147-52-4 (Base) Trade Name Unipen Nafcil Nallpen Naftopen

Manufacturer Wyeth Bristol Beecham Gist Brocades

Country US US US -

Year Introduced 1964 1976 1983 -

Raw Materials 6-Aminopenicillanic acid 2-Ethoxy-1-naphthoyl chloride Sodium bicarbonate Manufacturing Process A stirred suspension of 12.6 grams 6-aminopenicillanic acid in 130 ml dry alcohol-free chloroform was treated with 16 ml triethylamine and then with 13.8 grams of a solution of 2-ethoxy-1-naphthoyl chloride in 95 ml chloroform. After being washed successively with 58 ml each of 1 N and then 0.1 N hydrochloric acid the chloroform solution was extracted with N aqueous sodium bicarbonate (58 ml + 6 ml). The combined bicarbonate extracts were washed with 20 ml ether and then evaporated at low temperature and pressure to give the crude sodium salt of 2-ethoxy-1-naphthylpenicillin [also called sodium 6-(2-ethoxy-1-naphthamido)penicillinate] as a yellow powder (20.3 grams). This was dissolved in 20 ml water at 30°C and diluted with 180 ml n-butanol, also at 30°C, with stirring. Slow cooling to 0°C gave colorless needles of the product. References Merck Index 6199 Kleeman & Engel p. 615 PDR pp. 700, 1991 OCDS Vol. 1 p. 412 (1977)

2380

Nafiverine

I.N. p. 653 REM p. 1196 Doyle, F.P. and Nayler, J.H.C.; US Patent 3,157,639; November 17, 1964; assigned to Beecham Group Limited, England

NAFIVERINE Therapeutic Function: Spasmolytic Chemical Name: α-Methyl-1-naphthaleneacetic acid 1,4-piperazinediyldi-2,1ethanediyl ester Common Name: Structural Formula:

Chemical Abstracts Registry No.: 5061-22-3 Trade Name Naftidan

Manufacturer De Angeli

Country Italy

Year Introduced 1969

Raw Materials α-Methyl-1-naphthylacetic acid Thionyl chloride N,N'-Di-(β-hydroxyethyl)piperazine Manufacturing Process 15 grams of α-methyl-1-naphthylacetic acid were refluxed with 50 ml of thionyl chloride during 3 hours. The excess thionyl chloride was removed under reduced pressure and the product was also isolated by distillation under reduced pressure. Yield: 15.6 grams (96%). The α-methyl-1-naphthyl acetyl chloride boils at 120° to 124°C. 1.76 grams of N,N'-di-(β-hydroxyethyl)piperazine, 1.9 grams of sodium bicarbonate and 4.45 grams of α-methyl-1naphthyl acetyl chloride in 30 ml of anhydrous acetonitrile were refluxed with stirring during 5 hours. After cooling the mixture was filtered and the

Nafronyl oxalate

2381

acetonitrile evaporated off under reduced pressure. 5.2 grams of crude ester were obtained. The hydrochloride, melting at 220° to 221°C, may be prepared by dissolving the ester in absolute ethanol and treating the solution with anhydrous gaseous hydrogen chloride. References Merck Index 6200 I.N. p. 653 Pala, G.; British Patent 1,016,968; Jan. 12, 1966; assigned to Instituto de Angeli, SpA, Italy

NAFRONYL OXALATE Therapeutic Function: Vasodilator Chemical Name: Tetrahydro-α-(1-naphthalenylmethyl)-2-furanpropanoic acid 2-(diethylamino)ethyl ester acid oxalate Common Name: Naftidofuryl Structural Formula:

Chemical Abstracts Registry No.: 3200-06-4; 31329-57-4 (Base) Trade Name

Manufacturer

Country

Year Introduced

Dusodril

Roland

W. Germany

1968

Praxilene

Oberval

France

1968

Prazilene

Lipha

UK

1972

Praxilene

Formenti

Italy

1973

Praxilene

Biochimica

Switz.

1980

Citoxid

Disprovent

Argentina

-

2382

Naftifine

Raw Materials Oxalic acid β-Chloroethyl-N-diethylamine β-(1-Naphthyl)-β'-tetrahydrofurfurylisobutyric acid Manufacturing Process 30 grams (0.106 mol) of β-(1-naphthyl)-β'-tetrahydrofuryl isobutyric acid are heated under reflux for 8 1/2 hours in 230 cc of isopropanol with 14 grams (0.103 mol) of β-chloroethyl-N-diethylamine. After evaporation of the isopropanol in vacuo, the syrupy residue is treated with a solution of K2CO3. Extraction with ether is carried out after drying over Na2SO4. Distillation of the extract yields 28.5 grams of a very viscous yellow liquid with a BP0.95-1.09millibar = 198° to 202°C. The yield is 70.5% (theoretical quantity = 40.5 grams).1.3 grams (0.0103 mol) of dihydrated oxalic acid are dissolved while being made tepid in 8 cc of acetone. The cooled solution has added thereto 4 grams (0.0104 mol) of N-diethylaminoethyl-β-(1-naphthyl)-β'tetrahydrofuryl isobutyrate, obtained according to the process described above and dissolved in 10 cc of acetone. The solution is brought to boiling point for 15 minutes. After cooling to ambient temperature, it is placed in a refrigerator. Crystallization occurs after 2 hours, the crystals which have formed are separated by centrifuging, and after washing in hexane and drying in vacuo 3.5 grams of white crystals are obtained. After being recrystallized three times, in alcohol and then in a mixture of alcohol and ethyl acetate, the product is analytically pure and has a MP = 110° to 111°C (heating stage). References Merck Index 6201 Kleeman & Engel p. 615 OCDS Vol .2 p. 213 (1980) DOT 5 (1) 19 (1969) I.N. p. 654 Szarvasi, E. and Bayssat, M.; US Patent 3,334,096; August 1, 1967; assigned to Lipha, Lyonnaise Industrielle Pharmaceutique, France

NAFTIFINE Therapeutic Function: Antifungal Chemical Name: 1-Naphthalenemethanamine, N-methyl-N-(3-phenyl-2propenyl)-, (E)Common Name: Naftifine; Naftifugin Chemical Abstracts Registry No.: 65472-88-0

Nalbuphine

2383

Structural Formula:

Trade Name Naftifine

Manufacturer Sandoz (Novartis)

Country -

Year Introduced -

Raw Materials Methyl-(1-naphthylmethyl)amine hydrochloride Sodium carbonate Dimethylformamide Cinnamyl chloride Manufacturing Process To a mixture of 1.42 g of methyl-(1-naphthylmethyl)amine hydrochloride, 2.89 g of sodium carbonate and 10 ml of dimethylformamide is added, at room temperature, 1.25 g of cinnamyl chloride, dropwise. After 18 hours stirring, at room temperature, the mixture is filtered and the filtrate is evaporated in vacuo. The residue is dissolved in toluene and, after drying over sodium sulphate, evaporated to obtain the trans-N-(cinnamylmethyl)-Nmethyl-(1-naphthylmethyl)amine compound, boiling point 162-167°C/0.015 Torr. The free base may be converted, with isopropanolic hydrogen chloride solution, into the hydrochloride form, melting point 177°C (from propanol). References Berney Daniel; US Patent No. 4,282,251; August 4, 1981; Assigned to Sandoz Ltd. (Basel, CH)

NALBUPHINE Therapeutic Function: Analgesic Chemical Name: N-Cyclobutylmethyl-14-hydroxydihydronormorphinone Common Name: -

2384

Nalbuphine

Structural Formula:

Chemical Abstracts Registry No.: 20594-83-6; 23277-43-2 (Hydrochloride salt) Trade Name Nubain Nubain

Manufacturer Du Pont Du Pont

Country US UK

Year Introduced 1979 1983

Raw Materials 14-Hydroxydihydronormorphinone Cyclobutane carboxylic acid chloride Lithium aluminum hydride Manufacturing Process To a slurry of 110.5 g of 14-hydroxydihydronormorphinone in 2.5 liters of methylene chloride and 280 ml of triethylamine was added a solution of 106 g of cyclobutanecarboxylic acid chloride in 500 ml of methylene chloride. The temperature of the reaction mixture was maintained at 20°C to 25°C during the addition. After 5 minutes the reaction mixture was brought to reflux and heated for 5 hours. It was then cooled, washed with water, dried over sodium sulfate and evaporated to dryness. The residue was crystallized from benzene and pentane to give 138.5 g of the dicyclobutanecarbonyl derivative, melting point about 112°C (dec.). The dicyclobutanecarbonyl derivative (136.7 g) was dissolved in 200 ml of tetrahydrofuran and added dropwise to a suspension of 34.2 g of lithium aluminum hydride in 1 liters of tetrahydrofuran. The temperature of the mixture rose to reflux during the addition. Reflux was maintained for 2 hours after the addition was completed. After cooling, 110 ml of ethyl acetate was added dropwise, followed by 30 ml of water, followed by a solution of 53 g of ammonium chloride in 125 ml of water. The resulting mixture was filtered and the inorganic precipitate was washed with methanol. Evaporation of the combined filtrates gave 66 g of N-cyclobutylmethyl-14-

Nalidixic acid

2385

hydroxydihydronormorphinone, melting point 229°C to 231°C. References Merck Index 6203 DFU 2 (9) 613 (1977) Kleeman & Engel p. 616 PDR p. 858 OCDS Vol. 2 p. 319 (1980) DOT 16 (2) 51 (1980) I.N. p. 654 REM p. 1109 Blumberg, H., Pachter, I.J. and Matossian, Z.; US Patent 3,332,950; July 25, 1967; assigned to Endo Laboratories, Inc.

NALIDIXIC ACID Therapeutic Function: Antibacterial Chemical Name: 1-Ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3carboxylic acid Common Name:Structural Formula:

Chemical Abstracts Registry No.: 389-08-2 Trade Name Neggram Nalidixique Jicsron Baktogram Betaxina Chemiurin Cybis Dixiben Dixurol Enexina Entolon

Manufacturer Winthrop Winthrop Towa Yakuhin Farmakos Amelix Cifa Breon Benvegna I.T.I. S.I.T. Sawai

Country US France Japan Yugoslavia Italy Italy US Italy Italy Italy Japan

Year Introduced 1964 1974 1981 -

2386

Nalidixic acid

Trade Name Eucistin Faril Innoxalon Kusnarin Nali Nalcidin Nalidicron Nalidixico Nalidixin Nalidixol Naligen Naligram Nalissina Nalitucsan Nalix Nalixan Nalurin Narigix Naxuril Negabatt Nicelate Nogermin Notricel Pielos Poleon Renogram Restelon Sicmylon Specifin Unaserus Uralgin Uretrene Uriben Uriclar Uri-Flor Urigram Urisco Uristeril Urodixin Urogram Urolex Urolgin N Uromina Uroneg Valuren Wintomylon Wintron

Manufacturer San Carlo Saita Sanko Kodama Iltas Schoum San-A Level Spofa Hermes Sam Isis Armour Hishiyama Sigurta Neofarma Von Boch Taiyo Esterfarm Dessy Toyo Jozo Madaus Hortel S.T.I.P. Sumitomo Belupo Ltd. Maruishi Niichiko Bergamon Isei Ceccarelli Mitim R.P. Drugs Crosara A.G.I.P.S. Trima I.C.I. Ripari-Gero Italchimici Firma Sirt-B.B.P. Takata Ausonia Ibirn Intersint Daiichi Tobishi

Country Italy Italy Japan Japan Turkey Italy Japan Spain Czechoslovakia Spain Italy Yugoslavia Italy Japan Italy Finland Italy Japan Italy Italy Japan Spain Spain Italy Japan Yugoslavia Japan Japan Italy Japan Italy Italy UK Italy Italy Israel Italy Italy Italy Italy Italy Japan Italy Italy Italy Japan Japan

Year Introduced -

Nalmefene

2387

Raw Materials 2-Amino-6-methylpyridine Ethoxymethylene malonic acid diethyl ester Sodium hydroxide Ethyl iodide Manufacturing Process A warm solution containing 41 grams of 4-hydroxy-7-methyl-1,8naphthyridine-3-carboxylic acid and 39 grams of potassium hydroxide in 1 liter of ethanol and 200 cc of water was treated with 50 cc of ethyl iodide and the resulting mixture was refluxed gently overnight, acidified with hydrochloric acid and cooled. The resulting precipitate was collected and recrystallized twice from acetonitrile to yield 26 grams (56% yield) of 1-ethyl-7-methyl-4oxo-1,8-naphthyridine-3-carboxylic acid, MP 229° to 230°C. The starting material is prepared by reacting 2-amino-6-methylpyridine with ethoxymethylene-malonic acid diethyl ester and then reacting that product with sodium hydroxide. References Merck Index 6205 Kleeman & Engel p. 616 PDR p. 1922 OCDS Vol. 1 p. 429 (1977) & 2,370,469 (1980) DOT 1 (1) 16 (1965) I.N. p. 33 REM p. 1216 Lesher, G.Y. and Gruett, M.D.; US Patent 3,149,104; September 15, 1964; assigned to Sterling Drug Inc.

NALMEFENE Therapeutic Function: Antagonist to narcotics Chemical Name: Morphinan-3,14-diol, 17-(cyclopropylmethyl)-4,5-epoxy-6methylene-, (5alpha)Common Name: Nalmefene; Nalmetrene Chemical Abstracts Registry No.: 55096-26-9 Raw Materials Potassium t-butoxide Methyltriphenylphosphonium bromide Naltrexone

2388

Nalmefene

Structural Formula:

Trade Name Nalmefene Nalmefene Arthene Cervene Incystene Incystene Revex Revex

Manufacturer Mallinckrodt Inc. Somaxon Pharmaceuticals Ohmeda Baker Norton SSPharma Ivax Corporation Baxter Healthcare Corp Anesthesia And Critical Care Ohmeda

Country -

Year Introduced -

-

-

Manufacturing Process A dry, 2-liter, 3-neck, round bottom flask fitted with two stoppers and a magnetic stirring bar was charged with potassium t-butoxide (61.1 g, 0.545 mol) and methyltriphenylphosphonium bromide (194.4 g, 0.544 mol). Freshly distilled tetrahydrofuran (450 ml) was introduced at 20°C. The resultant thick, bright yellow dispersion was stirred at 20°C for 0.5 h and further dry tetrahydrofuran (100 ml) was added. A solution of dry naltrexone (30 g, 0.088 mol) in dry tetrahydrofuran (200 ml) was then added dropwise over 40 min. Then the reaction mixture was stirred for a further 1.25 h, then cooled to 10°C, and quenched with 20% aqueous ammonium chloride solution (75 ml) followed by water (100 ml). The organic layer was separated and the aqueous layer extracted with four 100 ml portions of chloroform. Solvent was evaporated from the tetrahydrofuran layer and the combined chloroform extracts, the residues combined and brought to pH 2 by addition of 2 N hydrochloric acid. The resultant precipitate was filtered, washed with chloroform and suspended in a mixture of chloroform (500 ml) and water (250 ml). Ammonium hydroxide was added to attain a pH of 8 and the aqueous layer separated. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent removed in vacuo. The resultant solid was dissolved in ethyl acetate (1400 ml), the solution filtered through a silica pad and the solvent evaporated. The product was recrystallized from chloroform and washed with hexane to yield pure 6-desoxy-6-methylenenaltrexone (also called nalmefene) as a white solid. Yield: 27.0 g, 88%. References Merck Index, Monograph number: 6447, Twelfth edition, 1996, Editor: S. Budavari

Nalorphine

2389

Merck and Co., Inc.; Meltzer P.C., Coe J. W.; US Patent No. 4,535,157; August 13, 1985; Assigned: Key Pharmaceuticals, Inc. (Miami, FL)

NALORPHINE Therapeutic Function: Narcotic antagonist Chemical Name: 7,8-Didehydro-4,5-epoxy-17-(2-propenyl)morphinan-3,6diol Common Name: N-Allylnormorphine Structural Formula:

Chemical Abstracts Registry No.: 62-67-9; 57-29-4 (Hydrochloride salt) Trade Name Nalline Lethidrone Nalorphine Norfin

Manufacturer MSD Wellcome Clin-Comar-Byla Lusofarmaco

Country US W. Germany France Italy

Year Introduced 1952 -

Raw Materials Normorphine Allyl bromide Sodium bicarbonate Manufacturing Process 6 grams of normorphine, 2.7 grams of allyl bromide, 2.65 grams of sodium bicarbonate, and 75 cc of methanol were mixed together, and the resulting mixture was heated under reflux with stirring for a period of about 5 1/2 hours. The reaction mixture was evaporated to dryness in vacuo, the residual material was extracted with 60 cc of boiling chloroform, 0.5 gram of activated charcoal was added, and the resulting mixture was filtered through a layer of diatomaceous silica. The filter cake was washed with four 10 cc portions of

2390

Naloxone

boiling chloroform, and the chloroform filtrate and washings were combined and evaporated to dryness in vacuo. The residual material was triturated with 25 cc of anhydrous ether until crystalline, the ethereal mixture was cooled, maintained at a temperature of 3°C overnight, filtered, and the crystalline mixture was washed with three 10 cc portions of ice-cold ether. The resulting crystalline product was dried to give 6.0 grams of N-allylnormorphine, yield approximately 87% of theory, according to US Patent 2,891,954. References Merck Index 6206 Kleeman & Engel p. 617 OCDS Vol. 1 p. 288 (1977) & 2,318 (1980) I.N. p. 655 REM p. 1106 Weijlard, J. and Erickson, A.E.; US Patent 2,364,833; December 12, 1944; assigned to Merck & Co., Inc. Weijlard, J.; US Patent 2,891,954; June 23, 1959; assigned to Merck and Co., Inc.

NALOXONE Therapeutic Function: Narcotic antagonist Chemical Name: 17-Allyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6-one Common Name: N-Allylnoroxymorphone; N-Allyl-1,4hydroxydihydronormorphinone Structural Formula:

Chemical Abstracts Registry No.: 465-65-6; 357-08-4 (Hydrochloride salt) Trade Name

Manufacturer

Country

Year Introduced

Narcan

Du Pont

US

1971

Narcan

Du Pont

UK

1975

Narcanti

Winthrop

W. Germany

1978

Naloxone Trade Name Narcan Narcan Nalone Talwin

Manufacturer Winthrop Crinos Endo Winthrop-Breon

Country France Italy US US

2391

Year Introduced 1980 1980 -

Raw Materials Oxymorphone Allyl bromide Hydrogen chloride

Cyanogen bromide Acetic anhydride

Manufacturing Process 10 grams of 14-hydroxydihydromorphinone (oxymorphone) was converted into its diacetate by warming it on the steam bath with 80 cc of acetic anhydride for about 2 hours. The acetic anhydride was removed on the water bath under a vacuum of about 30 mm absolute pressure. The melting point of the residue was 220°C. The residue was taken up in 100 cc of chloroform. An equal amount by weight of cyanogen bromide was added and the mixture was refluxed at about 60°C for about 5 hours. After refluxing, the mixture was washed with 100 cc of a 5% aqueous hydrochloric acid solution, dried over sodium sulfate and the chloroform removed by evaporation under a vacuum of about 30 mm. The residue had a melting point of 240°C. The residue was then heated at about 90°C for 16 hours on a steam bath with 300 cc of 20% aqueous hydrochloric acid solution, and treated with a small amount, e.g., 1 gram of charcoal. The hydrochloric acid was then removed under a vacuum of 15 mm, the residue dissolved in 30 cc of water and precipitated by the addition of 2.4 cc of concentrated aqueous ammonia. The precipitate was filtered off and dried. It consists of 14hydroxydihydronormorphinone. It is soluble in ethanol. The 14-hydroxydihydronormorphinone was suspended in 200 cc of pure ethyl alcohol, half its weight of sodium bicarbonate and half its weight of allyl bromide added and the resulting mixture was refluxed at about 75°C for 48 hours. The solution was cooled, e.g., to 10°C and filtered and the alcohol removed under a vacuum of 30 mm. The residue was dissolved in chloroform and filtered. The chloroform was removed under a vacuum of 30 mm and the residue was crystallized from ethylacetate. The crystallized product, N-allyl1,4-hydroxydihydronormorphinone, has a melting point of 184°C, is soluble in chloroform and insoluble in petroleum ether. The yield amounts to 20% based on the weight of the reacted 14-hydroxydihydromorphinone. References Merck Index 6208 Kleeman & Engel p. 618 PDR pp. 858, 1932 OCDS Vol. 1 p. 289 (1977) & 2,318,323 (1980) DOT 8 (8) 295 (1972); I.N. p. 655 REM p. 1106 Lewenstein, M.J. and Fishman, J.; US Patent 3,254,088; May 31,1966

2392

Naltrexone

NALTREXONE Therapeutic Function: Narcotic analgesic Chemical Name: Morphinan-6-one, 17-(cyclopropylmethyl)-4,5-α-oxy-3,14dihydoxyCommon Name: Naltrexone Structural Formula:

Chemical Abstracts Registry No.: 16590-41-3 Trade Name Antaxone Nalorex Naltima Naltrexone Nodict ReVia

Manufacturer Zambon Group DuPont Pharmaceuticals Intas Pharm. DuPont Merck Synergy (Sun) DuPont Pharmaceuticals

Country Italy India -

Year Introduced -

Raw Materials Codeine Acetic anhydride Oxalyl chloride Formic acid Palladium on carbon

4-Dimethylaminopyridine 1-Chloroethyl chloroformate (Chloromethyl)cyclopropane 3-Chloroperbenzoic acid Boron tribromide

Manufacturing Process Codeine is a component of gum opium and can also be produced by methylation of morphine using known prior art techniques. A solution of codeine (30 g, 100.2 mmol), acetic anhydride (18.4 g, 180.2 mmol), triethylamine (18.25 g, 180.2 mmol) and 4-dimethylaminopyridine (0.5 g) in dry ethyl acetate (620 ml) was stirred at rt. under nitrogen for 12 hr, added saturated aqueous sodium bicarbonate solution until no acetic anhydride detected. The organic portion was separated, washed with water (3

Naltrexone

2393

times 120 ml), dried over anhydrous sodium sulfate, and evaporated in vacuo to dryness to give 6-acetylcodeine as white solids (34.0 g, 99% yield). Preparation of 6-acetylnorcodeine hydrochloride. A solution of 6-acetylcodeine (10.0 g, 29.3 mmol), 1-chloroethyl chloroformate (5.51 g, 37.8 mmol), and proton sponge (1.0 g) in methylene chloride (80 ml) was heated at reflux for 80 min. The reaction mixture was evaporated in vacuo to dryness. The residue was chromatographed on silica gel with ethyl acetate to give 6-acetyl-17-(1-chloroethoxycarbonyl)norcodeine as an oil (12.13 g), which was dissolved in methanol with a few drops of conc. HCl. The solution was heated at reflux for 1 hr and evaporated in vacuo to almost dryness. The residue was added hexane and filtered to give 6acetylnorcodeine hydrochloride (10.7 g, 100% yield). Preparation of norcodeine hydrochloride. A solution of 6-acetylcodeine (10.0 g, 29.3 mmol), 1-chloroethyl chloroformate (5.56 g, 38.1 mmol), and proton sponge (1.0 g) in methylene chloride (50 ml) was heated at reflux for 50 min. The reaction mixture was evaporated in vacuo to about 30 ml. Methanol (25 ml) and concentrated HCl (2 ml) were added. The solution was heated at reflux for 40 min. and evaporated in vacuo to almost dryness. The residue was added hexane and filtered to give norcodeine hydrochloride (8.8 g, 93% yield). Preparation of 17-cyclopropylmethylnorcodeine. A mixture of norcodeine hydrochloride (11.48 g, 27.8 mmol), (chloromethyl)cyclopropane (5.14 g, 55.6 mmol), sodium carbonate (14.73 g, 139.0 mmol), and potassium iodide (4.61 g, 27.8 mmol) in ethanol (250 ml) was heated at reflux for 20 hr, cooled, and evaporated in vacuo to dryness. The residue was basified with NH4OH, and extracted with methylene chloride. The extract was washed with water and evaporated in vacuo to dryness. The residue (11.7 g) was chromatographed on silica gel with a eluting solvent system of methanol/ethyl acetate (10/90) to give 17cyclopropylmethylnorcodeine (10.68 g, 91% yield). Preparation of 17-cyclopropylmethylnorcodeinone. To a solution of DMSO (14.50 g, 185.6 mmol) in methylene chloride (80 ml) at -78°C, was added a solution of oxalyl chloride (11.78 g, 92.8 mmol) in methylene chloride (20 ml) in 20 min. After stirring at -78°C for 20 min., a solution of 17-cyclopropylmethylnorcodeine (9.0 g, 26.5 mmol) in methylene chloride (40 ml) was added dropwise in 50 min. The reaction mixture was stirred at -74° to -76°C for 3 hr, added triethylamine (9.39 g, 92.8 mmol), allowed to warm up to rt., added methylene chloride (200 ml), washed with water (10 times 50 ml), and evaporated in vacuo to dryness. The residue was mixed with hexane and filtered to give 17-cyclopropylmethylnorcodeinone (8.85 g, 99% yield). Preparation of 17-cyclopropylmethylnorcodeinone dienol acetate. A mixture of 17-cyclopropylmethylnorcodeinone (3.55 g, 10.5 mmol), acetic

2394

Naltrexone

anhydride (20 ml, 210.4 mmol), sodium acetate (1.3 g, 15.8 mmol), and toluene (6 ml) was heated at 71°-73°C for 14 hr. The reaction mixture was cooled, added methylene chloride (250 ml), water (50 ml), and sodium bicarbonate (73.5 g), stirred for 4 hr, and filtered. The organic portion of the filtrate was separated, washed with water (30 ml), dried over anhydrous sodium sulfate, and evaporated in vacuo to dryness. The residue (3.94 g) was chromatographed on silica gel with 100% ethyl acetate to give 17cyclopropylmethylnorcodeinone dienol acetate (2.87 g, 72% yield). Preparation of 17-cyclopropylmethyl-14-hydroxynorcodeinone. A solution of 17-cyclopropylmethylnorcodeinone (0.20 g, 0.59 mmol), formic acid (90%, 0.304 g), water (0.504 g), EtOAc (0.27 g), and hydrogen peroxide (30%, 0.17 g) was heated at 42°-43°C for 15 hr, added water (20 ml), basified with Na2CO3 (1.02g), and extracted with EtOAc (80 ml and 2 times 20 ml). The combined extract was washed with water, dried over anhydrous sodium sulfate, and evaporated in vacuo to dryness to give 17-cyclopropylmethyl-14hydroxynorcodeinone (0.10 g, 56% yield). The Rf value in TLC and the IR spectrum of the product were comparable to those obtained from an authentic sample. Preparation of 17-cyclopropylmethyl-14-hydroxynorcodeinone. A solution of 17-cyclopropylmethylnorcodeinone dienol acetate (1.00 g, 2.63 mmol), formic acid (8 ml, 90%), and hydrogen peroxide (0.37 g, 30%, 3.26 mmol) was heated at 44°-45°C for 6 hr, added water (20 ml) and ethyl acetate (80 ml), basified with sodium bicarbonate. The organic portion was separated, washed with water (15 ml), dried over anhydrous sodium sulfate and evaporated in vacuo to dryness, the residue (0.9 g) was chromatographed on silica gel with methanol/methylene chloride (2.5/97.5) to give 17cyclopropylmethyl-14-hydroxynorcodeinone (0.72 g, 78% yield). Preparation of 17-cyclopropylmethyl-14-hydroxynorcodeinone. A solution of 17-cyclopropylmethylnorcodeinone dienol acetate (0.5 g, 1.31 mmol), 3-chloroperbenzoic acid (0.36 g, 2.10 mmol) and oxalic acid (0.27 g, 2.90 mmol) in acetic acid (7 ml) was stirred at rt. overnight, added cold water (35 ml), basified with sodium carbonate, and extracted with methylene chloride (100 ml). The extract was washed with water (2 times 30 ml), dried over anhydrous sodium sulfate, and evaporated in vacuo to dryness. The residue (0.41 g) was chromatographed on silica gel to give 17cyclopropylmethyl-14-hydroxynorcodeinone (0.34 g, 74% yield). The Rf value in TLC and the IR spectrum of the product were comparable to those obtained from an authentic sample. Preparation of 3-methylnaltrexone. A mixture of 17-cyclopropylmethyl-14-hydroxynorcodeinone (0.30 g, 0.85 mmol) and Pd/C (5%, 0.45 g) in ethanol (35 ml) was hydrogenated in a Parr hydrogenator at rt. under 28 psi of hydrogen gas. The mixture was filtered. The filtrate was evaporated in vacuo to dryness to give 3-methylnaltrexone (0.30 g, 99% yield). Preparation of naltrexone from 3-methylnaltrexone.

Nandrolone decanoate

2395

A solution of 3-methylnaltrexone (0.48 g, 1.35 mmol) in methylene chloride (30 ml) was cooled with an ice-water bath, and then added a solution of boron tribromide (5.4 ml, 1 M solution in methylene chloride, 5.4 mmol). The reaction mixture was stirred at rt. for 15 hr, basified with NH4OH, and extracted with methylene chloride (60 ml). The extract was washed with water (2 times 15 ml), dried over anhydrous sodium sulfate, and evaporated in vacuo to dryness to give naltrexone (0.45 g, 98% yield). References Huang B.-S. et al.; US Patent No. 6,013,796; Assigned to Penick Corporation, Newark, N.J.

NANDROLONE DECANOATE Therapeutic Function: Anabolic Chemical Name: 17β-[(1-Oxodecyl)oxy]estr-4-en-3-one Common Name: 19-Nortestosterone decanoate; Norandrostenolone decanoate Structural Formula:

Chemical Abstracts Registry No.: 360-70-3; 434-22 Trade Name

Manufacturer

Country

Year Introduced

Deca-Durabolin

Organon

US

1962

Deca-Hybolin

Hyrex

US

1979

Deca-Noralone

Taro

Israel

-

Fortabolin

Deva

Turkey

-

Iebolan

I.E. Kimya Evi

Turkey

-

Kabolin

Legere

US

-

Methybol

Mepha

Switz.

-

2396

Nandrolone phenpropionate

Trade Name

Manufacturer

Country

Year Introduced

Nordecon

Ibsa

Switz.

-

Sterobolin

Neofarma

Finland

-

Turinabol-Depot

Jenapharm

E. Germany

-

Raw Materials 19-Nortestosterone Decanoic acid chloride Manufacturing Process 1 gram of 19-nortestosterone is dissolved in 3 ml of dry pyridine, after which the resulting solution is cooled to -20°C. A solution of 1.0 gram of decanoic acid chloride in 3 ml of dry benzene is added to the cooled solution. The mixture is maintained at -15°C for 16 hours and then poured into ice water. The aqueous liquid is extracted with benzene, the benzene solution is washed with respectively 1 N sodium hydroxide solution, 2 N hydrochloric acid and with water until neutral reaction. Then the solution is dried on sodium sulfate, filtered, and evaporated to dryness. The residue, 1.63 grams is dissolved in hexane, this solution is filtered over 30 grams of neutral aluminum oxide, and evaporated to dryness. On paper chromatographic investigation it turned out that the obtained 19nortestosterone 17-decanoate which at room temperature is an oil consists of a single compound, according to US Patent 2,998,423. References Merck Index 6212 Kleeman & Engel p. 620 PDR pp. 1033, 1286 OCDS Vol. 1 p. 171 (1977) I.N. p. 655 REM p. 999 Donia, R.A. and Ott, A.C.; US Patent 2,798,879; July 9, 1957; assigned to The Upjohn Company De Wit, E.D. and Overbeek, G.A.; US Patent 2,998,423; August 29, 1961; assigned to Organon Inc.

NANDROLONE PHENPROPIONATE Therapeutic Function: Anabolic Chemical Name: 17β-Hydroxyestr-4-en-3-one 3-phenylpropionate Common Name: 19-Nortestosterone β-phenylpropionate

Nandrolone phenpropionate

2397

Structural Formula:

Chemical Abstracts Registry No.: 62-90-8; 434-22-0 (Base) Trade Name Durabolin Nandrolin Activin Anticatabolin Hepa-Obaton Hybolin Improved Norabol Noralone Norandrol Norandros Norbalin Noromon Norstenol Sintabolin Strabolene Superanbolon Superbolin Turinabol

Manufacturer Organon Tutag Aristegui Falorni Noury Pharma Hyrex Pharmacia Taro Panther-Osfa Castillon Bieffe Ibsa Ravizza A.F.I. Isola-Ibi Spofa Labif Jenapharm

Country US US Spain Italy W. Germany US Sweden Israel Italy Spain Italy Switz. Italy Italy Italy Czechoslovakia Italy E. Germany

Year Introduced 1959 1979 -

Raw Materials 19-Nortestosterone β-Phenylpropionyl chloride Manufacturing Process An ice-cold solution of 1.5 grams of 19-nortestosterone and 1.5 ml of dry

2398

Naphazoline

pyridine in 10 ml of dry benzene is prepared and a solution of 1.5 ml of βphenylpropionyl chloride in 5 ml of dry benzene is added dropwise over a period of about 2 minutes with stirring. The resulting mixture is allowed to stand overnight under an atmosphere of nitrogen and then washed successively with cold 5% aqueous hydrochloric acid solution, cold 2.5% aqueous sodium hydroxide solution, and water. After drying over anhydrous sodium sulfate, the solvent is evaporated to give an almost colorless oil. Recrystallization from methanol gives white crystals of 19-nortestosterone 17β-phenylpropionate, MP 91° to 92.5°C. References Merck Index 6214 Kleeman & Engel p. 621 PDR p. 1286 OCDS Vol. 1 p. 171 (1977) I.N. p. 656 REM p. 999 Donia, R.A. and Ott, A.C.; US Patent 2,868,809; January 13, 1959; assigned to The Upjohn Company

NAPHAZOLINE Therapeutic Function: Nasal decongestant Chemical Name: 4,5-Dihydro-2-(1-naphthalenylmethyl)-1H-imidazole Common Name: 2-(1-Naphthylmethyl)imidazoline Structural Formula:

Chemical Abstracts Registry No.: 835-31-4 Trade Name Privine Albalon Naphcon Forte Clera Vasoclear Opcon Nafazair

Manufacturer Ciba Allergan Alcon Person Covey Smith, Miller and Patch Muro Pharmafair

Country US US US US US US US

Year Introduced 1942 1970 1975 1978 1979 1981 1983

Naphazoline Trade Name Actinophtyl Bactio-Rhin Biogan Coldan Degest-2 Gotinal Imidazyl Imidin Imizol Murine Naftazolina Naline Nasal Yer Nomaze Ocunasal Pivanol Privin Proculin Ran Rhinex S Rhinon Rimidol Rinofug Vasoconstrictor Vistalbalon

Manufacturer Gregoire Byk Liprandi Recip Sigmapharm Barnes Hind Promeco Tubi Lux Pharma Ysat Wernigerode Farmigea Abbott Bruschettini Ibsa Yer Fisons Sam-On Tek Ciba Ankerwerk Corvi Ysat Wernigerode Petrasch Leo Chimimport Export Pensa Pharm-Allergan

Country France Argentina Sweden Austria US Argentina Italy E. Germany Italy UK Italy Switz. Spain UK Israel Turkey W. Germany E. Germany Italy E. Germany Austria Sweden Rumania Spain W. Germany

2399

Year Introduced -

Raw Materials Naphthyl-(1)-acetonitrile Ethanol Methanol Ethylene diamine Manufacturing Process 2.7 parts of naphthyl-(1)-acetiminoethylether hydrochloride of the formula

(produced from naphthyl-(1)-acetonitrile and methanol) are dissolved in 12 parts of absolute alcohol. 1 part of ethylenediamine is then added and the

2400

Naphazoline hydrochloride

whole is heated to gentle boiling while passing nitrogen through it and simultaneously stirring until ammonia escapes no longer. The alcohol is then distilled and the residue mixed with 40 parts of benzene and 1.8 parts of caustic potash. Stirring is continued for some time whereby the imidazoline base is dissolved in benzene. The benzene residue is recrystallized several times from toluene. References Merck Index 6218 Kleeman & Engel p. 622 PDR pp. 728, 809, 1549 OCDS Vol. 1 p. 241 (1977) I.N. p. 657 REM p. 888 Sonn, A.; US Patent 2,161,938; June 13, 1939; assigned to the Society of Chemical Industry in Basle, Switzerland

NAPHAZOLINE HYDROCHLORIDE Therapeutic Function: Vasoconstrictor, Nasal decongestant Chemical Name: 2-Imidazoline, 2-(1-naphthylmethyl)-, monohydrochloride Common Name: Nafazolin(a) hydrochloride; Naftazolina hydrochloride; Naphazoline hydrochloride; Naphtazoline hydrochloride; Naphthizin(um) hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 550-99-2 Trade Name Albalon Clear Eyes

Manufacturer Allergan Farnam Companies, Inc.

Country Australia USA

Year Introduced -

Naphazoline Hydrochloride Niazol Rhinantin

Allergan

-

-

Dahuachem Dahuachem

China China

-

Naproxen Trade Name Rinofug Sanorin Vasoclear Vasocon

Manufacturer Sc Meduman Sa Galena CIBA Vision Novartis

Country Rumania Czech Republic USA

2401

Year Introduced -

Raw Materials Naphtyl-(1)-acetiminoethylether Ethylenediamine Manufacturing Process 2.7 parts of naphtyl-(1)-acetiminoethylether (produced from naphthyl-1acetonitrile) were dissolved in 12 parts of absolute alcohol. 1 part of ethylenediamine is then added and the mixture was heated to gentle boiling while passing it through nitrogen and simultaneously stirring until ammonia escaped no longer. The alcohol was is then distilled and the residue mixed with 40 parts of benzene and 1.8 parts of caustic potash. Stirring was continued for some time whereby the imidazoline base was dissolved in benzene. The benzene residue, is recrystallized several times from toluene. The 2-[naphthyl-1-methyl]-imidazoline represented the coloriless crystalls of melting point 252°-253°C. Its hydrochloride is easily soluble in water. References Sonn A., US Patent No. 2,161,938; June 13, 1939

NAPROXEN Therapeutic Function: Antiinflammatory Chemical Name: (+)-6-Methoxy-α-methyl-2-naphthaleneacetic acid Common Name: d-2-(6-Methoxy-2-naphthyl)propionic acid Structural Formula:

Chemical Abstracts Registry No.: 22204-53-1 Trade Name Naprosyn Naprosyne

Manufacturer Syntex Cassenne

Country UK France

Year Introduced 1973 1975

2402

Naproxen

Trade Name Proxen Naprosyn Naprosyn Naprosyn Naixan Congex Floginax Gibixen Laser Madaprox Naprium Naprius Naprux Naxyn Novonaprox Numide Prexan Veradol Xenar

Manufacturer Gruenenthal Recordati Syntex Syntex Tanabe Nemi Farmochimica Gibipharma Tosi-Novara Madariaga Radiumpharma Magis Andromaco Teva Novopharm Hosbon Lafare Schering Alfar Farma Clutici

Country W. Germany Italy Switz. US Japan Argentina Italy Italy Italy Spain Italy Italy Argentina Israel Canada Spain Italy W. Germany Italy

Year Introduced 1975 1975 1975 1976 1978 -

Raw Materials Sodium hydroxide Magnesium Cadmium chloride

2-Bromo-6-methoxynaphthalene Ethyl-2-bromopropionate

Manufacturing Process According to US Patent 3,658,858, a solution of 24 grams of 2-bromo-6methoxynaphthalene in 300 ml of tetrahydrofuran is slowly added to 2.5 grams of magnesium turnings and 100 ml of tetrahydrofuran at reflux temperature. After the addition is complete, 20 grams of cadium chloride is added, and the resultant mixture is refluxed for 10 minutes to yield a solution of di-(6-methoxy-2-naphthyl)cadmium (which can be separated by conventional chromatography, although separation is unnecessary). A solution of 18 grams of ethyl 2-bromopropionate in 20 ml of tetrahydrofuran is then added to the cooled reaction mixture. After 24 hours at 20°C, the product is hydrolyzed by adding 200 ml of 5 weight percent methanolic sodium hydroxide followed by heating to reflux for 1 hour. The reaction mixture is then diluted with excess 1 N sulfuric acid and extracted with ether. The ether phase is separated, evaporated to dryness and the residue is recrystallized from acetone-hexane to yield 2-(6-methoxy-2naphthyl)propionic acid. References Merck Index 6269 Kleeman & Engel p. 623 PDR p. 1801

Naratriptan

2403

OCDS Vol. 1 p. 86 (1977) DOT 9 (9) 384 (1973) & 10 (3) 95 (1974) I.N. p. 658 REM p. 1119 Alvarez, F.S.; US Patent 3,637,767; January 25, 1972; assigned to Syntex Corp., Panama Harrison, I.T.; US Patent 3,658,858; April 25, 1972; assigned to Syntex Corp., Panama Alvarez, F.S.; US Patent 3,663,584; May 16, 1972; assigned to Syntex Corp., Panama

NARATRIPTAN Therapeutic Function: Serotonin antagonist, Migraine therapy Chemical Name: 1H-Indole-5-ethanesulfonamide, N-methyl-3-(1-methyl-4piperidinyl)Common Name: Naratriptan Structural Formula:

Chemical Abstracts Registry No.: 121679-13-8 Trade Name Amerge GR 85548 X Naratriptan

Manufacturer Glaxo Wellcome GlaxoSmithKline GlaxoSmithKline

Country UK USA USA

Year Introduced -

Raw Materials N-Methyl-4-piperidone N-Methyl-1H-indole-5-ethanesulphonamide Oxalic acid 1-Methyl-4-piperidineacetaldehyde Palladium on carbon 4-Hydrazino-N-methyl-benzenethanesulphonamide Manufacturing Process N-Methyl-3-(1,2,3,6-tetrahydro-1-methyl-4-pyridinyl)-1H-indole-5ethanesulphonamide oxalate

2404

Naratriptan

A solution of N-methyl-1H-indole-5-ethanesulphonamide (1.0 g) in methanol (50 ml) containing potassium hydroxide (5.6 g) and N-methyl-4-piperidone (1.0 ml) was heated at reflux for 24 h, cooled, and the resulting solid filtered off (1.0 g). A sample of the solid (0.2 g) was dissolved in a hot methanolic solution of oxalic acid (0.06 g), the solution cooled, and the salt precipitated by adding ethyl acetate (20 ml) and dry ether (50 ml). The salt was filtered off, and dried in vacuo to give the title compound as a solid (0.12 g), m.p. 87°-90°C (shrinks). Analysis Found: C,52.2; H,5.6; N,9.5. C17H23N3O2S · C2H2O4 · 0.6H2O requires C,52.5; H,6.0; N,9.7%. N-Methyl-3-(1-methyl-4 -piperidinyl)-1H-indole-5-ethansulphonamide N-Methyl-3-(1,2,3,6-tetrahydro-1-methyl-4-pyridinyl)-1H-indole-5ethanesulphonamide oxalate (as the free base) (0.36 g, 0.001 mol) in absolute alcohol (70 ml) and anhydrous dimethylformamide (5 ml) was hydrogenated, in the presence of 5% palladium on activated carbon (0.36 g) at ambient temperature and atmospheric pressure. After 20 h, hydrogen absorption (25 cm3, theoretical = 24 cm3) ceased. The catalyst was filtered off and the solvent removed in vacuo to given an opaque gum which solidified as a soft white solid (0.3 g). Purification by flash chromatography (Sorbsil C60 silica gel, CH2Cl2/EtOH/0.88 ammonia; 50:80:1) gave a colorless oil (0.21 g) that was triturated with ether to give the title compound (0.17 g) m.p. 156°158°C. TLC SiO2(CH2Cl2/EtOH/0.88 ammonia; 50:8:1) Rf 0.4. N-Methyl-3-(1-methyl-4-piperidinyl)-1H-indole-5-ethanesulphonamide may be prepared the another way. A solution of 4-hydrazino-N-methyl-benzenethanesulphonamide (0.5 g) and 1methyl-4-piperidineacetaldehyde (0.35 g) in a mixture of water (10 ml) of 2 N hydrochloric acid (1.0 ml, 2.00 mmol) was stirred for 2 days at room temperature. A further quantity of the aldehyde (0.35 g) was added and stirring continued for a further 30 min. The solution was then basified with 8% sodium bicarbonate to pH 8 and extracted with chloroform (3 times 50 ml). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give the crude hydrazone as an oil (1.0 g). A solution of the hydrazone (1.0 g) in chloroform (20 ml) containing polyphosphate ester (10 g) was heated at reflux for 8 min. The solution was poured onto ice (200 g), stirred for 2 h treated with 2 M sodium carbonate (20 ml) and extracted with chloroform (3 times 50 ml). The combined organic extracts were dried (Na2SO4), evaporated in vacuo and the residue purified by flash chromatography (silica 9385, 100 g) eluting with CH2Cl2/EtOH/NH3(75:8:1) to give impure material as a yellow oil. Further flash chromatography (silica 9385, 100 g) eluting with CH2Cl2/EtOH/NH3 (100:8:1) gave the product as an oil (0.05 g). This was crystallised from ethyl acetate to give the title compound solid m.p. 156°-157°C. TLC SiO2(CH2Cl2/EtOH/NH3(50:8:1)) Rf 0.6. References Oxford A.W. et al.; US Patent No. 4,997,841; Mar. 5, 1991; Assigned to Glaxo Group Limited, England

Natamycin

2405

EPA No. 0,303,507 A2, 12.08.88

NATAMYCIN Therapeutic Function: Antibacterial (ophthalmic) Chemical Name: Natamycin Common Name: Pimaricin Structural Formula:

Chemical Abstracts Registry No.: 7681-93-8 Trade Name Pimafucine Pimafucin Pimafucort Pimafucin Natacyn Myprozine

Manufacturer Beytout Brocades Brocades Basotherm Alcon Lederle

Country France UK Italy W. Germany US US

Year Introduced 1964 1965 1966 1967 1979 -

Raw Materials Bacterium Streptomyces gilvosporeus Starch Corn steep liquor Manufacturing Process The Fermentation Process: The process by which this antifungal substance is produced is an aerobic fermentation of an aqueous nutrient medium

2406

Natamycin

inoculated with a pimaricin-producing strain of Streptomyces gilvosporeus. The nutrient medium contains an assimilable source of carbon such as starch, molasses, or glycerol, an assimilable source of nitrogen such as corn steep liquor and inorganic cations such as potassium, sodium or calcium, and anions such as sulfate, phosphate or chloride. Trace elements such as boron, molybdenum or copper are supplied as needed in the form of impurities by the other constituents of the medium. In more detail the nutrient medium used may contain sources of carbon such as starch, hydrolyzed starch, sugars such as lactose, maltose, dextrose, sucrose, or sugar sources such as molasses; alcohols, such as glycerol and mannitol; organic acids, such as citric acid and acetic acid; and various natural products which may contain other nutrient materials in addition to carbonaceous substances. Nitrogen sources include proteins, such as casein, zein, lactalbumin; protein hydrolyzates such proteoses, peptones, peptides, and commercially available materials, such as N-Z Amine which is understood to be a casein hydrolyzate; also corn steep liquor, soybean meal, gluten, cottonseed meal, fish meal, meat extracts, stick liquor, liver cake, yeast extracts and distillers' solubles; amino acids, urea, ammonium and nitrate salts. Such inorganic elements as sodium, potassium, calcium and magnesium; and chlorides, sulfates, phosphates and combinations of these anions and cations in the form of mineral salts may be advantageously used in the fermentation. The so-called trace elements, such as boron, cobalt, iron, copper, zinc, manganese, chromium, molybdenum and still others may also be used to advantage. Generally, these trace elements occur in sufficient quantities in the carbonaceous and nitrogenous constituents of the medium, particularly if derived from natural sources, or in the tap water, and the addition of further quantities of these trace elements may consequently be unnecessary. The fermentation liquor is aerated in the customary manner by forcing sterile air through the fermenting mixture usually at the rate of about 1 volume of air per volume of fermentation medium per minute. To minimize contamination with foreign microorganisms, the fermentation vessels should be closed and a pressure of 2 to 15 pounds above atmospheric pressure maintained in the vessel. In addition to the agitation provided by aeration, mechanical agitation is generally desirable. Antifoaming agents, such as 1% octadecanol in lard oil, may be added from time to time as required to prevent excessive foaming. Fermentation is conducted at a temperature preferably on the order of 26°C to 30°C but may be as low as 17°C or as high as 42°C. The time required for maximum production of the antifungal substance will vary considerably depending upon other conditions of the fermentation. Generally, about 48 hours is required before appreciable quantities of the antifungal substance are detected in the medium. The production of the antifungal substance increases with time, and the fermentation may run as long as 120 hours. The hydrogen ion conditions normally vary from about pH 6 to pH 8.0, although deviations from these values are permissible, according to British Patent 846,933. The reader is referred to the patents cited for detals of pimaricin purification.

Nedocromil disodium

2407

References Merck Index 6278 Kleeman & Engel p. 624 DOT 14 (6) 255 (1978) I.N. p. 659 REM p. 1230 Koninkijke Nederlandsche Gist- & Spiritusfabriek N.V., Netherlands; British Patent 844,289; August 10, 1960 American Cyanamid Company; British Patent 846,933; September 7, 1960

NEDOCROMIL DISODIUM Therapeutic Function: Antiallergic, Anti-asthmatic Chemical Name: 4H-Pyrano(3,2-g)quinoline-2,8-dicarboxylic acid, 9-ethyl6,9-dihydro-4,6-dioxo-10-propyl-, disodium salt Common Name: Nedocromil sodium Structural Formula:

Chemical Abstracts Registry No.: 69049-74-7; 69049-73-6 (Base) Trade Name

Manufacturer

Country

Year Introduced

Alocril

Allergan

USA

-

Cetimil

Lab. Lesvi

-

-

Irtan

Rhone-Poulenc Rorer

France

-

Halamid

Viatris

Germany

-

Halamid

ASTA Medica AWD

-

-

Kovilen

Mediolanum Farmaceutici S.p.A. Rhone-Poulenc Rorer

Italy

-

France

-

Nedocromil Disodium Tilade

Rhone-Poulenc Rorer

France

-

Tilade Mint.

Fisons

UK

-

Tilavist

Fisons

UK

-

Tilavist

Aventis Pharma AB

Sweden

-

2408

Nedocromil disodium

Raw Materials Allyl bromide 4-Acetamido-2-hydroxyacetophenone Sodium ethoxide Dimethyl acetylene dicarboxylate Polyphosphoric acid Manufacturing Process 4,6-Dioxo-10-propyl-4H,6H-pyrano[3,2-]quinoline-2,8-dicarbxylic acid disodium salt was prepared in 8 steps 1. 4-Acetamido-2-allylacetophenone 4-Acetamido-2-hydroxyacetophenone (19.3 g), allyl bromide (12.1 ml) and hydrous potassium carbonate (21.5 g) were stirred in dry dimethylformamide (250 ml) at room temperature for 24 hours. The reaction mixture was poured into water and the product was extracted with ethyl acetate. The organic solution was then washed well with water dried over magnesium sulphate and evaporated to dryness. The sub-title product was obtained as buff coloured solid (20.5 g). The structure of the product was confirmed by NMR and mass spectroscopy. 2. 4-Acetamido-3-allyl-2-hydroxyacetophenone The above allyl ether (18.4 g) was heated at 200-210°C for 4 hours. 17.1 g of the thermally rearranged sub- title product was obtained as a brown solid. Again the structure was confirmed by NMR and mass spectroscopy. 3. 4-Acetamido-2-hydroxy-3-propyl acetophenone The product of step 2 (17 g) was dissolved in glacial acetic acid and hydrogenated in the presence of Adams catalyst until hydrogen uptake had ceased. The catalyst was filtered off through a keiselguhr filter and the filtrate was evaporated to leave 13.0 g of almost colorless solid. The mass and NMR spectra confirmed the structure of product. 4. Ethyl-7-acetamido-4-oxo-8-propyl-4H-l-benzopyran-2-carboxylate A mixture of diethyl oxalate (19.3 g; 17.9 ml) and the above product of step 3 (12.4 g) in dry ethanol (100 ml) was added to a stirred solution of sodium ethoxide in ethanol (prepared by dissolving sodium (6.1 g) in dry ethanol (200 ml)). The reaction mixture was refluxed for 3 hours and then poured into dilute hydrochloric acid and chloroform. The chloroform layer was separated, washed with water and dried. The solvent was evaporated to leave a brown solid which was dissolved in ethanol (300 ml) containing concentrated hydrochloric acid (3 ml) and the whole was refluxed for 1 hour. The reaction mixture was poured into water and the product was extracted into ethyl acetate which was washed with water and dried. The solvent was evaporated to leave 10 g of a sticky solid which had mass and NMR spectra consistent with the expected product.

Nefazodone hydrochloride

2409

5. Ethyl 7-amino-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylate A solution of the amide of step 4 (10 g) in ethanol (300 ml), containing concentrated hydrochloric acid (5 ml), was refluxed for 8 hours. The reaction mixture was diluted with water and extracted into ethyl acetate. The extract was washed with water, dried and the solvent was evaporated to leave a dark brown semi-solid. This was chromatographed on a silica gel column, using ether as eluant to give 4.8 g of the required product whose structure was confirmed by mass and NMR spectral evidence; mp 84-87°C. 6.8-Ethoxycarbonyl-2-methoxycarbonyl-4,6-dioxo-10-propyl-4H,6Hpyrano[3.2-g]quinoline The amino benzopyran of step 5 (2.0 g) and dimethyl acetylene dicarboxylate (1.24 g; 1.01 ml) were refluxed in ethanol (30 ml) for 26 hours. The reaction mixture was cooled to 0°C and the insoluble yellow-brown solid was collected by filtration and washed with a little ethanol and dried to give 2.0 g of a product which was a mixture of maleic and fumaric esters obtained by Michael addition of the amine to the acetylene. This mixture of esters (2.0 g) was treated with polyphosphoric acid (30 ml) and heated on the steam bath with stirring for 20 minutes. The reaction mixture was then poured onto ice and stirred with ethyl acetate. The organic layer was separated, washed with water and dried. The solvent was evaporated to leave 1.6 g of a yellow orange solid. Recrystallisation of this solid from ethyl acetate gave the required product as fluffy orange needles, mp 187°-188°C. 7. 4,6-Dioxo-10-propyl-4H,6H-pyrano[3.2-g]quinoline-2,8-dicarboxylic acid The above bis ester (2.5 g) was refluxed with sodium bicarbonate (1.64 g) in ethanol (100 ml) and water (50 ml) for 1.5 hours. The whole was poured into water and acidified to precipitate a gelatinous solid. This was collected by filtration, refluxed with ethanol and the product was separated by centrifugation (1.4 g), mp 303°-304°C dec. The structure of the product was confirmed by mass and NMR evidence. 8. Disodium 4,6-dioxo-10-propyl-4H,6H-pyrano[3,2-g]quinoline-2,8dicarboxylate The bis acid from step 6 (1.35 g) and sodium bicarbonate (0.661 g) in water (150 ml) were warmed and stirred until a clear solution was obtained. This solution was filtered and the filtrate was freeze dried to give 1.43 g of the required disodium salt. References Cairns H., Cox D.; G.B. Patent 2,022,078, 1979-12-12

NEFAZODONE HYDROCHLORIDE Therapeutic Function: Antidepressant

2410

Nefazodone hydrochloride

Chemical Name: 3H-1,2,4-Triazol-3-one, 2,4-dihydro-2-(3-(4-(3chlorophenyl)-1-piperazinyl)propyl)-5-ethyl-4-(2-phenoxyethyl)-, monohydrochloride Common Name: Nefazodone hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 82752-99-6; 83366-66-9 (Base) Trade Name Dutonin Menfazona Nefadar Nefazodone Hydrochloride Reseril Rulivan Serzone

Manufacturer Bristol-Myers Squibb Laboratorios Menarini, S. A. Squibb-von Heyden Bristol-Myers Squibb

Country USA Italy

Year Introduced -

Germany USA

-

Mead Johnson Europharma Bristol-Myers Squibb

USA Australia

-

Raw Materials Hydrazine Thionyl chloride Sodium azide Sodium nitrite

1-(3-Chlorophenyl)-piperazine 1-Bromo-3-chloropropane Phenoxypropionic acid Triethyl orthopropionate

Manufacturing Process 1. 1-(3-Chloropropyl)-4-(3-chlorophenyl)piperazine hydrochloride A 25% NaOH solution (320 ml, 2.0 mol) is added dropwise to a stirred solution of 1-(3-chlorophenyl)-piperazine hydrochloride (196.5 g, 1.0 mol) and 1-bromo-3-chloropropane (99.0 ml, 1.0 mol) in acetone (200 ml) while maintaining temperature of 0°-10°C. After the addition is completed, the mixture is allowed to warm to room temperature and is stirred for 18 hours. The upper organic phase is then separated and concentrated under reduced pressure. The residual oil is taken up in 250 ml acetone and filtered. The filtrate is concentrated under reduced pressure and the oily residue is dissolved in 1 L of 15% boiling HCl solution. A viscous oil is separated from the cooled mixture and poured into 1 L of ice-H2O with vigorous stirring,

Nefazodone hydrochloride

2411

forming white precipitates. Recrystallization of the solid from boiling water gave 171.8 g (55.6% yield) of 1-(3-chloropropyl)-4-(3-chlorophenyl) piperazine hydrochloride; m.p 199.5°-200.5°C. 2. 1-(3-Chlorophenyl)-4-(hydrazinopropyl)piperazine 1-(3-Chloropropyl)-4-(3-chlorophenyl)piperazine hydrochloride (20.0 g, 0.065 mol) is suspended in isopropanol (65 ml) and anhydrous hydrazine (31.7 g, 0.988 mol) is added. The reaction mixture is heated at 70°-80°C for 2.5 hours and cooled to room temperature. The upper layer is separated and concentrated under reduced pressure. The residue is dissolved in isopropanol (50 ml) and the upper layer is separated, dried (Na2SO4), and concentrated to yield 16.5 g (94.5% yield) of 1-(3-chlorophenyl)-4-(3-hydrazinopropyl) piperazine (85% pure) as a viscous oil. The product is used directly without further purification or stored at room temperature in toluene or isopropanol solution by adding 1% MgO. The hydrazine is dissolved in isopropanol and 1% magnesium oxide is added. The mixture is stirred for 30 min and filtered. The filtrate is cooled with icebath and one equivalent of anhydrous HCl in isopropanol is added under vigorous stirring. The precipitates are collected by filtration and dried at 60°C under reduced pressure to afford white powder; mp 147°-150°C. 3. Phenoxypropionic acid (249.0 g, 1.50 mol) is dissolved in four equivalents of thionyl chloride (438.0 ml, 6.0 mol) and heated to reflux until the HCl evolution has ceased. The solution is then cooled to room temperature and concentrated under reduced pressure to give 281.0 g (100% yield) of phenoxypropionyl chloride as a brown oil which solidifies on cooling. 4. Phenoxypropionyl chloride (9.23 g, 0.05 mol) is dissolved in 100 ml acetone and cooled with an ice bath as sodium azide (3.6 g, 0.055 mol) in 10 ml water is added dropwise. After addition is completed, the reaction mixture is warmed to room temperature and stirred for 30 minutes. The solution is decanted and concentrated. The residue is dissolved in 100 ml ether and washed with saturated sodium bicarbonate and brine. The organic phase is separated, dried (MgSO4) and concentrated to give 6.52 g (68.0% yield) of phenoxypropionyl azide as a yellow oil which solidifies on cooling 5. Ethyl phenoxypropionate Phenoxypropionic acid (6.64 g, 0.04 mol) is mixed with excess ethanol (10 ml) and concentrated sulfuric acid (0.5 ml) is added. The reaction mixture is refluxed for 3 hours, cooled to room temperature and concentrated. The residue is washed with 1 N NaOH and brine, dried (Na2SO4), and concentrated to yield 7.32 g (94.3% yield) of the ester which can be used directly for the subsequent reaction without further purification. 6. Phenoxypropionyl hydrazide Ethyl phenoxypropionate (161 g, 0.83 mol) is cooled with an ice bath and anhydrous hydrazine (32 ml, 1 mol) is added dropwise. After the addition is completed, the solution is warmed to room temperature and stirred for 4 hours. The solution is then cooled with an ice bath under vigorous stirring.

2412

Nefazodone hydrochloride

After the white precipitate formed the mixture is kept in refrigerator for 14 hours. The solid is collected by filtration, washed with cold 10% ethanol/hexane and dried in reduced pressure at 50°C for 12 hours to give 134.7 g (90%) of phenoxypropionyl hydrazide as white powder. Mp 66°-70°C. The hydrochloride salt of phenoxypropionyl hydrazide is prepared by dissolving the hydrazide in dichloromethane, cooling with an ice bath and bubbling through anhydrous HCl gas until pH 3. The solid is collected by filtration, washed with cold dichloromethane and air-dried to give the hydrochloride salt as fine white powder, mp 172°-174°C. 7. Phenoxyethyl isocyanate Method A: Phenoxypropionyl azide (15.2 g, 0.08 mol) is dissolved in 50 ml toluene and heated with an external oil bath. At 75°-80°C (internal temperature) vigorous N2evolution is observed and the reaction is very exothermic. The solution is refluxed for further 30 min after the gas evolution has finished. The solution is concentrated and the residue is distilled in vacuo to give 7.8 g (60% yield) of phenoxyethyl isocyanate as a colorless oil (94°96°C, 1 mm Hg). Method B: Phenoxypropionyl hydrazide (125.9 g, 0.7 mol) is suspended in 650 ml ice-water and concentrated hydrochloric acid (123 ml, 1.47 mol) was added. The mixture is stirred for 20 min and toluene (350 ml) is added. A solution of sodium nitrite (53.1 g, 0.77 mol) in 200 ml water is added over a period 15 min. The internal temperature is kept below 15°C and if necessary, ice is directly added to the reaction mixture. After the addition is completed the mixture is stirred for a further 1 hour and filtered through Celite. The solid is washed with 30 ml toluene and the filtrate is separated. The aqueous layer is extracted with 200 ml toluene and the combined toluene solutions are dried over MgSO4. The dried toluene solution is filtered and added dropwise to a preheated flask at 95°-100°C. Nitrogen evolution occurs as the solution is dropped in. After the addition is complete, the reaction mixture is heated to gentle reflux until nitrogen evolution has ceased. The reaction mixture is cooled to room temperature and can be used directly in subsequent reactions. 1 ml of the reaction mixture is withdrawn and evaporated to dryness, and the weight of the residue is measured. This provides an estimate of the concentration of isocyanate per ml of reaction mixture. 8.2-3-(4-[3-Chlorophenyl]-1-piperazinyl)propyl]-4-(2-phenoxyethyl)semicarbazide) A solution of phenoxyethyl isocyanate (89 g, 0.55 mol) in toluene (450 ml) is generated in situ (see step 7) and cooled to -20°C. To the solution is added a solution of 1-(3-chlorophenyl)-4-(3-hydrazinopropyl)piperazine (131.2 g, 0.49 mol) in 100 ml toluene at the speed that the internal temperature is below 10°C. After the addition is completed the mixture is stirred for 30 min at 20°C and for 1.5 hours at 0°C and quenched with 150 ml 1 N NaOH solution. The mixture is stirred at 0°C for 10 min and filtered through celite. The filtrate is saturated with NaCl and separated. The aqueous layer is extracted with 100 ml toluene and the combined toluene solution was dried over Na2SO4, filtered and concentrated to give a viscous oil. A small amount sample was purified by column chromatography (5% MeOH/CH2Cl2) to give a colorless oil. The crude

Nefopam hydrochloride

2413

product is dissolved in isopropanol, cooled with ice bath, and two equivalents of HCl/isopropanol are added. The precipitates are collected by filtration and further purified by recrystallization from ethanol to give 170.6 g (69%) of hydrochloride salt as white crystal. Mp 172°-176°C. 9.2-[3-4-(3-Chlorophenyl)-1-piperazinyl]-propyl]-5-ethyl-4-(2-phenoxyethyl)2H-1,2,4-triazol-3(4H)-one monohydrochloride (Nefazodone monohydrochloride) 2-[3-(4-[3-Chlorophenyl-1-piperazinyl)propyl]-4-(2-phenoxyethyl)semicarbazidedihydrochloride (23.3 g, 46 mmol) is suspended in 50 ml toluene and refluxing with Dean-Stark apparatus to remove water. The mixture is then cooled to room temperature and triethyl orthopropionate (50 ml, about 5 eq) is added. The suspension is refluxed again with Dean-Stark apparatus. As toluene is distilled the suspension becomes a clear solution which is refluxed for 48 hours. Distillation under reduced pressure removes unreacted trietyl orthopropionate and the resulting residue is dissolved in 50 ml isopropanol, treated with HCl to pH 4, stirred at 0°C for 1 hour and standed in refrigerator for 12 hours. The solid is collected with filtration and recrystallized from ethanol to give 10.5 g (45%) of nefazodone monohydrochloride as white powder (95% pure by HPLC). Further purification is achieved by fractional recrystallization to give the product with 99.5% purity. mp 183°-185°C. References Lei B. et al.; US Patent No. 5,900,485; May 4, 1999; Assigned to Apotex, Inc., Weston, Canada Murthy K.S.K. et al.; US Patent No. 6,596,866 B2; Jul. 22, 2003; Assigned to Brantford Chemicals Inc., Banntford

NEFOPAM HYDROCHLORIDE Therapeutic Function: Muscle relaxant, Antidepressant Chemical Name: 3,4,5,6-Tetrahydro-5-methyl-1-phenyl-1H-2,5benzoxazocine hydrochloride Common Name: Structural Formula:

2414

Nefopam hydrochloride

Chemical Abstracts Registry No.: 13669-70-0 (Base) Trade Name Ajan Acupan Acupan Lenipan Oxadol Acupan

Manufacturer Kettelhack Riker Carnegie Riker Chiesi I.S.I. Boehringer Mannheim

Country W. Germany UK France Italy Italy Italy

Year Introduced 1976 1978 1981 1981 1982 1983

Raw Materials 2-Benzoylbenzoic acid 2-Methylaminoethanol 4-Toluenesulfonic acid Thionyl chloride Lithium aluminum hydride Hydrogen chloride Manufacturing Process The starting material is prepared by reacting 2-benzoylbenzoic acid with thionyl chloride and then with 2-methylaminoethanol. 20.0 grams (0.07 mol) of N-(2-hydroxyethyl)-N-methyl-o-benzoylbenzamide is suspended in 100 ml tetrahydrofuran and then slowly added in small portions to a solution of 5.5 grams (0.14 mol) of lithium aluminum hydride in 150 ml tetrahydrofuran with cooling and stirring. The mixture is then refluxed for 18 hours, cooled and then to it is successively added 5.5 ml water, 5.5 ml of 3.75 N sodium hydroxide and 16 ml water. After removal of precipitated salts by filtration, the solution remaining is concentrated under reduced pressure and the residue dried to yield 19.5 grams of crude product. Yield after conversion to the hydrochloride salt and recrystallization is 17.0 grams (89%), MP 128° to 133°C. 5-methyl-1-phenyl-1,3,4,6-tetrahydro-5H-benz[f] -2,5-oxazocine is prepared as follows. 3.0 grams (0.011 mol) of 2-([N-(2-hydroxyethyl)-Nmethyl]amino)methylbenzhydrol, prepared as described above, 3.0 grams ptoluenesulfonic acid and 15 ml benzene are heated together with stirring until all the benzene is distilled off. The residual oil is heated to 105°C and held at this temperature for 1 hour, then cooled and dissolved in 30 ml water. This aqueous solution is then basified to pH 10.0 with 12 N sodium hydroxide, extracted with ether, and the extracts washed with water, dried over anhydrous sodium sulfate and the solvent removed under reduced pressure. The 2.26 grams (81%) oil remaining is converted to the hydrochloride salt, MP 238° to 242°C. References Merck Index 6287 Kleeman & Engel p. 626 OCDS Vol. 2 p. 447 (1980) DOT 12 (7) 275 (1976)

Neomycin

2415

I.N. p. 661 Baltes, B.J.; US Patent 3,487,153; December 30, 1969; assigned to Rexall Drug and Chemical Company

NEOMYCIN Therapeutic Function: Antibacterial Chemical Name: O-2,6-Diamino-2,6-dideoxy-α-D-glucopyranosyl-(1->3)-Oβ-D-ribofuranosyl(1->5)-O-[2,6-diamino-2,6-dideoxy-α-D-glucopyranosyl(1->4)]-2-deoxy-D-streptamine Common Name: Framycetin Structural Formula:

Chemical Abstracts Registry No.: 1404-04-2; 4146-30-9 (Sulfate salt) Trade Name

Manufacturer

Country

Year Introduced

Myciguent

Upjohn

US

1951

Otobiotic

Schering

US

1954

Mycifradin

Upjohn

US

1957

Neobiotic

Pfizer

US

1958

Apokalin

A.L.

Norway

-

Biofradin

Uriach

Spain

-

Bykomycin

Byk Gulden

W. Germany

-

Cortisporin

Burroughs-Wellcome

US

-

Dexmy

Takeda

Japan

-

2416

Neomycin

Trade Name

Manufacturer

Country

Year Introduced

Endomixin

Lusofarmaco

Italy

-

Fradio

Nippon Kayaku, Co.

Japan

-

Fradyl

Christiaens

Belgium

-

Ivax

Boots

UK

-

Larmicin

Larma

Spain

-

Myacyne

Werner Schnur

W. Germany

-

Mytrex

Savage

US

-

Neobretin

Norbrook

UK

-

Neodecadron

MSD

US

-

Neointestin

Hosbon

Spain

-

Neolate

Therafarm

UK

-

Neomicina Roger

Roger

Spain

-

Neomin

Glaxo

UK

-

Neo-Polycin

Merrell Dow

US

-

Neopt

Sigma

Australia

-

Neosporin

Burroughs-Wellcome

US

-

Neosulf

Protea

Australia

-

Neo-Synalar

Syntex

US

-

Octicair

Pharmafair

US

-

Otocort

Lemmon

US

-

Siquent

Sigma

Australia

-

Tampovagan

Norgine

UK

-

Topisporin

Pharmafair

US

-

Tri-Thalmic

Schein

US

-

Raw Materials Bacterium Streptomyces fradiae Nutrient medium Manufacturing Process Neomycin has been produced by growing the organism, Strepromyces No. 3535, in a suitable nutrient medium under appropriate stationary or submerged aerobic (viz shaken) conditions, and then isolating and purifying the substance, e.g., by procedure of the sort described in the figure including various steps of adsorption, recovery by elution, separation from impurities, and precipitation.

Neomycin

Neomycin is usually used as the sulfate. References Merck Index 6300

2417

2418

Netilmicin

Kleeman & Engel 626 PDR pp.673, 738, 756, 888, 993, 1034, 1206, 1232, 1429, 1569, 1604, 1800 I.N. p. 663 REM p. 1181 Waksman, S.A. and Lechevalier, H.A.; US Patent 2,799,620; July 16, 1957; assigned to Rutgers Research and Educational Foundation Jackson, W.G.; US Patent 2,848,365; August 19, 1958; assigned to The Upjohn Company Miller, T.W.; US Patent 3,005,815; October 24, 1961; assigned to Merck & Co., Inc. Moses, W.; US Patent 3,022,228; February 20, 1962; assigned to S.B. Penick & Company Haak, W.J.; US Patent 3,108,996; October 29, 1963; assigned to The Upjohn Company

NETILMICIN Therapeutic Function: Antibiotic Chemical Name: 1-N-Ethylsisomicin Common Name: Structural Formula:

Chemical Abstracts Registry No.: 56391-56-1 Trade Name

Manufacturer

Country

Year Introduced

Netromycine

Schering

Switz.

1980

Certomycin

Byk-Essex

W. Germany

1980

Netillin

Kirby-Warrick

UK

1981

Netromicine

Unicet

France

1981

Nettacin

Essex

Italy

1982

Netromycin

Schering

US

1983

Nevirapine

2419

Raw Materials Sisomicin Acetaldehyde Sulfuric acid Sodium cyanoborohydride Manufacturing Process To a solution of 5 g of sisomicin in 250 ml of water add 1 N sulfuric acid until the pH of the solution is adjusted to about 5. To the solution of sisomicin sulfuric acid addition salt thereby formed, add 2 ml of acetaldehyde, stir for 10 minutes, then add 0.85 g of sodium cyanoborohydride. Continue stirring at room temperature for 15 minutes, then concentrate solution in vacuo to a volume of about 100 ml, treat the solution with a basic ion exchange resin [e.g., Amberlite IRA 401S (OH-)], then lyophilize to a residue comprising 1-Nethylsisomicin. Purify by chromatographing on 200 g of silica gel, eluting with lower phase of a chloroformmethanol-7% aqueous ammonium hydroxide (2:1:1) system. Combine the eluates as determined by thin layer chromatography and concentrate the combined eluates of the major component in vacuo to a residue comprising 1-N-ethylsisomicin (yield 1.25 g). Further purify by again chromatographing on 100 g of silica gel eluting with a chloroform-methanol3.5% ammonium hydroxide (1:2:1) system. Pass the combined, like eluates (as determined by thin layer chromatography) through a column of basic ion exchange resin and lyophilize the eluate to obtain 1-N-ethylsisomicin (yield 0.54 g). There is also a fermentation route to netilmicin as noted by Kleeman & Engel. References Merck Index 6322 DFU 3 (7) 527 (1978) Kleeman & Engel p. 627 PDR p. 1635 DOT 17 (8) 324 (1981) I.N. p. 666 REM p. 1183 Wright, J.J., Daniels, P.J.L., Mallams, A.K. and Nagabhushan, T.L.; US Patent 4,002,742; January 11, 1977; assigned to Schering Corp.

NEVIRAPINE Therapeutic Function: Antiviral Chemical Name: 5H-Dipyrido(3,2-b:2',3'-e)(1,4)diazepin-6-one, 5,11dihydro-11-cyclopropyl-4-methyl-

2420

Nevirapine

Common Name: Nevirapine Structural Formula:

Chemical Abstracts Registry No.: 129618-40-2 Trade Name Neve Nevimune Nevirapine NVP Viramune Viramune Viramune Viramine

Manufacturer Le Sante Cipla Limited Boehringer Ingelheim Pharma Roxane Laboratories Boehringer Ingelheim Pharma Cipla Limited Roxane Laboratories Boehringer Ingelheim Pharma

Country India India USA

Year Introduced -

USA Germany

-

India USA USA

-

Raw Materials Calcium oxide Cyclopropylamine Sodium hydride Diethylene glycoldimethyl ether 2-Chloro-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide Manufacturing Process There are 3 ways for preparing of nevirapine. 117.5 kg of 2-chloro-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide, 23.3 kg of calcium oxide and 59.4 kg of cyclopropylamine (molar ratio: 1:1:2.5) are heated to between 135° and 145°C in 235 L of diglyme (diethylene glycoldimethylether) in a 500 L VA autoclave over a period of 6 to 8 hours. The reaction mixture is then cooled to a temperature of 20°-30°C and filtered. The filter cake is washed with 58.8 L of diglyme. The filtrates are combined and initially 200 L of solvent is distilled off. The residue is then diluted with a further 117.5 L of diglyme. The resultant diluted solution is added over a period of 20 to 40 minutes to a suspension of 45.0 kg of 60% sodium hydride in 352.5 L of diglyme, heated to 130°C. The storage vessel and conduits are rinsed with a further 55.8 L of diglyme, and the mixture is stirred at a temperature of between 130° and 140°C for a further 30 to 60 minutes. The majority of the diglyme is then distilled off. Finally, the

Nevirapine

2421

remaining residue is carefully mixed with 470 L of water. After cooling to a temperature of about 25°C, 235.0 L of cyclohexane and 57.11 of glacial acetic acid are added to the reaction mixture. The mixture is then stirred for about 1 hour at temperature of 10° to 25°C. The resultant suspension is centrifuged and the centrifuged material is then washed with 235.0 L of methyl-tertbutylether and subsequently with 353.5 L of water and finally with 235 L of ethanol. In this way, after drying, 92.5 kg (83.5% of theory) of 11cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6one (nevirapine) is isolated. 117.5 kg of 2-chloro-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide, 46.7 kg of calcium oxide and 47.5 kg of cyclopropylamine (molar ratio: 1:2:2) are heated to 135° to 145°C in 235 L of diglyme (diethylene glycol dimethylether) in a 500 L VA autoclave over a period of 6 to 8 hours. The reaction mixture is then cooled to a temperature of 20° to 30°C and filtered. The filter cake is washed with 58.8 L of diglyme. The filtrates are combined and about 188 L of solvent is distilled off. The residue is then diluted with a further 117.5 L of diglyme. Over a period of 20 to 40 minutes, the resultant diluted solution is added to a suspension of 45.0 kg of 60% sodium hydride in 352.5 L of diglyme, heated to 130°C. The storage vessel and conduits are rinsed with a further 55.8 L of diglyme and the mixture is stirred at a temperature of 130° to 140°C for a further 30 to 60 minutes. The majority of the diglyme is then distilled off. Finally, the remaining residue is carefully mixed with 470.0 L of water. The reaction mixture is cooled to a temperature of about 25°C and 235.0 L of cyclohexane and 57.1 L of glacial acetic acid are added. The mixture is then stirred for about 1 hour at a temperature of 10o to 25°C. The resultant suspension is centrifuged and the centrifuged material is washed with 235.0 L of methyl tert-butylether, followed by 353.5 L of water and finally with 235 L of ethanol. In this way, after drying, 90.6 kg (81.7% of theory) of 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido-[3,2-b:2',3'e][1,4]diazepin-6-one (nevirapine) is isolated. 287.2 kg of 2-chloro-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide, 57.0 kg of calcium oxide and 87.1 kg of cyclopropylamine (molar ratio: 1:1:1.5) are heated in 574 L of diglyme (diethylene glycol-dimethylether) to 135°-145°C for about 30 minutes in a 1200 L VA stirring apparatus. This produces a pressure of 1.2-1.5 bar and about 50% of the starting material is reacted. To this mixture, over about 30 minutes at 135°-145°C, a further 58.1 kg of cyclopropylamine is added producing a pressure of 3.0-3.5 bar, and another 25% of the starting material is reacted. The mixture is then kept at 135°-145°C for a period of 5 to 6 hours. The reaction mixture is then cooled to a temperature of 20° to 30°C and filtered. The filter cake is washed with 144 L of diglyme. The filtrates are combined and 400 L of solvent is distilled off. The residue is then diluted with a further 287 L of diglyme. Over 20-40 minutes, the resultant diluted solution is added to a suspension of 110 kg of 60% sodium hydride in 862 L of diglyme, heated to 130°C. The storage vessel and conduits are rinsed with a further 144 L of diglyme and the mixture is stirred at a temperature of 130° to 140°C for another 30 to 60 minutes. The majority of the diglyme is then distilled off. Finally, the remaining residue is carefully mixed with 1150 L of water. After the reaction mixture has been cooled to a temperature of about 25°C, 575 L of cyclohexane and 147 L of glacial acetic acid are added. The mixture is then stirred for about 1 hour at a temperature of 10°-25°C. The resultant suspension is centrifuged and the centrifuged material is then washed with 575 L of methyl-tert-butylether, followed by 862 L of water and finally with 575 L of ethanol. In this way, after

2422

Niacinamide

drying, 225 kg (83.0% of theory) of 11-cyclopropyl-5,11-dihydro-4-methyl6H-dipyrido[3,2-b :2',3'-e][1,4 ]diazepin-6-one (nevirapine) is obtained. References Schneider H. et al.; US Patent No. 5,559,760; Oct. 29, 1996; Assigned to Boehringer Ingelheim KG, Ingelheim am Rhein, Germany

NIACINAMIDE Therapeutic Function: Enzyme cofactor vitamin Chemical Name: 3-Pyridinecarboxylic acid amide Common Name: Aminicotin; Niacinamide; Nicosylamide; Nicotilamid(e); Nicotinamide; Nicotinsaureamid; Nikotinsaureamid; Vitamin B3; Vitamin PP; Vitaminum pellagrapraeventivum; Witamina PP Structural Formula:

Chemical Abstracts Registry No.: 98-92-0 Trade Name Niacinamide Niazcol Nicotinamide Vitamin B3

Manufacturer Twinlab Locatelli Endur-Amide TM, Innovite Inc. Twinlab

Country USA -

Year Introduced -

Vitamin B3

Biocare

-

-

Raw Materials Gaseous ammonia Anhydrous ethyl acetate

Nicotinic aci

Manufacturing Process Gaseous ammonia was passed into nicotinic acid at a temperature between 200-235°C until the conversion to nicotinamide was 85%. The reaction mixture was colored light brown. The reaction mass was cooled and grounds to a fine powder. Fifty grams of this crude nicotinamide were boiled with 500 ml of anhydrous ethyl acetate until a dark solution was. obtained. A little solid

Nialamide

2423

remained in suspension. Gaseous ammonia was passed in below the surface of the ethyl acetate at a temperature between 60-70°C. After a short time ammonium nicotinate started to precipitate out of solution as a brown solid. Sufficient gaseous ammonia, was passed into the ethyl acetate solution to insure complete precipitation of the nicotinic acids as ammonium nicotinate. The solution was filtered at about 60-70°C. The filter cake consisted of ammonium nicotinate, which, upon drying, weighed 12.4 grams. The filtrate was stirred arid boiled for 20 minutes with one-half gram of activated carbon and two grams of activated adsorbent clay. The mixture was filtered hot. The filtrate was boiled twenty minutes with one-half gram of activated carbon and two grams of activated adsorbent clay and then filtered hot. The carbon and clay treatment was repeated once more. The final filtrate was cooled slowly with stirring to room temperature to precipitate white crystalline nieocinamide which, upon drying, weighed 26.7 grams and had a melting point of 129.5°C, and was over 99 percent pure. The mother liquor from the above filtration was boiled down to one-third of its volume and cooled to room temperature. A second crop of nicotinamide of three grams was obtained. References Truchan E. et al.; US Patent No. 2,993,051; July 18, 1961; Assigned to Cowles Chemical Company, Cleveland, Ohio, a corporation of Ohio

NIALAMIDE Therapeutic Function: Antidepressant Chemical Name: 4-Pyridinecarboxylic acid 2-[3-oxo-3-[(phenylmethyl)amino]propyl]hydrazide Common Name: Structural Formula:

Chemical Abstracts Registry No.: 51-12-7 Trade Name Niamid Niamide Niamid Nuredal Surgex

Manufacturer Pfizer Pfizer Taito Pfizer EGYT Firma

Country US France Japan Hungary Italy

Year Introduced 1959 1960 -

2424

Niaprazine

Raw Materials Isoniazid Methyl acrylate Benzylamine Manufacturing Process Methyl acrylate, 28.0 g (0.4 mol) was added dropwise during one hour to a solution containing 54.8 g (0.4 mol) of isonicotinic acid hydrazide (isoniazid) and 10 ml of glacial acetic acid in 400 ml of tertiary butyl alcohol. The resulting solution then was heated for 18 hours on a steam bath. Concentration of the reaction mixture to 100 ml yielded 13.0 g of unreacted isonicotinic acid hydrazide. The filtrate was concentrated to a thick syrup which was triturated with anhydrous ether and recrystallized from isopropyl alcohol; MP 87°C to 88.5°C. Elemental analysis of the product gave 1isonicotinyl-2-(β-carbomethoxyethyl)hydrazine. A slurry of 7.5 g (0.034 mol) of 1-isonicotinyl-2-(carbomethoxyethyl)hydrazine and 5 ml of benzylamine is heated with stirring at 130°C for three hours. The cooled mass is then recrystallized from ethyl acetate to yield white needles melting at 151.1°C to 152.1°C. References Merck Index 6330 Kleeman & Engel p. 628 OCDS Vol. 1 p. 254 (1977) I.N. p. 667 Bloom, B.M. and Carnahan, R.E.; US Patent 2,894,972; July 14, 1959; assigned to Chas. Pfizer and Co., Inc.

NIAPRAZINE Therapeutic Function: Antihistaminic Chemical Name: 1-(4-Fluorophenyl)-4-[3-(3-pyridoyl)amino]butyl-piperazine Common Name: Structural Formula:

Niaprazine

2425

Chemical Abstracts Registry No.: 27367-90-4 Trade Name Nopron Norpron

Manufacturer Carrion Riom

Country France Italy

Year Introduced 1976 -

Raw Materials Trioxymethylene 1-(4-Fluorophenyl)piperazine dihydrochloride Acetone Hydroxylamine hydrochloride Nicotinic acid chloride Lithium aluminum hydride Manufacturing Process 1st Stage: 10 ml of concentrated (10 N) hydrochloric acid and 240 ml of acetone were added to a solution of 217.5 g (1 mol) of 1-(4fluorophenyl)piperazine dihydrochloride in 400 ml of 96% ethanol. 50 g of powdered trioxymethylene were then added and the mixture was then slowly heated to reflux, which was maintained for 1 hour. A further 60 g of trioxymethylene were then added and heating to reflux was continued for a further 6 hours. The mixture was then cooled, the precipitate formed was filtered off, washed with acetone and recrystallized from 96% ethanol. The base was liberated from its salt by taking up the product in an aqueous solution of sodium bicarbonate. The precipitate of the base thus obtained was recrystallized from petroleum ether to give 160 g of the desired product; melting point 46°C; yield 64%. 2nd Stage: 45.5 g (0.65 mol) of hydroxylamine hydrochloride were added to a solution of 128 g (0.5 mol) of the amino-ketone obtained in the preceding stage in 100 ml of ethanol and 40 ml of water. The mixture was allowed to react for 15 minutes at room temperature and was then heated to reflux for ½ hour. A part of the solvent was then distilled off and the product was then allowed to crystallize on cooling. After recrystallization from 96% ethanol, 117 g of the desired product were obtained; melting point 170°C; yield 77%. 3rd Stage: 93 g (0.35 mol) of the oxime obtained in the preceding stage, in the form of the base, were added in portions to a suspension of 17 g (0.45 mol) of lithium aluminum hydride in 400 ml of anhydrous ether. The mixture was then heated to reflux for 15 hours. 10 ml of ethyl acetate and then 50 ml of dilute caustic soda were added slowly with the usual precautions to the mixture. The organic phase was separated, dried over anhydrous Na2SO4, the solvent was distilled off and the residue obtained was distilled under reduced pressure to give 51 g of a thick oil; boiling point (2 mm Hg), 142°C to 143°C; yield 58%.

2426

Nicardipine

4th Stage: 10 ml of triethylamine were added in a solution of 25.2 g (0.1 mol) of the amine obtained in the preceding stage in 100 ml of anhydrous chloroform and the mixture was cooled to 2°C to 3°C. While maintaining this temperature, 17 g (0.12 mol) of nicotinic acid chloride were added with vigorous agitation. After evaporation of the solvent, the residue was washed with water, the product taking the form of a mass. After recrystallization from ethyl acetate, a constant melting point of 131°C was obtained. References Merck Index 6331 Kleeman & Engel p. 628 DOT 13 (1) 29 (1977) I.N. p. 667 Mauvernay, R.Y., Busch, N., Simond, J. and Moleyre, J.; US Patent 3,712,893; January 23, 1973; assigned to SA Centre Europeen De Recherches Mauvernay, CERM

NICARDIPINE Therapeutic Function: Vasodilator Chemical Name: 2,6-Dimethyl-4-(3-nitrophenyl)-3-methoxycarbonyl-1,4dihydropyridine-5-carboxylic acid-2(N-benzyl-N-methylamino)ethyl ester hydrochloride Common Name: Structural Formula:

Chemical Abstracts Registry No.: 55985-32-5 Trade Name Nicodel Perdipin

Manufacturer Mitsui Yamanouchi

Country Japan Japan

Year Introduced 1981 1981

Nicergoline

2427

Raw Materials Acetoacetic acid N-benzyl-N-methylaminoethyl ester β-Aminocrotonic acid methyl ester m-Nitrobenzaldehyde Manufacturing Process A mixture of 4.98 g of acetoacetic acid N-benzyl-N-methylaminoethyl ester, 2.3 g of β-aminocrotonic acid methyl ester, and 3 g of m-nitrobenzaldehyde was stirred for 6 hours at 100°C in an oil bath. The reaction mixture was subjected to a silica gel column chromatography (diameter 4 cm and height 25 cm) and then eluted with a 20:1 mixture of chloroform and acetone. The effluent containing the subject product was concentrated and checked by thin layer chromatography. The powdery product thus obtained was dissolved in acetone and after adjusting the solution with an ethanol solution saturated with hydrogen chloride to pH 1-2, the solution was concentrated to provide 2 g of 2,6-dimethyl-4-(3'-nitrophenyl)1,4-dihydropyridine-3,5-dicarboxylic acid 3-methylester-5-β-(N-benzyl-N-methylamino)ethyl ester hydrochloride. The product thus obtained was then crystallized from an acetone mixture, melting point 136°C to 140°C (decomposed). References Merck Index 6334 DFU 2 (6) 409 (1977) (as Yc-93) & 4 (12) 911 (1979) OCDS Vol. 3 p. 150 (1984) DOT 18 (7) 325 (1982) I.N. p. 668 Murakami, M., Takahashi, K., Iwanami, M., Fujimoto, M., Shibanuma, T., Kawai, R. and Takenaka, T.; US Patent 3,985,758; October 12, 1976; assigned to Yamanouchi Pharmaceutical Co., Ltd.

NICERGOLINE Therapeutic Function: Vasodilator Chemical Name: 10-Methoxy-1,6-dimethylergoline-8β-methanol 5bromonicotinate (ester) Common Name: Nicotergoline; 1-Methyllumilysergol-8-(5-bromonicotinate)10-methyl ether Chemical Abstracts Registry No.: 27848-84-6

2428

Nicergoline

Structural Formula:

Trade Name Sermion Sermion Nicergolyn Nicotergoline Varson Vasospan

Manufacturer Farmitalia Specia Farnex Carlo Erba Almirall Exa

Country Italy France Italy Italy Spain Argentina

Year Introduced 1974 1975 -

Raw Materials 1-Methyl-lumilysergic acid 5-Bromonicotinyl chloride Hydrogen chloride

Lithium aluminum hydride Methanol

Manufacturing Process Preparation of 1-Methyl Lumilysergic Acid 8-Methyl Ester-10-Methyl Ether: Into a suspension of 10 grams of 1-methyl-lumilysergic acid in 600 cc of absolute methanol a stream of anhydrous hydrogen chloride is bubbled for 1.5 hours with strong cooling. The stream of hydrogen chloride is stopped and the mixture is allowed to stand for 30 minutes at 0°C, and is evaporated in vacuo to dryness. The residue is taken up with ice-cooled water made alkaline with concentrated ammonia and extracted with chloroform. The combined chloroform extracts are washed first with a 5% aqueous solution of sodium bicarbonate, then with water, and are thereafter dried over anhydrous sodium sulfate and finally evaporated in vacuo to dryness. Preparation of 1-Methyl Lumilysergol-10-Methyl Ether: To a boiling suspension of 2 grams of lithium aluminum hydride in 50 cc of anhydrous tetrahydrofuran, a solution of 1 gram of 1-methyl lumilysergic acid-8-methyl ester-10-methyl ether in 20 cc of anhydrous tetrahydrofuran is added dropwise and the resulting solution is refluxed for a further 2 hours. After cooling the resulting solution, aqueous tetrahydrofuran is added to destroy the excess reducing agent and the solution is filtered. Tetrahydrofuran is distilled off and the residue is recrystallized from acetone petroleum ether. Preparation of Nicergoline: To a solution of 1-methyl lumilysergol-10-methyl ether in pyridine, 5-bromonicotinyl chloride is used as an acylating agent at

Niceritrol

2429

room temperature. The mixture is stirred for 1 hour. Water and methanol are added and the resulting mixture is stirred for 1 hour, extracted with chloroform, and washed in sequence with 1% aqueous caustic soda, 5% aqueous sodium bicarbonate solution, and water. The resulting solution is dried over anhydrous sodium sulfate and the solvent is distilled off. By recrystallization of the residue from acetone petroleum ether, nicergoline is obtained, melting at 136° to 138°C. References Merck Index 6335 Kleeman & Engel p. 629 OCDS Vol. 2 p. 478 (1980) DOT 10 (12) 342 (1974) I.N. p. 668 Bernardi, L., Bosisio, G. and Goffredo, O.; US Patent 3,228,943; January 11, 1966; assigned to Societa Farmaceutici Italia, Italy

NICERITROL Therapeutic Function: Antihyperlipidemic Chemical Name: 3-Pyridinecarboxylic acid 2,2-bis[[(3-pyridinylcarbonyl) oxy]methyl]-1,3-propanediyl ester Common Name: Pentaerythritol tetranicotinate Structural Formula:

Chemical Abstracts Registry No.: 5868-05-3 Trade Name

Manufacturer

Country

Year Introduced

Cardiolipol

Gremy-Longuet

France

1972

Perycit

Sanwa

Japan

1979

Perycit

Tosi

Italy

1980

Perycit

Astra

Sweden

-

2430

Niclosamide

Raw Materials Nicotinic acid chloride Pentaerythritol Pyridine Manufacturing Process 160 grams of nicotinic acid chloride is charged into and made to react with 35 grams of pentaerythritol dissolved in 600 grams of dried, stabilized chloroform and 100 grams of carefully dried pyridine. Pyridine hydrochloride, pyridine and the excess of nicotinic acid chloride are removed through repeated extraction with water at a pH of approximately 3. Pentaerythritol nicotinate remains in the chloroform phase and is extracted by forming the hydrochloric acid salt of the ester using 1,000 ml of aqueous HCl at a pH of 1. The strongly acid extract is thereafter extracted several times with toluene. The acid extract is allowed to stand at room temperature for several hours in the presence of active carbon and the substance known as Versenate, i.e., the disodium salt of ethylene diamine tetraacetic acid; it is then filtered and pentaerythritol nicotinate is precipitated as a white, amorphous substance using 25% w/v aqueous ammonia, while stirring. Recrystallization of the product from ethyl alcohol gives flaky crystals, according to British Patent 1,022,880. References Merck Index 6336 Kleeman & Engel p. 630 I.N. p. 668 AB Bofors, Sweden; British Patent 1,022,880; March 16, 1966 AB Bofors, Sweden; British Patent 1,053,689; January 4, 1967

NICLOSAMIDE Therapeutic Function: Anthelmintic Chemical Name: 2',5-Dichloro-4'-nitrosalicylanilide Common Name: Structural Formula:

Nicomol

2431

Chemical Abstracts Registry No.: 50-65-7 Trade Name Yomesan Yomesan Yomesan Tredemine Niclocide Anti-Tenia Atenase Radeverm Teniarene Tenisid

Manufacturer Bayer Bayer Bayer Roger Bellon Miles Uranium I.C.N.-Usafarma Arzneimittelwerk Dresden A.M.S.A. Liba

Country W. Germany UK Italy France US Turkey Brazil E. Germany Italy Turkey

Year Introduced 1960 1961 1962 1964 1982 -

Raw Materials 5-Chlorosalicylic acid 2-Chloro-4-nitroaniline Phosphorus trichloride Manufacturing Process 17.2 g of 5-chlorosalicylic acid and 20.8 g of 2-chloro-4-nitroaniline are dissolved in 250 ml of xylene. While boiling, there are introduced slowly 5 g of PCl3.Heating is continued for 3 further hours. The mixture is then allowed to cool down and the crystals which separate are filtered off with suction. The crude product may be recrystallized from ethanol, melting at 233°C. References Merck Index 6356 Kleeman & Engel p. 630 PDR p. 1260 OCDS Vol. 2 p. 94 (1980) I.N. p. 669 REM p. 1236 Schraufstatter, E. and Gonnert, R.; US Patent 3,147,300; September 1, 1964; assigned to Farbenfabriken Bayer A.G.

NICOMOL Therapeutic Function: Anticholesteremic Chemical Name: Cyclohexanol-2,2,6,6-tetrakis(hydroxymethyl) tetranicotinate Common Name: -

2432

Nicomol

Structural Formula:

Chemical Abstracts Registry No.: 27959-26-8 Trade Name Cholexamine Acenol

Manufacturer Kyorin Kissei Pharmaceutical Co., Ltd.

Country Japan Japan

Year Introduced 1971 1981

Nicolanta

Sawai

Japan

-

Raw Materials 2,2,6,6-Tetramethylolcyclohexanol Nicotinic acid chloride Manufacturing Process To a mixture of 60 cc of benzene, 40 cc of pyridine and 17 g of hydrochloric acid salt of nicotinic acid chloride, was added 4.5 g of 2,2,6,6tetramethylolcyclohexanol, and the whole mixture was refuxed at 75°C to 80°C for 2.5 hours. After the mixture was cooled water was added. Precipitate formed was separated by filtration, washed thoroughly with water and dried. Recrystallization from dilute acetic acid gave 14 g of the final compound, melting point 177°C to 180°C. References Merck Index 6360 DOT 7 (5) 173 (1971) I.N. p. 670 Irikura, T., Sato, S., Abe, Y. and Kasuga, K.; US Patent 3,299,077; January 17, 1967; assigned to Kyorin Seiyaku KK

Nicotine

2433

NICOTINE Therapeutic Function: Ganglion depressant, Smoking deterrent Chemical Name: Pyridine, 3-(1-methyl-2-pyrrolidinyl)-, (S)Common Name: Nicotine; Nikotin Structural Formula:

Chemical Abstracts Registry No.: 54-11-5 Trade Name

Manufacturer

Country

Year Introduced

Nicotinell TTS

Novartis

-

-

Habitrol

Ciba-Geigy

-

-

Habitrol

Novartis

-

-

Nicabate

HMR

-

-

Nicoderm CQ

SKB

-

-

Paro

Esro

-

-

Toban

Pharmacia

-

-

Nicorette

GlaxoSmithKline

-

-

Raw Materials Extract from Nicotiana tabacum Calcium hydroxide Calcium sulfate Manufacturing Process The water extract from Nicotiana tabacum was prepared by distillation of nicotine contained liquor from tobacco leaves, as described in D.R. Patent No. 319,846; September 12, 1913. 5 kg this water extract or the same quantity of tobacco powder in water was mixed with 1.5 kg of grinded calcium hydroxide and 1.5 kg calcium sulfate. The mixture stood for 24 hours. The obtained mixture looked like a dry powder. It was extracted with ether. The ether was distilled and the residue contented 98% of clear nicotine - liquid with odor of pyridine; BP: 246C/735 mm; d420 =1.0097; [α]d20=- 166.5.

2434

Nicotinyl alcohol

References Hovler H.F.; DR Patent No. 320,897; Dec. 25, 1913 Dictionary of Organic Compounds edited by I. Hielbron and H.M. Bunbury, v.3, p. 60, 1946; London

NICOTINYL ALCOHOL Therapeutic Function: Vasodilator Chemical Name: 3-Pyridinemethanol Common Name: 3-Pyridylcarbinol Structural Formula:

Chemical Abstracts Registry No.: 100-55-0 Trade Name Roniacol Danaden Peritard Ronicol Thilocombin

Manufacturer Roche Cascan Ikapharm Roche Thilo

Country US W. Germany Israel UK W. Germany

Year Introduced 1949 -

Raw Materials 3-Cyanopyridine Ethanol Hydrogen Nitrosyl chloride Manufacturing Process The catalyst is prepared by suspending 5 kg of catalyst grade charcoal in 200 liters of water, in a pressure vessel, and adding thereto 25 liters of 4% (as Pd metal) aqueous palladous chloride. Air is displaced from the vessel and then hydrogen is passed into the aqueous mixture at a pressure of 3 to 5 psi, while stirring, until no further absorption is noted and the chloride is completely reduced to metal. To the aqueous suspension of the palladized charcoal catalyst thus obtained are added 20.8 kg of 3-cyano-pyridine (96% purity); and then are added 70

Nicotinyl alcohol

2435

liters of a hydrochloric acid solution prepared by diluting 30 liters of 36% HCl with 40 liters of water. This represents approximately 1.75 mols of HCl for each mol of 3-cyano-pyridine. The suspension is maintained at 10° to 15°C and stirred continuously while introducing a current of hydrogen at a pressure of 3 to 5 psi. When absorption of hydrogen ceases and the 3-cyanopyridine is completely reduced, the reaction mixture is filtered to remove the catalyst. The filter cake is washed with 40 liters of water in two equal portions, and the wash water is added to the filtrate. The combined liquors, which comprise an aqueous hydrochloric acid solution of 3-aminomethyl-pyridine hydrochloride, are then heated to a temperature of 60° to 65°C, and ethyl nitrite gas is passed into the heated solution. The ethyl nitrite is generated by placing 20 liters of 90% ethyl alcohol in a suitable vessel, diluting with 200 liters of water, and, while stirring, adding to the dilute alcohol 18.3 kg of nitrosyl chloride at the rate of 2.25 kg per hour. (The process using methyl nitrite is carried out by substituting a stoichiometrically equivalent quantity of methyl alcohol for the ethyl alcohol.) When all the ethyl nitrite has been added, the reaction mixture is refluxed for approximately one hour, then concentrated to dryness under reduced pressure (25 to 30 mm Hg) and at a maximum temperature of 70°C. The crystalline residue is dissolved in 35 liters of water and adjusted to a pH of 8 to 9 by addition (with cooling and stirring) of 11 to 12 kg of caustic soda. The sodium chloride formed is filtered off, and the filter cake is washed with 20 liters of normal butyl alcohol. This wash liquid is used for the first extraction of the product from the aqueous filtrate. The filtrate is then further extracted with four successive 20-liter portions of n-butyl alcohol. All the extracts are combined and concentrated in vacuo (100°C/20 mm) to remove the n-butyl alcohol. The residue is submitted to fractionation under reduced pressure. The forerun (up to 112°C/2 to 3 mm) consists of a small amount of n-butyl alcohol and some 3-pyridylcarbinol. The main fraction, boiling at 112° to 114°C/2 to 3 mm, consists of 3-pyridylcarbinol. References Merck Index 6369 Kleeman & Engel p. 633 I.N. p. 672 REM p. 852 Ruzicka, L. and Prelog, V.; US Patent 2,509,171; May 23, 1950; assigned to Ciba Limited, Switzerland Cohen, A.; US Patent 2,520,037; August 22, 1950; assigned to Hoffmann-La Roche Inc. Schlapfer, R.; US Patent 2,547,048; April 3, 1951; assigned to Hoffmann-La Roche Inc. Chase, G.O.; US Patent 2,615,896; October 28, 1952; assigned to HoffmannLa Roche Inc.

2436

Nifedipine

NIFEDIPINE Therapeutic Function: Coronary vasodilator Chemical Name: 1,4-Dihydro-2,6-dimethyl-4-(2'-nitrophenyl)-3,5pyridinedicarboxylic acid dimethyl ester Common Name: Structural Formula:

Chemical Abstracts Registry No.: 21829-25-4 Trade Name Adalat Adalat Adalat Adalat Adalate Procardia Alfadat Anifed Atanal Citilat Coral Corinfar Nifedicor Nifedin Nifelat Oxcord

Manufacturer Bayer Bayer Bayer Bayer Bayer Pfizer Alfa Zoja Sawai C.T. Tosi Arzneimittelwerk Dresden Schiapparelli Gentili Sidus Biosintetica

Raw Materials 2-Nitrobenzaldehyde Acetoacetic acid methyl ester Ammonia

Country W. Germany Italy Japan UK France US Italy Italy Japan Italy Italy E. Germany

Year Introduced 1975 1976 1976 1977 1979 1982 -

Italy Italy Argentina Brazil

-

Niflumic acid

2437

Manufacturing Process 45 grams 2-nitrobenzaldehyde, 80 cc acetoacetic acid methyl ester, 75 cc methanol and 32 cc ammonia are heated under reflux for several hours, filtered off, cooled and, after suction-filtration, 75 grams of yellow crystals of MP 172° to 174°C are obtained, according to US Patent 3,485,847. References Merck Index 6374 DFU 6 (7) 427 (1981) Kleemen & Engel p. 633 PDR p. 1423 OCDS Vol. 2 p. 283 (1980) DOT 8 (11) 438 (1972); 11 (4) 154 (1975) & 19 (3) 171 (1983) I.N. p. 673 REM p. 862 Bossert, F. and Vater, W.; US Patent 3,485,847; December 23, 1969; assigned to Farbenfabriken Bayer AG, Germany Bossert, F. and Vater, W.; US Patent 3,488,359; January 6, 1970; assigned to Farbenfabriken Bayer AG, Germany Bossert, F. and Vater, W.; US Patent 3,511,837; May 12, 1970; assigned to Farbenfabriken Bayer AG, Germany

NIFLUMIC ACID Therapeutic Function: Antiinflammatory Chemical Name: 2-[[3-(Trifluoromethyl)phenyl]amino]-3-pyridinecarboxylic acid Common Name: 2-[3-(Trifluoromethyl)anilino]nicotinic acid Structural Formula:

Chemical Abstracts Registry No.: 4394-00-7 Trade Name Nifluril Actol Flaminon

Manufacturer U.P.S.A. Von Heyden Squibb

Country France W. Germany Italy

Year Introduced 1968 1971 1979

2438

Nifuratel

Trade Name Forenol Landruma Nifluran Niflux

Manufacturer Roemmers Landerlan Eczacibasi Labofarma

Country Argentina Spain Turkey Brazil

Year Introduced -

Raw Materials Nicotinic acid m-Trifluoromethylaniline Potassium iodide Manufacturing Process Niflumic acid is prepared as follows: Nicotinic acid, m-trifluoromethylaniline, and potassium iodide are intimately mixed and heated on an oil bath at 140°C. The mixture melts to give a dark red liquid. The temperature of the oil bath is allowed to fall to 100°C and is maintained at this temperature for an hour and a half. The mixture puffs up and forms a yellow crystalline mass. After cooling to ordinary temperature, this mass is ground up in a mortar and extracted several times with small volumes of ether to remove excess mtrifluoromethylaniline. The residue is then washed twice with 10 ml of distilled water to remove m-trifluoromethylaniline hydrochloride and potassium iodide, and finally twice with 10 ml of 95% alcohol to remove colored resinous contaminants. After drying at 100°C, 2-(m-trifluoromethylanilino)nicotinic acid is obtained as pale yellow needles (from 70% ethanol) melting at 204°C (Kofler block). References Merck Index 6377 Kleeman & Engel p. 634 OCDS Vol. 1 p. 256 (1977) DOT 4 (2) 82 (1968) I.N. p. 34 Hoffmann, C. and Faure, A.; US Patent 3,415,834; December 10, 1968; assigned to Societe anonyme dite: Laboratoires UPSA, France

NIFURATEL Therapeutic Function: Vaginal antiinfective Chemical Name: 5-[(Methylthio)methyl]-3-[[(5-nitro-2-furanyl)methylene] amino]-2-oxazolidinone Common Name: Methylmercadone Chemical Abstracts Registry No.: 4936-47-4

Nifuratel

2439

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Macmiror

Poli

Italy

1965

Inimur

Woelm

W. Germany

1969

Omnes

Fumouze

France

1971

Magmilor

Calmic

UK

-

Polmiror

Poli

Italy

-

Tydantil

Poli

Italy

-

Raw Materials Methyl mercaptan 5-Nitro-2-furaldehyde Diethyl carbonate

Hydrazine hydrate Epichlorohydrin

Manufacturing Process In an initial step of reactions, methyl mercaptan is reacted with epichlorohydrin to give 1chloro-3-methylthio-2-propanol. That is reacted with hydrazine hydrate to give 3-methylmercapto-2-hydroxypropyl hydrazine. 11.8 grams of diethyl carbonate (0.1 mols) and a solution of sodium methoxide prepared from 0.12 gram of sodium in 4 cc of anhydrous methanol, were added to 13.2 grams of 3-methylmercapto-2-hydroxypropyl hydrazine. After the reaction vessel had been fitted with a Liebig condenser, the reaction mixture was heated by means of an oil bath which was gradually heated up to 110°C, to remove first methyl alcohol and then ethyl alcohol formed during the reaction. After about two-thirds of the theoretical amount of ethyl alcohol had been distilled off, the heating was discontinued and the reaction mixture was diluted with 50 cc of ethyl alcohol and poured into a 5-nitro-2furfuraldehyde solution prepared by boiling for 30 minutes 0.1 mol of nitrofurfuraldehyde diacetate in 100 ml of ethyl alcohol and 50 ml of 1:10 sulfuric acid. A yellow crystalline precipitate was immediately formed, which, after crystallization from acetic acid, melted at 182°C and consisted of N-(5-nitro2-furfurylidene)-3-amino-5-methyl-mercaptomethyl-2-oxazolidinone. References Merck Index 6380 Kleeman & Engel p. 635

2440

Nifurfoline

I.N. p. 674 Polichimica Sap, SpA, Italy; British Patent 969,126; September 9, 1964

NIFURFOLINE Therapeutic Function: Antibacterial Chemical Name: 3-(4-Morpholinylmethyl)-1-[[(5-nitro-2-furanyl)-methylene] amino]-2,4-imidazolidinedione Common Name:Structural Formula:

Chemical Abstracts Registry No.: 3363-58-4 Trade Name Furobactil Urbac

Manufacturer Carrion Merck Clevenot

Country France France

Year Introduced 1974 -

Raw Materials Nitrofurantoin Formaldehyde Morpholine Manufacturing Process 20 g of nitrofurantoin are placed in 100 cc of dimethylformamide and the solution is heated to 75°C to 80°C. This temperature is maintained and 100 cc of 40% formaldehyde are added, followed by 10 g of freshly distilled morpholine. The heating is continued for one hour, the mixture cooled and filtered and the precipitate obtained is washed with 95% alcohol. 20 g of the desired product are obtained as yellow crystals which melt at 206°C.

Nifuroxazide

2441

References Merck Index 6381 I.N. p. 674 Laboratorios del Dr. Esteve S.A.; British Patent 1,245,095; September 2, 1971

NIFUROXAZIDE Therapeutic Function: Antiseptic Chemical Name: 4-Hydroxybenzoic acid [(5-nitro-2-furanyl)methylene]hydrazide Common Name: Structural Formula:

Chemical Abstracts Registry No.: 965-52-6 Trade Name Ercefuryl Pentofuryl Antinal Dicoferin Enterokod Mucifural

Manufacturer Carriere Karlspharma Roques Andrade Genekod Robert and Carriere

Raw Materials 4-Hydroxybenzhydrazide 5-Nitrofurfural

Country France W. Germany France Portugal France France

Year Introduced 1964 1978 -

2442

Nifurtoinol

Manufacturing Process 13 g (0.1 mol) of 4-hydroxybenzhydrazide were dissolved in a boiling mixture of 100 ml of water and an equal volume of dimethylformamide. 15.5 g (0.11 mol) of 5-nitrofurfural dissolved in 31 ml of dimethylformamide were added to this hot solution, and the mixture was stirred and brought to the boiling point. The mixture was then allowed to stand for fifteen hours. The precipitate was separated, washed twice with 100 ml of water, and recrystallized by dissolving it in 250 ml of hot pyridine and pouring this solution into 250 ml of water. The 5-nitrofurfurylidene hydrazide of 4-hydroxybenzoic acid obtained was washed with water and methanol and was dried at a moderate temperature. It weighed 23 g (83.7% yield), and melted at 298°C. The percentage nitrogen determined by the micro-Dumas method was 15.41% (theory 15.27%). References Merck Index 6383 Kleeman & Engel p. 636 I.N. p. 675 Carron, M.C.E.; US Patent 3,290,213; December 6, 1966; assigned to S.A. des Laboratoires Robert et Carriere (France)

NIFURTOINOL Therapeutic Function: Antibacterial Chemical Name: 3-(Hydroxymethyl)-1-[[(5-nitro-2-furanyl)methylene]amino]-2,4-imidazolidinedione Common Name: Structural Formula:

Chemical Abstracts Registry No.: 1088-92-2

Nifurzide Trade Name Urfadyne Urfadyn Urfadyne Levantin Urfurine

Manufacturer Zambon Arsac Inpharzam Lek Zambon

Country W. Germany France Switz. Yugoslavia Spain

2443

Year Introduced 1969 1976 1981 -

Raw Materials Nitrofurantoin Formaldehyde Manufacturing Process Three liters of 5% formaldehyde solution (2,625 cc water and 375 cc 40% formalin) containing 50 g of nitrofurantoin is refluxed for about 5 minutes, then filtered hot and cooled. The crystallized product is filtered and washed with 1% formaldehyde solution. It is air dried and then further dried at 65°C. There is obtained 33 g of 3-hydroxymethyl-1-(5-nitrofurfurylideneamino) hydantoin. References Merck Index 6388 I.N. p. 676 Michels, J.G.; US Patent 3,446,802; May 27, 1969; assigned to The Norwich Pharmacal Co.

NIFURZIDE Therapeutic Function: Antibacterial, Antidiarrheal Chemical Name: N1-[5'-Nitro-2'-thenoyl]-N2-[5''-nitro-2''-furylacrylidene] hydrazine Common Name: Chemical Abstracts Registry No.: 39978-42-2 Trade Name Ricridene Ricridene

Manufacturer Anphar Lipha

Country Switz. France

Raw Materials Hydrazine Ethanol

5-Nitrothiophene carboxylic acid 5-Nitro-2-furylacrolein

Year Introduced 1981 -

2444

Nifurzide

Structural Formula:

Manufacturing Process (a) Ethyl-5-nitro-2-thiophene carboxylate:

17.4 g (mol/10 = 17.31 g) of 5-nitrothiophene carboxylic acid are dissolved in 85 ml of absolute ethanol. A stream of gaseous hydrochloric acid is caused to enter the boiling solution to the point of saturation, and for 5 hours. Evaporation to dryness takes place and then the solid residue is washed with a sodium bicarbonate solution. It is suction-filtered and washed with water. After drying, there are obtained 17.7 g of a yellow product with a melting point of 63°C to 65°C and the yield is 88% (theoretical yield = 88%). The N'-(5'-nitro-2'-thenoyl)hydrazide is prepared by reacting hydrazine with ethyl 5-nitro-2-thiophene carboxylate. (b) 6.3 g (mol/30 = 6.5 g) of N1-[5'-nitro-2'-thenoyl]hydrazide are dissolved in 100 ml of dry tetrahydrofuran. 5.6 g (mol/30 = 5.55 g) of 5-nitro-2-furyl acrolein in 56 ml of tetrahydrofuran are added. Heating under reflux takes place for 1 hour and, 25 minutes after starting the heating, the crystallization commences; the crystals are suction-filtered, washed with ether and dried. There are obtained 7.9 g (yield 70%-theoretical yield = 11.2 g) of a yellow solid of melting point 235°C to 236°C. Recrystallization (tepid dimethylformamide + ether) leaves the melting point unchanged. References Merck Index 6389 DFU 6 (6) 358 (1981) Kleeman & Engel p. 637

Nilutamide

2445

DOT 17 (7) 288 (1981) Szarvasi, E. and Fontaine, L.; US Patents 3,847,911; November 12, 1974; and 3,914,379; October 21, 1975; both assigned to Lipha, Lyonnaise Industrielle Pharmaceutique

NILUTAMIDE Therapeutic Function: Antiandrogen Chemical Name: 2,4-Imidazolidinedione, 5,5-dimethyl-3-(4-nitro-3(trifluoromethyl)phenyl)Common Name: Nilutamide Structural Formula:

Chemical Abstracts Registry No.: 63612-50-0 Trade Name Anandron Anandron Nilandron Nilutamide

Manufacturer Laboratoires Cassene Hoechst Marion Roussel Aventis Pharmaceuticals Triquim S.A.

Country France Germany France Argentina

Year Introduced -

Raw Materials Phenyl oxide Copper oxide 5,5-Diphenylhydantoin Dimethyl sulfoxide 2-Nitro-5-chloro-trifluoromethylbenzene Manufacturing Process There are at least five methods to prepare desired compound. 1. 1-(3'-Trifluoromethyl-4'-nitropheyl)-4,4-dimethyl-imidazoline-2,5-dione The following were introduced into 383.52 ml of phenyl oxide: 225.60 grams of 2-nitro-5-chloro-trifluoromethylbenzene, described in the German Patent

2446

Nilutamide

No. DRP 637,318, 128.10 grams of 5,5-dimethylhydantoin described in Beil., Vol. 24, 289 and 198.53 grams of cuprous oxide. The mixture was heated to 200°C for 24 hours, then cooled to 20°C and filtered. The residue was rinsed with phenyl oxide, then extracted with ethyl acetate. The ethyl acetate phase was concentrated to dryness under reduced pressure at 60°C and the residue was taken up in ammoniacal dichloroethane. The crystals obtained were dried at 60°C to obtain 66.55 grams of crude product which, after purification from aqueous ethanol yielded 62.55 grams of purified desired product. 2. 1-(3'-Trifluoromethyl-4'nitrophenyl)-4,4-dimethyl-imidazoline-2,5-dione The following were introduced into 282 ml of triglyme: 112.8 grams of 2nitro-5-chloro-trifluoromethylbenzene, 64.1 grams of 5,5-dimethyl-hydantoin and 33.5 grams of cuprous oxide. The mixture was heated to about 215°C ± 5°C for 4 hours, then cooled to 20°C and filtered. The triglyme solution was recovered and a 22 Be ammonia solution (1 volume), toluene (1 volume) and demineralized water (4 volume) were added to the solution of triglyme (1 volume). The solution was stirred at 20°C for 15 minutes, then cooled to about -10°C and stirred again at -10°C. After washing and drying, 47.6 grams of the desired product were obtained. 3. 1-(3'-Trifluoromethyl-4'-nitrophenyl)-4,4-dimethyl-imidazoline-2,5-dione 30 ml of dimethylsulfoxide and 24.8 grams of 2-nitro-5-chloro trifluoromethylbenzene were introduced at 20°C with stirring into 100 ml of dimethylsulfoxide, 12.80 grams of 5,5-dimethyl-hydantoin and 6.28 grams of potassium hydroxide in the form of flakes. The mixture was heated to 110°C for a period of time variable between 3 and 18 hours. The product was characterized and determined by thin layer chromatography. 4. 1-(3'-Trifluoromethyl-4'-nitrophenyl)-4,4-dimethyl-imidazoline-2,5-dione 71.5 grams of copper in powder form were added to 96.10 grams of 5,5dimethyl-hydantoin and 170.86 grams of 2-nitro-5-chloro trifluoromethylbenzene. The mixture was heated to 200°C for about 21 hours, the pressure being maintained at 450 millibars, then, was cooled to 20°C and taken up in 480 ml of ethanol. The product was characterized and determined by thin layer chromatography of the ethanol solution. 5. 1-(3'-Trifluoromethyl-4'-nitrophenyl)4,4-dimethyl-imidazoline-2,5-dione The following were introduced into 288 ml of phenyl oxide: 96.10 grams of 5,5-dimethyl-hydantoin, 170.86 grams of 2-nitro-5-chloro trifluoromethylbenzene and 89.40 grams of cupric oxide. The mixture was heated to 190°C for about 23 hours, then cooled to 20°C and filtered. The residue was characterized in the phenyl oxide filtrate by thin layer chromatography. The analytical results obtained for these 5 examples were identical to those obtained and indicated in French Patent No. 2,329,276. References Seuron P. et.al.; US Patent No. 5,166,358; Nov. 24, 1992; Assigned to Rousel Uclaf, Paris, France

Nilvadipine

2447

NILVADIPINE Therapeutic Function: Calcium entry blocker, Antihypertensive Chemical Name: 2-Cyano-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5pyridinedicarboxylic acid 3-methyl- 5-(1-methyl ethyl) ester Common Name: Nivadipine, Niprodipine Structural Formula:

Chemical Abstracts Registry No.: 75530-68-6 Trade Name Nilvadipine Tensan

Manufacturer Fujisawa Klinge

Country -

Year Introduced -

Raw Materials Isopropyl ester of 6-formyl-5-methoxycarbonyl-2-methyl-4-(3nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid Hydroxylamine hydrochloride Sodium acetate Acetic anhydride Manufacturing Process To a solution of isopropyl ester of 6-formyl-5-methoxycarbonyl-2-methyl-4-(3nitrophenyl)-1,4-dihydropyridine- 3-carboxylic acid (4.5 g) in acetic acid (35 ml) were added hydroxylamine hydrochloride (0.97 g) and sodium acetate (1.43 g), and the mixture was stirred at ambient temperature for 2.5 hours. After acetic anhydride (4.14 g) was added to this reaction mixture, the mixture was stirred at ambient temperature for 1.5 hours and at 95-100°C for additional 4 hours. The acetic acid and the excess of acetic anhydride were removed in vacuum, followed by adding water to the residue and it was neutralized with a saturated aqueous solution of sodium bicarbonate. This aqueous suspension was extracted twice with ethyl acetate, and the combined extract was washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure to give a reddish-brown oil (4.88 g), which was chromatographed over silica gel (150 g) with a mixture of

2448

Nimetazepam

benzene and ethyl acetate (10:1 by volume) as an eluent to give a crude crystals (2.99 g). These were recrystallized from ethanol to give yellow prisms (1.89 g) of isopropyl ester of 6-cyano-5-methoxycarbonyl-2-methyl-4-(3nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid melting point 148-150°C (yellow prisms from ethanol); [α]D20 = 222.4° (c = 1 in methanol). References Sato Yoshinari; US Patent No. 4,338,322; July 6, 1982; Assigned to Fujisawa Pharmaceutical Co., Ltd. (Osaka, JP)

NIMETAZEPAM Therapeutic Function: Tranquilizer Chemical Name: 1,3-Dihydro-1-methyl-7-nitro-5-phenyl-2H-1,4benzodiazepin-2-one Common Name:Structural Formula:

Chemical Abstracts Registry No.: 2011-67-8 Trade Name Erimin

Manufacturer Sumitomo

Country Japan

Year Introduced 1977

Raw Materials Hydrogen chloride Chromic anhydride

1-Methyl-5-nitro-3-phenylindole-2-carbonitrile Boron trifluoride etherate

Manufacturing Process To a suspension of 73.9 g of 1-methyl-5-nitro-3-phenylindole-2-carbonitrile in 1.5 liters of dry tetrahydrofuran is added dropwise a solution of 126 g of boron trifluoride etherate in 220 ml of dry tetrahydrofuran with stirring for 2 hours. After addition, stirring is continued for an additional 3 hours. To the

Nimodipine

2449

reaction mixture is added dropwise 370 ml of water and then 370 ml of concentrated hydrochloric acid with stirring under ice-cooling. The resulting precipitate is collected by filtration, washed with water followed by ethanol, and dried to give 56.3 g of crude 2-aminomethyl-1-methyl-5nitro-3-phenylindole hydrochloride, melting point 263°C to 267°C. To a suspension of 6.5 g of 2-aminomethyl-1-methyl-5-nitro-3-phenylindole in 65 ml of glacial acetic acid is added dropwise a solution of 6.5 g of chromic anhydride in 6.5 ml of water at 20°C with stirring. The mixture is stirred at room temperature overnight and thereto is added 195 ml of water. To the mixture is added dropwise 100 ml of 28% ammonia water with stirring under cooling. The resultant precipitate is collected by filtration, washed with water and dried to give 5.9 g of a crude product having melting point 135°C to 140°C. Fractional recrystallization from ethanol gives 3.8 g of 1-methyl-7nitro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2-one as yellow plates, melting point 153°C to 156°C. Further recrystallization from the same solvent gives pale yellow plates having melting point 156°C to 156.5°C. References Merck Index 6395 Kleeman & Engel p. 637 DOT 8 (9) 350 (1972); 11 (5) 195 (1975) & 13 (1) 31 (1977) I.N. p. 676 Yamamoto, H., Inaba, S., Okamoto, T., Hironashi, T., Ishizumi, K., Yamamoto, M., Maruyama, I., Mori, K. and Kobayashi, T.; US Patents 3,770,767; November 6, 1973; and 3,652,551; March 28, 1972; both assigned to Sumitomo Chemical Co.

NIMODIPINE Therapeutic Function: Vasodilator Chemical Name: 3,5-Pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-4(3-nitrophenyl)-, 2-methoxyethyl 1-methylethyl ester Common Name: Nimodipine Structural Formula:

2450

Nimorazole

Chemical Abstracts Registry No.: 66085-59-4 Trade Name Brainox Curban Grifonmod Modina Modus Myodipine Nemotan Nimotop Nimotop Nimodipine Norton Regental Sobrepina Trinalion Tropocer Vasotop Ziremex Nimocer

Manufacturer Euro-Labor. Rafarm Laboratorio Chile S.A. Pentafarma Berenguer Help Medochemie Ltd. Bayer AG Miles Bayer AG Farmasa Tecnofarma S.A. Farmoz Tecnimede Laboratorios Leti Cipla Limited Demo Synapse (A Div. of Microlabs)

Country Greece Chile Chile Greece Cyprus Germany Germany Brazil Chile Portugal Portugal Venezuela India India

Year Introduced -

Raw Materials 3'-Nitro-benzylideneacetoacetic acid isopropylester Acetoacetic acid β-metoxyethyl ester Ammonium hydroxide Manufacturing Process After 8 hours boiling of solution of 3.8 g of 3'-nitro-benzylideneacetoacetic acid isopropylester, 8 grams of acetoacetic acid β-metoxyethyl ester and 6 ml conc ammonia in 80 ml ethanol under reflux, 2,6-dimethyl-4-(3'-nitrophenyl)1,4-dihydropyridine 3-β-methoxyethyl ester 5-isopropyl ester of melting point 125°C (petroleum ether/ acetic ester) was obtained. Yield 49% of theory. References Meyer H. et al.; US Patent No. 3,799,934; March 26, 1974; Assigned to Farbenfabriken Bayer Aktiengesellschaft, Leverkusen, Germany Meyer H. et al.; US Patent No. 4,406,906; Sep. 27, 1983; Assigned to Bayer Aktiengesellschaft, Leverkusen, Fed. Rep. of Germany

NIMORAZOLE Therapeutic Function: Trichomonacidal

Nimorazole

2451

Chemical Name: N-β-Ethylmorpholino-(5)-nitroimidazole Common Name: Nitrimidazine Structural Formula:

Chemical Abstracts Registry No.: 6506-37-2 Trade Name Naxogin Naxogin Esclama Aceterol Forte Naxofem Nulogyl Sirledi

Manufacturer Carlo Erba Carlo Erba Farmitalia Bristol-Myers Ikapharm Bristol Causyth

Country UK Italy W. Germany W. Germany Israel UK Italy

Year Introduced 1970 1972 1973 1973 -

Raw Materials Ethylene oxide β-Chloroethyl morpholine Morpholine p-Toluenesulfonyl chloride 4(5)-Nitroimidazole sodium salt Manufacturing Process 6 g 4(5)-nitroimidazole sodium salt and 9 g β-chloroethylmorpholine are allowed to react in 200 ml dry toluene. The mixture is refluxed for 50 hours, then cooled and filtered from the solid residue. The solvent is evaporated under reduced pressure. The half-solid product thus obtained solidifies by addition of petroleum ether and ethyl ether. Crystallization from water results in N-β-ethylmorpholino-(5)-nitroimidazole (melting point 110°C to 111°C); from mother liquors N-β-ethylmorpholino(4)-nitroimidazole (melting point 104°C to 106°C) is obtained. The following procedure is given in US Patent 3,458,528: 78 grams (0.675 mol) of 5-nitroimidazole is dissolved in 1,500 ml of acetic acid upon the addition of 72 ml (0.57 mol) of boron trifluoride etherate. 175 ml (3.5 mols) of ethylene oxide in 175 ml of hexane, in a dropping funnel topped with a cold

2452

Nimustine

finger, is added slowly over 1 hour to the above solution maintained at 32° to 35°C with a water cooling bath. The mixture is concentrated under high vacuum to 100 to 150 ml volume. The residue is diluted with 500 ml of water, neutralized to pH 7 with aqueous sodium hydroxide, and extracted with 1.5 liters of ethyl acetate. The extract is dried and evaporated to yield 1-(2'hydroxyethyl)-5-nitroimidazole. 20 grams (0.127 mols) of 1-(2'-hydroxyethyl)-5-nitroimidazole in 50 ml of dry pyridine is reacted with 75 grams of p-toluenesulfonyl chloride at 15°C for 4 hours. The reaction mixture is poured into ice and water and the crystalline precipitate is separated by filtration, washed with water and air dried to yield 1-(2'-p-toluenesulfonyloxyethyl)-5-nitroimidazole; MP 126° to 127°C. 16 grams, (0.057 mol) of 1-(2'-p-toluenesulfonyloxyethyl)-5-nitroimidazole and 9.3 ml of morpholine are heated at 95°C for 4 hours. The reaction mixture is taken up in water and extracted with ether. Evaporation of the ether yields 1-(2'-N-morpholinylethyl)-5-nitroimidazole; MP 109° to 110°C. References Merck Index 6398 Kleeman & Engel p. 638 OCDS Vol. 2 p. 244 (1980) DOT 6 (5) 185 (1970) & 7 (5) 193 (1971) I.N. p.677 Giraldi, P.N. and Mariotti, V.; US Patent 3,399,193; August 27, 1968; assigned to Carlo Erba SpA, Italy Gal, G.; US Patent 3,458,528; July 29, 1969; assigned to Merck & Co., Inc. Carlson, J.A., Hoff, D.R. and Rooney, C.S.; US Patent 3,646,027; February 29, 1972; assigned to Merck & Co., Inc.

NIMUSTINE Therapeutic Function: Antitumor, Antileukemic Chemical Name: 1-(2-Chloroethyl)-1-nitroso-3-[(2-methyl-4-aminopyrimidin5-yl)-methyl]urea Common Name: ACNU Structural Formula:

Nisoldipine

2453

Chemical Abstracts Registry No.: 42471-28-3 Trade Name Nidran

Manufacturer Sankyo

Country Japan

Year Introduced 1979

Raw Materials 1-(2-Chloroethyl)-3-[(2-methyl-4-aminopyridin-5-yl)methyl]urea Sodium nitrite Hydrogen chloride Manufacturing Process 0.4 g of sodium nitrite was added with stirring, at 0°C to 5°C, to a solution of 450 mg of 1-(2-chloroethyl)-3-[(2-methyl-4-aminopyridin-5-yl)methyl]urea in 8 ml of 5% hydrochloric acid, and the reaction mixture was then stirred at 0°C to 10°C for an additional 1.5 hours. After completion of the reaction, the reaction mixture was made alkaline by the addition of sodium carbonate, whereupon crystals separated out in situ. The crystals were recovered by filtration, washed with water and then recrystallized from 6 ml of ethanol, to give 0.1 g of the pale yellow pure desired product having a decomposition point of 125°C. References Merck Index 6399 DFU 3 (1) 52 (1978) Kleeman & Engel p. 639 DOT 16 (12) 426 (1980) I.N. p. 677 Sankyo Co., Ltd.; British Patent 1,374,344; November 20, 1974 Nakao, H., Arakawa, M. and Fukushima, M.; US Patent 4,003,901; January 18, 1977; assigned to Sankyo Co., Ltd.

NISOLDIPINE Therapeutic Function: Coronary vasodilator Chemical Name: 3,5-Pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-4(2-nitrophenyl)-, methyl 2-methylpropyl ester Common Name: Nisoldipine Chemical Abstracts Registry No.: 63675-72-9

2454

Nitazoxanide

Structural Formula:

Trade Name Baymycard Corasol Nisoldipine Norvasc Sular Syscor Zadipina

Manufacturer Bayer Vital Sanitas Pharmax Miles AstraZeneca AstraZeneca SmithKline Beecham

Country Germany Chile -

Year Introduced -

Raw Materials 2'-Nitrobenzylideneacetoacetic acid methyl ester β-Aminocrotonic acid isopropyl ester Manufacturing Process Boiling a solution of 12.7 g of 2'-nitrobenzylideneacetoacetic acid methyl ester and 7.1 g of β-amino-crotonic acid isopropyl ester in 50 ml of methanol for 10 hours yielded 2,6-dimethyl-4-(2'-nitrophenyl)-1,4-dihydropyridine-3,5dicarboxylic acid 3-methyl ester-5-isopropyl ester of melting point 174°C (from ethanol). Yield 48% of theory. References Meyer H. et al.; US Patent No. 3,932,645; Jan. 13, 1976; Assigned to Farbenfabriken Bayer A G, Germany Kutsuma T. et al.; US Patent No. 4,672,068; Jun. 9, 1987; Assigned to Fujirebio Kabushiki Kaisha, Tokyo, Japan

NITAZOXANIDE Therapeutic Function: Anthelmintic Chemical Name: 2-[(5-Nitro-2-thiazolyl)carbamoyl]phenyl acetate

Nitrazepam

2455

Common Name: Nitazoxanide Structural Formula:

Chemical Abstracts Registry No.: 55981-09-4 Trade Name Alinia Cryptaz Nitazoxanide NTZ NTZ

Manufacturer Romark Laboratories, L.C. Unimed Pharmaceuticals, Inc. Romark Laboratories Romark Laboratories Unimed Pharmaceuticals, Inc.

Country USA USA USA USA

Year Introduced -

Raw Materials p-Metoxy-benzoyl chloride 2-Amino-5-nitrothiazole Triethylamine Manufacturing Process To a solution containing one mole p-metoxy-benzoyl chloride and one mole of carefully purified 2-amino-5-nitro-triazole in 200 ml of anhydrous tetrahydrofuran, one mole of triethylamine has been slowly added (about 10 minutes) while stirring. The reaction mixture, which became slightly warm, was stirred during 45 minutes and then poured under agitation, into 2 liters of distilled water. The stirring was continued until the precipitation of salicylamide, N-(5-nitro-2-thiazolyl)-, acetate (ester) was complete. The obtained precipitate was dried, washed with water, dried again and recrystallized from methanol. The yield about 60%; melting point 202°C. References Rossignol J.-F. et al.; US Patent No. 3,950,351; Apr. 13, 1976; Assigned to S.P.R.L. Phavic, Mouscron, Belgium Rossignol J.-F.; US Patent No. 5,578,621; Nov. 26, 1996

NITRAZEPAM Therapeutic Function: Anticonvulsant, Hypnotic

2456

Nitrazepam

Chemical Name: 1,3-Dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one Common Name: Structural Formula:

Chemical Abstracts Registry No.: 146-22-5 Trade Name Mogadan Mogadon Mogadon Mogadon Apodorm Arem Atempol Benzalin Cerson Dormicum Dormo-Puren Dumolid Eatan-N Hipsal Hypnotin Imadorm Imeson Insomin Ipersed Ipnozem Lagazepam Lyladorm Mitidin Nelbon Nelmat Neuchlonic Nitrados Nitrempax Noctem Noctene Numbon

Manufacturer Roche Roche Roche Roche A.L. Lennon Norgine Shionogi Belupo Ltd. Glebe Klinge Dumex Desitin Salvat Protea Scheurich Desitin Orion Sidus Biofarma Lagap M.P.S. Labs Savoma Sankyo Sawai Taiyo Berk Lafi Alfa Farm. Rio Ethicals Ikapharm

Country W. Germany France UK Italy Norway S. Africa UK Japan Yugoslavia Australia W. Germany Denmark W. Germany Spain S. Africa W. Germany W. Germany Finland Italy Turkey Switz. S. Africa Italy Japan Japan Japan UK Brazil Italy S. Africa Israel

Year Introduced 1965 1965 1965 1967 -

Nitrazepam Trade Name Ormodon Pacisyn Paxisyn Pelson Persopir Prosonno Quill Relact Remnos Rindepres Somitran Somnased Somnite Sonnolin Surem Tri Unisomnia

Manufacturer Ormed Medica Syntetic Infale Ion Von Boch Ellea Lemonier D.D.S.A. Disprovent Farmos Duncan Flockhart Norgine Dima Galen Vita Unigreg

Country S. Africa Finland Denmark Spain Italy Italy Italy Argentina UK Argentina Finland UK UK Italy UK Italy UK

2457

Year Introduced -

Raw Materials 2-Aminobenzophenone Glycine ethyl ester hydrochloride Nitric acid Manufacturing Process A mixture of 16.8 g of 2 -aminobenzophenone, 11.9 g of glycine ethyl ester hydrochloride and 200 cc of pyridine was heated to reflux. After one hour, 20 cc of pyridine was distilled off. The solution was refluxed for 15 hours, then 11.9 g of glycine ethyl ester hydrochloride was added and the refluxing was continued for an additional 4 hours. The reaction mixture was continued for an additional 4 hours. The reaction mixture was concentrated in vacuo, then diluted with ether and water. The reaction product, 5-phenyl-3H-1,4benzodiazepin-2(1H)-one, crystallized out, was filtered off, and then recrystallized from acetone in the form of colorless rhombic prisms, MP 182°C to 183°C. 48 g (0.2 mol) of 5-phenyl-3H-1 ,4-benzodiazepin-2(1 H)-one was dissolved in 250 cc of concentrated sulfuric acid by stirring at 15°C for ½ hour. The solution was then cooled to 0°C and a mixture of 9.1 cc of fuming nitric acid (90%, sp. gr. = 1.50) and 11.8 cc of concentrated sulfuric acid was added dropwise with stirring, keeping the temperature of the reaction mixture between -5°C and 0°C. After completion of the addition of the nitric acidsulfuric acid mixture, stirring was continued for 1 hour and the reaction mixture was stored in the refrigerator overnight. The mixture was then added dropwise to 2 kg of crushed ice with stirring and cooling, keeping the temperature at 0°C. After 1 hour of stirring in the cold, 640 cc of concentrated ammonium hydroxide was added dropwise at 0°C to pH 8. Stirring was continued for ½ hour and the crude product was filtered

2458

Nitrofurantoin

off, washed with a small amount of ice water and sucked dry overnight. The crude product was suspended in a mixture of 100 cc of methylene chloride and 1,700 cc of alcohol. 50 g of decolorizing charcoal was added and the mixture was refluxed with stirring for 2 hours. After standing overnight at room temperature 15 g of diatomaceous earth filter aid was added and the refluxing was resumed for 1½ hours. The mixture was filtered while hot. The clear, light yellow filtrate was concentrated in vacuo on the steam bath with stirring to about 600 cc. The concentrate was stirred and cooled in ice for about 2 hours; the precipitated crystalline product was filtered off, washed with some petroleum ether and sucked dry. The product, 7-nitro-5-phenyl-3H1,4-benzodiazepin-2(1H)-one, was recrystallized from a mixture of 1,000 cc of alcohol and 50 cc of methylene chloride to obtain white prisms melting at 224°C to 225°C. References Merck Index 6418 Kleeman & Engel p. 640 OCDS Vol. 1 p. 366 (1977) DOT 1 (4) 132 (1965) & 9 (6) 237 (1973) I.N. p. 678 REM p. 1064 Kariss, J. and Newmark, H.L.; US Patent 3,116,203; December 31, 1963; assigned to Hoffmann-LaRoche, Inc.

NITROFURANTOIN Therapeutic Function: Antibacterial (urinary) Chemical Name: 1-[[(5-Nitro-2-furanyl)methylene]amino]-2,4imidazolidinedione Common Name: N-(5-Nitro-2-furfurylidene)-1-aminohydantoin Structural Formula:

Nitrofurantoin

2459

Chemical Abstracts Registry No.: 67-20-9 Trade Name Furadantin Furadoine Trantoin Cyantin Furachel N-Toin Parfuran Alfuran Berkfurin Ceduran Chemiofuran Chemiofurin Cistofuran Cystit Dantafur Fua Med Furadoine Furalan Furaloid Furanex Furanite Furantoin Furatin Furedan Furil Furobactina Furophen Gerofuran Ituran Macrodantin Microdoine Micturol Nephronex Nierofu Nifuran Nifurantin Nitrofur C Novofuran Phenurin Profura Trantoin Trocurine Urantoin

Manufacturer Norwich Eaton Oberval McKesson Lederle Rachelle Upjohn Warner Lambert Alkaloid Berk Cedona Italfarmaco Torlan Crosara Heyden Norwich Eaton Med Oberval Lannett Edwards Elliott-Marion Saunders Spofa Hemofarm Scharper Off Esteve Pharbil Gerot Promonta Eaton Gomenol Liade Cortunon Hoyer Paul Maney Apogepha Leiras Novopharm Merckle Rachelle McKesson Labatec D.D.S.A.

Country US France US US US US US Yugoslavia UK Netherlands Italy Spain Italy W. Germany US W. Germany France US US Canada Canada Czechoslovakia Yugoslavia Italy Italy Spain Netherlands Austria W. Germany US France Spain Canada W. Germany Canada E. Germany Finland Canada W. Germany US US Switz. UK

Year Introduced 1953 1954 1969 1970 1970 1971 1974 -

2460

Nitrofurantoin

Trade Name Uretoin Urodil Urodin Urofuran Urolisa Urolong Uro-Tablinen Uvamin

Manufacturer Tokyo Tanabe Pharma-Selz Streuli Farmos Lisapharma Thiemann Sanorania Mepha

Country Japan W. Germany Switz. Finland Italy W. Germany W. Germany Switz.

Year Introduced -

Raw Materials n-Heptaldehyde 1-Aminohydantoin 5-Nitro-2-furaldoxime Manufacturing Process To a solution of 18.9 grams (0.166 mol) n-heptaldehyde in 25 ml of isopropanol is added, with stirring, a solution of 19.1 grams (0.166 mol) of 1aminohydantoin in 110 ml water acidified with concentrated HCl. The heavy white precipitate formed is filtered and washed, until acid free, with small amounts of water and ether. The yield of N-(n-heptylidene)-1-aminohydantoin is 14 grams of MP 150°C (with decomposition). This may be recrystallized from dimethylformamide. A mixture of 2.5 grams (0.016 mol) of 5-nitro-2-furaldoxime, 3.9 grams (0.018 mol) of N-(n-heptylidene)-1-aminohydantoin and 5 cc of sulfuric acid (density 1.84) is placed in a 250 cc beaker. It is heated with stirring at steam bath temperature for about 1.5 hours. Upon cooling, a solid precipitates which is collected by filtration, washed with water, isopropanol and ether in turn and dried at 110°C for 4 hours. There is obtained N-(5-nitro-2-furfurylidene)-1aminohydantoin in 96 to 98% yield, according to US Patent 2,927,110. References Merck Index 6445 Kleeman & Engel p. 641 PDR pp. 1278, 1606 OCDS Vol. 1 p. 230 (1977) I.N. p. 680 REM p. 1215 Hayes, K.J.; US Patent 2,610,181; September 9, 1952; assigned to Eaton Laboratories, Inc. Michels, J.G.; US Patent 2,898,335; August 4, 1959; assigned to The Norwich Pharmacal Company Gever, G. and O'Keefe, C.; US Patent 2,927,110; March 1, 1960; assigned to The Norwich Pharmacal Company

Nitrofurazone

2461

NITROFURAZONE Therapeutic Function: Topical antiinfective Chemical Name: 2-[(5-Nitro-2-furanyl)methylene]hydrazinecarboxamide Common Name: Nitrofural Structural Formula:

Chemical Abstracts Registry No.: 59-87-0 Trade Name Furacin Actin-N Amifur Escofuron Furesol Germex Monofuracin Muldacin Nifucin Nifuzon Nitrozone Yatrocin

Manufacturer Norwich Eaton Chesebrough-Pond Norwich Eaton Streuli A.F.I. Lennon Dainippon Mulda Jenapharm Pharmacia Century Italfarmaco

Country US US US Switz. Norway S. Africa Japan Turkey E. Germany Sweden US Italy

Year Introduced 1946 1981 -

Raw Materials Semicarbazide hydrochloride 2-Formyl-5-nitrofuran Manufacturing Process A mixture of 43 grams of semicarbazide hydrochloride and 31 grams of sodium acetate is dissolved in 150 cc of water. The pH of this solution is approximately 5. Ethyl alcohol (95% by volume) in the amount of 250 cc is added and the mixture is stirred mechanically. A solution of 53.5 grams of carefully purified 2-formyl-5-nitrofuran in 250 cc of the said alcohol is added dropwise to the semicarbazide solution at room temperature. After completing the addition of the aldehyde solution, the mixture is stirred for another hour. The precipitate is removed from the reaction mixture by filtration. It is washed

2462

Nizatidine

well with ethyl alcohol and dried to constant weight at 70°C in an oven. The product weighs 73 grams, corresponding to a yield of 97%. It is obtained in the form of pale yellow needles, which are not subjected to further purification, according to US Patent 2,416,234. References Merck Index 6446 Kleeman & Engel p. 641 PDR p. 1278 OCDS Vol. 1 p. 229 (1977) I.N. p. 680 REM p. 1163 Stillman, W.B. and Scott, A.B.; US Patent 2,416,234; February 18, 1947; assigned to Eaton Laboratories, Inc. Gever, G. and O'Keefe, C.; US Patent 2,927,110; March 1, 1960; assigned to The Norwich Pharmacal Company

NIZATIDINE Therapeutic Function: Antiulcer Chemical Name: 1,1-Ethenediamine, N-(2-(((2-((dimethylamino)methyl)-4thiazolyl)methyl)thio)ethyl)-N'-methyl-2-nitroCommon Name: Nizatidine Structural Formula:

Chemical Abstracts Registry No.: 76963-41-2 Trade Name Acinon Antizid Axid Axid Calmaxid Flectar Nizatidine Nizatidine Nizax Nizaxid Panaxid

Manufacturer Zeria Eli Lilly Eli Lilly Norgine Pharma Norgine AG Biomedica Eli Lilly Pharmascience Eli Lilly Norgine Pharma Norgine Pharma

Country France Greece USA Canada France France

Year Introduced -

Nizatidine Trade Name Peptodin Tazac Ulxit Zanizal

Manufacturer Kleva Ltd. Eli Lilly Australia Pty Limited Tyrol Pharma GmbH Bruno Farmaceutici S.p.A.

Country Greece Australia Germany Italy

2463

Year Introduced -

Raw Materials 2-Nitromethylenethiazolidine Methylamine 4-Chloromethyl-2-dimethylaminomethylthiazole dihydrochloride Manufacturing Process Nizatidine may be prepared by 2 ways. 1. A mixture of (25.7 g) 2-nitromethylenethiazolidine and acetonitrile (50 ml) was stirred and heated at 40°C under nitrogen. Methylamine gas (16.0 g) was passed into the stirred mixture over 45 minutes to give a solution. A slurry of 4-chloromethyl-2-dimethylaminomethylthiazole hydrochloride (40.0 g) (prepared as described in EP 49,618) in acetonitrile (50 ml) was added to the solution over a period of 4.5 hours whilst methylamine gas was bubbled through the reaction mixture such that methylamine (38.3 g) was added over the period (total methylamine added was 54.3 g). The temperature of the reaction mixture varied between 24° and 35°C during the addition. After the addition, the mixture was diluted with acetonitrile (50 ml) and stirred at ambient temperature for 17 hours. A solid was removed by filtration and the filtrate was split into 2 equal portions. Portion 1: The solution was evaporated to give a black oil which was partitioned between water (200 ml) and chloroform (200 ml). The separated chloroform phase was washed with saturated brine, then dried over magnesium sulphate, filtered and evaporated to give a reddish oil which was dissolved in acetone (200 ml), boiled under reflux, cooled to 40°C and then seeded with nizatidine. The mixture was left to stand at 0°-5°C for 64 hours. The mixture was filtered to give nizatidine (10.4 g, 37%) m.p. 118-122°C. The structure was confirmed by1H NMR. The product was 95.4% pure by HPLC. Portion 2: The mixture was evaporated to give an oil which was taken up in chloroform (200 ml) then washed with water (100 ml). The chloroform solution was washed with brine (100 ml), dried over magnesium sulphate, and then concentrated under reduced pressure at 45°C to give a brown oil. The oil was dissolved in acetone (200 ml) and activated charcoal (0.5 g) was added to the solution. The mixture was boiled under reflux for 10 minutes, then cooled to 45°C and filtered at this temperature to remove the charcoal. The filtrate was cooled to 20°C, seeded with nizatidine (0.05 g), then cooled 0°5°C for 45 minutes during which time crystallisation occurred. The mixture was filtered to give nizatidine (9.4 g, 32.2%). 2. A mixture of 2-nitromethylenethiazolidine (12.6 g) and water (30.0 ml) was stirred and heated at 40°C under argon. Methylamine (20.0 g of a 40% w/w aqueous solution) was added slowly over 30 minutes to the reaction mixture

2464

Nomifensine maleate

at 40°C. The mixture was cooled at ambient temperature and further methylamine (23.6 g of 40% w/w aqueous solution) was added over 2.5 hours and a solution of 4-chloromethyl-2-dimethylaminomethylthiazole dihydrochloride (25.0 g) in water (30 ml) was added over 5.5 hours with the addition of the thiazole starting simultaneously with the addition of the methylamine. The reaction mixture was left to stir for a further 15 minutes and then was concentrated under reduced pressure. The solid obtained was dissolved in a mixture of methyl ethyl ketone (200 ml), aqueous potassium carbonate solution (43 ml, 10% w/w). The mixture was warmed slightly to obtain a solution. The mixture was separated and the aqueous layer was washed with methyl ethyl ketone (2 times 130 ml and then 1 times 100 ml). The combined organic layers were evaporated under reduced pressure to yield crude nizatidine (approximately 25.2 g), which was shown to be 89.4% pure by HPLC. The crude solid was dissolved in dichloromethane (300 ml). The solution was washed with water (3 times 75 ml). The combined aqueous layer and the washings were back extracted with dichloromethane and the combined organic layers were dried and concentrated under reduced pressure to give nizatidine (21.1 g, 74.3% yield). The solid was dissolved in ethanol (45 ml) by warming on a steam bath. The solution was removed from the steam bath treated with activated charcoal (2.3 g) and the mixture was boiled for a further 8 minutes. The mixture was hot filtered. The filtrate was cooled and filtered to give nizatidine (13.8 g, 48% yield) which was shown to be 99.8% pure by HPLC. References Ph. Cornwall; U. S. Patent No. 6,069,256; May 30 2000; assigned Knoll aktiengesellshaft (Lundeligshaffen, D.E.)

NOMIFENSINE MALEATE Therapeutic Function: Psychostimulant Chemical Name: 8-Amino-1,2,3,4-tetrahydro-2-methyl-4-phenyl-isoquinoline maleate Common Name: Structural Formula:

Nonoxynol

2465

Chemical Abstracts Registry No.: 32795-47-4; 24526-64-5 (Base) Trade Name Alival Merital Alival Psicronizer Merital Neurolene Nomival

Manufacturer Hoechst Hoechst Hoechst Albert Pharma Hoechst Magis Leiras

Country W. Germany UK France Italy Canada Italy Finland

Year Introduced 1976 1977 1977 1977 1982 -

Raw Materials Sulfuric acid Hydrogen Maleic acid

α-Bromoacetophenone (2-Nitrobenzyl)methylamine Sodium borohydride

Manufacturing Process A solution of N-(2-aminobenzyl)-1-phenyl-2-methylaminoethanol-1 was prepared by the reaction of α-bromo-acetophenone and (2nitrobenzyl)methylamine, followed by hydrogenation of the nitro group by means of nickel on diatomaceous earth at room temperature and reduction of the CO group by means of sodium borohydride. The intermediate thus produced was dissolved in 100 ml of methylene chloride and introduced dropwise into 125 ml of sulfuric acid at 10° to 15°C. After a short standing, the reaction mixture was poured onto ice and rendered alkaline by means of a sodium hydroxide solution. By extraction with ether, there was obtained 1,2,3,4-tetrahydro-2-methyl-4-phenyl-8-amino-isoquinoline. The base is reacted with maleic acid to give the maleate; melting point of the maleate 199° to 201°C (from ethanol). References Merck Index 6515 DFU 1 (2) 72 (1976) Kleeman and Engel p. 642 PDR p. 941 DOT 13 (2) 77 (1977) I.N. p. 685 Farbwerke Hoechst AG, Germany; British Patent 1,164,192; September 17, 1969 Ehrhart, G., Schmitt, K., Hoffmann, I. and Ott, H.; US Patent 3,577,424; May 4, 1971; assigned to Farbwerke Hoechst AG.

NONOXYNOL Therapeutic Function: Spermatocide (vaginal)

2466

Nonoxynol

Chemical Name: α-(Nonylphenyl)-ω-hydroxypoly(oxy-1,2-ethanediyl) Common Name: Structural Formula:

Chemical Abstracts Registry No.: 26027-38-3 Trade Name Ortho-Delfen Semicid Intercept Gynol Shur-Seal C-Film Emko Encare Oval Glovan Igepal Ortho-Creme

Manufacturer Cilag Whitehall Ortho Ortho Milex Hommel Emko-Schering Patentex Teva G.A.F. Cilag

Country France US US US US Switz. US W. Germany Israel US US

Year Introduced 1971 1978 1980 1982 1983 -

Raw Materials Isononylphenol Sodium hydroxide Ethylene oxide Manufacturing Process 220 parts of isononylphenol prepared by condensation of phenol with an olefin mixture obtained by polymerization of propylene and containing essentially isononylenes are caused to react with 0.5 part of caustic alkali powder. The whole is heated to about 130°C to 135°C and the water formed is removed under reduced pressure, while stirring. Thereupon, ethylene oxide is introduced into the melt, while well stirring, during which operation care must be taken, that the temperature of the reaction mass is maintained between 180°C and 200°C. When about 300 parts of ethylene oxide are taken up, the reaction is interrupted. A water-soluble oil is obtained. References Merck Index 6518 PDR pp. 1661, 1900 I.N. p. 686 REM p. 1163

Nordazepam

2467

Steindorff, A., Balle, G., Horst, K. and Michel, R.; US Patent 2,413,477; September 3, 1940; assigned to General Aniline & Film Corp.

NORDAZEPAM Therapeutic Function: Tranquilizer Chemical Name: 7-Chloro-1,3-dihydro-5-phenyl-1(2H)-1,4-benzodiazepin-2one Common Name: Nordiazepam; Desmethyldiazepam Structural Formula:

Chemical Abstracts Registry No.: 1088-11-5 Trade Name Madar Vegesan

Manufacturer Ravizza Mack

Country Italy Switz.

Year Introduced 1973 1981

Raw Materials (2-Benzoyl-4-chlorophenyl-carbamoylmethyl)carbamic acid benzyl ester Hydrogen bromide Acetic acid Manufacturing Process A solution of 3.1 g of (2-benzoyl-4-chlorophenyl-carbamoylmethyl)carbamic acid benzyl ester in 30 cc of 20% hydrobromic acid in glacial acetic acid was stirred for 45 minutes at room temperature. On addition of 175 cc of anhydrous ether, a gummy solid precipitated. After several minutes the ether solution was decanted. The resultant 5-chloro-2-glycylaminobenzophenone was not isolated, but about 155 cc of ether was added to the residue and after chilling in an ice bath, 10% sodium hydroxide was added until the mixture was alkaline. The ether layer was then separated, washed twice with water and dried over sodium sulfate. After filtration, the ether solution was concentrated to dryness in vacuo. The residue was crystallized from benzene

2468

Norethandrolone

to yield 7-chloro-5-phenyl-3H-1,4-benzodiazepin-2(1H)-one. References Merck Index 6531 DOT 9 (6) 239 (1973) I.N. p. 688 Stempel, A.; US Patent 3,202,699; August 24, 1965; assigned to HoffmannLaRoche Inc.

NORETHANDROLONE Therapeutic Function: Androgen Chemical Name: 17-Hydroxy-19-norpregn-4-ene-3-one Common Name: Structural Formula:

Chemical Abstracts Registry No.: 52-78-8 Trade Name Nilevar Nilevar

Manufacturer Searle Searle

Country US France

Year Introduced 1956 1960

Raw Materials Norethindrone Hydrogen Manufacturing Process Through a mixture of 11 parts of charcoal containing 5% palladium and 2,000 parts of dioxane a stream of hydrogen is passed for 60 minutes. Then 86 parts of 17-ethynyl-19-nortestosterone (Norethindrone) in 1,500 parts of dioxane are added and the mixture is hydrogenated until 2 mols of hydrogen are absorbed. The catalyst is then removed by filtration and the solvent is

Norethindrone

2469

evaporated under vacuum. The crystalline residue is dissolved in 2,700 parts of benzene and thus applied to a chromatography column containing 5,000 parts of silica gel. The column is washed with 2,700 parts of benzene, 4,500 parts of a 10% solution of ethyl acetate in benzene and 27,000 parts of a 20% solution of ethyl acetate in benzene and is then eluted with 30,000 parts of a 30% solution of ethyl acetate in benzene. The resulting eluate is concentrated under vacuum and the residue is recrystallized from methanol and dried to constant weight at 75°C. The 17-ethyl-19-nortestosterone thus obtained melts at about 140°C to 141°C. References Merck Index 6537 Kleeman & Engel p. 644 OCDS Vol. 1 p. 170 (1977) I.N. p. 688 Colton, F.B.; US Patent 2,721,871; October 25, 1955; assigned to G.D. Searle & Co.

NORETHINDRONE Therapeutic Function: Progestin Chemical Name: 17-Hydroxy-19-nor-17α-pregn-4-en-20-yn-3-one Common Name: Norethisteron Structural Formula:

Chemical Abstracts Registry No.: 68-22-4 Trade Name Norlutin Ortho-Novum Norinyl Nor-QD Brevicon Conceplan Gesta-Plan

Manufacturer Parke Davis Ortho Syntex Syntex Syntex Gruenenthal D.A.K.

Country US US US US US W. Germany Denmark

Year Introduced 1957 1963 1964 1973 -

2470

Norethindrone

Trade Name Micronor Micronor Micronovum Modicon Monogest Norfor Norgestin Noriday Norlestrin Ovcon Primolut N Tri-Norinyl Utovlan

Manufacturer Ethnor Ortho Cilag Ortho Spofa Gremy-Longuet Janus Syntex Parke Davis Mead Johnson Schering Syntex Syntex

Country Australia US W. Germany US Czechoslovakia France Italy US US US UK US UK

Year Introduced -

Raw Materials 3-Methoxyestrone Ethyl orthoformate Lithium Potassium

Ammonia Acetylene Chromic acid

Manufacturing Process 7.5 grams of 3-methoxyestrone were dissolved in 750 cc of anhydrous dioxane in a three-neck flask, placed in a box and insulated with cotton wool. 2 liters of anhydrous liquid ammonia and 15 grams of lithium metal in the form of wire were added to the mechanically stirred solution. After stirring for one hour, 150 cc of absolute ethanol were added at such speed that no bumping occurred; when the blue color had disappeared, 500 cc of water were added in the same way. The ammonia was evaporated on the steam bath and the product collected with 2 liters of water. It was extracted with ether and then with ethyl acetate and the combined extract was washed to neutral and evaporated to dryness under vacuum, leaving 7.4 grams of a slightly yellow oil. The oil thus obtained was dissolved in 400 cc of methanol and refluxed during one hour with 150 cc of 4N hydrochloric acid. The mixture was poured into a sodium chloride solution and extracted with ethyl acetate, washed to neutral, dried and evaporated to dryness. The product was a yellow oil which showed an ultraviolet absorption maximum characteristic of a ∆4-3-ketone. A solution of 2.7 grams of chromic acid in 20 cc of water and 50 cc of acetic acid was added to the stirred solution of the above oil in 100 cc of acetic acid, maintaining the temperature below 20°C. After 90 minutes standing, 50 cc of methanol were added and the mixture concentrated under vacuum (20 mm). The residue was extracted with ether, washed to neutral and evaporated to dryness. The residual semicrystalline product (7 grams) was chromatographed over alumina and the fractions eluted with ether yielded 3.2 grams of ∆4-19norandrosten-3,17-dione having a MP of 163° to 167°C.

Norethindrone acetate

2471

A solution of 2 grams of ∆4-19-norandrosten-3,17-dione and 0.4 gram of pyridine hydrochloride in 50 cc of benzene free of thiophene was made free of moisture by distilling a small portion; 4 cc of absolute alcohol and 4 cc of ethyl orthoformate were added and the mixture was refluxed during 3 hours. 5 cc of the mixture were then distilled and after adding an additional 4 cc of ethyl orthoformate the refluxing was continued for 2 hours longer. The mixture was evaporated to dryness under vacuum and the residue was taken up in ether, washed, dried and evaporated to dryness. The residue was crystallized from hexane-acetone and then from ether to give ∆3,5-19-nor-3ethoxy-androstadien-17-onewith a MP of 140° to 142°C. One gram of potassium metal was dissolved in 25 cc of tertiary amyl alcohol by heating under an atmosphere of nitrogen. One gram of ∆3,5-19-nor-3ethoxyandrostadien-17-onein 25 cc of anhydrous toluene was added and nitrogen was passed during 15 minutes. Then acetylene (especially dried and purified) was passed during 14 hours through the mechanically stirred solution, at room temperature. The mixture was poured in water, acidified to pH 1 with dilute hydrochloric acid, heated on the steam bath for 30 minutes and then subjected to steam distillation to remove the organic solvents. The residue was filtered, dried and recystallized several times from ethyl acetate. The ∆4-19-nor-17αethinylandrosten-17β-ol-3-onethus obtained had a MP of 198° to 200°C (in sulfuric acid bath), 200° to 204°C (Kofler). References Merck Index 6538 Kleeman & Engel p. 644 PDR pp. 1104, 1297, 1358, 1372, 1793 OCDS Vol. 1 p. 164 (1977) & 2, 145 (1980) DOT 4 (1) 19 (1968) & 9 (4) 144 (1973) I.N. p. 688 REM p. 992 Djerassi, C., Miramontes, L. and Rosenkranz, G.; US Patent 2,744,122; May 1, 1956; assigned to Syntex SA, Mexico de Ruggieri, P.; US Patent 2,849,462; August 26, 1958

NORETHINDRONE ACETATE Therapeutic Function: Chemical Name: 19-Nor-17α-pregn-4-en-20-yn-3one, 17-hydroxy-, acetate Common Name: Chemical Abstracts Registry No.: 51-98-9

2472

Norethindrone acetate

Structural Formula:

Trade Name Norlestrin Milligynon Aygestrin Brevicon Norlutin-A Primolut-Nor

Manufacturer Parke Davis Schering Ayerst Syntex Parke Davis Schering

Country US France US US UK W. Germany

Year Introduced 1964 1978 1982 -

Raw Materials Norethindrone Acetic anhydride Hydrogen chloride Manufacturing Process 2.98 grams of 17-ethinyl-19-nor-testosterone (norethindrone) are suspended in 30 cc of acetic anhydride and a solution of 1.9 grams of p-toluenesulfonic acid in 19 cc of acetic anhydride is gradually added while cooling and stirring. Complete dissolution takes place after about one hour. After additional 30 to 60 minutes, a thick, pasty mass separates. The reaction is permitted to continue for a total period of 5 hours, whereupon water is added to the reaction mixture and the 3-enol-17-diacetate which separates after stirring for 1 to 2 hours is filtered off, washed until neutral and dried in vacuo over calcium chloride at room temperature. In order to prepare the monoacetate, the crude diacetate is suspended in 150 cc of methanol and, after adding 1.5 cc, concentrated hydrochloric acid, heated to boiling for 15 minutes in a nitrogen atmosphere. The crude monoacetate which separates upon the addition of water after cooling is filtered off, washed and dried in vacuo over calcium chloride at room temperature. The pure 17-acetete, obtained after repeated recrystallizations from methylene chloride/hexane has a MP of 161° to 162°C. References Merck Index 6538 Kleeman & Engel p. 645 PDR pp. 615, 1378 OCDS Vol. 1 p. 165 (1977)

Norethisterone enanthate

2473

I.N. p. 689 REM p. 992 Engelfried, O., Kaspar, E., Schenck, M. and Popper, A.; US Patent 2,964,537; Dec. 13, 1960; assigned to Schering AG, Germany

NORETHISTERONE ENANTHATE Therapeutic Function: Progestin Chemical Name: 19-Norpregn-4-en-20-yn-3-one, 17-((1-oxoheptyl)oxy)-, (17α)Common Name: Norethindrone enanthate; Norethisterone enanthate; Norethisterone heptanoate Structural Formula:

Chemical Abstracts Registry No.: 3836-23-5 Trade Name Norigest

Manufacturer Schering

Country -

Year Introduced -

Raw Materials 17-Ethinyl-19-nor-testosteron Enanthic acid Manufacturing Process 1 g 17-ethinyl-19-nor-testosteron was refluxed with 5 ml of enanthic acid anhydride on an oil bath at temperature 180°C 17 hours. Then the reaction mixture was distilled with water steam to the full disappearence of smell of enantic acid. After that it was washed with 2 N sodium hydroxide and finally with water to neutral, dried over sodium sulfate and evaporated to dryness. The oily residue was rubbed with some drops of methanol and stood at -8°C 24 hours to give the crystals of 3-endol diester; MP: 82°-84°C, 2 g of it was dissolved in 120 ml of methanol and heated with 1.2 ml concentrated hydrochloric acid. The partly saponified product was distilled with water steam

2474

Norethynodrel

to full disappearence of smell of enantic acid. The residue was mixed with ether, washed with 2 N sulfuric acid, 2 N sodium hydroxide, finally with water to neutral dried over sodium sulfate and evaporated to dryness. The residue was stirred with pentane and cooled for crystallization. Pure enanthate was crystallized after repeated solution in pentane. 17-α-Ethinyl-19nortestosterone enanthate had MP: 68°-71°C. References Engelfried O. et al.; D.B. Patent No. 1,017,166; June 16, 1956; Schering Aktiengesellschaft, Berlin

NORETHYNODREL Therapeutic Function: Progestin Chemical Name: 17-Hydroxy-19-nor-17α-pregn-5(10)-en-20-yn-3-one Common Name: 13-Methyl-17-ethynyl-17-hydroxy-1,2,3,4,6,7,8,9,11,12,13, 14,16,17-tetradecahydro-15H-cyclopenta-α-phenanthren-3-one Structural Formula:

Chemical Abstracts Registry No.: 68-23-5 Trade Name Enovid

Manufacturer Searle

Country US

Year Introduced 1957

Raw Materials 3-Methoxy-17-oxo-2,5-estradiene Acetylene Acetic acid Manufacturing Process Convenient starting materials are the ethers of 3-hydroxy-13-methyl1,4,6,7,8,9,11,12,13,14,16,17-dodecahydro-15H-cyclopenta-α-phenanthren-

Norfenefrine

2475

17-one described in US Patent 2,655,518, according to US Patent 2,691,028 where the following preparation is also described. The methyl ether is also designated as 3-methoxy-17-oxo-2,5-estradiene. A stirred solution of 10.6 parts of 3-methoxy-13-methyl-1,4,6,7,8,9,11,12,13, 14,16,17dodecahydro-15H-cyclopenta-α-phenanthren-17-one in 700 parts of anhydrous ether and 45 parts of dry toluene is cooled to 0°C and saturated with dry acetylene. While a slow stream of acetylene is passed through the reaction mixture, a solution of 20 parts of potassium t-amylate in 135 parts of anhydrous t-pentanol is added in the course of 15 minutes with stirring. Passage of acetylene and stirring are continued for an additional 4½ hours. After standing at 0°C for 16 hours, the mixture is washed with aqueous ammonium chloride solution until the aqueous phase is neutral, then with water and saturated sodium chloride solution. The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to a residue of about 250 parts. 500 parts of petroleum ether are added and after standing at 0°C for an hour, the mixture is filtered. The collected precipitate is recrystallized from ether. The resulting 3-methoxy-13-methyl-17-ethynyl1,4,6,7,8,9,11,12,13,14,16,17-dodecahydro-15H-cyclopenta-α-phenanthren17-ol melts at about 181° to 182°C. To a refluxing solution of 10 parts of 3-methoxy-17-ethynyl-17-hydroxy-13methyl-1,4,6,7,8,9,11,12,13,14,16,17-dodecahydro-15H-cyclopenta-αphenanthrene in 500 parts of methanol, 20 parts of glacial acetic acid are added. Refluxing is continued for 7 minutes, water is added to the point of turbidity and the reaction mixture is permitted to come to room temperature. The precipitate is collected on a filter and recrystallized from aqueous methanol. The 13-methyl-17-ethynyl-17-hydroxy-1,2,3,4,6,7,8,9,11,12,13,14, 16,17-tetradecahydro-15H-cyclopenta-α-phenanthren-3-one thus obtained melts at about 169° to 170°C. References Merck Index 6539 Kleeman & Engel p. 647 PDR p. 1680 OCDS Vol. 1 p. 186 (1977) DOT 4 (1) 22 (1968) I.N. p. 689 REM p. 993 Colton, F.B.; US Patent 2,691,028; October 5, 1954; assigned to G.D. Searle & Co. Colton, F.B.; US Patent 2,725,389; November 29, 1955; assigned to G.D. Searle & Co.

NORFENEFRINE Therapeutic Function: Adrenergic Chemical Name: α-(Aminomethyl)-3-hydroxybenzenemethanol

2476

Norfenefrine

Common Name: Norphenylephrine Structural Formula:

Chemical Abstracts Registry No.: 536-21-0; 4779-94-6 (Hydrochloride salt) Trade Name Zordel Coritat Esbufon Euro-Cir Molycor R Nevadral Normetolo Novadral Stagural Sympatosan Tonolift

Manufacturer Grelan Green Cross Schaper and Brummer Virgiliano Mepha Pharmacia Selvi Goedecke Stada Kwizda Teisan

Country Japan Japan W. Germany Italy Switz. Sweden Italy W. Germany W. Germany Austria Japan

Year Introduced 1970 -

Raw Materials Sodium iodide Hydrogen Hexamethylenetetramine

m-Acetoxyacetophenone Bromine

Manufacturing Process 100 parts of the hydrochloride of meta-hydroxy-ω-aminoacetophenone of melting point 220°C to 222°C (obtainable by brominating metaacetoxyacetophenone, causing the bromoketone to react with sodium iodide, adding hexamethylenetetramine to the iodide in an indifferent solvent and scission of the addition product in acid solution) are shaken in aqueous solution with hydrogen in presence of 2 parts of palladium catalyst until 2 atomic proportions of hydrogen have been absorbed. The catalyst is now filtered and the filtrate evaporated in a vacuum; and the crystalline and completely dry residue is dissolved in absolute alcohol and a precipitate is produced by adding dry ether. The hydrochloride of metahydroxyphenylethanolamine thus obtained forms white crystals of melting point 159°C to 160°C. References Merck Index 6540

Norfloxacin

2477

Kleeman & Engel p. 647 I.N. p.689 Legerlotz, H.; US Patent 2,312,916; March 2, 1943; assigned to Ciba Pharmaceutical Products Inc.

NORFLOXACIN Therapeutic Function: Antibacterial Chemical Name: 1-Ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3quinolinecarboxylic acid Common Name: Structural Formula:

Chemical Abstracts Registry No.: 70458-96-7 Trade Name Noroxin Sebercim Primoxin Noroxin Fulgram

Manufacturer MSD I.S.F. Sharp and Dohme MSD A.B.C.

Country Italy Italy W. Germany Switz. Italy

Year Introduced 1983 1983 1983 1983 -

Raw Materials 7-Chloro-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid Piperazine Manufacturing Process 36 g (0.134 mol) of 7-chloro-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3carboxylic acid, 46 g of piperazine and 210 cm3 of pyridine were heated under reflux for 6 hours, while stirring. After the starting material had dissolved, a precipitate appeared after heating for about 2 hours 30 minutes. The major part of the solvent was removed by concentration in vacuo (15 mm Hg; 100°C). In order to remove the pyridine as completely as possible, the residue was taken up in 200 cm3of water and the concentration in vacuo was repeated.

2478

Norgestimate

The residue, resuspended in 150 cm3 of water, was stirred. 150 cm3 of 2N NaOH were added thereto. The solution, which was slightly turbid, was treated with 5 g of animal charcoal and stirred for 30 minutes. After filtration, the pH was brought to 7.2 by adding acetic acid while stirring. The precipitate was filtered off, washed with water and dissolved in 250 cm3 of a 10% aqueous acetic acid. The acid solution (pH 4.4) was filtered and then brought to pH 7.2 by gradually added 2N NaOH. The suspension was heated to 90°C, while stirring. The crystals were separated and recrystallized from 280 cm3 of a mixture of DMF (1 volume) and ethanol (4 volumes). After drying in vacuo over phosphorus pentoxide, 29.5 g (yield 70%) of 1-ethyl-6-fluoro-4-oxo-7-piperazinyl-1,4dihydroquinoline-3-carboxylic acid, melting point 222°C, were obtained. In air, this product is hygroscopic and gives a hemihydrate. References Merck Index 6541 DFU 7 (8) 586 (1982) DOT 19 (6) 341 (1983) I.N. p. 689 Pesson, M.; US Patent 4,292,317; September 29, 1981; assigned to Laboratorie Roger Bellon (France) and Dainippon Pharmaceutical (Japan)

NORGESTIMATE Therapeutic Function: Progestin Chemical Name: 18,19-Dinorpregn-4-en-20-yn-3-one, 17-(acetyloxy)-13ethyl-, 3-oxime, (17α)Common Name: Dexnorgestrel acetime; Norgestimate Structural Formula:

Norgestrel

2479

Chemical Abstracts Registry No.: 35189-28-7 Trade Name Ortrel

Manufacturer Janssen Cilag

Country -

Year Introduced -

Raw Materials D-17β-Acetoxy-13β-ethyl-17α-ethynyl-gon-4-en-3-one Hydroxylamine hydrochloride Manufacturing Process A solution of 4.5 g of D-17β-acetoxy-13β-ethyl-17α-ethynyl-gon-4-en-3-one in 15 ml of pyridine and 2.0 g of hydroxylamine hydrochloride hydroxylamine hydrochloride is heated on a steam bath for 45 min. It is then cooled and poured into a large amount of ice-water, after which the solid which is thus produced is filtered off and air dried. Recrystallization from methylene chloride-ethanol gives D-17β-acetoxy-13α-ethyl-17α-ethynyl-gon-4-en-one oxime, m.p. 214-218°C; [α]D25 = +41°. References Tullar B.F., Greebbush E.; US Patent Dec. 18, 1956; Assigned to Sterling Drug Inc., Del., a corporation of Delaware

NORGESTREL Therapeutic Function: Progestin Chemical Name: 13-Ethyl-17-hydroxy-18,19-dinor-17α-pregn-4-en-20-yn-3one Common Name: 17α-Ethynyl-18-homo-19-nortestosterone Structural Formula:

Chemical Abstracts Registry No.: 797-63-7

2480

Normethadone

Trade Name Ovrette Eugynon Neogest Microlut Planovar Duoluton Prempak

Manufacturer Wyeth Schering Schering Schering Wyeth Schering Ayerst

Country US Italy UK W. Germany Japan Japan UK

Year Introduced 1968 1969 1974 1974 1979 1979 -

Raw Materials (+/-)-1,4-Dihydro-17α-ethynyl-18-homo-oestradiol 3-methyl ether Hydrogen chloride Manufacturing Process To 0.7 gram of (+/-)-1,4-dihydro-17α-ethynyl-18-homo-oestradiol 3-methyl ether in 36 cc methanol was added 1.6 cc water and 2.4 cc concentrated hydrochloric acid. After standing at room temperature for 2 hours ether was added, and the washed and dried ethereal solution was evaporated, yielding a gum which was dissolved in 5 cc benzene and the solution absorbed on 50 grams of an activated fuller's earth. Elution with light petroleum containing increasing proportions of benzene gave a crystalline by-product: further elution with benzene containing a small proportion of ether gave a crystalline product which was recrystallized from ethyl acetate, yielding 0.11 gram of (+/-)-17α-ethynyl-18-homo-19-nortestosterone. MP 203° to 206°C. References Merck Index 6543 Kleeman & Engel p. 648 PDR pp. 1952, 1958, 1965 OCDS Vol. 1 p.167 (1977); 2, 151 (1980) & 3, 84 (1984) DOT 4 (1) 24 (1968) I.N. p. 690 REM p. 993 Hughes, G.A. and Smith, H.; British Patent 1,041,280; September 1, 1966

NORMETHADONE Therapeutic Function: Narcotic analgesic, Antitussive Chemical Name: 3-Hexanone, 6-(dimethylamino)-4,4-diphenylCommon Name: Desmethylmethadone; Noramidone; Normetadone; Normethadone; Phenyldimazone

Normethadone

2481

Structural Formula:

Chemical Abstracts Registry No.: 467-85-6 Trade Name Normethadone

Manufacturer Isotec, Inc.

Country -

Year Introduced -

Raw Materials Sodium amide Magnesium Ethyl bromide

Diphenylacetonitrile 2-Dimethyaminoethylchloride

Manufacturing Process 65 g of thin powder sodium amide was added to a solution of 289 g diphenylacetonitrile in 300 ml benzene for 15-20 minutes at temperature 45°50°C. Then the mixture was cooled to about 25°C, 182 g 2dimethyaminoethylchloride was added dropwise. On ending the reaction it was heated to reflux for 15 minutes, diluted with water, the benzene layer separated and washed with diluted hydrochloric acid. The acid layer was alkalified with sodium hydroxide, extracted with ether and dried over potash. The ether was distilled off to dryness and the residue solidified to give colorless crystals of 4-dimethylamino-2,2-diphenylbutyronitrile. The C2H5MgBr was made from 66.5 g of magnesium, 300 ml dry ether and 33 g ethyl bromide and mixed with above prepared nitrile in 150 ml toluene. After the ending of reaction, the mixture was heated for 1.5 hour on the steam bath to give hard-grained bulk. It was mixed with 600 ml concentrate hydrochloric acid in 1500 ml water. On cooling 500 ml benzene was added and three layers arose. The middle layer crystallized shortly. The crystals were filtered off, washed with 100 ml 2 N hydrochloric acid and 3 x 100 ml acetone. 6Dimethylamino-4,4-diphenyl-3-hexanone was prepared as a hydrochloride. MP: 231°C. The salt may be transformed into the base by adding of an equivalent of any basic compound (triethyl amine, soda and so on). References Bockmuhl M., Ehrhart G.; D.B. Patent No. 865,314; July 8, 1949; Farbwerke Hoechst, vormals Meister Lucius and Bruning, Frankfurt/M.-Hochst

2482

Nortriptyline

NORTRIPTYLINE Therapeutic Function: Antidepressant Chemical Name: 3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)N-methyl-1-propanamine Common Name: Desmethylamitriptyline; Desitriptyline Structural Formula:

Chemical Abstracts Registry No.: 72-69-5; 894-71-3 (Hydrochloride salt) Trade Name Aventyl Nortrilen Aventyl Psychostyl Vividyl Noritren Altilev Pamelor Allegron Ateben Martimil Nortylin Norzepine Sensaval

Manufacturer Lilly Tropon Lilly Lilly Lilly Dainippon Squibb Sandoz Dista Sintyal Lafarquin Ikapharm Bial Pharmacia

Country UK W. Germany US France Italy Japan France US UK Argentina Spain Israel Portugal Sweden

Year Introduced 1963 1964 1965 1966 1967 1971 1976 1977 -

Raw Materials 5-(3-Chloropropylidene)dibenzo[a,d]cyclohepta[1,4]diene Methylamine Manufacturing Process A mixture of 114.5 g of 5-(3-chloropropylidene)dibenzo[a,d]cyclohepta[1,4] diene, 75 ml of benzene, and about 400 ml of methylamine is heated in an autoclave at 120°C for six hours. The excess methylamine is distilled from the reaction mixture under vacuum and the residue is stirred with 300 ml of water. Acidification of the mixture with hydrochloric acid causes the separation of the hydrochloride of 5-(3-methylaminopropylidene)dibenzo[a,d]

Novobiocin

2483

cyclohepta[1,4]diene. The product is collected by filtration and is purified by recrystallization from a mixture of absolute ethanol and ethyl acetate. MP 210°C to 212°C. References Merck Index 6558 Kleeman & Engel p. 651 PDR p. 1588 OCDS Vol. 1 p. 151 (1977) DOT 1 (1) 22 (1965) & 9 (6) 219 (1973) I.N. p. 691 REM p. 1096 Peters, L.R. and Hennion, G.F.; US Patent 3,281,469; October 25, 1966; assigned to Eli Lilly & Co.

NOVOBIOCIN Therapeutic Function: Antibiotic Chemical Name: N-[7-[[3-O-(Aminocarbonyl)-5,5-di-C-methyl-4-O-methyl-αL-lyxopyranosyl]oxy]-4-hydroxy-8-methyl-2-oxo-2H-1-benzopyran-3-yl]4-hydroxy-3-(3-methyl-2-butenyl)benzamide Common Name: Streptonivicin Structural Formula:

Chemical Abstracts Registry No.: 303-81-1 Trade Name

Manufacturer

Country

Year Introduced

Albamycin

Upjohn

US

1956

Cathomycin

MSD

US

1956

Cathomycine

Theraplix

France

1957

Albiocin

Upjohn

Japan

-

Inamycin

Hoechst

W. Germany

-

Robiocina

San Carlo

Italy

-

Stilbiocina

Donatello

Italy

-

2484

Noxiptilin

Raw Materials Bacterium Streptomyces spheroides Soybean meal Dextrose Manufacturing Process The preparation of novobiocin by fermentation is described in US Patent 3,049,534 as follows: A medium containing 2% soybean meal, 1% dextrose, 0.25% sodium chloride and 0.75% distiller's solubles was made up in tap water. About 25 ml of the prepared medium was placed in a 75 ml vial and sterilized by heating at 120°C for 20 minutes. The sterilized medium was then inoculated with a vegetative culture of Streptomyces spheroides MA-319 (NRRL 2449), and the vial loosely stoppered with cotton. The vial was then placed on a shaking machine with an amplitude of 1½ inches at 28°C for 6 days. At the end of this fermentation time, the fermented broth was assayed using the cylinder-plate method with Bacillus megatherium ATCC 9885 as the assay organism and found to have an activity of 600 units/ml or 30 mcg/ml of novobiocin. The production of larger quantities of novobiocin by submerged fermentation in suitable tanks is also described in US Patent 3,049,534. The preparation of novobiocin by a synthetic route is described in US Patent 2,966,484, as well as in US Patent 2,925,411. References Merck Index 6563 Kleeman & Engel p. 652 I.N. p. 693 REM p. 1212 Stammer, C.H.; US Patent 2,925,411; February 16, 1960 Walton, E. and Spencer, C.; US Patent 2,966,484; December 27, 1960; assigned to Merck & Co., Inc. Caron, E.L., Johnson, J.L., Hinman, J.W. and Hoeksema, H.; US Patent 2,983,723; May 9, 1961; assigned to The Upjohn Company Wolf, F.J.; US Patent 3,000,873; September 19, 1961; assigned to Merck & Co., Inc. Stammer, C.H. and Miller, I.M.; US Patent 3,049,475; August 14, 1962; assigned to Merck & Co., Inc. Miller, I.M.; US Patent 3,049,476; August 14, 1962; assigned to Merck & Co., Inc. Wallick, H.; US Patent 3,049,534; August 14, 1962; assigned to Merck & Co., Inc. French, G.H.; US Patent 3,068,221; December 11, 1962; assigned to The Upjohn Co.

NOXIPTILIN Therapeutic Function: Psychostimulant

Noxiptilin

2485

Chemical Name: 10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-one O-[2(dimethylamino)ethyl]oxime Common Name: Dibenzoxin Structural Formula:

Chemical Abstracts Registry No.: 3362-45-6; 4985-15-3 (Hydrochloride salt) Trade Name Agedal Agedal Nogedal Elronon Sipcar

Manufacturer Bayer Bayer Theraplix Deutsches Hydrierwerk Bernabo

Country W. Germany Italy France E. Germany Argentina

Year Introduced 1969 1975 1978 -

Raw Materials 5-Keto-10,11-dihydrodibenzo[a,d]cycloheptene Hydroxylamine hydrochloride Sodium amide β-(Dimethylamino)ethyl chloride Manufacturing Process 15 grams 5-keto-10,11-dihydrodibenzo-[a,d]cycloheptene dissolved in 225 ml of pyridine was mixed with 15 grams hydroxylamine hydrochloride, and the mixture was boiled under reflux for 22 hours. The bulk of the pyridine was then distilled off under reduced pressure, the residue was poured into water, and the aqueous mixture thus formed was extracted with ether. The ether extract was washed with water, dried and heated to distill off the ether. The solid residue was recrystallized from a mixture of benzene and light petroleum (BP 40° to 60°C). 12.8 grams of the recrystallized oxime had a MP of 167° to 169°C. A solution of 22 grams of the above described 5-oximino-10,11dihydrodibenzo-[a,d]cycloheptene in 120 ml benzene was treated with 7.8

2486

Noxytiolin

grams sodamide and the mixture was stirred and heated under reflux for 2 hours. At this stage, the 14.4 grams of hydrochloride of β-(dimethylamino) ethyl chloride was added and heating under reflux was continued for 16 hours. 50 ml water was then cautiously added to decompose unreacted sodamide and the benzene layer was separated and extracted with dilute (10%) aqueous hydrochloric acid. The aqueous acid extracts were made alkaline with concentrated aqueous potassium hydroxide solution and then extracted with ether. The ether extracts were dried, the solvent was removed and the residual oil was distilled under reduced pressure. The product was 14.5 grams of the fraction boiling at 160° to 164°C, under a pressure of 0.05 mm of mercury. References Merck Index 6566 Kleeman & Engel p. 653 DOT 6 (2) 56 (1970) I.N. p. 695 Wrigley, T.I. and Leeming, P.R.; British Patent 1,045,911; October 19, 1966; assigned to Pfizer Limited, England Schutz, S. and Hoffmeister, F.; US Patent 3,505,321; April 7, 1970; assigned to Farbenfabriken Bayer A.G.

NOXYTIOLIN Therapeutic Function: Antifungal Chemical Name: 1-Methyl-3-hydroxymethyl-2-thiourea Common Name: Structural Formula:

Chemical Abstracts Registry No.: 15599-39-0 Trade Name

Manufacturer

Country

Year Introduced

Noxyflex

Geistlich

UK

1964

Noxyflex

Innothera

France

1978

Gynaflex

Geistlich

Switz.

-

Nylidrin

2487

Raw Materials Methyl thiourea Formaldehyde Manufacturing Process 400 g methyl thiourea and 2.5 g NaHCO3 are dissolved in 400 ml formaldehyde solution of 35% concentration. After having been left at ordinary temperature for 2 to 3 hours, the solution is adjusted with dilute HCl to pH 7 to 7.5. After the reaction mixture had been left overnight at 15°C some of the final product crystallized and was filtered off using a Buchner funnel. The mother liquor was concentrated by evaporation in vacuo at a bath-temperature of 30°C. The crystals obtained were again collected by filtration using a Buchner funnel and were combined with the first crystalline fraction and dried in vacuo at ordinary temperature. Yield of pure substance 400 g; melting point 84°C to 86°C. References Merck Index 6567 Kleeman & Engel p. 653 DOT 4 (3) 106 (1968) I.N. p. 695 Aebi, A. and Hafstetter, E.; British Patent 970,414; January 12, 1960; assigned to Ed Geistlich Sohne AG fur Chemische Industrie.

NYLIDRIN Therapeutic Function: Vasodilator Chemical Name: 4-Hydroxy-α-[1-[(1-methyl-3-phenylpropyl)amino]ethyl] benzenemethanol Common Name: Buphenine Structural Formula:

Chemical Abstracts Registry No.: 447-41-6

2488

Nylidrin

Trade Name

Manufacturer

Country

Year Introduced

Arlidin

U.S.V.

US

1955

Arlibide

U.S.V.

Argentina

-

Bufedon

Cosmopharma

Netherlands

-

Buphedrin

Tatsumi

Japan

-

Dilatol

Tropon

W. Germany

-

Dilatropon

Draco

Sweden

-

Dilaver

Neopharma

Finland

-

Dilydrin

Medichemie

Switz.

-

Nyderal

Kobayashi

Japan

-

Nylin

Toho

Japan

-

Opino

Bayropharm

W. Germany

-

Penitardon

Woelm

W. Germany

-

Perdilat

Abdi Ibrahim

Turkey

-

Perdilatal

Smith and Nephew

UK

-

Pervadil

I.C.N.

Canada

-

Pharmadil

Pharmacia

Sweden

-

Rudilin

Darby

US

-

Rydrin

Kodama

Japan

-

Shatorn

Seiko

Japan

-

Tacodilydrin

Swiss Pharma

W. Germany

-

Tocodrin

Medichemie

Switz.

-

Vasiten

Crinos

Italy

-

Verina

Fujisawa

Japan

-

Raw Materials p-Benzoxy-α-bromopropiophenone 1-Phenyl-3-aminobutane Hydrogen Manufacturing Process 8 grams of the hydrobromide of 1-(p-benzoxyphenyl)-2-(α-methyl-γ-phenylpropylamino)-propanone-(1) were obtained by heating equivalent quantities of p-benzoxy-α-bromopropiophenone and 1-phenyl-3-amino-butane for an hour on the water bath in the absence of solvents. The product was purified by twice boiling with five times the quantity of acetic acid and filtration at 80°C, then shaken in contact with hydrogen with 0.8 gram of Raney nickel in 70 cc of pure methanol containing 0.96 gram (corresponding to 1 mol) of KOH. After 4 hours 2 mols of hydrogen had been taken up and the solution was filtered from the catalyst, evaporated in vacuo, and the residue triturated first with water to remove potassium bromide and then with methanol to remove potassium bromide. 3.7 grams (72% of the theoretical yield) of the compound specified, melting at 110° to 112°C, were obtained, as described in US Patent 2,661,373.

Nystatin

2489

References Merck Index 6577 Kleeman & Engel p. 123 PDR pp. 830, 993, 1606, 1809, 1999 OCDS Vol. 1 p. 69 (1977) I.N. p. 163 REM p. 892 Schopf, C. and Kunz, K.J.; US Patent 2,661,372; December 1, 1953; assigned to Troponwerke Dinklage & Co., Germany Kulz, F. and Schopf, C.; US Patent 2,661,373; December 1, 1953

NYSTATIN Therapeutic Function: Antifungal Chemical Name: Nystatin Common Name:Structural Formula:

Chemical Abstracts Registry No.: 1400-61-9

Trade Name

Manufacturer

Country

Year Introduced

Mycostatin

Squibb

US

1954

Mycostatine

Squibb

France

1956

Nysta-Dome

Dome

US

1964

Nilstat

Lederle

US

1970

Nysert

Norwich Eaton

US

1979

Multilind

F.A.I.R.

UK

1979

2490

Nystatin

Trade Name

Manufacturer

Country

Year Introduced

Nystex

Savage

US

1983

Biofanal

Pfleger

W. Germany

-

Candex

Dome

US

-

Candio-Hermal

Hermal

W. Germany

-

Herniocid

Mayrhofer

Austria

-

Korostatin

Holland Rantos

US

-

Mycolog

Squibb

US

-

Myco-Triacet

Lemmon

US

-

Mytrex

Savage

US

-

Nadostine

Nadeau

Canada

-

Nyaderm

K-Line

Canada

-

Nystacid

Farmos

Finland

-

Nyst-Olone

Schein

US

-

Rivostatin

Rivopharm

Switz.

-

Stereomycin

Medica

Finland

-

Raw Materials Bacterium Streptomyces noursei Nutrient medium Manufacturing Process A typical isolation and recovery procedure for nystatin is described in US Patent 2,797,183 and is shown in the following diagram: References Merck Index 6580 Kleeman & Engel p. 654 PDR pp.888, 1022, 1034, 1429, 1604, 1751 I.N. p. 696 REM p. 1230 Vandeputte, J. and Gold, W.; US Patent 2,786,781; March 26, 1957; assigned to Olin Mathieson Chemical Corporation Hazen, E.L. and Brown, R.F.; US Patent 2,797,183; June 15, 1957; assigned to Research Corporation Vandeputte, J.; US Patent 2,832,719; April 29, 1958; assigned to Olin Mathieson Chemical Corporation Renella, J.G.; US Patent 3,517,100; June 23, 1970; assigned to American Cyanamid Co.

Nystatin

2491

O

OBIDOXIME CHLORIDE Therapeutic Function: Antidote Chemical Name: Pyridinium, 1,1'-(oxybis(methylene))bis(4(hydroxyimino)methyl)-, dichloride Common Name: Obidoxime chloride Structural Formula:

Chemical Abstracts Registry No.: 114-90-9; 7683-36-5 (Base) Trade Name

Manufacturer

Country

Year Introduced

Toksobidin

Polfa-Starogard

-

-

Toxogonin

Merck KGaA

-

-

Raw Materials Pyridine-4-aldoxime bis-Chloromethyl ether α,α-Dichloro-dimethyl-ether Manufacturing Process 2 Methods of producing of obidoxime chloride: 1. Into a boiling agitated solution of 2.44 g pyridine-4-aldoxime in 10 ml absolute ethanol is added dropwise during the course of 25 min a solution of 1.14 g bis-chloromethyl ether in 5 ml absolute ethanol. The reaction mixture is then refluxed for 35 min, and then agitated for 5 h at room temperature. The precipitate of bis-[4-hydroxyimino-methyl-pyridinium-(1)-methyl]-ether-

2492

Octopamine hydrochloride

2493

dichloride is thoroughly washed with absolute acetone. The yield is 3.5 g which is 98% of the theoretical, and the melting point is 229°C. If convenient, the mother liquor can be reused to make additional product. 2. 12.2 g (0.1 mole) pyridine-4-aldoxime are dissolved with heating in 125 ml chloroform. Within 25 min, 8.5 g (0.075 mole), α,α-dichlorodimethyl ether in 20 ml chloroform are dropped while stirring into the boiling solution. The reaction mixture is heated for another 35 min. After standing for several hours, the precipitate is filtered off, washed with absolute ethanol, acetone and ether and dried at 80°C. Yield: 17.0 g, 95% of the theoretical, and the melting point is 225°C (dec.). References Luttringhaus A. et al.; US Patent No. 3,137,702; June 16, 1964; Assigned: E. Merck, Darmstadt, Germany

OCTOPAMINE HYDROCHLORIDE Therapeutic Function: Hypertensive Chemical Name: α-(Aminomethyl)-4-hydroxybenzene-methanol hydrochloride Common Name: Norsympatol hydrochloride; Norsynephrine hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 770-05-8; 104-14-3 (Base) Trade Name Norfen Depot-Norphen Norphen

Manufacturer Morishita Byk Gulden Byk Gulden

Raw Materials Phenol Aminoacetonitrile Hydrogen chloride Hydrogen

Country Japan W. Germany W. Germany

Year Introduced 1975 -

2494

Octreotide acetate

Manufacturing Process A solution of 33 grams of anhydrous aluminum chloride in 60 grams of nitrobenzene, to which a mixture of 14 grams of phenol and 9.3 grams of hydrochloride of amino-acetonitrile was added, had dry hydrochloric acid gas introduced into it for 3 hours, while stirring and cooling to keep the temperature between 20° and 30°C. The reaction mixture was then poured, with cooling, into 70 cc of water and the deposit obtained was sucked off, washed with acetone and dissolved in 300 cc of water. The solution thus prepared was decolorized with carbon, 50 grams of 30% sodium citrate solution was added to it, and then it was made slightly alkaline with ammonia. Thereupon hydroxy-4'-phenyl-1-amino-2-ethanone crystallized out in the form of leaflets. The yield was 7.7 grams. The hydrochloride of this base, obtained by evaporation to dryness of a solution of the base in dilute hydrochloric acid and subsequent treatment of the residue with ethyl alcohol and acetone, had a chlorine content of 18.84%, (calculated, 18.90%). This hydrochloride, on being dissolved in water and hydrogenated with hydrogen and a nickel catalyst, gave a good yield of hydrochloride of hydroxy4'-phenyl-1-amino-2-ethanol melting, after crystallization from a mixture of ethyl alcohol and butanone-2, at from 177° to 179°C with decomposition. References Merck Index 6599 Kleeman and Engel p. 655 I.N. p. 699 Asscher, M.; US Patent 2,585,988; February 19, 1952

OCTREOTIDE ACETATE Therapeutic Function: Antiulcer, Growth hormone inhibitor Chemical Name: L-Cysteinamide, D-phenylalanyl-L-cysteinyl-L-phenylalanylD-tryptophyl-L-lysyl-L-threonyl-N-(2-hydroxy-1-(hydroxymethyl)propyl)-, cyclic(2-7)-disulfide, (R-(R*,R*))-, acetate (salt) Common Name: Octreotide acetate Chemical Abstracts Registry No.: 79517-01-4; 83150-76-9 (Base) Trade Name

Manufacturer

Country

Year Introduced

Sandostatin

Novartis Pharma AG

Switz.

-

Sandostatin LAR

Novartis Pharma AG

Switz.

-

Octreotide acetate

2495

Structural Formula:

Raw Materials Threoninol Piperidine Tfifluoroethanol Iodine Threonino Trifluoroacetic acid

N,N-Diisopropylethylamine Diisopropylcarbodiimide Hydroxybenzotriazole Boc-D-Phe; Fmoc-Cys(Trt); Fmoc-Trp; Fmoc-Lys(Boc); Fmoc-Thr(tBu)

Manufacturing Process Synthesis of octreotide and derivative thereof can be carried out by two methods. The first method is synthesized initially by fragment condensation solution phase procedures. The synthetic process of octreotide has been described by Bauer et al. (1). The second method is the synthese by solidphase procedures. Edward et al. (2) isolated side chain protected octreotide with a total yield of 14% by cleaving the protected peptide from the resin with threoninol. Arano et al. (3) carried out another solid phase method for octreotide. and produced it in overall 31.8% yield based on the starting FmocThr(tBu)-ol-resin. The basic difference from the other procedures already described is that the introduction of the threoninol is carried out upon the protected peptidic structure (resin-free), which, when appropriately activated, leads quantitatively and without needing to make temporary protections upon the threoninol, to the protected precursor of octreotide, which in turn, with a simple acid treatment leads to octreotide with very high yields. At first the Fmoc-Cys-Cl-trityl-resin was prepared. The incorporation of the Fmoc-Cys(trt)-OH residue upon 2Cl-Trt resin is accomplished with an excess of 1 eq. of Fmoc-Cys(Trt) and 2.5 eq. of N,N'-diisopropylethylamine (DIEA). 2.93 g (5.0 mmol) of Fmoc-Cys(Trt) are incorporated upon 5 g of resin (f = 1.28 mmol/g of resin, 6.4 mmol). The resin and the amino acid are weighed in separate containers and left to dry in a vacuum with KOH, for a minimum of two hours. A 1/1 solution of DIEA and CH2Cl2 (DCM) (dry on a 4A sieve) is

2496

Octreotide acetate

prepared. The already dry amino acid is dissolved with dry DCM at a concentration of 0.1 g of resin per ml, adding the minimum quantity of dry DMF to complete the dissolution. 1/3 of the 1.8 ml (12.5 mmol) DIEA solution is added to this transparent solution in 1.8 ml of DCM. This is thoroughly homogenized and added to the dry resin. It is subjected to vigorous magnetic agitation for five minutes and the rest of the DIEA is added to the reaction; the mixture is allowed to react for forty minutes more. Then, 4 ml of dry MeOH are added and allowed to react for 10 minutes, after which the resin is filtered and the washings described below are carried out. Step 1 2 3 4

Reagent DMF 5% piperidine/(DMF/DCM) 20% piperidine/DMF DMF

Repetitions 3 1 1 3

Time(min) 1' 10' 15' 2'

The incorporation of the amino acids for obtaining of Boc-D-Phe-Cys-(Trt)-DTrp-Lys(Boc)-Thr(tBu)-Cys(Trt)-2-Cl-trityl-resin is carried out following a synthesis program such as that described below, using an excess of 2.5 equivalents of Fmoc-amino acid, N-hydroxybenzotriazol (HOBt) and diisopropylcarbodiimide (DIPCDI). Later the Fmoc group is deprotected with 20% of piperidine/DMF for 1 min + 5 min. Step 1* 2* 3* 4* 5* 6 7 8

Reagent DMF pip/DMF 20% pip/DMF 20% DMF Fmoc aminoacid HOBt DIPCDI DMF

Repetitions 5 5 1 1 5

Time(min) 1' 1' 5' 1' + + 40' 1'

[*for Thr] Control by Ninhydrin test; if (+), return to 5; if (-) follow step 1 forward following amino acid. The yields at the end of the synthesis are quantitative in obtaining Boc-D-PheCys(Trt)-Phe-D-Trp-Lys(Boc)-Thr(tBu)-Cys(Trt)-2Cl-trityl-resin. Preparation of Boc-D-Phe-Cys(Trt)-Phe-D-Lys(Boc)-Thr(tBu)-Cys(Trt) 250 mg (113 µmols) of Boc-D-Phe-Cys(Trt)-Phe-D-Trp-Lys(Boc)-Thr(tBu)Cys(Trt)-2Cl-trityl-resin are treated with 6.36 ml of mixture 7/2/1 or 5.5/0.5/4 of DCM/TFE(tfifluoroethanol)/AcOH, for two hours, under magnetic agitation. The suspension is then filtered and washed 3 times with 0.2 ml of the 7/2/1 mixture of DCM/TFE/AcOH. The solution is evaporated (if it is not desired to proceed with the oxidation) until dry, at reduced pressure, and the solid obtained is washed with water. The yield is quantitative. Obtaining of cycle (2-7)Boc-D-Phe-Cis-Phe-D-Trp-Lys(Boc)-Thr(tBu)-Cis-OH (Oxidized 1-7 fragment).

Octreotide acetate

2497

250 mg (113 mmols) of Boc-D-Phe-Cys(Trt)-Phe-D-Trp-Lys(Boc)-Thr(tBu)Cys(Trt)-COOH dissolved in 7 ml of the 7/2/1 mixture of DCM/TFE/AcOH, is slowly added to 290 mg (1.13 mmol) of iodine of 0.8 M concentration in the 7/2/1 mixture of DCM/TFE/AcOH. The reaction is allowed to evolve for 15 minutes. 4.3 ml of a Na2S2O7, 1 N solution is added to eliminate the iodine excess. The aqueous phase is extracted and washed three times with 1 ml of DCM, the entirety of the organic phases is extracted with a citric acid/water solution and is evaporated at reduced pressure to dryness. The solid obtained is washed with water. The yield fluctuates between 85 and 95%. Coupling of cycle (2-7)Boc-D-Phe-Cis-Phe-D-Trp-Lys(Boc)-Thr(tBu)-Cis-OH (Oxidized 1-7 fragment) with Throl. Over 250 mg (230 µmols) of (2-7)Boc-D-Phe-Cis-Phe-D-Trp-Lys(Boc)-Thr(tBu)Cis-OH(Oxidized 1-7 fragment), 103 mg (690 µmol) of HOBt and 72 mg (690 µmol) of threoninol are weighed out and dissolved in 10 ml of dry DMF/dry DCM (1:1); under vigorous agitation, 111 µL (690 µmols) of DIPCDI are added. The mixture is allowed to react for five hours at room temperature. It is evaporated to dryness until an oil is obtained, water is added, the mixture is well homogenized by ultrasound and lyophilized. The coupling is quantitative. Oxidation of Boc-D-Phe-Cys(Trt)-Phe-D-Trp-Lys(Boc)-Thr(tBu)-Cys(Trt)-Throl. Obtaining of cycle (2-7)Boc-D-Phe-Cis-Phe-D-Trp-Lys(Boc)-Thr(tBu)-CisThrol(Oxidized fragment 1-8). 250 mg (147 µmols) of Boc-D-Phe-Cys(Trt)-Phe-D-Trp-Lys(Boc)-Thr(tBu)Cys(Trt)-Throl dissolved in 8.26 ml of mixture 7/2/1 of DCM/TFE/AcOH, are slowly added to a solution of 290 mg (1.47 mmol) of iodine of 0.8 M concentration in the mixture 7/2/1 of DCM/TFE/AcOH. The reaction is allowed to evolve for 15 minutes. 4.3 ml of an Na2S2O7 1 N is added to eliminate the excess iodine. The aqueous phase is extracted and washed three times with 1 ml of DCM, the entirety of the organic phases is extracted with a solution of citric acid and water and is evaporated at reduced pressure to dryness. The solid obtained is washed with the help of a filter plate and water. Removal of protecting groups. Obtention of Octreotide. 230 mmols cycle (2-7)Boc-D-Phe-Cis-Phe-D-Trp-Lys(Boc)-Thr(tBu)-Cis-Throl (Oxidized 1-8 fragment)n are treated with 2 ml of trifluoroacetic acid (TFA) (95:5%) for five hours at ambient temperature. Later, the filtrate is dropped over 100 ml of dry and cold diethyl ether and the white precipitate obtained is once again centrifuged. The solid is resuspended in diethyl either and centrifuged again, repeating the operation five times more. The crude peptide is purified by preparative HPLC at 25% of CH3CN/H2O with 0.01% TFA in a 10 µml. References Bayer W. et al.; Eur. Patent Appl. 29,579, 1981 and Bayer W. et al.; US Patent No. 4,395,403; July 26, 1983; Assigned: Sandoz Ltd. (Basel, CH) Edward et al.; J. Med. Chem. 1994, 37, 3749-3757

2498

Ofloxacin

Arano et al.; Bioconjugate Chem. 1997, 8, 442-446 Obiols B. et al.; US Patent No. 6,346,601 B1; Feb. 12, 2002; Assigned to Lipotec S.A., Barcelona (ES)

OFLOXACIN Therapeutic Function: Antibacterial Chemical Name: 7H-Pyrido(1,2,3-de)-1,4-benzoxazine-6-carboxylic acid, 2,3-dihydro-9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-, ()Common Name: Mefoxacin; Ofloxacin Structural Formula:

Chemical Abstracts Registry No.: 82419-36-1; 83380-47-6 Trade Name Exocin Floxan Floxil Floxin Floxin Floxin Floxin Floxstat Oflo Oflomac Oflox Ofloxacin Ofloxacin Ofloxacin Ofloxacin Ofloxacin Ofloxin 200 Quinoxan Tarivid

Manufacturer Allergan Janssen-Cilag Cilag Aetna Inc. Janssen-Ortho Inc. Ortho McNeil Jannsen-Cilag Unique Macleods Pharmaceuticals Allergan JAKA-80 Nu-Pharm Inc. Ranbaxy Chemo Iberica Huanguan East Asia Chemical Co. Leciva Andromaco Hoechst

Country India India

Year Introduced -

Macedonia Canada India Spain China

-

Czech Republic Germany -

Ofloxacin Trade Name Tarivid Uroflox Urosin Zanocin Zanocin Zanocin

Manufacturer Hoechst Marion Roussel Houde Sifar Ranbaxy Guangzhow Ranbaxy Ireland Ranbaxy

Country India China Ireland India

2499

Year Introduced -

Raw Materials 3,4-Trifluoronitrobenzene Sodium dithionite N-Methylpiperazine

Dimethyl sulfoxide Ethyl polyphosphate Diethyl ethoxymethylenemalonate

Manufacturing Process 20 g of 2,3,4-trifluoronitrobenzene was dissolved in 150 ml of dimethyl sulfoxide, and to this mixture a solution of 10% potassium hydroxide was added dropwise while keeping the temperature at 18° to 20°C. Then, the mixture was stirred for 2 hours at room temperature and one liter of water was added to this reaction mixture and the mixture was shaken with chloroform. The water layer was acidified with hydrochloric acid and was extracted with chloroform. The extract was washed with water and was dried, then chloroform layer was concentrated. The residue was purified by silica gel column chromatography to provide 5.8 g of 2,3-difluoro-6-nitrophenol as yellow oil. 7.9 g of the 2,3-difluoro-6-nitrophenol, 50.1 g of 1,2-dibromoethane and 18.7 g of potassium carbonate were added to 80 ml of dimethylformamide and the mixture was stirred for 2.5 hours at from about 80° to 100°C (bath temperature). The reaction mixture was concentrated to dryness in vacuo and the residue was distributed between ethyl acetate and water. The organic solvent layer was washed with water and was dried, then the solvent was evaporated. The residue was dissolved in benzene and was purified by silica gel column chromatography to provide 7.7 g of 2-(2-bromoethoxy)-3,4difluoronitrobenzene as light yellow oil. 1.74 g of this product was dissolved in 30 ml of methanol and a solution of 6.44 g of sodium dithionite dissolved in 15 ml of water was added thereto. The mixture was stirred for 1 hour at room temperature. Methanol was evaporated and the residue was extracted with chloroform. After the extract was washed with water and dried, the solvent was evaporated to provide 0.44 g of 2-(2-bromoethoxy)-3,4-difluoroaniline. 1.82 g of this product and 3.03 g of potassium carbonate were added to 10 ml of dimethylformamide and the mixture was stirred for 1 hour at from about 80° to 100°C (bath temperature). The reaction mixture was added to ice-cold water and was extracted with ethyl acetate. After the extract was washed with water and dried, the solvent was distilled off at room temperature to provide 1.21 g of 7,8-difluoro-2,3-dihydro-4H-[1,4]benzoxazine with m.p. 48°-54°C. The mixture of 1.1 g of this product and 1.38 g of diethyl

2500

Olanzapine

ethoxymethylenemalonate was stirred for 2 hours at from about 130° to 135°C (bath temperature). The ethanol produced was evaporated and 20 g of ethyl polyphosphate was added to the residue. Then the mixture was stirred for 1.5 hours at from about 140° to 145°C (bath temperature). The reaction mixture was added to ice-cold water and was extracted with chloroform. The extract was washed fully with water. After drying, the solvent was evaporated and the residue was recrystallized from ethyl acetate. 1.3 g of ethyl 9,10difluoro-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6carboxylate was obtained as colorless needles with m.p. 265°-266°C. 1.15 g of this product was added to 12 ml of mixture of concentrated hydrochloric acid and acetic acid (1:4 by volume) and the mixture was stirred for 4 hours at 100° to 110°C (bath temperature). After cooling, the precipitated crystals were collected by filtration, washed with water, methanol and chloroform to give 0.78 g of 9,10-difluoro-7-oxo-2,3-dihydro-7Hpyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid as colorless needles with m.p. above 300°C. 1.0 g of 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3de][1,4]benzoxazine-6-carboxylic acid and 2.85 g of N-methylpiperazine were added to 15 ml of dimethylsulfoxide. The mixture was stirred at a temperature of from about 100° to 110°C (bath temperature) for 12 hours and the reaction mixture was concentrated to dryness in vacuo and 40 ml of water was added to the residue. Then the product was extracted with chloroform. The extract was dried and concentrated to dryness in vacuo. The residue was recrystallized from ethanol to provide 550 mg of 9-fluoro-3-methyl-10-(4methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido[1,2,3de][1,4]benzoxazine-6-carboxylic acid as colorless needles with m.p. 250°257°C (with decomposition). References Hayakawa I. et al.; US Patent No. 4,382,892; May 10, 1983; Assigned to Dalichi Selyaku Co., Ltd., Tokyo, Japan

OLANZAPINE Therapeutic Function: Antipsychotic Chemical Name: 10H-Thieno(2,3-b)(1,5)benzodiazepine, 2-methyl-4-(4methyl-1-piperazinyl)Common Name: Olanzapine Raw Materials Propionaldehyde Triethylamine 2-Fluoronitrobenzene N-Methylpiperazine

Dimethyl sulfoxide Malononitrile Stannous chloride

Olanzapine

2501

Structural Formula:

Chemical Abstracts Registry No.: 132539-06-1 Trade Name Joyzol Olan Olandus Olanex Oleanz Olexa Onza Zyprexa Zyprexa Zydis

Manufacturer Merind Limited Synapse (A Div. of Microlabs) Zydus Neurosciences Solus Sun Pharmaceuticals Industries Ltd. Protech Biosystems SPPL (Sarabhai Piramal Pharmaceuticals Ltd.) Eli Lilly Eli Lilly

Country India India

Year Introduced -

India India India

-

India

-

UK UK

-

Manufacturing Process 1. 2-Amino-5-methylthiophene-3-carbonitrile A mixture of sulphur (217.8 g, 6.79 mol), propionaldehyde (472.5 g, 587 mL, 8.13 mol) and dimethylformamide (1350 m) was placed in a 5 liter flangenecked flask fitted with air stirrer, air condenser, thermometer and dropping funnel. Triethylamine (576 mL, 4.13 mol) was added dropwise over 30 minutes to the cooled stirred reaction mixture whilst maintaining the pot temperature between 5°-10°C with an ice-bath. After addition was complete the pot was allowed to warm up to 18°C over 50 minutes, keeping the mixture well stirred. Then a solution of malononitrile (450 g, 6.8 mol) in dimethylformamide (900 mL) was added dropwise over 70 minutes keeping the pot temperature around 20°C throughout the addition. After addition was complete the mixture was stirred at 15°-20°C for a further 45 minutes then sampled for TLC. The mixture was then poured onto ice (4 liters)/water (8 liters) with stirring and this caused the required product to precipitate. After 10 minutes the stirrer was switched off and the solid allowed to settle. The aqueous liquor was decanted away and the solid isolated by filtration. The isolated solid was well washed with water (de-ionised, 4 liters), then dried over night in vacuo at 70°-75°C to give the title compound (585 g), m.p. 100°C.

2502

Oleandomycin

2. 2-(2-Nitroanilino)-5-methylthiophene-3-carbonitrile To a stirred slurry of sodium hydride (14.4 g, 50% dispersion in oil, 0.3 mol) in dry tetrahydrofuran (50 mL) under nitrogen was added, dropwise, a solution of 2-fluoronitrobenzene (28.2 g, 0.2 mol) and 2-amino-5methylthiophene3-carbonitrile (27.6 g, 0.2 mol) in dry tetrahydrofuran (250 mL). The mixture was stirred at 25°C for 24 hours, poured onto cracked ice and extracted into dichloromethane (3 times 500 mL). The combined extracts were washed with 2 N hydrochloric acid (2 times 200 mL), water (2 times 200 mL), dried over magnesium sulphate and the solvent removed under reduced pressure. The residue was crystallised from ethanol to give the title compound, (35.2 g), m.p. 99°-102°C. 3. 4-Amino-2-methyl-10H-thieno[2,3-b][1,5]benzodiazepine, hydrochloride To a stirred slurry of 2-(2-nitroanilino)-5-methylthiophene-3-carbonitrile (3 g, 0.011 mol) in ethanol (35 mL) at 50°C was added, over 10 minutes, a solution of anhydrous stannous chloride (6.95 g, 0.037 mol) in hydrochloric acid (26 mL, 5 M). The mixture was stirred under reflux for 1 hour, concentrated under reduced pressure and allowed to crystallise over night at 5°C. The salt was filtered, washed with a small amount of water, dried (4.3 g) m.p. >250°C, and used without further purification in the next stage. 4. 2-Methyl-10-(4-methyl-1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine Crude 4-amino-2-methyl-10H-thieno[2,3-b][1,5]benzodiazepine, hydrochloride (4.3 g) was refluxed in a mixture of N-methylpiperazine (15 mL), dimethylsulfoxide (20 mL) and toluene (20 mL) under a nitrogen atmosphere for 20 hours. The mixture was cooled to ca. 50°C, water (20 mL) added, and the product allowed to crystallise at 5°C over night. The product was filtered and crystallised from acetonitrile (30 mL) to give the title compound (1.65 g) m.p. 195°C. The structure of the compound was confirmed spectroscopically. References Chakrabarti J.K. et al.; US Patent No. 5,229,382; Jul. 20, 1993; Assigned to Lilly Industries, Basingstroke, England

OLEANDOMYCIN Therapeutic Function: Antibiotic Chemical Name: Oleandomycin Common Name: Troleandomycin Chemical Abstracts Registry No.: 3922-90-5

Oleandomycin

2503

Structural Formula:

Trade Name Matromycin Oleandocyn Oimicina Sigmamycin Taocin-O TAO Triolmicina

Manufacturer Pfizer Pfizer Morgan Pfizer Sankyo Roerig Ripari-Gero

Country US W. Germany Italy Japan Japan US Italy

Year Introduced 1956 -

Raw Materials Bacterium Streptomyces antibioticus Dextrose Soybean meal Manufacturing Process A slant of S. antibioticus ATCC 11891 was cultivated on agar under controlled conditions in order to develop spores for the purpose of inoculating a nutrient medium having the following composition: 20 g Cerelose (dextrose hydrate), 15 g soybean meal, 5 g distillers' solubles, 10 g cornmeal, and tap water, in a sufficient amount for a 1,000 ml solution, adjusted to pH 7.0 to 7.2 with potassium hydroxide. After the pH was adjusted, 5 g of calcium carbonate was added. This inoculum medium was then subjected to heat sterilization. The medium was then cooled and 2 ml of a spore suspension of an oleandomycin-producing strain of S. antibioticus was added under aseptic conditions. The cultivation of the organism was conducted in shaken flasks at 28% for a period of 48 hours. The mixture of broth and mycelium thus formed was then transferred under aseptic conditions to a 3-liter fermentor containing 2,000 ml of a sterile

2504

Olopatadine

fermentation medium having the following composition: 60 g Cerelose (dextrose hydrate), 18 g soybean meal, 5 g distillers' solubles, 12 g cornmeal and tap water in a sufficient amount for a 1,000 ml total volume, adjusted to pH 7.0 to 7.2 with potassium hydroxide. After the pH had been adjusted, 5 g of calcium carbonate, 5 ml of soybean oil antifoam and 0.020 g of Acridine Orange dye were added. The mixture was then autoclaved at 20 psi (250°F) for 15 minutes in order to sterilize the contents, before transferring the broth and mycelium thereto. After seeding the nutrient medium with the preformed inoculum previously described, the mixture was subjected to agitation and aeration under aseptic conditions for 72 hours; at 27°C to 28°C for the first 24 hours, then at 25°C to 26°C for the next 48 hours; during this period, the pH was in the range of 6.4 to 6.8. Aeration was accomplished by cultivation under submerged conditions at an air flow rate of one volume of air per volume of medium per minute. After termination of the process, the mycelium was removed by filtration and the filtered broth found to contain 450 γ of oleandomycin per ml of solution. References Merck Index 6703 Kleeman & Ensel P. 657 I.N. p. 701 Sobin, B.A., Routien, J.B. and Lees, T.W.; US Patent 2,757,123; July 31, 1956; assigned to Chas. Pfizer & Co., Inc. Ratajak, E.J. and Nubel, R.C.; US Patent 2,842,481; July 8, 1958; assigned to Chas. Pfizer & Co., Inc.

OLOPATADINE Therapeutic Function: Antiallergic Chemical Name: 11-((Z)-3-(Dimethylamino)propylidene)-6,11dihydrodibenz[b,e]oxepin-2-acetic acid Common Name: Doxepadine; Olopatadine Structural Formula:

Olopatadine Trade Name Patanol

Manufacturer Alcon

Country UK

2505

Year Introduced -

Chemical Abstracts Registry No.: 113806-05-6 Raw Materials Phthalide POCl3 Butyl lithium Sodium permanganate Magnesium Dibromoethane

p-Hydroxyphenyl acetic acid Boron trifluoride-ethylether complex Methyltriphenylphosphonium bromide Triphenylchloromethane 3-Dimethylaminopropyl chloride Trifluoroacetic anhydride

Manufacturing Process 402.4 g of phthalide and 200 g of sodium chloride and equal molecular quantity of p-hydroxyphenyl acetic acid are mixed with one another and stirred at 150°C for 6 hours. After completion of the reaction, the mixture is cooled until the temperature is brought back to room temperature, 4 L of aqueous 10% acetic acid solution is added thereto and the mixture is allowed to stand at room temperature overnight. After stirring the mixture at room temperature for 3 hours, deposited crystals are separated by filtration, and 6 L of water is added thereto. After stirring the mixture at room temperature for 30 minutes, the deposited crystals are separated by filtration. After the addition of 3 L of toluene to the crystals, the mixture is stirred at room temperature for one hour. The crystals are separated by filtration and dried over heating under reduced pressure to yield of 2-(4-acetoxyphenoxy)benzoic acid. 266.0 g of trifluoroacetic anhydride is added to the equal molecular quantity of 2-(4-acetoxyphenoxy)benzoic acid suspended in 5.0 L of methylene chloride and thereto. After stirring the mixture at room temperature for one hour, 19.4 g of boron trifluoride-ethylether complex is added thereto and the mixture is stirred at room temperature for two hours. The reaction solution is poured into ice water. After an organic solvent layer is separated from the mixture, the organic layer is washed with diluted aqueous sodium hydroxide solution and water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 335.3 g of methyl 11-oxodibenz[b,e]oxepin-2carboxylate as a white crystal melting point 130°-132°C Methyl 11-methylene-6,11-dihydrodibenz-[b,e]oxepin-2-acetate. In 100 ml of tetrahydrofuran is suspended 25 g of methyltriphenylphosphonium bromide and 40 ml of 1.6 N n-butyl lithium hexane solution is dropwise added thereto under a nitrogen atmosphere and ice-cooling. After stirring the mixture under ice-cooling for 30 minutes, a solution obtained by dissolving equal molar quantity of 11-oxo-6,11dihydrodibenz[b,e]oxepin-2-acetic acid in 250 ml of tetrahydrofuran is dropwise added thereto and the mixture is stirred at room temperature for two hours. The solvent is distilled away under reduced pressure and the residue is purified by column chromatography on silica gel (eluent: hexane:ethyl acetate = 3:1) to obtain the desired product as a colorless oily

2506

Olopatadine

matter. (11-(3-Dimethylaminopropylidene)-2-(2-triphenylmethyloxymethyl)-6,11dihydrodibenz[b,e]oxepin. Process A: 11-Hydroxy-2-(2-hydroxyethyl)-6,11-dihydrodibenz [b,e]oxepin In this process, 20 g of methyl 11-oxo-6,11-dihydrodibenz[b,e]oxepin-2acetate is dissolved in 500 ml of tetrahydrofuran. To the solution is added 6.0 g of lithium aluminum hydride and the mixture is stirred at room temperature for one hour. After decomposing an excess of the reagent by the addition of water to the solution, the mixture is filtered to remove an inorganic salts and the filtrate is concentrated to dryness under reduced pressure to obtain 17.7 g of the desired product as a white solid. Melting point: 132°-136°C. Process B: 11-Hydroxy-2-(2-triphenylmethyloxyethyl)-6,11dihydrodibenz[b,e]oxepin In this process, 17.2 g of 11-hydroxy-2-(2-hydroxyethyl)-6,11dihydrodibenz[b,e]oxepin is dissolved in 50 ml of pyridine. To the solution is added 30 g of triphenylchloromethane and the mixture is stirred at 50°C for 5 hours. After adding water and stirring the mixture for 2 hours, the solvent is distilled away under reduced pressure. The mixture is extracted with 1000 ml of ethyl acetate, washed with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent is distilled away under reduced pressure and the resultant residue is purified by column chromatography on silica gel (eluent: hexane:ethyl acetate = 3:1 ) to obtain 21.7 g of the desired product as a colorless amorphous. Process C: 11-Oxo-2-(2-triphenylmethyloxyethyl)-6,11dihydrodibenz[b,e]oxepin In this process, 10 g of 11-hydroxy-2-(2-triphenylmethyloxyethyl)-6,11dihydrodibenz[b,e]oxepin is dissolved in a solution comprising 800 ml of acetone, 1000 ml of water, 20 ml of saturated aqueous magnesium sulfate solution and 0.2 g of disodium phosphate. To the solution is dropwise added 2.6 g of aqueous sodium permanganate solution and the mixture is stirred at room temperature for 4.5 hours. Then, 100 ml of methanol is added thereto and the mixture is heated at reflux for 3 hours. After allowing the mixture to stand for cooling, the mixture is filtered and the filtrate is extracted with 1000 ml of ethyl acetate, washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is distilled away under reduced pressure and the resultant crude product is recrystallized from isopropanol to obtain 8.0 g of the desired product having melting point of 132°-134°C as a white crystal. Process D: 11-(3-Dimethylaminopropyl)-11-hydroxy-2-(2triphenylmethyloxyethyl)-6,11-dihydrodibenz[b,e]oxepin To a solution of 3-dimethylaminopropyl magnesium chloride obtained by reacting 0.2 g of magnesium with 1.0 g of 3-dimethylaminopropyl chloride in 10 ml of tetrahydrofuran under a nitrogen atmosphere using dibromoethane as a catalyst, is dropwise added a solution obtained by dissolving 2.0 g of 11-

Olopatadine

2507

oxo-2-(2-triphenylmethyloxyethyl)-6,11-dihydrodibenz[b,e]oxepin in 10 ml of tetrahydrofuran under ice cooling and the mixture is stirred at room temperature for one day. Aqueous ammonium chloride solution is added thereto and the pH of the mixture is adjusted to 7.0 with aqueous 4 N hydrochloric acid solution. The solvent is distilled away under reduced pressure. The mixture is extracted with 200 ml of methylene chloride and washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution in order. After drying the extract over anhydrous sodium sulfate, the solvent is distilled away under reduced pressure. The resultant residue is purified by column chromatography on silica gel (eluent: hexane:ethyl acetate:triethylamine = 10:10:1) to obtain 1.2 g of the desired product as a colorless amorphous. Process E: 11-(3-Dimethylaminopropylidene)-2-(2-triphenylmethyloxyethyl)6,11-dihydrodibenz[b,e]oxepin In this process, 1.2 g of 11-(3-dimethylaminopropyl)-11-hydroxy-2-(2triphenylmethyloxyethyl)-6,11-dihydrodibenz[b,e]oxepin is dissolved in 50 ml of pyridine. To the solution is dropwise added 0.8 g of phosphorusoxychloride under a nitrogen atmosphere and ice-cooling. After stirring the mixture at room temperature for one hour, the solvent is distilled away under reduced pressure. The residue is extracted with 100 ml of methylene chloride, and washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution in order. After drying the mixture over anhydrous sodium sulfate, the solvent is distilled away under reduced pressure. The resultant residue is purified by column chromatography on silica gel (eluent: hexane:ethylacetate:triethylamine = 10:10:1) to obtain 0.82 g of the desired product as a colorless oily matter. 11-(3-Dimethylaminopropylidene)-2-(2-hydroxyethyl)-6,11dihydrodibenz[b,e]oxepin 0.92 g of 11-(3-dimethylaminopropylidene)-2-(2-triphenylmethyloxyethyl)6,11-dihydro dibenz[b,e]oxepin is dissolved in a mixed solvent of 20 ml of water and 20 ml of dioxane. To the solution is added 60 mg of p-toluene sulfonic acid and the mixture is heated at reflux for two hours. The solvent is distilled away under reduced pressure and the residue is extracted with 200 ml of ethylacetate, washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium hydrochloride solution in oder and dried over anhydrous sodium sulfate. The solvent is distilled away under reduced pressure. The resultant residue is purified by column chromatography on silica gel (eluent: ethylacetate triethylamine = 10:1) to obtain 0.4 g of the desired product. Cis form white solid. Melting point: 100°-102°C (diethylether). 11-(3-Dimethylaminopropylidene)-6,11-dihydrodibenz [b,e]oxepin-2-acetic acid 2.2 g of 11-(3-dimethylaminopropylidene)-2-(2-hydroxyethyl)-6,11dihydrodibenz[b,e]oxepin is dissolved in 100 ml of acetone. The Jones reagent (Na2Cr2O7+ H2SO4) is added to the solution until the reaction solution shows an orange color and the mixture is stirred at room temperature for one hour. Sodium bicarbonate is added thereto and an inorganic substance is removed by filtration. The solvent of the filtrate is distilled away under reduced

2508

Omeprazole

pressure to obtain the desired product, 11-(3-Dimethylaminopropylidene)6,11-dihydrodibenz[b,e]oxepin-2-acetic acid. Cis form white crystal. Melting point: 118°-120°C (Isopropanol). References Oshima et al.; US Patent No. 5,116,863; May 26, 1992; Assigned to Kyowa Hakko Kogyo Co., Ltd., Tokyo, Japan Hayakawa E. et al.; US Patent No. 5,641,805, Jun. 24, 1997; Assigned to Alcon Laboratories, Inc. (Fort Worth, TX); Kyowa Hakko Kogyo Co. Ltd. (Tokyo, JP)

OMEPRAZOLE Therapeutic Function: Antiulcer Chemical Name: 1H-Benzimidazole, 5-methoxy-2-(((4-methoxy-3,5dimethyl-2-pyridinyl)methyl)sulfinyl)Common Name: Omeprazole Structural Formula:

Chemical Abstracts Registry No.: 73590-58-6 Trade Name Fordex Gastrium Gastrotem Helicid 10 Helicid 11 Lenar Lomak Losec Losec MUPS Lozol Norpramin Ocid Omegast Omegast Omepar

Manufacturer Leti Ache Temis Lostalo Leciva Colins Laboratories Ltd. Chemica Cipla Limited Astra AstraZeneca Medinfar Cepa Cadila Healthcare Lifesource Healthcare Agio Pharmaceuticals Ltd. Nabros Pharma

Country Czech Republic India India Sweden Sweden India India India India

Year Introduced -

Omeprazole Trade Name Omeprazole Omeprazole Omeprazole Omeprazole OmeprazoleRichter Omeprol Omez Omizac OMZ Osiren Pamoxan Pepticum Prazol Proseptin Sanamidol Ulceral Ultop Ulzol Zerocid Zolcer

2509

Manufacturer Balkanpharma New Life Pharmaceuticals Chemo Iberica Aurobindo Lyconsa

Country Bulgaria India Spain India Spain

Year Introduced -

Zdravle Dr. Reddy's Laboratories Ltd. Torrent Dexa Medica Chemia Italmex Laboratorios Andromaco Tecnoquimicos Beximco Inkeysa Tedec-Meiji Krka Pliva Sun Pharmaceuticals Industries Ltd. Aurobindo

Yugoslavia India India Spain Slovenia Horvatia India

-

India

-

Raw Materials 3,5-Lutidine Dimethyl sulfate Thionyl chloride Phthalic anhydride

Hydrogen peroxide Ammonium persulfate 5-Methyl-2-mercaptobenzimidazole Benzylammonium chloride

Manufacturing Process 3,5-Lutidine-N-Oxide Hydrogen peroxide (45%, 200 ml) was added dropwise at 60°-70°C during 2 hours to a mixture of 3,5-Lutidine (125 g, 1.16 mole) and acetic acid (400 ml). The mixture was heated to 90°C and maintained at 90°-100°C for 2 hours after which it was cooled to 60°C. Again hydrogen peroxide (45%, 200 ml) was added dropwise at 60°-70°C during 1 hour and then the mixture was heated to 90°C and maintained at 90°-100°C for 6 hours. Thereafter, acetic acid and water was distilled off under reduced pressure and the distillation residue obtained was used as a starting product for the nitration. 3,5-Dimethyl-4-nitropyridine-N-oxide To the distillation above obtained residue was added sulphuric acid (146 ml). Thereafter, a nitrating mixture consisting of sulphuric acid (250 ml) and nitric acid (280 ml) was added dropwise during 4 hours at 90°-100°C. The reaction

2510

Omeprazole

mixture was heated further at 90°-100°C for 6 hours, after which it was cooled and poured over crushed ice (4 kg), Caustic lye (50%, 1150 ml) was added to the yellow solution and the precipitated crystalline compound was filtered under suction. The cake was washed with water and dried in vacuuo oven to yield the product which melted at 171°-173°C. Yield 78.5%. A sample crystallized from acetone had a melting point of 174°-174.5°C. 3,5-Dimethyl-4-nitropyridine-N-oxide-dimethyl sulfate adduct To a suspension of 3,5-dimethyl-4-nitropyridine-N-oxide (150 g, 0.80 mole) in acetone (450 ml) was added dimethyl sulfate (90 ml, 0.95 mole). The mixture was heated to reflux until a clear solution was obtained and then allowed to cool to ambient temperature. An off-white crystalline solid separated out, which was filtered, washed with acetone and dried to yield 220 g of the adduct. Yield was 83.8% of theoretical. 3,5-Dimethyl-2-hydroxymethyl-4-nitropyridine 3,5-Dimethyl-4-nitropyridine-N-oxide-dimethyl sulfate adduct (220 g, 0.75 mole) was dissolved in methanol (1.0 ltr) and the solution heated to reflux. A solution of ammonium persulfate (140 gm) in water (200 ml) was added dropwise over 4 hours after which reflux was continued for 4 hours. Methanol was distilled off under reduced pressure and the residue was basified to pH 10 by addition of caustic lye (105 ml). The mixture was extracted with dichloromethane (2 times 400 ml). The dichloromethane layer was dried over sodium sulfate and filtered. The product was used as its solution in dichloromethane for the next reaction. 2-Chloromethyl-3,5-dimethyl-4-nitropyridine hydrochloride To the cooled dichloromethane solution of 3,5-dimethyl-2-hydroxymethyl-4nitropyridine was added thionyl chloride (60 ml, 0.85 mole) dropwise over a period of 2 hours and stirring was continued for a further 2 hours. Methanol (10 ml) was added to destroy excess thionyl chloride and separated product was filtered under suction and washed with dichloromethane. The cake was dried in vacuum oven to yield 55 g of a cream colored product. Melting point was 124°-126°C. 5-Methoxy-2-[(3,5-dimethyl-4-nitro-2-pyridinyl)methylthio]-1H-benzimidazole To a suspension of 5-methyl-2-mercaptobenzimidazole (36 g, 0.2 mole), 2chloromethyl-3,5-dimethyl-4-nitropyridine hydrochloride (47.4 g, 0.2 mole) and triethyl benzylammonium chloride (5 g) in a dichloromethane (500 ml) was added dropwise a solution of NaOH (17.6 gm, 0.44 mole) in water (30 ml). The addition was exothermic and the temperature was observed to rise to 40°C with reflux of dichloromethane - the reaction mixture was stirred for further 6 hours at ambient temperature and filtered. The cake was washed with water and dried in vacuum oven to yield 55.8 g of cream color product. Yield 81.1%; melting point 124°-128°C. 5-Methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridinyl)methylthio]-1Hbenzimidazole

Omeprazole

2511

5-Methoxy-2-[(3,5-dimethyl-4-nitro-2-pyridinyl)methylthio]-1Hbenzimidazole(50 g, 0.145 mole) was dissolved in methanol and heated to 45°C. A solution of sodium methoxide (50 g, 0.925 mole) in methanol (150 ml) was added dropwise over a period of 3 hours at 45°-60°C. Stirring was continued for another 2 hours and then methanol was distilled off under reduced pressure. To the cooled residue was added water (200 ml) followed by concentrated HCl (65 ml) until the pH of the mixture was 7.5. The reaction mixture was extracted with dichloromethane and the dichloromethane layer was washed with water (2 times 100 ml). The dichloromethane layer was dried over sodium sulfate and concentrated to yield the product as an amber color syrup. Yield was 40.1 gm, about 83.8% of theoretical. A solid sample was obtained by trituration of the syrup several times with petroleum ether. Melting point was 87°-90°C. 5-Methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridinyl)methylthio]-1Hbenzimidazolehydrochloride HCl gas was bubbled into a cooled solution of 5-methoxy-2-[(3,5-dimethyl-4methoxy-2-pyridinyl)methylthiol]-1H-benzimidazole (50 g) in dichloromethane (250 ml) until no more precipitation was observed. The reaction mixture was warmed to 40°C and again cooled to 10°C. The solid was filtered under suction and washed with dichloromethane to yield the product (49 g) as a cream colored fine granular solid. Yield was 88.2% of theoretical. Melting point 144°-148°C. Omeprazole from 5-methoxy-2-[(3,5-dimethyl-4-methoxy-2pyridinyl)methylthiol]-1H-benzimidazole To a solution of 5-methoxy-2-[(3,5-dimethyl-4-methoxy-2pyridinyl)methylthio]-1H-benzimidazole (32.9 g, 0.1 mole) in dichloromethane (200 ml) was added phthalic anhydride (20 g, 0.135 mole) and cooled in an ice salt bath. This was followed by addition of sodium carbonate (18 g, 0.17 mole) and water (20 ml). Hydrogen peroxide (12 ml, 45%, 0.16 mm mole) was added dropwise at -5°-0°C and the reaction mixture was stirred at the same temperature. When the reaction was complete as indicated by TLC, water (200 ml) was added, cooling bath was removed and the reaction mixture was stirred for 10 mins. The organic layer was separated and washed with 5% sodium carbonate solution. The separated dichloromethane solution was charcoalised and filtered through celite. The filtrate was concentrated to 100 ml and ethyl acetate 100 ml was added thereto. The separated solid was filtered, washed with ethyl acetate and dried in vacuum oven to yield 28.20 g of omeprazole. Yield 82.4% of theoretical. Melting point was 158°-160°C (dec.). References Singh S. et al.; US Patent No. 6,245,913 B1; Jun. 12, 2001; Assigned to Wockhardt Europe Limited, Dublin (IE)

2512

Ondansetron hydrochloride dihydrate

ONDANSETRON HYDROCHLORIDE DIHYDRATE Therapeutic Function: Serotonin antagonist Chemical Name: 4H-Carbazol-4-one, 1,2,3,9-tetrahydro-9-methyl-3-((2methyl-1H-imidazol-1-yl)methyl)-, hydrochloride, hydrate (1:1:2) Common Name: Ondansetron hydrochloride dihydrate Structural Formula:

Chemical Abstracts Registry No.: 103639-04-9; 99614-02-5 (Base) Trade Name Ondansetron hydrochloride Zofran

Manufacturer Chemo Iberica GlaxoSmithKline

Country Spain UK

Year Introduced -

Raw Materials Diethyl oxalate Sodium 2-Methylimidazole

9-Methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one Formol solution

Manufacturing Process Preparation of 3-ethoxalyl-9-methyl-1,2,3,9-tetrahydro-4H-carbozol-4-one 3.0 g (0.13 mole) of sodium metal are portionwise added to a stirred mixture containing 19.93 g (0.1 mole) of 9-methyl-1,2,3,9-tetrahydro-4H-carbazol-4one, 19.0 g (0.13 mole) of diethyl oxalate, 2 g of ethanol and 200 ml of dioxane. The slightly warming reaction mixture is stirred at 40° to 50°C for 4 hours, then 16 g of glacial acetic acid and finally 200 ml of water are added thereto at room temperature. After filtering off the yellow crystalline suspension, the precipitate is washed with water and dried to give the title compound in a yield of 24 g (80.2%), m.p. 118°-120°C. Preparation of 3-hydroxymethyl-9-methyl-1,2,3,9-tetrahydro-4H-carbazol-4one-3-glyoxylic acid lacton After adding 0.1 g of triethylamine to a stirred suspension containing 3.00 g (0.01 mole) of the 3-ethoxalyl-9-methyl-1,2,3,9-tetrahydro-4H-carbazol-4-

Opipramol

2513

one, in 20 ml of acetone, 1.13 g (0.015 mole) of formol solution are dropwise added to the mixture. The suspension becomes clear within 1 to 2 minutes and crystals begin to precipitate. After further stirring at 35° to 40°C for one hour, the reaction mixture is cooled down to room temperature, filtered off, the precipitate is washed with 50% acetone and dried to give 2.10 g (74.2%) of the title compound, m.p. 242°-244°C. Preparation of ondansetron base (chemically 9-methyl-3-[(2-methyl-1-Himidazol-1-yl)methyl]-1,2,3,9-tetrahidro-4-H-carbazol-4-one) A mixture containing 2.83 g (0.01 mole) of 3-hydroxymethyl-9-methyl-2,3,9tetrahydro-4H-carbazol-4-one-3-glyoxylic acid lactone, 15 ml of dioxane, 1.32 g of triethylamine, 1.0 g of ethanol and 1.64 g (0.02 mole) of 2methylimidazole is boiled under reflux while stirring for 5 hours. Thereafter, the reaction mixture is diluted with 45 ml of water and cooled down. The precipitate is filtered off, washed with aqueous dioxane and dried to obtain 2.56 g (87.3%) of the title compound, m.p. 220°-223°C. Preparation of 9-methyl-3-[(2-methyl-1-H-imidazol-1-yl)methyl]-1,2,3,9tetrahydro-4H-carbazol-4-one hydrochloride dihydrate The process above described is followed, except that after cooling down the reaction mixture to room temperature after boiling, 20 ml of 37% aqueous hydrochloric acid are added thereto. Then, the precipitate is filtered off, washed with isopropanol and dried to obtain 2.40 g (65.6%) of the title salt, m.p. 178°-180°C. The active agent content of the product was found to be 100.3% based on potentiometric titration with sodium hydroxide solution. The theoretical water content is 9.85% (calculated for C18H19N3OHCl2H2O).The water content measured is 10.03%. References Bod P. et al.; US Patent No. 5,478,949; Dec. 26, 1995; Assigned to Richter Gedeon Vegyeszeiti Gyar Rt., Budapest, Hungary

OPIPRAMOL Therapeutic Function: Antidepressant, Antipsychotic Chemical Name: 4-[3-(5H-Dibenz[b,f]azepin-5-yl)propyl]-1-piperazineethanol Common Name:Chemical Abstracts Registry No.: 315-72-0; 909-39-7 (Dihydrochloride salt) Raw Materials 5-(3-Toluene-p-sulfonyloxypropyl)dibenzazepine 1-(2-Hydroxyethyl)piperazine

2514

Opipramol

Structural Formula:

Trade Name Insidon Insidon Insidon Deprenil Ensidon Oprimol Pramolan

Manufacturer Geigy Geigy Geigy Yurtoglu Ciba Geigy Taro Polfa

Country W. Germany France Italy Turkey US Israel Poland

Year Introduced 1962 1962 1962 -

Manufacturing Process A solution of 5-(3-toluene-p-sulfonyloxypropyl)dibenzazepine (9.2g) and 1-(2hydroxyethyl)piperazine (8.6g) in anhydrous toluene (50 cc) is heated at boiling point under reflux for 4 hours. After cooling, distilled water (75 cc) is added. The aqueous phase is decanted. The toluene solution is washed with distilled water (25 cc) and then extracted with N hydrohloric acid (40 cc). The hydrochloric acid solution is made alkaline to phenolphthalein with sodium hydroxide (d = 1.33).The base which separates is extracted with chloroform (50 cc). The chloroform solution is dried over anhydrous sodium sulfate and then evaporated to dryness. There are obtained 5-[3-(4-β-hydroxyethylpiperazino)propyl]dibenzazepine (7.95g), the dihydrochloride of which, crystallized from ethanol, melts at about 210°C. References Merck Index 6727 Kleeman & Ensel P. 657 I.N. p. 703 Gaillot, P. and Gaudechon, J.; British Patent 881,398; November 1, 1961; assigned to Societe des Usines Chimiques Rhone-Poulenc

Orazamide

2515

ORAZAMIDE Therapeutic Function: Hepatoprotectant Chemical Name: 5-Aminoimidazole-4-carboxamide orotate Common Name: AICA orotate Structural Formula:

Chemical Abstracts Registry No.: 2574-78-9 Trade Name Aicamine Aicurat Aicamin Aicamin

Manufacturer Labaz Mack Crinos Fujisawa

Country France W. Germany Italy Japan

Year Introduced 1971 1962 1977 -

Raw Materials 4-Amino-5-imidazolecarboxamide Orotic acid Manufacturing Process 14.4 grams of 4-amino-5-imidazolecarboxamide (monohydrate) and 17.4 grams of orotic acid (monohydrate) were dissolved with heating in 600 cc of water. The solution is decolorized with Norit, cooled and then filtered off. 28.8 grams of a white crystalline salt (dihydrate) is obtained with MP 284°C (decomposition). References Merck Index 6739 Kleeman & Engel p. 658 I.N. p. 704 Haraoka, R. and Kamiya, T.; US Patent 3,271,398; September 6, 1966; assigned to Fujisawa Pharmaceutical Co., Ltd., Japan

2516

Orgotein

ORGOTEIN Therapeutic Function: Antiinflammatory Chemical Name: See Structural Formula Common Name: Ormetein Structural Formula: Orgotein is a complex protein with a molecular weight of about 33,000. It is a divalent metal (Mg, Cu, Zn) chelated structure Chemical Abstracts Registry No.: 9016-01-7 Trade Name Ontosein Peroxinorm Peroxinorm Oxinorm

Manufacturer Gruenenthal Protochemie Gruenenthal Zambeletti

Country W. Germany Switz. Japan Italy

Year Introduced 1980 1982 1982 -

Raw Materials Beef blood Ethanol Chloroform Manufacturing Process Fresh beef blood was centrifuged, e.g., at about 2,600 to 5,000 x g for 10 minutes at 0°C and the plasma decanted. The red blood cells were then washed at least twice and preferably repeatedly with 2 to 3 volumes of 0.9% saline solution. The washed red blood cells were lysed by mixing with 1.1 volumes of cold deionized water containing 0.02% detergent (Saponin). After a minimum of 30 minutes at 4°C with stirring, 0.25 volume (per volume of hemolysate) of ethyl alcohol at -15°C was slowly added while stirring followed by 0.31 volume (per volume of hemolysate) of chloroform, also at -15°C. Stirring was continued for about 15 minutes at -5°C or below, at which time, the mixture was a thick paste. The hemoglobin precipitation was carried out in a cold bath which was kept at below -10°C. After the paste had stood for a further 15 minutes at 4°C, 0.2 volume of cold 0.15 M NaCl solution was added, giving an easily poured suspension. The precipitate and excess chloroform were removed by centrifuging at about 12,000 to 20,000 x g at about -10°C for 10 minutes. The supernatant liquid was removed and if desired, filtered and briefly dialyzed against cold-deionized water, prior to lyophilization. The alcohol chloroform precipitate was dislodged, chloroform was removed, the pellet broken up and reextracted with about an equal amount of deionized water by blending the precipitate and the water in a blender and thereafter centrifuging. The reextraction solution was dialyzed and lyophilized with the main extract. If the process proceeds normally, the reextraction of the precipitated hemoglobin usually yields up to 30% of protein mixture present in the original supernatant. An additional reextraction may give an additional

Ornidazole

2517

5 to 15%. The lyophilized material was redissolved in 0.025 M tris-glycine buffer containing 0.001 M Mn2+ at pH 7.5 (usually to a concentration of 20 mg/ml). The solution was heated at or near 65°C for about 15 minutes. This step removes the carbonic anhydrase and other heat labile proteins from the solution. After heating, the solution was rapidly cooled in an ice bath to 5°C. The solution was then centrifuged at 20,000 x g at 0°C for 10 minutes to remove the precipitate. Filtration through "Versapore" works equally well. The supernatant was thoroughly dialyzed against deionized water to remove excess metal ions and buffer and then lyophilized. The resulting solid consists largely of orgotein. References Merck Index 6742 DOT 9 (1) 34 (1973) 11 (3) 103 (1975) and 13 (3) 105 (1977) I.N. p. 705 Huber, W.; US Patent 3,579,495; May 18, 1971; assigned to Diagnostic Data, Inc. Huber, W.; US Patent 3,687927; August 29, 1972; assigned to Diagnostic Data, Inc.

ORNIDAZOLE Therapeutic Function: Antiinfective Chemical Name: α-(Chloromethyl)-2-methyl-5-nitro-1H-imidazole-1-ethanol Common Name: Structural Formula:

Chemical Abstracts Registry No.: 16773-42-5 Trade Name

Manufacturer

Country

Year Introduced

Tiberal

Roche

W. Germany

1977

Tiberal

Roche

Italy

1981

Tiberal

Roche

France

1981

Tiberal

Roche

Switz.

1982

2518

Ornipressin

Trade Name Tiberal Kolpicid Madelen Ornidal

Manufacturer Roche Roche Finadiet Selvi

Country Australia Sweden Argentina Italy

Year Introduced 1983 1983 -

Raw Materials 1-(2,3-Epoxypropyl)-2-methyl-5-nitroimidazole Hydrogen chloride Manufacturing Process 5g of 1-(2,3-epoxypropyl)-2-methyl-5-nitroimidazole was added to 30 ml of concentrated aqueous hydrochloric acid. The solution was heated to the boiling point for 20 minutes, chilled, diluted with 30 ml of water and carefully neutralized with ammonia to a pH of 7 to 8. It was then saturated with ammonium sulfate. The precipitated oil crystallized after several days. Recrystallized from toluene, there was obtained the 1-(3-chloro-2hydroxypropyl)-2-methyl-5-nitroimidazole product melting at 77°C to 78°C. References Merck Index 6746 OCDS Vol. 3 p. 131 (1984) DOT 11 (9) 369 (1975) I.N. p. 706 REM p. 1224 Hoffer, M.; US Patent 3,435,049; March 25, 1969; assigned to HoffmannLaRoche, Inc.

ORNIPRESSIN Therapeutic Function: Vasoconstrictor Chemical Name: 8-L-Ornithinevasopressin Common Name: Chemical Abstracts Registry No.: 3397-23-7 Trade Name

Manufacturer

Country

Year Introduced

POR-8

Sandoz

W. Germany

1977

Raw Materials N-α-Carbobenzoxy-N-δ-toluenesulfonyl-L-ornithine Glycine ethyl ester

Ornipressin

2519

N-Carbobenzoxy-L-proline N-Carbobenzoxy-L-glutaminyl-L-asparaginyl-S-benzyl-L-cysteinyl-azide N-Carbobenzoxy-S-benzyl-L-cysteinyl-L-tyrosyl-L-phenylalanine azide Sodium Ammonia Structural Formula:

Manufacturing Process (a)N-α-carbobenzoxy-N-δ-p-toluenesulfonyl-L-ornithyl-glycine ethyl ester: 104 g of N-α-carbobenzoxy-N-δ-p-toluenesulfonyl-L-ornithine and 27 g of glycine ethyl ester are dissolved in 450 cc of acetonitrile, the mixture is cooled at 0°C, 51 g of dicyclohexyl carbodiimide are added and the mixture is shaken at room temperature for 4 hours. Precipitated dicyclohexyl urea is filtered off and washed with acetonitrile. The whole filtrate is evaporated in a vacuum. The residue crystallizes after the addition of petroleum ether. After recrystallization from n-propanol, 93 g of N-α-carbobenzoxy-N-δ-toluenesulfonyl-L-ornithylglycine ethyl ester are obtained; melting point 136°C; [α]D22 = -6.5° (96% ethanol). (b) N-carbobenzoxy-L-prolyl-N-δ-p-toluenesulfonyl-L-ornithyl-glycinamide: 90 g of N-α-carbobenzoxy-N-δ-p-toluenesulfonyl-L-ornithyl-glycine ethyl ester are dissolved in 800 cc of anhydrous acetic acid which has been saturated with hydrogen bromide. The mixture is left to stand for one hour at 20°C, evaporated in a vacuum at a temperature below 40°C and the residue washed carefully with diethyl ether. The residue is dissolved in 500 cc of acetonitrile, 25 cc of triethylamine and 43 g of N-carbobenzoxy-L-proline are added, cooling is effected at 0°C, 355 g of dicyclohexyl carbodiimide are then added and the mixture shaken overnight at 20°C. After filtering off dicyclohexyl urea, the filtrate is evaporated in a vacuum at 30°C, the residue dissolved in ethyl acetate and this solution is washed with dilute sulfuric acid and aqueous

2520

Ornipressin

ammonia. After drying over sodium sulfate, the ethyl acetate is removed by evaporation in a vacuum and the residue dissolved in 1 liter of absolute ethanol. The solution is cooled at 0°C, saturated with ammonia and left to stand overnight at 20°C. After evaporating in a vacuum at 30°C, the residue is recrystallized from dimethylformamide/ethyl acetate. 58 g of Ncarbobenzoxy-L-prolyl-N-δ-p-toluenesulfonyl-L-ornithyl-glycinamide are obtained: melting point 122°C (with decomposition). (c) N-carbobenzoxy-L-glutaminyl-L-asparaginyl-S-benzyl-L-cystsinyl-L-prolyl-Nδ-p-toluenesulfonyl-L-ornithyl-glycinamide: 100 g of N-carbobenzoxy-L-prolylN-δ-p-toluenesulfonyl-L-ornithyl-glycinamide are dissolved in 500 cc of anhydrous acetic acid which has been saturated with hydrogen bromide, the solution is left to stand for one hour at 20°C and is evaporated in a vacuum at a temperature below 40°C. The residue is carefully washed with diethyl ether and then added to a solution of 100 g of N-carbobenzoxy-L-glutaminyl-Lasparaginyl-S-benzyl-L-cysteinyl-azide and 26 cc of triethylamine in 1,000 cc of dimethylformamide. The mixture is left to stand overnight at 20°C, 3,000 cc of ethyl acetate are added thereto, the precipitate is filtered off and washing is effected with ethyl acetate. 105 g of N-carbo-benzoxy-Lglutaminyl-L-asparaginyl-S-benzyl-L-cysteinyl-L-prolyl-N-δ-p-toluenesulfonyl-Lornithyl-glycinamide are obtained; melting point 193°C; [α]D20 = 38.5°(dimethylformamide). (d) N-carbobenzoxy-S-benzyl-L-cysteinyl-L-tyrosyl-L-phenyl-alanyl-Lglutaminyl-L-asparaginyl-S-benzyl-L-cysteinyl-L-prolyl-N-δ-p-toluenesulfonyl-Lornithyl-glycinamide: 50 g N-carbobenzoxy-L-glutaminyl-L-asparaginyl-Sbenzyl-L-cysteinyl-L-prolyl-N-δ-p-toluenesulfonyl-L-ornithyl-glycinamide are dissolved in 250 cc of anhydrous acetic acid which has been saturated with hydrogen bromide and the solution is left to stand for one hour at 20°C. After evaporating the solvent in a vacuum at a temperature below 40°C, the residue is carefully washed with diethyl ether and a solution of 31.5 g of Ncarbobenzoxy-S-benzyl-L-cysteinyl-L-tyrosyl-L-phenylalanine-azide and 7.5 cc of triethylamine in 250 cc of dimethylformamide is added thereto. The mixture is left to stand for 2 days at 20°C. 1,000 cc of ethyl acetate are subsequently added and the precipitate is washed with ethyl acetate. After drying in a vacuum at 30°C. the product is washed with warm methanol. 45 g of Ncarbobenzoxy-S-benzyl-L-cysteinyl-L-tyrosyl-L-phenylalanyl-L-glutaminyl-Lasparaginyl-S-benzyl-L-cysteinyl-L-prolyl-N-δ-p-toluenesulfonyl-L-ornithylglycinamide are obtained; melting point 224°C. (e) L-cysteinyl-L-tyrosyl-L-phenylalanyl-L-glutaminyl-L-asparaginyl-L-cysteinylL-prolyl-L-ornirhyl-glycinamide: The necessary amount of sodium or potassium metal is added to a solution of 5 g of N-carbobenzoxy-S-benzyl-L-cysteinyl-Ltyrosyl-L-phenylalanyl-L-glutaminyl-L-asparaginyl-S-benzyl-L-cysteinyl-L-prolylN-δ-p-toluenesulfonyl-L-ornithyl-glycinamide in 1,200 cc of dry liquid ammonia, while stirring at the boiling temperature of the solution, to give a stable blue coloration. After the addition of 3 g of ammonium chloride, the solution is evaporated to dryness. The residue contains L-cysteinyl-L-tyrosyl-Lphenyl-alanyl-L-glutaminyl-L-asparaginyl-L-cysteinyl-L-prolyl-L-ornithylglycinamide. References Merck Index 6747

Orotic acid

2521

DOT 13 (11) 498 (1977) I.N. p. 706 Boissonnas, R. and Huguenin, R.; US Patent 3,299,036; January 17, 1967; assigned to Sandoz Ltd. (Switzerland)

OROTIC ACID Therapeutic Function: Hepatoprotectant Chemical Name: 4-Pyrimidinecarboxylic acid, 1,2,3,6-tetrahydro-2,6-dioxoCommon Name: Acide orotique; Acidum oroticum; Animal galactose factor; Orotic acid; Vitamin B13; Whey factor Structural Formula:

Chemical Abstracts Registry No.: 65-86-1 Trade Name

Manufacturer

Country

Year Introduced

Lactinium

Roland

-

-

Raw Materials Ketene Urea Sulfuric acid

Trichloroacetyl chloride Acetic acid Sodium hydroxide

Manufacturing Process 91.7 g (0.5 mol) of trichloroacetyl chloride was cooled to -35°C in a glass vessel by means of a cooling brine. In the course of 3 h, 27.0 g (0.06 mol) of pure ketene was introduced through a tube. After completion of the reaction, the vessel was immediately put under dry nitrogen to prevent penetration of moisture. So γ,γ,γ-trichloroacetoacetylchloride was produced. The reaction mixture containing the γ,γ,γ-trichloroacetoacetyl chloride was transfered under nitrogen to a dropping funnel and in the course of 15 min was added with vigorous agitation to a suspension of 69.0 g (1.15 mole) of urea in 90.0 g of anhydrous acetic acid. Water cooling was used so that the reaction temperature would not exceed 40°C. After completion of the addition, the reaction mixture was heated as rapidly as possible to 115°C, and held at

2522

Orphenadrine citrate

this temperature for 30 min. Subsequently there was cooling and one more 99.0 g of glacial acetic acid and 180.0 g of water were added. The precipitated 6-trichloromethyluracil was filtered off and dried at 60°C in a vacuum drying cabinet. The yield was 91.0 g or 80%. In a glass vessel equipped with an agitator, thermometer and pH electrode, 500 ml of water was placed and heated to 80°C. 50 g of 6trichloromethyluracil was then added. By means of the pH electrode, the addition of sodium hydroxide was automatically controlled so that the pH value throughout the whole hydrolysis was 6.5. Into, 165 ml of 5 N NaOH was consumed. Finally, the hydrolysis solution was cooled and the precipitated sodium orotate filtered off. The crude sodium orotate was again suspended at 80°C in water and brought into solution (pH 10.5) by addition of 30 ml of 5 N NaOH. After treatment with active charcoal, the solution was acidified with 30.0 g of 50% sulfuric acid. The solution was then cooled. The orotic acid was filtered off and carefully washed with water. After drying, 20.5 g of orotic acid, having a purity of 99.3% (titration) was obtained. This corresponds to a 60% yield. References Jackson B; US Patent No. 4,064,126; Dec. 20, 1977; Assigned: Lonza, Ltd., Gampel, Switzerland

ORPHENADRINE CITRATE Therapeutic Function: Muscle relaxant Chemical Name: N,N-Dimethyl-2-[(2-methylphenyl)phenylmethoxy] ethanamine citrate Common Name: Structural Formula:

Oseltamivir phosphate

2523

Chemical Abstracts Registry No.: 4682-36-4; 83-98-7 (Base) Trade Name Norflex Neocyten X-Otag Banflex Bio-Flex Flexin Mioflex Myotrol Norgesic Ro-Orphena Tega-Flex

Manufacturer Riker Central Tutag O'Neal Jones Foy Taro Formenti Legere Riker Robinson Ortega

Country US US US US US Israel Italy US US US US

Year Introduced 1959 1975 1976 1980 -

Raw Materials o-Methylbenzhydryl bromide β-Dimethylaminoethanol Citric acid Manufacturing Process As described in US Patent 2,567,351, o-methylbenzhydryl bromide is added slowly to β-dimethylaminoethanol at refluxing temperature. After the addition has been completed the mixture is refluxed and stirred for an additional 16 hours. The mixture is cooled and the bottom layer consisting of the crude hydrobromide salt of β-dimethylaminoethanol is drawn off. The excess amino alcohol is distilled from the upper layer in vacuo and the residue is reacted with citric acid. References Merck Index 6752 Kleeman & Engel p. 661 PDR pp. 1033, 1452 OCDS Vol. 1 p. 42 (1977) DOT 9 (6) 247 (1973) and 18 (2) 90 (1982) I.N. p. 707 REM p. 932 Rieveschi, G. Jr.; US Patent 2,567,351; September 11, 195 : assigned to Parke, Davis & Company Harms, A.F.; US Patent 2,991,225; July 4, 1961 ; assigned 1 NV Koninklijke Pharmaceutische Fabrieken, Netherlands

OSELTAMIVIR PHOSPHATE Therapeutic Function: Antiviral

2524

Oseltamivir phosphate

Chemical Name: 1-Cyclohexene-1-carboxylic acid, 4-(acetylamino)-5-amino3-(1-ethylpropoxy)-, ethyl ester, (3R,4R,5S)-, phosphate (1:1) Common Name: Oseltamivir phosphate Structural Formula:

Chemical Abstracts Registry No.: 204255-11-8; 196618-13-0 (Base) Trade Name Tamiflu

Manufacturer Hoffmann-La Roche Inc.

Country -

Year Introduced -

Raw Materials Shikimic acid Boron trifluoride diethyl etherate Sodium azide 1,8-Diazabicyclo[5.4.0]undec-7-ene Dimethoxypropane 4-Toluenesulfonic acid Triethylamine Methanesulfonyl chloride Trityl chloride N,N-Diisopropylethylamine Triphenylphosphine Chloromethyl methyl ether Acetic anhydride Potassium hydroxide Ethanol Ammonium chloride Phosphoric acid Dimethylaminophenol 2-(Diethylamino)ethyl(bicyclohexyl)-1-carboxylate Manufacturing Process To a suspension of shikimic acid (25 g, 144 mmol, Aldrich) in methanol (300 ml) was added p-toluenesulfonic acid (274 mg, 1.44 mmol, 1 mol %) and the mixture was heated to reflux for 2 h. After adding more p-toluenesulfonic acid (1 mol %) the reaction was refluxed for 26 h and was evaporated. The crude methyl ester (28.17 g) was suspended in acetone (300 ml) and was treated with dimethoxypropane (35 ml, 288 mmol) and was stirred at room temperature for 6 h and then was evaporated. The crude product was dissolved in ethyl acetate (400 ml) and was washed with saturated NaHCO3 (3 times 125 ml) and saturated NaCl. The organic phase was dried (MgSO4), filtered, and evaporated to afford crude 7-hydroxy-2,2-dimethyl-3a,6,7,7a-

Oseltamivir phosphate

2525

tetrahydro-benzo[1,3]dioxole-carboxylic acid methyl ester (about 2.94 g). To a solution of 7-hydroxy-2,2-dimethyl-3a,6,7,7a-tetrahydrobenzo[1,3]dioxole-carboxylic acid methyl ester (29.4 g, 141 mmol) in CH2Cl2, (250 ml) at 0°C was added triethylamine (29.5 ml, 212 mmol) followed by the addition of methanesulfonyl chloride (13.6 ml, 176 mmol) over a period of 10 min. The reaction was stirred at 0°C for 1 h and ice cold water (250 ml) was added. After transfer to a separatory funnel, the organic phase was washed with water, 5% citric acid (300 ml), saturated NaHCO3 (300 ml) and was dried (MgSO4), filtered, and evaporated. The crude product was filtered through a short plug of silica gel on a fritted glass funnel eluting with ethyl acetate. The filtrate was evaporated to afford 7-methanesulfonyloxy-2,2-dimethyl3a,6,7,7a-tetrahydro-benzo[1,3]dioxole-carboxylic acid methyl ester (39.5 g, 91%) as a viscous oil. To a solution of 7-methanesulfonyloxy-2,2-dimethyl-3a,6,7,7a-tetrahydrobenzo[1,3]dioxole-carboxylic acid methyl ester (35.85 g, 117 mmol) in methanol (500 ml) was added p-toluenesulfonic acid (1.11 g, 5.85 mmol, 5 mol %) and the solution was refluxed for 1.5 h and was evaporated. The residue was redissolved in methanol (500 ml) and was refluxed an additional 4 h. The solvent was evaporated and the crude oil was triturated with diethyl ether (250 ml). After completing the crystallization overnight at 0°C, the solid was filtered and was washed with cold diethyl ether, and dried to afford 3,4dihydroxy-5-methanesulfonyloxy-cyclohex-1-enecarboxylic acid methyl ester (24.76 g) as a white solid. Evaporation of the filtrate and crystallization of the residue from methanol/diethyl ether gave an additional 1.55 g. Obtained 26.3 g (85%) of the 3,4-dihydroxy-5-methanesulfonyloxy-cyclohex-1-ene-1carboxylic acid methyl ester. A suspension of 3,4-dihydroxy-5-methanesulfonyloxy-cyclohex-1-ene-1carboxylic acid methyl ester (20.78 g, 78 mmol) in tetrahydrofuran (400 ml) at 0°C was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (11.7 ml, 78 mmol) and was stirred at room temperature for 9 h at which time the reaction was complete. The reaction was evaporated and the crude residue was dissolved in CH2Cl2 (200 ml) and was washed with saturated NaCl (300 ml). The aqueous phase was extracted with CH2Cl2 (2 times 200 ml). The combined organic extracts were dried (MgSO4), filtered, and evaporated. The crude product was purified on silica gel (ethyl acetate) to afford 5-hydroxy-7oxa-bicyclo[4.1.0]hept-3-ene-3-carboxylic acid methyl ester (12 g, 90%) as a white solid. To a solution of 5-hydroxy-7-oxa-bicyclo[4.1.0]hept-3-ene-3-carboxylic acid methyl ester (4 g, 23.5 mmol) in CH2Cl2 (100 ml) was added N,N'diisopropylethylamine (12.3 ml, 70.5 mmol) followed by chloromethyl methyl ether (3.6 ml, 47 mmol, distilled from tech. grade). The solution was refluxed for 3.5 h and the solvent was evaporated. The residue was partitioned between ethyl acetate (200 ml) and water (200 ml). The aqueous phase was extracted with ethyl acetate (100 ml). The combined organic extracts were washed with saturated NaCl (100 ml), dried (MgSO4), filtered, and evaporated to afford 4.9 g of a solid residue of 5-methoxymethoxy-7-oxabicyclo[4.1.0]hept-3-ene-3-carboxylic acid methyl ester which was of suitable purity to use directly in the next step: melting point 62°-65°C (crude); melting point 64°-66°C (diethyl ether/hexane).

2526

Oseltamivir phosphate

To a solution of 5-methoxymethoxy-7-oxa-bicyclo[4.1.0]hept-3-ene-3carboxylic acid methyl ester (4.9 g, 22.9 mmol) in 8/1-MeOH/H2O (175 ml, v/v) was added sodium azide (7.44 g, 114.5 mmol) and ammonium chloride (2.69 g, 50.4 mmol) and the mixture was refluxed for 15 h. The reaction was diluted with water (75 ml) to dissolve precipitated salts and the solution was concentrated to remove methanol. The resulting aqueous phase containing a precipitated oily residue was diluted to a volume of 200 ml with water and was extracted with ethyl acetate (3 times 100 ml). The combined organic extracts were washed with saturated NaCl (100 ml), dried (MgSO4), filtered and evaporated. The crude was purified on silica gel (1/1-hexane/ethyl acetate) to afford 5-azido-4-hydroxy-3-methoxymethoxy-cyclohex-1-ene-1carboxylic acid methyl ester (5.09 g, 86%) as a pale yellow oil. Subsequent preparations of 5-azido-4-hydroxy-3-methoxymethoxy-cyclohex-1-ene-1carboxylic acid methyl ester provided material which was of sufficient purity to use in the next step without further purification. To a solution of 5-azido-4-hydroxy-3-methoxymethoxy-cyclohex-1-ene-1carboxylic acid methyl ester (6.47 g, 25.2 mmol) in CH2Cl2 (100 ml) at 0°C was added first triethylamine (4.4 ml, 31.5 mmol) then methanesulfonyl chloride (2.14 ml, 27.7 mmol). The reaction was stirred at 0°C for 45 min then was warmed to room temperature stirring for 15 min. The reaction was evaporated and the residue was partitioned between ethyl acetate (200 ml) and water (100 ml). The organic phase was washed with water (100 ml), saturated NaHCO3 (100 ml), saturated NaCl (100 ml). The water washes were extracted with a single portion of ethyl acetate which was washed with the same NaHCO3/NaCl solutions. The combined organic extracts were dried (MgSO4), filtered, and evaporated. The 5-azido-4-methansulfonyloxy-3methoxymethoxy-cyclohex-1-ene-1-carboxylic acid methyl ester was of suitable purity to be used directly in the next step. To a solution of 5-azido-4-methansulfonyloxy-3-methoxymethoxy-cyclohex-1ene-1-carboxylic acid methyl ester (8.56 g, 25 mmol) in THF (150 ml) at 0°C was added Ph3P (8.2 g, 31 mmol), initially adding a third of the amount while cooling and then after removing the ice bath adding the remainder of the Ph3P over a period of 10-15 min. After complete addition of the Ph3P the reaction was stirred at room temperature for 3 h with the formation of a white precipitate. To this suspension was added triethyl amine (5.2 ml, 37.5 mmol) and water (10 ml) and the mixture was stirred at room temperature for 12 h. The reaction was concentrated to remove THF and the residue was partitioned between CH2Cl2 (200 ml) and saturated NaCl (200 ml). The aqueous phase was extracted with several portions of CH2Cl2 and the combined organic extracts were dried (Na2SO4), filtered, and evaporated to afford a crude product which was purified on silica gel (10% MeOH/EtOAc) to afford 5methoxymethoxy-7-aza-bicyclo[4.1.0]hept-3-ene-3-carboxylic acid methyl aster (4.18 g, 78%) as an oil which typically contained trace amounts of triphenylphosphine oxide impurity. To a solution of 5-methoxymethoxy-7-aza-bicyclo[4.1.0]hept-3-ene-3carboxylic acid methyl aster (3.2 g, 15 mmol) in DMF (30 ml) was applied a vacuum on a rotary evaporator (40°C) for several minutes to degas the solution. To the solution was added sodium azide (4.9 g, 75 mmol) and ammonium chloride (1.6 g, 30 mmol) and the mixture was heated at 65°-

Oseltamivir phosphate

2527

70°C for 21 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (about 100 ml) and was filtered. The filtrate was evaporated and the residue was partitioned between diethyl ether (100 ml) and saturated NaCl (100 ml). The organic phase was washed again with saturated NaCl (100 ml), dried (MgSO4), filtered, and was evaporated. Additional crude product was obtained from the aqueous washings by extraction with ethyl acetate and treated in the same manner as described above. The crude product was purified on silica gel (5% MeOH/CH2Cl2) to afford 4-amino-5-azido-3-methoxymethoxy-cyclohex-1-ene-1-carboxylic acid methyl ester (2.95 g) as an oil which contained a small amount of triphenylphosphine oxide impurity from the previous step. 4-Amino-5-azido-3-methoxymethoxy-cyclohex-1-ene-1-carboxylic acid methyl ester (2.59 g, 10.2 mmol) was dissolved in 5% HCl/MeOH (30 ml) and the solution was stirred for 3 h at room temperature. Additional 5% HCl/MeOH (10 ml) was added stirring 1 h and the solvent was evaporated to afford 2.52 g of the HCl salt as a tan solid after high vacuum. To a suspension of the HCl salt in CH2Cl2 (50 ml) at 0°C was added triethylamine (3.55 ml, 25.5 mmol) followed by the addition of solid trityl chloride (5.55 g, 12.8 mmol) in one portion. The mixture was stirred at 0°C for 1 h and then was warmed to room temperature stirring for 2 h. The reaction was cooled to 0°C, triethylamine (3.6 ml, 25.5 mmol) was added and methane sulfonyl chloride (0.97 ml, 12.5 mmol) was added, stirring the resulting mixture for 1 h at 0°C and for 22 h at room temperature. The reaction was evaporated and the residue was partitioned between diethyl ether (200 ml) and water (200 ml). The organic phase was washed with water (200 ml) and the combined aqueous phases were extracted with diethyl ether (200 ml). The combined organic extracts were washed with water (100 ml), saturated NaCl (200 ml) and were dried (Na2SO4), filtered, and evaporated. The crude product was purified on silica gel (1/1-hexane/CH2Cl2) to afford 5-azido-7-trityl-7-aza-bicyclo[4.1.0]hept-2ene-3-carboxylic acid methyl ester (3.84 g, 86%) as a white foam. BF3Et2O (43 µl, 0.35 mmol) was added to a solution of 5-azido-7-trityl-7-azabicyclo[4.1.0]hept-2-ene-3-carboxylic acid methyl ester (104 mg, 0.24 mmol) in 3-pentanol (2.0 ml) under argon with stirring at room temperature. The pale solution was heated at 75°C for 1.5 h and then concentrated in vacuo to give a brown residue which was dissolved in dry pyridine (2.0 ml) and treated with acetic anhydride (235 ml) and a catalytic amount of dimethylaminophenol (few crystals) at 0°C. The reaction was allowed to warm to room temperature and stirred for 1.5 h, concentrated in vacuo and partitioned between ethyl acetate and brine. The organic layer was separated and washed sequentially with dilute HCl, saturated sodium bicarbonate, brine and dried over MgSO4. Concentration in vacuo followed by flash chromatography of the residue on silica gel (50% hexanes in ethyl acetate) gave 41 mg (53%) of the 4-acethylamino-5-azido-3-(1-ethyl-propoxy)cyclohex-1-ene-1-carboxylic acid methyl ester. To a solution of 4-acethylamino-5-azido-3-(1-ethyl-propoxy)-cyclohex-1-ene1-carboxylic acid methyl ester (268 mg, 0.83 mmol) in THF (7.0 ml) was added aqueous KOH (1.60 ml of a 1.039 N solution) at room temperature. After stirring for 19 h at room temperature the reaction was acidified to pH 4.0 with Amberlite IR-120 (H+) acidic resin. The resin was filtered and washed with water and ethanol. Concentration in vacuo gave the crude 4-

2528

Otilonium bromide

acethylamino-5-azido-3-(1-ethyl-propoxy)-cyclohex-1-ene-1-carboxyllic acid as a pale orange foam which was used for the next reaction without any further purification. To a solution of 4-acethylamino-5-azido-3-(1-ethyl-propoxy)-cyclohex-1-ene1-carboxyllic acid (crude from previous reaction, assume 0.83 mmol), ethyl alcohol (150 ml), and catalytic dimethylaminophenol in (CH2Cl2 (6.0 ml) was added 2-(diethylamino)ethyl(bicyclohexyl)-1-carboxylate (172 mg, 0.83 mmol) in one portion at room temperature. After several minutes a precipitate formed and after an additional 1 h of stirring the reaction was filtered and washed with CH2Cl2. Concentration in vacuo afforded a pale solid which was purified by flash chromatography on silica gel (50% hexanes in ethyl acetate) to give 272 mg (96%) of 4-acethylamino-5-azido-3-(1-ethyl-propoxy)cyclohex-1-ene-1-carboxyllic acid ethyl ester as a white solid. Triphenylphosphine (342 mg, 1.30 mmol) was added in one portion to a solution of 4-acethylamino-5-azido-3-(1-ethyl-propoxy)-cyclohex-1-ene-1carboxyllic acid ethyl ester (272 g, 0.80 mmol) in THF (17 ml) and water (1.6 ml). The reaction was then heated at 50°C for 10 h, cooled and concentrated in vacuo to give a pale white solid. Purification of the crude solid by flash chromatography on silica gel (50% methanol in ethyl acetate) gave 242 mg (96%) of the 4-acethylamino-5-amino -3-(1-ethyl-propoxy)-cyclohex-1-ene-1carboxyllic acid ethyl ester as a pale solid. The racemic mixture are separated into their individual, substantially optically pure isomers through well-known techniques such as, for example, the separation of diastereomeric salts formed with optically active adjuncts, e.g. acids or bases followed by conversion back to the optically active substances. So the 4-acethylamino-5-amino-3-(1-ethyl-propoxy)-cyclohex-1-ene-1carboxyllic acid ethyl ester,(3α,4β,5α) was obtained. The 4-acethylamino-5-amino-3-(1-ethyl-propoxy)-cyclohex-1-ene-1-carboxyllic acid ethyl ester, (3α,4β,5α) is dissolved in H3PO4 to give the corresponding water soluble salt form. References Bischofberger N.W. et al.; US Patent No. 5,763,483; June 9, 1998; Assigned: Gilead Sciences, Inc., Foster City. Calif.

OTILONIUM BROMIDE Therapeutic Function: Anticholinergic, Spasmolytic Chemical Name: Ammonium, diethyl(2-hydroxyethyl)methyl-, bromide, p-(o(octyloxy)benzamido)benzoate Common Name: Octylonium bromide; Otilnium bromide Chemical Abstracts Registry No.: 26095-59-0; 105360-89-2 (Base)

Otilonium bromide

2529

Structural Formula:

Trade Name Spasmomen Spasmomen 40

Manufacturer Minapharm Co. A.Menarini Pharmaceutical Industre's Group Ltd.

Country -

Year Introduced -

Doralin Menoctyl Pasminox 40 Spasen Spasmoctyl

Menarini Hellas A.E. Menarini Beta F.I.R.M.A. S.p.A. Menarini

-

-

Raw Materials Sodium hydroxide N-Diethylaminoethanol Methyl bromide

2-Diethylamine-ethyl-p-aminobenzoate o-Octyloxybenzoyl chloride 2-Diethylaminoethyl chloride

Manufacturing Process 3 Methods of producing of p-[2-(n-octyloxy)benzoyl]aminobenzoate of Ndiethylammoniumethanol: 1. 21.20 g (0.1 mole) of o-octyloxybenzoyl chloride and aqueous 10% NaOH are added at room temperature, with stirring and by slow dropping to 23.63 g (0.1 mole) of 2-diethylamine-ethyl-p-aminobenzoate in 100 ml of water, in such a manner as to keep the reaction mixture slightly alkaline. After concluding the slow dropping the solution is kept under stirring for 1 h and then the precipitate is collected. This precipitate, p-[2-(n-octyloxy)benzoyl] aminobenzoate of N-diethylammoniumethanol dried and recrystallized from hexane, has a melting point of 81°-82°C. 2. To 31.3 g (0.1 mole) of p-[2-(n-octyloxy)benzoyl]aminobenzoate acid in 300 ml of ethanol, are added 4.0 g (0.1 mole) of finely ground NaOH and the whole is heated to reflux for 1 h. Then 20.25 g (0.15 mol) of 2-

2530

Oxaceprol

diethylaminoethyl chloride are slowly dropped under stirring and the heating is continued for 4 h. After cooling, the sodium chloride formed is filtered off and the solvent is separated by distillation, and the excess of the base, under a reduced pressure. The residue of p-[2-(n-tyloxy)benzoyl]aminobenzoate of Ndiethylammoniumethanol, recrystallized from hexane, has a melting point of 81°-82°C. 3. 11.7 g (0.1 mole) of N-diethylaminoethanol in 200 ml of anhydrous pyridine are added by careful dropping, 34.7 g (0.1 mole) of the chloride of p[2-(n-octyloxy)benzoyl]aminobenzoate acid and the mixture is heated in a water-bath for 3 h. The solvent is then separated by vacuum concentration, the residue is taken up with water, alkalinized and extracted with ether. The collected ether extracts, anhydridised owing to the separation of the solvent, leave a residue of p-[2-(n-tyloxy)benzoyl]aminobenzoate of Ndiethylammoniumethanol which, recrystallized from hexane, has a melting point of 81°-82°C. p-[2-(n-Octyloxy)benzoyl]aminobenzoate of N-diethylmethylammoniumethyl bromide may be prepared by reaction of the p-[2-(n-octyloxy) benzoylaminobenzoate of N-diethylammoniumethanol with methylating agents such as methylbromide. References Chelardoni M. et al.; US Patent No. 3,536,723; Oct. 27, 1970; Assigned: A. Menarini Societa in Accomandita Semplice, Florence, Italy, a Italian corporate body

OXACEPROL Therapeutic Function: Antirheumatic Chemical Name: N-Acetyl-4-hydroxy-L-proline Common Name: Aceprolinum Structural Formula:

Chemical Abstracts Registry No.: 33996-33-7 Trade Name Jonctum AHP-2000

Manufacturer Merrell Chephasaar

Country France W. Germany

Year Introduced 1970 1975

Oxacillin sodium Trade Name Jonctum Tejuntivo

Manufacturer Merrell Valderrama

Country Italy Spain

2531

Year Introduced 1978 -

Raw Materials L-Hydroxyproline Acetic anhydride Manufacturing Process 16.7 g (0.127 mol) of L-hydroxyproline are dissolved in 400 ml of pure boiling acetic acid. With vigorous boiling and agitation, a mixture of 13.7 ml (0.154 mol) of rectified acetic anhydride and 250 ml of pure acetic acid is added during 25 minutes. Without discontinuing the stirring, contents of the flask are cooled by simply causing fresh air to circulate externally round the flask until the temperature of the mixture is reduced to about 35°C. The acetic acid is removed by using a rotary evaporator without exceeding 35°C under a vacuum of about 15 mm Hg. After one hour, 20 ml of anhydrous toluene are added, then 10 ml of anhydrous acetone; the mixture is homogenized and concentrated again as above during 30 minutes. Then 25 ml of acetone are added again, and subsequently 20 ml of toluene, the product being concentrated again; gradually the solution is converted into an amber-colored crystallized paste. Finally, 30 ml of acetone are added to the residue, and stirring is carried out until the oily fraction surrounding the crystals is dissolved. The product is then cooled in an ice chamber, centrifuged, washed with anhydrous acetone and eventually dried, After recrystallization from acetone, crystals are obtained, melting point 132°C. References Merck Index 90 Kleeman & Engel p. 662 DOT 12 (1) 9 (1976) I.N. p. 709 Coirre, P. and Coirre, B.; British Patent 1,246,141; September 15, 1971

OXACILLIN SODIUM Therapeutic Function: Antibacterial Chemical Name: 3,3-Dimethyl-6-(5-methyl-3-phenyl-4isoxazolecarboxamido)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2carboxylic acid, sodium salt Common Name: 6-(5-Methyl-3-phenyl-2-isoxazoline-4-carboxamido) penicillanic acid, sodium salt; 5-Methyl-3-phenyl-4-isoxazolylpenicillin, sodium salt

2532

Oxacillin sodium

Structural Formula:

Chemical Abstracts Registry No.: 7240-38-2; 66-79-5 (Base) Trade Name Resistopen Prostaphlin Cryptocillin Bristopen Penstapho Bactocill Oxabel Penistafil Stapenor Staphcillin V

Manufacturer Squibb Bristol Hoechst Bristol Bristol Beecham Sarva Antibioticos Bayer Banyu

Country US US W. Germany France Italy US Belgium Spain W. Germany Japan

Year Introduced 1962 1962 1962 1963 1966 1972 -

Raw Materials Benzaldehyde Thionyl chloride Hydroxylamine 6-Aminopenicillanic acid

Chlorine Sodium bicarbonate Ethyl acetoacetate

Manufacturing Process (A) Benzaldoxime: (Reference, Vogel, Textbook of Practical Organic Chemistry, page 883) -Materials: (Theoretical yield, 121.1 grams of free oxime), 106.1 grams (1.0 mol) of benzaldehyde (NF grade), 69.5 grams (1.0 mol) of hydroxylamine hydrochloride (practical grade), 68.0 grams (1.7 mol) of sodium hydroxide (pellet). Procedure: The sodium hydroxide is dissolved in 200 ml water and the benzaldehyde is added. With continued stirring the hydroxylamine hydrochloride is added in portions. Some heat is developed and eventually the benzaldehyde dissolves. The solution is stirred for 15 minutes and then cooled in an ice-bath. A waxy, crystalline mass separates, and after further cooling it is collected by suction and dried in air. Yield is 86 to 149 grams. This crude material is suitable for step (B).

Oxacillin sodium

2533

(B) Benzohydroximic Chloride: [Reference, G.W. Perrold et al, J. Am. Chem. Soc., 79, 462 (1957)] - Materials: 121 grams (0.77 mol) of crude benzaldoxime from step (A), 500 ml of 8.3 N hydrochloric acid, chlorine. Procedure: The crude product from (A) is suspended in the hydrochloric acid, cooled in an ice-salt mixture, and chlorine is passed into the mixture with stirring for ½ to 1 hour. Transient blue and green colors may be noticed in the mixture during this time. The temperature will probably rise to 3° to 5°C. The solid is collected by suction filtration and dried for an hour or so on the filter before use in (C). If at all possible, it should be used on the day of preparation. Yield is 71 grams (after 1½ hours on the filter). (C) 5-Methyl-3-Phenyl-4-Isoxazolecarboxylic Acid: [Reference, A. Quilico and R. Rusco, Gazz. Chim. Ital. 67, 589 (1937); C.A. 32, 21177] - Materials: 71 grams (0.45 mol) of crude benzohydroximic chloride from (E), 78 grams (0.60 mol) of ethyl acetoacetate (practical grade), 34 grams (0.60 mol) of sodium methoxide (95% minimum), 400 ml of methanol (reagent grade). Procedure: The sodium methoxide is cautiously added in portions to 200 ml of methanol with stirring. Some heat is evolved. To this warm solution is rapidly added the ethyl acetoacetate with continued stirring. The solution is stirred for 10 minutes and then cooled in an ice-salt-acetone mixture (-25°C). If desired a Dry Ice-acetone cooling bath may be used to shorten the addition time. The crude material from (B) is dissolved in 200 ml of methanol. At this point it is probably easier to filter this mixture by suction to remove a large amount of insoluble solid, which is probably sodium chloride. The solid may be rinsed with more methanol. The filtrate is chilled in ice-water and added to the cooled methanolic solution of the sodium derivative of ethyl acetoacetate at a rate which keeps the temperature of the re. action mixture below 0°C. The addition time will be 15 to 20 minutes if ice-salt-acetone is used as a coolant. This reaction is extremely exothermic. The reaction mixture is stirred overnight at room temperature and filtered to remove the sodium chloride. The filtrate is stripped in vacuo and the crude ester (literature reports MP 48°C) is dissolved in 150 ml of ethanol; 28 grams (0.70 mol of sodium hydroxide in 90 ml of water is added and the solution is refluxed for 2 hours. After removal of the ethanol in vacuo the residue is dissolved in water and extracted twice with ether. Dissolved ether is removed from the aqueous solution in vacuo and it is acidified to pH 2 with concentrated hydrochloric acid. The crystalline crude acid is dried briefly and then recrystallized from acetonitrile to give 32 grams of white product; MP 193° to 194.5°C (literature reports 189° to 190°C). Concentration of the mother liquor gives an additional 5 grams of material having a MP of 192.5 to 194°C. The 37 grams of material represents an 18% overall yield from benzaldehyde. (D) The acid is converted to the acid chloride by reaction with thionyl chloride. (E) 5-Methyl-3-Phenyl-4-Isoxazolylpenicillin: A solution of 4.43 grams of 5methyl-3-phenylisoxazole-4-carbonyl chloride in 120 ml acetone was added

2534

Oxaflozane hydrochloride

gradually to a stirred solution of 4.32 grams of 6-aminopenicillanic acid in 168 ml of 3% aqueous sodium bicarbonate and 50 ml acetone. When addition was complete the mixture was stirred at room temperature for 4 hours and then extracted with ether (2 x 200 ml), only the aqueous phase being retained. This aqueous solution was covered with 50 ml ether and adjusted to pH 2 by the addition of N hydrochloric acid. After separating the layers, the aqueous phase was extracted with two further 50 ml portions of ether. The combined ether solutions (which at this stage contained the free penicillin acid) were washed with water and then neutralized by shaking with 20 ml N sodium bicarbonate solution. The aqueous phase was separated, washed with ether, and evaporated at low temperature and pressure to leave the crude sodium salt of 5-methyl-3-phenyl-4-isoxazolylpenicillin as a white solid, which was finally dried in vacuo over phosphorus pentoxide and found to weigh 7.34 grams. References Merck Index 6777 Kleeman & Engel p. 662 PDR pp. 673, 708, 1606 OCDS Vol. 1 p. 413 (1977) DOT 1 (3) 115 (1965) I.N. p. 709 REM p. 1197 Doyle, F.P. and Nayler, J.H.C.; US Patent 2996,501; August 15, 1961

OXAFLOZANE HYDROCHLORIDE Therapeutic Function: Antidepressant Chemical Name: 2-(3-Trifluoromethyl)phenyl-4-isopropyl-tetrahydro-1,4oxazine hydrochloride Common Name: Structural Formula:

Chemical Abstracts Registry No.: 26629-86-7; 26629-87-8 (Base)

Oxaflozane hydrochloride Trade Name Conflictan Conflictan

Manufacturer Sarbach Riom Lab

Country France France

2535

Year Introduced 1982 -

Raw Materials Bromine Isopropylamine (3-Trifluoromethyl)phenyl magnesium bromide

2-Chloroethylvinyl ether Hydrogen chloride

Manufacturing Process (1) 1,2-Dibromo-2-(2-chloro)ethoxyethane: 640 g of bromine (4 mols) are added dropwise, with stirring, to 426 g (4 mols) of 2-chloroethylvinyl ether dissolved in 1,040 ml of chloroform maintained at -10°C. When addition is ended, the solvent and then the residue are distilled in vacuum to obtain 690 g of product. Yield = 65%. (2) 2-(3-Trifluoromethyl)-2-(2-chloro)ethoxy-1-bromoethane: (3Trifluoromethyl)phenyl magnesium bromide is prepared under the normal conditions for magnesium derivatives, from 48.6 g of magnesium turnings and 455.7 g of (3-trifluoromethyl)bromobenzeneand 1.5 liters anhydrous ether. To the solution of the magnesium compound so obtained the following solution is added dropwise, with stirring so as to maintain a slight reflux of ether: 1,2dibromo-2-(2-chloro)-ethoxyethane: 550 g. Anhydrous ether: 300 ml. After the addition, reflux heating is continued for two hours, cooling is carried out and there is hydrolysis by the mixture: Ice: 500 g. Concentrated HCl: 200 ml. The organic phase is decanted, washed in NaCl saturated water and dried on anhydrous Na2SO4; the ether is distilled and the residue is rectified in vacuum to obtain 361 g of the product. Yield = 54%. According to gas phase chromatography, the product so obtained is about 95% pure and it can be used in further reactions without a second rectification. (3) 2-(3-Trifluoromethyl)phenyl-4-isopropyl tetrahydro-1,4-oxazine hydrochloride: The following mixture is heated in an autoclave at 100°C; 2-(3trifluoromethyl)-2-(2-chloro)-ethoxy-1-bromoethane: 33.15 g (0.1 mol); isopropylamine: 20 g (0.34 mol); toluene: 100 ml. After filtration of the isopropylamine hydrochloride and bromohydrate, the solvent is stripped and the residue is admixed with ~ 4 N HCl and the aqueous phase is washed with ether. The aqueous phase is treated with 50% aqueous NaOH, the amine is ether-extracted and, after drying on anhydrous Na2SO4, the ether is distilled and the residue is rectified in vacuum to obtain 14 g of the product. Yield = 50%.

2536

Oxaflumazine disuccinate

The hydrochloride is crystallized by adding ethyl acetate to the base and then adding the necessary amount of pure alcohol saturated in dry HCl. Melting point 164°C. References Merck Index 6780 DFU 3 (9) 667 (1978) Kleeman & Engel p. 663 DOT 18 (10) 536 (1982) I.N. p. 709 Mauvernay, R.Y., Busch, N., Moleyre, J. and Simond, J.; US Patent 3,637,680; January 25, 1972; assigned to Societe Anonyme: Centre Europeen De Recherches Mauvernay

OXAFLUMAZINE DISUCCINATE Therapeutic Function: Neuroleptic, Antihistaminic, Spasmolytic Chemical Name: N-3-(2-Trifluoromethyl-10-phenothiazinyl)-propyl-N'-2-[2(1,3-dioxanyl)]ethyl-piperazine disuccinate Common Name: Structural Formula:

Chemical Abstracts Registry No.: 41761-40-4; 16498-21-8 (Base) Trade Name Oxaflumine

Manufacturer Diamant

Country France

Year Introduced 1970

Raw Materials N-[2-(3,1-Dioxanyl)ethyl]piperazine 2-Trifluoromethylphenothiazine Succinic acid

1-Bromo-3-chloropropane Sodium

Oxametacine

2537

Manufacturing Process Preparation of N-(3-chloropropyl)-N'-[2-(1,3-dioxanyl)-ethyl]-piperazine: A solution of 30 g (0.15 mol) of N-[2-(1,3-dioxanyl)-ethyl]-piperazine and 11.8 g (0.075 mol) of 1-bromo-3-chloropropane in 150 ml of dry benzene was refluxed with stirring for 5 hours. After cooling, the N-[2-(1,3-dioxanyl)ethyl]-piperazinium bromide which had precipitated was filtered off, the filtrate was concentrated in vacuo and the residual oil was distilled. 14.1 g (68%yield) of N-(3-chloropropyl)-N'-[2-1,3-dioxanyl)-ethyl]-piperazine which occurred as a light yellow oil were obtained. Boiling point: 152°C to 155°C under 0.07 mm Hg (nD23 = 1.4940). The disuccinate prepared in acetone and recrystallized from acetone melts at 104°C to 105°C on a hot stage microscope. The sodium derivative of the 2-trifluoromethylphenothiazine was prepared from 26.7 g (0.1 mol) of 2-trifluoromethylphenothiazine and 2.3 g (0.1 g atom) of sodium in 500 ml of liquid ammonia. After the reaction was completed, the ammonia was driven off and 500 ml of dry toluene were added. A solution of 25 g (0.09 mol) of N-(3-chloropropyl)-N'-[2-(1,3dioxanyl)-ethyl]-piperazine in 200 ml of toluene was added drop by drop to this solution which was then refluxed with stirring for 18 hours. After cooling, the precipitate which had formed was filtered and the filtrate was washed with water, dried and concentrated in vacuo. 33 g of brown oil, the N-3-(2trifluoromethyl-10-phenothiazinyl)-propyl-N'-2-[2-(1,3-dioxanyl)]-ethylpiperazine, were obtained. A warm solution of 4.4 g of the base obtained in 100 ml of acetonitrile was added to a warm solution of succinic acid in 200 ml of acetonitrile. After standing for 15 hours at 0°C. the crystalline product was obtained, melting point 138°C. References Merck Index 6781 Kleeman & Engel p. 663 DOT 6 (3) 89 (1970) I.N. p. 709 Societe Industrielle Pour La Fabrication Des Antibiotiques (S.I.F.A.); British Patent 1,103,311; February 14, 1968

OXAMETACINE Therapeutic Function: Antiinflammatory Chemical Name: 1-(4-Chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-1Hindole-3-acetamide Common Name: Indoxamic acid Chemical Abstracts Registry No.: 27035-30-9

2538

Oxametacine

Structural Formula:

Trade Name Flogar Flogar Dinulcid

Manufacturer A.B.C. U.C.B. Pharmascience

Country Italy France France

Year Introduced 1976 1981 1983

Raw Materials 1-p-Chlorobenzoyl-2-methyl-5-methoxy-3-indoleacetic acid Thionyl chloride Hydroxylamine hydrochloride Manufacturing Process 1 g of 1-p-chlorobenzoyl-2-methyl-5-methoxy-3-indoleacetic acid [J. Am. Chem. Soc. 85, 488-489 (1963)] is treated in a nitrogen stream with 10 ml thionyl chloride in which it promptly dissolves. The solution is quickly evaporated in vacuum and the residue (which typically is of a deep browngreen color) is distempered, twice or three times, with a few ml anhydrous benzene which is removed in vacuum each time. The resulting residue is thoroughly distempered with 5 ml anhydrous ether which dissolves most of the color impurities, and separated by filtering, purified by crystallizing from plenty of anhydrous ether, yielding a crystalline mass of needles of strawyellow color, melting point 124°C to 127°C. Yield: 0.700 g. Found: Cl % 18.62 (calculated 18.84). The product is relatively stable towards water and aqueous alkalies in which it proves to be insoluble even after dwelling therein several hours at room temperature. It reacts, better if at elevated temperature, with lower alcohols with which it forms the corresponding esters, and with ammonia under suitable conditions for forming the amide (melting point 219°C to 221°C). A solution of 1.330 g sodium hydroxide in 20 ml water is slowly admixed with 2.330 g hydroxylamine hydrochloride while cooling, whereupon 1 g chloride of 1-p-chlorobenzoyl-2-methyl-5-methoxy-3-indoleacetic acid is distempered in this neutral or slightly alkaline solution by vigorously stirring during a few minutes.

Oxamniquine

2539

The acid chloride reacts with the free hydroxylamine with considerable rapidity apparently without dissolving. The reaction is completed when a sample of the suspension shows to become clear on adding aqueous alkali. The crystalline pale-yellow mass of product is separated by filtering, lavishly washed with water and dried in vacuum. The crude product yield is actually quantitative. The product is purified with excellent yields by repeatedly crystallizing from hot dioxane and washing with ether: melting point 181°C to 182°C (dec.). References Merck Index 6788 I.N. p. 710 De Martlis, F., Arrigoni-Martelli, E. and Tamietto, T.; US Patent 3,624,103; November 30, 1971; assigned to Instituto Biologico Chemioterapico (A.B.C.) SpA (Italy)

OXAMNIQUINE Therapeutic Function: Antischistosomal Chemical Name: 1,2,3,4-Tetrahydro-2-[[(1-methylethyl)amino]methyl]-7nitro-6-quinolinemethanol Common Name: Structural Formula:

Chemical Abstracts Registry No.: 21738-42-1 Trade Name Vansil Vansil

Manufacturer Pfizer Pfizer

Country US France

Year Introduced 1980 1981

Raw Materials Bacterium Aspergillus sclerotiorum Huber Soybean meal Glucose 2-Isopropylaminomethyl-6-methyl-7-nitro-1,2,3,4-tetrahydroquinoline Manufacturing Process (1) Four fermenters are set up, each one of which contained 2.0 liters of the

2540

Oxamniquine

following medium, sterilized for 35 minutes at 15 psi, respectively: Soybean meal Glucose NaCl K2HPO4 Yeast extract Tap water to

5 grams 20 grams 5 grams 5 grams 5 grams 1 liter

pH adjusted with sulfuric acid to 6.5 The fermenters are inoculated with 7.5% by volume of a 24-hour old culture of Aspergillus sclerotiorum Huber grown at 28°C in 50 ml aliquots of the above described soybean-glucose medium contained in 300 ml Erlenmeyer flasks, placed on a shaker rotating at approximately 230 rpm. The inoculated fermenters are agitated at 1,380 rpm and each aerated with 1 liter of air per minute and at a temperature of 28°C for 47 hours. A silicone antifoam is added when required. At the end of the 47 hour period, the pH of the fermentation broth rose to 6.8 to 6.9. Sulfuric acid is then added with sterile precautions to restore the pH to 6.5. (2) 0.75 g of 2-isopropylaminomethyl-6-methyl-7-nitro-1,2,3,4tetrahydroquinoline as hydrogen maleate, dissolved in 75 ml of sterile water, is added to each of the four fermenters and agitation and aeration are continued for a further 23 hours. The whole fermentation broths from each fermenter are pooled, the pH adjusted to 8.0 with sodium hydroxide and the 8.2 liters of fermentation broth thus obtained are extracted by agitating vigorously with 16.4 liters of methylene chloride for 10 minutes. The solvent extract is then dried over anhydrous sodium sulfate and subsequently evaporated to dryness at a temperature below 40°C (dry weight 5.567 g). (3) The dark brown residue from (2) is extracted four times with methanol at room temperature, decanting the solution from the insoluble material. The combined methanol extracts, total volume about 200 ml, are then filtered and treated with 3 g of sodium borohydride, added in portions over a period of 30 minutes with stirring, to reduce any 6-formyl compound present to the 6hydroxymethyl compound. The methanol solution is then allowed to stand overnight at room temperature and is thereafter diluted with 1 liter of ether. The solution is washed 4 times with 500 ml of water and the resulting pale yellow ethereal solution is dried over magnesium sulfate. The ether is next removed by vacuum distillation from a water bath at 40°C. The residue is dissolved in about 75 ml of isopropanol at 50°C, filtered to remove any insoluble particles and cooled overnight in the refrigerator. The product is collected and dried in vacuo to yield 0.5 g of 6-hydroxymethyl-2isopropylaminomethyl-7-nitro-1,2,3,4-tetrahydroquinoline as pale yellow crystals of melting point 147°C to 149°C. A further 0.5 g of crude material is obtained from the mother liquors of the recrystallization. Total yield is therefore 1.0 g (0.0036 mol) from 3.0 g (0.0079 mol) of starting material, i.e., 45% of the theoretical amount. References Merck Index 6791 OCDS Vol. 2 p. 372 (1980)

Oxandrolone

2541

DOT 17 (4) 152 (1981) I.N. p. 710 REM p. 1236 Richards, H.C.; US Patent 3,821,228; June 28, 1974; assigned to Pfizer, Inc.

OXANDROLONE Therapeutic Function: Androgen Chemical Name: 17β-Hydroxy-17-methyl-2-oxa-5α-androstan-3-one Common Name: Structural Formula:

Chemical Abstracts Registry No.: 53-39-4 Trade Name Anavar Anatrophill Vasorome Oxandrolone Spa Lonavar

Manufacturer Searle Searle Kowa SPA Searle

Country US France Japan Italy Italy

Year Introduced 1964 1965 1969 1979 -

Raw Materials 17β-Hydroxy-17α-methyl-5α-androst-1-en-3-one Lead tetraacetate Sodium borohydride Manufacturing Process To a solution of 6.36 parts of 17β-hydroxy-17α-methyl-5α-androst-1-en-3-one in 95 parts of acetic acid and 12 parts of water is added 40 parts of lead tetracetate and 0.6 part of osmium tetroxide. This mixture is stored at room temperature for about 24 hours, then is treated with 2 parts of lead tetracetate. Evaporation to dryness at reduced pressure affords a residue, which is extracted with benzene. The benzene extract is washed with water, and extracted with aqueous potassium bicarbonate. The aqueous extract is washed with ether, acidified with dilute sulfuric acid, then extracted with ethyl

2542

Oxaprozin

acetate-benzene. This organic extract is washed with water, dried over anhydrous sodium sulfate, and concentrated to dryness in vacuo. To a solution of the residual crude product in 20 parts of pyridine is added 10 parts of 20% aqueous sodium bisulfite and the mixture is stirred for about 20 minutes at room temperature. This mixture is then diluted with water, washed with ethyl acetate, acidified with dilute sulfuric acid, and finally extracted with benzene. The benzene extract is washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness at reduced pressure to produce crude 17β-hydroxy17α-methyl-1-oxo-1,2-seco-A-nor-5α-androstan-2-oic acid, which after recrystallization from aqueous isopropyl alcohol melts at about 166° to 173°C (decomposition). An aqueous slurry of 6 parts of 17β-hydroxy-17α-methyl-1-oxo-1,2-seco-Anor-5α-androstan-2-oic acid in 200 parts of water is made alkaline to pH 10 by the addition of dilute aqueous sodium hydroxide, then is treated with 6 parts of sodium borohydride. This mixture is allowed to react at room temperature for about 3 hours. Benzene is added and the resulting mixture is acidified carefully with dilute hydrochloric acid. The benzene layer is separated, and the aqueous layer is further extracted with benzene. The combined benzene extracts are washed successively with aqueous potassium bicarbonate and water, dried over anhydrous sodium sulfate, then evaporated to dryness in vacuo. The resulting residue is triturated with ether to afford pure 17β-hydroxy-17α-methyl-2-oxa-5α-androstan-3-one, MP about 235° to 238°C, according to US Patent 3,128,283. References Merck Index 6794 Kleeman & Engel p. 664 PDR p. 1677 OCDS Vol. 1 p. 174 (1977) I.N. p. 710 REM p. 999 Pappo, R.; US Patent 3,128,283; April 7, 1964; assigned to G.D. Searle and Co. Pappo, R.; US Patent 3,155,684; November 3, 1964; assigned to G.D.Searle 81 Co.

OXAPROZIN Therapeutic Function: Antiinflammatory Chemical Name: 2-Oxazolepropanoic acid, 4,5-diphenylCommon Name: Oxaprozin Chemical Abstracts Registry No.: 21256-18-8

Oxaprozin

2543

Structural Formula:

Trade Name Danoprox Daypro Daypro Dayrun Duraprox Duraprox Oxaprozin Oxaprozin

Manufacturer TRB Chemedica Pfizer Pharmacia CSC Pharmaceuticals Gerolymatos Aventis Pasteur Apotex Inc. Dr. Reddy's Laboratories Ltd.

Country Switz. Austria Greece France India

Year Introduced -

Raw Materials Pyridine Benzoin Succinic anhydride Acetic acid Manufacturing Process A clean dry reactor of 20 gallon (91 liters) capacity was charged with pyridine (9.25 kg), benzoin (16.5 kg) and succinic anhydride (11.7 kg.). The reactor was purged with nitrogen and a nitrogen atmosphere was maintain throughout the process. The mixture was heated without agitation until it became liquid at 85°C. Agitation was commenced and the mixture was heated at 90°-95°C for 1.5 hours. A solution of ammonium acetate (12.0 kg) in glacial acetic acid (35.0 kg) was charged to the header of the reactor and added to the reaction mixture over 15 minutes, maintaining the temperature between 90° and 95°C. The container for the solution and the header were washed with glacial acetic acid (4.0 kg) and the washing liquid was added to the reaction mixture. The reaction mixture was held at 90°-95°C for 2 hours. The reaction mixture was cooled to 50°C and transferred via a line filter to a reactor of 50 gallon (227 liters) capacity. The first reactor, lines and filter were washed with glacial acetic acid (4.0 kg.) which was combined with the reaction mixture. The reaction mixture was heated with agitation to 90°-95°C over 30 minutes and water (21.0 kg.) was added maintaining the temperature at 90°-95°C. The reaction mixture was then cooled to 20°-25°C over 55 minutes by means of water in the jacket of the reactor and then cooled to 10°-15°C by means of brine in the jacket and left overnight. The product was filtered on a ceramic filter and sucked well dry. The product on the filter was washed with a prefiltered mixture of glacial acetic acid (25.5 kg.) and water (12.5 kg) and

2544

Oxaprozin

sucked well dry. Pre-filtered water (50.0 kg) and the filter cake were added to a reactor of 50 gallon (227 liters) capacity. The mixture was stirred at room temperature for 30 minutes and filtered on a ceramic filter and the product was sucked well dry. The product on the filter was washed twice with prefiltered water (10 kg each time) and sucked well dry. The product was then dried in a Mitchell oven at 80°C for 16-18 hours. The yield of crude β-(4,5diphenyloxazol-2-yl)propionic acid was 15.9 kg (69.8%). This material only just failed specification for acceptable purity because although TLC analysis showed only very faint trace impurities. Recrystallisation of crude β-(4,5-Diphenyloxazol-2-yl)propionic acid Methanol (62.0 kg) was added to a reactor of 50 gallon capacity (227 liters). 15.9 kg of the crude oxazole above prepared was added with agitation. The mixture was heated to reflux. All the solid dissolved. The mixture was then cooled to 50°C and transferred to a reactor of 20 gallon (91 liters) capacity. The larger reactor and transfer lines were washed through with methanol at about 40°C twice (3 kg each time). The mixture was cooled over 1 hour 50 minutes with agitation, gradually at first, to 15°-20°C by means of cooling water on the jacket of the reactor. The product was then filtered on a ceramic filter and sucked well dry. The product on the filter was washed twice with methanol (5 kg each time) and sucked well dry. The wash liquors were combined with the filtration liquors and retained. The product from the filter was dried in an air oven at 55°-60°C for 18 hours. The yield of β-(4,5diphenyloxazol-2-yl)propionic acid was 12.1 kg. TLC investigation showed the product to be pure. Melting point 160.5°-161.5°C. Another crop of product was obtained from the methanol liquors as follows. The liquors were added to a reactor of 20 gallon (91 liters) capacity and the solvent was distilled off for 9 hours until solid appeared. The mixture was then cooled to 15° to 20°C over 1 3/4 hours using cooling water in the jacket of the reactor. The mixture was cooled to 10°C using brine in the jacket and stirred at this temperature for 30 minutes. The product was then filtered on a ceramic filter and sucked well dry. The product on the filter was washed twice with methanol (5 kg each time) and sucked well dry. The product was dried in an air oven at 55°-60°C for 18 hours. The yield was 2.14 kg. This product may also have been acceptably pure but its purity was not investigated. It was therefore retained as crude product to be resubjected to recrystallisation with methanol. The yield for the recrystallisation was thus 12.1 kg from a consumption of 13.76 kg of crude product, that is 88%. The overall yield of pure product is 69.8% times 88%, that is, 61.4%. References Weston G.O.; US Patent No. 4,190,584; Feb. 26, 1980; Assigned to John Wyeth and Brother Limited, Maidenhead, England Brown K.; US Patent No. 3,578,671; May 11, 1971; Assigned to John Wyeth and Brother Limited, Taplow, Maidenhead, Berkshire, England

Oxatomide

2545

OXATOMIDE Therapeutic Function: Antiallergic Chemical Name: 1-[3-[4-(Diphenylmethyl)-1-piperazinyl]propyl]-2benzimidazolone Common Name: Oxatimide Structural Formula:

Chemical Abstracts Registry No.: 60607-34-3 Trade Name Tinset Tinset Tinset Finsedyl

Manufacturer Janssen Janssen Janssen Microsules

Country W. Germany UK Switz. Argentina

Year Introduced 1981 1982 1983 -

Raw Materials 1-(3-Chloropropyl)-2H-benzimidazol-2-one 1-(Diphenylmethyl)piperazine Manufacturing Process A mixture of 53 parts of 1-(3chloropropyl)-2H-benzimidazol-2one, 5 parts of 1-(diphenylmethyl)piperazine, 6.4 parts of sodium bicarbonate and 200 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with waterseparator. After cooling, water is added and the layers are separated. The 4methyl-2pentanone phase is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue is crystallized from a mixture of 2,2'-oxybispropane and a small amount of 2-propanol. The product is filtered off and dried, yielding 1-[3-[4-(diphenylmethyl)-1piperazinyl]propyl]-2H-benzimidazole-2-one; melting point 153.6°C. References Merck Index 6798

2546

Oxazepam

DFU 3 (6) 465 (1978) OCDS Vol. 3 p. 173 (1984) DOT 16 (7) 219 (1980); 18 (7) 341 and (9) 440 (1982) I.N. p. 711 Vandenberk, J., Kennis, L.E.J., Van der Aa, M.J.M.C. and Van Heertum, A.H.M.T.; US Patent 4,200,641; April 29, 1980; assigned to Janssen Pharmaceutica N.V.

OXAZEPAM Therapeutic Function: Tranquilizer Chemical Name: 7-Chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4benzodiazepin-2one Common Name: Structural Formula:

Chemical Abstracts Registry No.: 604-75-1 Trade Name Serax Adumbran Seresta Praxiten Serpax Anxiolit Aplakil Aslapax Benzotran Droxacepam Durazepam Enidrel Hilong Iranil Isochin Limbial

Manufacturer Wyeth Thomae Wyeth Byla Wyeth Wyeth Gerot Aristegui Asla Protea Jeba Durachemie Syncro Banyu Iltas Tosi Chiesi

Country US W. Germany France UK Italy Austria Spain Spain Australia Spain W. Germany Argentina Japan Turkey Italy Italy

Year Introduced 1965 1965 1966 1966 1967 -

Oxazepam Trade Name Nesontil Noctazepam Oxpam Propax Psicopax Psiquiwas Purata Quen Quilibrex Sedokin Serepax Sigacalm Sobile Uskan Vaben Wakazepam

Manufacturer Promeco Brenner I.C.N. Cipan Bama-Geve Wassermann Lennon Ravizza Isnardi Geymonat Sud Ferrosan Siegfried Lafarquin Desitin Rafa Wakamoto

Country Argentina W. Germany Canada Portugal Spain Spain S. Africa Italy Italy Italy Denmark Switz. Spain W. Germany Israel Japan

2547

Year Introduced -

Raw Materials 7-Chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one-4-oxide Acetic anhydride Sodium hydroxide Manufacturing Process (A) Suspend 10 g of 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2one 4-oxide in 150 ml of acetic anhydride and warm on a steam bath with stirring until all the solid has dissolved. Cool and filter off crystalline, analytically pure 3-acetoxy-7-chloro-1,3-dihydro-5-phenyl-2H-1,4benzodiazepin-2-one, melting point 242°C to 243°C. (B) Add to a suspension of 3.4 g of 3-acetoxy-7-chloro-1,3-dihydro-5-phenyl2H-1,4-benzodiazepin-2-one in 80 ml of alcohol.6 ml of 4 N sodium hydroxide. Allow to stand after complete solution takes place to precipitate a solid. Redissolve the solid by the addition of 80 ml of water. Acidify the solution with acetic acid to give white crystals. Recrystallize from ethanol to obtain 7chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one, melting point 203°C to 204°C. References Merck Index 6799 Kleeman & Engel p. 664 PDR p. 1980 OCDS Vol. 1 p. 366 (1977) and 2, 402 (1980) DOT 1 (3) 102 (1965) and 9 (6) 238 (1973) I.N. p. 711 REM p. 1063 Bell, S.C.; US Patent 3,296,249; January 3, 1967; assigned to American Home Products Corp.

2548

Oxazolam

OXAZOLAM Therapeutic Function: Tranquilizer Chemical Name: 7-Chloro-5-phenyl-5'-methyltetrahydrooxazolo[5.4-b]2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-one Common Name: Oxazolazepam Structural Formula:

Chemical Abstracts Registry No.: 24143-17-7 Trade Name Serenal Quiadon Convertal Hializan Tranquit

Manufacturer Sankyo Merck Roemmers Pharma-investi Promonta

Country Japan W. Germany Argentina Spain W. Germany

Year Introduced 1970 1980 -

Raw Materials 5-Chloro-2-chloroacetylaminobenzophenone Isopropanolamine Manufacturing Process To a solution of 12.0 g of 5-chloro-2-chloroacetylaminobenzophenone and 3.2 g of isopropanolamine in 100 ml of ethanol was added 3.3 g of sodium acetate. The resulting mixture was heated under reflux with stirring for 12 hours. After completion of the reaction, the solvent was distilled off and the residue was extracted with dichloromethane. The extract was washed with water, dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was recrystallized from ethanol to give 10.6 g of the desired product melting at 186°C to 188.5°C. References Merck Index 6801

Oxeladin

2549

DOT 8 (1) 18 (1972) and 9 (6) 239 (1973) I.N. p. 712 REM p. 1064 Tachikawa, R., Takagi, H., Kamioka, T., Midayera, T., Fukunaga, M. and Kawano, Y.; US Patents 3,772,371; November 13, 1973; and 3,914,215; October 21, 1975; both assigned to Sankyo Co., Ltd.

OXELADIN Therapeutic Function: Antitussive Chemical Name: α,α-Diethylbenzeneacetic acid 2-[2-(diethylamino)ethoxy] ethyl ester Common Name: Structural Formula:

Chemical Abstracts Registry No.: 468-61-1; 16485-39-5 (Citrate) Trade Name

Manufacturer

Country

Year Introduced

Silopentol

Schulte

W. Germany

1970

Ethochlon

Hokuriku

Japan

1970

Fustopanox

Ottia Pharm.

Japan

1970

Paxeladine

Beaufour

France

1974

Dorex

Woelm

W. Germany

-

Hihustan

Maruko

Japan

-

Hustopan

Ohta

Japan

-

Marukofon

Maruko

Japan

-

Neoasdrin

Toa

Japan

-

Neobex

Lampugnani

Italy

-

Neusedan

Nippon Zoki

Japan

-

Pectamol

Malesci

Italy

-

Pectussil

Kwizda

Austria

-

Tussilisin

Ibirn

Italy

-

Tussimol

B.D.H.

UK

-

2550

Oxeladin

Raw Materials Phenylacetonitrile Sodium Potassium hydroxide

Ethyl chloride β,β'-Dichlorodiethyl ether Diethylamine

Manufacturing Process Preparation of Diethylphenylacetonitrile: 25 grams of sodium was dissolved in 300 ml liquid ammonia containing 0.3 gram ferric chloride and 59 grams phenylacetonitrile was added slowly with stirring. After about 15 minutes a cooled solution of 80 grams of ethyl chloride in 200 ml dry ether was added and the mixture stirred for 1 hour. The ammonia was then allowed to evaporate, water added and the ether layer separated, dried, concentrated and the residual oil distilled in vacuo to yield diethylphenylacetonitrile as an oil, BP 85°C/1 mm. Preparation of Diethylphenylacetic Acid: 46 grams of the foregoing nitrile was added to 140 ml ethylene glycol containing 36 grams potassium hydroxide and the mixture refluxed with stirring for about 20 hours. The mixture was diluted with water, extracted with light petroleum (BP 60° to 80°C) to remove traces of impurities and then acidified to yield diethylphenylacetic acid which was recrystallized from dilute ethanol (40% v/v ethanol in water). Preparation of 2-(β-Chloroethoxy)Ethyl Diethylphenylacetate: 19.2 grams of the foregoing acid was added to a solution of 4 grams of sodium hydroxide in 40 ml ethylene glycol. 28.6 grams β,β'-dichlorodiethyl ether was added and the mixture refluxed for 1 hour. After removal of solvent under reduced pressure, 150 ml water was added to the residue and the product extracted with ether. The ethereal solution was dried, concentrated and the residue distilled in vacuo to yield the product as an oil, BP 140°C/0.7 mm. Preparation of 2-(β-Diethylaminoethoxy)Ethyl Diethylphenylacetate: A mixture of 21 grams of 2-(β-chloroethoxy)ethyl diethylphenylacetate and 14 grams diethylamine was heated under pressure in a sealed tube at 140°C for 5 hours. After cooling, the mixture was dissolved in dilute hydrochloric acid and extracted with ether to remove traces of neutral impurities. The acid layer was then made alkaline with 10% w/v sodium hydroxide solution with cooling, and re-extracted with two portions of ether. The ether extract was dried, the ether distilled off and the residue distilled in vacuo to yield the product as an oil, BP 140°C/0.1 mm. References Merck Index 6803 Kleeman & Engel p. 665 OCDS Vol. 1 p. 90 (1977) I.N. p. 712 Petrow, V., Stephenson, O. and Wild, A.M.; US Patent 2,885,404; May 5, 1959; assigned to The British Drug Houses Limited, England

Oxendolone

2551

OXENDOLONE Therapeutic Function: Antiandrogen Chemical Name: 16β-Ethyl-17β-hydroxyestr-4-ene-3-one Common Name: Structural Formula:

Chemical Abstracts Registry No.: 33765-68-3 Trade Name Prostetin

Manufacturer Takeda

Country Japan

Year Introduced 1981

Raw Materials Ethyl orthoformate 16β-Ethylestra-4-ene-3,17-dione Sodium borohydride Hydrogen chloride Manufacturing Process To a solution of 3.0 g of 16β-ethylestra-4-ene-3,17-dione dissolved in 150 ml of dioxane, are added 15 g of ethyl orthoformate and 0.1 g of ptoluenesulfonic acid, followed by stirring for 2 hours at room temperature. The reaction solution is poured into 300 ml of a 5% aqueous solution of sodium hydrogen carbonate and the resultant mixture is extracted with ether. The ether layer is washed with water and dried, followed by evaporation of the solvent to give crude crystals of 3-ethoxy-16β-ethylestra-3,5-diene-17-one. The crystals are recrystallized from ether to give 3.0 g of the compound melting at 114°C to 115°C. To a solution of 3.0 g of the enol-ether compound obtained above in 50 ml of methanol, is added 1.5 g of sodium borohydride. After standing for 1.5 hours at room temperature, the reaction solution is poured into 300 ml of water. The resulting precipitates are collected by filtration and recrystallized from ether to give 2.8 g of 3-ethoxy-16β-ethylestra-3,5-dien-17β-ol melting at 131°C to 133°C. To a solution of 2.5 g of 3-ethoxy-16β-ethylestra-3,5-diene-17β-ol dissolved in

2552

Oxethazine

50 ml of methanol is added 1.2 ml of concentrated hydrochloric acid, followed by stirring for 10 minutes. The reaction solution is poured into 250 ml of water. The precipitated crystals are collected by filtration and recrystallized from ether to give 2.3 g of 16β-ethyl-17β-hydroxyestra-4-en-one melting at 152°C to 153°C. References Merck Index 6804 DFU 5 (9) 44 (1980) I.N. p. 712 Hiraga, K., Yoshioka, K., Goto, G., Nakayama, R. and Masuoka, M.; US Patent 3,856,829; December 24, 1974; assigned to Takeda Chemical Industries, Ltd.

OXETHAZINE Therapeutic Function: Local anesthetic Chemical Name: 2,2'-[(2-Hydroxyethyl)imino]bis[N-(1,1-dimethyl-2phenylethyl)-N-methylacetamide] Common Name: Oxetacaine Structural Formula:

Chemical Abstracts Registry No.: 126-27-2; 13930-31-9 (Hydrochloride salt) Trade Name Oxaine Emoren Mucaine Mutesa Stomacain Strocain Tepilta Topicain

Manufacturer Wyeth Wassermann Wyeth Wyeth Byla Teisan-Pfizer Eisai Wyeth Chugai

Country US Italy UK France Japan Japan W. Germany Japan

Year Introduced 1960 -

Oxetorone fumarate

2553

Raw Materials Chloro-N-methyl-N-ω-phenyl-tert-butyl acetamide Ethanolamine Manufacturing Process Chlor-N-methyl-N-ω-phenyl-tert-butyl acetamide (23.95 g) (0.1 mol) is added to n-butanol (150.0 cc) containing anhydrous potassium carbonate (50.0 g). To the stirred refluxing solution is added dropwise freshly distilled ethanolamine (3.1 g) (0.05 mol). Stirring and refluxing is maintained for twenty hours. Upon cooling the solution is filtered; the residue is washed with n-butanol. The combined filtrates are washed with aqueous sodium carbonate solution then water and finally dried over anhydrous magnesium sulfate. The solvent is distilled under vacuum leaving a dry solid residue. The residue is dissolved in dry benzene to which is added n-hexane to crystallize the product melting at 104°C to 104.5°C. Yield 71-73%. Analysis-Carbon: calc. 71.9%; found 71.93%; hydrogen: calc. 8.8%; found 8.9%; nitrogen: calc. 9.0%; found 9.0%. To make the hydrochloride salt, the bisacetamide or, by another name, 1,11diphenyl-2,2,3,9,10,10-hexamethyl-4,8-diketo-6-(β-hydroxyethyl)-3,6,9triazaundecane is dissolved in n-butanol. The solution is chilled and then dry hydrogen chloride gas is passed into the solution causing an oil to separate. To the heavy oil ether is added and then stirred causing crystallization to occur. MP 146°C to 147°C. Analysis for nitrogen: calc. 83%. found 8.2%. To make the acetate salt, the bisacetamide (4.7 g) (0.01 mol) is dissolved in ethyl acetate to which is added glacial acetic acid (0.6 g) (0.01 mol). Ether is added to precipitate the acetate as a gum which is washed with hexane, and finally added to dry ether. Allow to stand for crystallization. MP 141°C. Analysis for nitrogen: calc. 8.0%; found 8.2%. Other salts are: sulfate, MP 56°C; acid oxalate, MP 127°C; tartrate, MP 45°C; picrate, MP 151°C to 152°C. References Merck Index 6806 Kleeman & Engel p. 666 OCDS Vol. 1 p.72 (1977) I.N. p. 712 Seifter, J., Hanslick, R.S. and Freed, M.E.; US Patent 2,780,646; February 5, 1957;assigned to American Home Products Corp.

OXETORONE FUMARATE Therapeutic Function: Serotonin antagonist, Antihistaminic

2554

Oxetorone fumarate

Chemical Name: 6-(3-Dimethylamino-1-propylidene)-12H-benzofuro[2,3-e] benz[b]oxepin fumarate Common Name: Structural Formula:

Chemical Abstracts Registry No.: 34522-46-8; 26020-55-3 (Base) Trade Name Nocertone Nocertone Oxedix

Manufacturer Labaz Labaz Labaz

Country France W. Germany -

Year Introduced 1975 1976 -

Raw Materials Ethyl iodide Magnesium Sulfuric acid

γ-Dimethylaminopropyl chloride 6-Oxo-benzo[b]benzofurano[2,3-e]oxepin Fumaric acid

Manufacturing Process (A) Preparation of 6-(3-dimethylaminopropyl)-6-hydroxybenzo[b]benzofurano [2,3-e]oxepin - In a 250 ml flask equipped with a vertical condenser, a dropping-funnel, a dip thermometer and a stirrer, 1.5 g of magnesium turnings and a crystal of iodine were heated until vaporization of the iodine and then cooled, after which 20 ml of dry tetrahydrofuran were added. The mixture was heated under reflux and a solution of 0.2 g of ethyl iodide in 5 ml of dry tetrahydrofuran was allowed to flow into the reaction medium. When the reaction started, a solution of 6.2 g of γ-dimethylaminopropyl chloride in 20 ml of dry tetrahydrofuran was added and the mixture so obtained was heated under reflux until the complete disappearance of the magnesium turnings. The reaction medium was then cooled in an ice bath, after which there was added thereto a solution in 45 ml of tetrahydrofuran of 7 g of 6-oxo-benzo[bl]-benzofurano[2,3-e]oxepin. The reaction mixture was allowed to stand for 20 hours at a temperature of 20°C, and was then poured into a saturated aqueous solution of ammonium chloride maintained at a temperature of 5°C. The mixture was extracted with ether and the organic portion was washed and dried over anhydrous sodium sulfate. After evaporation of the solvent, 9.4 g of crude product were obtained, which after recrystallization from isopropanol, provided 6.7 g of pure 6-(3dimethylaminopropyl)-6-hydroxybenzo[b]benzofurano[2,3-e]oxepin, melting

Oxfendazole

2555

point 160°C (yield, 71%). (8) Preparation of 6-(3-dimethylaminopropylidene)-benzo[b]benzofurano[2,3e]oxepin and its fumarate -In an Erlenmeyer flask 6.2 g of 6-(3dimethylaminopropyl)-6-hydroxybenzo[b]benzofurano[2,3-e]oxepin prepared as described above were dissolved in 108 ml of a 10% solution of sulfuric acid. The solution obtained was heated to boiling point for 15 minutes. After cooling, 100 ml of chloroform were added and the solution was made alkaline with a 5% solution of sodium hydroxide. The solution was then extracted with chloroform, washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated and the resulting oily residue composed of 6-(3dimethylaminopropylidene)-benzo[b]benzofurano[2,3-e]oxepin was then directly treated with a solution of fumaric acid in isopropanol to give 6.5 g of 6-(3-dimethylaminopropylidene)-benzo[b]benzofurano[2,3-e]oxepin fumarate (yield, 85%). The fumarate had a melting point of 160°C when recrystallized from isopropanol. References Merck Index 6807 Kleeman & Engel p. 667 OCDS Vol. 3 p. 247 (1984) DOT 11 (1) 19 (1975) I.N. p. 712 Binon, F. and Descamps, M.L.V.; US Patent 3,651,051; March 21, 1972; assigned to Labora. toires Labaz

OXFENDAZOLE Therapeutic Function: Anthelmintic Chemical Name: Carbamic acid, (5-(phenylsulfinyl)-1H-benzimidazol-2-yl)-, methyl ester Common Name: Oxfendazole Structural Formula:

Chemical Abstracts Registry No.: 53716-50-0 Trade Name Autoworm Oxfendazole

Manufacturer Coopers AroKor Holdings Inc.

Country -

Year Introduced -

2556

Oxfendazole

Trade Name Benzelmin Benzelmin Repidose Interzol Oxfenil

Manufacturer Syntex Wyeth Sante animale Agrovet Werfft Sanofi

Country -

Year Introduced -

Raw Materials Sodium hydride Thiophenol Sulfuric acid Acetic anhydride Sodium acetate Hydrogen Sodium bisulfite

2-Amino-4-chloro-1-nitrobenzene Sodium phenyl mercaptide Sodium bicarbonate 1,3-Bismethoxycarbonyl-S-methylisothiourea Palladium on carbon Peracetic acid Acetic acid

Manufacturing Process 5.0 g of 2-amino-4-chloro-1-nitrobenzene is added to a solution of sodium phenyl mercaptide, prepared under nitrogen from 2.53 g 57% sodium hydride and 6.2 ml thiophenol in 20 ml dimethylformamide, with a 10 ml dimethylformamide rinse. The mixture is stirred under nitrogen for 3 h at 20°30°C and then diluted with water. The crude product is washed with water and hexane, then recrystallized from methanol, yielding 2-amino-4-phenylthio-1nitrobenzene. 6.0 g of 2-amino-4-phenylthio-1-nitrobenzene is dissolved in 80 ml acetic anhydride and treated with a few drops of sulfuric acid. The mixture is left at 20°-30°C for 2 h then a little sodium acetate added and the solvent removed under vacuum. The residue is treated with water, filtered and recrystallized from methanol yielding 2-acetamido-4-phenylthio-1-nitrobenzene. 7.0 g of 2-acetamido-4-phenylthio-1-nitrobenzene is dissolved in 70 ml chloroform and treated, at -20°C to -15°C, with a solution of 5.0 g 40% peracetic acid in 10 ml methanol. The mixture is allowed to warm slowly to 20°C and stirred for 4 h. The reaction mixture is extracted with sodium bisulfite solution, then sodium bicarbonate solution, dried and evaporated. The residual gum of 2-acetamido-4-phenylsulfinyl-1-nitrobenzene is treated with 20 ml 5 N sodium hydroxide and 40 ml methanol at 20°-25°C for 1 h. Water is then added and essentially pure 2-amino-4-phenyl-sulfinyl-1-nitrobenzene filtered off. Recrystallization may be effected from benzene. 5.4 g of 2-amino-4-phenylsulfinyl-1-nitrobenzene is hydrogenated at 1 atmosphere pressure in 500 ml methanol in the presence of 5.0 g 5% palladized carbon, until the theoretical uptake of hydrogen has occurred. The catalyst is removed by filtration and the filtrate stripped under vacuum. The residue is recrystallized from methanol-benzene, yielding 1,2-diamino-4phenylsulfinylbenzene. A mixture of 5.5 g of 1,2-diamino-4-phenylsulfinylbenzene, 4.3 g of 1,3-bismethoxycarbonyl-S-methylisothiourea and 1.2 ml acetic acid in 100 ml

Oxiconazole nitrate

2557

ethanol and 100 ml water is refluxed for 4 h. The mixture is cooled and essentially pure 6-phenylsulfinyl-2-carbomethoxyaminobenzimidazole filtered off and washed with methanol. Recrystallization may be effected from methanol-chloroform (melting point 253°C, dec.). References Beard C.C. et al.; US Patent No. 3,929,821; Dec. 30, 1975; Assigned: Syntex (U.S.A.) Inc., Palo Alto, Calif.

OXICONAZOLE NITRATE Therapeutic Function: Antifungal Chemical Name: 1-(2,4-Dichlorophenyl)-2-(1H-imidazol-1-yl)-O-(2,4dichlorobenzyl)-ethanone oxime nitrate Common Name: Structural Formula:

Chemical Abstracts Registry No.: 64211-46-7 Trade Name

Manufacturer

Country

Year Introduced

Myfungar

Siegfried

Switz.

1983

Oceral

Roche

Switz.

1983

Raw Materials 1-(2,4-Dichlorophenyl)-2-(1H-imidazol-1-yl)ethanone oxime Sodium hydride 2,4-Dichlorobenzyl chloride Nitric acid Manufacturing Process 13.5 g of 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)-ethanone oxime are dissolved in 100 ml dimethylformamide (DMF) and 1.2 g of sodium hydride are mixed in, whereupon an exothermic reaction is allowed to take place on

2558

Oxilofrine

its own with stirring. After cessation of evolution of hydrogen, a solution of 9.8 g of 2,4-dichlorobenzyl chloride in 10 cc DMF is added dropwise with continuous stirring and the stirring is carried on for 2 hours further. The reaction is then taken to completion at a bath temperature of 80°C, after which the reaction mixture is evaporated in a rotation evaporator under reduced pressure and the residue is dissolved in 100 ml ethanol. After filtering off of undissolved matter, the solution is stirred with 300 ml 2N nitric acid for the conversion of free base to the nitrate. The liquid standing over the heavy deposits which have separated out is separated off by decanting, whereupon an isomer is obtained which after recrystallization from ethanol is obtained in a yield of 5.2 g and having a melting point of 137°C to 138°C. References DFU 6 (2) 99 (1981) DOT 19 (12) 884 (1983) I.N. p. 713 Mixich, G., Thiele, K. and Fischer, J.; US Patent 4,124,767; November 7, 1978; assigned to Siegfried AG.

OXILOFRINE Therapeutic Function: Sympathomimetic, Analeptic Chemical Name: Benzenemethanol, 4-hydroxy-α-(1-(methylamino)ethyl)-, (R*,S*)Common Name: Hydroxyephedrine; Methyloxedrine; Methylsynephrine; Oxilofrine; Oxyephedrine Structural Formula:

Chemical Abstracts Registry No.: 365-26-4 Trade Name Carnigen

Manufacturer Aventis Pharma Deutschland GmbH

Country -

Year Introduced -

Oxitefonium bromide

2559

Raw Materials Sodium Bromine Caustic soda Palladium Ethanol absolute

p-Hydroxypropiophenone Benzyl bromide Methylbenzylamine Hydrogen

Manufacturing Process The p-benzyloxypropiophenone used for the transformation is prepared by adding to a solution of 6.9 g of sodium in 230 ml of absolute alcohol 45.0 g of p-hydroxypropiophenone and 54.0 g of benzyl bromide, and boiling for 1 h in a reflux apparatus. The excess of alcohol is then distilled and the residue is extracted with ether and water. After drying it the ethereal solution is evaporated and the residue is recrystallized from alcohol of 95% strength. The yield amounts to 60.0 g. The p-benzyloxypropiophenone melts at 100°-101°C. 55.0 g of p-benzyloxypropiophenone are dissolved in 250 ml of methylene chloride and brominated with 38.0 g of bromine. As soon as all of the bromine has been introduced drop by drop, the methylene chloride solution is washed with caustic soda solution and water. The solvent is eliminated in a vacuum and the residue is dissolved in petroleum ether. The crystalline mass which soon separates is filtered by suction and washed with petroleum ether. When recrystallized from hexahydrobenzene the p-benzyloxybromopropiophenone melts at 80°C. 40.0 g of p-benzyloxybromopropiophenone are then transformed in an alcoholic solution with 30.0 g of methylbenzylamine. After the whole has been allowed to stand for 1 day, the excess of alcohol is distilled in a vacuum and the residue is dissolved with ether. By washing with water, the benzylmethylamine hydrobrornide then formed is eliminated and the ether is removed by evaporation. The ether residue soon begins to crystallize and the p-benzyloxymethylbenzylaminopropriophenone is obtained with a good yield; when recrystallized from petroleum ether of low boiling point it melts at 58°60°C. 15.0 g of p-benzyloxymethylbenzylaminopropriophenone are dissolved in alcohol and the solution is hydrogenated with palladium and hydrogen. As soon as the required quantity of hydrogen has been absorbed the palladium is filtered by suction and the alcohol is evaporated in a vacuum The residue is recrystallized and the p-hydroxyphenylmethylaminopropanol is obtained. References Bockmuhl M. et al.; US Patent No. 1,877,756; September 20, 1932

OXITEFONIUM BROMIDE Therapeutic Function: Anticholinergic, Spasmolytic

2560

Oxitefonium bromide

Chemical Name: Ammonium, diethyl(2-hydroxyethyl)methyl-, bromide, αphenyl-2-thiopheneglycolate Common Name: Oxitefonium bromide; Oxytefonium bromide Structural Formula:

Chemical Abstracts Registry No.: 17989-37-6 Trade Name Oxitefonium bromide

Manufacturer Sintofarm Group

Country -

Year Introduced -

Raw Materials Phenyl-(α-thienyl)hydroxyacetic acid 2-Diethylaminoethyl chloride Methyl bromide Manufacturing Process Phenyl-(α-thienyl)hydroxyacetic acid (4.86 g), 2-diethylaminoethyl chloride (2.85 g) and 75 ml of isopropyl alcohol were refluxed for 15 h. After the addition of 50 ml of absolute alcohol to the cold mixture, it was treated with Norite (activated charcoal) at room temperature, filtered, and the solvents removed under reduced pressure. The residue crystallised when triturated with absolute ether. After recrystallisation from absolute alcohol, the phenyl(α-thienyl)hydroxyacetate of 2-diethylaminoethyl hydrochloride melted at 181182°C. The producing of phenyl-(α-thienyl)hydroxyacetate of 2diethylmethylaminoethyl bromide may be carried out by methylation of phenyl-(α-thienyl)hydroxyacetate of 2-diethylaminoethyl hydrochloride with methylbromide. References Blicke F.F., Arbor A.; US Patent No. 2,541,025; Feb. 13, 1951; Assigned: Regents of The University of Michigan, Ann Arbor, Mich., a corporation of Michigan

Oxitriptan

2561

OXITRIPTAN Therapeutic Function: Antidepressant, Antiepileptic Chemical Name: 5-Hydroxytryptophan Common Name: 5-Hydroxytryptophan Structural Formula:

Chemical Abstracts Registry No.: 56-69-9 Trade Name Levotonine Pretonine Tript-Oh Levothym Quietim Stimolomens Telesol

Manufacturer Panmedica Arkodex Sigma Tau Karlspharma Nativelle lrbi Lasa

Country France France Italy W. Germany France Italy Spain

Year Introduced 1973 1973 1980 -

Raw Materials β-(5-Benzyloxyindolyl-3)-α-acetylamino-α-methylthiopropionic acid methanethiol ester Hydrogen Sulfuric acid Manufacturing Process β-(5-Benzyloxyindolyl-3)-α-acetylamino-α-methylthiopropionic acid methanethiol ester (449 mg) was added to 10 ml of ethanol and further 1 ml of triethylamine was added to the mixture. Then, the reaction mixture was refluxed for 17 hours, after condensation under reduced pressure and subsequent separation of the residue by column chromatography (silica gel, ethyl acetate), 353 mg of methyl β-(5-benzyloxyindolyl-3)-α-acetylamino-αmethylthiopropionate was obtained as colorless glasslike substance in the yield of 81.5%. Recrystallization of the substance from methanol water afforded 287 mg of crystals. Raney nickel (3.5 cc) was suspended in 10 ml of ethanol and 356 mg of methyl β-(5-benzyloxyindolyl-3)-α-aminoacetyl-α-methylthiopropionate was added to the mixture together with 20 ml of ethanol. Then, the reaction

2562

Oxitropium bromide

mixture was stirred for 1 hour at room temperature and thereafter filtered to remove insoluble substances. The residue was washed with 100 ml of ethanol and 50 ml of acetone and both the filtrate and the wash liquid were combined and concentrated under reduced pressure. By column chromatography (silica gel and acetone), 210 mg of methyl β-(5-hydroxyindolyl-3)-αacetylaminopropionate as colorless glasslike substance in the yield of 90%. To 430 mg of methyl β-(5-hydroxyindolyl-3)-α-acetylaminopropionate was added 50 ml of 10% sulfuric acid and the reaction mixture was refluxed under heating for 10 hours. After condensation under reduced pressure to 15 ml volume, the reaction solution was neutralized with ammonia to pH 4, to afford the extract. The resulting extract was filtered and washed with water to afford 265 mg of 5-hydroxytryptphan in the yield of 78%. References Merck Index 4771 Kleeman and Engel p. 668 I.N. p. 714 Tsuchihashi, G. and Ogura, K.; U.S. Patent 4,001,276; January 4,1977; assigned to Sagami Chemical Research Center (Japan)

OXITROPIUM BROMIDE Therapeutic Function: Anticholinergic bronchodilator Chemical Name: (-)-N-Ethylnorscopolamine methobromide Common Name: OTB Structural Formula:

Chemical Abstracts Registry No.: 30286-75-0 Trade Name Ventilat

Manufacturer Boehringer Ingelheim

Country W. Germany

Year Introduced 1983

Oxolamine citrate

2563

Raw Materials (-)-Norscopolamine Methyl bromide

Ethyl bromide Sodium carbonate

Manufacturing Process 14.5 g (0.05 mol) of (-)-norscopolamine and 5.4 g (0.05 mol) of ethyl bromide were dissolved in 300 cc of acetonitrile, 5.3 g (0.05 mol) of anhydrous sodium carbonate were suspended in the solution, and the suspension was heated at the boiling point for 10 hours. After a boiling time of 2.5 and 5 hours, respectively, the supply of ethyl bromide and sodium carbonate in the reaction mixture was replenished by adding each time 5.4 g (0.05 mol) of ethyl bromide and 5.3 g (0.05 mol) of anhydrous sodium carbonate. At the end of 10 hours of boiling, the inorganic sodium salts which had separated out were separated by vacuum filtration, the filter cake was washed with acetonitrile, and the acetonitrile was distilled out of the filtrate. The distillation residue was dissolved in ether, the solution was extracted with a small amount of water and then dried, and the ether was distilled off, yielding raw (-)-N-ethylnorscopolamine. 7.0 g (0.022 mol) of (-)-N-ethylnorscopolamine were dissolved in acetonitrile, 10.4 g (0.11 mol) of methyl bromide were added to the solution, and the mixture was allowed to stand at room temperature. The crystalline precipitate formed thereby was collected and recrystallized from acetonitrile.8.9 g (97.8% of theory) of white crystalline (-)-N-ethylnorscopolamine methobromide, melting point 203°C to 204°C (decomposition), were obtained. References Merck Index A-10 DFU4 (2) 117 (1979) DOT 19 (7) 416 and (8) 444 (1983) Zeile, K., Banholzer, R., Walther, G., Schulz, W. and Wick, H.; US Patent 3,472,861; Oct. 14, 1969; assigned to Boehringer Ingelheim GmbH.

OXOLAMINE CITRATE Therapeutic Function: Antitussive, Antiinflammatory Chemical Name: 1,2,4-Oxadiazole, 5-(2-(diethylamino)ethyl)-3-phenyl-, citrate Common Name: Oxolamine citrate Raw Materials 3-Chloropropionyl chloride N-Hydroxybenzamidine Diethyl amine

2564

Oxolamine citrate

Structural Formula:

Chemical Abstracts Registry No.: 1949-20-8 ; 959-14-8 (Base) Trade Name Bredon Broncatar Perebron Prilon Flogobron Oxolamine citrate Oxolamine citrate

Oxolamine citrate Kalamin Oxadron Regal Aledron

Manufacturer Organon Pulitzer Angelini Francesco Cassenne Intersint Milen Yick-Vic Chemicals and Pharmaceuticals (HK) Ltd. Shanghai Lansheng Corporation

Country -

Year Introduced -

-

-

Ilsan Ilac Fustery Andromaco IQFA

-

-

Manufacturing Process 18.7 g 3-chloro-propionyl chloride in 50 ml of dry ether was added dropwise with stirring to the cooled with ice solution 40 g of N-hydroxybenzamidine in 450 ml dry ester. A dense precipitate had fallen. The mixture was stirred 0.5 hour at room temperature and then was filtered off. The precipitate was thoroughly washed with water for a removal hydrochloride of starting Nhydroxybenzamidine whereas N-(amino)phenylmethylene-3-Cl-propionamide didnt solve. It was dried in vacuum over P2O5. Yield of clean product 94% from theoretical. MP: 98°-99°C. The solution of 9.2 g diethyl amine in 50 ml dry benzene was added dropwise to a suspension of above prepared N(amino)phenylmethylene-3-Cl-propionamide in dry benzene with stirring and cooling. The mixture was warmed and stirred else 2 hours after adding. Then it was cooled, washed two times with water and dried over CaCl2. Then the solvent was removed. The residue was distilled in vacuum. Diethyl-[2-(3phenyl[1,2,4]oxadiasol-5)ethyl]amine (oxolamine) had BP: 127°C/0.4 mm. Yield 10.5 g.

Oxolinic acid

2565

In practice it is usually used as citrate. References Angelini F.; D.B. Patent No. 1,097,998; Sept. 30, 1959

OXOLINIC ACID Therapeutic Function: Antibacterial (urinary) Chemical Name: 1-Ethyl-1,4-dihydro-4-oxo-1,3-dioxolo[4,5-g]quinoline-3carboxylic acid Common Name: Structural Formula:

Chemical Abstracts Registry No.: 14698-29-4 Trade Name Prodoxol Urotrate Ossian Utibid Nidantin Decme Emyrenil Gramurin Oksaren Ossion Oxoboi Oxoinex Oxol Oxolin Pietil Tilvis Tropodil Urinox Uro-Alvar

Manufacturer Warner Substantia Bioindustria Warner Lambert Sasse/Goedecke Poli Emyfar Chinoin Belupo Ltd. Bioindustria B.O.I. Inexfa Casen Prodes Argentia Scharper Elea Syncro Alvarez-Gomez

Country UK France Italy US W. Germany Italy Spain Hungary Yugoslavia Italy Spain Spain Spain Spain Argentina Italy Argentina Argentina Spain

Year Introduced 1974 1974 1974 1975 1978 -

2566

Oxolinic acid

Trade Name

Manufacturer

Country

Year Introduced

Uropax

Lefa

Spain

-

Uroxol

Ausonia

Italy

-

Raw Materials 3,4-Methylenedioxyaniline Diethyl ethoxymethylenemalonate Sodium hydroxide Ethyl iodide Manufacturing Process A mixture of 27 parts by weight of 3,4-methylenedioxyaniline and 43 parts by weight of diethyl ethoxymethylenemalonate is heated at 80° to 90°C for 3 hours. The mixture is then heated at 80° to 90°C for 1 hour under about 15 mm pressure to remove the byproduct ethyl alcohol formed. The residue is recrystallized from ligroin (BP 60° to 90°C) to give diethyl[(3,4methylenetlioxyanilino)methylene] malonate as a yellow solid melting at 100° to 102°C. The analytical sample from ligroin melts at 101° to 102°C. A mixture of 48 parts by weight of diethyl[(3,4-methylenedioxyanilino) methylene] malonate and 500 parts by weight of diphenyl ether is refluxed for 1 hour. The mixture is allowed to cool to about 25°C with stirring and 500 parts by weight of petroleum ether are added. Filtration gives 3-carbethoxy6,7-methylenedioxy-4-hydroxy-quinoline as a brown solid, MP 276° to 281°C. Several recrystallizations from dimethylformamide gives almost colorless analytical material, MP 285° to 286°C, (decomposes). A mixture of 26 parts of 3-carbethoxy-6,7-methylenedioxy-4-hydroxyquinoline,16 parts of sodium hydroxide and 50 parts of dimethylformamide is heated at 70° to 75°C for 2 hours, then 31 parts of ethyl iodide is added over 1 hour with continued heating and stirring. After an additional 3 to 4 hours of heating (at 70° to 75°C) and stirring, the mixture is diluted with 500 parts of water, refluxed for 3 to 4 hours, acidified with concentrated hydrochloric acid and filtered to yield 18 to 22 parts of 1-ethyl-1,4-dihydro-6,7-methylenedioxy-4-oxo-3-quinoline-carboxylic acid, MP 309° to 314°C (decomposes). The analytical sample from dimethylformamide melts at 314° to 316°C (decomposes). References Merck Index 6814 Kleeman & Engel p. 670 OCDS Vol. 2 pp. 370, 387(1980) and 3, 185 (1984) I.N. p. 34 Kaminsky, D. and Meltzer, R.I.; US Patent 3,287,458; November 22, 1966; assigned to Warner-Lambert Pharmaceutical Company

Oxomemazine

2567

OXOMEMAZINE Therapeutic Function: Antihistaminic Chemical Name: N,N,β-Trimethyl-10-H-phenothiazine-10-propanamine 5,5dioxide Common Name: Structural Formula:

Chemical Abstracts Registry No.: 3689-50-7; 4784-40-1 (Hydrochloride salt) Trade Name Doxergan Imakol Dysedon Rectoplexil Toplexil

Manufacturer Specia Rhone Poulenc Meiji Specia Specia

Country France W. Germany Japan France France

Year Introduced 1964 1965 -

Raw Materials Phenothiazine Sodium amide 3-Dimethylamino-2-methylpropyl chloride Hydrogen peroxide Manufacturing Process Phenothiazine is reacted with 3-dimethylamino-2-methylpropyl chloride in the presence of sodium amide to give 3-(10-phenthiazinyl)-2-methyl-1dimethylaminopropane. 11.9 g of of this intermediate is dissolved with agitation in glacial acetic acid (120 cc). Pure sulfuric acid (d = 1.83; 0.5 cc) is added and a mixture of glacial acetic acid (10 cc) and hydrogen peroxide (8.5 cc of a solution containing 38 g of hydrogen peroxide in 100 cc) is then run in over 20 minutes. The temperature rises from 25°C to 35°C and is then kept at 60°C for 18 hours. The mixture is cooled and water (150 cc) is added and, with cooling, aqueous sodium hydroxide (d = 1.33; 220 cc). The resulting

2568

Oxprenolol

mixture is extracted with ethyl acetate (3 x 100 cc), the solvent is evaporated on a water bath and the residue is recrystallized from heptane (150 cc). 3(9,9-dioxy-10-phenthiazinyl)-2-methyl-1-dimethylaminopropane (78 g) is obtained, MP 115°C. The corresponding hydrochloride prepared in ethyl acetate and recrystallized from a mixture of ethanol and isopropanol melts at 250°C. References Merck Index 6815 Kleeman & Engel p. 670 DOT 2 (4)145 (1966) I.N. p. 715 Jacob, R.M. and Robert, J.G.; US Patent 2,972,612; February 21, 1961; assigned to Societe des Usines Chimiques Rhone-Poulenc (France)

OXPRENOLOL Therapeutic Function: Antiarrhythmic Chemical Name: 1-[(1-Methylethyl)amino]-3-[2-(2-propenyloxy)phenoxy]-2propanol Common Name: Structural Formula:

Chemical Abstracts Registry No.: 6452-71-7; 6452-73-9 (Hydrochloride salt) Trade Name Trasicor Trasicor Trasicor Trasicor Trasacor Captol Cordexol Coretal

Manufacturer Ciba Geigy Ciba Geigy Ciba Geigy Ciba Geigy Ciba Geigy Protea Lagap Polfa

Country Italy W. Germany UK France Japan Australia Switz. Poland

Year Introduced 1970 1971 1972 1975 1976 -

Oxybutymin chloride

2569

Raw Materials Epichlorohydrin Isopropylamine

Pyrocatechol monoallyl ether

Manufacturing Process 75 grams of pyrocatechol monoallyl ether, 75 grams of epichlorohydrin, 75 grams of potassium carbonate and 400 ml of acetone are stirred and heated at the boil for 12 hours. The potassium carbonate is then filtered off. The solvent is distilled off in a water-jet vacuum. The residual oil is dissolved in ether and agitated with 2 N sodium hydroxide solution. The ether is separated, dried and distilled off. The residue is distilled in a water-jet vacuum. 3-(ortho-allyloxy-phenoxy)-1,2-epoxypropane passes over at 145° to 157°C under 11 mm Hg pressure. A solution of 15 grams of 3-(ortho-allyloxyphenoxy)-1,2-epoxypropane and 15 grams of isopropylamine in 20 ml of ethanol is refluxed for 4 hours. The excess amine and the alcohol are then distilled off under vacuum, to leave 1-isopropylamino-2-hydroxy-3-(orthoallyloxy-phenoxy)-propane which melts at 75° to 80°C after recrystallization from hexane. References Merck Index 6820 Kleeman & Engel p. 671 OCDS Vol.1 p.117 (1977) and 2, 109 (1980) DOT 6 (1) 25 (1970) I.N. p. 716 Ciba Limited, Switzerland; British Patent 1,077,603; August 2, 1967

OXYBUTYNIN CHLORIDE Therapeutic Function: Spasmolytic Chemical Name: α-Cyclohexyl-α-hydroxybenzeneacetic acid 4-(dietylamino)2-butynyl ester hydrochloride Common Name: Structural Formula:

2570

Oxycodone hydrochloride

Chemical Abstracts Registry No.: 1508-65-2; 5633-20-5 (Base) Trade Name

Manufacturer

Country

Year Introduced

Ditropan

Marion

US

1975

Ditropan

Scharper

Italy

-

Raw Materials Methyl phenylcyclohexylglycolate 4-Diethylamino-2-butynyl acetate Sodium methylate Manufacturing Process A mixture of 394.2 grams of methyl phenylcyclohexylglycolate and 293.1 grams of 4-diethylamino-2-butynyl acetate was dissolved with warming in 2.6 liters of n-heptane. The solution was heated with stirring to a temperature of 60° to 70°C and 8.0 grams of sodium methoxide were added. The temperature of the mixture was then raised until the solvent began to distill. Distillation was continued at a gradual rate and aliquots of the distillate were successively collected and analyzed for the presence of methyl acetate by measurement of the refractive index. The reaction was completed when methyl acetate no longer distilled, and the refractive index observed was that of pure heptane (nD26 = 1.3855). About 3½ hours were required for the reaction to be completed. The reaction mixture was then allowed to cool to room temperature, washed with water, and extracted with four 165 ml portions of 2 N hydrochloric acid. The aqueous extracts were combined and stirred at room temperature to permit crystallization of the hydrochloride salt of the desired product. Crystallization was completed by cooling the slurry in an ice bath, and the product was collected by filtration, pressed dry, and recrystallized from 750 ml of water. Yield of pure crystalline material, 323 grams. References Merck Index 6823 Kleeman & Engel p. 672 PDR p. 1076 OCDS Vol. 1 p. 93 (1977) I.N. p. 716 REM p.919 Mead Johnson and Company; British Patent 940, 540; October 30, 1963

OXYCODONE HYDROCHLORIDE Therapeutic Function: Narcotic analgesic

Oxycodone hydrochloride

2571

Chemical Name: Morphinan-6-one, 4,5α-epoxy-14-hydroxy-3-methoxy-17methyl- hydrochloride Common Name: Dihydrohydroxycodeinone hydrochloride; Hydrooxycodeinona; Hydroxydihydrocodeinonum hydrochloricum; Ossicodone; Oxiconum; Oxikon; Oxycodeinone hydrochloride; Oxycodone hydrochloride; Thecodin Structural Formula:

Chemical Abstracts Registry No.: 76-42-6 (Base); 124-90-3 Trade Name Oxyfast Endone Oxynorm Roxicodone Percodan Codeinona

Manufacturer Purdue Pharma, L.P. Boots Mundipharma Roxane Endo Pharmaceuticals Inc. Higiene

Country -

Year Introduced -

Raw Materials Dibutylurea t-BuMe2SiCl Peracetic acid Acetic acid Hydrogen

Codeine sulfate trihydrate Ammonium hydroxide Aluminum isopropoxide Potassium sodium tartrate tetrahydrate Palladium on carbon

Manufacturing Process Preparation of codeinone from codeine: Codeinone was prepared by oxidation of codeine sulfate trihydrate. A reaction mixture was prepared containing codeine sulfate trihydrate (10.4 g), deionized water (20 g) and isopropyl acetate (87.2 g) at ambient temperature. The reaction mixture was agitated and the resultant mixture cooled to about 20°C. Concentrated ammonium hydroxide (18.0 g) was added in several portions and the mixture was maintained at a temperature of about 20°C with stirring. Sting was continued for about 15 min, and then a small portion of the aqueous layer was withdrawn to check for pH value, which was to be advantageously maintained between 11.0 and 12.0. The aqueous layer was

2572

Oxycodone hydrochloride

then separated and reextracted with isopropyl acetate (35 g). The combined organic layers (isopropyl acetate) were concentrated in vacuo to near dryness at temperature 45°C. The residual isopropyl acetate solvent was chased by adding 18 g of toluene. The concentration process was then repeated in vacuo. Codeine free base dissolved in a mixture of toluene (177 g) and cyclohexanone (47.4 g) at 45°C was then transferred to the reaction flask which was equipped with magnetic stirrer, thermocouple, Dean-Stark trap with condenser attached, addition funnel with an extender (about 4 inches height), and a nitrogen inlet adapter. The mixture was heated to boiling temperature (about 116-118°C) under a nitrogen atmosphere and 26 g (30 ml) of distillate were collected in the Dean-Stark trap. A solution of aluminum isopropoxide (3.5 g) in 35.5 g (41 ml) of toluene was then added to the addition funnel. The heating rate was adjusted and the aluminum isopropoxide/toluene solution was added into the reaction mixture at such a rate that the total volume was added over a 10-20 min period [approximately the same volume (41 ml) of distillate was collected in the Dean-Stark trap]. After completion of the addition, collection of the distillate was continued such that 57 g (66 ml) of distillate was collected in the Dean-Stark trap at a similar distillation rate. The heat source was removed and the mixture allowed to cool down to ambient temperature (under nitrogen atmosphere) over a period of about 30 min. Reaction completeness was determined by withdrawing a small sample from the batch, extracting it with a saturated sodium bicarbonate solution and ethyl acetate, concentrating the organic layer, redissolving it with the HPLC mobile phase, and analyzing the sample on HPLC. An aqueous solution of 13 wt. % Rochelle salt was then prepared by dissolving 19.5 g of potassium sodium tartrate tetrahydrate in 130.5 g of deionized water at 20°C. The aqueous Rochelle salt solution (90 ml) was added into the reaction mixture in one portion at ambient temperature, the batch stirred for about 10 min and filtered. Both layers were saved. The organic layer was washed with 60 ml of aqueous Rochelle salt solution (both layers were saved). The organic layer was washed with a mixture of 30 ml brine solution and 30 ml 5% sodium bicarbonate solution (both layers were saved). All aqueous layers were then combined and extracted with 43 g (50 ml) of toluene. The aqueous layer was discarded. The organic layers were then combined and concentrated in vacuo at temperature 55°C to near dryness. 22 g (25 ml) of toluene was added and the resultant organic layer concentrated in vacuo twice more to remove residual cyclohexanone. Subsequently, 11.8 g (15 ml) of 2-propanol was added and the mix slurried at 0-5°C for at least eight hours under a nitrogen atmosphere. Solids were then filtered. The latter operation was repeated until no solids were left in the flask. The chilled wet cake was then rinsed with chilled (5-10°C) 2-propanol (12 g, 15 ml), and filter dried. The wet cake was then rinsed with heptane (6.8 g, 10 ml) and dried. The resulting solids were vacuum dried at 50°C to a constant weight. A yield of 5.2 to 6.45 g (65.4 to 81.2%) of white solids, with HPLC purity of about 96-99.3% was obtained. The compound was stored in a dark and cool place. Preparation of dienolsilyl ether of codeinone: Codeinone (6.0 g) with toluene (104 g) was added to a reaction flask equipped with a mechanical stirrer, thermocouple, Dean-Stark trap with condenser attached, and a nitrogen inlet. The batch was heated to reflux and about 27.7 g (32 ml) of distillate was collected in the Dean-Stark trap. The

Oxycodone hydrochloride

2573

contents were then cooled to 20°C under a nitrogen atmosphere. A solution of dibutyl urea (DBU) (4.22 g) in toluene (3 g) was added in one portion. Subsequently, a solution of t-BuMe2SiCl (4.22 g) in toluene (5 g) was likewise added in one portion. The batch was slowly warmed to 58°C and stirred at this temperature for about 2 hours. Completion of the reaction was adjudged by withdrawing a 20 small sample from the batch, extracting it with a mixture of ethyl acetate and saturated sodium bicarbonate solution, spotting the organic layer on a TLC plate, and then eluting it with a mobile phase of 9:1 mixture of dichloromethane and methanol plus 3-4 drops of concentrated ammonium hydroxide. If the reaction was determined to be incomplete, stirring was continued at 58°C for an additional 2 hours and a TLC check performed once more. Alternatively reaction completion was accomplished by adding about 5-10% more of both DBU and t-BuMe2SiCl to the reaction mixture at the same temperature. The contents were then cooled to 20°C, and a mixture of 5% sodium bicarbonate solution (80 ml) and 60 ml of water was added in one portion. Stirring continued for about 10 min. The aqueous layer was then separated and discarded. The organic layer was washed with a mixture of 50 ml brine and 50 ml saturated ammonium chloride solution (the aqueous layers were discarded). The organic layer was concentrated to near dryness in vacuo at temperature 50°C, and the residue diluted with 33.2 g of toluene to make up a 20 wt % stock solution. Yield was approximately quantitative. The stock solution was found to be stable at ambient temperature under nitrogen atmosphere for at least 6 months. Preparation of 14-hydroxycodeinone from denolsilyl ether of codeinone: Peracetic acid solution (107.7 g of 9.0 wt % peracetic acid) at ambient temperature was added to a reaction flask equipped with mechanical stirrer and thermocouple, nitrogen inlet adapter and addition funnel. A 20 wt % stock solution of the dienolsilyl ether of codeinone (41.7 g) was added through the addition funnel over a period of about 5 min and the temperature of the contents maintained at 28°C. The batch was stirred at 22°C for at least 3 hours. In order to test reaction completeness, a small sample was withdrawn from the batch and quenched with saturated sodium bicarbonate solution, and extracted with ethyl acetate. The EtOAc layer was spotted onto a TLC plate and subsequently checked for the disappearance of starting dienolsilyl ether of codeinone. The TLC mobile phase was a mixture of 95:5 of dichloromethane and methanol plus 3-5 drops of concentrated ammonium hydroxide. If the reaction was adjudged incomplete, the mixture was stirred at the same temperature for an additional 2 hours then analyzed by TLC again. Alternatively completion of the reaction was pushed by the addition of 10 g of peracetic acid (9.0 wt %) and stirring for an additional 1 h (analysis was then once more performed using TLC). Upon determination of the completion of the reaction 20.0 g of 10 wt. % of aqueous sodium hydrogen sulfate solution was added in one portion, and the resultant admixture stirred for 10 min at ambient temperature. The batch was then concentrated in vacuo at 45°C to dryness. Subsequently water (180 g), toluene (69 g), ethyl acetate (36 g) were added and vigorous stirring for about 10 min undertaken. The resulting layers were separated and the aqueous layer saved in a flask. The organic layer was washed thrice with a solution of 26 ml of 2.5% HCl. The combined aqueous layers were then filtered through a pad of wet (with water) hyflo-supercel filter aid. Subsequently, EtOAc (85 g) was added to the filtrate and concentrated

2574

Oxycodone hydrochloride

ammonium hydroxide added in a quantity to adjust the pH of the aqueous layer to about 11. The mixture was stirred for 10 min at about 60°C and the layers were separated and saved. The aqueous layer was washed with EtOAc (50 g) and then discarded. The combined organic layers were concentrated in vacuo to dryness at 50°C. To the residue was added 2-propanol (13 g), and the resultant mixture stirred at 5-10°C for at least 5 hours. The solids were filtered, the flask and solids rinsed with the chilled (5°C) filtrate followed by chilled (5-10°C) 2-propanol (10 g) and heptane (8 g). The solid was then vacuum dried at 50°C to a constant weight. A yield of between 3.50-4.96 g (55%-78%) of 14-hydroxycodeinone free base with a purity of over 96A% was obtained. Preparation of oxycodone from 14-hydroxycodeinone by catalytic hydrogenation: 14-Hydroxycodeinone (4.98 g) and acetic acid (155 g) were added to a Parr shaker equipped with hydrogen inlet and outlet connectors. The mixture was shaken for about 5 min to completely dissolve the 14-hydroxycodeinone at ambient temperature. The system was then evacuated and the Parr shaker was filled with nitrogen. In one portion, under the nitrogen atmosphere, 10% Pd/C (50% water wet, 4.0 g) was added. The system was then evacuated, and was filled with hydrogen gas to a pressure of about 38 psi. The hydrogen inlet from the supply tank was then closed and the mixture was shaken at an initial pressure of 38 psi for about 3 hours (at ambient temperature). After 3 hours of shaking, the system was evacuated and filled with nitrogen. The contents were filtered over a hyflo-supercel filtering pad (3 g, wetted with water). The Parr bottle and wet cake were then rinsed with acetic acid (2 x 21 g). The filtrate was concentrated in vacuo to dryness at 50°C. The residue was then dissolved with deionized water (50 g), and the pH adjusted to about 11.0 to 12.0 using 20% aqueous KOH solution and concentrated ammonium hydroxide (4 g). The mixture was then extracted with ethyl acetate (4 x 135 g), and the combined organic layers concentrated in vacuo to dryness. A yield of 3.51 to 4.26 g of crude oxycodone with HPLC purity of over 85A% (70.0 to 85.0% yield) was obtained. Preparation of oxycodone from 14-hydroxycodeinone by catalytic transfer hydrogenation method: 14-Hydroxycodeinone (4.98 g) and acetic acid (137 g) were added to a reaction flask (3-neck, 250 ml) equipped with mechanical stirrer, addition funnel, thermocouple and nitrogen-inlet adapter. The system was evacuated and the flask filled with nitrogen. Subsequently, 5% Pd/C (50% water wet, 3.0 g) in one portion was added under the nitrogen atmosphere. While the mixture was stirred for about 5 min at ambient temperature, a solution of sodium hypophosphite (6.0 g) in deionized water (25 g) was prepared. The aqueous sodium hypophosphite solution was transferred into the addition funnel, and added to the reaction mixture over a period of about 30 min at about 22°C. The mixture was then warmed to about 45°C and stirred for about 1 hour. Upon the reaction was complete, the batch was cooled to ambient temperature under the nitrogen atmosphere, and the contents filtered over a hyflo-supercel filtering pad (3.0 g, wetted with water). The flask and wet cake were rinsed with acetic acid (20 g). The filtrate was concentrated in vacuo to

Oxydibutanol

2575

near dryness at temperature 50°C. The residue was dissolved with deionized water (50 g) and the pH adjusted to 11.0 to 12.0 with 20% aqueous KOH solution and concentrated ammonium hydroxide (about 4 g). The mixture was then extracted with ethyl acetate (4 x 135 g) and the combined organic layers concentrated to dryness in vacuo. Crude oxycodone with an HBLC purity of over 85% was obtained in a yield of 70.0 to 85.0% (3.51 to 4.26 g). References Chiu Fang-Ting, Lo Young S.; US Patent No. 6,469,170; October 22, 2002; Assigned to Boehringer Ingelheim Chemicals, Inc. (Petersburg, VA)

OXYDIBUTANOL Therapeutic Function: Choleretic, Spasmolytic Chemical Name: 4,4'-Oxybisbutan-2-ol Common Name: Dihydroxydibutyl ether; Hydroxybutyloxide; Oxydibutanol Structural Formula:

Chemical Abstracts Registry No.: 821-33-0 Trade Name Dyskineacutebyl Dis-Cinil Dihydroxydibutyl ether

Manufacturer Saunier Lusofarmaco Joulty

Country -

Year Introduced -

Raw Materials Butyl magnesium bromide β-Cyanoethyloxide Nickel Raney Hydrogen Manufacturing Process To a solution of 3 mols butylmagnesiumbromide in ether was added dropwise an one mol of β-cyanoethyloxide. The mixture was refluxed for 1 hour. Then after cooling to the mixture was added hydrochloric acid. An organic layer was dried under sodium sulfate and evaporated. An oil layer was distilled in vacuum. The oxo-3-butane oxide has a boiling point 123-125°C at 15 mm.

2576

Oxyfedrine

A mixture of 100 g of oxo-3-butane oxide, 500 ml ethanol and 15 g Nickel Reney was loaded in autoclave and heated at 45-50°C. In autoclave was introduced a hydrogene. After cooling the mixture was filtered and ethanol was distilled off. 1,1'-Dimethyl-3,3'-oxydipropanol was distilled at 160161°C/18 mm. References Merck Index, Monograph number: 7094, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. FR Patent No. 1,267,084; June 5, 1961; Assigned to Joulty M.A., resident of France

OXYFEDRINE Therapeutic Function: Coronary vasodilator Chemical Name: (R)-3-[(2-Hydroxy-1-methyl-2-phenylethyl)amino]-1-(3methoxyphenyl)-1-propanone Common Name: Structural Formula:

Chemical Abstracts Registry No.: 15687-41-9; 16777-42-7 (Hydrochloride salt) Trade Name Ildamen Ildamen Ildamen Ildamen Modacor Myofedrin Timoval

Manufacturer Homburg Chugai Homburg Farmades I.S.H. Apogepha Homburg

Country W. Germany Japan Italy Italy France E. Germany W. Germany

Year Introduced 1966 1970 1972 1973 -

Raw Materials m-Methoxyacetophenone L-Norephedrine

Paraformaldehyde

Oxymesterone

2577

Manufacturing Process 45 grams of m-methoxy acetophenone, 8 grams of paraformaldehyde and 30.2 grams of 1 norephedrine were mixed with about 135 cc of isopropanol HCl solution to provide a pH of 4 and the mixture refluxed for 4 hours. The reaction mixture was cooled and the crystals filtered off on a suction filter. 3[1-phenyl-1-hydroxypropyl-(2)-amino]-1-(m-methoxyphenyl)-propanone-(1) HCl was obtained which after recrystallization from methanol had a MP of 190° to 193°C. References Merck Index 6830 Kleeman & Engel p. 673 OCDS Vol. 2 p. 40 (1980) I.N. p. 718 Thiele, K.; US Patent 3,225,095; December 21, 1965; assigned to Deutsche Gold-und Silber-Scheideanstalt, Germany

OXYMESTERONE Therapeutic Function: Anabolic, Androgen Chemical Name: 4,17beta-Dihydroxy-17-methylandrost-4-en-3-one Common Name: Hydroxymethyltestosterone; Methandrostenediolone; Ossimesterone; Oximesteronum; Oxymesterone; Oxymestrone Structural Formula:

Chemical Abstracts Registry No.: 145-12-0 Trade Name

Manufacturer

Country

Year Introduced

Anamidol

Iwaki

-

-

Oranabol

Farmitalia Carlo Erba

-

-

Balnimax

Geve

-

-

2578

Oxymesterone

Raw Materials Sulfuric acid Sodium chloride Potassium hydroxide Acetic acid Hydrogen peroxide Sodium bisulfite

4,5-Oxido-17α-methyltestosterone Sodium bicarbonate 17α-Methyltestosterone Trimethylcarbinol Osmium tetroxide Acetic acid

Manufacturing Process 2 Methods of producing of 4-hydroxy-17α-methyltestosterone: 1. A solution of 1.0 g of crude 4,5-oxido-17α-methyltestosterone in 50 ml of methanol is allowed to stand at room temperature overnight with 10 ml of water and 1 ml of concentrated sulfuric acid. It is then poured into water containing sodium chloride and extracted three times with ethyl acetate. The solvent is washed with water, then with 10% sodium bicarbonate solution and again with water to neutrality. The residue remaining after evaporation of the solvent is crystallized from methanol, giving 17α-methyl-androstane4β,5α,17β-triol-3-one with a melting point of 203°-205°C. A solution of 0.22 g of 17α-methyl-androstane-4β,5α,17β-triol-3-one in 100 ml of methanol is allowed to stand at room temperature for 22 h, under nitrogen, with 0.30 g of potassium hydroxide in 4 ml of water and 20 ml of methanol. The solution is then neutralized with acetic acid, concentrated in vacuo, diluted with water and extracted three times with ethyl acetate. The extract is washed with water and the solvent removed by distillation. The remaining residue is chromatographed over Florisil 30-60 mesh. The fractions eluted with benzene and benzene-ether (10:1) are combined and by crystallization from ether-petroleum ether give 4-hydroxy-17α-methyltestosterone (0.120 g) melting at 168°-170°C. 2. A solution of 20.0 g of 17α-testosterone in 500 ml of trimethylcarbinol is treated by addition of 56 ml of 30% hydrogen peroxide and 1.0 g of osmium tetroxide in 80 ml of trimethylcarbinol. After the mixture has stood at room temperature for 22 h, 12 ml of hydrogen peroxide are added. The reaction mixture is allowed to stand at room temperature for an additional 20 h, then concentrated in vacuo to 1/3 of its original volume, diluted with water, and the reaction product extracted with ethyl acetate. The extract is washed with water, several times with 10% sodium bisulfite solution, then with 4% sodium bicarbonate solution and finally with water to neutrality. The residue remaining after evaporation of the solvent does not show ultraviolet absorption. 1.0 g of this crude substance, by crystallization from methanol, gives l7αmethylandrostane-4,5,17β-triol-3-one (0.400 g) melting at 192°-194°C. A solution of 20.0 g of crude 17β-methylandrostane-4,5,17β-triol-3-one in 1 L of methanol is heated under reflux in a stream of nitrogen for 20 min; then 20.0 g of potassium hydroxide in 40 ml of water and 200 ml of methanol are added. 5 min after the addition, the solution is treated by addition of 20 ml of acetic acid and concentrated in vacuo. The residue is diluted with water containing sodium chloride and extracted three times with ethyl acetate. The extract is washed with 10% sodium bicarbonate solution and then with water to neutrality. The residue remaining after evaporation of the solvent is

Oxymetazoline hydrochloride

2579

dissolved in acetone; addition of petroleum ether gives 4-hydroxy-17αmethyl-testosterone (8.0 g) melting at 168°-170°C. The mother liquors chromatographed over Florisil 30-60 mesh yield an additional 5.0 g of the same substance melting at 168°-170°C. References Camerino B. et al; US Patent No. 3,060,201; Oct. 23, 1962; Assigned: Societa Farmaceutici Italia, Milan, Italy, a corporation of Italy

OXYMETAZOLINE HYDROCHLORIDE Therapeutic Function: Nasal decongestant Chemical Name: 3-[(4,5-Dihydro-1H-imidazol-2-yl)methyl]-6-(1,1dimethylethyl)-2,4-dimethylphenol hydrochloride Common Name: Structural Formula:

Chemical Abstracts Registry No.: 2315-02-8; 1491-59-4 (Base) Trade Name Nasivin Iliadine Afrin Nostrilla Alrin Atomol Dristan Duration Nasivin Nasafarma Nezeril Oxymeta Pikorin Rhinolitan

Manufacturer Merck Merck Clevenot Schering Boehringer Ingelheim Teva Allen and Hanburys Whitehall Plough Bracco Novofarma Draco Schein Medica Kettelhack Riker

Country W. Germany France US US Israel UK US US Italy Spain Sweden US Finland W. Germany

Year Introduced 1961 1964 1964 1982 -

2580

Oxymorphone

Trade Name Sinerol Utabon

Manufacturer Draco Uriach

Country Sweden Spain

Year Introduced -

Raw Materials Hydrogen chloride Ethylene diamine Formaldehyde Sodium hydroxide

2,4-Dimethyl-6-t-butylphenol 4-Toluenesulfonic acid Sodium cyanide Hydrogen chloride

Manufacturing Process 10 grams 2,6-dimethyl-3-hydroxy-4-tertiary butylbenzylcyanide (produced by chloromethylation of 2,4-dimethyl-6-tertiary butyl-phenol with formaldehyde and HCl and conversion of the substituted benzyl chloride with NaCN; crystals, from alcohol, melting at 135° to 137°C) and 10.7 grams ethylenediaminemono-p-toluenesulfonate are heated in an oil bath to approximately 235°C for 1½ hours, whereby ammonia is evolved. The free base is obtained from the p-toluene-sulfonic acid imidazoline salt which is difficultly soluble in water, by conversion with 50 cc of a 10% NaOH solution. Said base is recrystallized from benzene, and 7.5 grams (62% of the theoretical yield) 2-(2',6'-dimethyl3'-hydroxy-4'-tertiary butylbenzyl)-2-imidazoline, MP 180° to 182°C, are obtained. By dissolving the free base in an ethyl alcohol solution of hydrochloric acid and adding ether, the hydrochloride can be produced in the usual manner. Said hydrochloride melts, when recrystallized from alcoholic ether, at 300° to 303°C and is decomposed. References Merck Index 6834 Kleeman & Engal p. 674 PDR pp. 677, 728, 1606, 1899 OCDS Vol. 1 p. 242 (1977) I.N. p. 719 REM p. 889 Fruhstorfer, W. and Muller-Calgan, H.; US Patent 3,147,275; September 1, 1964; assigned to E. Merck AG, Germany

OXYMORPHONE Therapeutic Function: Narcotic analgesic Chemical Name: 4,5α-Epoxy-3,14-dihydroxy-17-methylmorphinan-6-one Common Name: Dihydrohydroxymorphinone

Oxymorphone

2581

Structural Formula:

Chemical Abstracts Registry No.: 76-41-5 Trade Name Numorphan

Manufacturer Endo

Country US

Year Introduced 1959

Raw Materials Thebaine Hydrogen peroxide Hydrogen bromide Hydrogen Manufacturing Process Thebaine is dissolved in aqueous formic acid and treated with 30% H2O2; neutralization with aqueous ammonia gives 14-hydroxycodeinone. It is hydrogenated to give oxycodone. 90 ml of concentrated hydrobromic acid are heated to 90°C. 9 grams of 14-hydroxydihydrocodeinone (oxycodone) are then added under stirring and the mixture is quickly heated to 116°C and kept at this temperature under reflux condenser for 20 minutes, with continued stirring. The resulting brown solution is diluted with about 90 ml of water and chilled with ice. Aqueous 10% sodium hydroxide solution is now added to alkaline reaction and the liquid is extracted 3 times with 100 cc portions of chloroform. The layers are separated and the aqueous phase is filtered and acidified by the addition of concentrated aqueous hydrochloric acid, treated with charcoal and filtered. The filtrate is treated with concentrated aqueous ammonia until the mixture gives a pink color on phenolphthalein paper. The liquid is extracted seven times with 100 cc portions of chloroform, the extracts are combined, dried with anhydrous sodium sulfate and evaporated. The residue is dissolved in ethanol by refluxing and the ethanol evaporated nearly to dryness. 100 cc of benzene are then added, the mixture is refluxed for ½ hour and set aside for crystallization. After cooling, the desired compound is collected by filtration, 2.3 grams of a white crystalline powder are obtained; MP 245° to 247°C. This powder consisting of 14-hydroxydihydromorphinone can be purified by recrystallization from benzene, ethylacetate or ethanol. From benzene it generally forms diamond shaped platelets, while needles are obtained from ethylacetate.

2582

Oxypendyl

On heating, the crystals are discolored from about 200°C on, and melt at 246° to 247°C to a black liquid, which decomposes with strong volume increase if the temperature is raised further by a few degrees. References Merck Index 6837 Kleeman & Engel p. 675 PDR p. 859 OCDS Vol. 1 p. 290 (1977) and 2, 319 (1980) I.N. p. 719 REM p. 1105 Lewenstein, M.J. and Weiss, U.; US Patent 2,806,033; September 10, 1957

OXYPENDYL Therapeutic Function: Antiemetic Chemical Name: 4-[3-(10H-Pyrido[3,2-b][1,4]benzothiazin-10-yl)propyl]-1piperazineethanol Common Name: Structural Formula:

Chemical Abstracts Registry No.: 5585-93-3; 17297-82-4 (Dihydrochloride salt) Trade Name Pervetral

Manufacturer Homburg

Country W. Germany

Year Introduced 1962

Raw Materials 10-(γ-N-Piperazinopropyl)-4-azaphenthiazine Ethylene chlorohydrin Manufacturing Process 32 parts of 10-(γ-N-piperazinopropyl)-4-azaphenthiazine in 200 cc of butanol

Oxypertine

2583

with 9 parts of ethylene chlorohydrin and 14 parts of finely powdered potash are heated for 4 hours under reflux while stirring vigorously. After cooling, extraction is carried out with dilute hydrochloric acid, the substance is finally washed with water and the combined hydrochloric acid aqueous phase is washed twice with ether. The base is then liberated with concentrated sodium hydroxide solution and taken up in chloroform. The chloroform solution is dried with potash and concentrated by evaporation. 26.4 parts of (10-γ-N-Bhydroxyethylpiperazino-N1-propyl)-4-azaphenthiazine are distilled over at 280°C to 300°C/6 mm. The dihydrochloride is obtained in isopropanol with isopropanolic hydrochloric acid. The product melts at 218°C to 220°C. References Merck Index 6838 Kleeman & Engel p. 676 OCDS Vol. 1 p. 430 (1977) I.N.p. 719 Deutsche Gold-und Silber Scheideanstalt; British Patent 893,284; April 4, 1962

OXYPERTINE Therapeutic Function: Antipsychotic, Neuroleptic Chemical Name: 1H-Indole, 5,6-dimethoxy-2-methyl-3-(2-(4-phenyl-1piperazinyl)ethyl)Common Name: Oxypertine; Oxipertinum Structural Formula:

Chemical Abstracts Registry No.: 153-87-7 Trade Name Oxypertine capsules

Manufacturer Sanofi-Synthelabo

Country -

Year Introduced -

2584

Oxyphenbutazone

Trade Name Oxypertine

Manufacturer Bulk Drugs and Intermediates Inc.

Country -

Year Introduced -

Oxypertine

Shanghai Lansheng Corporation

-

-

Raw Materials 1-Phenylpiperazine Acetic acid [3-(2-Methyl-5,6-dimethoxy)indolyl] glyoxalyl chloride

Lithium aluminum hydride Sodium hydroxide

Manufacturing Process A cold, stirred solution of 1-phenyl-piperazine in tetrahydrofuran was treated all at once with [3-(2-methyl-5,6-dimethoxy)indolyl]glyoxalyl chloride. There was an immediate voluminous precipitate of a white crystalline solid which was removed by filtration. The filtrate was taken to dryness and the residual light brown gum was stirred and shaken with water, ethyl acetate and acetic acid. The mixture was warmed on a steam bath and the resulting solid was collected after cooling in an ice bath thus affording 1-[(3-(2-methyl-5,6dimethoxy)indolyl)glyoxalyl]-4-phenylpiperazine as a near white solid, melting point 163°-174°C. A solution of 1-[(3-(2-methyl-5,6-dimethoxy)indolyl)glyoxalyl]-4-phenyl piperazine in tetrahydrofuran was added over a 10 min period to a stirred suspension of lithium aluminum hydride in tetrahydrofuran. The mixture was refluxed and stirred for 6.5 h and the excess lithium aluminum hydride then destroyed by the dropwise addition of 10% sodium hydroxide solution. The mixture was filtered, the insoluble material was washed with boiling chloroform, and the filtrate dried over anhydrous sodium sulfate and concentrated to dryness. The residual light orange oil was crystallized from a benzene-hexane mixture giving 1-[(3-(2-methyl-5,6-dimethoxy)indolyl)ethyl]4-phenyl piperazine. References Bethlehem S.A.; US Patent No. 3,183,313; June 8, 1965; Assigned: Sterling Drug Inc., New york, N.Y., a corporation of Delaware

OXYPHENBUTAZONE Therapeutic Function: Antiinflammatory Chemical Name: 4-Butyl-1-(4-hydroxyphenyl)-2-phenyl-3,5pyrazolidinedione Common Name: p-Hydroxyphenylbutazone

Oxyphenbutazone

2585

Structural Formula:

Chemical Abstracts Registry No.: 129-20-4 Trade Name Tanderil Tandearil Tanderil Tanderil Tanderil Artroflog Artzone Butaflogin Butapirone Buteril Butilene Deflogin Fibutox Flanaril Floghene Flogistin Flogitolo Flogodin Iltazon Imbun Inflamil Ipebutona Iridil Isobutil Miyadril Optimal Optone Oxalid Oxibutol Oxybutazone Oxybuton

Manufacturer Geigy Geigy Ciba Geigy Geigy Geigy Magis Continental Ethicals Chemiepharma Brocchieri Protea Frencia Valeas Phermador Osfa Chibi Scharper Isnardi Firma Iltas Merckle Leiras Ipecsa Farmila Panther-Osfa Fako Dojin Lennon U.S.V. Asla I.C.N. Streuli

Country UK US France W. Germany Italy Italy S. Africa Italy Italy S. Africa Italy Italy S. Africa Italy Italy Italy Italy Italy Turkey W. Germany Finland Spain Italy Italy Turkey Japan S. Africa US Spain Canada Switz.

Year Introduced 1960 1961 1961 1961 1962 -

2586

Oxyphenbutazone

Trade Name Phlogase Phlogistol Phlogont Phloguran Pirabutina Piraflogin Rapostan Rheumapax Tantal Teneral Validil Visobutina

Manufacturer Adenylchemie Helopharm Azuchemie Ikapharm Ellea Jamco Mepha Erco Sawai Eczacibasi Von Boch I.S.F.

Country W. Germany W. Germany W. Germany Israel Italy Italy Switz. Denmark Japan Turkey Italy Italy

Year Introduced -

Raw Materials Sodium Hydrogen n-Butylmalonic acid ethyl ester p-Benzyloxy hydrazobenzene Manufacturing Process 43.2 parts of n-butyl malonic acid ethyl ester are added to a solution of 4.6 parts of sodium in 92 parts by volume of absolute alcohol. 39 parts of pbenzyloxy hydrazobenzene (MP 88° to 90°C) are added. About two-thirds of the alcohol is distilled off and 92 parts by volume of absolute xylene are added. Without removing the sloping condenser, the mixture is stirred for 12 hours at a bath temperature of 140° to 145°C. It is then cooled to 0° to 5°C, 100 parts of ice are added, the xylene is removed, the aqueous solution is extracted twice with chloroform and made acid to Congo red at 0° to 5°C with 6 N hydrochloric acid. The precipitate is taken up in chloroform, the solution obtained is washed twice with water, then with saturated salt solution, dried over Na2SO4and evaporated under vacuum (bath temperature 20°C). The residue is recrystallized from alcohol and produces 1-(p-benzyloxyphenyl)-2-phenyl-4-nbutyl-3,5-dioxo-pyrazolidine (C) as tiny white needles which melt at 132° to 133°C. 16.6 parts of (C) are suspended in 166 parts by volume of ethyl acetate and, in the presence of 16.6 parts of Raney nickel, hydrogen is allowed to act at room temperature and atmospheric pressure. After 6 hours the calculated amount of hydrogen has been taken up. The residue obtained after filtering and evaporating is taken up in benzene and extracted twice with diluted sodium carbonate solution. The alkali extract is then made acid to Congo red with 6 N hydrochloric acid and the precipitate is taken up in ethyl acetate. The solution obtained is washed twice with salt solution, dried with sodium sulfate and evaporated. The residue is recrystallized from ether/petroleum ether. 1-(p-hydroxyphenyl)-2-phenyl-4-n-

Oxyphencyclimine

2587

butyl-3,5-dioxo-pyrazolidine melts at 124° to 125°C. References Merck Index 6840 Kleeman & Engel p. 677 PDR p. 1606 OCDS Vol. 1 p. 236 (1977) I.N. p. 720 REM p. 1119 Hafliger, F.; US Patent 2,745,783; May 15, 1956; assigned to J.R. Geigy AG, Switzerland

OXYPHENCYCLIMINE Therapeutic Function: Spasmolytic Chemical Name: α-Cyclohexyl-α-hydroxybenzeneacetic acid (1,4,5,6tetrahydro-1-methyl-2-pyrimidinyl)methyl ester Common Name: Structural Formula:

Chemical Abstracts Registry No.: 125-53-1; 125-52-0 (Hydrochloride salt) Trade Name

Manufacturer

Country

Year Introduced

Vio-Thene

Rowell

US

1959

Daricon

Pfizer

US

1959

Setrol

Flint

US

1961

Gastrix

Rowell

US

1973

Manir

Valpan

France

1975

Caridan

B.D.H.

UK

-

Cycmin

Toyo

Japan

-

Inomaru S

Sawai

Japan

-

Norma

Sankyo

Japan

-

Oximin

A.F.I.

Norway

-

Sedomucol

Asla

Spain

-

2588

Oxyphencyclimine

Trade Name Spazamin Ulcociclina Ulcomin Vagogastrin

Manufacturer G.P. Confas Remedia Benvegna

Country Australia Italy Israel Italy

Year Introduced -

Raw Materials 1,3-Diaminobutane Benzoyl formic acid Magnesium

Ethyl chlorimidoacetate Cyclohexyl bromide

Manufacturing Process To a stirred solution of 8.8 grams (0.1 mol) of 1,3-diaminobutane in 150 ml of ethanol maintained at 0° to 5°C, there was added 25.8 grams (0.1 mol) of ethyl chlorimidoacetate hydrochloride during a period of 20 minutes. After the mixture had been stirred at 0° to 5°C for two hours, it was acidified at this temperature by the addition of ethanolic hydrogen chloride. The mixture was warmed to room temperature and filtered to remove 4.3 grams of solid ammonium chloride. The filtrate was concentrated to approximately 40 ml, filtered and refrigerated. The solid which separated was isolated, washed with acetone and dried. There was obtained 7.4 grams (40% of the theoretical yield) of 2-chloromethyl-4-methyl-1,4,5,6-tetrahydropyrimidine hydrochloride melting at 158° to 160°C. In a second step, cyclohexyl bromide was reacted with magnesium, then with benzoyl formic acid to give cyclohexylphenyl glycolic acid. A solution of 1.8 grams (0.01 mol) of 2-chloromethyl-1-methyl-1,4,5,6-tetrahydropyrimidine hydrochloride in 5 ml of water was made alkaline with 5 ml of 50% NaOH and extracted with ether. The ether solution, which contained the basic chloride, was dried over calcium sulfate and added to a solution of 2.3 grams (0.01 mol) of α-cyclohexylphenylglycolic acid in 75 ml of isopropanol. The solution was distilled to remove the ether, and 0.1 gram of powdered potassium iodide added to the residual isopropanol solution which was then refluxed for 6 hours. The solid which had separated was redissolved by the addition of 20 ml of ethanol and the solution charcoaled, concentrated, and cooled. The solid which separated, 1-methyl-1,4,5,6-tetrahydro-2-pyrimidylmethyl αcyclohexylphenyl-glycolate hydrochloride, weighed 1.4 grams and melted at 228° to 229°C with decomposition after recrystallization from ethanol. References Merck Index 6841 Kleeman & Engel p. 677 OCDS Vol. 2 p. 75 (1980) I.N. p. 720 REM p.917 Chas. Pfizer & Co., Inc.; British Patent 795,758; May 28, 1958

Oxyphenisatin acetate

2589

OXYPHENISATIN ACETATE Therapeutic Function: Laxative Chemical Name: 3,3-Bis[4-(acetyloxy)phenyl]-1,3-dihydro-2H-indol-one Common Name: Acetphenolisatin; Endophenolphthalein; Diphesatin Structural Formula:

Chemical Abstracts Registry No.: 115-33-3 Trade Name Lavema Isalax Acetalax Bisco-Zitron Bydolax Darmoletten Eulaxin Fenisan Laxatan Laxanormal Med-Laxan Nourilax Obstilax Promassolax Prulet Regal Sanapert Schokolax Veripaque

Manufacturer Winthrop Vale Harvey Biscova Moore Omegin Pliva Chemimportexport Divapharma Uquifa Med Noury Pharma Zirkulin Ysat Wernigerode Mission Ferrosan Trogalen Dallmann Winthrop

Raw Materials Diphenolisatin Acetic anhydride

Country US US Australia W. Germany UK W. Germany Yugoslavia Rumania W. Germany Spain W. Germany Netherlands W. Germany E. Germany US Denmark Austria W. Germany UK

Year Introduced 1959 1963 -

2590

Oxyphenonium bromide

Manufacturing Process 235 gravimetrical parts of acetic acid anhydride (90%) are poured over 106 gravimetrical parts of diphenolisatin (Berichte der Deutschen Chemischen Gesselschsft, 18, 1885, p. 2641) and the mixture is heated on the water-bath while stirring. The solid starting material temporarily dissolves almost entirely and shortly afterwards the reaction product turns into a crystalline paste. In order to complete the reaction the heating on the water-bath is continued for a short time and then the whole is left to get cold. The reaction product may, for instance, be separated in the following manner: To the cold reaction mixture is gradually added about the same volumetrical quantity of alcohol; in this manner the excess of acetic acid anhydride is destroyed and the paste becomes thinner. Then the fluid is drawn off and the product washed with alcohol. For complete cleansing another extraction is made with warm alcohol and the product crystallized, for instance, from 10 parts of acetic acid. The product represents a light, fine crystalline powder, which is difficultly soluble or even insoluble in the usual organic solvents. Its melting point lies at 242°C. References Merck Index 6842 Kleeman & Engel p. 678 OCDS Vol. 2 p. 350 (1980) I.N. p. 720 Preiswerk, E.; US Patent 1,624,675; April 12, 1927; assigned to HoffmannLaRoche Chemical Works

OXYPHENONIUM BROMIDE Therapeutic Function: Anticholinergic, Spasmolytic Chemical Name: [Ethanaminium, 2-((cyclohexylhydroxyphenylacetyl)oxy)N,N-diethyl-N-methyl-, bromide Common Name: Oxiphenoni bromidum; Oxyphenonium bromide Structural Formula:

Chemical Abstracts Registry No.: 50-10-2; 14214-84-7 (Base)

Oxypyrronium bromide Trade Name A-Spasm Antispasmin Oxyphenonium bromide Oxyphenonium bromide Antrenyl Antrenyl Antrenyl Calmulcer Oxyphenon Spasmophen Spastrex Antrenyl Duplex Drag (aH)

2591

Manufacturer Acme Laboratories Ltd. Pharmacia Co - Dupnitza Yick-Vic Chemicals and Pharmaceuticals (HK) Ltd. Pharm Products

Country -

Year Introduced -

-

-

Ciba Ciba-Geigy Swiss Pharma Sons Leciva Polfa-Pabianice Propan-Generics Ciba-Geigy AG Pharma Schweiz

-

-

Raw Materials 2-Diethylaminoethanol Cycloxehylhydroxyphenylacetic acid methyl ester Methyl bromide Manufacturing Process 1 mol cycloxehylhydroxyphenylacetic acid methyl ester was mixed with 1 mol 2-diethylaminoethanol in presence of 1 mol sodium methylate to give cycloxehylhydroxyphenylacetic acid 2-diethylamino-ethyl ester. 5 parts by weight of it was dissolved in 50 volumes glacial acetic acid and a gaseous methyl bromide was introduced. The mixture was heated to about 50°C and crystallization of cycloxehylhydroxyphenylacetic acid diethylaminoethyl ester methyl bromide has shortly after begun. On cooling the crystals was filtered off and recrystallized from mixture of ethyl acetate ant a little ethanol to give the oxyphenonium bromide. MP: 189°-191°C. References Swit.R. Patent No. 259,958; Sept. 18, 1944; Assigned to Ciba

OXYPYRRONIUM BROMIDE Therapeutic Function: Anticholinergic, Spasmolytic Chemical Name: Pyrrolidinium, 1,1-dimethyl-2-(hydroxymethyl)-, bromide, α-phenylcyclohexaneglycolate Common Name: Oxipyrroni bromidum; Oxypyrronium bromide

2592

Oxypyrronium bromide

Structural Formula:

Chemical Abstracts Registry No.: 561-43-3; 116533-64-3 (Base) Trade Name Oxypyrronium bromide

Manufacturer Shanghai Lansheng Corporation

Country -

Year Introduced -

Raw Materials Sodium Methanol Methyl bromide Sodium hydroxide

Methylphenylcyclohexylglycolate 1-Methyl-2-hydroxymethylpyrrolidine Hydrochloric acid

Manufacturing Process The 1-methyl-2-hydroxymethylpyrrolidine was obtained by the process of Application No 21193/56 (Serial No. 820,503). A methanolic solution of sodium methoxide [from sodium (0.6 g) and methanol (15 ml)] was added dropwise during 3 h to a boiling solution of methyl phenylcyclohexylglycollate (33.7 g) and 1-methyl-2hydroxymethylpyrrolidine (23.4 g) in heptane (400 ml) and the methanol that separated was removed by means of a Dean and Stark apparatus. At the end of 4 h no further separation of methanol occurred and the solvent was removed under reduced pressure. The residue was dissolved in either and the etheral solution, after washing with water (3 x 50 ml), was extracted with 5 N hydrochloric acid (3 x 100 ml). The (1-methyl-2-pyrrolidyl)methyl phenylcyclokexylglycollate hydrochloride (35.5 g 71%) crystallised out of the acid extract as colourless needles, melting point 181°-196°C. Extraction of this hydrochloride (33.0 g) with hot ethanol (150 ml) left the sparingly soluble (1-methyl-2-pyrrolidyl)methyl phenylcyclokexylglycollate hydrochloride (aform) (7.6 g), melting point 220°-222°C. The (1-methyl-2-pyrrolidyl)methyl phenylcyclokexylglycollate hydrochloride (aform) (15.0 g) was dissolved in water, basified with sodium hydroxide solution and the resultant oil extracted into ether. The extracts were dried over magnesium sulfate, the ether evaporated and the residue dissolved in acetone (100 ml). Methyl bromide (7.8 g, 2 mole) was added to the acetone solution and the mixture warmed on a steam bath for 15 min. The solution was cooled and the solid filtered off, washed with a little acetone and dried to give the

Oxyquinol

2593

(1,1-dimethyl-2-pyrrolidyl)methyl α-phenylcyclokexylglycollate bromide, melting point 185°-186°C. (86%). References GB Patent No. 850,260; Nov. 28, 1957; Assigned: Beecham Research Laboratories Limited, a British Company, of Brockham Park, Betchworth, Surrey

OXYQUINOL Therapeutic Function: Antiseptic Chemical Name: Quinolin-8-ol Common Name: Hydroxychinolinium sulfuricum; Oxichinolini sulfas; Oxychinol; Oxyquinol; Oxyquinoline sulfate; Oxyquinolini sulfas Structural Formula:

Chemical Abstracts Registry No.: 134-31-6; 148-24-3 (Base) Trade Name Chinosol 8-Hydroxyquinoline sulfate Hydroxyquinoline sulfate

Manufacturer Chinosolfabrik GFS Chemicals

Country -

Year Introduced -

Shanghai Lansheng Corporation

-

-

8-Hydroxyquinoline sulfate 8-Hydroxyquinoline sulfate 8-Quinolinol Sulfate

AroKor Holdings Inc.

-

-

Tianjin Mid-Chem Co., Ltd. Eastman Kodak Company Nile Co.

-

-

-

-

-

-

Oxymeria Gargle

2594

Oxytetracycline

Raw Materials o-Nitrophenol o-Aminophenol Sulfuric acid Manufacturing Process The mixture of 1.4 kg o-nitrophenol, 2.1 kg o-aminophenol, 6 kg glycerine (d = 1.26) and 5 kg sulfuric acid (d = 1.848) was heated at reflux to temperature 130°-140°C. This temperature was kept for 1.5 hours. The obtained oxyquinoline precipitated, the liquid was removed with water-steam distillation. The residue was diluted with water and alkalized with sodium hydroxide and sodium carbonate to the strong alkaline reaction. The repeated distillation with water steam gave the oil, which hardened as the long needles by cooling. MP: 75°-76°C recrystallized from diluted ethanol. In practice it is usually used as sulfate salt. References Skraup Z.H.; DR Patent No. 14,976; Feb. 16, 1881; Wien Dictionary of Organic Compounds edited by I. Heilbron and H.M. Bunbury, v.2, p.326, 1946, London

OXYTETRACYCLINE Therapeutic Function: Antibiotic Chemical Name: 4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro3,5,6,10,12,12a-hexahydroxy-6-methyl-1,11-dioxo-2naphthacenecarboxamide Common Name: Structural Formula:

Chemical Abstracts Registry No.: 79-57-2; 2058-46-0 (Hydrochloride salt)

Oxytetracycline Trade Name Terramycin Gynamousse Oxy-Kesso-Tetra Oxlopar E.P. Mycin Chrysocin Clinimycin Copharoxy Crisamicin Devacyclin Dura-Tetracyclin Egocin Elaciclina Galenomycin Geocycline Geomycin I.A.-Loxin Imperacin Macocyn Oksisiklin Ossitetra Otesolut Oxacycline Oxeten Oxymycin Proteroxyna Stecsolin Tetra-Tablinen Tetrafen

Manufacturer Pfizer Pfizer McKesson Parke Davis Edwards Pliva Glaxo Cophar Frumtost Deva Dura Krka I.F.L. Galen I.E. Kimya Evi Pliva Inter-Alia Pharm. I.C.I. Mack Uranium Pierrel Jenapharm Crookes Mochida Chelsea Proter Squibb Sanorania Drifen

Country US France US US US Yugoslavia UK Switz. Spain Turkey W. Germany Yugoslavia Spain UK Turkey Yugoslavia UK UK W. Germany Turkey Italy E. Germany UK Japan UK Italy UK W. Germany Turkey

2595

Year Introduced 1950 1966 1970 1974 1983 -

Raw Materials Soybean meal Glucose

Bacterium Streptomyces rimosus

Manufacturing Process Medium Soybean meal Cerelose Distillers' solubles Sodium chloride Distilled water to

Grams 10 10 0.5 5 1,000 ml

The pH was adjusted to 7.0 with sodium hydroxide and calcium carbonate was added at the rate of 1 g/l. 500 ml portions of the above medium were added to Fernbach flasks which

2596

Oxytocin

were then sterilized at 121°C for 30 minutes. Upon cooling, the flasks were inoculated with a suspension of the growth of s. rimosus obtained from the surface of beef lactose agar slants, and the flasks were shaken for 4 days at 28°C on a rotary shaker having a displacement of 2" at an rpm of 200. At the end of this period the broth was found to contain 640 C.D.U/ml and 400 chloramphenicol units/ml. The mycelium was separated from the broth by filtration and the latter was adjusted to pH 9.0. The antibiotic was extracted from the broth with n-butanol, and when the ultraviolet absorption spectrum was observed on the butanol solution of the antibiotic, peaks in the absorption curve were found at 385 and 270 millimicrons. References Merck Index 6846 Kleeman & Engel p. 680 PDR pp. 887, 1413, 1533, 1606 OCDS Vol. 1 p. 212 (1977) and 2, 226 (1980) I.N. p. 721 REM pp. 1206, 1260 Sobin, B.A., Finlay, A.C. and Kane, J.H.; US Patent 2,516,080; July 18, 1950; assigned to Chas. Pfizer & Co., Inc.

OXYTOCIN Therapeutic Function: Oxytocic Chemical Name: Oxytocin (a complex peptide) Common Name: Structural Formula:

Oxytocin

2597

Chemical Abstracts Registry No.: 50-56-6 Trade Name Syntocinon Syntocinon Uteracon Atonin-O Endopituitrina Orasthin Oxitocin Oxystin Oxytal Partocon Partolact Pitocin Pituitan

Manufacturer Sandoz Sandoz Hoechst Teikoku Zoki I.S.M. Hoechst Chinoin Arzneimittelwerk Dresden A.L. Ferring Medica Sankyo Nippon Zoki

Country US France US Japan Italy W. Germany Italy E. Germany

Year Introduced 1957 1958 1964 -

Norway Sweden Finland Japan Japan

-

Raw Materials Hydrogen Glycine lower alkyl ester L-Leucine lower alkyl ester Ammonia Hydrogen chloride L-Tyrosine lower alkyl ester

α-Benzyl-L-aspartic acid-α-lower alkyl ester L-Isoleucine lower alkyl ester S,N-Ditrityl-L-cysteine diethylamine salt N-Trityl glutamic acid-γ-lower alkyl ester Benzyl-L-proline hydrochloride

Manufacturing Process As described in US Patent 2,938,891, in the process for producing oxytocin, the steps comprise: (a) Adding dicyclohexyl carbodiimide to a solution of the α-benzyl-L-aspartic acid-β-lower alkyl ester in methylene chloride, cooling the mixture to about 0°C, adding thereto the N-trityl glutamic acid-γ-lower alkyl ester, allowing the mixture to stand at room temperature to complete condensation, acidifying the reaction mixture with acetic acid, filtering off precipitated dicyclohexyl urea, and separating the resulting (N-trityl-γ-lower alkyl-L-glutamyl)-α-benzylL-aspartic acid-β-lower alkyl ester. (b) Dissolving the (N-trityl-γ-lower alkyl-L-glutamyl)-α-benzyl-1-aspartic acidβ-lower alkyl ester in ethanol, adding triethylamine and palladium black to said solution, introducing hydrogen at room temperature thereinto to split off the benzyl group, and separating the (N-trityl-γ-lower alkyl-L-glutamyl)-Laspartic acid-β-lower alkyl ester. (c) Adding dicyclohexyl carbodiimide to a solution of the diethylamine salt of S,N-ditrityl-L-cysteine and the hydrochloride of the lower alkyl ester of Ltyrosine in methylene chloride, allowing the mixture to stand at a temperature between room temperature and about 35°C to complete condensation, acidifying the reaction mixture with acetic acid, filtering off precipitated

2598

Oxytocin

dicyclohexyl urea, and separating the resulting lower alkyl ester of S,Nditrityl-L-cysteinyl-L-tyrosine. (d) Refluxing the aqueous alcoholic solution of said ester with an alcoholic alkali metal hydroxide solution to saponify the lower alkyl ester group, neutralizing the saponification mixture by the addition of hydrochloric acid, extracting the neutralized mixture with ether, and separating the resulting (S,N-ditrityl-L-cysteinyl)-L-tyrosine. (e) Adding triethylamine to a solution of said S,N-ditrityl compound in chloroform, and precipitating the triethylamine salt of (S,N-ditrityl-Lcysteinyl)-L-tyrosine by the addition of petroleum ether. (f) Adding dicyclohexyl carbodiimide to a solution of said triethylamine salt of (S,N-ditrityl-L-cysteinyl)-L-tyrosine and the hydrochloride of the lower alkyl ester of L-isoleucine in methylene chloride, allowing the mixture to stand at room temperature to complete condensation, acidifying the reaction mixture with acetic acid, filtering off precipitated dicylohexyl urea, and separating the resulting (S,N-ditrityl-L-cysteinyl)-L-tyrosyl-L-isoleucine lower alkyl ester. (g) Refluxing the aqueous alcoholic solution of said ester with an alcoholic alkali metal hydroxide solution to saponify the lower alkyl ester group, neutralizing the saponification mixture by the addition of hydrochloric acid, extracting the neutralized mixture with ether, and separating the resulting (S,N-ditrityl-L-cysteinyl)-L-tyrosine-L-isoleucine. (h) Adding dicyclohexyl carbodiimide to a solution of the diethylamine salt of S,N-ditrityl-L-cysteine and the hydrochloride of benzyl-L-proline in methylene chloride, allowing the mixture to stand at about room temperature to complete condensation, acidifying the reaction mixture with acetic acid, filtering off precipitated dicyclohexyl urea, and separating the resulting (S,Nditrityl-L-cysteinyl)-L-prolinebenzyl ester. (i) Refluxing said benzyl ester with an aqueous alcoholic alkali metal hydroxide solution to saponify the benzyl ester group, neutralizing the saponification mixture by the addition of hydrochloric acid, extracting the neutralized mixture with chloroform, and separating the resulting (S,N-ditritylL-cysteinyl)-L-proline. (j) Adding diethylamine to a solution of said dipeptide compound in ether to yield the diethylamine salt of (S,N-ditrityl-L-cysteinyl)-L-proline. (k) Adding dicyclohexyl carbodiimide to a solution of the diethylamine salt of (S,N-ditrityl-L-cysteinyl)-L-proline and the hydrochloride of the L-leucine lower alkyl ester in methylene chloride, allowing the mixture to stand at a temperature between about 25° and 30°C to complete condensation, acidifying the reaction mixture with acetic acid, filtering off precipitated dicyclohexyl urea, and separating the resulting (S,N-ditrityl-L-cysteinyl)-Lprolyl-L-leucine lower alkyl ester. (l) Refluxing said lower alkyl ester with an aqueous alcoholic alkali metal hydroxide solution to saponify the lower alkyl ester group, neutralizing the saponification mixture by the addition of hydrochloric acid, extracting the

Oxytocin

2599

neutralized mixture with ether, and separating the resulting S,N-ditrityl-Lcysteinyl-L-prolyl-L-leucine. (m) Adding dicyclohexyl carbodiimide to a solution of the diethylamine salt of S,N-ditrityl-L-cysteinyl-L-prolyl-L-leucine and the hydrochloride of the glycine lower alkyl ester in methylene chloride, allowing the mixture to stand at a temperature between about 25° and 30°C to complete condensation, acidifying the reaction mixture with acetic acid, filtering off precipitated dicyclohexyl urea, and separating the resulting (S,N-ditrityl-L-cysteinyl)-Lprolyl-L-leucyl-glycine lower alkyl ester. (n) Adding aqueous hydrochloric acid to a mixture of said lower alkyl ester in a solvent selected from the group consisting of acetone and acetic acid, allowing the mixture to stand at a temperature of about 35°C to complete selective detritylation of the N-trityl group, and separating the resulting (Strityl-L-cysteinyl)-L-prolyl-L-leucyl glycine lower alkyl ester. (o) Adding dicyclohexyl carbodiimide to a solution of the diethylamine salt of the (N-trityl-γ-lower alkyl-L-glutamyl)-L-aspartic acid-β-lower alkyl ester obtained according to step (b) and the hydrochloride of the (S-trityl-Lcysteinyl)-L-prolyl-L-leucyl glycine lower alkyl ester in methylene chloride, allowing the mixture to stand at about room temperature to complete condensation, filtering off precipitated dicyclohexyl urea, and separating the resulting (N-trityl-γ-lower alkyl-L-glutamyl)-(β-lower alkyl-L-aspartyl)-(S-tritylL-cysteinyl)-L-prolyl-L-leucyl glycine lower alkyl ester. (p) Adding aqueous hydrochloric acid to a mixture of said lower alkyl ester in a solvent selected from the group consisting of acetone and acetic acid, allowing the mixture to stand at room temperature to complete selective detritylation of the N-trityl group, and separating the resulting hexapeptide compound (γ-lower alkyl-L-glutamyl)-(β-lower al kyl-L-aspartyl)-(S-trityl-Lcysteinyl)-L-prolyl-L-leucyl glycine lower alkyl ester. (q) Adding dicyclohexyl carbodiimide to a solution of the diethylamine salt of (S,N-ditrityl-L-cysteinyl)-L-tyrosyl-L-isoleucine obtained according to step (g) and the hydrochloride of (γ-lower alkyl-L-glutamyl)-(β-lower alkyl-L-aspartyl)(S-trityl-L-cysteinyl)-L-prolyl-L-leucyl glycine lower alkyl ester in methylene chloride, allowing the mixture to stand at about room temperature to complete condensation, filtering off precipitated dicyclohexyl urea, and separating the resulting (S,N-ditrityl-L-cysteinyl)-L-tyrosyl-L-isoleucyl-(γ-lower alkyl-L-glutamyl)-(β-lower alkyl-L-aspartyl)-(S-trityl-L-cysteinyl)-L-prolyl-Lleucyl glycine lower alkyl ester. (r) Dissolving said lower alkyl ester in a lower alkanol, saturating the resulting solution at a temperature of about -15° to -20°C with ammonia gas, allowing the mixture to stand in a sealed container at room temperature to complete replacement of the lower alkyl ester group by the amide group, and separating the resulting triamide (S,N-ditrityl-L-cysteinyl)-L-tyrosyl-L-isoleucylL-glutaminyl-L-asparaginyl-(S-trityl-L-cysteinyl)-L-prolyl-L-leucyl glycine amide. (s) Dissolving said triamide in an anhydrous solvent selected from the group consisting of chloroform, a mixture of chloroform and acetic acid, and a mixture of methylene chloride and thioglycolic acid, saturating the solution with gaseous hydrochloric acid at room temperature to complete detritylation,

2600

Oxytocin

and separating the resulting L-cysteinyl-L-tyrosyl-L-isoleucyl-L-glutaminyl-Lasparaginyl-L-cysteinyl-L-prolyl-L-leucyl glycine amide. (t) Dissolving said nonapeptide triamide in water and agitating the solution in oxygen to cause conversion thereof into oxytocin. References Merck Index 6849 Kleeman & Engel p. 681 PDR pp. 1382, 1596, 1966, 1989 I.N. p. 722 REM pp. 949, 957 Velluz, L., Amiard, G., Bartos, J., Goffinet, B. and Heymes, R.; US Patent 2,938,891; May 31, 1960; assigned to Uclaf, France Velluz, L., Amiard, G. and Heymes, R.; US Patent 3,076,797; February 5, 1963; assigned to Roussel-UCLAF SA, France

P

PACLITAXEL Therapeutic Function: Antineoplastic Chemical Name: 5β,20-Epoxy-1,2α,4,7,10β,13α-hexahydroxytax-11-en-9one 4,10-diacetate 2-benzoate 13-(α-phenylhippurate) Common Name: 7-epi-Taxol; Paclitaxel; Plaxicel Structural Formula:

Chemical Abstracts Registry No.: 33069-62-4 Trade Name Altaxel Betaxel Biotax Genexol Intaxel Onxol Paclitax Paclitaxel Paclitaxel

Manufacturer Cytomed (A div. of Alembic) Biological E. Limited Bio Therap. Samyang Dabur Pharmaceuticals Ltd. IVAX Pharmaceuticals, Inc. Cipla Limited Dabur Pharmaceuticals Ltd. Taihua Natural Plant Pharmaceutical Company

2601

Country India India India USA India India China

Year Introduced -

2602

Paclitaxel

Trade Name Paclitaxel Paclitaxel Paclitaxel-Ebewe Paxen Taxol Taxol (A) Taxol (A)

Manufacturer Shanghai Jinhe BioTechnologyCo., Ltd. Bristol - Myers Squibb Co. Ebewe Ivax-CR a.s. Polysciences Inc. Bristol-Myers Squibb Bristol-Myers Squibb

Country China

Year Introduced -

USA

-

Austria Czech Republic USA Italy USA

-

Raw Materials t-Butyl isocyanate Triethylamine Trimethylsilyl chloride Hydrogen fluoride Thiophenol Potassium butoxide 7-SDMS Baccatin III

p-Nitrophenylsulfonyl chloride (2R,3S)-β-Phenyl-isoserine methyl ester Benzaldehyde dimethylacetal 4-Toluenesulfonic acid Sodium bicarbonate Benzoyl chloride Triethylamine trihydrofluoride

Manufacturing Process (2R,3S)-β-Phenyl-isoserine methyl ester (4.35 g, 22 mM) is dissolved in dry THF (100 ml) and the flask cooled to 0°C. To the mixture is added t-butyl isocyanate (2.8 ml, 25 mM). TLC after 15 min shows some starting material left so additional isocyanate (0.5 ml) is added. TLC after 1 h shows no starting material so the solvent is concentrated under reduced pressure to give the N(t-butylaminocarbonyl)-β-phenyl isoserine methyl ester. Triethylamine (4.8 ml, 34.4 mmol) is added to a stirred solution of methyl (2R,3S)-phenylisoserinate (7.26 g, 31.3 mmol) in methylene chloride (80 ml) at 0°C. To this slurry of is added trimethylsilyl chloride (4.4 ml, 34.7 mmol). Additional methylene chloride (45 ml) is added. The mixture is cooled to 65°C and triethylamine (9.8 ml, 70.3 mmol) is added. p-Nitrophenylsulfonyl chloride (6.93 g, 31.3 mmol) is added. The reaction rate is too slow at -65°C so the temperature is gradually raised to 0°C. Hydrogen fluoride (10% aqueous, 5 equivalents) is added. The aqueous phase is separated from the organic (methylene chloride) phase and methanol is added to the organic phase. The methylene chloride is removed under reduced pressure and the methyl (2R,3S)-3-(4-nitrobenzenesulfonamido)-3-phenyl-2-hydroxypropionate is obtained, melting point 187-189°C. Benzaldehyde dimethylacetal (200 µl, 1.33 mmol) and a catalytic amount of p-toluenesulfonic acid (37 mg) are added to methyl (2R,3S)-3-(4nitrobenzenesulfonamido)-3-phenyl-2-hydroxypropionate (315 mg, 0.83 mmol) in toluene 5 ml. The mixture is heated at 100°C under reduced pressure (15 mm mercury) with no condenser. After 1 h the crude reaction mixture is diluted with ethyl acetate and washed with water (2 times). After drying the organic layer over magnesium sulfate the crude material is purified by column chormatography (silica gel; eluting with ethyl acetate/cyclohexane, 35/65) to give the (2S,4S,5R)-2,4-diphenyl-3-(4-nitrobenzenesulfonamido)-5methoxycarbonyl-1,3-oxazolidine, melting point 118°-120°C.

Paclitaxel

2603

Water (8 ml), methanol (8 ml) and THF (8 ml) are added to (2S,4S,5R)-2,4diphenyl-3-(4-nitrobenzenesulfonamido)-5-methoxycarbonyl-1,3-oxazolidine (1.50 g, 3.19 mmol). Potassium carbonate (1.018 g, 7.71 mmol) is then added. The resulting mixture is stirred at 20°-25°C until complete by TLC. After 5 h the reaction is complete and the reaction mixture is extracted with basic methylene chloride (2 times). The aqueous phase is then acidified with hydrochloric acid and extracted with ethyl acetate. The ethyl acetate phase is then washed with water, saline and dried over magnesiuim sulfate. Concentration of the organic phase (ethyl acetate) gives the (2S,4S,5R)-2,4diphenyl-3-(4-nitrobenzenesulfonamido)-5-carboxy-1,3-oxazolidine, melting point 61°-65°C. Then the (2S,4S,5R)-2,4-diphenyl-3-(4-nitrobenzenesulfonamido)-5-carboxy1,3-oxazolidine react with the 7-SDMS Baccatin III, that is 7-(3-methylbut-2yl)dimethylsilyl baccatin III (Baccatin III: 7,11-methano-1H-cyclodeca(3,4) benz(1,2-b)oxet-5-one,6,12b-bis(acetyloxy)-12(benzoyloxy)-1,2a,3,4,4a,6, 9,10,11,12,12a,12b-dodecahydro-4,9,11-trihydroxy-4a,8,13,13-tetramethyl-, (2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS), isolated from Taxus baccata). (2S,4S,5R)-2,4-Diphenyl-3-(4-nitrobenzenesulfonamido)-5-carboxy-1,3oxazolidine(323 mg, 0.711 mmol) is mixed with toluene (2.5 ml) at 20°-25°C. Dicyclohexylcarbodiimide (160 mg, 0.775 mmol) is then added to the reaction mixture. 7-SDMS Baccatin III (156 mg, 0.218 mmol) is added followed by 4(dimethylamino)pyridine (35 mg, 0.286 mmol) and the reaction mixture is stirred at 20°-25°C until complete (1 h) by TLC. Sodium bicarbonate (50% aqueous, 10 ml) and more toluene (5 ml) is added to the reaction mixture and then stirred at 20°-25°C for 2 h. The reaction mixture is filtered through a medium frit to remove the urea byproduct. After filtering the phases are separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with aqueous sodium bicarbonate (50%), water and saline. The organic phases are dried over magnesium sulfate, filtered and then concentrated. The concentrate is purified by column chromatograpy (silica gel; eluting with ethyl acetate/cyclohexane, 20/80) to give the 7-SDMS baccatin III 13-(2R,4S,5R)- and (2S,4S,5R)-2,4-diphenyl-3(4-nitrobenzenesulfonamido)-1,3-oxazolidine-5-carboxylic acid ester. THF (13.5 ml) and DMF (1.5 ml) are cooled to -35°C and degased by alternating reduced pressure and nitrogen three times. Thiophenol (0.22 ml, 2.14 mmol) is added followed by potassium butoxide/THF (1.978 M, 0.7 ml, 1.38 mmol). After 5 min, 7-SDMS baccatin III 13-(2R,4S,5R)- and (2S,4S,5R)-2,4-diphenyl-3-(4-nitrobenzenesulfonamido)-1,3-oxazolidine-5carboxylic acid ester (877 mg, 0.762 mmol) is added. After the solids are added, the reaction mixture is slowly warmed to -10°C. The mixture is stirred at -10°C until the red color fades to yellow. After 3 h the bath is dropped allowing the mixture to warm to 20-25°C. At 20°-25°C the reaction is stirred for 1 h before assaying by TLC and HPLC. Sodium bisulfite (241 mg, 2.31 mmol) is added in water (5 ml). The mixture is stirred at 20°-25°C and after approximately 115 h the reaction is complete (by TLC) giving the free amine 7-SDMS baccatin III 13-(2R,3S)-3-amino-3-phenyl-2-hydroxypropionate. Sodium bicarbonate (485 mg, 5.77 mmol) and water (10 ml) are added to 7SDMS baccatin III 13-(2R,3S)-3-amino-3-phenyl-2-hydroxypropionate. The mixture is cooled to 0°C and then benzoyl chloride (150 ml, 1.3 mmol) is added. After 1 hr the reaction is complete and the reaction mixture is diluted

2604

Pamidronate sodium

with water and extracted with ethyl acetate. The organic phases are combined and washed with water, saline and dried over magnesium sulfate. Chromatography of the crude product (silica gel column; 20% to 100% ethyl acetate gives the 7-SDMS baccatin III 13-(2R,3S)-3-benzamido-3-phenyl-2hydroxypropionate. 7-SDMS Baccatin III 13-(2R,3S)-3-benzamido-3-phenyl-2-hydroxypropionate (126 mg, 0.128 mmol) is dissolved in acetonitrile (2.5 ml). Triethylamine trihydrofluoride (123 mg, 0.763 mmol) is added under nitrogen and the resulting mixture is stirred at 5°C until complete by HPLC. When complete, the mixture is extracted with methyl t-butylether and washed with sodium bicarbonate solution. The aquesous washes are back extracted and combined with the organic phase. The combined organic phases are washed with water and saline, dried over magnesium sulfate, filtered and concentrated to give the Taxol (Paclitaxel), as needle from methanol with melting point 213-216°C. References Wuts P.G.M., Kelly R.C.; US Patent No. 6,057,452; May 2, 2000; Assigned to Pharmacia and Upjohn Company Haugwitz R.D. et al.; US Patent No. 4,942,184; July 17, 1990; Assigned: USA as represented by the Department of Health and Human Services, Washington, D.C. Stella V.J., Mathew A.E.; US Patent No. 4,960,790; Octouber 2, 1990; Assigned: University of Kansas, Lawrence, Kans

PAMIDRONATE SODIUM Therapeutic Function: Bone resorption suppressant Chemical Name: 3-Amino-1-hydroxypropane-1,1-diphosphonate, disodium salt Common Name: Dinatrium pamidronat; Disodium pamidronate: Pamidronate sodium Structural Formula:

Chemical Abstracts Registry No.: 57248-88-1; 40391-99-9 (Base)

Pancuronium bromide Trade Name Aredia Aredia Aredia Aredia Pamidronate Disodium Pamidronate Disodium Pamidronate Disodium Pamisol

2605

Manufacturer Novartis American Pharmaceutical Partners, Inc. Chiron Inc. Ciba-Geigy Novartis Pharmaceuticals

Country India -

Year Introduced -

-

-

Haorui Pharma-Chem Inc.

-

-

Bedford Laboratories

-

-

David Bull Laboratories

-

-

Raw Materials Mannitol Pamidronic acid Sodium hydroxide Manufacturing Process For a batch size of 5 L, 587.5 g (3.2 moles) of mannitol is dissolved in 3.5 L of water. Pamidronic acid (31.6 g, 0.133 moles) is mixed with a 1.0 L aliquot of the mannitol solution to form a slurry. The slurry is then transferred into the remainder of the mannitol solution, and stirred for at least 15 min. Aqueous 1 N sodium hydroxide (270 ml) is then added and the mixture is stirred until a clear, colorless solution results. The pH is then adjusted to 6.50.1 using either 1 M aqueous phosphoric acid or 1 N aqueous sodium hydroxide, as needed. The solution is then filtered through a 0.22 micron filter, and filled at 20°C into vials at 4.0 ml (4.172 g)/vial, under sterile conditions. The aqueous solution is frozen at -37°C and lyophilized (20 mbar, 20°-40°C) to yield 1,250 vials, each containing 30 mg of amorphous disodium pamidronate. The vials are sealed under positive nitrogen pressure. The disodium pamidronate is amorphous (noncrystalline) by X-ray diffraction and contains 0.7 wt-% water. References Shinal E.C.; US Patent No. 6,160,165; Dec. 12, 2000; Assigned: Aesgen, Inc., Princeton

PANCURONIUM BROMIDE Therapeutic Function: Muscle relaxant Chemical Name: 1,1'-[3α,17β-Bis(acetyloxy)-5α-androstane-2β,16βdiyl]bis[1-methylpiperidinium] dibromide

2606

Pancuronium bromide

Common Name: Structural Formula:

Chemical Abstracts Registry No.: 15500-66-0 Trade Name Pavulon Pancuronium Pavulon Pavulon Myoblock Pavalon

Manufacturer Organon-Teknika Organon Organon-Teknika Organon Organon-Sankyo Ravasini

Country UK W. Germany France US Japan Italy

Year Introduced 1968 1969 1971 1972 1973 1973

Raw Materials Piperidine m-Chloroperbenzoic acid Acetic anhydride

3,17-Diacetoxy-5α-androstane-2,16-diene Sodium borohydride Methyl bromide

Manufacturing Process A solution of 2α,3α,16α,17α-diepoxy-17β-acetoxy-5α-androstane (25 grams), prepared from 3,17-diacetoxy-5α-androstane-2,16-diene (Chem. Abs. 1960, 54, 8908) by treatment with m-chlor-perbenzoic acid, in piperidine (120 ml) and water (40 ml) was boiled under reflux for 5 days, the solution was concentrated and the product precipitated by the addition of water. The solid was collected, dissolved in dilute hydrochloric acid, filtered to give a clear solution and precipitated by the addition of sodium hydroxide solution. Crystallization from acetone gave 2β,16β-bis-piperidino-5α-androstan-3α-ol17-one (18.9 grams), MP 179-185°C. A solution of sodium borohydride (8 grams) in water (16 ml) was added to a stirred solution of 2β,16β-bis-piperidino-5α-androstan-3α-ol-17-one (17 grams) in tetrahydrofuran (70 ml) and methanol (30 ml) and the solution stirred at room temperature for 16 hours. The product was precipitated by the addition of water, filtered off, dried, and crystallized from acetone to give the diol (14.9 grams). A solution of the piperidino-diol (9 grams) in acetic anhydride (18 ml) was heated at 90°C for 1 hour, the solution cooled, excess acetic anhydride

Pantethine

2607

destroyed by the careful addition of water, and the resulting solution carefully made alkaline with 2 N caustic soda solution to precipitate a solid product. The solid was dried, extracted with n-hexane and the solution filtered free of insoluble material before percolation down a column (4 x 1'' diameter) of alumina. Elution with n-hexane gave a fraction (4.2 grams) which was crystallized twice from ether to give the diacetate, MP 176°-180°C. Methyl bromide (17 grams) was added to a solution of the bispiperidinodiacetate (4 grams) in methylene chloride (10 ml) and the resulting solution allowed to stand at room temperature for 4 days. The solution was evaporated to dryness, the residue triturated with ether, and filtered to give the bis-methobromide (5.2 grams), MP 206°C. Recrystallization from acetonemethylene chloride gave material MP 214°-217°C. References Merck Index 6870 Kleeman and Engel p. 681 PDR p. 1288 OCDS Vol. 2 p. 163 (1980) DOT 5 (3) 104 (1969) I.N.p. 726 REM p. 924 Hewett, C.L. and Savage, D.S.; US Patent 3,553,212; January 5, 1971; assigned to Organon Inc.

PANTETHINE Therapeutic Function: Growth factor, Antihyperlipidemic Chemical Name: Butyramide, N,N'-(dithiobis (ethyleneiminocarbonylethylene))bis(2,4-dihydroxy-3,3-dimethyl-, D-(+)Common Name: LBF disulfide form; Pantethine; Pantetina Structural Formula:

Chemical Abstracts Registry No.: 16816-67-4

2608

Pantethine

Trade Name Atarone Lipodel Obliterol Pantogen

Manufacturer Country Vinas Shanghai Lansheng Corporation Faes Maruko -

Year Introduced -

Raw Materials Hydrazine hydrate Methyl D-pantothenate Super-filtrol Bis(β-aminoethyl)disulfide dihydrochloride Carbon Manufacturing Process To 11 g of hydrazine hydrate (85%) cooled in an ice bath are added 11.5 g of methyl d-pantothenate and the cold mixture is stirred vigorously. After the reaction takes place and the mixture is warmed to 30°C, it is allowed to stand at room temperature for two days, and then evaporated to dryness in vacuo at 50°C. The residue (14.7 g) of pantothenyl hydrazide is a clear glassy oil. To 7.3 g of crude d-pantothenyl hydrazide dissolved in 21 ml of water and stirred in a beaker cooled on an ice bath is added sufficient. 6 N hydrochloric acid to shift the pH to 4. Then a solution of 1.7 g of sodium nitrite in 5 ml of water is added dropwise over a period of one hour, keeping the pH at 4 by additions of 6 N hydrochloric acid. After stirring for one-half hour, 2.8 g of bis(β-aminoethyl)disulfide dihydrochloride are added. The pH is then adjusted to 8.5 with 50% aqueous sodium hydroxide solution and the solution allowed to stir for one and one-half hours. It is then acidified to pH 7.5 and concentrated in vacuo to clear colorless viscous oil. The pure product can be isolated from this oil by the next method. The crude bis(Npantothenylamidoethyl)disulfide so obtained is purified by dissolving the crude reaction product in 45 ml of anhydrous n-butanol and pouring the resulting solution through a chromatograph column containing 272 g of activated carbon. The column is washed with n-butanol and fractions are collected from time to time and the fractions containing solids assaying about 25 to 40% pure bis(N-pantothenylamidoethyl)disulfide against Lactobacillus: helveticus 80 poured onto a chromatograph column containing 136 g of an alkaline earth aluminum silicate known commercially as Super -filtrol. The column is washed thoroughly with anhydrous n-butanol and the washings and main solution discarded. N-Butanol saturated with water is poured through the column to elute the bis(N-pantothenylamidoethyl)disulfide and the resulting solution evaporated to dryness in vacuum at low temperature to obtain the desired product in pure form. Instead of pouring the anhydrous n-butanol solution onto the alkaline earth aluminum silicate chromatograph column, one can simply repeat the treatment with a carbon chromatograph column to obtain the pure product. In some instances, the first carbon treatment produces fractions containing pure bis(N-pantothenylamidoethyl)disulfide and in those cases it is, of course, not necessary to treat the fraction with alkaline earth aluminum silicate nor again with activated carbon.

Pantoprazole sodium

2609

References Snell E.E., More J.A.; US Patent No. 2,625,565; Assigned to Parke, Davis and Company, Detroit, Mich., a corporation of Michigan

PANTOPRAZOLE SODIUM Therapeutic Function: Antiulcer Chemical Name: 1H-Benzimidazole, 5-(difluoromethoxy)-2-(((3,4-dimethoxy2- pyridinyl)methyl)sulfinyl)-, sodium salt Common Name: Pantoprazole sodium Structural Formula:

Chemical Abstracts Registry No.: 138786-67-1; 102625-70-7 (Base) Trade Name Controloc Pangest Pantoloc Pepmark Protium Protonix Somac

Manufacturer Byk Gulden Beta Solvay Pharma Unimarck Pharma (India) Ltd. Lupin Laboratories Ltd. Wyeth Pharmaceuticals Pharmacia and Upjohn

Country Germany India USA -

Year Introduced -

Raw Materials Sodium hydroxide 5-Difluoromethoxy-1H-benzimidazole-2-thiol Sodium thiosulfate Sodium hypochlorite 2-Chloromethyl-4,5-dimethoxy-3-methylpyridinium chloride Manufacturing Process 2-Chloromethyl-4,5-dimethoxy-3-methylpyridinium chloride (about 1.5 g) are added to a solution of 5-difluoromethoxy-1H-benzimidazole-2-thiol in 10 ml of ethanol and 10 ml of 1 N sodium hydroxide solution. The yellow reaction mixture is stirred at 20°C for 1 hour, a further 10 ml of water are added,

2610

Pantothenic acid

whereupon a colorless solid precipitates out, the mixture is stirred for a further 5 hours and filtered and the residue is rinsed with 1 N sodium hydroxide solution and water and dried to constant weight. The 5difluoromethoxy-2-[(4,5-dimethoxy-2-pyridyl)methylthio]-1H-benzimidazole is obtained as an oil. 5-Difluoromethoxy-2-[(4,5-dimethoxy-2-pyridyl)methylthio]-1H-benzimidazole (about 1 g) are dissolved in 10 ml of dioxane and 2 ml of 1 N sodium hydroxide solution. An equimolar amount of a titrated aqueous sodium hypochlorite solution, to which 1 mole per liter of sodium hydroxide solution has been added, is first added dropwise, while cooling with ice. After one hour a further equivalent and after 3 hours half the equimolar amount of sodium hypochlorite are added, to achieve complete reaction. After a reaction time of 4 hours, 5 ml of 5% strength sodium thiosulfate solution and another 25 ml of dioxane are added and the upper dioxane phase is separated off, washed once with 5 ml of sodium thiosulfate solution and concentrated on a rotary evaporator. The oily residue is dissolved in 20 ml of water and 10 ml of ethyl acetate and the solution is brought to pH 7 with about 100 ml of a buffer solution of pH 6.8. The solid which has precipitated out is filtered off with suction over a suction filter, washed with water, extracted by stirring at 0C with acetone and dried. 5-Difluoromethoxy-2-[(4,5-dimethoxy-2pyridyl)methanesulfinyl]-1H-benzimidazole is prepared; yield about 85%. In practice it is usually used as sodium salt. References Kohl B. et al, US Patent No. 4,758,579; July 19, 1988; Assigned to BYK Gulden Lomberg Chemische Fabrik GmbH (Konstanz, DE)

PANTOTHENIC ACID Therapeutic Function: Vitamin Chemical Name: β-Alanine, N-(2,4-dihydroxy-3,3-dimethyl-1-oxobutyl)-, (R)Common Name: Achromothrichiefaktor; Acidum pantothenicum; Chick antidermatitis factor; Filtrat-Faktor; Kueken-Antidermatitis-Faktor; Pantothenic acid; Pantothensaeure Structural Formula:

Chemical Abstracts Registry No.: 79-83-4

Papain

2611

Trade Name

Manufacturer

Country

Year Introduced

Panto-250

Bio-Tech Pharmacal

-

-

Raw Materials Isobutylaldehyde Potassium chromate Hydrochloric acid β-Alanine

Formaldehyde Sodium cyanide α-Phenylethylamine

Manufacturing Process Isobutylaldehyde reacted with formaldehyde in the presence potassium chromate as a result 2,2-dimethyl-3-hydroxy-propanal was obtained. The 2,2-dimethyl-3-hydroxy-propanal was treated by sodium cyanide so 2,4dihydroxy-3,3-dimethyl-butironitrile was prepared. The 2,4-dihydroxy-3,3-dimethyl-butironitrile was treated hydrochloric acid and D,L-3-hydroxy-4,4-dimethyl-dihydro-furan-2-one (D,L-pantolacton) was obtained. The racemic mixture of D- and L-pantolactons was a division of Dand L- isomers by the adding of α-phenylethylamine. So D-pantolacton was isolated. Acrylic acid contacted with NH3and β-alanine was obtained. D-Pantalacton reacted with β-alanine as a result 3-(2,4-dihydroxy-3,3dimethyl-butyrylamino)-propanoic acid was produced. References Kleemann A., Engel J.; Pharmazeutische Wirkstoffe, GeorgThieme Verlag Stuttgart. New York, 1982

PAPAIN Therapeutic Function: Enzyme, Wound adhesion inhibitor Chemical Name: Enzyme; used to prevent wound adhesions Common Name: Structural Formula: Has folded polypeptide chain of 212 residues with a molecular weight of about 23,400 Chemical Abstracts Registry No.: 9001-73-4

2612

Papain

Trade Name Papain Panafil Prevenzyme

Manufacturer Green Cross Rystan Legere

Country Japan US US

Year Introduced 1969 -

Raw Materials Papaya fruit Methanol Manufacturing Process Crude papain, obtained as the dried exudate of the fruit and leaves of Carica papaya L., Caricaceae, is usually found to have been contaminated during collection, drying, or storage by insects, rodent hair and excreta, botanical plant parts, sand, etc. and may thereby become further contaminated by harmful bacteria and enteric organisms. Heretofore papain has been purified by dispersing the crude enzymes in water, filtering and spray-drying. In this procedure, however, the soluble contaminants are retained in the dried product. It has also been known to purify papain by dispersing it in water and adding acetone to reprecipitate the enzymes leaving many of the acetone-soluble and water-soluble impurities in the supernatant liquid. The material thus purified possesses a very disagreeable sulfidelike taste probably due to the reaction between the acetone and reactive sulfhydryl groups present in the papaya latex. It has now been found that an enzyme mixture of high purity which contains none of the objectionable sulfidelike taste can be obtained by dispersing the crude enzymes in water, adding a quantity of a water-miscible lower-alkanol to the incipient precipitation point of the proteolytic enzymes thereby retaining the maximum proteolytic activity (i.e., the maximum amount of the proteolytic enzymes) in the solvent phase while precipitating the major portion of the lower-alkanol insoluble contaminants, removing the loweralkanol insoluble contaminants and precipitated inert materials, for example, by filtration or centrifugation, and then adding an additional quantity of the water-miscible lower-alkanol sufficient to precipitate the proteolytic enzymes. The following is a specific example of the conduct of the present process. 100 g of crude papain were stirred with 120 ml of 0.01 M cysteine hydrochloride for one hour during which time the papain was completely dispersed. To the dispersion was added slowly and with vigorous stirring 147 ml of methanol. The mixture, which contained 55% methanol by volume, was stirred for about thirty minutes and centrifuged and the clear supernatant liquid was removed and saved. The precipitate was washed with 50 ml of 55% aqueous methanol, and the mixture was centrifuged again. The precipitate containing the undesirable, insoluble contaminants was discarded, and the clear wash liquid was combined with the main supernatant. To the combined clear supernatant liquid was added slowly and with vigorous stirring 265 ml of methanol to give a mixture containing 75.5% methanol by volume. The enzymes were precipitated as a taffylike gum which was isolated by decantation of the supernatant liquid containing the undesirable, soluble contaminants and traydrying. Alternatively, the precipitated enzymes can be redissolved in pure

Papaverine monophosadenine

2613

water and spray-dried. References Merck Index 6878 PDR pp. 1033, 1576 REM p. 1038 Losuk, A.; US Patent 3,011,952; December 5, 1961; assigned to Sterling Drug, Inc.

PAPAVERINE MONOPHOSADENINE Therapeutic Function: Vasodilator, Platelet aggregation inhibitor Chemical Name: Papaverine adenosine 5-monophosphate Common Name: Papaverine adenylate Structural Formula:

Chemical Abstracts Registry No.: 58-74-2 (Base) Trade Name Lempav Ty-Med Artegodan Cepaverin Cerespan Dylate Omnopon Pameion Panergon Papaverlumin Papaversan

Manufacturer Lemmon Artesan Eurand U.S.V. Elder Roche Simes Mack Pidefe Abello

Country US W. Germany Italy US US UK Italy W. Germany Spain Spain

Year Introduced 1975 -

2614

Paraflutizide

Trade Name Pavabid Pavacron Pavagrant Pavakey Pavatym Paver Spastretten Sustaverine Udip

Manufacturer Marion Cenci Amfre-Grant Key Everett Mulda Tropon I.C.N. Marion

Country US US US US US Turkey W. Germany US US

Year Introduced -

Raw Materials Papaverine base Adenosine-5'-monophosphoric acid Manufacturing Process To 3.65 g (0.01 mol) of monohydrated adenosine-5'-monophosphoric acid, brought into suspension in a mixture of 45 ml of water and 5 ml of ethanol, are added 339 g (0.01 mol) of papaverine base (melting point, 147°C). The mixture is gently heated until a final temperature of 40°C is reached. The solution obtained is then filtered and the filtrate is concentrated under vacuum. The remaining product quickly crystallizes. After drying to 50°C to constant weight, there are obtained 6.68 g of desired product, in the monohydrated state, as a white crystalline powder, which melts at 140°C and is very soluble in water. References Merck Index 6880 Kleeman and Engel p. 683 PDR pp. 830, 875, 993, 1079, 1569, 1606, 1810 OCDS Vol. 1 p. 347 (1977) DOT 11 (8) 315 (1975) I.N. p. 728 REM p. 852 Mauvernay, R.Y.; US Patent 3,823,234; July 9, 1974; assigned to Centre Europeen de Recherches Mauvernay C.E.R.M.

PARAFLUTIZIDE Therapeutic Function: Diuretic Chemical Name: 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 3,4-dihydro-6chloro-3-((4-fluorophenyl)methyl)-, 1,1-dioxide Common Name: Paraflutizide

Paramethadione

2615

Structural Formula:

Chemical Abstracts Registry No.: 1580-83-2 Trade Name Paraflutizide

Manufacturer Shanghai Lansheng Corporation

Country -

Year Introduced -

Raw Materials Potassium bichromate ρ-Fluorophenylethyl alcohol Hydrochloric acid 5-Chloro-2,4-disulphamylaniline Manufacturing Process A mixture of 5.0 g (0.0357 g/mol) of ρ-fluorophenylethyl alcohol, 2.0 g (0.007 g/mol) of 5-chloro-2,4-disulphamylaniline, 2.0 g (0.0068 g/mol) of potassium bichromate and 15 ml of concentrated hydrochloric acid (0.176 g/mol) and 25 ml of water is heated under reflux for 1 h. The mixture is allowed to cool, and 15 ml of ether are added to separate the excess of ρ-fluorophenylethyl alcohol. The aqueous layer is decanted and frozen for 2 h and the precipitate is separated, washed with water and dried in vacuum over phosphoric anhydride. There are collected 1.35 g (yield 47.5%) of the 1,1-dioxide of 3-ρfluorophenyl-methyl-7-sulphamyl-6-chloro-3,4-dihydrobenzo-1,2,4-thiadiazine, which when recrystallised from 30 ml of 50% alcohol on "Norit" active carbon takes the form of a white crystalline substance, melting point is 239°C. References GB Patent No. 961,641; July 31, 1962; Assigned: Les Laboboratoires Dausse, a French Body Corporate,of 58-60, Rue de la Glaciere, Paris, France

PARAMETHADIONE Therapeutic Function: Anticonvulsant Chemical Name: 5-Ethyl-3,5-dimethyl-2,4-oxazolidinedione

2616

Paramethadione

Common Name: Isoethadione Structural Formula:

Chemical Abstracts Registry No.: 115-67-3 Trade Name Paradione

Manufacturer Abbott

Country US

Year Introduced 1949

Raw Materials Methyl ethyl ketone Urea Methanol

Sodium cyanide Sodium Dimethyl sulfate

Manufacturing Process About 143.1 grams (one mol) of 5-methyl-5-ethyloxazolidine-2,4-dione is dissolved in 300 cc of methanol containing 23 grams of sodium. To the above mixture is added 126 grams of dimethyl sulfate in 10 cc portions while the temperature is maintained at about 50°C by external cooling. The mixture is then heated briefly to boiling, cooled, diluted with about 500 cc of water and extracted with two 250 cc portions of benzene. The benzene extract is separated, washed once with sodium bicarbonate solution and once with water. The benzene is removed by evaporation on a steam bath and the residue is fractionally distilled. The material boiling at 112° to 116°C at 25 mm pressure is taken; nD25=1.4495. Upon further fractionation, a very pure specimen boils at 101°-102°C at 11 mm. The 5-methyl-5-ethyloxazolidine-2,4-dionemay be prepared by reacting methyl ethyl ketone with sodium cyanide and with ammonium thiocyanate followed by desulfurization. This intermediate may also be prepared by condensing α-hydroxy-α-methylbutyramide with ethyl chlorocarbonate or by condensing ethyl α-hydroxy-α-methylbutyrate with urea. Another method described (Traube and Aschar, Ber., 46, 2077-1913) consists in the condensation of ethyl α-hydroxy-α-methylbutyrate with guanidine followed by hydrolysis. References Merck Index 6890 Kleeman and Engel p. 685 PDR p. 545 OCDS Vol. 1 p. 232 (1977) I.N. p. 730 REM p. 1080

Paramethasone acetate

2617

Spielman, M.A.; US Patent 2,575,693; November 20, 1951; assigned to Abbott Laboratories

PARAMETHASONE ACETATE Therapeutic Function: Glucocorticoid Chemical Name: 6α-Fluoro-11β,17,21-trihydroxy-16α-methylpregna-1,4diene-3,20-dione Common Name: Structural Formula:

Chemical Abstracts Registry No.: 1597-82-6; 53-33-8 (Base) Trade Name Haldrone Dilar Paramezone Monocortin Stemex Cortidene Metilar Paramesone Sintecort Triniol

Manufacturer Lilly Cassenne Recordati Gruenenthal Syntex I.F.L. Syntex Tanabe Medicamenta I.F.L.

Country US France Italy W. Germany US Spain UK Japan Portugal Spain

Year Introduced 1961 1962 1962 1963 1970 -

Raw Materials Hydrogen chloride 5α,11β,17α,21-Tetrahydroxy-6β-fluoro-16α-methylallopregnane-3,20dione-21-acetate 3-ethylene glycol ketal

2618

Parapenzolate bromide

Manufacturing Process A solution of 0.144 g of the 3-ethylene glycol ketal of 5α,11β,17α,21 tetrahydroxy-6β-fluoro-16α-methylallopregnane-3,20-dione-21 acetate in 12 ml of chloroform and 0.1 ml of absolute alcohol was cooled to -10°C in an icesalt bath and a stream of anhydrous hydrochloric acid was gently bubbled through the solution for 2.5 hours while the temperature was maintained between -5°C and -15°C. The solution was then diluted with 25 ml of chloroform, washed with dilute sodium bicarbonate and water, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure at 60°C or less to give 6α-fluoro-11β,17α,21-trihydroxy-16α-methyl-4-pregnene3,20-dione 21-acetate. References Merck Index 6891 Kleeman and Engel p. 686 OCDS Vol. 1 p. 200 (1977) I.N. p. 730 REM p. 969 Lincoln, F.H., Schneider, W.P. and Spero, G.B.; US Patent 3,557,158; January 19, 1971; assigned to The Upjohn Co.

PARAPENZOLATE BROMIDE Therapeutic Function: Antiulcer Chemical Name: N-Methyl-4-piperidylbenzilate methobromide Common Name: Structural Formula:

Chemical Abstracts Registry No.: 5634-41-3

Parapenzolate bromide Trade Name Spacine Vagopax Vagopax

Manufacturer Unilabo Essex Centrane

Country France Italy France

2619

Year Introduced 1968 1976 -

Raw Materials Methyl iodide Diphenylchloroacetyl chloride Silver bromide N-Methyl-4-piperidinol HCl Manufacturing Process N-methyl-4-piperidyl benzilate and the methiodide: An intimate mixture of 0.1 mol of N-methyl-4-piperidinol hydrochloride and 0.1 mol diphenylchloroacetyl chloride is heated at 160°C to 180°C until the evolution of hydrogen chloride ceases (usually about 4 to 5 hours). The melt is then dissolved in 500 ml of water and the resultant mixture heated on a steam bath for about ½ hour, after which time complete solution is effected. The acid solution is cooled and rendered alkaline with ammonium hydroxide solution whereupon the ester is precipitated. The ester is purified either by removal by filtration and recrystallization from benzene petroleum ether or by extracting the mixture with benzene and precipitating the ester by the addition of petroleum ether. After recrystallization there is obtained about 0.06 mol of N-methyl-4-piperidyl benzilate, melting point 162°C to 163°C. To a solution of 0.05 mol of the above obtained ester in about 100 ml of anhydrous benzene there are added 15 ml of methyl iodide. The ensuing mixture is refluxed for several hours whereupon the quaternary salt is deposited and removed by filtration. Recrystallization from ethanol or ethanolether yields the quaternary salt, melting point 199°C to 200°C. N-methyl-4piperidyl benzilate methobromide: To a suspension of 0.15 mol of freshly prepared silver bromide in 300 ml of anhydrous methanol is added a solution of 0.1 mol of quaternary iodide obtained as above. The mixture is stirred and refluxed for several hours after which time transhalogenation is complete. The mixture is cooled, the insoluble silver salt removed by filtration and the methanolic solution of the quaternaty bromide is concentrated in vacuo. The residue is recrystallized from methanol or methanol-ether yielding the quaternary bromide in quantitative amounts, melting point 237°C to 238°C. References OCDS Vol. 2 p. 75 (1980) DOT6 (3) 92 (1970) I.N. p. 731 Papa, D.; British Patent 788,126; December 23, 1957; assigned to Schering Corp.

2620

Pargyline hydrochloride

PARGYLINE HYDROCHLORIDE Therapeutic Function: Antihypertensive Chemical Name: N-Methyl-N-2-propynylbenzenemethanamine hydrochloride Common Name: N-Methyl-N-propargylbenzylamine hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 306-07-0; 555-57-7 (Base) Trade Name Eutonyl

Manufacturer Abbott

Country US

Year Introduced 1963

Raw Materials N-Methylbenzylamine Sodium carbonate Propargyl bromide Hydrogen chloride Manufacturing Process A mixture of 23.8 grams (0.2 mol) of propargyl bromide, 24.2 grams (0.2 mol) of N-methylbenzylamine and 400 ml of anhydrous ethanol in the presence of 42.4 grams (0.4 mol) of anhydrous sodium carbonate was heated at the boiling temperature and under reflux for a period of 17 hours. The sodium carbonate was then removed by filtration and the alcohol was removed by distillation under reduced pressure. The residue was treated with 300 ml of dry ether and the resulting solution was filtered to remove sodium bromide. The filtrate was dried and fractionally distilled under reduced pressure to obtain the desired N-methyl-N-propargylbenzylamine which boiled at 96°97°C at 11 mm pressure. Analysis calculated for C11H13N: C = 82.97%; H = 8.23%; N = 8.80%. Found: C = 82.71%; H = 8.51%; N = 8.93%. The hydrochloride salt of this amine was prepared by dissolving the amine in ether and adding ethereal hydrogen chloride to the ether solution. The solid hydrochloride salt which precipitated was recrystallized from an ethanol-ether mixture and was found to melt at 154° - 155°C.

Paromomycin

2621

References Merck Index 6902 Kleeman and Engel p. 688 PDR p. 523 OCDS Vol. 1 p. 54 (1977) and 2, 27 (1980) DOT9 (6) 217 (1973) I.N. p. 732 REM p. 850 Martin, W.B. US Patent 3,155,584; November 3, 1964; assigned to Abbott Laboratories

PAROMOMYCIN Therapeutic Function: Amebicidal Chemical Name: O-2,6-Diamino-2,6-dideoxy-β-L-idopyranosyl-(1-->3)-O-βD-ribofuranosyl-(1-->5)-O-[2-amino-2-deoxy-α-D-glucopyranosyl(1-->4)]-2-deoxystreptamine Common Name: Catenulin; Aminosidine; Crestomycin; Hydroxymycin; Neomycin E; Paucimycin Structural Formula:

Chemical Abstracts Registry No.: 7542-37-2 Trade Name Humatin Humatin Humatin Humagel

Manufacturer Parke Davis Parke Davis Parke Davis Parke Davis

Country US W. Germany Italy France

Year Introduced 1960 1961 1961 1963

2622

Paromomycin

Trade Name Aminosidine Aminoxidin Gabbromycin Gabbroral Paramicina

Manufacturer Kyowa Farmalabor Montedison Farmalabor Ragionieri

Country Japan Italy Italy Italy Italy

Year Introduced -

Raw Materials Glucose Soybean meal Bacterium Streptomyces rimosus forma paromomycinus Manufacturing Process As described in US Patent 2,916,485: 12 liters of a nutrient medium having the following composition is placed in a 30 liter fermenter equipped with stainless steel fittings including sparger, impeller, baffles and sampling lines and the medium is sterilized by heating at 121°C for two hours.

Glucose monohydrate Glycerol Casein, acid hydrolyzed Peptone Brewer's yeast Corn steep solids Soybean oil meal Acetone-butanol fermentation residue Sodium chloride Calcium carbonate Water sufficient to make

Percent 0.5 0.5 0.3 0.25 0.1 0.25 0.25 0.25 0.5 0.1 100%

The medium is cooled and inoculated with 20 ml of a suspension of the spores from two Mover's sporulation agar slant cultures of Streptomyces rimosus forma paromomycinus in sterile 0.1% sodium heptadecyl sulfate solution. The inoculated culture mixture is incubated at 26°C for sixty hours during which time the mixture is stirred at 200 rpm and sterile air is passed into the medium through the sparger at the rate of 12 liters per minute. A portion of the resulting incubated culture mixture is employed for inoculation of 16 liters of a nutrient medium having the following composition:

Glucose monohydrate Soybean oil meal Sodium chloride Calcium carbonate Ammonium chloride Hog stomach residue, saline extracted Water sufficient to make

Percent 1.0 1.0 0.5 0.1 0.167 0.5 100%

The pH of the latter nutrient medium is adjusted to 7.5 with 10 N sodium hydroxide solution and is placed in a 30 liter glass fermenter equipped with

Paromomycin

2623

sparger, impeller, baffles and sampling line, The medium is sterilized by heating at 121°C for two hours, is allowed to cool and is then inoculated with 800 ml of the culture mixture obtained as described above. The resulting culture mixture is incubated at 26°C for 94 hours during which time the mixture is stirred at 200 rpm and sterile air is passed into the medium through the sparger at the rate of 16 liters per minute. During the incubation, foaming is avoided by the addition, as needed, of crude lard and mineral oils containing mono-and diglycerides. At the end of the incubation period the fermentation culture mixture is adjusted to pH 2 with concentrated hydrochloric acid, the solid material present is removed by filtration, and the filter cake is washed with water. The washings are combined with the main filtrate, adjusted to pH 7.0; and 15.5 liters of the filtered culture liquid is introduced into a columnar exchanger (1.5'' i.d.) packed with 380 ml of carboxylic acid resin which has been preliminarily washed in succession with two liters of an aqueous solution of 37.5 grams of sodium hydroxide and with two liters of water. The column containing paromomycin is washed with two hold-up volumes of water and is eluted with 0.5 N hydrochloric acid. The first 19.4 liters of percolate contains little or no paromomycin and varies in pH from 6 to 7.3. When the pH of the eluate begins to fall below 6.0, two liters of the eluate are collected. The two liter portion of the eluate, collected as indicated, is neutralized to pH 6 with 10 N sodium hydroxide solution and is filtered. The filtrate is concentrated by evaporation in vacuo to a volume of approximately one liter. An adsorption column is prepared by pouring a slurried aqueous mixture of 65 grams of acid-washed activated charcoal (Darco G-60) and 50 grams of diatomaceous earth in a 1.5'' column and 300 ml of the concentrated filtrate is added. The column is washed with 400 ml of water and eluted successively with 325 ml of water, 425 mi of 1% aqueous acetone and 400 ml of 10% aqueous acetone. The water and acetone eluates are concentrated and lyophilized to give paromomycin hydrochloride as a powder. The product is purified by taking up the powder in methanol, adding a large excess of acetone to the solution, recovering the precipitate which forms by filtration. The product, paromomycin hydrochloride, has an optical rotation [α]D25 = +56.5° (1% in water). By analysis it contains 35.71% carbon, 6.95% hydrogen, 8.24% nitrogen and 21.5% chlorine. In order to obtain paromomycin in free base form, the hydrochloride is dissolved in water as a 3% solution, the solution is poured into an adsorption column containing an anion exchange resin (Amberlite IR-45 or preferably IRA-411 or IRA-400) in the hydroxyl form and the column is washed with a small amount of water. The aqueous percolate is concentrated to dryness by lyophilization, and the solid product obtained is purified by taking up in boiling absolute ethanol, cooling and recovering the solid product paromomycin; [α]D25 = +64° (1% in water). By analysis it contains 45.17% carbon, 7.44% hydrogen and 10.35% nitrogen.

2624

Paroxetine hydrochloride

References Merck Index 6903 Kleeman and Engel p. 688 I.N. p. 733 REM P. 1221 Davisson, J.W. and Finlay, A.C.; US Patent 2,895,876; July 21, 1959; assigned to Chas. Pfizer and Co., Inc. Frohardt, R.P., Haskell, T.H., Ehrlich, J. and Knudsen, M.P.; US Patent 2,916,485; Dec. 8, 1959; assigned to Parke, Davis and Company

PAROXETINE HYDROCHLORIDE Therapeutic Function: Antidepressant Chemical Name: Piperidine, 3-((1,3-benzodioxol-5-yloxy)methyl)-4-(4fluorophenyl)-, hydrochloride, (3S-trans)Common Name: Paroxetine hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 78246-49-8; 61869-08-7 (Base) Trade Name Paxil Paxyl

Manufacturer SmithKline Beecham Pharmaceuticals SK Beecham

Country France

Year Introduced -

-

-

Raw Materials Methyl-4-(4-fluorophenyl)N-methyl-nipecotinate Hydrochloric acid Formaldehyde Thionyl chloride Sulfuric acid

4-(4-Fluorophenyl)-1-methyl-1,2,3,6tetrahydropyridine Sodium methoxide Tartaric acid, dibenzoate, (-)Palladium on carbon 3,4-Methylenedioxyphenol

Paroxetine hydrochloride

2625

Manufacturing Process 251 g of methyl-4-(4-fluorophenyl)-N-methyl-nipecotinate, 8 g of sodium methoxide and 500 ml benzene were refluxed for 2 h. The benzene solution was washed with cold water and evaporated to give the pure α-ester which was dissolved in a mixture of 320 ml of water and 450 ml concentrated hydrochloric acid. The solution was slowly distilled to remove methanol and finally evaporated to dryness in vacuo. 400 ml thionyl chloride were added in small portions to the solid. The mixture was allowed to stand for 3 h at room temperature and was then evaporated to dryness in vacuo with tetrachloroethane giving methyl-4-(4-fluorophenyl)-Nmethylnipecotic acid chloride. The acid chloride was added in small portions to a solution of 160 g (-)-menthol in 800 ml pyridine at a temperature of 0°-5°C. The mixture was allowed to stand at room temperature to the next day. Ice water and 50% sodium hydroxide were added, and the mixture was extracted with ether. The ether was dried with anhydrous magnesium sulphate, filtered and evaporated. Distillation in vacuo gave the menthol ester in a yield of 7580%. Boiling point at 0.05 mm Hg was 165°-170°C. Racemic 4-(4-fluorophenyl)-1-methyl-1,2,3,6-tetrahydropyridine (50 g) was dissolved in a mixture of 21.6 ml of concentrated sulfuric acid and 50 ml of water. To the solution were added 25 ml of concentrated hydrochloric acid and 22.4 ml of 37% formaldehyde solution. The mixture was refluxed for 5 h, cooled, and 125 ml of concentrated ammonia were added. The mixture was extracted with 50 ml of toluene. Drying of the toluene solution and distillation gave 38 g of 4-(4-fluorophenyl)-3-hydroxymethyl-1-methyl-1,2,3,6tetrahydropyridine with boiling point 110°-120°C at 0.1 mm Hg. 13 g of the racemic compound and 22 g of (-)-dibenzoyltartaric acid were dissolved in 105 ml of hot methanol. On cooling, 9 g of salt of (-)-4-(4fluorophenyl)-3-hydroxymethyl-1-methyl-1,2,3,6-tetrahydropyridine crystallized. Melting point 167°-168°C. 38 g of (-)-4-(4-fluorophenyl)-3-hydroxymethyl-1-methyl-1,2,3,6tetrahydropyridine were dissolved in 350 ml of 99% ethanol, 5 g of 5% palladium on carbon were added, and the mixture was treated with hydrogen until 4500 ml were absorbed. The catalyst was filtered off, and the solution was evaporated to yield 37.5 g of (+)-b-4-(4-fluorophenyl)-3-hydroxymethyl1-methylpiperidine. To a solution of sodium in methanol (125 ml) were added 3,4methylenedioxyphenol (29 g) and the (+)-b-4-(4-fluorophenyl)-3hydroxymethyl-1-methylpiperidine (37,5 g). The mixture was stirred and refluxed. After removal of the solvent in vacuo, the evaporation residue was poured into a mixture of ice (150 g), water (150 ml), and ether (200 ml). The ether layer was separated, and the aqueous layer was extracted with ether. The combined ether solutions were washed with water and dried with anhydrous magnesium sulphate, and the ether was evaporated. The residue was triturated with 200 ml of 99% ethanol and 11.5 ml of concentrated hydrochloric acid, yielding 30 g of (-)-b-4-(4-fluorophenyl-3-(1,3-benzdioxolyl(3)-oxymethyl)-1-methylpiperidine, hydrochloride were obtained. Melting point 202°C.

2626

Parsalmide

References Christensen J.A., Squires R.F.; US Patent No. 4,007,196; Feb. 8, 1977; Assigned: A/S Ferrosan, Denmark Lemmens J.M. et al.; US Patent No. 6,686,473 B2; Feb. 3, 2004; Assigned: Synthon BCT Technologies, LLC, Chapel Hill, NC (US)

PARSALMIDE Therapeutic Function: Muscle relaxant, Antiinflammatory, Analgesic Chemical Name: Benzamide, 5-amino-N-butyl-2-(2-propynyloxy)Common Name: Parsalmide; Sinovial Structural Formula:

Chemical Abstracts Registry No.: 30653-83-9 Trade Name Parsalmide Parsal

Manufacturer Country Shanghai Lansheng Corporation Midy -

Year Introduced -

Raw Materials Thionyl chloride Butylamine Sodium Sulfuric acid

5-Acetamido-O-salicylic acid Sodium hydroxide Propargyl bromide Isopropyl alcohol

Manufacturing Process 5-Acetylamino-2-acetoxybenzoyl chloride was obtained by reaction of 5acetylamino-2-acetoxy-benzoic acid with thionylchloride. 5-Acetylamino-N-butyl-2-hydroxybenzamide was produced in the result of treatment of 5-acetylamino-2-acetoxybenzoyl chloride with butylamine in the

Pasiniazid

2627

presence of sodium hydroxide. 5-Acetamino-N-(n-butyl)-2-propargyloxybenzamide was obtained by reaction of 5-acetylamino-N-butyl-2-hydroxybenzamide with propargylbromide in the presence of sodium, isopropyl alcohol and sulfuric acid. 28.8 g (0.1 mole) 5-acetamino-N-(n-butyl)-2-propargyloxybenzamide in 320 ml of 4 N sulfuric acid was heated, under stirring, at 90°-95°C for 2 h. The clear solution was cooled and its pH adjusted to 1 with 1 N NaOH; after filtering, further alkali was subsequently added until a pH of 10 was obtained. At this point the product was separated by filtration and recrystallized from ethanol at 60°C to give 16.6 g (a yield of 68%) of chromatographically pure 5-amino-N-(n-hutyl)-2-propargyloxybenzamide; melting point 85°-87°C. References Gradnik B. et al.; US Patent No. 3,739,030; June 12, 1973; Assigned: Societe d'Etudes de Recherches et d'Applications Scientifiques et Medicales E.R.A.S.M.E., Paris, France Kleemann A., Engel J.; Pharmazeutische Wirkstoffe, GeorgThieme Verlag Stuttgart, New York, 1982

PASINIAZID Therapeutic Function: Antitubercular Chemical Name: Isonicotinic acid hydrazide compound with 4-amino-salicylic acid Common Name: Pasiniazid; Umenazid Structural Formula:

Chemical Abstracts Registry No.: 2066-89-9 Trade Name Pasinazid

Manufacturer Yick-Vic Chemicals and Pharmaceuticals (HK) Ltd.

Raw Materials Isonicotinoyl hydrazine

Country -

Year Introduced -

2628

Pecilocin

4-Aminosalicylic acid Manufacturing Process 10 parts by weight of isonicotinoyl hydrazine was dissolved in 200 by volume of methanol by stirring at 60°C. Then 11.2 parts 4-aminosalycylic acid was added at 60°C. On cooling a salt of both compounds crystallized as yellow prisms with MP: 135°-140°C (decomposed). Isonicotinic acid hydrazide compound with 4-aminosalicylic acid may be prepared from the same components by using 750 parts of water by volume as a solvent. 10 parts 4-aminosalicylic acid was dissolved in 600 volume parts of water containing 39 parts by volume 2 N ammonium hydroxide. 9 parts by weight isonicotinoyl hydrazide was added and the mixture was heated to 30°C. The solution was acidified with 49 parts by volume of 2 N acetic acid. On cooling isonicotinic acid hydrazide compound with 4-amino-salicylic acid crystallized, which decomposed at 135°-140°C. The yield was almost quantitative. References F. Hoffmann-La Roche and Co. Aktiengesellschaft, Basel (Switzerland); S.R. Patent No. 303,085; April 4, 1952

PECILOCIN Therapeutic Function: Antibiotic Chemical Name: 2-Pyrrolidinone, 1-(8-hydroxy-6-methyl-2,4,6dodecatrienoyl)-, (E,E,E)-(R)Common Name: Pecilocin; Supral Structural Formula:

Chemical Abstracts Registry No.: 19504-77-9

Pecilocin Trade Name Variotin

Manufacturer Country Shanghai Lansheng Corporation -

2629

Year Introduced -

Raw Materials Sucrose Paecilomyces varioti Bainier var. antibioticus ATCC 13435 Sodium nitrate Ferric sulfate Manufacturing Process Paecilomyces varioti Bainier var. antibioticus ATCC 13435 was inoculated into 10 liters of a culture medium having a pH of 6 and containing 3.0% sucrose, 0.3% sodium nitrate, 0.2% potassium dihydrogen phosphate, 0.05% magnesium sulfate, 0.05% potassium chloride and 0.001% ferrous sulfate. The cultivation was carried out in a small-aerated tank at a temperature of 25°C. After cultivation for 60 hours, the production of 30 units of pecilocin (variotin) was accomplished. The fermentation broth was then separated from the mycelium by filtration and the filtrate was extracted twice with 3 litres of ethyl acetate. The combined extracts were concentrated under reduced pressure. The concentrate was dissolved into 100 ml of methanol and, after filtering off the insoluble material which formed on refrigeration of the resulting solution, the methanolic solution was concentrated under reduced pressure. Thus 1.8 g of pecilocin having an activity of 120 u/mg were obtained. The mycelium separated from the fermentation broth by filtration was treated with 1 liter of methanol and, after thorough grinding and stirring, was centrifugally separated. The methanol was distilled off from the methanol extract under reduced pressure and the residue extracted with ethyl acetate. The extract was concentrated under reduced pressure and the resulting concentrate was dissolved in about 100 ml of methanol. After removing the insoluble materials, which appeared on refrigeration, the methanol solution was concentrated under reduced pressure and 0.8 g of pecilocin having an activity of 90 u/mg were obtained. 100 liters of the same medium as used above were charged into the 200 liters fermentation tank. 50 g of steamed rice which had been inoculated with Paecilomyces varioti Bainier var. antibioticus ATCC 13435 and fully sporulated after cultivation for a week were seeded in the tank and cultivated with aeration and agitation at a temperature of 26°-27°C for 90 hours, said aeration being carried out by sparging of sterilized air at the rate of 90 liters per minute. At the end of 90 hours, the fermentation broth showed a pecilocin content of 16 u/ml. 86 liters of the cultured solution including the mycelium were extracted twice with 30 liters of ethyl acetate and centrifuged in a Sharples centrifugal machine. The combined extracts were concentrated under reduced pressure and about 55 g of brownish colored syrup were obtained. This syrup was dissolved in 250 ml of methanol and then refrigerated. The insoluble materials, which appeared were removed by filtration. The clarified methanol solution was then concentrated under reduced pressure and the resulting syrup was dissolved in ether and the insoluble materials were filtered off. The ether solution was concentrated under reduced pressure to a volume of about 25 ml and the concentrate mixed with ten times its volume of

2630

Pelargonic acid

petroleum ether and refrigerated. Oily material, which precipitated were separated from the solvent by decantation and washed with a small volume of petroleum ether. After drying, the treated oily materials were dissolved in 300 ml of carbon tetrachloride and then refrigerated. Brownish-red colored oily materials, which had formed were removed by decantation and the solution in carbon tetrachloride was concentrated under reduced pressure, thereby 6.6 g of a slightly yellow oily substance having an activity of 145 µ/mg were obtained. One gram of this oily substance was subjected to a 47 tube counter-current distribution employing a 1:1 mixture of 70% methanol and carbon tetrachloride as the solvent. The results of bio-assay, ultra-violet absorption and weight measurements showed that the biologically active component was distributed mainly in tubes No 12 - 32 and that tube No 21 showed the highest concentration of active component. The samples of tubes No 15 - 26 were combined and again counter-currently distributed, 130 tubes being used. As a result of this counter-current distribution, the pecilocin was distributed in tubes No 47 - 73 of which tube No 61 showed the highest content of pecilocin. Distribution curves were plotted from bio-assay, UV-absorption and weight measurements and these curves agreed well with theoretical curve. It was thus proved that variation is a single substance. The samples of tubes No 58 - 63 were combined and concentrated under reduced pressure whereby 110 mg of colorless oily substance having a pecilocin activity of 166 u/mg were obtained. References Yusuke Sumiki et al.; G.B. Patent No. 866,425; April 7, 1959; Assigned to Japan Antibiotics Research Association, an incorporated body organized under laws of Japan, Tokyo, Japan and Nippon Kayaku Kabushiki Kaisha, Japan

PELARGONIC ACID Therapeutic Function: Fungicide Chemical Name: Nonanoic acid Common Name: Structural Formula:

Chemical Abstracts Registry No.: 112-05-0 Trade Name Pellar

Manufacturer Crookes Barnes

Country US

Year Introduced 1960

Pemirolast potassium

2631

Raw Materials Oleic acid Oxygen Manufacturing Process A body of liquid, 18 inches high, comprising a 35% (by weight) solution of technical (95%) oleic acid in n-propanol, is maintained at a temperature of 86°C in a reactor. The solution also contains dissolved therein 0.042% by weight of cobalt, in the form of cobalt naphthenate. From the bottom of the reactor very fine bubbles of air are passed into and through the solution at the rate of about 0.3 cubic feet per minute, measured at standard conditions, per square foot for 72 hours. The gases leaving the reactor are first passed through an ice water reflux condenser and then vented to the atmosphere. At the end of the 72 hour period the reaction mixture is separated into its components. It is found that 60% of the oleic acid has been consumed in the reaction. For each pound of oleic acid consumed there are obtained 0.30 pound of azelaic acid (representing an efficiency of 46%, calculated on the basis that the technical oleic acid is 100% oleic acid), 0.13 pound of pelargonic acid (representing an efficiency of 23%) and 0.21 pound of 9,10dihydroxystearic acid (representing an efficiency of 19%). References Merck Index 6923 MacKenzie, J.S. and Morgan, C.S. Jr.; US Patent 2,820,046; January 14, 1958; assigned to Celanese Corp. of America

PEMIROLAST POTASSIUM Therapeutic Function: Antiallergic, Antiulcer Chemical Name: 4H-Pyrido(1,2-a)pyrimidin-4-one-9-methyl-3-(1H-tetrazol5-yl), potassium salt Common Name: Artimast; Pemirolast pottassium Structural Formula:

Chemical Abstracts Registry No.: 100299-08-9; 69372-19-6 (Base)

2632

Pemirolast potassium

Trade Name Alamast

Manufacturer Santen

Country -

Year Introduced -

Raw Materials 3-Methylpyridine N,N-Dimethylaniline Sodium azide Potassium hydroxide

Ferric nitrate hexahydrate Sodium hydroxide Ethyl ethoxymethylenecyanoacetate

Manufacturing Process Ferrous nitrate hexahydrate (60 mg) followed by sodium (4.5 g, 0.196 gatom) were added to liquid ammonia. To this mixture was added a solution of 3-methylpyridine (10.0 g, 0.093 mole) in N,N-dimethylaniline (21 ml) over a period of 5 min. The ammonia was allowed to evaporate and the residue heated under nitrogen by means of an oil bath maintained at 180°C for 18 h. The cooled residue was treated with ice (50 g) followed by 2 N sodium hydroxide (50 ml). The mixture was triturated for 2 h and then filtered. The collected solid was washed with boiling toluene (2 times 100 ml). The toluene layer was separated from the combined filtrate and washings, concentrated to about 50 ml and extracted with 5% aqueous acetic acid (5 times 20 ml). The combined extracts were filtered and reduced to dryness. The residue was recrystallized from methylcyclohexane to give 2-amino-3-methylpyridine acetate (4.9 g, 29%), melting point 85°-95°C. The acetate (2.5 g, 1.37 mmoles) was briefly suspended in 1 N sodium hydroxide (50 ml). The mixture was extracted with methylene chloride. The extract was washed with water, dried, and concentrated to give 2-amino-3-methylpyridine as an oil. A solution of 2-amino-3-methylpyridine (5.0 g, 0.0462 mole) and ethyl ethoxymethylenecyanoacetate (7.82 g, 0.0462 mole) in toluene (4 ml) was heated for 15 min by means of an oil bath maintained at 100°C. The solution was cooled and the crude product (9.1 g, 85%) collected by filtration. The product was recrystallized from 2-propanol to give an analytical sample of ethyl 2-cyano-3-(3-methyl-2-pyridylamino)acrylate, melting point 144°146°C. Aluminum chloride (3.51 g, 0.0263 mole) was added to cold (-30°C) tetrahydrofuran (180 ml). Sodium azide (5.12 g, 0.0788 mole) was added and the mixture heated under reflux for 30 min. The mixture was cooled to 5°C. Ethyl 2-cyano-3-(3-methyl-2-pyridylamino)acrylate (5.0 g, 0.0216 mole) was added and the mixture heated under reflux for 18 h. The tetrahydrofuran was removed under reduced pressure. The residue was treated with ice water (100 ml) and acidified to pH 3 with 6 N hydrochloric acid. The mixture was filtered and the collected solid recrystallized from N,N-dimethylformamide to give the 9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (2.5 g, 50.7%). Melting point 310°-311°C, dec. Potassium hydroxide was added dropwise to a stirred mixture of 9-methyl-3(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one in water .The mixture was diluted with water to a volume of about 300 ml and was then heated to a temperature of 50°C during 2 min. The mixture was filtered and the water removed from the filtrate by lyophilization. The residue was recrystallized from water:ethanol to give the 9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-

Pemoline

2633

a]pyrimidin-4-one potassium salt. References Juby P.F.; US Patent No. 4,122,274; Oct. 24, 1978; Assigned: Bristol-Myers Company, New York, N.Y.

PEMOLINE Therapeutic Function: Psychostimulant Chemical Name: 2-Imino-5-phenyl-4-oxazolidinone Common Name: Phenoxazole; Phenylisohydantoin Structural Formula:

Chemical Abstracts Registry No.: 2152-34-3 Trade Name Deltamine Cylert Cylert Antimeran Betanamin Dynalert Hyton Kethamed Nitan Phenoxine Pioxol Pondex Revibol Ronyl Sigmadyn Sofro Stimul Tradon Vidil

Manufacturer Aron Abbott Abbott Nichiiko Sanwa Restan Pharmacia Medo Teva P.C.B. Horner Chinoin Pliva Rona Spemsa Thilo Nadrol Beiersdorf Waldheim

Country France UK US Japan Japan S. Africa Sweden UK Israel Belgium Canada Hungary Yugoslavia UK Italy W. Germany W. Germany W. Germany Austria

Year Introduced 1960 1975 1975 -

2634

Penbutolol

Raw Materials Mandelic acid ethyl ester Guanidine Manufacturing Process It is preferably prepared by reacting mandelic acid ethyl ester with guanidine in boiling alcoholic solution whereby it is obtained as difficultly soluble precipitate with a yield of 90%. This compound is a white, crystalline compound melting at 256°-257°C with decomposition. It is readily soluble in concentrated aqueous alkali hydroxide solutions and in concentrated aqueous mineral acids. References Merck Index 6931 Kleeman and Engel p. 690 PDR p. 509 DOT 9 (6) 212 (1973) I.N. p. 736 REM p. 1137 Schmidt, L. and Scheffler, H.; US Patent 2,892,753; June 30, 1959; assigned to C.H. Boehringer Sohn, Germany

PENBUTOLOL Therapeutic Function: Beta-adrenergic blocker Chemical Name: 1-(2-Cyclopentylphenoxy)-3-[(1,1-dimethylethyl)amino]-2propanol Common Name: Structural Formula:

Chemical Abstracts Registry No.: 38363-40-5 Trade Name

Manufacturer

Country

Year Introduced

Betapressin

Hoechst

W. Germany

1980

Penciclovir Trade Name Betapressin Betapressin

Manufacturer Hoechst Hoechst

Country Switz. Italy

2635

Year Introduced 1982 1983

Raw Materials 2-Cyclopentylphenol Epichlorohydrin t-Butylamine Manufacturing Process 21.8 g (0.1 mol) of 1,2-epoxy-3-(2'-cyclopentylphenoxy)propane, boiling at 113°C to 115°C/0.2 mm Hg (prepared from 2-cyclopentylphenol and epichlorhydrin in the presence of alkali) were dissolved in 250 ml of ethanol; to this solution, there were added dropwise, while stirring.8.9 g (0.15 mol) of t-butylamine. The reaction mixture was stirred for 2 hours at 60°C and then the solvent and the excess t-butylamine were removed by distillation. The residue which had been purified via the aqueous hydrochloride, crystallized, after removal of the ether by evaporation, upon rubbing or inoculation and yielded, after recrystallization from n-heptane, the 1-t-butylamino-2-hydroxy3-(2'-cyclopentylphenoxy)propane which was found to melt at 69°C to 70°C. References Merck Index 6935 DFU 1 (10) 494 (1976) Kleeman and Engel p. 691 DOT 17 (12) 555 (1981) and 18 (10) 551 (1982) I.N. p. 737 Ruschig, H., Schmitt, K., Lessenich, H. and Hartfelder, G.; US Patent 3,551,493; Dec. 29, 1970; assigned to Farbwerke Hoechst A.G. (W. Germany)

PENCICLOVIR Therapeutic Function: Antiviral Chemical Name: 6H-Purin-6-one, 1,9-dihydro-2-amino-9-(4-hydroxy-3(hydroxymethyl)butyl)Common Name: Penciclovir Chemical Abstracts Registry No.: 39809-25-1

2636

Penciclovir

Structural Formula:

Trade Name Denavir Vectavir Vectavir

Manufacturer Novartis Consumer Health SmithKline Beecham Consumer Healthcare Beecham

Country France

Year Introduced -

UK

-

Raw Materials Triphenylphosphine 2,2-Dimethoxypropane Carbon tetrabromide Hydrochloric acid

Triethyl 1,1,2-ethanetricarboxylate 4-Toluenesulfonic acid monohydrate Lithium aluminum hydride Sodium hydroxide

Manufacturing Process To a suspension of lithium aluminum hydride (2.87 g, 76 mmol) in tetrahydrofuran (125 ml), a solution of triethyl 1,1,2-ethanetricarboxylate (9.2 ml, 9.85 g, 40 mmol) in tetrahydrofuran (25 ml) was added dropwise with stirring over 2 hours. The inorganic salts were filtered off and washed with ethanol (100 ml). The filtrate and washings were combined and the solvent was evaporated under reduced pressure to afford a colourless oil (4.85 g). To a suspension of this oil in acetone (100 ml) 2,2-dimethoxypropane (25 ml) and p-toluenesulphonic acid monohydrate (2.3 g, 12 mmol) were added. The mixture was stirred for 1 hour. The resulting solution was neutralised with Amberlite IR 45 (methanol washed), filtered and the solvent evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with chloroform-methanol mixtures (40:1 and 25:1) to afford 5-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxan as a colourless liquid (3.01 g, 47%). To an ice-cooled solution of 5-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxan (1.92 g, 12 mmol) and carbon tetrabromide (7.96 g, 24 mmol) in dimethylformamide (100 ml) triphenylphosphine (6.30 g, 24 mmol) was added and the solution was left at 4°C overnight. To this solution methanol (20 ml) was added and the solvent was then evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane-acetone (12:1) to afford 5-(2-bromoethyl)-2,2-dimethyl1,3-dioxan as a clear colourless liquid (0.89 g, 40%). To a solution of 5-(2-bromoethyl)-2,2-dimethyl-1,3-dioxan (0.75 g, 3.7 mmol) in dry dimethylformamide (12 ml) 2-amino-6-chloropurine (0.68 g, 4.0 mmol) and then anhydrous potassium carbonate (0.83, 6.0 mmol) were added. The solution was stirred at room temperature for 5 hours and left at 4°C

Penfluridol

2637

overnight. The solution was filtered and the solvent removed. The residue was purified by column chromatography on silica gel, eluting with chloroformmethanol mixtures (80:1 and 60:1) to afford 2-amino-6-chloro-9-[2-(2,2dimethyl-1,3-dioxan-5-yl)ethyl]purine as a white crystalline solid (0.74 g, 64%), melting point 125°-126°C. 2-Amino-6-chloro-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)-ethyl]purine (0.59 g, 1.9 mmol) in hydrochloric acid (1.0 M, 4 ml) was stirred at 60°C for 24 hours. The solution was diluted with water and neutralised with Amberlite IR 45. The mixture was filtered, the resin washed with water and the solvent evaporated under reduced pressure. The residue was recrystallised from water to afford 9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine (238 mg, 49%), melting point 275°-277°C. References Javest R.L., Harnden M.R.; US Patent No. 5,075,445; Dec. 24, 1991; Assigned: Beecham Group p.l.c., Middlesex, United Kingdom

PENFLURIDOL Therapeutic Function: Antipsychotic Chemical Name: 1-[4,4-Bis(4-fluorophenyl)butyl]-4-[4-chloro-3(trifluoromethyl)phenyl]-4-piperidinol Common Name: Structural Formula:

Chemical Abstracts Registry No.: 26864-56-2 Trade Name Semap Semap Flupidol Longoran Micefal Semap

Manufacturer Janssen-Le Brun Janssen Zambeletti Isis Spofa Abic

Country W. Germany France Italy Yugoslavia Czechoslovakia Israel

Year Introduced 1975 1975 1979 -

2638

Pengitoxin

Raw Materials 4,4-Bis(p-fluorophenyl)butyl chloride 4-(4-Chloro-α,α,α-trifluoro-m-tolyl)-4-piperidinol Manufacturing Process A mixture of 24 parts of 4,4-bis(p-fluorophenyl)butyl chloride, 20.9 parts of 4(4-chloro-α,α,α-trifluoro-m-tolyl)-4-piperidinol, 13.8 parts of sodium carbonate, a few crystals of potassium iodide in 600 parts of 4-methyl-2pentanone is stirred and refluxed for 60 hours. The reaction mixture is cooled and 150 parts of water is added. The organic layer is separated, dried, filtered and evaporated. The oily residue is crystallized from diisopropylether, yielding 4-(4chloro-α,α,α-trifluoro-m-tolyl)-1-[4,4-bis(p-fiuorophenyl)butyl]-4piperidinol; melting point 106.5°C. References Merck Index 6939 Kleeman and Engel p. 691 OCDS Vol. 2 p. 334 (1980) DOT 10 (5) 167 (1974) I.N. p. 737 Hermans, H.K.F. and Niemegeers, C.J.E.J.; US Patent 3,575,990; April 20, 1971; assigned to Janssen Pharmaceutica N.V. (Belgium)

PENGITOXIN Therapeutic Function: Cardiotonic Chemical Name: Gitoxin pentaacetate Common Name: Pengitoxin; Pentaacetylgitoxin Chemical Abstracts Registry No.: 7242-04-8 Trade Name

Manufacturer

Country

Year Introduced

Pengitoxin

Shanghai Lansheng Corporation

-

-

Raw Materials Gitoxin Acetic anhydride Potassium bicarbonate Hydrochloric acid

Penicillamine

2639

Structural Formula:

Manufacturing Process Gitoxin is isolated from leaves of Digitalis purpurea L. genus Scrofphulariaceae. 10.0 g pure gitoxin are boiled under reflux with 1 L pure acetic anhydride. Gitoxin thereby goes into solution in the course of 1 h. The boiling is discontinued after 1 h and the acetic anhydride distilled off in a vacuum as completely as possible. After taking up the oily residue with 500 ml chloroform, the solution is successively washed with 200 ml of 2 N potassium bicarbonate solution, 0.1 N hydrochloric acid and water. After drying the chloroform solution with anhydrous sodium sulfate, the chloroform is first distilled off over an open flame and then on a water bath at 40°C in a vacuum, a substantially crystalline residue thereby being obtained. The 12.8 g of crude product obtained are recrystallized from 12 times the amount of a mixture of pyridine, methanol and water (25:10:65) to give rhombic crystals, melting point 151°-155°C. References GB Patent No. 1,043,029; Sept. 21, 1966; Assigned: VEB Arzneimittelwerk Dresden, of 35, Wilhelm-Pieck-Strasse, 8122 Radebeul 1, Germany

PENICILLAMINE Therapeutic Function: Antiarthritic Chemical Name: 3-Mercapto-D-valine

2640

Penicillamine

Common Name: Dimethylcysteine Structural Formula:

Chemical Abstracts Registry No.: 52-67-5; 2219-30-9 (Hydrochloride salt) Trade Name Cuprimine Trolovol Pendramine Pemine Trolovol Depen Artamin Cuprenil Cupripen Depamine Distamine Gerodyl Metalcapase Reumacillin Rhumantin Sufortanon

Manufacturer MSD Bayer B.D.H. Lilly Bayer Wallace Biochemie Polfa Rubio Berk Dista Gea Knoll Medica Gea Lacer

Country US W. Germany UK Italy France US Austria Poland Spain UK UK Denmark W. Germany Finland Denmark Spain

Year Introduced 1963 1963 1973 1975 1979 1979 -

Raw Materials Sodium hydroxide Potassium benzyl penicillin Hydrogen sulfide

Phenylhydrazine Mercuric chloride

Manufacturing Process (a) Preparation of mercuric chloride complex of penicillamine: To a solution of 372 g (1 mol) of potassium benzyl-penicillin in 940 ml of distilled water at room temperature is added a solution of 40 g (1 mol) of sodium hydroxide in 180 ml of distilled water over a period of one-half hour. The solution is then stirred for two hours at room temperature. While maintaining room temperature, 67 ml of concentrated hydrochloric acid is added at a slow rate. This solution is then added, over a period of time of one-half hour, to a solution of 271 g (1 mol) of HgCl2 in 3.52 liters of distilled water in the presence of 50 g of Hyflo and 5 ml of octyl alcohol. After one hour of agitation, the resulting mixture is treated with 185 ml of concentrated hydrochloric acid and filtered.

Penicillin G benzathine

2641

(b) Removal of benzylpenilloaldehyde: To the filtrate obtained in step (a), warmed to 50°C is slowly added 108 g (1 mol) of phenyl hydrazine. The mixture is cooled to room temperature and 84 ml of concentrated hydrochloric acid are added. The mixture is agitated briefly and the precipitated benzylpenilloaldehyde phenyl hydrazone is filtered off. (c) Preparation of isopropylidene penicillamine hydrochloride: To the filtrate obtained in step (b) is added at 20°C to 25°C a total of 85 g of hydrogen sulfide. The precipitated HgS is filtered off and the filtrate is concentrated under reduced pressure to a volume of 200 to 500 ml. Following a polish filtration, the product-rich concentrate is mixed with 1.5 liters of isobutyl acetate. The mixture is refluxed at about 40°C under reduced pressure in equipment fitted with a water separation device. When no further water separates, the batch is cooled to 30°C and filtered. The reactor is washed with 1 liter of acetone, which is used also to wash the cake. The cake is further washed with 200 ml of acetone. The acetone washes are added to the isobutyl acetate filtrate and the mixture is refluxed for 20 to 30 minutes. After a holding period of one hour at 5°C. the crystals of isopropylidene penicillamine hydrochloride are filtered and washed with 200 ml of acetone. On drying for twelve hours at 25°C this product, containing 1 mol of water, weighs about 178 g (73%). (d) Preparation of penicillamine hydrochloride: The 178 g of isopropylidene penicillamine hydrochloride obtained in step (c) is dissolved in 350 ml of distilled water. The solution is heated at 90°C to 95°C for one to one and onehalf hours, removing acetone by distillation through an efficient column. There is then added 2.6 liters of isobutyl acetate. The mixture is refluxed at a temperature of about 40°C under reduced pressure in equipment fitted with a water separation device. When no further water separates, the pressure is adjusted so that the mixture distills at a vapor temperature of 83°C to 88°C. A total of 650 ml of distillate is collected. The batch is allowed to cool to 50°C and then filtered. The crystals are washed with isobutyl acetate and then dried at 35°C for 24 hours. The virtually anhydrous penicillamine hydrochloride obtained weighs about 128 g (69% from potassium benzyl-penicillin). References Merck Index 6940 Kleeman and Engel p. 693 PDR pp. 1153, 1872 DOT 9 (7) 302 (1973) I.N. p. 738 REM p. 1225 Restivo, A.R., Dondzila, F.A. and Murphy, H. Jr.; US Patent 3,281,461; October 25, 1966; assigned to E.R. Squibb and Sons, Inc. Sota, K., Ogawa, T. and Sawada, J.; US Patent 4,150,240; April 15, 1979; assigned to Taisho Pharmaceutical Co., Ltd. (Japan)

PENICILLIN G BENZATHINE Therapeutic Function: Antibacterial

2642

Penicillin G benzathine

Chemical Name: Penicillin G compound with N,N'-dibenzylethylenediamine Common Name: Benzethacil Structural Formula:

Chemical Abstracts Registry No.: 1538-09-6 Trade Name

Manufacturer

Country

Year Introduced

Bicillin

Wyeth

US

1951

Permapen

Pfizer

US

1953

Neolin

Lilly

US

1954

Extencilline

Specia

France

-

Benzetacil-Simple

Antibioticos

Spain

-

Brevicilina-Simple

Wassermann

Spain

-

Brunocillin

Mepha

Switz.

-

Cepacilina

Cepa

Spain

-

Depotpen

Dauelsberg

W. Germany

-

Diaminocillina

Farmalabor

Italy

-

Durabiotic

Teva

Israel

-

Longacillin

Besy

Brazil

-

LPG

C.S.L.

Australia

-

Megacillin

Merck-Frosst

Canada

-

Pen-Di-Ben

Bago

Argentina

-

Pendysin

Jenapharm

E. Germany

-

Penidural

Wyeth

UK

-

Peniroger Retard

Roger

Spain

-

Pipercilina

Iskia

Spain

-

Retarpen

Biochemie

Austria

-

Tardocillin

Bayer

W. Germany

-

Tardopenil

Farmabion

Spain

-

Penicillin G benzathine

2643

Raw Materials Ethylenediamine Benzaldehyde Sodium penicillin G Manufacturing Process Ethylenediamine (15 g, 0.25 mol) was added dropwise to 100 ml 98-100% formic acid in a two-necked 500 ml flask, fitted with an addition tube and reflux condenser with drying tube, cooled in an ice-bath. After complete addition of the base, 53 g of benzaldehyde (0.5 mol) was added in one lot. The ice-bath was removed and the flask was heated to the refluxing temperature. The initial rate of carbon dioxide evolution was too rapid to measure. After twenty minutes, the rate was circa 100 ml per minute and decreased rapidly to 8 ml per minute in one hour. Heating at reflux was continued for 35 hours. Following the refluxing most of the excess formic acid was removed under reduced pressure. Hydrochloric acid (200 ml 6 N) was added to the viscous amber residue and heated under reflux, After 15 minutes, bumping necessitated cooling and filtering to remove crystalline dihydrochloride, which after washing with isopropanol was dried, MP circa 300°C. The mother liquors were refluxed one hour and cooled, obtaining an additional amount of product, MP circa 300°C. The filtrate was concentrated in vacuo to 100 ml, cooled and made alkaline with 40% NaOH. The supernatant oil was extracted with ether, dried, and fractionated from a stillpot packed with glass wool and heated in a sand-bath at 320°C. The first fraction at 106°C at 0.6-0.7 mm was Nbenzylethylenediamine (dipicrate, MP 222°C). The N,N'dibenzylethylenediamine was collected at 177°C to 206°C at 0.6-1.0 mm as a colorless liquid. To a solution of 60 g of sodium penicillin G in 800 cc of distilled water cooled to 0°C to 4°C in an ice-bath, a solution of 35 g of N,N'dibenzylethylenediamine diacetate in 200 cc of distilled water is added dropwise with stirring. The thick slurry is filtered with suction, washed twice with 100 cc of cold water, dried by suction and spread out in a thin layer for completion of drying. The product weighed 80 g. The air-dried powder has a broad melting point, sintering at 100°C, melting above 110°C to a cloudy liquid becoming clear at 135°C. References Merck Index 6948 Kleeman and Engel p. 85 PDR pp. 1406, 1941, 1989 I.N. p. 126 REM p. 1197 Szabo, J.L.and Bruce,W.F.; US Patent 2,627,491; February 3, 1953; assigned to Wyeth, Inc.

2644

Penicillin G hydrabamine

PENICILLIN G HYDRABAMINE Therapeutic Function: Antibacterial Chemical Name: N,N'-Bis(dehydroabietyl)ethylenediamine dipenicillin G Common Name: Structural Formula:

Chemical Abstracts Registry No.: 3344-16-9 Trade Name Compocillin

Manufacturer Abbott

Country US

Year Introduced 1954

Raw Materials Dehydroabietylamine Ethylene dibromide Penicillin G Manufacturing Process A mixture of 142.5 g of "Rosin Amine D" containing about 70% dehydroabietylamine and 30% dihydro and tetrahydroabietylamine, 47.0 g of ethylene dibromide, and 60.6 g of triethylamine is dissolved in 350 cc of anhydrous xylene and refluxed for about 16 hours. Thereafter the triethylamine dibromide salt formed is separated from the solution by filtering the cool reaction mixture and washing with ether. The solution is then concentrated under reduced pressure to dryness to remove the ether, xylene and excess triethylamines present. The viscous oil resin is slurried twice with 250 cc portions of methanol to remove any unreacted primary amines. The oil residue after being washed with methanol is dissolved in ethyl alcohol and 75 cc of concentrated hydrochloric acid is added dropwise to the warm alcohol

Penicillin G procaine

2645

solution of the base. The dihydrochloride salts of the several hydroabietyl ethylenediamines precipitates immediately from solution. The salt is then separated by filtering and is washed twice with 100 cc portions of cooled ethyl alcohol. The dihydrochloride salts of the dehydroabietyl, dihydroabietyl and tetrahydroabietyl ethylenediamine mixture have a melting point of about 292°C to 295°C. On subjecting the mixture to solubility analyses it is found that the dehydroabietyl ethylenediamine is present in substantially the same proportion as is the dehydroabietylamine in the original "Rosin Amine D." An amyl acetate-penicillin acid solution (10 liters) having a potency of 100,000 U/ml which is sufficient to supply 565 g (2 mols) of penicillin acid is added with constant agitation to 505 g of crude N,N'-bis-(dehydroabietyl)ethylenediamine dissolved in 500 ml of amyl acetate. A slight excess of the ethylenediamine bases is added to the mixture until precipitation is completed. The reaction is preferably carried out in a cold room having a temperature of about 5°C. The precipitation salts comprise about 70% N,N'bis-(dehydroabietyl)-ethylenediamine-dipenicillin salt and approximately 2530% of the N,N'-bis-(dihydroabietyl)-ethylenediamine-and N,N'-bis(tetrahydroabietyl)-ethylenediamine-dipenicillin salts are recovered by filtration and are washed with about 1/10 solution volume of amyl acetate. The crude preparation is further washed with 1/10 solution volume of diethyl ether and dried. The melting point of the product is about 153°C when taken on a microblock. The total yield of the crude precipitation obtained in the above manner comprising about 1 kg is then dissolved in chloroform so as to form a 15% solution of a crude penicillin salt. To the filtered chloroform solution is added ethyl acetate slowly and with agitation until the solution becomes turbid as crystallization begins. Thereafter crystallization is allowed to proceed undisturbed for about 30-60 minutes in a cold room having a temperature of about 5°C. Sufficient ethyl acetate is slowly added to provide a final concentration of about 50% ethyl acetate and the mixture is allowed to stand in the cold room for one hour to complete crystallization. The precipitate is filtered and washed with about 750 ml of ethyl acetate and thereafter washed with the same volume of ether. The crystals are dried in vacuo and a yield of about 900 g of N,N'-bis-(dehydroabietyl)-ethylenediamine-dipenicillin G is obtained. The penicillin product melts with decomposition at a temperature of 170°C to 172°C on a Kofler hot stage. Solubility analysis of the product shows the product to be 95.3% pure. References Merck Index 6951 I.N. p. 739 De Rose, A.F.; US Patent 2,812,326; November 5, 1957; assigned to Abbott Laboratories

PENICILLIN G PROCAINE Therapeutic Function: Antibacterial

2646

Penicillin G procaine

Chemical Name: Penicillin G compound with 2-(diethylamino)ethyl paminobenzoate Common Name: Structural Formula:

Chemical Abstracts Registry No.: 54-35-3 Trade Name Duracillin Flo-Cillin Ledercillin Wycillin Diurnal Penicillin Abbocillin Ampin-Penicillin Aquacaine Aquasuspen Aqucilina Cilicaine Distaquaine Excolicin Farmaproina Francacilline Hypercillin Hypropen Intrasept Klaricina Novocillin Penifasa Peniroger Procain Premocillin Procapen Prokapen Retardillin

Manufacturer Lilly Bristol Lederle Wyeth Upjohn Abbott Badische Arzneim. C.S.L. SK Kauelsberg Antibioticos Sigma Distillers Jenapharm Cepa Franca Cutter Biochemie Streuli Clariana Solac Lifasa Roger Premo Orion Weifa EGYT

Country US US US US US US W. Germany Australia W. Germany Spain Australia UK E. Germany Spain Canada US Austria Switz. Spain France Spain Spain US Finland Norway Hungary

Year Introduced 1948 1949 1949 1949 1950 1951 -

Penicillin O Trade Name Sanciline Procaina Therapen I.M.

Manufacturer Santos Therapex

Country Spain Canada

2647

Year Introduced -

Raw Materials Penicillin G Procaine Manufacturing Process There was added to 250 ml of a concentrated butyl acetate extract containing 74,000 units of the acid form of penicillin per ml, 50 ml of a butyl acetate solution containing 0.238 g per ml of procaine base. The solution was agitated for one hour. The precipitate which formed was very gummy and not in the form of discrete crystals. This precipitate was crystallized by scratching the side of the vessel and agitating further. After this treatment 18.25 g of crystalline procaine penicillin was obtained which assayed 1010 units per mg representing a yield of 99.6% of the activity contained in the concentrated extract. References Merck Index 6953 PDR pp. 1408, 1742, 1941, 1989 I.N. p. 739 REM p. 1198 Bardolph, M.P.; US Patent 2,739,962; March 27, 1956; assigned to Commercial Solvents Corp.

PENICILLIN O Therapeutic Function: Antibacterial Chemical Name: 3,3-Dimethyl-7-oxo-6-[[(2-propenylthio)acetyl]amino]-4thia-1-azabicyclo[3.2.0]-heptane-4-carboxylic acid Common Name: Allylmercaptomethylpenicillin Structural Formula:

2648

Penicillin O

Chemical Abstracts Registry No.: 87-09-2 Trade Name Cero-O-Cillin

Manufacturer Upjohn

Country US

Year Introduced 1950

Raw Materials Lactose Bacterium Penicillium Corn steep liquor N-(2-Hydroxyethyl)allylmercaptoacetamide Manufacturing Process A culture medium is prepared in the following proportions: Lactose Corn steep solids Calcium carbonate N-(2-Hydroxyethyl)-allylmercaptoacetamide Water

125 g 150 g 25 g 0.140 g 5,000 cc

The culture medium is distributed in 200 cc portions in 1 liter Erlenmeyer flasks, sterilized, inoculated with a spore suspension of Penicillium mold strain Q-176, and stoppered with cotton plugs. The flasks are maintained at a temperature of about 23°C to 26°C and shaken constantly for five days. The flask contents are then filtered to remove the mold mycelium, the filtrate cooled to about 0°C, acidified to about pH 2.2 with o-phosphoric acid and shaken with an equal volume of amyl acetate. The amy acetate layer is separated and extracted with three 100 cc portions of cold water to which cold N/10 sodium bicarbonate solution is added during the course of each extraction until a pH of about 7.1 to 7.3 is attained in the aqueous phase. The aqueous extracts are combined, cooled to about 0°C. acidified to about pH 2.2 with o-phosphoric acid and extracted with three 100 cc portions of ether. The ether extracts are combined, and are passed through a chromatographic type silica adsorption column about 30 mm in diameter and 300 mm long, and containing a pH 6.2 phosphate buffer. The silica column is developed by percolation with six 100 cc portions of ether containing successively increasing amounts of methanol in the order of 0.5, 1.5%, 2, 2.5, and 3 percent. The developed silica column is divided into about 12 equal sections and each section is eluted with three 30 cc portions of M/15 phosphate buffer of pH 7.0. The eluates are assayed bacteriologically to determine their penicillin content. Most of the antibiotic activity originates in a single bank in the silica column and results from the presence of allylmercaptomethylpenicillin. The eluates obtained from this band are combined, cooled to about 0°C, acidified to about pH 2.2and extracted with three 50 cc portions of chloroform. The combined chloroform extracts are then passed through a silica adsorption column containing a pH 6.2 phosphate buffer. This silica gel column is developed by percolation with three 100 cc portions of chloroform containing successively increasing amounts of methanol in the order of 1, 2 and 3 percent. The developed silica column is then divided into 12 equal sections and each section is eluted with three 30 cc portions of M/15 phosphate buffer of pH 7.0.

Penicillin V

2649

Again, most of the total antibiotic activity originates in a single band in the silica column. The eluates obtained by extraction of the silica column sections which comprise this band are combined, cooled to about 0°C, acidified to about pH 2.2 and extracted with three 100 cc portions of ether. The ether extracts are combined and extracted with about 75 cc of a cool dilute aqueous solution of sodium hydroxide to which N/10 sodium hydroxide solution is added during the course of the extraction so that a final pH of about 7.0 is obtained in the aqueous phase. From this aqueous solution the sodium salt of allylmercaptomethylpenicillin is separated, for example, by freezing and evaporation in vacuo from the frozen state. References Merck Index 6955 I.N. p. 58 Behrens, O.K., Jones, R.G., Soper, Q.F. and Corse, J.W.; US Patent 2,623,876; December 30, 1952; assigned to Eli Lilly and Co.

PENICILLIN V Therapeutic Function: Antibacterial Chemical Name: 3,3-Dimethyl-7-oxo-6-[(phenoxyacetyl)amino]-4-thia-1azabicyclo[3.2.0]-heptane-2-carboxylic acid Common Name: 6-Phenoxyacetamidopenicillanic acid; Phenoxymethylpenicillin Structural Formula:

Chemical Abstracts Registry No.: 87-08-1 Trade Name Oracilline V-Cillin Pen-Vee Calcipen Fenocin Fenospen Ibaden Intalpen

Manufacturer Theraplix Lilly Wyeth Farmabion Dumex Farmalabor Lek Inter-Alia Pharm.

Country France US US Spain Denmark Italy Yugoslavia UK

Year Introduced 1954 1955 1955 -

2650

Penicillin V

Trade Name Ospen Penorline Rivopen V V-Tablopen Weifapenin

Manufacturer Biochemie Allard Rivopharm Arzneimittelwerk Dresden Weifa

Country Austria France Switz. E. Germany Norway

Year Introduced -

Raw Materials Phenoxyacetyl chloride 6-Aminopenicillanic acid Manufacturing Process The following description is taken from US Patent 2,941,995. A solution of phenoxyacetyl chloride (360 mg) in dry acetone (5 ml) was added dropwise during 10 minutes to a stirred solution of 6-aminopenicillanic acid (450 mg, approximately 75% pure) in 3% aqueous bicarbonate (18 ml), and acetone (12 ml). When addition was complete the mixture was stirred at room temperature for 30 minutes and then extracted with ether (30 ml in 3 portions), only the aqueous phase being retained. This aqueous solution was covered with butanol (5 ml) and adjusted to pH 2 by the addition of N hydrochloric acid. After separating the layers, the aqueous phase was extracted with two 2.5 ml portions of butanol, adjusting to pH 2 each time. The combined butanol solutions (which at this stage contained the free penicillanic acid) were washed with water (3 x 2 ml) and then shaken with water (10 ml) to which sufficient 3% sodium bicarbonate solution was added to bring the aqueous phase to pH 7. The butanol solution was further extracted with two 5 ml portions of water to each of which was added enough bicarbonate solution to produce an aqueous phase of pH 7. The combined aqueous solutions were washed with ether (20 ml) and then evaporated at low temperature and pressure to leave the crude sodium salt of phenoxymethyl penicillin which, after drying in a vacuum desiccator, was obtained as a slightly hygroscopic powder (591 mg). References Merck Index 6957 Kleeman and Engel p. 716 PDR pp. 673, 694, 1071, 1381, 1606, 1723, 1770, 1968 I.N. p. 760 REM p. 1199 Behrens, O.K., Jones, R.G., Soper, Q.F. and Corse, J.W.; US Patent 2,562,410; July 31, 1951; assigned to Eli Lilly and Company Sheehan, J.C.; US Patent 3,159,617; December 1, 1964; assigned to Arthur D. Little, Inc. Doyle, F.P., Nayler, J.H.C. and Rolinson, G.N.; US Patent 2,941,995; June 21, 1960; assigned to Beecham Research Laboratories Limited, England

Penicillin V hydrabamine

2651

PENICILLIN V HYDRABAMINE Therapeutic Function: Antibacterial Chemical Name: N,N'-Bis(dehydroabietyl)ethylendiamine bis(phenoxymethylpenicillin) Common Name: Structural Formula:

Chemical Abstracts Registry No.: 6591-72-6 Trade Name Compocillin-V Flavopen

Manufacturer Abbott G.P.

Country US Australia

Year Introduced 1954 -

Raw Materials Penicillin V Dehydroabietylethylenediamine Manufacturing Process The crude dihydrochlorides of dehydroabietylethylenediamine bases (985 g) are extracted with a solution of about 3 liters of chloroform and 3 liters of water which is adjusted to about pH 10 and a second extraction is performed using a solution of about 2 liters of chloroform and the mixture readjusted to about pH 10 with 6 N NaOH if necessary. The chloroform layer containing the mixed free bases is separated from the aqueous layer containing NaCl and is washed with about 1/10 its volume of water to remove any NaCl in the wet chloroform solution. The chloroform solution containing a mixture of the free bases having a volume of about 5 liters is dried with anhydrous Na2SO4 and then filtered to obtain a clear solution containing about 0.85 kg of the mixed

2652

Penimepicycline

free bases. Approximately 1,000 g of phenoxymethylpenicillin acid (Penicillin V) is dissolved directly in about 5 liters of ethyl acetate to a concentration of 20% w/v. The resulting solution is filtered to remove any insoluble salts. The penicillin V acid (1,000 g) may also be obtained by extracting an aqueous solution of 1,110 g of the potassium salt of phenoxymethylpenicillin at a temperature of about 5°C, this solution being adjusted to pH 2-3 by the addition of 6 N sulfuric acid, twice with a total of 5 liters of ethyl acetate so that the final washed combined volume will have a concentration of about 20% w/v. The abovementioned ethyl acetate solution having a volume of about 5 liters is then dried with anhydrous Na2SO4 and filtered to obtain a clear ethyl acetate solution of phenoxymethylpenicillin acid. In place of the hydrochlorides of the above described bases any other acid salt thereof can be used, including both inorganic and organic salts such as phosphoric, sulfuric, and acetic acids. Also, in place of the mentioned penicillin, any of the other common salts of penicillin can be used as a source of penicillin acid. The chloroform solution of the free bases prepared in the above manner is then slowly added to the ethyl acetate solution of the penicillin V acid prepared in the above manner. A clear solution forms which rapidly becomes turbid as the bases react with the penicillin acid and crystallization commences. The reaction mixture is allowed to stand overnight in a cool room having a temperature of about 5°C after thoroughly agitating the mixture. Thereafter, the crystalline N,N'-bis-(dehydroabietyl)-ethylenediaminedipenicillin V is filtered to separate therefrom the cooled mother liquor which contains the unprecipitated N,N'-bis-(dihydroabietyl)-ethylenediaminedipenicillin salt and N,N'-bis-(tetrahydroabietyl)-ethylenediamine-dipenicillin salt and other impurities. The precipitate is washed thoroughly with about 4 liters of a mixture of chloroform and ethyl acetate (1:1) which is divided into three separate portions. After the final washing, the crystals are substantially colorless. The crystalline penicillin salt is thoroughly dried under vacuum at a temperature of about 50°C. The N,N'-bis-(dehydroabietyl)-ethylenediaminedipenicillin V salt is obtained having purity as determined by solubility analysis in excess of about 90% and melts with decomposition at 163°C to 165°C on a Kofler hot stage. References Merck Index 6959 I.N. p. 494 De Rose, A.F.; US Patent 2,812,326; November 5, 1957; assigned to Abbott Laboratories

PENIMEPICYCLINE Therapeutic Function: Antibiotic Chemical Name: 4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-

Penimepicycline

2653

3,6,10,12,12a-pentahydroxy-N-((4-(2-hydroxyethyl)-1-piperazinyl) methyl)-6-methyl-1,11-dioxo-2-naphthacenecarboxamide salt with phenoxymethylpenicillin Common Name: Mepenicycline; Penimepiciclina; Penimecycline Structural Formula:

Chemical Abstracts Registry No.: 4599-60-4 Trade Name Penimepicyclina Duamin Tonsil Ultrabiotic

Manufacturer Elenco Farmaci Luso-Farmaco Gap Latino

Country -

Year Introduced -

Raw Materials Tetracycline Formaldehyde

1-(2-Hydroxyethyl)piperazine Penicillin V

Manufacturing Process N-(41-β-hydroxyethyl-11-piperazinylmethyl)tetracycline was obtained by reaction of tetracycline with 1-(2-hydroxyethyl)piperazine in the presence of formaldehyde. 8.6 g of N-(41-β-hydroxyethyl-11-piperazinylmethyl)tetracycline and 35.0 g

2654

Penmestrol

phenoxymethyl-penicilline, were dissolved in 300 ml methanol, with agitation. The solution was filtered on a Buchner filter, and the filtrate was taken up with 900 ml anhydrous ether with strong agitation, again filtered under pressure, and the filter cake was washed twice with 50 ml anhydrous ether. The product was; dried in vacuum. 84.0 g were obtained of a penimepicycline as yellowish white powder. References Gradnik B., Pedrazzoli A.; GB Patent No. 891,004; March 7, 1962; Assigned: Societe D'Etudes de Recherches et D'Applications Scientifiques et Medicales E.R.A.S.M.E., of 67 Avenue de Wagram, Paris 17, France, a French body corporate Kleemann A., Engel J.; Pharmazeutische Wirkstoffe, GeorgThieme Verlag Stuttgart, New York, 1982

PENMESTEROL Therapeutic Function: Androgen Chemical Name: 3-(Cyclopentyloxy)-17-methyl-androsta-3,5-dien-17β-ol Common Name: Penmesterol; Penmestrol Structural Formula:

Chemical Abstracts Registry No.: 67-81-2 Trade Name Penmesterol

Manufacturer Shanghai Lansheng Corporation

Country -

Year Introduced -

Raw Materials Androsteaedione 4-Toluenesulfonic acid Methyl magnesium bromide

Orthoformate Cyclopentanol

Manufacturing Process A) 14 g of ethyl enolether of androstenedione, melting at 149°-151°C (obtained in a yield of 85% of the theoretical amount by treating androsteaedione with ethyl orthoformate), were added to a boiling solution of

Pentaerythritol tetranitrate

2655

37 ml of cyclopentanol and 0.450 g of p-toluenesulfonic acid in 2.5 L of benzene. The mixture was distilled over an approximately 40 minute period, so that the ethanol, which evolved during the exchange reaction, was evaporated off completely. Then 0.5 ml of pyridine was added to the remaining solution and the mixture was concentrated under vacuum to dryness. The residue, taken up with a mixture of methanolmethylene chloride containing a few drops of pyridine, gave 13.8 g of cyclopentyl enolether of androstenedione melting at 181°183°C. Yield about 85%. B) The cyclopentyl enolether of androstenedione was converted to the corresponding cyclopentyl enolether of 17α-methyl testosterone as follows: In a 3-necked flask fitted with a dropping funnel, reflux condenser, stirrer and nitrogen inlet tube, there was placed a solution of 25 g of methyl magnesium bromide in 150 ml of ether. With stirring and under an atmosphere of nitrogen, a solution of 4.1 g of androstenedione 3-cyclopentyl enolether in 80 ml of anhydrous benzene was added slowly. The reaction mixture was refluxed for 1 hour and allowed to stand overnight at room temperature. The mixture was then treated with an aqueous solution of 30% ammonium chloride, the organic layer separated off, washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue taken up with dilute methanol to yield 3.2 g of a white product. Crystallization from methanol containing few drops of pyridine give the pure 17α-methyltestosterone 3-cyclopentyl enolether; MP: 148-152°C; [α]D =-150° (dioxane). References Ercoli A.; US Patent No. 3,019,241; Jan. 30, 1962

PENTAERYTHRITOL TETRANITRATE Therapeutic Function: Coronary vasodilator Chemical Name: 2,2-Bis[(nitroxy)methyl]-1,3-propanediol dinitrate Common Name: PETN; Pentanitrolum Structural Formula:

2656

Pentaerythritol tetranitrate

Chemical Abstracts Registry No.: 78-11-5 Trade Name Pentanitrine Peritrate Pentritol Pentafin Vasodiatol Metranil Pentryate Tranite D-Lay Peridex Antime SK-Petin Perispan Pentraspan Pentraspan Cardiacap Dilcoran Duotrate Hasethrol Hypothurol Lentrat Neo-Corodil Neo-Corovas Nitrodex Nitropent Pectolex Penritol Pentalong Peritrine Perynitrate

Manufacturer Promedica Warner Lambert Armour Tutag Rowell Meyer Fellows-Testagar Westerfield Robins Century SKF U.S.V. Glenwood Vitarine Consol. Chem Godecke Marion Shionogi Nissin Medinova Ethica Amfre-Grant Dexo A.C.O. Shionogi Langley Isis-Chemie Norgine Barlow Cote

Country France US US US US US US US US US US US US US UK W. Germany US Japan Japan Switz. Canada US France Sweden Japan Australia E. Germany Belgium Canada

Year Introduced 1948 1952 1955 1956 1958 1960 1960 1961 1962 1962 1971 1971 1980 1983 -

Raw Materials Pentaerythritol Nitric acid Manufacturing Process Cooling water was turned on and 420 parts nitric acid of 94% strength was introduced into the nitrator. The amount of acid was such that the ratio of nitric acid to pentaerythritol was 4.29. The agitator was started and the agitator speed adjusted to 120 rpm. 92 parts pentaerythritol, which had been screened previously through a 14-mesh screen was used in each charge. About 45 parts pentaerythritol was added to the nitrator at such a rate that the temperature in the nitrator gradually rose to 110°F. This required about 12 minutes. Time was allowed for the temperature rise to cease before each succeeding increment of material was added.

Pentagastrin

2657

After reaching 110°F the charge was maintained at about said temperature from 12 to 14 minutes during which time approximately 30 parts pentaerythritol was added to the nitrator. During the following 14 minutes, approximately, the remainder of the 92 parts pentaerythritol was added in like manner to the charge and the temperature gradually reduced. The pentaerythritol was introduced into the acid in finely divided and welldispersed particles and not in large unitary quantities. The entire 92 parts of pentaerythritol tetranitrate was introduced in 35 to 40 minutes. The pentaerythritol thus obtained was separated from the spent acid by filtering or drowning in water. To recover the spent acid the charge was passed onto a nutsch and filtered. The crude product was washed with water, then with a weak water-soluble alkali solution, such as sodium carbonate for example, and subsequently with water in order to remove the acid. After the removal of acid, the nitrate was dried by suction on the nutsch for about 15 minutes. The dried material was refined by means of acetone treatment or other suitable refining means. About 210 parts refined pentaerythritol tetranitrate per charge was obtained. References Merck Index 6977 DFU 4 (5) 351 (1979) Kleeman and Engel p. 695 PDR pp. 1382, 1606 I.N. p. 741 REM p. 854 Acken, M.F. and Vyverberg, J.C. Jr.; US Patent 2,370,437; February 27,1945; assigned to E.I. du Pont de Nemours and Co.

PENTAGASTRIN Therapeutic Function: Gastrosecretory hormone Chemical Name: N-Carboxy-β-alanyl-L-tryptophyl-L-methionyl-Laspartylphenyl-L-alaninamide N-tert-butylester Common Name: Chemical Abstracts Registry No.: 5534-95-2 Trade Name

Manufacturer

Country

Year Introduced

Peptavlon

I.C.I.

UK

1967

Gastrodiagnost

Merck

W. Germany

1970

Pentagastrin

I.C.I.

Japan

1973

Peptavlon

Ayerst

US

1976

Peptavlon

I.C.I.

France

1981

Acignost

VEB Berlin Chemie

E. Germany

-

2658

Pentagastrin

Structural Formula:

Raw Materials L-Tryptophanyl-L-methionyl-L-aspartyl-L-phenylalanine amide trifluoroacetate N-t-Butyloxycarbonyl-β-alanine 2,4,5-trichlorophenyl ester Manufacturing Process A solution of 3.55 parts of L-tryptophanyl-L-methionyl-L-aspartyl-Lphenylalanine amide trifluoroacetate in 30 parts of dimethylformamide is cooled to 0°C, and 1.01 parts of triethylamine are added. The mixture is stirred while 1.84 parts of N-tert-butyloxycarbonyl-β-alanine 2,4,5trichlorophenyI ester are added at 0°C. The reaction mixture is kept at 0°C for 48 hours and then at 20°-23°C for 24 hours. The mixture is added to a mixture of 100 parts of ice-water, 0.37 part of concentrated hydrochloric acid (SG 1.18), 1.2 parts of acetic acid and 20 parts of ethyl acetate. The mixture is stirred for 15 minutes at 0°-10°C and is then filtered. The solid residue is washed with water and then with ethyl acetate, and is dried at 40°-50°C under reduced pressure. There is thus obtained N-tert-butyloxycarbonyl-βalanyl-L-tryptophanyl-L-methionyl-L-aspartyl-L-phenylalanine amide, MP 213°C with de composition. References Merck Index 6978 PDR p. 2004 DOT 3 (4) 150 (1967) I.N. p. 742 REM p. 1273 Hardy, P.M., Kenner, G.W., Sheppard, R.C., MacLeod, J.K. and Morley, J.S.; British Patent 1,042,487; assigned to Imperial Chemical Industries Limited, England Hardy, P.M., Kenner, G.W., Sheppard, R.C., Morley, J.S. and MacLeod, J.K.; US Patent 3,896,103; July 22, 1975; assigned to Imperial Chemical Industries Ltd.

Pentamidine isethionate

2659

PENTAMIDINE ISETHIONATE Therapeutic Function: Antiprotozoal Chemical Name: Ethanesulfonic acid, 2-hydroxy-, compd. with 4,4'-(1,5pentanediylbis(oxy))bis(benzenecarboximidamide) (2:1) Common Name: Pentamidine isethionate Structural Formula:

Chemical Abstracts Registry No.: 140-64-7; 100-33-4 (Base) Trade Name Nebupent Nebupent Pentacarinat Pentamidine isethionate Pentam 300 Pneumopent

Manufacturer Fujisawa Healthcare Inc American Pharmaceutical Partners, Inc. Rhone - Poulenc Rorer Fujisawa Healthcare Inc

Country USA USA

Year Introduced -

USA USA

-

Fujisawa Healthcare Inc Fisons Corporation

USA -

-

Raw Materials p,p'-Dicyano-1:5-diphenoxy-pentane Ethyl alcoholic ammonia Manufacturing Process 2.5 g of p,p'-dicyano-1,5-diphenoxy-pentane (obtained by the interaction of phydroxybenzonitrile and pentamethylene-dibromide in aqueous alkaline solution, melting point 114°C) are dissolved in 15 cc of nitrobenzene and 2.5 cc of absolute ethyl alcohol added. The solution is saturated with dry hydrochloric acid gas at 0°C and allowed to stand for 48 h. It is then diluted with dry ether and the precipitated 1,5-diphenoxypentane, 4,4'di(ethoxycarbonimidoyl) dihydrochlorid is filtered and washed with ether. 4 g of 1,5-diphenoxypentane, 4,4'-di(ethoxycarbonimidoyl) dihydrochloride are mixed with 30 cc. of 6 % ethyl alcoholic ammonia and heated in a closed vessel at 50°C for 5 h. The alcohol is removed and the residual 1,5diphenoxypentane, 4,4'-diamidino dihydrochloride is twice recrystallised from

2660

Pentapiperide methosulfate

dilute hydrochloric acid and finally purifled by dissolving in water and precipitating with acetone. Its melts at 236°C, dec. Pentamidine isetionate salt may be produced by the reaction pentamidine base with isethionic acid. References Ewins A.J. et al.; US Patent No. 2,277,861; March 31, 1942; Assigned: May and Baker, Limited, London, England, a company of Great Britain and Northern Ireland

PENTAPIPERIDE METHOSULFATE Therapeutic Function: Spasmolytic Chemical Name: α-(1-Methylpropyl)benzeneacetic acid 1-methyl-4piperidinyl ester methosulfate Common Name: Pentapiperium methosulfate Structural Formula:

Chemical Abstracts Registry No.: 7681-80-3; 7009-64-3 (Base) Trade Name Quilene Crylene Crilin Perium Togestal

Manufacturer Warner Lambert Auclair Ayerst Rover Biosedra

Country US France Italy US France

Raw Materials Phenylacetonitrile Thionyl chloride Sodium amide 1-Methyl-4-piperidinol

Sec-Butyl bromide Dimethyl sulfate Sodium hydroxide

Year Introduced 1969 1971 1973 -

Pentazocine hydrochloride

2661

Manufacturing Process Phenylacetonitrile is alkylated with secondary butyl bromide and the resultant nitrile is hydrolyzed to 3-methyl-2-phenylvaleric acid. The acid is converted to the acid chloride with thionyl chloride and the acid chloride is in turn reacted with 1-methyl-4-piperidinol. Finally dimethyl sulfate is reacted with the ester. References Merck Index 6988 Kleeman and Engel p. 697 OCDS Vol. 2 p. 76 (1980) DOT 6 (2) 61 (1970) I.N. p. 743 Martin, H. and Habicht, E.; US Patent 2,987,517; June 6, 1961; assigned to Cilag Chemie Limited, Switzerland

PENTAZOCINE HYDROCHLORIDE Therapeutic Function: Analgesic Chemical Name: 2,6-Methano-3-benzazocin-8-ol, 1,2,3,4,5,6-hexahydro6,11-dimethyl-3-(3-methyl-2-butenyl)-, hydrochloride, (2R,6R,11R)-relCommon Name: Pentazocine hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 64024-15-3; 68964-90-9; 359-83-1 (Base) Trade Name Pentazocine Hydrochloride

Manufacturer Mallinckrodt Inc.

Country -

Year Introduced -

Raw Materials Methyliodide Hydrogen Hydrobromic acid Hydrochloric acid

4-Methoxybenylmagnesium chloride 3,4-Dimethylpyridine Palladium on charcoal

2662

Pentazocine hydrochloride

Manufacturing Process A solution of 3,4-dimethylpyridine was added to a methyliodid. Then to the resulting solution containing 1,3,4-trimethylpyridinium iodide the 4methoxybenzylmagnesium chloride was added. After reaction process the 1,3,4-trimethyl-2-(4-methoxy-benzyl)-pyridine was obtained. To the solution of 1,3,4-trimethyl-2-(4-methoxy-benzyl)-pyridine was reduced by hydrogen over 10% palladium-on-charcoal, and when reduction was complete, the catalyst was removed by filtration and the filtrate taken to dryness. The residue was recrystallized to give 2-(4-methoxybenzyl)-1,3,4trimethyl-1,2,5,6-tetrahydropyridine. To the 2-(4-methoxybenzyl)-1,3,4-trimethyl-1,2,5,6-tetrahydropyridine the solution of hydrobromic acid was added and heated under reflux.The product obtained was recrystallized and yield N-methyl-1,2,3,4,5,6-hexahydro-6,11dimethyl-8-hydroxy-2,6-methano-3-benzazocine (2'-hydroxy-2,5,9trimethylbenzo-6-morphen), which then was demethylated by bromcyan (BrCN). As a result the racemic cis-1,2,3,4,5,6-hexahydro-6,11-dimethyl-8hydroxy-2,6-methano-3-benzazocine was obtained (that is a. 2'-hydroxy-5,9dimethyl-6,7-benzomorphen). A mixture of 8.7 g racemic cis-1,2,3,4,5,6-hexahydro-6,11-dimethyl-8hydroxy-2,6-methano-3-benzazocine, 6.0 g of 1-bromo-3-methyl-2-butene, 5.0 g of sodium bicarbonate, and 125 ml of N,N-dimethylformamide was stirred and refluxed for approximately 4.5 hours. The reaction mixture was then filtered, and the solid on the filter was washed with ethanol. The filtrate and the wash liquor were combined, concentrated under reduced pressure, and then extracted with chloroform. The chloroform extract was concentrated under reduced pressure to yield a syrup which weighed 15.8 g. This syrup was dissolved in 120 ml of diethyl ether and the resulting solution was filtered to remove approximately 0.5 g of a brown amorphous solid. The filtrate was extracted with a mixture of 5 ml of concentrated hydrochloric acid and 20 ml of water. To the extract there was added 5 ml of concentrated ammonium hydroxide solution and ice. A pale tan syrup separated from solution and after stirring, this syrup solidified. The resulting pale tan solid was collected and dried; it weighed 10.6 g. After two recrystallizations from a mixture of methyl alcohol and water, with charcoaling, the 1,2,3,4,5,6-hexahydro-3-(3-methyl-2butenyl)-6,11-dimethyl-8-hydroxy-2,6-methano-3-benzazocine weighed 8.2 g and melted at 145°-147°C. The1,2,3,4,5,6-hexahydro-3-(3-methyl-2-butenyl)-6,11-dimethyl-8-hydroxy2,6-methano-3-benzazocinewas soluble in a mixture of 0.35 ml of 2 N hydrochloric acid and 0.15 ml of water to the extent of 10%, the pH of the 1% solution being 2.80; and when the pH of the 1% solution was gradually raised by addition of 10 N sodium hydroxide solution, a precipitate formed at pH 5.4. The 1,2,3,4,5,6-hexahydro-3-(3-methyl-2-butenyl)-6,11-dimethyl-8hydroxy-2,6-methano-3-benzazocine hydrochloride melted at 245°-247°C, dec. References Albertson N. F.; US Patent No. 3,936,462; Feb. 3, 1976; Assigned: Sterling Drug Inc., New York, N.Y.

Pentetrazol

2663

Archer S.; US Patent No. 4,105,659; Aug. 8, 1978; Assigned: Sterling Drug Inc., New York, N.Y.

PENTETRAZOL Therapeutic Function: Analeptic, Central stimulant Chemical Name: 5H-Tetrazolo[1,5-a]azepine, 6,7,8,9-tetrahydroCommon Name: Corazol; Leptazol; Pentamethylentetrazol; Pentetrazol; Pentylenetetrazol Structural Formula:

Chemical Abstracts Registry No.: 54-95-5 Trade Name Pentylenetetrazole Angioton Cardiamine Cardional Cardiotonico Cardiotonicum Inocor Analeptin

Manufacturer Spectrum Chemicals and Laboratory Products, Inc. Leo Chropi Oliveira C.F. Blomberg Bengen Biotica

Country -

Year Introduced -

-

-

Raw Materials Cyclohexanone Nitric acid Sulfuric acid Manufacturing Process A solution of 9.8 g cyclohexanone and 8.6 g HNO3 in about 250 ml benzene were slowly added dropwise to 20 ml concentrate sulfuric acid in 100 ml benzene by ice cooling and stirring. After ending of a generation of N2 (0.1 moles) to a corresponding quantity of cyclohexane (0.1 moles). Acid layer was diluted with ice, and made neutral with strong alkaline to give a reaction product as oil. Then it was exrtacted with chloroform, all solvents were distilled and the residue was diluted with water. The desired 6,7,8,9tetrahydro-5H-tetrazoloazepine dropped. Yield was 7.5 g after recrystallization from ester or distillation. M.P: 65°C.

2664

Penthienate bromide

References Firma Knoll and Co. in Ludwigshafen a. Rh. und Dr. Karl Fridrich Shmidt in Heidelberg; D.R. Patent No. 427,858; July 20, 1923

PENTHIENATE BROMIDE Therapeutic Function: Anticholinergic Chemical Name: 2-[(Cyclopentylhydroxy-2-thienylacetyl)oxy]-N,N-diethyl-Nmethylethanaminium bromide Common Name: Structural Formula:

Chemical Abstracts Registry No.: 60-44-6 Trade Name Monodral Monodral

Manufacturer Winthrop Kanebo, Ltd.

Country US Japan

Year Introduced 1954 1970

Raw Materials 2-Diethylaminoethyl chloride Cyclopentyl-(α-thienyl)hydroxyacetic acid Methyl bromide Manufacturing Process An aqueous solution of 13.8 g of 2-diethylaminoethyl chloride hydrochloride was neutralized with sodium hydroxide, and the free 2-diethylaminoethyl chloride was extracted with ether. The ether extracts were dried over anhydrous magnesium sulfate, filtered, and the filtrate was added to a solution of 13.6 g of cyclopentyl-(α-thienyl)hydroxyacetic acid in 100 ml of isopropyl alcohol. The mixture was then distilled through a 25-cm Vigreauxtype column until the temperature of the vapors reached 80°C. The residual solution was refluxed overnight and then transferred to a beaker along with 350 ml of isopropyl alcohol. The crystalline hydrochloride had meanwhile separated out, and this was filtered, washed with isopropyl alcohol, ether and then dried, giving 23 g, melting point 172°C to 173.5°C. Recrystallization from 400 ml of isopropyl alcohol gave 20.3 g of 2-diethylaminoethyl

Pentifylline

2665

cyclopentyl-(α-thienyl)hydroxyacetate hydrochloride, melting at 174°C to 175°C; deep yellow-orange color with concentrated sulfuric acid. The hydrochloride may then be converted to the methobromide by reaction with methyl bromide. References Merck Index 6996 Kleeman and Engel p. 699 I.N. p. 744 Blicke, F.F.; US Patent 2,541,634; February 13, 1951; assigned to Regents of the University of Michigan

PENTIFYLLINE Therapeutic Function: Vasodilator, Diuretic Chemical Name: 1H-Purine-2,6-dione, 3,7-dihydro-1-hexyl-3,7-dimethylCommon Name: Hexyltheobromine; Pentifylline Structural Formula:

Chemical Abstracts Registry No.: 1028-33-7 Trade Name

Manufacturer

Country

Year Introduced

Pentifylline

Shanghai Lansheng Corporation

-

-

Cosaldon retard mono Aventis

-

-

1-Hexyltheobromine

Fluorochem

-

-

1-Hexyltheobromine

Trans World Chemicals, Inc.

-

Raw Materials Theobromine Theobromine sodium n-Hexyl chloride or n-hexyl bromide

2666

Pentobarbital sodium

Manufacturing Process The mixture 25 g theobromine, 38 ml 4 N sodium hydroxide, 60 ml isopropanol, and 17 g n-hexyl chloride were heated 24 hours to 100°C in autoclave. The solvent was removed and the residual alkaline solution was extracted with chloroform, water layer was acidified. Yield of 1-hexyl-3,7dimethylxanthine was 88%; MP: 82°-83°C. The product may be prepared from theobromine sodium. 20.2 g theobromine sodium, 20 n-hexyl bromide and 100 ml toluene were ground 10 hours at 100°C in a ball mill. After above written treatment 22.3 g (84.5%) 1-hexyltheobromine was prepared; MP: 84°C. References Eidebenz E., von Schuh H.G.; D.B. Patent No. 860,217; Oct. 28, 1950; Chemishe Werke Albert, Wiesbaden-Biebrich.

PENTOBARBITAL SODIUM Therapeutic Function: Hypnotic, Sedative Chemical Name: 5-Ethyl-5-(1-methylbutyl)-2,4,6-(1H,3H,5H)pyrimidinetrione monosodium salt Common Name: Structural Formula:

Chemical Abstracts Registry No.: 57-33-0; 76-74-4 (Base) Trade Name Nembutal Butylone Hypnol Mintal Nebralin Neodrom Novopentobarb Penbon

Manufacturer Abbott Hartz Stickley Tanabe Dorsey Minden Novopharm Adams

Country US Canada Canada Japan US W. Germany Canada Australia

Year Introduced 1941 -

Pentorex tartrate Trade Name Pentanca Pentogen Pentone Prodormol Repocal Sombutol Somnotol Sopental

Manufacturer Anca Paul Maney Faulding Teva Desitin Farmos M.T.C. Continental Ethicals

Country Canada Canada Australia Israel W. Germany Finland Canada S. Africa

2667

Year Introduced -

Raw Materials Sodium di-n-Butyl ethyl 1-methyl-n-butylmalonate Butanol Urea Manufacturing Process Sodium (9.6 parts) was dissolved in butanol (192 parts) and di-n-butyl ethyl 1-methyl-n-butylmalonate (62.8 parts) and urea (14.4 parts) were added to the warm solution with agitation. The mixture was then heated to reflux temperature in three quarters of an hour and maintained for 2 hours. The reaction mass was kept, water (150 parts) added, the aqueous portion separated, and the butanol layer extracted with water (3 x 50 parts). The combined aqueous extracts were then given 3 small extractions with benzene, the aqueous liquors separated, charcoaled, filtered and precipitated with concentrated hydrochloric acid (acid to congopaper). The solid was collected, washed with water, dissolved in N-sodium hydroxide and reprecipitated with carbon dioxide. On recrystallization, from aqueous alcohol, the pentobarbitone was obtained. References Merck Index 6998 Kleeman and Engel p. 700 PDR pp. 531, 872, 1989 OCDS Vol. 1 p. 268 (1977) I.N. p. 745 REM p. 1067 The Geigy Co. Ltd.; British Patent 650,354; February 21, 1951

PENTOREX TARTRATE Therapeutic Function: Anorexic Chemical Name: Benzeneethanamine, α,α,β-trimethyl-, tartrate (1:1) Common Name: Pentorex tartrate; Phenpentermine tartrate

2668

Pentorex tartrate

Structural Formula:

Chemical Abstracts Registry No.: 434-43-5 (Base); 22876-60-4 Trade Name Liprodene Modatrop

Manufacturer Anphar-Rolland Nordmark

Country -

Year Introduced -

Raw Materials 2-Phenylbutanone-3 Sodium cyanide Sulfuric acid

Methyl magnesium bromide Acetic acid

Manufacturing Process To a solution of 105.6 g of 2-phenylbutanone-3 in 110 ml ether was added dropwise a solution of methylmagnesium bromide (prepared from 19.4 g magnesium and 94.7 g methyl bromide in 400 ml of ether) for 60-90 min. Then the mixture was refluxed for 1 hour. After cooling to the mixture was added diluted sulfuric acid and then extracted with ether. Organic layer was dries with sodium sulfate. After evaporation of ether the 2-phenyl-3methylbutanol was distilled, B.P. 116-118°C/20 mm, yield 105 g, nd22 1.5152. To 25.5 g of NaCN at 10-20°C ware added dropwise under stirring 64 ml of glacial acetic acid and ten at 20°C a mixture of 70 ml concentrated sulfuric acid and 64 ml of glacial acetic acid. To the prepared mixture at 20-25°C was added dropwise 82 g of 2-phenyl-3-methylbutanol. The mixture was stirred at 45-50°C for 10-20 min and then at 75°C for 30 min. To the reaction mixture was added 750 ml of water. The acids was neutralized with sodium carbonate. Product was extracted with ether and distilled. Boiling point of (dimethylbenzylcarbinyl)formamide 173-176°C/0 mm, yield 63 g. 52.3 g of (dimethylbenzylcarbinyl)formamide, 245 ml concentrated hydrochloric acid and 196 ml of water were refluxed for 6 hours. The unreacted compounds was extracted with ether. The residuum was stirred with sodium hydroxide and extracted with ether. By distillation was obtained 48.2 g of 2-amino-2-methyl-3-phenylbutane; B.P. 109-111°C/20 mm. Hydrochloride of 2-amino-2-methyl-3-phenylbutane have melting point 164166°C. In practice it is usually used as tartrate salt.

Pentoxifylline

2669

References Brevet Special de Medicament 931,804, April 17, 1963; Assigned to Nordmak Werke Gesellschaft mit Beschraenkter Haftung, residant en Allemagne

PENTOXIFYLLINE Therapeutic Function: Vasodilator Chemical Name: 3,7-Dihydro-3,7-dimethyl-1-(5-oxohexyl)-1H-purine-2,6dione Common Name: Oxpentifylline; Vazofirin Structural Formula:

Chemical Abstracts Registry No.: 6493-05-6 Trade Name Trental Torental Trental Trental Trental Agapurin Techlon

Manufacturer Albert Roussel Hoechst Hoechn Albert Pharma Hoechst Spofa Sawai

Country W. Germany France UK Italy Japan Czechoslovakia Japan

Year Introduced 1972 1974 1975 1976 1977 -

Raw Materials 1-Bromo-5-hexanone Theobromine sodium Manufacturing Process A solution of 35.4 g of 1-bromohexanone-5 in 200 ml of ethanol was gradually mixed at the reflux temperature with vigorous stirring with 39.7 g of theobromine-sodium in 100 ml of water. After 3 hours reflux the unreacted theobromine was filtered off with suction, the filtrate was evaporated to dryness, the residue was dissolved in water and the solution was extracted with chloroform. The chloroform was distilled off and 1-(5'-oxohexyl)-3,7-

2670

Pentoxyverine citrate

dimethylxanthine was obtained as residue; after recrystallization from isopropanol, it melted at 102°C to 103°C (about 25% yield, calculated on the reacted theobromine). References Merck Index 7002 Kleeman and Engel p. 701 PDR p. 947 OCDS Vol. 2 p. 466 (1980) I.N. p. 746 Mohler, W., Reiser, M. and Popendiker, K.; US Patent 3,737,433; June 5, 1973; assigned to Chemische Werke Albert A.G. (W. Germany)

PENTOXYVERINE CITRATE Therapeutic Function: Antitussive Chemical Name: Cyclopentanecarboxylic acid, 1-phenyl-, 2-(2(diethylamino)ethoxy)ethyl ester, citrate (1:1) Common Name: Carbapentane citrate; Carbetopentane citrate; Pentoxiverini citras; Pentoxyverine citrate Structural Formula:

Chemical Abstracts Registry No.: 23142-01-0; 77-23-6 (Base) Trade Name Asthma Carbex

Manufacturer Nichiiko Etna

Country -

Raw Materials Sodium amide Sulfuric acid

Phenylacetonitrile 1,4-Dibromobutane

Year Introduced -

Peplomycin sulfate Thionyl chloride

2671

2-(2-Diethylaminoethoxy)ethanol

Manufacturing Process 1-Phenylcyclopentane carbonitrile was obtained by treatment of phenylacetonitrile with sodium amide and 1,4-dibrombutane. 1-Phenyl-1-cyclopentane carboxylic acid was produced in the result of reaction of 1-phenylcyclopentane carbonitrile with sulfuric acid. 1-Phenyl-1-cyclopentanecarbonyl chloride was obtained by treatment of 1phenyl-1-cyclopentane carboxylic acid with thionyl chloride. A mixture of 0.5 mol of 1-phenyl-1-cyclopentanecarbonyl chloride and of 0.5 mol of 2-(2-diethylaminoethoxy)ethanol (herein-after referred to as the amino alcohol) in 300 ml of toluene is heated under reflux for 20 h. The mixture is thereafter made alkaline by means of an aqueous solution of caustic soda and decanted; the toluenic layer is washed with water and concentrated in vacuo. The residue is distilled under high vacuum. After two fractional distillations, the 2-(2-diethylaminoethoxy)ethyl 1-phenylcyclopentane-carboxylate is obtained, in 85% yield. Boiling point 164°C/0.1 mm. Hg. References Morren H.; GB Patent No. 753,779; August 1, 1956 Kleemann A., Engel J.; Pharmazeutische Wirkstoffe, GeorgThieme Verlag Stuttgart. New York, 1982

PEPLOMYCIN SULFATE Therapeutic Function: Antineoplastic Chemical Name: 3-[(S)-1'-Phenylethylamino]propylaminobleomycin sulfate Common Name: Chemical Abstracts Registry No.: 68247-85-8 (Base) Trade Name Pepleo

Manufacturer Nippon Kayaku, Co.

Country Japan

Raw Materials Bleomycinic acid N-[(S)-1'-Phenylethyl]-1,3-diaminopropane Sulfuric acid

Year Introduced 1981

2672

Peplomycin sulfate

Structural Formula:

Manufacturing Process In 400 ml of dimethylformamide was dissolved 15.0 g of bleomycinic acid (copper-containing form). To the solution kept at 0°C by cooling were added 1.1 ml of N-methylmorpholine and 10.3 g of 6-chloro-1-pchlorobenzenesulfonyloxybenzotriazole (CCBT) as an activating compound. The mixture was stirred for 5 minutes at 0°C, then admixed with 5.3 g of N[(S)-1'-phenylethyl]-1,3-diaminopropane and further stirred for 1 hour. After termination of the reaction by adding 200 ml of a 25% aqueous acetic acid solution, the reaction mixture was mixed with 5 liters of cold acetone to precipitate the reaction product. The precipitate was collected by filtration, washed with acetone, and dissolved in 500 ml of distilled water. The resulting aqueous solution was immediately adjusted to pH 6.0 and poured into a column containing 2 liters of CM-Sephadex C-25 (NH4+type) packed in 0.05 M aqueous ammonium chloride solution to adsorb bleomycins. Using aqueous ammonium chloride solution, elution was performed by passing through the column 20 liters of eluent in which the concentration of ammonium chloride was continually increased from 0.05 to 1.0 M. The unreacted bleomycinic acid was found in the effluent at the ammonium chloride concentration of about 0.05 M and NK631 at the ammonium chloride concentration of about 0.45 M. Both fractions, which showed UV absorption at 292 nm;, were separately collected. The NK631-containing fraction was poured into a resin column containing 2.6 liters of Amberlite XAD-2. The column was then washed thoroughly with water and eluted with 0.01 N hydrochloric acid in methanol-water (4:1 v/v). A total

Pergolide mesylate

2673

of 2.5 liters of the blue fraction, which showed UV absorption at 292 mµ, was collected. After evaporating off the methanol from the eluent fraction, the concentrate was adjusted to pH 6.0 with Dowex 44 (OH- type, an anionexchange resin composed of a copolymer of epichlorohydrin and ammonia) and was freeze-dried to obtain 16.1 g (92% yield) of NK631 dihydrochloride (copper-containing form) in the form of blue amorphous powder. By similar treatment, 280 mg of the unreacted bleomycinic acid (coppercontaining form) were recovered. In 200 ml of distilled water was dissolved 10.0 g of the NK631 dihydrochloride (copper-containing form). The solution was poured into a column containing 600 ml of Amberlite XAD-2 packed in distilled water. The column was washed successively with 2 liters of an aqueous solution containing 5% of EDTA-Na2, 2.5 liters of a 5% aqueous sodium sulfate solution, and 630 ml of distilled water. The column was then eluted with 0.0025 N sulfuric acid in methanol-water mixture (1:1 v/v). A total of 900 ml of fractions containing a substance which showed UV absorption at 290 mµ was collected. After removal of methanol by distillation, the residual liquid was adjusted to pH 6.0 with Dowex 44 (OHtype) and freeze-dried to obtain 9.3 g (95% yield) of NK631 monosulfate (copper-free form) in the form of pale yellowish-white amorphous powder. References Merck Index 7011 DFU 6 (2) 101 (1981) DOT 17 (8) 331 (7981) Takita, T., Fujii, A., Fukuoka, T., Muraoka, Y., Yoshioka, O. and Umezawa, H.; US Patent 4,195,018; March 25, 1980; assigned to Nippon Kayaku K.K. Umezawa, H., Maeda, K., Takita, T., Nakayama, Y., Fujii, A. and Shimada, N.; US Patent 3,846,400; November 5, 1974; assigned to Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai.

PERGOLIDE MESYLATE Therapeutic Function: Dopamine agonist Chemical Name: Ergoline, 8-β-((methylthio)methyl)-6-propyl-, methanesulfonate (1:1) Common Name: Pergolide mesilate Chemical Abstracts Registry No.: 66104-23-2; 66104-22-1 (Base) Trade Name Celance Permax Nopar

Manufacturer Eli Lilly Eli Lilly Lilly

Country -

Year Introduced -

2674

Pergolide mesylate

Structural Formula:

Raw Materials 9,10-Dihydrolysergol Propionic anhydride Dimethyl disulfide Sodium hydroxide

Sodium iodide Lithium aluminum hydride Tri-n-butylphosphine

Manufacturing Process Dimethyl disulfide (73.6 ml, 0.79 mol) and tri-n-butylphosphine (79.6 ml, 0.32 mol) were added to a solution of 9,10-dihydrolysergol in (8.1 g, 0.032 mol) in the 150 ml of anhydrous DMF and were stirred at room temperature for 6 hours under a nitrogen atmosphere. Dimethyl disulfide of the reaction mixture was removed under vacuo. A solution of the residue in ethyl acetate was extracted with 3.7% HCl (aq.). The aqueous layer was basified with ammonium hydroxide to a pH of 10 and then extracted with ethyl acetate. Removal of ethyl acetate followed by a silica gel column purification eluting with 10% MeOH/CH2Cl2 gave5.5.g of D-6-methyl-8β(methylthiomethyl)ergoline (60%). A solution of D-6-methyl-8β-(methylthiomethyl)ergoline (0.4 g, 0.0014 mol) and NaI (0.63 g, 0.0042 mol) in 10 ml of propionic anhydride was refluxed for 40 hours. The reaction mixture was guenched with a 10% Na2CO3 solution and extracted by ethyl acetate. The combined organic layers were washed with a saturated brine solution, dried with magnesium sulfate and concentrated to produce oil. The oil was purified by silica gel column, eluting with 10% MeOH/CH2Cl2 to give 0.33 g of D-1,6-dipropionyl-8β(methylthiomethyl)ergoline. LiAlH4 (0.6 g, 0.0156 mol) was slowly added to a solution of D-1,6dipropionyl-8β-(methylthiomethyl)ergoline in the 20 ml anhydrous THF at 0°C under nitrogene atmosphere. The mixture was stirred at 0°C for 30 min and then at room temperature for 4 hours. The reaction was cooled to 0°C and 0.6 ml of water was slowly added. The mixture was stirred at 0°C for 10 min and 1.8 ml of 15% NaOH (aq.) and 2.5 ml of water were added respectively. The mixture was stirred for 30 min at room temperature and then filtered. Excess of the solvent was removed under reduced pressure to give 150 mg of 8β-((methylthio)methyl)-6-propyl-ergoline or pergolide (yield: 68%). Ergoline,

Perhexiline maleate

2675

8-((methylthio)methyl)-6-propyl-, monomethanesulfonate, (8β)- may be prepared by mixing of components in solution. References Wu E.S.C., Wu M.; US Patent No. 6,388,079, May 14; Assigned to Scinopharm Singapore Pte Ltd., Singapore (SG)

PERHEXILINE MALEATE Therapeutic Function: Coronary vasodilator Chemical Name: 2-(2,2-Dicyclohexylethyl)piperidine maleate Common Name: Structural Formula:

Chemical Abstracts Registry No.: 6724-53-4; 6621-47-2 (Base) Trade Name Pexid Pexid Pexid Pexid Corzepin Daprin

Manufacturer Merrell-Tourade Merrell Merrell Merrell Prodes Gerardo Ramon

Country France W. Germany Italy UK Spain Argentina

Year Introduced 1973 1974 1974 1975 -

Raw Materials Ethyl formate α-Picoline Sodium hydroxide Maleic acid

Cyclohexylmagnesium bromide Hydrogen chloride Hydrogen

2676

Periciazine

Manufacturing Process 1,1-Dicyclohexyl-2-(2'-pyridyl)ethanol hydrochloride (5 grams) was dehydrated by heating with 25 ml of concentrated hydrochloric acid at steam bath temperature for 10 minutes. 70 ml of water were added to the reaction mixture to give the crystalline hydrochloride salt. The product, 1,1dicyclohexyl-2-(2'-pyridyl)ethylene hydrochloride, was recrystallized from methanol-ethyl acetate to yield a white solid melting at 150°-151.5°C. 1,1-Dicyclohexyl-2-(2'-pyridyl)ethylene hydrochloride (15 grams) in 150 ml of ethanol was hydrogenated in the presence of platinum oxide at about 60 pounds per square inch of hydrogen pressure. The product, 1,1-dicyclohexyl2-(2'-piperidyl)ethane hydrochloride, crystallized from a mixture of methanol and methyl ethyl ketone as a white solid melting at 243° to 245.5°C. The hydrochloride salt was neutralized with 10% sodium hydroxide solution and the free base so produced was dissolved in ether. The ether solution was dried over anhydrous magnesium sulfate. Addition of an excess of maleic acid in methanol to the solution yielded the acid maleate salt which melted at 188.5°-191°C. The starting material was obtained by reacting ethyl formate with cyclohexylmagnesium bromide to give dicyclohexylcarbinol. That is oxidized to dicyclohexylketone and then reacted with α-picoline. References Merck Index 7026 Kleeman and Engel p. 703 DOT 10 (8) 299 (1974) I.N. p. 747 REM p. 854 Richardson-Merrell Inc.; British Patent 1,025,578; April 14, 1966 Horgan, S.W., Palopoli, F.P. and Schwoegler, E.J.; US Patent 4,069,222; January 17, 1978; assigned to Richardson-Merrell Inc.

PERICIAZINE Therapeutic Function: Neuroleptic Chemical Name: 10H-Phenothiazine-2-carbonitrile, 10-(3-(4hydroxypiperidino)propyl)Common Name: Periciazine; Pericyazine Chemical Abstracts Registry No.: 2622-26-6

Periciazine

2677

Structural Formula:

Trade Name Aolept Neuleptil Neuleptil Neuleptil Neuleptil Nemactil Neulactil Neuperil Neuleptil

Manufacturer Bayer Vital Rhone-Poulenc Rorer Vitoria Gerot Alkaloid Rhone-Poulenc Rorer Rhone-Poulenc Rorer Orion Aventis Pharma B.V.

Country -

Year Introduced -

Raw Materials Hydrochloric acid Sodium hydroxide

4-Hydroxypiperidine 2-Cyano-10-(3-methanesulfonyloxypropyl) phenthiazine

Manufacturing Process 2-Cyano-10-(3-methanesulfonyloxypropyl)phenthiazine and 4hydroxypiperidine in toluene were heated under reflux with stirring. The reaction mixture was allowed to cool and water was added. The resulting toluene solution layer was decanted and washed twice with water. The toluene solution was then stirred with 5% hydrochloric acid. The hydrochloride of the desired phenthiazine base precipitated in gummy condition in the aqueous layer. This was decanted and treated with sodium hydroxide (density 1.33). It was then extracted three times with ethyl acetate. The extracts were dried over sodium sulfate, filtered and concentrated in vacuum. A resinous product was obtained. This product was dissolved in a mixture of benzene and cyclohexane and chromatographed on a column containing alumina. The chromatographed product was eluted successively with mixtures of benzene and cyclohexane and then with benzene and finally with a mixture of benzene and ethyl acetate. The eluates were evaporated to yield a crude product. This product was recrystallised from aqueous ethanol (40% water) and yielded 2cyano-10-[3-(4-hydroxy-1-piperidyl)propyl]phenthiazine as white crystals. References Jacob R.M., Robert J.G.; US Patent No. 3,150,129; Sept. 22, 1964; Assigned: Rhone-Poulenc S.A., Paris, France, a corporation of France

2678

Perimethazine

PERIMETHAZINE Therapeutic Function: Tranquilizer Chemical Name: 1-[3-(2-Methoxyphenothiazin-10-yl)-2-methylpropyl]-4piperidinol Common Name: Structural Formula:

Chemical Abstracts Registry No.: 13093-88-4 Trade Name

Manufacturer

Country

Year Introduced

Leptryl

Roger Bellon

France

1970

Raw Materials 3-Methoxy-10-(3-chloro-2-methylpropyl)phenthiazine 4-Hydroxypiperidine Manufacturing Process A solution of 3-methoxy-10-(3-chloro-2-methylpropyl)phenthiazine (9.65 grams) and 4-hydroxypiperidine (6.1 grams) in xylene (10 cc) is heated under reflux for 5 hours. After cooling the mixture is diluted with ether (60 cc) and the basic compounds are extracted by agitation with water (30 cc) and 4 N hydrochloric acid (20 cc). The aqueous acid phase is made alkaline with 4 N sodium hydroxide solution (23 cc) and the liberated base is extracted with ether. The ethereal solution is washed with water (60 cc) and dried over sodium sulfate. Finally the solvent is distilled off on a water-bath. The solid residue obtained is recrystallized from a mixture (15:85) of benzene and cyclohexane and there is obtained 3-rnethoxy-10-[2-methyl-3-(4hydroxy-1-piperidyl)-propyl]-phenthiazine (5.7 grams) as a white crystalline powder, MP 137°-138°C. References Merck Index 7030 Kleeman and Engel p. 704 DOT 6 (4) 190 (1970)

Perindopril erbumine

2679

I.N. p. 748 Jacob, R.M. and Robert, J.G.; US Patent 3,075,976; January 29, 1963; assigned to Societe des Usines Chimiques Rhone-Poulenc, France

PERINDOPRIL ERBUMINE Therapeutic Function: Antihypertensive Chemical Name: 1H-Indole-2-carboxylic acid, octahydro, 1-{2-[(1ethoxycarbonyl)butyl)amino]-1-oxopropyl}-, (2S-(1(R*(R*)),2-α,3a-β,7aβ))-, compd. with 2-methyl-2-propanamine (1:1) Common Name: Perindopril erbumine Structural Formula:

Chemical Abstracts Registry No.: 107133-36-8; 82834-16-0 (Base) Trade Name Aceon Acertil Coverex Coversum Coversum Coversyl Coversyl Coversyl Perigard Perindopril Erbumine Prestarium Prexanil

Manufacturer Solvay Pharmaceuticals Inc. Les Laboratoires Servier Egis Pharmaceuticals Ltd. Les Laboratoires Servier Itherapia Servier Serdia Pharmaceuticals (India) Ltd. Paranova Oy Glenmark Pharmaceuticals Ltd. Les Laboratoires Servier

Country USA France Hungary France Germany France India

Year Introduced -

Finland India

-

France

-

Les Laboratoires Servier Servier Pharma

France France

-

Raw Materials 2-Carboxyindole Sodium hydroxide Rhodium

Sulfuric acid (+)-α-Methylbenzylamine Pyruvic acid

2680

Perindopril erbumine

Palladium on charcoal 4-Toluenesulfonic acid L-Norvaline 1-Hydroxybenzotriazole Hydrogen

Triethylamine Tin Thionyl chloride Dicyclohexylcarbodiimide

Manufacturing Process Heat 5 kg of 2-carboxyindole suspended in ethanol in the presence of sulfuric acid to boiling for 8 hours. Evaporate off take up the crystalline mass with hexane. After filtering off and drying, 5.3 kg of 2-ethoxycarbonylindole crystals are obtained. Melting point: 123°-125°C. Suspend, in a reactor, 10 kg of 2-ethoxycarbonylindoline obtained previously in 110 liters of hydrochloric ethanol. Next, add 20 kg of granulated tin. Keep stirring for approximately 2 days at room temperature. Evaporate off the ethanol, take up the residue with water and add 110 liters of toluene. Stir for approximately 20 min. Alkalify with aqueous ammonia. Separate off the aqueous phase and extract once again with 150 liters of toluene. Combine the toluene phases and wash them with water. Separate off the toluene phases, filter. Remove the water by distilling the water-toluene azeotrope. Cool and pass through a stream of anhydrous HCl gas. Cool. Evaporate down and wash with pure toluene. Weight obtained of (R,S)-2-ethoxycarbonylindoline 10.11 kg. Yield: 84%. 2.15 kg of (R,S)-2-ethoxycarbonylindoline dissolved in ethanol are saponified with 12.5 liters of sodium hydroxide with stirring for 24 hours. After washing the alkaline solution, neutralize with concentrated hydrochloric acid. After filtering off, washing and drying, 1.57 kg of white crystals of the (R,S)-2carboxyindoline are obtained. Yield: 86%. Melting point: 188°-189°C. 6.05 kg of (R,S)-2-carboxyindoline are added to a solution of 4.49 kg of (+)α-methylbenzylamine in anhydrous ethanol. A white precipitated product is obtained which, after filtering off, is digested in refluxing isopropanol. After cooling, the solid is filtered off and washed with a little isopropanol. 1 kg of the obtained salt was dissolved in 5 liters of water and neutralizing with an aqueous hydrochloric acid solution. The precipitate is filtered off, washed with water and dried and (S)-2-carboxyindoline was prepared. Place 25 kg of (S)-2-carboxyindoline, obtained previously, in 110 liters of methanol in a vessel. Keep stirred. Charge the rhodium (5% dry) catalyst into a mixer. Start up the stirring in a hydrogenator, charge the methanolic suspension of (S)-2-carboxyindoline by passing it through the mixer and rinse the assembly with water. Heat to 60°C and pressurize with hydrogen (30 bars). Filter off the catalyst on a single-plate filter. Collect the hydroalcoholic liquors in a reactor and evaporate the methanol off under vacuum. After concentrating, charge approximately 300 kg of dioxane. Heat to boiling and add water until a solution is obtained. Allow to cool. Filter off and dry. 22.3 kg of crystals of (2S,3aS,7aS)-2-carboxyoctahydroindole are obtained. Yield: 86.1%. Place 35 kg of L-norvaline in approximately 300 kg of denatured ethanol in a reactor. Introduce approximately 60 kg of thionyl chloride, slowly and gradually. After stirring for a quarter of an hour, heat to reflux for 3 hours and

Perindopril erbumine

2681

then evaporate off the ethanol under vacuum. Take up the residue with 300 liters of cyclohexane and heat to boiling. Allow to cool, filter, wash with cyclohexane and dry. 52.9 kg of ethyl L-norvalinate hydrochloride are obtained, that is a 97.6% yield. Place 45 kg of ethyl N-norvalinate hydrochloride approximately 110 liters of water in a vessel equipped with a stirrer. Alkalify, then pour 23 kg of pyruvic acid very gradually into the solution obtained previously and stir the reaction mixture for 30 min. Place an aqueous suspension of charcoal containing 5% palladium and the alkaline solution of ethyl L-norvalinate obtained previously in a hydrogenation apparatus. Hydrogenate under pressure (30 bars) at room temperature for approximately one day. Filter under vacuum and evaporate the filtrate under reduced pressure, filter off and dry. Treat the residue obtained with ethanol; remove the insoluble material, consisting of sodium chloride, by filtration and rinse it with ethanol. Combine the ethanolic solutions; evaporate off the ethanol under reduced pressure and crystallize the residue from acetonitrile 34.3 kg of N-[(S)-1-carbethoxybutyl]-(S)-alanine are obtained, that is a 63.9% yield. In a 30-liter reactor, reflux 12.5 kg of (2S,3aS,7aS)-2-carboxyperhydroindole, 50 kg of para-toluenesulfonic acid and 14.2 kg of benzyl alcohol and 38.4 kg of toluene, removing the water formed with the aid of a continuous separator. When no more water separates out, cool, filter off the precipitate of paratoluenesulfonate of the benzyl ester of (2S,3aS,7aS)-2carboxyoctahydroindole formed, and dry. Yield: 91.3%. Add approximately 3.5 kg of triethylamine to a suspension of approximately 5 kg of para-toluenesulfonate of the benzyl ester of (2S,3aS,7aS)-2carboxyoctahydroindole in approximately 60 kg of ethyl acetate, followed by approximately 6 kg of 1-hydroxybenzotriazole, approximately 7.5 kg of the N[(S)-1-carbethoxybutyl]-(S)-alanine and approximately 7.0 kg of dicyclohexylcarbodiimide. Stir, cooling slightly for approximately 3 hours, then filter off the dicyclohexylurea formed and wash the organic phase with water. The dried organic phase is evaporated to dryness and benzyl ester of (2S,3aS,7aS)-1-{2-[1-(ethoxycarbonyl)-(S)-butylamino]-(S)propionyl}octahydroindole-2-carboxylic acid was obtained. Yield: 92.3%. Dissolve, in a hydrogenator, 14 kg of benzyl ester of the (2S,3aS,7aS)-1-{2[1-(ethoxycarbonyl)-(S)-butylamino]-(S)-propionyl}octahydroindole-2carboxylic acid in cyclohexane. Add the charcoal containing 5% palladium and approximately 50 liters of water. Hydrogenate at ordinary temperature and pressure until the theoretical volume of hydrogen has been absorbed. Filter, wash the insoluble material with cyclohexane, separate off the organic phase and wash the aqueous phase again with cyclohexane. Isolate the (2S,3aS,7aS)-1-{2-[1-(ethoxycarbonyl)-(S)-butylamino]-(S)propionyl}octahydroindole-2-carboxylic acid from the aqueous phase by freeze-drying. In practice it is used combined with 2-methyl-2-propanamine. References Vincent M. et al.; US Patent No. 4,914,214; April 3, 1990; Assigned:Adir Et Cie, Neuilly-sur-Seine, France

2682

Perisoxal citrate

PERISOXAL CITRATE Therapeutic Function: Antiinflammatory, Analgesic Chemical Name: 3-(2-Piperidino-1-hydroxyethyl)-5-phenylisoxazole citrate Common Name: Structural Formula:

Chemical Abstracts Registry No.: 2055-44-9 (Base) Trade Name

Manufacturer

Country

Year Introduced

Isoxal

Shionogi

Japan

1979

Raw Materials Citric acid 3-(2-Methylthio-2-piperidinoacetyl)-5-phenylisoxazole Sodium borohydride Manufacturing Process Crude crystals of 3-(2-methylthio-2-piperidinoacetyl)-5-phenilisoxazole (1.631 g) are suspended in 20 ml of methanol without being further purified and the suspension is stirred after a portionwise addition (in about 10 minutes) of 143 mg (3.78 mmol) of sodium borohydride at room temperature for about 30 minutes. The methanol in the reaction mixture (pale yellow solution) is then removed by evaporation under reduced pressure to leave a residue which is subsequently dissolved in 30 ml of benzene. The benzene solution is shaken four times with 20 ml of 4 N hydrochloric acid each time to extract the basic substance. Each of the hydrochloric acid layers is washed once with 20 ml of benzene and combined together to be neutralized with potassium carbonate while being ice-cooled until it becomes basic (pH = 10).

Perlapine

2683

The liberated crystalline substance is extracted twice with 50 ml of dichloromethane each time. After being separated, the dichloromethane layers are combined and washed once with 30 ml of water and dried over sodium sulfate. The solvent of the layer is removed by evaporation under reduced pressure to leave a crystalline residue (72.56 mg, 53% crude yield). Recrystallization of this product from dichloromethane-ether (1:4) affords needles of 3-(2-piperidino-1-hydroxyethyl)-5-phenylisoxazole (701 mg, 51.3% as an overall yield calculated based on the starting material, melting point 104°C to 106°C. The product thus obtained may be reacted with citric acid to give the citrate. References Merck Index 7038 DFU 4 (4) 269 (1979) I.N. p. 748 Hirai, S. and Kawata, K.; US Patent 3,939,167; February 17, 1976; assigned to Shionogi and Co., Ltd.

PERLAPINE Therapeutic Function: Hypnotic Chemical Name: 6-(4-Methyl-1-piperazinyl)-11H-dibenz[b,e]azepine Common Name: 6-(4-Methyl-1-piperazinyl)morphanthridine Structural Formula:

Chemical Abstracts Registry No.: 1977-11-3 Trade Name Hypnodin Pipnodine

Manufacturer Takeda Takeda

Country Japan Japan

Year Introduced 1974 -

2684

Perlapine

Raw Materials o-Aminodiphenylmethane N-Methylpiperazine Phosphorus oxychloride

Aluminum chloride Phosgene

Manufacturing Process The 5.6-dihydro-6-oxo-morphanthridine used as a starting material is usefully obtained in the following way. 30.2 grams of o-aminodiphenylmethane are dissolved in 65 ml of absolute toluene and, while stirring and at a temperature of between 0° and -10°C, 140 ml of 20% phosgene solution in toluene are added drop by drop. By bubbling phosgene slowly through it the milky mixture is heated within 30 minutes to reflux temperature, which is maintained during some 20 minutes. While stirring vigorously, dry nitrogen is passed into the boiling reaction mixture for 10 minutes. After evaporation of the solvent there are obtained by vacuum distillation 29.7 grams (86% of the theory of o-isocyanatodiphenylmethane of boiling point 169°C/12 mm Hg. 21.1 grams of aluminum chloride are heated in 110 ml of o-dichlorobenzene to 80°C and, while stirring, a solution of 29.7 grams of oisocyanatodiphenylmethane in 60 ml of o-dichlorobenzene is added drop by drop, whereupon the temperature of the mixture rises to 120°C. This temperature is maintained for one hour while stirring. After cooling the reaction mixture is poured into 200 ml of 2 N hydrochloric acid, whereupon a brown precipitate is formed. After steam distillation the residue is isolated by filtration and crystallized from acetone/water. There are obtained 28.6 grams (97% of the theory) of 5,6-dihydro-6-oxo-morphanthridine of melting point 201°-203°C. A mixture of 4.9 grams of 5,6-dihydro-6-oxo-morphanthridine, 37 ml of phosphorus oxychloride and 1.5 ml of dimethylaniline is heated for 3 hours at reflux, The viscous oil, obtained by evaporation of the reaction mixture in vacuo at 60°C, is diluted with 20 ml of absolute dioxane and, after adding 30 nil of N-methylpiperazine, heated for 4 hours at reflux. The resulting clear solution is evaporated in vacuo at 60°C to dryness. The residue is distributed between ether and ammonia water. The ethereal solution is separated, washed with water and then extracted with 1 N acetic acid. The acetic acid extract is mixed with ammonia water and then extracted with ether. The ethereal solution is washed with water, dried over sodium sulfate, filtered through alumina and evaporated. The residue is caused to crystallize from ether/petroleum ether, and recrystallized from acetone/petroleum ether. 6.0 grams (88% of the theory) of 6-(4-methyl-1-piperazinyl)-morphanthridine of melting point 138°-138.5°C are obtained. References Merck Index 7040 Kleeman and Engel p. 705 OCDS Vol. 2 p. 425 (1980) DOT 11 (2) 76 (1975) I.N. p. 748

Perphenazine

2685

Schmutz, J., Hunziker, F. and Kunzle, F.M.; US Patent 3,389,139; June 18, 1968; assigned to Dr. A. Wander, SA, Switzerland

PERPHENAZINE Therapeutic Function: Tranquilizer Chemical Name: 4-[3-(2-Chlorophenothiazin-10-yl)propyl]-1piperazineethanol Common Name: Chlorpiprazine Structural Formula:

Chemical Abstracts Registry No.: 58-39-9 Trade Name Trilafon Decentan Etrafon Fentazin F-Mon Peratsin Perfenil Perphenan Phenazine Triavil Trilifan Triomin

Manufacturer Schering Merck Schering Allen and Hanburys Nippon Shinyaku Farmos Scalari Taro I.C.N. MSD Cetrane Yamanouchi

Country US W. Germany US UK Japan Finland Italy Israel Canada US France Japan

Year Introduced 1957 -

Raw Materials 2-Bromoethanol Piperazine

1-Bromo-3-chloropropane 2-Chlorophenothiazine

Manufacturing Process A mixture of 155 parts of 2-chloro-10-(γ-chloropropyl)phenothiazine, 76 parts

2686

Peruvoside

of sodium iodide, 216 parts of piperazine and 2,000 parts of butanone is refluxed for 8 hours, concentrated and extracted with dilute hydrochloric acid. The extract is rendered alkaline by addition of dilute potassium carbonate and benzene or chloroform extracted. This extract is washed with water, dried over anhydrous potassium carbonate, filtered and evaporated. Vacuum distillation at 0.1 mm pressure yields 2-chloro-10-[γ-(N-piperazino)propyl]phenothiazine at about 214°-218°C. A stirred mixture of 5 parts of 2-chloro-10-[γ-(Npiperazino)propyl]phenothiazine, 1.92 parts of 2-bromoethanol, 2.11 parts of potassium carbonate and 35 parts of toluene is refluxed for 5 hours. The mixture is treated with water and benzene and the organic layer is separated, washed with water, dried over anhydrous potassium carbonate, filtered and evaporated. The residue is distilled at about 240°-244°C and 0.15 mm pressure to yield 2-chloro-10-[γ-(N'-β-hydroxyethyl-N-piperazino)propyl]phenothiazine according to US Patent 2,838,507. The 2-chloro-10-(γ-chloropropyl)phenothiazine starting material is produced from 2-chlorophenothiazine and 1-bromo-3-chloropropane. References Merck Index 7044 Kleeman and Engel p. 705 PDR pp. 1217, 1617, 1655 OCDS Vol. 1 p. 383 (1977) DOT 9 (6) 228 (1973) I.N. p. 749 REM p. 1090 Cusie, J.W. and Hamilton, R.W.; US Patent 2,838,507; June 10, 1958; assigned to G.D. Searle and Co. Sherlock, M.H. and Sperber, N.; US Patent 2,860,138; November 11, 1958; assigned to Schering Corporation

PERUVOSIDE Therapeutic Function: Cardiotonic Chemical Name: Card-20(22)-enolide, 3-((6-deoxy-3-O-methyl-α-Lglucopyranosyl)oxy)-14-hydroxy-19-oxo-, (3β,5β)Common Name: Peruvoside Chemical Abstracts Registry No.: 1182-87-2 Trade Name

Manufacturer

Country

Year Introduced

Peruvoside

Indena

-

-

Peruvoside

ZYF Pharm Chemical

-

-

Peruvoside

2687

Structural Formula:

Raw Materials Fruits or seeds of ApocynaceaThevetia peruviana Column of silica gel Manufacturing Process Peruvoside is obtained employing the fruit or seeds of ApocynaceaThevetia peruviana by the fermentation and the separation the extracted glucoside mixture by chromatography. Two kilograms of the ground fruit of ApocynaceaThevetia peruviana is mixed with 100 g of grain chaff and moistened with 900 ml of hot water (approximately 60°C). The mixture is mixed with 20 ml of toluene and maintained at 45°-55°C in a closed vessel for 5 days. The thus fermented material is extracted six times with 1200 ml portions of acetone. The combined extracts are concentrated at 30°C under reduced pressure, until there remains about 600 ml of a dark colored aqueous concentrate. The latter is shaken out with an equal volume of petroleum ether. The organic phase is discarded after recovering the petroleum ether. The thus degreased aqueous concentrate is extracted six times with 500 ml portions of dichloromethane. The dichloromethane extracts are dried over sodium sulfate, combined, and concentrated to about 100 ml. Then the residue is stirred into 250 ml of petroleum ether. After standing overnight, the thus-separated crystallized product is vacuum-filtered, washed petroleum ether and dried at about 40°C. The thus obtained crude glycoside mixture (21 g) is dissolved in a mixture of chloroform/methanol and chromatographed on a column of silica gel. There is thus isolated a small amount of oil and fat, a total of 15.5 g of cerberine, acetylperuvoside and neriifolin, 2.2 g of pure peruvoside, MP: 160°-163°C; [α]22d=70° (c = 1.3 in CH3OH), corresponding to a yield 0.11%, based on the quantity of fruit of Thevetia peruviana employed as the starting material. One kilogram of ground seeds of Thevetia peruviana is mixed with 300 g of grain chaff and moistened with 500 ml of hot water (60°C). After addition of 10 ml of toluene the mixture is allowed to stand in a sealed vessel for 5 days at 45°-55°C. Thereafter, the moist drug material is extracted six times with

2688

Phanquinone

500 ml portions of methanol. The extracts are concentrated at about 30°C to about 300 ml. Without degreasing, glycosides are extracted from this aqueous concentrate with three 300 ml portions followed by three 100 ml portions of chloroform. The chloroform extracts are concentrated at about 40°C to a volume of about 200 ml. This concentrate is then mixed with 500 ml of petroleum ether. After standing overnight, the crystallized product, which separated, is vacuum-filtered, washed with petroleum ether, and dried at 40°C. Yield of rude glycoside: 46.9 g. From this product, after the usual separation by chromatography, 5.1 g of pure peruvoside is obtained, MP: 161°-164°C. Yield 0.51%, based on the weight of the non-degreased seeds of Thevetia peruviana. References Balsam et al.; US Patent No. 3,713,980; Jan. 30, 1973; Assigned to Merck Patent Gesellshaft mit beschrankter Haftung, Darmstadt, Germany

PHANQUINONE Therapeutic Function: Antiamebic Chemical Name: 4,7-Phenanthroline-5,6-quinone Common Name: Fanquinonum; Phanchinonum; Phanquinone; Phanquone Structural Formula:

Chemical Abstracts Registry No.: 84-12-8 Trade Name Phanquinone Phanquinone

Manufacturer Yick-Vic Chemicals and Pharmaceuticals (HK) Ltd. ZYF Pharm Chemical

Raw Materials Sulfuric acid 6-Methoxy-4:7-phenanthroline Nitric acid Caustic soda

Country -

Year Introduced -

-

-

Phenacaine

2689

Manufacturing Process 2 parts of 6-methoxy-4:7-phenanthroline are mixed with 10 parts by volume of concentrated sulfuric acid and while cooling with a mixture of ice and sodium chloride, with 6 parts by volume of fuming nitric acid (density = 1.51), and the whole is heated for 2 h at 120°C. The reaction solution is poured on to ice, its pH value is adjusted to 7 by means of a 10 N solution of caustic soda, after standing for 2 h the whole is filtered with suction to remove the precipitate which separates, and the latter is washed with hot water. After recrystallising the product from methyl alcohol and drying it at 100°C under 0.1 mm pressure, there are obtained 1.8 parts (i.e. 90 % of the calculated yield) of 4:7-phenanthroline-5:6-quinone in the form of pale yellow crystals melting at 295°C. References GB Patent No. 688,802; March 11, 1953; Assigned: CIBA Limited, a body corporate, Basle, Switzerland

PHENACAINE Therapeutic Function: Local anesthetic Chemical Name: Ethanimidamide, N,N'-bis(4-ethoxyphenyl)Common Name: Fenacaine; Phenacaine; Tanicaine Structural Formula:

Chemical Abstracts Registry No.: 101-93-9 Trade Name

Manufacturer

Country

Year Introduced

Phenacaine

ZYF Pharm Chemical

-

-

Raw Materials Hydrogen chloride Phenacetin (4-ethoxyacetanilide) Manufacturing Process Phenacetin (4-ethoxyacetanilide) was treated with slowly current of gaseous

2690

Phenacetin

hydrogen chloride for 15 hours at 150°C. On cooling the product was poured into 20 volumes of water and heated. Then it was cooled to room temperature, filtered off and excess of alkali was added. The precipitated crude product was at first re-crystallized from 60% ethanol, then from benzene-ligroin to give pure acetamidine as a white needles; MP: 121°C. References Tauber E.; D.R. Patent No. 79,868; March 16, 1894

PHENACETIN Therapeutic Function: Analgesic Chemical Name: Acetamide, N-(4-ethoxyphenyl)Common Name: Acetophenetidin Structural Formula:

Chemical Abstracts Registry No.: 62-44-2 Trade Name Phenacetin

Manufacturer Environmental Health and Safety

Country -

Year Introduced -

Raw Materials 4-Ethoxyaniline Acetic anhydride Sodium hydrosulfite Manufacturing Process A mixture of 10 g of 4-ethoxyaniline and 8.6 g of acetic anhydride in 28 g of dry benzene was refluxed for 4 hours. To the reaction mixture was added a small amount of Na2S2O4. After cooling the phenacetin was crystallized; yield 12.5 g (96%), M.P. 136°C. References Merck Index, Monograph number: 7344, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc.

Phenactropinium chloride

2691

Friedlander, Berichte, 1893, 25, 178 Lumiere A., 1906, [3], 33, 785

PHENACTROPINIUM CHLORIDE Therapeutic Function: Antihypertensive Chemical Name: α-Hydroxybenzeneacetic acid 8-methyl-8-[(2-oxo-2phenyl)-ethyl]-8-azoniabicyclo[3.2.1]-oct-3-yl ester chloride Common Name: Structural Formula:

Chemical Abstracts Registry No.: 3784-89-2 Trade Name Trophenium Trophenium

Manufacturer American Cyanamid (AHP) Duncan Flockhart

Country US UK

Year Introduced 1961 -

Raw Materials Homatropine Phenacyl chloride Manufacturing Process 330 g (1.2 M) of homatropine were dissolved in 1 liter of dry methyl ethyl ketone and gently refluxed on a water-bath during the gradual addition of a solution of 204 g (1.32 M) redistilled phenacyl chloride in 200 ml of the same solvent. After 10 to 15 minutes 1 g of previously prepared homatropine phenacyl chloride was added to avoid formation of a supersaturated solution of the quaternary compound. Reflux was continued for 9 hours, then the thick suspension was allowed to cool, filtered and washed with 200 ml methyl ethyl ketone to yield 490 g (95%) slightly creamy solid, MP 188°C to 191°C. For purification the crude quaternary salt was dissolved in hot ethyl alcohol (2 ml/g) and warm dry acetone (8 ml/g) was stirred into the clear filtrate. On cooling, 387 g (78 % recovery) of a pure white powder, MP 195°C to 197°C, were obtained, in which the ionizable chlorine assayed at 99.7% of the theoretical value.

2692

Phenaglycodol

References Merck Index 7067 I.N. p. 752 Johnston, R.G. and Spencer, K.E.V.; US Patent 2,828,312; March 25, 1958; assigned to T. and H. Smith, Ltd. (UK)

PHENAGLYCODOL Therapeutic Function: Tranquilizer Chemical Name: 2-(4-Chlorophenyl)-3-methyl-2,3-butanediol Common Name: Structural Formula:

Chemical Abstracts Registry No.: 79-93-6 Trade Name Ultran Felixyn

Manufacturer Lilly Radiumpharma

Country US Italy

Year Introduced 1975 -

Raw Materials Sodium cyanide Hydrogen chloride Ethanol Magnesium

p-Chloroacetophenone Sodium hydroxide Methyl iodide

Manufacturing Process To a mixture of 460 g of p-chloroacetophenone, 350 ml of ether and 500 ml of water are added 410 g of sodium cyanide, with vigorous stirring. The reaction mixture is cooled to about 5°C to 10°C and 700 ml of concentrated hydrochloric acid are added at such a rate that no hydrogen cyanide is formed and the temperature of the mixture does not rise above 10°C. After the addition of the acid is complete, the reaction mixture is stirred for about three hours at room temperature, and allowed to separate into an aqueous and an organic phase. The organic phase is removed from the aqueous phase, and the aqueous phase and any salt which may have separated in the course of the reaction are washed with about 300 ml of ether. The combined ether washings and organic phase are dried over anhydrous magnesium sulfate, and

Phenaglycodol

2693

the ether is removed by evaporation in vacuo at room temperature. The residue is poured with stirring into 800 ml of concentrated hydrochloric acid kept at about 0°C by cooling with solid carbon dioxide. The acid mixture is saturated with gaseous hydrogen chloride at 0°C, and stirred at room temperature overnight. The resulting precipitate of p-chloroatrolactamide is removed by filtration, washed by slurrying with water and dried. After recrystallization from ethanol, p-chloroatrolactamide melts at about 105°C to 107°C. A mixture of 200 g of p-chloroatrolactamide and 1 liter of 25% sodium hydroxide solution is refluxed with stirring for about sixteen hours. The reaction mixture is then poured over cracked ice and diluted with water to a volume of about 3 liters. The aqueous solution is washed with two 1 liter portions of ether, and acidified with concentrated hydrochloric acid, whereupon a precipitate of p-chloroatrolactic acid forms. The precipitated acid is removed by filtration, and is dissolved in 500 ml of ether, washed with two 250 ml portions of water and dried. The ether is removed by evaporation. pchloroatrolactic acid thus prepared melts at about 117°C to 120°C. A mixture of 185 g of p-chloroatrolactic acid, 600 ml of ethanol and 60 ml of concentrated sulfuric acid is refluxed for about twelve hours. About half the solvent is then removed by evaporation in vacuo at room temperature, the residue is poured over cracked ice, and diluted with water to a volume of about 2 liters. The ethyl p-chloroatrolactate formed in the reaction is extracted with two 1 liter portions of ether. The combined ether extracts are washed with successive 200 ml portions of water, 5% sodium carbonate solution, and water, and are dried over anhydrous magnesium sulfate. The dried ether solution is subjected to fractional distillation, and the fraction boiling at about 90°C to 100°C at a pressure of 0.1 mm of mercury, is collected. The distillate consists of ethyl p-chloroatrolactate. To a solution of 2 mols of methylmagnesium iodide in 1.5 liters of ether are added with vigorous stirring 107 g (0.5 mol) of ethyl p-chloroatrolactate. The reaction mixture is stirred for about sixteen hours, and is then decomposed by the addition of about 320 ml of saturated aqueous ammonium chloride solution. After standing, the ether layer is decanted from the mixture and the aqueous phase and the precipitated salts are washed with several 500 ml portions of ether. The combined ether solution and washings are washed with successive 500 ml portions of 5% ammonium chloride solution and water, are dried over anhydrous magnesium sulfate, and are evaporated to dryness in vacuo. The crystalline residue consisting of 2-p-chlorophenyl-3-methyl-2,3butanediol, is recrystallized from a mixture of benzene and petroleum ether. 2-p-chlorophenyl-3-methyl-2,3-butanediol thus prepared melts at about 66°C to 67°C. References Merck Index 7070 Kleeman and Engel p. 709 OCDS Vol. 1 p. 219 (1977) I.N. p. 752 Mills, J.; US Patent 2,812,363; November 5, 1957; assigned to Eli Lilly and Co.

2694

Phenazocine

PHENAZOCINE Therapeutic Function: Narcotic analgesic Chemical Name: 2,6-Methano-3-benzazocin-8-ol, 1,2,3,4,5,6-hexahydro6,11-dimethyl-3-(2-phenylethyl)Common Name: Fenatsokin; Phenazocine; Phenobenzorphan; Xenagol Structural Formula:

Chemical Abstracts Registry No.: 127-35-5 Trade Name Phenazocine

Manufacturer SmithKline French (GSK)

Country -

Year Introduced -

Raw Materials 3,4-Lutidine Lithium aluminum hydride Methyl iodide Palladium on barium Hydrobromic acid Acetic anhydride Ethereal solution of p-methoxybenzylmagnesium chloride Manufacturing Process 25.0 g 3,4-lutidine methyl iodide in 60 ml of dry ethyl ether is stirred while 400 ml of a 0.3958 N ethereal solution of p-methoxybenzylmagnesium chloride is added at room temperature. The mixture is stirred for 30 minutes and then decomposed with a solution of 100 ml of water containing 25 g of ammonium chloride and 10 ml of concentrated ammonium hydroxide. The layers are separated. The organic layer is extracted with a solution of 75 ml of water and 17 ml of concentrated hydrochloric acid. The extracts are neutralized and taken into ether. The volatiles are evaporated to leave a light yellow oil, the dehydro base. The oily residue is then hydrogenated at 17 p.s.i. of hydrogen with 5% palladium-on-barium sulfate in 100 ml of 2 N hydrochloric acid for six hours. The reaction mixture is filtered, made alkaline and taken through ether to give the tetrahydro base as a clear oil. The oily tetrahydro base (about 10.0 g) in 150 ml of 48% hydrobromic acid is heated at 135°C for 24 hours, and then quenched in an ice Treating with base

Phenazopyridine hydrochloride

2695

and taking through chloroform gives a brown residue of the isomeric mixture of 2'-hydroxy-2,5,9-trimethyl-6,7-benzmorphan. This residue is triturated with ether, cooled and the resulting slurry filtered. The solid product is dissolved in a minimum of dry ethanol and made acid with ethereal hydrogen chloride. The cooled mixture is filtered to give the hydrochloride salt of the N-methyl-iso-benzmorphan, MP: 279-282°C, after recrystallization from ethanol. The base melts at 215°C. The ethereal filtrate is evaporated. A residue is neutralized to give the crude normal N-methyl-benzmorphan isomer, MP: 229-230°C. The hydrochloride salt of this isomer is formed, MP: 196-198°C, as a hydrate. A mixture of 10.0 g of the N-methyl-iso-benzmorphan isolated above in 15 ml of acetic anhydride is heated on the steam bath for about an hour, then quenched in an ice slurry. The mixture is then neutraliized and taken through ether to give the O-acetate derivative, iso-2'-acetoxy-2,5,9-trimethyl-6,7-benzomorphan. The crude acetate (9.5 g) is reacted with 5.0 g of cyanogen bromide in 100 ml of chloroform at reflux for several hours. The volatiles are removed in vacuo to leave a residue, which is refluxed in 150 ml of dilute hydrochloric acid for 24 hours. The mixture is cooled, neutralized and taken through chloroform to give the desired base with two methyl groups as a viscous syrup which crystallized slowly, MP: 173-175°C from methanol. The base, 6.5 g, is reacted with 5.0 g of phenylacetyl chloride in the presence of an excess of sodium carbonate in water. The mixture is stirred for several hours, diluted with water and taken into ether to give the N-phenacetylated compound. This compound in ether (250 ml) is reacted with an excess of 1.5 M ethereal lithium aluminum hydride at reflux overnight. The reaction mixture is evaporated to dryness, after quenching carefully with water and hydrobromic acid, to give the crude 2'-hydroxy-5,9-dimethyl-2-phenethyl-6,7-benzomorphan hydrobromide salt which is optionally recrystallized from ethanol, MP: 272273°C. The hydrobromide salt in the normal series melts at 170-173°C. The base is isolated by neutralizing of the hydrobromide salt in an ether alkali mixture, with following separating and evaporating the organic solvent. References Gordon M. et al.; US Patent No. 2,959,594; November 8, 1960; Assigned to Smith Kline and French Laboratories, Philadelphia, Pa., a corporation of Pennsylvania

PHENAZOPYRIDINE HYDROCHLORIDE Therapeutic Function: Urinary analgesic, Antiseptic, Diagnostic aid Chemical Name: 2,6-Pyridinediamine, 3-(phenylazo)-, monohydrochloride Common Name: Phenazopyridine hydrochloride; Azopirin Chemical Abstracts Registry No.: 94-78-0 (Base); 136-40-3

2696

Phenazopyridine hydrochloride

Structural Formula:

Trade Name Phenazopyridine Hydrochloride Azopirin Cystamine Phenazopyridine Hydrochloride Phenazopyridine Hydrochloride Prodium Sedural Urisept Urophenyl Urologin

Manufacturer AroKor Holdings Inc.

Country -

Year Introduced -

Barcymex Mc-Clung Xi'an Boojie Pharmaceutical and Chemical Technology Co., Ltd. Azide Chemical Co., Ltd.

-

-

-

-

Breckenridge Teva Kahira Nadeau Delta

-

-

Raw Materials Phenyldiazene 2,6-Diaminopyridine Manufacturing Process Phenyldiazene chloride reacted with 2,6-diaminopyridine and in the result 2,6diamino-3-(phenylazo)pyridine was obtained. In practice it is usually used as monohydrochloride. References Kleemann A., Engel J.; Pharmazeutische Wirkstoffe, GeorgThieme Verlag Stuttgart. New York, 1982

Phendimetrazine tartrate

2697

PHENDIMETRAZINE TARTRATE Therapeutic Function: Antiobesity Chemical Name: 3,4-Dimethyl-2-phenylmorpholine bitartrate Common Name: 3,4-Dimethyl-2-phenyltetrahydro-1,4-oxazine bitartrate Structural Formula:

Chemical Abstracts Registry No.: 50-58-8; 634-03-7 (Base) Trade Name Plegine Statobex Bacarate Prelu-2 Sprx 105 Obezine X-Trozine Hyrex-105 Adipost Slyn-LL Trimcaps Adipo II Adphen Amphasub Anoxine T Arcotrol Bacarate Bontril Di-Ap-Trol Dyrexan Ephemet Fringanor Melfiat Neo-Nilorex

Manufacturer Ayerst Lemmon Tutag Boehringer Ingelheim Tutag Western Research Rexar Hyrex Ascher Edwards Mayrand Sig Ferndale Palmedico Winston Pharm. Arco Reid-Provident Carnrick Foy Trimen Canright Sobio Reid-Rowell A.V.P.

Country US US US US US US US US US US US US US US US US US US US US US France US US

Year Introduced 1961 1972 1972 1980 1980 1981 1981 1983 1983 1983 1983 -

2698

Phendimetrazine tartrate

Trade Name Obe-Del Obepar Obesan Obex-LA Pan-Rexin Phenazine Reducto Reton Stodex Symetra Trimstat Wehless Weightrol X-Trozine

Manufacturer Marlop Parmed SCS Pharmalab Rio Ethicals Pan American Jenkins Arcum Tri-State Jalco Westerfield Laser Hauck N. Amer. Pharm. Rexar

Country US US S. Africa S. Africa US US US US US US US US US US

Year Introduced -

Raw Materials Propiophenone 2-Methylaminomethanol

Bromine Formic acid

Manufacturing Process A mixture of 61 grams 1-phenyl-1-oxo-2-(N-methyl-N-ethanolamino)-propane hydrochloride and 100 cc 98-100% formic acid was refluxed at the boiling point at atmospheric pressure for 45 minutes on an oil bath. Thereafter, the oil bath temperature was increased to 180°C and as much of the excess unreacted formic acid as possible was distilled off. A vigorous evolution of carbon dioxide developed during the distillation, which ceased after approximately 45 additional minutes. The honey-yellow syrup which remained as the distillation residue was worked up by admixing it with about six volumes of water and adjusting the aqueous mixture to alkaline reaction with concentrated sodium hydroxide. An oily phase separated out which was extracted with ether. The ether extract was washed with water and dried over potassium carbonate. The solvent was distilled off and the distillation residue was fractionally distilled in vacuo. The base boils at 132°-133°C at 12 mm. The yield was 93% of theory. Reaction with tartaric acid gave the final product. The starting material is produced by reacting propiophenone with bromine and then reacting the α-bromopropiophenone produced with 2methylaminomethanol. References Merck Index 7088 Kleeman and Engel p. 711 PDR pp. 633, 679, 778, 928, 948, 992, 1448, 1450, 1807 OCDS Vol. 1 p. 260 (1977) and 2, 261 (1980) I.N. p. 754 REM p. 892

Phenelzine sulfate

2699

Heel, W. and Zeile, K.; US Patent 2,997,469; August 22, 1961; assigned to C.H. Boehringer Sohn, Germany

PHENELZINE SULFATE Therapeutic Function: Psychostimulant Chemical Name: (2-Phenethyl)hydrazine sulfate Common Name: Structural Formula:

Chemical Abstracts Registry No.: 156-51-4; 51-71-8 (Base) Trade Name Nardil Nardelzine

Manufacturer Parke Davis Substantia

Country US France

Year Introduced 1959 -

Raw Materials Phenethyl bromide Hydrazine hydrate Manufacturing Process To a refluxing solution containing 147.5 grams of 85% hydrazine hydrate in 500 cc of ethanol was added, during a period of 5 hours, 92.5 grams of phenethylbromide (0.50 mol) in 150 cc of ethanol. Stirring and refluxing were continued for two hours. The ethanol was removed by distillation and the residue extracted repeatedly with ether. The ether was dried with potassium carbonate and the product base collected by distillation, BP 74°C/0.1 mm, yield 52.3 grams (77%). The base is reacted with sulfuric acid in propanol to give the sulfate. References Merck Index 7089 Kleeman and Engel p. 711

2700

Phenethicillin potassium

PDR p. 1368 OCDS Vol. 1 p. 74 (1977) I.N. p. 754 REM p. 1096 Biel, J.H.; US Patent 3,000,903; September 19, 1961; assigned to Lakeside Laboratories, Inc.

PHENETHICILLIN POTASSIUM Therapeutic Function: Antibacterial Chemical Name: 3,3-Dimethyl-7-oxo-6-[(1-oxo-2-phenoxypropyl)amino]-4thia-1-azabicycyclo[3.2.0]heptane-2-carboxylic acid potassium salt Common Name: Penicillin MY Structural Formula:

Chemical Abstracts Registry No.: 132-93-4; 147-55-7 (Base) Trade Name Syncillin Ro-Cillin Chemiphen Semopen Dramcillin-S Maxipen Darcil Alpen Altocillin Bendralan Broxil Metilpen Optipen Pen-200 Peniplus Penopen Penorale Synthecilline Synthepen

Manufacturer Bristol Rowell Squibb Massengill White Roerig Wyeth Schering Caber Antibioticos Beecham Boniscontro-Gazzone C.S.L. Pfizer Fumouze Pliva Lusofarmaco Bristol Meiji

Country US US US US US US US US Italy Spain UK Italy Australia W. Germany France Yugoslavia Italy France Japan

Year Introduced 1959 1960 1960 1960 1960 1960 1960 1960 -

Phenformin

2701

Raw Materials α-Phenoxypropionic acid Isobutyl chloroformate 6-Aminopenicillanic acid Potassium 2-ethylhexanoate Manufacturing Process Triethylamine (1.5 ml) was added to a cold solution (10°C) of αphenoxypropionic acid (1.66 g, 0.01 mol) in 15 ml of pure dioxane, with stirring and cooling to 5°C to 10°C while isobutyl chloroformate (1.36 g, 0.01 mol) in 5 ml of dioxane was added dropwise. Then the mixture was stirred for ten minutes at 5°C to 8°C. A solution of 6-amino-penicillanic acid (2.16 g, 0.01 mol) in 15 ml of water and 2 ml of triethylamine was then added dropwise while the temperature was maintained below 10°C. The resulting mixture was stirred in the cold for 15 minutes then at room temperature for 30 minutes, diluted with 30 ml of cold water and extracted with ether which was discarded. The cold aqueous solution was then covered with 75 ml of ether and acidified to pH 2 with 5 N H2SO4. After shaking, the ether layer containing the product 6-(α-phenoxypropionamido)penicillanic acid, was dried for ten minutes over anhydrous sodium sulfate and filtered. Addition of 6 ml of dry n-butanol containing 0.373 g/ml of potassium 2-ethylhexanoate precipitated the potassium salt of the product as a colorless oil which crystallized on stirring and scratching and was collected, dried in vacuo and found to weigh 2.75 g, to melt at 217°C to 219°C. References Merck Index 7093 Kleeman and Engel p. 712 OCDS Vol. 1 p. 410 (1977) I.N. p. 755 Beecham Research Laboratories, Ltd.; British Patent 877,120; September 13, 1961

PHENFORMIN Therapeutic Function: Antidiabetic Chemical Name: N-(2-Phenylethyl)imidodicarbonimidic diamide Common Name: Phenethyldiguanide Chemical Abstracts Registry No.: 114-86-3 Raw Materials β-Phenylethylamine Dicyandiamide

Hydrogen chloride

2702

Phenformin

Structural Formula:

Trade Name DBI Meltrol Adiabetin Antipond Cronoformin De Be J Debeone Diabis Dibein Dibophen Insoral Kataglicina Prontoformin

Manufacturer Geigy U.S.V. Pharm. Arcana Arcana Guidotti Isa U.S.V. Funk Pharmacia Polfa U.S.V. Marxer Guidotti

Country US US Austria Austria Italy Brazil US Spain Sweden Poland US Italy Italy

Year Introduced 1959 1971 -

Manufacturing Process 15.76 g of β-phenylethylamine hydrochloride and 8.4 g of dicyandiamide were ground and intimately mixed. The mixture was heated in an oil bath in a 3neck flask fitted with a thermometer and stirrer, and the mixture began to melt at a bath temperature of 125°C and was completely fluid at 130°C. Further heating at 145°C to 150°C initiated an exothermic reaction and the temperature of the fusion mixture (156°C) exceeded the oil bath temperature (150°C) by 6°. Heating was continued for one hour at bath temperature of 148°C to 150°C. The reaction mixture was cooled, dissolved in about 100 cc of methanol and filtered. The methanol filtrate was concentrated under reduced pressure, cooled and the product (β-phenylethylbiguanide hydrochloride) filtered off and recrystallized from 95% isopropanol. References Merck Index 7099 OCDS Vol. 1 p. 75 (1977) I.N. p. 755 Shapiro, S.L. and Freedman, L.; US Patent 2,961,377; November 22, 1960; assigned to US Vitamin and Pharmaceutical Corp.

Phenglutarimide hydrochloride

2703

PHENGLUTARIMIDE HYDROCHLORIDE Therapeutic Function: Anticholinergic, Antiparkinsonian Chemical Name: Glutarimide, 2-(2-(diethylamino)ethyl)-2-phenyl-, hydrochloride Common Name: Phenglutarimide hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 1674-96-0; 1156-05-4 (Base) Trade Name

Manufacturer

Country

Year Introduced

Ciba 10870

Ciba Pharmaceutical Products, Inc.

-

-

Raw Materials Acetic acid Acetic anhydride Sulfuric acid Hydrochloric acid Potassium salt of 2-phenyl-2-(β-diethylaminoethyl)-pentane-1,5-diacid mononitrile Manufacturing Process 350 parts by weight of the potassium salt of 2-phenyl-2-(βdiethylaminoethyl)-pentane-1,5-diacid mononitrile are dissolved with heating in 700 parts by volume of glacial acetic acid, 850 parts by volume of acetic anhydride are added, and then 250 parts by volume of concentrated sulfuric acid introduced portionwise. The temperature of the reaction mixture in this operation rises to 120-130°C. When the reaction subsides, the whole is finally maintained for a further 15 min on the boiling water bath. The solvent is removed on the water bath under reduced pressure, the residue poured onto ice and caustic soda solution, and the whole extracted with chloroform. The chloroform solution washed with water, dried over potassium carbonate and the solvent evaporated. The crystalline residue, consisting of 3-phenyl-3-(βdiethylaminoethyl)-2,6-dioxopiperidine. After recrystallization from a mixture of ethyl acetate and ligroin, melts at 118-120°C. The hydrochloride (produced by dissolving the base in ethyl acetate and adding an equivalent quantity of hydrochloric acid gas dissolved in ethyl

2704

Phenindamine tartrate

acetate) melts, after recrystallization from a mixture of methyl alcohol and ethyl acetate, at 168-172°C. References Hoffmann K., Tadmann E.; US Patent No. 2,664,424; Dec. 29, 1953; Assigned to Ciba Pharmaceutical Products, Inc., Summit, N.J.

PHENINDAMINE TARTRATE Therapeutic Function: Antihistaminic Chemical Name: 2,3,4,9-Tetrahydro-2-methyl-9-phenyl-1Hindeno[2,1,c]pyridine tartrate Common Name: 2-Methyl-9-phenyl-2,3,4,9-tetrahydro-1-pyridindene tartrate Structural Formula:

Chemical Abstracts Registry No.: 569-59-5; 82-88-2 (Base) Trade Name Thephorin Nolahist Nolamine Pernovin PV-Tussin

Manufacturer Roche Carnrick Carnrick Chinoin Reid-Rowell

Country US US US Hungary US

Raw Materials Acetophenone Formaldehyde Hydrogen bromide Potassium thiocyanate

Methylamine Sodium hydroxide Hydrogen

Year Introduced 1947 -

Pheniprazine

2705

Manufacturing Process A mixture of 750 grams of 1-methyl-3-benzoyl-4-hydroxy-4-phenylpiperidine and 2,500 cc of 48% hydrobromic acid is refluxed for about 20 minutes. It is then poured into 8 liters of water. An oily precipitate appears which on standing crystallizes. It is filtered and crystallized from about 3.5 liters of alcohol. 2-Methyl-9-phenyl-2,3-dihydrel-pyridindene hydrobromide, MP 201°203°C, is obtained. A mixture of 680 grams of 2-methyl-9-phenyl-2,3-dihydrol-pyridindene hydrobromide, 6,000 cc of water and about 100 grams of Raney-nickel catalyst is hydrogenated at room temperature and at about 1,000 lb pressure for a period of three hours. The catalyst is filtered. The clear filtrate is treated with a solution of 240 grams potassium thiocyanate in 400 cc of water. A heavy solid precipitates from which the supernatant liquid is decanted. The residue is dissolved in 10 liters of boiling alcohol with stirring in the presence of nitro gen. The solution is cooled to room temperature under nitrogen, and then allowed to stand overnight. 2-Methyl-9-phenyl-tetrahydro1-pyridindene thiocyanate separates in crystals of MP 188°-189°C. From the concentrated filtrate an additional amount is obtained. The corresponding free base, prepared by treating the slightly soluble thiocyanate in aqueous suspension with sodium hydroxide and extracting with ether, has a MP of 90°91°C. It forms a tartrate of MP 160°C. The starting material was prepared by reacting acetophenone, methylamine and formaldehyde followed by treatment of the intermediate with sodium hydroxide. References Merck Index 7103 Kleeman and Engel p. 713 PDR pp. 781, 1448 I.N. p. 756 Plati, J.T. and Wenner, W.; US Patent 2,470,108; May 17,1949; assigned to Hoffmann-La Roche Inc.

PHENIPRAZINE Therapeutic Function: Antihypertensive Chemical Name: (1-Methyl-2-phenylethyl)hydrazine Common Name: Chemical Abstracts Registry No.: 55-52-7

2706

Pheniramine maleate

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Catron

Lakeside

US

1959

Catroniazide

Lakeside

-

Raw Materials 1-Phenyl-2-propylidenylhydrazine Acetic acid Hydrogen Manufacturing Process A solution containing 741 g (5.0 mols) of 1 -phenyl-2-propylidenylhydrazine, 300 g (5.0 mols) of glacial acetic acid and 900 cc of absolute ethanol was subjected to hydrogenation at 1,875 psi of hydrogen in the presence of 10 g of platinum oxide catalyst and at a temperature of 30°C to 50°C (variation due to exothermic reaction). The catalyst was removed by filtration and the solvent and acetic acid were distilled. The residue was taken up in water and made strongly alkaline by the addition of solid potassium hydroxide. The alkaline mixture was extracted with ether and the ether extracts dried with potassium carbonate. The product was collected by fractional distillation, BP 85°C (0.30 mm); yield 512 g (68%). The hydrochloride salt was formed in a mixture of 1:10 isopropyl alcohol:diisopropyl ether and recrystallized from acetonitrile, yield 87%, MP 124°C to 125°C. References Merck Index 7105 OCDS Vol. 1 p. 74 (1977) I.N. p. 757 Biel, J.H.; US Patent 2,978,461; April 4, 1961; assigned to Lakeside Laboratories, Inc.

PHENIRAMINE MALEATE Therapeutic Function: Antihistaminic Chemical Name: N,N-Dimethyl-γ-phenyl-2-pyridine-propanamine maleate

Pheniramine maleate

2707

Common Name: Prophenpyridine Structural Formula:

Chemical Abstracts Registry No.: 132-20-7; 86-21-5 (Base) Trade Name Trimeton Maleate Avil Citra Forte Daneral Dristan Fenamine Fiogesic Inhiston Poly-Histine Ru-Tuss S.T. Forte Triaminic Tussirex

Manufacturer Schering Albert Roussel Doyle Hoechst Whitehall Fawns and McAllan Sandoz Upjohn Bock Boots Scot-Tussin Dorsey Scot-Tussin

Country US W. Germany US UK US Australia US US US US US US US

Year Introduced 1948 -

Raw Materials 2-Benzylpyridine β-Dimethylaminoethyl chloride Potassium amide Maleic acid Manufacturing Process According to US Patent 2,676,964: to 1.0 mol of potassium amide in 3 liters of liquid ammonia, is added 1.0 mol of 2-benzylpyridine. After 15 minutes, 1.1 mols of β-dimethylaminoethyl chloride are added. The ammonia is allowed to evaporate and the reaction product decomposed with water and ether extracted. The ether layer is dried over sodium sulfate and after evaporation the residue is distilled, giving the 3-phenyl-3-(2-pyridyl)-N,Ndimethylpropylamine, BP 139°-142°C/1-2 mm. The maleate is produced by reaction with maleic acid. References Merck Index 7106

2708

Phenmetrazine

Kleeman and Engel p. 713; PDR pp. 674, 688, 692, 849, 1583, 1662, 1899 OCDS Vol. 1 p. 77 (1977) I.N. p. 757 REM p. 1131 Sperber, N., Papa, D. and Schwenk, E.; US Patent 2,567,245; September 11, 1951; assigned to Schering Corporation Sperber, N., Papa, D. and Schwenk, E.; US Patent 2,676,964; April 27, 1954; assigned to Schering Corporation

PHENMETRAZINE Therapeutic Function: Antiobesity Chemical Name: 3-Methyl-2-phenylmorpholine Common Name: Oxazimdrine Structural Formula:

Chemical Abstracts Registry No.: 134-49-6; 1707-14-8 (Hydrochloride salt) Trade Name Preludin Anorex Cafilon Marsin

Manufacturer Boehringer Ingelheim Pfizer Yamanouchi Ikapharm

Country US US Japan Israel

Year Introduced 1956 -

Raw Materials Bromopropiophenone Hydrogen Benzyl ethanolamine Hydrogen chloride Manufacturing Process 10 grams of β-phenyl-α-methyl-β,β'-dihydroxy-diethylamine hydrochloride (produced by hydrogenation in the presence of palladium and charcoal of βphenyl-α-methyl-β-keto-β'-hydroxy-N-benzyl-diethylamine hydrochloride obtained from bromopropiophenone by reacting with benzyl-ethanolamine), are warmed with 10% hydrochloric acid for 6 hours on a water bath.

Phenobarbital

2709

After working up in the usual manner, the hydrochloride of the 2-phenyl-3methyl-morpholine crystallizes out from methanolic hydrochloric acid and acetone, MP = 182°C, according to US Patent 2,835,669. References Merck Index 7108 Kleeman and Engel p. 714 PDR p. 678 OCDS Vol. 1 p. 260 (1977) I.N. p. 757 REM p. 892 Thoma, O.;US Patent 2,835,669; May 20, 1958; assigned to C.H. Boehringer Sohn, Germany Siemer, H. and Hengen, O.; US Patent 3,018,222; January 23, 1962; assigned to Ravensberg GmbH, Germany

PHENOBARBITAL Therapeutic Function: Anticonvulsant, Antiepileptic, Hypnotic, Sedative Chemical Name: Barbituric acid, 5-ethyl-5-phenylCommon Name: Phenobarbital; Fenemal; Fenobarbital; Fenobarbiton; Phenylethylbarbituric acid Structural Formula:

Chemical Abstracts Registry No.: 50-06-6 Trade Name Phenobarbital Phenobarbital Dormital Hypnogen Leonal Noctinal Sedabar Sednotic Sedo Sedonal

Manufacturer Inter-Chemical Ltd. Zxchem Acromax Fragner Leo Faes Saunders Medical Arts Avicopharma Assia

Country -

Year Introduced -

2710

Phenoperidine hydrochloride

Raw Materials Urea Phenylethylmalonic diethyl ester Sodium Ethanol absolute Sulfuric acid Manufacturing Process 528 g phenylethyl malonic diethyl ester is dissolved in 500 ml of absolute alcohol. There is then added 140 g urea to the mixture. To this mixture is then added a solution of 57.5 g sodium in 1000 ml absolute alcohol, at such rate that one-half the solution is added during the first hour, a quarter the second hour; an eighth the third hour, and the final eighth during the 4 hours. Then the alcohol is distilled from the reaction mixture. When the alcohol has all been removed, 250 ml xylol is added to the mixture. The reaction mixture is cooled to room temperature and 3 L of water added. The xylene layer was separated and the water solution washed with another 200 ml portion of xylene There is then added to the water solution a 10% excess of a 50% by weight solution of sulfuric acid. The phenobarbital is precipitated as nearly white fluffy crystals, which are filtered off. When dried, they showed 100% phenobarbital by titration. This product may be purified by recrystallization. The unreacted ester in the xylene solution was recovered by distilling off the xylene, and then the phenylethyl malonic ester. References Inman M.T., Bitler W.P.; US Patent No. 2,358,072; Sept. 12, 1944; Assigned to Kay-Fries Chemicals, Inc., West Haverstraw, N.Y., a corporation of New York

PHENOPERIDINE HYDROCHLORIDE Therapeutic Function: Analgesic Chemical Name: 1-(3-Hydroxy-3-phenylpropyl)-4-phenyl-4piperidinecarboxylic acid ethyl ester hydrochloride Common Name: 3-(4-Carboethoxy-4-phenylpiperidino)-1-phenyl-1-propanol hydrochloride Chemical Abstracts Registry No.: 3627-49-4; 562-26-5 (Base) Trade Name

Manufacturer

Country

Year Introduced

Operidine

Janssen

US

1965

Lealgin

Leo

Sweden

-

R-1406

Le Brun

France

-

Phenoperidine hydrochloride

2711

Structural Formula:

Raw Materials Hydrogen Phenylacetonitrile Benzoylethylene Bis-chloroethyl toluene sulfonyl amide Manufacturing Process The starting materials for the overall process are phenylacetonitrile with bischloroethyl toluene sulfonyl amide. These react to give a product which hydrolyzes to normeperidine (4-carboethoxy-4-phenylpiperidine). Condensation of that material with benzoylethylene gives the ketone: β-(4carboethoxy-4-phenylpiperidino)propiophenone. A reaction mixture was prepared containing 4 grams of β-(4-carboethoxy-4phenylpiperidino)-propiophenone hydrochloride, 100 ml of methanol and about 0.5 gram of platinum oxide catalyst. The mixture was placed in a low pressure hydrogenation apparatus and was hydrogenated at a temperature of about 27°C and a pressure of about 3.5 atmospheres of hydrogen to convert the keto group of the β-(4-carboethoxy-4-phenylpiperidino)-propiophenone to a hydroxy group, and to form 3-(4-carboethoxy-4-phenylpiperidino)-1-phenyl-1propanol hydrochloride. After the hydrogenation was complete, the catalyst was separated from the reaction mixture by filtration, and the filtrate was evaporated to dryness in vacuo leaving a residue containing 3-(4carboethoxy-4-phenylpiperidino)-1-phenyl-l-propanol hydrochloride. The residue was digested with ethyl acetate thereby causing 3-(4-carboethoxy-4phenylpiperidino)-1-phenyl-1-propanol hydrochloride to crystallize. This compound melted at about 188°-189°C after being recrystallized three times from an ethyl acetate-methanol solvent mixture, according to US Patent 2,951,080. References Merck Index 7125 Kleeman and Engel p. 715 OCDS Vol. 1 p. 302 (1977) I.N. p. 759 Pohland, A.; US Patent 2,951,080; August 30, 1960; assigned to Eli Lilly and Company

2712

Phenoxybenzamine hydrochloride

Cutler, F.A., Jr. and Fisher, J.F.; US Patent 2,962,501; November 29, 1960; assigned to Merck and Co., Inc.

PHENOXYBENZAMINE HYDROCHLORIDE Therapeutic Function: Adrenergic blocker Chemical Name: N-(2-Chloroethyl)-N-(1-methyl-2-phenoxyethyl) benzenemethanamine hydrochloride Common Name: Structural Formula:

Chemical Abstracts Registry No.: 63-92-3; 59-96-1 (Base) Trade Name

Manufacturer

Country

Year Introduced

Dibenzyline

SKF

US

1953

Dibenzyran

Rohm Pharma

W. Germany

-

Raw Materials 1-Phenoxy-2-propanol Ethanolamine Hydrogen chloride

Thionyl chloride Benzyl chloride

Manufacturing Process Step 1: In a 500 ml flask equipped with gas inlet tube, dropping funnel and reflux condenser is placed 139 grams of 1-phenoxy-2-propanol. A stream of dry air is bubbled through the alcohol while 55 grams of thionyl chloride is added dropwise with external cooling. The stream of dry air is continued for about six hours or until most of the hydrogen chloride has been expelled and then another 55 grams of thionyl chloride is added. The reaction mixture is allowed to stand twenty-four hours, a few drops of pyridine are added and the mixture heated 4 hours on the steam bath. The cooled reaction mixture is poured into water, the crude product is washed with dilute sodium bicarbonate solution and finally taken up in benzene. The benzene is distilled at ordinary pressure and the residue distilled in vacuo to yield 60-70% of 1-phenoxy-2chloropropane, BP 93°-94°C/5 mm.

Phenprocoumon

2713

Step 2: To 494 grams of ethanolamine, heated to approximately 150°C in a 500 ml flask equipped with stirrer, condenser and dropping funnel, is added 465 grams of 1-phenoxy-2-chloropropane with mechanical stirring. The reaction mixture is then heated to reflux for 3 hours, cooled and poured into a liter of water. The organic layer is extracted into ether and the ether solution is extracted with dilute hydrochloric acid. The aqueous acid solution is then made alkaline with 40% sodium hydroxide solution and the organic base is extracted into ether. Removal of the ether leaves N-(phenoxyisopropyl)ethanolamine which, after recrystallization from hexane, melts at 70.5°-72°C. Step 3: To 43 grams of N-(phenoxyisopropyl)ethanolamine dissolved in 500 ml of alcohol in a 1,000 ml flask equipped with stirrer and condenser is added 28 grams of benzyl chloride and 18.5 grams of sodium bicarbonate. The mixture is stirred and refluxed for 10 hours and then approximately half the alcohol is removed by distillation. The remaining solution is poured into 500 ml of water and the organic material extracted with 3 100-ml portions of ether. The combined ether extracts are washed with water, dried over anhydrous potassium carbonate and filtered. After removal of the ether, the residue is distilled in vacuo to yield N-(phenoxyisopropyl)-Nbenzylethanolamine, BP 163°-168°C/0.2 mm. Step 4: A solution of 20 grams of the above amino alcohol is dissolved in 50 ml of dry chloroform and treated with dry hydrogen chloride until acid. Then a solution of 9 grams of thionyl chloride in 50 ml of dry chloroform is added and the reaction mixture is heated on a water bath at 50°-60°C for 2 hours. Most of the chloroform is removed by distillation under reduced pressure. Addition of ether to the residue causes the product to crystallize. After recrystallization from a mixture of alcohol and ether, the N-(phenoxyisopropyl)-N-benzyl-βchloroethylamine hydrochloride melts at 137.5°-140°C. References Merck Index 7134 Kleeman and Engel p. 716 PDR p. 1713 OCDS Vol. 1 p. 55 (1977) I.N. p. 760 REM p. 905 Kerwin, J.F. and Ullyot, G.E.; US Patent 2,599,000; June 3, 1952; assigned to Smith, Kline and French Laboratories

PHENPROCOUMON Therapeutic Function: Anticoagulant Chemical Name: 4-Hydroxy-3-(1-phenylpropyl)-2H-1-benzopyran-2-one Common Name: 3-(1-Phenylpropyl)-4-hydroxycoumarin

2714

Phenprocoumon

Structural Formula:

Chemical Abstracts Registry No.: 435-97-2 Trade Name

Manufacturer

Country

Year Introduced

Liquamar

Organon

US

1958

Falithrom

Fahlberg-List

E. Germany

-

Fencumar

Medica

Finland

-

Marcumar

Roche

W. Germany

-

Raw Materials Methanol Sodium Sodium hydroxide

Diethyl-(1'-phenylpropyl)malonate Acetylsalicylic acid chloride

Manufacturing Process 8.3 parts by weight of powdered sodium in 300 parts by volume of benzene, 100 parts by weight of diethyl (1'-phenylpropyl)-malonate and 72 parts by weight of acetylsalicylic acid chloride are reacted together to form diethyl 1(o-acetoxybenzoy1)-1-(1'-phenylpropyl)malonate, which boils at 195°198°C/0.03 mm Hg. 10.3 parts of weight of diethyl 1-(o-acetoxybenzoyl)-1-(1'-phenylpropyl)malonate are dissolved in 60 parts by volume of absolute ether and to this solution are added portion. wise at 10°C, while stirring, 2.6 parts by weight of sodium methylate. The reaction mixture is stirred for 4 hours, whereupon it is poured into ice water. The ether solution is washed neutral with ice water. After having distilled off the ether, a thick oil consisting of 3-carbethoxy-3-(1'phenylpropyl)-4-oxo-dihydrocoumarinis obtained. This compound crystallized in butyl oxide and has a MP of 108°-109°C. The 3-carbethoxy-3-(1'-phenylpropyl)-4-oxo-dihydrocoumarinmay be hydrolyzed and decarboxylated as follows. The crude product is heated to 85°C for 1/2 hour with 100 parts by volume of 5% aqueous sodium hydroxide, while agitating or stirring. To remove traces of undissolved oil, the cooled solution is treated with 1 part by weight of charcoal, whereupon it is filtrated and acidified to Congo reaction with dilute sulfuric acid. The 3-(1'phenylpropyl)-4-hydroxycoumarin formed is separated off and recrystallized in 80% ethanol, whereupon it melts at 178°-179°C according to US Patent 2,701,804.

Phensuximide

2715

References Merck Index 7139 Kleeman and Engel p. 718 I.N. p. 761 REM p. 827 Hegedus, B. and Grussner, A.; US Patent 2,701,804; February 8, 1955; assigned to Hoffmann-La Roche Inc. Schroeder, C.H. and Link, K.P.; US Patent 2,872,457; February 3, 1959; assigned to Wisconsin Alumni Research Foundation Preis, S., West, B.D. and Link, K.P.; US Patent 3,239,529: March 8, 1966; assigned to Wisconsin Alumni Research Foundation

PHENSUXIMIDE Therapeutic Function: Anticonvulsant Chemical Name: 1-Methyl-3-phenyl-2,5-pyrrolidinedione Common Name: N-Methyl-α-phenylsuccinimide Structural Formula:

Chemical Abstracts Registry No.: 86-34-0 Trade Name

Manufacturer

Country

Year Introduced

Milontin

Parke Davis

US

1953

Lifene

Debat

France

-

Petimid

Dincel

Turkey

-

Succitimal

Katwijk

Netherlands

-

Raw Materials Phenylsuccinic anhydride Methyl amine Acetyl chloride Manufacturing Process 10 grams of phenylsuccinic anhydride is dissolved in 250 ml of absolute ether and the solution is treated with dry methylamine until a precipitate ceases to form. After standing for ½ hour the ether is decanted off and the residue is

2716

Phentermine hydrochloride

washed with 40 ml of water by decantation. The mixture is filtered and the precipitate washed with 10 ml of water. By acidification of the filtrate, a white precipitate is obtained. After drying it weighs 8 grams and melts at 136°140°C. The two precipitates are combined and recrystallized from aqueous alcohol to give β-N-methylphenylsuccinamic acid which melts at 158°-160°C. 9 grams of β-N-methylphenylsuccinamic acid and 200 ml of acetyl chloride are heated together on a steam bath for ½ hour. The excess acetyl chloride is removed by distillation and 50 ml of water are added to the thick residue. After allowing for hydrolysis of the excess acetyl chloride the water is decanted and the yellow residue dissolved in 75 ml of ether. The resulting solution is treated with charcoal twice and dried over anhydrous magnesium sulfate. On partial evaporation of the ether a white solid precipitates. There is obtained 4 grams of N-methyl-α-phenylsuccinimide which melts at 71°-73°C. References Merck Index 7140 Kleeman and Engel p. 718 PDR p. 1367 OCDS Vol. 1 p. 226 (1977) I.N. p. 762 REM p. 1080 Miller, C.A. and Long, L.M.; US Patent 2,643,258; June 23, 1953; assigned to Parke, Davis and Company

PHENTERMINE HYDROCHLORIDE Therapeutic Function: Antiobesity Chemical Name: α,α-Dimethylbenzeneethanamine hydrochloride Common Name: α-Benzylisopropylamine hydrochloride; Phenyl-tertbutylamine hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 1197-21-3; 122-09-8 (Base) Trade Name Wilpo Linyl Fastin

Manufacturer Dorsey Roussel Beecham

Country US France US

Year Introduced 1961 1962 1973

Phentermine hydrochloride Trade Name Adipex-P Ona Mast Obestin Oby-Trim Duromine Ex-Adipos Ionamin Jonakraft Lipopil Minobese Mirapront Netto-Longcaps Panbesy Panshade Parmine Phentermine Phentermyl Regulin Span R/D Teramine

Manufacturer Lemmon Mast Ferndale Rexar Riker Eurand Pennwalt Kraft Pharm Roussel Maestretti Restan Bracco Heyden Asperal Pan American Parmed Schein Diethelm Kwizda Metro Med Legere

Country US US US US UK Italy UK US Italy S. Africa Italy W. Germany Belgium US US US W. Germany Austria US US

2717

Year Introduced 1976 1980 1980 1982 -

Raw Materials Isobutyryl chloride Ammonia Hydrogen chloride Bromine Calcium hydroxide

Sodium Benzyl bromide Benzene Potassium hydroxide

Manufacturing Process Preparation of isobutyrophenone: In a 12 liter, 3-necked flask, 1,280 grams of aluminum chloride was covered with 2,000 cc of dry thiophene-free benzene and a solution of 919 grams of isobutyryl chloride, (BP 92°-94°C) in 1 liter of benzene was added slowly with stirring. After heating for 3 hours at reflux, the solution was cooled and poured over a mixture of 1 liter of concentrated hydrochloric acid and 5 kg of ice. The benzene layer was separated, the aqueous layer extracted with benzene, and the combined benzene solutions were washed, dried and concentrated in vacuo. The residue was distilled rapidly to give 1,051 grams of isobutyrophenone, boiling at 81°-89°C at 1 mm, yield 83.4%. Preparation of 1,3-Diphenyl-2,2-Dimethylpropanone-1: Sodamide was prepared from 12.5 grams of sodium added in small portions to 600 cc of liquid ammonia with 1 gram of hydrous ferric chloride as catalyst. The ammonia was replaced by 200 cc of dry toluene and without delay a solution of 74 grams of isobutyrophenone and 76.5 grams of benzyl bromide in 200 cc of benzene was slowly added with stirring. The reaction mixture was heated on a boiling water bath for 48 hours. Water was then added, the organic layer separated and the product isolated by distillation. The 1,3-diphenyl-2,2-

2718

Phentermine hydrochloride

dimethylpropanone-1 boiled from 142°-143°C at a pressure of 3 mm, nD201.5652. Preparation of α,α-Dimethyl-β-Phenylpropionamide: Sodamide was prepared from 7.6 grams of sodium in 350 cc of liquid ammonia with 0.9 gram of hydrous ferric chloride. The ammonia was replaced by 250 cc of toluene, the mixture was heated to 60°C and 71.4 grams of 1,3-diphenyl-2,2-dimethyl propanone-1 dissolved in 150 cc of toluene was added. The mixture was stirred and heated on a steam bath for 5 hours. A clear red color appeared in 15 minutes and disappeared after about an hour. After cooling, water was added, the organic layer was washed, dried, and concentrated to give 36.5 grams of α,α-dimethyl-β-phenyl propionamide which crystallized slowly after the addition of an equal volume of petroleum ether. The product melted at 62°C after crystallization from benzene-petroleum ether. Preparation of Di-(β-Phenyl-α,α-Dimethylethyl)Urea: 3.5 grams of α,αdimethyl-β-phenylpropionamide in 420 cc of water was added to a solution of 87.5 grams of potassium hydroxide and 35 grams of bromine in 350 cc of water. After 2 hours at 60°C, the product was obtained on crystallization from ethanol, melting at 184°C. Preparation of ω-Phenyl-tert-Butylamine: 24 grams of the urea derivative obtained as indicated above, were well mixed with 96 grams of calcium hydroxide in a flask immersed in an air bath and provided with a dropping funnel the stem of which reached the bottom of the flask. The mixture was heated to 240°-260°C (inside temperature) for 7 hours during which time 86 cc of water was slowly added. The vapors were collected in a receiver cooled with ice. After extraction with ether and distillation, the product was obtained as a colorless liquid boiling from 80°-84°C at 9 mm according to US Patent 2,590,079. The ether solution may be dried and saturated with hydrogen chloride and the precipitated hydrochloride recrystallized from a mixture of 50 parts alcohol and 100 parts of acetone. The pure hydrochloride is thus obtained as a white crystalline substance having a MP of 195°-196°C, according to US Patent 2,408,345. References Merck Index 7141 Kleeman and Engel p. 719 PDR pp. 660, 1033, 1034, 1246, 1450, 1606, 1999 OCDS Vol. 1 p. 72 (1977) I.N. p. 762 REM p. 892 Shelton, R.S. and Van Campen, M.G., Jr.; US Patent 2,408,345; September 24, 1946; assigned to The Wm. S. Merrell Company Abell, L.L., Bruce, W.F. and Seifter, J.; US Patent 2,590,079; March 25, 1952; assigned to Wyeth Incorporated

Phentolamine hydrochloride

2719

PHENTOLAMINE HYDROCHLORIDE Therapeutic Function: Adrenergic blocker Chemical Name: 3-[[(4,5-Dihydro-1H-imidazol-2-yl)methyl](4-methylphenyl) amino]phenol hydrochloride Common Name: 2-(m-Hydroxy-N-p-tolylanilinomethyl)-2-imidazoline hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 73-05-2; 50-60-2 (Base) Trade Name Regitine Regitine Regitine

Manufacturer Ciba Ciba Geigy Ciba

Country US Japan UK

Year Introduced 1952 -

Raw Materials Hydrogen chloride N-(p-Methylphenyl)-m'-hydroxyphenylamine 2-Chloromethylimidazoline HCl Manufacturing Process 199.24 parts of N-(p-methylphenyl)-m'-hydroxyphenylamine and 77.52 parts of 2-chloromethylimidazoline hydrochloride are heated for sixteen hours in an oil bath having a temperature of 150°C, while stirring and introducing a current of nitrogen. The viscous contents of the flask are then cooled to about 100°C, mixed with 400 parts by volume of hot water, and stirred for a short time. After further cooling to about 60°C, 200 parts by volume of water and 500 parts by volume of ethyl acetate at 60°C are added, and the aqueous layer is separated. The excess of starting material may be recovered from the ethyl acetate. The aqueous portion is chilled in a cooling chamber at -10°C, whereupon the

2720

Phenyl aminosalicylate

hydrochloride of 2-[N-(p-methylphenyl)-N-(m'-hydroxyphenyl)-aminomethyl]imidazoline crystallizes. Upon being concentrated and cooled the mother liquor yields a further quantity of the hydrochloride. The combined quantities of hydrochloride are treated with a small quantity of cold water, dried with care, and washed with ethyl acetate. The product is then crystallized from a mixture of alcohol and ethyl acetate, and there is obtained a hydrochloride melting at 239°-240°C. References Merck Index 7143 Kleeman and Engel p. 719 PDR p. 809 OCDS Vol. 1 p. 242 (1977) I.N. p. 762 REM p. 906 Miescher, K., Marxer, A. and Urech, E.; US Patent 2,503,059; April 4, 1950; assigned to Ciba Pharmaceutical Products, Inc.

PHENYL AMINOSALICYLATE Therapeutic Function: Antibacterial (tuberculostatic) Chemical Name: 4-Amino-2-hydroxybenzoic acid phenyl ester Common Name: Fenamisal Structural Formula:

Chemical Abstracts Registry No.: 133-11-9 Trade Name Pheny-Pas-Teb-Amin Fenil-PAS

Manufacturer Purdue Frederick Farmabion

Raw Materials p-Nitrosalicylic acid Phosphorus oxychloride Phenol Hydrogen

Country US Spain

Year Introduced 1959 -

Phenylbutazone

2721

Manufacturing Process 183 g of p-nitrosalicylic acid are dissolved in 564 g of phenol by heating to 140°C to 150°C on an oil bath. When all the p-nitrosalicylic acid is dissolved, 153 g of phosphorus oxychloride are run in, drop by drop, over a period of about 2 hours, while maintaining the temperature at about 150°C. The still warm mixture is run into 2 liters of water with agitation. The precipitate formed is filtered off, washed with water until phenol is removed and then dried. There are thus obtained 250 g of 2-hydroxy-4-nitrophenylbenzoate which melts at 154°C to 155°C. In a hydrogenation autoclave are introduced 92 g of 2-hydroxy-4nitrophenylbenzoate preceded by 200 cc of ethyl acetate; Raney nickel, obtained from 30 g of alloy, is added with 300 cc of ethyl acetate. Hydrogenation under pressure (100 to 120 kg) at ordinary temperature is carried out during a period of about 12 hours. The nickel is filtered off and the ethyl acetate is removed by distillation on the water bath under a vacuum of 300 mm. There is thus obtained 80 g of crude damp 2-hydroxy-4amnophenylbenzoate which after recrystallization from isopropyl alcohol melts at 153°C. References Merck Index 7151 OCDS Vol. 2 p. 89 (1980) I.N. p. 415 Freire, SA.; US Patent 2,604,488; July 22, 1952; assigned to Soc. des Usines Chimiques Rhone-Poulenc (France)

PHENYLBUTAZONE Therapeutic Function: Antiinflammatory, Antiarthritic Chemical Name: 4-Butyl-1,2-diphenyl-3,5-pyrazolidinedione Common Name: 3,5-Dioxo-1,2-diphenyl-4-n-butylpyrazolidine Structural Formula:

2722

Phenylbutazone

Chemical Abstracts Registry No.: 50-33-9 Trade Name Butazolidin Butazolidin Azolid Acrizeal Alkabutazona Anuspiramin Artropan Bulentin Butacal Butacote Butadion Butadiona Butadyne Butalan Butalgin Butalgina Butaluy Butaphen Butapirazol Butarex Butartril Butazina Butazone Butiwas Simple Butoroid Butrex Carudol Chembuzone Demoplas Digibutina Diossidone Ecobutazone Elmedal Equi Bute Eributazone Fenibutasan Fenibutol Flexazone IA-But Intalbut Kadol Merizone Neo-Zoline Neuplus Novobutazone Novophenyl

Manufacturer Geigy Ciba Geigy U.S.V. Pharm. S.S. Pharm Lovens Farbios Polifarma Sanwa Langley Geigy Streuli Miquel Bio-Chimique Lancet Fawns and McAllan Esteve Miluy Mulda Polfa Adams Chiesi Vis DDSA Wassermann Virax SCS Pharmalab Lab. Franc. Therap. Chemo-Drug Adenylchemie Bicsa Eliovit I.C.N. Thiemann Fort Dodge Labs Eri Santos Atral Berk Inter-Alia Pharm. Inter-Alia Pharm. Midy Meriot Neo Toyo Novopharm Novopharm

Country US France US Japan Denmark Spain Italy Japan Australia UK Switz. Spain Canada Australia Australia Spain Spain Turkey Poland Australia Italy Italy UK Spain Australia S. Africa France Canada W. Germany Spain Italy Canada W. Germany US Canada Spain Portugal UK UK UK Italy Canada Canada Japan Canada Canada

Year Introduced 1952 1954 1971 -

Phenylbutazone Trade Name Panazone Phenbutazol Phenyl Betazone Phenylone Pilazon Pirarreumol Praecirheumin Rectofasa Reumasyl Reumazin Reumuzol Reupolar Rheumaphen Schemergen Sedazole Servizolidin Shigrodin Spondyril Tetnor Tevcodyne Therazone Ticinil Todalgil Tokugen Uzone Wescozone Zolidinium

Manufacturer Propan-Lipworth Smallwood Barlow Cote Medic Kobayashi Hermes Pfleger Lifasa Leiras Mohan Farmos Farmos Reiss Azusa Toho Servipharm Ikapharm Dorsch Drugs, Ltd. Tevcon Western Serum De Angeli Lopez-Brea Sawai Kempthorne Prosser Saunders Kwizda

Country S. Africa Canada Canada Canada Japan Spain W. Germany Spain Finland Japan Finland Finland W. Germany Japan Japan Switz. Israel W. Germany UK US US Italy Spain Japan New Zealand Canada Austria

2723

Year Introduced -

Raw Materials Hydrazobenzene Diethyl-n-butyl malonate Sodium Ethanol Manufacturing Process 7.6 parts of sodium are dissolved in 190 parts by volume of absolute alcohol; 65 parts of diethyl-n-butyl malonate and 65 parts of hydrazobenzene are added. The alcohol is slowly distilled off and the reaction mixture heated for 12 hours at a bath temperature of 150°C and finally in vacuo, until no more alcohol comes off. The product is dissolved in water, clarified with a little animal charcoal and 15% hydrochloric acid is slowly added until an acid reaction to Congo red paper is produced. 1,2-Diphenyl-3,5-dioxo-4-n-butyl-pyrazolidine separates as an oil, which rapidly become crystalline. It crystallizes from alcohol as colorless needles with a MP of 105°C.

2724

Phenylephrine hydrochloride

References Merck Index 7157 Kleeman and Engel p. 720 PDR pp. 830, 891, 1606, 1999 OCDS Vol. 1 p. 236 (1977) and 2, 388, 474 (1980) I.N. p. 763 REM p. 1120 Stenzl, H.; US Patent 2,562,830; July 31, 1951; assigned to J.R. Geigy AG, Switzerland

PHENYLEPHRINE HYDROCHLORIDE Therapeutic Function: Adrenergic Chemical Name: (R)-3-Hydroxy-α-[(methylamino)methyl]benzenemethanol hydrochloride Common Name: m-Methylaminoethanolphenol hydrochloride; Metaoxedrin Structural Formula:

Chemical Abstracts Registry No.: 61-76-7 Trade Name Neosynephrine Mydfrin Nostril Adrianol Atrohist Bromphen Codimal Comhist Congespirin Coryban Dallergy Deconsal Decontabs Degest Derizene

Manufacturer Badrial Alcon Boehringer Ingelheim Anasco Adams Schein Central Norwich Eaton Bristol-Myers Pfipharmecs Laser Adams Zenith Barnes Hind Hollister-Stier

Country France US US W. Germany US US US US US US US US US US US

Year Introduced 1953 1979 1982 -

Phenylephrine hydrochloride Trade Name Donatussin Dristan Dura-Vent E.N.T. Entex Extendryl Fenilfar Histalet Histamic Histaspan Histor Hycomine Isonefrine Isophrine Isotropina Korigesic Matafa-Lind Naldecon Nasophen Neosinefrina Newphrine Nostril Pediacof Phenergan Protid PV-Tussin Quelidrine Rinisol Ru-Tuss Singlet S-T Forte Synasal Tear-Efrin Tussar Tussirex Tympagesic Visopt Zeph

Manufacturer Laser Whitehall Dura Springbok Norwich Eaton Fleming Farmila Reid-Rowell Metro Med U.S.V. Pharm. Hauck Du Pont Tubi Lux Pharma Broemmel Tubi Lux Pharma Trimen Anasco Bristol Premo Reunidos Vitarine Boehringer Ingelheim Winthrop-Breon Wyeth La Salk Reid-Rowell Abbott Farmos Boots Lakeside Scot-Tussin Texas Pharm Tilden Yates U.S.V. Pharm. Scot-Tussin Adria Sigma Scott and Turner

Country US US US US US US Italy US US US US US Italy US W. Germany US US Spain US US US US US US US US US Finland US US US US US US US US Australia Australia

2725

Year Introduced -

Raw Materials Hydrogen m-Hydroxymethylaminoacetophenone Hydrogen chloride Manufacturing Process 4.5 g of the hydrochloride of m-hydroxymethylaminoacetophenone are

2726

Phenylpropanolamine hydrochloride

dissolved in a small amount of water; to the solution a solution of colloidal palladium obtained from palladiumchloride is added, and the mixture is treated with hydrogen. After diluting the reaction liquid with acetone it is filtered, and the residue obtained after the evaporation of the filtrate in vacuo, and complete drying over pentoxide of phosphorus is then dissolved in absolute alcohol, and to this is added about the same volume of dry ether, until turbidity just commences to occur. After a short time the hydrochloride of the m-hydroxyphenylethanolmethylamine will separate out as a colorless mass of crystals at a melting point of 142°C to 143°C. References Merck Index 7167 PDR pp. 555, 562, 570, 677, 688, 701, 727, 784, 855, 865, 880, 928, 991, 1246, 1272, 1276, 1404, 1447, 1606, 1662, 1735, 1807, 1813, 1824, 1899, 1923, 1973, 1999 OCDS Vol. 1 p. 63 (1977); 2, 265 (1980) and 3, 20 (1984) I.N. p. 764 REM p. 889 Legerlotz, H.; US Patent 1,932,347; October 24, 1933; assigned to Frederick Stearns and Co.

PHENYLPROPANOLAMINE HYDROCHLORIDE Therapeutic Function: Nasal decongestant, Anorexic Chemical Name: α-(1-Aminoethyl)benzenemethanol hydrochloride Common Name: dl-Norephedrine hydrochloride; 2-Amino-1-phenyl-1propanol hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 154-41-6; 14838-15-4 (Base) Trade Name Propadrine Dexatrim Dietac Obestat Permatrim

Manufacturer MSD Thompson Menley and James Lemmon Lee

Country US US US US US

Year Introduced 1941 1980 1980 1980 1980

Phenylpropanolamine hydrochloride Trade Name Nobese Dexatrim Extra Propagest Acutr im Help Appedrine Bromphen Codimal Comtrex Congespirin Control Corvban-D Co-Tylenol Cremacoat Decontabs Dietrim Dimetane-D.C. Dura Vent E.N.T. Entex Fiogesic Head and Chest Histaminic Hycomine Korigesic Kronohist Monydrin Naldecon Nolamine Ornade Poly-Histine Prolamine Rhindecon Rhinolar Ru-Tuss Sinubid Sinulin Tinaroc Triaminic Tuss-Ornade

Manufacturer O'Neal Jones Thompson Carnrick Ciba Geigy Verex Thompson Schein Central Bristol-Myers Bristol-Myers Thompson Pfipharmecs McNeil Vicks Zenith Legere Robins Dura Springbok Norwich Eaton Sandoz Procter and Gamble Metro Med Du Pont Trimen Ferndale Draco Bristol Carnrick SKF Bock Thompson McGregor McGregor Boots Parke Davis Carnrick Remeda Dorsey SKF

Raw Materials Benzaldehyde Nitroethane Sodium bisulfite Hydrogen Hydrogen chloride

Country US US US US US US US US US US US US US US US US US US US US US US US US US US Sweden US US US US US US US US US US Finland US US

2727

Year Introduced 1981 1981 1982 1983 1983 -

2728

Phenyltoloxamine

Manufacturing Process In one route as described in US Patent 2,151,517, 10.7 kg of technical benzaldehyde is vigorously agitated with a solution of 11.0 kg of sodium bisulfite in 50.0 liters of water until the formation of the addition-product is complete. Simultaneously, 8.25 kg of nitroethane is dissolved in a solution of 4.5 kg of caustic soda in 20.0 liters of water and the resultant warm solution is added with vigorous stirring to the magma of benzaldehyde sodium bisulfite. The mixture is agitated for 30 minutes and then allowed to stand overnight. The aqueous portion of the mixture is now siphoned off from the supernatant layer of oily phenylnitropropanol and replaced with a fresh solution of 11.0 kg of sodium bisulfite in 50.0 liters of water. The mixture of phenylnitropropanol and bisulfite solution is now vigorously agitated for 15 minutes in order to remove and recover small amounts of unreacted benzaldehyde, and is then again allowed to stratify. This time, the phenylnitropropanol is siphoned off and filtered to remove a small amount of resinous material. The aqueous solution of sodium bisulfite remaining behind is reacted with benzaldehyde, as described above, thus making the process continuous. The 1-phenyl-2-nitropropanol thus obtained is a colorless oil, specific gravity 1.14 at 20°C, odorless when pure, volatile with steam and boiling at 150° to 165°C under a pressure of 5 mm of mercury. It is soluble in alcohol, ether, acetone, chloroform, carbon tetrachloride, benzene and glacial acetic acid. The yield of 1-phenyl-2-nitropropanolobtained by this procedure is 17.1 to 17.7 kg. It is hydrogenated and converted to the hydrochloride in subsequent steps. The hydrogen chloride has a melting point of 192°-194°C. In an alternative route described in US Patent 3,028,429 propiophenone may be reacted with an alkyl nitrite to give isonitrosopropiophenone which is then hydrogenated and finally converted to the hydrochloride. References Merck Index 7189 Kleeman and Engel p. 721 PDR pp. 674, 688, 702, 727, 781, 784, 850, 854, 865, 875, 1033, 1084, 1246, 1277, 1388, 1404, 1431, 1454, 1583, 1606, 1719, 1730, 1735, 1805, 1807, 1869, 1999 I.N. p. 766 REM p. 889 Kamlet, J.; US Patent 2,151,517 March 21, 1939 Wilbert, G. and Sosis, P.; US Patent3,028,429; April 3, 1962; assigned to Nepera Chemical Co., Inc.

PHENYLTOLOXAMINE Therapeutic Function: Antihistaminic

Phenyltoloxamine

2729

Chemical Name: N,N-Dimethyl-2-[2-(phenylmethyl)phenoxy]ethanamine Common Name: Bistrimin Structural Formula:

Chemical Abstracts Registry No.: 92-12-6; 6152-43-8 (Hydrochloride salt) Trade Name Bristalin Bristamine Codipront Ephepect Floxamine Fluidol Histionex Netux Pholtex Quadrahist Rinurel Tussionex Raw Materials

Manufacturer Bristol Banyu Mack Bolder Durst Metadier-Tours Strasenburgh Roussel Riker Schein Warner Pennwalt

Country US Japan W. Germany W. Germany US France US France UK US UK US

Year Introduced 1952 -

o-Benzylphenol Methanol Sodium Dimethylaminoethyl chloride Manufacturing Process Sodium methylate is made by dropping 11.7 g of sodium strips into 199 ml of absolute methanol in a 1-liter three-necked flask. 93.9 g of o-benzylphenol are dissolved in 200 ml of dry toluene and added to the sodium methylate solution. The solution is distilled until the boiling point of toluene is reached. At the end of the distillation, enough toluene is added to restore the original volume of solvent. 109.5 g of dimethylaminoethyl chloride hydrochloride and 200 ml of toluene are placed in a 1-liter Erlenmeyer flask, cooled in an ice bath, and decomposed with 167.5 g of 20% sodium hydroxide solution. The toluene and water layers are separated, and the water layer is extracted again with 50 ml of toluene. The toluene layers are combined, washed with saturated salt solution, and dried over anhydrous potassium carbonate.

2730

Phenyramidol

The dried dimethylaminoethyl chloride solution is poured into the toluene solution of the sodium salt of o-benzylphenol, heated to reflux, and refluxed 16 hours. After refluxing, enough water is added to the mixture to dissolve the precipitated solid. The layers are separated, and the toluene layer is further washed with water until the water extract is just slightly alkaline. The toluene solution is then made acid with 6N hydrochloric acid and extracted with water until no cloudiness is produced when the extract is made alkaline. The acidic aqueous extract is washed with ether, then made alkaline with 20% sodium hydroxide solution, and extracted into ether. The ether solution is washed several times with water, then with saturated salt solution, and is dried over anhydrous potassium carbonate. The dried solution is filtered and distilled. The product distills at 143.5°C/1 mm; 69.7 g of pale yellow oil are recovered. 57.1 g of the free base are dissolved in ether and precipitated with dry HCl. 66.0 g of crude hydrochloride are recovered. The hydrochloride is dissolved in 130 ml of reagent acetone by boiling, filtered hot, and allowed to cool. The crystalline material obtained on cooling is filtered, washed with a little acetone, washed with ether, and dried in vacuo. 44.8 g, MP 119.5°C to 121°C, are recovered from the first crop of crystals. Ethyl acetate may also be used as the solvent for recrystallization. References Merck Index 7197 Kleeman and Engel p. 721 PDR p. 1606 OCDS Vol. 1 p. 115 (1977); I.N. p. 766 Binkley, S.B. and Cheney, L.C.; US Patent 2,703,324; March 1, 1955; assigned to Bristol Laboratories, Inc.

PHENYRAMIDOL Therapeutic Function: Analgesic, Muscle relaxant Chemical Name: α-[(2-Pyridinylamino)methyl]benzenemethanol Common Name: Fenyramidol Structural Formula:

Chemical Abstracts Registry No.: 553-69-5; 326-43-2 (Hydrochloride salt)

Phenytoin Trade Name Analexin Cabral Fenprin Anabloc Aramidol Bonapar Evasprine Firmalgil Miodar Pheniramidol Vilexin

Manufacturer Mallinckrodt Inc. Kali-Chemie RBS Irbi A.B.C. Minerva-Chemie Millot Firma I.S.M. Pulitzer Vitrum

Country US W. Germany Italy Italy Italy Netherlands France Italy Italy Italy Sweden

2731

Year Introduced 1960 1962 1962 -

Raw Materials 2-Aminopyridine Lithium amide Styrene oxide Manufacturing Process A mixture containing 188 g (0.20 mol) of 2-arninopyridine, 0.55 g of lithium amide and 75 cc of anhydrous toluene was refluxed for 1.5 hours. Styrene oxide (12.0 g = 0.10 mol) was then added to the reaction mixture with stirring over a period of ten minutes. The reaction mixture was stirred and refluxed for an additional 3.5 hours. A crystalline precipitate was formed during the reaction which was removed by filtration, MP 170°C to 171°C. 1.5 g. The filtrate was concentrated to dryness and a dark residue remained which was crystallized from anhydrous ether; yield 6.0 g. Upon recrystallization of the crude solid from 30 cc of isopropyl alcohol, 2.0 g of a light yellow solid was isolated; MP 170° to 171°C. References Merck Index 7203 Kleeman and Engel p. 399 OCDS Vol. 1 p. 165 (1977) I.N. p. 422 Biel, J.H.; US Patent 3,040,050; June 19, 1962; assigned to Lakeside Laboratories, Inc.

PHENYTOIN Therapeutic Function: Antiepileptic Chemical Name: 5,5-Diphenyl-2,4-imidazolidinedione Common Name: Diphenylhydantoin

2732

Phenytoin

Structural Formula:

Chemical Abstracts Registry No.: 57-41-0 Trade Name Dilantin Ditan Aleviatin Citrullamon Didan Difhydan Dihydan Dihydantoin Dintoina Diphentyn Enkefal Epanutin Epinat Fenantoin Hydantin Hydantol Lehydan Novophenytoin Phenhydan Pyoredol Solantyl Tacosal Zentropil

Manufacturer Parke Davis Mallard Dainippon Sudmedica Canfield Leo Carrion Orion Recordati I.C.N. Leiras Parke Davis Nyegaard A.C.O. Medica Fujinaga Leo Novopharm Desitin Roussel Roussel Helvepharm Nordmark

Country US US Japan W. Germany US Sweden France Finland Italy Canada Turkey W. Germany Norway Sweden Finland Japan Sweden Canada W. Germany France France Switz. W. Germany

Year Introduced 1938 1980 -

Raw Materials Benzophenone Potassium cyanide Ammonium carbonate Manufacturing Process 10 g of benzophenone (1 mol), 4 g of potassium cyanide (1.22 mols) and 16 g of ammonium carbonate (3.3 mols) are dissolved in 100 cc of 60% (by volume) ethyl alcohol and the mixture warmed under a reflux condenser without stirring at 58° to 62°C. After warming the mixture for 10 hours a

Phethenylate sodium

2733

partial vacuum is applied and the temperature is raised enough to permit concentration of the reaction mixture to two-thirds of its initial volume. A slight excess of mineral acid, such as sulfuric or hydrochloric acid is added to acidify the mixture which is then chilled and the solid which separates is filtered off. It is then treated with an aqueous solution of dilute sodium hydroxide to dissolve the hydantoin from the solid unreacted benzophenone. After filtration, the alkaline extract is then acidified to cause the separation of solid pure diphenylhydantoin which is filtered off and dried. It melts at 293° to 296°C. A net yield of about 95% is obtained by the procedure described above. If the time of warming the reaction mixture is increased three-or four-fold, practically 100% net yields are obtained. The same high net yields are also obtained by heating for even longer periods of time. For example, by heating for 90 hours, a 100% net yield, or 67% gross yield, is obtained. References Merck Index 7204 Kleeman and Engel p. 722 PDR pp. 1334, 1337 DOT 9 (6) 245 (1973) I.N. p. 767 REM p. 1081 Henze, H.R.; US Patent 2,409,754; October 22, 1946; assigned to Parke, Davis and Company

PHETHENYLATE SODIUM Therapeutic Function: Anticonvulsant Chemical Name: 5-Phenyl-5-(2-thienyl)-2,4-imidazolidinedione monosodium salt Common Name: Structural Formula:

Chemical Abstracts Registry No.: 510-34-9

2734

Pholedrine sulfate

Trade Name Thiantoin

Manufacturer Lilly

Country US

Year Introduced 1950

Raw Materials Phenyl-(2-thienyl)ketone Potassium cyanide Ammonium carbonate Manufacturing Process The 5-phenyl-5-(2-thienyl)hydantoin is prepared by heating a mixture of 5.64 g (0.03 mol) of phenyl-(2-thienyl)ketone, 3.25 g (0.03 mol) of potassium cyanide and 10.2 g (0.09 mol) of ammonium carbonate in 75 cc of 50% ethanol for 28 hours at a temperature of about 110°C. An additional 3.25 g of potassium cyanide and 3 g of ammonium carbonate are added and the mixture heated for 24 hours at about 110°C. The reaction mixture is removed and about half of the liquid evaporated, an oil separating during the process. The mixture is acidified with concentrated hydrochloric acid and extracted with two 100 cc portions of ether. The extracts, which contain the 5-phenyl-5-(2-thienyl)hydantoin, are combined and the combined ether extracts are shaken with two 25 cc portions of 5% potassium hydroxide solution. The alkaline solution, which dissolves the 5phenyl-5-(2-thienyl)hydantoin to form the potassium salt thereof, is acidifed with hydrochloric acid and heated to expel ether. By the process of purification, 4.3 g of 5-phenyl-5-(2-thienyl)hydantoin is obtained, and from the ether layer, 2.2 g of unreacted ketone. The yield of the 5-phenyl-5-(2-thienyl)hydantoin is about 56%. The melting point of the purified 5-phenyl-5-(2-thienyl)hydantoinis about 256°C to 257°C. References Merck Index 7206 Spurlock, J.J.; US Patent 2,366,221; January 2, 1945

PHOLEDRINE SULFATE Therapeutic Function: Sympathomimetic, Mydriatic, Analeptic, Vasopressor Chemical Name: Phenol, p-(2-(methylamino)propyl)- sulfate Common Name: Foledrine; Methylparedrine; Pholedrine sulfate Chemical Abstracts Registry No.: 370-14-9 (Base); 6114-26-7

Phthalylsulfathiazole

2735

Structural Formula:

Trade Name Pholedrine Sulfate Paredrinol Pressitan Pulsotyl

Manufacturer ZYF Pharm Chemical Sigma-Aldrich Allard CHINOIN - BUDAPES

Country -

Year Introduced -

Raw Materials p-Methoxybenzylmethylketone Hydrogen Nickel Manufacturing Process 100 g β-(methoxyphenyl)isopropylamine prepared, for example by reduction of p-methoxybenzylmethylketone with hydrogen and nickel catalyst in presence of ammonia or by Mannix's method, 250 ml ethanol and calculated quantity of solution of formaldehyde and 70 g activated aluminum shaving were heated for 6 hours by stirring. The mixture was filtered, the solvent was removed in vacuum and the residue was dissolved in ethanol contained hydrochloric acid. The prepared hydrochloride of β-(pmethoxyphenyl)isopropylmethylamine had MP: 174°C. In practice it is usually used as sulfate. References Knoll A.-G.; D.R. Patent No. 665,793; May 27, 1936; Assigned to Chemishe Fabriken in Ludvigshafen, Rhein, Germany Knoll A.-G.; D.R. Patent No. 674,753; May 27, 1936; Assigned to Chemishe Fabriken in Ludvigshafen, Rhein, Germany

PHTHALYLSULFATHIAZOLE Therapeutic Function: Antibacterial (intestinal) Chemical Name: 2-[[[4-[(2-Thiazolylamino)sulfonyl]phenyl]amino] carbonyl]benzoic acid Common Name: -

2736

Phthalylsulfathiazole

Structural Formula:

Chemical Abstracts Registry No.: 85-73-4 Trade Name Sulfathalidine Talidine AFI-Ftalyl Colicitina Enterosteril Ftalysept Gelotamide Lyantil Novosulfina Phtalazol Phthalazol Sulfatalyl Talisulfazol Thalazole

Manufacturer MSD Clin Midy A.F.I. Panthox and Burck Ripari-Gero Ferrosan Choay Syntex Daltan Medosan Geistlich Knoll Pharmacia Chemiek May and Baker

Country US France Norway Italy Italy Denmark France France Italy Switz. Australia Sweden E. Germany UK

Year Introduced 1946 1948 -

Raw Materials Phthalic anhydride Sulfathiazole Manufacturing Process 5 g of phthalic anhydride was added to a boiling suspension of 10 g of sulfathiazole in 100 cc of alcohol. The mixture was then refluxed for 5 minutes after the addition was complete at which time all of the solids were in solution. The solution was then cooled and diluted with an equal volume of water, The white solid precipitate which formed was filtered and recrystallized from dilute alcohol, yielding 2-N4-phthalylsulfanilamidothiazole,which decomposes above 260°C, according to US Patent 2,324,015. References Merck Index 7261 Kleeman and Engel p. 723 OCDS Vol. 1 p. 132 (1977) I.N. p. 769

Phytate sodium

2737

Moore, M.L.; US Patent 2,324,013; July 13, 1943; assigned to Sharp and Dohme, Incorporated Moore, M.L.; US Patent 2,324,014; July 13, 1943; assigned to Sharp and Dohrne, Incorporated Moore, M.L.; US Patent 2,324,015; July 13, 1943; assigned to Sharp and Dohme, Incorporated

PHYTATE SODIUM Therapeutic Function: Hypocalcemic Chemical Name: myo-Inositol hexakis(dihydrogen phosphate) sodium salt Common Name: Structural Formula:

Chemical Abstracts Registry No.: 83-86-3 (Acid) Trade Name Rencal Iliso

Manufacturer Squibb Made

Country US Spain

Year Introduced 1962 -

Raw Materials Corn steep water Lime Cation exchange resin Manufacturing Process Cereal grains are particularly rich in phytates; corn steep water produced in the wet milling of corn, is one of the best sources of such material. To recover the phytate from corn steep water it is customary to neutralize the same with

2738

Phytonadione

an alkaline material, suitably lime, causing the phytate to precipitate as a crude salt which can be removed readily by filtration. This material contains substantial amounts of magnesium, even though lime may have been employed as precipitant, and traces of other metallic ions, as well as some proteinaceous materials and other contaminants from the steep water. It may be partially purified by dissolving in acid and reprecipitating but, nevertheless, such commercial phytates do not represent pure salts. They always contain some magnesium, appreciable amounts of iron and nitrogenous materials, and traces of heavy metals, such as copper. Heretofore, no economical method for preparing pure phytic acid was known. The classical method was to dissolve calcium phytate in an acid such as hydrochloric acid, and then add a solution of a copper salt, such as copper sulfate to precipitate copper phytate. The latter was suspended in water and treated with hydrogen sulfide, which formed insoluble copper sulfide and released phytic acid to the solution. After removing the copper sulfide by filtration, the filtrate was concentrated to yield phytic acid as a syrup. The phytic acid in the form of a calcium phytate press cake may however be contacted with a cation exchange resin to replace the calcium with sodium to yield phytate sodium. References Merck Index 7269 I.N. p. 25 Baldwin, A.R., Blatter, L.K. and Gallagher, D.M.; US Patent 2,815,360; December 3, 1957; assigned to Corn Products Refining Co.

PHYTONADIONE Therapeutic Function: Prothrombogenic vitamin Chemical Name: 2-Methyl-3-(3,7,11,15-tetramethyl-2-hexadecenyl)-1,4naphthalenedione Common Name: Vitamin K; Phytomeanadion; Phylloquinone Structural Formula:

Phytonadione

2739

Chemical Abstracts Registry No.: 84-80-0 Trade Name Mephyton Konakion Aquamephyton Mono-Kay Eleven-K Hymeron Kanavit Kativ-N Kayeine Kaywan K-Eine Keipole Kennegin Kephton Kinadione Kisikonon K-Top Wan Monodion Nichivita-K One-Kay Synthex P Vita-K Vitamine K1

Manufacturer MSD Roche MSD Abbott Nippon Shinyaku Yamanouchi Spofa Takeda Kanto Eisai Hokuriku Kyowa Kowa Toyo Jozo Chugai Kyorin Sawai Maruko Nichiiko Mohan Tanabe Kobayashi Delagrange

Country US US US US Japan Japan Czechoslovakia Japan Japan Japan Japan Japan Japan Japan Japan Japan Japan Japan Japan Japan Japan Japan France

Year Introduced 1941 1959 1960 1961 -

Raw Materials 2-Methyl-1,4-naphthohydroquinone Phytol Hydrogen Manufacturing Process 11 parts by weight of 2-methyl-1,4-naphthohydroquinone, 30 parts by volume of water-free dioxane and 1.5 parts by volume of boron trifluoride etherate are heated to 50°C. While agitating and introducing nitrogen, 10 parts by weight of phytol dissolved in 10 parts by volume of dioxane are added in the course of 15 minutes. Thereupon, the dark colored reaction mixture is stirred for 20 additional minutes at 50°C, cooled down and 60 parts by volume of ether are added. The reaction mixture is washed first with water, then with a mixture of 3 parts of N-sodium hydroxide and 2 parts of a 2.5% solution of sodium hydrosulfite and again with water. The aqueous extracts are washed with ether. The ether solutions are collected, dried over sodium sulfate and concentrated, toward the end under reduced pressure. The waxlike condensation product so obtained is mixed with 60 parts by volume of petroleum ether (boiling limits 30°C to 40°C) and agitated with hydrogen in the presence of a little active palladium lead catalyst (Pd-CaCO3

2740

Picoperine

catalyst, the activity of which is reduced by the addition of lead and quinoline). During the operation, the condensation product separates in the form of a voluminous white precipitate. The latter is separated by filtration in the absence of air while adding an inert coarse-grained adsorption agent (for example, aluminum silicate salt for filter purposes), and washed with cooled petroleum ether. Thereupon, the 2-methyl-3-phytyl-1,4-naphthohydroquinone is extracted from the filter cake by means of ether, the ethereal solution is concentrated to 100 parts by volume and the reaction product is oxidized by stirring the solution with 6.6 parts by weight of silver oxide during 30 minutes. The solution is filtered through sodium sulfate, the latter is rinsed with ether and the solvent is evaporated. There are obtained 5.7 parts by weight of 2-methyl-3-phytyl-1,4-naphthoquinone (vitamin K1) in the form of a golden yellow oil. References Merck Index 9834 Kleeman & Engel p. 724 PDR pp. 1140, 1488 I.N. p. 770 REM p. 1011 Isler, O. and Doebel, K.; US Patent 2,683,176; July 6, 1954; assigned to Hoffmann-La Roche, Inc.

PICOPERINE Therapeutic Function: Antitussive Chemical Name: N-(2-Piperidinoethyl)-N-(2-pyridylmethyl)aniline Common Name: Picoperamidine Structural Formula:

Chemical Abstracts Registry No.: 21755-66-8 Trade Name

Manufacturer

Country

Year Introduced

Coben

Takeda

Japan

1971

Picosulfate sodium

2741

Raw Materials N-(2-Pyridylmethyl)aniline Sodium amide 2-Piperidinoethyl chloride Manufacturing Process To a simultaneously stirred and refluxed suspension of 5.6 parts by weight of sodamide in 60 parts by volume of anhydrous toluene, there is added dropwise a solution of 18.4 parts by weight of N-(2-pyridylmethyl)aniline in 20 parts by volume of anhydrous toluene. After the addition is complete, the mixture is refluxed for two hours under constant stirring. To the resulting mixture there is added dropwise a solution of 14.9 parts by weight of 2-piperidinoethyl chloride in 20 parts by volume of anhydrous toluene and the whole mixture is stirred and refluxed for another two hours. After cooling, water is added carefully to decompose the unreacted sodamide, the separated toluene layer is dried over anhydrous sodium sulfate and the solvent removed under reduced pressure. The residual oil is subjected to distillation under reduced pressure, the fraction boiling in the range of 185°C to 198°C/4 mm Hg being collected. Purification of the fraction by redistillation under reduced pressure gives 22.5 parts by weight of N-(2-piperidinoethyl)-N-(2-pyridylmethyl)-aniline which boils at 195°C to 196°C/4 mm Hg. Yield 76.3%. References Merck Index 7285 DOT 8 (5) 185 (1972) I.N. p. 771 Mitano, S. and Kase, Y.; US Patent 3,471,501; October 7, 1969; assigned to Takeda Chemical Industries, Ltd.

PICOSULFATE SODIUM Therapeutic Function: Laxative Chemical Name: 4,4'-(2-Pyridinylmethylene)bisphenol-bis(hydrogen sulfate) (ester) disodium salt Common Name: Picosulfol Chemical Abstracts Registry No.: 10040-45-6 Raw Materials 2-Pyridine aldehyde Sodium hydroxide

2-Chlorophenol Chlorosulfonic acid

2742

Picosulfate sodium

Structural Formula:

Trade Name Guttalax Laxoberal Laxoberal Laxoberon Contumax Evacuol Gocce Euchessina Gocce Lassative Aicardi Laxante Azoxico Laxidogol Picolax Skilax Trali

Manufacturer De Angelini Thomae W.B. Pharm. Teijin Casen Almirall Antonetto Aicardi Bescansa Dolorgiet Falqui Prodes Sintyal

Country Italy W. Germany UK Japan Spain Spain Italy Italy Spain W. Germany Italy Spain Argentina

Year Introduced 1967 1972 1975 1980 -

Manufacturing Process Preparation of 3,3'-Dichloro-4,4'-Dioxy-Diphenyl-(2-Pyridyl)-Methane: 75 g (0.7 mol) of 2-pyridinaldehyde are dropped during about 1 hour to a homogeneous mixture [obtained between 0° and 10°C from 107 ml of concentrated sulfuric acid and 292.9 g (2.28 mols) of 2-chlorophenol], maintaining the temperature between 0° and 5°C. The mixture is stirred for ½ hour at this temperature, which is then allowed to rise spontaneously, taking care not to exceed 30°C. After stirring for 1½ hours, the mixture is maintained overnight at room temperature, then it is dissolved, with external cooling, with a 10% sodium hydroxide solution, filtered with charcoal and neutralized with 5% hydrochloric acid. The precipitate obtained, consisting of crude product, filtered, washed with water, dried, triturated with ether and dried again, weighs 211 g. The isomer 2,4'-dioxy-3,3'-dichloro-diphenyl-(2-pyridyl)-methane is removed by thoroughly washing with 430 ml of 95°C boiling alcohol, obtaining 167 g of isomer-free product (yield 69%). The 3,3'-dichloro-4,4'-dioxy-diphenyl-(2pyridyl)-methane is a white solid, crystallizing from 95% alcohol; MP 212° to 215°C.

Picosulfate sodium

2743

Preparation of 4,4'-Dioxy-Diphenyl-(2-Pyridyl)-Methane: 100 g of 3,3'dichloro-4,4'-dioxydiphenyl-(2-pyridyl)-methane, obtained as above described, are dissolved in 660 ml of 10% sodium hydroxide and 49 g of Raney-nickel alloy are added to the solution with vigorous stirring, at room temperature and during 4 hours. The mixture is stirred overnight at room temperature, then it is filtered and brought to pH 5 with 10% acetic acid. The precipitate obtained, filtered, washed and dried is then dissolved in 1,500 ml of 95°C boiling alcohol to eliminate the insoluble salts. The residue obtained after the evaporation of the alcoholic solution weighs 74 g (yield 92%). The yield in respect to 2-pyridinaldehyde is 63.5%. The compound is a white solid, crystallizing from 95% alcohol; MP 248° to 250.5°C, according to US Patent 3,558,643. Preparation of Disodium 4,4'-Disulfoxy-Diphenyl-(2-Pyridyl)-Methane: In ½ hour, 102 g chlorosulfonic acid are added to a solution of 100 g 4,4'dihydroxydiphenyl-(2-pyridyl)methane in 750 ml of anhydrous pyridine, the temperature being maintained at between 0° and 5°C. Towards the end of the addition of acid, a precipitate is formed which is slowly redissolved during subsequent agitation. Upon completion of the addition, the mixture is agitated for 7 hours at ambient temperature. The solution is then poured into 3 liters of water/ice obtaining a clear solution of dark yellow color which is rendered alkaline upon phenolphthalein with 30% NaOH and extracted with ethyl ether to eliminate the majority of the pyridine. The mixture is filtered with active charcoal, the pH adjusted to 8 with hydrochloric acid 1:1 and extracted with chloroform to remove the 4,4'-dihydroxydiphenyl-(2-pyridyl)-methane which has not reacted. The aqueous solution is then concentrated to dryness at an outside temperature of 40° to 45°C and at low pressure. The residue, obtained by drying in a vacuum at 40° to 45°C is triturated in a mortar with ethyl ether and, after filtration, is extracted with 3,400 ml boiling absolute ethanol. The ethanol extract is separated from the undissolved part by filtration, cooled and the product which crystallizes by cooling is filtered and dried at 40°C in a vacuum. In that manner the disodium (4,4'-disulfoxy-diphenyl)-(2pyridyl)methane bi-hydrate is obtained, which takes the form of a white solid, according to US Patent 3,528,986. References Merck Index 7286 Kleeman & Engel p. 725 DOT 8 (8) 302 (1972) I.N. p. 771 Pala, G.; US Patent 3,528,986; September 15, 1970; assigned to Istituto de Angeli S.p.A., Italy Pala, G.; US Patent 3,558,643; January 26, 1971; assigned to Istituto de Angeli S.p.A., Italy

2744

Pifarnine

PIFARNINE Therapeutic Function: Antiulcer Chemical Name: 1-(1,3-Benzodioxol-5-ylmethyl)-4-(3,7,11-trimethyl-2,6,10dodecatrienyl)piperazine Common Name: Structural Formula:

Chemical Abstracts Registry No.: 56208-01-6 Trade Name

Manufacturer

Country

Year Introduced

Pifazin

Pierrel

Italy

1983

Raw Materials 1-Bromo-3,7,11-trimethyl-2,6,10-dodecatriene Piperonylpiperazine Triethylamine Manufacturing Process A solution of 45 mmols of 1-bromo-3,7,11-trimethyl-2,6,10-dodecatriene (obtained from synthetic farnesol, commercially available and containing four isomers) in 10 ml of benzene was added dropwise at 0°C to a stirred solution of 45 mmols of piperonylpiperazine in 60 ml of benzene containing 5 g of triethylamine. The mixture was stirred for 2 hours and then the precipitated triethylammonium bromide was filtered off. The benzene solution was washed first with water and then with K2CO3 solution and finally dried (K2CO3). Removal of benzene under reduced pressure gave a crude oily residue which was dissolved in acetone and treated at 5°C to 8°C with a slight excess of 37% HCl solution. The precipitated hydrochloride was filtered, washed with acetone and with absolute ethanol. The corresponding base was purified on a silica gel column and the purity of all fractions was checked by thin layer chromatography and gas liquid chromatography. Thin layer chromatography on silica gel gave three spots in the solvent system ethylacetate-petrol ether 1:1. Gas liquid chromatography showed three peaks indicating the presence of four possible isomers. The pure product was a colorless oil.

Pilocarpine hydrochloride

2745

References Merck Index 7299 DFU 2 (12) 829 (1977) Kleeman and Engel p. 725 I.N. p. 772 Zumin, S.T., Riva, M. and Iafolla, G.; US Patent 3,875,163; April 1, 1975; assigned to Pierrel S.p.A. (Italy)

PILOCARPINE HYDROCHLORIDE Therapeutic Function: Cholinergic Chemical Name: 2(3H)-Furanone, 3-ethyldihydro-4-[(1-methyl-1H-imidazol5-yl)methyl]-, (3S-cis)-, monohydrochloride Common Name: Pilocarpine hydrochloride; Pilokarpin hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 54-71-7; 92-13-7 (Base) Trade Name Andre Carpine Pilokarpine hydrochloride Pilokarpine hydrochloride Pilokarpine hydrochloride

Manufacturer Andre Laboratries Pvt. Ltd. Merck KGaA

Country India Germany

Year Introduced -

Boehringer Ingelheim Pharma KG Sigma

Germany

-

-

-

Raw Materials Sodium hydride Palladium on carbon Diisobutylaluminum hydride Hydrogen chloride

Ethyl diethylphosphonoethoxyacetate 1-Methylimidazole-5-aldehyde 2-Diethylphosphonobutyric acid 4-Dimethylaminopyridine

Manufacturing Process The 1-methylimidazole-5-aldehyde is easily accessible from sarcosine methyl ester hydrochloride and dimethylamino-2-azaprop-2-en-1-

2746

Pilocarpine hydrochloride

ylidenedimethylammonium. 0.14 mol of ethyl diethylphosphonoethoxyacetate is slowly added dropwise with stirring and under inert gas to a suspension of 0.14 mol of NaH (paraffinfree) in 250 ml of abs. THF, the mixture is stirred for 1 h at 20°C and a solution of 0.093 mol of 1-methylimidazole-5-aldehyde in 100 ml of abs. THF is added dropwise. After stirring at 20°C for 10 min, the solvent is distilled off in vacuo, the residue is taken up in a little H2O, and the solution is acidified with 1 N HCl and washed several times with ether. The aqueous phase is rendered alkaline using 2 N NaOH with cooling (0°-5°C) and extracted several times with CH2Cl2. After drying of the organic extracts with Na2SO4, the solvent is removed in vacuo and 2-ethoxy-3-[(1-methyl-1H-imidazol-5yl)methyl]-acrilic acid ethyl ester. Yield: 99% of theory. 122 ml of 45% diisobutylaluminum hydride solution (328 mmol) are slowly added dropwise under inert gas, with stirring and ice cooling, to a solution of 137 mmol of 2-ethoxy-3-[(1-methyl-1H-imidazol-5-yl)methyl]-acrilic acid ethyl ester in 600 ml of abs. C6H6. Stirring of the mixture is continued for a further 30 min at 0°-5°C and 600 ml of CH3OH, then 100 ml of H2O, are slowly added. The hydroxide precipitate is filtered off with suction and washed several times with hot CH3OH. After drying of the combined filtrates the solvents are distilled off in vacuo and the residue is crystallized using C2H5OH. 2-ethoxy-3-[(1-methyl-1H-imidazol-5-yl)methyl]-prop-2-en-1-ol was obtained. Yield: 100% of theory. The crude product is pure enough for the subsequent reaction. Recrystallization of an analytical sample from CH3OH/acetone: melting point 129°C. A solution of 58 mmol of 2-ethoxy-3-[(1-methyl-1H-imidazol-5-yl)methyl]prop-2-en-1-ol in 116.6 ml of HCl (= 116.6 mmol) is stirred at 30°-35°C for 1.5 h and concentrated in vacuo at the same temperature. The residual HCl is removed by distillation with CHCl3 in vacuo. After seeding, the residue crystallizes at 20°C (15 h) 1-hydroxy-3-[(1-methyl-1H-imidazol-5-yl)methyl]propan-2-one hydrochloride. The crystallizate is filtered off with suction, washed with a little CH3OH and dried in vacuo. Yield: 86% of theory; melting point 190°C. About 80-90% of the equivalent amount of NaOCH3 solution in CH3OH is slowly added dropwise at 20°C with stirring and exclusion of moisture to a suspension of 21.24 mmol of 1-hydroxy-3-[(1-methyl-1H-imidazol-5yl)methyl]-propan-2-one hydrochloride in 80 ml of CH3OH, in the course of which the pH of 6.5 is not to be exceeded. The solvent is distilled off in vacuo at a maximum of 30°C and the residue of 1-hydroxy-3-[(1-methyl-1Himidazol-5-yl)methyl]-propan-2-one is purified by flash chromatography (silica gel; CHCl3/CH3OH). Yield: 100% of theory; viscous, orange-colored oil. Catalytic amounts of 4-dimethylaminopyridine and a solution of 21.3 mmol of 1-hydroxy-3-[(1-methyl-1H-imidazol-5-yl)methyl]-propan-2-one in 80 ml of CH2Cl2 are added to a solution of 26.44 mmol of 2-diethylphosphonobutyric acid in 40 ml of purified CH2Cl2. After cooling to 0°-5°C, a solution of 23.5 mmol of dicyclohexylcarbodiimide in 60 ml of CH2Cl2 is added dropwise and the mixture is stirred for 1 h at 0°-5°C and for 2 h at 20°C. The crystallized

Pimefylline nicotinate

2747

dicyclohexylurea is filtered off with suction and the filtrate is washed with H2O and saturated NaHCO3 solution. After drying of the organic phase the solvent is distilled off at 30°C in vacuo and the residue of 2-diethoxy-phosphoryl)butyric acid 3-[(1-methyl-1H-imidazol-5-yl)methyl]-2-oxo-propyl ester is purified by flash chromatography (silica gel; ethyl acetate/CH3OH). Yield: 95% of theory of a viscous, orange-colored oil. A mixture of 5 mmol each of 80% NaH and 15-crown-5 in 50 ml of absol. toluene is stirred at 20°C under inert gas for 10 min and a solution of 5 mmol of 2-diethoxy-phosphoryl)-butiric acid 3-[(1-methyl-1H-imidazol-5-yl)methyl]2-oxo-propyl ester in 50 ml of absol. toluene is then added dropwise. Stirring is continued for a further 15 min under inert gas and the mixture is hydrolyzed with a little water until phase separation is detectable. After separating off the organic phase, the aqueous layer is saturated with NaCl and extracted several times with CHCl3. The combined organic phases are the solvent is distilled off at 40°C in vacuo and the residue 3-ethyl-4-[(1-methyl1H-imidazol-5-yl)methyl]-5H-furan-2-one is purified twice by flash chromatography (silica gel; ethyl acetate/CH3OH). Yield: 52% of theory; virtually colorless oil. 1.36 mmol of 3-ethyl-4-[(1-methyl-1H-imidazol-5-yl)methyl]-5H-furan-2-one in 15.5 ml of CH3OH are hydrogenated for 5 h at 50 bar and 60°C using 210 mg of Pd/carbon (10%). After filtering off the catalyst and distilling off the solvent at 30°C in vacuo, the oily residue (about 250 mg) is treated with 10 ml of 1 N HCl and the mixture is stirred for 3 h at 20°C. The hydrochloric acid is distilled off in vacuo at 35°-40°C, the oily residue is taken up in a little CH3OH and ether is added. The precipitate of pilocarpine hydrochloride is recrystallized from CH3OH/ether. Yield: 73% of theory; melting point 210°C. References Reimann E.; US Patent No. 5,530,136; Jan. 25, 1996; Assigned: Merck Patent Gesellschaft Mit Beschrankter Haftung, Darmsstadt, Germany Reuther G.R.; US Patent No. 5,059,531; Oct. 22, 1991; Assigned: Merck Patent Gesellschaft Mit Beschrankter Haftung, Darmsstadt, Germany Courtois D. et al.; US Patent No. 5,569,593; Oct. 29, 1996; Assigned: Nestec S.A.,Vevey, Switzerland

PIMEFYLLINE NICOTINATE Therapeutic Function: Coronary vasodilator Chemical Name: 3,7-Dihydro-1,3-dimethyl-7-[2-[(3-pyridinylmethyl)amino] ethyl]-1H-purine-2,6-dione nicotinate Common Name: 7-(β-3'-Picolylaminoethyl)theophylline nicotinate

2748

Pimefylline nicotinate

Structural Formula:

Chemical Abstracts Registry No.: 10058-07-8; 10001-43-1 (Base) Trade Name Teonicon Teonicon

Manufacturer Bracco Neopharmed

Country Italy Japan

Year Introduced 1975 -

Raw Materials 7-(2-Bromethyl)theophylline 3-Picolylamine Nicotinic acid Manufacturing Process 77 g 7-(β-bromoethyl)-theophylline (C.A. 50, 12071f) and 57.8 g 3picolylamine in 750 ml toluene were refluxed 16 hours with vigorous agitation. The 3-picolylamine hydrobromide formed was filtered off, and the filtrate was evaporated in a vacuum to about one-third of its original volume. About 300 to 400 ml diisopropyl ether were added, and the solution was seeded with a few pure crystals of the desired product. 7-(β-3'-picolylaminoethyl)-theophylline crystallized over a period of a few hours. It was filtered off with suction, washed with a little diisopropyl ether, and dried. The yield of crude product was 69.3 g (82%), its MP 103° to 106°C. The MP was 111° to 112°C after recrystallization from isopropyl acetate. The compound was identified by microanalysis. 39.3 g 7-(β-3'-picolylaminoethyl)-theophylline were dissolved in 300 ml boiling isopropanol, and 15.4 g nicotinic acid were added to the solution in which the acid promptly dissolved. The nicotinate formed crystallized after a short time. It was filtered with suction and dried. The yield was 52.3 g (95.5%). The MP of 159° to 160°C was not significantly changed by recrystallization from ethanol. References Merck Index 7306

Pimozide

2749

Kleeman & Engel p. 727 Suter, H. and Zutter, H.; US Patent 3,350,400; October 31, 1967; assigned to Eprova Limited, Switzerland

PIMOZIDE Therapeutic Function: Antipsychotic Chemical Name: 1-[1-[4,4-Bis(4-fluorophenyl)butyl]-4-piperidinyl]-1,3dihydro-2H-benzimidazol-2-one Common Name: Structural Formula:

Chemical Abstracts Registry No.: 2062-78-4 Trade Name Orap Opiran Orap Orap Orap Norofren Oralep Pimotid

Manufacturer Janssen Cassenne Janssen Fujisawa Janssen Dif-Dogu Abic Medica

Country W. Germany France UK Japan Italy Turkey Israel Finland

Raw Materials Thionyl chloride Cyclopropyl-di-(4-fluorophenyl)-carbinol Hydrogen 4-(2-Oxo-1-benzimidazolinyl)piperidine

Year Introduced 1971 1971 1971 1974 1977 -

2750

Pinazepam

Manufacturing Process To a solution of 130 parts cyclopropyl-di-(4-fluorophenyl)-carbinol in 240 parts benzene are added dropwise 43 parts thionyl chloride. The whole is refluxed until no more gas is evolved. The reaction mixture is then evaporated. The residue is distilled in vacuo, yielding 4-chloro1,1-di-(4-fluorophenyl)-1-butene, boiling point 165°C to 167°C at 6 mm pressure; nD20: 1.5698; d2020:1.2151. A solution of 61 parts 4-chloro-1,1-di-(4-fluorophenyl)-1-butene in 400 parts 2-propanol is hydrogenated at normal pressure and at room temperature in the presence of 5.5 parts palladium-on-charcoal catalyst 10% (exothermic reaction: temperature rises to about 30°C). After the calculated amount of hydrogen is taken up, hydrogenation is stopped. The catalyst is filtered off and the filtrate is evaporated. The oily residue is distilled in vacuo, yielding 1chloro-4,4-di-(4-fluorophenyl)-butane, boiling point 166°C to 168°C at 6 mm pressure; nD20: 1.5425; d2020:1.2039. To a mixture of 4.4 parts of 4-(2-oxo-1-benzimidazolinyl)-piperidine, 3.3 parts sodium carbonate, a few crystals of potassium iodide in 200 parts 4-methyl-2pentanone are added portionwise 6.2 parts 1-chloro-4,4-di-(4-fluorophenyl)butane. After the addition is complete, the whole is stirred and refluxed for 65 hours. After cooling the reaction mixture, there are added 70 parts water. The organic layer is separated, dried over potassium carbonate, filtered and evaporated. The solid residue is triturated in diisopropyl-ether, filtered off again and recrystallized from a mixture of 120 parts acetone and 80 parts 4methyl-2-pentanone, yielding the crude product. After recrystallization of this crop from 80 parts acetone, 1-[4,4-di-(4fluorophenyl)-butyl]-4-(2-oxo-1benzimidazolinyl)-piperidine is obtained, melting point 217°C to 219°C. References Merck Index 7310 Kleeman & Engel p. 727 PDR p. 1091 OCDS Vol. 2 p. 390 (1980) DOT 5 (1) 36 (1969); 7 (5) 176 (1971); and 9 (6) 235 (1973) I.N. p. 774 REM p. 1092 Janssen, P.A.J.; US Patent 3,196,157; July 20, 1965; assigned to Research Laboratorium Dr. C. Janssen N.V. (Belgium)

PINAZEPAM Therapeutic Function: Antidepressant Chemical Name: 7-Chloro-1,3-dihydro-5-phenyl-1-(2-propynyl)-2H-1,4benzodiazepin-2-one Common Name: -

Pinazepam

2751

Structural Formula:

Chemical Abstracts Registry No.: 52463-83-9 Trade Name

Manufacturer

Country

Year Introduced

Domar

Zambeletti

Italy

1975

Duna

Zambeletti

Italy

-

Raw Materials Propargyl bromide 2-Amino-5-chlorobenzophenone Hydrazine hydrate Phthalimidoacetyl chloride Manufacturing Process 46.3 g (0.2 mol) of 2-amino-5-chlorobenzophenone were dissolved in 100 ml (1.28 mols) of propargyl bromide and the mixture refluxed for 4 hours. Thereafter, the whole was evaporated to dryness and the residue recrystallized from methanol to give 32.4 g (60.2%) of the desired 2-propargylamino-5chlorobenzophenone; melting point 92°C to 93°C. 2.7 g (0.01 mol) of the 2-propargylamino-5-chlorobenzophenone obtained as above and 2.23 g (0.01 mol) of phthalimidoacetyl chloride were added to 30 ml of chloroform and the whole was refluxed overnight. Thereafter, the reaction mixture was evaporated to dryness and the residue recrystallized from methanol to give 2.66 g (58.3%) of the desired 2-(Npropargyl)phthalimidoacetamide-5-chlorobenzophenone. Melting point: 176°C. A suspension of 22.8 g (0.05 mol) of 2-(N-propargyl)-phthalimidoacetamido5-chlorobenzophenone in 250 ml ethanol containing 7.5 g hydrazine hydrate (0.15 mol) was heated under reflux for 2 hours, at the end of which time the reaction mixture was set aside overnight at ambient (25°C) temperature. Thereafter, the crystalline phthalyl hydrazide which had precipitated out was removed by filtration and washed with 3 x 50 ml aliquots of chloroform. The filtrate and washings were diluted with water and exhaustively extracted with chloroform. The chloroform extract was then evaporated and the residue washed with 100 ml hexane to promote crystallization. The crude 7-chloro-1propargyl-3H-1,4-benzodiazepine-2(1H)-one was recrystallized from a methanol-water mixture to give 10.5 g (71.4%) of the pure product. Melting point: 140°C to 142°C.

2752

Pindolol

References Merck Index 7316 Kleeman & Engel p. 728 DOT 12 (4) 147 (1976) I.N. p. 774 Podesva, C. and Vagi, K.; US Patent 3,842,094; October 15, 1974; assigned to Delmar Chemicals Ltd. (Canada)

PINDOLOL Therapeutic Function: Beta-adrenergic blocker Chemical Name: 2-Propanol, 1-(1H-indol-4-yloxy)-3-((1-methylethyl)amino)Common Name: Pindolol: Prindolol Structural Formula:

Chemical Abstracts Registry No.: 13523-86-9 Trade Name Betadren Cardilate Lizenil

Manufacturer Lagap Teikoku Nippon Kayaku

Country -

Year Introduced -

Raw Materials Sodium amide Hydrogen Epichlorohydrin Isopropylamine

Ammonia Palladium on aluminum oxide Sodium hydroxide Tartaric acid

Manufacturing Process 4-Hydroxyindole is obtained by debenzylation of 4-benzyloxyindole with hydrogen in the presence of a 5% palladium catalyst on aluminium oxide. 10.0 g of 4-hydroxyindole and subsequently 7.4 ml of epichlorohydrin are added while stirring in an atmosphere of nitrogen to a solution of 2.73 g of sodium hydroxide in 65 ml of water. Stirring is effected at room temperature

Pioglitazone hydrochloride

2753

for a further 15 h, the reaction mixture is extracted 4 times with 50 ml of methylene chloride and the combined organic layers which have been dried over magnesium sulfate are evaporated at reduced pressure. So 3-chloro-1(4-indolyloxy)-2-propanol is obtained. The 3-chloro-1-(4-indolyloxy)-2-propanol is dissolved in 50 ml of toluene and 50 ml of isopropylamine and heated to the boil for 45 h. Evaporation to dryness is effected in a vacuum, the residue is shaken out thrice between ethyl acetate and a 1 N tartaric acid solution and a 5 N sodium hydroxide solution is then added to the combined tartaric acid phases until an alkaline reaction is obtained. The alkaline solution is shaken out thrice with 50 ml of methylene chloride, the extracts are dried over magnesium sulfate and the solvent evaporated in vacuum. The residue is crystallized from ethyl acetate/ether to give the 4-(2-hydroxy-3-isopropylaminopropoxy)indole. References Troxler F., Hofmann A.; GB Patent No. 1,138,968; Jan. 13, 1966; Assigned: Sandoz Ltd., of Lichtstrasse 35, Basle, Switzerland, a Swiss Body Corporate

PIOGLITAZONE HYDROCHLORIDE Therapeutic Function: Antidiabetic Chemical Name: (+-)-2,4-Thiazolidinedione, 5-((4-(2-(5-ethyl-2-pyridinyl) ethoxy)phenyl)methyl), monohydrochloride Common Name: Pioglitazone hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 112529-15-4; 111025-46-8 (Base) Trade Name

Manufacturer

Country

Year Introduced

Actos

Eli Lilly

USA

-

Actos

Takeda Pharmaceuticals

USA

-

Actos

Takeda Chemical Industry

Japan

-

2754

Pioglitazone hydrochloride

Raw Materials Palladium on carbon Hydrogen bromide 4-Fluoronitrobenzene NaNO2 Methyl acrylate

2-(5-Ethyl-2-pyridyl)ethanol Copper oxide Sodium hydride Sodium methylate Sodium acetate

Manufacturing Process To a solution of 2-(5-ethyl-2-pyridyl)ethanol (53.0 g) and 4-fluoronitrobenzene (47.0 g) in DMF (500 ml) was added portionwise under ice-cooling 60% sodium hydride in oil (16.0 g). The mixture was stirred under ice-cooling for one hour, then at room temperature for 30 min, poured into water and extracted with ether. The ether layer was washed with water and dried (MgSO4). The solvent was evaporated off to give 4-[2-(5-ethyl-2pyridyl)ethoxy]nitrobenzene as crystals (62.0 g, 62.9%). Recrystallization from ether-hexane gave colorless prisms, melting point 53°-54°C. A solution of 4-[2-(5-ethyl-2-pyridyl)ethoxy]nitrobenzene (60.0 g) in methanol (500 ml) was hydrogenated at room temperature under one atmospheric pressure in the presence of 10% Pd-C (50% wet, 6.0 g). The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residual oil was dissolved in acetone (500 ml)methanol (200 ml). To the solution was added a 47% HBr aqueous solution (152 g). The mixture was cooled, to which was added dropwise a solution of NaNO2 (17.3 g) in water (30 ml) at a temperature not higher than 5°C. The whole mixture was stirred at 5°C for 20 min, then methyl acrylate (112 g) was added thereto and the temperature was raised to 38°C. Cuprous oxide (2.0 g) was added to the mixture in small portions with vigorous stirring. The reaction mixture was stirred until nitrogen gas evolution ceased, and was concentrated under reduced pressure. The concentrate was made alkaline with concentrated aqueous ammonia, and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4) The solvent was evaporated off to leave methyl 2-bromo-3-{4-[2-(5-ethyl-2pyridyl)ethoxy]phenyl}propionate as a crude oil (74.09 g, 85.7%). A mixture of the crude oil of methyl 2-bromo-3-{4-[2-(5-ethyl-2pyridyl)ethoxy]phenyl}propionate (73.0 g) thiourea (14.2 g), sodium acetate (15.3 g) and ethanol (500 ml) was stirred for 3 hours under reflux. The reaction mixture was concentrated under reduced pressure, and the concentrate was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, to which were added water (200 ml) and ether (100 ml). The whole mixture was stirred for 10 min to yield 5-{4-[2-(5-ethyl-2pyridyl)ethoxy]benzyl}-2-imino-4-thiazolidinone as crystals (0.3 g, 523.0%). Recrystallization from methanol gave colorless prisms, melting point 187°188°C, dec. A solution of 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2-imino-4thiazolidinone (23.5 g) in 2 N HCl (200 ml) was refluxed for 6 hours. The solvent was evaporated off under reduced pressure, and the residue was neutralized with a saturated aqueous solution of sodium hydrogencarbonate. The crystals (23.5 g, 97.5%) which precipitated were collected by filtration

Pipamazine

2755

and recrystallized from DMF-H2O to give 5-{4-[2-(5-ethyl-2pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione as colorless needles (20.5 g, 86.9%), melting point 183°-184°C. In practice it is usually used as hydrochloride salt. References Meguro K., Fujita T.; US Patent No. 4,687,777; August 18, 1987; Assigned: Takeda Chemical Industries, LTD., Osaka, Japan

PIPAMAZINE Therapeutic Function: Antiemetic Chemical Name: 1-[3-(2-Chloro-10H-phenothiazin-10-yl)propyl]-4pyridinecarboxamide Common Name: Structural Formula:

Chemical Abstracts Registry No.: 84-04-8 Trade Name Mornidine Nausidol

Manufacturer Searle Gremy-Longuet

Country US France

Year Introduced 1959 -

Raw Materials 4-Piperidinecarboxamide 2-Chloro-10-(γ-chloropropyl)phenothiazine Manufacturing Process To a stirred and refluxing suspension of 4.95 parts of 4piperidinecarboxamide, 1 part of sodium iodide and 8.4 parts of potassium carbonate in 40 parts of butanone there are added in the course of 30 minutes 9.3 parts of 2-chloro-10-(γ-chloropropyl)phenothiazine in 40 parts of

2756

Pipamperone

butanone. Stirring and refluxing are continued for 12 hours after which the mixture is cooled and filtered. The filtrate is concentrated under vacuum to give a residue which is recrystallized from a mixture of 2-propanol and petroleum ether. The 1-[γ-(2'-chloro-10'-phenothiazine)propyl]piperidine-4carboxamide thus obtained melts at approximately 139°C. This base is dissolved in a small amount of 2-propanol and treated with a 25% solution of hydrogen chloride in 2-propanol. Upon treatment of this solution with anhydrous ether a hydrochloride precipitates as a white solid melting at about 196°C to 197°C with formation of bubbles. References Merck Index 7326 Kleeman & Engel p. 729 OCDS Vol. 1 p. 385 (1977) I.N. p. 775 Cusic, J.W. and Sause, H.W.; US Patent 2,957,870; October 25, 1960; assigned to G.D. Searle & Co.

PIPAMPERONE Therapeutic Function: Antipsychotic Chemical Name: 1'-[4-(4-Fluorophenyl)-4-oxobutyl]-[1,4'-bipiperidine]-4'carboxamide Common Name: Floropipamide Structural Formula:

Chemical Abstracts Registry No.: 1893-33-0 Trade Name

Manufacturer

Country

Year Introduced

Dipiperon

Janssen

W. Germany

1961

Dipiperon

Janssen-Le Brun

France

1968

Piperonil

Lusofarmaco

Italy

1970

Propitan

Eisai

Japan

-

Pipamperone

2757

Raw Materials Piperidine hydrochloride Potassium cyanide Sulfuric acid

1-Benzyl-4-piperidone γ-Chloro-4-fluorobutyrophenone Hydrogen

Manufacturing Process To a stirred solution of 130.4 parts of potassium cyanide and 243.2 parts of piperidine hydrochloride in a mixture of 800 parts of water and 320 parts of ethanol is added portionwise 378 parts of 1-benzyl-4-piperidone. After about one hour a solid starts to precipitate. Stirring is continued for 24 hours. The reaction mixture is filtered and the solid is recrystallized from 1,200 parts of diisopropyl ether. On cooling to room temperature a first crop of 1-benzyl-4cyano-4-piperidinopiperidine melting at about 104°C to 106°C is obtained. By concentrating and further cooling of the mother liquor a second crop of the above compound is obtained. A mixture of 14.1 parts of 1-benzyl-4-cyano-4-piperidinopiperidine and 40 parts of 90% sulfuric acid is heated on a steam bath for 10 minutes. Without further heating, the mixture is stirred until a temperature of about 20°C is obtained. The mixture is then poured into 150 parts of ice-water and the resultant solution is alkalized with excess ammonium hydroxide solution. The aqueous solution is decanted from the precipitated oil. On treating this oil with 80 parts of acetone, crystallization sets in. After one hour the solid is filtered off and dried to yield 1-benzyl-4-piperidinopiperidine-4-carboxamide melting at about 137.5°C to 140°C. A mixture of 215 parts of 1-benzyl-4-piperidinopiperidine-4-carboxamide, 1,200 parts of isopropyl alcohol, 1,000 parts of distilled water and 157 parts of hydrogen chloride is debenzylated under atmospheric pressure and at a temperature of about 40°C in the presence of 40 parts of a 10% palladiumon-charcoal catalyst. After the calculated amount of hydrogen is taken up, hydrogenation is stopped. The mixture is filtered and the filtrate is evaporated. The semisolid residue is treated with a mixture of 80 parts of acetone and 80 parts of benzene and evaporated again. The residue is triturated in 200 parts of methanol and filtered, yielding the dihydrochloride of 4-piperidinopiperidine-4-carboxamide melting at about 299°C to 300.8°C with decomposition. A sample of 20 parts of the dihydrochloride is dissolved in 30 parts of water. The aqueous solution is alkalized with 15 parts of 44% sodium hydroxide and stirred for a short time. The solid obtained is filtered off yielding crude product. To separate the free base from organic and inorganic salts, it is extracted overnight in a Soxhlet apparatus with toluene. The toluene extract is evaporated and the solid residue is filtered off, yielding 4piperidinopiperidine-4-carboxamide melting at about 118.5°C to 119.5°C. To a mixture of 4.1 parts of 4-piperidinopiperidine-4-carboxamide, 6.4 parts of sodium carbonate, and a few crystals of potassium iodide in 100 parts of anhydrous toluene is added dropwise a solution of 5.6 parts of γ-chloro-4fluorobutyrophenone and 40 parts of anhydrous toluene at a temperature of 30°C to 40°C. The mixture is stirred and refluxed for 48 hours. The reaction mixture is cooled and divided between 50 parts of water and 60 parts of chloroform. The combined organic layers - toluene and chloroform - are dried over potassium carbonate, filtered, and evaporated. The oily residue solidifies

2758

Pipazethate

on treatment with 80 parts of ether. After cooling for 30 minutes at 0°C, there is obtained 1-[γ-(4-fluorobenzoyl)propyl]-4-piperidinopiperidine-4-carboxamide melting at about 124.5°C to 126°C. References Merck Index 7327 Kleeman & Engel p. 729 OCDS Vol. 2 p. 388 (1980) I.N. p. 775 Janssen, P.A.J.; US Patent 3,041,344; June 26, 1962; assigned to Research Laboratorium Dr. C. Janssen N.V. (Belgium)

PIPAZETHATE Therapeutic Function: Antitussive Chemical Name: 10H-Pyrido[3,2-b][1,4]benzothiadiazine-10-carboxylic acid 2-(2-piperidinoethoxy)ethyl ester Common Name: Structural Formula:

Chemical Abstracts Registry No.: 2167-85-3; 6056-11-7 (Hydrochloride salt) Trade Name Theratuss Dipect Lenopect Selvigon

Manufacturer Squibb Draco Draco Homburg

Country US Sweden Sweden W. Germany

Raw Materials 1-Azaphenothiazine carboxylic acid chloride Piperidinoethoxy ethanol

Year Introduced 1962 -

Pipebuzone

2759

Manufacturing Process 8.5 parts of 1-azaphenothiazine carboxylic acid chloride and 14 parts of piperidino-ethoxyethanol were introduced into 100 parts of chlorobenzene and the mixture boiled under reflux for 5 minutes. After cooling off the precipitated hydrochloride salt of piperidino-ethoxyethanol was filtered off on a suction filter. Water was added to the filtrate and the pH thereof adjusted to 5 to 6 with dilute HCl. The aqueous phase was then removed, a caustic soda solution added thereto and then extracted with ether. The ethyl extract was washed with water, then dried with potash and the ether distilled off. 9.4 parts of the piperidino-ethoxy-ethyl ester of 1-azaphenothiazine carboxylic acid were obtained. This product was dissolved in 20 parts of isopropanol and the solution neutralized with isopropanolic HCl. The monohydrochloride which precipitated out after recrystallization from isopropanol had a melting point of 160°C to 161°C. References Merck Index 7328 Kleeman & Engel p. 730 OCDS Vol. 1 p. 390 (1977) I.N. p. 775 Schuler, W.A.; US Patent 2,989,529; June 20, 1961; assigned to Degussa (Germany)

PIPEBUZONE Therapeutic Function: Antiinflammatory Chemical Name: 1,2-Diphenyl-3,5-dioxo-4-n-butyl-4-(N'methylpiperazinomethyl)pyrazolidine Common Name: Structural Formula:

Chemical Abstracts Registry No.: 27315-91-9

2760

Pipemidic acid

Trade Name Elarzone

Manufacturer Dausse

Country France

Year Introduced 1973

Raw Materials Phenylbutazone Formaldehyde N-Methylpiperazine Manufacturing Process 77 g (0.25 mol) of phenylbutazone, 30 ml of a 30% strength solution of formaldehyde and 50 ml of ethyl alcohol are introduced into a 500 ml flask, 25 g (0.25 mol) of N-methylpiperazine are slowly added to this mixture which is stirred mechanically. The mixture is then heated for one hour on a water bath, left to cool, and crystallization started by scratching. After being left in the refrigerator overnight the mixture, which has set solid, is triturated with 50 ml of isopropyl alcohol and the solid product filtered off and dried in vacuo over phosphorus pentoxide. 63 g (60% yield) of 1,2diphenyl-3,5-dioxo-4-n-butyl-4-(N'-methylpiperazinomethyl)pyrazolidine are obtained, melting at 129°C after recrystallization from 150 ml of isopropyl alcohol. References Merck Index 7329 Kleeman & Engel p. 730 DOT 9 (11) 476 (1973) I.N. p. 775 Dausse, S.A.; British Patent 1,249,047; October 6, 1971

PIPEMIDIC ACID Therapeutic Function: Antibacterial (urinary) Chemical Name: 8-Ethyl-5,8-dihydro-5-oxo-2-(1-piperazinyl)pyrido[2,3d]pyrimidine-6-carboxylic acid Common Name: Piperamic acid Structural Formula:

Pipemidic acid

2761

Chemical Abstracts Registry No.: 51940-44-4 Trade Name Pipram Deblaston Pipram Dolcol Pipram Pipedac Deblaston Filtrax Gastrurol Memento Nuril Pipedase Pipemid Pipurin Priper Septidron Tractur Uropimid Urotractin Uroval

Manufacturer Bellon Madaus RBS Pharma Dainippon Bellon Mediolanum Madaus Biomedica Foscama Gibipharma Volpino Prodes Scalari Gentili Brocchieri Syncro Ethimed Baldacci C.T. Zambeletti Firma

Country France W. Germany Italy Japan Italy Italy Switz. Italy Italy Argentina Spain Italy Italy Italy Argentina S. Africa Italy Italy Italy Italy

Year Introduced 1975 1975 1978 1979 1979 1980 1981 -

Raw Materials Sodium hydroxide Diethyl sulfate Piperazine hydrate

6-Amino-2-methylthiopyrimidine Ethoxymethylene malonic acid diethyl ester

Manufacturing Process A mixture containing 1.33 g of 5,8-dihydro-8-ethyl-2-methylthio-5oxopyridol[2,3-d]pyrimidine-6-carboxylic acid, 1.94 g of piperazine hexahydrate and 20 ml of dimethyl sulfoxide was heated at 110°C for 1 hour with stirring. The separated solid was collected by filtration, washed with ethanol, and then dried at such a temperature that did not rise above 50°C to give 1.57 g of the trihydrate of the product as nearly colorless needles, MP 253° to 255°C. The starting material may be produced by reacting 6-amino-2methylthiopyrimidine with ethoxymethylene malonic acid diethyl ester. The intermediate thus produced is converted by boiling in diphenyl ether to 6ethoxycarbonyl-2-methylthio-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine. That is hydrolyzed by sodium hydroxide to cleave the ethoxy group and then ethylated with diethyl sulfate to give the starting material. References Merck Index 7332 Kleeman & Engel p. 731

2762

Pipenzolate bromide

DOT 11 (10, 408 (1975) & 12 (3) 99 (1976) I.N. p. 36 Minami, S., Matsumoto, J.-I., Kawaguchi, K., Mishio, S., Shimizu, M., Takase, Y. and Nakamura, S.; US Patent 3,887,557; June 3, 1975; assigned to Dainippon Pharmaceutical Co. Ltd., Japan Minami, S., Matsumoto, J.-I., Kawaguchi, K., Mishio, S., Shimizu, M., Takase, Y. and Nakamura, S.; US Patent 3,962,443; June 8, 1976; assigned to Dainippon Pharmaceutical Co. Ltd., Japan

PIPENZOLATE BROMIDE Therapeutic Function: Spasmolytic Chemical Name: 1-Ethyl-3-[(hydroxydiphenylacetyl)oxy]-1methylpiperidinium bromide Common Name: N-Ethyl-3-piperidyl benzilate methobromide Structural Formula:

Chemical Abstracts Registry No.: 125-51-9 Trade Name Piptal Piptal Piper

Manufacturer Merrell National Roger Bellon Panthox and Burck

Country US France Italy

Year Introduced 1955 1960 -

Raw Materials N-Ethyl-3-chloropiperidine Benzilic acid Methyl bromide Manufacturing Process N-ethyl-3-chloropiperidine was prepared according to the method of Fuson and Zirkle described in Volume 70, J. Am. Chem. Soc., p 2760. 12.0 g (0.081 mol) of N-ethyl-3-chloropiperidine was mixed with 18.6 g (0.081 mol) of benzilic acid and 80 cc of anhydrous isopropyl alcohol as a solvent. The mixture was refluxed for 72 hours. The solution was then filtered and concentrated at 30 mm of mercury. The concentrate was dissolved in water, acidified with hydrochloric acid and extracted with ether to remove the

Piperacillin sodium

2763

unreacted benzilic acid. The aqueous layer was neutralized with sodium bicarbonate and the product was extracted with ether. The ethereal solution of the product was dried with potassium carbonate, the ether was removed by distillation and the residue was distilled at 0.12 to 0.18 mm of mercury, the BP being 194° to 198°C. A yield of 16.5 g (60% of theoretical) of N-ethyl-3-piperidyl-benzilate was obtained. 34 g (0.1 mol) of the basic ester is dissolved in 75 cc of isopropyl alcohol and treated with 9.5 g (0.1 mol) of methyl bromide. The mixture is allowed to stand at room temperature until precipitation is complete. The product is removed by filtration and washed with isopropyl alcohol, yield 33 g, MP 175° to 177°C. On recrystallization from isopropyl alcohol, the MP was raised to 179° to 180°C dec. References Merck Index 7333 Kleeman & Engel p. 732 I.N. p 776 Biel, J.H.; US Patent 2,918,406; December 22, 1959; assigned to Lakeside Laboratories, Inc.

PIPERACILLIN SODIUM Therapeutic Function: Antibiotic Chemical Name: Sodium salt of 6-[D(-)-α-(4-ethyl-2,3-dioxo-1piperazinocarbonylamino)phenylacetamido]penicillanic acid Common Name: Structural Formula:

Chemical Abstracts Registry No.: 59703-84-3; 61477-96-1 (Base)

2764

Piperacillin sodium

Trade Name

Manufacturer

Country

Year Introduced

Pentcillin

Toyama

Japan

1980

Pipril

Lederle

W. Germany

1980

Pipril

Lederle

Switz.

1980

Piperallin

Toyama

France

1981

Pipril

Lederle

UK

1982

Avocin

Cyanamid

Italy

1982

Pipracil

Lederle

US

1982

Pentocillin

Sankyo

Japan

-

Raw Materials Diethyl oxalate Trimethylsilyl chloride Phosgene

N-Ethylethylenediamine Sodium 2-ethylhexanoate 6-[D(-)-α-Aminophenylacetamido] penicillanic acid

Manufacturing Process To a suspension of 0.9 g of 6-[D(-)-α-aminophenylacetamido]penicillanic acid in 30 ml of anhydrous ethyl acetate were added at 5°C to 10°C 0.55 g of triethylamine and 0.6 g of trimethylsilyl chloride. The resulting mixture was reacted at 15°C to 20°C for 3 hours to form trimethylsilylated 6-[D(-)-αaminophenylacetamido]penicillanic acid. To this acid was then added 1 g of 4-ethyl-2,3-dioxo-1-piperazinocarbonyl chloride (from the reaction of N-ethylethylenediamine and diethyl oxalate to give 2,3-dioxo-4-ethyl-piperazine which is then reacted with phosgene) and the resulting mixture was reacted at 15°C to 20°C for 2 hours. After the reaction, a deposited triethylamine hydrochloride was separated by filtration, and the filtrate was incorporated with 0.4 g of n-butanol to deposit crystals. The deposited crystals were collected by filtration to obtain l.25 g of white crystals of 6-[D(-)α-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido]penicillanic acid. Into a solution of these crystals in 30 ml of tetrahydrofuran was dropped a solution of 0.38 g of a sodium salt of 2-ethylhexanoic acid in 10 ml of tetrahydrofuran, upon which white crystals were deposited. The deposited crystals were collected by filtration, sufficiently washed with tetrahydrofuran and then dried to obtain 1.25 g of sodium salt of 6-[D(-)-α-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetamido] penicillanic acid, melting point 183°C to 185°C (decomposition), yield 90%. References Merck Index 7335 DFU 3 (11) 829 (1978) Kleeman & Engel p. 732 PDR p. 1026 OCDS Vol. 3 p. 207 (1984) DOT 17 (1) 29 (1981) I.N. p. 776 REM p. 1199

Piperidolate

2765

Saikawa, I,, Takano, S., Yoshida, C., Takashima, O., Momonoi, K., Kuroda, S., Komatsu, M., Yasuda, T. and Kodama, Y.; US Patents 4,087,424; May 2, 1978; 4,110,327; Aug. 29, 1978; 4,112,090; September 5, 1978; all assigned to Toyama Chemical Co., Ltd.

PIPERIDOLATE Therapeutic Function: Spasmolytic Chemical Name: α-Phenylbenzeneacetic acid 1-ethyl-3-piperidinyl ester Common Name: N-Ethyl-3-piperidyl diphenylacetate Structural Formula:

Chemical Abstracts Registry No.: 82-98-4; 129-77-1 (Hydrochloride salt) Trade Name Dactil Dactil Cactiran Crapinon Dactylate Edelel

Manufacturer Merrell National Roger Bellon Kyorin Sanzen Sawai Mochida

Country US France Japan Japan Japan Japan

Year Introduced 1954 1958 -

Raw Materials Furfural Acetic acid Hydrogen bromide

Hydrogen Ethylamine Diphenylacetyl chloride

Manufacturing Process To obtain the free base, 34 g (0.256 mol) of N-ethyl-3-piperidinol and 20 g (0.22 mol) of diphenylacetyl chloride were mixed in 80 cc of isopropanol and the solution was refluxed for 2 hours. The isopropanol was evaporated in vacuo at 30 mm pressure, the residue was dissolved in 150 cc of water and the aqueous solution was extracted several times with ether. The aqueous solution was then neutralized with potassium carbonate and extracted with

2766

Piperocaine

ether. The ethereal solution was dried over anhydrous potassium carbonate and the ether removed by distillation. The product was then distilled at its boiling point 180° to 181°C at 0.13 mm of mercury whereby 14 g of a clear yellow, viscous liquid was obtained. The nitrogen content for C21H25NO2 was calculated as 4.33% and the nitrogen content found was 4.21%. The starting material was produced by the reaction of furfural with ethylamine followed by hydrogenation to give N-ethyl-N-(2-tetrahydrofurfuryl)amine. Treatment of that material with hydrogen bromide in acetic acid gives N-ethyl3-piperidinol. References Merck Index 7345 Kleeman & Engel p. 733 OCDS Vol. 1 p.91 (1977) I.N. p. 778 Biel, J.H.; US Patent 2,918,407; December 22, 1959; assigned to Lakeside Laboratories, Inc.

PIPEROCAINE Therapeutic Function: Local anesthetic Chemical Name: 1-Piperidinepropanol, 2-methyl-, benzoate (ester) Common Name: Piperocaine Structural Formula:

Chemical Abstracts Registry No.: 136-82-3 Trade Name Piperocaine Isocaine

Manufacturer ZYF Pharm Chemical Iso-Sol

Country -

Raw Materials 2-Methylpiperidine Hydrogen chloride Benzoyl chloride

γ-Chloropropylbenzoate Sodium hydroxide 3-Chloropropanol

Year Introduced -

Piperylone

2767

Manufacturing Process The γ-chloropropylbenzoate was obtained by treatment of benzoyl chloride with 3-chloropropanol. 15.0 g of 2-methyl piperidine and 15.0 g of γ-chloropropylbenzoate are mixed, and heated under a reflux at a temperature of 120°-140°C for 30-40 min. The reaction mixture is then cooled, and treated with 100 ml of ether, and the precipitated secondary amine hydrochloride (i.e., some of the hydrochloride of the unchanged piperidine) filtered off. Hydrogen chloride gas is passed into the filtrate, and crude γ-(2-methylpiperidino)propylbenzoate hydrochloride thereby precipitated. The ether is decanted from the precipitate, and the latter is dissolved in 20 ml of cold water. This solution is treated with 5 ml of 40% sodium hydroxide and 5 ml of benzoyl chloride and the resulting mixture shaken vigorously until the odor of the benzoyl chloride has disappeared. In this manner any unchanged secondary amine is converted into an amide. The alkaline solution, which contains the free base, γ-(2methylpiperidino)propylbenzoate in suspension is extracted with ether, and the ether extract is evaporated and dried. References McElvain S.M.; US Patent No. 1,784,903; Dec. 16, 1930 Kleemann A., Engel J.; Pharmazeutische Wirkstoffe, GeorgThieme Verlag Stuttgart, New York, 1982

PIPERYLONE Therapeutic Function: Analgesic Chemical Name: 4-Ethyl-1-(1-methyl-4-piperidyl)-3-phenyl-3-pyrazolin-5one Common Name: Piperylone Structural Formula:

Chemical Abstracts Registry No.: 2531-04-6 Trade Name

Manufacturer

Country

Year Introduced

Palerol

Novartis

-

-

2768

Pipethanate ethobromide

Raw Materials α-Ethylbenzoylacetic acid ethyl ester N-Methyl-piperidyl-4-hydrazine Manufacturing Process A mixture of 8.8 parts of α-ethylbenzoylacetic acid ethyl ester and 5,3 parts of N-methyl-piperidyl-4-hydrazine is allowed to stand for 30 min at 22°C, after which the mixture is heated for 5 hours to 130°C under a pressure of 12 mm. After 4 hours 1-(N-methylpiperidyl-4)-3-phenyl-4-ethylpyrazolone-5 begins crystallize out. The reaction mixture is allowed to cool, after which the crystal mass is triturated with ether and then recrystallized from methanol-ether or from acetone. Melting point 159-161°C. References Merck Index, Monograph number: 7632, Twelfth edition, 1996, Editor: S. Budavari Merck and Co., Inc. Jucker E., Erbnoether A., Lindenmann J.; US Patent No. 2,903,460, Assigned to Sandoz A.G., Basel, Switzerland

PIPETHANATE ETHOBROMIDE Therapeutic Function: Anticholinergic, Antiulcer Chemical Name: Benzilic acid, 2-piperidinoethyl ester ethobromide Common Name: Piperilate ethyl bromide Structural Formula:

Chemical Abstracts Registry No.: 4546-39-8 (Base) Trade Name Panpurol

Manufacturer Nippon Shinyaku

Country Japan

Year Introduced -

Pipobroman

2769

Raw Materials Pipethanate hydrochloride Sodium hydroxide Ethyl bromide Manufacturing Process Pipethanate hydrochloride is dissolved in water and the solution is made alkaline by adding 10% sodium hydroxide solution. The crystals that are separated are filtered off and recrystallized from dilute ethanol. The monohydrate thereby obtained is dehydrated at 100°C under reduced pressure for 20 minutes. The products that are now in the form of a syrup due to loss of water of crystallization are further dehydrated for 2 days in a desiccator over phosphorus pentoxide whereupon the anhydrous pipethanate is obtained. 3.8 g of the anhydrous pipethanate prepared by the method described is dissolved in 15 cc of acetone, 18 g of purified ethyl bromide is added, and the mixture heated for 8 hours in a sealed tube at 100°C to 110°C. After cooling the crystals are separated and isolated by filtration. They are then washed with acetone to give 5.2 g (95.6%) of pipethanate ethylbromide with a decomposition point of 218°C to 220°C. The crystals are almost pure. References Merck Index 7346 DOT 7 (1) 23 (1971) I.N. p. 779 Nippon Shinyaku Co., Ltd.; British Patent 1,148,858; April 16, 1969

PIPOBROMAN Therapeutic Function: Antineoplastic Chemical Name: 1,4-Bis-(3-bromo-1-oxopropyl)piperazine Common Name: Structural Formula:

Chemical Abstracts Registry No.: 54-91-1

2770

Pipotiazine

Trade Name Vercyte Vercyte Vercite Amedel

Manufacturer Abbott Abbott Abbott Dainippon

Country US France Italy UK

Year Introduced 1966 1970 1972 1973

Raw Materials Piperazine 3-Bromopropionyl chloride Manufacturing Process To a solution of 17.2 g (0.10 mol) of 3-bromopropionyl chloride in 100 ml of anhydrous benzene was added dropwise with stirring a solution of 8.6 g (0.10 mol) of anhydrous piperazine in 20 ml of dry chloroform over a period of 30 minutes. The temperature rose spontaneously to 45°C during the addition. After the temperature ceased to rise, stirring was continued for another hour. The reaction mixture was then filtered to remove the piperazine hydrochloride by-product. The filtrate was evaporated to dryness and the residue recrystallized from ethanol to obtain the desired N,N'-bis-(3bromopropionyl)piperazine as a white crystalline solid melting at 103°C to 104°C. The identity of the product was further established by elemental analysis. References Merck Index 7355 Kleeman & Engel p. 735 OCDS Vol. 2 p. 299 (1980) I.N. p. 779 REM p. 1156 Abbott Laboratories; British Patent 921,559; March 20, 1963

PIPOTIAZINE Therapeutic Function: Neuroleptic Chemical Name: 10H-Phenothiazine-2-sulfonamide, 10-(3-(4-(2hydroxyethyl)-1-piperidinyl)propyl)-N,N-dimethylCommon Name: Pipothiazine; Pipotiazine Chemical Abstracts Registry No.: 39860-99-6 Trade Name

Manufacturer

Country

Year Introduced

Piportil

Rhone-Poulenc Rorer

-

-

Piportil

Aventis

-

-

Pipotiazine

2771

Structural Formula:

Raw Materials Hydrochloric acid Sodium amide 4-Hydroxyethyl piperidine Sodium hydroxide

1-Chloro-3-tetrahydropyranyloxy propane Methanesulfonyl chloride Phenthiazine-2-sulfonic acid dimethylamide

Manufacturing Process 10-(3-Tetrahydropyranyloxypropyl)phenthiazine-2-sulfonic acid dimethylamide prepared by condensing 1-chloro-3-tetrahydropyranyloxy propane with phenthiazine-2-sulfonic acid dimethylamide (melting point 140°C) in xylene in the presence of sodamide. 10-(3-Hydroxypropyl)phenthiazine-2-sulfonic acid dimethylamide was prepared by the action of hydrochloric acid in ethanol on 10-(3tetrahydropyranyloxypropyl)phenthiazine-2-sulfonic acid dimethylamide. 10-(3-Methanesulphonyloxypropyl)phenthiazine-2-sulphonic acid dimethylamide, was obtained by condensing methanesulphonyl chloride in anhydrous pyridine with 10-(3-hydroxypropyl)phenthiazine-2-sulfonic acid dimethylamide. 10-(3-Methanesulphonyloxypropyl)phenthiazine-2-sulfonic acid dimethylamide and 4-hydroxyethyl piperidine in toluene were heated under reflux with stirring. The reaction mixture was allowed to cool and water was added. The resulting toluene solution layer was decanted and washed twice with water. The toluene solution was then stirred with 5% hydrochloric acid. The hydrochloride of the desired phenthiazine base precipitated in gummy condition in the aqueous layer. This was decanted and treated with sodium hydroxide. It was then extracted three times with ethyl acetate. The extracts were dried over sodium sulfate, filtered and concentrated in vacuum. A resinous product was obtained. This product was dissolved in a mixture of benzene and cyclohexane and chromatographed on a column containing alumina. The chromatographed product was eluted successively with mixtures of benzene and cyclohexane and then with benzene and finally with a mixture of benzene and ethyl acetate. The eluates were evaporated to yield a crude product. This product was recrystallised from aqueous ethanol and yielded 10[3-[4-(2-hydroxyethyl)piperidyl]propyl]phenthiazine-2-sulfonic acid dimethylamide.

2772

Pipoxolan hydrochloride

References Jacob R.M., Robert J.G.; US Patent No. 3,150,129; Sept. 22, 1964; Assigned: Rhone-Poulenc S.A., Paris, France a corporation of France

PIPOXOLAN HYDROCHLORIDE Therapeutic Function: Spasmolytic Chemical Name: 5,5-Diphenyl-2-[2-(1-piperidinyl)ethyl]-1,3-dioxolan-4-one hydrochloride Common Name: Structural Formula:

Chemical Abstracts Registry No.: 18174-58-8; 23744-24-3 (Base) Trade Name Rowapraxin

Manufacturer Rowa/Wagner

Country W. Germany

Year Introduced 1969

Raw Materials Benzilic acid β-Chloropropionaldehyde diethylacetal Piperidine Hydrogen chloride Manufacturing Process 33 g (0.14 mol) of benzilic acid and 22 g (0.13 mol) of βchloropropionaldehyde diethyl acetal were dissolved in 100 ml of glacial acetic acid by heating. After cooling to 40°C, a slow stream of dry HCl gas was introduced while stirring for 2½ hours. After evaporating the glacial acetic acid in vacuo, the reforming oil was taken up in CH2Cl2 and treated with solid KHCO3. After the evolution of CO2 had ended, water was added and the organic phase was neutralized by means of KHCO3 solution. After drying, the solvent was removed; the remaining oil distilled over under high vacuum at 0.001 mm and at 120° to 130°C to yield the compound 2-(β-chloroethyl)-4,4-

Pipradrol hydrochloride

2773

diphenyl-1,3-dioxolan-5-one hydrochloride. This compound was boiled with 12 g of dry piperidine in 120 ml of absolute benzene for 12 hours under reflux, a total of 6 g of piperidine hydrochloride being separated out. This was filtered off and the benzene solution was concentrated by evaporation. The residue was taken up in a little chloroform and the solution was applied to a dry aluminum oxide column (according to Brockmann); it was thereafter extracted with chloroform. After concentrating the solution by evaporation, an oil was obtained, which was taken up in absolute diethylether. Introduction of dry HCl gas into the cooled solution gave a precipitate which was dissolved and allowed to crystallize from isopropanol/ether. MP 193° to 199°C. References Merck Index 7358 Kleeman & Engel p. 736 DOT 6 (3) 95 (1970) I.N. p. 780 Rowa-Wagner Kommanditgesellschaft Arzneimittelfabrik, Germany; British Patent 1,109,959; April 18, 1968

PIPRADROL HYDROCHLORIDE Therapeutic Function: Central stimulant Chemical Name: 2-Piperidinemethanol, α,α-diphenyl-, hydrochloride Common Name: Pipradrol hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 71-78-3; 467-60-7 (Base) Trade Name Alertonic

Manufacturer Adcock Ingram Ltd.

Country -

Year Introduced -

Raw Materials Hydrogen

α,α-Diphenyl-2-pyridinemethanol hydrochloride

2774

Piprinhydrinate

Formaldehyde Formic acid

Adams' platinum catalyst Hydrochloric acid

Manufacturing Process A mixture of 48 g (0.167 mole) of α,α-diphenyl-2-pyridinemethanol hydrochloride (Emraert et al., Ber. 72B, 1188 (1939); 74B, 714 (1940), 160 ml of ethanol, and 3 0.5 g of Adams' platinum catalyst was shaken under an initial hydrogen pressure of 60 pounds. The theoretical amount of hydrogen was absorbed in 5 hours. The reaction mixture was refluxed, diluted with enough water to dissolve all the white solid, and filtered hot from the catalyst. The filtrate was cooled and filtered; yield of 38 g of α,α-diphenyl-alpha-(2piperidyl)methanol white product melting at 308-309°C with decomposition. A mixture of 3.5 grams (0.013 mole) of the above α,α-diphenyl-alpha-(2piperidyl)methanol, 4 g (0.05 mole) of formaldehyde (37%), and 6 grams (0.1 mole) of formic acid was refluxed for 2 days. The reaction mixture was treated with 1.3 g (0.013 mole) of conc. hydrochloric acid and vacuum distilled on the steam bath. The residue was recrystallized from butanone to give the α,αdiphenyl-alpha-(2-piperidyl)methanol hydrochloride which melted at 228229°C (dec.). References Merck Index, Monograph number: 7638, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. Werner H.W., Tilford Ch.H.; US Patent No. 2,624,739; Jan. 6, 1953; Assigned to The Wm. Merrel Company, Ohio, a corporation of Delavere

PIPRINHYDRINATE Therapeutic Function: Antihistaminic, Antiemetic Chemical Name: 4-Diphenylmethoxy-1-methylpiperidine-, compd. with 8chlorotheophylline (1:1) Common Name: Diphenylpyraline teoclate; Piprinhydrinate Chemical Abstracts Registry No.: 606-90-6 Trade Name Piprinhydrinate Piprinhydrinate

Manufacturer Kraeber and Co. GmbH Transo-Pharm

Raw Materials 1-Methyl-4-piperidinol Benzhydryl bromide 8-Chlorotheophylline

Country -

Year Introduced -

Piprinhydrinate

2775

Structural Formula:

Manufacturing Process A mixture of 46 g of 1-methyl-4-piperidinol (0.4 mol), 49.4 g of benzhydryl bromide (0.2 mol) and 100 ml of xylene was refluxed for approximately 24 hours. The reaction mixture separated into two phases with the upper phase containing the desired ether compound dissolved in xylene. The lower phase consisted of the hydro bromide salt of the excess 1-methyl-4-piperidinol. The upper phase was separated from the lower phase and the desired benzhydryl ether recovered in the crude state by distilling off the xylene under reduced pressure. The crude benzhydryl ether was a clear reddish oil. It was dissolved in 75 ml of 20% hydrochloric acid and the aqueous acid solution then washed three times with 50 ml portions each of ethyl ether. The aqueous acid solution was then decolorized with activated carbon and thereafter slowly admixed with 75 ml of 28% aqueous ammonia. The benzhydryl ether separated as an oily material and was removed from the aqueous mixture by extraction with three 50 ml portions of ethylether. On evaporation of the ethyl ether from the ethyl ether solution, the benzhydryl ether was recovered as a pale yellow oil. The benzhydryl ether was dissolved in 60 ml of isopropanol and the isopropanol solution acidified to a PH of 3 with dry hydrogen chloridemethanol solution. The acidic propanol solution was then diluted with ethyl ether until a faint turbidity was observed. In a short time, the crystalline hydrochloride salt of the benzhydryl ether separated from the propanol solution. The crystallized salt was recrystallized once from 75 ml of isopropanol with the aid of ethyl ether in order to further purify the material. A yield 24.5 g of the pure hydrochloride salt 1-methylpiperldyl-4-benzhydryl ether (diphenylpyraline) was obtained. This was 39% of the theoretical yield. The pure material had a melting point of 206°C. 107 g (0.5 mole) 8-chlorotheophylline was dissolved in the diluted solution of ammonia contained 0.5 moles NH3. 1 equivalent of this ammonim salt was mixed with 1 equivalent hydrochloride of 1-methylpiperldyl-4-benzhydryl ether in 150 ml of water. 4-Diphenylmethoxy-1-methylpiperidine compound of 8chlorotheophylline precipitated, filtered off, washed, dried. Yield was quantitative. MP: 151-152°C. References Howland L. et al.; US Patent No. 2,479,843; August 23, 1949; Assigned to Nopco Chemical Company, Harrison,N.J., a corporation of New Jersey

2776

Piprozolin

Schuler W.A.; D.B. Patent No. 934,890; July 8, 1949; Chemische Fabrik Promonta Gesellschaft mit beschrunkter Haftung, Hamburg

PIPROZOLIN Therapeutic Function: Choleretic Chemical Name: [3-Ethyl-4-oxo-5-(1-piperidinyl)-2-thiazolidinylidene]acetic acid ethyl ester Common Name: Structural Formula:

Chemical Abstracts Registry No.: 17243-64-0 Trade Name Probilin Probilin Coleflux Epsyl Secrebil

Manufacturer Goedecke Parke Davis Finadiet Exa Isnardi

Country W. Germany Italy Argentina Argentina Italy

Year Introduced 1977 1979 -

Raw Materials Ethyl thioglycolate Piperidine Diethyl sulfate

Sodium ethylate Ethyl cyanoacetate

Manufacturing Process Ethyl thioglycolate and ethyl cyanoacetate are first reacted in the presence of sodium ethylate to give 4-oxo-thiazolidin-2-ylideneacetic acid ethyl ester. That is reacted with diethyl sulfate and then with piperidine to give piprozolin. References Merck Index 7361 DFU 2 (10) 681 (1977)

Piracetam

2777

Kleeman & Engel p. 737 OCDS Vol. 2 p. 270 (1980) DOT 14 (1) 26 (1976) I.N. p. 781 Satzinger, G., Herrmann, M. and Vollmer, K.O.; US Patent 3,971,794; July 27, 1976; assigned to Warner-Lambert Co.

PIRACETAM Therapeutic Function: Psychotropic Chemical Name: 2-Oxo-1-pyrrolidineacetamide Common Name: Structural Formula:

Chemical Abstracts Registry No.: 7491-74-9 Trade Name Nootropyl Nootropil Nootrop Normabrain Gabacet Ciclocetam Ciclofalina Encefalux Eumental Genogris Gericetam Huberdasen Ideaxan Merapiran Nootron Nootropicon Norotrop Norzetam Oikamid Pirroxil Pyramen Stimubral Stimucortex

Manufacturer UCB UCB-Smit UCB Chemie Cassella-Riedel Carrion Callol Almirall Bama-Geve Wassermann Vita Level Hubber Millot Finadiet Biosintetica Sidus Drifen Albert Pharma Pliva S.I.T. Pharmachim Lusofarmaco Kalifarma

Country France Italy W. Germany W. Germany France Spain Spain Spain Spain Spain Spain Spain France Argentina Brazil Argentina Turkey Spain Yugoslavia Italy Bulgaria Portugal Spain

Year Introduced 1972 1974 1974 1974 1980 -

2778

Pirbuterol

Raw Materials 2-Pyrrolidone Sodium hydride

Ethyl chloroacetate Ammonia

Manufacturing Process 2-Pyrrolidone is first reacted with sodium hydride, then with ethyl chloroacetate to give ethyl 2-oxo-1-pyrrolidine acetate. A solution of 0.3 mol of ethyl 2-oxo-1-pyrrolidine acetate in 300 ml of methanol, saturated with ammonia at 20° to 30°C, is heated at 40° to 50°C for 5 hours, while continuously introducing ammonia. The reaction mixture is evaporated to dryness and the residue recrystallized from isopropanol. 2-Oxo1-pyrrolidineacetamide is obtained in a yield of 86%. MP 151.5° to 152.5°C. References Merck Index 7363 Kleeman & Engel p. 737 DOT 9 (6) 215 (1973) & (8) 327 (1973) I.N. p. 781 Morren, H.; US Patent 3,459,738; August 5, 1969; assigned to UCB (Union Chimique-Chemische Bedrijven), Belgium

PIRBUTEROL Therapeutic Function: Bronchodilator Chemical Name: 2-Hydroxymethyl-3-hydroxy-(1-hydroxy-2-tertbutylaminoethyl)pyridine Common Name: Structural Formula:

Chemical Abstracts Registry No.: 38677-81-5 Trade Name

Manufacturer

Country

Year Introduced

Exirel

Pfizer Taito

Japan

1982

Exirel

Pfizer

UK

1983

Exirel

Pfizer

Switz.

1983

Pirenzepine hydrochloride

2779

Raw Materials N-tert-Butyl-2-(5-benzyloxy-6-hydroxymethyl-2-pyridyl)-2hydroxyacetamide Diborane Hydrogen Manufacturing Process To 78 ml of a 1 M solution of diborane in tetrahydrofuran under nitrogen and cooled to 0°C is added dropwise over a period of 40 minutes 13.5 g of N-tertbutyl-2-(5-benzyloxy-6-hydroxymethyl-2-pyridyl)-2-hydroxyacetamide in 250 ml of the same solvent. The reaction mixture is allowed to stir at room temperature for 3.5 hours, and is then heated to reflux for 30 minutes and cooled to room temperature. Hydrogen chloride (70 ml, 1.34 N) in ethanol is added dropwise, followed by the addition of 300 ml of ether. The mixture is allowed to stir for 1 hour and is then filtered, yielding 11.0 g, melting point 202°C (dec.). The hydrochloride dissolved in water is treated with a sodium hydroxide solution to pH 11 and is extracted into chloroform (2 x 250 ml). The chloroform layer is dried over sodium sulfate, concentrated to dryness in vacuo, and the residue recrystallized from isopropyl ether, 3.78 g, melting point 81°C to 83.5°C. A solution of 1.7 g of 2-hydroxymethyl-3-benzyloxy-(1-hydroxy-2-tert-butylaminoethyl)pyridine in 30 ml of methanol containing 1.2 ml of water is shaken with 700 mg of 5% palladiumon-charcoal in an atmosphere of hydrogen at atmospheric pressure. In 17 minutes the theoretical amount of hydrogen has been consumed and the catalyst is filtered. Concentration of the filtrate under reduced pressure provides 1.4 g of the crude product as an oil. Ethanol (5 ml) is added to the residual oil followed by 6 ml of 1.75 N ethanolic hydrogen chloride solution and, finally, by 5 ml of isopropyl ether. The precipitated product is filtered and washed with isopropyl ether containing 20% ethanol, 1.35 g, melting point 182°C (dec.). References Merck Index 7364 DFU 2 (1) 60 (1977) OCDS Vol. 2 p. 280 (1980) DOT 19 (2) 113 (1983) & (7) 384 (1983) I.N. p. 782 Barth, W.E.; US Patents 3,700,681; October 24, 1972; 3,763,173; October 2, 1973; 3,772,314; November 13, 1973; all assigned to Pfizer, Inc.

PIRENZEPINE HYDROCHLORIDE Therapeutic Function: Antiulcer, Antiemetic Chemical Name: 6H-Pyrido(2,3-b)(1,4)benzodiazepin-6-one, 5,11-dihydro11-((4-methyl-1-piperazinyl)acetyl)-, dihydrochloride

2780

Pirenzepine hydrochloride

Common Name: Pirenzepine hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 29868-97-1; 28797-61-7 (Base) Trade Name

Manufacturer

Country

Year Introduced

Droxol

Microsules Bernabo

-

-

Gasteril

Ripari-Gero

-

-

Gastril

Torrent

-

-

Gastropin

Boehringer-Ingelheim

-

-

Gastrosed

Amsa

-

-

Ulcosan

Dompe

-

-

Raw Materials Triethylamine 5,11-Dihydro-6H-pyrido[2,3-b][1,4]benzo-diazepin-6-one N-Methylpiperazine Chloroacetyl chloride Manufacturing Process 48.4 g of 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzo-diazepin-6-one were refluxed in 900 ml of absolute dioxane for 15 minutes. Thereafter, over a period of 45 minutes, 28 ml of chloroacetyl chloride and 52 ml of triethylamine were simultaneously added dropwise to the mixture. The mixture was refluxed for eight hours and then vacuum-filtered after having cooled. The filtrate was evaporated in vacuum. The crystalline residue was recrystallized from acetonitrile in the presence of activated charcoal. MP: 212°-213°C (with decomposition). Yield: 85% of theory. A mixture of 67.5 g of 11-chloroacetyl-5,11-dihydro-6H-pyrido[2,3b][1,4]benzodiazepin-6-one, 183 ml of N-methylpiperazine and 1.37 liters of absolute benzene was refluxed for 18 hours. Thereafter, the crystalline precipitate was vacuum filtered off, dissolved in aqueous 20% hydrochloric acid, the solution was evaporated in vacuum, the crystalline residue was

Piretanide

2781

dissolved in 250 ml of water while heating, the solution was admixed with 150 ml of isopropanol and active charcoal, filtered, and 2.5 liters of isopropanol were added to the filtrate. After cooling, the precipitate was vacuum filtered off, yielding 70% of theory of the 5,11-dihydro-11-[(4'-methyl-1'-piperazinyl)acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one dihydrochloride, M.P. 257259°C (decomp.). The free base of pirenzepine, obtained from the dihydrochloride by making an aqueous solution thereof alkaline with dilute sodium hydroxide and extracting it with chloroform, had MP: 226°-228°C after recrystallization from methanol/ether. References Schmidt G. et al.; US Patent No. 3,743,734; July 3, 1973; Assigned to Boehringer Ingelheim G.m.b.H., am Rhein, Germany

PIRETANIDE Therapeutic Function: Diuretic Chemical Name: 3-N-Pyrrolidino-4-phenoxy-5-sulfamylbenzoic acid Common Name: Structural Formula:

Chemical Abstracts Registry No.: 55837-27-9 Trade Name Arelix Arelix Tauliz

Manufacturer Hoechst Cassella-Riedel Hoechst

Country Italy W. Germany W. Germany

Year Introduced 1980 1982 -

Raw Materials 3-N-Succinimido-4-phenoxy-5-sulfamylbenzoic acid methyl ester Sodium borohydride Sodium hydroxide

2782

Piribedil

Manufacturing Process 12.3 g (0.03 mol) of 3-N-succinimido-4-phenoxy-5-sulfamylbenzoic acid methyl ester are dissolved or suspended in 100 ml of absolute diglyme. 9 g of boron trifluoride etherate are added direct to this mixture and a solution of 2.4 g (~0.063 mol) of NaBH4 in 80 ml of diglyme is then added dropwise at room temperature with stirring. As the reaction proceeds exothermically, it is necessary to cool with ice water. The reaction is normally complete after the dropwise addition and a short period of stirring thereafter. The excess reducing agent is then decomposed by means of a little water (foaming), the solution is filtered and about 300 ml of water are added while stirring. The 3-N-pyrrolidino-4phenoxy-5-sulfamylbenzoic acid methyl ester which has crystallized out is recrystallized from methanol in the form of colorless crystals, melting point 191°C to 192°C. 61 g of 3-N-pyrrolidino-4-phenoxy-5-sulfamylbenzoic acid methyl ester are suspended in 350 ml of 1 N NaOH and the suspension is heated for one hour on the waterbath. 3-N-pyrrolidino4-phenoxy-5-sulfamylbenzoic acid is precipitated from the clear solution by means of 2 N HCl while stirring well. The almost pure crude product can be recrystallized from methanol/water in the form of light yellow platelets, melting point 225°C to 227°C, with decomposition. References Merck Index 7366 DFU 2 (6) 393 (1977) OCDS Vol. 3 p. 58 (1984) DOT 18 (6) 274 (1982) & (10) 555 (1982) I.N. p. 782 Bormann, D., Merkel, W. and Muschaweck, R.; US Patents 4,010,273; March 1, 1977; 4,093,735; June 6, 1978; 4,111,953; September 5, 1978; 4,118,397; October 3, 1978; and 4,161,531; July 17, 1979; all assigned to Hoechst AG

PIRIBEDIL Therapeutic Function: Vasodilator Chemical Name: 2-[4-(1,3-Benzodioxol-5-ylmethyl)-1-piperazinyl]pyrimidine Common Name: Structural Formula:

Piritramide

2783

Chemical Abstracts Registry No.: 3605-01-4 Trade Name Trivastal Trivastan Trivastal Circularina

Manufacturer Eutherapie Servier Pharmacodex Searle

Country France Italy W. Germany -

Year Introduced 1969 1975 1975 -

Raw Materials 2-Chloropyrimidine 1-(3':4'-Methylenedioxybenzyl)-piperazine Manufacturing Process To a solution of 21 g of 1-(3':4'-methylenedioxybenzyl)-piperazine in solution in 300 cc of anhydrous xylene there were added 28 g of anhydrous potassium carbonate and then 11.3 g of 2-chloropyrimidine. The suspension was then heated for 9 hours at boiling point (130°C). After this time, the mixture was cooled and extracted several times with 10% hydrochloric acid. The acid solution obtained was washed with ether and then rendered alkaline with potassium carbonate; the oily product which was separated was extracted with chloroform and this, after drying with potassium carbonate and evaporation, gave an oily residue weighing 20 g. By dissolution in boiling ethanol and crystallization, 15 g of crystals melting at 96°C were recovered. References Merck Index 7368 Kleeman & Engel p. 739 DOT (As ET-495) 6 (1) 29 (1970) & 10 (9) 324, 340 (1974) I.N. p. 783 Regnier, G., Canevari, R. and Laubie, M.; US Patent 3,299,067; January 17, 1967; assigned to Science Union Et Cie, Societe Francaise De Recherche Medicale (France)

PIRITRAMIDE Therapeutic Function: Analgesic Chemical Name: 1-(3,3-Diphenyl-3-cyanopropyl)-4-piperidino-4piperidinecarboxamide Common Name: Pirinitramide Chemical Abstracts Registry No.: 302-41-0

2784

Piroheptine

Structural Formula:

Trade Name Dipidolor Dipidolor Piridolan

Manufacturer Janssen Janssen Leo

Country W. Germany UK Sweden

Year Introduced 1969 1972 -

Raw Materials 3,3-Diphenyl-3-cyanopropyl bromide 4-Piperidino-4-piperidinecarboxamide Manufacturing Process A mixture of 84 parts of 3,3-diphenyl-3-cyanopropyl bromide, 41 parts of 4piperidino-4-piperidinecarboxamide, 64 parts of sodium carbonate, a small amount of potassium iodide and 1,200 parts of anhydrous toluene was stirred, and heated under reflux for 48 hours. At the end of this time the reaction mixture was allowed to cool to room temperature, and 500 parts of water were added. The resultant precipitate was removed by filtration, and triturated with diisopropyl ether. The crystalline material thus obtained was removed by filtration, and recrystallized from 320 parts of acetone, to give 1-(3,3diphenyl-3-cyanopropyl)-4-piperidino-4-piperidinecarboxamide, melting at about 149°C to 150°C. References Merck Index 7373 Kleeman & Engel p. 739 OCDS Vol. 1 p. 308 (1977) DOT 5 (3) 107 (1969) I.N. p. 783 N.V. Research Laboratorium Dr. C. Janssen; British Patent 915,835; January 16, 1963 Janssen, P.A.J.; US Patent 3,080,360; March 5, 1963; assigned to Research Laboratorium Dr. C. Janssen N.V.

PIROHEPTINE Therapeutic Function: Antiparkinsonian

Piroheptine

2785

Chemical Name: 3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1ethyl-2-methylpyrrolidine Common Name: Structural Formula:

Chemical Abstracts Registry No.: 16378-21-5 Trade Name Trimol

Manufacturer Fujisawa

Country Japan

Year Introduced 1974

Raw Materials 2-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-ylidene)-1pyrroline Ethyl iodide Sodium borohydride Manufacturing Process (1) To 3.8 g of 2-methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5ylidene)-1-pyrroline, there were added 8 g of ethyl iodide. This mixture was placed into a closed vessel and heated at 80°C in a water-bath for one hour. After completing the reaction, the reaction mixture was cooled and the unreacted ethyl iodide was distilled off to yield 5.5 g of 1-ethyl-2methyl-3(10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-ylidene)-1-pyrrolinium iodide in the form of yellow crystals. These crystals were recrystallized from a mixture of acetone and ether to yield yellow needles of the melting point 223°C. (2)1-Ethyl-2-methyl-3-(10,11)-dihydro-5H-dibenzo[a,d]cycloheptene-5ylidene)-1-pyrroliniumiodide (4.7 g) was dissolved in 7 cc of methanol. To this solution there were added 1.4 g of sodium boron hydride within about 80 minutes with stirring and stirring of the solution was continued for two hours to complete the reaction. The reaction mixture was acidified with 10% aqueous hydrochloric acid solution and then the methanol was distilled off. The residual solution was alkalized with 20% aqueous sodium hydroxide solution and extracted with ether. The ether layer was dried over magnesium sulfate and the ether was distilled off. The resulting residue was further distilled under reduced pressure to yield 2.0 g of 1-ethyl-2-methyl-3-(10,11)dihydro-5H-dibenzo[a,d]cycloheptene-5-ylidene)pyrrolidine (boiling point 167°C/4 mm Hg.).

2786

Piromidic acid

References Merck Index 7375 DOT 9 (6) 247 (1973) & 10 (9) 325 (1974) I.N. p. 784 Deguchi, Y., Nojima, H. and Kato, N.; US Patent 3,454,495; July 8, 1969; assigned to Fujisawa Pharmaceutical Co., Ltd. (Japan)

PIROMIDIC ACID Therapeutic Function: Antibacterial (urinary) Chemical Name: 8-Ethyl-5,8-dihydro-5-oxo-2-(1-pyrrolidinyl)pyrido[2,3d]pyrimidine-6-carboxylic acid Common Name: Structural Formula:

Chemical Abstracts Registry No.: 19562-30-2 Trade Name Panacid Pirodal Bactramyl Septural Adelir Coltix Panerco Purim Reelon Uriclor Urisept Zaomeal

Manufacturer Dainippon I.S.F. Carrion Gruenenthal Teikoku Gerardo Ramon Erco Mayoly-Spindler Sanken Almirall Srbolek Isei

Country Japan Italy France W. Germany Japan Argentina Denmark France Japan Spain Yugoslavia Japan

Year Introduced 1972 1977 1978 1978 -

Raw Materials Pyrrolidine Sodium hydroxide Diethyl sulfate

6-Amino-2-methylthiopyrimidine Ethoxymethylene malonic acid diethyl ester

Piroxicam

2787

Manufacturing Process 150 mg of 6-carboxy-5,8-dihydro-8-ethyl-2-methylthio-5-oxopyrido[2,3d]pyrimidine was added to 30 ml of absolute ethanol containing 1.1 g of dissolved pyrrolidine, and the mixture was reacted for 5 hours at 95°C in a sealed tube. The solvent was removed by distillation, and the residue was recrystallized from methanol-chloroform. There were obtained 111 mg of 6carboxy-5,8-dihydro-8-ethyl-5-oxo-2-pyrrolidino-pyrido[2,3-d]pyrimidine having a MP of 314° to 316°C. The starting material is produced by reacting 6-amino-2-methylthiopyrimidine with ethoxymethylene malonic acid diethyl ester. That intermediate is thermally treated in diphenyl ether to give 6-ethoxycarbonyl-2-methylthio-5oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine. The ethoxy group is hydrolyzed off with sodium hydroxide and one nitrogen is ethylated with diethyl sulfate to give the starting material. These are the same initial steps as used in the pipemidic acid syntheses earlier in this volume. References Merck Index 7377 Kleeman and Engel p. 739 OCDS Vol. 2 p. 470 (1980) DOT 7 (5) 188 (1971) I.N. p. 36 Dainippon Pharmaceutical Co. Ltd., Japan; British Patent 1,129,358; October 2, 1968 Minami, S., Shono, T., Shmmizu, M. and Takase, Y.; US Patent 3,673,184; June 27, 1972; assigned to Dainippon Pharmaceutical Co. Ltd. Pesson, M.E. and Geiger, S.W.; US Patent 4,125,720; November 14, 1978; assigned to Laboratoire Roger Bellon

PIROXICAM Therapeutic Function: Antiinflammatory, Analgesic Chemical Name: 2H-1,2-Benzothiazine-3-carboxamide, 4-hydroxy-2-methylN-2-pyridinyl-, 1,1-dioxide Common Name: Piroksikam; Pyroxycam Structural Formula:

2788

Piroxicam

Chemical Abstracts Registry No.: 36322-90-4 Trade Name

Manufacturer

Country

Amida

Euphoric Pharmaceuticals Pvt. Ltd. Qif Apotex Inc. Pharmaetica Star Sintyal Krka Pfizer Sedico Szabo Recalcine Egis Beta Intas Lichtenstein Opus Cipla Limited Diba Glaxo Wellcome Poznan S.A. Norton Healthcare Ltd. IPCA laboratories Ltd. Pharmachim Holding EAD, Sopharma AD

-

Year Introduced -

Canada Slovenia USA Egypt Hungary India Poland UK India Bulgaria

-

Piroxicam Piroxicam

Chemo Iberica Nantong General Pharmaceutical Factory

Spain China

-

Piroxicam Piroxicam Piroxicam Piroxicam Piroxicam

Pharmaline Jelfa S.A. LaborMed Pharma Zdravle Darou Paksh Pharmaceutical Company Leciva Jenapharm

Livan Poland Rumania Yugoslavia Iran

-

Ratiopharm

Germany

-

Stada Arzneimittel AG Teva Procaps Slovakofarma Medichrom Zdravle Rolab

Germany Israel Yugoslavia -

-

Anartrir Apo-Piroxicam Artril Dacam Desinflam Erazon Feldene gel Feldoral Sedico Flogostop Foldox Hotemin Oxa Piroflam Piroflam Piroflam Pirox Piroxan Piroxicam Piroxicam Piroxicam Piroxicam

Piroxicam Piroxicam Jenapharm PiroxicamRatiopharm Piroxicam Stada Piroxicam-Teva Proxigel Reumador Reumaplus Roxicam Roxikam

Czech Republic Germany -

Piroxicam Trade Name Roxikam Sinalgico Tetram

Manufacturer Zdravje Finadiet Nycomed

Country -

2789

Year Introduced -

Raw Materials Methyl iodide Methyl 3-oxo-1,2-benzoisothyazolin-2-acetate 1,1-dioxide Sodium hydroxide Sodium methoxide Hydrochloric acid Manufacturing Process 189.6 g (3.51 mol) of sodium methoxide in 1.4 L of dry dimethylsulfoxide was stirred at room temperature (~ 25°C), while under a dry nitrogen atmosphere. To the stirred slurry, there were then added in one complete portion 300 g (1.17 moles) of methyl 3-oxo-1,2-benzoisothyazolin-2-acetate 1,1-dioxide (Chemische Berichte, vol. 30, p. 1267 (1897)) and flask containing the system was then immediately immersed in an ice-methanol bath. The resulting deep red solution was cooled to 30°C and the ice bath removed. The solution was then stirred under dry nitrogen at 30°C for 4 min, cooled quickly to 18°C and then immediately poured into 4.8 L of 3 N hydrochloric acid solution admixed with ice. The resulting slurry was stirred for 15 min, filtered, then washed with water to give 250 g of crude product. Recrystallization from a chloroform-ethanol mixture (1:1) in the presence of charcoal, then afforded a 61% yield of methyl 3,4-dihydro-4-oxo-2H-1,2benzothiazine-3-carboxylate 1,1-dioxide, melting point 173-174°C after two recrystallizations from isopropanol. A 22 L round-bottomed flask charged with 800 g (3.13 moles) of methyl 3,4dihydro-4-oxo-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide, 3.2 l of water, 9.6 l of 95% ethanol, 673 ml of methyl iodide (1.53 kg, 10.87 moles) and 3.14 L of 1 N aqueous sodium hydroxide. The reaction mixture was then stirred for 30 min at room temperature, under nitrogen atmosphere and then solution was stored for 23 h. The slurry was then chilled at 0°C and filtered. After washing the filter cake twice with water, ethanol and then diethyl ether there were obtained 537 g of methyl 3,4-dihydro-2-methyl-4-oxo-2H-1,2benzothiazine-3-carboxylate 1,1-dioxide, melting point 165°-168°C after recrystallization from 1.25 L of acetonitrile. In 3 L round-bottomed flask there were placed methyl 3,4-dihydro-2-methyl4-oxo-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide, 2-aminopyridin and dry xylene. Nitrogen gas was then bubbled into the suspension for 5 min, then the reaction mixture was heated to begin a period of slow distillation, with complete solution effected during the first 10 min of heating. After 5.5 h, the period of slow distillation was discontinued and reaction mixture was allowed to heat at reflux for approximately 16 h. After that the reaction mixture was cooled to room temperature and filtered. The solid material was crystallized from chloroform with methanol and againe from methanol and then there were obtained piroxicam, melting point 197°-200°C, dec.

2790

Pirozadil

References Lombardino J.G.; US Patent No. 3,591,584; July 6, 1971; Assigned: Pfizer Inc., New York, N.Y.

PIROZADIL Therapeutic Function: Antihyperlipidemic, Platelet aggregation inhibitor Chemical Name: 2,6-Pyridinemethanol-bis(3,4,5-trimethoxybenzoate) Common Name: Structural Formula:

Chemical Abstracts Registry No.: 54110-25-7 Trade Name

Manufacturer

Country

Year Introduced

Pemix

Prodes

Spain

1982

Raw Materials 3,4,5-Trimethoxybenzoic acid Thionyl chloride Pyridine-2,6-dimethanol Manufacturing Process 15 kg (70.7 mols) of 3,4,5-trimethoxybenzoic acid and 65 liters of benzene were introduced into a reactor, to which mixture was added 27.4 liters of thionyl chloride. The mass was heated to 56°C to 70°C during a period of 5 hours. The excess of benzene and thionyl chloride was distilled under vacuum. The residue was kept under vacuum at 120°C to 123°C for 1 hour, to obtain a hard crystalline solid. A solution comprising 3.24 kg (23.3 mols) of pyridine-2,6-dimethanol in 35 liters of pure pyridine was added to the residue and the mass was heated to 80°C for 2½ hours. The reaction mass became brown in color. The chlorhydrate of pyridine so formed was cooled and crystallized. The resulting reaction mass was then poured into water. The precipitate obtained was

Pirprofen

2791

filtered, repeatedly rinsed with water, and dissolved in 400 liters of methanol. The resulting solution was filtered with activated charcoal. From this filtration 50 liters of methanol were distilled at normal pressure and then crystallized. 8.35 kg (15.8 mols) of pyridine-2,6dimethanol trimethoxybenzoate were obtained, which represented a yield of 68%. The product was a white crystalline solid which melted at 119°C to 126°C. Recrystallization in methanolone gave a product which melted at 126°C to 127°C. References Merck Index 7379 DFU 6 (5) 290 (1981) DOT 18, Suppl. 1 Instituto International Terapeutico; British Patent 1,401,608; July 30, 1975

PIRPROFEN Therapeutic Function: Antiinflammatory Chemical Name: α-(3-Chloro-4-pyrrolinophenyl)-propionic acid Common Name: Structural Formula:

Chemical Abstracts Registry No.: 31793-07-4 Trade Name

Manufacturer

Country

Year Introduced

Rengasil

Ciba Geigy

France

1981

Rengasil

Ciba Geigy

Switz.

1981

Raw Materials Ethyl α-(3-chloro-4-aminophenyl)-propionate hydrochloride 1,4-Dibromo-2-butene Manufacturing Process To the mixture of 85.5 g ethyl α-(3-chloro-4-aminophenyl)-propionate hydrochloride, 142 g sodium carbonate and 600 ml dimethyl formamide, 107

2792

Pivampicillin

g 1,4-dibromo-2-butene are added dropwise while stirring and the whole is refluxed for 5 hours and allowed to stand overnight at room temperature. The mixture is filtered, the filtrate evaporated in vacuo, the residue is triturated with hexane, the mixture filtered, the residue washed with petroleum ether and the filtrate evaporated. The residue is combined with 280 ml 25% aqueous sodium hydroxide and the mixture refluxed for 8 hours. After cooling, it is diluted with water, washed with diethyl ether, the pH adjusted to 5 to 5.2 with hydrochloric acid and extracted with diethyl ether. The extract is dried, filtered, evaporated and the residue crystallized from benzene-hexane, to yield the α-(3-chloro-4-pyrrolinophenyl)-propionic acid melting at 94°C to 96°C. References Merck Index 7380 DFU 1 (1) 23 (1976) OCDS Vol. 2 p. 69 (1980) DOT 11 (3) 103 (1975) I.N. p. 784 Carney, R.W.J. and De Stevens, G.; US Patent 3,641,040; February 8, 1972; assigned to Ciba Geigy Corp.

PIVAMPICILLIN Therapeutic Function: Antibacterial Chemical Name: 6-[(Aminophenylacetyl)amino]-3,3-dimethyl-7-oxo-4-thia1-azabicyclo[3.2.0]heptane-2-carboxylic acid (2,2-dimethyl-1oxopropoxy)methyl ester Common Name: Structural Formula:

Pivampicillin

2793

Chemical Abstracts Registry No.: 33817-20-8; 26309-95-5 (Hydrochloride salt) Trade Name Maxifen Berocillin Pondocillina Pivatil Pivatil Pondocillin Acerum Bensamin Brotacilina Co-Pivam Crisbiotic Dancilin Devonian Diancina Inacilin Isvitrol Kesmicina Lancabiotic Novopivam Oxidina Penimenal Pibena Piva Pivabiot Pivadilon Pivambol Pivamkey Pivapen Pivastol Piviotic Sanguicillin Tam-Cilin Tryco Vampi-Framan

Manufacturer Sharp and Dohme Boehringer Ingelheim Sigma Tau MSD Chibret Burgess Jeba Turro Escaned Sanchez-Covisa Crisol Hemofarm Perga Septa Inibsa Therapia Kessler Lanzas Osiris Sanitas Alalan Jebena Efesal Galepharma Iberica De La Cruz B.O.I. Pereira Juste Graino Miquel Zdravlje Quimia Durban Oftalmiso

Country W. Germany W. Germany Italy Italy France UK Spain Spain Spain Spain Spain Yugoslavia Spain Spain Spain Spain Spain Spain Argentina Argentina Spain Spain Spain Spain Spain Spain Spain Spain Spain Spain Yugoslavia Spain Spain Spain

Year Introduced 1972 1972 1972 1972 1973 1980 -

Raw Materials Hydrogen Potassium D(-)-α-azidobenzylpenicillinate Chloromethyl pivalate Manufacturing Process (A) Pivaloyloxymethyl D(-)-α-azidobenzylpenicillinate: To a suspension of potassium D(-)α-azidobenzylpenicillinate (4.14 g) and potassium dicarbonate

2794

Pivmecillinam

(1.5 g) in acetone (100 ml) and 10% aqueous sodium iodide (2 ml), chloromethyl pivalate (2.7 ml) was added and the mixture refluxed for 2 hours. After cooling, the suspension was filtered and the filtrate evaporated to dryness in vacuo. The remaining residue was washed repeatedly by decantation with petroleum ether to remove unreacted chloromethyl pivalate. The oily residue was taken up in ethyl acetate (100 ml), and the resulting solution washed with aqueous sodium bicarbonate and water, dried and evaporated in vacuo to yield the desired compound as a yellowish gum, which crystallized from ether, melting point 114°C to 115°C. (B) Pivaloyloxymethyl D(-)-α-aminobenzylpenicillinate, hydrochloride: To a solution of pivaloyloxymethyl D(-)-α-azidobenzylpenicillinate (prepared as described above) in ethyl acetate (75 ml) a 0.2 M phosphate buffer (pH 2.2) (75 ml) and 10% palladium on carbon catalyst (4 g) were added, and the mixture was shaken in a hydrogen atmosphere for 2 hours at room temperature. The catalyst was filtered off, washed with ethyl acetate (25 ml) and phosphate buffer (25 ml), and the phases of the filtrate were separated. The aqueous phase was washed with ether, neutralized (pH 6.5 to 7.0) with aqueous sodium bicarbonate, and extracted with ethyl acetate (2 x 75 ml). To the combined extracts, water (75 ml) was added, and the pH adjusted to 2.5 with 1 N hydrochloric acid. The aqueous layer was separated, the organic phase extracted with water (25 ml), and the combined extracts were washed with ether, and freeze-dried. The desired compound was obtained as a colorless, amorphous powder. The purity of the compound was determined iodometrically to be 91%. A crystalline hydrochloride was obtained from isopropanol with a melting point of 155°C to 156°C (dec.). References Merck Index 7387 Kleeman & Engel p. 741 OCDS Vol. 1 p. 414 (1977) DOT 8 (4) 148 (1972) & 19 (6) 331 (1983) I.N. p. 785 REM p. 1201 Frederiksen, E.K. and Godtfredsen, W.O.; US Patent 3,660,575; May 2, 1972; assigned to Lovens Kemiske Fabrik Produktionsaktieselskab (Denmark) Binderup, E.T., Petersen, H.J, and Liisberg, S.; US Patent 3,956,279; May 11, 1976; assigned to Leo Pharmaceutical Products Ltd. (Denmark)

PIVMECILLINAM Therapeutic Function: Antibacterial Chemical Name: 6-[[(Hexahydro-1H-azepin-1-yl)methylene]amino]-3,3dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid (2,2dimethyl-1-oxopropoxy)methyl ester Common Name: Amdinocillin pivoxil

Pivmecillinam

2795

Structural Formula:

Chemical Abstracts Registry No.: 32886-97-8 Trade Name Selexid Melysin Selexid Negaxid

Manufacturer Leo Takeda Leo Sigma Tau

Country UK Japan Switz. Italy

Year Introduced 1977 1979 1980 1980

Raw Materials N-Formylhexamethyleneimine Oxalyl chloride Pivaloyloxymethyl 6-aminopenicillinate tosylate Sodium bicarbonate Manufacturing Process The starting material N-formylhexamethyleneimine was prepared from hexamethyleneimine and chloral. 12.7 g of N-formylhexamethyleneimine were dissolved in 250 ml of dry ether. While stirring and cooling, 8.5 ml of oxalyl chloride in 50 ml of dry ether were added dropwise, whereafter the mixture was stirred overnight at room temperature. The precipitated amide chloride was filtered off and washed with dry ether, and was placed in an exsiccator. 27.5 g of pivaloyloxymethyl 6-aminopenicillinate tosylate was suspended in 1,500 ml of ethyl acetate with continuous stirring and cooling in an ice bath and 950 ml of ice-cold aqueous sodium bicarbonate (2%) were added. The ethyl acetate layer was separated and was shaken with 750 ml of ice-water containing 25 ml of aqueous sodium bicarbonate (2%), whereafter it was dried over magnesium sulfate at 0°C. After filtration, the solution was evaporated to dryness in vacuo. The residue was dissolved in a solution of 15.5 ml of dry triethylamine in 75 ml of dry alcohol-free chloroform. To this solution, 10 g of the above prepared amide chloride dissolved in 75 ml of dry

2796

Pixifenide

alcohol-free chloroform were added dropwise at a temperature of about 20°C. After standing for half an hour at -20°C, the temperature was raised to 0°C within 15 minutes and the solution was evaporated to dryness in vacuo. The residue was stirred with 750 ml of ether. Undissolved triethylamine hydrochloride was filtered off, and the filtrate was again evaporated to dryness in vacuo. The residue was reprecipitated from acetone (200 ml) - water (150 ml). After recrystallization from cyclohexane an analytically pure product was obtained with a melting point of 118.5°C to 119.5°C. References Merck Index 391 Kleeman & Engel p. 741 DOT 19 (6) 331 (1983) I.N. p. 786 REM p. 1201 Lund, F.J.; US Patent 3,957,764; May 18, 1976; assigned to Lovens Kemiske Fabrik Produktionsartieselskab (Denmark)

PIXIFENIDE Therapeutic Function: Antiinflammatory Chemical Name: 1-[[4-[1-(Hydroxyimino)ethyl]phenoxy]acetyl]piperidine Common Name: N-(p-1-Nitrosoethyl)phenoxyacetylpiperidine; Pifoxime Structural Formula:

Chemical Abstracts Registry No.: 31224-92-7 Trade Name Flamanil

Manufacturer Salvoxyl-Wander

Raw Materials p-Hydroxyacetophenone Methanol Hydroxylamine Chloroacetic acid Piperidine

Country France

Year Introduced 1975

Pizotyline hydrochloride

2797

Manufacturing Process (A) Preparation of p-Acetylphenoxyacetic Acid: p-Hydroxy-acetophenone is treated with chloroacetic acid in aqueous solution in the presence of sodium hydroxide. The desired acid is then isolated from its sodium salt in a total yield of 80 to 82%, excess of p-hydroxy-acetophenone having been extracted with methylene chloride. (B) Preparation of Methyl p-Acetylphenoxy-Acetate: A mixture of 80 g of the acid obtained in (A) and 200 ml of methyl alcohol in 600 ml of dichloromethane is refluxed in the presence of sulfuric acid. The desired ester is isolated in accordance with a method known per se, and recrystallized. When the refluxing period is 12 hours, the ester is obtained with a yield of 70%. When the refluxing period is 18 hours, the yield for this ester is 85%. (C) Preparation of N-(p-Acetylphenoxy-Acetyl)-Piperidine: The ester from (B) is refluxed for 8 hours with 2.5 mols of thoroughly dried piperidine. Then 1 volume of water is added and the product is left to crystallize in the cold. The desired amide is obtained in an 80% yield. (D) Preparation of N-(p-[1-Isonitrosoethyl]-Phenoxy-Acetyl)-Piperidine: The amide from (C) is refluxed for 5 hours with technical (98%) hydroxylamine and alcohol denatured with methanol. The desired product is obtained in a 75% yield. In semiindustrial synthesis, to achieve better yields, it is possible to omit (A), by directly preparing the ester (B) by reaction of p-hydroxy acetophenone on ethyl 2-bromoacetate in the presence of potassium carbonate in butanone. The yield of ester is 90%, and elimination of excess of phydroxyacetophenone is effected by washing with sodium hydroxide. References Merck Index 7300 Kleeman & Engel p. 725 DOT 12 (2) 50 (1976) Mieville, A.; US Patent 3,907,792; September 23, 1975

PIZOTYLINE HYDROCHLORIDE Therapeutic Function: Migraine therapy Chemical Name: 4-(9,10-Dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thien-4ylidene-1-methylpiperidine hydrochloride Common Name: Pizotifen Chemical Abstracts Registry No.: 15574-96-6 (Base)

2798

Pizotyline hydrochloride

Structural Formula:

Trade Name Sandomigran Sandomigran Sanomigran Mosegor Sanmigran Polomigran

Manufacturer Sandoz Sandoz Wander Wander Salvoxyl-Wander Polfa

Country Italy W. Germany UK W. Germany France Poland

Year Introduced 1972 1974 1975 1976 1976 -

Raw Materials Phosphorus Hydrogen chloride Phthalic anhydride Magnesium

Thienyl-(2)-acetic acid 1-Methyl-4-chloropiperidine Phosphorus pentoxide

Manufacturing Process (A) Preparation of Thenylidene-(2)-Phthalide: 24.2 g of thienyl-(2)-acetic acid, 52.0 g of phthalic acid anhydride, 4.0 g of anhydrous sodium acetate and 125 ml of 1-methylpyrrolidone-(2) are heated while stirring in an open flask for 3 hours to 205° to 208°C, while nitrogen is passed through. It is then cooled and the viscous reaction mixture poured into 1 liter of water. The precipitated substance is filtered off, washed with water and then dissolved in 200 ml of chloroform. After filtering off some undissolved substance, shaking is effected twice with 100 ml of 2 N sodium carbonate solution and then with water, drying is then carried out over sodium sulfate and the volume is reduced by evaporation. The crude phthalide is repeatedly recrystallized from ethanol, while treating with animal charcoal. It melts at 114° to 115°C. (B) Preparation of o-[2-Thienyl-(2')-Ethyl]Benzoic Acid: 24.0 g of thenylidene(2)-phthalide, 8.8 g of red pulverized phosphorus, 240 ml of hydrochloric acid (d = 1.7) and 240 ml of glacial acetic acid are heated to boiling under nitrogen and while stirring vigorously. 70 ml toluene are then added and 6.0 g of red phosphorus added in small portions over a period of 1 hour. It is then poured into 3 liters of ice water, stirred with 300 ml of chloroform and the phosphorus removed by filtration. The chloroform phase is then removed, the aqueous phase extracted twice more with 200 ml of chloroform and the united extracts shaken out 4 times,

Pizotyline hydrochloride

2799

each time with 200 ml of 2 N sodium hydroxide solution. The alkaline solution is then rendered acid to Congo red reagent, using hydrochloric acid and extracted 3 times with chloroform. After drying over sodium sulfate and evaporating the solvent, the residue is chromatographed on aluminum oxide (Activity Stage V). The substance eluted with benzene and benzene/chloroform (1:1) is recrystallized from chloroform/hexane (1:1); MP 107° to 109°C. (C) Preparation of 9,10-Dihydro-4H-Benzo[4,5]Cyclohepta[1,2-b]Thiophen(4)-One: 200 ml of 85% phosphoric acid and 112 g of phosphorus pentoxide are heated to 135°C. 7.0 g of o-[2-thienyl-(2')-ethyl]benzoic acid are then introduced while stirring thoroughly over a period of 30 min. Stirring is then continued for another hour at 135°C and the reaction mixture is then stirred into 1 liter of ice water. Extraction is then effected 3 times, using 250 ml ether portions, the ethereal extract is washed with 2 N sodium carbonate solution, dried over sodium sulfate and reduced in volume by evaporation. The residue is boiled up with 55 ml of ethanol, the solution freed of resin by decanting and then stirred at room temperature for 6 hours with animal charcoal. It is then filtered off, reduced in volume in a vacuum and the residue distilled. BP 120° to 124°C/0.005 mm, nD24.5 = 1.6559. (D) Preparation of 4-[1'-Methyl-Piperidyl-(4')]-9,10-Dihydro-4HBenzo[4,5]Cyclohepta[1,2b]Thiophen-(4)-ol: 0.94 g of magnesium filings which have been activated with iodine are covered with a layer of absolute tetrahydrofuran and etched with a few drops of ethylene bromide. A solution of 5.0 g of 1-methyl-4-chloropiperidine in 5 ml of tetrahydrofuran is then added dropwise and boiling then effected for a further hour under reflux. After cooling to room temperature, the solution of 4.5 g of 9,10-dihydro-4Hbenzo[4,5]cyclohepta[1,2-b]thiophen-(4)-one in 5 ml of tetrahydrofuran is added dropwise. Stirring is carried out first for 3 hours at room temperature and then for 2 hours at boiling temperature, it is then cooled and poured into 300 ml of icecold 20% ammonium chloride solution. It is then shaken out with methylene chloride, the methylene chloride solution washed with water and shaken 3 times with 30 ml portions of aqueous 2 N tartaric acid solution. The tartaric acid extract is rendered alkaline while cooling thoroughly and then extracted twice with methylene chloride. After washing with water, drying over potassium carbonate and reducing in volume by evaporation, the residue is recrystallized from ethanol. MP 197° to 199°C. (E) Preparation of 4-[1'-Methyl-Piperidylidene-(4')]-9,10-Dihydro-4HBenzo[4,5]Cyclohepta[1,2-b]Thiophene Hydrochloride: 2 g of 4-[1'-methylpiperidyl-(4')]-9,10-dihydro4H-benzo[4,5]cyclohepta[1,2-b]thiophen-(4)-ol, 60 ml of glacial acetic acid and 20 ml of concentrated hydrochloric acid are boiled for 30 minutes under reflux. After evaporating in a vacuum, the residue is triturated with 3 ml of acetone, the precipitated hydrochloride is then filtered off and it is recrystallized from isopropanol/ether. MP 261° to 263°C (decomposition). References Merck Index 7389 Kleeman & Engel p. 742

2800

Poloxalkol

DOT 9 (6) 221 (1973) I.N. p. 786 Jucker, E., Ebnother, A., Stoll, A., Bastian, J.-M. and Rissi, E.; US Patent 3,272,826; September 13, 1966; assigned to Sandoz Ltd., Switzerland

POLOXALKOL Therapeutic Function: Pharmaceutic aid (surfactant) Chemical Name: Poly(oxyethylene)-poly(oxypropylene)-poly(oxyethylene) Common Name: Poloxalene Structural Formula: HO(CH2CH2O)a[CH(CH3)CH2O]b(CH2CH2O)cH Average values for a, b, c are a= 12, b = 34, c = 12 Chemical Abstracts Registry No.: 9003-11-6 Trade Name Polykol Therabloat

Manufacturer Upjohn Norden

Country US US

Year Introduced 1958 -

Raw Materials Propylene glycol Ethylene oxide Manufacturing Process (A) In a 1-liter 3-necked round bottom flask equipped with a mechanical stirrer, reflux condenser, thermometer and propylene oxide feed inlet, there were placed 57 g (0.75 mol) of propylene glycol and 7.5 g of anhydrous sodium hydroxide. The flask was purged with nitrogen to remove air and heated to 120°C with stirring and until the sodium hydroxide was dissolved. Then sufficient propylene oxide was introduced into the mixture as fast as it would react until the product possessed a calculated molecular weight of 2,380. The product was cooled under nitrogen, the NaOH catalyst neutralized with sulfuric acid and the product filtered. The final product was a waterinsoluble polyoxypropylene glycol having an average molecular weight of 1,620 as determined by hydroxyl number or acetylation analytical test procedures. (B) The foregoing polyoxypropylene glycol having an average 1,620 molecular weight was placed in the same apparatus as described in procedure (A), in the amount of 500 g (0.308 mol), to which there was added 5 g of anhydrous sodium hydroxide. 105 g of ethylene oxide was added at an average temperature of 120°C, using the same technique as employed in (A). The amount of added ethylene oxide corresponded to 17.4% of the total weight of the polyoxypropylene glycol base plus the weight of added ethylene oxide.

Polyestradiol phosphate

2801

References Merck Index 7431 I.N. p. 789 REM p. 1320 Lundsted, L.G.; US Patent 2,674,619; April 6, 1954; assigned to Wyandotte Chemicals Corporation

POLYESTRADIOL PHOSPHATE Therapeutic Function: Estrogen Chemical Name: Estra-1,3,5(10)-triene-3,17 diol (17-beta)-, polymer with phosporic acid Common Name: Polymeric ester of phosphoric acid and estradiol Structural Formula: Estradiol phosphate polymer Chemical Abstracts Registry No.: 28014-46-2 Trade Name Estradurin Estradurin Estradurin

Manufacturer Ayerst Abello Leo

Country US Spain Sweden

Year Introduced 1957 -

Raw Materials Estradiol Phosphorus oxychloride Manufacturing Process 3 g of estradiol was dissolved in 75 ml of anhydrous pyridine. The solution was cooled to -10°C, whereupon a solution of 1.1 ml of phosphorus oxychloride in 10 ml of anhydrous pyridine was added with agitation. After the addition, which required 7 minutes, the reaction mixture was kept at -10°C for a further period of 3 hours, and then it was left standing at room temperature for 15 hours. A clear solution thus resulted, to which finely crushed ice was then added. The resulting solution was evaporated in vacuum to dryness. After drying in a vacuum desiccator, 3.8 g of a white powder was obtained. This powder was suspended in 2 ml of pyridine, and 25 ml of 0.5 N sodium hydroxide was added, whereupon a solution was obtained which was then diluted with water to 100 ml. The solution was then dialyzed through a cellophane membrane against 4 liters of water for 10 hours, with stirring. The dialysis was repeated 2 additional times, with fresh amounts of water. To the dialyzed solution there was added 2 ml of 1 N hydrochloric acid, whereupon polyestradiol phosphate

2802

Polyethylene glycol 3350

was precipitated as a white bulky precipitate. This was centrifuged off and washed repeatedly with 0.1 N hydrochloric acid. Thereafter it was dried in a vacuum desiccator. The yield was 3 g of polyestradiol phosphate. The analysis shows 0.65% of water, 1.35% of pyridine and 9.3% of phosphorus (calculated on a dry sample). References Merck Index 7439 PDR p. 618 I.N. p. 790 REM p. 987 Diczfalusy, E.R., Ferno, O.B., Fex, H.J., Hogberg, K.B. and Linderot, T.O.E.; US Patent 2,928,849; March 15, 1960; assigned to Leo AB, Sweden

POLYETHYLENE GLYCOL 3350 Therapeutic Function: Laxative Chemical Name: Synthetic polyglycol having an average molecular weight of 3350 Common Name: Structural Formula:

Chemical Abstracts Registry No.: 25322-68-3 Trade Name MiraLax Polyethylene Glycol 3350

Manufacturer Braintree Laboratories Schwarz Pharma

Country -

Year Introduced -

Raw Materials Ethylene oxide Polyethylene glycol 400 Potassium hydroxide Manufacturing Process Polyethylene glycol 3350 was obtained by polymerization of ethylene oxide in an autoclave at 80-100°C using as a catalyst dipotassium alcogolate of polyethylene glycol 400. Dipotassium alcogolate of polyethylene glycol 400 was synthesized by a

Polymyxin

2803

heating of the dry mixture of polyethylene glycol 400 and potassium hydroxide. The molecular weight of polymer was regulated by the ratio of monomer:catalyst. References Bailey F.E. and Koleske J.// Poly(ethylene oxide). N.Y., Acad. Press, 1976

POLYMYXIN Therapeutic Function: Antibacterial Chemical Name: See structure Common Name: Structural Formula: Complex antibiotic Chemical Abstracts Registry No.: 1406-11-7 Trade Name Aerosporin Cortisporin Mastimyxin Neo-Polycin Neosporin Octicair Ophthocort Otobiotic Otocort Polyfax Polysporin Pyocidin Topisporin Tri-Thalmic

Manufacturer Burroughs-Wellcome Burroughs-Wellcome Chassot Merrell Dow Burroughs-Wellcome Pharmafair Parke Davis Schering Lemmon Pitman-Moore Burroughs-Wellcome Berlex Pharmafair Schein

Country US US Switz. US US US US US US US US US US US

Year Introduced 1951 -

Raw Materials Bacterium Bacillus polymyxa Nutrient medium Corn meal Manufacturing Process As described in US Patent 2,595,605, in a pilot plant tank 225 liters of a medium containing the following ingredients was prepared: 2% ammonium sulfate, 0.2% potassium dihydrogen phosphate, 0.05% magnesium sulfate

2804

Polythiazide

heptahydrate, 0.005% sodium chloride, 0.001% ferrous sulfate heptahydrate, 0.5% yeast extract, 1% dextrose, 1% calcium carbonate and 3% corn meal. The fermentation medium was adjusted to pH 7.3 to 7.4. It was then sterilized for 30 minutes at 110°C. After sterilization the pH was about 7. To the medium was added 225 ml of mineral oil. The fermentation medium was inoculated with Bacillus polymyxa prepared as follows: A culture of Bacillus polymyxa in a tube with Trypticase soybean broth was incubated overnight at 25°C. 5 ml of this culture was transferred to 100 ml of the tank medium in a 500 ml Erlenmeyer flask which was incubated for 48 hours at room temperature. This 100 ml culture served as inoculum for one tank. During the course of fermentation the medium was aerated at the rate of 0.3 volume of air per volume of mash per minute. The temperature was maintained at about 27°C. Samples of mash were taken every 8 hours in order to determine pH and the presence of contaminants and spores. After 88 hours of fermentation the pH was about 6.3 and an assay using Escherichia coli showed the presence of 1,200 units of polymyxin per cubic centimeter. The polymyxin was extracted and purified by removing the mycelia, adsorbing the active principle on charcoal and eluting with acidic methanol. Polymyxin is usually used as the sulfate. References Merck Index 7445 Kleeman & Engel p. 743 PDR pp.671, 732, 738, 757, 888, 1034, 1232, 1380, 1415, 1429, 1606, 1645 DOT 8 (1) 21 (1972) I.N. p. 790 REM p. 1202 Ainsworth, G.C. and Pope, C.G.; US Patent 2,565,057; August 21, 1951; assigned to Burroughs Wellcome & Co. (U.S.A.) Incorporated Petty, M.A.; US Patent 2,595,605; May 6, 1952; assigned to American Cyanamid Company Benedict, R.G. and Stodola, F.H.; US Patent 2,771,397; November 20, 1956; assigned to the US Secretary of Agriculture

POLYTHIAZIDE Therapeutic Function: Diuretic Chemical Name: 6-Chloro-3,4-dihydro-2-methyl-3-[[(2,2,2-trifluoroethyl) thio]methyl]-2H-1,2,4-benzothiadiazine-7-sulfonamide-1,1-dioxide Common Name: Chemical Abstracts Registry No.: 346-18-9

Polythiazide

2805

Structural Formula:

Trade Name Renese Drenusil Renese Renese Envarese Minizide Nephril Polyregulon Toleran

Manufacturer Pfizer Pfizer Pfizer Pfizer Pfizer Pfizer Pfizer Yamanouchi Medica

Country US W. Germany Italy France France US UK Japan Finland

Year Introduced 1961 1962 1962 1965 -

Raw Materials 4-Amino-2-chloro-5-(methylsulfamyl)benzenesulfonamide Sodium Mercaptoacetaldehyde dimethylacetal Trifluoroethyl iodide Manufacturing Process (A) Preparation of trifluoroethylthioacetaldehyde dimethylacetal: To 4.6 g (0.2 mol) of metallic sodium dissolved in 75 ml of absolute methanol is rapidly added 24.4 g (0.2 mol) of mercaptoacetaldehyde dimethylacetal followed by dropwise addition of 42.0 g (0.2 mol) of trifluoroethyl iodide. The resulting reddish mixture is refluxed on a steam bath for one hour. One half of the alcohol is removed by concentration and the remainder diluted with several volumes of water and extracted with ether. The combined ether extracts are dried over sodium sulfate, the ether then removed at reduced pressure and the residue distilled to about 30 g (BP 82°C/25 mm). (B) Preparation of 4-Amino-2-Chloro-5-(Methylsulfamyl)Benzenesulfonamide: The 5-substituted-2,4-disulfamyl anilines may be prepared by procedures described in the literature, for example, the general procedures in Monatsch. Chem. vol. 48, p 87 (1927), which involves the treatment of a m-substituted aniline with from 10 to 20 parts by weight of chlorosulfonic acid followed by the gradual addition of from about 90 to 170 parts by weight of sodium chloride. The resultant mixture is heated at approximately 150°C for about 2

2806

Porfimer sodium

hours after which the reaction mixture is poured into water and the resultant 5substituted aniline-2,4-disulfonyl chloride is filtered and is then treated with concentrated ammonium hydroxide or suitable amine by standard procedures to obtain the corresponding disulfonamide. (C) Preparation of 2-Methyl-3-(2,2,2-Trifluoroethyl)Thiomethyl-6-Chloro-7Sulfamyl-3,4-Dihydro-1,2,4-Benzothiadiazine-1,1-Dioxide: To 4.6 g (0.015 mol) of 4-amino-2-chloro5-(methylsulfamyl)benzenesulfonamide in 30 ml of the dimethyl ether of ethylene glycol is added 4.08 g (0.02 mol) of 2,2,2trifluoroethylmercaptoacetaldehyde dimethylacetal followed by 1 ml of ethyl acetate saturated with hydrogen chloride gas. The resulting solution is refluxed for 1.5 hours, cooled and then slowly added to cold water dropwise with stirring. The crude product is filtered, dried and recrystallized from isopropanol (3.2 g), MP 202° to 202.5°C. A second recrystallization from isopropanol raised the MP to 202° to 203°C. References Merck Index 7457 Kleeman & Engel p. 743 PDR pp. 1409, 1421 OCDS Vol. 1 p. 360 (1977) I.N. p. 791 REM p. 940 McManus, J.M.; US Patent 3,009,911; November 21, 1961; assigned to Chas. Pfizer & Co., Inc.

PORFIMER SODIUM Therapeutic Function: Antineoplastic, Photosensitizer Chemical Name: Photofrin porfimer sodium (porfimer sodium disigned also as polyporphin oligomer containing ester and ether linkage) Common Name: Porfimer Sodium; Photofrin II Trade Name PhotoBarr Photofrin II Photofrin II Photofrin II

Manufacturer Axcan Pharma Inc. Lederle Parenterals, Inc. QLT Phototherapeutics Inc. Wyeth-Ayerst Lederle Parenterals, Inc.

Country Canada USA -

Year Introduced -

Photofrin II

Axcan Scandipharm Inc.

USA

-

Raw Materials Acetic acid Sodium hydroxide Sodium acetate

Hematoporphyrin hydrochloride Sulfuric acid

Porfimer sodium

2807

Structural Formula:

Chemical Abstracts Registry No.: 87806-31-3 Manufacturing Process 285 ml of acetic acid was added to a 1000 ml Erlenmeyer flask containing Teflon-coated magnetic stirring bar. Stirring the acetic acid, slowly 15 ml of concentrated sulfuric acid was added; weighing out 15.0 g of hematoporphyrin hydrochloride (preferably obtained from Roussel Corporation, Paris, France); adding to the acid solution; the reaction acetic mixture was stirred for 1 h. To the reaction acetic mixture 3 L of 5% sodium acetate was added. The 5% sodium acetate solution now contains a dark red precipitate which is preferably allowed to stand for 1 h with occasional stirring; the dark red precipitate is then again filtered, preferably using the above-identified filter mechanism; the filter cake from the filtering process is then washed with glass-distilled water until the filtrate is at pH of 5.5-6.0 (1500-2500 ml of wash water may be required); and the filter cake is then preferably allowed to dry in air at room temperature. The air-dried precipitate is ground, using for instance, a mortar and pestle until a fine powder is obtained. The powder may then be transferred to a 250 ml round bottom flask. The flask is then attached to a rotating evaporator and rotation under vacuum is maintained at room temperature for preferably 24 h and hemoporphyrin acetate was obtained. Acetylated hematoporphyrin (1 part by weight) is dissolved in 0.1 N sodium hydroxide (50 parts by volume) and stirred for 1 h at room temperature. After the stir period the solution is adjusted to pH 9.4 to 9.6 with 1 N hydrochloric acid. It is filtered through a 5 µm filter and then concentrated to (12.5 parts) of its original volume in an ultrafilter with 10,000 molecular weight cut off membranes. The solution is then purified via diafiltration maintaining constant volume with 120 volumes of water and keeping the pH at 9.4 to 9.6 with 0.1 N sodium hydroxide. This is also done at room temperature. After the purification, the solution is removed from the ultrafilter, diluted to 3/8 (18.8 parts) of its original volume and pH adjusted to 7.5 to 7.7 with 1 N hydrochloric acid. The solution is then stored at 4°C for 14 to 21 days. After

2808

Povidone-iodine

storage, the solution is pH adjusted to 9.4 to 9.6 with 0.1 N sodium hydroxide and concentrated to 1/4 (12.5 parts) of its original volume. The solution is then repurified as above. The solution is diluted to 3/8 (18.8 parts) of its original volume and pH adjusted to 7.5 to 7.7 with 1 N hydrochloric acid. The solution is then analyzed and, if necessary, it is adjusted to between 13 to 18 mg/ml by the addition of water. The solution is then filtered through a 0.22 µm filter into bottles for storage at 1°C to 4°C to await further processing. References Dougherty T.J. et al.; US Patent No. 4,649,151; March 10, 1987; Assigned: Health Research, Inc., Buffalo, N.Y. Zawadzki R.K., Clauss S.L.; US Patent No. 5,244,914; Sep. 14, 1993; Assigned: American Cyanamid Company, Stamford, Conn.

POVIDONE-IODINE Therapeutic Function: Topical antiinfective Chemical Name: 1-Ethenyl-2-pyrrolidinone homopolymer compound with iodine Common Name: PVP-I Structural Formula:

Chemical Abstracts Registry No.: 25655-41-8 Trade Name

Manufacturer

Country

Year Introduced

Betadine Betadine Efodine Vagidine Clinidine Mallisol ACU-Dyne Batticon Betadine Ginecologico Betaisodona

Purdue Frederick Sarget Fougera Beecham Clinipad Mallard Acme Laboratories Ltd. Trommsdorff Chinoin Mundipharma

US France US US US US US W. Germany Italy Austria

1957 1970 1978 1981 1982 1983 -

Povidone-iodine Trade Name Braunol Chem-O-Dine Difexon Disadine Isodine Jodobac Jodocur Neojodin Nutradine Pevidine Polydine Povadyne Proviodine Summer's Eve Topionic

Manufacturer Braun Remedia Bago Stuart Purdue Frederick Bode Farm. Milanese Iwaki Restan Berk Fischer Chaston Rougier Fleet Rius

Country W. Germany S. Africa Argentina UK US W. Germany Italy Japan S. Africa UK Israel US Canada US Spain

2809

Year Introduced -

Raw Materials Polyvinylpyrrolidone Iodine Manufacturing Process 12 g of dry polyvinylpyrrolidone having a K value of 90 (water content about 2 to 3%) was added to 6 g of solid iodine crystals in a glass bottle containing a few pebbles and beads. This was rolled for 3 days on a roller mill with occasional manual stirring to loosen the material caked on the sides of the bottle. Analysis showed that the thus-obtained product contained 35.4% total iodine and 31.91% available iodine. The material was heat-treated at 95°C for 64 hours in a closed glass bottle with occasional stirring. On completion of this treatment, analysis showed that the material contained 35.3% total iodine, 25.7% available iodine, according to US Patent 2,706,701. References Merck Index 7595 PDR pp. 880, 888, 1432 DOT 7 (4) 149 (1971) I.N. p. 793 REM p. 1164 Beller, H. and Hosmer, W.A.; US Patent 2,706,701; April 19, 1955; assigned to General Aniline & Film Corporation Hosmer, W.A.; US Patent 2,826,532; March 11, 1958; assigned to General Aniline & Film Corporation Siggia, S.; US Patent 2,900,305; August 18, 1959; assigned to General Aniline & Film Corporation

2810

Practolol

PRACTOLOL Therapeutic Function: Antiarrhythmic Chemical Name: N-[4-[2-Hydroxy-3-[(1-methylethyl)amino]propoxy]phenyl] acetamide Common Name: 1-(4-Acetamidophenoxy)-3-isopropylamino-2-propanol Structural Formula:

Chemical Abstracts Registry No.: 6673-35-4 Trade Name

Manufacturer

Country

Year Introduced

Eraldin

I.C.I.

UK

1970

Eraldin

I.C. Pharma

Italy

1972

Dalzic

Rhein Pharma

W. Germany

1973

Eraldine

I.C.I. Pharma

France

1973

Cardiol

Orion

Finland

-

Pralon

Farmos

Finland

-

Raw Materials 4-Acetamidophenol Epichlorohydrin Isopropylamine Manufacturing Process The 1-(4-acetamidophenoxy)-2,3-epoxypropane used as starting material may be obtained as follows. To a solution of 4.5 parts of 4-acetamidophenol and 1.5 parts of sodium hydroxide in 50 parts of water at 15°C, there is added 3.5 parts of epichlorohydrin. The mixture is stirred for 16 hours at ambient temperature, filtered and the solid residue is washed with water. There is thus obtained 1-(4-acetamidophenoxy)-2,3-epoxypropane, MP 110°C. A mixture of 2 parts of 1-(4-acetamidophenoxy)-2,3-epoxypropane and 10 parts of isopropylamine is stirred at ambient temperature for 16 hours. The resulting solution is evaporated to dryness under reduced pressure and the residue is crystallized from butyl acetate. There is thus obtained 1-(4acetamidophenoxy)-3-isopropylamino-2-propanol, MP 134° to 136°C.

Prajmaline bitartrate

2811

References Merck Index 7597 OCDS Vol. 2 pp. 106, 108 (1980) DOT 6 (5) 188 (1970) I.N. p. 794 Howe, R. and Smith, L.H.; US Patent 3,408,387; October 29, 1968; assigned to Imperial Chemical Industries Limited, England

PRAJMALINE BITARTRATE Therapeutic Function: Antiarrhythmic Chemical Name: 17R,21α-Dihydroxy-4-propylajmalanium bitartrate Common Name: Structural Formula:

Chemical Abstracts Registry No.: 2589-47-1; 35080-11-6 (Base) Trade Name Neo-Gilurtymal Neo-Aritmina

Manufacturer Giulini Byk Gulden

Country W. Germany Italy

Year Introduced 1973 1979

Raw Materials Ajmaline Sodium bicarbonate Allyl bromide Tartaric acid Manufacturing Process 1 g of ajmaline was dissolved in 4 cc of chloroform, and 1 cc of allyl bromide

2812

Pralidoxime chloride

was added to the resulting solution. The reaction mixture thus obtained was allowed to stand for 24 hours at room temperature. Thereafter, the clear reaction solution was briefly cooled to a temperature below 0°C, whereby crystallization set in. The crystals were filtered off and were then recrystallized from a mixture of absolute methanol and absolute ether. The purified colorless crystalline product was identified to be N-(b)-allyl-ajmalinium-bromide having a melting point of 252°C to 254°C. 75 g of N-(b)-n-propyl-ajmalinium-bromide were suspended in 3 liters of an aqueous saturated solution of sodium bicarbonate, and the suspension was admixed with 3 liters of chloroform. The resulting mixture was vigorously stirred for six to eight hours. Thereafter, the chloroform phase was separated and evaporated to dryness. 68 g of a yellow syrup remained as a residue. The aldehyde base was dissolved in about 150 cc of acetone and, while stirring and cooling on an ice bath, the solution was slowly admixed with a solution of 25 g of tartaric acid in 2 liters of acetone. The fine white precipitate formed thereby was separated by vacuum filtration, washed with ether and dried. The raw product, weighing 80 g, was recrystallized once from a mixture of ethanol and ether, yielding 50 g of N-(b)-n-propyl-ajmalinium hydrogen tartrate having a melting point of 149°C to 152°C (decomposition). References Merck Index 7598 Kleeman & Engel p. 744 I.N. p. 794 Keck, J.; US Patent 3,414,577; December 3, 1968; assigned to Boehringer Ingelheim G.m.b.H. (Germany)

PRALIDOXIME CHLORIDE Therapeutic Function: Antidote (nerve gas) Chemical Name: 2-[(Hydroxyimino)methyl]-1-methylpyridinium chloride Common Name: 2-PAM chloride Structural Formula:

Chemical Abstracts Registry No.: 51-15-0; 495-94-3 (Base)

Pralidoxime chloride Trade Name Contrathion Protopam Combo Pen

Manufacturer Specia Ayerst Rodana Res. Corp.

Country France US US

2813

Year Introduced 1961 1964 -

Raw Materials 2-Pyridinealdoxime Nitrosyl chloride Methyl chloride

α-Picoline Dimethyl sulfate Sodium hydroxide

Manufacturing Process As described in US Patent 3,123,613, the preparation of the intermediate product, 2-pyridinealdoxime methomethylsulfate, is as follows. 1 kg of 2pyridinealdoxime is dissolved in 6 liters of acetone and filtered until clear. 2 kg (2 equivalents) of freshly distilled dimethyl sulfate are added and the solution mixed. In about 30 minutes crystals start to appear, after which a cooling bath is used to keep the temperature at about 30° to 35°C until the reaction is nearly complete (about 2 hours). The mixture is allowed to stand at room temperature overnight, the crystals filtered off and washed on a filter with acetone. The product is obtained as colorless needles, which melt at 111° to 112.5°C. The methylsulfate is not stable indefinitely. For preparation of pure chloride salt it is desirable to use methylsulfate which gives no titratable acidity with sodium hydroxide using bromophenol blue as indicator. 10 g of 2-pyridinealdoxime methomethylsulfate are then dissolved in 6 cc of concentrated hydrochloric acid, and 60 cc of isopropanol is added with stirring. Crystals appear almost instantly. After 2 hours standing at room temperature, the crystals are separated by filtration and washed with acetone. The product had a melting point of 227° to 228°C and the yield was 85%. An alternative route is described in US Patent 3,155,674. (A) Preparation of 1-Methyl-2-Picolinium Chloride: 98 ml of α-picoline is dissolved in 200 ml of methanol, cooled and 85 ml (at -68°C) of methyl chloride is added. The solution is charged to an autoclave, sealed and the nitrogen pressure of 300 psig is established. The mixture is heated at 120° to 130°C for 2 hours, cooled and opened. The resulting solution is then evaporated to dryness in vacuo, yielding a residue of 110 g. This residue is then dissolved in 50 ml of water and extracted with two 50 ml portions of ether. The aqueous phase is then diluted to 150 ml with water and an assay for ionic chloride is performed which indicates the presence of chloride ion equivalent to 721 mg/ml of l-methyl-2picolinium chloride. (B) Preparation of 2-(Hydroxyiminomethyl)-1-Methyl Pyridinium Chloride: An aqueous solution of 15 ml of 1-methyl-2-picolinium chloride having a concentration of 477 mg/ml is covered with 50 ml of benzene in an atmosphere of nitrogen and cooled to below 10°C. An aqueous solution of sodium hydroxide is added dropwise and the mixture is stirred for 5 minutes and allowed to stratify. The aqueous phase is then drawn off and the benzene

2814

Pramipexole dihydrochloride

solution is added slowly to a solution of 3 ml of nitrosyl chloride in 175 ml of benzene containing 0.5 ml of dimethyl formamide at about 10°C in an atmosphere of nitrogen with good agitation. The mixture is then stirred for 1.5 hours and then extracted with four 5 ml of portions of water. The aqueous extracts are then concentrated in vacuo, 30 ml of isopropanol is added and the concentration is repeated. 20 ml of isopropanol is then added to the concentrated mixture, and the mixture is cooled to room temperature and filtered, yielding 3.04 g of crude 2-(hydroxyiminomethyl)-1-methylpyridinium chloride, melting at 202° to 214°C with decomposition. The filtrate is then further concentrated to a 7 g residue which is crystallized from absolute alcohol and yields 0.9 g of 2-(hydroxyiminomethyl)-1-methyl pyridinium chloride melting at 221° to 225°C with decomposition. References Merck Index 7599 Kleeman & Engel p. 744 PDR p. 648 I.N. p. 794 REM p. 901 Bloch, L.P.; US Patent 3,123,613; March 3, 1964; assigned to Campbell Pharmaceuticals, Inc. Ellin, R.I., Easterday, D.E. and Kondritzer, A.A.; US Patent 3,140,289; July 7, 1964; assigned to the US Secretary of the Army McDowell, W.B.; US Patent 3,155,674; November 3, 1964; assigned to Olin Mathieson Chemical Corporation

PRAMIPEXOLE DIHYDROCHLORIDE Therapeutic Function: Antiparkinsonian, Antipsychotic Chemical Name: 2,6-Benzothiazolediamine-4,5,6,7-tetrahydro-N6-propyl, dihydrochloride, (6S)Common Name: Pramipexole dihydrochloride Structural Formula:

Chemical Abstracts Registry No.: 104632-25-9; 104632-26-0 (Base) Trade Name

Manufacturer

Country

Year Introduced

Mirapex

Pharmacia and Upjohn

USA

-

Pramipexole dihydrochloride

2815

Raw Materials Phthalic anhydride Ethyldiisopropyl amine Acetic acid Thiourea n-Propanal Hydrobromic acid

4-Aminocyclohexanol hydrochloride Potassium dichromate Bromine Hydrazine hydrate Hydrochloric acid Sodium borohydride

Manufacturing Process 75.5 g (0.5 mol) of 4-aminocyclohexanol hydrochloride and 74.0 g (0.5 mol) of phthalic acid anhydride are mixed with 65 g (0.5 mol) of ethyldiisopropyl amine and 1000 ml of toluene and boiled for 36 hours with a water separator. Then water is added, the toluene phase is separated off and the aqueous phase is extracted several times with chloroform. The organic phases are combined, dried and concentrated. The concentrated residue is recrystallised from isopropanol and 4-(phthalimido)-cyclohexanol was obtained. Yield: 95 g (77.8%). Melting point 175°-176°C. 95 g (0.388 mol) of 4-(phthalimido)-cyclohexanol are dissolved in 600 ml of chloroform and, after the addition of 450 ml of water and 120 ml of sulfuric acid, 90 g (0.3 mol) of potassium dichromate are added in batches. The internal temperature of the mixture is maintained at between 25° and 30°C by slight cooling. The mixture is stirred for a further 3 hours, then the chloroform phase is separated off and the mixture extracted twice more with chloroform. After drying and concentration of the extracts 82 g (86.9%) of 4(phthalimido)-cyclohexanone was obtained. 48.6 g (0.2 mol) of 4-(phthalimido)cyclohexanone are dissolved in glacial acetic acid, mixed with 36% of hydrobromic acid in glacial acetic acid and then 32 g (0.2 mol) of bromine in glacial acetic acid is added dropwise with cooling. The mixture is then concentrated by evaporation in vacuo and the residue is triturated several times with diethylether. The ether extracts are discarded and the residue is dissolved in of ethanol. After thiourea have been added the mixture is refluxed for 5 hours. It is then concentrated by evaporation, made alkaline with sodium hydroxide solution and extracted with chloroform. After drying and concentration of the extracts, the residue is purified by column chromatography on silica gel (eluant: chloroform/methanol = 1/1). The 2-amino-6-phthalimido-4,5,6,7-tetrahydro-benzthiazol was obtained. Melting point 244-246°C, dec. Yield: 30 g (50%). 9.5 g (31.7 mmol) of 2-amino-6-phthalimido-4,5,6,7-tetrahydro-benzthiazole are suspended in 100 ml of ethanol and, after the addition of 1.8 g (36 mmol) of hydrazine hydrate, refluxed for 2 hours. The mixture is then concentrated and purified by column chromatography on silica gel using methanol as eluant. The 2,6-diamino- 4,5,6,7-tetrahydro-benzthiazole was obtained. To a solution of 2,6-diamino- 4,5,6,7-tetrahydro-benzthiazole in dimethylformamide are added n-propanal and the mixture is heated to 50°C for 1 hour. After cooling, the reaction solution is mixed with sodium borohydride and heated to 50°C for 30 min. The solvent is largely eliminated in vacuo. Whilst cooling with ice, the residue is mixed with water and 2 N hydrochloric acid until a pH of 1 is obtained. The aqueous solution is extracted

2816

Pramiverin

with ethylacetate and the organic phase discarded. The aqueous phase is mixed with potassium carbonate until an alkaline reaction is obtained and then extracted with ethyl acetate. The organic phase is dried and concentrated. The 2-amino-6-n-propylamino-4,5,6,7-tetrahydro-benzthiazole dihydrochloride crystallizes out when ethereal hydrochloric acid is added. Yield: 42%. Melting point: 286°-288°C. References Griss G. et al.; US Patent No. 4,886,812; Dec. 12, 1989; Assigned: Dr. Karl Thomae GmbH, Biberach an der Riss, Fed. Rep. of Germany

PRAMIVERIN Therapeutic Function: Spasmolytic Chemical Name: N-(1-Methylethyl)-4,4-diphenylcyclohexanamine Common Name: Primaverine; Propaminodiphen Structural Formula:

Chemical Abstracts Registry No.: 14334-40-8; 14334-41-9 (Hydrochloride salt) Trade Name Sistalgin Sistalgin

Manufacturer Bracco Cascan

Country Italy W. Germany

Year Introduced 1974 1976

Raw Materials Isopropylamine 4,4-Diphenyl-cyclohexen-(2)-one Hydrogen Manufacturing Process 20 g 4,4-diphenyl-cyclohexen-(2)-one, 10 g isopropylamine, and 50 ml tetrahydrofuran are agitated for 10 hours in a bomb tube at 200°C. Subsequently, the reaction mixture is cooled, and the tetrahydrofuran and the

Pramoxine hydrochloride

2817

excess isopropylamine are distilled off. The remaining Schiff base is dissolved in methanol and after the addition of 2 g platinum oxide, the base is hydrogenated at normal pressure and room temperature until a quantity of hydrogen corresponding to 2 mols has been absorbed. The mixture is filtered off from the catalyst, made acidic with dilute hydrochloric acid, and the methanol is removed under vacuum. The remaining aqueous solution is made alkaline with solution of sodium hydroxide and extracted with ether. After drying and concentrating the ether extract, there is obtained 17 g 1-isopropylamino-4,4-diphenyl-cyclohexane, boiling point 164°C to 165°C/0.05 mm. The hydrochloride melts at 230°C. References Merck Index 7602 Kleeman & Engel p. 745 DOT 11 (8) 320 (1975) I.N. p. 795 Unger, R., Sommer, S., Schorscher, E. and Encakel, H.J.; US Patent 3,376,312; April 2, 1968; assigned to E. Merck A.G. (Germany)

PRAMOXINE HYDROCHLORIDE Therapeutic Function: Local anesthetic Chemical Name: 4-[3-(4-Butoxyphenoxy)propyl]morpholine hydrochloride Common Name: Pramocaine hydrochloride; Proxazocain hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 637-58-1; 140-65-8 (Base) Trade Name Tronothane Tronothane Proctofoam Prax Analpram Anusol

Manufacturer Abbott Abbott Reed Carnrick Ferndale Ferndale Parke Davis

Country US France US US US US

Year Introduced 1954 1956 1975 1980 -

2818

Pranoprofen

Trade Name F.E.P. Fleet Relief Otic-HC Pramosone Tronolane Zone-A

Manufacturer Boots Fleet Hauck Ferndale Ross U.A.D. Labs

Country US US US US US US

Year Introduced -

Raw Materials Hydroquinone monobutyl ether Potassium hydroxide γ-Morpholinopropyl chloride Hydrogen chloride Manufacturing Process About 5.6 g of potassium hydroxide is dissolved in about 150 cc of refluxing ethanol, and then about 16.6 g of hydroquinone monobutyl ether is added to the alcoholic solution. When the hydroquinone is dissolved, about 16.3 g of γmorpholinopropyl chloride (dissolved in a small amount of ethanol) is added to the refluxing solution. The solution is refluxed for about 24 hours and then cooled. The product is recovered by filtering the reaction mixture and then removing the solvent by vacuum distillation. The oily residue is acidified and shaken with ether. The acidic phase is made strongly alkaline with 40% sodium hydroxide, and the oil which separates is extracted into ether. The ethereal phase is dried, and the solvent removed by vacuum distillation. The product distills at 183° to 184°C at a pressure of 2.8 mm. The hydrochloride salt of the foregoing base is prepared by dissolving the base in ether and acidifying with hydrochloric acid and is found to have a MP of 181° to 183°C. References Merck Index 7603 Kleeman & Engel p. 745 PDR pp. 684, 875, 880, 928, 1316, 1565, 1808 OCDS Vol. 1 p. 18 (1977) I.N. p. 795 REM p. 1057 Wright, H.B. and Moore, M.B.; US Patent 2,870,151; January 20, 1959; assigned to Abbott Laboratories

PRANOPROFEN Therapeutic Function: Analgesic, Antiinflammatory Chemical Name: 2-(5H-[1]Benzopyrano[2,3-b]-pyridin-7-yl)propionic acid Common Name: -

Prasterone

2819

Structural Formula:

Chemical Abstracts Registry No.: 52549-17-4 Trade Name Niflan

Manufacturer Yoshitomi

Country Japan

Year Introduced 1981

Raw Materials Ethyl 2-cyano-2-(5H-[1]benzopyrano[2,3-b]-pyridin-7-yl)propionate Hydrogen chloride Manufacturing Process A mixture of 100 g of ethyl 2-cyano-2-(5H-[1]benzopyrano[2,3-b]-pyridin-7yl)propionate, 500 ml of glacial acetic acid and 200 g of concentrated hydrochloric acid is refluxed for 48 hours. The reaction mixture is concentrated, and the residue is dissolved in hot water. The solution is adjusted to pH 2 to 3 by addition of 10% sodium hydroxide. The resulting crystalline precipitate is washed thoroughly with water, and recrystallized from aqueous dioxane to give 74 g of 2-(5H-[1]benzopyrano[2,3-b]-pyridin-7yl)propionic acid as white crystals melting at 183°C to 183.5°C. References Merck Index 7604 DFU 2 (3) 217 (1977) (As Y-8004) & 2 (12) 829 (1977) Nakanishi, M., Oe, T. and Tsuruda, M.; US Patent 3,931,205; January 6, 1976; assigned to Yoshitomi Pharmaceutical Industries, Ltd.

PRASTERONE Therapeutic Function: Glucocorticoid Chemical Name: Androst-5-en-17-one, 3-hydroxy-, (3β)Common Name: Dehydroandrosterone; Dehydroepiandrosterone; Dehydroisoandrosterone; Prasterone Chemical Abstracts Registry No.: 53-43-0

2820

Pravastatin sodium

Structural Formula:

Trade Name Aslera Prasterone Deandros

Manufacturer Genelabs Technologies, Inc. Proquina SA Schering AG

Country -

Year Introduced -

Raw Materials 16-Dehydropregnenolon-3β-acetate Hydroxylamine hydrochloride Phosphorus pentachloride Manufacturing Process To a solution of 1 gram of 16-dehydropregnenolon-3β-acetate in 10 ml pyridine is added 0.22 gram of hydroxylamine hydrochloride, and the mixture is allowed to stand at room temperature for four days. One gram of 16dehydropregnenolon-3β-acetate oxime is dissolved in 30 ml of hot dioxane, and then the solution is cooled in an ice bath until about one-half of the dioxane has solidified. Then 1 gram of phosphorus pentachloride is added and the mixture is shaken until all the dioxane has melted. The mixture is maintained at 35°C, for seventy-five minutes, then an excess of ice is added and the solution is again allowed to stand at 35°C. After about thirty minutes, a solution of 5 ml of concentrated hydrochloric acid in 10 ml of water is added, and the mixture is diluted with water, extracted with ether and the ethereal extract washed with dilute sodium hydroxide solution. The ether is removed on a steam bath and the residue is worked up to yield dehydroisoandrosterone. References Tendick F.H., Lawson E.J.; US Patent No. 2,335,616; Nov. 30, 1943; Assigned to Parke Davis and Company, Detroit, Mich., a corporation of Michigan

PRAVASTATIN SODIUM Therapeutic Function: Antihyperlipidemic Chemical Name: (1S-(1-α(β-S*,δ-S*),2α,6α,8β(R*),8a-α))-1Naphthaleneheptanoic acid 1,2,6,7,8,8a-hexahydro-2-methyl-8-(2methyl-1-oxobutoxy)-β,δ,6-trihydroxy-, monosodium salt

Pravastatin sodium

2821

Common Name: Eptastation sodium; Pravastatin sodium Structural Formula:

Chemical Abstracts Registry No.: 81131-70-6; 81093-37-0 (Base) Trade Name Apo-Pravastatin Apo-Pravastatin Lipostat Prastatin Prava Pravachol Pravachol Pravachol Pravator

Manufacturer Apotex Inc. Cobalt Pharmaceuticals Inc. Bristol-Myers Squibb Emcure Pharmaceuticals Ltd. B.-M. Sq./South Africa Bristol-Meyers Squibb Silanes Generic Solus

Country Canada France India S. Africa France -

Year Introduced -

Raw Materials Nocardia autotrophica subsp. amethystina FERM P-6183 2-Methyl-8-(2-methyl-1-oxobutoxy)-β,δ-dihydroxy(1S-(1-α(β-S*,δ-S*),2α,6-α,8-β(R*),8a-α))-1-1,2,6,7,8,8ahexahydronaphthaleneheptanoate sodium Sodium hydrogen carbonate Mortierella maculata nov. spec. E-97 [NCAIM(P)F 001266] Manufacturing Process Pravastatin was isolated as products of enzymatic hydroxylation by some kinds of microorganisms of [1S-[1-α(R*),7β,8β(2S*,4S*)8αβ]]-2methylbutanoic acid 1,2,3,7,8,8a-hexahydro-7-methyl-8-[2-(tetrahydro-4hydroxy-6-oxo-2))-pyran-2-yl)ethyl]-1-naphthalenic lactone (campactin) or their carboxylic acid or their salts (products of animal metabolism of microorganisms from the genera Nocardia, Streptomyces et cetera). Pravastatin may be preparated by using the microorganisms of genera Nocardia (method 1) and Mortierella (method 2). Method 1 Cultivation of Nocardia autotrophica subsp. amethystine

2822

Pravastatin sodium

Cells of Nocardia autotrophica subsp. amethystina FERM P-6183 was inoculated from a slant culture by means of a platinum loop into each of twenty 500 ml Erlenmeyer flasks, each containing 100 ml of a culture medium having the following composition: glucose - 1.0%, peptone - 0.2%, meat extract - 0.1%, yeast extract - 0.1%, corn steep liquor 0.3%, tap water balance.. Shaking was then carried out at 26°C and 220 r.p.m. for 2 days, at which time sodium 2-methyl-8-(2-methyl-1-oxobutoxy)-β,δ-dihydroxy(1S-(1-α(βS*,δ-S*),2-α,6-α,8-β(R*),8a-α))-1-1,2,6,7,8,8ahexahydronaphthaleneheptanoate was added to a final concentration of 0.05% w/v. Incubation was continued at 26°C and 220 r.p.m. for a further 5 days. Preparation of pravastatin After completion of the cultivation, the reaction mixture was filtered and the pH of the filtrate was adjusted to a value of 3 by the addition of trifluoroacetic acid. The acidified filtrate was then extracted three times, each with 1 liter of ethyl acetate, to give extracts containing a mixture (6-α and 6-β) of (1S-(1α,β- S*,δ-S*),2-α,8-βR*),8a-α))-1-naphthaleneheptanoic acid 1,2,6,7,8,8ahexahydro-2-methyl-8-(2-methyl-1-oxobutoxy)-β,δ,6-trihydroxy. This extract was then immediately transferred into a 5% w/v aqueous solution of sodium hydrogen carbonate, and the pH of the mixture was adjusted to a value of 7.0 by the addition of 2 N hydrochloric acid. The mixture was then adsorbed on a Diaion HP-20 column. The column was washed with water and then eluted with 50% v/v aqueous acetone to give a fraction containing (1S(1-α,β- S*,δ-S*),2-α,6-α,8-βR*),8a-α))-1-naphthaleneheptanoic acid 1,2,6,7,8,8a-hexahydro-2-methyl-8-(2-methyl-1-oxobutoxy)-β,δ,6-trihydroxy-, monosodium salt (pravastatin). This was freeze-dried, to give 200 mg of pravastatine. Method 2 Cultivation of Mortierella maculata nov. spec. E-97 [NCAIM(P)F 001266] A spore suspension was prepared with 5 ml of a 0.9% sodium chloride solution obtained from a 7-10 day old, malt extract-yeast extract agar slant culture of Mortierella maculata nov. spec. E-97 [NCAIM(P)F 001266] strain able to 6-β-hydroxylate compactin and the suspension was used to inoculate 100 ml inoculum medium PI (glucose-50 g, soybean meal-20 g, in 1000 ml tap water) sterilized in a 500 ml Erlenmeyer flask. 5 liters working volume a bioconversion culture medium is prepared (glucose20 g, glycerine-20 g, soybean meal-20 g, peptone-5 g, potassium dihydrogen phosphate-0.5 g, polypropylene glycol 2000-1 g, in 1000 ml tap water); the components of the culture medium are added corresponding to 5 liters. Then it was sterilized for 45 min at 121°C and seeded with 500 ml of the inoculum culture. Before sterilization the pH of the medium was adjusted to 7.0 value. The fermentation was carried out at 28°C, with a stirring rate of 400 rpm and

Prazepam

2823

with an aeration rate from bottom direction 60 liters/hour for 4 days. At the 2nd day after the transfer the culture started to foam heavily, which can be decreased by the addition of further polypropylene glycol 2000. The pH reached 6.3-7.5 by the 4th day. The feeding of the sodium 2-methyl-8-(2methyl-1-oxobutoxy)-β,δ-dihydroxy(1S-(1-α(β- S*,δ-S*),2-α,6-α,8-β(R*),8aα))-1-1,2,6,7,8,8a-hexahydronaphthaleneheptanoate substrate is allowed to be started if the pH of the broth is above 6.3. Preparation of pravastatin At the 4th day of the fermentation 2.5 g compactin substrate is added in sterile filtered aqueous solution. Calculated for the volume of the broth 0.51.0% glucose was added into the culture depending on the pH in the form of 50% solution sterilized at 121°C for 25 min in parallel with the substrate feeding. After 24 hours the compactin substrate is consumed from the culture (is detected by HPLC) and was converted to pravastatin. By lyophilization of the aqueous residue 1.3 g pravastatin was obtained. The chromatographically pure product was crystallized from a mixture of ethanol and ethyl acetate. Melting point: 170-173°C (decomp.). References Terahara A., Tanaka M.; US Patent No. 4,537,859; Aug. 27, 1985; Assigned: Sankyo Company, Limited, Tokyo, Japan Jekkel A., et al.; US Patent No. 6,682,913 B1; Jan. 27, 2004; Assigned: Institute for Drug Research Ltd.

PRAZEPAM Therapeutic Function: Tranquilizer Chemical Name: 7-Chloro-1-(cyclopropylmethyl)-1,3-dihydro-5-phenyl-2H1,4-benzodiazepin-2-one Common Name: Structural Formula:

Chemical Abstracts Registry No.: 2955-38-6

2824

Prazepam

Trade Name Demetrin Centrax Demetrin Lysanxia Prazene Trepidan Centrax Demetrin Reapam Verstran

Manufacturer Goedecke Parke Davis Cosmopharma Substantia Parke Davis Sigma Tau Warner William Parke Davis Goedecke Warner-Chilcott

Country W. Germany US Switz. France Italy Italy UK France W. Germany US

Year Introduced 1973 1977 1978 1979 1980 1980 1981 1982 -

Raw Materials Phthalimidoacetyl chloride Manganese dioxide Hydrazine hydrate

Lithium aluminum hydride 2-Amino-5-chlorobenzophenone Cyclopropane carboxylic acid chloride

Manufacturing Process Preparation of 2-Cyclopropylcarbonylamido-5-Chlorobenzophenone: To 400.5 g (1.73 mols) of 2-amino-5-chlorobenzophenone dissolved in 220 g (2.18 mols) of triethylamine and 3.5 liters of tetrahydrofuran is added cautiously 181 g (1.73 mols) of cyclopropanecarboxylic acid chloride. The reaction is refluxed 2½ hours and allowed to cool to room temperature. The solvent is then removed under vacuum to obtain 2-cyclopropylcarbonylamido-5chlorobenzophenone as a residue which is dissolved in 1 liter of methylene chloride, washed twice with 5% hydrochloric acid, and then twice with 10% potassium hydroxide. The methylene chloride solution is then dried over anhydrous magnesium sulfate, filtered and the solvent removed under vacuum. The residue is recrystallized from 1,500 ml of methanol, charcoaltreating the hot solution to give 356 g of 2-cyclopropylcarbonylamido-5chlorobenzophenone, MP 105° to 105.5°C (69% yield). Preparation of 2-Cyclopropylmethylamino-5-Chlorobenzhydrol: To a slurry of 94.8 g (2.47 mols) of lithium aluminum hydride in 1.2 liters of tetrahydrofuran is added with stirring a solution of 356 g (1.18 mols) of 2cyclopropylcarbonylamido-5-chlorobenzophenone in 1.8 liters of tetrahydrofuran. The addition takes 80 minutes while maintaining gentle refluxing, and the reaction mixture is then refluxed overnight and allowed to cool to room temperature over a period of 3 days. The complex formed in the reaction mixture is then hydrolyzed with water. During the hydrolysis, 500 ml of tetrahydrofuran is added to facilitate stirring. At a point where the flocculant white precipitate settles quickly when stirring is interrupted, the mixture is filtered, the filter cake washed with solvent, the combined filtrates dried over magnesium sulfate, filtered and the solvent removed under vacuum to obtain 2-cyclopropylmethylamino-5chlorobenzhydrol as a residue. The residue is recrystallized from 1,300 ml of Skelly B, giving 315 g of 2-cyclopropylmethylamino-5-chlorobenzhydrol, MP 85° to 85.5°C (93% yield).

Prazepam

2825

Preparation of 2-Cyclopropylmethylamino-5-Chlorobenzophenone: To a solution of 315 g (1.09 mols) of 2-cyclopropylmethylamino-5-chlorobenzhydrol in 4 liters of benzene is added 453.6 g (5.22 mols) of manganese dioxide, freshly prepared according to the method of Attenburrow et al, J.C.S. 1952, 1104. The mixture is then refluxed for 1¼ hours, filtered, and the filtrate evaporated under vacuum. The reddish residue is recrystallized from 510 ml of 90% acetone-10% water, giving 181 g of pure 2-cyclopropylmethylamino5-chlorobenzophenone, MP 79° to 80°C (58% yield). Upon concentration of the mother liquor a second crop of 2-cyclopropylmethylamino-5chlorobenzophenone weighing 34.1 g and melting at 76.5°-78°C are obtained. Preparation of 2-(N-Phthalimidoacetyl-N-Cyclopropylmethyl) -Amino-5Chlorobenzophenone: To a solution of 36.0 g (0.126 mol) of 2cyclopropylmethylamino-5-chlorobenzophenone in 500 ml of tetrahydrofuran is added 50.7 g (0.252 mol) of phthalimidoacetyl chloride. The resulting solution is refluxed for 16 to 24 hours, the solvent removed under vacuum, the residual oil crystallized from 200 ml of ethanol and recrystallized from 500 ml of 80% ethanol-20% tetrahydrofuran giving 44.7 g of 2-(N-phthalimidoacetylN-cyclopropylmethyl)-amino-5-chlorobenzophenone, MP 163° to 164°C (75% yield). Preparation of 1-Cyclopropylmethyl-5-Phenyl-7-Chloro-1H-1,4-Benzodiazepine2(3H)-one: To a solution of 39.5 g (0.0845 mol) of 2-(N-phthalimidoacetyl-Ncyclopropylmethyl)amino5-chlorobenzophenone in a mixture of 423 ml of chloroform and 423 ml of ethanol is added 9.52 g (0.1903 mol) of hydrazine hydrate and 9.52 ml of water. This solution is allowed to stand at room temperature. In 3 hours a precipitate begins to form in the solution. After standing 16 to 24 hours a voluminous pulpy white precipitate forms. The solvents are removed under vacuum while keeping the temperature under 40°C and the residue is partitioned between dilute ammonia water and ether. The aqueous layer is separated and washed with ether, the ether extracted with 5% hydrochloric acid, the acidic solution is made basic with 10% sodium hydroxide and again extracted with ether. Since some spontaneous crystallization occurs in the ether, the solvent is removed without drying under vacuum and the residue is recrystallized from 35 ml of ethanol giving 18.0 g of 1-cyclopropylmethyl-5-phenyl-7-chloro-1H-1,4-benzodiazepine-2(3H)-one, MP 145° to 146°C (65% yield), according to US Patent 3,192,199. References Merck Index 7608 Kleeman & Engel p. 747 PDR p. 1320 OCDS Vol. 2 p. 405 (1980) DOT 2 (3) 119 (1966); 9 (6) 237 (1973); & 10 (5) 179 (1974) I.N. p. 796 REM p. 1063 McMillan, F.H. and Pattison, I.; US Patent 3,192,199; June 29, 1965 Wuest, H.M.; US Patent 3,192,200; June 29, 1965

2826

Praziquantel

PRAZIQUANTEL Therapeutic Function: Anthelmintic Chemical Name: 2-(Cyclohexylcarbonyl)-1,2,3,6,7,11b-hexahydro-4Hpyrazino[2,1-a]isoquinolin-4-one Common Name: Structural Formula:

Chemical Abstracts Registry No.: 55268-74-1 Trade Name Cesol Biltricide Cenaride Biltricide Biltricide Droncit

Manufacturer Merck Bayer Merck Clevenot Bayer Miles Bayvet

Country W. Germany W. Germany France France US US

Year Introduced 1980 1980 1981 1983 1983 -

Raw Materials 2-Cyclohexylcarbonyl-4-oxo-2,3,6,7-tetrahydro-4H-pyrazino[2,1-a] isoquinoline Hydrogen Manufacturing Process 15 g of a nickel-aluminum alloy (1:1) is introduced in incremental portions and under agitation into 200 ml of 20% sodium hydroxide solution within 5 minutes; the mixture is maintained at 80°C for 45 minutes, then allowed to settle, decanted off, washed with water, and 1,000 ml of 1% (-)-tartaric acid solution is added thereto, adjusted to pH 5 with 1 N sodium hydroxide solution. The mixture is heated under agitation for 90 minutes to 80°C, decanted, and washed with water and methanol. The thus-obtained (-)tartaric acid-Raney nickel catalyst is added to a solution of 2cyclohexylcarbonyl-4-oxo-2,3,6,7-tetrahydro-4H-pyrazino[2,1-a]isoquinoline. The reaction mixture is hydrogenated under normal pressure and at room temperature. After the catalyst has been filtered off and the solvent evaporated, 2-cyclohexylcarbonyl-4-oxo-1,2,3,6,7,11b-hexahydro-4Hpyrazino[2,1-a]isoquinoline, melting point 136°C to 138°C, is produced.

Prazosin

2827

References Merck Index 7609 Kleeman & Engel p. 748 PDR p. 1249 DOT 13 (3) 121 (1977) & 17 (10) 429 (1981) I.N. p. 796 REM p. 1237 Seubert, J., Thomas, H. and Andrews, P.; US Patent 4,001,411; January 4, 1977; assigned to Merck Patent G.m.b.H. (Germany)

PRAZOSIN Therapeutic Function: Antihypertensive Chemical Name: 1-(4-Amino-6,7-dimethoxy-2-quinazolinyl)-4-(2furanylcarbonyl)piperazine Common Name: Furazosin Structural Formula:

Chemical Abstracts Registry No.: 19216-56-9; 19237-84-4 (Hydrochloride salt) Trade Name Hypovase Minipress Minipress Minipress Minipress Minipress

Manufacturer Pfizer Pfizer Pfizer Pfizer Pfizer Pfizer Taito

Country UK US W. Germany Italy France Japan

Year Introduced 1974 1976 1977 1978 1979 1981

Adversuten

Arzneimittelwerk Dresden

E. Germany

-

Orbisan Pratsiol Prazac Sinetens Vasoflex

Mack Orion Erco Carlo Erba Alkaloid

W. Germany Finland Denmark UK Yugoslavia

-

2828

Prednimustine

Raw Materials Piperazine 2,4-Dichloro-6,7-dimethoxyquinazoline Ammonia 2-Furoyl chloride Manufacturing Process Preparation of 2-Chloro-4-Amino-6,7-Dimethoxyquinazoline: To 800 ml of a solution of anhydrous ammonia in tetrahydrofuran at room temperature is added 30 g of 2,4-dichloro-6,7-dimethoxyquinazoline [F.H.S. Curd et al., J. Chem. Soc., p 1759 (1948)]. The mixture is stirred for 44 hours. The precipitate (29 g, MP 267° to 268°C) is filtered and recrystallized from methanol to yield 19 g of 2-chloro-4-amino-6,7-dimethoxyquinazoline, MP 302°C (dec.). Preparation of 2-(1-Piperazinyl)-4-Amino-6,7-Dimethoxyquinazoline: To 5 g of 2-chloro-4-amino-6,7-dimethoxyquinazoline, is added 20 g of a 25% solution of piperazine in ethanol. The mixture is heated at 160°C for 16 hours in a pressure bottle. The solvent is then evaporated and the residue is recrystallized from methanol/water. Preparation of 2[4-(2-Furoyl)-Piperazinyl]-4-Amino-6,7-Dimethoxyquinazoline: To 0.10 mol 2-(1-piperazinyl)-4-amino-6,7-dimethoxyquinazoline in 300 ml methanol is added with vigorous stirring, 0.10 mol 2-furoyl chloride. After addition is complete, the mixture is stirred for 3 hours at room temperature. The solids are filtered to give the desired product, MP 278° to 280°C. References Merck Index 7610 Kleeman & Engel p. 748 PDR pp. 1420, 1421 OCDS Vol. 2 p. 382 (1980) & 3, 194 (1984) DOT 11 (2) 67, 80 (1975) I.N. p. 796 REM p. 844 Hess, H.-J.E.; US Patent 3,511,836; May 12, 1970; assigned to Chas. Pfizer & Co., Inc.

PREDNIMUSTINE Therapeutic Function: Cancer chemotherapy Chemical Name: Prednisolone 21-[4'-[p-bis(2-chloroethyl)amino]phenyl] butyrate Common Name: Prednisolone chlorambucil ester

Prednimustine

2829

Structural Formula:

Chemical Abstracts Registry No.: 29069-24-7 Trade Name Stereocyt Sterecyt Mostarina

Manufacturer Bellon Leo Abello

Country France Switz. Spain

Year Introduced 1978 1981 -

Raw Materials Prednisolone p-[N-Bis(β-chloroethyl)amino]phenyl butyric acid Thionyl chloride Manufacturing Process p-[N-bis(β-chloroethyl)amino] phenyl butyric acid was dissolved in a mixture of 150 ml dry benzene and 8.04 ml dry pyridine. The solution was cooled in an ice bath, and a solution of thionyl chloride in 30 ml dry benzene was slowly added with stirring under anhydrous conditions. The reaction mixture was then kept at room temperature for 1 hour and thereafter poured into a mixture of 5.0 N HCl and crushed ice. The benzene solution was immediately washed with water, with cold 1.0 N NaHCO3 and finally with cold water. After drying over anhydrous sodium sulfate, the benzene was removed in vacuo. The residue is the p-[N-bis(βchloroethyl)amino]phenyl butyric anhydride which could be used without any further purification. To a solution of 42.0 g of p-[N-bis(β-chloroethyl)amino]phenyl butyric anhydride in 500 ml dry pyridine was added 24.4 g of prednisolone. The reaction mixture was kept at room temperature for 24 hours under anhydrous condition. It was then poured into a mixture of concentrated HCl and crushed ice and extracted with ether-ethyl acetate (1:1). The organic phase was washed several times with cold 1.0 N K2CO3 and finally

2830

Prednisolamate

water. After drying over CaCl2 the solvent was removed in vacuo. The residue is prednisolone 21-[4'-[p-bis(β-chloroethyl)amino]phenyl]butyrate which after crystallization from methanol/water had a melting point of 163°C to 164°C. References Merck Index 7612 DFU 1 (3) 137 (1976) Kleeman & Engel p. 749 OCDS Vol. 3 p. 93 (1984) DOT 16 (3) 84 (1980) I.N. p. 797 Fox, H.J., Hogberg, K.B. and Konyves, I.; US Patent 3,732,260; May 8, 1973; assigned to A.B. Leo

PREDNISOLAMATE Therapeutic Function: Glucocorticoid Chemical Name: 11β,17,21-Trihydroxypregna-1,4-diene-3,20-dione 21-N,Ndiethylglycine ester Common Name: Prednisolamate; Prednisolone diethylaminoacetate Structural Formula:

Chemical Abstracts Registry No.: 5626-34-6 Trade Name Prednisolamate

Manufacturer Pfizer and Co.

Raw Materials Prednisolone Chloroacetyl chloride Diethylamine

Country -

Year Introduced -

Prednisolone

2831

Manufacturing Process To a solution of 30 g prednisolone and 10.2 ml pyridine in 99 ml dimethylformamide, cooled to 0°C in an ice bath and protected from atmospheric moisture, was added dropwise with stirring 9.6 ml chloroacetyl chloride. Stirring was continued for 1 hour at 0°C, then stopped and the reaction allowed to come to room temperature and stand overnight. The following morning the reaction mixture was poured with vigorous stirring into a vessel containing 360 ml 1 N sulfuric acid, and the product washed with fresh portions of water to neutral wash was obtained. The product was thoroughly dried in a vacuum desiccator and recrystallized from isopropyl alcohol, using 200 ml solvent. The yield was better than 80%, and the compound had MP: 240.6°-242.8°C and [α]D = +114.6° (Dioxane). Two grams of this prednisolone chloracetate and 40 ml of colorless, freshly distilled diethylamine were refluxed, with stirring, under nitrogen for one hour. The excess diethylamine was removed in vacuum at room temperature. The residue was taken up in 100 ml CHCl3, and a small amount of water; the CHCl3, was washed with one 50 ml portion of 5% aqueous sodium bicarbonate and two 50 ml portions of water, and dried over sodium sulfate. The chloroform was then concentrated to dryness in vacuum. The residue was recrystallized from acetone-hexane yielded prednisolone 21-diethylaminoacetate 1.67 g; MP: 175.0°-197.2°C. This product (1 g) was suspended in a mixture of 15 ml acetone and 1.5 ml chloroform. The suspension was cooled to 0°C in an ice bath, and with vigorous stirring the ethereal HCl solution was slowly added until the resulting mixture gave an acid reaction to the congo red paper. The product was removed by filtration and recrystallized from ethanol. The yield was approximately 80%; MP: 239.4°-239.8°C; [α]D = +120.7° (water). The product was the hydrochloride salt of the prednisolone-N,Ndiethylaminoacetate, very active therapeutically and excellently watersoluble. References Ch.Pfizer and Co., Inc., a corporation of the State Delaware, USA; G.B. Patent No. 862,370; Aug. 31, 1956

PREDNISOLONE Therapeutic Function: Glucocorticoid Chemical Name: 11β,17,21-Trihydroxypregna-1,4-diene-3,20-dione Common Name: Metacortandralone; ∆1-Hydrocortisone Chemical Abstracts Registry No.: 50-24-8 Raw Materials Hydrocortisone

Bacterium Corynebacterium simplex

2832

Prednisolone

Structural Formula:

Trade Name Sterane Meticortelone Delta-Cortef Hydeltra Paracortol Sterolone Prednis Ulacort Cosilone Adnisolone Aprednislon Caberdelta Cordrol Cortalone Cortisolone Cotolone Dacortin Decaprednil Decortasmyl Delta-Hycortol Delta-Larma Deltalone Deltasolone Deltidrosol Deltisolon Domucortone Encortolone Fernisolon Ibisterolon Keteocort -H Neodelta Normosona Novoprednisolone Panafcortelone Predartrina Prednicen

Manufacturer Pfizer Schering Upjohn MSD Parke Davis Rowell U.S.V. Pharm. Fellows-Testagar Person Covey Adams Arcana Caber Vita Elixir Halsey S.I.T. Truxton Igoda Dorsch Larec Medica Larma D.D.S.A. Knoll Poli Ferring Medici Domus Polfa Ferndale I.B.I. Desitin Amelix Normon Novopharm Glebe Farmochimica Central

Country US US US US US US US US US Australia Austria Italy US US Italy US Spain W. Germany Ecuador Finland Spain UK Australia Italy Sweden Italy Poland US Italy W. Germany Italy Spain Canada Australia Italy US

Year Introduced 1955 1955 1955 1955 1957 1957 1957 1960 1963 -

Prednisolone Trade Name Predni-Coelin Prednicort Predni-Helvacort Predni-H-Tablinen Predniretard Prelone Ropredlone Scherisolon Serilone Stermin Vitacort

Manufacturer Pfleger Cortec Helvepharm Sanorania Boots-Dacour Langley Robinson Schering Serpero Schlicksup Vitarine

Country W. Germany Denmark Switz. W. Germany France Australia US W. Germany Italy US US

2833

Year Introduced -

Manufacturing Process The following procedure is described in US Patent 2,837,464: from a solution of 3 grams of yeast extract (Difco) in 3.0 liters of tap water containing 13.2 grams of potassium dihydrogen phosphate and 26.4 grams disodium hydrogen phosphate (pH of the solution, 6.9) 27 portions of 100 ml each are withdrawn, placed in 300 ml Erlenmeyer flasks and sterilized by autoclaving for 15 minutes at 15 pounds steam pressure (120°C). After autoclaving and cooling of the broth, one ml of suspension of Corynebacterium simplex (ATCC 6946) is placed in each flask. The flasks are then shaken on a shake table at 220 rpm and 28°C for 24 hours. Into each of 27 Erlenmeyer flasks are placed 150 mg of Kendall's Compound F (hydrocortisone). The flasks and contents are then sterilized for 15 minutes at 15 pounds steam pressure (120°C). To each flask are then added 5.0 ml of ethanol. The 24-hour bacterial culture is then transferred aseptically and the resulting suspensions are shaken on a shake table at 220 rpm and 28°C for 48 hours. The pH at the end of the shake period is 7.0. The contents of all the flasks are combined and extracted with a total of 9.0 liters of chloroform in 3 equal portions. The combined extracts are then concentrated to a residue which weighs 3.75 grams. The MP of the residue is 227°-232°C. From 2.75 grams of this crude material on sludging with 50 ml of acetone and cooling, there is recovered on filtration 1.35 grams of ∆1,4pregnadiene-11β,17α,21-triol-3,20-dione,MP 237°-239°C (dec.). Additional product can be recovered from the mother liquor. Recrystallization from acetone raised the MP to 239°-241°C (dec.). References Merck Index 7613 Kleeman & Engel p. 750 PDR pp. 830, 1569, 1606 OCDS Vol. 1 p. 192 (1977) & 2, 178 (1980) I.N. p. 797 REM p. 969 Nobile, A.; US Patent 2,837,464; June 3, 1958; assigned to Schering Corporation

2834

Prednisolone acetate

Oliveto, E.P. and Gould, D.H.; US Patent 2,897,216; July 28, 1959; assigned to Schering Corporation

PREDNISOLONE ACETATE Therapeutic Function: Glucocorticoid Chemical Name: 11β,17,21-Trihydroxypregna-1,4-diene-3,20-dione 21acetate Common Name: Structural Formula:

Chemical Abstracts Registry No.: 52-21-1 Trade Name Sterane Nisolone Savacort Econapred Pred Mild Pred Cor 100 Alto-Pred Cortipred Deltacortilen Dermo-Nydol Durapred Hexacorton Ibisterolon-Pommada Inflanefran Key-Pred Metimyd Meticortelone

Manufacturer Phipharmex Ascher Savage Alcon Allergan Hauck Alto Italsuisse S.I.F.I. Brichard Federal Spirig I.B.I. Allergan Hyrex Schering Essex

Country US US US US US US US Italy Italy France US Switz. Italy W. Germany US US Italy

Year Introduced 1955 1962 1969 1973 1974 1977 -

Prednisolone phosphate sodium Trade Name Predate Predicort Prednifor Prenema Pricortin Sigpred Ulacort Ultracortenol

Manufacturer Legere Dunhall Vifor Nortech Premedics Sig Fellows-Testagar Dispersa

Country US US Switz. US US US US Switz.

2835

Year Introduced -

Raw Materials Prednisolone Acetic anhydride Manufacturing Process To a solution of 0.85 gram of 1,4-pregnadiene-11β,17α,21-triol-3,20-dione (prednisolone) in 5 ml of pyridine are added 3 ml of acetic anhydride. The reaction mixture is allowed to stand at room temperature overnight and is then diluted with ice water. The resulting precipitate is filtered from the mixture and recrystallized from acetone-hexane. There is recovered 0.45 gram of 1,4-pregnadiene-11β,17α,21-triol-3,20-dione 21-acetate, MP 235°239°C. On recrystallization, the MP rose to 237°-239°C. References Merck Index 7613 Kleeman & Engel p. 750 PDR pp. 1033, 1633 OCDS Vol. 1 p. 192 (1977) I.N. p. 798 REM p. 969 Nobile, A.; US Patent 3,134,718; May 26, 1964; assigned to Schering Corporation

PREDNISOLONE PHOSPHATE SODIUM Therapeutic Function: Glucocorticoid Chemical Name: 11β,17,21-Trihydroxypregna-1,4-diene-3,20-dione 21(dihydrogen phosphate) disodium salt Common Name: Chemical Abstracts Registry No.: 125-02-0

2836

Prednisolone phosphate sodium

Structural Formula:

Trade Name Hydeltrasol Inflamase Optival PSP-IV Alto-Pred Caberdelta Codelsol Hydrosol Key-Pred S.P. Metreton Nor-Preds Parisolon Predate S Prednesol Savacort Sodasone Solucort Solu-Pred

Manufacturer MSD Cooper Vision White Tutag Alto Caber MSD Rocky Mtn. Hyrex Schering North Amer. Pharm. Riker Legere Glaxo Savage Fellows-Testagar Chibret Myers-Carter

Country US US US US US Italy UK US US US US US US US US US France US

Year Introduced 1957 1969 1969 1972 -

Raw Materials Prednisolone Sodium hydroxide Phosphoric acid

Sodium iodide Methanesulfonyl chloride

Manufacturing Process Preparation of Prednisolone 21-Methanesulfonate: Seventy liters of dry pyridine and 7.5 kg of prednisolone are charged to a 30-gallon jacketed glasslined still. The mixture is agitated until complete solution is obtained. About 40 liters of pyridine are distilled at high vacuum while maintaining the batch temperature below 40°C. The solution is cooled to 0°C, and 2.2 liters of methanesulfonyl chloride are charged. The batch temperature is maintained between 0°C and +3°C during charging of the methanesulfonyl chloride. An atmosphere of flowing nitrogen is maintained in the still, and the mixture is

Prednisolone phosphate sodium

2837

agitated during the last stages of the addition. The mixture is then aged for one hour, and 15 gallons of ice water are added cautiously to the still while maintaining the temperature between 0° and 5°C. The still contents are then transferred to a jacketed kettle equipped with an agitator, and 62 kg of cracked ice in 15 gallons of deionized water are added. The batch is aged one hour and a solution of 2 liters of concentrated (37%) hydrochloric acid in 4 gallons of deionized water is added. The batch is centrifuged and the centrifuge cake washed free of pyridine with deionized water. The centrifuge cake is then vacuum-dried at 50°C to a moisture content of about 1%, which requires about 3 days of drying. Yield about 7.77 kg (92%), according to US Patent 2,932,657. Preparation of Prednisolone 21-Iodide: To a 30-gallon jacketed glass-lined still 64.5 lb (31.0 liters) of dimethylformamide are charged by vacuum. The still contents are agitated as 7.74 kg of dry (less than 1% moisture) prednisolone 21-methanesulfonate are charged. Then 4.02 kg of sodium iodide are charged. The still contents are heated to 57° to 60°C by means of a steam jacket and held at this temperature for 30 minutes. The batch is cooled to 35°C and 12 gallons of deionized water are added at the rate of about 1 gallon per minute. In the event the solution becomes cloudy, addition of water is interrupted and the mixture agitated for five minutes before resumption of water addition. After all of the water is added, the batch is transferred to a 50 gallon kettle equipped with agitator and an additional 16.7 gallons of deionized water are added. The batch is cooled to 0° to 5°C and aged for one hour. The batch is filtered and the filter cake washed and vacuum dried at 30° to 35°C to a moisture content of less than 1%. Yield about 7.95 kg (96%), according to US Patent 2,932,657. Preparation of Prednisolone 21-Disodium Phosphate: Acetonitrile (50.0 ml) containing phosphoric acid (90%; 1.0 ml) was treated with triethylamine (3.0 ml) and the solution added to 11β,17α-dihydroxy-21-iodopregna-1,4-diene-3,20dione (1.0 gram; powdered). The mixture was refluxed for 2.75 hours and the solvent was then evaporated under reduced pressure to give a yellow oil. The oil was taken up in methanol (25 ml) and titrated to pH 10.9 with sodium hydroxide in methanol (N) using a pH meter. The precipitate was filtered off and the filtrate evaporated to a gum under reduced pressure. The gum was taken up in methanol (5 ml), filtered through filter paper and acetone (100 ml) was added to the filtrate. The precipitate was filtered off, washed with acetone and dried at 100°C/1 mm for 0.75 hour giving a pale yellow solid, prednisolone disodium phosphate (0.74 gram), which was completely soluble in water, according to US Patent 2,936,313. References Merck Index 7615 Kleeman & Engel p. 752 PDR pp. 1033, 1633 I.N. p. 798 REM p. 970 Sarett, L.H.; US Patent 2,789,117; April 16, 1957; assigned to Merck & Co., Inc. Christensen, B.G., Hirschmann, R.F. and Putter, I.; US Patent 2,932,657; April 12, 1960; assigned to Merck & Co., Inc.

2838

Prednisolone stearoylglycolate

Elks, J. and Phillipps, G.H.; US Patent 2,936,313; May 10, 1960; assigned to Glaxo Laboratories Limited, England

PREDNISOLONE STEAROYLGLYCOLATE Therapeutic Function: Glucocorticoid Chemical Name: 11β,17-Dihydroxy-21-[[[(1-oxoctadecyl)oxy]acetyl]oxy] pregna-1,4-diene-3,20-dione Common Name: Prednisolone steaglate Structural Formula:

Chemical Abstracts Registry No.: 5060-55-9 Trade Name Deturgylone Erbacort Estilsona Glistelone Glitisone Prenisol Rollsone Sintisone Verisone

Manufacturer Dausse Erba Erba Erba Vis Cifa Bellon Erba Tiber

Country France Italy Italy Italy Italy Italy France Italy Italy

Year Introduced 1970 -

Raw Materials Prednisolone Potassium stearate

Prednisolone-21-chloroacetate Stearoyl-glycolyl chloride

Prednisolone tebutate

2839

Manufacturing Process This material can be prepared, e.g., by reaction of prednisolone-21chloroacetate in solvent with the sodium or potassium salt of the corresponding aliphatic or aromatic acid, or by reaction of prednisolone with the chloride of the corresponding acyl-glycolic acid, in the presence of a hydrochloric acid acceptor. Alternative (A): 3 grams (0.0068 mol) prednisolone chloroacetate dissolved in 200 ml tetrahydrofuran and 10 ml H2O are added with 2.7 grams (0.0084 mol) K stearate and 0.06 g NaI and heated to boiling, under stirring, for 36 hours, then evaporated in vacuum to dryness. The residue is washed with H2O to disappearance of the Cl-ion from the filtrate. Crystallization from diluted alcohol results in prednisolone-21-stearoylglycolate (MP 104°-105°C). Alternative (B): 3.6 grams (0.01 mol) prednisolone and 4.32 grams (0.012 mol) stearoylglycolyl-chloride, separately dissolved in dry dioxane, are added with 0.89 ml (0.011 mol) dry pyridine. The mixture is kept at 60°C for 20 hours, then poured into water-ice and filtered. Crystallization from diluted ethanol results in prednisolone-21-stearoyl-glycolate (MP 104°-105°C). References Merck Index 7618 Kleeman & Engel p. 753 DOT 3 (1) 18 (1967) I.N. p. 799 Giraldi, P.N. and Nannini, G.; US Patent 3,171,846; March 2, 1965; assigned to Carlo Erba SpA, Italy

PREDNISOLONE TEBUTATE Therapeutic Function: Glucocorticoid Chemical Name: 21-(3,3-Dimethyl-1-oxobutoxy)-11β,17-dihydroxypregna1,4-diene-3,20-dione Common Name: Prednisolone-21-tert-butyl acetate Chemical Abstracts Registry No.: 7681-14-3 Raw Materials tert-Butyl acetyl chloride Prednisolone

2840

Prednisolone tebutate

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Hydeltra TBA

MSD

US

1956

Codelcortone TBA

MSD

US

-

Predate TBA

Legere

US

-

Prednisol TBA

Pasadena

US

-

Rodelta TBA

Rocky Mtn.

US

-

Manufacturing Process A solution of about 10 parts of tertiary-butyl acetyl chloride in 45 parts of dry chloroform is added portionwise to a cold solution of 25 parts of ∆1,4-3,20diketo-11β,17α,21-trihydroxy-pregnadiene(prednisolone) in 125 parts of anhydrous pyridine. The resulting solution is allowed to stand for about 15 hours at 0° to 5°C, and the reaction solution is poured into 750 parts of water. The resulting aqueous mixture is extracted four times with 250 parts of chloroform each extraction. The combined chloroform layers are washed with water, dilute aqueous hydrochloric acid solution, water, 5% aqueous sodium bicarbonate solution, and finally with water. The chloroform extract is dried over magnesium sulfate, and the chloroform is evaporated in vacuo to give a residual oil. This oil is triturated with alcohol until it crystallizes, and is then recrystallized from ethanol to give substantially pure ∆1,43,20-diketo11β,17α,21-trihydroxy-pregnadiene21-tertiary-butyl acetate. References Merck Index 7619 Kleeman & Engel p. 754 PDR pp. 1033, 1183 I.N. p. 798 REM p. 970 Sarett, L.H.; US Patent 2,736,734; February 28, 1956; assigned to Merck & Co., Inc.

Prednisone

2841

PREDNISONE Therapeutic Function: Glucocorticoid Chemical Name: 17α,21-Dihydroxy-pregna-1,4-diene-3,11,20-trione Common Name: Deltacortisone Structural Formula:

Chemical Abstracts Registry No.: 53-03-2 Trade Name Meticorten Deltasone Deltra Paracort Lisacort Servisone Orasone Wojtab Adasone Alto-Pred Colisone Cortan Cortancyl Cortialper Dacortin Decortin Decortisyl Decorton Deidrocortisone Deltacortene Delta Dome Delta Prenovis Deltison Erftopred Fernisone

Manufacturer Schering Upjohn MSD Parke Davis Fellows-Testagar Lederle Rowell Philips Roxane Adams Alto Merck-Frosst Halsey Roussel Santos Igoda Merck Roussel Salfa Stip Lepetit Dome Vister Ferring Erfto Ferndale

Country US US US US US US US US Australia US Canada US France Spain Spain W. Germany UK Italy Italy Italy US Italy Sweden W. Germany US

Year Introduced 1955 1955 1955 1960 1960 1970 1972 1981 -

2842

Prednisone

Trade Name Hostacortin Inocortyl Keteocort Keysone Liquid Pred Marnisonal Marvidiene Me-Korti Nisone Nizon Novoprednisone Nurison Panafcort Parmenison Predniartrit Prednicen-M Prednifor Prednilonga Predni-Tablinen Predni-Wolner Prednovister Predsol Predsone Presone Pronison Propred Rectodelt Ropred Sarogesic Sone Sterapred Supopred Urtilone Wescopred Winpred

Manufacturer Hoechst Liposeptine Desitin Key Muro Juan Martin Panther-Osfa Farmos Llorente Bosnalijek Novopharm Noury Pharma Protea Kwizda Maipe Seymour Vifor Dorsch Sanorania Wolner Substancia Morgan Century Langley Galenika Medac Trommsdorff Robinson Saron Fawns and McAllan Mayrand Europa Recherche Therap. Saunders I.C.N.

Country W. Germany France W. Germany US US Spain Italy Finland Spain Yugoslavia Canada Netherlands Australia Austria Spain US Switz. W. Germany W. Germany Spain Spain Italy US Australia Yugoslavia Australia W. Germany US US Australia US Spain France Canada Canada

Year Introduced -

Raw Materials Bacterium Corynebacterium simplex Cortisone Manufacturing Process From a solution of 30 grams of yeast extract (Difco) in 3.0 liters of tap water containing 13.2 grams of potassium dihydrogen phosphate and 26.4 grams of disodium hydrogen phosphate (pH of the solution 6.9) 27 portions of 100 ml each are withdrawn, placed in 300 ml Erlenmeyer flasks and sterilized by autoclaving for 15 minutes at 15 pounds steam pressure (120°C). After autoclaving and cooling of the broth one ml of a suspension of

Prenalterol

2843

Corynebacterium simplex (ATCC 6946) is placed in each flask. The flasks are then shaken on a shake table at 220 rpm and 28°C for 24 hours. Into each of 27 Erlenmeyer flasks are placed 150 mg of Kendall's Compound E (cortisone). The flasks and contents are then sterilized for 15 minutes at 15 pounds steam pressure (120°C). To each flask are then added 5.0 ml of ethanol. The 24-hour bacterial culture is then transferred aseptically and the resulting suspensions are shaken on a shake table at 220 rpm and 28°C for 48 hours. The final pH is 7.2. The contents of all the flasks are combined and extracted with a total of 9.0 liters of chloroform in three equal portions. The combined extracts are then concentrated to a residue which is crystallized from acetone-hexane. There results 1.1 grams of ∆1,4-pregnadiene-17α,21-diol-3,11,20-trione,MP 210°215°C (dec.). Several additional recrystallizations raised the MP to 230°232°C (dec.). References Merck Index 7621 Kleeman & Engel p. 755 PDR pp.830, 993, 1268, 1573, 1606, 1723, 1837 OCDS Vol. 1 p. 192 (1977) I.N. p. 799 REM p. 970 Djerassi, C., Rosenkranz, G. and Berlin, J.; US Patent 2,579,479; December 25, 1951; assigned to Syntex SA, Mexico Nobile, A.; US Patent 2,837,464; June 3, 1958; assigned to Schering Corporation Oliveto, E.P. and Gould, D.H.; US Patent 2,897,216; July 28, 1959; assigned to Schering Corporation

PRENALTEROL Therapeutic Function: Adrenergic Chemical Name: 4-[2-Hydroxy-3-[(1-methylethyl)amino]propoxy]phenol Common Name: Structural Formula:

Chemical Abstracts Registry No.: 57526-81-5

2844

Prenylamine

Trade Name Coleb Hyprenan Varbian

Manufacturer Astra Astra Ciba

Country W. Germany UK UK

Year Introduced 1981 1981 1981

Raw Materials 4-Hydroxyphenoxypropylene oxide Isopropylamine Manufacturing Process A solution of 100 g (1.7 mols) of isopropylamine in 60 cc of water was stirred into a solution of 4-hydroxyphenoxypropylene oxide. After the exothermic reaction has subsided, the reaction mixture was heated for two hours at 60°C. Thereafter, the aqueous ethanol was distilled off, and the solid residue was dissolved in aqueous hydrochloric acid comprising more than the theoretical stoichiometric molar equivalent of hydrochloric acid. The aqueous acid solution was extracted with ether and was then made alkaline with sodium hydroxide, whereby a solid crystalline precipitate was formed which was filtered off and dried over phosphorus pentoxide. The product was 1,1-(4'-hydroxyphenoxy)2-hydroxy-3-isopropylamino-propane. Its hydrochloride had a melting point of 166°C to 169°C. References Merck Index 7639 DFU 4 (1) 46 (1979) OCDS Vol. 3 p. 30 (1984) DOT 17 (5) 199 (1981) & 18 (4) 190 (1982) I.N. p. 801 Koppe, H., Engelhardt, A., Ludwig, G. and Zeile, K.; US Patent 3,637,852; January 25, 1972; assigned to Boehringer Ingelheim G.m.b.H. (Germany)

PRENYLAMINE Therapeutic Function: Coronary vasodilator Chemical Name: N-(1-Methyl-2-phenylethyl)-γ-phenylbenzenepropanamine Common Name: Structural Formula:

Prenylamine

2845

Chemical Abstracts Registry No.: 390-64-7 Trade Name Synadrin Segontin Segontin Segontine Agozol Angiovigor Angorsan Cardional Corditin-Same Coredamin Crepasin Daxauten Epocol Eucardion Falicor Herzcon Incoran Irrorin Lactamine Newsantin NP 30 Nyuple Onlemin Plactamin Prectolact Rausetin Reocorin Roinin Seccidin Wasangor

Manufacturer Hoechst Hoechst Hoechst Hoechst Tableta Violani-Farmavigor Isola-Ibi Unipharm Savoma Meiji Hoei Woelm Pharma Teisan-Nagase Vita Fahlberg-List Sana I.T.A. Alfa Farm. Daisan Sawai Sanken Ohta Ono Morishita Showa Yakuhin Tanabe Farmochimica Mohan Nippon Kayaku, Co. Wassermann

Country UK Italy W. Germany France Rumania Italy Italy Israel Italy Japan Japan W. Germany Japan Italy E. Germany Japan Italy Italy Japan Japan Japan Japan Japan Japan Japan Japan Italy Japan Japan Italy

Year Introduced 1961 1962 1964 -

Raw Materials Phenyl acetone 1,1-Diphenyl-propylamine-(3) Palladium Hydrogen Manufacturing Process 10.6 g of 1,1-diphenylpropylamine-(3) are hydrogenated by means of palladium with 6.7 g of phenyl acetone in 200 cc of methanol at 50°C. The calculated amount of hydrogen is taken up. The separated oily base is dissolved by heating with alcohol. After filtration water is added until turbidity sets in. 24.5 g of 2-(1',1'-diphenylpropyl-3'-amino)-3-phenyl-propane are obtained with a boiling point at 195°C to 198°C under a pressure of 0.5 mm of mercury, which after prolonged standing crystallizes out. Melting point

2846

Pridinol hydrochloride

about 38°C to 40°C. Hydrochloride (prepared in usual manner): melting point 188°C to 190°C. References Merck Index 7641 Kleeman & Engel p. 759 OCDS Vol. 1 p. 76 (1977) I.N. p. 801 Ehrhart, G., Ott, H. and Lindner, E.; US Patent 3,152,173; October 6, 1964; assigned to Farbwerke Hoechst A.G. (Germany)

PRIDINOL HYDROCHLORIDE Therapeutic Function: Antiparkinsonian, Anticholinergic Chemical Name: 1,1-Diphenyl-3-piperidino-1-propanol hydrochloride Common Name: Pridinol; Ridinol Structural Formula:

Chemical Abstracts Registry No.: 968-58-1 Trade Name Hikiceton Konlax Loxeen Myoson

Manufacturer Tatsumi Nippon Shinyaku Hommel Strathmann

Country -

Year Introduced -

Raw Materials Bromobenzene 1-Piperidinopropionic acid n-butyl ester Magnesium Manufacturing Process 24 parts by weight of 1-piperidinopropionic acid n-butyl ester (BP: 137-

Prilocaine hydrochloride

2847

138°C) was added dropwise to solution of phenyl magnesium bromide from 157 parts by weight of bromobenzene and 24 parts of magnesium. There was a spontaneous heating and the ether boiled. The mixture refluxed for 2 hours after the completion adding. Then it was poured into mixture of 200 parts of 37% hydrochloric acid and 800 parts (by weight) of ice with stirring. Hydrochloride of α,α-diphenyl-1-piperidinepropanol precipitated. It was filtered off, washed with ether, diluted hydrochloric acid and dried over sodium hydroxide in vacuum dessicator. The colorless crystals were light dissolved in hot water and had MP: 216°C. The base is the colorless powder with MP: 119-120°C. References Eisleb O.; D.B. Patent No. 875,660; May 4 1953; Fabwerke Hoechst, vormals Meister Lucius and Bruning, Frankfurt/M/-Hoechst

PRILOCAINE HYDROCHLORIDE Therapeutic Function: Local anesthetic Chemical Name: N-(2-Methylphenyl)-2-(propylamino)-propanamide hydrochloride Common Name: Propitocaine hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 1786-81-8; 721-50-6 (Base) Trade Name

Manufacturer

Country

Year Introduced

Xylonest

Astra

W. Germany

1963

Citanest

Astra

UK

1974

Citanest

Astra

US

1966

Citanest

Pierrel

Italy

1968

Citanest

Bellon

France

1973

2848

Primidone

Raw Materials o-Toluidine α-Bromopropionyl bromide n-Propylamine Manufacturing Process One mol of ortho-toluidine is dissolved in 800 ml of glacial acetic acid. The mixture is cooled to 10°C whereupon 1.1 mols of α-bromopropionylbromide is added. The mixture is vigorously stirred for about a minute and a solution of sodium acetate (330 grams of CH3COONa·3H2O in 1,380 ml of water) or another buffering or alkalizing substance or solution is added in one portion. The reaction mixture is then shaken for half an hour. The precipitate formed is filtered off, washed with water and dried. The product is sufficiently pure for further processing. Yield: 70-80% of theory. MP 133°-134°C. One mol of α-bromopropio-ortho-toluidine is mixed with a solution of 3 mols of n-propylamine in 500 ml of water-free benzene and the reaction mixture is heated in an autoclave to 80°C for 8 hours. After cooling the reaction mixture is treated as described above. The base is obtained as a colorless oil. BP 159°-162°C/0.1 mm. Yield 55%. The base is then converted to the hydrochloride by reaction with HCl. References Merck Index 7646 DFU 8 (12) 1021 (1983) Kleeman & Engel p. 760 OCDS Vol. 1 p. 17 (1977) I.N. p. 802 REM p. 1053 Aktiebolaget Astra: Apotekarnes Kemiska Fabriker, Sweden; British Patent 839,943; June 29, 1960

PRIMIDONE Therapeutic Function: Anticonvulsant Chemical Name: 5-Ethyldihydro-5-phenyl-4,6(1H,5H)-pyrimidinedione Common Name: 2-Desoxyphenobarbital; Primaclone Chemical Abstracts Registry No.: 125-33-7 Raw Materials α,α-Phenylethylmalonic acid diamide Formamide

Primidone

2849

Structural Formula:

Trade Name Mysoline Mysoline Cyral Liskantin Majsolin Midone Mylepsinum Mysedon Primidone Primoline Primron Prysoline Resimatil Sertan

Manufacturer I.C.I. Ayerst Gerot Desitin Pliva Protea ICI Pharma Medica Schein Darby Fujinaga Abic Labaz Chinoin

Country France US Austria W. Germany Yugoslavia Australia W. Germany Finland US US Japan Israel W. Germany Hungary

Year Introduced 1953 1954 -

Manufacturing Process 50 parts of α,α-phenylethylmalondiamide and 150 parts of formamide are boiled together under reflux for 2 hours. The mixture is then cooled to 0°C and filtered. The solid residue is washed with 50 parts of ethanol and then crystallized from 660 parts of an 80% ethanol water mixture. There is obtained 5-phenyl-5-ethylhexahydropyrimidine-4,6-dione, MP 281°C-282°C. References Merck Index 7649 Kleeman & Engel p. 761 PDR pp. 631, 830, 1606 OCDS Vol. 1 p. 276 (1977) I.N. p. 803 REM p. 1081 Boon, W.R., Carrington, H.C. and Vasey, C.H.; US Patent 2,578,847; December 18, 1951; assigned to Imperial Chemical Industries Limited, England

2850

Probenecid

PROBENECID Therapeutic Function: Antiarthritic Chemical Name: 4-[(Dipropylamino)sulfonyl]benzoic acid Common Name: Structural Formula:

Chemical Abstracts Registry No.: 57-66-9 Trade Name Benemid Benemide Benecid Benuryl Colbenemid Panuric Perdurine Probemid Probenicid Probenemid Procid Solpurin Urecid Uroben

Manufacturer MSD Theraplix Kaken I.C.N. MSD Propan-Lipworth Pharma-Union Lefa Lederle Merck-Banyu Protea Salfa Frosst Mitim

Country US France Japan Canada UK S. Africa Belgium Spain US Japan Australia Italy Australia Italy

Year Introduced 1952 1954 -

Raw Materials p-Carboxybenzene sulfonyl chloride Di-n-propylamine Manufacturing Process 24.0 grams (0.11 mol) of p-carboxybenzenesulfonyl chloride was added in small portions to a suspension of 20.0 grams (0.146 mol) of di-n-propylamine in 100 milliliters of 10% sodium hydroxide with vigorous stirring at a temperature of 15°-25°C. Stirring was continued for 15 minutes after the final addition. The clear solution was treated with decolorizing carbon and filtered.

Probucol

2851

The product was precipitated by the addition of an excess of hydrochloric acid. The crude product was purified by reprecipitation from bicarbonate solution and recrystallization from dilute alcohol. The yield was 20.0 grams (64%) melting at 194°-196°C. References Merck Index 7656 Kleeman & Engel p. 761 PDR pp. 705, 830, 993, 1142, 1150, 1606, 1999 OCDS Vol. 1 p. 135 (1977) I.N. p. 804 REM p. 944 Miller, C.S.; US Patent 2,608,507; August 26, 1952; assigned to Sharp & Dohme, Inc.

PROBUCOL Therapeutic Function: Antihyperlipidemic Chemical Name: Bis(3,5-di-tert-butyl-4-hydroxyphenyl)acetone mercaptole Common Name: Structural Formula:

Chemical Abstracts Registry No.: 23288-49-5 Trade Name Lorelco Lurselle Lurselle Lurselle Lurselle Lurselle Biphenabid Lesterol

Manufacturer Merrell Dow Lepetit Lepetit Dow-Lepetit Merrell Lepetit Merrell Dow Lepetit

Country US France UK Switz. W. Germany Italy -

Year Introduced 1977 1980 1980 1980 1980 1982 -

2852

Procainamide hydrochloride

Raw Materials Acetone 2,6-Di-tert-butyl-4-mercaptophenol Manufacturing Process Bis(3,5-di-tert-butyl-4-hydroxyphenyl) acetone mercaptole, melting at 125°C to 126°C is prepared by employing 2,6-di-tert-butyl-4-mercaptophenol and acetone as starting materials. In one representative procedure, the 2,6-ditert-butyl-4-mercaptophenol (47.5 g, 0.2 mol) is dissolved in methanol (50 ml) heated at a temperature of 50°C. A catalytic amount of concentrated hydrochloric acid (1 ml) is added, followed by acetone (5.8 g, 0.1 mol). The temperature of the mixture rises to about 60°C, and is maintained at about 60°C to 65°C for 1.5 hours. The mixture is cooled, diluted with water and about 10 ml of aqueous sodium bicarbonate and extracted with ether. The ether extract is evaporated, and the product is obtained as a residue, which is recrystallized from ethanol and then from isopropanol to obtain the bis(3,5-ditert-butyl-4-hydroxyphenyl) acetone mercaptole as a crystalline solid melting at about 125°C to 126°C. In another representative procedure about 2.3 mols of 2,6-di-tert-butyl-4mercaptophenol is dissolved in about 1,700 ml of methanol under a nitrogen atmosphere; about 100 ml of concentrated hydrochloric acid and 180 ml of acetone are added, and the mixture is stirred and maintained at a temperature of about 35°C to 50°C, for 1.5 hours. The mixture is then cooled to room temperature and filtered, and the bis(3,5-di-tert-butyl-4hydroxyphenyl) acetone mercaptole product is collected as a colorless crystalline solid filter cake. The product is washed with water and aqueous sodium bicarbonate and purified by recrystallization from ethanol. References Merck Index 7657 DFU 2 (2) 128 (1977) Kleeman & Engel p. 762 PDR p. 1229 OCDS Vol. 2 p. 126 (1980) DOT 14 (1) 33 (1978) I.N. p. 804 REM p. 864 Barnhart, J.W. and Shea, P.J.; US Patent 3,862,332; January 21, 1975; assigned to The Dow Chemical Co.

PROCAINAMIDE HYDROCHLORIDE Therapeutic Function: Antiarrhythmic Chemical Name: Benzamide, p-amino-N-(2-(diethylamino)ethyl)-, monohydrochloride

Procainamide hydrochloride

2853

Common Name: Amidoprocaine; Novocainamidum; Procainamide hydrochloride; Prokainamid Structural Formula:

Chemical Abstracts Registry No.: 614-39-1; 51-06-9 (Base) Trade Name PAD Procamide Procan Procanbid Promine Pronestyl Roxyl

Manufacturer Astra Zambon Parke-Davis Warner Lambert Major Sarabhai Chemicals Star

Country USA India -

Year Introduced -

Raw Materials Sodium ethoxide Diethyl aminoethane Hydrogen 4-Nitrobenzoyl chloride Nickel Manufacturing Process To the solution of 4-nitro-benzoylchloride the diethyl aminoethane and sodium ethoxide were added and mixed. As a result of reaction a N-(2-diethylaminoethyl)-4-nitro-benzamide was obtained. The N-(2-diethylamino-ethyl)-4-nitro-benzamide was reduced by hydrogen Ni as catalyst to give N-(2-diethylamino-ethyl)-4-amino-benzamide (procainamide). In practice it is usually used as hydrochloride salt. References Baltzy R. et al.; J. Am. Chem. Soc. 64, 2231 (1942); Yamazaki M.Y. et al.; J. Pharm. Soc. Japan 73, 294 (1953)

2854

Procaine

PROCAINE Therapeutic Function: Local anesthetic, Analgesic, Antiviral Chemical Name: Benzoic acid, 4-amino-, 2-(diethylamino)ethyl ester Common Name: Cocainum novum; Factor H3; Novocainum; PABAdiethylaminoethanol; Procaine; Prokain; Stoff H3; Vitamin H3 Structural Formula:

Chemical Abstracts Registry No.: 59-46-1 Trade Name Endocaina Isocain Novadren Polocaine Unicaine

Manufacturer Lafage Bernburg Sopharma Polfa Kay

Country -

Year Introduced -

Raw Materials Ethylene chlorohydrin p-Nitrobenzoyl chloride Diethyl amine Tin Manufacturing Process The equal quantity of ethylene chlorohydrin and p-nitrobenzoyl chloride was heated on an oil bath at temperature 120°-125°C till the ending of the isolation of hydrogen chloride. The mixture was poured into water to give the oil, which has soon hardened. It was recrystallized from diluted ethanol as white needles of p-nitrobenzoylchloro ethanol; MP: 56°C. 2 g of above prepared product and 2 g of diethyl amine were heated at 100°120°C for 10 hours in the soldered tube to give 4-nitobenzoic acid diethylaminoethyl ether as an oily viscous mass. It was dissolved in hydrochloric acid and reduced with tin to procaine, which has precipitated as oil after adding sodium carbonate. 4-Aminobenzoic acid diethylaminoethyl

Procarbazine hydrochloride

2855

ester crystallized from diluted ethanol with two molecules of water as white needles; MP: 51°C. It crystallized without water from napthaline; MP: 58°60°C, and formed monohydrochloride with MP: 156°C. References Farbwerke vorm. Meister Lucius and Bruning in Hochst a. M.; D.R. Patent No. 179,627; November 27, 1904

PROCARBAZINE HYDROCHLORIDE Therapeutic Function: Cancer chemotherapy Chemical Name: N-(1-Methylethyl)-4-[(2-methylhydrazino)methyl] benzamide hydrochloride Common Name: Ibenmethyzin Structural Formula:

Chemical Abstracts Registry No.: 366-70-1; 671-16-9 (Base) Trade Name Natulan Natulan Natulan Natulan Matulane Natulan

Manufacturer Roche Roche Roche Roche Roche Nippon Roche

Country France W. Germany UK Italy US Japan

Year Introduced 1965 1966 1966 1967 1969 1973

Raw Materials Methanol Sodium hydroxide Hydrogen bromide Bromine Isopropylamine

1-Methyl-1,2-dicarbobenzoxyhydrazine 4-Methylbenzoic acid Thionyl chloride Sodium hydride Hydrogen chloride

2856

Procarbazine hydrochloride

Manufacturing Process 544 grams of 4-methylbenzoic acid was boiled with 550 ml of thionyl chloride until a clear solution was obtained. After the excess thionyl chloride was distilled off, the residue was fractionated, yielding 605 g of 4-methylbenzoyl chloride; BP 91°C/9 mm Hg, nD24 = 1.5532. This was dissolved in 550 ml of absolute benzene and the so-formed solution added to a mixture of 248 ml of absolute methanol and 550 ml of absolute benzene. After the exothermic reaction had terminated, the reaction mixture was boiled for a further 20 hours, then concentrated in vacuo and the product, 4-methylbenzoic acid methyl ester, isolated by conventional means. It could be purified by distillation, and the purified product boiled at 91°C/9 mm Hg, MP 32°C. 574 grams of this ester were dissolved in 1200 ml of carbon tetrachloride and, while boiling and exposing to a UV lamp, treated dropwise with a solution of 109 ml of bromine in 400 ml of carbon tetrachloride. After all of the bromine had been dropped in, the mixture was heated for a further hour, concentrated in vacuo and the residue crystallized from low boiling petroleum ether, yielding as colorless fine crystals, 4-(bromo-methyl)-benzoic acid methyl ester, which melted at 52°C. For the reaction of this ester with 1-methyl-1,2dicarbobenzoxy-hydrazine, the following procedure was followed. 309 grams of a 27% suspension of sodium hydride in an inert solvent was treated with 300 ml of dimethylformamide, and a solution of 1095 grams of 1methyl-1,2-dicarbobenzoxy-hydrazine in dimethylformamide was added thereto. When all the material had been added and the hydrogen evolution had nearly come to a standstill, the mixture was heated for an hour at about 80°C in order to carry the formation of the sodium salt to completion. A mixture of 759 grams of 4-(bromo-methyl)-benzoic acid methyl ester in 700 ml of dimethylformamide was then dropped in, and finally the reaction mixture was heated for an hour at 80°C. After cooling, the reaction mixture was poured into 10 liters of ice water and the condensation products taken up in ether. The thereby obtained crude methyl ester (nD24 = 1.1558) was used without further purification for the next step. It was dissolved in about 2,200 ml of dioxane, treated with a solution of 133 grams of sodium hydroxide in 870 ml of water, and the resulting mixture stirred for about 24 hours at room temperature. It was then poured into 10 liters of ice water and neutral materials were extracted with ether. The aqueous phase was rendered acid with concentrated hydrochloric acid (weak Congo red) and the separated acid taken up in ether. The isolated crude acid was recrystallized from dibutyl ether, yielding colorless crystals of 4-[(2-methyl-1,2-dicarbobenzoxy-hydrazino)-methyl]-benzoic acid, which melted at 112°C. The so-obtained product was sufficiently pure for further reaction. 15 grams of 4-[(2-methyl-1,2-dicarbobenzoxy-hydrazino)-methyl]-benzoic acid were boiled with an excess of thionyl chloride for 1 hour under reflux. The unconverted thionyl chloride was distilled off in vacuo, the residue twice dissolved each time in 75 ml of absolute benzene and then concentrated in vacuo. The so-obtained 4-[(2-methyl-1,2-dicarbobenzoxyhydrazino)-methyl]benzoyl chloride, a viscous light yellow oil, was dissolved in 50 ml of absolute benzene and with stirring mixed with a solution of 4.45 grams of isopropylamine in 100 ml of absolute benzene. By cooling, the temperature of

Procaterol

2857

the reaction mixture was kept below 30°C. After the mixing had been completed, the reaction mixture was maintained first at room temperature for 3 hours and then for ½ hour at 40°C. It was then cooled down and poured into about 100 ml of ice water. After the addition of a mixture of methylene chloride and ether (40 ml + 200 ml), the organic phase was separated and then washed with water, dilute hydrochloric acid, water, dilute sodium hydroxide and again with water. The solvents were then evaporated, yielding 4-[(2-methyl-1,2dicarbobenzoxyhydrazino)-methyl]-benzoic acid isopropylamide as a yellow oil, which crystallized upon triturating with ether; MP 90°-92°C. This product was then covered with 70 ml of a 33% solution of hydrogen bromide in glacial acetic acid, and then permitted to stand for 2 hours with occasional swirling, whereupon a thick slurry of crystals was formed. The precipitate was filtered off, washed with 20 ml of glacial acetic acid and finally with ether, yielding crystals of 4-[(2-methyl-hydrazino)-methyl]-benzoic acid isopropylamide hydrobromide, which after recrystallization from methanol/ether melted at 216°-217°C (dec.). 87.5 grams of 4-[(2-methyl-hydrazino)-methyl]-benzoic acid isopropylamide hydrobromide (obtained as described above) were dissolved in 550 ml of water. To this solution, there were added 1,000 ml of methylene chloride and, while cooling with ice and stirring under nitrogen atmosphere, 1,200 grams of potassium carbonate portionwise. The methylene chloride layer was separated and the aqueous slurry extracted three times with 500 ml of methylene chloride in a nitrogen atmosphere. The united methylene chloride extracts were concentrated in vacuo. The residue was dissolved under nitrogen in 100 ml of methanol and treated, while cooling with ice, with 40 ml of a 45% methanolic hydrochloric acid solution, which induces immediate crystallization. The crystals were filtered off and recrystallized from methanol, yielding 4-[(2methyl-hydrazino)-methyl]-benzoic acid isopropylamide hydrochloride melting at 223°-226°C. References Merck Index 7662 Kleeman & Engel p. 763 PDR p. 1491 OCDS Vol. 2 p. 27 (1980) I.N. p.805 REM p. 1153 Bollag, W., Gutmann, H., Hegedus, B., Kaiser, A., Langemann, A., Muller, M. and Zeller, P.; US Patent 3,520,926; July 21, 1970; assigned to Hoffmann-La Roche Inc.

PROCATEROL Therapeutic Function: Bronchodilator Chemical Name: 8-Hydroxy-5-[1-hydroxy-2-[(1-methylethyl)amino]butyl]2(1H)-quinolinone

2858

Procaterol

Common Name: Structural Formula:

Chemical Abstracts Registry No.: 72332-33-3 Trade Name

Manufacturer

Country

Year Introduced

Meptin

Otsuka

Japan

1981

Raw Materials α-Bromobutyric acid bromide Isopropylamine 8-Hydroxycarbostyril Lithium aluminum hydride Manufacturing Process 50 g of α-bromobutyric acid bromide, 50 g of anhydrous aluminum chloride and 400 ml of carbon disulfide were added to 20 g of 8-hydroxycarbostyril. The resulting mixture was heated at a temperature of 50°C for 13 hours and the carbon disulfide layer was removed by decantation. Crushed ice was added to the residue, and the precipitated crystals were filtered, washed with water and recrystallized from methanol to obtain 27 g of 5-(α-bromobutyryl)8-hydroxycarbostyril having a melting point of 218°C to 219°C (with coloring and decomposition). To 5 g of the thus obtained 5-(α-bromobutyryl)-8hydroxycarbostyril was added 100 ml of isopropylamine, and the mixture was heated at a temperature of 50°C for 4 hours followed by concentration to dryness. Crystals which formed upon addition of water were filtered, washed with water and then recrystallized from methanol to obtain 4.6 g of a methanol solvate of 5-(α-isopropylaminobutyryl)-8-hydroxycarbostyril having a melting point of 136°C to 137°C (with foaming and decomposition). 20 g of tetrahydrofuran was added to 1 g of 5-(α-isopropylaminobutyryl)-8hydroxycarbostyril hydrochloride, and the resulting mixture was added dropwise to a suspension of 0.12 g of lithium aluminum hydride in 10 ml of tetrahydrofuran while stirring at room temperature. After completion of the addition, a small amount of water was added to the reaction mixture to decompose any excess of lithium aluminum hydride. The reaction mixture was then poured into 50 ml of ice-water and the aqueous layer of the resulting solution was separated and concentrated to dryness. The precipitated crystals

Prochlorperazine

2859

were filtered, washed with acetone and dissolved in water. The solution was adjusted to pH of 8 with aqueous sodium hydroxide to precipitate crystals which were then filtered and recrystallized from ethanol to obtain 0.8 g of 5(1-hydroxy-2-isopropylamino)butyl-8-hydroxycarbostyril monohydrate having a melting point of 141°C to 142°C (with cooling and decomposition). References Merck Index 7663 DFU 3 (2) 135 (1978) OCDS Vol. 3 p. 184 (1984) DOT 17 (6) 256 (1981) Nakagawa, K., Yoshizaki, S., Tanimura, K. and Tamada, S.; US Patent 4,026,897; May 3, 1977; assigned to Otsuka Pharmaceutical Co. (Japan)

PROCHLORPERAZINE Therapeutic Function: Antiemetic, Antipsychotic Chemical Name: 2-Chloro-10-[3-(4-methyl-1-piperazinyl)propyl]-10Hphenothiazine Common Name: Chlormeprazine Structural Formula:

Chemical Abstracts Registry No.: 58-38-8; 84-02-6 (Maleate) Trade Name Compazine Tementil Anti-Naus Combid Klometil Mitil Nibromin-A Normalmin Novamin

Manufacturer SKF Specia Protea SKF Farmos Lennon Maruko Sawai Shionogi

Country US France Australia US Finland S. Africa Japan Japan Japan

Year Introduced 1956 1957 -

2860

Procyclidine hydrochloride

Trade Name Pasotomin Stemetil Vertigon

Manufacturer Yoshitomi May and Baker SKF

Country Japan UK UK

Year Introduced -

Raw Materials 3-Chloro-10-[3-(di-N-2-chloroethyl)aminopropyl]phenthiazine hydrochloride 1-Methylpiperazine Manufacturing Process 3-Chloro-10-[3-(di-N-2-chloroethyl)aminopropyl]phenthiazine hydrochloride (1.8 g) is heated in a sealed tube for 4 hours at 140°C with a 290 g/l aqueous solution (9 cc) of monomethylpiperazine. The contents of the tube are treated with chloroform (40 cc). The aqueous layer is decanted and the chloroform layer is shaken with N hydrochloric acid (15 cc followed by 2 cc). The aqueous solution is treated with sodium hydroxide (d = 1.33, 10 cc) and chloroform (20 cc). After evaporation of the solvent, the base (1.5 g) is obtained. A solution of maleic acid (1 g) in ethanol (5 cc) is added and after recrystallization from water, 3-chloro10-[3-(4'-methyl-1'piperazinyl)propyl]phenothiazine dimaleate is obtained, melting point 228°C (inst .). References Merck Index 7665 Kleeman & Engel p. 764 PDR pp. 1606, 1706 OCDS Vol. 1 p. 381 (1977) DOT 9 (6) 228 (1973) I.N. p. 806 REM p. 809 Horclois, R.J.; US Patent 2,902,484; September 1, 1959; assigned to Societe des Usines Chimiques Rhone-Poulenc, France

PROCYCLIDINE HYDROCHLORIDE Therapeutic Function: Antiparkinsonian Chemical Name: α-Cyclohexyl-α-phenyl-1-pyrrolidinepropanol hydrochloride Common Name: Chemical Abstracts Registry No.: 1508-76-5; 77-37-2 (Base)

Procyclidine hydrochloride

2861

Structural Formula:

Trade Name Kemadrin Kemadrine Arpicolin Kemadren Osnervan Procyclid

Manufacturer Burroughs-Wellcome Wellcome R.P. Drugs Gayoso Wellcome Wellcome I.C.N.

Country US France UK Spain W. Germany Canada

Year Introduced 1956 1965 -

Raw Materials Acetophenone Magnesium Paraformaldehyde Hydrogen

Pyrrolidine Hydrogen chloride Bromobenzene

Manufacturing Process 1,1-Diphenyl-3-pyrrolidinopropan-1-ol (30 grams) was dissolved in glacial acetic acid (120 ml), Adams' platinum catalyst (6 grams) added, and the mixture shaken in an atmosphere of hydrogen until the equivalent of 3.4 molecules had been taken up per molecule of compound. Water was added, the catalyst removed by filtration, excess of ammonia added, and the liberated base extracted with ether. The ethereal extract was dried and evaporated and the residue recrystallized from light petroleum (BP 40°-60°C). The 1-cyclohexyl-1-phenyl3-pyrrolidinopropan-1-ol (19.3 grams) so obtained had a melting point of 85.5°-86.5°C. The hydrochloride recrystallized from a mixture of ethanol and ethyl acetate, melted with decomposition at 226°227°C according to US Patent 2,891,890. The starting material is prepared by the reaction of acetophenone, paraformaldehyde and pyrrolidine to give ω-pyrrolidinopropiophenone. That is in turn reacted with phenyl magnesium bromide to give 1,1-diphenyl-3pyrrolidinpropan-1-ol. References Merck Index 7667 Kleeman & Engel p. 765 PDR p. 745 OCDS Vol. 1 p. 47 (1977) DOT 18 (2) 88 (1982)

2862

Proglumetacin maleate

I.N. p. 806 REM p. 932 Bottorff, E.M.; US Patent 2,826,590; March 11, 1958; assigned to Eli Lilly and Company Harfenist, M. and Magnien, E.G.; US Patent 2,842,555; July 8, 1958; assigned to Burroughs Wellcome & Co. (U.S.A.) Inc. Adamson, D.W.; US Patent 2,891,890; June 23, 1959; assigned to Burroughs Wellcome & Co. (U.S.A.) Inc.

PROGLUMETACIN MALEATE Therapeutic Function: Antiinflammatory Chemical Name: N'-2-[1-(p-Chlorobenzoyl)-5-methoxy-2-methyl-3indoleacetoxy]-ethyl-N-3-(N-benzoyl-N',N'-di-n-propyl-DLisoglutaminoyl)-oxypropyl piperazine dimaleate Common Name: Protacine Structural Formula:

Chemical Abstracts Registry No.: 57132-53-3 (Base)

Proglumide Trade Name Afloxan Proxil

Manufacturer Rotta Rorer

Country Italy Italy

2863

Year Introduced 1981 1981

Raw Materials N'-(2-Hydroxyethyl)-N-3-(N-benzoyl-N',N'-di-n-propyl-DL-isoglutaminoyl)oxypropylpiperazine 1-(p-Chlorobenzoyl)-5-methoxy-2-methyl-3-indoleacetic acid N,N'-Dicyclohexylcarbodiimide Maleic acid Manufacturing Process To a titrated solution of 400 cc of ethyl acetate containing 0.1 mol of N'-(2hydroxyethyl)-N-3-(N-benzoyl-N',N'-di-n-propyl-DL-isoglutaminoyl)-oxypropyl piperazine [obtained by dissolving 71.9 g (0.105 mol) of the corresponding dioxalate in 500 cc of water, bringing this solution to a pH of between 9 and 10 with sodium bicarbonate and finally extracting the oily emulsion thus formed twice in succession with a total of 400 cc of ethyl acetate], there are added successively 35.8 g (0.1 mol) of 1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3indoleacetic acid and 20.6 g (0.1 mol) of N,N'-dicyclohexylcarbodiimide. This is left at room temperature for 24 hours, and after having filtered the N,N'dicyclohexyl urea precipitate the organic phase is then washed with dilute HCl, a solution of sodium bicarbonate and a saturated solution of sodium chloride. The ethyl acetate is dried with anhydrous sodium sulfate, filtered and dried off. The oily residue is dissolved in 600 cc of methanol; the di-oxalate is precipitated by the addition of a solution of oxalic acid in methanol. Yield 85%, melting point 190°C to 192°C (crystallized by methanol). Microcrystalline substance, creamy white color. By the same method one can obtain the dimaleate. Yield, 83%; melting point, 146°C to 148°C (crystallized by ethanol). Microcrystalline pale cream colored substance. References Merck Index 7679 DFU 5 (3) 142 (1980) DOT 17 (4) 157 (1981) Makovec, F., Senin, P. and Rovati, L.; US Patent 3,985,878; October 12, 1976; assigned to Rotta Research Laboratorium S.p.A.

PROGLUMIDE Therapeutic Function: Gastric antisecretory Chemical Name: Glutaramic acid, 4-benzamido-N,N-dipropyl-, DL-

2864

Proglumide

Common Name: Proglumide; Xilamida; Xylamide Structural Formula:

Chemical Abstracts Registry No.: 6620-60-6 Trade Name Milid Milid Promid Promid Snol

Manufacturer Popular Rotta Research Laboratorium spa Kaken Opfermann Inexfa

Country -

Year Introduced -

-

-

Raw Materials Glutamic acid Benzoyl chloride Dipropylamine Acetic anhydride Manufacturing Process 588 g L-(+)-glutamic acid [commercial grade], are gradually added, in small portions, while stirring, to 2400 ml 2 N NaOH, in such a manner that the internal temperature does not exceed 5°C by external cooling (ice or brine). When all the glutamic acid has been added and is dissolved there is added to the reaction mixture with continued stirring and in such a manner that the internal temperature does not exceed 15°C, 471 ml benzoyl chloride and 1600 ml 3 N NaOH from two separatory funnels, the addition being made in the following manner: add at once 94.2 ml benzoyl chloride, then, dropwise 160 ml 3 N NaOH (from the other funnel), the speed of addition is regulated so that the pH of the mixture does not exceed 8 (universal indicator paper) and the temperature does not exceed 15°C. When the 160 ml of the 3 N NaOH solution have all been added, add 47.1 ml benzoyl chloride, then slowly add 160 ml 3 N NaOH, again add 47.1 ml of benzoyl chloride, followed by the dropwise addition of the same volume of 3 N NaOH solution. This procedure of alternate addition is continued until the benzoyl chloride and 3 N NaOH solution have all been added. At this point one adds an additional 1125 ml of the 3 N NaOH solution at a speed, which keeps the temperature below 15°C

Prolintane hydrochloride

2865

and the pH under 8, using universal indicator paper for testing the pH. When all has been added, including the last addition of NaOH, stirring is continued for an additional 30 minutes. The reaction mixture is then acidified, dropwise, with concentrated HCI until congo red paper turns blue. The acid solution is stirred for 5 additional minutes, then transferred to a suitable container and stored for 10-18 hours at +5°C. The solids are filtered repulped in a mortar with 600 ml ice water and filtered again. The solids are washed on the filter with 400 ml ice water and pressed dry. The material is then spread out in a thin layer and dried in the air to obtain N-benzoylaminoglutamic acid, MP: 136°-140°C. 1500 g of N-benzoylaminoglutamic acid, obtained above, are added under stirring to 6 liters of acetic anhydride, previously placed in a flask, equipped with a reflux condenser and a stirrer. The stirred mixture is maintained at room temperature for 8 hours without cooling bath and let stand overnight at room temperature. The reaction mixture is filtered, pressed dry, then dried in an air current for one hour at 60°-70°C, and one hour at 100°C to obtain Nbenzoylaminoglutamic acid anhydride. Yield: 8.50 g (61%). To an aqueous solution of dipropylamine (334 ml of amine in sufficient water to yield 1400 ml aqueous solution), are added over a period of 60-75 minutes, under efficient stirring and with cooling to -3°C, 312 g of Nbenzoylaminoglutamic acid anhydride in such a manner that the temperature remains between -2°C and -4°C. When the addition is completed, stirring is continued for 10-15 minutes at -3°C and 650 ml glacial acetic acid are added. The temperature is allowed to rise to 6°C. The stirring is continued for 60-80 minutes. The reaction mixture is seeded by adding 2-3 g of previously prepared 4-benzamido-N,N-dipropylglutaramic acid which initiates precipitation of the desired product. The product is purified by dissolving the crude material in 20 times by weight of water and adding a stoichiometric amount of NaHCO3, or a slight excess at 60°-70°C. The mixture is acidified with 20% acetic acid with vigorous stirring at room temperature to obtain a pH of 5.5. The stirring is continued for an additional 10-15 minutes, the product 4-benzamido-N,N-dipropylglutaramic acid is filtered, washed with stirring with 700 ml of water for 15 minutes, filtered again and dried in air current at 25°C to constant weight. Yield 140 g; MP: 142°-145°C. References Rotta Research Laboratorium S.p.A., an Italian Joint Stock Company, of San Fruttuoso di Monza, Milan, Italy; G.B. Patent No. 1,108,819; July 31, 1964

PROLINTANE HYDROCHLORIDE Therapeutic Function: Analeptic, Stimulant, Antidepressant Chemical Name: Pyrrolidine, 1-(1-(phenylmethyl)butyl)-, hydrochloride Common Name: Prolintane hydrochloride; Promotil

2866

Prolintane hydrochloride

Structural Formula:

Chemical Abstracts Registry No.: 1211-28-5 Trade Name

Manufacturer

Country

Year Introduced

Catorid

Boehringer Ingelheim

-

-

Catovit

Boehringer Ingelheim

-

-

Katovit

Thomae

-

-

Promotil

Boehringer Ingelheim

-

-

Raw Materials Benzyl chloride Magnesium α-Pyrrolidinovalero nitrile Manufacturing Process 390 g benzyl chloride was added dropwise to 72 g of magnesium powder in the mixture of 1:1 of benzene and tetrahydrofuran by stirring and at temperature not above 40°C. The Grignard reagent was diluted with 750 ml of benzene-tetrahydrofuran (1:1). Then a solution of α-pyrrolidinovalero nitrile in 400 ml of benzene-tetrahydrofuran was added dropwise by stirring at temperature not above 40°C. After that the mixture was stirred 3 hours at 40°C and some hours at room temperature. At last the main part of solvents was distilled off in vacuum and ice with hydrochloric acid was added to the residue to an acidic pH. 1 L of benzene was added. The acid layer was separated. Benzene layer was shook with diluted hydrochloric acid. The combined acidic water layers were alkalized with ammonia to alkaline reaction. The oil dropped out was dissolved in benzene. The solvent was removed and the residue was distilled in vacuum to give 275 g 1-phenyl-2-pyrrolidinylpentane (prolintane); BP: 90-92°C at 0.36 mm. In practice it is usually used as hydrochloride salt. References Kottler A., Seeger E.; D.B. Patent No. 1,088,962; April 26, 1956

Prolonium iodide

2867

PROLONIUM IODIDE Therapeutic Function: Iodine source Chemical Name: 1,3-Propanediaminium, 2-hydroxy-N,N,N,N',N',N'hexamethyl-, diiodide Common Name: Diiodomedrine; Hydroxytrimethonium iodide; Ksameprol; Prolonii iododum; Prolonium iodide Structural Formula:

Chemical Abstracts Registry No.: 123-47-7 Trade Name Prolonium iodide

Manufacturer Yick-Vic Chemicals and Pharmaceuticals (HK) Ltd.

Country -

Year Introduced -

Prolonium iodide

AJAY NORTH AMERICA, L.L.C.

-

-

Prolonium iodide Hexajodin Prolonium iodide Micoiodina

Alfa Chem Galenika ZYF Pharm Chemical VETEM TECNICA SpA

-

-

Raw Materials Dimethylamine Epichlorohydrin Methyliodide Manufacturing Process Tetramethyldiaminoisopropanol can be produced by reaction of dimethylamine with epichlorhydrin. 146 parts of symmetrical tetramethyldiaminoisopropanol are mixed with 600 parts of benzene and 284 parts of methyliodide are slowly added whilst cooling and stirring. An oil which crystallizes after some time separates. It is separated from the benzene and crystallized from hot alcohol. The symmetrical hexamethyldiaminoisopropylalcoholiodide forms white crystals, melting point 270°-275°C (dec.).

2868

Promazine hydrochloride

References Callsen J.; US Patent No. 1,526,627; Feb. 17, 1925; Assigned: Farbenfabriken Vorm. Friedr. Bayer and Co., of Leverkusen, near Cologne on the Rhine, Germany Kleemann A., Engel J.; Pharmazeutische Wirkstoffe, GeorgThieme Verlag Stuttgart, New York, 1982

PROMAZINE HYDROCHLORIDE Therapeutic Function: Tranquilizer Chemical Name: N,N-Dimethyl-10H-phenothiazine-10-propanamine hydrochloride Common Name: Structural Formula:

Chemical Abstracts Registry No.: 53-60-1; 58-40-2 (Base) Trade Name Sparine Atarzine Calmotal Eliranol Frenil Neuroplegil Promanyl Promazettes Promezerine Protactyl Savamine Sediston Starazine Talofen Tranquazine Raw Materials Phenothiazine

Manufacturer Wyeth Saunders S.I.T. Wyeth Polfa Gentili Paul Maney Barlow Cote Barlow Cote Wyeth Banyu Serono Star Pierrel Anthony

Country US Canada Italy Italy Poland Italy Canada Canada Canada W. Germany Japan Italy Finland Italy US

Year Introduced 1956 -

Promegestone

2869

3-Dimethylamino-1-chloropropane Sodium amide Hydrogen chloride Manufacturing Process 30 grams of phenothiazine, 120 grams of xylene and 7 grams of sodamide (80%) are mixed and heated under reflux. 23 grams of 3-dimethylamino-1chloropropane, diluted with its own weight of xylene, is then added little by little during one hour, while maintaining the temperature of the reaction mixture; heating under reflux is then continued for a further hour. After cooling, the mixture is taken up in 400 cc of water and rendered slightly acid with hydrochloric acid. The xylene is decanted, the aqueous layer is rendered strongly alkaline with caustic soda and the base which separates is extracted with ether. On rectification of the ether extract, there is obtained N-(3'dimethyl-amino-propyl)-phenothiazine which boils at 208°-210°C under 3 mm. The hydrochloride of this base melts at 181°C (Maquenne block). References Merck Index 7688 Kleeman & Engel p. 768 PDR p. 1989 OCDS Vol. 1 p. 377 (1977) I.N. p. 810 REM p. 1090 Charpentier, P.; US Patent 2,519,886; August 22, 1950; assigned to Societe des Usines Chimiques Rhone-Poulenc, France

PROMEGESTONE Therapeutic Function: Progestin Chemical Name: 17α,21-Dimethyl-19-nor-∆4,9-pregnadiene-3,20-dione Common Name: Structural Formula:

Chemical Abstracts Registry No.: 34184-77-5

2870

Promestriene

Trade Name Surgestone

Manufacturer Cassenne

Country France

Year Introduced 1983

Raw Materials 17α-Methyl-19-nor-∆(5(10))-pregnene-3,20-dione Bromine Pyridine Manufacturing Process 16.3 cc of a solution of 29% of bromine in methanol were added with agitation under a nitrogen atmosphere to a solution of 8.50 g of 17α-methyl19-nor-∆5(10)-pregnene-3,20-dionein 85 cc of pyridine cooled to 0°C and the mixture was stirred for 30 minutes at 0°C. The temperature was allowed to return to room temperature and the mixture was stirred for 16 hours. The mixture was added to 850 cc of water-ice mixture and 82 cc of hydrochloric acid were added thereto. The mixture was extracted with methylene chloride and the combined extracts were washed with water until the wash waters were neutral, were dried over magnesium sulfate and distilled to dryness to obtain 8.480 g of crude product which is purified by crystallion from isopropyl ether to obtain 5.810 g of 17α-methyl-19-nor-∆4,9pregnadiene-3,20-dione melting at 106°C. The mother liquors from the purification of the product were combined and evaporated to dryness. The residue was fractionated by chromatography over silica gel (Kieselgel) and elution with a 7:3 mixture of benzene-ethyl acetate. The first fractions were discarded and the ensuing fraction was evaporated to obtain colorless crystals. The product was purified by mixing with five volumes of boiling isopropyl ether and the crystals formed after cooling were recovered by vacuum filtration, were washed twice with two volumes of isopropyl ether and dried in a ventilated atmosphere to obtain 17α,21-dimethyl-19-nor-∆4,9pregnadiene-3,20-dione melting at 152°C. References DFU 3 (6) 469 (1978) DOT 19 (7) 416 (1983) I.N. p. 810 Warnant, J. and Farcilli, A.; US Patents 3,679,714; July 25, 1972; and 3,761,591; Sept. 25, 1973; both assigned to Roussel UCLAF

PROMESTRIENE Therapeutic Function: Glucocorticoid Chemical Name: 17β-Methoxy-3-propoxyestra-1,3,5(10)-triene Common Name: Promestriene

Promestriene

2871

Structural Formula:

Chemical Abstracts Registry No.: 39219-28-8 Trade Name Colpotrophine

Manufacturer Chengdu Yuyang Hige-tech Developing Co.,Ltd.

Country -

Year Introduced -

Colpotrophine 1% creme

Theramex

-

-

Raw Materials Estradiol n-Propyl bromide Dimethyl sulfate

Sodium Dimethyl sulfoxide

Manufacturing Process An ethanolic solution of sodium ethoxide is prepared by reacting 3 g of sodium with 300 ml of absolute ethanol. 30 g of estradiol are dissolved in the resultant solution and there are then added thereto, with stirring, 30 ml of npropyl bromide. Reaction is continued for 3 hours with stirring at 60°C and then the reaction mixture is concentrated under vacuum at 30°C to about 50 ml. The residue is taken up in 500 ml of benzene and then washed twice with 250 ml of a 0.25 N solution of sodium hydroxide and then with distilled water to neutrality. The solution is then dried over sodium sulphate and concentrated to give 32 g of crude product (yield 93%), which on recrystallization from 100 ml of methanol gives 31 g (yield 89%) of pure product; MP: 100°-101°C. 40 g of the 3-propyl-ether obtained above is dissolved in 400 ml of anhydrous dimethyl sulphoxide. Several crystals of triphenylmethane are added to the solution (as a coloured indicator) followed by freshly prepared until a permanent red colour is obtained. There is then added about 50% excess dimethylsulfinyl sodium. The reaction mixture is allowed to stand for about 15 minutes at ambient temperature and is then cooled on an ice bath. 40 ml of redistilled dimethyl sulphate are then slowly added to the mixture, which is then stirred for 15 minutes at room temperature. The excess methyl sulphate is then destroyed by the addition of about 2 L of 2 N sodium hydroxide and the mixture stirred for about 2 hours. The pH of the reaction mixture must be alkaline at the end of the operation. The reaction mixture is extracted with benzene and the benzene fractions are washed with distilled water to neutrality. The benzene extracts are then dried over sodium sulphate and concentrated under vacuum at 33°C to give 42 g of crude product which on

2872

Promethazine hydrochloride

repeated recrystailisation from ethanol gives a pure white product promestriene in a yield of 78%; MP: 66°-67°C. The purity of the end product is controlled by gas phase and thin layer chromatography. References Societe Generale de Recherches et Dapplications Sogeras, a French body Corporate, Paris, France G.B. Patent No. 1,337,198; March 17, 1972

PROMETHAZINE HYDROCHLORIDE Therapeutic Function: Antihistaminic Chemical Name: N,N,α-Ttrimethyl-10H-phenothiazine-10-ethanamine hydrochloride Common Name: Proazamine hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 58-33-3; 60-87-7 (Base) Trade Name Phenergan Ganphen Remsed Lemprometh Bromethacon Baymethazine Atosil Avomine Diphergan Dorme Fargan Fellozine Fenazil Fenergan

Manufacturer Wyeth Tutag Endo Lemmon Alcon Bay Bayer May and Baker Polfa A.V.P. Farmitalia Fellows-Testagar Sella Rhodia Iberica

Country US US US US US US W. Germany UK Poland US Italy US Italy Spain

Year Introduced 1951 1971 1973 1974 1981 1982 -

Promethazine hydrochloride Trade Name Hiberna Lenazine Lergigan Mopergan Pelpica Perduretas Phencen Pipolphen Progan Promet Promethapar Promethazine Promine Prorex Prothazine Prothia Prothiazine Provigan Pyrethia Quadnite Rivozine Sayamol V-Gan Zipan

Manufacturer Yoshitomi Lennon Recip Wyeth P.C.B. Medea Central Nakataki Adams Legere Parmed Lederle Laser Hyrex Knoll Kanto Novis Reid-Provident Shionogi Reid-Provident Rivopharm Cinfa Hauck Savage

Country Japan S. Africa Sweden US Belgium Spain US Japan Australia US US US US US Australia Japan Israel US Japan US Switz. Spain US US

2873

Year Introduced -

Raw Materials Phenothiazine 1-Dimethylamino-2-propyl chloride Sodium amide Hydrogen chloride Manufacturing Process 30 grams of phenothiazine, 120 grams of xylene, and 7 grams of sodamide (85%) are mixed and heated under reflux. A solution of 23 grams of the base obtained by the action of sodium hydroxide on the hydrochloride of 1dimethylamino-2-chloropropane, in 25 grams of xylene, is then added little by little during one hour, while maintaining the temperature of the reaction mixture; heating under reflux is then continued for a further hour. After cooling, the mixture is taken up in 400 cc of water and rendered slightly acid with hydrochloric acid. The xylene is decanted, the aqueous layer is rendered strongly alkaline with caustic soda and the base which separates is extracted with ether. The ethereal extract is rectified, the fraction which boils at 190°192°C under 3 mm being recovered. This is diluted with acetone or ethyl acetate and dry hydrochloric acid is added. The hydrochloride of N-(2'dimethylamino-2'-methyl-ethyl)-phenothiazine separates, according to US Patent 2,530,451.

2874

Propafenone hydrochloride

References Merck Index 7691 Kleeman and Engel p. 769 PDR pp.861, 993, 1033, 1959, 1968, 1989 OCDS Vol. 1 pp. 373, 377 (1977) I.N. p. 811 REM p. 1129 Charpentier, P.; US Patent 2,530,451; November 21, 1950; assigned to Societe des Usines Chimiques Rhone-Poulenc, France Berg, S.S. and Ashley, J.N.; US Patent 2,607,773; August 19, 1952; assigned to Societe des Usines Chimiques Rhone-Poulenc, France

PROPAFENONE HYDROCHLORIDE Therapeutic Function: Antiarrhythmic Chemical Name: 2'-(2-Hydroxy-3-propylaminopropoxy)-3phenylpropiophenone hydrochloride Common Name: Fenoprain Structural Formula:

Chemical Abstracts Registry No.: 34183-22-7; 54063-53-5 (Base) Trade Name Rytmonorm Rytmonorm Rytmonorm Baxarytmon Normorytmin

Manufacturer Knoll Knoll Knoll Helopharm Knoll

Country W. Germany Italy Switz. W. Germany W. Germany

Raw Materials n-Propylamine 2'-Hydroxy-3-phenylpropiophenone Epichlorohydrin Hydrogen chloride

Year Introduced 1978 1983 1983 -

Propallylonal

2875

Manufacturing Process 2'-(2,3-epoxypropoxy)-3-phenylpropiophenone - 24.8 g of the sodium salt of 2'-hydroxy-3-phenylpropiophenone were mixed with 40 cm3 of 1-chloro-2,3epoxypropane (epichlorohydrin) and the mixture heated on a boiling water bath while stirring, using a reflux condenser. The initially pasty-to-solid mixture liquefied after about 2 hours, sodium chloride separating out. Thereafter it was heated for a further 2 hours while stirring, using a reflux condenser. The mixture was then allowed to cool and subsequently freed, by filtration, from the sodium chloride formed. The filtrate was concentrated in vacuo, and the excess 1-chloro-2,3-epoxypropane thus separated from the desired 2'-(2,3-epoxypropoxy)-3-phenylpropiophenone. The latter remained as a yellowish oil which solidified in the cold, but did not crystallize. Purification of the intermediate product, by distillation in vacuo, was not necessary, particularly as the substance only boiled at a temperature of 280°C/12 mm Hg and at the same time decomposed. 2'-(2-hydroxy-3-propylaminopropoxy)-3-phenylpropiophenone hydrochloride The above product was treated with 20 cm3 of n-propylamine and the mixture warmed on a water bath for approximately 4 hours, while stirring, using a reflux condenser. Thereafter, the excess n-propylamine was distilled off. On cooling, the residue solidified to give a viscous yellow mass. 20 cm3 of 1 M aqueous hydrochloric acid were added to it, and the whole was boiled for 1 hour under reflux, while stirring. The mixture was then poured into a suitable vessel and allowed to crystallize at room temperature. The crude product was drained thoroughly by suction and subsequently crystallized from a mixture of acetone/methanol (80:20, v/v). Approximately 25 g (66.2% of theory) of a white crystalline substance were obtained. The melting point of the hydrochloride was 173°C to 174°C. References Merck Index 7698 DFU 2 (5) 325 (1977) Kleeman and Engel p. 770 I.N. p. 812 Sachse, R.; British Patent 1,307,455; February 21, 1973; assigned to Helopharm W. Petrick & Co. K.G.

PROPALLYLONAL Therapeutic Function: Hypnotic Chemical Name: 2,4,6(1H,3H,5H)-Pyrimidinetrione, 5-(2-bromo-2-propenyl)5-(1-methylethyl)Common Name: Acidum isopropyl-bromallyl-barbituricum; Bromoaprobarbital; Ibomalum; Propallilonalum; Propallylonal; Propyallylonal

2876

Propallylonal

Structural Formula:

Chemical Abstracts Registry No.: 545-93-7 Trade Name Noctal Noctal

Manufacturer Cassella-Riedel UCB

Country -

Year Introduced -

Raw Materials Isopropylbarbituric acid Sodium 1,2-Dibrom-2.3-propylene Manufacturing Process 1). 170 parts of isopropylbarbituric acid are gradually added at room temperature to a sodium ethylate solution prepared from 23 parts of sodium and warming at 80°-85°C with brisk agitation, and finally 240 parts of 1,2dibrom-2.3-propylene are permitted to flow in slowly. After heating for several hours at 90°-100°C the reaction is completed. After blowing off the alcohol the 5-(2-bromoallyl)-5-isopropylbarbituric acid is recovered in almost quantitative yield in the form of colorless crystals. After re-crystallization from dilute acetic acid the acid shows a melting point of 181°C. 2). 250 parts of dibrompropylene are added to a clear solution of 170 parts of isopropylbarbituric acid in dilute caustic soda solution containing 40 parts of sodium hydroxide, in the cold, and the mixture is briskly shaken. After a short time colorless crystals begin to separate out and the separation continues steadily with further shaking but only gradually. The precipitated 5-(2bromoallyl)-5-isopropylbarbituric acid is filtered by suction and re-crystallized from water or dilute acetic acid. MP: 181°C. Any untransformed isopropylbarbituric acid is recovered from the filtrate after separating out the unchanged dibrompropylene, by precipitation with concentrated hydrochloric acid. References Boedecker F.; US Patent No. 1,622,129; March 22, 1927; Assigned to the firm I.D. Riedel A.G., of Berlin-Britz, Germany

Propanidid

2877

PROPANIDID Therapeutic Function: Anesthetic Chemical Name: 4-[2-(Diethylamino)-2-oxoethoxy]-3-methoxybenzeneacetic acid propyl ester Common Name: Structural Formula:

Chemical Abstracts Registry No.: 1421-14-3 Trade Name Epontol Epontol Epontol Epontol Fabontal Sombrevin

Manufacturer Bayer Bayer Theraplix Bayer Bayer Gedeon Richter

Country W. Germany Italy France Japan Hungary

Year Introduced 1965 1967 1967 1970 -

Raw Materials Sodium Homovanillic acid n-propyl ester Chloracetic acid-N,N-diethylamide Manufacturing Process To a solution of 4 g of sodium in 200 ml of n-propanol is added 39 g of homovanillic acid-n-propyl ester (boiling point 160°C to 162°C/4 mm Hg) and the mixture is concentrated by evaporation under vacuum. After dissolving the residue in 200 ml of dimethylformamide and the addition of 0.5 g of sodium iodide,26.2 g of chloracetic acid-N,N-diethylamide are added dropwise with stirring at an internal temperature of 130°C, and the mixture is further heated at 130°C for three hours. From the cooled reaction mixture the precipitated salts are removed by filtering off with suction. After driving off the dimethylformamide under vacuum, the product is fractionated under vacuum, and 44.3 g of 3-methoxy-4-N,N-diethylcarbamido-methoxyphenylacetic acidn-propylester are obtained as a yellowish oil of boiling point 210°C to 212°C/0.7 mm Hg.

2878

Propantheline bromide

References Merck Index 7705 OCDS Vol. 2 p. 79 (1980) DOT 2 (3) 110 (1966) I.N. p.813 REM p. 1047 Hiltman, R., Wollweber, H., Hoffmeister, F. and Wirth, W.; US Patent 3,086,978; April 23, 1963; assigned to Farbenfabriken Bayer A.G. (Germany)

PROPANTHELINE BROMIDE Therapeutic Function: Spasmolytic Chemical Name: N-Methyl-N-(1-methylethyl)-N-[2-[(9H-xanthen-9ylcarbonyl)oxy]ethyl]-2-propanaminium bromide Common Name: Diisopropylaminoethyl xanthene-9-carboxylate methobromide Structural Formula:

Chemical Abstracts Registry No.: 50-34-0 Trade Name Pro-Banthine Probanthine Apopant Banlin Corigast Ercoril Giquel Ketaman Neo-Banex

Manufacturer Searle Searle A.L. Paul Maney Searle Erco Danal Desitin Neo

Country US France Norway Canada W. Germany Denmark US W. Germany Canada

Year Introduced 1953 1981 -

Propantheline bromide Trade Name Neo-Dexabine Neo-Gastrosedan Neo-Metantyl Pantheline Panthene Pervagal Probital Prodixamon Propanthel Suprantil Tensilan

Manufacturer Noury Pharma Star Zambon Protea Vangard Zambeletti Searle A.L. I.C.N. Prodotti Erma Desitin

Country Netherlands Finland Italy Australia US Italy US Norway Canada Italy W. Germany

2879

Year Introduced -

Raw Materials Xanthene-9-carboxylic acid β-Diisopropylaminoethyl chloride Methyl bromide Manufacturing Process 365 parts of β-diisopropylaminoethyl chloride and 565 parts of xanthene-9carboxylic acid dissolved in 800 parts of isopropanol is heated to reflux for 5 hours. The solution is then cooled, diluted with dry ether and the crystalline precipitate of β-diisopropylaminoethyl xanthene-9-carboxylate hydrochloride is collected on a filter and dried. This salt melts at 111°-112°C. 38 parts of the foregoing salt are dissolved in the minimum of water and treated with an aqueous solution of potassium carbonate. The suspension of βdiisopropylaminoethylxanthene-9-carboxylate thus formed is extracted with ether and the ether extract is dried and evaporated. There is thus obtained 33 parts of the free base which are treated with 10 parts of methyl bromide in 100 parts of chloroform for 22 hours at 70°-80°C. The reaction mixture is chilled, diluted with anhydrous ether and the quaternary salt thus precipitated is collected on a filter and washed with dry ether and then with butanone. βDiisopropylaminoethyl xanthene-9-carboxylate methobromide thus obtained melts at 152°-153°C. After recrystallization from isopropanol it melts at 157°155°C. References Merck Index 7708 Kleeman & Engel p. 771 PDR pp. 830, 1569, 1606, 1694, 1723 OCDS Vol. 1 p. 394 (1977) I.N.p.813 REM p. 919 Cusic, J.W. and Robinson, R.A.; US Patent 2,659,732; November 17, 1953; assigned to G.D. Searle & Co.

2880

Proparacaine hydrochloride

PROPARACAINE HYDROCHLORIDE Therapeutic Function: Local anesthetic Chemical Name: Benzoic acid, 3-amino-4-propoxy-, 2-(diethylamino)ethyl ester, monohydrochloride Common Name: Proparacaine hydrochloride; Proparakain hydrochloride; Proximetacainum hydrochloride; Proxymetacaine hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 5875-06-9 Trade Name Alcaine Ophthaine Ophthetic

Manufacturer Alcon AmeriSource Allergan

Country USA -

Year Introduced -

Raw Materials Thionyl chloride γ-Diethylaminoethanol

3-Nitro-4-propyl-oxy-benzoic acid Hydrochloric acid

Manufacturing Process 3-Nitro-4-propyl-oxy-benzoic acid is first converted to the acid chloride by refluxing with thionyl chloride, and after removal of the excess thionyl chloride the acid chloride is reacted with γ-diethylaminoethanol in benzene solution. The γ-diethylaminoethanol-3-nitro-4-propylbenzoate hydrochloride obtained is then reduced in the presence Fe and HCl, to give the γ-diethylaminoethanol-3amino-4-propylbenzoate. The hydrochloride of the free base (prepared by reacting the free base with hydrochloric acid) may be recrystallized from acetone. References Vliet E. B. et al.; US Patent No. 2,288,334; June 30, 1942; Assigned: Abbott Laboratories, North Chicago, Ill., a corporation of Illinois

Propicillin potassium

2881

PROPICILLIN POTASSIUM Therapeutic Function: Antibiotic Chemical Name: 4-Thia-1-azabicyclo(3.2.0)heptane-2-carboxylic acid, 3,3dimethyl-7-oxo-6- (2-phenoxybutyramido)-, monopotassium salt Common Name: Phenoxypropylpenicillin potassium; Propicillin potassium Structural Formula:

Chemical Abstracts Registry No.: 1245-44-9; 551-27-9 (Base) Trade Name

Manufacturer

Country

Year Introduced

Oracillin

Takeda

-

-

Raw Materials Triethylamine 2-Phenoxybuturic acid Isobutyl chloroformate 6-Aminopenicillanic acid Manufacturing Process Triethylamine (1.5 ml) was added to a cold solution (10°C) of 2phenoxybuturic acid (2.16 g, 0.01 mole) in 15 ml of pure dioxane, with stirring and cooling to 5°-10°C, then isobutyl chloroformate (1.36 g, 0.01.mole) in 5 ml of dioxane was added dropwise. Then the mixture was stirred for ten minutes at 5°-8°C. A solution of 6-aminopenicillanic acid (2.16 g, 0.01 mole) in 15 ml of water and 2 ml of triethylamine was then added dropwise while the temperature was maintained below 10°C. The resulting mixture was stirred in the cold for 15 minutes then at room temperature for 30 minutes, diluted with 30 ml of cold water and extracted with ether, which was discarded. The cold aqueous solution was then covered with 75 ml of ether and acidified to pH 2 with 5 N sulfuric acid. After shaking, the ether layer containing the product 6-(2-phenoxybutyramido)penicillanic acid, was separeted, dried over anhydrous sodium sulphate, solvent was removed to give 1.03 g of product propicillin; MP: 175°-179°C (became dark at 170°C),

2882

Propiram fumarate

contained the β-lactam structure as shown by infrared analysis and inhibited Staph. Aureus Smith at concentration 0.05 mcg/ml. In practice it is usually used as potassium salt. References Beecham Research Laboratories Ltd., Brendford, Middlesex, England; G.B. Patent No. 3,316,248; April 25, 1967

PROPIRAM FUMARATE Therapeutic Function: Analgesic Chemical Name: N-[1-Methyl-2-(1-piperidinyl)ethyl]-N-2pyridinylpropanamide fumarate Common Name: Structural Formula:

Chemical Abstracts Registry No.: 13717-04-9; 15686-91-6 (Base) Trade Name

Manufacturer

Country

Year Introduced

Algeril

Bayropharm

Italy

1974

Algeril

Bayer

W. Germany

1974

Dirame

Schering

-

-

Raw Materials Fumaric acid 2-(1-Piperidine-isopropyl)aminopyridine Propionic anhydride

Propofol

2883

Manufacturing Process 20 g of 2-(1-piperidino-isopropyl)aminopyridine and 50 ml of propionic anhydride are heated to 120°C for 8 hours. The mixture is then evaporated under vacuum and the residue taken up in water. The base is precipitated from the solution with a caustic soda solution, taken up in ether and dried with potassium carbonate. After driving off the ether and distillation under vacuum, there are obtained 18 grams of N-propionyl-2-(1-piperidinoisopropyl)aminopyridine of BP 162°-163°C/0.5 mm Hg. The base is then reacted with fumaric acid to give the final product. References Merck Index 7733 Kleeman & Engel p. 772 DOT 10 (11) 309 (1974) I.N. p. 815 Hiltmann, R., Wollweber, H., Hoffmeister, F., Wirth, W. and Kroneberg, H.-G.; US Patent 3,163,654; December 29, 1964; assigned to Farbenfabriken Bayer AG, Germany Wollweber, H., Hiltmann, R., Hoffmeister, F. and Kroneberg, H.-G.; US Patent 3,594,477; July 20, 1971; assigned to Farbenfabriken Bayer AG, Germany

PROPOFOL Therapeutic Function: Anesthetic Chemical Name: Phenol-2,6-diisopropyl Common Name: Disoprofol; Propofol Structural Formula:

Chemical Abstracts Registry No.: 2078-54-8 Trade Name

Manufacturer

Country

Year Introduced

Cleofol Inj.

Themis Pharmaceuticals Ltd.

India

-

Diprivan

AstraZeneca UK Limited

Italy

-

Diprivan

Zeneca

Italy

-

Diprivan

ICI India Limited

India

-

2884

Propofol

Trade Name Pofol Propofol Propofol Abbott Propofol 1% Fresenius Propofol Lipuro Propovan Recofol

Manufacturer Dong Kook Pharmaceutical Co. Baxter Abbott Laboratories Fresenius Kabi

Country Korea

Year Introduced -

USA Austria

-

B. Braun Melsungen AG Bharat Serum and Vaccines Pvt. Ltd. Leiras OY

Germany India

-

Germany

-

Raw Materials Phenol Aluminum turnings Propylene Isopropyl (2-isopropylphenyl) ether Fluorided alumina Manufacturing Process 2 Methods of preparation of 2,6-diisopropylphenol 1. To vessel with flushed nitrogen at an elevated temperature to 165°C 490 parts of phenol was placed, then 4.5 parts of aluminum turnings were added in small increments.The reaction mixture was accompanied by evolution of hydrogen for 15 min, then the mixture was allowed to cool to about 60°C and agitation discontinued. Aluminum phenoxide catalyst mixture was ready. The reaction vessel was heated to 150°C and pressurized with propylene. The temperature then increased slowly. The start of the reaction was evidenced by a drop in the propylene pressure at 190°C and at a pressure of 21-35 atm. The product was hydrolyzed and fractionated to yield 105 parts of 2,6diisopropylphenol. Boiling point: 135.5-136.5°C. 2. To 15 g of isopropyl (2-isopropylphenyl) ether was added 8 g of 1% fluorided alumina. The mixture was placed in a 300 cc stirred autoclave and the system was flushed with nitrogen and left under a nitrogen atmosphere. The autoclave was heated to 150°C for 1 h with stirring during which time the pressure reached 200 psig. The cooled reaction mixture was taken up in acetone, filtered, and the solvent was removed on a rotary evaporator. The residue was analyzed by gas-liquid phase chromatography (glpc) which showed the presence of 2,6-diisopropylphenol (60%). References Ecke G.G., et al.; US Patent No. 2,831,898; April 22, 1958; Assigned: Ethyl Corporation, New York, N.Y., a corporation of Delaware Firth B.E., Rosen T.J.; US Patent No. 4,447,657; May 8, 1984; Assigned: UOP Inc., Des Plaines, III

Propoxyphene hydrochloride

2885

PROPOXYPHENE HYDROCHLORIDE Therapeutic Function: Analgesic Chemical Name: (S)-α-[2-(Dimethylamino)-1-methylethyl]-αphenylbenzeneethanol propanoate hydrochloride Common Name: Dextropropoxyphene hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 1639-60-7; 469-62-5 (Base) Trade Name Darvon Antalvic SK-65 Propoxychel Dolene-65 Prophen 65 Darvocet-N Depronal SA Develin Doloxene Erantin Liberen Lorcet Wygesic

Manufacturer Lilly Houde SKF Rachelle Lederle Halsey Lilly Warner Goedecke Lilly Boehringer Mannheim Lisapharma U.A.D. Labs Wyeth

Country US France US US US US US UK W. Germany UK W. Germany Italy US US

Year Introduced 1957 1963 1973 1973 1973 1981 -

Raw Materials Benzyl chloride Magnesium Hydrogen chloride

Propionic anhydride α-Methyl-β-dimethylaminopropiophenone

Manufacturing Process A solution of benzylmagnesium chloride prepared from 63.3 grams (0.5 mol)

2886

Propronolol hydrochloride

of benzyl chloride, 30.5 grams (1.25 mol) of magnesium and 750 cc of ether was added dropwise with stirring to a solution of 61.9 grams (0.35 mol) of αmethyl-β-dimethylaminopropiophenone (prepared by the method of Burchalter et al, JACS 70 page 4186, 1948), in 150 cc of ether. When all of the Grignard reagent had been added, the solution was refluxed for about 1 hour. The reaction mixture was then decomposed by the addition of saturated aqueous ammonium chloride solution. The ether solution containing the 1,2-diphenyl-2hydroxy-3-methyl-4-dimethylaminobutane formed in the reaction was decanted from the granular precipitate and dried over anhydrous magnesium sulfate. Dry hydrogen chloride gas was passed into the ether solution until precipitation was completed. The solid was removed by filtration and was recrystallized from a mixture of methanol and ethyl acetate. The α-dl-1,2diphenyl-2-hydroxy-3-methyl-4-dimethylaminobutane hydrochloride thus obtained melted at about 231° to 232°C. A mixture of 50 grams of α-dl-1,2-diphenyl-2-hydroxy-3-methyl-4dimethylaminobutane hydrochloride, 50 grams of propionic anhydride and 50 cc of pyridine was refluxed for about 5 hours. The reaction mixture was cooled to 50°C and ethyl ether was added to the point of incipient precipitation. The hydrochloride salt of α-dl-1,2-diphenyl-2-propionoxy-3-methyl-4dimethylaminobutane formed in the reaction precipitated upon cooling and was removed by filtration and washed with anhydrous ether. On recrystallization from a mixture of methanol and ethyl acetate, α-dl-1,2diphenyl-2-propionoxy-3-methyl-4-dimethylaminobutane hydrochloride melted at 170°-171°C. References Merck Index 7739 Kleeman & Engel p. 285 PDR pp. 993, 1044, 1606, 1723, 1808, 1996, 1999 OCDS Vol. 1 pp. 50, 298 (1977) and 2, 57 (1980) I.N. p. 816 REM p.1114 Pohland, A.; US Patent 2,728,779; December 27, 1955; assigned to Eli Lilly and Company

PROPRANOLOL HYDROCHLORIDE Therapeutic Function: Beta-adrenergic blocker Chemical Name: 1-(Isopropylamino)-3-(1-naphthyloxy)-2-propanol hydrochloride Common Name: Chemical Abstracts Registry No.: 318-98-9; 525-66-6 (Base)

Propronolol hydrochloride

2887

Structural Formula:

Trade Name Inderal Dociton Avlocardyl Inderal Angilol Arcablock Bedranol Berkolol Beta-Neg Beta-Tablinen Cardinol Caridolol Corotrend Deralin Detensol Dideral Frekven Herzbase Herzul Inderide Indobloc Kemi Nedis Noloten Novopranol Obsidan Oposim Pranolol Pronovan Propranolol Propranur Pur-Bloka Pylapron Reducor Sawatal Tonum

Manufacturer I.C.I. Rhein Pharma I.C.I. Ayerst D.D.S.A. Arcana Berk Lagap Ellem Sanorania Protea Sankyo Siegfried Abic Desbergers Dif-Dogu Ferrosan Nichiiko Ono Ayerst Homburg Otsuka Omega Beta Novopharm Iris-Chemie Richet A.L. A.L. Lederle Henning Lennon Kyorin Leiras Sawai Tubi Lux Pharma

Country UK W. Germany France US UK Austria Switz. UK Italy W. Germany Australia Japan Switz. Israel Canada Turkey Denmark Japan Japan US W. Germany Japan Argentina Argentina Canada E. Germany Argentina Norway Norway US W. Germany S. Africa Japan Finland Japan Italy

Year Introduced 1965 1965 1967 1968 -

2888

Propylhexedrine

Raw Materials 1-Naphthol Isopropylamine Epichlorohydrin Hydrogen chloride Manufacturing Process In a first step, 1-naphthol was reacted with epichlorohydrin to give 1-chloro3-(1-naphthoxy)-2propanol. A mixture of 4.4 parts of 1-chloro-3-(1napntnoxy)-2-propano and 16 parts of isopropylamine is heated in a sealed vessel at 70°-80°C for 10 hours. The vessel is cooled and to the contents there are added 50 parts of water. The mixture is acidified with 2 N hydrochloric acid, and washed with 50 parts of ether. The aqueous phase is decolorized with carbon, and then added to 50 parts of 2 N sodium hydroxide solution at 0°C. The mixture is filtered, The solid residue is washed with water, dried, and crystallized from cyclohexane. There is thus obtained 1isopropylamino-3-(1-naphthoxy)-2-propanol, MP 96°C. The base may be converted into the hydrochloride as follows. 4.65 parts of the base are dissolved in 60 parts of warm acetone. To the warm solution there are added 2 parts of 10 N hydrochloric acid. The mixture is allowed to cool, and is then filtered. The solid residue is washed with acetone and then dried. The solid is crystallized from propanol, and there is thus obtained 1isopropylamino-3-(1-naphthoxy)-2-propanol hydrochloride MP 163°C. References Merck Index 7740 Kleeman & Engel p. 773 PDR pp. 622, 993, 1999 OCDS Vol. 1 p. 117 (1977) and 2, 105, 107, 212 (1980) DOT 19 (3) 172 (1983) I.N. p. 816 REM p. 906 Crowther, A.F. and Smith, L.H.; US Patent 3,337,628; August 22, 1967; assigned to Imperial Chemical Industries Limited, England

PROPYLHEXEDRINE Therapeutic Function: Nasal decongestant Chemical Name: N,α-Dimethylcyclohexaneethanamine Common Name: Hexahydrodesoxyephedrine Chemical Abstracts Registry No.: 101-40-6; 6192-98-9 (Hydrochloride salt)

Propylhexedrine

2889

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Benzedrex

SKF

US

1949

Dristan

Whitehall

US

-

Eggobesin

Fahlberg-List

E. Germany

-

Eventin

Minden

W. Germany

-

Raw Materials Cyclohexylacetone N-Methylformamide Sulfuric acid Sodium hydroxide Manufacturing Process 33.6 grams of cyclohexylacetone, a compound known to the art, dissolved in 13 grams of 85% formic acid is caused to interact with 72.0 grams of Nmethyl formamide at 160°-180°C for 4 hours. This results in the formation of the formyl derivative of the amine, according to the following reaction: C6H11-CH2-C(O)-CH3+ 2HCONHCH3 => C6H11-CH2-CH(NCH3-CHO)-CH3+ CH3NH2+ CO2 The formyl derivative is then hydrolyzed by refluxing with 50% sulfuric acid for about 4 hours, after which the hydrolysate is extracted with ether to remove the acid-insoluble material and the aqueous solution made strongly alkaline with any suitable alkalizing agent, for example, sodium hydroxide, to liberate the amine. The amine is then taken up in ether, dried over potassium hydroxide and purified by distillation, preferably under reduced pressure. βcyclohexylisopropylmethylamine thus obtained boils at 90.0°-92°C at 22 mm Hg. References Merck Index 7761 Kleeman & Engel p. 774 OCDS Vol. 1 p. 37 (1977) I.N. p. 817 REM p. 890 Ullyot, G.E.; US Patent 2,454,746; November 23, 1948; assigned to Smith, Kline and French Laboratories

2890

Propyliodone

PROPYLIODONE Therapeutic Function: Diagnostic aid Chemical Name: 1(4H)-Pyridineacetic acid, 3,5-diiodo-4-oxo-, propyl ester Common Name: Propiliodon; Propyliodone Structural Formula:

Chemical Abstracts Registry No.: 587-61-1 Trade Name Propyliodone Dionosil oily

Manufacturer GlaxoSmithKline GlaxoSmithKline

Country -

Year Introduced -

Raw Materials Chloroacetic acid 3,5-Diiodo-4-1H-pyridone Isopropanol Manufacturing Process 15 parts of 3,5-diiodo-4-pyridone-N-acetic acid, (prepared from 3,5-diiodo-41H-pyridone and chloroacetic acid), 60 parts of isopropanol, and 1 part of concentrated sulfuric acid are boiled for an hour in a vessel fitted with a reflux condenser. The solution is then cooled, whereupon crystals of isopropyl 3,5diiodo-4-pyridone-N-acetate separate out by filtration, washed with ethanol and dried. MP: 215°C. References Branscombe D.J.; G.B. Patent No. 517,382; July 25, 1938; Imperial Chemical Industries Limited, of Imperial Chemical House, Millbank, London Pharmazeutishe Wirkstoffe von A. Kleemann und J. Engel. 2., neubearbeitete und erweiterte Auflage; Georg Thime Verlag Stuttgart New York 1982; p. 775

Propyromazine bromide

2891

PROPYROMAZINE BROMIDE Therapeutic Function: Spasmolytic, Anticholinergic Chemical Name: 1-Methyl-1-(1-phenothiazin-10-ylcarbonylethyl) pyrrolidinium bromide Common Name: Diaspasmyl; Propyromazine bromide Structural Formula:

Chemical Abstracts Registry No.: 145-54-0 Trade Name

Manufacturer

Country

Year Introduced

Propyromazine bromide

Astra (AstraZeneca)

-

-

Raw Materials Pyrrolidine 2-Bromo-1-phenothiazin-10-yl-propan-1 Methyl bromide Manufacturing Process 185 g pyrrolidine and 334 g 2-bromo-1-phenothiazin-10-yl-propan-1 were refluxed in 2500 ml toluene for three hours. On cooling the solution the precipitated pyrrolidine hydrochloride was separated and collected, and the filtrate was evaporated to dryness. The crystalline residue 272 g was recrystallized from a mixture of five parts of light petroleum. MP of 1phenothiazin-10-yl-2-pyrrolidin-1-yl-propan-1-one 94.5-95.5°C. Its brommethylate 1-methyl-1-(1-methyl-2-oxo-2-phenothiazin-10-ylethyl)pyrrolidinium, bromide was prepared by reaction with equivalent quantity of methyl bromide. References Dahlbom J.R., T.K.I. B. Ekstrand; US Patent No. 2,615,886; January 10, 1951; Assigned to Aktiebolaget Astra, Apotekarnes Kremiska Fabriker, Sodertalje, Sweden

2892

Proquazone

Pharmazeutishe Wirkstoffe von A. Kleemann und J. Engel; 2., neubearbeitete und erweiterte Auflage, p. 776, 1982; Georg Thime Verlag Stuttgart New York

PROQUAZONE Therapeutic Function: Antiinflammatory Chemical Name: 1-Isopropyl-7-methyl-4-phenyl-2(1H)-quinazolinone Common Name: Structural Formula:

Chemical Abstracts Registry No.: 22760-18-5 Trade Name

Manufacturer

Country

Year Introduced

Biarison

Sandoz

Italy

1977

Biarison

Sandoz

Japan

1977

Biarison

Sandoz

France

1977

Biarison

Sandoz

Switz.

1977

Biarison

Wander

W. Germany

1979

Raw Materials 4-Methyl-2-isopropylaminobenzophenone Urethane Manufacturing Process A mixture of 5.9 g of 4-methyl-2-isopropylaminobenzophenone, 13.9 g urethane and 500 mg of zinc chloride is heated at a temperature of 190°C for 1½ hours. There is then additionally added 7 g of urethane and 250 mg of zinc chloride, and the heating continued at a temperature of 190°C for an additional 2½ hours. The resulting mixture is cooled to about 100°C and diluted with chloroform. The resulting mixture is then filtered and the filtrate washed first with water and then with brine. The organic phase is separated,

Proscillaridin

2893

dried over anhydrous sodium sulfate and concentrated in vacuo to remove substantially all of the chloroform and obtain an oily residue which is dissolved in a small amount of about 20 ml of methylene chloride. The resulting solution is then diluted with about 40ml of ethyl acetate and concentrated in vacuo to crystallize 1-isopropyl-7-methyl-4-phenyl-2(1H)-quinazolinone; melting point 137°C to 138°C. References Merck Index 7775 DFU 1 (11) 540 (1976) Kleeman and Engel p. 777 OCDS Vol. 2 p. 386 (1980) DOT 8 (3) 116 (1972) and 13 (12) 534 (1977) I.N. p. 818 Linder, J., Mattner, P.G. and Salmond, W.G.; US Patent 3,759,720; September 18, 1973; assigned to Sandoz-Wander Inc. Denzer, M.; US Patent 3,793,324; February 19, 1974 Ott, H.; US Patent 3,925,548; December 9,1975; assigned to Sandoz, Inc.

PROSCILLARIDIN Therapeutic Function: Cardiotonic Chemical Name: 3-[(6-Deoxy-α-L-mannopyranosyl)oxy]-14-hydroxybufa4,20,22-trienolide Common Name: Structural Formula:

Chemical Abstracts Registry No.: 466-06-8

2894

Proscillaridin

Trade Name Talusin Talusin Apocerpin Bunosquin Caradrin Cardimarin Cardiolidin Cardion Cardon Herzo Mitredin Procardin Procillan Proherz Proscillan Proscillar Prosiladin Prostosin Proszin Protasin Purosin-TC Sandoscill Scillaridin Silamarin A Stellarid Talusin Urgilan Wirnesin

Manufacturer Knoll Biosedra Kotani Seiko Kowa Santen Nichiiko Nippon Chemiphar Kanto Toho Nippon Shoji Mohan Hokuriku Shinshin Streuli Toyo Jozo Sawai Iwaki Teisan Bayropharm Tatsumi Sandoz Morishita Wakamoto Tobishi-Mochida Dainippon Simes Inpharzam

Country W. Germany France Japan Japan Japan Japan Japan Japan Japan Japan Japan Japan Japan Japan Switz. Japan Japan Japan Japan W. Germany Japan W. Germany Japan Japan Japan Japan Italy W. Germany

Year Introduced 1964 1968 -

Raw Materials Squill Manufacturing Process 350 g of dried and cut squill were fermented at 50°C for two hours in 1.1 liters of water. The suspension was then extracted three times with 1.1 liters of ethyl acetate. The extracts were united and evaporated to dryness, the residue was dissolved in 2 ml of dioxane and chromatographed in a twentyfold quantity (based on the amount of dried residue) of silica gel. The proscillaridin was then eluated with toluene to which increasing quantities of a methanol-dioxane mixture were added. The main fraction, containing proscillaridin, was evaporated to dryness. The residue was crystallized out of methanol. Pure proscillaridin was obtained with a melting point of 227°C to 230°C; α20D = -93.5°C (in methanol). The same result was obtained by fermentation on the aqueous suspension of the cut squill at room temperature for 24 hours and working up in the manner described.

Prothipendyl hydrochloride

2895

References Merck Index 7776 Kleeman & Engel p. 777 DOT 3 (3) 97 (1967) I.N. p.819 Steidle, W. US Patent 3,361,630; January 2, 1968; assigned to Knoll A.G. (Germany)

PROTHIPENDYL HYDROCHLORIDE Therapeutic Function: Sedative, Antihistaminic Chemical Name: N,N-Dimethyl-10H-pyrido[3,2-b][1,4]benzothiazine-10propanamine hydrochloride Common Name: Structural Formula:

Chemical Abstracts Registry No.: 1225-65-6; 303-69-5 (Base) Trade Name Timovan Dominal Prosyl Tolnate

Manufacturer Ayerst Homburg Kanto SKF

Country US W. Germany Japan UK

Year Introduced 1960 -

Raw Materials 1-Azaphenothiazine Sodium amide 3-Dimethylaminopropyl chloride Hydrogen chloride Manufacturing Process A mixture of 20 g (0.1 mol) of 1-azaphenothiazine, 4.3 g (0.11 mol) of sodamide and 300 ml of dry toluene is stirred and refluxed for eight hours. A slow stream of dry nitrogen gas is used to sweep out the ammonia as formed. The mixture is cooled and 110 ml of a 1 M solution of 3-dimethylaminopropyl chloride in toluene is added dropwise, with stirring. Subsequently, the mixture

2896

Protionamide

is stirred and refluxed for fifteen hours, cooled, and concentrated in vacuo. The viscous residue is refluxed with 500 ml of chloroform and filtered hot. The chloroform filtrate is treated with activated charcoal and again filtered. The filtrate is concentrated and the residue distilled to give about 19.8 g (69% yield) of product, an oil distilling at about 195°C to 198°C (under 0.5 mm pressure of mercury). To a solution of 16.4 g (0.058 mol) of the free base in 75 ml of dry acetonitrile is added dropwlse while cooling (ice bath) and stirring 14.5 ml (0.053 mol) of 3.6 N ethereal hydrogen chloride. An equal volume of anhydrous ether is added and the product altered, dried and recrystallized from monochlorobenzene. The product melts at about 177°C to 178°C with sintering at about 176°C. The yield is about 11.0 g (60%). References Merck index 7789 Kleeman & Engel p. 779 OCDS Vol. 1 p. 430 (1977) I.N. p. 821 Yale, H.L. and Bernstein, J.; US Patent 2,943,086; June 28, 1960; assigned to Olin Mathieson Chemical Corp.

PROTIONAMIDE Therapeutic Function: Antitubercular Chemical Name: 2-Propyl-4-pyridinecarbothioamide Common Name: α-Propyl-isonicotinic thioamide Structural Formula:

Chemical Abstracts Registry No.: 14222-60-7 Trade Name Ektebin Protionizina Entelohi Peteha Promid

Manufacturer Bayer Farmitalia Kyowa Saarstickstoff-Fatol Biofarma

Country W. Germany Italy Japan W. Germany Turkey

Year Introduced 1969 1970 -

Protionamide Trade Name Prothionamide Trevintix Tuberamin Tuberex Tubermide

Manufacturer Toho Theraplix Meiji Shionogi Sankyo

Country Japan France Japan Japan Japan

2897

Year Introduced -

Raw Materials Ethyl oxalate Hydrogen chloride Phosphoric anhydride Cyanacetamide Ammonia

Sodium ethylate Hydrogen Methyl-n-propyl ketone Phosphorus oxychloride Hydrogen sulfide

Manufacturing Process (A) Ethyl Butyryl-Pyruvate: 146 grams of ethyl oxalate are condensed with 86 grams of methyl-(n)-propyl-ketone in the presence of sodium ethylate prepared from 25 grams of sodium. 135 grams of product, having a boiling point of 113°C/6 mm, are obtained. (B) 3-Cyano-4-Carbethoxy-6-(n)-Propyl-2-Pyridone: The 135 grams of the product just obtained are condensed with 62 grams of cyanacetamide in the presence of 24 cc of piperidine in 1200 cc of 95% alcohol. 64 grams of a product, melting at 152°C, are obtained. (C) 6-(n)-Propyl-2-Pyridone-4-Carboxylic Acid: The 64 grams of the product just obtained are treated with 500 cc of concentrated hydrochloric acid at boiling point. 40 grams of a product, having a melting point of 285°C, are obtained. (D) Ethyl 2-Chloro-6-(n)-Propyl-Isonicotinate: The 40 grams of the acid just obtained are treated with 80 grams of phosphorus oxychloride and 95 grams of phosphorus pentachloride. The phosphorus oxychloride is distilled and the reaction mixture is treated with 400 grams of absolute alcohol. 40 grams of chlorinated ester, having a BP of 115°-116°C/2 mm, are obtained. (E) Ethyl 2-(n)-Propyl-Isonicotinate: The product just obtained is dechlorinated by catalytically hydrogenating it in an alcoholic medium in the presence of palladium black and potassium acetate. 30 grams of ester, having a boiling point of 121°-125°C/7 mm, are obtained. (F) 2-(n)-Propyl-Isonicotinamide: The 30 grams of the ester just obtained are treated with 40 cc of concentrated ammonia saturated with gaseous ammonia. 20 grams of product, having a melting point of 135°C, are obtained. (G) 2-(n)-Propyl-Isonicotinic-Nitrile: The 20 grams of the amide just obtained are treated with 32 grams of phosphoric anhydride. 11 grams of nitrile, having a BP of 90°-95°C/4 mm, are obtained. (H) 2-(n)-Propyl-Isonicotinic Thioamide: The 11 grams of nitrile just obtained,

2898

Protizinic acid

dissolved in 40 cc of ethanol containing 4 grams of triethanolamine, are treated with hydrogen sulfide. 8 grams of the desired product, having a melting point of 142°C, are obtained. References Merck Index 7791 Kleeman & Engel p. 780 DOT 3 (1) 24 (1967) I.N. p. 821 Chimie et Atomistique, France; British Patent 800,250; August 20, 1958

PROTIZINIC ACID Therapeutic Function: Antiinflammatory Chemical Name: 7-Methoxy-α,10-dimethylphenothiazine-2-acetic acid Common Name: Structural Formula:

Chemical Abstracts Registry No.: 13799-03-6 Trade Name Pirocrid Pirocrid P.R.T.

Manufacturer Theraplix Mochida Mochida

Country France Japan Japan

Year Introduced 1974 1979 -

Raw Materials Sodium Hydrogen chloride thanol Methyl iodide Diethyl carbonate Sodium hydroxide Methyl (7-methoxy-10-methyl-3-phenthiazinyl)acetate Manufacturing Process Methyl ethyl (7-methoxy-10-methyl-3-phenthiazinyl)malonate is prepared by reacting a solution of sodium (4.37 grams) in anhydrous ethanol (110 cc) with a solution of methyl (7-methoxy-10-methyl-3-phenthiazinyl)acetate (59 grams) in ethyl carbonate (180 cc). The reaction mixture is heated at about

Protizinic acid

2899

105°-110°C for 3 hours and the ethanol formed is distilled off as it is formed. The reaction mixture is acidified with N hydrochloric acid (200 cc) and the oil formed is extracted with methylene chloride (200 cc). The methylene chloride solution is washed with water (210 cc), treated with decolorizing charcoal (5 grams), dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure (20 mm Hg) giving an oil (77 grams) which is crystallized from methanol (300 cc) to yield methyl ethyl (7-methoxy-10methyl-3-phenthiazinyl)-malonate (62.4 grams) melting at 80°-82°C. Methyl ethyl (7-methoxy-10-methyl-3-phenthiazinyl)malonate (62.2 grams) followed by methyl iodide (45.7 grams) is added to a solution of sodium (4.45 grams) in anhydrous ethanol (500 cc). The reaction mixture is heated under reflux for 1 hour at 45°C, then for 6 hours at 55°C, and finally concentrated to dryness under reduced pressure (20 mm Hg). The residue is taken up in methylene chloride (300 cc) and water (250 cc), filtered in the presence of a filtration adjuvant, washed with methylene chloride (150 cc) and water (150 cc), and decanted. The aqueous solution is extracted once again with methylene chloride (100 cc), and the combined organic solutions washed with water (100 cc), aqueous 0.1 N sodium hyposulfite solution (200 cc) and finally with water (200 cc). After drying over anhydrous sodium sulfate and evaporation to dryness under reduced pressure (20 mm Hg), there is obtained an oil (64.8 grams) which is dissolved in methylene chloride (100 cc) and chromatographed over alumina (650 grams). After elution with methylene chloride, a fraction of 2.5 liters is recovered and concentrated to dryness under reduced pressure (20 mm Hg) to give methyl ethyl methyl-(7-methoxy10-methyl-3-phenthiazinyl)malonate (59.7 grams) melting at 70°-72°C. 1 N sodium hydroxide solution (296 cc) is poured over a period of 3 hours into a solution of methyl ethyl methyl-(7-methoxy-10-methyl-3phenthiazinyl)malonate (59.7 grams) in ethanol (600 cc) heated under reflux in an atmosphere of nitrogen. The reaction mixture is concentrated to dryness under reduced pressure (20 mm Hg), the residue obtained acidified with N hydrochloric acid (300 cc) and the gum formed extracted with methylene chloride (150 cc). The organic solution is washed with water (200 cc), treated with decolorizing charcoal (10 grams), dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure (20 mm Hg). The oil obtained (48 grams) is dissolved in N sodium hydroxide solution (200 cc) and the aqueous solution washed with diethyl ether (300 cc), treated with decolorizing charcoal (5 grams) and acidified with N hydrochloric acid (200 cc). The oil formed is dissolved in methylene chloride (350 cc), the solution washed with water (100 cc), treated with decolorizing charcoal (5 grams) and dried over anhydrous sodium sulfate. The solution is concentrated to dryness under reduced pressure (20 mm Hg) to give an oil (35.6 grams) which crystallizes slowly. On recrystallization from diisopropyl ether (180 cc) a product (19.5 grams), melting at 123°-124°C, is obtained. Further recrystallization from diisopropyl ether (290 cc) yields 2-(7-methoxy-10methyl-3-phenthiazinyl)propionic acid (12.9 grams) melting at 124°-125°C. References Merck Index 7792 Kleeman & Engel p. 782 DOT 8 (12) 452 (1972)

2900

Protokylol

I.N. p. 36 Farge, D., Jeanmart, C. and Messer, M.N.; US Patent 3,450,698; June 17, 1969; assigned to Rhone-Poulenc SA, France

PROTOKYLOL Therapeutic Function: Bronchodilator Chemical Name: 4-[2-[[2-(1,3-Benzodioxol-5-yl)-1-methylethyl]amino]-1hydroxyethyl]-1,2-benzenediol Common Name: Structural Formula:

Chemical Abstracts Registry No.: 136-70-9; 136-69-6 (Hydrochloride salt) Trade Name Caytine Ventaire Asmetil Atma-Sanol Beres Biturix Palison

Manufacturer Lakeside Marion Benvegna Sanol Simes Nemi Farmasimes

Country US US Italy W. Germany Italy Argentina Spain

Year Introduced 1959 1974 -

Raw Materials Chloroacetylcatechol 3,4-Methylenedioxyphenylisopropanolamine Hydrogen Manufacturing Process 3,4-Methylenedioxyphenylisopropanolamine is reacted with chloroacetylcatechol in a 3:1 mol ratio in 60% ethanol at reflux temperature with continuous stirring. Stirring and refluxing were continued for another five hours after which the reaction mixture was cooled and then acidified with 20 cc of concentrated aqueous HCl. The acid solution was concentrated in vacuo to a viscous consistency and the residue dissolved in acetone. On standing, the aminoketone precipitated and was filtered. The precipitate was dissolved in isopropyl alcohol and permitted to recrystallize. An alcoholic solution of this

Protriptyline

2901

aminoketone precipitate was reduced with PtO2 and hydrogen, clarified by filtration, concentrated to dryness in vacuo and the residue crystallized from acetone giving the desired product. References Merck Index 7798 Kleeman and Engel p. 783 I.N. p.821 Biel, J.H.; US Patent 2,900,415; August 18, 1959; assigned to Lakeside Laboratories, Inc.

PROTRIPTYLINE Therapeutic Function: Psychostimulant Chemical Name: N-Methyl-5H-dibenzo[a,d]cycloheptene-5-propylamine Common Name: Amimetilina; 5-(3-Methylaminopropyl)-5Hdibenzo[a,d]cycloheptene Structural Formula:

Chemical Abstracts Registry No.: 438-60-8; 1225-55-4 (Hydrochloride salt) Trade Name Vivactil Maximed Concordin Concordine Triptil

Manufacturer MSD Sharp and Dohme MSD MSD Merck-Frosst

Country US W. Germany Italy France Canada

Year Introduced 1967 1968 1972 1973 -

Raw Materials Formamide Thionyl chloride Potassium amide

3-Methylaminopropanol-1 5H-Dibenzo[a,d]cycloheptene Potassium hydroxide

2902

Protriptyline

Manufacturing Process Preparation of 3-(N-Formyl-N-Methyl)-Aminopropanol-1: A mixture of 40 grams of 3-methylaminopropanol-1 and 20 grams of formamide is heated while stirring for 4 hours at 165°C. The crude product is fractionated in vacuo using a Widmer column yielding substantially pure 3-(N-formyl-N-methyl)aminopropanol-1. Preparation of 3-(N-Formyl-N-Methyl)-Aminopropyl Chloride: 50 grams of 3(N-formyl-N-methyl)-aminopropanol-1 obtained above is dissolved in a mixture of 100 ml of chloroform and 25 grams of pyridine. 40 grams of thionyl chloride is then slowly added while maintaining the temperature below 65°C. After 6 hours of refluxing, the mixture is washed with water, then with sodium bicarbonate solution and again with water and then dried over magnesium sulfate and the solvent distilled off in vacuo. Fractional distillation at 1 mm pressure yields substantially pure 3-(N-formyl-N-methyl)aminopropyl chloride. Preparation of 5-[3-(N-Formyl-N-Methyl)-Aminopropyl]-5HDibenzo[a,d]Cycloheptene: To a suspension of 3.9 grams of potassium amide is slowly added a solution of 19.2 grams (0.1 mol) of 5Hdibenzo[a,d]cycloheptene in 600 ml of ether with stirking. The suspension is refluxed with stirring for 3 hours, then cooled to room temperature and a solution of 0.1 mol of 3-(N-formyl-N-methyl)-aminopropyl chloride in 100 ml of ether added. The mixture is then refluxed with stirring for 5 hours and then 100 ml of water added. The ether layer is then washed with dilute hydrochloric acid, then water and then dried over magnesium sulfate and evaporated to dryness yielding 5-[3-(N-formyl-N-methyl)-aminopropyl]-5Hdibenzo[a,d]cycloheptene. Preparation of 5-(3-Methylaminopropyl)-5H-Dibenzo[a,d]Cycloheptene from 5[3-(N-Formyl-N-Methyl)-Aminopropyl]-5H-Dibenzo[a,d]Cycloheptene: 29.5 grams of 5-[3-(N-formyl-N-methyl)aminopropyl]-5H-dibenzo[a,d]cycloheptene is refluxed for 24 hours under nitrogen in a solution of 36.3 grams of potassium hydroxide in 378 ml of n-butanol. After cooling to room temperature, the solvent is evaporated in vacuo, the residue is stirred with 200 ml of water, 300 ml of n-hexane, the layers separated, the water layer extracted with 100 ml of n-hexane and the combined hexane layers washed with water (2 x 100 ml) and then with 0.5 N sulfuric acid (100, 80, 80 ml). The acid solution is then alkalized and extracted with ether (2 x 150 ml and 1 x 100 ml), dried over MgSO4 and the solution evaporated to dryness yielding substantially pure 5-(3-methylarninopropyl)-5H-dibenzo[a,d]cycloheptene according to US Patent 3,244,748. References Merck Index 7804 Kleeman & Engel p. 783 PDR p. 1220 OCDS Vol. 1 p. 152 (1977) I.N. p. 822 REM p. 1097 Tishler, M., Chemerda, J.M. and Kollonitsch, J.; US Patent 3,244,748; April 5, 1966; assigned to Merck & Co., Inc.

Proxazole citrate

2903

Tishler, M., Chemerda, J.M. and Kollonitsch, J.; US Patent 3,271,451; September 6, 1966; assigned to Merck & Co., Inc.

PROXAZOLE CITRATE Therapeutic Function: Spasmolytic Chemical Name: N,N-Diethyl-3-(1-phenylpropyl)-1,2,4-oxadiazole-5ethanamine citrate Common Name: Propaxoline citrate Structural Formula:

Chemical Abstracts Registry No.: 132-35-4; 5696-49-3 (Base) Trade Name Recidol Pirecin Mendozal Flou Solacil Toness

Manufacturer Lampugnani Yoshitomi Beaufour Elea Finadiet Angelini

Country Italy Japan France Argentina Argentina Italy

Year Introduced 1967 1970 1976 -

Raw Materials α-Ethylbenzamidoxime Citric acid

β-Chloropropionyl chloride Diethylamine

Manufacturing Process α-Ethylbenzamidoxime and anhydrous potassium carbonate are suspended in chloroform. To this mixture, under continuous stirring and controlling of the reaction temperature to remain beyond 15°C, there is slowly added βchloropropionyl chloride. After addition of the acid chloride, stirring is

2904

Proxibarbal

continued for a further hour. Then with cooling there is added portionwise a small amount of water. Further amounts of water are introduced into the reaction mixture and the chloroform solution containing the β-chloropropionyl α-ethylbenzamidoxime is separated. To this solution there is added in about 20 minutes a solution of diethylamine in CHCl3 while the temperature is kept below 35°C. The reacting mixture is heated to boiling, water formed during the reaction being distilled off thereby. After two hours the distillate contains no more water and the reaction is finished. Water is added to dissolve diethylamine hydrochloride formed during the reaction, and the chloroform layer containing the product is separated from the aqueous layer. The product may be purified by distillation; it boils at 132°C at 0.2 mm pressure. It is converted to the citrate by reaction with citric acid. References Merck Index 7805 Kleeman & Engel p. 784 OCDS Vol. 2 p. 271 (1980) I.N. p. 822 Palazzo, G. and Silvestrini, B.; US Patent 3,141,019; July 14, 1964; assigned to Angelini Francesco, Aziende Chimiche Riunite, Italy

PROXIBARBAL Therapeutic Function: Sedative Chemical Name: 5-(2-Hydroxypropyl)-5-(2-propenyl)-2,4,6(1H,3H,5H) pyrimidinetrione Common Name: Proxibarbital Structural Formula:

Chemical Abstracts Registry No.: 2537-29-3 Trade Name Axeen Centralgol Ipronal Vasalgin

Manufacturer Hommel Valpan Polfa Chinoin

Country W. Germany France Poland Hungary

Year Introduced 1962 1965 -

Proxymetacaine

2905

Raw Materials Diallylbarbituric acid Sulfuric acid Water Manufacturing Process 9 Parts of diallyl-barbituric acid are added to a precooled mixture of 15.5 parts of concentrated sulfuric acid and 0.5 part of water while stirring intensively, the mixture being cooled so that its temperature does not exceed 25°C. The honey-colored viscous solution is stirred vigorously and all at once into 45 parts of water, whereupon the mixture warms up to 35°C to 40°C and, after several seconds, solidifies into a thick pulp, which is then heated as quickly as possible to 95°C, at which temperature a clear solution is formed. This is cooled slowly until the 5-allyl-5-(β-hydroxypropyl)-barbituric acid begins to form coarse-grained crystals, after which the mass is cooled rapidly to 20%. The crystallized 5-allyl-5-(β-hydroxypropyl)-barbituric acid is centrifuged off, 55 to 58 parts of mother liquor and 10 to 13 parts of crude product being obtained. The latter is dispersed in 20 parts of saturated aqueous sodium chloride solution and after two hours is again centrifuged off. The thus-washed crude product is dissolved in a mixture of 12 parts of ethanol and 20 parts of benzene, with mild warming if necessary. 1 Part of sodium chloride and 1.5 parts of saturated aqueous sodium chloride solution are added to the obtained solution in ethanol-benzene, and whole thoroughly admixed. When the brine layer has settled, it is separated and the aforedescribed washing repeated. The clear solution is concentrated under reduced pressure until incipient formation of crystals and is then poured into 30 parts of benzene, whereupon a thick crystalline pulp is forthwith formed which, after being cooled to room temperature, is centrifuged off. The so-obtained 5-allyl5-(β-hydroxypropyl)-barbituric acid is dried at 70°C under reduced pressure and can be used for therapeutic purposes without further purification. Melting point 164°C to 165°C. Yield: 5 parts. References Merck Index 7806 I.N. p. 822 Hommel A.G.; British Patent 953,387; March 25, 1964

PROXYMETACAINE Therapeutic Function: Local anesthetic Chemical Name: 3-Amino-4-propoxybenzoic acid 2-(diethylamino)ethyl ester Common Name: Proparacaine; Proxymetacaine

2906

Proxyphylline

Structural Formula:

Chemical Abstracts Registry No.: 499-67-2 Trade Name Diocaine

Manufacturer Dioptic

Country -

Year Introduced -

Raw Materials 4-Propoxynitrobenzoyl chloride Diethylaminoethanol Granulated tin Manufacturing Process Equal molecular proportions of 4-propoxynitrobenzoyl chloride and diethylaminoethanol are mixed. They react forming hydrochloride of (diethylamino)ethyl 4-propoxy-3-nitrobenzoate as a pale yelllow leaflets; MP: 124.8-126.8°C. The reaction is completed when there is no further tendency to warm itself spontaneously. Ten parts by weight of the latter substance are dissolved in a mixture of twenty-five parts by weight of hydrochloric acid and twenty parts by weight of alcohol, and the solution treated with twelve parts by weight of granulated tin, keeping the temperature at about 35°C. A colorless solution is obtained from which the tin is removed by precipitation with hydrogen sulfide. On addition of sodium carbonate solution, 3-Amino-4propoxybenzoic acid 2-(diethylamino)ethyl ester separates as an oil. When treated with one equivalent of hydrochloric acid it forms a hydrochloride, which is readily soluble in water and crystallizes from a mixture of absolute alcohol and ethyl acetate in white prisms MP: 182.0-183.3°C. References Wildman E.A.; US Patent No. 1,317,250; September 30, 1919; Assigned to Parke Davis and Company, of Detroit,Michigan, a corporation Climton R.O. et al.; J.A.C.S. v.74 p. 592-598, 1952

PROXYPHYLLINE Therapeutic Function: Diuretic, Cardiac stimulant, Smooth muscle relaxant, Vasodilator

Proxyphylline

2907

Chemical Name: 1H-Purine-2,6-dione, 3,7-dihydro-7-(2-hydroxypropyl)-1,3dimethyl Common Name: Hydroxypropyltheophylline; Proxifillina; Proxiphyllinum; Proxyphylline Structural Formula:

Chemical Abstracts Registry No.: 603-00-9 Trade Name Monophyllin Monophyllin Neofyllin Neofyllin Purophyllin Spasmolysin Theon

Manufacturer AFI Yoshitomi Abigo Pharmacia Siegfried Kade Draco

Country -

Year Introduced -

Raw Materials Theophylline 1-Chloro-2-propanol Sodium hydroxide Manufacturing Process A mixture of 270 g (1.5 moles) of anhydrous theophylline and 213 g (2.25 moles) of 1-chloro-2-propanol in 750 ml of water is heated to boiling in an apparatus equipped with a mechanical agitator, reflux condenser, thermometer, and dropping funnel. A 25 per cent solution of sodium hydroxide in water, containing 90 g (2.25 moles) of sodium hydroxide, is added to the refluxing mixture over a period of 2 hours. Refluxing is continued for 1 hour after all the sodium hydroxide has been added. The water is removed as completely as possible by distillation under reduced pressure, using a boiling water bath as the source of heat. The residue, consisting of a sticky, resinous mass or white solid, is treated with 700 ml of anhydrous ethyl alcohol and heated until the remaining insoluble solid is loose and granular. The solid is separated by filtering of the hot mixture. When the filtrate cools, a white, crystalline mass separates which is filtered off and washed with cold anhydrous ethyl alcohol. The material is purified by crystallization from anhydrous ethyl alcohol. The purified product is 7-β-hydroxypropyl theophylline, M. P. 135-136°C. The pH of a 5% per cent solution in distilled

2908

Prozapine

water falls within the range of 5.5 to 7.0. 1 g dissolves in approximately 1 ml of water at 20°C and in about 14 ml of anhydrous ethyl alcohol. It is considerably more soluble in boiling anhydrous ethyl alcohol. References Rice R. V.; US Patent No. 2,715,125; Aug. 9, 1955; Assigned to N. J., assignor to Gane's Chemical Works, Inc., Carlstadt, N. J., a corporation of New York

PROZAPINE Therapeutic Function: Choleretic, Spasmolytic Chemical Name: 1-(3,3-Diphenylpropyl)cyclohexamethyleneimine Common Name: Prozapine; Hexadiphane Structural Formula:

Chemical Abstracts Registry No.: 3426-08-2 Trade Name Prozapine

Manufacturer ZYF Pharm Chemical

Country -

Year Introduced -

Raw Materials Hydrochloric acid Phenyl magnesium bromide Sodium amide Hydrogen Thionyl chloride

α,α-Diphenyl-7-hexamethyleneimino butyronitrile Sodium hydroxide Hexamethyleneiminoethyl phenyl ketone Palladium on charcoal

Manufacturing Process The 1st method of preparation of the 1,1-diphenyl-3-hexamethyleneimino propane:

Pseudoephedrine sulfate

2909

A vigorously stirred suspension of 0.2 to 1 mole of sodium amide in 200 ml of xylene, in which were dissolved 0.1 mole of α,α-diphenyl-7hexamethyleneimino butyronitrile was boiled for 12 hours. Thereupon the excess of sodium amide was decomposed with water and the xylene layer was separated, washed with water and extracted with hydrochloric acid. This acidic extract was made strongly alkaline with concentrated lye and the separated base was extracted with ether. After drying, the ether was evaporated and the 1,1-diphenyl-3-hexamethyleneimino propane distilled in vacuo. The boiling point was 170-174°C/1 mm, the refractive index nD20 = 1.5636, and the density d420 = 1.009. From the oil obtained several acid additions and quaternary ammonium salts can be obtained by reaction with acids containing a non-toxic anion or esters thereof. The hydrochloric acid salt, for instance, melts at 189-192°C, the methiodide at 174-177°C under decomposition. Another method of preparation of the 1,1-diphenyl-3-hexamethyleneimino propane: To a solution of 0.4 mole of phenyl magnesium bromide in ether were added 42.3 g (0.183 mole) of hexamethyleneiminoethyl phenyl ketone, dissolved in dry ether, followed by 250 ml of dry benzene. The temperature of the mixture was slowly raised until all the ether had been driven off, after which the solution was heated to boiling under reflux of the benzene for 6 hours. The reaction mixture was then cooled and a solution of ammonium chloride was added. The benzene layer was washed with water and dried on potassium carbonate, filtered from the potassium carbonate, and the solvent was then evaporated. Recrystallization of the residue from petroleum ether (B.P. 6080°C) yielded 44 g of 1,1-diphenyl-3-hexamethyleneimino propanol-1 with a melting point of 81°C. To 31 g of 1,1-diphenyl-3-hexamethyleneimino propanol-1, dissolved in chloroform, an excess of thionyl chloride was added and the mixture was heated under reflux for 3 hours. Thereupon the reaction mixture was evaporated to dryness under reduced pressure and the residue was recrystallized by dissolving in warm ethanol and diluting this solution with ethyl acetate. An aqueous solution of the 1,1-diphenyl-1-chloro-3hexamethyleneimino propane hydrochloride thus obtained was hydrogenated with hydrogen gas in the presence of a buffered palladium-charcoal catalyst at a pressure of 3 atm. The 1,1-diphenyl-3-hexamethyleneimino propane obtained was purified by distillation under reduced pressure. The boiling point was 170-174°C/1 mm. References Paul A. J. Janssen, David K. De Jongh; US Patent No. 2,881165; Apr. 7, 1959; Assigned to N. V. Nederlandsche Cornbinatie voor Chemische Industrie, Amsterdam, Netherlands, a limited liability company of the Netherlands

PSEUDOEPHEDRINE SULFATE Therapeutic Function: Bronchodilator

2910

Pseudoephedrine sulfate

Chemical Name: Benzenemethanol, α-((1S)-1-(methylamino)ethyl)-, (αS)-, sulfate (2:1) (salt) Common Name: Pseudoephedrine sulfate Structural Formula:

Chemical Abstracts Registry No.: 7460-12-0; 90-82-4 (Base) Trade Name Afrinol Demazin sinus Drixora Lertamine-D Pseudoephedrine sulfate Pseudoephedrine sulfate

Manufacturer Schering Schering-Plough Magpharm Pharmaceuticals White Pharma BASF AG

Country S. Africa

Year Introduced -

Germany

-

Knoll AG

Germany

-

Raw Materials Hydrobromic acid Bromine Methylamine

Propionaldehyde Phenyl magnesium bromide

Manufacturing Process Propionaldehyde was brominated by bromine and the propanoilbromide was obtained. Then propanoilbromide reacted with methanol and hydrobromic acid yielding 1,2-dibromo-1-methoxypropane. 1,2-Dibromo-1-methoxypropane in turn with phenylmagnesium-bromide gave the product, which after hydrolysis yielded 1-phenyl-1-methoxy-2bromopropane. To the solution of 1-phenyl-1-methoxy-2-bromopropane methylamine was added and as a result of the reaction 1-phenyl-1-methoxy-2methylaminopropane was obtained. After that 1-phenyl-1-methoxy-2methylaminopropane on hydrolysis with hydrobromic acid yielded 1-phenyl-1hydroxy-2-methylaminopropane, i.e. racemic pseudoephedrine. The racemic base was resolved, by crystallization of their tartrates, into l- and dpseudoephedrine. The base l-pseudoephedrine forms white rhombic crystals, melting point 118°C. The salt pseudoephedrine sulfate may be prepeared by

Pseudonorephedrine

2911

treatment of pseudoephedrine base with sulfuric acid. References Manske and Holmes, The Alkaloids, Vol III, pp.343-344, 351-361, Academic Press (1953)

PSEUDONOREPHEDRINE Therapeutic Function: Sympathomimetic, Anorexic Chemical Name: Benzenemethanol, α-((1S)-1-aminoethyl)-, (αS)Common Name: Cathine, Katine; ψ-Norephedrine; Norisoephedrine; Norpseudoephedrine; Pseudonorephedrine Structural Formula:

Chemical Abstracts Registry No.: 492-39-7 Trade Name Beloform Cathine Norpseudoephedrine

Manufacturer Neue Formulierung BlueRunners Trading Dev. Co. Shanghai Lansheng Corporation

Country -

Year Introduced -

-

-

Raw Materials Thionyl chloride Norephedrine hydrochloride, (+)Manufacturing Process 60 ml thionylchloride was added to 20 g (+)-norephedrine hydrochloride by cooling. Then the mixture was gradually heated to +35°C. Finally it was heated 20 minutes at 45°C. After that the excess thionylchloride was removed in vacuum, the residue was stirred with 100 ml acetone and 2-amino-1chloro-1-phenylpropane hydrochloride was filtered off. It was dissolved in 100 ml 2 N hydrochloric acid, heated to reflux for 3 hours, and distilled to dryness in vacuum. The crystalline residue was mixed with acetone, filtered off and dried. Yield was 17.5 g crude product, which was cleaned by fractional

2912

Pyrantel pamoate

crystallization to give 13 g (65%) (+)-norpseudoephedrine hydrochloride 166°-168°C. The may be converted to the base by adding of equivalent of any base. References Pfanz H., Wieduwilt H.; D.D. Patent No. 13,785; Feb. 8, 1956

PYRANTEL PAMOATE Therapeutic Function: Anthelmintic Chemical Name: E-1,4,5,6-Tetrahydro-1-methyl-2-[2-(2-thienyl)vinyl] pyrimidine pamoate Common Name: Structural Formula:

Chemical Abstracts Registry No.: 22204-24-6; 15686-83-6 (Base) Trade Name Antiminth Helmex Cobantrin Combantrin Combantrin Lombriareu Piranver

Manufacturer Roerig Roerig Pfizer Taito Pfizer Pfizer Areu ICN-Usafarma

Country US W. Germany Japan France Italy Spain Brazil

Year Introduced 1972 1972 1973 1973 1975 -

Raw Materials Tartaric acid Pamoic acid

Thiophene-2-carboxaldehyde 1,2-Dimethyl-1,4,5,6-tetrahydropyrimidine

Pyrathiazine

2913

Manufacturing Process A solution of 0.1 mol of each of thiophene-2-carboxaldehyde and 1,2dimethyl-1,4,5,6-tetrahydropyrimidine in dimethyl carbonate (0.2 mol) is held at 27°C for 48 hours. The reaction mixture is then stripped to give a 65% yield of product as the free base. The base may be isolated as the tartrate as follows: A portion of reaction mixture is added to a well stirred solution of tartaric acid in ethanol at 27°C. The mixture is stirred for two hours and the product recovered by filtration. The filter cake is washed with cold ethanol followed by ether and air-dried. MP 144°-147°C. The tartrate salt is recrystallized by dissolving in hot methanol, filtering, adding hot ethanol to the filtrate and cooling. The product is collected and airdried. MP 148°-150°C. A second crop is obtained from the filtrate for a total yield of 59%. The tartrate is then metathesized with pamoic acid (Merck Index #6867) to give pyrantel pamoate as the product. References Merck Index 7856 Kleeman & Engel p. 786 PDR p. 1403 OCDS Vol. 1 p. 266 (1977) and 2, 303 (1980) DOT 8 (11) 431 (1972); 17 (1) 41 (1981); and (6) 262 (1981) I.N. p. 825 REM D. 1237 Kasubick, R.V. and McFarland, J.W.; US Patent 3,502,661; March 24,1970; assigned to Chas. Pfizer & Co., Inc.

PYRATHIAZINE Therapeutic Function: Antihistaminic Chemical Name: 10-[2-[1-(Pyrrolidinyl)ethyl]phenothiazine Common Name: Parathiazine Structural Formula:

2914

Pyrazinamide

Chemical Abstracts Registry No.: 84-08-2 Trade Name

Manufacturer

Country

Year Introduced

Pyrrolazote

Upjohn

US

1949

Raw Materials Phenothiazine Sodium amide β-Pyrrolidinoethyl chloride Manufacturing Process To a stirred suspension of 4.29 g (0.11 mol) of sodium amide in 100 ml of dry toluene was added 19.9 g (0.1 mol) of phenothiazine. The solution was heated at reflux for two hours, the sodium salt of phenothiazine precipitating from solution. The toluene suspension of the sodium salt of phenothiazine was cooled to room temperature, whereupon there was added dropwise with continued stirring 13.36 g (0.1 mol) of β-pyrrolidinoethyl chloride in 50 ml of dry toluene. After addition was complete, the solution was heated under reflux, with stirring, for an additional 15 hours. Upon cooling, the toluene was extracted with dilute hydrochloric acid and the toluene then discarded. The aqueous acid solution was made alkaline with dilute sodium hydroxide, the crude N-(β-pyrrolidinoethyl)-phenothiazine separating as a brownish oil. The oil was extracted with ether, the ether solution dried with anhydrous magnesium sulfate, and then filtered. Dry hydrogen chloride was passed into the ether solution and a semisolid mass, which crystallized after scratching, separated therefrom. The crude N-(β-pyrrolidinoethyl)-phenothiazine was separated from the ether and, after two crystallizations from isopropanol, 17.0 g of desired product, melting at 196°C to 197°C (uncorr.), was obtained. References Merck Index 7857 OCDS Vol. 1 p. 373 (1977) I.N. p. 731 Hunter, J.H. and Reid, W.B. Jr.; US Patent 2,483,999; October 4, 1949; assigned to The Upjohn Co.

PYRAZINAMIDE Therapeutic Function: Antibacterial (tuberculostatic) Chemical Name: Pyrazinecarboxamide Common Name: Chemical Abstracts Registry No.: 98-96-4

Pyrazinamide

2915

Structural Formula:

Trade Name Aldinamide Pirilene Eprazin Isopyratsin Pezatamid Piraldina Pirazimida Pyrafat Pyrazide P.Z.A. Tebrazid Tisamid Zinamide

Manufacturer MSD Lepetit Krugmann Leiras Hefa-Frenon Bracco Madaus Cerafarm Saarstickstoff-Fatol SCS Pharmalab Servipharm Continental Pharma Orion MSD

Country US France W. Germany Finland W. Germany Italy Spain W. Germany S. Africa Switz. Belgium Finland UK

Year Introduced 1955 1981 -

Raw Materials Pyrazine-2,3-dicarboxamide Sodium hydroxide Manufacturing Process 166 Parts of pyrazine-2,3-dicarboxamide (1 mol) is slurried in 1,000 parts of 1 N aqueous sodium hydroxide. The reaction mixture is heated at 95°C to 98°C until a clear solution results. Thereupon the mixture is cooled with ice to about 5°C and acidified to approximately a pH of 1. The cold reaction mixture is allowed to stand until precipitation of the pyrazine-2-carboxamide-3carboxylic acid is substantially complete whereupon it is recovered by filtration and dried at 50°C to 60°C. 100 Parts of pyrazine-2-carboxamide-3-arboxylic acid is heated in a reaction vessel provided with an intake for inert gas. The reaction mixture is heated in a bath held at 220°C and nitrogen is introduced. The solid material melts and effervesces and sublimed pyrazinamide vapors are carried out of the reaction vessel in the nitrogen stream. They are introduced into a suitably cooled condenser, condensing in the form of a white sublimate. After the reaction is proceeding vigorously the bath temperature is raised to 255°C and then gradually and slowly allowed to drop to 190°C over a period of time sufficient to permit the reaction to go substantially to completion. The sublimed pyrazinamide, if desired, is further purified by recrystallization from water or alcohol.

2916

Pyridinol carbamate

References Merck Index 7858 Kleeman & Engel p. 787 OCDS Vol. 1 p. 277 (1977) I.N. p. 826 REM p. 1216 Webb, J.S. and Ark, H.G. Jr.; US Patent 2,780,624; February 5, 1957; assigned to American Cyanamid Co.

PYRIDINOL CARBAMATE Therapeutic Function: Antiarteriosclerotic Chemical Name: Bis[methylcarbamic acid]-2,6-pyridinediyldimethylene diester Common Name: Pyricarbate Structural Formula:

Chemical Abstracts Registry No.: 1882-26-4 Trade Name Movecil Angioxine Anginin Angiovital Angioxil Angiperl Arteriolangal Aterin Aterofal Atero-Flavin Aterollano Ateronova Atover Carbatona Cicloven Colesterinex Dual-Xol

Manufacturer Erba Roussel Banyu I.S.M. Firma Sawai Lanzas Ilsan Nativelle Indelfar Llano Cheminova Oti Turro A.G.I.P.S. Galenika Lifepharma

Country Italy France Japan Italy Italy Japan Spain Turkey Italy Spain Spain Spain Italy Spain Italy Switz. Spain

Year Introduced 1969 1971 -

Pyridinol carbamate Trade Name Duaxol Duvaline Gasparol Meduxal Plavolex Prodectin Ravenil Sospitan Vasagin Vasapril Vasmol Vasocil Vasoverin Veranterol

Manufacturer Argentia Almirall Castejon Allard Wolner Kobanyai Caber Kali-Chemie Sidus Cifa Lifasa Magis Biochimica Asla

Country Argentina Spain Spain France Spain Hungary Italy W. Germany Italy Italy Spain Italy Switz. Spain

2917

Year Introduced -

Raw Materials Methyl isocyanate 2,6-Dihydroxymethylpyridine hydrochloride Manufacturing Process (A) 15.7 g (0.1 mol) of 2,6-dihydroxymethylpyridine hydrochloride are suspended in 176 ml of acetonitrile, and 20.8 ml (0.15 mol) of triethylamine are added to the suspension. Thereafter 13 ml (0.22 mol) of methyl isocyanate are added dropwise to the reaction mixture at 20°C to 25°C. The reaction mixture is stirred at 20°C to 30°C for one hour, thereafter boiled for 3 hours, and finally the solvent is evaporated under reduced pressure. 35 to 40 g of a greyish, crystalline residue are obtained, which is a mixture of 2,6dihydroxymethylpyridine-bis-(N-methylcarbamate) and triethylamine hydrochloride. The obtained residue is dissolved in 80 ml of hot water, decolorized with 2 g of activated carbon when hot, and filtered after 30 minutes of stirring. The filtrate is cooled, the resulting crystal suspension is stirred at 0°C to 5°C for 3 hours, the solids are filtered off, and dried at 50°C to 60°C. 23.3 g (94.4%) of 2,6-dihydroxymethylpyridine-bis(N-methylcarbamate) are obtained. The product melts at 134°C to 135°C; its purity is 99.8% (determined by UV spectrophotometry). When examined by thin layer chromatography, the product is uniform. (B) 23.3 g of 2,6-dihydroxymethylpyridine-bis(N-methylcarbamate), prepared as described above, are dissolved in a boiling mixture of 46.6 ml of methanol and 46.6 ml of water. When the dissolution is complete, the solution is allowed to cool under slow stirring, without applying any external cooling means. The crystals start to separate at 48°C to 50°C. When the temperature of the mixture falls spontaneously below 35°C, it is cooled externally to 0°C to 5°C, and allowed to stand at this temperature for about 8 hours. The separated substance is filtered off and dried at 50°C to 100°C. 22.65 g of 2,6dihydroxymethylpyridine-bis(N-methylcarbamate) are obtained. The quality of the product meets pharmaceutical requirements.

2918

Pyridofylline

The yield of this crystallization procedure is 95.7%. The above process provides the γ2 modification of 2,6-dihydroxymethylpyridine-bis(Nmethylcarbamate), which can be tabletted directly. The substance melts at 134°C to 136°C, its purity is 99.9% (determined by UV spectrophotometry). References Merck Index 7874 Kleeman & Engel p. 787 DOT 5 (1) 16 (1969) I.N. p. 826 Sprung, M., Toth, J., Kovatsits, M., Sztrokay, K., Szen, T., Gorgenyi, K., Boor, A., Forgacs, L.,Szabo, J. and Kruzics, A.; British Patent 1,548,334; July 11, 1979; assigned to Richter Gedeon Vegyeszeti Gyar R.T. (Hungary)

PYRIDOFYLLINE Therapeutic Function: Coronary vasodilator Chemical Name: 1H-Purine-2,6-dione, 3,7-dihydro-1,3-dimethyl-7-(2(sulfooxy)ethyl)-, compd. with 5-hydroxy-6-methyl-3,4pyridinedimethanol (1:1) Common Name: Pyridofylline; Theodoxine Structural Formula:

Chemical Abstracts Registry No.: 53403-97-7 Trade Name

Manufacturer

Country

Year Introduced

Pyridofylline

Debarge

-

-

Pyridostigmine bromide

2919

Raw Materials Theophylline Chlorosulfonic acid Pyridoxine

Potassium hydroxide Monochlorhydrin ethylene glycol

Manufacturing Process A solution of 100 g of theophylline in 500 ml 1 M solution of KOH was prepared potassium theophylline. To that potassium theophylline was added 120 ml monochlorhydrin ethylene glycol, a mixture was heated at 130°C for 4 hours. The product was dissolved in ethanol and filtered. After crystallization was obtained 7-(2-hydroxyethyl)theophylline. 100 g of 7-(2-hydroxyethyl)-theophylline was refluxed in 2.1 L of dry chloroform, then was added dropwise 47 g of HSO3Cl and mixture was refluxed for 2 hours. After filtration the solid product [O-(7-theophyllinylethyl) sulfuric acid] was washed with chloroform and ether and dried in vacuum for 4 hours at 80°C. Pyridofylline was obtained by mixing 110 g o-(7-theophyllinylethyl) sulfuric acid and 72 g pyridoxine in ethanol. References Albert M., Debarge E.J.J.; Brevet Special de Medicament; FR 828M, Dec. 23, 1960

PYRIDOSTIGMINE BROMIDE Therapeutic Function: Cholinergic Chemical Name: 3-[[(Dimethylamino)carbonyl]oxy]-1-methylpyridinium bromide Common Name: Structural Formula:

Chemical Abstracts Registry No.: 101-26-8

2920

Pyridoxine hydrochloride

Trade Name Mestinon Mestinon Regonol Mestinon Kalymin

Manufacturer Roche Roche Organon Roche Arzneimittelwerk Dresden

Country US Japan US France E. Germany

Year Introduced 1955 1970 1973 1981 -

Raw Materials 3-Hydroxypyridine Dimethyl carbamic acid chloride Methyl bromide Manufacturing Process 12 parts by weight of dimethyl-carbamic acid chloride, dissolved in 20 parts by weight of xylol, are added dropwise to a boiling solution of 19 parts by weight of 3-hydroxypyridine in 120 parts by weight of xylol. Heating is continued under reflux for 3 hours. When the solution has cooled down, it is separated from the precipitated 3-hydroxypyridine hydro chloride and washed with water. After drying over sodium sulfate, the xylol is distilled off and the residue fractionated under reduced pressure. The N,N-dimethyl-carbamic acid ester of 3-hydroxypyridine distills at 148°C under a pressure of 15 mm. A solution of 20 parts by weight of methyl bromide in 30 parts by weight of acetone is added to a solution of 35 parts by weight of N,N-dimethyl-carbamic acid ester of 3-hydroxypyridine in 70 parts by weight of acetone. After standing for a lengthy period (1 or 2 days), the N,N-dimethyl-carbamic acid ester of 3-hydroxy-1-methyl-pyridinium-bromide separates. It can be recrystallized from absolute alcohol. The colorless, strongly hygroscopic crystals melt at 151°-152°C. References Merck Index 7877 Kleeman and Engel p. 789 PDR pp. 1289, 1491 I.N. p. 826 REM p. 900 Urban, R.; US Patent 2,572,579; October 23,1951; assigned to Hoffmann-La Roche Inc.

PYRIDOXINE HYDROCHLORIDE Therapeutic Function: Enzyme cofactor vitamin Chemical Name: 3,4-Pyridinedimethanol, 5-hydroxy-6-methyl-, hydrochloride

Pyridoxine hydrochloride

2921

Common Name: Adermine hydrochloride; Piridossina hydrochloride; Piridoxina hydrochloride; Pyridoxine hydrochloride; Pyridoxinium chloride; Pyridoxol hydrochloride; Vitamin B6 hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 58-56-0; 65-23-6 (Base) Trade Name

Manufacturer

Country

Year Introduced

Pyridoxine hydrochloride Pyridoxine hydrochloride

Roche

-

-

Takeda Chemical Industry

Japan

-

Raw Materials Formamide Maleic anhydride Sodium bicarbonate

Ethyl α-alaninate hydrochloride Hydrogen chloride Lithium aluminum hydride

Manufacturing Process To 35 g of ethyl α-alaninate hydrochloride is added 10 g of formamide and the resulting mixture is heated slowly to 105°C over a period of 30 to 45 min. After heating at 105°C for 10 min, about 75 ml of toluene is added. After standing for about 1 h, the mixture is then refluxed for about 6 h. After cooling the ammonium chloride formed is removed and the resulting solution is evaporated to remove the solvent. The ethyl N-formyl-α-alaninate is obtained by distillation at 100°C. To a moxture of 25 ml of alcohol free chloroform and 11.36 g of P2O5 is added over 20 min a solution of 5.81 g of ethyl N-formyl-α-alaninate in 15 ml of alcohol free chloroform at about 30°C the resulting reaction mixture is refluxed for 1 h, cooled and the solvent decanted. The hard mass remaining is broken up and a solution of 27 g of potassium hydroxide in 27 ml of water and 34 ml of methanol is gradually added keeping the temperature at 1020°C. The resulting solution is refluxed for 1 h, cooled and extracted with 10 x 15 ml of methylene chloride. The 4-methyl-5-ethoxy oxazole is recovered, after removing the solvent, by distilling at 75-80°C at 10 mm pressure. Upon mixing 1.27 g of 4-methyl-5-ethoxy oxazole (0.01 mole), 0.98 g of maleic anhydride (0.01 mole) and 2.5 ml of dry benzene, a yellow color appears and heat is evolved, requiring cooling. After 3-4 min the evolution of heat ceases and the color fades. The mixture is then refluxed for about 18 h, after which the solvent is decanted and the residue treated with a small

2922

Pyrilamine

quantity of water. To the residue is added 40 ml of ethanol and the solution is then saturated with gaseous HCl. The acidic solution is refluxed for 3.5 h. After cooling the solvent is evaporated and crystalline residue containing diethyl 2-methyl-3-hydroxy-pyridine-4,5-dicarboxylate hydrochloride is converted to the free base by reaction with aqueous sodium bicarbonate. The resulting solution is extracted with ether and the ether extacts dried. The ether solution containing diethyl 2-methyl-3-hydroxy-pyridine-4,5dicarboxylate is treated with 0.5 g of lithium aluminum hydride. The resulting mixture is stirred for 2 h and allowed to stand overnight. The ether layer is removed and the aqueous layer is saturated with carbon dioxide. The resulting residue is extracted three times with hot ethanol and gaseous HCl is passed into the ethanol extracts. After allowing the acidified ethanol solution to stand for 2-3 h, crystals of pyridoxine hydrochloride are deposited and recovered by filtration. Melting point 203.5°-205°C, dec. References Chase G.O.; US Patent No. 3,222,374; Dec. 7, 1965; Assigned: Hoffmann-La Roche Inc., Nutley, N. J. Coffen D.L.; US Patent No. 4,026,901; May 31, 1977; Assigned: Hoffmann-La Roche Inc., Nutley, N. J.

PYRILAMINE Therapeutic Function: Antihistaminic Chemical Name: N-[(4-Methoxyphenyl)methyl]-N',N'-dimethyl-N-2-pyridinyl1,2-ethanediamine (often used as the maleate) Common Name: Mepyramine; Pyranisamine Structural Formula:

Chemical Abstracts Registry No.: 91-84-9; 6036-95-9 (Hydrochloride salt); 59-33-6 (Maleate salt) Trade Name Neo-Antergan Thylogen Statomin

Manufacturer MSD Rorer Bowman

Country US US US

Year Introduced 1948 1949 1950

Pyrilamine Trade Name Pyra-Maleate Copsmine Stamine Albatussin Allergan Amfeta Anthisan Citra Forte Codimal Copsamine Fiogesic Histalet Histavet-P Kontristin Kriptin Kronohist Midol PMS Poly-Histine Primatene PV-Tussin Pyra Pyramal Statomin Triaminic

Manufacturer Mallinckrodt Inc. Durst Tutag Bart Wiedenmann Bama-Geve May and Baker Boyce Central Durst Sandoz Reid-Rowell Burns-Biotec Eczacibasi Whitehall Ferndale Glenbrook Bock Whitehall Reid-Rowell Mallinckrodt Inc. Columbus Bowman Dorsey

Country US US US US Switz. Spain UK US US US US US US Turkey US US US US US US US US US US

2923

Year Introduced 1950 1950 1951 -

Raw Materials 4-Methoxybenzaldehyde 2-Aminopyridine

1-Dimethylamino-2-chloroethane Sodium amide

Manufacturing Process 43 g of α-p-methoxybenzylaminopyridine (from 4-methoxybenzaldehyde reaction with 2-aminopyridine) are heated in 60 cc of toluene to 95°C to 100°C. 18 g of sodamide (85%) and 110 cc of a 40% toluene solution of 1dimethylamino-2-chloroethane are added in small amounts alternately with shaking; the addition takes 1 hour. Toluene is distilled off, first at normal pressure, then under reduced pressure, until there remains a pasty mass. The mass is taken up with dilute hydrochloric acid and ether, neutralized to pH 7, and p-methoxybenzylaminopyridine separates. After making alkaline using excess of potash, it is extracted with benzene, dried and distilled. The product thereby obtained, N',N'-dimethylaminoethyl-N-p-methoxybenzyl-αaminopyridine boils at 185°C to 190°C/2 mm. The monohydrochloride melts at 135°C (block Maquenne). References Merck Index 7883 Kleeman and Engel p. 561

2924

Pyrimethamine

PDR pp. 654, 674, 692, 784, 850, 875, 925, 1447, 1583, 1900 OCDS Vol. 1 p.51 (1977) I.N. p. 597 REM p. 1129 Horclois, R.J.; US Patent 2,502,151; March 28, 1950; assigned to Societe des Usines Chimiques Rhone-Poulenc

PYRIMETHAMINE Therapeutic Function: Antimalarial Chemical Name: 5-(4-Chlorophenyl)-6-ethyl-2,4-pyrimidinediamine Common Name: Structural Formula:

Chemical Abstracts Registry No.: 58-14-0 Trade Name Daraprim Daraprim Erbaprelina Fansidar Malocide Pirimecidan Pyrimethamin-Heyl Tindurin

Manufacturer Burroughs-Wellcome Burroughs-Wellcome Erba Roche Specia Cidan Heyl EGYT

Country US W. Germany Italy France France Spain W. Germany Hungary

Year Introduced 1953 1969 -

Raw Materials p-Chlorophenylacetonitrile Guanidine Diazomethane

Sodium ethoxide Ethyl propionate

Manufacturing Process p-Chlorophenylacetonitrile (36.5 grams) and ethyl propionate (25.5 grams) were added to a solution of sodium ethoxide (from 5.75 grams sodium) in absolute ethanol (150ml). The solution was heated on a steam bath for 6 hours. After cooling, the whole was poured into water and the oil extracted

Pyrisuccideanol dimaleate

2925

well with ether, the ether solution was discarded and the aqueous solution neutralized with 1 N sulfuric acid. A heavy oil separated which was taken into ether, washed with water, bicarbonate solution and again with water. After drying, the ether was removed to give a thick oil which solidified on standing (34.6 grams). After recrystallization from an ether-petroleum ether mixture it formed needles, MP 108°-112°C. The above keto-nitrile (15 grams) was methylated with a solution of diazomethane in ether. (The diazomethane solution was prepared using 20 grams of N-nitrosomethylurea.) The ether and excess diazomethane were evaporated on the steam bath and the oil dissolved in ethanol (50 ml). To this was added a solution of guanidine in ethanol (100 ml) (prepared from 8.1 grams of the hydrochloride). The solution was refluxed for 5 hours, the alcohol removed and the residue treated with 5 N sodium hydroxide. The insoluble material was then filtered. After purification by precipitation from dilute acetic acid with sodium hydroxide and by recrystallization from ethanol the product formed clear colorless needles (8.0 grams), MP 218°-220°C as described in US Patent 2,602,794. References Merck Index 7884 Kleeman & Engel p. 791 PDR pp. 741, 1484 OCDS Vol. 1 p. 262 (1977) DOT 16 (5) 174 (1980) I.N. p.827 REM p. 1219 Hitchings, G.H., Russell, P.B. and Falco, E.A.; US Patent 2,576,939; December 4, 1951; assigned to Burroughs Wellcome & Co. (USA.) Inc. Hitchings, G.H. and Falco, E.A.; US Patent 2,579,259; December 18, 1951; assigned to Burroughs Wellcome & Co. (USA.) Inc. Hitchings, G.H., Russell, P.B. and Falco, E.A.; US Patent 2,602,794; July 8, 1952; assigned to Burroughs Wellcome & Co. (USA.) Inc. Jacob, R.M.: US Patent 2,680,740; June 8,1954; assigned to Societe des Usines Chimiques Rhone-Poulenc (France)

PYRISUCCIDEANOL DIMALEATE Therapeutic Function: Cerebrotonic Chemical Name: 2-(Dimethylamino)ethyl(5-hydroxy-4-(hydroxymethyl)-6methyl-3-pyridyl)methyl succinate salt with maleic acid (1:2) Common Name: Pirisuccideanoli maleas; Pirisudanol maleate; Pyrisuccideanol dimaleate Chemical Abstracts Registry No.: 53659-00-0; 33605-94-6 (Base)

2926

Pyrisuccideanol dimaleate

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Nadex Forte

Novartis Pharma

-

-

Raw Materials Succinic anhydride Thionyl chloride Formic acid Pyridoxine hydrochloride

Dimethylamino ethanol Pyridine Maleic acid

Manufacturing Process Process of preparation of 2-(dimethylamino)ethyl(5-hydroxy-4(hydroxymethyl)-6-methyl-3-pyridyl)methyl succinate includes four steps. a. Into a 4 liter flask provided with a stirrer there were poured 2.1 liters of pure and anhydrous acetone, and 100 g of dried pyridoxine hydrochloride were added under stirring. The mixture was cooled whilst stirring at 0°C and then gaseous HCl was bubbled through the solution for 6 hours. After another hour the temperature was allowed to rise to room temperature and the stirring was maintained for a further hour. The mixture was then cooled to 15°C and the 3,4-isopropylidene pyridoxine was obtained in the form of its hydrochloride (100 g). The free base was obtained by treatment above hydrochloride with a solution of Na2CO3. 82 g of base was obtained melting at 111°C. b. 100 g of succinic anhydride, 100 g of dimethylaminoethanol and 100 ml of anhydrous acetone were placed into a 2 liter flask and were refluxed for 3 hours. The solution was then concentrated to one third of its original volume by evaporation and cooled. A precipitate appeared, which was separated and recrystallized from acetone. 140 g of product was obtained, with a melting point of 78°C. The chloride was prepared from this compound by treatment of 420 g of the compound with freshly distilled SOCl2 1.85 liter. After elimination of nonreacted SOCl2, the product obtained was treated by benzene and dried, to yield 620 g of the hydrochloride of the chloride acid. 120 g of the compound

Pyrithyldione

2927

of step (a) above (0.57 mole) were dissolved in 0.5 liter of pyridine. After cooling there were slowly added at about 5°C, during 90 minutes, 170 g (0.69 mole) of the hydrochloride previously obtained, dissolved in 0.2 liter of chloroform. The solution was stirred for 10 hours, then evaporated to dryness (350 g). The residue was dissolved in 0.3 liter of water and was neutralized by an aqueous solution of NH3 saturated by K2CO3. There was obtained an oily substance which was extracted with chloroform. The extract was concentrated to dryness (170 g). c. In this step the blocking group linking the OH in position 3 to the CH2OH in position 4 of the pyridoxine ring was broken by hydrolysis with formic acid. 52 g of the product of step (b) above were treated with 1.650 liter of 1% solution of formic acid and 0.250 liter of ethyl alcohol. The mixture was boiled for 30 minutes, evaporated again treated with ethyl alcohol and evaporated. There were obtained 37 g of an oily substance. d. Maleate was obtained by reacting 37 g (0.115 mole) of above product of step (c) dissolved in 120 ml of acetone with 27 g (0.230 mole) of maleic acid dissolved in 130 ml of acetone. Yield 51 g. MP: 134°C. References Esanu A.; US Patent No. 3,717,636; Feb. 20, 1973; Assigned to Societe d’Etudes Produits Chimiques Issy-Les-Moulineaux, France

PYRITHYLDIONE Therapeutic Function: Hypnotic, Sedative Chemical Name: 3,3-Diethyl-2,4-(1H,3H)pyridinedione Common Name: Structural Formula:

Chemical Abstracts Registry No.: 77-04-3 Trade Name Presidon Persedon

Manufacturer Roche Roche

Country US W. Germany

Year Introduced 1948 -

2928

Pyritinol

Raw Materials Methyl formate Diketene Ethyl bromide

Sodium methylate Ammonia

Manufacturing Process 108 g of sodium methylate were suspended in 500 ml of toluene. 120 g of methyl formate were dropped into the sodium methylate suspension thus formed at a rate so that temperature did not exceed 30°C. Thereafter a solution of 157 g of α,α-diethylacetoacetamide in 500 ml of toluene were added so that the temperature did not exceed 50°C. The mixture was stirred for one hour at 50°C and then overnight at room temperature. The reaction mixture was poured into 700 ml of ice water, permitted to stratify, the aqueous layer was separated, covered with a layer of 200 ml of toluene and then treated while stirring with 200 g of 50% sulfuric acid. Finally the reaction mixture, which was acid to congo red, was warmed at 50°C and the toluene containing layer was separated. The aqueous layer was extracted with four 200 ml portions of toluene at 50°C and then discarded. The toluene extracts were combined and then concentrated in vacuo at 60°C. There were obtained 135 g of crystalline residue which was recrystallized from 200 ml of toluene. The 3,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydropyridine thus obtained melted at 96°C. The α,α-diethylacetoacetamide used as starting material was obtained by converting diketene with aqueous ammonia to acetoacetamide and alkylating twice with ethyl bromide in the presence of sodium alcoholate. References Merck Index 7893 Kleeman & Engel p. 793 I.N. p. 828 Hinderling, R .,Lutz, A.H. and Schnider, O.; U.S. Patent 3,019,230; January 30, 1962; assigned to Hoffmann-La Roche Inc.

PYRITINOL Therapeutic Function: Neurotropic Chemical Name: 3,3'-(Dithiodimethyiene)bis[5-hydroxy-6-methyl-4-pyridine methanol] Common Name: Pyrithioxin Chemical Abstracts Registry No.: 1098-97-1; 10049-83-9 (Dihydrochloride salt)

Pyritinol

2929

Structural Formula:

Trade Name Encephabol Enbol Biocefalin Bonol Cefalogen Cerebropirina Cerebrotrofina Cervitalin Chioebon Divalvon Encebrovit Encefabol Encefort Encerebron Enerbol Evolubran Fulneurina Gladius Leonar Life Maind Miriplex Musa Neurotin Neuroxin Piritinol Piritiomin Sawaxin Scintidin Tonobrein Tonomentis

Manufacturer Merck Chugai Benvegna Ikapharm Montefarmaco Chemil N.C.S.N. Savoma Kyowa Yakuhin Osaka Nippon Kayaku, Co. Sierochimica Bracco Intersint Pulitzer Polfa A.B.C. Fulton SKF Kalopharma S.I.T. Also Poli Poli Nakataki Yamanouchi Magis Hishiyama Sawai I.C.I. C.T. Ion

Country W. Germany Japan Italy Israel Italy Italy Italy Italy Japan Japan Italy Italy Italy Italy Poland Italy Italy Italy Italy Italy Italy Italy Italy Japan Japan Italy Japan Japan Italy Italy Italy

Year Introduced 1963 1971 -

2930

Pyrovalerone hydrochloride

Raw Materials Methanol Potassium xanthogenate Ammonia 3,4-Bisbromoethyl-4-hydroxy-5-methyl-pyridinium bromide Manufacturing Process To a solution of 60 g of potassium xanthogenate in 240 cc of water there is added dropwise, while being cooled with ice, a solution of 42 g of 3,4-bisbromomethyl-4-hydroxy-5-methyl-pyridinium-bromide in 1 liter of water so that the temperature remains between 2°C and 5°C. After stirring for 1 hour at the same temperature, the water is decanted off and the residue is triturated with acetone. Yield: 25 g of 4-hydroxymethyl-5-hydroxy-6-methylpyridyl-(3)-methylxanthogenate; melting point: 170°C to 171°C (alcohol, decomposition). 40 g of 4-hydroxymethyl-5-hydroxy-6-methyl-pyridyl-(3)-methylxanthogenate are left standing at room temperature for 5 days in a mixture of 800 cc of alcohol and 400 cc of aqueous NH3-solution, and subsequently concentrated under vacuum to about 50 cc. The precipitated bis(4-hydroxymethyl-5hydroxy-6-methyl-3-pyridylmethyl) disulfide is sucked off. Yield: 20 g of the disulfide; melting point: 218°C to 220°C (butanol, decomposition). References Merck Index 7894 Kleeman & Engel p. 793 DOT 9 (6) 215 (1973) I.N. p. 828 Zima, O. and Schorre, G.; US Patent 3,010,966; November 28, 1961; assigned to E. Merck A.G. (Germany)

PYROVALERONE HYDROCHLORIDE Therapeutic Function: Psychostimulant Chemical Name: 1-(4-Methylphenyl)-2-(1-pyrrolidinyl)-1-pentanone hydrochloride Common Name: Chemical Abstracts Registry No.: 1147-62-2; 3563-49-3 (Base) Trade Name

Manufacturer

Country

Year Introduced

Thymergix

Joullie

France

1973

Pyrrobutamine

2931

Structural Formula:

Raw Materials p-Methylvalerophenone Bromine Pyrrolidine Hydrogen chloride Manufacturing Process 23.1 grams of α-bromo-p-methyl-valerophenone, obtained by bromination of p-methyl-valerophenone, are dissolved in 50 ml of benzene and 25 ml of pyrrolidine are added at 0°C. The whole is boiled for 20 minutes, cooled, washed twice with water, dried and acidified with about 50 ml of 2 N hydrochloric acid. After evaporation, it is recrystallized from methanolacetone-ether. 22.6 grams of α-pyrrolidino-p-methyl-valerophenone hydrochloride, melting point 178°C, equivalent to a yield of 88.5% of the theoretical are obtained according to British Patent 927,475. References Merck Index 7914 Kleeman and Engel p. 794 OCDS Vol. 2 p. 124 (1980) DOT 10 (5) 188 (1974) I.N. p. 829 Dr. A. Wander SA, Switzerland; British Patent 927,475; May 29, 1963 Dr. Karl Thomae, GmbH, Germany; British Patent 933,507; August 8, 1963

PYRROBUTAMINE Therapeutic Function: Antihistaminic Chemical Name: 1-[4-(4-Chlorophenyl)-3-phenyl-2-butenyl]-pyrrolidine Common Name: Chemical Abstracts Registry No.: 91-82-7

2932

Pyrrobutamine

Structural Formula:

Trade Name Pyronil Co-Pyronil Proladyl

Manufacturer Lilly Lilly Lilly

Country US UK -

Year Introduced 1952 -

Raw Materials Pyrrolidine Paraformaldehyde Magnesium

Acetophenone p-Chlorobenzyl chloride Hydrogen chloride

Manufacturing Process A mixture of 1,800 ml of absolute ethanol, 427 g (6 mols) of pyrrolidine, and a trace of methyl orange is cooled in an ice bath and gaseous hydrogen chloride is bubbled through the mixture until a red color develops, indicating that all of the amine has been converted to the hydrochloride. The addition of hydrogen chloride is stopped, the ice bath is removed and to the solution are added 720 g of acetophenone, 270 g of paraformaldehyde and 10 ml of concentrated hydrochloric acid. The mixture is stirred and refluxed vigorously for one hour. An additional 180 g of paraformaldehyde are then added, and refluxing is continued for about three hours. The hot solution is poured into 6 liters of acetone and the mixture is chilled overnight. A precipitate of ω-(Npyrrolidino)-propiophenone hydrochloride separates. The precipitate is filtered off, washed with cold acetone, and dried in air. ω-(N-pyrrolidino)-propiophenone hydrochloride thus prepared melted at about 163°C to 164°C after recrystallization from acetone. To a suspension of 4 mols of ω-(N-pyrrolidino)-propiophenone hydrochloride in 1,500 ml of water and 100 g of ice in a separatory funnel are added a 50% aqueous solution containing 200 g of sodium hydroxide, and 2 liters of ether. The mixture is shaken vigorously until all of the suspended matter dissolves. The ether is then removed, washed with 1 liter of water and dried over anhydrous magnesium sulfate. The anhydrous ether solution of ω-(Npyrrolidino)-propiophenone thus prepared is added to a Grignard reagent prepared from 6 mols of p-chlorobenzyl chloride and 6 mols of magnesium turnings in 3,000 ml of anhydrous ether. The ethereal solution of the ketone is added to the Grignard reagent at such a rate that rapid refluxing is

Pyrrolnitrin

2933

maintained. After all of the ketone has been added, the reaction mixture is stirred for 2 hours and is decomposed by pouring it over a mixture of 500 g of ice and 6 mols of concentrated hydrochloric acid. The hydrochloric acid addition salt of 1-p-chlorophenyl-2-phenyl-4-N-(pyrrolidino)-butanol-2 formed in the reaction separates at the ether-water interface as a white crystalline material. The aqueous phase is removed and discarded, and the mixture of ether and hydrochloride salt is converted to 1-p-chlorophenyl-2-phenyl-4-(Npyrrolidino)-butanol-2 by treatment with 10% sodium hydroxide solution. The base is removed by extraction with ether, and the ether extracts are dried over magnesium sulfate. 1-p-chlorophenyl-2-phenyl-4-(N-pyrrolidino)-butanol-2 melted at about 109°C to 110°C after recrystallization from petroleum ether. A solution of 200 g of 1-p-chlorophenyl-2-phenyl-4-(N-pyrrolidino)-butanol-2 in 750 ml of concentrated hydrochloric acid is refluxed for 9 hours thereby causing a dehydration of the butanol compound. and the formation of the hydrochloric acid addition salt of a 1-p-chlorophenyl-2-phenyl-4-(Npyrrolidino)-butene. The hydrochloride salt formed crystallizes in the oily lower layer of the two phase reaction mixture and is removed therefrom by filtration. The filtrate is again refluxed for 9 hours, cooled to 0°C, and a second crop of the hydrochloric acid addition salt of the dehydration product is obtained and filtered off. The filtrate containing residual amounts of 1-pchlorophenyl-2-phenyl-4-(N-pyrrolidino)-butanol-2 is again refluxed for 9 hours to yield an additional crop of the salt of the dehydration product. The several fractions of the butene compound are combined and triturated with several small portions of hot acetone and recrystallized from alcohol-ether mixture. The hydrochloric acid addition salt of the dehydration product, 1-pchlorophenyl-2-phenyl-4-(N-pyrrolidino)-butene hydrochloride, melts at about 227°C to 228°C. References Merck Index 7916 Kleeman & Engel p. 794 OCDS Vol. 1 p. 78 (1977) I.N. p. 829 Mills, J.; US Patent 2,655,509; October 13, 1953; assigned to Eli Lilly & Co.

PYRROLNITRIN Therapeutic Function: Antifungal Chemical Name: 1H-Pyrrole, 3-chloro-4-(3-chloro-2-nitrophenyl)Common Name: Pyrrolnitrin Chemical Abstracts Registry No.: 1018-71-9

2934

Pyrrolnitrin

Structural Formula:

Trade Name Micutrin Lilly 52230

Manufacturer Searle Farmaceutici Eli Lilly and Company

Country -

Year Introduced -

Raw Materials Piperidine Sodium Sulfuryl chloride

1-(2-Nitro-3-chlorophenyl)-1,3-butanedione Diethyl aminomalonate

Manufacturing Process A mixture of 2.0 g of 1-(2-nitro-3-chlorophenyl)-1,3-butanedione, 1.9 g of diethyl aminomalonate, 1.5 ml of absolute ethyl alcohol and two drops of piperidine was refiuxed for 5 hours. After cooling, the reaction mixture was allowed to stand and then crystals were separated. The crystals were collected by filtration and then dried to obtain 2.5 g of colorless crystals. The crystals were recrystallized from a mixed solvent of benzene and ether to obtain diethyl N-[1-methyl-3-(2-nitro-3-chlorophenyl)-3oxopropylidene]aminomalonate as colorless needles having MP: 134°-136°C. A solution of 0.8 g of diethyl N-[1-methyl-3-(2-nitro-3-chlorophenyl)-3oxopropylidene]aminomalonate in 4 ml of absolute tetrahydrofuran was added dropwise with stirring to a solution prepared with 8 ml of absolute ethanol and 100 mg of metallic sodium. After the reaction mixture was refluxed for 4.5 hours, the solvents were distilled off under reduced pressure. The residue was added with an ice-water and the solution was extracted with ether. The extract was washed with water, dried over anhydrous magnesium sulfate, after which ether was distilled off. The residue was recrystallized from benzene to obtain ethyl 3-(2-nitro-3-chlorophenyl)-5-methylpyrrole-2-carboxylate as colorless needles having MP: 220°-223°C. 1.2 g of ethyl 3-(2-nitro-3-chlorophenyl)-5-methyl-pyrrole-2-carboxylate is suspended in 12 ml of acetic acid. A solution of 2.1 g of sulfuryl chloride in 3 ml of acetic acid is added dropwise to the suspension with stirring at about 200°C. The reaction mixture stood overnight is stirred for one hour at 30°C, one hour at 40°C, and then two hours at 50°C. Thereafter, this mixture is poured into ice water. The mixture is extracted with ethyl acetate. The extract is washed with an aqueous solution of potassium hydrogen carbonate and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. Ethyl 3-(2-nitro-3-chlorophenyl)-4-chloro- 5-trichloromethylpyrrole-2carboxylate is obtained as pale-brown viscous oil. A mixture of ethyl 3-(2-nitro-3-chlorophenyl)-4-chloro-5-

Pyrvinium pamoate

2935

trichloromethylpyrrole-2-carboxylate, prepared from 40 mg of ethyl 3-(2nitro-3-chlorophenyl)-4-chloro- 5-methylpyrrole-2-carboxylate and sulfuryl chloride, and 5 ml of 10% sodium hydroxide aqueous solution was heated for two hours on a water bath. The reaction mixture was acidified with 10% sulfuric acid and the resultant acidic solution was extracted with ethyl acetate and the extract was dried. The solvent was distilled off to yield 370 mg of 3(2-nitro-3-chlorophenyl)-4-chloro-pyrrole-2,5-dicarboxylic acid having a melting point of 298°C. (decomp.). Decarboxylation of this dicarboxylic acid gave almost quantitavily the disered 3-chloro-4-(2'-nitro-3'-chlorophenyl)pyrrole; MP: 125°C. (recrystallized from benzene). References Umio S. et al.; US Patent No. 3,428,648; Feb. 18, 1969; Assigned to Fujisawa Pharmaceutical Co., Ltd., Osaka, a comoany of Japan Nakano H., Umio S. et al., Tetrahedron Letters No 7 pp. 737-740, 1966

PYRVINIUM PAMOATE Therapeutic Function: Anthelmintic Chemical Name: 6-(Dimethylamino)-2-[2-(2,5-dimethyl-1-phenyl-1H-pyrro3-yl)ethenyl]-1-methylquinolium salt with pamoic acid (2:1) Common Name: Pyrvinium embonate; Viprynium embonate Structural Formula:

2936

Pyrvinium pamoate

Chemical Abstracts Registry No.: 3546-41-6 Trade Name Povan Povanyl Antioxur Molevac Neo-Oxypaat Oxialum Pamovin Pamoxan Pirok Poquil Privonium Pyrcon Pyrvin Tolapin Tru Vanquin Vermitiber

Manufacturer Parke Davis Parke Davis Esteve Parke Davis Katwijk Wolner Merck-Frosst Uriach Bilim Parke Davis Sankyo Rivopharm Jenapharm Farmos Taro Elea Parke Davis Tiber

Country US France Spain W. Germany Netherlands Spain Canada Spain Turkey Japan Switz. E. Germany Finland Israel Argentina Italy Italy

Year Introduced 1959 1981 -

Raw Materials Pyrvinium chloride Sodium pamoate Manufacturing Process A hot, filtered solution of 2.27 grams of pyrvinium chloride dihydrate in 250 ml of water is added slowly to a solution of 2.25 grams of sodium pamoate monohydrate in 50 ml of water. A red precipitate immediately forms. The mixture is heated at about 90°-100°C for 5 minutes more and then filtered. The reaction product is washed with hot water and dried at about 75°C in a vacuum. This preparation melts at about 210°-215°C with prior softening from about 190°C. References Merck Index 7927 Kleeman & Engel p. 796 PDR p. 1384 I.N. p. 830 REM p. 1237 Van Lare, E. and Brooker, L.G.S.; US Patent 2,515,912; July 18, 1950; assigned to Eastman Kodak Company Elslager, E.F. and Worth, D.F.; US Patent 2,925,417; February 16, 1960; assigned to Parke, Davis & Company

Q

QUETIAPINE FUMARATE Therapeutic Function: Antipsychotic Chemical Name: Ethanol, 2-(2-(4-dibenzo[b,f][1,4]thiazepin-11-yl-1piperazinyl) ethoxy)-, (E)-2-butenedioate (2:1) salt Common Name: Quetiapine fumarate Structural Formula:

Chemical Abstracts Registry No.: 111974-72-2 Trade Name Quel Seroquel

Manufacturer Innova (IPCA) AstraZeneca

Country India UK

Year Introduced -

Raw Materials Phosphorous oxychloride N,N-Dimethylaniline Sodium hydroxide

Dibenzo[b,f][1,4]thiazepine-11(10-H)-one 1-(2-Hydroxyethoxy)ethylpiperazine

2937

2938

Quetiapine fumarate

Manufacturing Process A 2 liter round-bottom flask equipped with a magnetic stirring bar and reflux condenser with a nitrogen inlet was charged with 115.0 g (0.506 mole) of dibenzo[b,f][1,4]thiazepine-11(10-H)-one (made by the method disclosed by J. Schmutz et al. Helv. Chim. Acta., 48: 336, 1965), phosphorous oxychloride 700 ml (7.5 moles) and N,N-dimethylaniline 38.0 g (0.313 mole). The suspension was heated to gentle refluxing using a heating mantle. After 6 h of heating, the resulting amber solution was allowed to cool to room temperature (from about 18°-25°C) and was analyzed by TLC using silica gel plates, developed with ether-hexane (1:1) and detected with ultraviolet light. Analysis revealed the desired "imino chloride". Excess phosphorous oxychloride, was removed in vacuo using a rotary evaporator. The brown syrupy residue was dissolved in 1500 ml of toluene, treated with 500 ml of an ice-water mixture and stirred for 30 min. The toluene layer was separated, washed twice with 200 ml of water and dried with anhydrous magnesium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated in vacuo using a rotary evaporator to give the crude "imino chloride" as a light yellow solid: 115.15 g (92.6% yield): melting point 106°-108°C. The above "imino chloride", 114.0 g (0.464 mole), and 1000 ml of xylene were placed in a 3 L 3-necked round bottom flask equipped with a mechanical stirrer, reflux condenser with a nitrogen inlet and a heating mantle. The resulting yellow solution was treated with 161.7 g (0.928 mole) of 1-(2hydroxyethoxy)ethylpiperazine, rinsing with 200 ml of xylene. This reaction mixture was heated at gentle reflux for 30 h during which time a brown oil began to separate. The reaction mixture was cooled to room temperature. TLC analysis (silica gel, methanol: methylene chloride 1:9, ultraviolet light and iodine detection) indicated complete consumption of the "imino chloride". The mixture was treated with 700 ml of 1 N sodium hydroxide and 700 ml of diethyl ether. The layers were separated and the aqueous phase was extracted once with 500 ml of diethyl ether. The combined ether extract was treated with 400 ml of 1 N hydrochloric acid. The acidic extract was treated with solid sodium carbonate portionwise to give a brown oil which was extracted four times with 400 ml of methylene chloride. These methylene chloride extracts were combined and dried with anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated in vacuo using a rotary evaporator to yield the crude product as a viscous amber oil, 194.5 g, which was purified by flash chromatography as follows. The crude product in a minimum of methylene chloride was applied to a column of silica gel packed in methylene chloride. The column was eluted under nitrogen pressure with 4 L portions each of methylene chloride, and 2%, 4% and 6% methanol:methylene chloride (2:98: 4:96, 6:94 respectively). The title product began to elute with 4% methanol:methylene chloride (4:96). Combination of the pure fractions and removal of the solvent in vacuo gave the title 11-[4-[2-(2-hydroxyethoxy)ethyl]-1piperaziny]dibenzo[b,f][1,4]thiazepine 138.7 g (77.7% yield). A portion of a 11-[4-[2-(2-hydroxyethoxy)ethyl]-1piperaziny]dibenzo[b,f][1,4]thiazepine 2.1 g (5.47 mmol) was dissolved in 20 ml of ethanol and treated with 0.67 g (5.7 mmol) of fumaric acid. Upon heating, complete solution was effected for a few minutes after which the salt began to crystallize. After 1 h at room temperature, the resulting solid was collected by filtration and dried in vacuo in a drying pistol over refluxing

Quinapril hydrochloride hydrate

2939

ethanol to give the 11-[4-[2-(2-Hydroxyethoxy)ethyl]-1piperaziny]dibenzo[b,f][1,4]thiazepine, hemifumarate, 2.4 g, melting point 172°-173°C. References Parikh B.V. et al.; Patent WO 97/45124; Dec. 4, 1997; Assigned: Zeneca Limited [GB/GB]; Stanhope Gate, London Wiy 6LN (GB) Warawa E.J., Migler B.M.; US Patent No. 4,879,288; Nov. 7, 1989; Assigned: ICI Americas INC., Wilmington, Del.

QUINAPRIL HYDROCHLORIDE HYDRATE Therapeutic Function: Antihypertensive Chemical Name: 3-Isoquinolinecarboxylic acid, 1,2,3,4-tetrahydro-2-(2-((1(ethoxycarbonyl)-3-phenylpropyl)amino)-1-oxopropyl)-, monohydrochloride, (3S-(2(R*(R*)),3R*))-, monohydrate Common Name: Quinapril hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 90243-99-5; 85441-61-8 (Base) Trade Name Accupril Accupril Accupril Accupril Accupro

Manufacturer Warner Pfizer Teva Pharmaceuticals Parke-Davis Parke Davis GmbH/Godecke AG

Country USA -

Year Introduced -

Raw Materials t-Butyl alanine Triethylamine Benzyl alcohol Hydrogen

Ethyl 2-bromo-4-phenylbutanoate Hydrogen chloride Polyphosphoric acid Palladium on carbon

2940

Quinapril hydrochloride hydrate

Manufacturing Process A solution of 2.0 g of t-butyl alanine (S-form) and 3.78 g of ethyl 2-bromo-4phenylbutanoate in 25 ml of dimethylformamide was treated with 1.8 ml of triethylamine and the solution was heated at 70°C for 18 h. The solvent was removed at reduced pressure and the residue was mixed with water and extracted with ethyl ether. The organic layer was washed with water and dried over magnesium sulfate. Concentration of the solvent at reduced pressure gave the oily t-butyl ester of the intermediate which was found to be sufficiently pure by gas liquid chromatography for further use. A solution of 143.7 g of this t-butyl ester in 630 ml of trifluoroacetic acid was stirred at room temperature for one hour. The solvent was removed at reduced pressure and the residue was dissolved in ethyl ether and again evaporated. This operation was repeated. Then the ether solution was treated dropwise with a solution of hydrogen chloride gas in ethyl ether until precipitation ceased. The solid, collected by filtration, was a mixture of diastereoisomers, melting point 153°-165°C. In order to separate the preferred, S,S-isomer, a suspension of 10.0 g of the mixture in 200 ml of methylene chloride was stirred at room temperature for five min and filtered; the solid was washed with additional methylene chloride and finally ether. The solid material, melting point 202°-208°C (dec.) was the less preferred diastereoisomer having the R,S-configuration (S referring to the portion derived from L-alanine). The preferred S,S-diastereoisomer was recovered from the filtrate after concentration and trituration of the residue with ether; melting point 137°-139°C. The free amino acid (S,S-form) was prepared by treatment of an aqueous solution of the hydrochloride with saturated sodium acetate. The ethyl α-[(1carboxyethyl)amino]benzenebutanoate hydrochloride (S,S) was filtered, washed efficiently with cold water and recrystallized from ethyl acetate; melting point 149°-151°C. Benzyl alcohol, 750 ml, was treated with 150 g of commercial polyphosphoric acid and warmed and stirred at 90°C to obtain a homogeneous mixture. Solid 1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid (S-form) 165.2 g was added. The mixture was stirred 4 h at 95°-105°C and then allowed to stand at room temperature for 18 h. A solution of 18.5 g gaseous hydrochloric acid in 2.5 L of anhydrous ether was added, and the product separated slowly on cooling overnight. Filtration gave the crude tetrahydro-3-isoquinolinecarboxylic acid phenylmethyl ester hydrochloride (S-form). This was purified by recrystallization from ethanol twice to give material with melting point 190.5°191°C. Ethyl 7α-[(1-carboxyethyl)amino]benzenebutanoate hydrochloride (S,S) was coupled with 1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid phenylmethyl ester free base (S-form) yield 2-[2-[[1-(ethoxycarbonyl)-3phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid phenylmethyl ester maleate (S,S,S) 61%; melting point 151°-153°C (recrystallized from ethyl acetate). 2-[2-[[1-(Ethoxycarbonyl)-3-phenylpropyl[amino]-1-oxopropyl]-1,2,3,4tetrahydro-3-isoquinolinecarboxylic acid, phenylmethyl ester, maleate, (S,S,S) was dissolved in tetrahydrofuran was catalytically debenzylated with hydrogen and 20% Pd/carbon at low pressure. The catalyst was filtered off and the 2-

Quinestrol

2941

[2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4tetrahydro-3-isoquinolinecarboxylic acid hydrochloride hydrate (S,S,S) was precipitated as a relatively nonhydroscopic solid by the addition of a 10 fold quantity of ether. Melting point 105°-120°C; yield: 56%. References Hoefle M. L., Klutchko S.; US Patent No. 4,344,949; August 17, 1982; Assigned: Warner-Lambert Company, Morris Plains, N.J.

QUINESTROL Therapeutic Function: Estrogen Chemical Name: 3-(Cyclopentyloxy)-19-nor-17α-pregna-1,3,5(10)-trien-20yn-17-ol Common Name: 17α-Ethinylestradiol 3-cyclopentyl ether Structural Formula:

Chemical Abstracts Registry No.: 152-43-2 Trade Name

Manufacturer

Country

Year Introduced

Estrovis

Goedecke

W. Germany

1968

Estrovis

Warner

UK

1969

Estrovis

Warner Lambert

US

1979

Agalacto-Quilea

Elea

Argentina

-

Basaquines

Boehringer Mannheim

-

-

Raw Materials 17α-Ethynyl estradiol Cyclopentyl bromide Manufacturing Process A solution of 1.5 grams of 17α-ethynyl estradiol in 50 cc of absolute ethanol is

2942

Quinethazone

added slowly to a mixture of 3 grams of cyclopentyl bromide and 2 grams of potassium carbonate. This mixture is heated to reflux and stirred for 3 hours, then filtered. Most of the alcohol is eliminated by distillation and the resulting solution diluted with water, and cooled in an ice-bath. The product which precipitates is collected by filtration, washed and dried. After recrystallization from methanol the 3-cyclopentyl ether of 17α-ethynyl estradiol shows a melting point of 107° to 108°C. References Merck Index 7959 Kleeman and Engel p. 797 PDR p. 1347 DOT 17 (4) 163 (1981) I.N. p. 832 REM p. 988 Ercoli, A.; US Patent 3,159,543; December 1, 1964; assigned to Francesco Vismara SpA, Italy Ercoli, A., Gardi, R. and Pedrali, C.; US Patent 3,231,567; January 25, 1966; assigned to Francesco Vismara SpA, Italy

QUINETHAZONE Therapeutic Function: Diuretic Chemical Name: 7-Chloro-2-ethyl-1,2,3,4-tetrahydro-4-oxo-6quinazolinesulfonamide Common Name: Chinethazonum Structural Formula:

Chemical Abstracts Registry No.: 73-49-4 Trade Name Hydromox Aquamox

Manufacturer Lederle Lederle

Country US UK

Raw Materials 7-Chloro-2-ethyl-6-sulfamyl-4-quinazolinone Sodium borohydride

Year Introduced 1962 -

Quingestanol acetate

2943

Manufacturing Process For preparation of the desired tetrahydroquinazolinone, 103 parts of aluminum chloride were added to 25,000 parts by volume of diethylene glycol dimethyl ether while cooling in an ice bath. The mixture was then stirred with warming and 200 parts of 7-chloro-2-ethyl-6-sulfamyl-4-quinazolinone added. A second solution of 140 parts of sodium borohydride in 7,000 parts of dry diethylene glycol dimethyl ether was then added gradually. An orange mixture resulted which was kept at 85°C until the reaction was complete. The reaction mixture was then cooled to approximately 0°C and 4,000 parts of water slowly added. Dilute HCl was then added to form a strongly acidic clear solution which was evaporated to dryness. Following this, the solid was triturated with cold water to yield 90 parts of a solid. Fibrous crystals were obtained by recrystallization from 50% acetone. References Merck Index 7960 Kleeman and Engel p. 797 PDR p. 1010 OCDS Vol. 1 p. 354 (1977) I.N. p. 833 REM p. 940 Cohen, E. and Vaughan, J.R., Jr.; US Patent 2,976,289; March 21, 1961; assigned to American Cyanamid Company

QUINGESTANOL ACETATE Therapeutic Function: Progestin Chemical Name: 19-Norpregna-3,5-dien-20-yn-17-ol-3-(cyclopentyloxy) acetate, (17α)Common Name: Structural Formula:

Chemical Abstracts Registry No.: 3000-39-3; 10592-65-1 (Base)

2944

Quingestanol acetate

Trade Name Demovis Demovis Delovis

Manufacturer Parke Davis Vister Substantia

Country Italy Italy France

Year Introduced 1972 -

Raw Materials Lithium Acetic anhydride 3-Cycloethylenedioxy-10-cyano-17α-ethynyl19-nor-δ(5)-androstene-17β-ol

Ammonia Cyclopentanol

Manufacturing Process The starting material for the purposes of this discussion is 3cycloethylenedioxy-10-cyano-17α-ethynyl-19-nor-∆5-androstene-17β-ol (I). A solution of 10-cyano-3-monoketal (I) in 60 cc of dry ether and 60 cc of dry dioxane is dropped into 400 cc of liquid ammonia. Then, 1.2 g of lithium in small pieces are introduced over a period of 90 minutes and the mixture is maintained under stirring until the blue color of the solution is discharged. 10 g of ammonium chloride are added and the stirring is continued for some hours longer at room temperature. The moist ammonia is left to evaporate cautiously, maintaining the mixture on water-bath and diluting the resulting solution with water. After repeated extractions with ether, an oily residue is obtained consisting of a mixture of ∆5(6) and ∆5(10) isomers of 17α-ethynyl-19nor-androstene-17β-ol-3-one 3-ethylene ketal (II). To a solution of 1 g of the mixture of 3-ketal-isomers of compound (II) in 10 cc of acetic anhydride is added a solution of 700 mg of p-toluenesulfonic acid in 7 cc of acetic anhydride. The reaction mixture is kept at room temperature and under stirring for 5 hours. After some time a crystalline product begins to precipitate and the precipitation is complete by diluting with water. The precipitate is filtered and crystallized from methanol to give 17α-ethynyl-19nortestosterone 3,17-diacetate (III), melting point 175°C to 178°C. A solution of 1 g of the diacetate (III) in 100 cc of n-heptane containing 2.5 cc of cyclopentanol and 50 mg of p-toluenesulfonic acid is heated under reflux for 20 hours. After cooling, a few drops of pyridine are added and the solvent is eliminated by evaporation under vacuum. The residue is taken up with methanol to give 3-cyclopentyl enolether of 17α-ethynyl-19-nortestosterone acetate which, after recrystallization from methanol, melts at 182°C to 184°C. References Kleeman and Engel p. 798 DOT 9 (5) 182 (1973) I.N. p. 833 Ercoli, A. and Gardi, R.; US Patent 3,159,620; December 1, 1964; assigned to Francesco Vismara S.p.A. (Italy)

Quinidine

2945

QUINIDINE Therapeutic Function: Antiarrhythmic Chemical Name: Cinchonan-9-ol, 6'-methoxy-, (9S)Common Name: Chinidin; β-Chinin; Chinotin; Cinchotin; Conchinin; Conquinine; Kinidin; Pitauine; Quinidine; β-Quinine Structural Formula:

Chemical Abstracts Registry No.: 56-54-2 Trade Name Quinidine Natcardine

Manufacturer Glaxo Smithkline Franco Indian Pharmaceuticals Ltd.

Country -

Year Introduced -

Raw Materials Quinine Benzophenone Sulfuric acid Manufacturing Process 100 g quinine, 60 g benzophenone in 1 L of dry toluene and 50 g sodium methylate refluxed for 12 hours at 105°-110°C. Then 150 g absolute isopropanol was added and the mixture refluxed for 6 hours. After cooling the solution was extracted with deluted H2SO4, the sodium hydroxide was added to an acidic extract. The precipitate of the diastereoisomers was filtered off and washed with water to neutral pH. They was divided by usual methods (with help of tartrate or rhodanide). Yield: 45% quinidine and 45% quinine. References Dietrich H. et al; D.B. Patent No. 877,611; 8 July 1949; Assigned to C.F.Boehringer and Soehne G.m.b.H., Manheim-Waldorf.

2946

Quinidine polygalacturonate

QUINIDINE POLYGALACTURONATE Therapeutic Function: Antiarrhythmic Chemical Name: D-Galacturonic acid, homopolymer, compd. with (9S)-6'methoxycinchonan-9-ol Common Name: Structural Formula: Quinidine polygalacturonate Chemical Abstracts Registry No.: 65484-56-2 Trade Name Cardioquin Cardioquin Cardioquine Galactoquin Galatturil-Chinidina Naticardina Neochinidin Ritmocor

Manufacturer Purdue Frederick N.A.P.P. Berenguer-Beneyto Mundipharma Francia Chinoin Brocchieri Malesci

Country US UK Spain W. Germany Italy Italy Italy Italy

Year Introduced 1960 1970 -

Raw Materials Polygalacturonic acid Quinidine Manufacturing Process 100 grams of polygalacturonic acid are dissolved in 1 liter of a 60% (v/v) mixture of methanol and water. The neutralization equivalent of the polygalacturonic acid is determined by titration with tenth-normal alkali on an aliquot sample. A stoichiometric equivalent of quinidino alkaloid dissolved in 2,500 cc of 80% methanol is slowly added, with continued stirring. The pH of the reaction mixture is taken both before and after the addition of the last portion of the quinidine-methanol solution. The mixture is gently warmed (30° to 50°C), and the pH determined at 20 minute intervals. At the end of 4 hours, or when the reaction has gone to completion as evidenced by the pH of the mixture (between pH 6.5 and 7.5), the stirring is then stopped and the mixture cooled to 0°C and filtered. The solvent is evaporated to dryness under reduced pressure, utilizing as little heat as is feasible. The dried residue is powdered and suspended in 10 volumes of methanol and filtered. The insoluble powder is dried, and is quinidine polygalacturonate, melting at 180°C with decomposition. References Merck Index 7966

Quinupramine

2947

PDR p. 1433 OCDS Vol. 1 p. 339 (1977) I.N. p. 833 REM p.859 Halpern, A.; US Patent 2,878,252; March 17, 1959; assigned to Synergistics, Inc.

QUINUPRAMINE Therapeutic Function: Antidepressant Chemical Name: 5-(3-Quinuclidinyl)-10,11-dihydro-dibenzo[b,f]azepine Common Name: Structural Formula:

Chemical Abstracts Registry No.: 31721-17-2 Trade Name

Manufacturer

Country

Year Introduced

Kinupril

Fournier

France

1979

Raw Materials Iminodibenzyl Sodium amide 3-Phenylsulfonyloxyquinuclidine Manufacturing Process 3.9 g of iminodibenzyl were added in one batch to a suspension of 0.96 g of sodium amide in 50 ml of anhydrous toluene. The mixture was heated to reflux temperature for a period of 6 hours. A solution of 5.34 g of 3phenylsulfonyloxyquinuclidine in 15 ml of anhydrous toluene was added dropwise over a period of 75 minutes to the suspension at reflux temperature and the latter was maintained for 150 minutes after the completion of the addition. The reaction mixture was cooled to ambient temperature and treated with 75 ml of distilled water and 75 ml of ethyl acetate.

2948

Quinupramine

The decanted aqueous phase was extracted three times with a total of 150 ml of ethyl acetate. The combined organic solutions were filtered over Clarcel and extracted three times with a total of 150 ml of an iced normal aqueous methane-sulfonic acid solution. The combined acid extracts were rendered alkaline on an ice bath with 30 ml of 10 N caustic soda solution. The separated oil was extracted four times with a total of 200 ml of ether. The combined ethereal extracts were washed twelve times with a total of 360 ml of distilled water, dried over anhydrous magnesium sulfate in the presence of 0.3 g of animal charcoal and evaporated under reduced pressure on a water bath at 40°C. The oily residue obtained (3.8 g) was dissolved in 30 ml of boiling acetonitrile. After cooling for 2 hours at 3°C, the crystals formed were separated, washed with 5 ml of acetonitrile and dried at ambient temperature at low pressure. 1.6 g of 5-(3-quinuclidinyl)-10,11-dihydrodibenzo[b,f]azepine, melting point 150°C, were obtained. References Merck Index 8006 DFU 3 (7) 548 (1978) Kleeman and Engel p. 799 DOT 16 (4) 122 (1980) I.N. p.835 Gueremy, C. and Wirth, P.C.; British Patent 1,252,320; November 3, 1971; assigned to Societe Generale De Recherches Et D'Applications Scientifiques Sogeras

R

RABEPRAZOLE Therapeutic Function: Antiulcer Chemical Name: 1H-Benzimidazole, 2-(((4-(3-methoxypropoxy)-3-methyl-2pyridinyl)methyl)sulfinyl)Common Name: Pariprazole; Rabeprazole Structural Formula:

Chemical Abstracts Registry No.: 117976-89-3 Trade Name Pariet Pariet Pariet

Manufacturer Eisai Co. Janssen-Cilag Torrent

Country Belgium -

Year Introduced -

Raw Materials (-)-Diethyl D-tartrate N,N-Diisopropylethylamine Titanium (IV) isopropoxide Cumene hydroperoxide (80%) 2-[[[4-(3-Methoxypropoxy)-3-methyl-2-pyridinyl]methyl]thio]-1Hbenzimidazole Manufacturing Process Asymmetric synthesis of (-)-2-[[[4-(3-methoxypropoxy)-3-methyl-2pyridinyl]methyl]sulphinyl]-1H-benzimidazole

2949

2950

Raloxifene hydrochloride

2.1 g (6.3 mmol) of 2-[[[4-(3-methoxypropoxy)-3-methyl-2pyridinyl]methyl]thio]-1H-benzimidazole was dissolved in 50 ml of toluene. To the solution was added 40 µl (2.2 mmol) of water, 1.6 ml (9.4 mmol) of (-)diethyl D-tartrate and 1.1 ml (3.8 mmol) of titanium (IV) isopropoxide. The mixture was stirred for 60 minutes at 50°C and then cooled to room temperature. 0.44 ml (2.6 mmol) of N,N-diisopropylethylamine and 1.1 ml (6.0 mmol) of cumene hydroperoxide (80%) were added. After stirring for 2 h at room temperature the mixture consisted of 9% sulphide, 4% sulphone and 86% sulphoxide according to achiral HPLC. To the mixture toluene (50 ml) was added and the resultant solution was extracted three times with an aqueous ammonia (12%) solution with a total volume of 150 ml. The combined aqueous layers were neutralized by the addition of concentrated acetic acid (30 ml). Thereafter, the workup procedure employed extraction, evaporation and flash chromatography yielding 1.62 g of the title compound with a purity of 99.9% (achiral analysis) and with an enantiomeric excess of 90% (chiral analysis). After treating the material with acetonitrile there was a precipitate that could be removed by filtration. Concentrating the filtrate afforded 1.36 g (60%) of the title compound as an oil with an optical purity of 91.5%. Asymmetric synthesis of (+)-2-[[[4-(3-methoxypropoxy)-3-methyl-2pyridinyl]methyl]sulphinyl]-1H-benzimidazole 2.1 g (6.3 mmol) of 2-[[[4-(3-methoxypropoxy)-3-methyl-2pyridinyl]methyl]thio]-1H-benzimidazole was dissolved in 50 ml of toluene. To the solution was added 40 µl (2.2 mmol) of water, 1.6 ml (9.4 mmol) of (+)diethyl L-tartrate and 1.1 ml (3.8 mmol) of titanium (IV) isopropoxide. The mixture was stirred for 60 minutes at 50°C and then cooled to room temperature. 0.44 ml (2.6 mmol) of N,N-diisopropylethylamine and 1.1 ml (6.0 mmol) of cumene hydroperoxide (80%) were added to the solution. After stirring for 2 h at room temperature the mixture consisted of 9% sulphide, 4% sulphone and 85% sulphoxide according to HPLC. To the mixture toluene (50 ml) was added and the resultant solution was extracted three times with an aqueous ammonia (12%) solution with a total volume of 150 ml. The combined aqueous layers were neutralized by the addition of concentrated acetic acid (30 ml). Thereafter, the workup procedure employed extraction, evaporation and flash chromatography yielding 1.63 g of the title compound with a purity of 99.9% (achiral analysis) and with an enantiomeric excess (e.e.) of 91% (chiral analysis). After treating the material with acetonitrile, there was a precipitate that could be removed by filtration. Concentrating the filtrate afforded 1.1 g (49%) of the title compound as an oil with an optical purity of 96%. References Larson et al; US Patent No. 5,948,789; Sep. 7, 1999; Assigned to Astra Aktiebolag, Sodertalje, Sweden

RALOXIFENE HYDROCHLORIDE Therapeutic Function: Antiestrogen

Raloxifene hydrochloride

2951

Chemical Name: Methanone, (6-hydroxy-2-(4-hydroxyphenyl)benzo(b)thien3-yl)(4-(2-(1-piperidinyl)ethoxy)phenyl)-, hydrochloride Common Name: Keoxifen hydrochloride; Radoxifene hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 82640-04-8; 84449-90-1 (Base) Trade Name

Manufacturer

Country Year Introduced

Evista

Eli Lilly

USA

-

Raw Materials 3-Methoxybenzenethiol Polyphosphoric acid Thionyl chloride

Methyl 4-(2-piperidinoethoxy)benzoate α-Bromo-4-methoxyacetophenone

Manufacturing Process 4-(2-Piperidinoethoxy)benzoic acid, hydrochloride A 183 g portion of methyl 4-(2-piperidinoethoxy)benzoate was dissolved in 600 ml of methanol, and 200 ml of 5 N sodium hydroxide was added. The mixture was stirred at ambient temperature for 48 hours, the solvent was evaporated, and the residue was dissolved in 1 liter of water. The solution was cooled to below 10°C, and was acidified with cold 6 N hydrochloric acid. The product crystallized, and was collected by filtration and washed with methanol at -40°C. The solids were recrystallized from 3400 ml of methanol to obtain 167 g of the expected product, melting point 274°-277°C. 6-Hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene A 100 g portion of 3-methoxybenzenethiol and 39.1 g of potassium hydroxide dissolved in 300 ml of water were added to 750 ml of denatured ethanol, and the flask was put in a cooling bath. A total of 164 g of α-bromo-4methoxyacetophenone was then added in small portions, and the mixture was stirred for 10 minutes in the cooling bath after the addition was complete and then for 3 hours at ambient temperature. The solvent was then evaporated off in vacuum, and 200 ml of water was added. The mixture was extracted with ethyl acetate, and the organic layer was washed twice with water, twice with aqueous sodium bicarbonate solution, and twice with aqueous sodium chloride solution. The organic layer was then dried over magnesium sulfate, filtered

2952

Raloxifene hydrochloride

and evaporated under vacuum to obtain 202 g of crude α-(3methoxyphenylthio)-4-methoxyacetophenone, which was recrystallized from methanol and washed with hexane to obtain 158 g of purified product, m.p. 53°C. A 124 g portion of the above intermediate was added in small portions to 930 g of polyphosphoric acid at 85°C. The temperature rose to 95°C during the addition, and the mixture was stirred at 90°C for 30 minutes after the addition was complete, and was then stirred an additional 45 minutes while it cooled without external heating. One liter of crushed ice was then added to the mixture, and an external ice bath was applied to control the temperature while the ice melted and diluted the acid. 500 ml of additional water was added, and the light pink precipitate was filtered off and washed, first with water and then with methanol. The solids were dried under vacuum at 40°C to obtain 119 g of crude 6-methoxy-2-(4-methoxyphenyl)-benzo[b]thiophene. The crude product was slurried in hot methanol, filtered, and washed with cold methanol, and the solids were recrystallized from 4 liters of ethyl acetate, filtered, washed with hexane and dried to obtain 68 g of purified intermediate product, m.p. 187°-190.5°C. 90 g of pyridine hydrochloride was added to a flask equipped with a distillation head, condenser and collecting flask, and was heated with stirring until the temperature in the distillation head was 220°C. The distillation apparatus was then removed, the pot was cooled to 210°C, and 30 g of the above prepared 6-methoxy-2-(4-methoxyphenyl)-benzo[b]thiophene was added. The mixture was stirred at 210°C for 30 minutes, and was then poured into 250 ml of icewater. The precipitate was extracted into 500 ml of ethyl acetate, and the organic layer was washed with 150 ml of saturated aqueous sodium bicarbonate and then with 150 ml of saturated aqueous sodium chloride. The organic layer was then dried over magnesium sulfate, filtered and evaporated to dryness under vacuum to obtain 25.5 g of the desired intermediate product, m.p. >260°C. 6-Hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b] thiophene, hydrochloride Under a nitrogen blanket, a mixture of 3 g of 4-(2-piperidinoethoxy)benzoic acid hydrochloride, 2 drops of dimethylformamide, 2.5 ml of thionyl chloride and 40 ml of chlorobenzene was heated at 70°-75°C for about one hour. The excess thionyl chloride and 15-20 ml of solvent were then distilled off. The remaining suspension was cooled to ambient temperature, and to it were added 100 ml of dichloromethane, 2.7 g of 6-methoxy-2-(4-methoxyphenyl) benzo[b]thiophene and 10 g of aluminum chloride. The solution was stirred for about one hour, 7.5 ml of ethanethiol was added, and the mixture was stirred for 45 minutes more. Then 40 ml of tetrahydrofuran was added, followed by 15 ml of 20% hydrochloric acid, with an exotherm to reflux. Fifty ml of water and 25 ml of saturated aqueous sodium chloride was added. The mixture was stirred and allowed to cool to ambient temperature. The precipitate was collected by filtration and washed successively with 30 ml of water, 40 ml of 25% aqueous tetrahydrofuran, and 35 ml of water. The solids were then dried at 40°C under vacuum to obtain 5.05 g of product, which was identified by NMR as 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl] benzo[b]thiophene hydrochloride; melting point 217°C.

Ramipril

2953

Purification of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2piperidinoethoxy)benzoyl]benzo[b]thiophene hydrochloride 200 g of crude 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2piperidinoethoxy)benzoyl]benzo[b]thiophene hydrochloride, typical of the product of Example 16 above, was added to 4400 ml of methanol and 60 ml of deionized water in a 5-liter flask. The slurry was heated to reflux, whereupon most of the crude product went into solution. The remaining solid was removed by filtration under vacuum, using a filter aid pad. A distillation head was then attached to the flask, and solvent was distilled off until the volume of the remaining solution was about 1800 ml. The heating mantle was then turned off, and the solution was cooled very slowly overnight, with constant stirring. The crystalline product was then collected by vacuum filtration, and the flask was washed out with filtrate to obtain all of the product. The crystals were washed on the filter with two 100 ml portions of cold (below 0°C) methanol, and the washed product was dried at 60°C under vacuum to obtain 140 g of dried product. The product was slurried in 3000 ml of methanol and 42 ml of water, heated to reflux and cooled very slowly. The product was filtered and dried as above to obtain 121 g of highly purified product, melting point 259°-260°C. References Jones C.D.; US Patent No. 4,418,068; Nov. 29, 1983; Assigned to Eli Lilly and Company, Indianapolis, IN

RAMIPRIL Therapeutic Function: Antihypertensive Chemical Name: Cyclopenta(b)pyrrole-2-carboxylic acid, octahydro-1-(2-((1(ethoxycarbonyl)-3-phenylpropyl)amino)-1-oxopropyl), (2S-(1(R*(R*)),2α,3a-β,6a-β))Common Name: Ramipril Structural Formula:

Chemical Abstracts Registry No.: 87333-19-5

2954

Ramipril

Trade Name Altace Altace Cardace Cardace Corpril Delix Tritace Tritace Unipril Vasotop

Manufacturer Libbs Aventis Hoechst Aventis Pasteur Ranbaxy Global Consumer Healthcare Hoechst Hoechst Marion Roussel Aventis Astra Simes Provet AG

Country Germany India India

Year Introduced -

Germany Germany -

-

Raw Materials Platinum on carbon Benzyl alcohol Thionyl chloride Dicyclohexylcarbodiimide

Cyclopentenopyrrolidine Methyl 3-chloro-2-acetylamino-propionate HOBt (oxybenztriazol)

Manufacturing Process N-(1-S-Carbethoxy-3-phenyl-propyl)-S-alanyl-2-cis,endoazabicyclo-[3.3.0]octane-3-S-carboxylicacid 1. Methyl 2-acetylamino-3-(2-oxo-cyclopentyl)-propionate 269 g of methyl 3-chloro-2-acetylamino-propionate and 257 g of cyclopentenopyrrolidine in 1.5 liters of dimethylformamide were kept at room temperature for 24 hours. The mixture was concentrated in vacuo, the residue was taken up in a little water and the aqueous mixture was adjusted to pH 2 with concentrated hydrochloric acid and extracted twice with 4 liter portions of ethyl acetate. On concentration of the organic phase, a light yellow oil remained. Yield: 290 g. 2. cis,endo-2-Azabicyclo-[3.3.0]-octane-3-carboxylic acid hydrochloride 270 g of the acetylamino derivative prepared under (1) were refluxed in 1.5 liters of 2 N hydrochloric acid for 45 minutes. The mixture was concentrated in vacuo, the residue was taken up in glacial acetic acid, 5 g of Pt/C (10% of Pt) were added and hydrogenation was carried out under 5 bar. After filtration, the mixture was concentrated and the residue was crystallized from chloroform/diisopropyl ether. Melting point 205°-209°C. Yield: 150 g. 3. Benzyl cis,endo-2-azabicyclo-[3.3.0]-octane-3-carboxylate hydrochloride 40 g of the carboxylic acid prepared under (2) were added to an ice-cold mixture of 390 g of benzyl alcohol and 65 g of thionyl chloride and the mixture was left to stand at room temperature for 24 hours. After concentration in vacuo, 47 g of the benzyl ester were crystallized from chloroform/isopropanol.Melting point: 175°C (hydrochloride).

Ranitidine

2955

4. Benzyl N-(2-S-carbethoxy-3-phenyl-propyl)-S-alanyl-cis,endo-2-azabicyclo[3.3.0]-octane-3-S-carboxylate 14 g of the benzyl ester prepared according to (3) were reacted with 6.7 g of HOBt (oxybenztriazol), 13.8 g of N-(1-S-carbethoxy-3-phenyl-propyl)-Salanine and 10.2 g of dicyclohexylcarbodiimide in 200 ml of dimethylformamide. After the mixture had been stirred for 3 hours at room temperature, the dicyclohexylurea which had precipitated was filtered off the filtrate was concentrated, the residue was taken up in 1 liter of ethyl acetate and the mixture was extracted by shaking with 3 x 500 ml of 5% NaHCO3 solution. The organic phase was concentrated and the residue was chromatographed over a column of 1 kg of silica gel using ethyl acetate/petroleum ether in the ratio 2:1. The isomer eluted first was the S,S,S-compound, and concentration of a later eluate gave the S,S,Rcompound. The products were obtained as an oil. The structure of them was confirmed NMR. 5. N-(1-S-Carbethoxy-3-phenyl-propyl)-S-alanyl-cis,endo-2-azabicyclo[3.3.0]- octane-3-S-carboxylic acid 8.0 g of the L,L,L-benzyl ester from (4) were dissolved in 100 ml of ethanol and were debenzylated hydrogenolytically under normal pressure, with addition of 0.5 g of 10% Pd/C. This reaction could also have been carried out under pressure, together with a shortening of the reaction time. After the calculated amount of hydrogen had been taken up, the catalyst was filtered off and the residue was concentrated in vacuo. The product crystallized from ether, in almost quantitative yield. Melting point: 110°-112°C (decomposition). The NMR and mass spectra obtained are in agreement with the given structure; [α]D = +15.6° (c = 1, methanol). References Teez et al.; US Patent No. 4,727,160; Feb. 23, 1988; Assigned to Hoechst Aktiengesellschaft, Frankfurt am Main, Fed. Rep. of Germany

RANITIDINE Therapeutic Function: Antiulcer, Antiallergic Chemical Name: N-[2-[[[5-(Dimethylamino)methyl-2-furanyl]methyl]thio] ethyl]-N'-methyl-2-nitro-1,1-ethenediamine Common Name: Chemical Abstracts Registry No.: 66357-35-5 Raw Materials N-Methyl-1-(methylthio)-2-nitroetheneamine 2-[[[5-(Dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine

2956

Ranitidine

Structural Formula:

Trade Name Zantac Zantac Zantic Zantac Sostril Zantic Zantac Zantac Zantac Zantac Acidex Ranidil Taural TorioI Ulcex Vizerul

Manufacturer Glaxo Glaxo Glaxo Glaxo Cascan Glaxo Glaxo Glaxo Glaxo Glaxo Syncro Duncan Roemmers Vita Guidotti Montpellier

Country UK Italy Switz. France W. Germany W. Germany Netherlands Sweden Canada US Argentina Italy Argentina Spain Italy Argentina

Year Introduced 1981 1981 1982 1982 1982 1982 1982 1983 1983 1983 -

Manufacturing Process N-methyl-1-(methylthio)-2-nitroetheneamine (230 g) in water (400 ml) was stirred and heated at 45°C to 50°C. 2-[[[5-(Dimethylamino)methyl-2furanyl]methyl]thio]ethanamine (321 g) was added dropwise over 4 hours and the resultant solution stirred for a further 3.5 hours. The solution was then heated at reflux for 1/2 hour, cooled to 70°C and 4methylpentan-2-one (2 liters) added. The water was removed by azeotropic distillation under reduced pressure (260 torrs) and the resultant solution treated with charcoal (10 g) at 50°C. The solution was filtered and cooled to 10°C. N-[2-[[[5-dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'methyl-2-nitro-1,1-ethenediamine (380 g) was filtered off and dried, melting point 69°C to 70°C. References Merck Index 8019 DFU 4 (9) 663 (1979) PDR p. 919 OCDS Vol. 3 p. 131 (1984)

Razoxane

2957

DOT 18 (12) 665 (1982) I.N. p. 839 REM p. 798 Price, B.J., Clitherow, J.W. and Bradshaw, J.; US Patent 4,128,658; December 5, 1978; assigned to Allen and Hanburys Ltd.

RAZOXANE Therapeutic Function: Antitumor Chemical Name: dl-1,2-Bis(3,5-dioxopiperazin-1-yl)propane Common Name: Structural Formula:

Chemical Abstracts Registry No.: 21416-87-5 Trade Name Razoxin

Manufacturer I.C.I.

Country UK

Year Introduced 1977

Raw Materials Formamide 1,2-Diaminopropane tetraacetic acid Manufacturing Process 1,2-Diaminopropane tetraacetic acid (100 g) and formamide (400 ml) are heated together at reduced pressure under nitrogen at 100°C to 110°C for 1 hour, and then at 150°C to 155°C for 4 hours. The brown solution is evaporated under reduced pressure at 80°C to 90°C and the residue is taken up in methanol (120 ml) and cooled in the refrigerator overnight. Filtration, followed by washing with methanol and vacuum drying at 65°C gives dl-1,2bis(3,5-dioxopiperazin-1-yl)propane (62 g, 70%) as a very pale cream microcrystalline solid, melting point 237°C to 239°C. References Merck Index 8026

2958

Reboxetine mesylate

DFU 2 (7) 473 (1977) Kleeman and Engel p. 800 DOT 13 (12) 546 (1977) Creighton, A.M.; US Patents 3,941,790; March 2, 1976; and 4,275,063; June 23, 1981; both assigned to National Research Development Corp.

REBOXETINE MESYLATE Therapeutic Function: Antidepressant Chemical Name: ()-(2R*)-2-((αR*)-α-(o-ethoxyphenoxy)benzyl)morpholine, monomethanesulfonate Common Name: Reboxetine mesilate Structural Formula:

Chemical Abstracts Registry No.: 98769-82-5; 98769-81-4 (Base) Trade Name Edronax Lonol Davedax Norebox

Manufacturer Pharmacia and Upjohn Promeco Bracco S.p.A. Pharmacia and Upjohn

Country -

Year Introduced -

Raw Materials 2-[α-(2-Ethoxyphenoxy)-benzyl]-morpholin-3-one Borane Manufacturing Process To 2-[α-(2-ethoxyphenoxy)benzyl]-morpholin-3-one in 60 ml of anhydrous THF there was added dropwise under stirring a solution of BH3 in THF. The whole was heated at reflux for 3 hours and dropwise addition under cold conditions (0-(-5)°C) was then made of 3 ml of methanol and then of 3 ml of 23% HCl. The solvent was removed under reduced pressure. The residue was

Relaxin

2959

diluted with H2O, made alkaline and extracted with chloroform. The organic extracts were washed to neutrality, dried and evaporated to dryness, to obtain 2-[α-(2-ethoxyphenoxy)benzyl]-morpholine. Yield >90%; one diastereoisomer, M.P. 170-171°C. In practice it is usually used as monomethanesulfonate salt. References Melloni P. et al.; US Patent No. 4,229,1980; Assigned to Farmitalia Carlo Erba, S.p.A., Milan, Italy

RELAXIN Therapeutic Function: Ovarian hormone Chemical Name: Polypeptide of approximately 6,000 molecular weight Common Name: Releasin Structural Formula: See Chemical name Chemical Abstracts Registry No.: 9002-69-1 Trade Name Releasin Cervilaxin

Manufacturer Warner Lambert National

Country US US

Year Introduced 1956 1957

Raw Materials Hog ovaries Acetone Manufacturing Process 500 pounds of frozen hog ovaries (relaxin content: 20,200 G.P.U./lb) are ground with 50 pounds of solid carbon dioxide (Dry Ice) in a Fitzpatrick mill using a 1/4 inch screen. The resulting finely divided tissue-carbon dioxide homogenate at a temperature of -20°C is stirred into a 1.6 N HCl solution prepared by mixing 15 liters of concentrated (12 N) HCl with 100 liters of water. The homogenate is added to the aqueous acid over a period of approximately 1 hour so that the temperature of the mixture does not fall below -5°C. The resulting slurry is stirred for 6 hours and then allowed to stand overnight. The following day, a quantity of 200 gallons of acetone is added to the suspension followed by stirring for 8 hours. The mixture is again allowed to stand overnight. The following day, the clear supernatant liquid is decanted from the suspension and the tissue residue is removed by filtration. The filter

2960

Remifentanil hydrochloride

cake (tissue residue) is repulped with 35 gallons of a mixture of 0.3 volume 12 N HCl, 9.7 volumes water and 30.0 volumes acetone and the resulting suspension is filtered. The filtrates are combined with the supernatant liquid obtained by decantation to form the acid-acetone extract with a volume of 275 gallons. The relaxin content of the extract is 9.4 G.P.U./ml or 19,600 G.P.U./lb ovaries extracted, an activity yield of about 97 percent. References Merck Index 8031 I.N. p.841 Doczi, J.; US Patent 3,096,246; July 2, 1963; assigned to Warner-Lambert Pharmaceutical Co.

REMIFENTANIL HYDROCHLORIDE Therapeutic Function: Analgesic, Anesthetic Chemical Name: 1-Piperidinepropanoic acid, 4-(methoxycarbonyl)-4-((1oxopropyl)phenylamino)-, methyl ester, monohydrochloride Common Name: Remifentanil hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 132539-07-2; 132875-61-7 (Base) Trade Name Ultiva

Manufacturer Glaxo Wellcome Operations Ltd.

Country USA

Year Introduced -

Raw Materials 4-Methoxycarbonyl-4-[(1-oxopropyl)phenylamino]-piperidine Methyl acrylate 2-Butanone

Repaglinide

2961

Manufacturing Process 3-[4-Methoxycarbonyl-4-[(1-oxopropyl)phenylamino]-1-piperidine]propanoic acid, methyl ester To a solution of 4-methoxycarbonyl-4-[(1-oxopropyl)phenylamino]-piperidine (200 mg, 0.68 mmol) in acetonitrile (1.1 ml) is added methyl acrylate (124 µl, 1.36 mmol) at room temperature. The solution is stirred at 50°C for 2 hours, cooled to room temperature, and concentrated to an oily residue. The residue is chromatographed on silica gel (ethyl acetate) to give 3-[4methoxycarbonyl-4-[(1-oxopropyl)phenylamino]-1-piperidine]propanoic acid, methyl ester as an oil: 253 mg, 97%. An equimolar amount of oxalic acid is added to a solution of the free base in ethyl acetate. The precipitated salt is recrystallized by adding methanol and heating until the solid goes back into solution. Upon cooling the salt precipitates as a white solid; oxalate salt. It is recrystallized from methanol and 2-butanone; m.p. 170°-172°C. The hydrochloride salt may be make by dissolving the free base in toluene, saturating the solution with dry hydrogen chloride and concentrating to a solid. The solid is then recrystallized from appropriate solvent. References Feldman et al.; US Patent No. 5,019,583; May 28, 1991; Assigned to Glaxo Inc., Research Triangle Park, N.C.

REPAGLINIDE Therapeutic Function: Antidiabetic Chemical Name: Benzoic acid, 2-ethoxy-4-(2-((3-methyl-1-(2-(1piperidinyl)phenyl)butyl)amino)-2-oxoethyl)-, (S) Common Name: Repaglinide Structural Formula:

Chemical Abstracts Registry No.: 135062-02-1

2962

Repaglinide

Trade Name Eurepa NovoNorm Prandin Repaglinide

Manufacturer Torrent Pharmaceuticals Ltd. Novo Nordisk Medley Novo Nordisk

Country India Denmark USA Denmark

Year Introduced -

Raw Materials Triphenylphosphine Triethylamine

3-Ethoxy-4-ethoxycarbonyl-phenylacetic acid 3-Methyl-1-(2-piperidino-phenyl)-1-butylamine

Manufacturing Process Ethyl 2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-3-methyl-1-butyl}aminocarbonylmethyl]-benzoate 3 g (11.9 mmols) of 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid, 3.7 g (14.3 mmols) of triphenylphosphine, 3.3 ml (23.8 mmols) of triethylamine and 1.15 ml (11.9 mmols) of carbon tetrachloride were added successively to a solution of 2.9 g (11.9 mmols) of 3-methyl-1-(2-piperidino-phenyl)-1-butylamine in 29 of acetonitrile. The mixture was then stirred for 15 hours at room temperature, the solvent was removed in vacuo, and the residue was taken up in a mixture of ethyl acetate and water. The organic phase was dried over sodium sulfate, filtered and concentrated by evaporation in vacuo. The evaporation residue was purified by column chromatography on silaca gel (toluene/acetone = 10/1). Yield: 4.9 g (85% of theory). M.p. 143°-145°C (petroleum/ether). High-melting-point form (B) of 2-ethoxy-4-[N-{1-(2piperidinophenyl)-3-methyl-1-butyl}-aminocarbonylmethyl]-benzoic acid. A mixture of 4.7 g (9.7 mmols) of ethyl 2-ethoxy-4-[N-{1-(2-piperidinophenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoate and 14.7 ml of 1 N sodium hydroxide was stirred in 47 ml of ethanol for 2 hours at 60°C, then neutralized with 14.7 ml of 1 N hydrochloric acid and cooled to 0°C. The mixture was filtered to remove the precipitated colorless crystals, and the crystals were washed with ice water and with a little ice cold ethanol and then dried at 100°C/1 Torr. Yield: 3.9 g (88% of theory). M.p. 140°-142°C. Upon further recrystallization from ethanol/water (2/1) the melting point remained constant. Low-melting-point form (A) of 2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-3methyl-1-butyl}-aminocarbonylmethyl]-benzoic acid. 1 g of the high-melting-point form (B) of 2-ethoxy-4-[N-{1-(2-piperidinophenyl)-3-methyl-1-butyl}-aminocarbonyl-methyl]-benzoic acid was dissolved at room temperature in 5 ml of acetone, and 5 of petroleum ether (m.p. 60°70°C) were added. Upon trituration, crystallization gradually set in. The same quantity of petroleum ether was added again, and after crystallization had ended, the mixture was filtered. The crystals were washed with petroleum ether, and the almost colorless crystals were dried for 2 hours at 60°C/0.1 Torr. Yield: 0.7 g. M.p. 95°-98°C (clear beginning at 135°C). The IR-spectra for this form are identical to the IR-spectra for the form (A), melting point 90°-92°C.

Reproterol

2963

High-melting-point form (B) of 2-ethoxy-4-[N-{1-2-piperidino-phenyl)-3methyl-1-butyl}-aminocarbonylmethyl]-benzoic acid 1 g of the low-melting-point form (A) of 2-ethoxy-4-[N-{1-(2-piperidinophenyl)-3-methyl-1-butyl}-amino-carbonylmethyl]-benzoic acid was dissolved in 10 ml of ethanol/water (2/1) while heating over a steam bath. The solution was then cooled to 0°C, whereupon crystallization began. The mixture was filtered, and the residue was washed with a little ice-cold ethanol and dried at 100°C/1 Torr. Yield: 0.8 g. M.p. 140°-142°C. Foamy form (C) of 2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-3-methyl-1-butyl}aminocarbonylmethyl]-benzoic acid 1.5 g of the high-melting-point form (B) of 2-ethoxy-4-[N-{1-(2-piperidinophenyl)-3-methyl-1-butyl}-amino-carbonylmethyl]-benzoic acid was dissolved in 5 ml of methanol while heating. The solution was then cooled to 0°C with trituration. The crystals precipitated thereby were separated by filtration, washed with a little cold methanol, and dried for 2 hours at 60°C/0.1 Torr. Yield of adduct (with 1 times CH3OH): 1.2 g. M.p. 85°-90°C. The adduct was converted into the methanol-free foamy form (C) by heating for 24 hours at 60°C/5 Torr over phosphorus pentoxide. Melting range: 75°-85°C. References Grell et al.; US Patent No. 5,216,167; Jun. 1, 1993; Assigned to Dr. Karl Thomae GmbH, Biberach an der Riss, Fed. Rep. of Germany Grill et al.; US Patent No. 5,312,924; May 17, 1994; Assigned to Dr. Karl Thomae GmbH, Biberach an der Riss, Fed. Rep. of Germany

REPROTEROL Therapeutic Function: Bronchodilator Chemical Name: 7-[3-[[2-(3,5-Dihydroxyphenyl)-2-hydroxyethyl] amino]propyl]-3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione Common Name: Structural Formula:

2964

Reproterol

Chemical Abstracts Registry No.: 54063-54-6; 13055-82-8 (Hydrochloride salt) Trade Name Bronchospasmin Bronchospasmin Bronchodil Asmaterol Tiffen

Manufacturer Homburg Farmades Berlimed Lusofarmaco Tosi

Country W. Germany Italy UK Italy Italy

Year Introduced 1977 1981 1981 -

Raw Materials Theophylline Palladium on carbon Benzylamine

1-Bromo-3-chloropropane 3,5-Dihydroxy-ω-bromoacetophenone Hydrogen

Manufacturing Process Theophylline is reacted first with 1-bromo-3-chloropropaneto give chloropropyl theophylline, then with benzylamine to give benzylaminopropyltheophylline. That is reacted with 3,5-dihydroxy-ω-bromoacetophenone to give the starting material. 500 g of 7-[3-[2-(3,5-dihydroxyphenyl)-2-oxoethyl-benzylamino]-propyl]theophylline hydrochloride obtained as above were dissolved in 5 liters of dimethyl acetamide. There were added 25 g of a 10% palladium-carbon catalyst, the mixture heated to 70°C and hydrogenated with stirring at this temperature and 2 bar pressure until the speed of hydrogenation perceptibly slowed (about 2 hours). Subsequently, the mixture was filtered and after addition of a further 25 g of the palladium catalyst hydrogenated at 6 bar to the end (2 to 3 hours). The mixture was filtered, the greatest part of the solvent distilled off at a water jet vacuum, and the residue treated with 8 liters of ethanol. The solution was cooled for 12 hours with flowing water and the precipitated material filtered off with suction. Then it was boiled for one hour with 2 liters of methanol with stirring and the passing through of nitrogen, allowed to cool to 25°C and filtered off with suction. After drying in a vacuum at 55°C there were obtained 391 g (= 94.5% of theory) of pure 7[3-[2-(3,5-dihydroxyphenyl)-2-hydroxyethylamino]propyl]-theophylline hydrochloride. Melting point 263°C to 265°C. References Merck Index 8035 Kleeman and Engel p. 800 OCDS Vol. 3 p. 231 (1984) DOT 13 (2) 552 (1977) I.N. p. 842 Klingler, K.H. and Bickel, E.; US Patent 4,150,227; April 17, 1979; assigned to Degussa (Germany)

Rescimetol

2965

RESCIMETOL Therapeutic Function: Antihypertensive Chemical Name: Methylreserpate 3'-methoxy-4'-hydroxycinnamate Common Name: Structural Formula:

Chemical Abstracts Registry No.: 73573-42-9 Trade Name

Manufacturer

Country

Year Introduced

Toscara

Nippon Chemiphar

Japan

1982

Raw Materials Methylreserpate 3'-methoxy-4'-ethoxycarboxycinnamate Sodium Methanol Manufacturing Process 28 mg of a metal sodium were dissolved in 25 ml of anhydrous methanol, and one drop of water was added thereto. 1.5 g of methylreserpate 3'-methoxy-4'ethoxycarboxycinnamate in 25 ml of tetrahydrofuran were added thereto. The mixture was then stirred at room temperature for 2 hours. One drop of acetic acid was added thereto, and the solvent was evaporated. The residue was extracted with chloroform, the extract was washed with saturated sodium bicarbonate solution and then with water.

2966

Rescinnamine

The chloroform layer was dried over sodium sulfate, and the solvent was evaporated, so that there was obtained a brown amorphous matter. This was recrystallized from chloroform-hexane, and there was then obtained 1.0 g (78% of yield) of methylreserpate 3'-methoxy-4'-hydroxycinnamate which was characterized as pale yellow needles having a melting point of 259°C to 260°C. References Merck Index 8038 DFU 3 (3) 183 (1978) (As CD-3400) and 5 (12) 635 (1980) DOT 18 (10) 551 (1982) Kametani, T.; US Patent 3,898,215; August 5, 1975; assigned to Nippon Chemiphar Co., Ltd.

RESCINNAMINE Therapeutic Function: Antihypertensive Chemical Name: 11,17α-Dimethoxy-18β-[[1-oxo-3-(3,4,5trimethoxyphenyl)-2-propenyl]-oxy]-3β,20α-yohimban-16α-carboxylic acid methyl ester Common Name: 3,4,5-Trimethoxycinnamoyl methyl reserpate Structural Formula:

Chemical Abstracts Registry No.: 24815-24-5

Rescinnamine Trade Name Moderil Aldatense Anaprel Apolon Aporecin Aporesin Apotension Apoterin Atension Caniramine Cartric Cinnaloid Colstamin Daisaloid Isocalsin Paresinan Rescamin Rescimin Rescinate Rescisan Rescitens Resiloid Rosex Rozex Sciminan Seripinin Sinselpin

Manufacturer Pfizer Searle Servier Toyama Kayaku A.L. Santen Seiko Santen Hokuriku Sanwa Taito Pfizer Kowa Mohan Kowa Wakamoto Pharmacia Torlan Ohta Pharmacia Fargal Nippon Shoji Teikoku Teisan Kotani Fuji Zoki Kobayashi

Country US France France Japan Japan Norway Japan Japan Japan Japan Japan Japan Japan Japan Japan Japan Sweden Spain Japan Sweden Italy Japan Japan Japan Japan Japan Japan

2967

Year Introduced 1956 -

Raw Materials 3,4,5-Trimethoxycinnamic acid Methyl reserpate Thionyl chloride Rauwolfia plants Manufacturing Process 4.0 grams of 3,4,5-trimethoxycinnamic acid, MP 125.5° to 127°C was refluxed for 35 minutes under anhydrous conditions with 6.0 parts by volume of redistilled thionyl chloride. The excess thionyl chloride was removed under vacuum and by distilling from the residue two portions of dry benzene. The crystalline residue was crystallized twice from hexane-ether to yield 3,4,5-trimethoxycinnamoyl chloride which was obtained in the form of bright yellow prisms, MP 95° to 96°C.

2968

Reserpine

To a solution of 0.80 part by weight of methyl reserpate in 10 parts by volume of dry distilled pyridine at 10° to 15°C were added in portions during 20 minutes with stirring and external cooling 1.1 parts by weight of 3,4,5trimethoxycinnamoyl chloride. The reaction was carried out under nitrogen. After standing at room temperature for 65 hours the pyridine was removed under reduced pressure and at a temperature of 50° to 60°C. A brown solid froth-like material was obtained which was chromatographed on 30 parts by weight of alumina (activity II-III). The fractions eluted with benzene-acetone mixtures, on crystallization from benzene yielded 3,4,5-trimethoxycinnamate of methyl reserpate in the form of needles, which on recrystallization from methanol melted at 232° to 234°C as described in US Patent 2,854,454. The 3,4,5-trimethoxycinnamic ester of methyl reserpate is also present in Rauwolfia plants and obtainable in purified form therefrom by extraction as described in US Patents 2,974,144 and 2,876,228. References Merck Index 8039 Kleeman and Engel p. 801 PDR p. 1422 OCDS Vol. 1 p. 319 (1977) I.N. p. 843 REM p. 909 Ulshafer, P.R.; US Patent 2,854,454; September 30, 1958 Ordway, H.W. and Guercio, P.A.; US Patent 2,876,228; March 3, 1959; assigned to Chas. Pfizer and Co., Inc. Klohs, M.W., Draper, M.D. and Keller, F.; US Patent 2,974,144; March 7, 1961; assigned to Riker Laboratories, Inc.

RESERPINE Therapeutic Function: Antihypertensive Chemical Name: 11,17α-Dimethoxy-18β-[(3,4,5-trimethoxybenzoyl)oxy]3β,20α-yohimban-16β-carboxylic acid methyl ester Common Name: 3,4,5-Trimethoxybenzoyl methyl reserpate Chemical Abstracts Registry No.: 50-55-5 Raw Materials Rauwolfia plant bark Methanol

Reserpine

2969

Structural Formula:

Trade Name Serpasil Sndril Rau-Sed Crystoserpine Serpine Serfin Reserpoid Serpiloid Serpanray Vio-Serpine Serpena Serpate Rausaingle Sertabs Eskaserp Serolfia Resercen Banasil Roxinoid Respital Raurine D-Lay Lemiserp Abesta Broserpine Cardioserpine Chloroserpine Demi-Regroton Diupres Diutensin HHR

Manufacturer Ciba Lilly Squibb Dorsey Pitman-Moore Parke Davis Upjohn Riker Panray Rowell Haag Vale Philips Roxane Table Rock SKF Mallard Central Ulmer MSD Premo Westerfield Lemmon A.N.A. Brothers Pharm Star Schein U.S.V. MSD Wallace Schein

Country US US US US US US US US US US US US US US US US US US US US US US France US Finland US US US US US

Year Introduced 1953 1954 1954 1954 1954 1954 1954 1954 1954 1955 1955 1955 1955 1955 1955 1955 1956 1956 1956 1956 1961 1962 -

2970

Reserpine

Trade Name Hydro-Fluserpine Hydromox Hydropres Hydroserpine Key-Serpine Lemiserp Metatensin Naquival Neo-Serp Raulen Rausan Rausedan

Manufacturer Schein Lederle MSD Schein Key Lemmon Merrell Dow Schering Neo Paul Maney Wassermann Arzneimittelwerk Dresden

Country US US US US US US US US Canada Canada Spain E. Germany

Year Introduced -

Rauvilid Rauwita Regroton Renese-R Resedril Rese-Lar Reser-Ar Resercrine

Pharmacia Lifasa U.S.V. Pfipharmecs Estedi Perga Luar Casgrain and Charbonneau

Sweden Spain US US Spain Spain US Canada

-

Reserfia Reserpur Resine Resomine Rivasin Slutensin Ser-Ap-Es Serolfia Serpalan Serpax Serpedin Serpena Serpentil Serpipur Serpivite Serpoid Serpone Serpresan Sertina SK-Reserpine Unipres Vio-Serpine V-Serp

Medic A.F.I. Kirk Bonjean Giulini Bristol Ciba Ascher Lannett Verdun Pharmacia Haag Pliva Kwizda Vitarine Canfield Hartz Maipe Fellows-Testagar SKF Reid-Rowell Rowell Vangard

Canada Norway US Belgium W. Germany US US US US Canada Sweden US Yugoslavia Austria US US Canada Spain US US US US US

-

Ribavirin

2971

Manufacturing Process 7,000 parts by weight of powdered bark from the root of Rauwolfia serpentina Benth, are percolated with about 35,000 parts by volume of methanol. After evaporating the methanol extract, 1,050 parts by weight are obtained of a dark colored powder which is treated several times with water for removal of soluble constituents. The insoluble residue remaining from this operation is subsequently masticated five times, in each case with 1,500 parts by volume of 10% aqueous acetic acid, the solution being best separated from the smeary residue by centrifuging. The brown acetic acid solution, which for further working up can be concentrated at low temperature to a small volume or be diluted with half the volume of water, possesses a pH of about 3.9. This solution is extracted by shaking with 3,500 to 4,000 parts by volume of chloroform divided into 3 to 4 portions. These chloroform extracts are washed once with potassium carbonate solution and twice with water, dried with sodium sulfate and evaporated to dryness under reduced pressure. The residue, amounting to 70 to 80 parts by weight, forms a green-brown colored powder. For further purification, this residue is dissolved in benzene and chromatographed over 1,000 to 1,200 parts by weight of neutral aluminum oxide (activity H-III according to Brockmann). On elution with benzene there are first obtained small quantities of a yellow oil and 0.9 part by weight of an inactive crystallizate of melting point 238°C to 239°C, after which the substance of sedative activity follows. As soon as the major quantity of the active substance has been eluted, further elution is carried out with a mixture of 2 parts by volume of benzene and 1 part by volume of acetone. In this manner the residue of the sedative substance is obtained and after that a further inactive crystallizate of melting point 141°C to 143°C. The eluate fractions containing the sedative substance are evaporated to dryness. By recrystallization of the residue from hot acetone or a mixture of chloroform and ether.6.5 to 7 parts by weight of reserpine are obtained in the form of almost colorless crystals of melting point 262°C to 263°C (with decomposition). References Merck Index 8042 Kleeman and Engel p. 802 PDR pp. 710, 812, 993, 1011, 1168, 1185, 1231, 1409, 1449, 1606, 1634, 1723, 1820, 1876, 1999 I.N. p. 843 REM p. 908 Schwyzer, R. and Mueller, J.; US Patent 2,833,771; May 6, 1958; assigned to Ciba Pharmaceutical Products, Inc.

RIBAVIRIN Therapeutic Function: Antiviral Chemical Name: 1,2,4-Triazole-3-carboxamide, 1-β-D-ribofuranosylCommon Name: Ribavirin; Tribavirin

2972

Ribavirin

Structural Formula:

Chemical Abstracts Registry No.: 36791-04-5; 66510-90-5 Trade Name Copegus Rebetol Rebetol Rebetol Ribasphere Ribavin Ribavirin Ribavirin Ribavirin Ribavirin-Meduna Virazole Virazole

Manufacturer Roche Laboratories Schering-Plough Labo N.V. Schering - Plough Corp. Fulford GALT (India) Ltd. Three Rivers Pharmaceuticals Lupin Laboratories Ltd. Dragon Hwa ChemPharm Co. Valeant Pharmaceuticals International ICN Pharmaceuticals Inc. Meduna Arzneimittel ICN Switzerland AG Valeant Pharmaceuticals International

Country USA Belgium USA India USA

Year Introduced -

India China

-

USA

-

USA Germany Switz. USA

-

Raw Materials Triethyl orthoformate 1-Cyanoformidic acid hydrazide Triethylamine Enzyme Nucleoside Phosphorylase (Calf Spleen) Manufacturing Process 3-Cyano-1,2,4-triazole A mixture of triethyl orthoformate (150 ml) and 1-cyanoformidic acid hydrazide, K. Matsuda and L. T. Morin, J. Org. Chem., 26:3783 (1961), (25.2 g, 0.30 mol) was cooled to 0°C and a solution (4.0 ml) of dioxane saturated with anhydrous hydrogen chloride was added with stirring. The mixture was stirred with cooling in an ice bath for 5 hours and stirring at 25°C was continued for 15 hours. The mixture was evaporated to dryness and ether

Ribavirin

2973

(500 ml) was added to the residue. The solution was filtered, washed with water, and the organic layer was dried over magnesium sulfate. The solution was filtered and the ether was removed. Crystallization of the product from ethyl acetate-benzene provided 16.0 g (56.8%) of 3-cyano-1,2,4-triazole with a melting point of 185°-187°C. All properties of the compound were identical with those of a sample prepared by the method of Cipens and Grinsteins, Latvijas PSR Zinatnu Adad. Vestis., Kim Ser., 1965 (2), 204-208. Chem Abst., 63, 13243 (1965). 1,2,4-Triazole-3-thiocarboxamide A mixture of 3-cyano-1,2,4-triazole (4.7 g, 0.050 mol), ethanol (50 ml) and triethylamine (8.0 ml) was stirred at room temperature while hydrogen sulfide gas was bubbled into the mixture for 4 hours. The solvent was removed and water was added to the residue to provide 2.7 g of product. Recrystallization from water afforded pure 1,2,4-triazole-3-thiocarboxamide with a melting point of >350°C. 1-β-D-Ribofuransyl-1,2,4-triazole-3-carboxamide Synthesis of 1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide from 1,2,4triazole-3-carboxamide via Purified Calf Spleen Nucleoside Phosphorylase. The samples were incubated at 25°C for 5 minutes and then frozen in dry ice/isopropanol to stop the reaction. Aliquots of the thawed samples were then spotted on silica gel together with standard solutions of 1,2,4-triazole-3carboxamide and 1-β-D-ribofuranosyl-1,2,4-triazole- 3-carboxamide and separated in isopropanol:NH4OH:H2O (7:1:2). Areas of the chromatograms coinciding with 1,2,4-triazole-3-carboxamide were removed and counted to determine the percent of conversion of 1,2,4 -triazole-3-carboxamide to 1-βD-ribofuranosyl-1,2,4-triazole-3-carboxamide. 1,2,4-Triazole-3-carboxamide may be also converted to 1-β-D-ribofuranosyl1,2,4-triazole-3-carboxamide by reaction with the enzyme Nucleoside Phosphorylase at a pH within the range of about 7 to 8, at an enzyme concentration about 0.15 mg/ml, and a temperature approximately 25° to about 35°C. Satisfactory results have been obtained when the triazole base is present in a concentration greater than 5 x 10-5M and ribose-1-phosphate is present at a concentration greater than 2 x 105M. Generally are required for the reactionabout 0.5 to about 1 hour. The source of the enzyme may be animal, tissue, or bacteria. The principal bacterial sources are E. coli and yeast, Brevebacterium, while a variety of animal sources exist, including beef spleen, rat liver, calf liver, calf thymus, beef liver, monkey brain, horse liver, calf spleen, human erythrocytes, fish skin, and fish muscle. References Witkowski et al.; US Patent No. 3,976,545; Aug. 24, 1976; Assigned to ICN Pharmaceuticals, Inc., Irvine, Calif. Fujishima et al.; US Patent No. 4,614,719; Sep., 30, 1986; Assigned to Yamasa Shoyu Kabushiki Kaisha, Chiba, Japan

2974

Riboflavin

RIBOFLAVIN Therapeutic Function: Enzyme cofactor vitamin Chemical Name: 7,8-Dimethyl-10-(D-1-ribityl)isoalloxazine Common Name: Lactoflavin; Lattoflavina; Ovoflavin; Riboflavin; Vitamin B2; Vitamin G; Witamina B2 Structural Formula:

Chemical Abstracts Registry No.: 83-88-5 Trade Name Riboflavin Riboflavin Riboflavin Riboflavin Riboflavin Riboflavin Riboflavin Riboflavin Riboflavin Riboflavin Vitamin B2

Manufacturer Roche Vitamins Takeda Chemical Industry Cytoplan Ltd Hubei Guangji Pharmaceutical Co. Ltd. BASF AG BASF Health and Nutrition A/S F.Hoffmann-La Roche AG Takeda Europe GmbH Hoffmann - La Roche Inc. Merck and Company, Inc. Pharmadass Ltd

Raw Materials o-Amino-biphenyl Sodium nitrite Tetraacetyl-ribitylxylidine Barbituric acid Hydrogen peroxide

Country Germany Japan China

Year Introduced -

Germany Denmark

-

Germany Germany USA USA -

-

Riboflavin

2975

Manufacturing Process A solution of o-biphenyl diazonium sulfate is prepared as follows: o-aminobiphenyl 21.1 g (0.125 mole), is dissolved by warming in a mixture of 100 ml of glacial acid and 136 ml of water. To this solution is added a mixture: 11.2 ml of concentrated sulfuric acid and 25 ml of water. The temperature is then lowered to 0° to 5°C and 8.65 g (0.125 mole) of sodium nitrite is added in small portions to the: stirred solution over a one hour period. The solution is stirred for an additional two hours at 0° to 5°C after the addition of the nitrite is complete. A solution of ribitylxylidine is prepared as follows: a stirred suspension of 42.3 g (0.10 mole) of tetraacetylribitylxylidine and 85 ml of water is heated to 95° to 100°C. To this material is added, over a five to 10 minute period, exactly 0.40 mole of aqueous 25 to 30% sodium hydroxide solution, the temperature being held at 95° to 100°C. Shortly after the addition of the caustic solution, the mixture becomes homogeneous, the temperature rises suddenly, and a rapid evolution of steam occurs. The light, straw-colored solution is then stirred for a one hour at 95° to 100°C to insure completeness of reaction. With the resulting ribitylxylidine solution at a temperature of 90°C, 166 ml of 57.5 percent (v./v.) aqueous acetic acid is added, and the solution is then cooled to 0° to 5°C. The solution of o-biphenyl diazonium sulfate is now added to the ribitylxylidine solution at such a rate as to maintain the temperature of the resulting mixture below 8°C. The mixture is then stirred at 0° to 5°C for 24 hours. After the stirring period is complete the crude product is isolated by filtration; the wet product is slurried in 500 ml of water, refiltered, washed with 200 ml of water, and air-dried at 50° to 60°C. The dried material is pulverized to give about 44 g of 2-(o-biphenylazo)-4,5-dimethyl-1-ribitylamino-beiizene which is obtained as a granular, orange product; m.p. 134°-139°C, dec. To a mixture of 225 ml of ethyl acetate and 40.5 ml of glacial acetic acid is added 43.6 g (0.10 mole) of 2-(o-biphenylazo)-4,5-dimethyl-l-ribitylaminobenzene, prepared as described above, and 16.9 g (0.132 mole) of barbituric acid. The resulting mixture is refluxed with stirring for about 90 hours, at the end of which period an 0.5 ml test sample of the reaction solution, when mixed with 15 ml of 26% aqueous hydrochloric acid, gives a light straw color showing completion of the reaction. If the reaction is incomplete, the reaction mixture is refluxed for additional five hours periods until a test for completion of the reaction is obtained. The reaction mixture is cooled to 10°C for one hour and filtered. The crude product is washed successively with 50 ml of cold ethyl acetate and 50 ml of cold water, then air-dried at 70°C to give about 37 g of crude riboflavin, which is obtained as a brownish-yellow powder; yield approximately 98.5% of theory. Crude riboflavin, prepared as described above starting with 43.6 g of 2-(obiphehylazo)-4,5-dimethyl-1-ribityl amino-benzene, is washed with 50 ml of cold ethyl acetate, slurried with 180 ml of methanol at 65°C for thirty minutes. The methanol slurry is cooled to 10°C for thirty minutes, filtered, and the filtered material washed with 40 ml of cold methanol. The methanol washed riboflavin is then slurried with 180 ml of water at 80°C for thirty minutes, the slurry is cooled to 70°C, filtered, and the filtered material is washed with 40 ml of hot (70°C) water. The hot water-washed riboflavin is

2976

Ribostamicin

dissolved in a mixture of 70 ml of hydrochloric acid and 23 ml of water by warming to 45°C. The aqueous hydrochloric acid solution is treated with a 1.5 ml of 30% hydrogen peroxide solution to oxidize impurities and filtered through a filter precoated with diatomaceous silica (Super-Cel). The oxidized, filtered solution is poured, with vigorous agitation, into 900 ml of water at 95° to 100°C. The resulting riboflavin slurry is cooled slowly to 10°C, filtered, and the filtered material is washed with 2 x 50 ml of water and 4 x 50 ml portions of methanol. The washed material is air-dried, at 70°C, to give about 30 g of riboflavin; yield about 80% of theory based on the 42.3 g of tetraacetylribitylxylidine used as starting material. References Howe Ch.A. et al.; US Patent No. 2,807,611; Sept. 24, 1957; Assignted to Merck and Co., Inc., Rahway, N.J., a corporation of New Jersey

RIBOSTAMICIN Therapeutic Function: Antibiotic Chemical Name: O-2,6-Diamino-2,6-dideoxy-α-D-glucopyranosyl-(1-->4)-O[β-D-ribofuranosyl-(1-->5)]-2-deoxy-D-streptamine Common Name: Ribostamin Structural Formula:

Chemical Abstracts Registry No.: 25546-65-0 Trade Name

Manufacturer

Country

Year Introduced

Vistamycin

Meiji Seika

Japan

1972

Ribomycine

Delalande

France

1977

Ribostamin

Delalande

Italy

1979

Ibistacin

I.B.I.

Italy

1979

Landamycin

Delalande

W. Germany

1980

Rifampin

2977

Raw Materials Bacterium Streptomyces thermoflavus Glucose Soybean meal Manufacturing Process Streptomyces thermoflavus SF-733 strain was inoculated to 15 liters of a liquid medium (pH 7.0) containing glucose 2.5%, soybean meal 3.5%, soluble vegetable protein 1.0% and NaCl 0.25% and shake-cultured in a jarfermenter at 28°C for 3 days. 10 liters of culture filtrate (potency, 200 meg/ml) obtained by filtering culture broth at pH 4.0 was adjusted to pH 7.0 and applied to a column filled with 1 liter of Amberlite IRC 50 (NH4+type, Rohm and Haas) to adsorb active ingredient on ion-exchange resin. After washing with water the column was eluted with 0.5 N ammonia water. Active fractions were concentrated in vacuo and freeze-dried. 5.9 g of crude powder thus obtained was dissolved in 10 ml of water, applied to a column filled with 400 ml of Dowex 1 x 2 (OH-type, Dow Chemicals) and developed chromatographically with water to give 250 ml of active fraction which was concentrated in vacuo, whereby 2.1 g of light yellow powder of SF-733 substance was obtained. 2.0 g of this powder was dissolved in 3 ml of water, applied to a column filled with 100 ml of Amberlite CG 50 (NH4+type) washed with water and eluted with 0.2 N ammonia water. 400 ml of active fraction was collected, concentrated in vacuo and freeze-dried to give 600 mg of white powder of free base of SF-733 substance. This powder was dissolved in about 5 ml of water and concentrated to syrup and added with about 50 ml of ethanol. The mother liquor together with white precipitate thus formed was concentrated in vacuo to dryness. 650 mg of ethanol-solvate-like white powder was dissolved in 65 ml of methanol. The solution became cloudy immediately after dissolution and crystals were gradually separated. After tightly sealed and left alone at 30°C overnight crystals were collected by means of glass filter and washed with about 1 ml of methanol. The crystals were held on calcium chloride as a drying agent at room temperature in vacuo and then dried on phosphorus pentoxide as a drying agent at 60°C for 19 hours in vacuo to give 440 mg of free base crystals of SF-733 substance. Yield: 73%. References Merck Index 8106 Kleeman and Engel p. 807 DOT 9 (3) 112 (1973) I.N. p. 848 Shomura, T., Ezaki, N., Tsuruoka, T., Niwa, T., Akita, E. and Niida, T.; US Patent 3,661.892; May 9, 1972; assigned to Meiji Seika Kaisha, Ltd. (Japan)

RIFAMPIN Therapeutic Function: Antitubercular

2978

Rifampin

Chemical Name: 5,6,9,17,19,21-Hexahydroxy-23-methoxy-2,4,12,16,18, 20,22-heptamethyl-8-[N-(4-methyl-1-piperazinyl)formimidoyl]-2,7(epoxypentadeca[1,11,13]trienimino)-naphtho[2,1-b]furan-1,11(2H)dione 21-acetate Common Name: 3-[(4-Methyl-1-piperazinyl)iminomethyl]rifamycin SV; Rifaldazine; Rifamycin AMF; Rifampicin Structural Formula:

Chemical Abstracts Registry No.: 13492-46-1 Trade Name Rifadin Rifadin Rimactan Rifadine Rimactane Rifadin Rimactan Rimactane Rifadin Archidyn Arficin Benemicin Fenampicin Feronia Riasin Rifa Rifagen Rifam Rifapiam Rifaprodin Rifarm Rifobac Rifonilo Riforal

Manufacturer Lepetit Merrell Ciba Lepetit Ciba Geigy Daiichi Ciba Ciba Dow Lepetit Belupo Ltd. Polfa Antibioticos Lifepharma Yurtoglu Gruenenthal Morgens Nobel Piam Prodes Pharmacal Llade Aristegui Llade

Country Italy UK W. Germany France UK Japan Japan US US Italy Yugoslavia Poland Spain Spain Turkey W. Germany Spain Turkey Italy Spain Finland Spain Spain Spain

Year Introduced 1968 1969 1969 1969 1969 1971 1971 1971 1971 -

Rifapentine Trade Name Rimapen Ripamisin Rofact Santadin Seamicin Tubocin

Manufacturer Orion Deva I.C.N. Santa Farma Galepharma Iberica Farmakhim

Country Finland Turkey Canada Turkey Spain Bulgaria

2979

Year Introduced -

Raw Materials 3-Formylrifamycin SV 1-Amino-4-methylpiperazine Manufacturing Process 3-Formylrifamycin SV is treated with 1-amino-4-methylpiperazine in tetrahydrofuran to give rifampin. References Merck Index 8113 Kleeman and Engel p. 808 PDR pp. 810, 1236 DOT 5 (1) 24 (1969) I.N. p. 848 REM p. 1233 Maggi, N. and Sensi, P.; US Patent 3,342,810; September 19, 1967; assigned to Lepetit SpA, Italy

RIFAPENTINE Therapeutic Function: Antibiotic, Antibacterial (leprostatic), Antibacterial (tuberculostatic) Chemical Name: Rifamycin, 3-(((4-cyclopentyl-1-piperazinyl)imino)methyl)Common Name: Rifapentine Chemical Abstracts Registry No.: 61379-65-5; 71950-35-1

Trade Name

Manufacturer

Country

Year Introduced

Priftin

Aventis Pharmaceuticals

-

-

Priftin

Hoechst Marion Rou

-

-

Rifapentine

Balkanpharma-Razgrad AD

-

-

Rifapentine

Hebei Xingang Biochemistry Co., Ltd.

China

-

2980

Riluzole

Structural Formula:

Raw Materials 3-Formylrifamycin SV Cyclopentyl bromide Manufacturing Process

N-Nitrosopiperazine Lithium aluminum hydride 3-(4-Cyclopentyl-1-piperazinyl) iminomethylrifamycin SV

0.01 mole of 3-formylrifamycin SV is dissolved in tetrahydrofuran and to the obtained solution 0.011 mole of 1-amino-4-cyclopentylpiperazine is added to the reaction mixture at room temperature. After 30 minutes, the reaction is completed since thin layer chromatography of the mixture shows disappearance of the starting 3-formylrifamycin SV. The solvent is then evaporated off and the residue is crystallized from ethyl acetate. The title product, which melts at 179°-180°C, is obtained in a 55% yield. The elementary analysis is in agreement with the theoretical values. The starting 1-amino-4-cyclopentylpiperazine (b.p. 80°-82°C/0.1 mm Hg) is obtained by alkylating N-nitrosopiperazine with cyclopentyl bromide in ethanol in the presence of NaHCO3 and reducing the so-obtained 1-nitroso-4cyclopentylpiperazine with LiAlH4 in ethyl ether. References Cricchio et al.; US Patent No. 4,002,752; Jan. 11, 1977; Assigned to Gryppo Lepetit, S.p.A., Milan, Italy

RILUZOLE Therapeutic Function: Neuroprotective Chemical Name: Benzothiazole, 2-amino-6-trifluoromethoxy-

Riluzole

2981

Common Name: Riluzole; Rilutek Structural Formula:

Chemical Abstracts Registry No.: 1744-22-5 Trade Name Rilutek PK-26124

Manufacturer RPR EMD Biosciences, Inc.

Country -

Year Introduced -

Raw Materials Sodium nitrite Potassium thiocyanate Tin

4-Amino-3-nitrobenzotrifluoride Copper thiocyanate

Manufacturing Process To a stirred solution of 74.6 g (0.5 mol) of benzylisothiocyanate in 500 mL toluene was added dropwise 46.6 g (0.5 mol) of aniline. The solution was refluxed 18 hours. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was recrystallized from an appropriate solvent to yield N-phenyl-N'-benzylthiourea. Isothiocyanates which are not commercially available may be prepared from aliphatic or aryl primary amines by the following methods: Kurita and Iwakura, Org. Synth. 59, 195; Jochims, Chem. Ber. 101, 1746 (1968); or Castro, Pena, Santos, and Vega, J. Org. Chem. 49, 863 (1984). To a stirred solution of 20.6 g (0.10 mol) 4-amino-3-nitrobenzotrifluoride in 30 mL conc. H2SO4 and 30 mL H2O at 0°C was added dropwise 37.5 mL 20% sodium nitrite. The mixture was stirred for 90 min at 0-5°C. Potassium thiocyanate (10 g in 20 mL H2O) was added dropwise and stirred 15 min. The reaction was poured into a vigorously stirred slurry of 18 g (0.148 mol) copper thiocyanate in 60 mL H2O. Gas evolution began and the mixture foamed. The reaction was stirred two hours at 3°C and then heated to 70°C for 20 min. The reaction was cooled to 25°C and stirred an additional 18 hours. The solution was filtered and the water was extracted with toluene (3 x 100 mL). The toluene layer was dried (Na2SO4), filtered, and concentrated under reduced pressure to yield 3-nitro-4-thiocyanatebenzotrifluoride as a purple oil. The product was purified by silica gel chromatography. The column was eluted initially with hexane followed by hexane/CH2Cl2 (7:3) to yield an oil which was crystallized from heptane to yield a yellow 3-nitro-4thiocyanatebenzotrifluoride, m.p. 72-73°C. To a vigorously stirred solution of 4.0 g (0.16 mol) 3-nitro-4thiocyanatebenzotrifluoride in 50 mL conc. HCl was added 16.0 g (0.135 mol) granulated tin over one hour. The reaction changed from an orange to very

2982

Rimantadine hydrochloride

pale yellow to white. The reaction was stirred at 25°C for 20 hours. The reaction solution was diluted with H2O (250 mL) and conc. NH4OH was added dropwise. The product precipitated along with the tin salts. The solid was filtered and boiled in CHCl3 (3 x 200 mL). The aqueous layer was extracted with CHCl3. All the CHCl3 washings were combined, dried (MgSO4), filtered, and concentrated under reduced pressure to yield a dark brown solid. The crude 2-amino-5-trifluoromethylbenzothiazole hydrochloride was dissolved in hot Et2O and filtered. To the filtrate was added a solution of freshly prepared Et2O/HCl. The product precipitate was filtered and washed with Et2O to yield a white solid of 2-amino-5-trifluoromethylbenzothiazole hydrochloride, m.p. 255.-257°C. References Merck Index, Monograph number: 8389, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. Johnson G., Pavia M. R.; US Patent No. 4,826,860; May 2, 1989; Assigned to Warner-Lambert Company (Morris Plaines, NJ)

RIMANTADINE HYDROCHLORIDE Therapeutic Function: Antiviral Chemical Name: 1-Adamantanemethylamine, α-methyl-, hydrochloride Common Name: Remantadine hydrochloride; Rimantadine hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 1501-84-4; 13392-28-4 (Base) Trade Name Flumadine Rimantadine hydrochloride

Manufacturer Forest Pharmaceuticals, Inc. Tai Yuan Pharmaceutical Factory

Raw Materials 1-Adamantylmethylketone Acetamide Formic acid

Country China

Year Introduced -

Rimiterol

2983

Manufacturing Process A mixture of 3 g of 1-adamantylmethylketone, 4 g of acetamide and 1.35 ml of 86% formic acid was boiled for 3.5 hours. Then the mixture was cooled, deluted with water and extracted with ether. The ether solution was dried over alkali, filtered and saturated with dry hydrogen chloride. The resulting precipitate was filtered off and boiled with 30 ml of concentrated hydrochloric acid for 5 hours. The reaction mixture was cooled, and the resulting precipitate was filtered off. After recrystalliszation from a mixture of absolute ethanol and ether 2.32 g of the desired product was obtained (64% to starting ketone). MP 345°-347°C. Rimantadine may be also prepared by refluxing of the 1adamantylmethylketone and ammonium formate in diethylene glycol or by hydrogenization of 1-adamantylmethyl ketoxime in the presence of a platinum on carbon catalyst at a room temperature and pressure. References Polis Y. et al.; US Patent No. 3,852,352; Dec. 3, 1974 Liu J.; US Patent No. 4,551,552; Nov. 5, 1985; Assigned to E.I. Du Pont de Nemours and Company, Wilmington, Del.

RIMITEROL Therapeutic Function: Bronchodilator Chemical Name: 4-(Hydroxy-2-piperidinylmethyl)-1,2-benzenediol Common Name: Erythro-3,4-dihydroxyphenyl-2-piperidinylcarbinol Structural Formula:

Chemical Abstracts Registry No.: 32953-89-2; 31842-61-2 (Hydrogen bromide) Trade Name

Manufacturer

Country

Year Introduced

Pulmadil

Riker

UK

1974

Asmaten

Riker

-

-

2984

Rimiterol

Raw Materials 4-Bromoveratrole 2-Cyanopyridine Sodium hydroxide Hydrogen

Magnesium Hydrogen chloride Hydrogen bromide

Manufacturing Process To a stirred suspension of 5.0 grams (0.21 gram atom) of magnesium turnings in 15 ml of tetrahydrofuran under nitrogen is added 43.4 grams (0.2 mol) of 4-bromoveratrole to maintain constant reflux. An additional 40 ml of solvent is added and the Grignard reagent thus prepared is heated on a steam bath for one hour. This solution is then added dropwise to a solution of 20.8 grams (0.2 mol) of 2-cyanopyridine in 300 ml of ether. The mixture is stirred overnight at room temperature, decomposed by addition of 250 ml of 10% hydrochloric acid and the separated aqueous layer is made alkaline with 40% sodium hydroxide solution. This mixture is extracted with methylene chloride and the dried extract concentrated. The residue is distilled and the fraction at 190° to 235°C/12 mm is crystallized to give 3,4-dimethoxyphenyl-2-pyridyl ketone, MP 93° to 94°C. A solution of 0.5 gram of the above ketone in 15 ml of 48% hydrobromic acid is refluxed for 1.5 hours and then concentrated in vacuo. The residue is dissolved in ethanol, toluene is added, the solution concentrated and the residue stripped with toluene to yield 3,4-dihydroxyphenyl-2-pyridyl ketone hydrobromide, MP 246° to 247°C (decomposition). A mixture of 0.5 gram of platinum oxide and a solution of 2.0 grams (0.0067 mol) of 3,4-dihydroxyphenyl-2-pyridyl ketone hydrobromide in 20 ml of water and 80 ml of ethanol is hydrogenated on the Parr apparatus using an initial hydrogen pressure of 50 psi at room temperature. The reaction mixture is filtered, the filtrate concentrated in vacuo and the residue triturated with acetone to give erythro-3,4-dihydroxyphenyl-2-piperidinylcarbinol hydrobromide, MP 210° to 211°C (decomposition). Treatment of the above hydrobromide with aqueous sodium bicarbonate followed by extraction with ethyl acetate yields the free base of the carbinol MP 203° to 204°C which may be reacted with other acids to give other acid addition salts. References Merck Index 8117 Kleeman and Engel p. 809 OCDS Vol. 2 p. 278 (1980) DOT 10 (11) 272 (1974) I.N. p. 849 Kaiser, C. and Ross, S.T.; US Patent 3,705,169; December 5, 1972; assigned to Smith Kline and French Laboratories

Risedronate sodium

2985

RISEDRONATE SODIUM Therapeutic Function: Bone calcium regulator Chemical Name: Phosphonic acid, (1-hydroxy-2-(3-pyridinyl)ethylidene)bis-, monosodium salt Common Name: Risedronate sodium Structural Formula:

Chemical Abstracts Registry No.: 115436-72-1; 105462-24-6 (Base) Trade Name

Manufacturer

Country

Year Introduced

Actonel

Aventis

-

-

Actonel

Procter and Gamble

USA

-

Raw Materials 3-Pyridine acetic acid Phosphorus trichloride

Chlorobenzene Celite 545

Manufacturing Process A 3-neck round-bottom flask fitted with a reflux condenser and a magnetic stir bar is charged with 6.94 grams (0.04 mole) 3-pyridine acetic acid 9.84 grams (0.14 mole) phosphorus acid, and 150 ml of chlorobenzene. This reaction mixture is heated on a boiling water bath, and 16.5 grams (0.12 mole) phosphorus trichloride is added dropwise with stirring. This reaction mixture is heated for 2 1/2 hours during which time a viscous yellow oil forms. The reaction mixture is then cooled in an ice bath and the chlorobenzene solution is decanted off from the solidified product. The reaction flask containing this solidified product is charged with 150 ml of water and heated in a boiling water bath for several hours. The hot solution is then filtered through Celite 545 300 ml of methanol is added to the warm filtrate solution, and a precipitate develops. After cooling in ice for 1 hour, the precipitate is filtered off and then washed with methanol/water (1/1 volume/volume), methanol, and ether, and air dried. The product may be recrystallized from hot water. Yield is approximately 5.9 grams (52%). The sample is characterized by P-31 and C-13 NMR. It may be converted into the sodium salt with equivalent of NaOH.

2986

Risperidone

References Benedict et al.; US Patent No. 5,583,122; Dec. 10, 1996; Assigned to The Procter and Gamble Company, Cincinnati, Ohio

RISPERIDONE Therapeutic Function: Antipsychotic, Neuroleptic Chemical Name: 4H-Pyrido(1,2-a)pyrimidin-4-one, 6,7,8,9-tetrahydro-3-(2(4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl)ethyl)-2-methylCommon Name: Risperidone Structural Formula:

Chemical Abstracts Registry No.: 106266-06-2 Trade Name

Manufacturer

Country

Year Introduced

Rasin

Pfizer

-

-

Respidon

Torrent Pharmaceuticals Ltd.

India

-

Risperdal

Janssen-Ortho Inc.

-

-

Risperidone

Janssen-Cilag

-

-

Rispolept

Janssen-Cilag SpA

-

-

Raw Materials 1,3-Difluorobenzene 1-Acetyl-4-piperidine-carbonyl chloride Aluminum chloride Hydroxylamine hydrochloride Potassium iodide 3-(2-Chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2a]pyrimidin-4-one monohydrochloride Manufacturing Process To a stirred mixture of 65 parts of 1,3-difluorobenzene, 130 parts of aluminium chloride and 195 parts of dichloromethane was added dropwise a solution of 95 parts of 1-acetyl-4-piperidine-carbonyl chloride in 65 parts of dichloromethane while cooling. Upon completion, stirring was continued for 3

Ritodrine

2987

hours at room temperature. The reaction mixture was poured into a mixture of crushed ice and hydrochloric acid. The product 1-acetyl-4-(2,4difluorobenzoyl)piperidine as a residue. A mixture of 48 parts of 1-acetyl-4(2,4-difluorobenzoyl)-piperidine and 180 parts of a hydrochloric acid solution 6 N was stirred and refluxed for 5 hours. The reaction mixture was evaporated and the residue was stirred in 2-propanol. The product was filtered off and dried, yielding 39 parts (83%) of (2,4-di-fluorophenyl)(4piperidinyl)methanone hydrochloride. A mixture of 12 parts of above product, 12 parts of hydroxylamine hydrochloride and 120 parts of ethanol was stirred at room temperature and 10.5 parts of N,N-diethylethanamine were added. The whole was stirred and 25 refluxed for 3 hours. After cooling, the precipitated product was filtered off and dried, yielding 11 parts (100%) of (2,4-di-fluorophenyl)(4-piperidinyl)methanone oxime. A mixture of 11 parts of (2,4-difluorophenyl)(4-piperidinyl)-methanone oxime, 25 parts of potassium hydroxide and 25 parts of 30 water was stirred and refluxed for 2 hours. The reaction mixture was cooled and extracted with methylbenzene. The extract was dried, filtered and evaporated. The residue was crystallized from petroleum ether, yielding 6;8 parts of 6-fluoro-3-(4piperidinyl)-1,2-benzisoxazole. A mixture of 5.3 parts of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4Hpyrido[1,2-a]pyrimidin-4-one monohydrochloride, 4.4 parts of 6-fluoro-3-(4piperidinyl)-1,2-benzisoxazole, 8 parts of sodium carbonate, 0.1 parts of potassium iodide and 90 parts of N,N- dimethylformamide was stirred overnight at 85°-90°C. After cooling the reaction mixture was poured into water. The product was filtered off and crystallized from a mixture of N,Ndimethylformamide and 2-propanol. The product was filtered off and dried, yielding 3.8 parts (46%) of 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1piperidinyl] ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]-pyrimidin- 4one: melting point 170°C. References Kennis et al.; European Patent Office No. 0 196 132 A2, 13.03.86

RITODRINE Therapeutic Function: Muscle relaxant (obstetric) Chemical Name: erythro-p-Hydroxy-α-[1-[(p-hydroxyphenethyl)amino] ethyl]benzyl alcohol Common Name: N-(p-Hydroxyphenylethyl)-4-hydroxynorephedrine Chemical Abstracts Registry No.: 26652-09-5; 23239-51-2 (Hydrochloride salt)

2988

Ritodrine

Structural Formula:

Trade Name Pre-Par Yutopar Pre-Par Pre-Par Yutopar Yutopar Miolene Utopar

Manufacturer Duphar Duphar Duphar Duphar/Thomae Merrell Dow Astra Lusofarmaco Ferrosan

Country Italy UK France W. Germany US US Japan Denmark

Year Introduced 1975 1976 1976 1976 1980 1980 -

Raw Materials Hydrogen chloride Hydrogen Hydrogen bromide

2-Bromo-4'-benzyloxypropiophenone 2-(4-Methoxyphenyl)ethylamine

Manufacturing Process A solution of 44 grams of 2-bromo-4'-benzyloxypropiophenone and 44 grams of 2-(4-methoxyphenyl)ethylamine in 270 ml of ethanol was refluxed for 3 hours. Then the ethanol was distilled off in vacuo and the concentrate mixed with ether. The resulting crystallizate was sucked off after which the filtrate was mixed with an excess of 2 N hydrochloric acid. As a result of this the hydrochloride of 4'-benzyloxy-2-[2-(4-methoxyphenyl)ethylamino]propiophenone slowly crystallized. This substance was also sucked off, washed with water and alcohol, and dried in vacuo. After recrystallization from dilute alcohol the yield was 25.5 grams of a product with a melting point of 217° to 218°C. 12 grams of the product thus obtained were dissolved in a mixture of 300 ml of ethanol and 90 ml of water. After 42 ml of 1% palladium chloride solution and 3.9 grams of Norit had been added to this solution it was hydrogenated at room temperature and at a pressure of 1.1 atmospheres until approximately 760 ml of hydrogen had been taken up. Then the catalyst was removed by filtration and the solvent of the filtered solution was evaporated entirely in vacuo. The resulting residue, which consisted of the hydrochloride of 4'-hydroxy-2-[2(4-methoxyphenyl)ethylamino]propiophenone, was mixed with 30 ml of a 48% hydrobromic acid solution and the mixture was boiled until no methylbromide developed any more, which was the case after approximately

Ritonavir

2989

45 minutes. Then the reaction mixture was stored in the refrigerator, after which the hydrobromide of 4'-hydroxy-2-[2-(4hydroxyphenyl)ethylamino]propiophenone crystallized. It was sucked off and converted into the hydrochloride by again dissolving the resulting substance in water, discoloring the solution with a little Norit and then adding an equal volume of concentrated hydrochloric acid. As a result of this the hydrochloride crystallized. The yield was 9.6 grams of a product with a melting point of 136° to 138°C. After this product had been recrystallized once again it was reduced to the amino alcohol. For this purpose a solution of 3.2 grams of the hydrochloride in 160 ml of distilled water was provided with 0.5 gram of Norit and 8 ml of 1% palladium chloride solution and the mixture was hydrogenated at room temperature and at a pressure of 1.1 atmospheres until no hydrogen was taken up any more. The catalyst was then removed by filtration, after which the filtrate was concentrated in vacuo. To the concentrated solution of the reduced product was then added an excess of dilute ammonia, as a result of which the base of the 1-(4-hydroxyphenyl)-2-[2-(4-hydroxyphenyl)ethlamino] propanol precipitated as a tough mass. After the mixture had been stored in the refrigerator for some time, the product was sucked off, washed with water and dried in vacuo. This base was a resinous mass with a melting point of approximately 88° to 90°C. Yield was 2.3 grams. References Merck Index 8121 Kleeman and Engei p. 810 PDR p. 609 OCDS Vol. 2 p. 39 (1980) DOT 10 (1) 23 (1974) I.N. p. 850 Claassen, V., Van Dijk, J. and Moed, H.D.; US Patent 3,410,944; November 12, 1968; assigned to North American Philips Company, Inc.

RITONAVIR Therapeutic Function: Antiviral Chemical Name: 2,4,7,12-Tetraazatridecan-13-oic acid, 10-hydroxy-2methyl-5-(1-methylethyl)-1-(2-(1-methylethyl)-4-thiazolyl)-3,6-dioxo8,11-bis(phenylmethyl)-, 5-thiazolylmethyl ester, (5S(5R*,8R*,10R*,11R*))Common Name: Ritonavir Chemical Abstracts Registry No.: 155213-67-5 Trade Name Norvir Ritomune Ritonavir

Manufacturer Abbott Laboratories Cipla Limited Abbott Laboratories

Country USA India USA

Year Introduced -

2990

Ritonavir

Structural Formula:

Raw Materials Oxalyl chloride N-((Benzyl)oxy)carbonyl)-L-phenylalaninal Lithium hydroxide Phosphorous pentasulfide Zinc Vanadium(III) chloride Potassium t-butoxide Ethyl chloroacetate Ethyl formate α-Acetoxyisobutyryl bromide Sodium borohydride Thioformamide Trifluoroacetic acid Ethyl 2-chloro-2-formylacetate Phenylboric acid Barium hydroxide octahydrate N-Methylmorpholine Lithium aluminum hydride Formamide 4-Nitrophenyl chloroformate Isobutyramide Phosphorus pentasulfide 1,3-Dichloroacetone Methylamine Triethylamine 4-Dimethylaminopyridine N-Ethyl-N'-dimethylaminopropyl carbodiimide Manufacturing Process The synthesis of (2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl) methoxycarbonyl)amino)-1,6-diphenyl- 3-hydroxyhexane consists of 20 steps. 1. N-((Benzyl)oxy)carbonyl)-L-phenylalaninal. It was prepared from 50 g (0.175 mol) of N-(((benzyl)oxy)-carbonyl-L-phenylalaninol in 200 ml of dichloromethane under N2 atmosphere at -60°C by treating with 131 ml of a 2 M solution of oxalyl chloride in dichloromethane, a solution of 24.5 ml of anhydrous dimethyl sulfoxide in 870 ml of anhydrous dichloromethane for about 2 hours. The resulting solution was stirred at -60°C for 1 h, then treated over a period of 15 min with 97 ml of triethylamine in order that the internal temperature remained below -50°C. After addition the solution was stirred at -60°C for 15 min, then, with the cooling bath in place, was treated rapidly with a solution of 163 g of citric acid in 550 ml of water. The resulting slurry was stirred vigorously for 10 min, allowed to warm, diluted to 1 liter with water, and separated. The organic layer was washed with 700 ml of water followed by a mixture of 550 ml of water and 150 ml of saturated aqueous NaHCO3, dried over MgSO4, and concentrated in vacuo at 20°C to give the crude desired compound as a light yellow solid.

Ritonavir

2991

2. (2S,3R,4R,5S)-2,5-Bis-(N-(((benzyl)oxy)carbonyl)amino)-3,4-dihydroxy1,6-diphenylhexane and (2S,3S,4S,5S)-2,5-bis-(N(((benzyl)oxy)carbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane. A suspension of 78.5 g of VCl3 (tetrahydrofuran)3and 16 g of zinc dust in 400 ml of dry dichloromethane was stirred under N2 atmosphere for 1 h at 25°C. A solution of 0.175 mol of N-(((benzyl)oxy)carbonyl)-L-phenylalaninal in 200 ml of dichloromethane was then added and the resulting mixture was stirred at ambient temperature under N2 for 16 h. The resulting mixture was added to 500 ml of 1 M aqueous HCl, diluted with 500 ml of hot chloroform, and shaked vigorously for 2 min. The layers were separated, and the organic layer was washed with 1 M aqueous HCl and separated. Filtration of the organic phase provided the crude desired product as a solid residue. The residue was slurried in 1.25 liters of acetone, treated with 5 ml of concentrated H2SO4, and stirred for 16 h at ambient temperature. The resulting mixture was filtered, and the residue (residue A) was washed with 50 ml of acetone. The combined filtrate was concentrated to a volume of 250 ml, diluted with 1000 ml of dichloromethane, washed three times with water and once with saturated brine, dried over MgSO4 and concentrated to give a viscous oil. The oil was taken up in 1000 ml of 1 M HCl in methanol (prepared from 71 ml of acetyl chloride and 1000 ml of methanol) and stirred at ambient temperature for 2 h. The resulting precipitate was filtered, washed with methanol, and airdried on the filter to provide 26.7 g of the desired compound as a white solid. The filtrate was concentrated and filtered to give a second crop (8.3 g) of (2S,3R,4R,5S)-2,5-bis-(N-(((benzyl)oxy)carbonyl)amino)-3,4-dihydroxy-1,6diphenylhexane. Residue A (above, 2.65 g) was suspended in 75 ml of tetrahydrofuran (THF) and 75 ml of 1 M aqueous HCl and refluxed for 24 h. After concentration of the resulting solution in vacuo, the residue was taken up in 10% methanol in chloroform, washed two times with water, dried over Na2SO4 and concentrated in vacuo to provide (2S,3S,4S,5S)-2,5-bis-(N-(((benzyl)oxy)carbonyl)amino)3,4-dihydroxy-1,6-diphenylhexane as a white solid 3.(2S,3R,4S,5S)-3-Acetoxy-2,5-bis-(N-(((benzyl)oxy)carbonyl)amino)-3bromo-1,6-diphenylhexane. A suspension of 25 g (44 mmol) of the compound prepared in the step 2 in 500 ml of 2:1 dichloromethane/hexane was treated with 23 g of aacetoxyisobutyryl bromide. The resulting mixture was stirred at ambient temperature until the reaction clarified, washed twice with 200 ml portions of saturated NaHCO3, dried over MgSO4, and concentrated in vacuo to give 30.8 g of the crude desired compound. A portion was purified by silica gel chromatography using 9:1 dichloromethane:ethyl acetate to provide the pure desired compound as a white solid. 4.(2S,3R,4R,5S)-2,5-Bis-(N-(((benzyl)oxy)carbonyl)amino)-3,4-epoxy-1,6diphenylhexane. A solution of 35.56 g (52.8 mmol) of the above compound (step 3) in 375 ml of dioxane was treated with 255 ml of 1 N aqueous sodium hydroxide and stirred at ambient temperature for 16 h, during which the desired compound precipitated. The resulting mixture was filtered, and the residue was washed

2992

Ritonavir

with water and dried to provide 22.23 g (76%) of the desired compound as a white solid. 5.(2S,3S,5S)-2,5-Bis-(N-(((benzyl)oxy)carbonyl)amino)-1,6-diphenyl-3hydroxyhexane. A mixture of 39.2 g (71.2 mmol) of (2S,3R,4R,5S)-2,5-bis-(N(((benzyl)oxy)carbonyl)amino)-3,4-epoxy-1,6-diphenylhexane in 600 ml of THF was treated under N2 with 13 g (0.36 mol) of sodium borohydride. The resulting mixture was treated dropwise with 27.7 ml (0.36 mol) of trifluoroacetic acid. After being stirred for 3.5 h at ambient temperature, the resulting mixture was quenched with 1 N aqueous HCl, diluted with water, and stirred for 16 h. The resulting mixture was filtered, washed with water, and dried to provide 22.85 g (58%) of the hydroxide octahydrate in 400 ml of 1,4dioxane and 400 ml desired compound as a white solid. 6. (2S,3S,5S)-2,5-Diamino-1,6-diphenyl-3-hydroxyhexane. A suspension of 32 g of the crude resultant compound of step 5 and 55.5 g (176 mmol) of barium hydroxide octahydrate in 400 ml of water was refluxed for 4 h. The resulting mixture was filtered, and the residue was rinsed with dioxane. The combined filtrates were concentrated to a volume of approximately 200 ml and extracted with 4 x 400 ml portions of chloroform. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography using first 2% isopropylamine in chloroform and then 2% isopropylamine/2% methanol in chloroform to provide 10.1 g (81%) of the pure desired compound as a white solid. 7. (4S,6S,1'S)-6-(1-Amino-2-phenylethyl)-4-benzyl-2-phenyl-3-aza-2bora-1oxacyclohexane. A solution of 11.28 g (40 mmol) of (2S,3S,5S)-2,5-diamino-1,6-diphenyl-3hydroxyhexane and 4.88 g (40 mmol) of phenylboric acid in 1 liter of toluene was refluxed and the water azeotropically removed with the aid of a Dean Stark trap until the distillate was clear. The solvent was then removed in vacuo to provide the crude desired compound which was used immediately without further purification. 8. Thioformamide. To a cooled (0°C) solution of formamide (30.5 mL, 0.76 mol) in 1 L of diethyl ether was added 89 g (0.19 mol) of phosphorous pentasulfide in small portions with stirring. The reaction mixture was allowed to warm to ambient temperature, stirred for 2 h, filtered, and concentrated in vacuo to afford thioformamide as a yellow offensive smelling oil which was used without purification. 9. Ethyl 2-chloro-2-formylacetate. To 0.5 mol of potassium t-butoxide (500 mL of a 1 M solution in THF) and 500 mL of dry THF cooled to 0°C was added dropwise a solution of ethyl chloroacetate (0.5 mol, 53.5 mL) and ethyl formate (0.5 mol, 40.4 mL), in

Ritonavir

2993

200 mL of THF over 3 hours. After completion of addition, the reaction mixture was stirred for 1 hour and allowed to stand overnight. The resulting solid was diluted with diethyl ether and cooled in an ice bath. Then, the pH was lowered to approximately 3 using 6 N HCl. The organic phase was separated, and the aqueous layer was washed 3 times with diethyl ether. The combined ethereal portions were dried over Na2SO4 and concentrated in vacuo. The crude desired compound was stored at -30°C and used without further purification. 10. Ethyl thiazole-5-carboxylate. 250 mL of dry acetone, 7.5 g (0.123 mol) of thioformamide, and 18.54 g (0.123 mol) of ethyl 2-chloro-2-formylacetate were refluxed for 2 hours. The solvent was removed in vacuo, and the residue was purified by chromatography (SiO2, 6 cm o.d. column, 100% CHCl3, Rf = 0.25) to provide 11.6 g (60%) of the desired compound as a light yellow oil. 11. 5-(Hydroxymethyl)thiazole. To a precooled (ice bath) lithium aluminum hydride (76 mmol) in 250 mL of THF was added ethyl thiazole-5-carboxylate (11.82 g, 75.68 mmol) in 100 mL of THF dropwise over 1.5 hours to avoid excess foaming. The reaction was stirred for an additional hour, and treated cautiously with 2.9 mL of water, 2.9 mL of 15% NaOH, and 8.7 mL of water. The solid salts were filtered, and the filtrate set aside. The crude salts were refluxed in 100 mL of ethyl acetate for 30 min. The resulting mixture was filtered, and the two filtrates were combined, dried over Na2SO4 and concentrated in vacuo. The product was purified by silica gel chromatography eluting sequentially with 0%-2%-4% methanol in chloroform, to provide the desired compound, Rf = 0.3 (4% methanol in chloroform), which solidified upon standing in 75% yield. 11. ((5-Thiazolyl)methyl)-(4-nitrophenyl)carbonate. A solution of 3.11 g (27 mmol) of 5-(hydroxymethyl)thiazole and excess Nmethyl morpholine in 100 ml of methylene chloride was cooled to 0°C and treated with 8.2 g (41 mmol) of 4-nitrophenyl chloroformate. After being stirred for 1 h, the reaction mixture was diluted with CHCl3, washed with 1 N HCl, saturated aqueous NaHCO3, and saturated brine, dried over NaSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (SiO2, 1-2% MeOH/CHCl3, Rf = 0.5 in 4% MeOH/CHCl3) to yield 5.9 g (78%) of the desired compound as a yellow solid. 12.(2S,3S,5S)-5-Amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6diphenyl-3-hydroxyhexaneand (2S,3S,5S)-2-amino-5-(N-((5thiazolyl)methoxycarbonyl)amino-1,6-diphenyl-3-hydroxyhexane. A solution of 500 mg (1.76 mmol) of (2S,3S,5S)-2,5-diamino-1,6-diphenyl-3hydroxyhexane and 480 mg (1.71 mmol) of ((5-thiazolyl)methyl)-(4nitrophenyl)carbonate in 20 ml of THF was stirred at ambient temperature for 4 hours. After removal of the solvent in vacuo, the residue was purified by silica gel chromatography using first 2% then 5% methanol in chloroform to provide a mixture of the two desired compounds. Silica gel chromatography of

2994

Ritonavir

the mixture using a gradient of 0-1-2% methanol in 93:2 isopropylamine: chloroform provided 110 mg (16%) of (2S,3S,5S)-5-amino-2-(N-((5thiazolyl)-methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane (Rsubfsub 0.48, 96:2:2 chloroform:methanol:isopropylamine) and 185 mg (28%) of (2S,3S,5S)-2-amino-5-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl3-hydroxyhexane (Rf 0.44, 96:2:2 chloroform:methanol:isopropylamine). 13. (2S,3S,5S)-5-Amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6diphenyl-3-hydroxyhexane. A solution of 40 mmol of crude (4S,6S,1'S)-6-(1-amino-2-phenylethyl)-4benzyl-2-phenyl-3-aza-2-bora-1-oxa cyclohexane in 700 ml of anhydrous THF was cooled to -40°C and treated dropwise for 1 h with a solution of 7.83 g (27.9 mmol) of ((5-thiazolyl)methyl)-(4-nitrophenyl)carbonate in 300 ml of dry THF. The resulting solution was allowed to warm to 0°C for 3 h, then to ambient temperature for 16 h. The solvent was removed in vacuo, and the residue was taken up in 700 ml of ethyl acetate, washed with 3 x 150 ml of 1 N NaOH and one 150 ml of brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. Purification of the residue by silica gel chromatography using methanol/chloroform mixtures provided the desired compound mixed with its regioisomer. A second chromatography using 1-3% isopropylamine in chloroform provided 5.21 g of the desired compound which solidified upon standing. 14. 2-Methylpropane-thioamide. A suspension of 100 g (1.15 mol) of isobutyramide in 4 L of diethyl ether was stirred vigorously and treated in portions with 51 g (0.115 mol) of P4S 10. The resulting mixture was stirred at ambient temperature for 2 h, filtered, and concentrated in vacuo to provide 94.2 g (80%) of the crude desired compound. 15. 4-(Chloromethyl)-2-isopropylthiazole hydrochloride. A mixture of 94.0 g (0.91 mol) of 2-methylpropane-thioamide, 115.7 g (0.91 mol) of 1,3-dichloroacetone, and 109.7 g (0.91 mol) of MgSO4 in 1.6 liters of acetone was refluxed for 3.5 h. The resulting mixture was allowed to cool, filtered, and the solvent was removed in vacuo to provide the crude desired compound as a yellow oil. 16. 2-Isopropyl-4-(((N-methyl)amino)methyl)thiazole. A solution of 40 g of 4-(chloromethyl)-2-isopropylthiazole hydrochloride in 100 ml of water was added dropwise with stirring to 400 ml of 40% aqueous methylamine. The resulting solution was stirred for 1 h, then concentrated in vacuo. The residue was taken up in chloroform, dried over Na2SO4, and concentrated in vacuo. Purification of the residue by silica gel chromatography using 10% methanol in chloroform provided 21.35 g (55%) of the desired compound. 17. N-(((4-Nitrophenyl)oxy)carbonyl)-L-valine methyl ester. A solution of 66.1 g (0.328 mol) of 4-nitrophenyl chloroformate in 1.2 liters of

Ritonavir

2995

CH2Cl2 was cooled to 0°C and treated with L-valine methyl ester hydrochloride. The resulting mixture was treated slowly, with stirring, with 68.9 ml (0.626 mol) of 4-methylmorpholine. The resulting solution was allowed to slowly warm to ambient temperature and was stirred overnight. After washing with 3 portions of 10% NaHCO3, the solution was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography by eluting with chloroform to provide the desired compound. 18. N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine methyl ester. A solution of 15.7 g (92 mmol) of 2-isopropyl-4-(((N-methyl)amino)methyl)thiazole in 200 ml of THF was combined with a solution of 20.5 g (69 mmol) of N-(((4-nitrophenyl)oxy)carbonyl)-L-valine methyl ester. The resulting solution was treated with 1.6 g of 4-dimethylaminopyridine and 12.9 ml (92 mmol) of triethylamine, heated at reflux for 2 h, allowed to cool, and concentrated in vacuo. The residue was taken up in CH2Cl2, washed extensively with 5% aqueous K2CO3, dried over Na2SO4, and concentrated in vacuo. The resulting product mixture was purified by silica gel chromatography using chloroform as an eluent to provide 16.3 g (54%) of the desired compound. 19. N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine. A solution of 1.42 g (4.3 mmol) of the resultant compound of step 18 in 17 ml of dioxane was treated with 17.3 ml of 0.50 M aqueous LiOH. The resulting solution was stirred at ambient temperature for 30 min, treated with 8.7 ml of 1 M HCl, and concentrated in vacuo. The residue was taken up in dichloromethane, washed with water, dried over Na2SO4, and concentrated in vacuo to provide 1.1 g (81%) of the desired compound. 20. (2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino) carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6diphenyl-3-hydroxyhexane A solution of 70 mg (0.223 mmol) of N-((N-methyl-N-((2-isopropyl-4thiazolyl)methyl)amino)carbonyl)-L-valine, 79 mg (0.186 mmol) of (2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl3-hydroxyhexane, 30 mg (0.223 mmol) of 1-hydroxybenzotriazole hydrate, and 51 mg (0.266 mmol) of N-ethyl-N'-dimethylaminopropyl carbodiimide in 2 ml of THF was stirred at ambient temperature for 16 h. The resulting solution was concentrated in vacuo, and the residue was purified by silica gel chromatography using 97:3 CH2Cl2/CH3OH to provide 100 mg (74%) of the desired compound (Rf 0.4, 95:5 CH2Cl2:CH3OH) as a solid, melting point 61°63°C. The structure of the described compounds was confirmed by NMR and mass spectrum analysis. 2,4,7,12-Tetraazatridecan-13-oic acid, 10-hydroxy-2-methyl-5-(1methylethyl)-1-(2-(1-methylethyl)-4-thiazolyl)-3,6-dioxo-8,11bis(phenylmethyl)-, 5-thiazolylmethyl ester, (5S-(5R*,8R*,10R*,11R*))- and

2996

Rizatriptan benzoate

(2S,3S,5S)-5-(N-(N-((N-methyl-N-((2-isopropyl-4thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane have the same structural formula. References Al-Razzak et al.; US Patent No. 5,484,801; Jan. 16, 1996; Assigned to Abbott Laboratories, Abbott Park, III

RIZATRIPTAN BENZOATE Therapeutic Function: Serotoninergic Chemical Name: 1H-Indole-3-ethanamine, N,N-dimethyl-5-(1H-1,2,4-triazol1-ylmethyl)-, monobenzoate Common Name: Rizatriptan benzoate Structural Formula:

Chemical Abstracts Registry No.: 145202-66-0 Trade Name

Manufacturer

Country

Year Introduced

Maxalt

Merck Sharp and Dohme

UK

-

Maxalt-MLT

Merck Sharp and Dohme

UK

-

Raw Materials 1,2,4-Triazole sodium salt Tin(II) chloride dihydrate Formaldehyde Benzoic acid

Palladium on carbon 4-Hydrazine Sodium cyanoborohydride

Rizatriptan benzoate

2997

Manufacturing Process 1. 1-(4-Nitrophenyl)methyl-1,2,4-triazole 4-Nitrobenzylbromide (21.6 g, 0.1 mol) was added to a rapidly stirred suspension of 1,2,4-triazole sodium salt (9.1 g, 0.1 mol) in anhydrous DMF (100 ml) and the mixture stirred at room temperature for 16 h. Ethyl acetate (400 ml) was added followed by water (250 ml) and the layers separated. The organic phase was washed with water (3 x 250 ml), dried (MgSO4) and evaporated. The residue was chromatographed on silica gel eluting with ethyl acetate to give the title-product (10.6 g, 52%); m.p. 98°-100°C. 2. 1-(4-Aminophenyl)methyl-1,2,4-triazole hydrochloride A solution of 1-(4-nitrophenyl)methyl-1,2,4-triazole (10.0 g, 49 mmol) in ethanol (50 ml), ethyl acetate (50 ml), 5 N HCl (10 ml) and water (10 ml) was hydrogenated over 10% Pd/C (1.0 g) at 40 p.s.i., in a Parr apparatus, until an uptake of 188 p.s.i., had been observed (approx 10 mins). The catalyst was removed by filtration and the solvent removed under vacuum. The residue was azeotroped with ethanol (2 times) to give the titleamine hydrochloride (10.6 g, 100%). 3. 1-(4-Hydrazinophenyl)methyl-1,2,4-triazole A solution of sodium nitrite (3.28 g, 48 mmol) in water (20 ml) was added to a solution of the preceding amine hydrochloride (10.0 g, 48 mmol), in concentrated HCl (40 ml), at such a rate that the temperature did not exceed -10°C. After addition was complete the solution was stirred at 0°C for 0.25 h and then added portionwise to a rapidly stirred solution of SnCl2 x 2H2O (40 g) in concentrated HCl (40 ml). The solution was warmed to room temperature and basified with 20% aqueous NaOH solution. The solution was extracted with ethyl acetate (3 x 250 ml) and the combined extracts dried (MgSO4) and filtered. The solution was evaporated to dryness to give the desired hydrazine (5.0 g, 56%) m.p. 109°-112°C. 4. 2-[5-(1,2,4-Triazol-1-ylmethyl)-1H-indol-3-yl]ethylamine 4-Chlorobutanal dimethylacetal (3.22 g, 21.1 mmol) was added to a stirred solution of the preceding hydrazine (5.0 g, 26.4 mmol) in ethanol/water (5:1, 180 ml) and 5 N HCl (4.5 ml) and the solution refluxed for 4 h. The solvents were removed under vacuum and the residue chromatographed on silica gel, eluting with CH2Cl2/EtOH/NH3 (30:8:1) to give the desired tryptamine (2.4 g, 38%). 5. N,N-Dimethyl-2-[5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]ethylamine benzoate A solution of formaldehyde (37% w/w solution, 0.19 g), in methanol (10 ml), was added to a mixture of the preceding tryptamine (0.36 g, 1.5 mmol), NaCNBH3 (0.225 g, 3.6 mmol) and glacial acetic acid (0.45 g), in methanol (10 ml). The mixture was stirred at room temperature for 2 h before adding saturated K2CO3 (50 ml) and evaporating the methanol. The residue was

2998

Rociverine

extracted with ethyl acetate (3 x 100 ml) and the combined extracts washed with brine (100 ml), dried (K2CO3), and evaporated. The crude product was chromatographed on silica gel eluting with CH2Cl2/EtOH/NH3 (20:8:1) to give the free base of the title-compound (0.21 g, 52%).The benzoate salt of N,Ndimethyl-2-[5-(1,2,4-triazol-1-yl-methyl)-1H-indol-3-yl]ethylamine was prepared by addition of a solution of benzoic acid in diethyl ether to a solution of the free base in ethanol/diethyl ether (1:4). The precipitated salt was recrystallised from ethanol, mp 178°-180°C. References Baker et al.; US Patent No. 5,298,520; Mar. 29, 1994; Assigned to Merck Sharp and Dohme Limlted, Hertfordshire, England

ROCIVERINE Therapeutic Function: Spasmolytic Chemical Name: 1-(Diethylamino)-2-propyl-cis-2-hydroxy-2cyclohexyicyclohexane-1-carboxylate Common Name: Structural Formula:

Chemical Abstracts Registry No.: 53716-44-2 Trade Name

Manufacturer

Country

Year Introduced

Rilaten

Guidotti

Italy

1979

Raw Materials 2-Phenyl-2-hydroxycyclohexane carboxylic acid Hydrogen 1-Bromo-2-propanol Diethylamine

Rolitetracycline

2999

Manufacturing Process 5.6 g of 2-phenyl-2-hydroxy-cyclohexane-carboxylic acid were dissolved in 75 cc of glacial acetic acid and reduced in the presence of 0.1 g of platinum oxide under hydrogen pressure of 22 kg/cm2 at a temperature of 70°C to 80°C. Hydrogen absorption being completed, the solution was filtered and evaporated to one-fifth of its volume and cooled in a refrigerator. The precipitate was filtered, washed with water, and then crystallized from ligroin, thus yielding 4 g of 2-cyclohexyl-2-hydroxy-cyclohexane-carboxylic acid, melting point (Kofler) 122°C to 124°C. This material was esterified with 1bromo-2-propanol by means of 85% H2SO4 yielding 1-bromoisopropyl-2cyclohexyl-2-hydroxycyclohexanecarboxylate. Finally this compound was treated with diethylamine and triethylamine at 120°C to give rociverine. References Merck Index 8125 DFU 4 (4) 276 (1979) I.N. p. 852 Turbanti, L; US Patents 3,700,675; and 3,700,775; both dated October 24, 1972

ROLITETRACYCLINE Therapeutic Function: Antibacterial Chemical Name: 4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro3,6,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-N-(1-pyrrolidinylmethyl)-2-naphthacenecarboxamide Common Name: Structural Formula:

Chemical Abstracts Registry No.: 751-97-3

3000

Rolitetracycline

Trade Name Syntetrin Velacycline Transcycline Anergomycil Bristacin Farmaciclina Hostacyclin-PRM Kinteto Quadraciclina Reverin Solvocillin Tetrafarmed Tetraldina Tetraverin

Manufacturer Bristol Squibb Hoechst C.N.N. Bristol Banyu Selvi Hoechst Fujita Squibb Hoechst Fabr. Antibiot. Neopharmed Italsuisse Polfa

Country US US France Italy Japan Italy Japan Japan Italy Italy Rumania Italy Italy Poland

Year Introduced 1959 1960 1961 -

Raw Materials Tetracycline Paraformaldehyde Pyrrolidine hydrochloride Manufacturing Process 1 g (0.00225 mol) of anhydrous tetracycline base, 0.101 g (0.0038 mol) of paraformaldehyde and 0.302 g (0.0025 mol) pyrrolidine hydrochloride are refluxed in 25 ml absolute ethanol. After two hours an additional 0.101 g paraformaldehyde is added and refluxing is continued for two more hours. The solution is then cooled and two drops of concentrated hydrochloric acid are added. The product, N'-(1-pyrrolidyl-methyl)-tetracycline hydrochloride, forms and is isolated as a crystalline, antibacterially active solid differing in specific rotation from tetracycline hydrochloride. The product is converted to the free base by solution in water followed by the addition of one equivalent of sodium hydroxide. Thus for isolation, the alcoholic solution of N'-(1-pyrrolidyl-methyl)tetracycline hydrochloride is diluted with 5.0 ml ether to precipitate the product, which is collected by filtration and dried in vacuo over P2O5. The product is a crystalline solid melting at about 158°C to 165°C with decomposition. References Merck Index 8127 Kleeman and Engel p. 810 OCDS Vol. 1 p. 216 (1977) I.N. p. 853 Cheney, L.C., Risser, W.C. and Gottstein, W.J.; US Patent 3,104,240; September 17, 1963; assigned to Bristol-Myers Co.

Ropinirole hydrochloride

3001

ROPINIROLE HYDROCHLORIDE Therapeutic Function: Antianginal, Antihypertensive, Antiparkinsonian Chemical Name: 2H-Indol-2-one, 1,3-dihydro-4-(2-(dipropylamino)ethyl)-, monohydrochloride Common Name: Ropinirole hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 91374-20-8; 91374-21-9 (Base) Trade Name

Manufacturer

Country

Year Introduced

Requip

GlaxoSmithKline

USA

-

Ropinirole Hydrochloride

GlaxoSmithKline

USA

-

Raw Materials 4-(2-Di-n-propylaminoethyl)-7-hydroxy-2(3H)-indolone hydrobromide 5-Chloro-1-phenyl-1H-tetrazole Phenyl tetrazole ether Palladium on carbon Manufacturing Process A mixture of 3.44 g (9.63 mmoles) of 4-(2-di-n-propylaminoethyl)-7-hydroxy2(3H)-indolone hydrobromide (U. S. Pat. No. 4,314,944), 22 cc of dimethylformamide, 1.79 g (9.91 mmoles) of 5-chloro-1-phenyl-1H-tetrazole, 220 cc of acetone, 10 cc of water and 2.90 g (21 mmoles) of anhydrous potassium carbonate was refluxed for about 3 hours at which time thin layer chromatographic analysis (silica gel GF, 75-23-2 ethyl acetate-methanol-conc. ammonium hydroxide) indicated that the reaction was complete. After cooling the reaction mixture in an ice-bath, the inorganic salts were removed by filtration and washed with acetone. The combined filtrates were concentrated in vacuo. The residual syrup was diluted with saturated brine and extracted with three portions of diethyl ether. The gathered extracts were dried over anhydrous magnesium sulfate, clarified with charcoal and treated with ethereal hydrogen chloride until precipitation was complete. The solid was slurried in diethyl ether and decanted several times, filtered and air-dried to give 3.8 g (86%) of tan 4-(2-di-n-propylaminoethyl)-7-(1-phenyl-1Htetrazol-5-yloxy)-2(3H)-indolone hydrochloride. Recrystallization from 200 cc of hot acetonitrile gave 2.6 g (59%) of microcrystalline product, m.p. 245°C.

3002

Ropivacaine hydrochloride monohydrate

Evaporation of the mother liquor and recrystallization of the residue from 25 cc of hot acetonitrile gave an additional 400 mg of product, m.p. 244°-245°C. A mixture of 2.64 g (5.78 mmoles) of the phenyl tetrazole ether, 200 cc of glacial acetic acid and 1.49 g of 10% palladium-on-carbon was hydrogenated in a Parr apparatus at 50 p.s.i. for 20 hours at 50°C. The warm reaction mixture was filtered through glass fiber filterpaper and the catalyst washed thoroughly with hot glacial acetic acid. The filtrate was concentrated in vacuo, the pale yellow waxy residue distributed in water and ethyl acetate. After acidification of the aqueous phase with 3 N hydrochloric acid, the organic phase was separated and extracted once with 1 N hydrochloric acid. The combined aqueous phases were adjusted to pH 8.5 with aqueous 10% sodium hydroxide and extracted with a mixture of ethyl acetate and diethyl ether. The combined organic extract was back-washed once with saturated brine, dried over anhydrous magnesium sulfate, clarified with charcoal, treated with ethereal hydrogen chloride and evaporated to dryness in vacuo to give 1.64 g (96%) of pale yellow crystalline solid; 4-(2-di-n-propylaminoethyl)-2(3H)indolone hydrochloride. Recrystallization from 260 cc of hot acetonitrile which was concentrated to about 50 cc gave 1.26 g (74%) of pale yellow microcrystalline powder, melting point 240°-242°C. The hydrochloride salt (500 mg) is shaken in the presence of ether/5% sodium carbonate solution. The ether layer is separated, dried and evaporated to give the free base which is used to prepare other salt forms such as the methanesulfonate, ethanedisulfonate, sulfate or sulfamate by reacting aliquots of the base in ether with an excess of each acid. References Gallagher, Jr.; US Patent No. 4,452,808; Jun. 5, 1984; Assigned to Smithkline Beckman Corporation, Philadelphia, Pa.

ROPIVACAINE HYDROCHLORIDE MONOHYDRATE Therapeutic Function: Local anesthetic Chemical Name: 2-Piperidinecarboxamide, N-(2,6-dimethylphenyl)-1-propyl-, monohydrochloride, (S)-, monohydrate Common Name: Ropivacaine hydrochloride Structural Formula:

Ropivacaine hydrochloride monohydrate

3003

Chemical Abstracts Registry No.: 132112-35-7; 84057-95-4 (Base) Trade Name

Manufacturer

Country

Year Introduced

Naropin

AstraZeneca

-

-

Ropivacaine hydrochloride

AstraZeneca

Japan

-

Raw Materials Isobutyl methyl ketone 1-Bromopropane Sodium iodide

Pipecoloxylidide hydrochloride Tartaric acid, dibenzoate, (-)-

Manufacturing Process The process for preparation of ropivacaine includes three steps. Step 1, resolution Pipecoloxylidide hydrochloride (1.0 kg), acetone (3.75 L), and water (0.85 L) were charged. NaOH (aq) was added to pH>11. The phases, thus formed, were separated and the organic phase was diluted with water (1.4 L). L-(-)Dibenzoyltartaric acid (0.67 kg), dissolved in acetone (3.75 L), was added. The solution was seeded. The crystal slurry was cooled to 2°C. The crystals were collected by centrifugation and were washed with acetone followed by isobutyl methyl ketone. The product was not dried. The moist crystalline product was extracted with isobutyl methyl ketone (3.60 L) and diluted NaOH (2.60 L) at pH>11. The phases were separated. The organic phase was washed with water (0.6 L) and was used directly in the next step. Yield (calculated on the dry basis) about 0.39 kg of (S)-pipecoloxylidide (about.90%). Step 2, alkylation and salt precipitation K2CO3 (0.32 kg), NaI (catalytical amount), and 1-bromopropane (0.28 kg) and about 5% of water, were added to the organic phase from the previous step. The mixture was heated to reflux to complete the reaction. The excess of bromopropane was removed by distillation. The reaction mixture was extracted with water (1.70 L). Acetone (1.70 L) was added to the organic phase followed by HCl (aq) to pH about 2. The solution was seeded. The crystal slurry was cooled to 9°C. The crystals were collected by centrifugation and were washed with acetone. The product was used directly in the next step and was not dried. Yield (calculated on the dry basis): 0.47 kg of ropivacaine hydrochloride (about 0.90%). As an alternative, the following procedure was followed: K2CO3 (0.32 kg), NaI (catalytical amount), 1-bromopropane (0.28 kg) and water (1.70 L) were added to the organic phase from the previous step. The mixture was heated to reflux to complete the reaction. The excess of bromopropane was removed by distillation. The reaction mixture was separated. Acetone (1.70 L) was added to the organic phase followed by HCl (aq) to pH about 2. The solution was seeded. The crystal slurry was cooled to

3004

Rosiglitazone maleate

9°C. The crystals were collected by centrifugation and were washed with acetone. The product was used directly in the next step and was not dried. Yield (calc. on the dry basis): 0.47 kg of ropivacaine hydrochloride (about 0.90%). Step 3, recrystallisation Ropivacaine hydrochloride, from the previous step, was slurried in acetone (1.0 L) at reflux temperature. Water (0.60 L) was added. The resulting mixture was filtered and acetone (7.6 L) was added at >40°C. The solution was seeded. The slurry of crystals was cooled to 3°C. The crystals were collected by centrifugation and were washed with acetone. The crystals were dried at 30°-40°C in vacuum. Yield: about 0.42 kg of ropivacaine hydrochloride monohydrate (about 80%). The stucture of the end product was confirmed by NMR analysis. References Jaksch P.; US Patent No. 5,959,112; Sep. 28, 1999; Assigned to Astra Aktiebolag, Sodertalje, Sweden

ROSIGLITAZONE MALEATE Therapeutic Function: Hypoglycemic, Antiinflammatory, Analgesic Chemical Name: 2,4-Thiazolidinedione, 5-((4-(2-(methyl-2-yridinylamino) ethoxy)phenyl)methyl)-, maleate (1:1) Common Name: Rosiglitazone maleate Structural Formula:

Chemical Abstracts Registry No.: 122320-73-4 (Base); 155141-29-0 Trade Name

Manufacturer

Country

Year Introduced

Avandia

GlaxoSmithKline

-

-

BRL 49653

GlaxoSmithKline

-

-

Rosoxacin

3005

Raw Materials 4-Fluorobenzaldehyde 2-(N-Methyl-N-(2-pyridyl)amino)ethanol Potassium t-butoxide 2,4-Thiazolidinedione Maleic acid Manufacturing Process To 100 g of 2-(N-methyl-N-(2-pyridyl)amino)ethanol in 500 ml DMF was added 100 g of 4-fluorobenzaldehyde. The reaction mixture was stirred for 10 min at room temperature and 80 g of potassium tertiary butoxide was added to the reaction mixture. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to 5-10°C and under the cold conditions, 1.5 L of water was added and stirred for 15 min. The mixture was extracted with ethyl acetate. The combined organic layer was washed with 3 times 1 L water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 148 g (88%) of 4-[2-(Nmethyl-N-(2-pyridyl)amino)ethoxy)benzaldehyde. 4-[2-(N-Methyl-N-(2-pyridyl)amino)ethoxy]benzaldehyde was converted into highly crystalline 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl] thiazolidine-2,4-dione by Knoevenegal condensation with 2,4thiazolidinedione. 800 g of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy] benzyl]thiazolidine-2,4-dione and 280 g maleic acid were dissolved in 1.3 L of acetone in 5 L three necked round bottom flask. The reaction mixture was heated to 50-55°C and the solution was filtered and slowly cooled to obtain 986 g of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine2,4-dione maleate, (yield 95%; M.P. 120-122°C). References Sharad Kumar Vyas; US Patent No. 6,515,132; Feb. 4, 2003; Assigned to Torrent Pharmactuticals, Ltd., Ahmedabad (IN)

ROSOXACIN Therapeutic Function: Antibacterial, Antigonorrheal Chemical Name: 1-Ethyl-1,4-dihydro-4-oxo-7-(4-pyridyl)-3quinolinecarboxylic acid Common Name: Acrosoxacin Chemical Abstracts Registry No.: 40034-42-2

3006

Rosoxacin

Structural Formula:

Trade Name Eradacin Eracine Winuron Eradacil Winoxacin Roxadyl

Manufacturer Sterling Winthrop Winthrop Winthrop Winthrop Winthrop Winthrop

Country UK France W. Germany Canada Switz. -

Year Introduced 1981 1981 1981 1983 1983 -

Raw Materials Acetic acid Iron Ethyl iodide Sodium hydroxide

4-(3-Nitrophenyl)pyridine Ethoxymethylene malonic acid diethyl ester Sodium hydride

Manufacturing Process To a stirred suspension containing 5.1 g of 57% sodium hydride dispersed in mineral oil and 150 ml of dimethylformamide was added in portions 32.6 g of ethyl 1,4-dihydro-4-oxo-7-(4-pyridyl)-3-quinolinecarboxylate [tautomeric with ethyl 4-hydroxy-7-(4-pyridyl)-3-quinolinecarboxylate] followed by the addition of 18.7 g of ethyl iodide. The resulting reaction mixture was heated on a steam bath for three hours with stirring and then concentrated in vacuo to remove the solvent. The semisolid residue was shaken well with a mixture of chloroform and water, and a small quantity of amorphous brown solid was filtered off. The layers were separated and the chloroform layer was evaporated in vacuo to remove it. To the oily residue containing ethyl 1-ethyl-1,4-dihydro-4-oxo-7-(4-pyridyl)-3quinolinecarboxyiate was added excess 10% aqueous sodium hydroxide solution and ethanol, and the solution was heated on a steam bath for fortyfive minutes to hydrolyze the ethyl ester to the corresponding carboxylic acid. The alkaline solution was diluted to a volume of about 500 ml with water, decolorizing charcoal was added and the mixture filtered. The filtrate was neutralized with acetic acid whereupon the carboxylic acid separated as a solid. The solid was collected and dried in a rotary evaporator. The solid was boiled with ethanol, the solution chilled and the resulting solid collected. The solid was recrystallized from dimethylformamide (about 150 ml) using decolorizing charcoal. The filtrate was chilled, diluted with about one-half volume of ethanol and the separated crystalline product was collected, recrystallized again from dimethylformamide and dried in vacuo to yield 4.3 g 1-ethyl-1,4-dihydro-4-oxo-7-(4-pyridyl)-3-quinolinecarboxylic acid, melting

Rosoxacin

3007

point 272°C to 273°C raised by further recrystallization to 290°C. 4-(3-nitrophenyl)pyridine is reduced with iron in acetic acid to give 4-(3aminophenyl)pyridine. That in turn is reacted with ethoxymethylene malonic acid diethyl ester and then thermally rearranged to give the starting material References Merck Index 8136 DFU 5 (4) 199 (1980) Kleeman and Engel p. 811 OCDS Vol. 3 p. 185 (1984) DOT 18 (3) 147 (1982) I.N. p. 855 Carabateas, P.M.; US Patent 3,922,278; November 25, 1975; assigned to Sterling Drug, Inc. Lesher, G.Y. and Carabateas, P.M.; US Patents 3,753,993; August 21, 1973 and 3,907,808; September 23, 1975; both assigned to Sterling Drug, Inc. Lorenz, R.R. and Thielking, W.H.; US Patent 4,107,167; August 15, 1978; assigned to Sterling Drug, Inc.

S

SALICYLANILIDE Therapeutic Function: Antifungal Chemical Name: 2-Hydroxy-N-phenylbenzamide Common Name: N-Phenylsalicylamide Structural Formula:

Chemical Abstracts Registry No.: 87-17-2 Trade Name Salinidol Ansadol Hyanilid

Manufacturer Doak Rorer Peau Seche

Country US US US

Year Introduced 1946 1947 -

Raw Materials Salicylic acid Aniline Manufacturing Process Salicylanilide is ordinarily made by reacting salicylic acid with aniline in the presence of phosphorus trichloride at an elevated temperature. The theoretical proportions of reactants are usually employed for best results, that is, one mol each of aniline and salicylic acid to a third of a mol of phosphorus trichloride. An improved process employs an inert organic solvent as a reaction diluent.

3008

Salicylic acid

3009

References Merck Index 8188 I.N. p. 861 Majewski, T.E., Parsey, E.S. and Skelly, N.E.; US Patent 3,221,051; November 30, 1965 Majewski, T.E., Stoesser, W.C. and Parsey, E.S.; US Patent 3,231,611;January 25, 1966; assigned to The Dow Chemical Company

SALICYLIC ACID Therapeutic Function: Keratolytic Chemical Name: 2-Hydroxybenzoic acid Common Name: Structural Formula:

Chemical Abstracts Registry No.: 69-72-7 Trade Name Saligel Fomac Aveenobar Barseb Cantharone Compound W Duofilm Egocappol Fostex Fungi-Nail Hydrisalic Jabon Salicilico Keralyt Komed Night-Cast Occlusal Pernox Sal Ac Salactic Sebucare Sebulex

Manufacturer Stiefel Dermik Rydelle Barnes Hind Seres Whitehall Stiefel Ego Westwood Kramer Pedinol Imba Westwood Barnes Hind Seres Gen Derm Westwood Gen Derm Pedinol Westwood Westwood

Country US US US US US US US Australia US US US Spain US US US US US US US US US

Year Introduced 1978 1979 -

3010

Saquinavir mesylate

Trade Name Tinver Verrex Verrusal Viranol Wart-Off Whitfield's Ointment

Manufacturer Barnes Hind C and M C and M Amer. Dermal Pfipharmecs Fougera

Country US US US US US US

Year Introduced -

Raw Materials Sodium phenolate Nutrient medium Naphthalene

Bacterium Pseudomonas Carbon dioxide

Manufacturing Process Made by reacting sodium phenolate and carbon dioxide. May also be made by microbiological oxidation of naphthalene by forming an aqueous nutrient medium for microorganisms capable of oxidizing naphthalene to salicylic acid of the genus Pseudomonas containing basal mineral salts, 0.5 to 4 wt % of finely divided naphthalene and 0.1 to 1 wt % of a boron compound, inoculating the nutrient medium with an inoculum containing a microorganism capable of oxidizing naphthalene to salicylic acid of the genus Pseudomonas, the inoculated nutrient medium having an initial pH value of about 4 to 9, incubating the inoculated nutrient medium at a temperature of about 25° to 50°C for a period of about 2 to 7 days and then recovering salicylic acid from the nutrient medium. References Merck Index 8190 PDR pp.580, 653, 777, 905, 985, 1397, 1417, 1575, 1696, 1779, 1890, 1898 I.N. p. 37 REM p. 785 Zaiic. J.E. and DunlaD. W.J.: US Patent 3274,074; SeDtember 20.1966; assisned to Kerr-McGee Oil Industhes, Inc.

SAQUINAVIR MESYLATE Therapeutic Function: Antiviral Chemical Name: Butanediamide, N1-(3-(3-(((1,1-dimethylethyl) amino)carbonyl)octahydro-2(1H)-isoquinolinyl)-2-hydroxy-1(phenylmethyl)propyl)-2-((2-quinolinylcarbonyl)amino)-, (3S(2(1R*(R*),2S*),3-α,4a-β,8a-β))-, monomethanesulfonate (salt) Common Name: Saquinavir mesylate

Saquinavir mesylate

3011

Structural Formula:

Chemical Abstracts Registry No.: 149845-06-7; 127779-20-8 (Base) Trade Name Fortovase Invirase Invirase Saquinavir

Manufacturer Roche Laboratories Hoffmann - La Roche Inc. Roche Laboratories Roche Laboratories

Country USA USA USA

Year Introduced -

Raw Materials Quinaldic acid N-(Benzyloxycarbonyl)-L-asparagine N-Ethylmorpholine Dicyclohexylcarbodiimide Rhodium on carbon Benzyl chloroformate Citric acid N-Hydroxysuccinimide Hydroxybenzotriazole Palladium on carbon Sodium hydroxide 1,2,3,4-Tetrahydro-3(S)-isoquinolinecarboxylic acid 3(S)-(Benzyloxyformamido)-1,2(S)-epoxy-4-phenylbutane Manufacturing Process A suspension of 12.676 g (71.6 mmol) of 1,2,3,4-tetrahydro-3(S)isoquinolinecarboxylic acid (Chem. Pharm. Bull. 1983, 31, 312) in 200 ml of 90% acetic acid was hydrogenated at 80°C and under 140 atm pressure over 5% rhodium-on-carbon for 24 h. The mixture was left to cool to room temperature and the catalyst was then filtered off. The filtrate was evaporated to give a gum which was dissolved in 10 ml of ethyl acetate and added slowly to 100 ml of vigorously stirred diisopropyl ether. A resinous precipitate was produced. The supernatant liquors were removed by decantation and the precipitate was extracted with hot ethyl acetate. This hot solution was poured into a vigorously stirred mixture of 150 ml of diethyl ether/diisopropyl ether (1:1) to give a pale grey solid which was collected by filtration, washed with diethyl ether and dried. There were obtained 5.209 g of a mixture of decahydroisoquinoline-3(S)-carboxylic acids consisting of predominantly (about 65%) the 4aS,8aS isomer together with the 4aR,8aR isomer (about 25%) and about 10% of the trans isomers. 9.036 g (49.4 mmol) of the foregoing mixture of decahydroisoquinoline-3(S)-

3012

Saquinavir mesylate

carboxylic acids were dissolved in 50 ml (50 mmol) of 1 M sodium hydroxide solution and the resulting solution was cooled to 0°C. 7.40 ml (51.87 mmol) of benzyl chloroformate and 58.7 ml (58.7 mmol) of 1 M sodium hydroxide solution were added dropwise over a period of 1 h while maintaining a temperature of 0°-5°C by cooling. The mixture was then stirred for a further 2 h, during which time the mixture was allowed to warm to room temperature. 100 ml of diethyl ether were added and the mixture was filtered, whereby the insoluble R,R-isomer was removed. The aqueous layer of the filtrate was separated and adjusted to pH 1.5-2 by the addition of concentrated hydrochloric acid, whereby an oil precipitated. The mixture was extracted twice with 100 ml of ethyl acetate each time. The combined organic extracts were washed with water, dried over anhydrous sodium sulphate and evaporated to give an oil. This oil was dissolved in 35 ml of ethyl acetate and 2.85 ml (25 mmol) of cyclohexylamine were added. The white precipitate was collected by filtration to give, after several fractional recrystallizations from methanol/ethyl acetate, 2.38 g of the cyclohexylamine salt of 2(benzyloxycarbonyl)-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxylic acid. 2.334 g of the cyclohexylamine salt of 2-benzyloxycarbonyl)-decahydro(4aS,8aS)-isoquinoline-3(S)-carboxylic acid were partitioned between 50 ml of ethyl acetate and 50 ml of 10% citric acid solution. The organic phase was separated, washed with water, filtered and evaporated to give 1.87 g of 2(benzyloxycarbonyl)-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxylic acid in the form of a colorless gum. A solution of 0.634 g (2.0 mmol) of 2-(benzyloxycarbonyl)-decahydro(4aS,8aS)-isoquinoline-3(S)-carboxylic acid in 6 ml of dimethoxyethane was treated with 0.23 g (2.0 mmol) of N-hydroxysuccinimide and 0.412 g (2.0 mmol) of dicyclohexylcarbodiimide. The mixture was stirred at room temperature for 18 hours. The mixture was filtered and the filtrate was evaporated to give 0.879 g of the N-hydroxysuccinimide ester of the foregoing acid in the form of a pale yellow oil. A solution of 0.828 g (2.0 mmol) of the foregoing N-hydroxysuccinimide ester in 5 ml of dichloromethane was stirred, cooled to 0°C and treated with 0.219 g (3.0 mmol) of tert.butylamine. The mixture was stirred at 0°C for 2 h and then at room temperature for 4.5 h. The mixture was then washed with 2 M hydrochloric acid, sodium carbonate solution and sodium chloride solution, dried over anhydrous magnesium sulphate and evaporated. The residue was dissolved in 20 ml of diethyl ether and filtered. The filtrate was evaporated to give 0.712 g of 2(benzyloxycarbonyl)-N-tert-butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)carboxamide in the form of a white solid. A solution of 0.689 g (1.85 mmol) of 2-benzyloxycarbonyl)-N-tert-butyldecahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide in 20 ml of ethanol was hydrogenated in the presence of 0.01 g of 10% palladium-on-carbon at room temperature and under atmospheric pressure for 18 h. The catalyst was removed by filtration and the solvent was removed by evaporation to give in quantitative yield N-tert-butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)carboxamide as a clear oil. A solution of 440 mg of N-tert-butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)carboxamide and 549 mg of 3(S)-(benzyloxyformamido)-1,2(S)-epoxy-4phenylbutane in 6 ml of ethanol was stirred at 60°C for 7 h. A further 54 mg of 3(S)-(benzyloxyformamido)-1,2(S)-epoxy-4-phenylbutane were added and

Saquinavir mesylate

3013

the solution was stirred at 20C for 16 h. The solvent was removed by evaporation and the residue was chromatographed on silica gel using diethyl ether/n-hexane/methanol (47.5:47.5:5) for the elution to give 771 mg of 2[3(S)-(benzyloxyformamido)-2(R)-hydroxy-4-phenylbutyl-N-tert.butyldecahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide as a white solid. A solution of 747 mg of 2-[3(S)-(benzyloxyformamido)-2(R)-hydroxy-4phenylbutyl-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide in 40 ml of ethanol was hydrogenated over 10% palladium-on-carbon at 20°C and under atmospheric pressure for 5 h. The catalyst was removed by filtration and the filtrate was evaporated to give 561 mg of 2-[3(S)-amino2(R)-hydroxy-4-phenylbutyl]-N-tert-butyl-decahydro-(4aS,8aS) -isoquinoline3(S)-carboxamide as a buff colored solid. A solution of 561 mg of 2-[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N-tertbutyl-decahydro-(4aS,8aS) -isoquinoline-3(S)-carboxamide and 372 mg of N(benzyloxycarbonyl)-L-asparagine in 20 ml of dry tetrahydrofuran was cooled in an ice/salt mixture. 189 mg of hydroxybenzotriazole, 161 mg of Nethylmorpholine and 317 mg of dicyclohexylcarbodiimide were added and the mixture was stirred for 16 h. The mixture was then diluted with ethyl acetate and filtered. The filtrate was washed with aqueous sodium bicarbonate solution and sodium chloride solution. The solvent was removed by evaporation and the residue was chromatographed on silica gel using dichloromethane/methanol (9:1) for the elution to give 434 mg of 2-[3(S)[[N-(benzyloxycarbonyl)-L-asparaginyl]amino]-2(R)-hydroxy-4-phenyl butyl]N-tert-butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide as a white solid from methanol/diethyl ether. A solution of 195 mg of 2-[3(S)-[[N-(benzyloxycarbonyl)-Lasparaginyl]amino]-2(R)-hydroxy-4-phenyl butyl]-N-tert.butyl-decahydro(4aS,8aS)-isoquinoline-3(S)-carboxamide in 20 ml of ethanol was hydrogenated at room temperature and atmospheric pressure for 18 h over 10 mg of 10% palladium-on-charcoal. The catalyst was filtered off and the filtrate was evaporated under reduced pressure to give 154 mg of 2-[3(S)-[(Lasparaginyl)amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-decahydro(4aS,8aS)-isoquinoline-3(S)-carboxamide. A solution of 154 mg of 2-[3(S)-[(L-asparaginyl)amino]-2(R)-hydroxy-4phenylbutyl]-N-tert-butyl -decahydro(4aS,8aS)-isoquinoline-3(S)-carboxamide and 52 mg of quinaldic acid in 6 ml of dry tetrahydrofuran was cooled in an ice/salt mixture. 41 mg of hydroxybenzotriazole, 35 mg of N-ethylmorpholine and 68 mg of dicyclohexylcarbodiimide were added and the mixture was stirred for 64 h. The mixture was diluted with ethyl acetate and filtered. The filtrate was washed with aqueous sodium bicarbonate solution and with sodium chloride solution and then evaporated. The residue was chromatographed on silica gel using dichloromethane/methanol (9:1) for the elution to give 50 mg of N-tert-butyl-decahydro-2-[2(R)-hydroxy-4-phenyl3(S)-[[N-(2-quinolylcarbonyl)-L-asparaginyl]amino]butyl]-(4aS,8aS)isoquinoline-3(S)-carboxamide as a white solid. The salt of saquinovir mesylate was obtained by the reaction of N-tert-butyldecahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-[[N-(2-quinolylcarbonyl)-Lasparaginyl]amino]butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide with monomethanesulfonic acid.

3014

Scopolamin hydrobromide

References Martin J.A., Redshaw S.; US Patent No. 5,196,438; March 23, 1993; Assigned: Hoffmann-La Roche Inc., Nutley, N.J.

SCOPOLAMIN HYDROBROMIDE Therapeutic Function: Sedative, Antiemetic Chemical Name: Benzeneacetic acid, α-(hydroxymethyl)-, (1α,2β,4β,5α,7β)9-methyl-3-oxa-9-azatricyclo(3.3.1.02,4)non-7-yl ester, (αS)-, hydrobromide Common Name: Escopolamona hydrobromide; Hyoscine hydrobromide; Joscina hydrobromide; Oscine hydrobromide; Scopolamine hydrobromide; Skopolamin hydrobromide Structural Formula:

Chemical Abstracts Registry No.: 114-49-8; 51-34-3 (Base) Trade Name Hyoscine hydrobromide Hyoscine hydrobromide Hyoscinhydrobromid

Manufacturer GlaxoSmithKline Consumer Healthcare Roche Consumer Health

Country UK

Year Introduced -

Austria

-

Germany

-

UK

-

Austria Austria USA Switz.

-

Scopolamin Hydrobromide Inj.

Boehringer Ingelheim Pharma KG Alcon GlaxoSmithKline Consumer Healthcare Roche Consumer Health Roche Consumer Health Hope Pharmaceuticals Novartis Consumer Health Hospira Healthcare Corporation

Canada

-

Vorigeno

Anexo IV.c.

Spain

-

Isopto-Hyoscine Joy-rides Junior Kwells Kwells Scopace Scopoderm TTS

Secnidazole

3015

Raw Materials Roots of Scopolia atropoides Hydrochloric or acetic acid Potassium carbonate Manufacturing Process Scopolamin was isolated from roots of Scopolia atropoides genus Solanaceae. Alkaloids fraction was obtained from roots by extraction with benzene. First of all the atropine was isolated. Then after isolation of the atropine, the extract containing the scopolamin and other alkaloids was washed by slightly acidic solution (this solution was acidified with the hydrochloric or acetic acid). To the acidic solution the potassium carbonate was added, then scopolamin was extracted with chloroform, ether or their mixture. The organic extracts were combined and evaporated under reduce presser. Concentrated residue was washed with water, filtered and dried. Scopolamin by obtaining of d-bromcamphar sulfoacid derivatives may be differented on d- and l-isomers. Scopolamin may be isolated from seeds of Datura innoxia genus Solanaceae. Scopolamin is used as salt of hydrobromic acid References "Pharmaceutical Chemistry" Leningrad, "Medicine", 1966

SECNIDAZOLE Therapeutic Function: Antiamebic, Antiprotozoal Chemical Name: α,2-Dimethyl-5-nitro-1H-imidazole-1-ethanol Common Name: Structural Formula:

Chemical Abstracts Registry No.: 3366-95-8

3016

Secnidazole

Trade Name

Manufacturer

Country

Year Introduced

Flagentyl

Rhone Poulenc

Switz.

1980

Raw Materials Nitric acid Hydrogen chloride

1-(2-Acetoxypropyl)-2-methylimidazole

Manufacturing Process 1-(2-Acetoxypropyl)-2-methylimidazole (18.2 g) is gradually dissolved in fuming nitric acid (d = 1.52; 25 cc) with stirring, the temperature being kept at about 2°C. Phosphorus pentoxide (20 g) is added, with caution, to the resulting solution and while maintaining the temperature at about 2°C. Afterwards, the reaction mixture is stirred for a further 3 hours 30 minutes at 2°C and poured onto ice (180 g). The solution obtained is treated with ammonium hydroxide (d = 0.92; 105 cc), saturated with sodium chloride, and then extracted with ethyl acetate (total 650 cc). The combined organic extracts are washed with a saturated aqueous sodium chloride solution (50 cc) and then dried over sodium sulfate. The volatile products are evaporated under reduced pressure (20 mm Hg) and a mixture of 1-(2-acetoxypropyl)-2-methyl-4-nitroimidazole and 1-(2acetoxypropyl)-2-methyl-5-nitroimidazole (18.6 g) is obtained in the form of a red oil. A solution of a mixture of 1-(2-acetoxypropyl)-2-methyl-4-nitroimidazole and of 1-(2-acetoxypropyl)-2-methyl-5-nitroimidazole (18.6 g) (prepared as described above) in 4N hydrochloric acid (186 cc) is heated at 90°C for 90 minutes. The cooled solution is treated with ammonium hydroxide (d = 09; 100 cc), saturated with sodium chloride, and then extracted with ethyl acetate (total 550 cc). The combined organic extracts are washed with a saturated aqueous sodium chloride solution (50 cc) and then dried over sodium sulfate. The volatile products are evaporated under reduced pressure (25 mm Hg); the residual brown oil weighs 9.2 g. This oil (5.8 g) is dissolved in methyl ethyl ketone (20 cc) and chromatographed over silica (232 g) contained in a column 45 cm in diameter. The column is eluted with methyl ethyl ketone; the first 600 cc of eluate are discarded and 500 cc of eluate are then collected and concentrated under reduced pressure (25 mm Hg);a partially crystalline product (2.4 g) is thus obtained. 1-(2-Hydroxypropyl)-2-methyl-5-nitroimidazole (0.96 g), melting point 72°C, is obtained on recrystallization from water (4 cc). References Merck Index 8267 DFU 4 (4)280 (1979) Kleeman and Engel p. 817 DOT 17 (2) 62 (1981) I.N. p. 867 Jeanmart, C. and Messer, M.N.; British Patent 1,278,757; June 21, 1972; assigned to Rhone-Poulenc S.A. (France)

Secobarbital sodium

3017

SECOBARBITAL SODIUM Therapeutic Function: Hypnotic Chemical Name: 5-(1-Methylbutyl)-5-(2-propenyl)-2,4,6(1H,3H,5H)pyrimidinetrione monosodium salt Common Name: Meballymal sodium; Quinalbarbitone sodium Structural Formula:

Chemical Abstracts Registry No.: 30943-3; 76-73-3 (Base) Trade Name Seconal Dormatylan Dormona Immenoctal Ional Sodium Novosecobarb Proquinal Quinbar Sebar Secaps Secocaps Secogen Seral Tuinal

Manufacturer Lilly Herz-Jew-Apotheke Wiedenmann I.S.H. Yoshitomi Novopharm Protea Adams Vangard Saunders M.T.C. Paul Maney Medic Lilly

Country US Austria Switz. France Japan Canada Australia Australia US Canada Canada Canada Canada US

Year Introduced 1945 -

Raw Materials Allyl bromide Sodium hydroxide

Propyl-methyl-carbinyl barbituric acid

Manufacturing Process Propyl-methyl-carbinyl allyl barbituric acid (also called allyl 1-methyl-butyl barbituric acid) may be prepared as follows: 1 mol of propyl-methyl-carbinyl barbituric acid is dissolved in a suitable vessel in a 10 to 35% aqueous solution of 1 mol of potassium hydroxide. To this are added somewhat in excess of 1 mol of allyl bromide, and alcohol equal to about 10% of the total

3018

Secobarbital sodium

volume of the solution. The vessel is agitated for 50 to 75 hours. At the end of this time, the solution, which may still exhibit two layers, is concentrated to about one-half its volume to remove the excess allyl bromide and the alcohol. On cooling, an oily layer, which is propyl-methyl-carbinylallyl barbituric acid, separates out as a sticky viscous mass. It is dried, washed with petroleum ether, and dissolved in the minimum amount of benzene. Any unreacted propyl-methyl-carbinyl barbituric acid, which does not dissolve, is filtered off. The addition of petroleum ether to the clear filtrate causes the propyl-methylcarbinylallyl barbituric acid to precipitate as an oily mass. This is separated, washed with petroleum ether, and dried in vacuo. After some time it hardens into a whitish solid, which if it was prepared from a 1bromo-pentane which had some of its isomer 3-bromo-pentane copresent with it has a melting point of about 80°to 83°C. However, by using a pure 2bromo-pentane, and/or by recrystallizing a number of times from dilute alcohol, the melting point may be raised to 98° to 100°C, corrected. One part by weight of propyl-methyl-carbinyl allyl barbituric acid is added to enough alcohol to facilitate handling, in this case conveniently about six times its weight. To this is added a solution of sodium hydroxide, preferably carbonate-free or substantially so, containing 40/238 parts by weight of sodium hydroxide, which is the amount of sodium hydroxide necessary to combine in equal molecular proportions with the propyl-methyl-carbinyl allyl barbituric acid. This solution is filtered clear, and is then evaporated under vacuum until the sodium propyl-methyl-carbinyl allyl barbiturate (alternatively named sodium allyl 1-methyl-butyl barbiturate) separates out in solid form. The salt as thus obtained in solid form contains a varying amount of moisture. If it is desired to have a stable salt substantially free from contaminants, the alcohol used for dissolving the barbituric acid is absolute alcohol, and the sodium hydroxide is added as a very concentrated aqueous solution so that the reaction which occurs to form the salt is in a substantially alcoholic solution. By having a substantially alcoholic solution, decomposition of the salt during the process of drying is effectively avoided; and the drying may be carried to a point where materially less than 1% of moisture remains, so that the salt is substantially anhydrous. In this way a stable salt substantially free from decomposition products formed during preparation or drying or on standing is obtained. This salt may be used safely for making aqueous solutions for intravenous injection; for such aqueous solutions, when freshly made, are clear solutions substantially free from haziness. Sodium propyl-methyl-carbinyl allyl barbiturate is a white hygroscopic solid, readily soluble in water and alcohol, and insoluble in ether. References Merck Index 8268 Kleeman and Engel p. 816 PDR pp. 1067, 1989 OCDS Vol. 1 p.269 (1977) I.N. p. 867 REM p. 1068 Shonle, H.A.; US Patent 1,954,429; April 10, 1934; assigned to Eli Lilly and Company

Secretin

3019

SECRETIN Therapeutic Function: Diagnostic aid (organ function) Chemical Name: Polypeptide peptide containing 27 amino acid residues containing the amino acids: L-His; L-Asp; L-Ser; Gly; L-Thr; L-Phe; L-Glu; L-Glu(NH2) ; L-Leu; L-Arg; L-Ala; and L-Val-NH2 Common Name:Structural Formula:

Chemical Abstracts Registry No.: 1393-25-5 Trade Name Secretin-Boots Secretin-Kabi Secrepan Secretine Sinbio Secretolin

Manufacturer Warren Teed Kabi Eisai Fimex Hoechst

Country US US Japan France -

Year Introduced 1970 1981 -

3020

Selegiline

Raw Materials Tetrapeptide: L-Thr-L-Phe-L-Thr-L-Ser Tetrapeptide: L-His-L-Ser-β-Benzyl-L-Asp-L-Gly Manufacturing Process The gastrointestinal hormone secretin is prepared by fragment condensation. The tetrapeptide L-Thr-L-Phe-L-Thr-L-Ser is coupled to the C-terminal nonadecapeptide of the hormone, and the tetrapeptide L-His-L-Ser-β-benzyl-LAsp-Gly is coupled to the tricosapeptide resulting from the first coupling. References Merck Index 8269 Kleeman and Engel p.817 PDR p. 1428 DOT 10 (6) 210 (1974) and 16 (13) 87 (1980) I.N. p. 868 REM p. 1277 Bodanszky, M., Ondetti, M.A., von Saltza, M.H., Narayanan, V.L. and Levine, S.D.; US Patent 3,767,639; October 23, 1973; assigned to E.R. Squibb and Sons, Inc.

SELEGILINE Therapeutic Function: Antidepressant Chemical Name: N-(1-Phenylisopropyl)-N-methyl-prop-2-ynylamine Common Name: Deprenil; Deprenaline Structural Formula:

Chemical Abstracts Registry No.: 14611-51-9 Trade Name Eldepryl Deprenyl Jumex

Manufacturer Britannia EGYT Medimpex

Country UK Hungary Hungary

Year Introduced 1982 -

Selenium sulfide

3021

Raw Materials L-N-(2-phenylisopropyl)methylamine Propargyl bromide Manufacturing Process 50 g of L-N-(2-phenylisopropyl)methylamine are dissolved in 62.5 ml of toluene, whereupon 13 ml of propargyl bromide are added dropwise within about 20 minutes at a temperature in the range of 50°C to 60°C. The reaction mixture is stirred at 80°C for 3 hours, whereupon it is cooled and the toluene solution is extracted with 125 ml of a 5% hydrochloric acid solution. The acidic layer is separated and made alkaline. The precipitated oil is isolated, washed with benzene and evaporated. The residue is subjected to fractional distillation in vacuo. L-N-(2-phenylisopropyl)methylamine distills off at 65°C to 67°C (0.6 mm Hg, nD20= 1.5083). The L-N-(1-phenylisopropyl)-N-methylprop-2-ynylamine is obtained at 92°C to 93°C (0.8 mm Hg, nD20= 1.5180). The melting point of the hydrochloride is 141°C. References Merck Index 2876 DFU 4 (2) 128 (1979) DOT 19 (1) 29 (1983) I.N. p. 869 Chinoin Gyogyszer-es Vegyeszeti Termekek Gyara R.T.; British Patents 1,031,425; June 2, 1966; and 1,153,578; May 29, 1969

SELENIUM SULFIDE Therapeutic Function: Dermatological Chemical Name: Selenium sulfides Common Name: Structural Formula: Se4S4and Se2S6 Chemical Abstracts Registry No.: 7488-56-4 Trade Name Selsun Bioselenium Caspiselenio Exsel Iosel Sebusan Selenol Sel-O-Rinse

Manufacturer Abbott Uriach Kin Herbert Owen Laake N. D.and K. U.S.V.

Country US Spain Spain US US Finland Denmark US

Year Introduced 1951 -

3022

Sertindole

Trade Name Selsorin Selsun Blue Selukos

Manufacturer Farmos Ross Kabi

Country Finland US W. Germany

Year Introduced -

Raw Materials Selenious acid Hydrogen sulfide Manufacturing Process Selenium disulfide, SeS2, may be made by the reaction of selenious acid, H2SeO3, and hydrogen sulfide. Its manufacture is described by B.W. Nordlander in US Patents 1,860,154 and 1,860,336. It is prepared in a detergent suspension for therapeutic use. References Merck Index 8283 PDR pp.552, 930, 1563 I.N. p.869 REM p. 1165 Baldwin, M.M. and Young, A.P. Jr.; US Patent 2,694,669; November 16, 1954; assigned to Abbott /Laboratories

SERTINDOLE Therapeutic Function: Neuroleptic, Antipsychotic Chemical Name: 2-Imidazolidinone, 1-(2-(4-(5-chloro-1-(4-fluorophenyl)-1Hindole-3-yl)-1-piperidinyl)ethyl)Common Name: Sertindole Structural Formula:

Sertindole

3023

Chemical Abstracts Registry No.: 106516-24-9 Trade Name

Manufacturer

Country

Year Introduced

Serdolect

Lundbeck

Czech Republic

-

Serlect

Abbott Laboratories

UK

-

Sertindole

Lundbeck

-

-

Raw Materials Copper bronze Sodium acetate Acetic anhydride Acetic acid Sodium carbonate Platinum oxide Tartaric acid, L1-(2-Chloroethyl)imidazolon

Potassium 2,5-dichlorobenzoate Potassium N-(4-fluorophenyl)glycinate Potassium carbonate Sodium borohydride Methyl isobutyl ketone Hydrogen Sodium hydroxide

Manufacturing Process 2 Methods of preparation of N-(4-fluorophenyl)-N-(2-carboxyphenyl)glycin 1. A suspension comprising potassium 2,5-dichlorobenzoate (100 g, 0.44 mol, 1 eq.), potassium N-(4-fluorophenyl)glycinate (190 g, 0.92 mol, 2.1 eq.), potassium carbonate (36.2 g, 0.26 mol, 0.6 eq. CO3-), copper bronze (2.8 g, 0.04 mol Cu, 0.1 eq.) and 250 ml demineralised water was heated at reflux under N2 atmosphere for 20.5 h and then cooled to 50°C. 2.5 ml water and 5 g activated carbon were added to the reaction mixture which, except for the Cu-bronze, was homogeneous. The mixture was allowed to cool under stirring for 1 h and filtered. The filter cake was washed with 2 times 125 ml water. The filtrate was poured on a mixture of ice (2 L) and 37% aq. HCl (3-400 ml) under vigorous stirring, thereby crystallising the crude product as a fine, crystalline, yellow-brown material. The suspension was stirred at 75°-80°C for 30 min, cooled to 15°-20°C, and filtered, and the filter cake was washed with 500 ml water and dried under air stream over night at 50°C. Yield of N-(4-fluorophenyl)-N-(2-carboxyphenyl)glycin 113 g (80.3%). After recristalyzation of the product with toluene and reflux for 30 min the N(4-fluorophenyl)-N-(2-carboxyphenyl)glycine of purity > 98%, have the melting point 190°-192°C. 2. 21.0 kg potassium 2,5-dichlorobenzoate was added to a 180 L reactor and 36.0 L water was added. This mixture was heated under stirring until substantially all solids were dissolved 60°-70°C and 25.0 kg potassium N-(4fluorophenyl)glycinate was added slowly. The mixture was heated until all materials were dissolved, i.e. at about 80°C and added to a mixture of 7.67 kg K2CO3, 582 g Cu-bronze and 7 L water. The combined mixture was refluxed overnight (about 15 h) and cooled to 50°C. 1 kg activated carbon suspended in 5 L water was added followed by 40 L water. The mixture was stirred under cooling for 1 h, and filtered on a nutch covered with filter aid. The filter cake was washed with 10 L water and the green filtrate was slowly during about 2 h poured on a mixture of 22.5 L 37% HCl and 30 L water

3024

Sertindole

under gentle heating (45°-50°C) and stirring. The mixture was heated to 72°C, cooled to 25°C and filtered. The filter cake was washed with water (2 times 10 L) and dried on trays overnight at 60°C. Yield 26.7 kg of a pale yellow crystalline crude product. The crude product, 26.7 kg, was transferred to a 200 L reactor and 150 L toluene added and the mixture was heated to the reflux temperature (90°C) under N2 cover. Then the mixture was destilled until a temperature of 110°C was reached (5 L distillate). 5 L toluene was added, and the mixture was refluxed at 110°C for 2 h, cooled to about 60°C and left overnight at 27°C. The mixture was filtered and the filter cake was washed with toluene (3 times 15 L) and dried, thereby obtaining 21.0 kg of the pure N-(4-flourophenyl)-N-(2-carboxyphenyl)glycin. The N-(4-flourophenyl)-N-(2-carboxyphenyl)glycin (717.1 g, 2.22 mol), sodium acetate (36.4 g, 0.44 mol, 0.2 eq.) and acetic anhydride were placed in a 4 L three necked flash equipped with mechanical stirrer and reflux condenser. The suspension was heated under stirring until reflux. The reaction mixture was refluxed for 1 h and was cooled to room temperature on ice/water bath. The homogenous suspension was under stirring poured onto ice (2 L) and was neutralised with concentrated NaOH (appr. 6 L) until a pH of 6-7. During the neutralisation the temperature was kept under appr. 30°C, which required the adding of a further 5-6 L of ice. Thereby the 1-(4flourophenyl)-3-acetoxy-5-chloroindole precipitated and was isolated by filtration. The product was washed thoroughly with 3 L of water and 2 L of nheptane and dried over night in vacuum at 60°C. Yield: 600.5 g (89.1%), melting point 109°-112°C. 1-(4-Flourophenyl)-3-acetoxy-5-chloroindole (100.0 g, 0.33 mol) was dissolved in 1000 ml EtOH. During the next hour sodium borohydride pellets (18.7 g, 1.5 eq.) were added batchwise at reflux. The reaction mixture was stirred over night at reflux and cooled to room temperature. Concentrated HCl (appr. 50 ml until pH 1) was added and the reaction mixture was stirred at room temperature for 1 h 200 ml demineralized water was added, and the resulting suspension was filtrated. The filter cake was washed with further 50 ml water and 10 ml EtOH. The obtained 1-(4-fluorophenyl)-5-chloroindole was dried over night in vacuum at 50°C. Yield: 68.4 g (84.7%), melting point 91°93°C. 5-Chloro-1-(4-fluorophenyl)indole (6.70 kg) and 4-piperidone-monohydrate, hydrochloride (8.38 kg) were transferred to a 200 L reactor under N2 cover. Acetic acid (67 L) was added and the reaction mixture was heated to 60°C. Concentrated HCl (37%, 33.5 L) was added during 0,5 h and then the mixture was heated to the reflux temperature (85°C) and refluxed for 1 h (final temperature 95°C). After cooling to 30°C, 33.5 L acetone was added followed by further cooling to 25°C. Filtration, wash (acetone 20 L) and drying in vacuum at 60°C gave the 5-chloro-1-(4-fluorophenyl)-3-(1,2,3,6tetrahydropyridin-4-yl)indole as a white powder, yield 8.94 kg. 5-Chloro-1-(4-fluorophenyl)-3-(1,2,3,6-tetrahydropyridin-4-yl)indole (6.0 kg, 16.5 mol), 1-(2-chloroethyl)imidazolon (3.19 kg, 1.3 eq.), sodium carbonate (anhydrous) and methyl isobutyl ketone (60 L) were mixed. The reaction mixture was heated under N2-cover and stirring until 90°-95°C, and was stirred over night at this temperature. The next day the reaction mixture was filtered while still hot. The apparatus and filter cake were washed with further 2.5 L of methyl isobutyl ketone. The combined filtrates were left over night for

Sertindole

3025

crystallisation. The 1-[2-[4-[5-chloro-1-(4-flourophenyl)-1H-indol-3-yl]1,2,3,6-tetrahydro-1-pyridyl]ethyl]-2-imidazolidinone was isolated on a nutch, washed with 7.5 L n-heptane and dried over night in vacuum at 60°C. Yield: 5.39 kg (74.3%), melting point 146.4°C. 1-[2-[4-[5-Chloro-1-(4-flourophenyl)-1H-indol-3-yl]-1,2,3,6-tetrahydro-1pyridyl]ethyl]-2-imidazolidinone(3.5 kg) was dissolved in acetic acid (98100%, 29 L) while being heated until 40°C. Activated carbon was added and the suspension was stirred for 1 h, left over night and filtered. The filter cake was washed with 6 L acetic acid. The combined filtrates were added to a 50 L hydrogeneration reactor which was covered by N2. 70 g PtO2 was added, the apparatus was closed and N2 blownthrough for 5 min. Hydrogeneration was carried out in an H2-flow (2.5 L per min) for 8.25 H. The reaction mixture was blown through with nitrogen, activated carbon was added and the mixture was filtered on a closed nutch. The filtrate was combined with corresponding filtrates of three other hydrogenerations and evaporated in vacuum at appr. 50°C. The filtrate was flushed off with 3 times 10 L toluene at 50°-60°C. The remanence was dissolved in 146 L ethanol and to this suspension a 40°C suspnsion of 5.22 kg L-(+)-tartaric acid in 16 L demineralised water was added under stirring. The suspension was left over night with no cooling or stirring. The crystallised tartrate was filtered on a nutch and washed with 15 L ethanol. The crude 1-[2-[4-[5-chloro-1-(4-fluorophenyl)-1-H-indol-3-yl]-1piperidinyl]ethyl]-2 -imidazolidinone, tartrate was recrystallised from 190 L ethanol and 30 L demineralised water by heating until boiling (appr. 78°C). The suspension was left over night for crystallasation with no cooling or stirring. The next day the suspension was cooled to appr. 18°C and the tartrate was filtered off, washed with 60 L ethanol and dried over night under air stream at 60°C. 7.96 kg 1-[2-[4-[5-chloro-1-(4flourophenyl)-1H-indol-3-yl]-1,2,3,6tetrahydro-1-pyridyl]ethyl]-2-imidazolodione, tartrate was suspended in 25 L demineralised water and 30 L dichloromethane was added. A total of 3 L 27% NaOH-solution, pH = 9, was added to the suspension under stirring. The mixture was stirred for 1 h (pH still = 9), whereafter the dichloromethane phase was separated. The water phase was extracted with further 15 L dichloromethane. The combined dichloromethane phases were dried with Na2SO4 and were evaporated. The product was flushed off with 5 L acetone, 35 L acetone was added and the suspension was heated until reflux. The crystallised product did not dissolve completely. Heating was discontinued and the mixture was left over night with gentle cooling. The crystallised 1-[2-[4-[5-chloro-1-(4flourophenyl)-1H-indol-3-yl]-1-piperidinyl]ethyl]-2- imidazolidinone was isolated on a notch, washed with further 5 L acetone and dried over night under air stream at 60°C. Yield: 4.90 kg (83.2%), melting point 154.7°C. References Sommer M.B.; US Patent No. 6,335,463 B1; Jan. 1, 2002; Assigned: H. Lundbeck A/S, Valby-Copenhagen (DK)

3026

Sertraline hydrochloride

SERTRALINE HYDROCHLORIDE Therapeutic Function: Antidepressant Chemical Name: 1-Naphthalenamine, 1,2,3,4-tetrahydro-4-(3,4dichlorophenyl)-N-methyl-, (1S-cis)-, hydrochloride Common Name: Sertraline hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 79559-97-0; 79617-96-2 (Base) Trade Name Lustral Riva-Sertraline Serlift Serlin Zoloft

Manufacturer Pfizer Riva Ranbaxy Zydus Pfizer

Country UK India USA

Year Introduced -

Raw Materials Aluminum chloride Potassium t-butoxide Hydrogen bromide Thionyl chloride Titanium tetrachloride Hydrogen chloride

3,4-Dichlorobenzoyl chloride Diethyl succinate Hydrogen Methylamine Mandelic acid, D-

Manufacturing Process Anhydrous AlCl3 (219 g, 1.64 moles) was added in portions over a 35 to 40 min period to a stirred solution of 3,4-dichlorobenzoyl chloride (313.5 g, 1.50 moles) in benzene (1.125 L) and dichloromethane (75 ml), with the mixture maintained at 3° to 5°C during the addition period. The reaction mixture was held at 0° to 5°C for another hour and then poured into 2.5 L of ice/water and stirred until the complex had decomposed. The organic and aqueous layers were then separated and the organic layer combined with one ethyl acetate

Sertraline hydrochloride

3027

wash of the aqueous layer. The resulting organic solution was washed twice with water and once with saturated brine solution, dried (anhyd. MgSO4), treated with decolorizing carbon and evaporated under vacuum to yield white solid of 3,4-dichlorobenzophenone, which was recystallized from 400 ml of hot ethyl acetate-pentane (156.8 g, 41% yield, melting point 100°-102°C. A solution of 3,4-dichlorobenzophenone (398 g, 1.58 moles) in t-butyl alcohol (1500 ml) was treated sequentially with potassium t-butoxide (169 g, 1.5 moles) and diethyl succinate (402 ml, 2.4 moles). A mildly exothermic reaction ensued and the initially clear solution set up as a solid mass. The reaction mixture was slowly heated to reflux, at which it became a stirrable white suspension, and then stirred at reflux under nitrogen for about 16 h. The reaction mixture was then cooled and poured into 2 L of ice/water. The resulting mixture was acidified with 10% HCl and extracted with ethyl acetate (3 times 1 L). The combined ethyl acetate extract was extracted with 1 N NH4OH (3 times 1 L) and the combined aqueous basic extract washed with ethyl acetate (2 L), cooled to 0° to 5°C, acidified slowly to a pH below 1.0 with concentrated HCl and extracted with ethyl acetate (4 times 2 L). The combined ethyl acetate extract was dried (MgSO4) and evaporated under vacuum to a light yellow oil slightly contaminated with diethyl succinate (477 g, 80% yield). An analytical sample of 3-ethoxycarbonyl-4-(3,4dichlorophenyl)-4-phenylbut-3-enoic acid was crystallized from petroleum ether (melting point 128°-130°C). A suspension of 3-ethoxycarbonyl-4-(3,4-dichlorophenyl)-4-phenylbut-3-enoic acid (227 g, 0.60 mole) in 48% aqueous HBr - glacial acetic acid (1:1, 1.80 L) was stirred at reflux for 36 h and then cooled to room temperature. A gum separated from the reaction mixture, which was isolated by decantation of the aqueous layer and then dissolved in ethyl acetate (2 L). The resulting organic solution was extracted with 10% aqueous NH4OH (2 times 2 L). The combined extract was cooled to 0° to 5°C, acidified slowly to a pH below 1.0 with concentrated HCl and extracted with ethyl acetate (4 times 1 L). The combined ethyl acetate extract was washed with water, dried (MgSO4) and evaporated under vacuum to a light brown oil (120 g), which was the 4-(3,4dichlorophenyl)-4-phenylbut-3-enoic acid and crystallized from hexane (91.4 g, 50% yield, melting point 115°-120°C). A solution of 4-(3,4-dichlorophenyl)-4-phenylbut-3-enoic acid (223 g, 0.73 mole) in ethyl acetate (2 L) was hydrogenated over 8 g of 5% Pd/C catalyst at atmospheric pressure and room temperature until hydrogen uptake ceased (24 h). The catalyst was separated by filtration and the filtrate evaporated under vacuum to a light brown oil containing traces of solvent (ca. 100% yield). An analytical sample of the 4-(3,4-dichlorophenyl)-4-phenylbutanoic acid was crystallized from hexane (melting point 118°-120°C). A solution of 4-(3,4-dichlorophenyl)-4-phenylbutanoic acid (228 g, 0.74 mole) in toluene (1.2 L) was treated with thionyl chloride (66 ml, 0.90 mole) and the resulting solution heated at reflux for 75 min, with provision made for trapping HCl gas given off from the refluxing reaction solution. The reaction solution was then evaporated under vacuum to about 230 g of a light brown oil. The oil was dissolved in carbon disulfide (360 ml) and the resulting solution added to a well stirred suspension of AlCl3 (1.5 kg, 12.5 moles) in carbon disulfide (1.20 L), with the mixture held below 8°C during the addition

3028

Sertraline hydrochloride

period, forming a brown mass. After the addition was completed, the reaction mixture was stirred for about 16 h at room temperature and then slowly poured on ice (vigorous reaction). The resulting suspension was extracted with ethyl acetate (2 times 4 L). The combined extract was washed with water, washed with saturated aqueous sodium bicarbonate solution, dried and evaporated under vacuum to a residue, which was crystallized from hexane (500 ml) to yield the 4-(3,4-dichlorophenyl)-3,4-dihydro-1-(2H)naphthalenone (104.1 g, 48% yield, melting point 99°-101°C). A solution of 4-(3,4-dichlorophenyl)-3,4-dihydro-1-(2H)-naphthalenone (50 g, 0.17 mole) in tetrahydrofuran (800 ml.) was cooled to 0° to 5°C and treated with 52 ml (1.20 moles) of methylamine (condensed at 0°C). Titanium tetrachloride (10 ml, 0.087 mole) was added dropwise to the resulting solution (vigorous reaction), with the reaction mixture stirred at below 10°C during the addition period. After the addition was completed, the reaction mixture was stirred for 17 h at room temperature under nitrogen and then filtered. The solids were washed thoroughly with tetrahydrofuran and the combined filtrates were concentrated under vacuum to 600 ml. to remove excess methylamine. Further evaporation of an aliquot to dryness and trituration with hexane yielded the Schiff base (melting point 145°-146°C). The Schiff base-containing concentrate was hydrogenated for 2 h over 5.0 g of 10% Pd/C catalyst at atmospheric pressure and room temperature. Hydrogen uptake ceased within the 2 h reaction period. After removal of the catalyst by filtration, the reaction mixture was evaporated under vacuum to a residue. The residue was dissolved in anhydrous ether (1 L) and the resulting solution treated with gaseous hydrogen chloride to yield a white precipitate, containing about 70% cis-racemate and 30% tras-racemate of N-methyl-4-(3,4dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine hydrochloride. The HCl salt cis-racemate and trans-racemate of N-methyl-4-(3,4dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine hydrochloride, was dissolved in hot methanol (2 L). Upon addition of ether (1200 ml) and cooling overnight, cis-(1S)(1R)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1naphthalenamine hydrochloride precipitated (47 g, melting point 290°-291°C). The supernatant was evaporated under vacuum to dryness and the residue triturated with acetone. The triturated residue (ca. 90% cis-racemate, 10% trans-racemate) was recrystallized from methanol:ether (1:1) to yield another 20 g of the same product. The total yield of cis-(1S)(1R)-N-methyl-4-(3,4dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine hydrochloride was 67g, 68% yield; melting point 289°-290°C. 67.1 g of cis-(1S)(1R)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1naphthalenamine hydrochloride was partitioned between 20% aqueous NaOH and ethyl acetate to yield a solution of the cis-racemate free base (60.2 g, 0.197 mole) in ethyl acetate. This solution was dissolved in absolute ethanol (600 ml) and the resulting solution treated with D-(-)-mandelic acid (29.94 g, 0.197 mole). The resulting mixture was warmed on a steam bath to effect solution and then held overnight at room temperature to afford a white crystalline solid. This solid was separated by filtration, washed with ether and air dried (38.7 g, melting point 188°-189°C), and then cis-(1S)-N-methyl-4(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine mandelate recrystallized from hot absolute ethanol (32.6 g, melting point 190°-191°C). An additional crop (4.4 g, melting point 190°-191°C) was obtained by evaporation of the mother liquors under vacuum to residues, followed by

Sevelamer hydrochloride

3029

crystallization of the residues from boiling ethanol (150 ml). The mandelate salt were suspended in ethyl acetate (about 2 L). The ethyl acetate suspension was treated with 10% aqueous NaOH solution, thereby converting the amine to the free base. The resulting ethyl acetate solution was then dried, diluted with ether (2 L) and then treated with excess gaseous hydrogen chloride to give a gelatinous suspension which crystallized overnight. The crystalline HCl salt product was separated by filtration, washed with ether and air dried. The cis-(1S)-N-methyl-4-(3,4-dichlorophenyl)1,2,3,4-tetrahydro-1-naphthalenamine hydrochloride 25.96 g, 39% yield, with melting point 243°-245°C. References Welch W.M. et al; US Patent No. 4,536,518; August 20, 1985; Assigned: Pfizer Inc., New York., N.Y.

SEVELAMER HYDROCHLORIDE Therapeutic Function: Antihyperphosphatemic Chemical Name: poly(2-Propen-1-amine hydrochloride) cross-linked with epichlorohydrin Common Name: Sevelamer hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 152751-57-0 Trade Name Renagel Renagel Renagel

Manufacturer Chugai Pharmaceutical Co., Ltd. GelTex Pharmaceuticals, Inc. Genzyme Corporation

Country -

Year Introduced -

USA

-

Raw Materials Poly(allylamine hydrochloride) Sodium hydroxide Epichlorohydrin Manufacturing Process Poly(allylamine hydrochloride) (50% w/w, 426 kg) was charged to a 1000 L

3030

Sevoflurane

reactor and water (200 L) was added. Sodium hydroxide solution (32% w/w, 208 kg) was added, followed by 85 L of water. The mixture was stirred for 1 h and filtered to a 2500 L reactor. The transfer line was rinsed with water (217 kg) and acetonitrile (1300 L) added. The temperature was adjusted to 40°C and epichlorohydrin (20 kg) added. The mixture was stirred at 40° to 50°C for 1.5 h and then heated to reflux for 16 h. The resulting product slurry may be isolated and washed in decanter centrifuge. The crude gel suspension of epichlorohydrin cross-linked poly(allylamine hydrochloride) was fed to an Alfa Laval CHNX 318 at 9.5 to 12.3 L/min with bowl speeds of 2500 rpm to 3250 rpm and differential speeds between 1.3 and 10 rpm. The discharged gel had a moisture content of 75% to 82%. References McDonnell P.D. et al.; US Patent No. 6,600,011 B2; July 29, 2003; Assigned: Genzyme Corporation, Cambridge, MA (US)

SEVOFLURANE Therapeutic Function: Anesthetic Chemical Name: Ether, fluoromethyl 2,2,2-trifluoro-1-(trifluoromethyl)ethylCommon Name: Sevoflurane Structural Formula:

Chemical Abstracts Registry No.: 28523-86-6 Trade Name

Manufacturer

Country

Year Introduced

Sevoflurane

Abbott Laboratories

UK

-

Ultane

Abbott Laboratories

USA

-

Raw Materials Chlorine Potassium carbonate Potassium fluoride Tetrahydrothiophene 1,1-dioxide Chloromethyl 1,1,1,3,3,3-hexafluoro-2-propyl ether Methyl 1,1,1,3,3,3-hexafluoroisopropyl ether

Sibutramine hydrochloride

3031

Manufacturing Process 164 g (2.31 mole) of chlorine is slowly bubbled into a flask containing 370 g (2.03 mole) of methyl 1,1,1,3,3,3-hexafluoroisopropyl ether illuminated with a 250 watt incandescent lamp, starting at room temperature. The product is washed with a potassium carbonate solution until neutral, dried over MgSO4 and vacuum distilled to yield 304 g (1.5 mole) of chloromethyl 1,1,1,3,3,3hexafluoroisopropyl ether (chloromethyl 1,1,1,3,3,3-hexafluoro-2-propyl ether), boiling point 78°C. A solution of chloromethyl 1,1,1,3,3,3-hexafluoro-2-propyl ether (754 g, 3.49 moles) in dry tetrahydrothiophene 1,1-dioxide (203 g, 3,49 moles) were stirred and heated to 130°C in a creased flask fitted with a fractional distillation assembly. A distillate (200 ml), b748 56.0° to 62°C, was collected during 5 h. Then the reaction mixture was cooled to room temperature, dry potassium fluoride (100 g, 1.74 moles) was added, and the cycle of operations was repeated 3 times at temperatures between 138° to 185°C to give distillates (100 ml, 100 ml and 50 ml), b746 58° to 61°C, 55.5° to 57°C, and 54.2° to 55.9°C, respectively. From this portionwise addition of potassium fluoride (503 g, 8.7 moles) there was obtained distillates totalling 672 g, b746 54.2° to 62.0°C, which by GLC analysis was about 92% fluoromethyl and 6.8% chloromethyl 1,1,1,3,3,3-hexafluoro-2-propyl ether. Fractional distillation of 659 g gave a forerun (46 g), b745 53.5° to 57.0°C, and then 99.6% pure fluoromethyl 1,1,1,3,3,3-hexafluoro-2-propyl ether (505 g), b745 57.0° to 57.7°C. References Regan B.M., Longstreet J.C.; US Patent No. 3,683,092; August 8, 1972; Assigned: Baxter Laboratories, Inc., Morton Grove Croix L.S. et al; US Patent No. 3,476,860; Nov. 4, 1969; Assigned: Air Reduction Company, Incorpora, New York, N.Y.

SIBUTRAMINE HYDROCHLORIDE Therapeutic Function: Antidepressant, Anorexic Chemical Name: Cyclobutanemethanamine, 1-(4-chlorophenyl)-N,Ndimethyl-α-(2-methylpropyl)-, hydrochloride Common Name: Sibutramine hydrochloride Structural Formula:

3032

Sibutramine hydrochloride

Chemical Abstracts Registry No.: 84485-00-7; 106650-56-0 (Base) Trade Name Meridia Reductil Reductil Reductil

Manufacturer Abbott Laboratories Abbott Laboratories Knoll AG Teva Pharmaceuticals

Country USA Germany Israel

Year Introduced -

Raw Materials 4-Chlorobenzyl cyanide 1,3-Dibromopropane Sodium hydride Magnesium Hydrochloric acid Potassium hydroxide Thionyl chloride Ethyl bromide Diethylene glycoldimethyl ether Manufacturing Process A solution of 4-chlorobenzyl cyanide and 1,3-dibromopropane in dry dimethylsulfoxide was added dropwise under nitrogen to a stirred mixture of sodium hydride dispersed in mineral oil and dimethylsulfoxide at a temperature in the range 30° to 35°C. The mixture was stirred at room temperature for 2 h and propan-2-ol and then water were added dropwise. The mixture was filtered through a diatomaceous earth sold under the Registered Trade Mark CELITE and the solid residue washed with ether. The ether layer was separated, washed with water, dried and evaporated. 1-(4Chlorophenyl)-1-cyclobutanecarbonitrile was isolated by distillation. 1-(4-Chlorophenyl)-1-cyclobutanecarbonitrile (37.6 g) was added to a solution of potassium hydroxide (32.4 g) in diethyleneglycol (370 ml) and the mixture heated under reflux for three and a 0.5 h The reaction mixture was poured into an ice/water mixture and the resulting solution was washed with ether. The aqueous layer was added to a mixture of concentrated hydrochloric acid (100 ml) and ice and the resulting precipitate of 1-(4-chlorophenyl)-1cyclobutanecarboxylic acid (melting point 86°-88°C) collected, washed with water and dried. 1-(4-Chlorophenyl)-1-cyclobutane carboxylic acid (10.5 g) was heated under reflux with thionyl chloride (20 ml) for 2.5 h. Excess thionyl chloride was evaporated off and the acid chloride of the above acid distilled (boiling point 82°-96°C /0.2 mm Hg). A solution of the acid chloride in dry tetrahydrofuran was added slowly to the product of the reaction of magnesium turnings and ethyl bromide in dry tetrahydrofuran. Water was added followed by 5 N hydrochloric acid with cooling. The reaction mixture was extracted with ether, washed with water, sodium bicarbonate solution, dried. The solvent was removed by evaporation and 1-isobutyl-1-(4-chlorophenyl)cyclobutane obtained by distillation. The 1-isobutyl-1-(4-chlorophenyl)cyclobutane, diethylene glycoldimethyl ether, water and concentrated hydrochloric acid were mixed and heated under reflux. The mixture was poured into water aqueous NaOH was added and the product extracted into ether. Evaporation gave a dark oil. A sample of this oil, water and formic acid were mixed and formaldehyde added. The mixture was heated under reflux and then concentrated hydrochloric acid and propan-2-ol were added. Evaporation to

Sildenafil citrate

3033

dryness gave N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]isobutyl hydrochloride as a white solid. References Jeffery J.E. et al.; US Patent No. 4,746,680; May 24, 1988; Assigned: The Boots Company p.l.c., England

SILDENAFIL CITRATE Therapeutic Function: Vasodilator Chemical Name: Piperazine, 1-((3-(4,7-dihydro-1-methyl-7-oxo-3-propyl-1Hpyrazolo(4,3-d)pyrimidin-5-yl)-4-ethoxyphenyl)sulfonyl)-4-methyl-, 2hydroxy-1,2,3-propanetricarboxylate (1:1) Common Name: Sildenafil citrate Structural Formula:

Chemical Abstracts Registry No.: 171599-83-0; 139755-83-2 (Base) Trade Name Alsigra Androz Caverta Edegra Erix Juan

Manufacturer Alembic Ltd. Torrent Pharmaceuticals Ltd. Ranbaxy Laboratories Limited Sun Pharmaceuticals Industries Ltd. Unichem Laboratories Ltd. IRM Pharma

Country India India India India

Year Introduced -

India India

-

3034

Sildenafil citrate

Trade Name Mamforce Pefomax-50 Penegra Progra Silagra Uplift-50 Viagra Viagra Viagra Vigreks Viraha Virecta

Manufacturer Mankind Pharma Pvt. Ltd. Bestochem Formulations (I) Ltd. Zydus Alidac Protech Biosystems Cipla Limited Wallace Pharmaceuticals Ltd. Pfizer Allscripts Ranbaxy Medley Pharmaceuticals Pvt. Ltd. Micro Labs Seagull Labs (I) Pvt. Ltd.

Country India India

Year Introduced -

India India India India USA USA India India

-

India India

-

Raw Materials Dimethyl sulfate 4-Methylpiperidine Sodium hydroxide Stannous chloride dihydrate Hydrochloric acid 2-Ethoxybenzoyl chloride Nitric acid 4-Dimethylaminopyridine Thionyl chloride Triethylamine Hydrochloric acid Hydrogen peroxide Sodium carbonate Chlorosulfonic acid 3-n-Propylpyrazole-5-carboxylic acid ethyl ester Manufacturing Process A mixture of 3-n-propylpyrazole-5-carboxylic acid ethyl ester (24.1 g, 0.132 mol) (prepared by the method of Chem. Pharm. Bull., 1984, 32, 1568) and dimethyl sulfate (16.8 g, 0.133 mol) were heated to 90°C for 2.5 h. The mixture was dissolved in dichloromethane and the solution washed with sodium carbonate solution. The organic phase was separated, dried (MgSO4) and evaporated under vacuum to give a solid. Chromatography on silica gel (300 g), eluting with dichloromethane gave the 1-methyl-3-n-propylpyrazole5-carboxylic acid ethyl ester as a colourless oil (20.4 g, 79%). 1-Methyl-3-n-propylpyrazole-5-carboxylic acid ethyl ester (20.2 g, 0.10 mol) was suspended in 6 N aqueous sodium hydroxide solution (50 ml, 0.30 mol). The mixture was heated to 80°C for 2 h then diluted with water (50 ml) and acidified with concentrated hydrochloric acid (25 ml). Filtration gave the 1methyl-3-n-propylpyrazole-5-carboxylic acid as pale brown crystals (12.3 g, 71%), melting point 150°-154°C. 1-Methyl-3-n-propylpyrazole-5-carboxylic acid (12.1 g, 0.072 mol) was added portionwise to a mixture of oleum (13 ml) and fuming nitric acid (11 ml), keeping the temperature below 60°C. After the addition, the mixture was heated at 60°C overnight and then cooled to room temperature before being poured onto ice. Filtration of the precipitate gave the 1-methyl-4-nitro-3-npropylpyrazole-5-carboxylic acid as a white solid (11.5 g, 75%), melting point 124°-127°C.

Sildenafil citrate

3035

1-Methyl-4-nitro-3-n-propylpyrazole-5-carboxylic acid (11.3 g, 0.053 mol) was added to thionyl chloride (50 ml) and the resulting mixture heated under reflux for 3 h. The reaction mixture was then cooled and excess thionyl chloride removed by evaporation under vacuum. The oily residue was dissolved in acetone (50 ml) and the solution cautiously added to a mixture of ice (50 g) and concentrated aqueous ammonium hydroxide solution (50 ml). The precipitate was collected by filtration to provide the 1-methyl-4-nitro-3-npropylpyrazole-5-carboxamide as a pale yellow solid (8.77 g, 78%), melting point 141°-143°C. 1-Methyl-4-nito-3-n-propylpyrazole-5-carboxamide (3.45 g, 16.2 mmol) and stannous chloride dihydrate (18.4 g, 81 mmol) were suspended in ethanol and the mixture heated under reflux for 2 h. The resulting solution was cooled to room temperature, basified to pH 9 by the addition of 2 N aqueous sodium hydroxide solution and extracted with dichloromethane (3 x 150 ml). The organic extracts were combined, dried (MgSO4) and evaporated under vacuum. Trituration of the residue with ether gave the 4-amino-1-methyl-3-npropylpyrazole-5-carboxamide as an off-white solid (2.77 g, 94%), melting point 98°-101°C. A solution of 2-ethoxybenzoyl chloride (6.1 g, 33.0 mmol) in dichloromethane (50 ml) was added to a stirred solution of 4-amino-1-methyl-3-npropylpyrazole-5-carboxamide (3.0 g, 16.4 mmol), 4-dimethylaminopyridine (0.02 g, 0.1 64 mmol) and triethylamine (3.34 g, 33.0 mmol) in dichloromethane (50 ml) at 0°C. The resulting mixture was allowed to warm to room temperature and stirred for a further 2 h. The solvent was evaporated under vacuum, the residue dissolved in a 19:1 mixture of dichloromethane and methanol (250 ml), and then the solution washed with 1 N hydrochloric acid (100 ml), dried (MgSO4) and evaporated under vacuum. The crude material was chromatographed on silica gel (200 g), eluting with a 97:3 mixture of dichloromethane and methanol, to give a pink solid; crystallisation from ethyl acetate-hexane gave the 4-(2-ethoxybenzamido)-1-methyl-3-npropylpyrazole-5-carboxamide as a pale pink solid (2.2 g, 40%), melting point 153°-155°C. 4-(2-Ethoxybenzamido)-1-methyl-3-n-propylpyrazole-5-carboxamide (223 g, 0.676 mol) was added portionwise to a solution of sodium hydroxide (54 g, 1.35 mol) and 30% hydrogen peroxide solution (224 ml) in water (2000 ml). Ethanol (700 ml) was added and the resulting mixture heated under reflux for 2.5 h, cooled, then evaporated under vacuum. The resulting solid was treated with 2 N hydrochloric acid (380 ml), with external cooling, and the mixture was extracted with dichloromethane (1 x 700 ml, 3 x 200 ml). The combined organic extracts were washed successively with saturated aqueous sodium carbonate solution (3 x 400 ml) and brine (300 ml), then dried (Na2SO4) and evaporated under vacuum. Chromatography of the residue on silica gel (1000 g), using a methanol in dichloromethane elution gradient (0-1%), followed by trituration of the crude product with ether (300 ml), gave the 5-(2ethoxyphenyl)-1-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin7-one as a colourless solid (152.2 g, 72%), melting point 143°-146°C. 5-(2-Ethoxyphenyl)-1-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3d]pyrimidin-7-one (10.0 g, 32.1 mmol) was added portionwise to chlorosulfonic acid (20 ml) at 0°C under a nitrogen atmosphere. After being stirred overnight, the reaction solution was cautiously added to ice-water (150

3036

Silymarin

ml) and the aqueous mixture extracted with a 9:1 mixture of dichloromethane and methanol (4 x 100 ml). The combined extracts were dried (Na2SO4) and evaporated under vacuum to give the required 5-(5-chlorosulphonyl-2ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin7-one as a white solid (12.8 g, 97%), melting point 179°-181°C. 4-Methylpiperidine was added to a stirred suspension of 5-(5-chlorosulphonyl2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3d]pyrimidin-7-one in ethanol at room temperature. The resulting mixture was stirred for 4 days before removing the solvent by evaporation under vacuum. The residue was dissolved in a 9:1 mixture of dichloromethane and methanol and the solution washed with saturated aqueous sodium carbonate solution. The aqueous phase was further extracted with dichloromethane-methanol mixtures (3 x 100 ml) and all the organic fractions were combined, dried (MgSO4) and evaporated under vacuum to give a solid. Crystallisation from a mixture of methanol-dimethylformamide gave the 5-[2-ethoxy-5-(4methylpiperidinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7Hpyrazolo[4,3-d]-pyrimidin-7-one as an off-white solid, melting point 187°189°C. After addition of citric acid to the 5-[2-ethoxy-5-(4methylpiperidinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7Hpyrazolo[4,3-d]-pyrimidin-7-one (sildenafil) the it's salt is obtained, namely sildenafil citrate. References Bell A.S. et al.; EU Patent No. 0 463 756 A1; Jan. 2, 1992; Assigned: Pfizer Limited Ramsgate Road Sandwich

SILYMARIN Therapeutic Function: Hepatoprotectant Chemical Name: 2-[2,3-Dihydro-3-(4-hydroxy-3-methoxyphenyl)-2(hydroxymethyl)-1,4-benzodioxin-6-yl]-2,3-dihydro-3,5,7-trihydroxy-4H1-benzopyran-4-one Common Name: Silybin; Silibinine Structural Formula:

Silymarin

3037

Chemical Abstracts Registry No.: 27359-03-1 Trade Name Legalon Legalon Legalon Silliver Apihepar Cardornerin Cronol Dura Silymarin Emil Eparfit Escarmine Flavobion Halodren Hepadestal Hepagerina Hepalar Hepallolina Hepato-Framan Laragon Sematron Silarine Silepar Silgen Silibancol Silimazu Silirex

Manufacturer Madaus I.B.I. Roger Bellon Abbott Panchemie Homburg Deiters Kappa Durachemie Horus Europa Dreikehl Spofa Escaned Krugmann Kairon Larma Callol Oftalmiso Roemmers Madariaga Vir Ibirn Morgens Durban Mazuelos Lampugnani

Country W. Germany Italy France Italy Austria Spain Spain W. Germany Spain Spain Spain Czechoslovakia Spain W. Germany Spain Spain Spain Spain Argentina Spain Spain Italy Spain Spain Spain Italy

Year Introduced 1969 1971 1974 1977 -

Raw Materials Silybum marianum fruit Ethyl acetate Manufacturing Process Silymarin comprising polyhydroxyphenyl chromanones is recovered from the dried fruit of Silybum marianum Gaertn. by separating the fatty oils therefrom, extracting the remaining solid residue with ethyl acetate, evaporating the ethyl acetate and dissolving the dry residue in a solvent mixture comprising methanol, water and petroleum ether to form a two-phase system wherein the chromanones are contained in the lower phase, recovering the polyhydroxyphenyl chromanones from the lower phase after subjecting same to multiple counter-current contact with petroleum ether. References Merck Index 8372 Kleeman and Engel p. 818 DOT 7 (6) 216 (1971)

3038

Simethicone

I.N. p. 873 Madaus, R.; US Patent 3,773,932; November 20, 1973; assigned to Dr. Madaus and Co. (Germany)

SIMETHICONE Therapeutic Function: Antiflatulent Chemical Name: alpha-(Trimethylsilyl)-omega-methylpoly(oxy (dimethylsilylene)), mixture with silicon dioxide Common Name: Structural Formula: Dimethyl polysiloxane Chemical Abstracts Registry No.: 8050-81-5 Trade Name Mylicon Silain Celluzyme Gelusil Mylanta Phazyme Riopan-Plus Simeco Tri-Cone

Manufacturer Stuart Robins Dalin Parke Davis Stuart Reed and Carnrick Ayerst Wyeth Glaxo

Country U.S. U.S. U.S. U.S. U.S. U.S. U.S. U.S. U.S.

Year Introduced 1960 1961 -

Raw Materials Dimethyl diethoxy silane Trimethyl ethoxy silane Sodium hydroxide Manufacturing Process In a 5 liter three-necked flask, fitted with a reflux condenser, agitator and thermometer, were placed 1,393 grams (9.41 mols) of redistilled (CH3)2Si(OEt)2, and 1,110 grams (9.41 mols) of (CH3)3SiOEt. To this solution was added 254 grams (14.11 mols) of water containing 7.5 grams of NaOH, (approximately 1 NaOH per 100 silicon atoms). This insured the formation of only straight chain polymers. The mixture was heated to 40°C and the temperature continued to rise for nearly an hour. After adding 50 cc (20% excess) more water, the mixture was refluxed for two hours and then allowed to stand overnight. Alcohol was then distilled off, until the temperature reached 100°C. 1,706.6 grams of distillate was collected (theory 1,430 grams). This alcohol was poured into four times its volume of water and an insoluble oil separated (457

Simfibrate

3039

grams). The insoluble fraction was added back to the copolymer residue from the distillation and 555 cc of 20% hydrochloric acid was added. The acid mixture was refluxed for two hours, and the silicon oils were carefully washed with distilled water until neutral. The yield was 1,420 grams (theory, 1,469 grams). References Merck Index 8374 PDR pp. 650, 829, 916, 1352, 1444, 1569, 1783, 1981 REM p. 814 Hyde, J.F.; U.S. Patent 2,441,098; May 4, 1948; assigned to Corning Glass Works

SIMFIBRATE Therapeutic Function: Antihyperlipidemic Chemical Name: 2-(4-Chlorophenoxy)-2-methylpropanoic acid 1,3propanediyl ester Common Name: Structural Formula:

Chemical Abstracts Registry No.: 14929-11-4 Trade Name Cholesorbin Cholesolvin Liposolvin

Manufacturer Takeda Cyanamid Tosi-Novara

Raw Materials α-(p-Chlorophenoxy)isobutyric acid 1,3-Propanediol

Country Japan Italy Italy

Year Introduced 1971 1977 -

3040

Simvastatin

Manufacturing Process A mixture of 22 grams of α-(p-chlorophenoxy)isobutyric acid, 3.8 grams of 1,3-propanediol, 0.5 gram of p-toluenesulfonic acid and 150 ml of xylene was refluxed. When the theoretically calculated amount of water had been removed, the xylene solution was washed with dilute aqueous sodium bicarbonate and then the xylene was distilled off. The residue was distilled under reduced pressure to give 11 grams (47% yield) of 1,3-propanediol bis[α-(p-chlorophenoxy)isobutyrate] boiling at 197° to 200°C/0.03 mm Hg. References Merck Index 8377 Kleeman and Engel p.819 DOT 7 (6) 221 (1971) I.N. p.874 Nakanishi, M., Kuriyama, T., Oe, T. and Kobayakawa, T.; US Patent 3,494,957; Feb. 10, 1970; assigned to Yoshitomi Pharmaceutical Industries, Ltd., Japan

SIMVASTATIN Therapeutic Function: Antihyperlipidemic Chemical Name: Butanoic acid, 2,2-dimethyl-, (1S,3R,7S,8S,8aR)1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-(2-((2R,4R)-tetrahydro-4hydroxy-6-oxo-2H-pyran-2-yl)ethyl)-1-naphthalenyl ester Common Name: Simvastatin; Sinvastatin; Synvinolin; Velastatin Structural Formula:

Chemical Abstracts Registry No.: 79902-63-9 Trade Name

Manufacturer

Biosim

Biochem Pharma Industries India

Country

Year Introduced -

Clinfar

Merck

Netherlands

-

Detrovel

Pratapa

-

-

Simvastatin Trade Name Liponorm Lipovas Lovacor Redusterol Simgal Simlo Simvacard Sinvascor Simvastatin Simvor Vasilip Vero-Simvastatin Zocor

Manufacturer Gentili Banyu Farmasa Raffo Galena a.s. IPCA laboratories Ltd. Merck Balducci/Hexal Biogal Ranbaxy Krka Okasa Pharma Merck

Country Czech Republic India Czech Republic Hungary India Slovenia India Netherlands

3041

Year Introduced -

Raw Materials Lovastatin Phenylboronic acid Methyl iodide 1,3-Propanediol Manufacturing Process A suspension of Lovastatin (350 g, 0.865 mmol), phenylboronic acid (110.8 g, 0.909 mmol) and toluene (1.75 L) was heated under a nitrogen atmosphere at 100-105°C for 55 min. The water was separated from the reaction mixture. The solution was cooled and 1.39 L of toluene was removed by vacuum distillation at 40-50°C. The concentrated solution was treated with hexanes (3.15 L) at 40-50°C. The resulting suspension was cooled to 0-5C for 2 hours and the product was filtered and washed with hexanes (350 mL). The product was dried at 35-40°C under vacuum to provide 427.9 g (37%) of lovastatin phenylboronate at >99% purity by HPLC. A 2 L 3-necked flask was charged with pyrrolidine (56 mL, 0.67 mol) and dry THF (453 g) under a nitrogen atmosphere. n-Butyl lithium (419 mL, 1.6 M hexane solution, 0.67 mol) was added dropwise at -20°C over a period of 1 hour. The solution was maintained at this temperature for 30 min and then cooled to -55°C. A solution of lovastatin phenylboronate (101.7 g, 0.20 mol) in 274.7 g of THF was cooled to -50°C and then added to the cold lithium pyrrolidide solution at a rate such that the internal temperature was between -50°-55°C during the addition. The mixture was held at this temperature for 4 hours and then methyl iodide (116.4 g, 0.82 mol) was added at a temperature below -55°C. The reaction was stirred for 13 hours at -20°C and then quenched with 500 mL of 2 M HCl at a temperature below 0°C. After warming to 20°C, the layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with 5% NaHSO3 solution and deionized water. The solution was filtered through a Celite pad and concentrated to yield 102.8 g (98.4%) of crude Simvastatin phenylboronate at >95% purity by HPLC. A portion of the above material (50.0 g) was charged into a nitrogen purged flask with acetonitrile (100 mL). The suspension was heated at 110°C for 3 hours and then cooled to - 10°C

3042

Sincalide

for 1 hour. The product was filtered and washed with 25 mL of acetonitrile and dried under vacuum to provide 43.7 g of Simvastatin phenylboronate at >99% purity by HPLC. A suspension of simvastatin phenylboronate (30.0 g) and 1,3-propanediol (450 mL) was heated at 105-107°C at 0.2 mm Hg. After 1 hour, 182 mL of distillate was collected and the reaction was cooled to 20-25°C. Deionized water (270 mL) was added and toluene (3 times 75 mL) was used to extract the mixture. The combined toluene layers were washed with water (60 mL). The organic solution was heated at reflux for 1 hour and water was azeotropically removed. The solution was concentrated to a final volume of 24 mL under vacuum at 48-50°C. To the concentrated solution was added hexanes (215 mL) over 10 min. The resulting slurry was cooled to 0-5°C and filtered. The crude Simvastatin was washed at 0-5°C with hexanes and dried under vacuum to yield 21.0 g (88%) of Simvastatin. References Keshava K.S. et al.; US Patent No. 6,307,066; Oct. 23, 2001; Assigned to Brantford Chemicals Inc.

SINCALIDE Therapeutic Function: Choleretic Chemical Name: 1-De(5-oxo-L-proline)-2-de-L-glutamine-5-Lmethioninecaerulein Common Name: Structural Formula:

Sincalide

3043

Chemical Abstracts Registry No.: 25126-32-3 Trade Name Kinevac Kinevac

Manufacturer Squibb Squibb

Country US W. Germany

Year Introduced 1976 1977

Raw Materials t-Butyloxycarbonyl-L-aspartyl-L-tyrosyl-L-methionylglycyl-L-tryptophyl-Lmethionyl-L-aspartyl-L-phenylalanine amide Sulfuric acid Manufacturing Process The starting material in the following synthesis is: t-butyloxycarbonyl-Laspartyl-L-tyrosyl-L-methionylglycyl-L-tryptophyl-L-methionyl-L-aspartyl-Lphenylalanine amide designated (SM). (A) A solution of (SM) (320 mg) in trifluoroacetic acid (7 ml) was kept under nitrogen at room temperature for 15 minutes. Ether (100 ml) was added and the precipitate filtered, washed thoroughly with ether and dried. This material (280 mg) was added to concentrated sulfuric acid (20 ml), cooled at -20°C. The solution was kept in the dry ice-acetone bath at -20°C for 75 minutes. The sulfuric acid solution was poured into ice water (80 ml). The precipitate was centrifuged, resuspended in ice water (30 ml) and 4N sodium hydroxide was added until a clear solution was obtained. After reacidification to pH 4 with dilute sulfuric acid, the precipitate formed was centrifuged, washed twice with ice water and dried. Yield 155 mg. Chromatograph of DEAE Sephadex (with ammonium carbonate buffer) yielded the desired octapeptide sulfate ester: 30 mg. (B) A solution of (SM) (330 mg) in trifluoroacetic acid (7 ml) was kept under nitrogen at room temperature for 15 minutes. Ether (100 ml) was added and the precipitate was filtered, washed thoroughly with ether and dried. This material (300 mg) was added in portions to concentrated sulfuric acid (18 ml) cooled at -20°C with vigorous stirring. After 15 minutes a solution of potassium bisulfate in concentrated sulfuric acid (408 mg in 3 ml) was added. The reaction mixture was stirred for 75 minutes at -15°C and then stored at 7°C for 285 minutes. The sulfuric acid solution was poured into cold ether (400 ml); precipitate was filtered, washed with cold ether, and suspended in cold water. Complete solution was then achieved by careful addition of 2N sodium hydroxide. Acidification with N hydrochloric acid led to the precipitation of the desired octapeptide sulfate ester. Yield 200 mg. References Merck Index 8380 DOT 13 (9) 356 (1977) I.N. p. 874 REM p. 1277 Ondetti, M.A., Pluscec, J., Sheehan, J.T., Jorpes, J.E. and Mott, V.; US Patent 3,723,406; March 27, 1973; assigned to E.R. Squibb and Sons, Inc.

3044

Sirolimus

SIROLIMUS Therapeutic Function: Immunosuppressive, Antifungal Chemical Name: Rapamycin Common Name: Rapamycin; Sirolimus Structural Formula:

Chemical Abstracts Registry No.: 53123-88-9 Trade Name Rapamune Rapamycin Rapamycin

Manufacturer Wyeth Laboratories Fujian Kerui Pharmaceutical Co., Ltd. Wyeth-Ayerst Canada Inc.

Country UK China

Year Introduced -

Canada

-

Raw Materials Nutrient medium Streptomyces hygroscopicus NRRL 5491 Manufacturing Process Streptomyces hygroscopicus NRRL 5491 was grown and maintained on oatmeal-tomato paste agar slants (T. G. Pridham et al.; Antibiotic Annual 1956-1957, Medical Encyclopedia Inc., New York, p. 947) and in Roux bottles containing the same medium. Good growth was obtained after 7 days of incubation at 28°C. Spores from one Roux bottle were washed off and suspended into 50 ml of sterile distilled water. This suspension was used to inoculate the first stage inoculum.

Sisomicin

3045

The first-stage inoculum medium consisted of Emerson broth [R. L. Emerson et al., J. Bacteriol, 52, 357 (1946)] 0.4% peptone, 0.4% sodium chloride, 0.25% yeast extract and 1% glucose; pH 7.0; flasks containing the above medium were inoculated with 1 % of the spore suspension described above. The inoculated flasks were incubated for 30 hours at 28°C on a reciprocating shaker set at 65 r.p.m. (4 inch stroke). Production stage The production stage was run in 250-liter New Brunswick fermenters Model F250, equipped with automatic antifoam addition system and pH recordercontroller. The fermenters were charged with 160 L of an aqueous production medium consisting of the following constituents: 1.0% soluble starch; 0.5% (NH4)2SO4; 0.5% K2HPO4; 1.5% glucose (Cerelose); 0.025% MgSO4; 0.005% ZnSO4; 0.001% MnSO4; 0.002% FeSO47H2O; 0.2% CaCO3; 0.5% "Blackstrap" molasses; 0.5% hydrolyzed casein; 0.2% lard oil; pH 7.1 to 7.3 of first stage inoculum. Incubation temperature: 28°C; aeration: 0.5 vol/vol/min; agitation: 250 r.p.m. The fermenters were sterilized at 121°C for 45 min, cooled and inoculated with one flask inoculum). A titre of ca. 20 µg/ml, determined by microbiological assay on agar plates seeded with Candida albicans, was reached in 5 days. The fermentation was stopped. The fermentation mixture was extracted twice with 1 v/v of nbutanol. The combined butanol extracts were washed with 1 v/v of water, dried with anhydrous sodium sulfate and evaporated to dryness under reduced pressure to yield a residue. The oily residue was extracted 3 times with 2 L of methanol. The combined methanol extracts were passed through diatomaceous earth (Celite) and evaporated to dryness to yield an oily residue containing crude Rapamycin. References Sehgal S.N. et al.; US Patent No. 3,929,992, Dec. 30; Assigned to Ayerst McKenna and Harrison Ltd., Montreal, Canada

SISOMICIN Therapeutic Function: Antibiotic Chemical Name: O-2,6-Diamino-2,3,4,6-tetradeoxy-α-D-glycero-hex-4enopyranosyl-(1-4)-O-(3-deoxy-4-C-methyl-3-(methylamino)-β-Larabinopyranosyl-(1-6)]-2-deoxy-D-streptamine Common Name: Rickamicin Chemical Abstracts Registry No.: 32385-11-8; 53179-09-2 (Sulfate salt)

3046

Sisomicin

Structural Formula:

Trade Name Pathomyci n Extramycin Extramycin Baymicina Sisomin Sisomicin Mensiso Sissolline Siseptin Baymicine Extramycin

Manufacturer Byk-Essex Bayer Bayer Bayer Schering Essex Menarini Cetrane Essex Bayer Yoshitomi

Country W. Germany W. Germany Switz. Italy Switz. Italy Italy France Japan France Japan

Year Introduced 1976 1976 1978 1978 1978 1978 1979 1980 1981 1981 1981

Raw Materials Bacterium Micromonspora inyoensis Dextrin Soybean meal Manufacturing Process Tank fermentation of Micromonospora inyoensis - Germination stage 1: Under aseptic conditions, add a lyophilized culture (or cells obtained from a slant culture) of M. inyoensis to a 300 ml shake flask containing 100 ml of the following sterile medium: Beef extract Tryptone Yeast extract Dextrose Starch Calcium carbonate Tap water

3g 5g 5g 1g 24 g 2g 1,000 ml

Incubate the flask and its contents for 5 days at 35°C on a rotary shaker (280 rpm, 2'' stroke).

Sisomicin

3047

Germination stage 2: Aseptically transfer 25 ml of the fermentation medium of Germination stage 1 to a 2-l shake flask containing 500 ml of the above described sterile germination medium. Incubate the flask and its contents for 3 days at 28{]C on a rotary shaker (280 rpm, 2'' stroke). Fermentation stage: Aseptically transfer 500 ml of the medium obtained from Germination stage 2 to a 14-l fermentation tank containing 9.5 l of the following sterile medium: Dextrin Dextrose Soybean meal Calcium carbonate Cobalt chloride Tap water Antifoam (GE 60)

50 g 5g 35 g 7g 10-6M 1,000 ml 10 ml

Prior to sterilizing the above described medium, adjust the pH to 8. Aerobically ferment for 66 to 90 hours while stirring at 250 rpm with air input at 4.5 l/l/min and 25 psi. The potency of the antibiotic produced at the end of this period reaches a peak of 150 to 225 mcm/ml and remains relatively constant. The pH of the fermentation medium changes slightly during the antibiotic production, varying in the range of 6.8 to 7.3. Isolation of Antibiotic 66-40 - The whole broth is adjusted to pH 2 with 6N sulfuric acid. (For the purpose of this example, quantities are given in terms of 170 l of fermentation broth obtained by pooling acidified broth from 17 batches.) The acidified broth is stirred for about 15 minutes and then filtered. Wash the mycelium with water and combine the washings with the filtrate. Adjust the pH of the filtrate to 7 with 6N ammonium hydroxide. To the neutralized filtrate, add sufficient oxalic acid to precipitate calcium and filter. Reneutralize the filtrate with ammonium hydroxide. Charge the filtrate onto a cationic exchange adsorption column containing 1,500 to 2,000 g of IRC-50 Amberlite in its ammonium form. Discard the eluate, wash the resin with water, and elute with 2N ammonium hydroxide. Collect 400 ml fractions and monitor by disc testing with S. aureus ATCC-6538P. Combine active fractions and evaporate to dryness under vacuum obtaining about 28 g of crude Antibiotic 6640 having an activity of about 500 mcm/g. Purification of Antibiotic 66-40 - Dissolve 28 g of crude Antibiotic 6640 in 100 ml of distilled water and charge to an anion exchange adsorption column (Dowex 1 x 2) in the hydroxyl form. Slurry 2,000 g of the resin in water into a column 2,5" in diameter and 36" high. Elute the column with distilled water at a rate of about 23 ml/min collecting 100 ml fractions and monitor with a conductivity meter and by disc testing against Staphylococcus aureus. The disc testing provides a gross separation of antibiotic-containing eluate fractions from those devoid of antibiotic. To insure that the fractions are properly combined, a portion of each fraction is paper chromatographed using the lower phase of a chloroform:methanol:17% ammonium hydroxide system (2:1:1). Each paper is sprayed with ninhydrin and the eluates containing like material are combined and lyophilized yielding about 5.7 g of Antibiotic 66-40 assaying about 900 mcm/mg.

3048

Sobrerol

References Merck Index 8384 Kleeman and Engel p. 819 DOT 8 (8) 315 (1972) and 12 (10) 407 (1976) I.N. p. 875 REM p. 1183 Weinstein, M.J., Luedemann, G.M. and Wagman, G.H.; US Patent 3,832,286; August 27, 1974; assigned to Schering Corp.

SOBREROL Therapeutic Function: Mucolytic Chemical Name: 5-Hydroxy-α,α,4-trimethyl-3-cyclohexene-1-methanol Common Name: Pinol hydrate Structural Formula:

Chemical Abstracts Registry No.: 498-71-5 Trade Name Sobrepin Lysmucol

Manufacturer Corvi Schering

Country Italy Switz.

Year Introduced 1970 1983

Raw Materials α-Pinene oxide Manufacturing Process To 19 l of well-agitated distilled water plus 18 g of ditertiary-butyl-p-cresol was added 19.84 kg (130 mols) of pure α-pinene oxide that was about half racemic, half d-form. The temperature was maintained at 30°C to 50°C, first with ice bath cooling and then with tap water cooling. The addition of the pinene oxide required 1,5 hours. After the addition was complete and the exothermic reaction was about over, the mixture was stirred for 2,5 hours at about 30°C, and then centrifuged to separate the crude sobrerol from the liquid phase consisting of oil and water.

Sodium gluconate

3049

The crude sobrerol was washed with naphtha and then air dried to yield 14.81 kg (87.5 mols) of pure sobrerol, [α]D25 -77.0°. It was found that 1 liter of the aqueous phase from the reaction contained 22 g of sobrerol, so, therefore, the entire aqueous phase contained 0.42 kg (2.5 mols) of sobrerol. References Merck Index 8395 I.N. p. 877 Klein, E.A.; US Patent 2,815,378; December 3, 1957; assigned to The Glidden Co.

SODIUM GLUCONATE Therapeutic Function: Electrolyte replenisher Chemical Name: D-Gluconic acid, monosodium salt Common Name: Natrium gluconicum; Natriumglukonat; Sodium gluconate Structural Formula:

Chemical Abstracts Registry No.: 527-07-1 Trade Name

Manufacturer

Country

Year Introduced

Sodium Sodium Sodium Sodium Sodium Sodium Sodium

JUNGBUNZLAUER INC. GFS Chemicals Hudong Household Auxiliaries SINOTRANS HEBEI COMPANY Envitech, Inc. Global Calcium Hangzhou Linan Jinlong Chemical Co., Ltd. Scancem Chemicals AS

-

-

-

-

gluconate gluconate gluconate gluconate gluconate gluconate gluconate

Natriumglukonat Raw Materials

Glucose Aspergillus niger CCM 8004 Manufacturing Process

3050

Somatotropin

D-Gluconic acid was prepared by fermentation of glucose with Aspergillus niger CCM 8004 at 30°C. The fermentation medium contained 150 g/dm-3 glucose, 0.59 g/dm-3 ammonium sulfate, 0.25 g/dm-3 potassium chloride, 0.25 g/dm-3 potassium dihydrophosphate, 0.25 g/dm-3 MgSO4·7H2O, 1.0 g/dm-3 Ca(NO3)2·4H2O, and 1.5 g/dm-3 of a 50% corn-steep liquor. The pH of the culture was maintained at the value of 6.5 during the growth phase and 5.5 (maximum glucose oxidase activity) during the production phase by addition of 11.7 M sodium hydroxide solution. Gluconic acid concentration was determined by HPLC analysis. By neutralization of D-gluconic acid with sodium hydroxide was obtained monosodium D-gluconate. References Znad H., Blazej M., Bales V., Markos J., Chem. Pap., 2004, 58, 1, 23

SOMATOTROPIN Therapeutic Function: Growth stimulant Chemical Name: See under Structural Formula Common Name: Somatropin Structural Formula: Proteins of molecular weights ranging from 22.124 for human growth hormone (HGH) to 47,400 for bovine growth hormone Chemical Abstracts Registry No.: 9002-72-6 Trade Name Somatotrope Wachtungshormon Crescormon Grorm Asellacrin Crescormon Nanormon Corpormon Somacton Somatormone

Manufacturer Choay Kabi Sumitomo Serono Calbiochem Kabi Hormonchemie Nikken Ferring Byla

Country France W. Germany UK Italy US US W. Germany Japan W. Germany France

Year Introduced 1951 1970 1973 1975 1976 1978 1978 -

Raw Materials Human pituitary glands Acetone Manufacturing Process It has been found that the growth hormone can be obtained in crystalline

Somatrem

3051

form from human pituitary glands by procedures comprising (1) extraction of the fresh glands with acetone, (2) extraction of the acetone residue with aqueous salt solutions, (3) precipitation from aqueous salt solutions by the addition of suitable miscible organic solvents of alkaline and acid pH, and finally crystallization from aqueous salt solutions by the addition of suitable miscible organic solvents. References Merck Index 8562 DOT 14 (9) 422 (1978) I.N. p. 880 REM pp. 952, 955 Lewis, U.J. and Brink, N.G.; US Patent 2,974,088; March 7, 1961; assigned to Merck and Co., Inc.

SOMATREM Therapeutic Function: Growth stimulant Chemical Name: Somatotropin (human), N-L-methionylCommon Name: Somatrem Structural Formula: Proteins of molecular weights ranging from 22.124 for human growth hormone (HGH) to 47,400 for bovine growth hormone, NL-methionylChemical Abstracts Registry No.: 82030-87-3 Trade Name

Manufacturer

Country

Year Introduced

Protropin

Genentech

-

-

Raw Materials Human growth hormone Trypsin Manufacturing Process Highly purified human growth hormone was isolated from fresh glands by the procedure involving gel filtration of Sephadex. The hormone was oxidized by performing acid. Both the native and the oxidized product were submitted to digestion with trypsin as well as with chymotrypsin, while only native hormone was hydrolyzed with pepsin. These digests were fractionated on ion-exchange resin columns. Some of fraction required further purification by paper chromatography in a system consisting of 1-butanol/acetic acid/water (4:1:5) and by high-voltage electrophoresis on paper in a buffer of pH 2.3. Human growth hormone is contained 188 amino acids. From sedimentation equilibre

3052

Sorbitol

studies the molecular weight of the hormone was shown to be 21,500. 1000 ml of sterile intramuscular preparation containing 2.5 mg of chymotripsin hydrolyzed bovine growth hormone and 2.5 mg methylprednisolone is prepared from the following types and amounts of materials containing (per ml); 1) 2.5 mg chymotripsin hydrolyzed bovine growth hormone (powder), 2) 2.5 mg methylprednisolone (micronized), 3) 30 mg polyethylene glycol (40 000), 4) 9 mg sodium chloride, 5) 2 mg polysorbate 80, 1.8 mg methylparaben, 0.2 mg propylparaben and watef q.s. to 1000 ml. The parabens are added to most of the water and dissolved with stirring and heating to 65-70°C. The mixture is cooled to room temperature and ingredient 3, 4 and 5 are added. The resulting solution was made up to 100 ml with water and sterilized by filtration. Ingredient 1 and 2 are sterilized with ethylene oxide and added aseptically. The final preparation is packaged in sterile containers with 1 ml of the final product. This is used advantageously in the treatment of arthritis and to avoid negative nitrogene balance. References Sprague J. M., D. Hill; US Patent No. 3,118,815; Sept. 17, 1946; Assigned to Sharp and DOHME, Incorporated, Philadelphia, Pa., a corporation of Maryland Li Ch.H., Liu W.-K., Dixon J,S.; J. Am. Chem. Soc. 88, 2050 (1966)

SORBITOL Therapeutic Function: Cholecystokinetic, Diuretic, Pharmaceutic aid Chemical Name: D-Glucitol Common Name: d-Glucitol; Sorbit; Sorbitol Structural Formula:

Chemical Abstracts Registry No.: 50-70-4 Trade Name Sorbitol

Manufacturer Memphis Co.

Country -

Year Introduced -

Sorbitol Trade Name Sorbitol Sorbitol Sorbit Sach Sorbostyl Amp. Cystosol Resulax

Manufacturer Delalande Co. GreatVista Chemicals MUP Co. Delalande Co. Baxter Tika

Country -

3053

Year Introduced -

Raw Materials Polyethyleneimine Glutaraldehyde

Cells of Zymomonas mobilis Substrate solution (glucose, fructose, protein)

Manufacturing Process 20 ml of a suspension of CTAB-permeabilized cells of Zymomonas mobilis were mixed with 80 ml of a 4% carrageenan solution and the mixture was poured into shallow dishes and allowed to rigidify. The rigidified immobilizate was then divided into 3x3x3 mm cubes, exposed to a solution of 0.3 M KCl overnight and then divided into batches and exposed to one of the following treatments: (A) Cubes stabilized with potassium ions were used without further treatment for production of sorbitol/gluconic acid. (B) Cubes were incubated with a 1.0% solution of polyethyleneimine at room temperature for 30 min and then treated with glutaraldehyde at 4°C for 30 min. Comparison of two rigidification methods: A volume of 450 ml of cubes treated by the method described in (A) were reacted in a 1.5 liter fluidized bed fermenter with a substrate solution comprised of 100 g/L glucose, 100 g/L fructose and a protein concentration of 6.1 g/L, at a D of 0.053 h-1, and titrated with 3 N KOH. After 48 hours, 68.8% of the substrate was converted with a resulting production of 3.65 g sorbitol/L*h and 0.6 g sorbitol/g protein*h. After approximately 50 days, the productivity of the fermenter was reduced by about one half. Cubes treated as described (B) using glutaraldehyde at a concentration of 0.5%, were reacted in a 1.6 liter fermenter with a substrate solution comprised of 100 g/L glucose, 100 g/L fructose and a protein concentration of 8.6 g/L, at a D of 0.055 h-1, and titrated with 3 N KOH. After 48 hours, 90.0% of the substrate was converted with a resulting production of 4.95 g sorbitol/L*h and 0 58 g sorbitol/g protein*h. After 75 days, the productivity of the fermenter was reduced by only 3.5%. References Merck Index, Monograph number: 8873, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc.

3054

Sotalol hydrochloride

Rehr B., Sahm G.; US Patent No. Mar.2, 1993; Assigned to Forshungszentrum Juelich GmbH, Juelich, Fed. Rep. of Germany

SOTALOL HYDROCHLORIDE Therapeutic Function: Beta-adrenergic blocker, Antiarrhythmic Chemical Name: Methanesulfonamide, N-(4-(1-hydroxy-2-((1methylethyl)amino)ethyl)phenyl)-, monohydrochloride Common Name: Sotalol hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 959-24-0; 3930-20-9 (Base) Trade Name Sotagard Sotalol Hydrochloride Sotalol Hydrochloride

Manufacturer Glaxo Teva Taizhou Dongdong Pharmachem Co., Ltd.

Country -

Year Introduced -

Betapace

Berlex

-

-

Raw Materials Aniline Bromacetyl bromide Carbon disulfide Palladium on carbon Hydrochloric acid

Methansulfonyl chloride Aluminum chloride Isopropylamine Sodium borohydride

Manufacturing Process As a resulting of reaction of methansulfonylchloride reacted with aniline methansulfonanilide was obtained. The methansulfonanilide reacted with bromacetylbromide at the presence of AlCl3 and CS2 and 4-(bromacetyl)methansulfonanilide was prepeared. Then to the 4-(bromacetyl)-methansulfonanilide isopropylamine was added to give 4-(1-oxo-2-isopropylaminoethyl)methansulfonanilide.

Sparfloxacin

3055

The 4-(1-oxo-2-isopropylaminoethyl)methansulfonanilide was reduced by hydrogenesation in the presence of Pd-C catalyst and sodium borohydride. So 4-(1-hydroxy-2-isopropylaminoethyl)methansulfonanilide was obtained. The 4-(1-hydroxy-2-isopropylaminoethyl)methansulfonanilide hydrochloride may be prepared by treatment of base with hydrochloric acid. References Kleemann A., Engel J.; Pharmazeutische Wirkstoffe, GeorgThieme Verlag Stuttgart. New York, 1982

SPARFLOXACIN Therapeutic Function: Antibacterial Chemical Name: 3-Quinolinecarboxylic acid, 1,4-dihydro-5-amino-1cyclopropyl-6,8-difluoro-7-(3,5-dimethyl-1-piperazinyl)-4-oxo-, cisCommon Name: Esparfloxacino; Sparfloxacin Structural Formula:

Chemical Abstracts Registry No.: 110871-86-8 Trade Name Acespar 200 Dinor Sparflo Sparfloxacin Sparfloxacin Zagam Zagam

Manufacturer Plethico Pharmaceuticals Nucron Pharma Dr. Reddy's Laboratories Ltd. China Pharm Chemical Co., Ltd. Skymax Laboratories Pvt. Ltd. Aetna Inc. Aventis Pharma

Country India India India China

Year Introduced -

India

-

USA Ireland

-

Raw Materials Ethyl orthoformate

Ethyl pentafluorobenzoylacetate

3056

Sparfloxacin

Acetic anhydride Sodium hydride Benzylamine Acetic acid Cyclopropylamine

Ethyl orthoformate Sulfuric acid cis-2,6-Dimethylpiperazine Potassium carbonate Palladium on carbon

Manufacturing Process A mixture of the known compound, ethyl pentafluorobenzoylacetate [J. Org. Chem., 35, 930 (1970)] (25 g), ethyl orthoformate (20 g), and acetic anhydride (23 g) was refluxed for 2 h. The reaction mixture was evaporated to dryness under reduced pressure. The residue was dissolved in diethyl ether and allowed to react with cyclopropylamine (5.1 g) to give ethyl 2pentafluorobenzoyl-3-cyclopropylaminoacrylate (28 g), melting point 89°C. The ethyl 2-pentafluorobenzoyl-3-cyclopropylaminoacrylate (28 g) was dissolved in dry tetrahydrofuran and allowed to react with 60% sodium hydride (3.85 g) at room temperature to give ethyl 1-cyclopropyl-5,6,7,8tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (18.4 g), melting point 170°-171°C. A mixture of ethyl 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4oxoquinoline-3-carboxylate (28.2 g), benzylamine (9.8 ml), anhydrous potassium carbonate (23.6 g), and acetonitrile (140 ml) was heated at 100°110°C for 1 h to give ethyl 5-benzylamino-1-cyclopropyl-6,7,8-trifluoro-1,4dihydro-4-oxoquinoline-3-carboxylate (21.4 g), which was recrystallized from ethanol, melting point 134°-135°C. The ethyl 5-benzylamino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4oxoquinoline-3-carboxylate (20 g) was dissolved in acetic acid (100 ml) and ethanol (150 ml), and hydrogenolyzed in the presence of 5% palladiumcarbon (0.5 g) to give ethyl 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro4-oxoquinoline-3-carboxylate (14.1 g), which was recrystallized from chloroform-ethanol, melting point 236°-237°C. A mixture of the ethyl 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4oxoquinoline-3-carboxylate (12.6 g), acetic acid (80 ml), water (50 ml), and concentrated sulfuric acid (9 ml) was heated at 100°-110°C for 40 min to give 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (11.1 g), which was recrystallized from chloroform-ethanol, melting point 294°-295°C. A mixture of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4oxoquinoline-3-carboxylic acid (1.25 g), cis-2,6-dimethylpiperazine (2.0 g), and dimethylformamide was stirred at room tempersture for 24 h. The reaction mixture was evaporated to dryness under reduced pressure and water was added to the residue. The mixture was extracted with chloroform and the extract was dried. After evaporation of chloroform, ethanol was added to the residue. The resulting crystals were filtered and recrystallized from chloroform-ethanol to give 5-amino-1-cyclopropyl-6,8-difluoro-7-(cis-3,5dimethyl-1-piperazinyl)-1,4-dihydro- 4-oxoquinoline-3-carboxylic acid (1.4 g), melting point: 258°-260°C.

Spectinomycin

3057

References Conrath G.; US Patent No. 5,478,829; Dec. 26, 1995; Assigned: Rhone-DPC Europe, Antony, France

SPECTINOMYCIN Therapeutic Function: Antibacterial Chemical Name: Decahydro-4a,7,9-trihydroxy-2-methyl-6,8bis(methylamino)-4H-pyrano-[2,3-b][1,4]benzodioxin-4-one Common Name: Actinospectacin Structural Formula:

Chemical Abstracts Registry No.: 1695-77-8; 22189-32-8 (Hydrochloride salt) Trade Name Trobicin Trobicin Stanilo Trobicin Trobicine Trobicin Kempi

Manufacturer Upjohn Upjohn Upjohn Upjohn Upjohn Upjohn Alter

Country US Italy W. Germany UK France Japan Spain

Year Introduced 1971 1973 1973 1973 1974 1978 -

Raw Materials Nutrient medium Bacterium Streptomyces spectabilis Manufacturing Process A lyophilized culture of Streptomyces spectabilis, NRRL 2792, was used to seed the following sterile agar medium on tubed slants:

Maltose

Grams 10

3058

Spectinomycin Tryptone K2HPO4 NaCl FeSO4 Agar Deionized water to make 1 liter

5 0.5 0.5 0.1 20

The slants were incubated for 7 days at 30°C, after which time sporulation was complete. The spores from the agar slants were used, in an aqueous suspension, to inoculate 100 ml of preseed medium in a 500 ml Erlenmeyer flask. The sterile preseed medium consisted of:

Dried whole yeast Glucose Pancreatic digest of casein (N-Z-Amine B) Tap water to make 1 liter adjusted

Grams 10 10 5 to pH 7.2 before sterilizing

The seed flash was incubated for 24 hours at 32°C on a reciprocating shaker after which it was used as an inoculum for a 20 liter seed fermenter in the amount of approximately 5%. the 20 liter seed fermenter contained a sterile medium consisting of:

Glucose Cornstarch Distiller's solubles Brewer's yeast Corn steep liquor Tap water to make 1 liter adjusted

Grams 15 25 15 10 20 to pH 7.2 before sterilizing

The 20 liter seed fermenter was incubated for 24 hours at 32°C and aerated at the rate of 6 standard liters or about 0.2 standard cubic feet of air per minute and agitated with a sweep stirrer. The 20 liter seed fermenter was used to inoculate 250 liters of the same medium in a 100 gallon fermentation tank. 1,200 ml of lard oil were added during the fermentation to control foaming. The tank was agitated with a propeller and aerated at the rate of 75 standard liters of air per minute. After 96 hours of fermentation the beer assayed 500 mcg/ml (18.3 mcg/mg on a dry basis) of actinospectacin. Actinospectacin is assayed by its activity against Klebsiella pneumoniae by standard agar diffusion procedure and based on crystalline actinospectacin sulfate according to US Patent 3,234,092. References Merck Index 8584 Kleeman and Engel p. 821 PDR p. 1864 DOT 8 (3) 107 (1972) I.N. p. 884 REM p. 1211

Spiperone

3059

Jahnke, H.K.; US Patent 3,206,360; September 14, 1965; assigned to The Upjohn Co. Bergy, M.E. and De Boer, C.; US Patent 3,234,092; February 8, 1966; assigned to The Upjohn Company Peters, V.J.; US Patent 3,272,706; September 13, 1966; assigned to The Upjohn Company Nara, T., Takasawa, S.,Okachi, R., Kawamoto, I., Kumakawa, M., Yamamoto, M. and Sato, S.; US Patent 3,819,485; June 25, 1974; assigned to Abbott Laboratories

SPIPERONE Therapeutic Function: Tranquilizer Chemical Name: 8-[4-(4-Fluorophenyl)-4-oxobutyl]-1-phenyl-1,3,8triazaspiro[4.5]decan-4-one Common Name: Structural Formula:

Chemical Abstracts Registry No.: 749-02-0 Trade Name Spiropitan Spiroperidol

Manufacturer Eisai Janssen

Country Japan -

Year Introduced 1969 -

Raw Materials Formamide 4-Carbamoyl-4-N-anilinopiperidine 4-Chloro-p-fluoro-butyrophenone Manufacturing Process A mixture of 4-carbamoyl-4-N-anilinopiperidine and formamide is heated for 12 hours at 170°C. After cooling, the reaction mixture is divided between 100parts water and 900 parts chloroform. The organic layer is separated, dried over MgSO4 filtered and the filtrate is evaporated. The semisolid residue is stirred in ethyl acetate. The undissolved part is filtered off, washed with ethyl acetate, and dried, yielding 1-oxo-4-phenyl-2,4,8triazaspiro[4.5]decane.

3060

Spiramycin

A mixture of 3.2 parts 4-chloro-p-fluoro-butyrophenone, 3.5 parts 1-oxo-4phenyl-2,4,8-triazaspiro(4,5)decane, 2 parts Na2CO3 and 0.1 part KI in 200 parts hexone is refluxed with stirring for 50 hours. The mixture is cooled to room temperature, 200 parts water are added and the layers are separated. The organic layer is dried over 10 parts MgSO4, filtered and the solvent removed under reduced pressure on the water bath. The residue is treated with 50 parts diisopropylether. The precipitate is filtered on a Buchner filter and recrystallized from 20 parts hexone at room temperature. The solid is filtered off and dried to yield 1-oxo-4-phenyl-8-[3-(4-fluorobenzoyl)-propyl] -2,4,8triazaspiro(4.5)decane, melting point 190° to 193.6°C, as a light brown amorphous powder. References Merck Index 8596 Kleeman and Engel p. 821 I.N. p. 885 Janssen, P.A.J.; US Patent 3,155,669; November 3, 1964; assigned to Research Laboratorium Dr. C. Janssen NV, Belgium Janssen, P.A.J.; US Patent 3,155,670; November 3, 1964; assigned to Research Laboratorium Dr. C. Janssen NV, Belgium Janssen, P.A.J.; US Patent 3,161,644; December 15, 1964; assigned to Research Laboratorium Dr. C. Janssen NV, Belgium

SPIRAMYCIN Therapeutic Function: Antibacterial Chemical Name: Spiramycin Common Name: Chemical Abstracts Registry No.: 8025-81-8 Trade Name Rovamycine Rovamycina Apyrectol Spiramycine Bykomycetin Selectomycin Spiramycin

Manufacturer Specia Carlo Erba Theranol Byk Gulden Gruenenthal Kyowa

Raw Materials Bacterium Streptomyces ambofaciens Nutrient medium

Country France Italy France W. Germany Japan

Year Introduced 1972 1979 -

Spironolactone

3061

Structural Formula:

Manufacturing Process The process for producing spiramycin comprises inoculating an aqueous nutrient medium with a culture of the NRRL No. 2420, allowing aerobic fermentation to take place and separating from the culture medium the spiramycin thus formed. The culture medium also contains the antibiotic substance known as Congocidin which, however, does not possess the same useful properties as spiramycin and which can be isolated in crystalline form. The separation of the two antibiotic substances is readily achieved. References Merck Index 8597 Kleeman and Engel p. 822 I.N. p. 885 REM p. 1224 Ninet, L. and Verrier, J.; US Patent 2,943,023; June 28, 1960; assigned to Societe des Usines Chimiques Rhone-Poulenc Ninet, L., Pinnert S.and Preud'homme, J.; US Patent 3,000,785; September 19, 1961;assigned to Societe des Usines Chimiques Rhone-Poulenc

SPIRONOLACTONE Therapeutic Function: Diuretic Chemical Name: 7α-(Acetylthio)-17α-hydroxy-3-oxopregn-4-ene-21carboxylic acid

3062

Spironolactone

Common Name: Structural Formula:

Chemical Abstracts Registry No.: 52-01-7 Trade Name Aldactone Aldactone Altex Diatensec Acelat Airolactone Aldactazide Aldopur Aldospirone Alexan Almatol Alpamed Alpolasnon Aporasnon Dairopeal Deverol Dira Duraspiron Euteberol Hokulaton Idrolattone Lacalmin Lacdene Nefurofan Osyrol Penantin Practon Sagisal Sincomen Spiresis Spiretic Spiridon

Manufacturer Searle Searle Cenci Searle Endopharm Horita Searle Heumann Teva Sanwa Fujisawa Sawai Nihon Yakuhin NNichiiko Daito Koeki Waldheim Kakenyaku Kako Durachemie Merckle Hokuriku Zoja Tatsumi Tsuruhara Maruko Hoechst Teikoku Genekod Sagitta Schering Farmos D.D.S.A. Orion

Country US France US UK W. Germany Japan US W. Germany Israel Japan Japan Japan Japan Japan Japan Austria Japan W. Germany W. Germany Japan Italy Japan Japan Japan W. Germany Japan France W. Germany W. Germany Finland UK Finland

Year Introduced 1959 1960 1980 1981 -

Stallimycin hydrochloride Trade Name Spirix Spirolong Spironazide Spiropal Spiro-Tablinen Spirotone Suracton Uractone Urosonin Xenalone

Manufacturer Benzon SKF Schein A.F.I. Sanorania Protea Toho Iyaku SPA Isei Mepha

Country Denmark Italy US Norway W. Germany Australia Japan Italy Japan Switz.

3063

Year Introduced -

Raw Materials 17α-(2-Carboxyethyl)-17β-hydroxyandrosta-4,6-dien-3-one lactone Thioacetic acid Manufacturing Process A mixture of approximately 11 parts of 17α-(2-carboxyethyl)-17βhydroxyandrosta-4,6-dien-3-one lactone and 10 parts of thioacetic acid is heated at 85° to 95°C for ½ hour. Excess thioacetic acid is removed by vacuum distillation at this point, and the residue is twice recrystallized from methanol, affording 7α-acetylthio-17α-(2-carboxyethyl)-17β-hydroxyandrost4-en-3-one lactone, melting at approximately 134° to 135°C. Heated above this melting point, the product solidifies and melts again at approximately 201° to 202°C (with decomposition). References Merck Index 8610 Kleeman and Engel p. 822 PDR pp.830, 993, 1388, 1606, 1674, 1999 OCDS Vol.1 p.206 (1977) 2, 172 (1980) and 3, 91 (1984) I.N. p. 886 REM p. 941 Cella, J.A. and Tweit, R.C.; US Patent 3,013,012; December 12, 1961; assigned to G.D.Searle and Co.

STALLIMYCIN HYDROCHLORIDE Therapeutic Function: Antibiotic Chemical Name: N''-(2-Amidinoethyl)-4-formamido-1,1',1''-trimethylN,4':N',4''-ter-(pyrrole-2-carboxamide) hydrochloride Common Name: Distamycin A

3064

Stallimycin hydrochloride

Structural Formula:

Chemical Abstracts Registry No.: 6576-51-8; 636-47-5 (Base) Trade Name

Manufacturer

Country

Year Introduced

Herperal

Farmitalia

Italy

1978

Raw Materials Bacterium Streptomyces distallicus Dextrose Corn steep liquor Manufacturing Process A spore suspension obtained upon washing a culture of Streptomyces distallicus is added to 3,000 ml of a sterile medium consisting of the following: Dextrose Corn steep liquor extract CaCO3 (NH4)2SO4 NaCl

2% 2% 1% 0.3% 0.3%

Fermentation is continued at 28°C for 40 hours at a stirring rate of 150 to 250 rpm and a rate of air flow of 1 to 2 l/min/l of culture medium. 300 ml of a suspension of the vegetative mycelium of this culture are used for inoculating 6,000 ml of a similar sterile culture medium. At this production stage, the culture is kept fermenting for 85 to 100 hours (pH 7.6 at 28°C) at a stirring rate of 350 to 450 rpm and a rate of air flow of 1 to 1.5 l/min/l of culture medium. To 17 l of a culture obtained by submerged fermentation as mentioned above, siliceous earth is added and the batch is filtered. The mixture of mycelium and the siliceous earth are agitated for 1 hour with 2.5 l of butanol. This treatment is repeated twice. The butanolic extracts are combined, washed with water, evaporated to dryness (about 10 g) and boiled with acetone (80 ml). The

Stanolone

3065

residue (5.41 g of yellowish powder) is distamycin. 5 g of distamycin is extracted six times with ethanol. The ethanolic extracts are combined, concentrated and filtered through a column containing 70 g of alumina. Elution is carried out with the same solvent. The effluent (central fractions) is collected and evaporated to dryness to yield 0.43 g of pure distamycin A: decomposition point, 183°C to 185°C. The product can be further purified by crystallization from aqueous n-butanol. References Merck Index 8623 Kleeman and Engel p. 824 DOT 13 18) 322 (1977) I.N. p. 887 Arcamone, F., Canevazzi, G., Grein, A. and Bizioli, F.; US Patent 3,190,801; June 22, 1965; assigned to Societa Farmaceutici Italia

STANOLONE Therapeutic Function: Androgen Chemical Name: 17-Hydroxyandrostan-3-one Common Name: Androstanolone Structural Formula:

Chemical Abstracts Registry No.: 521-18-6 Trade Name

Manufacturer

Country

Year Introduced

Neodrol

Pfizer

US

1953

Anabolex

Lloyd

UK

-

Anaprotin

Cuxson

UK

-

Androlone

Orma

Italy

-

Ophthovitol

Winzer

W. Germany

-

Pesomax

Boniscontro

Italy

-

Protona

Gremy-Longuet

France

-

Stanaprol

Pfizer

-

-

3066

Stanozolol

Raw Materials 3,17-Androstandione Selenium dioxide Sodium borohydride Manufacturing Process A solution of 1.0 g of 3,17-androstandione in 50 ml of methanol and containing 1 g of selenium dioxide, was allowed to remain in an ice-chest overnight. The formed 3,3-dimethoxyandrostan-17-one was not separated. 1 g of solid potassium hydroxide and 2.5 g of sodium borohydride in 2.5 ml of water were added and the mixture allowed to react at room temperature for 24 hours. The solution was then poured into a large excess of water, extracted with methylene chloride, the organic layer dried and evaporated to a residue. The residue was dissolved in ether, and a small amount of selenium removed by filtration. The ether was boiled off and the organic material dissolved in 100 ml of boiling acetone. 25 ml of diluted hydrochloric acid were added, the solution boiled for 5 minutes and then allowed to cool. Upon crystallization, 0.85 g of androstan-17β-ol-3-one was obtained, melting point 175°C to 178°C. References Merck Index 8646 Kleeman and Engel p. 54 I.N. p. 88 Oliveto, E.P. and Hershberg, E.B.; US Patent 2,927,921; March 8, 1960; assigned to Schering Corp.

STANOZOLOL Therapeutic Function: Anabolic Chemical Name: 17-Methyl-2H-5α-androst-2-eno[3,2-c]pyrazol-17β-ol Common Name: Androstanazole Structural Formula:

Chemical Abstracts Registry No.: 10418-03-8

Stanozolol Trade Name Winstrol Strombaject Stromba Winstol Stromba Anasynth

Manufacturer Winthrop Winthrop Sterling Zamba Winthrop Causyth

Country US W. Germany UK Italy France Italy

3067

Year Introduced 1961 1961 1961 1962 1964 -

Raw Materials 17β-Hydroxy-17α-methyl-4-androsteno[3,2-c]pyrazole Lithium Ammonia Manufacturing Process To a stirred solution of 1.00 gram of 17β-hydroxy-17α-methyl-4androsteno[3,2-c]pyrazole in 200 ml of tetrahydrofuran and 400 ml of liquid ammonia was added 2.12 grams of lithium wire during 5 minutes. The dark blue mixture was stirred for 45 minutes. A solution of 40 ml of tertiary-butyl alcohol in 160 ml of diethyl ether was added with stirring. After 15 minutes, 25 ml of ethanol was added with stirring. The mixture turned colorless after several hours, and the liquid ammonia was allowed to evaporate and the mixture was allowed to warm to room temperature over a period of about 15 hours. The solvent was evaporated to yield a colorless solid residue, which was taken up in ethyl acetate-ice water. The two layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, saturated sodium chloride solution and filtered through anhydrous sodium sulfate. The solvent was evaporated to yield 1.20 grams of light tan crystals, MP 151° to 155°C, ultraviolet maximum at 224 mµ (E = 4,095). Two recrystallizations from ethanol afforded: 1st crop, 0.619 grams (62%) of colorless crystals (dried at 120°C in vacuo for 17 hours), MP 232.8° to 238.0°C, ultraviolet maximum at 224 mµ (E = 4,840); 2nd crop, 0.142 gram (14%) of colorless crystals, MP 234° to 242°C. References Merck Index 8647 Kleeman and Engel p. 825 PDR p. 1935 DOT 15 (6) 278 (1979) I.N. p. 888 REM p. 1000 Manson, A.J.; US Patent 3,030,358; April 17, 1962; assigned to Sterling Drug Inc.

3068

Stavudine

STAVUDINE Therapeutic Function: Antiviral Chemical Name: Thymidine, 2',3'-didehydro-3'-deoxyCommon Name: Estavudina; Stavudine Structural Formula:

Chemical Abstracts Registry No.: 3056-17-5 Trade Name d4T d4T Stavir Stavudine Stavudine Zerit

Manufacturer Bristol-Myers Squibb Cipla Limited Cipla Limited Bristol-Myers Squibb Cipla Limited Bristol-Myers Squibb

Country India India USA India USA

Year Introduced -

Raw Materials Thymidine Sodium hydroxide KOtBu Anhydronucleoside

Methanesulfonyl chloride Oxetane Tetrabutylammonium fluoride

Manufacturing Process A 3 liter, 3 necked round-bottomed flask was equipped with an overhead stirrer and paddle, a 500 ml dropping funnel and a Claisen adapter containing a drying tube and a thermometer. Thymidine (200 g, 0.82 M) and pyridine (750 ml) were added to the flask. The mixture was stirred and warmed with a water bath (20 min) to give a clear solution. The solution was then cooled in an ice bath to 0°-3°C and the dropping funnel was charged with methanesulfonyl chloride (206.5 g, 1.08 M). The methanesulfonyl chloride was then added dropwise over 40 min with no noticeable exotherm. The solution was stirred at 0°C for 1 h and then stored at 5°C for 18 h. The light brown mixture was then poured onto rapidly stirred water (3 L) containing ice (approx. 500 g). The desired product crystallised immediately. After stirring for 0.5 h, the product was collected by filtration and washed several times with water (3 times 100 ml). The white solid was then dried under vacuum

Stavudine

3069

overnight (322 g, 98% yield). The product was recrystallised from hot acetone to give 267 g of the 3',5'-di-O-(methanesulfonyl)thymidine as white solid (81% yield), melting point 169°-171°C (lit. 170°-171°C). 3',5'-Di-O-(methanesulfonyl)thymidine (248 g, 0.62 M) was added in portions to a stirred solution of sodium hydroxide (74.7 g, 1.87 M) in water (1.6 L). On addition the reaction mixture became a yellow-orange solution. This stirred solution was then heated to reflux for 2 h. Once the reaction mixture had cooled to room temperature, 6 N hydrochloric acid (100 ml) was added. The reaction mixture was concentrated in vacuo by removing 1.3 L of water. The resulting slurry was cooled in an ice bath for 2 h. The solid was then filtered and washed sparingly with ice water, and then vacuum dried to constant weight (103.7 g, 74%). The 1-(3,5-anhydro-2-deoxy-β-D-threopentofuranosyl)thymine, melting point 188°-190°C (lit. 190°-193°C) was used without further purification. 2 Methods of preparation of 1-(2,3-dideoxy-β-D-glycero-pent-2enofuranosyl)thymine 1. To a 3-necked, 1 L round-bottomed flask equipped with a mechanical stirrer, thermometer and nitrogen inlet was added dry DMSO (400 ml) and oxetane (90.0 g, 0.402 M). To this solution was added 97% KOtBu (74 g, 0.643M) in 1.5 g portions over 25 min. The temperature was maintained between 18° and 22°C by means of an external ice bath. After the addition was complete the reaction was stirred for a further 1 h and no further rise in temperature was observed and TLC indicated that the reaction was approximately 90% complete. The reaction was stirred at 21°C for 16 h, after which time TLC indicated that the reaction was complete. The viscous solution was poured onto cold (4°C) toluene (3 L), resulting in a beige colored precipitate. The temperature of the mixture rose to 7°C upon addition of the DMSO solution. The mixture was occasionally swirled over 20 min, then filtered on a 18.5 cm Buchner funnel. The collected yellowish solid was washed twice with cold toluene and allowed to dry under suction for 1 h. The solid was dissolved in 300 ml of water, whereupon two layers formed. The mixture was placed in a separatory funnel and the upper layer (containing residual toluene) was discarded. The aqueous layer was placed in a 1 L beaker equipped with a pH probe, magnetic stirring bar and thermometer. The temperature was cooled to 10°C by the use of an external ice bath. Concentrated HCl was added dropwise to the stirred solution at a rate in which the temperature was kept below 15°C. After the addition of HCl (50.5 ml, 0.61 M) the pH = 70.1 and a precipitate began to form. To this thick mixture was added potassium chloride (70 g) and stirring was continued at 5°C for 1 h. The precipitate was collected and sucked dry for 2 h, then air dried for 16 h. The solid was crushed up and slurried in hot acetone (500 m) and filtered. The residue in the filter paper was rinsed with hot acetone (2 times 200 ml), then slurried again with hot acetone (300 ml), filtered, and washed once more with hot acetone (2 times 100 ml). The combined filtrate was concentrated to dryness to give 51.3 g (57%) of the 1-(2,3-dideoxy-β-Dglycero-pent-2-enofuranosyl)thymine (d4T) as an off-white solid, melting point 165°-166°C. 2. Tetrabutylammonium fluoride (0.22 mL, 0.22 mM, 1.0 M) was added to a suspension of the 1-(3,5-anhydro-2-deoxy-beta;-D-threopentofuranosyl)thymine (25 mg, 0.11 mM) in dry THF (3 ml). The mixture

3070

Streptokinase

was heated to reflux for 18 h, at which time the reaction appeared to be complete. After cooling, the solvents were removed in vacuo and the residue was dissolved in CH2Cl2/MeOH/NH4OH (90:10:1). Purification was performed on a 20 mm flash chromatography column, eluting with CH2Cl2/MeOH/NH4OH (90:10:1). Concentration of the fractions containing the product afforded 18 mg (72%) of the dideoxy-β-D-glycero-pent-2-enofuranosyl)thymine (d4T). References Starrett J.E. et al.; US Patent No. 4,904,770; Feb. 27, 1990; Assigned: Bristol-Myers Company, New York, N.Y.

STREPTOKINASE Therapeutic Function: Enzyme Chemical Name: Streptococcal fibrinolysin Common Name: Structural Formula: Complex enzyme mixture Trade Name Streptase Streptase Kabikinase Awelysin Varidase

Manufacturer Hoechst Hoechst Kabi Arzneimittelwerk Dresden Lederle

Country France US US E. Germany UK

Year Introduced 1970 1977 1980 -

Chemical Abstracts Registry No.: 9002-01-1 Raw Materials Bacterium Streptococcus haemolyticus Nutrient medium Manufacturing Process The following description is from US Patent 2,701,227: To 50 liters of distilled water there was added 10.17 kg of enzyme hydrolyzed casein (N-Z-Amine). The temperature was raised to 100°C and held until the casein digest solution was clear. The container was then cooled rapidly to 15°C and the cooled solution filtered through a coarse grade of filter paper. A small amount of toluene was added as a preservative and the solution stored at 2°C for 4 days, at the end of which time it was again filtered to remove any insoluble material. The following ingredients were then added to the casein digest solution:

Streptokinase

3071

1,165.0 grams of KH2PO4 dissolved in 8 liters of distilled water; 35.0 grams of cysteine in approximately 800 cc of 10% HCl (the least amount of 10% HCl required to obtain a clear solution); 35 grams of glycine dissolved in 100 cc of distilled water; 300 grams dextrose in 2 liters of distilled water; 3.5 grams of uracil in 1 liter of distilled water; 3.5 grams of adenine sulfate in 1 liter of distilled water; 0.35 gram of nicotinic acid in 35 cc of distilled water; 0.59 gram of pyridoxine dissolved in 59 cc of distilled water; 7.0 grams of tryptophane in 1 liter of distilled water; 1.75 grams of calcium pantothenate in 70 cc of distilled water; 0.875 gram of thiamin hydrochloride dissolved in 87.5 cc of distilled water; 0.175 gram of riboflavin dissolved in 1,000 cc of distilled water; 55.65 cc of thioglycollic acid in 100 cc of distilled water; 700 grams of KHCO3 in 500 cc of distilled water and 700 cc of a trace element salt solution containing 11.5 kg of MgSO4; 50 g of CuSO4·5H2O; 50 g of ZnSO4·7H2O; 20 g MnCl2·4H2O; 50 g of FeSO4·7H2O; 1 liter of HCl per 100 liters of solution. The medium was then adjusted to pH 7.2 and sterilized by filtration. The above sterilized medium was inoculated with 11 liters of seed inoculum having a bacterial count of approximately 20 billion per cc. The tank was fermented at 37°C without pH adjustment, aeration, or other modification for 14 hours at the end of which time 320 cc of 50% dextrose was added. After this the pH was adjusted to 7.0 at 15 minute intervals with 5.0 N sodium hydroxide. The volume of sodium hydroxide required for neutralization was noted and 115% of this volume of 50% dextrose solution added after each pH adjustment. At the end of about 8 hours the bacterial count had ceased to increase and the fermentation was terminated. At this time the fermentation medium contained approximately 1,000 units of streptokinase per cc. References Merck Index 8683 Kleeman and Engel p. 826 PDR pp.944, 963, 1428 I.N. p. 891 REM p. 1037 Ablondi, F.B. and Adam, J.N. Jr.; US Patent 2,701,227; February 1, 1955; assigned to American Cyanamid Company Mowat, J.H., Krupka, G.C. and Nalesnyk, S.; US Patent 2,753,291; July 3, 1956; assigned to American Cyanamid Company Singher, H.O. and Zuckerman, L.; US Patent 3,016,337; January 9, 1962; assigned to Ortho Pharmaceutical Corporation Siegel, M., Palombo, G. and Beumgarten, W.; US Patent 3,042,586; July 3, 1962; assigned to Merck and Co., Inc. von Polnitz, W., Schwick, H.G. and Bickhard, J.H.; US Patent 3,063,913; November 13, 1962; assigned to Behringwerke AG, Germany von Polnitz, W., Schwick, H.G. and Bickhard, J.H.; US Patent 3,063,914; November 13, 1962; assigned to Behringwerke AG, Germany Baumgarten, W. and Cole, R.B.; US Patent 3,107,203; October 15, 1963; assigned to Merck and Co., Inc. von Polnitz, W., Schwick, H.G. and Bickhard, J.H.; US Patent 3,138,542; June 23, 1964; assigned to Behringwerke AG, Germany

3072

Strepromycin

STREPTOMYCIN Therapeutic Function: Antitubercular Chemical Name: O-2-Deoxy-2-(methylamino)-α-L-glucopyranosyl-(1-2)-O-5deoxy-3-C-formyl-α-L-lyxofuranosyl-(1-4)-N,N'-bis(aminoiminomethyl)-Dstreptamine Common Name: Structural Formula:

Chemical Abstracts Registry No.: 57-92-1 Trade Name Streptomycin Streptomycine Cidan-Est Darostrep Estrepto E Estrepto Level Estreptomicina Estreptomicina Normon Estrepto Wolner Estreptomade Neodiestostreptobap Orastrep Servistrep Solvo-Strep Streptaguaine Streptobretin Streptosol Strycin

Manufacturer MSD Diamant Cidan SCS Pharmalab Wassermann Level Cepa Normon Wolner Made Martin Santos Dista Servipharm Heyl Dista Norbrook Therapex Squibb

Raw Materials Nutrient medium Bacterium Streptomyces griseus

Country US France Spain S. Africa Spain Spain Spain Spain Spain Spain Spain UK Switz. W. Germany UK UK Canada US

Year Introduced 1945 1961 -

Streptozocin

3073

Manufacturing Process A medium is prepared having the following composition in tap water: 1.0% glucose; 0.5% peptone; 0.3% meat extract; and 0.5% NaCl. This medium is distributed in appropriate vessels to a depth of 1 to 2 inches, sterilized at 10 pounds steam pressure for 45 to 50 minutes, and then cooled. The medium in each vessel is then inoculated with a heavy aqueous suspension of spores of a strain of Actinomyces griseus, and the inoculated media are maintained at an incubation temperature of 22° to 28°C for 10 days. The growth is then filtered off and the filtrates are combined for further treatment. To a batch of approximately 10 liters of filtered broth is added 150 grams of activated charcoal. The mixture is stirred continuously for about 5 minutes and is then filtered. The slightly yellowish (almost colorless) filtrate is discarded and the charcoal residue is washed several times with distilled water and finally with 95% ethanol. The washed material is then suspended in 1.5 liters of 95% ethanol, made 0.15 normal with hydrochloric acid. The suspension is stirred for about an hour and allowed to stand in the cold for about 10 hours more with occasional stirring. The suspension is then filtered, the charcoal residue discarded, and the yellowish clear filtrate thus obtained is poured into 10 liters of ether, with stirring. A brown-colored aqueous layer separates and is drawn off. The alcohol-ether solution is washed with 100 cc of water and the brown aqueous layer is drawn off and added to the first aqueous layer. The aqueous solution is neutralized to pH 6 to 7 with dilute sodium hydroxide and any precipitate that forms is filtered off and discarded. A faintly colored aqueous solution containing streptomycin is thus obtained. References Merck Index 8685 Kleeman and Engel p. 827 PDR p. 1410 I.N. p. 892 REM p. 1260 Waksman, S.A. and Schatz, A.: US Patent 2,449,866; September 21, 1948; assigned to Rutgers Research and Endowment Foundation Bartels, C.R., Bryan, W.L. and Berk, B.; US Patent 2,868,779; January 13, 1959; assigned to Olin Mathieson Chemical Corporation

STREPTOZOCIN Therapeutic Function: Antineoplastic Chemical Name: 2-Deoxy-2-(3-methyl-3-nitrosoureido)-D-glucopyranose Common Name: -

3074

Streptozocin

Structural Formula:

Chemical Abstracts Registry No.: 18883-66-4 Trade Name

Manufacturer

Country

Year Introduced

Zanosar

Upjohn

US

1982

Raw Materials Bacterium Streptomyces achromogenes Nutrient medium Manufacturing Process On a sterile maltose-tryptone agar slant of the following composition: 1 g maltose; 0.5 g tryptone; 0.05 g K2HPO4; 0.01 g FeSO4·7H2O; 1.5 g agar; and sufficient distilled water to make 100 ml, Streptomyces achromogenes var. streptozoticus was grown for 7 days at 28°C. The culture thus produced was used as an inoculum for the following sterile medium: 1 g glucose; 1 g beef extract; 0.5 g Bacto peptone (Difco); 0.5 g NaCl; and sufficient distilled water to make 100 ml. The pH was adjusted to 7.0 before sterilization. The inoculated medium was incubated in shake flasks for 3 days at 28°C on a reciprocating shaker and 75 ml of the resulting growth was used to inoculate 12 l of sterile medium of the same formulation. The medium was incubated in a 20 l stainless steel bottle, at 28°C for 2 days, the contents being stirred continuously with sparged air at the rate of 6 l of free air per minute. The resulting growth was used to inoculate 250 l of the following sterile medium. 2 g Bacto peptone (Difco); 2.5 g blackstrap molasses; 2 g glucose; 0.25 g NaCl; and sufficient distilled water to make 100 ml. The pH was adjusted to 7.0 before sterilization. This medium was incubated in a 100 gallon stainless steel fermentor, at 24°C with sparged air being introduced at the rate of 50 l/min and with agitation by an impeller. After 66 hours of fermentation the beer was harvested. To 100 gallons of harvested beer was added 17 pounds of diatomite, and 35 pounds of activated carbon. The mixture was stirred well and then filtered, the cake was water-washed with 10 gallons of tap water, and then washed with 25 gallons of acetone followed by 30 gallons of 1:1 aqueous acetone. The acetone solutions of streptozotocin were pooled and dried in vacuo to 3.88 pounds. References Merck Index 8695

Succinylcholine dichloride

3075

DFU 4 (2) 137 (1979) DOT 19 (5) 242 (1983) I.N. p. 892 REM p. 1156 Bergy, M.E., De Boer, C., Dietz, A., Eble, T.E., Herr, R.R. and Johnson, L.E.; US Patent 3,027,300; March 27, 1962; assigned to The Upjohn Co.

SUCCINYLCHOLINE DICHLORIDE Therapeutic Function: Muscle relaxant Chemical Name: Choline, chloride, succinate (2:1) Common Name: Choline succinate dichloride; Diacetylcholine dichloride; Suxamethonium chloride Structural Formula:

Chemical Abstracts Registry No.: 71-27-2; 306-40-1 (Base) Trade Name Anectine Anectine Flo-Pak Esculin Myolaxin Nicolin Quelicin Relaxin Scoline Scoline Succinylcholine Chloride

Manufacturer Glaxo Wellcome Glaxo Wellcome Embil Star Asta Abbott Laboratories Kyorin Evans Glaxo Wellcome Organon

Country USA

Year Introduced -

Raw Materials Sodium hydroxide Succinic acid chloroanhydride Methyl chloride Dimethylaminoethanol hydrochloride Manufacturing Process For the first time Fusko with coworkers synthesied the succinylcholine in 1949 year.

3076

Succinylsulfathiazole

By the etherification of succinic acid chloroanhydride with dimethylaminoethanol hydrochloride in the presence of sodium hydroxide succinylcholine was prepared. Then the obtained succinylcholine was purified. To the succinylcholine the methylchloride was added (1:2 mols) and the succinylcholine dichloride was obtained as white powder. The succinylcholine is used as succinylcholine diiodide. This salt may be prepeared identicaly. References Haletsky A.M.; Pharmaceutical Chemistry, "Medicina". Leningrad, 1966, 762 p.

SUCCINYLSULFATHIAZOLE Therapeutic Function: Antibacterial (intestinal) Chemical Name: 4-Oxo-4-[[4-[(2-thiazolylamino)-sulfonyl]phenyl]amino] butanoic acid Common Name: Structural Formula:

Chemical Abstracts Registry No.: 116-43-8 Trade Name Sulfasuxidine Thiacyl Colistatin Cremosu xidine

Manufacturer MSD Theraplix Smith and Nephew MSD

Raw Materials 2-Sulfanilamidothiazole Succinic anhydride

Country US France UK UK

Year Introduced 1942 1946 -

Sucralfate

3077

Manufacturing Process 3.92 g of succinic anhydride was added to a boiling suspension of 10 g of 2sulfanilamidothiazole in 100 cc of alcohol. The mixture was then refluxed for five minutes after the addition was complete at which time all of the solids were in solution. The solution was then cooled and diluted with an equal volume of water. The white solid precipitate which formed was filtered and recrystallized from dilute alcohol, yielding 2-N4-succinylsulfanilamidothiazole, melting at 184°C to 186°C. References Merck Index 8753 Kleeman and Engel p. 831 OCDSVol. 1 p. 132 (1977) I.N. p. 894 Moore, M.L.; US Patents 2,324,013 and 2,324,014; both dated July 13, 1943; assigned to Sharp and Dohme, Inc.

SUCRALFATE Therapeutic Function: Antiulcer Chemical Name: Hexadeca-µ-hydroxytetracosahydroxy[µ8-[1,3,4,6-tetra-Osulfo-β-D-fructofuranosyl-α-D-glucopyranosidetetrakis(hydrogen sulfato)(8-)]]hexadecaaluminum Common Name: Structural Formula:

3078

Sucralfate

Chemical Abstracts Registry No.: 54182-58-0 Trade Name Antepsin Ulcogant Carafate Ulogant Antepsin Ulsanic Andapsin Sulcrate Ulcerlmin

Manufacturer Baldacci Cascan Marion Merck Ayerst DuPont Farmos Nordic Chugai

Country Italy W. Germany US Switz. UK Australia Sweden Canada Japan

Year Introduced 1975 1980 1981 1982 1982 1983 1983 -

Raw Materials Sulfur trioxide Sodium hydroxide Sucrose Aluminum dihydroxychloride Pyridine Manufacturing Process A disaccharide is added to a pyridine SO3 complex solution, which is prepared by reacting 5 to 6 times the molar amount of liquid SO3 as much as that of disaccharide with 5 to 10 times the amount of pyridine as that of the disaccharide at 0°C to 5°C, for sulfation at 50°C to 70°C for 3 to 7 hours. After the completion of sulfation, the greater part of pyridine is removed by decantation. The obtained solution exhibits an acidity that is so strong that it is improper to apply the reaction with aluminum ion and, therefore, sodium hydroxide is added for neutralization. After the remaining pyridine is removed by concentration, 100 unit volumes of water per unit volume of the residue is added thereto. To the solution is then added aluminum ion solution mainly containing aluminum dihydroxychloride, the pH of which is 1.0 to 1.2, in such an amount that the aluminum ion is present in an amount of 4 to 6 molar parts of the amount of disaccharide to provide a pH of 4 to 4.5. The mixture is reacted under stirring at room temperature and the formed disaccharide polysulfate-aluminum compound is allowed to precipitate. After filtration, the residue is washed with water and dried. References Merck Index 8755 PDR p. 1074 I.N. p. 894 REM p. 815 Nitta, Y., Namekata, M., Tomita, E. and Hirota, Y.; US Patent 3,432,489; March 11, 1969; assigned to Chugai Seiyaku K.K. (Japan)

Sufentanil

3079

SUFENTANIL Therapeutic Function: Analgesic Chemical Name: N-[4-(Methoxymethyl)-1-[2-(2-thienyl)ethyl]-4-piperidinyl]N-phenylpropanamide Common Name: Structural Formula:

Chemical Abstracts Registry No.: 56030-54-7 Trade Name Sufenta Sufenta

Manufacturer Janssen Janssen

Country Netherlands US

Year Introduced 1983 -

Raw Materials N-[4-(Methoxymethyl)-4-piperidinyl]-N-phenylpropanamide 2-Thiopheneethanol Manufacturing Process A mixture of 4.1 parts of N-[4-(methoxymethyl)-4-piperidinyl]-Nphenylpropanamide, 5.3 parts of sodium carbonate and 120 parts of 4methyl-2-pentanone is stirred and refluxed with water-separator. Then there are added 4.1 parts of 2-thiopheneethanol methanesulfonate ester and stirring at reflux is continued for 18 hours. The reaction mixture is cooled, washed twice with water and evaporated. The oily residue is purified by columnchromatography over silica gel, using a mixture of trichloromethane and 5% of methanol as eluent. The first fraction is collected and the eluent is evaporated. The oily residue is converted into the hydrochloride salt in 2,2'oxybispropane. The free base is liberated again in the conventional manner. After extraction with 2,2'-oxybispropane, the latter is dried, filtered and evaporated. The oily residue solidifies on triturating in petroleum-ether. The solid product is filtered off and crystallized from petroleum-ether at -20°C, yielding, after drying, N-[4-(methoxymethyl)-1-[2-(2-thienyl)ethyl]-4piperidinyl]-N-phenylpropanamide; melting point 98.6°C. References Merck Index A-12

3080

Sulbactam sodium

DFU 2 (5) 334 (1977) PDR p. 959 I.N. p. 895 Janssen, P.A.J. and Daele, H.P.V.; US Patent 3,998,834; December 21, 1976; assigned to Janssen Pharmaceutica N.V. (Belgium)

SULBACTAM SODIUM Therapeutic Function: Beta-lactamase inhibitor Chemical Name: 4-Thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, 3,3dimethyl-7-oxo-, 4,4-dioxide, (2S-cis), sodium salt Common Name: Sulbactam sodium Structural Formula:

Chemical Abstracts Registry No.: 69388-84-7; 68373-14-8 (Base) Trade Name

Manufacturer

Country

Year Introduced

Sulbactam-Sodium

Antibiotic Co.

Bulgaria

-

Raw Materials Bromine NaNO2 Iron Sodium 2-ethylhexanoate

6-Aminopenicillanic acid Hydrochloric acid Potassium permanganate

Manufacturing Process Sulbactam sodium is semi-synthetic antibiotic of penicillinic group. Start material for it's synthesis is 6-aminopenicillanic acid. First 6-aminopenicillanic acid was isolated in 1957 year from benzylpenicilline as resalt of treating of it by penicillinaze. Benzylpenicilline is produced by microorganism of genus Streptomyces. Further, 6-aminopenicillanic acid reacted with bromine, hydrochloric acid and NaNO2. As a result the 6,6-dibromopenicillanic acid was obtained. 6,6-Dibromopenicillanic acid was oxidized by KMnO4, to give 6,6-dibromo-1,1-

Sulbenicillin

3081

dioxopenicillanic acid. The 6,6-dibromo-1,1-dioxopenicillanic acid in presence of Fe was converted to the 1,1-dioxopenicillanic acid (sulbactam acid). The sulbactam acid was treated by sodium 2-ethylhexanoate and crude sulbactam sodium was obtained. References Gomis D.B. et al.; Fast high performance liquid chromatography method for in-process control of sulbactam. Analytica Chimica Acta, 498, (2003), 1-8

SULBENICILLIN Therapeutic Function: Antibacterial Chemical Name: 3,3-Dimethyl-7-oxo-6-[(phenylsulfoacetyl)amino]-4-thia-1azabicyclo[3.2.0]heptane-2-carboxylic acid Common Name: Sulfocillin Structural Formula:

Chemical Abstracts Registry No.: 41744-40-5; 28002-18-8 (Sodium salt) Trade Name

Manufacturer

Country

Year Introduced

Lillacillin

Takeda

Japan

1973

Kedacillina

Bracco

Italy

1982

Raw Materials α-Sulfophenacetyl chloride 6-Aminopenicillanic acid Manufacturing Process To a suspension of 1.08 parts by weight of 6-aminopenicillanic acid in 8 parts by volume of water is added 1.48 parts by weight of sodium bicarbonate. After the mixture is dissolved, a solution of 1.18 parts by weight of α-

3082

Sulfacetamide

sulfophenylacetyl chloride in 10 parts by volume of diethylether is gradually added thereto. The mixture is stirred at a temperature in the neighborhood of 0°C for 1 hour. The aqueous layer is washed twice with 10 parts by volume of portions of ether and adjusted to pH 1.2 with cation exchange resin of polystyrene sulfonic acid type under constant cooling. Then the solution is washed twice with 15 parts by volume of portions of ethyl acetate, followed by extraction twice with 15 parts by volume of portions of n-butanol. The extracts are combined and washed twice with 15 parts by volume of portions of water and, then, extracted with an aqueous solution of sodium bicarbonate. The extract is adjusted to pH 6.5, washed with ether and lyophilized to give the sodium salt of α-sulfobenzylpenicillin. Yield is 1.2 parts by weight. References Merck Index 8762 DOT 8 (5) 199 (1972) and 9 (4) 149 (1973) I.N. p. 895 REM p. 1201 Morimoto, S., Nomura, H., Fugono, T., Maeda, K. and Ishiguro, T.; US Patent 3,600,379; May 2, 1972; assigned to Takeda Chemical Industries, Ltd. (Japan)

SULFACETAMIDE Therapeutic Function: Antimicrobial Chemical Name: N-[(4-Aminophenyl)sulfonyl]acetamide Common Name: N'-Acetylsulfanilamide Structural Formula:

Chemical Abstracts Registry No.: 144-80-9 Trade Name

Manufacturer

Country

Year Introduced

Sulamyd

Schering

US

1941

Urosulfon

Consol. Midland

US

1955

Sulfacidin

Crookes

UK

-

Sultrin

Ortho

US

-

Triple Sulfa

Fougera

US

-

Trysul

Savage

US

-

Sulfachlorpyridazine

3083

Raw Materials 4-Aminobenzenesulfonamide Acetic anhydride Sodium hydroxide Manufacturing Process 17.2 grams of 4-aminobenzene-sulfonamide are heated to boiling with 75 cc of acetic anhydride for 1 hour and thereupon the diacetyl product caused to separate by stirring into ice water. After recrystallization from alcohol the 4acetylaminobenzene-sulfonacetyl-amide forms colorless prisms of melting point 253°C with decomposition. The product is easily soluble in alkalies and forms neutral salts. The acetylation can also take place with acetyl chloride. Instead of the 4-aminobenzene-sulfonamide also 4-acetylaminobenzenesulfonamide can be employed. The action of 4-acetylaminobenzene-sulfonic acid chloride on acetamide yields the same product. By heating the diacetyl compound with sodium hydroxide solution partial saponification of the acetyl groups takes place. 25.6 grams of diacetyl compound are heated to boiling for some hours with 100 cc of 2N sodium hydroxide solution. The precipitate produced by acidification of the solution with acetic acid is filtered off and treated with dilute sodium carbonate solution. The 4-aminobenzene-sulfonacetylamide passes into solution while the simultaneously formed 4-acetylaminobenzene-sulfonamide remains undissolved. It is filtered with suction and the filtrate again acidified with acetic acid. The 4-aminobenzene-sulfon-acetamide separates out and is recrystallized from water. It forms colorless lustrous rhombic crystals of MP 181°C. References Merck Index 100 Kleeman and Engel p. 833 PDR pp. 888, 1306, 1606 OCDS Vol. 1 p. 123 (1977) I.N. p. 897 REM p. 1176 Dohrn, M. and Diedrich, P.; US Patent 2,411,495; November 19, 1946; assigned to Schering Corporation

SULFACHLORPYRIDAZINE Therapeutic Function: Antibacterial Chemical Name: 4-Amino-N-(6-chloro-3-pyridazinyl)benzenesulfonamide Common Name: Chemical Abstracts Registry No.: 80-32-0

3084

Sulfachlorpyridazine

Structural Formula:

Trade Name Sonilyn Nefrosul Consulid Cosulfa Durasulf Sulfaclorazina

Manufacturer Mallinckrodt Inc. Riker Ciba Geigy Elliott-Marion Dessy Ellem

Country US US US Canada Italy Italy

Year Introduced 1962 1974 -

Raw Materials 3,6-Dichloropyridazine Sulfanilamide Manufacturing Process 1.9 parts of 3,6-dichloropyridazine, 3.4 parts of sulfanilamide, 2.7 parts of potassium carbonate and 1 part of sodium chloride were ground together. The solid mixture was heated with stirring and as the dichloropyridazine and sulfanilamide melted, the mixture became a slurry. When the bath temperature had reached 140°C a sudden evolution of carbon dioxide occurred which lasted about 5 minutes, after which the mixture set in fine granules. When no more carbon dioxide was evolved, heating was stopped and the reaction mixture was heated with sufficient water to dissolve it and the solution allowed to cool. Unreacted sulfanilamide was collected by filtration. Excess dichloropyridazine was removed from the filtrate by extraction with a water immiscible organic solvent such as ether. The basic solution was chilled and poured into one-half volume of 1:3 acetic acid. Sufficient hydrochloric acid was added to bring the mixture to pH 4. The crude 3-sulfanilamido-6-chloropyridazine which precipitated was purified by solution in 6 parts of 1:100 ammonium hydroxide, charcoal treatment and precipitation by pouring of the filtrate into dilute acetic acid. References Merck Index 8770 Kleeman and Engel p. 833 OCDS Vol. 1 pp. 124, 131 (1977) I.N. p. 897 Lester, M.M. and English, J.P.; US Patent 2,790,798; April 30, 1957; assigned to American Cyanamid Company

Sulfacytine

3085

SULFACYTINE Therapeutic Function: Antibacterial Chemical Name: 4-(Amino-N-(1-ethyl-1,2-dihydro-2-oxo-4-pyrimidinyl) benzenesulfonamide Common Name: N-Sulfanilyl-1-ethylcytosine; Sulfacitine Structural Formula:

Chemical Abstracts Registry No.: 17784-12-2 Trade Name

Manufacturer

Country

Year Introduced

Renoquid

Glenwood

US

1975

Renoquid

Parke Davis

US

1983

Raw Materials Sodium Hydrogen bromide Potassium cyanate Bromine

3-(Ethylamino)propionitrile N-Acetylsulfanilyl chloride Methanol Sodium hydroxide

Manufacturing Process The N-(N-acetylsulfanilyl)-1-ethylcytosine used as a starting material is prepared as follows: To a solution of 333 grams of 3-(ethylamino)propionitrile in 1,697.3 ml of 2 N hydrochloric acid is added 275 grams of potassium cyanate, the resulting solution is concentrated under reduced pressure to a syrup, and the syrup is heated at 90° to 100°C for 6 hours and then evaporated to dryness at 90° to 100°C under reduced pressure. The residue is extracted with 1,600 ml of hot absolute ethanol, and the extract is concentrated to 500 ml and chilled. The crystalline 1-(2-cyanoethyl)-1ethylurea obtained is isolated, washed with cold absolute ethanol, and dried, melting point 88° to 91°C. This intermediate (58.7 grams) is added to a solution of 11.5 grams of sodium in 500 ml of methanol and the resulting solution is heated under reflux for 30 minutes. After cooling, the mixture, containing 1-ethyl-5,6-dihydrocytosine, is treated with a slight excess of gaseous hydrogen bromide and evaporated to dryness. The residue is extracted, first with 500 ml, then with 100 ml of hot isopropyl alcohol, the extracts are combined and chilled, and the crystalline 1-ethyl-5,6-

3086

Sulfadiazine

dihydrocytosine hydrobromide obtained is isolated and dried, MP 167.5° to 169.5°C. This salt (88.8 grams) is dissolved in 200 ml of nitrobenzene at 174°C, 22.6 ml of bromine is added over a period of 8 minutes, and the mixture is kept at 170° to 175°C until hydrogen bromide evolution ceases (about 15 minutes). Upon cooling, there is obtained crude 1-ethylcytosine hydrobromide, which is isolated, washed with ether, and dried, MP 170° to 187°C. This salt is heated at 90° to 100°C with 70 ml of N,N-dimethylformamide and 60 ml of piperidine, and the resulting solution is chilled to give 1ethylcytosine, MP 238° to 243°C. A mixture of 10.5 grams of 1-ethylcytosine, 18.6 grams of N-acetylsulfanilyl chloride, and 50 ml of pyridine is stirred at room temperature for 2 days. The precipitated solid is removed by filtration, and the filtrate is evaporated at 60°C under reduced pressure to a syrup. The syrup is triturated with 0.25N hydrochloric acid, and the solid N-(N-acetylsulfanilyl)-1-ethylcytosine obtained is isolated and dried. This solid is suitable for use without further purification. A solution of 65 grams of N-(N-acetylsulfanilyl)-1-ethylcytosine in 380 ml of 2 N aqueous sodium hydroxide is heated under reflux for 1 hour. Upon cooling, the solution is treated with charcoal, purified by filtration, and acidified with acetic acid. The solid N-sulfanilyl-1-ethylcytosine that precipitates is isolated, washed with water, and dried, MP 166.5° to 168°C following successive crystallizations from butyl alcohol and from methanol. References Merck Index 8771 Kleeman and Engel p. 834 PDR p. 926 OCDS Vol. 2 p. 113 (1980); DOT 12 (9) 370 (1976) I.N. p. 898 REM p. 1172 Doub, L.and Krolls, U.; US Patent 3,375,247; March 26,1968; assigned to Parke, Davis and Company

SULFADIAZINE Therapeutic Function: Antibacterial Chemical Name: 4-Amino-N-2-pyrimidinylbenzenesulfonamide Common Name: Sulfanilylaminopyrimidine; Sulfapyrimidine Chemical Abstracts Registry No.: 68-35-9

Sulfadiazine

3087

Structural Formula:

Trade Name Sulfadiazine Adiazin Adiazine Coco-Diazine Di-Azu-Mul Flamazine Lipo-Diazine Magmoid Sulfadiazine Sulfadets Sulfolex Theradia Theradiazine Ultradiazin

Manufacturer Lederle Star Theraplix Lilly First Texas Smith and Nephew Donley Evans Pitman-Moore Dymond Medica Daiichi Daiichi Atabay

Country US Finland France US US UK US US Canada Finland Japan Japan Turkey

Year Introduced 1941 -

Raw Materials 2-Aminopyrimidine p-Nitrobenzenesulfonyl chloride Iron Hydrogen chloride Manufacturing Process 5.4 parts of 2-amino-pyrimidine were covered with 15 parts of anhydrous pyridine. The reaction mixture was treated with 14 parts of pnitrobenzenesulfonyl chloride and the whole heated briefly on the steam bath and let stand 45 minutes at room temperature. To the reaction mixture were added 80 parts of hot alcohol and the precipitate was filtered off and washed with water. The solid was dissolved in dilute caustic solution and the solution was filtered, cooled and acidified. The 2-(p-nitrobenzenesulfonamido)pyrimidine precipitated and was collected. The crude 2-(p-nitrobenzenesulfonamido)-pyrimidine from the preceding step was suspended in 130 parts alcohol and 1.5 parts of concentrated hydrochloric acid were added. The suspension was then heated to reflux and 30 parts of iron powder were added with mechanical stirring. The mixture was refluxed and stirred for 24 hours with occasional addition of concentrated hydrochloric acid. The reaction mixture was then made slightly basic and filtered hot and the residues were extracted with several portions of boiling alcohol. The

3088

Sulfadimethoxine

filtrate and wash solutions were combined and evaporated. The 2(sulfanilamido)-pyrimidine was recrystallized from boiling water with decolorizing charcoal added, according to US Patent 2,410,793. References Merck Index 8772 Kleeman and Engel p. 834 OCDS Vol. 1 p. 124 (1977) DOT 16 (8) 261 (1980) I.N. p. 898 REM p. 1173 Sprague, J.M.; US Patent 2,407,966; September 17, 1946; assigned to Sharp and Dohme, Inc. Winnek, P.S. and Roblin, R.O. Jr.; US Patent 2,410,793; November 5, 1946; assigned to American Cyanamid Company

SULFADIMETHOXINE Therapeutic Function: Antibacterial Chemical Name: 4-Amino-N-(2,6-dimethoxy-4-pyrimidinyl) benzenesulfonamide Common Name: Sulforthomidine; Sulphormethoxine Structural Formula:

Chemical Abstracts Registry No.: 122-11-2 Trade Name Madribon Madrigid Abcid Albon Ancosul Asthoxin Bensulfa

Manufacturer Roche Roche Daiichi Roche Anchor Kobayashi Caber

Country US US Japan US US Japan Italy

Year Introduced 1958 1959 -

Sulfadimethoxine Trade Name Chemiosalfa Crozinal Deltin Deposol Diasulfa Diazinol Dimetossilina Dimetossin Dimetoxan Dimetoxin Dimexin Duramid Emerazina Fultamid Hachimetoxin Ipersulfa Jatsulph Lensulpha Levisul Madribon Madroxin Melfa Micromega Mition D Neostreptal Neosulfamyd Omnibon Oxazina Redifal Risulpir Ritarsulfa Scandisil Sulfabon Sulfadomus Sulfaduran Sulfalon Sulfastop Sulfathox Sulfoplan Sulf -Reten Sulmethon Sulmetoxyn Sulxin Sumetamin Tempodiazina

Manufacturer Salfa Borromeo Wassermann Pliva Crosara Washington Lister Caber Nessa Nissin Fuso Deva Croce Bianca Fulton Toyo Ion Clinimed Lennon A.F.I. Roche Polfa Tanabe Sidus Taisho Locatelli Libra Yamanouchi Made A.M.S.A. Lisapharma Benvegna Firma Vaillant Medici Domus Janus Sumitomo Vis SCS Pharmalab Gea Pons Mohan Nichiiko Chugai Samva C.I.F.

Country Italy Italy Italy Yugoslavia Italy Italy Italy Italy Spain Japan Japan Turkey Italy Italy Japan Italy S. Africa S. Africa Italy Italy Poland Japan Italy Japan Italy Italy Japan Spain Italy Italy Italy Italy Italy Italy Italy Japan Italy S. Africa Denmark Spain Japan Japan Japan Japan Italy

3089

Year Introduced -

3090

Sulfadoxine

Raw Materials Sodium sulfanilamide 4-Phenylsulfonyl-2,6-dimethoxypyrimidine Manufacturing Process 1.4 g of 4-phenylsulfonyl-2,6-dimethoxypyrimidine and 4 g of sodium sulfanilamide (both dried over potassium hydroxide) were very finely ground and heated in an oil bath for 10 hours at 120°C (inside temperature). The reaction mixture was taken up in 30 ml of water and treated with 3 ml of 2 N sodium hydroxide solution. After standing for one hour at 0°C, the turbid solution was filtered and the filtrate was made alkaline with sodium carbonate. After again standing for one hour at 0°C, the precipitate was filtered off (1.9 g of regenerated sulfanilamide) and the filtrate was neutralized with acetic acid, whereupon crystallization resulted. The isolated crystals of 4-sulfanilamido2,6-dimethoxypyrimidine weighed 1.3 g (84% of theory), melting point 190°C to 196°C. References Merck Index 8775 Kleeman and Engel p. 835 OCDS Vol. 1 pp. 125, 129 (1977) I.N. p. 899 Bretschneider, H. and Klotzer, W.; US Patent 2,703,800; March 8,1955; assigned to Oesterreichische Stickstoffwerke AG Bretschneider, H. and Klotzer, W.; US Patent 3,127,398; March 31, 1964; assigned to Hoffmann-LaRoche, Inc.

SULFADOXINE Therapeutic Function: Antibacterial Chemical Name: 4-Amino-N-(5,6-dimethoxy-4-pyrimidinyl) benzenesulfonamide Common Name: Sulforthomidine; Sulformethoxine Structural Formula:

Chemical Abstracts Registry No.: 2447-57-6

Sulfadoxine Trade Name Fanasil Fansidar

Manufacturer Roche Roche

Country Italy US

3091

Year Introduced 1973 1982

Raw Materials Thiourea Sodium Methanol Methyl iodide

α-Methoxycyanoacetic acid methyl ester Phenyltrimethylammonium toluene sulfonate p-Acetylaminobenzenesulfonyl chloride

Manufacturing Process (a) α-methoxy-cyanoacetic acid methyl ester is condensed with thiourea, in the presence of sodium methylate, to form 2-thio-4-amino-5-methoxy-6hydroxy-pyrimidine. (b) The product thus obtained is methylated in a sodium methylate solution with methyl iodide to form 2-methylthio-4-amino-5-methoxy-6-hydroxypyrimidine of MP 203°C, from water. (c) The latter product is methylated with phenyltrimethylammoniumtoluenesulfonate to form 2-methylthio-4-amino-5,6-dimethoxy-pyrimidine of MP 112° to 115°C, from 20% methanol. (d) 0.9 gram of 2-methylthio-4-amino-5,6-dimethoxy-pyrimidine are dissolved in 3 ml of absolute pyridine. At 0°C, 1.2 grams of pacetylaminobenzenesulfonyl chloride are added thereto and the mixture is shaken until all the material is dissolved. The solution is allowed to stand for 22 hours at 0°C and the pyridine eliminated in vacuo at 20°C. To the resulting product are added 20 ml of water and 3 ml of glacial acetic acid, whereupon the whole mixture is heated to the boil, thus causing crystallization. The crude product obtained is dissolved in 40 ml of 2.5% soda solution, and the solution obtained is filtered and supersaturated with gaseous carbon dioxide. There is thus obtained 1.5 grams (85%) of 2-methylthio-4-(N4-acetyl-sulfanilamido)5,6-dimethoxy-pyrimidine of MP 220° to 221°C, from 50% ethanol. (e) 1.3 grams of 2-methylthio-4-(N4-acetyl-sulfanilamido)-5,6-dimethoxypyrimidineare dissolved in 25 ml of water and 0.4 gram of anhydrous sodium carbonate, then refluxed for 3 ½ hours in the presence of 6 to 7 grams of Raney nickel. Then, a solution of 1 gram of sodium hydroxide in 3 ml of water is added thereto and heating continued for another hour. The catalyst is filtered off and the filtrate acidified to Congo red with hydrochloric acid. The pH is then brought to 5 by means of ammonia, thus causing crystallization. There is thus obtained 0.51 gram of 4-sulfanilamido-5,6-dimethoxy-pyrimidine of MP 190° to 194°C, from 50% ethanol. References Merck Index 8776 PDR p. 1484 I.N. p. 899 REM p. 1176

3092

Sulfaethidole

Bretschneider, H., Klotzer, W. and Schantl, J.; US Patent 3,132,139; May 5, 1964; assigned to Hoffmann-La Roche Inc.

SULFAETHIDOLE Therapeutic Function: Antibacterial Chemical Name: 4-Amino-N-(5-ethyl-1,3,4-thiadiazol-2-yl) benzenesulfonamide Common Name: Structural Formula:

Chemical Abstracts Registry No.: 94-19-9 Trade Name Sul-Spansion Globucid Spasmo-Urosulf Sulfa-Perlongit Urosulf

Manufacturer SKF Schering T.A.D. Boehringer Ingelheim T.A.D.

Country US W. Germany W. Germany W. Germany

Year Introduced 1956 -

Raw Materials 2-Amino-5-ethyl-1,3,4-thiadiazole p-Acetylaminobenzenesulfonyl chloride Manufacturing Process 0.163 mol of 2-amino-5-ethyl-1,3,4-thiadiazole was covered with 43 parts of anhydrous pyridine. To the mixture was added 50 parts (0.214 mol) of pacetylaminobenzenesulfonyl chloride with vigorous shaking at 50°C to 60°C. The reaction mixture was then heated to 125°C. When the mixture had cooled somewhat it was placed in a Claisen flask and 27.6 parts (0.69 mol) of sodium hydroxide dissolved in 110 parts of water was added through a dropping funnel while distilling off a mixture of pyridine and water. The distillation was stopped when the temperature reached 100°C and the residual liquor in the flask heated at 95°C for 30 minutes.

Sulfaguanidine

3093

The reaction mixture was then poured into 1,650 parts of hot water, the pH adjusted to 8 to 9, decolorizing charcoal was added and the whole was heated on the steam for 15 minutes. The charcoal was filtered off and the hot filtrate neutralized and cooled. The 2-(sulfanilamido)-5-ethyl-1,3,4-thiadiazole was purified by repeated crystallization from boiling water. References Merck Index 8777 Kleeman and Engel p. 836 OCDS Vol. 1 p. 125 (1977) I.N. p. 900; Roblin, R.O. Jr. and Winner, P.S.; US Patent 2,358,031; September 12, 1944; assigned to American Cyanamid Co.

SULFAGUANIDINE Therapeutic Function: Antimicrobial Chemical Name: 4-Amino-N-(aminoiminomethyl)benzenesulfonamide Common Name: Sulfanilylguanidine Structural Formula:

Chemical Abstracts Registry No.: 57-67-0 Trade Name Sulfaguanidine Aseptil-Guanadina Aterian Devaguanil Ganidan Guabeta Guasept Resulfon

Manufacturer Lederle Wassermann Takeda Deva Specia O.T.W. Ferrosan Nordmark

Raw Materials Iron Guanidine hydrochloride Hydrogen chloride p-Nitrobenzenesulfonyl chloride

Country US Italy Japan Turkey France W. Germany Denmark W. Germany

Year Introduced 1941 -

3094

Sulfaguanol

Manufacturing Process 10 parts of guanidine hydrochloride (0.1 mol) was dissolved in 75 parts of water and the pH adjusted to 8 to 9. The solution was warmed to 50°C to 60°C and kept at this temperature while a slurry of 25 parts (0.113 mol) of pnitrobenzenesulfonyl chloride was added slowly with mechanical stirring. The pH was kept at 8 to 9 by the addition of 40% sodium hydroxide solution. At the end of the reaction the solution was cooled and filtered from the separated solid. The p-nitrobenzene sulfonyl guanidine was recrystallized from hot water. 5 parts (0.024 mol) of p-nitrobenzene sulfonyl guanidine was dissolved in 50 parts of boiling 95% alcohol and to the solution was added 0.5 part of concentrated hydrochloric acid. The solution was heated to reflux and 6 parts of iron dust was added. The suspension was refluxed for 3 hours, made basic with potassium carbonate, and filtered hot. The alcohol was evaporated off and the p-aminobenzene sulfonyl guanidine recrystallized from boiling water with the addition of decolorizing charcoal. References Merck Index 8779 Kleeman and Engel p. 837 OCDS Vol. 1 p. 123 (1977) I.N. p. 900 Winnek, P.S.; US Patent 2,218,490; October 15, 1940; assigned to American Cyanamid Co. Winnek, P.S.; US Patent 2,229,784; January 28, 1941; assigned to American Cyanamid Co. Winnek, P.S.; US Patent 2,233,569; March 4, 1941; assigned to American Cyanamid Co.

SULFAGUANOL Therapeutic Function: Antibacterial Chemical Name: N1-[(4,5-Dimethyl-2-oxazolyl)amidino]sulfanilamide Common Name: Sulfadimethyloxazolylguanidine Chemical Abstracts Registry No.: 27031-08-9 Trade Name Enterocura Enterocura

Manufacturer Nordmark De Angeli

Country W. Germany Italy

Raw Materials Acetoin Hydrogen chloride N(1)-[p-Aminobenzenesulfonyl]-N(3)-cyanoguanidine

Year Introduced 1973 1981

Sulfalene

3095

Structural Formula:

Manufacturing Process 23.9 grams (0.1 mol) of N1-[p-amino benzene sulfonyl]-N3-cyanoguanidine and 13.2 grams (0.15 mol) of acetoin are thoroughly stirred in a mixture of 120 cc of water and 120 cc of methanol. 25 cc of concentrated hydrochloric acid are added dropwise with stirring to this suspension at 40°C. A clear solution is obtained after 30 minutes which solution is kept at 40°C for another hour. Thereafter, the methanol is distilled off in a vacuum, the remaining solution is treated with charcoal and the pH of the filtered solution is quickly brought to 11 by addition of 10% soda lye with quick stirring. The compound at first precipitated is redissolved at a pH of 11. The solution is treated another time with charcoal and is filtered. Thereafter, a mixture of anhydrous acetic acid and water in a proportion of 1:1 is added with stirring and cooling until a pH of 7 is reached. Thus, the reaction product separates with crystallization. For purification, the product is recrystallized from 15 times the amount of a 9:1 mixture of acetone and water. The resulting N1-[p-amino benzene sulfonyl] -N3-(4,5-dimethyl-oxazolyl-(2)]-guanidine is obtained as colorless crystals having a MP of 233° to 236°C. References Merck Index 8780 Kleeman and Engel p. 838 DOT 9 (5) 185 (1973) I.N. p. 900 Loop, W., Baganz, H., Kohlmann, F.-W. and Schultze, H.; US Patent 3,562,258; Feb. 9, 1971; assigned to Nordmark-Werke GmbH, Germany

SULFALENE Therapeutic Function: Antibacterial Chemical Name: 4-Amino-N-(3-methoxypyrazinyl)benzenesulfonamide

3096

Sulfalene

Common Name: Sulfamethopyrazine Structural Formula:

Chemical Abstracts Registry No.: 152-47-6 Trade Name Longum Kelfizina Kelfizine Kelfizine

Manufacturer Farmitalia Farmitalia Farmitalia Bellon

Country W. Germany Italy UK France

Year Introduced 1962 1962 1969 1969

Raw Materials 2-Aminopyrazine Sodium Bromine Sodium hydroxide

p-Acetylaminobenzenesulfonyl chloride Hydrogen Methanol

Manufacturing Process 2-Amino-3,5-Dibromo-Pyrazine: 112.7 ml of bromine in 375 ml of acetic acid are slowly added at 0° to +2°C, while stirring, to a solution of 95.11 grams of 2-amino-pyrazine and 326.5 grams of acetic acid trihydrate (CH3COONa·3H2O) in 1,480 ml of acetic acid. This addition requires about 2 to 3 hours and it is carried out in the dark. The mixture is then allowed to stand at room temperature (25° to 30°C) for 15 to 16 hours. About 1.5 liters of acetic acid are distilled off under vacuum (12 to 14 mm Hg) at 35°C and the brown and viscous residue is poured into 500 grams of ice-water under stirring. Aqueous 20% sodium hydroxide is added in order to obtain a pH = 8 and then the product is filtered and air-dried. The air-dried product is extracted 6 times with 150 ml of ether; the filtered ethereal solutions are evaporated to dryness and the residue (50 to 52 grams) is crystallized from hot water. The yield is 34.36 grams, melting at 114°C. 2-Amino-3-Methoxy-5-Bromo-Pyrazine: 7 grams of 2-amino-3,5-dibromopyrazine are boiled for 9 hours in a methanolic solution of sodium methylate (obtained from 0.65 gram of Na and 18.5 ml of methanol). By cooling a crystalline product is obtained, filtered and washed once with methanol and 2 to 3 times with water. The yield is 5.4 grams, melting at 138°C. 2-Amino-3-Methoxy-Pyrazine: 3 grams of 2-amino-3-methoxy-5-bromopyrazine are hydrogenated, in methanolic solution at room temperature and at atmospheric pressure, in the presence of 1 gram of palladium over charcoal

Sulfamerazine

3097

(10%) and 0.9 gram of potassium hydroxide. When the stoichiometric amount of hydrogen is absorbed, the suspension is filtered and the filtrate is evaporated to dryness. The residue is extracted with acetone, the acetonic solution is evaporated and the residue (1.8 grams, melting at 75° to 82°C) is crystallized from cyclohexane. The yield is 1.5 grams, melting at 85°C. 2-(p-Acetylaminobenzene-sulfonamido)-3-Methoxy-Pyrazine: 1.5 grams of 2amino-3-methoxy-pyrazine dissolved in 15 ml of anhydrous pyridine are treated, under cooling and stirring, with 2.81 grams of pacetylaminobenzenesulfonyl chloride, at small portions in about 30 minutes. The mixture is allowed to stand for 20 hours at room temperature and then is heated to 50°C for 4 hours. The solution is concentrated to one-third of its volume, under vacuum, and poured into ice-water under stirring. The precipitate is filtered and washed with water. 2.21 grams melting at 218° to 220°C are obtained. The MP (crystallized from alcohol) is 224°C. 2-Sulfanilamido-3-Methoxy-Pyrazine: 1.5 grams of the product from the preceding step and 7 to 8 ml of aqueous 10% sodium hydroxide are boiled for 1 hour. The cooled solution is slightly acidified to pH 6 with aqueous 2 N hydrochloric acid and the product is filtered. The yield is 1.25 grams, melting at 175°C. References Merck Index 8781 Kleeman and Engel p. 838 OCDS Vol. 1 p. 125 (1977) I.N. p. 901 Camerino, B. and Palamidessi, G.; US Patent 3,098,069; July 16, 1963; assigned to Societa Farmaceutici Italia, Italy

SULFAMERAZINE Therapeutic Function: Antibacterial Chemical Name: 4-Amino-N-(4-methyl-2-pyrimidinyl)benzenesulfonamide Common Name: Sulfamethyldiazine; Methylsulfadiazine Structural Formula:

Chemical Abstracts Registry No.: 127-79-7

3098

Sulfameter

Trade Name Sulfamerazine Dosulfin Mebacid Polagin Percoccide Romezin Septosil Solumedine Spanbolet

Manufacturer Lederle Geigy VEB Berlin Chemie De Angeli A.C.F. Tanabe EGYT Specia Norden

Country US W. Germany E. Germany Italy Netherlands Japan Hungary France US

Year Introduced 1943 -

Raw Materials 2-Amino-6-methyl pyrimidine p-Acetylaminobenzenesulfonyl chloride Hydrogen chloride Manufacturing Process To a well agitated solution of 6.95 grams of 2-amino-6-methyl pyrimidine in 40 cc of pyridine, 15 grams of p-acetylaminobenzenesulfonyl chloride are added in small portions over a 30 minute period. The reaction mixture is then heated on a steam bath for 30 minutes, the free pyridine being then removed under reduced pressure and the residue mixed with cold water, and the latter mixture is vigorously stirred. The solid reaction product is removed by filtration and washed with cold water. There is obtained a yield of 14 grams of crude 2-(pacetylaminobenzenesulfonamido)-6-methyl pyrimidine, which on recrystallization from alcohol and water melts at 238° to 239°C. The crude product is hydrolyzed by suspending it in 400 cc of 2 N hydrochloric acid and warming until solution is complete. The solution is neutralized with sodium carbonate and the precipitated 2-(sulfanilamido)-6-methyl pyrimidine is removed by filtration. The latter on recrystallization from alcohol and water shows a melting point of 225° to 226°C. References Merck Index 8783 Kleeman and Engel p. 839 OCDS Vol. 1 pp. 124, 128 (1977) I.N. p. 901 REM p. 1173 Sprague, J.M.; US Patent 2,407,966; September 17, 1946; assigned to Sharp and Dohme, Inc.

SULFAMETER Therapeutic Function: Antibacterial

Sulfameter

3099

Chemical Name: 4-Amino-N-(5-methoxy-2-pyrimidinyl)benzenesulfonamide Common Name: Sulfamethoxydiazine Structural Formula:

Chemical Abstracts Registry No.: 651-06-9 Trade Name Sulla Bayrena Durenat Durenate Fortesul Kirocid Kiron Ultrax

Manufacturer Robins Bayer Pharma Bayer/Schering Bayer Pliva Schering Schering Chemie Linz

Country US France W. Germany UK Yugoslavia W. Germany W. Germany Austria

Year Introduced 1968 -

Raw Materials Phosphorus oxychloride Guanidine carbonate Zinc

Methoxymalonic acid ester Carbethoxy-sulfanilic acid chloride Sodium hydroxide

Manufacturing Process 2-Amino-5-methoxy pyrimidine is obtained having a melting point of about 300°C by condensation of methoxymalonic acid ester with guanidine carbonate in the presence of sodium ethylate. The resultant reaction product is then converted to 2-amino-5-methoxy-4,6-dichloropyrimidine (melting point 216°C to 217°C) by heating this reaction product with phosphorus oxychloride. The dichloro compound is then suspended in water with zinc dust and is tested in the presence of caustic alkaline or carbonates to produce the 2-aminod-methoxy pyrimidine compound, melting point 80°C to 82°C, (benzene). 12.6 g of 2-amino-5-methoxy pyrimidine, 26.4 g of carbethoxy-sulfanilic acid chloride and 50 cc of dry pyridine are heated for 30 minutes with frequent shaking to a temperature of 80°C. The reaction product is then mixed with 200 cc of water and with dilute hydrochloric acid (0.1 N) until the reaction is acid to Congo Red indicator. A precipitate is formed which is then filtered under suction, washed with distilled water, and dried at 150°C. A practically quantitative yield is recovered of 2-(p-carbethoxyaminobenzene-sulfonamido)5-methoxypyrimidine, melting point 248°C to 250°C.

3100

Sulfamethazine

To hydrolyze the sulfapyrimidine compound, the same is heated at 90°C with 200 cc of 2 N potassium hydroxide solution for about one hour until complete solution is obtained. The resultant solution is then cooled to room temperature (25°C) and acidified with acetic acid to precipitate the hydrolyzed product, which is then recrystallized from dilute acetone admixed with animal charcoal. References Merck Index 8785 Kleeman and Engel p. 841 OCDS Vol. 1 pp. 125, 129 (1977) I.N. p. 902 Diedrich, P.; US Patent 3,214,335; October 26, 1965; assigned to Schering A.G. (Germany)

SULFAMETHAZINE Therapeutic Function: Antimicrobial Chemical Name: 4-Amino-N-(4,6-dimethyl-2-pyrimidinyl)benzenesulfonamide Common Name: Sulfamezathine; Sulfadimerazine; Sulfamidine; Sulfadimethylpyrimidine; Sulfadimidine (UK Name) Structural Formula:

Chemical Abstracts Registry No.: 57-68-1 Trade Name Cremomethazine Deladine Intradine Rigesol Rivodine S-Dimidine Sulphix

Manufacturer MSD Delmaak Norbrook Ferrosan Rivopharm Protea Protina

Country US S. Africa UK Denmark Switz. Australia W. Germany

Year Introduced 1947 -

Sulfamethizole

3101

Raw Materials p-Aminobenzenesulfonamidoguanidine Sodium acetylacetonate Manufacturing Process A flask heated in an oil bath is filled with 600 ml water and 60 g (1 mol) glacial acetic acid (or an equivalent quantity of diluted acetic acid). While stirring 235 g (1.1 mols) anhydrous p-aminobenzenesulfonamidoguanidine (or an equivalent quantity of a nonanhydrous product) and 122 g (1 mol) sodium acetylacetonate 100% purity (or an equivalent quantity of product of a lower purity) are introduced into the flask while stirring. The temperature of the reaction mixture is brought to 102°C to 103°C, the mixture is further stirred at this temperature during 24 hours. The pH value of the mixture, which should range between 5 and 6 is checked during the reaction. On expiry of the reaction period heating is cut off, the mass being cooled or allowed to cool down to 60°C. Filtering under suction is effected, the solids on the filter being washed with 100 ml water at 80°C. After drying of the product on the filter 256 g of 2-paminobenzenesulfonamido-4,6-dimethylpyrimidine, melting point 196°C to 197°C, purity 99.5% are obtained. The output is 92% of the theory calculated with respect to the sodium acetylacetonate employed. References Merck Index 8786 I.N. p. 839 REM p. 1173 Sprague, J.M.; US Patent 2,407,966; September 17, 1946; assigned to Sharp and Dohme, Inc. Garzia, A.; US Patent 3,119,818; January 28, 1964; assigned to Istituto Chemioterapico Italiano SpA

SULFAMETHIZOLE Therapeutic Function: Antibacterial Chemical Name: 4-Amino-N-(5-methyl-1,3,4-thiadiazol-2-yl) benzenesulfonamide Common Name: Sulfamethylthiadiazole Chemical Abstracts Registry No.: 144-82-1

3102

Sulfamethizole

Structural Formula:

Trade Name Thiosulfil Sulfurine Ultrasul Sulfasol Renasul Famet Harnway Rufol Salimol S-Methizole Starisil Sulfa Gram Sulfametin Urobiotic Urokinon Urokizol Urolex Urosol Urosul Utrasul

Manufacturer Ayerst Table Rock Webcon Hyrex Century Calmic Nichiiko Debat Maruishi Protea Star Beach Pharmacia Roerig Chugai Chugai Ohio Medical Kanto Mohan Chicago Pharmacal

Country US US US US US Australia Japan France Japan Australia Finland US Sweden US Japan Japan US Japan Japan US

Year Introduced 1953 1963 1963 1963 1966 -

Raw Materials Acetaldehyde thiosemicarbazone p-Acetaminobenzolsulfonyl chloride Calcium ferricyanide Manufacturing Process To 10 grams acetaldehyde-thiosemicarbazone in 80 grams pyridine gradually 20 grams p-acetaminobenzolsulfonyl chloride is added. The reaction mixture is heated about 1 hour on a water bath and is then charged in 1 liter water, to which some acetic acid is added. The bottom sediment is sucked off and washed with water, after which it is crystallized by alcohol. 20 grams of the condensation product thus obtained is cleared in 100 cc water at about 30°C, after which 45 grams calcium ferricyanide dissolved in about 100 cc water is added. The reaction mixture is made slightly alkaline and held at a temperature of about 80°C for 2 to 3 hours. It is important that the reaction

Sulfamethoxazole

3103

mixture during the whole period of 2 to 3 hours is steadily held alkaline. After the said 2 to 3 hours the liquid is cooled and the bottom sediment, which has a greenish color, is filtered off. The liquid sucked off eventually is treated with active carbon, filtered and made slightly acid by means of acetic acid, at which 2-amino-benzolsulfonamido-5-methyl-1,3,4-thiodiazol (melting point 204° to 206°C) is precipitated. References Merck Index 8787 Kleeman and Engel p. 839 PDR pp. 650, 1533 OCDS Vol. 1 p. 125 (1977) I.N. p. 901 REM p. 1174 Hubner, O.; US Patent 2,447,702; August 24, 1948; assigned to H. Lundbeck & Co., Kemisk Pharmaceutisk Laboratorium A/S, Denmark

SULFAMETHOXAZOLE Therapeutic Function: Antibacterial Chemical Name: 4-Amino-N-(5-methyl-3-isoxazolyl)benzenesulfonamide Common Name: Sulfisomezole Structural Formula:

Chemical Abstracts Registry No.: 723-46-6 Trade Name Gantanol Urobax Azo Gantanol Bactrim Comoxol Cotrim Gantaprim

Manufacturer Roche Shionogi Roche Roche Squibb Lemmon Ausonia

Country US US US US US US Italy

Year Introduced 1961 1980 -

3104

Sulfamethoxypyridazine

Trade Name Metoxal Septra Sinomin Sulfatrim Urobak

Manufacturer Farmos Burroughs-Wellcome Shionogi Schein Shionogi

Country Finland US Japan US Japan

Year Introduced -

Raw Materials Ethyl 5-methylisoxazole-3-carbamate Sodium hydroxide Acetylsulfanil chloride Manufacturing Process Preparation of 3-Amino-5-Methylisoxazole: 1.7 grams of ethyl 5methylisoxazole-3-carbamate was heated on a boiling water-bath with 5 cc of a 10% aqueous sodium hydroxide solution for 8 hours, then the reaction mixture was extracted several times with ether or benzene and the extract was cooled followed by the removal of the solvent and drying. The residue was solidified after a while and gave prismatic crystals, melting point 61° to 62°C, of 3-amino-5-methylisoxazole by recrystallization from benzene. Preparation of 3-Acetylsulfanilamido-5-Methylisoxazole: 0.9 gram of 3-amino5-methylisoxazole in 5 cc of pyridine was allowed to react with 2.0 grams of acetylsulfanil chloride accompanied by the generation of heat. After about one hour, water was added to the reaction mixture and the crystal precipitated out was recrystallized from alcohol to give 2.5 grams of 3-acetylsulfanilamido-5methylisoxazole, melting point (decomposition) 220° to 221°C. Preparation of 3-Sulfanilamido-5-Methylisoxazole: 2 grams of 3acetylsulfanilamido-5-methylisoxazole was heated with 10 cc of an aqueous sodium hydroxide solution on a water-bath for one hour and after cooling the reactant was acidified by addition of acetic acid. The precipitate thus formed was recrystallized from dilute alcohol to give 15 grams of colorless prisms of 3-sulfanilamido-5-methylisoxazole, melting point 167°C. References Merck Index 8789 Kleeman and Engel p. 840 PDR pp. 673, 763, 830, 993, 1034, 1473, 1606, 1738; DOT 7 (5) 189 (1971) I.N. p. 901 REM p. 1174 Kano, H., Nishimura, H., Nakajima, K. and Ogata, K.; US Patent 2,888,455; May 26, 1959; assigned to Shionogi & Co., Ltd., Japan

SULFAMETHOXYPYRIDAZINE Therapeutic Function: Antibacterial

Sulfamethoxypyridazine

3105

Chemical Name: 4-Amino-N-(6-methoxy-3-pyridazinyl)benzenesulfonamide Common Name: Structural Formula:

Chemical Abstracts Registry No.: 80-35-3 Trade Name Kynex Midicel Aseptilex Asey-Sulfa B-Sulfamethoxy Davosin Durasul Exazol Fercasulf Lederkyn Lentosulfa Longamid Longisul Jarabe Metazina Microcid Novosulfin Oroxin Paramid Supra Pirasulfon S.D.M. Sulfabon Sulamin Sulfadazina Sulfadepot Sulfadin Sulfaintensa Sulfalex Sulfamizina Sulfamyd Sulfapyrazin Sulfatar Sulfocidan Sulforetent Sulfo-Rit

Manufacturer Lederle Parke Davis Wassermann Quimia Biokema Parke Davis Estedi Andreu Arco Lederle I.S.F. A.L. Landerlan Piam Borromeo Galenika Otsuka Kwizda Neo Barlow Cote Biokema Pliva Guidi Almirall C.I.F. Robert De Angeli Wells Libra Bosnalijek Arnaldi Cidan Cifa Aristochimica

Country US US Spain Spain Switz. W. Germany Spain Spain Switz. UK Italy Norway Spain Italy Italy Yugoslavia Japan Austria Canada Canada Switz. Yugoslavia Italy Spain Italy Spain Italy Italy Italy Yugoslavia Italy Spain Italy Italy

Year Introduced 1957 1957 -

3106

Sulfamoxole

Trade Name Sultirene Unisulfa

Manufacturer Specia Angelini

Country France Italy

Year Introduced -

Raw Materials 3-Sulfanilamido-6-chloropyridazine Sodium Methanol Manufacturing Process The following description is taken from US Patent 2,712,012: 2.3 parts of clean sodium metal is dissolved in 50 parts of anhydrous methyl alcohol. 11.4 parts of 3-sulfanilamido-6-chloropyridazine is added and the mixture heated in a sealed tube 13 hours at 130° to 140°C. After the tube has cooled it is opened and the reaction mixture filtered, acidified with dilute acetic acid, then evaporated to dryness on the steam bath. The residue is dissolved in 80 parts of 5% sodium hydroxide, chilled and acidified with dilute acetic acid. The crude product is filtered and then recrystallized from water to give 3sulfanilamido-6-methoxypyridazine of melting point 182° to 183°C. References Merck Index 8790 Kleeman and Engel p. 842 OCDS Vol. 1 pp. 124, 131 (1977) I.N. p. 902 Clark, J.H.; US Patent 2,712,012; June 28, 1956; assigned to American Cyanamid Co. Murphy, D.M. and Shepherd, R.G.; US Patent 2,833,761; May 6, 1958; assigned to American Cyanamid Co.

SULFAMOXOLE Therapeutic Function: Antibacterial Chemical Name: 4-Amino-N-(4,5-dimethyl-2-oxazolyl)benzenesulfonamide Common Name: Sulfadimethyloxazole Structural Formula:

Chemical Abstracts Registry No.: 729-99-7

Sulfamoxole Trade Name Sulfuno Justamil Justamil Naprin Oxasulfa Tardamide

Manufacturer Nordmark Anphar-Rolland Anphar-Rolland Upjohn Trinum Gruenenthal

Country W. Germany France Italy US Italy W. Germany

3107

Year Introduced 1960 1961 1964 -

Raw Materials 2-Amino-4,5-dimethyloxazole p-Acetaminobenzenesulfonyl chloride Hydrogen chloride Manufacturing Process 11.2 g of 2-amino-4,5-dimethyloxazole (0.1 mol), 46.8 g of anhydrous pacetaminobenzenesulfonyl chloride (0.2 mol) and 60 cc of methylene chloride are mixed and then treated while stirring and with exclusion of water with 12.0 g (0.2 mol) of anhydrous trimethylamine, dissolved in 60 cc of benzene. After adding the trimethylamine, the mixture is heated for 30 minutes to 40°C, left to stand for 12 hours and then the solvent is distilled off. The distillation residue is heated with 300 cc of water until the residual organic solvents are driven off. The residue is filtered and thoroughly washed with water. Yield of condensation product: 46.4 g. The mass is triturated with 80 cc of cold 2.5% caustic soda solution, filtered and thoroughly washed with water. The residue which is insoluble in caustic soda solution consists of bis-(pacetaminobenzenesulfonyl)-2-amino-4,5-dimethyloxazole. It melts indefinitely between 201°C and 206°C with decomposition (browning). Yield: 42.3 g corresponding to 83.6%. The 42.3 g of the bis-compound are heated under reflux in 210 cc of 96% ethanol containing 10% of hydrogen chloride, to the boiling point of the alcohol. After dissolution, the substance is boiled for 20 minutes under reflux. It is cooled, filtered and washed with alcohol. By concentrating the mother liquor and the washing liquid by evaporation, further amounts of substance are obtained. The total amount of the hydrochloride obtained is stirred with 50 cc of water and the mixture is mixed with 15 cc of 45% caustic soda solution. After complete dissolution, the mixture is treated with decolorizing carbon and the filtrate is brought to a pH value of 5.5 by means of hydrochloric acid. 17.6 g of p-aminobenzenesulfonyl-2-amino-4,5-dimethyloxazole are obtained as colorless crystals with a melting point of 193°C to 194°C (corrected), corresponding to a yield of 65.9% calculated on the basis of the 2-amino-4,5dimethyloxazole used. References Merck Index 8797 Kleeman and Engel p. 843 OCDS Vol. 1 p. 124 (1977) DOT 12 (9) 377 (1976)

3108

Sulfaphenazole

I.N. p. 903 Loop, W., Luhrs, E. and Hauschildt, P.; US Patent 2,809,966; October 15, 1957; assigned to Nordmark-Werke G.m.b.H. (Germany)

SULFAPHENAZOLE Therapeutic Function: Antibacterial Chemical Name: 4-Amino-N-(1-phenyl-1H-pyrazol-5-yl)benzenesulfonamide Common Name: Structural Formula:

Chemical Abstracts Registry No.: 526-08-9 Trade Name Sulfabid Fenazolo Merian Microsulf Orisul Orisulf Plisulfan Sulfapadil Sulfazol Sulfenal Sulforal Sulfostat Sulphena

Manufacturer Purdue Frederick S.A.M. Dainippon Novafarnova Ciba Ciba Pliva Padil Barlocco Kanto Farber-R.E.F. Bieffe Nisshin

Country US Italy Japan Italy W. Germany UK Yugoslavia Italy Italy Japan Italy Italy Japan

Year Introduced 1962 -

Raw Materials 3-Amino-2-phenylpyrazole Sodium hydroxide p-Carbethoxyamino-benzenesulfonyl chloride Manufacturing Process Into a solution of 15.9 grams of 3-amino-2-phenyl-pyrazole in 60 cc of anhydrous pyridine, 29 grams of p-carbethoxyamino-benzenesulfonyl chloride are introduced within about 25 minutes. When the reaction subsides, heating

Sulfasalazine

3109

is carried out for a further hour to 90° to 95°C internal temperature. The reaction solution is then poured into 300 cc of 2 N hydrochloric acid. The precipitate is filtered with suction and recrystallized from dilute alcohol. The 3(p-carbethoxyaminobenzene sulfonamido)-2-phenyl-pyrazole is obtained thus in white crystals of MP 175° to 176°C. These are taken up in 250 cc of 2 N caustic soda solution and heated for 1 hour on a boiling water bath. With hydrochloric acid, the pH is then adjusted to 6 to 7 and the precipitate is filtered with suction and crystallized from 75% ethyl alcohol. The resulting 3-(p-aminobenzenesulfonamido)-2-phenyl-pyrazole crystallizes in white crystals and has a melting point of 177° to 178°C. References Merck Index 8810 Kleeman and Engel p. 844 OCDS Vol. 1 p. 124 (1977) I.N. p. 904 Druey, J. and Schmidt, P.; US Patent 2,858,309; October 28, 1958: assigned to Ciba Pharmaceutical Products Inc.

SULFASALAZINE Therapeutic Function: Antibacterial Chemical Name: 2-Hydroxy-5-[[4-[(2-pyridinylamino)sulfonyl]phenyl]azo]benzoic acid Common Name: Salicylazosulfapyridine; Salazosulfapyridine Structural Formula: Chemical Abstracts Registry No.: 599-79-1

3110

Sulfathiazole

Trade Name Azulfidine Salazopyrine Salazopyrin Salazopyrin S.A.S-500 Sulcolon Rorasul Colo-Pleon Salisulf

Manufacturer Pharmacia Pharmacia Pharmacia Green Cross Rowell Lederle Rorer Henning Giuliani

Country US France UK Japan US US US W. Germany Italy

Year Introduced 1952 1958 1968 1969 1972 1974 1975 -

Raw Materials α-(p-Aminobenzenesulfonamido)pyridine Sodium nitrite Hydrogen chloride Salicylic acid Manufacturing Process 50 g of α-(p-aminobenzenesulfonylamido)pyridine are dissolved in a mixture of 50 cc of concentrated hydrochloric acid and 25 cc of water and diazotized with a solution of 13.8 g sodium nitrite. In the meantime 28 g of salicylic acid, 24 g of potassium hydroxide and 12 g of sodium carbonate are dissolved in water. The diazo suspension is added in portions to the alkaline solution of salicylic acid and the alkalinity maintained at a sufficiently high level during the whole reaction by means of addition of further quantities of potassium hydroxide solution. After 2 days the reaction mixture is heated for ½ hour at 50°C. After cooling the azo compound formed is precipitated by means of hydrochloric acid and filtered off. References Merck Index 8818 Kleeman and Engel p. 812 PDR pp. 830, 993, 1426, 1606 OCDS Vol. 2 p. 114 (1980) I.N. p. 860 REM p. 1175 Askelof, E.E.A., Svartz, N. and Willstaedt, H.C.; US Patent 2,396,145; March 5, 1946; assigned to A.B. Pharmacia (Sweden)

SULFATHIAZOLE Therapeutic Function: Antibacterial Chemical Name: Benzenesulfonamide, 4-amino-N-2-thiazolylCommon Name: Norsulfazol(um); Solfatiazolo; Sulfamida-Tiazol;

Sulfinpyrazole

3111

Sulfanilamidothiazole; Sulfathiazole; Sulfatiazole; Sulfonazolum; Sulfothiazole; Sulphathiazole; Tiazin; Thiazylsulfonamide Structural Formula:

Chemical Abstracts Registry No.: 72-14-0 Trade Name Tiazol Sulfathiazole Sulfathiazole Sulfathiazole

Manufacturer C. and C. Carolina Animal Chemicals Co. Ofichem B.V. Shanghai Sunve Pharmaceutical Corporation

Country -

Year Introduced -

Raw Materials 4-Acetamidobenzolsufonyl chloride 2-Aminothiasole Manufacturing Process 116 parts 4-acetamidobenzolsufonyl chloride (prepared from acetanilide and chlorosulfonic acid) was mixed with 100 parts 2-aminothiasole in 1000 parts water by cooling and stirred for some hours. The bis-amide obtained was filtered off and re-crystallized from 50% ethanol to give bis-(pacetylaminobenzolsulfo)-2-aminothiazol with MP: 129°C. 10 parts above bis-amide was heated with 10% sodium hydroxide solution for 0.5 hour on water bath. On cooling and filtration the alkaline solution was acidified with glacial acetic acid. The amide obtained was cleared by recrystallized from water to give N1-2-thiazolylsulfanilamide; MP: 202°-203°C. References Hartmann M., Merz E.; D.R. Patent No. 742,753; Dec. 18, 1938; Gesellshaft fur Chemishe Industrie in Basel, Schweiz.

SULFINPYRAZONE Therapeutic Function: Antiarthritic (uricosuric) Chemical Name: 1,2-Diphenyl-4-[2-(phenylsulfinyl)ethyl]-3,5pyrazolidinedione

3112

Sulfinpyrazole

Common Name: Structural Formula:

Chemical Abstracts Registry No.: 57-96-5 Trade Name Anturane Anturan Antazone Enturen Novopyrazone Pyrocard Zynol

Manufacturer Geigy Ciga Geigy I.C.N. Geigy Novopharm Trima Horner

Country US France Canada Italy Canada Israel Canada

Year Introduced 1959 1960 -

Raw Materials Sodium Hydrazobenzene Ethanol (β-Phenylmercaptoethyl)-malonic acid diethyl ester Manufacturing Process 296 parts of (β-phenylmercapto-ethyl)-malonic acid diethyl ester and then 203 parts of hydrazobenzene are added while stirring to a warm sodium ethylate solution obtained from 23 parts of sodium and 400 parts by volume of absolute alcohol. About half the alcohol is then distilled off, after which 200 parts by volume of absolute xylene are gradually added without removing the inclined condenser. The temperature of the oil bath is kept at about 130°C for 12 hours while continuously stirring so that the alcohol still present and that which is liberated distills off but the xylene remains as solvent. After cooling, 400 parts by volume of water are stirred in. The aqueous layer is separated from the xylene, shaken out twice with 40 parts by volume of chloroform and then made acid to Congo red paper with concentrated hydrochloric acid. The oil which separates is taken up in ethyl acetate and the solution obtained is washed with water. After drying over sodium sulfate the solvent is distilled off under reduced pressure and the residue is recrystallized from alcohol. 1,2-diphenyl-3,5-dioxo-4-(β-phenylmercapto-ethyl)-pyrazolidine melts at 106° to 108°C.

Sulfisomidine

3113

References Merck Index 8828 Kleeman and Engel p. 845 PDR pp. 788, 830, 1606, 1999 OCDS Vol. 1 p. 238 (1977) DOT 15 (2) 61 (1979) I.N. p. 907 REM p. 1115 Hafliger, F.; US Patent 2,700,671; January 25, 1955; assigned to J.R. Geigy AG, Switzerland

SULFISOMIDINE Therapeutic Function: Antibacterial Chemical Name: 4-Amino-N-(2,6-dimethyl-4-pyrimidinyl)benzenesulfonamide Common Name: Sulfadimetine; Sulfaisodimidine; Sulfasomidine Structural Formula:

Chemical Abstracts Registry No.: 515-64-0 Trade Name Elkosin Elosine Aristamid Domion Entamidine Isosulf Sulfamethin

Manufacturer Ciba Ciba Geigy Nordmark Dainippon Nippon Shoji A.L. Chemiek. Bitterfeld

Raw Materials Iron p-Nitrobenzenesulfonyl chloride Hydrogen chloride 6-Amino-2,4-dimethylpyrimidine

Country US France W. Germany Japan Japan Norway E. Germany

Year Introduced 1951 1953 -

3114

Sulfisoxazole

Manufacturing Process This starting material can be prepared as follows. 123 parts of finely powdered 6-amino-2,4-dimethylpyrimidine are suspended in 250 parts of dry pyridine and 222 parts of p-nitrobenzenesulfonyl chloride added at 50°C to 55°C. The whole is then warmed for 2 hours to 55°C. Water is added to the crystalline aggregate obtained, the precipitated bis-N-(pnitrobenzenesulfonyl)-6-amino-2,4-dimethylpyrimidine filtered off by suction and washed with water. It is purified by recrystallizing from methyl ethyl ketone. On slowly heating it decomposes; on rapidly heating it melts at about 210°C to 215°C with decomposition. 49.3 parts of bis-N-(p-nitrobenzenesulfonyl)-6-amino-2,4-dimethylpyrimidine are heated to boiling for one hour with 12.3 parts of 6-amino-2,4dimethylpyrimidine in 50 parts of dry pyridine. After cooling, the 6-(pnitrobenzenesulfonamido)-2,4-dimethylpyrimidine formed is precipitated with water and filtered off by suction. It is purified by dissolving in dilute caustic soda and precipitating with acid. On recrystallization from dilute alcohol it melts (with decomposition) at 188°C to 189°C. On reaction, for example, with iron and hydrochloric acid, 6-(paminobenzenesulfonamido)-2,4-dimethylpyrimidine, melting point 236°C is obtained. References Merck Index 8831 Kleeman and Engel p. 846 I.N. p. 907 Hartmann, M., von Meyenburg, H. and Druey, J.; US Patent 2,429,184; October 14, 1947; assigned to Ciba Pharmaceutical Products, Inc.

SULFISOXAZOLE Therapeutic Function: Antibacterial Chemical Name: 4-Amino-N-(3,4-dimethyl-5-isoxazolyl)benzenesulfonamide Common Name: Sulfafurazole Structural Formula:

Sulfisoxazole

3115

Chemical Abstracts Registry No.: 127-69-5 Trade Name Gantrisin Unisulf Entusul Sosol SK-Soxazole Soxomide Sulfalar Soxo Koro-Sulf Amidoxal Azo-Gantrisin Dow-Sulfisoxazole Gansol Isoxamin Novosoxazole Pancid Pediazole Sulfagan Sulfagen Sulfapolar Sulfazin Sulfazole Sulfizole Sulfoxol Sulsoxin Thiasin TL-Azole Urazole Urogan US-67 V-Sul

Manufacturer Roche Lemmon U.S.V. Mc Kesson SKF Upjohn Parke Davis Sutcliff/Case Holland Rantos Polfa Roche Dow Abdi Ibrahim Fuso Novopharm Lister Ross Ohio Medical Verdun Farmos Shionogi Protea I.C.N. Neopharma Reid-Provident Yamanouchi Zenith Propan-Lipworth Adams Saunders Vangard

Country US US US US US US US US US Poland US US Turkey Japan Canada Italy US US Canada Finland Japan Australia Canada Finland US Japan US S. Africa Australia Canada US

Year Introduced 1949 1964 1964 1970 1971 1972 1973 1974 1978 -

Raw Materials Hydrogen chloride 3,4-Dimethyl-5-aminoisoxazole p-Acetaminobenzene sulfonic acid chloride Manufacturing Process 112 parts of 3,4-dimethyl-5-amino-isoxazole were dissolved in a mixture of 100 volume parts of pyridine and 200 volume parts of acetone. The mixture is cooled with cold water and 240 parts p-acetamino-benzene sulfonic acid chloride are added in small portions under stirring at temperatures of below 30°C. The mixture is left standing overnight at 20° to 30°C and then the 5acetamino-benzene-sulfonylamino-3,4-dimethyl-isoxazole is precipitated by

3116

Sulforidazine

the addition of water. Recrystallized from acetic acid or alcohol it forms small prisms of the melting point 210°C. 100 parts of the 5-acetamino-benzene-sulfonyl-amino-3,4-dimethyl-isoxazole are boiled under reflux with 500 volume parts 15 to 20% aqueous hydrochloric acid for 30 to 45 minutes until all is dissolved. 500 parts crystallized sodium acetate are added and the liquid left cooling for crystallization. The sulfanilamido-3,4-dimethyl-isoxazole is sucked off, washed with water and dried. In the pure state it forms white prisms with the melting point of 193°C. References Merck Index 8832 Kleeman and Engel p. 837 PDR pp. 1473, 1487, 1558, 1606, 1999 OCDS Vol. 1 p. 124 (1977) I.N. p. 900 REM p. 1175 Wuest, H.M. and Hoffer, M.; US Patent 2,430,094; November 4, 1947; assigned to Hoffmann-La Roche, Inc.

SULFORIDAZINE Therapeutic Function: Neuroleptic Chemical Name: 10H-Phenothiazine, 10-(2-(1-methyl-2-piperidyl)ethyl)-2methylsulfonylCommon Name: Solforidazine; Sulforidazine Structural Formula:

Chemical Abstracts Registry No.: 14759-06-9 Trade Name

Manufacturer

Country

Year Introduced

Sulforidazine

ZYF Pharm Chemical

-

-

Inofal

Sandoz

-

-

Sulfoxone sodium

3117

Raw Materials 2-Methylsulfonylphenothiazine Sodium methylate 2-(2-Chloroethyl)-1-methylpiperidine Manufacturing Process A mixture of 96.5 g 2-methylsulfonylphenothiazine, 50 g 2-(2-chloroethyl)-1methylpiperidine, 62 g diethyl carbonate and 2 g sodium methylate was heated at 135°C for 1 hour and then at 180-190°C for 2.5 hours. The product was dissolved in benzene (500 ml) and the solution was extracted with 700 ml of 15% aqueous solution tartaric acid. The extract was washed with benzene. After addition of sodium carbonate solution to the extract was obtained a precipitate which was dissolved in benzene. This solution was washed with water and concentrated. 2-Methylsulfonyl-10-(2-(1-methyl-2piperidyl)ethyl)phenothiazin was recrystallized from acetone, melting point 121-123°C. References Renz J., Bourquin J.-P., Winkler H., Gagnaux P., Ruesch P., Achwarb G.; FR Patent No. 1,459,476; Nov. 30, 1965; Assigned to SANDOZ S.A.

SULFOXONE SODIUM Therapeutic Function: Antibacterial (leprostatic) Chemical Name: Disodium [sulfonylbis(p-phenylenimino)]dimethanesulfinate Common Name: Aldesulfone sodium Structural Formula:

Chemical Abstracts Registry No.: 144-75-2 Trade Name

Manufacturer

Country

Year Introduced

Diasone Sodium

Abbott

US

1947

3118

Sulindac

Raw Materials Diaminodiphenyl sulfone Sodium formaldehyde sulfoxylate Manufacturing Process About 20 grams of diamino diphenyl sulfone is dissolved in about 500 cc of ethyl alcohol (3A made up of 5 parts methyl alcohol and 100 parts of ethyl alcohol) by placing the ingredients in a flask provided with a reflux condenser and warming over a water bath. About 24 grams of pure grade, very finely powdered (40 to 60 mesh) sodium formaldehyde sulfoxylate is then rapidly added to the alcohol solution of diamino diphenyl sulfone and the mixture refluxed in the usual manner. It was found that the mixture should be refluxed for a total of 5 hours and that a precipitate starts to form near the 3 hour period. The reaction mixture is then cooled to 15°C and kept at this temperature for about 1 hour. The precipitate formed in the filtrate is filtered off rapidly and drained as much as possible to remove mother liquor and then washed with small amounts of cold alcohol. The solid product is immediately placed in a desiccator and dried over sulfuric acid for about 20 hours. References Merck Index 8848 Kleeman and Engel p. 847 OCDS Vol. 1 p. 140 (1977) I.N. p. 51 REM p. 1217 Rosenthal, S.M. and Bauer, H.; US Patent 2,234,981; March 18, 1941; assigned to the US Secretary of the Treasury Raiziss, G.W., Clemence, L.R.W. and Freifelder, M.; US Patent 2,256,575; September 23, 1941; assigned to Abbott Laboratories

SULINDAC Therapeutic Function: Antiinflammatory Chemical Name: (Z)-5-Fluoro-2-methyl-1-[[4-(methylsulfinyl)phenyl] methylene]-1H-indene-3-acetic acid Common Name: Chemical Abstracts Registry No.: 38194-50-2 Raw Materials Hydrogen Sodium periodate Propionic anhydride Cyanacetic acid

p-Fluorobenzaldehyde p-Methylthiobenzaldehyde Polyphosphoric acid

Sulindac

3119

Structural Formula:

Trade Name Imbaral Clinoril Arthrocine Clinoril Clinoril Clinoril Clinoril Aflodac Algocetil Citireuma Lyndak Mobilin Reumofil Sudac Sulene Sulic Sulinol

Manufacturer Sharp and Dohme MSD Chibret MSD MSD Banyu Kyorin Benvegna Francia C.T. Tiber Teva Ausonia Errekappa Scalari Crosara Farnex

Country W. Germany Italy France UK US Japan Japan Italy Italy Italy Italy Israel Italy Italy Italy Italy Italy

Year Introduced 1976 1976 1977 1977 1978 1982 1982 1982 -

Manufacturing Process The following process sequence is described in US Patent 3,654,349: p-Fluoro-α-Methylcinnamic Acid: 200 grams (1.61 mols) pfluorobenzaldehyde, 3.5 grams (2.42 mols) propionic anhydride and 155 grams (1.61 mols) sodium propionate are mixed in a 1 liter three-necked flask which had been flushed with nitrogen. The flask is heated gradually in an oilbath to 140°C. After 20 hours the flask is cooled to 100°C and the contents are poured into 8 liters of water. The precipitate is dissolved by adding 302 grams potassium hydroxide in 2 liters of water. The aqueous solution is extracted with ether, and the ether extracts washed with potassium hydroxide solution. The combined aqueous layers are filtered, acidified with concentrated HCl, filtered and the collected solid washed with water, thereby producing pfluoro-α-methylcinnamic acid which is used as obtained.

3120

Sulindac

p-Fluoro-α-Methylhydrocinnamic Acid: To 177.9 grams (0.987 mol) p-fluoro-αmethylcinnamic acid in 3.6 liters ethanol is added 11.0 grams of 5% Pd/C and the mixture reduced at room temperature under a hydrogen pressure of 40 psi. Uptake is 31/32 pounds (97% of theoretical). After filtering the catalyst, the filtrate is concentrated in vacuo to give the product p-fluoro-αmethylhydrocinnamic acid used without weighing in next step. 6-Fluoro-2-Methylindanone: To 932 grams polyphosphoric acid at 70°C on the steam bath is added 93.2 grams (0.5 mol) p-fluoro-α-methylhydrocinnamic acid slowly with stirring. This temperature is gradually raised to 95°C and the mixture kept at this temperature for 1 hour. The mixture is allowed to cool and added to 2 liters of water. The aqueous layer is extracted with ether, the ether solution washed twice with saturated sodium chloride solution, 5% Na2CO3 solution, water, and then dried. The ether filtrate is concentrated with 200 grams silica-gel, and added to a five pound silica-gel column packed with 5% ether-petroleum ether. The column is eluted with 5 to 10% etherpetroleum ether and followed by TLC to give 6-fluoro-2-methylindanone. 5-Fluoro-2-Methylindene-3-Acetic Acid: A mixture of 18.4 grams (0.112 mol) of 6-fluoro2-methylindanone, 10.5 grams (0.123 mol) cyanacetic acid, 6.6 grams acetic acid and 1.7 grams ammonium acetate in 15.5 ml dry toluene is refluxed with stirring for 21 hours, as the liberated water is collected in a Dean Stark trap. The toluene is concentrated and the residue dissolved in 60 ml of hot ethanol and 14 ml of 2.2 N aqueous potassium hydroxide solution. 22 grams of 85% KOH in 150 ml of water is added and the mixture refluxed for 13 hours under N2. The ethanol is removed under vacuum, 500 ml water added, the aqueous solution washed well with ether and then boiled with charcoal. The aqueous filtrate is acidified to pH 2 with 50% hydrochloric acid, cooled and the precipitate collected in this way dried 5-fluoro-2-methylindenyl-3-acetic acid (MP 164° to 166°C) is obtained. 5-Fluoro-2-Methyl-1-(p-Methylthiobenzylidene)-3-Indenylacetic Acid: 15 grams (0.072 mol) 5-fluoro-2-methyl-3-indenylacetic acid, 14.0 grams (0.091 mol) p-methylthiobenzaldehyde and 13.0 grams (0.24 mol) sodium methoxide are heated in 200 ml methanol at 60°C under nitrogen with stirring for 6 hours. After cooling the reaction mixture is poured into 750 milliliters of ice-water, acidified with 2.5 N hydrochloric acid and the collected solid triturated with a little ether to produce 5-fluoro-2-methyl-1-(p-methylthiobenzylidene)-3indenylacetic acid (MP 187° to 188.2°C). 5-Fluoro-2-Methyl-1-(p-Methylsulfinylbenzylidene)-3-Indenylacetic Acid: To a solution of 3.4 grams (0.01 mol) 5-fluoro-2-methyl-1-(pmethylthiobenzylidene)-3-indenylacetic acid in a 250 ml mixture of methanol and 100 ml acetone is added a solution of 3.8 grams (0.018 mol) of sodium periodate in 50 ml water with stirring. 450 ml water is added after 18 hours and the organic solvents removed under vacuum below 30°C. The precipitated product is filtered, dried and recrystallized from ethyl acetate to give 5-fluoro-2-methyl-1-(pmethylsulfinylbenzylidene)-3-indenylacetic acid. Upon repeated recrystallization from ethylacetate there is obtained cis-5-fluoro-2-methyl-1(p-methylsulfinylbenzylidene)-3-indenylacetic acid (MP 184° to 186°C).

Sulisobenzone

3121

References Merck Index 8863 Kleeman and Engel p. 847 PDR p. 1147 OCDS Vol. 2 p. 210 (1980) DOT 12 (2) 496 (1976) I.N. p. 909 REM p. 1120 Hinkley, D.F. and Conn, J.B.; US Patent 3,647,858; March 7, 1972; assigned to Merck & Co., Inc. Shen, T.-Y., Greenwald, R.B., Jones, H., Linn, B.O. and Witzel, B.E.; US Patent 3,654,349; April 4, 1972; assigned to Merck and Co., Inc.

SULISOBENZONE Therapeutic Function: Sunscreen agent Chemical Name: 5-Benzoyl-4-hydroxy-2-methoxybenzenesulfonic acid Common Name: Structural Formula:

Chemical Abstracts Registry No.: 4065-45-6 Trade Name Uval Cyasorb Spectra-Sorb Sungard Uvinul

Manufacturer Dome Cyanamid Cyanamid Miles G.A.F.

Country US US US US US

Year Introduced 1965 -

Raw Materials 2-Hydroxy-4-methoxybenzophenone Chlorosulfonic acid Manufacturing Process 663 g of dichloroethane and 74.6 g 2-hydroxy-4-methoxybenzophenone were

3122

Suloctidil

charged into a 3-neck flask equipped with stirrer, thermometer, reflux condenser and dropping funnel and a heating mantle. The solution was heated to the reflux temperature (85°C to 86°C) and was dehydrated by distilling off 66.5 g 1,2-dichloroethane. While maintaining at reflux, 30 g chlorosulfonic acid was added slowly over a period of about two hours. The rate of addition was regulated by the speed of evolution of the HCl. After all the chlorosulfonic acid was added, the charge was still maintained at reflux for an additional 15 minutes to remove traces of HCl. It was then cooled to 5°C and filtered. The filter cake was washed with 500 g cold 1,2-dichloroethane and dried. 98 g of product were obtained. References Merck Index 8865 I.N. p. 909 Cofrancesco, A.J.; British Patent 1,136,525; December 11, 1968; assigned to General Aniline & Film Corp.

SULOCTIDIL Therapeutic Function: Spasmolytic, Vasodilator Chemical Name: 1-(4-Isopropylthiophenyl)-2-n-octylaminopropanol Common Name: Structural Formula:

Chemical Abstracts Registry No.: 54063-56-8 Trade Name Sulocton Flavisco Locton Fluversin Bemperil Cerebro Circleton Dulasi Duloctil Euvasal Ibisul

Manufacturer Cooper Searle Lepetit Searle Sidus Sidus I.B.I. Durron Searle Selvi I.B.I.

Country Switz. France Italy W. Germany Argentina Italy Italy Italy UK Italy Italy

Year Introduced 1978 1980 1980 1980 -

Sulpiride Trade Name Locton Polivasal Sudil Sulc Sulodene Suloktil Sutidil Tamid

Manufacturer Lepetit Coli Errekappa Tosi Alfa Farm. Yurtoglu Krka Serpero

Country Italy Italy Italy Italy Italy Turkey Yugoslavia Italy

3123

Year Introduced -

Raw Materials α-Bromo-4-isopropylthiopropiophenone n-Octylamine Sodium borohydride Manufacturing Process (a) To 28.7 g of α-bromo-4-isopropylthiopropiophenone (0.1 mol) in 100 ml of isopropanol there are rapidly added 14.2 g of n-octylamine while stirring, and then the mixture is brought to 80°C for 1 hour. The solvent is evaporated under vacuum, the residue is diluted with 1 liter of ether and is left to stand overnight in the refrigerator. The precipitate obtained is filtered and dried. There are thus obtained 25 g of α-n-octylamino-4-isopropylthiopropiophenone hydrobromide. Yield: 60%; melting point: 162°C to 164°C. (b) 41.6 g of the preceding product (0.1 mol) in 200 ml of methanol are cooled in an ice bath to 0°C. There is added drop by drop while stirring a solution of 4.1 g of NaBH4 in 50 ml of water and 2 ml of 5% NaOH. Next, the mixture is stirred for 2 hours at room temperature. The methanol is evaporated under vacuum, diluted with 200 ml of water and extracted with methylene chloride or ether. The organic phase is dried on MgSO4 and the solvent is evaporated under vacuum. The oily residue obtained solidifies rapidly and is recrystallized in pentane. 33.2 g are thus obtained. Yield: 90%; melting point: 62°C to 63°C. References Merck Index 8870 Kleeman and Engel p. 849 OCDS Vol. 3 p. 26 (1984) DOT 13 (3) 107 (1977) I.N. p. 910 Lambelin, G.E., Gillet, C.L. and Roba, J.L.; US Patent 4,228,187; October 14, 1980; assigned to Continental Pharma

SULPIRIDE Therapeutic Function: Tranquilizer, Digestive aid

3124

Sulpiride

Chemical Name: 5-(Aminosulfonyl)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2methoxybenzamide Common Name: Structural Formula:

Chemical Abstracts Registry No.: 15676-16-1 Trade Name Dogmatil Dogmatil Dogmatil Dogmatil Dogmatil Dogmatil Abilit Betamac Chamionil Coolspan Digton Dobren Eglonyl Equilid Eusulpid Guastil Isnamide Kapiride Lavodina Lusedan Meresa Miradol Misulvan Modal Neogama Neuromyfar Normum Omperan Paratil Psicosen

Manufacturer Delagrange Schurholz Delagrange Delagrange Fujisawa Squibb Sumitomo Sawai Vita Hishiyama Areu Ravizza Alkaloid Lepetit C.T. Uriach Isardi Kappa Turro Bryan Dolorgiet Mitsui Bernabo Rafa Hormosan Emyfar Serpero Taiho Medica Centrum

Country France W. Germany Italy Switz. Japan UK Japan Japan Italy Japan Spain Italy Yugoslavia Italy Italy Spain Italy Spain Spain Spain W. Germany Japan Argentina Israel W. Germany Spain Italy Japan Finland Spain

Year Introduced 1969 1972 1972 1972 1973 1983 -

Sulprostone Trade Name Pyrikappl Quiridil Sato Seeglu Sicofrenol Sulpiril Sulpisidan Suprium Sursumid Tepavil Tonofit Trilan Ulpir Vipral

Manufacturer Isei Zoja Scharper Teikoku Basileos Leiras Llano Orion Sarm Prodes Europa Esseti Lesvi Roemmers

Country Japan Italy Italy Japan Spain Finland Spain Finland Italy Spain Spain Italy Spain Argentina

3125

Year Introduced -

Raw Materials 1-Ethyl-2-aminomethylpyrrolidine 2-Methoxy-5-sulfamylbenzoic acid Manufacturing Process 1-Ethyl-2-aminomethylpyrrolidine is reacted with 2-methoxy-5sulfamoylbenzoic acid to give sulpiride. References Merck Index 8875 Kleeman and Engel p. 849 OCDS Vol. 2 p. 94 (1980) DOT 9 (6) 244 (1973) I.N. p. 911 Miller, C.S., Engelhardt, E.L. and Thominet, M.L.; US Patent 3,342,826; Sept. 19, 1967; assigned to Societe d'Etudes Scientifiques et Industrielles de L'lle-de-France, France

SULPROSTONE Therapeutic Function: Contraceptive Chemical Name: N-Methanesulfonyl-9-oxo-11α,15α-dihydroxy-5-cis-13trans-16-phenoxy-α-tetranorprostadienamide Common Name: Chemical Abstracts Registry No.: 60325-46-4

3126

Sulprostone

Structural Formula:

Trade Name Nalador Nalador

Manufacturer Schering Schering

Country W. Germany Switz.

Year Introduced 1981 1983

Raw Materials Chromic anhydride (4-Carbohydroxy-n-butyl)triphenylphosphonium bromide Acetic acid Methanesulfonyl isocyanate Sodium methylsulfinylmethide 2-[5α-Hydroxy-3α(tetrahydropyran-2-yloxy)-2β-(3α-tetrahydropyran-2yloxy-4phenoxy-trans-1-buten-1-yl)cyclopent-1α-yl]-acetaldehyde α-hemiacetal Manufacturing Process 9α-Hydroxy-11α,15α-bis-(tetrahydropyran-2-yloxy)-16-phenoxy-cis-5-trans13-ω-tetranorprostadienoicacid: To a solution of 1.6 g (3.6 mmols) (4carbohydroxy-n-butyl)triphenylphosphonium bromide in a dry nitrogen atmosphere in 6.0 ml dry dimethyl sulfoxide was added 3.24 ml (6.5 mmols) of a 2.0 M solution of sodium methylsulfinylmethide in dimethyl sulfoxide. To this red ylide solution was added dropwise a solution of 613 mg (1.29 mmols) 2-[5α-hydroxy-3α-(tetrahydropyran-2-yloxy)-2α-(3α-tetrahydropyran-2-yloxy4-phenoxytrans-1-buten-1-yl)cyclopent-1α-yl] acetaldehyde, γ-hemiacetal in 5.0 ml dry dimethyl sulfoxide over a period of 20 minutes. After an additional 2 hours stirring at room temperature, the reaction mixture was poured onto ice water. The basic aqueous solution was washed twice with ethyl acetate (20 ml) and acidified to pH 3 with 10% aqueous hydrochloric acid. The acidic solution was extracted with ethyl acetate (3 x 20 ml) and the combined organic extracts washed once with water (10 ml), dried (MgSO4) and evaporated to a solid residue. This solid residue was triturated with ethyl acetate and the filtrate concentrated. Yield: 754 mg of 9α-hydroxy-11α,15α-

Sultopride hydrochloride

3127

bis-(tetrahydropyran-2-yloxy)-16-phenoxy-cis-5-trans-13ωtetranorprostadienoic acid was collected. 9-Oxo-11α,15α-bis-(tetrahydropyran-2-yloxy)-16-phenoxy-cis-5-trans-13-ωtetranorprostadienoicacid: To a solution cooled to -10°C under nitrogen of 754 mg (1.3 mmols) 9α-hydroxy-11α,15α-bis-(tetrahydropyran-2-yloxy)-16phenoxy-cis-5-trans-13-ω-tetranorprostadienoic acid in 13 ml reagent grade acetone was added dropwise to 0.56 ml (1.41 mmols) of Jones' reagent (chromic anhydride). After 20 minutes at -10°C, 0.260 ml 2-propanol was added and the reaction mixture was allowed to stir an additional 5 minutes at which time it was combined with 75 ml ethyl acetate, washed with water (3 x 10 ml), dried (MgSO4)and concentrated to give 752 mg of 9-oxo-11α,15α-bis(tetrahydropyran-2-yloxy)-16-phenoxy-cis-5-trans-13-ω-tetranorprostadienoic acid, which was chromatographed on silica gel using ethyl acetate as eluent to afford 505 mg of pure intermediate. N-Methanesulfonyl-9-oxo-11α,15α-dihydroxy-5-cis-13-trans-16-phenoxy-ωtetranorprostadienamide:To 1.0 mmols of 9-oxo-11α,15α-bis(tetrahydropyran-2-yloxy)-16-phenoxy-cis-5-trans-13-ω-tetranorprostadienoic acid in 40 ml THF is added 2 ml triethylamine. After 15 minutes of stirring at room temperature 10.0 ml of 0.1 M methanesulfonylisocyanate in THF is added. After a further 1 hour of stirring, the reaction mixture is neutralized with acetic acid and the solvent removed by evaporation (in vacuo). The resultant residue is taken up in methylene chlorine and washed successively with water and sodium bicarbonate to yield, after drying and solvent evaporation, N-methanesulfonyl-9-oxo-11α,15α-bis-(tetrahydropyran-2-yloxy)16-phenoxy-cis-5-trans-13-ω-tetranorprostadienamide. This intermediate is then hydrolyzed overnight with acetic acid/water and purified by column chromatography to give the desired N-methanesulfonyl-9-oxo-11α,15αdihydroxy-5-cis-13-trans-16-phenoxy-ω-tetranorprostadienamide. References Merck Index 8877 DFU 3 (1) 59 (1978) OCDS Vol. 3 p. 9 (1984) DOT 18 (7) 331 (1982) I.N. p. 911 Bindra, J.S. and Johnson, M.R.; US Patents 4,024,179; May 17, 1977; and 4,244,887; January 13, 1981; both assigned to Pfizer, Inc.

SULTOPRIDE HYDROCHLORIDE Therapeutic Function: Neuroleptic Chemical Name: N-(1-Ethyl-2-pyrrolidylmethyl)-2-methoxy-5ethylsulfonylbenzamide hydrochloride Common Name: -

3128

Sultopride hydrochloride

Structural Formula:

Chemical Abstracts Registry No.: 53583-79-2 (Base) Trade Name Barnetil Barnotil Topral

Manufacturer Delagrange Vita Alkaloid

Country France Italy Yugoslavia

Year Introduced 1976 1983 -

Raw Materials Phosphorus trichloride N-Ethyl-α-aminomethylpyrrolidine 2-Methoxy-5-ethylsulfonylbenzoic acid Manufacturing Process A solution of 17.22 g of N-ethyl-α-aminomethylpyrrolidine in 360 ml of pyridine is placed in a 1 l balloon flask. A solution of 3.51 g of phosphorus trichloride in 40 ml of pyridine is added at ambient temperature. After the mixture has been stirred for 1 hour, 10 g of 2-methoxy-5-ethylsulfonylbenzoic acid is introduced. The mixture is heated under reflux for 4 ½ hours. After cooling, the solvent is evaporated under vacuum and the residue is dissolved in 200 ml of 20% sodium hydroxide. The solution is extracted with 200 ml of chloroform. The organic solution is dried and filtered and the solvent is evaporated under vacuum; the residue is dissolved in 150 ml of ethanol and the solution is acidified with hydrochloric acid. The hydrochloride is dried without heating and recrystallized from 100 ml of absolute ethanol. 7.2 g of N-(1-ethyl-2pyrrolidyl-methyl-2-methoxy-5-ethylsulfonylbenzamide hydrochloride is produced. Melting point: 190°C to 193°C. References Merck Index 8879 DFU 1 (2) 83 (1976) Kleeman and Engel p. 851 DOT 13 (4) 154 (1977) I.N. p. 911 Societe D'Etudes Scientifiques et Industrielles de L'lle-de-France; British Patent 1,394,559; May 21, 1975

Sultroponium

3129

SULTOSILIC ACID PIPERAZINE SALT Therapeutic Function: Antihyperlipidemic Chemical Name: 2-Hydroxy-5-[[(4-methylphenyl)sulfonyl]oxy] benzenesulfonic acid, piperazine salt Common Name: Structural Formula:

Chemical Abstracts Registry No.: 57775-27-6; 57775-26-5 (Free acid) Trade Name Mimedran

Manufacturer Esteve

Country Spain

Year Introduced 1982

Raw Materials 2,5-Dihydroxybenzenesulfonic acid Pyridine Tosyl chloride Piperazine Manufacturing Process The monotosylation of 2,5-dihydroxybenzenesulfonic acid is carried out in a pyridine medium by treating it with tosyl chloride, thus preferably isolating the 2-hydroxy-5-tosyloxybenzenesulfonic acid, pyridine salt. This product subjected to reflux with an alcoholic solution of piperazine yields 2-hydroxy-5tosyloxybenzenesulfonic acid, piperazine salt. References DFU 6 (11) 688 (1981) Esteve-Subirana, A.; US Patent 3,954,767; May 4, 1976

SULTROPONIUM Therapeutic Function: Spasmolytic

3130

Sumatriptan succinate

Chemical Name: Endo(+/-)-3-(3-hydroxy-1-oxo-2-phenylpropoxy)-8-methyl8-(3-sulfopropyl)-8-azoniabicyclo[3.2.1]octane hydroxide, inner salt Common Name: Structural Formula:

Chemical Abstracts Registry No.: 15130-91-3 Trade Name Sultroponium-B

Manufacturer Biotherax

Country France

Year Introduced 1970

Raw Materials Atropine Propane-1,3-sultone Manufacturing Process To a cold solution of 29 g of atropine in 250 ml of acetone a solution of 13 g of propane-1,3-sultone in 100 ml of acetone is generally added. The combined solution is left for 48 hours. The white precipitate of fine crystalline needles is separated, washed several times with acetone, and then recrystallized from ethanol. It melts at 220°C. References Merck Index 8880 Kleeman and Engel p. 851 DOT 6 (3) 97 (1970) I.N. p. 912 Raudnitz, J.P.M. and Wahl, H.; British Patent 1,082,445; September 6, 1967

SUMATRIPTAN SUCCINATE Therapeutic Function: Serotoninergic Chemical Name: 1H-Indole, 3-(2-(dimethylamino)ethyl)-N-methyl-5methanesulfonamide, butanedioic acid salt (1:1) Common Name: Sumatriptan succinate

Sumatriptan succinate

3131

Structural Formula:

Chemical Abstracts Registry No.: 103628-48-4; 103628-46-2 (Base) Trade Name Imigran Imitrex Sumatriptan Succinate Suminat

Manufacturer GlaxoSmithKline Glaxo Wellcome Chemo Iberica Sun Pharmaceuticals Industries Ltd.

Country UK UK Spain India

Year Introduced -

Raw Materials Hydrogen chloride (Phenylthio)acetaldehyde Nickel Raney Sodium borohydride Dimethylamine Succinic acid 4-Hydrazino-N-methylbenzenemethanesulphonamide hydrochloride Manufacturing Process A solution of (phenylthio)acetaldehyde (6.05 g) in absolute ethanol (180 ml) was added over 10 min to a solution of 4-hydrazino-Nmethylbenzenemethanesulphonamide hydrochloride (10 g) in water (180 ml) with cooling. After addition of the aldehyde was complete, the mixture was stirred at 5°C for a period of 14 h. The precipitated solid was filtered off, washed with water (200 ml), hexane (200 ml) and dried in vacuo to give the N-methyl-4-[2-[2-(phenylthio)ethylidene]hydrazino]benzenemethanesulphonamide (10.95 g), melting point 110°-112°C. A solution of the N-methyl-4-[2-[2(phenylthio)ethylidene]hydrazino]benzenemethane-sulphonamide in absolute ethanol (300 ml) was saturated with hydrogen chloride gas (ca. 30 min) whilst being cooled in an ice-water bath, allowed to stir at room temperature for 3 h and filtered. The filtrate was concentrated in vacuo and chromatographed to afford a foam, which solidified on trituration with ether to an amorphous powder (2.17 g). A sample was recrystallized from hexane-dichloromethane to give the N-methyl-3-(phenylthio)-1H-indole-5-methanesulphonamide, melting point 133°-134°C. To a solution of N-methyl-3-(phenylthio)-1H-indole-5-methanesulphonamide (460 mg) in absolute ethanol (50 ml) was added Raney nickel [4.6 g, 50% slurry in water, washed to neutrality with deionized water (60 ml)] and the reaction mixture refluxed for 16 h under an atmosphere of nitrogen. On

3132

Sumatriptan succinate

cooling to room temperature, the supernatant was removed and the Raney nickel extracted with ethanol (2x50 ml, which was brought to a gentle reflux for 15 min under an atmosphere of nitrogen). The combined extracts were filtered through a sand-celite pad and concentrated in vacuo. Chromatography of the residue, afforded an oil (87 mg) which crystallized from ether-hexane to give the N-methyl-1H-indole-5-methanesulphonamide (90 mg), melting point 127°-129°C. To N,N-diethyl chloroacetamide (800 mg) at 0°C was added phosphorous oxychloride (250 µl) over a period of 30 sec. After the addition was complete, the mixture was allowed to stir at 0°C for 15 min and then at room temperature for 20 min. The N-methyl-1H-indole-5-methanesulphonamide (300 mg) was added at 0°C and the mixture warmed to 65°C, whereupon it dissolved. The mixture was stirred for 2 h at this temperature then poured onto ice (ca. 5 g) and chloroform (5 ml) and stirred vigorously for 1 h. A solid was filtered off, washed with water (50 ml), and hexane (100 ml) and dried in vacuo to give the 3-(chloroacetyl)-N-methyl-1H-indole-5methanesulphonamide (192 mg). A solution of the 3-(chloroacetyl)-N-methyl-1H-indole-5methanesulphonamide (160 mg) in ethanolic dimethylamine (30 ml, 33% w/v solution in ethanol) was heated to reflux for 2 h. On cooling to room temperature the solvent was removed in vacuo and the residue was chromatographed to afford the 3-[(dimethylamino)acetyl]-N-methyl-1Hindole-5-methanesulphonamide, melting point 230°C, dec. To a suspension of the 3-[(dimethylamino)acetyl]-N-methyl-1H-indole-5methanesulphonamide (46.5 mg) in 1-propanol (5 ml) was added sodium borohydride (62 mg). The reaction mixture was brought to reflux for a period of 3 h, then an additional quantity of borohydride (60 mg) was added. After refluxing for a further 1 h, the mixture was allowed to cool to room temperature and quenched with 2 N HCl (10 ml). The aqueous solution was washed with ethyl acetate (5 ml) then neutralized (NaHCO3 solution) and extracted with ethyl acetate (3 x 15 ml). The combined extracts were concentrated in vacuo and the residue chromatographed to give the 3-[2(dimethylamino)ethyl]-N-methyl 1H-indole-5-methanesulphonamide as a gum (2 mg) which was shown by TLC. Succinic acid in hot methanol was added to a hot solution of the the 3-[2(dimethylamino)ethyl]-N-methyl-1H-indole-5-methanesulphonamide in absolute ethanol and the mixture was heated to reflux with stirring to give a solution. The solution was allowed to cool with stirring to room temperature, and the resultant suspension was farther cooled in an ice-bath for 2 h. The solid was filtered off, washed with ethanol, and dried in vacuo to give the 3[2-(dimethylamino)ethyl]-N-methyl-1H-indole-5-methanesulphonamide, salt with succinic acid (1:1). References William A.; GB Patent No. 2162 522 A; Feb. 5 1986; Assigned: Glaxo Group Limited (United Kingdom), Clarges House, 6-12 Clarges Street, London W 1Y 8DH

Syrosingopine

3133

SYROSINGOPINE Therapeutic Function: Antihypertensive Chemical Name: 18-[[4-[(Ethoxycarbonyl)oxy]-3,5-dimethoxybenzoyl]oxy]11,17-dimethoxyyohimban-16-carboxylic acid methyl ester Common Name: Structural Formula:

Chemical Abstracts Registry No.: 84-36-6 Trade Name Singoserp Syringia Aurugopin Elumonon Hipotensor Zambe Neoreserpan Nichiserpine-S Novoserpina Raunova Rosidil Siroshuten Tesamurin

Manufacturer Ciba Toyo Jozo Nisshin Tatsumi Zambeletti Panthox and Burck Nichiiko Ghimas Zambeletti Nippon Chemiphar Isei Zensei

Country US Japan Japan Japan Italy Italy Japan Italy Italy Japan Japan Japan

Year Introduced 1958 1975 -

Raw Materials Methyl reserpate O-Carbethoxysyringoyl chloride Manufacturing Process 1 part by weight of methyl reserpate and 1.9 parts by weight of Ocarbethoxysyringoyl chloride were dissolved in 20 parts by volume of anhydrous pyridine and allowed to stand at 5°C for 3 days. An equal volume

3134

Syrosingopine

of ice was then added, and the mixture evaporated to dryness in vacuo. The residue was dissolved in 50 parts by volume of chloroform and washed in succession with three 50 parts by volume portions of 2% sodium hydroxide solution and two 50 parts by volume portions of water. The chloroform solution was dried over sodium sulfate and evaporated to dryness. The residue was dissolved in 15 parts by volume of benzene and chromatographed on a 10 part by weight column of II-III grade alumina. Eluates of benzene, 90 benzene: 10 acetone, 80 benzene: 20 acetone, 60 benzene: 40 acetone; and acetone were removed. From the 90 benzene: 10 acetone eluate there was recovered crystalline methyl O-(O'-carbethoxysyringoyl)-reserpate, melting point 175°C to 178°C, on crystallization from acetone. References Merck Index 8901 Kleeman and Engel p. 853 OCDS Vol. 1 p. 319 (1977) I.N. p. 917 Lucas, R.A.; US Patent 2,813,871; November 19,1957; assigned to Ciba Pharmaceutical Products, Inc.

T

TACROLIMUS Therapeutic Function: Immunosuppressive Chemical Name: Tsukubaenolide Common Name: Efrimus; Tacrolimus; Tsukubaenolide Structural Formula:

Chemical Abstracts Registry No.: 104987-11-3 Trade Name FK-506 Fujimycin Protopic Protopic Ointment Tacrolimus

Manufacturer Fujisawa Fujisawa Fujisawa Fujisawa Fujisawa

Country Japan Japan USA USA Japan

Raw Materials Glycerin

Calcium carbonate

3135

Year Introduced -

3136

Tacrolimus

Starch Glucose Adekanol Peanut powder Yeast

Soluble starch Cottonseed meal Corn steep liquor Gluten meal Streptomyces tsukubaensis No. 9993, FERM BP-927

Manufacturing Process The novel 17-allyl-1,14-dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-1methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatrcyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone (FR-900506), substance can be produced by culturing a FR-900506 substance(s)-producing strain belonging to the genus Streptomyces (e.g. Streptomyces tsukubaensis No. 9993, FERM BP-927) in a nutrient medium. Fermentation A culture medium (160 ml) containing glycerin (1%), corn starch (1%), glucose (0.5%), cottonseed meal (1%), dried yeast (0.5%), corn steep liquor (0.5%) and calcium carbonate (0.2%) (adjusted to pH 6.5) was poured into each of ten 500 ml-Erlenmeyer flasks and sterilized at 120°C for 30 min. A loopful of slant culture of Streptomyces tsukubaensis No. 9993 was inoculated to each of the medium and cultured at 30°C for 4 days on a rotary shaker. The resultant culture was inoculated to a medium containing soluble starch (5%), peanut powder (0.5%), dried yeast (0.5%), gluten meal (0.5%), calcium carbonate (0.1%) and Adekanol (deforming agent, Trade Mark, maker Asasi Denka Co.) (0.1%) (150 liters) in a 200-liter jar-fermentor, which had been sterilized at 120°C for 20 min in advance, and cultured at 30C for 4 days under aeration of 150 liters/minutes and agitation of 250 rpm. Isolation and Purification The cultured broth thus obtained was filtered with an aid of diatomaseous earth (5 kg). The mycelial cake was extracted with acetone (50 liters), yielding 50 liters of the extract. The acetone extract from mycelium and the filtrate (135 L) were combined and passed through a column of a non-ionic adsorption resin "Diaion HP-20" (Trade Mark, maker Mitsubishi Chemical Industries Ltd.) (10 L). After washing with water (30 L) and 50 % aqueous acetone (30 L), elution was carried out with 75 aqueous acetone. The eluate (30 liters) was evaporated under reduced pressure to give residual water (2 L). This residue was extracted with ethyl acetate (2 L) three times. The ethyl acetate extract was concentrated under reduced pressure to give an oily residue. The oily residue was mixed with twice weight of acidic silica gel (special silica gel grade 12, maker Fuji Devison Co.), and this mixture was slurried in ethyl acetate. After evaporating the solvent, the resultant dry powder was subjected to column chromatography of the same acidic silica gel (800 ml) which was packed with n-hexane. The column was developed with nhexane (3 L), a mixture of n-hexane and ethyl acetate (4:1 v/v, 3 L) and ethyl acetate (3 L). The fractions containing the object compound were collected and concentrated under reduced pressure to give an oily residue. The oily residue was dissolved in a mixture of n-hexane and ethyl acetate (1:1 v/v, 30 ml) and subjected to column chromatography of silica gel (maker Merck Co., Ltd. 230-400 mesh) (500 ml) packed with the same solvents system. Elution was carried out with a mixture of n-hexane and ethyl acetate

Talampicillin

3137

(1:1 v/v, 2 liters and 1:2 v/v, 1.5 L) and ethyl acetate (1.5 L). Fractions containing the first object compound were collected and concentrated under reduced pressure to give crude FR-900506 substance (3 g) in the form of yellowish powder. This powder of the FR-900506 substance could be transformed into a form of white crystals by recrystallization thereof from acetonitrile. Melting point: 127°-129°C. References Okuhara M. et al.; US Patent No. 5,110,811; May 5, 1992; Assigned: Fujisawa Pharmaceutical Company, Ltd., Osaka, Japan

TALAMPICILLIN Therapeutic Function: Antibacterial Chemical Name: (2S)-6-[(Aminophenylacetyl)amino]-3,3-dimethyl-7-oxo-4thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid 1,3-dihydro-3-oxo-1isobenzofuranyl ester Common Name: Phthalidyl-D-α-aminobenzylpenicillanate Structural Formula:

Chemical Abstracts Registry No.: 47747-56-8; 39878-70-1 (Hydrochloride salt) Trade Name Talpen Yamacillin Talampicillina Talat Talmen

Manufacturer Beecham Yamanouchi Midy Polifarma Prodes

Raw Materials Ampicillin

3-Bromophthalide

Country US Japan Italy Italy Spain

Year Introduced 1975 1977 1980 -

3138

Talniflumate

Manufacturing Process A fine suspension of 25.18 grams (0.05 mol) of potassium salt of enamine protected ampicillin and 10.65 grams (0.05 mol) 3-bromophthalide were reacted in a 1:2 mixture of acetone/ethyl acetate (1,500 ml) for 24 hours. After filtration the organic layer was washed twice with 250 ml portions of 1 N sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. Addition of ether crystallized the phthalide enamine protected α-aminophenylacetamido penicillanate in 85% yield. The enamine protecting group was removed by dissolving 10 grams in aqueous acetone (250 ml water to 250 ml acetone) and vigorously stirring this solution at pH 2.5 for 1 hour. The acetone was removed in vacuo and the ester, which was salted out of the aqueous phase as a sticky yellow gum, was dissolved in ethyl acetate (200 ml) and washed twice with 200 ml portions of 1 N sodium bicarbonate and brine and dried over anhydrous magnesium sulfate. Careful addition of dry ester (about 50 ml) to the dry ethyl acetate layer yielded the ampicillin phthalide ester as hydrochloric salt as a fine white amorphous solid in 80% yield. References Merck Index 8912 Kleeman and Engel p. 854 OCDS Vol. 2 p. 438 (1980) DOT 12 (7) 283 (1976) & 15 (8) 349 (1979) I.N. p. 919 REM p. 1201 Ferres, H.; US Patent 3,860,579; January 14, 1975; assigned to Beecham Group Limited, England Murakami, M., Isaka, I., Kashiwagi, T., Matsui, H., Nakano, K., Takahashi, K., Horiguchi, H. and Koda, A.; US Patent 3,951,954; April 20, 1976; assigned to Yamanouchi Pharmaceutical Co., Ltd., Japan

TALNIFLUMATE Therapeutic Function: Antiinflammatory, Analgesic Chemical Name: 2-[[3-(Trifluoromethyl)phenyl]amino]-3-pyridine carboxylic acid 1,3-dihydro-3-oxo-1-isobenzofuranyl ester Common Name: Chemical Abstracts Registry No.: 66898-62-2 Raw Materials 2-(3'-Trifluoromethylanilino)nicotinic acid 3-Bromophthalide

Tamoxifen

3139

Structural Formula:

Trade Name Somalgen

Manufacturer Bago

Country Argentina

Year Introduced 1972

Manufacturing Process 49 ml of triethylamine were added to a suspension of 2-(3'trifluoromethylanilino)nicotinic acid (70.6 g in 250 ml of dimethylformamide). After stirring for 30 minutes 53.3 g of 3-bromophthalide were added. The reaction mixture was maintained at 25°C to 30°C during 4 hours. Ethyl acetate (750 ml) was poured into the reaction mixture. This solution was filtered and extracted with water (4 x 250 ml), discarding the water layer. The organic layer was dried with anhydrous magnesium sulfate and then filtered. The solution was concentrated under vacuum at 30°C to 35°C until reduced to half of its original volume and then cooled to 5°C to allow the crystallization of the compound. Thus, the cake was filtered, washed with cool ethyl acetate, and dried under vacuum. Yield: 74% (76.7 g) of phthalidyl ester of 2-(3'-trifluoromethylanilino)-pyridin-3-carboxylic acid, melting point: 165°C to 167°C. References Merck Index 8921 DFU 4 (6) 448 (1979) OCDS Vol. 3 p. 146 (1984) DOT 19 (7) 99 (1983) I.N. p. 919 Bago, S.; US Patent 4,168,313; September 18, 1979

TAMOXIFEN Therapeutic Function: Antiestrogen, Antineoplastic Chemical Name: 2-[4-(1,2-Diphenyl-1-butenyl)phenoxy]-N,Ndimethylethanamine Common Name: -

3140

Tamoxifen

Structural Formula:

Chemical Abstracts Registry No.: 10540-29-1; 54965-24-1 (Citrate) Trade Name Nolvadex Nolvadex Nolvadex Nolvadex Nolvadex Nolvadex Nolvadex Tamofen Valodex

Manufacturer I.C.I. I.C.I. I.C. Pharma I.C.I. I.C.I. Stuart Sumitomo Rhone Poulenc Abic

Country UK W. Germany Italy France Switz. US Japan Israel

Year Introduced 1973 1976 1976 1977 1978 1978 1981 -

Raw Materials Bromobenzene Magnesium 4-(β-Dimethylaminoethoxy)-α-ethyldesoxybenzoin Manufacturing Process To the Grignard reagent prepared from 0.59 part of magnesium, 3.95 parts of bromobenzene and 50 parts of ether there are added 7.5 parts of 4-(βdimethylaminoethoxy)-α-ethyldesoxybenzoin in 50 parts of ether. After heating under reflux for 3 hours, the mixture is decomposed by the addition of a solution of 60 parts of ammonium chloride in 150 parts of water. The mixture is separated, and the ethereal layer is dried with anhydrous sodium sulfate, and the ether is evaporated. The residue is crystallized from methanol. There is thus obtained 1-(p-β-dimethylaminoethoxyphenyl)-1,2diphenylbutan-1-ol, melting point 120°C to 121°C. 2.15 parts of 1-(p-β-dimethylaminoethoxyphenyl)-1,2-diphenylbutan-1-ol, 25 parts of ethanol and 0.8 part of 10 N hydrochloric acid are heated together under reflux for 3 hours. The solution is evaporated to dryness under reduced pressure and the residue is extracted with methylene chloride. The methylene chloride extract is decolorized with charcoal and then evaporated to dryness. The residue is dissolved in 100 parts of water, the solution is basified by the addition of sodium hydroxide solution, and the precipitated solid is extracted three times, each time with 50 parts of ether. The combined extracts are dried

Tamsulosin hydrochloride

3141

with anhydrous sodium sulfate and then evaporated. The residue is crystallized from aqueous methanol, and there is thus obtained 1-(p-βdimethylaminoethoxyphenyl)-1,2-diphenylbut-1-ene, melting point 95°C to 96°C. References Merck Index 8923 Kleeman and Engel p. 854 PDR p. 1783 OCDS Vol. 2 p. 127 (1980) & 3, 70 (1984) DOT 10 (2) 71 (1974) I.N. p. 920 REM p. 990 Harper, M.J.K., Richardson, D.N. and Walpole, A.L.; British Patent 1,013,907; December 22, 1965; assigned to Imperial Chemical Industries, Ltd. (UK)

TAMSULOSIN HYDROCHLORIDE Therapeutic Function: Antihypertensive Chemical Name: 5-[2-[[2-(2-Ethoxyphenoxy)ethyl]amino]propyl]-2methoxy-benzenesulfonamide monohydrochloride, (R)Common Name: Amsulosin hydrochloride; Tamsulosin hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 106463-17-6; 106133-20-4 (Base) Trade Name Contiflo OD Flomax Flomax Flomax Flomax Flomax Flomax Flomax

Manufacturer Ranbaxy Laboratories Limited Medvantx Abbott Laboratories Physicians TC. Allscripts Yamanouchi Boehringer-Ingelheim GlaxoWellcome

Country India

Year Introduced -

-

-

3142

Tanphetamin

Trade Name Omnic Tamsulosin Hydrochloride

Manufacturer Yamanouchi Yamanouchi

Country Year Introduced Netherlands Netherlands -

Raw Materials 5-{2-[2-(2-Ethoxyphenoxy)ethylamino]-1-hydroxy-2-methylethyl}-2methoxybenzenesulfonamide hydrochloride Thionyl chloride Palladium on carbon Hydrogen Manufacturing Process In 1,000 ml of acetonitrile was suspended 17 g of 5-{2-[2-(2ethoxyphenoxy)ethylamino]-1-hydroxy-2-methylethyl}-2methoxybenzenesulfonamide hydrochloride and while stirring the suspension, 9 g of thionyl chloride was added dropwise to the suspension at room temperature, whereby the product first dissolved and then began to crystallize gradually. After stirring the mixture for two days, the crystals formed were recovered by filtration, washed with chloroform and dried to provide 15 g of 5-{1-chloro-2-[2-(2-ethoxyphenoxy)ethylamino]-2-methylethyl}-2methoxybenzenesulfonamide hydrochloride. Melting point: 197°-200°C. In methanol was dissolved the 5-{1-chloro-2-[2-(2ethoxyphenoxy)ethylamino]ethyl}-2-methoxybenzenesulfonamide hydrochloride and after adding thereto 10% palladium carbon, dechlorination was performed under hydrogen stream at normal temperature and pressure. The palladium carbon was filtered away and the filtrate was concentrated under reduced pressure to provide the 2-methoxy-5-{2-[2-(2ethoxyphenoxy)ethylamino]ethyl}benzenesulfonamide hydrochloride, which was recrystallized from 120 ml of a mixture of methanol and ethanol (1:4 by volume ratio) to provide the colorless crystals thereof. The melting point of the 5-{2-[2-(2-ethoxyphenoxy)ethylamino]-2-methylethyl}-2methoxybenzenesulfonamide hydrochloride: 254°-256°C. References Niigata K., Fujikura T.; US Patent No. 5,447,958; Sep. 5, 1995; Assigned: Yamanouchi Pharmaceutical Co., Ltd., Tokyo, Japan

TANPHETAMIN Therapeutic Function: Antiobesity Chemical Name: d-Amphetamine tannate Common Name: Dexamphetamine tannate

Tazarotene

3143

Structural Formula: A complex of amphetamine, C6H5CH2CH(CH3)NH2and tannic acid Chemical Abstracts Registry No.: 1407-85-8 Trade Name

Manufacturer

Country

Year Introduced

Synatan

Neisler

US

1955

Obotan

Mallinckrodt Inc.

US

-

Proptan

Irwin, Neisler

US

-

Raw Materials d-Amphetamine Tannic acid Manufacturing Process Approximately 75 grams of d-amphetamine as a free base was dissolved in 300 ml of isopropanol (solution A). Approximately 200 grams of NF tannic acid was dissolved in 700 milliliters of slightly warmed isopropanol (solution B). Solution B was poured, with rapid stirring, into solution A to provide an almost immediate precipitation of the insoluble tannate complex. The solution was cooled to room temperature and the product filtered off and dried. During the filtration, most of the isopropanol was removed by washing with acetone, and the precipitate dried at 140°F to yield a light tan product. The amount of precipitate was approximately 200 grams of tannate salt but more could be obtained by concentration of the mother liquors. References Merck Index 8930 I.N. p. 301 Cavallito, C.J.; US Patent 2,950,309; August 23, 1960; assigned to Irwin, Neisler and Company

TAZAROTENE Therapeutic Function: Keratolytic Chemical Name: 3-Pyridinecarboxylic acid, 6-((3,4-dihydro-4,4-dimethyl-2H1-benzothiopyran-6-yl)ethynyl)-, ethyl ester Common Name: Tazarotene Chemical Abstracts Registry No.: 118292-40-3

3144

Tazarotene

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Avage

Allergan

-

-

Tazorac

Allergan

-

-

Zorac

Allergan

-

-

Raw Materials Thiophenol Phosphoric acid Acetyl chloride Hydrogen chloride Chlorophosphate Hydrogen chloride Dicyclohexylcarbodiimide Copper iodide Diethyl chlorophosphate

1-Bromo-3-methyl-2-butene Phosphorus pentoxide Stannic chloride Butyl lithium Diisopropylamine 6-Chloronicotinic acid Dimethylaminopyridine Sodium hydroxide Bis(triphenylphosphine)palladium(II) chloride

Manufacturing Process A mixture of 14.91 g (135.324 mmol) of thiophenol and 5.5 g (137.5 mmol) of NaOH in 100 ml acetone was heated at reflux for 2.5 h and then treated dropwise with a solution of 20 g (134.19 mmol) of 1-bromo-3-methyl-2butene in 20 ml acetone. This solution was refluxed for 40 h and then stirred at room temperature for 24 h. Solvent was then removed in vacuo, the residue taken up in water, and extracted with 3 times 50 ml ether. Ether extracts were combined and washed with 3 times 30 ml of 5% NaOH solution, then water, saturated NaCl solution and dried. Solvent was then removed in vacuo and the residue further purified by kugelrohr distillation (80°C, 0.75 mm) to give the phenyl-3-methylbut-2-enylsulfide as a pale yellow oil. To a solution of 15.48 g (86.824 mmol) of phenyl-3-methylbut-2-enylsulfide in 160 ml benzene were added successively 12.6 g (88.767 mmol) of phosphorus pentoxide and 11 ml of 85% phosphoric acid. This solution was refluxed with vigorous stirring under argon for 20 h, then cooled to room temperature. The supernatant organic layer was decanted and the syrupy residue extracted with 3 times 50 ml ether. Organic fractions were combined and washed with water, saturated NaHCO3 and saturated NaCl solution and then dried. Solvent was removed in vacuo and the residue purified by kugelrohr distillation (80°C, 0.5 mm) to give the 4,4-dimethylthiochroman as a pale yellow oil.

Tazarotene

3145

A solution of 14.3 g (80.21 mmol) of 4,4-dimethyl thiochroman and 6.76 g (86.12 mmol) of acetyl chloride in 65 ml benzene was cooled in an ice bath and treated dropwise with 26.712 g (102.54 mmol) of stannic chloride. The mixture was stirred at room temperature for 12 h, then treated with 65 ml water and 33 ml conc. hydrogen chloride and heated at reflux for 0.5 h. After being cooled to room temperature, the organic layer was separated and the aqueous layer extracted with 5 times 50 ml benzene. The recovered organic fractions were combined and washed with 5% sodium carbonate solution, water, saturated NaCl solution and then dried. The solvent was removed in vacuo and the residue purified by flash chromatography (silica; 5% ethyl acetate in hexanes) followed by kugelrohr distillation (150°C, 0.7 mm) to give the 4,4-dimethyl-6-acetylthiochroman as a pale yellow oil. To a solution of 1.441 g (14.2405 mmol) of diisopropylamine in 30 ml dry tetrahydrofuran under argon at -78°C was added dropwise 9 ml of 1.6 M (14.4 mmol) n-butyl lithium in hexane. After stirring this solution at -78°C for 1 h, it was treated dropwise with a solution of 2.95 g (13.389 mmol) of 4,4dimethyl-6-acetylthiochroman in 5 ml of dry tetrahydrofuran. After another hour of stirring at -78°C, the solution was treated with 2.507 g (14.53 mmol) of diethyl chlorophosphate and brought to room temperature, where it was stirred for 3.75 h. This solution was then transferred using a double ended needle to a solution of lithium diisopropylamide (prepared as above using 2.882 g (28.481 mmol) of diisopropylamine and 18 ml of 1.6 M (28.8 mmol) n-butyl lithium in hexane) in 60 ml dry tetrahydrofuran at -78°C. The cooling bath was removed and the solution stirred at room temperature for 15 h, then quenched with water and acidified to pH 1 with 3 N hydrogen chloride. The mixture was stirred at room temperature for 12 h, then treated with 65 ml water and 33 ml conc. hydrogen chloride and heated at reflux for 0.5 h. After being cooled to room temperature, the organic layer was separated and the aqueous layer extracted with 5 times 50 ml benzene. The recovered organic fractions were combined and washed with 5% sodium carbonate solution, water, saturated NaCl solution and then dried. The solvent was removed in vacuo and the residue purified by flash chromatography (silica; 5% ethyl acetate in hexanes) followed by kugelrohr distillation (150°C, 0.7 mm) to give the 4,4-dimethyl-6-ethynylthiochroman as a pale yellow oil. A mixture of 15.75 g (0.1 mol) 6-chloronicotinic acid, 6.9 g (0.15 mol) ethanol, 22.7 g (0.11 mol) dicyclohexylcarbodiimide and 3.7 g dimethylaminopyridine in 200 ml methylene chloride was heated at reflux for 2 h. The mixture was allowed to cool, solvent removed in vacuo and residue subjected to flash chromatography to give the ethyl 6-chloronicotinate as a low-melting white solid. 2 Methods of preparation of the ethyl 6-[2-(4,4-dimethylthiochroman-6yl)ethynyl]nicotinate. 1. Reaction vessels used in this procedure were flame dried under vacuum and all operations carried out in an oxygen-free, argon or nitrogen atmosphere. To a solution of 465.7 mg (2.3019 mmol) of 4,4-dimethyl-6ethynyl-thiochroman in 4 ml of dry tetrahydrofuran at 0°C was added dropwise 1.5 ml of 1.6 M (2.4 mmol) n-butyl lithium in hexane. This was stirred at 0°C for 10 min and at room temperature for 10 min, cooled again to 0°C and then treated with a solution of 330 mg (2.4215 mmol) of fused ZnCl2 in 4 ml dry tetrahydrofuran using a double ended needle. Thereafter the

3146

Tazobactam sodium

solution was stirred at 0°C for 30 min, then at room temperature for 10 min. A solution of 426.3 mg (2.2967 mmol) of ethyl 6-chloronicotinoate in 4 ml dry tetrahydrofuran was transferred by double ended needle into a suspension of 430 mg (0.37 mmol) of tetrakistriphenylphosphine palladium in 4 ml dry tetrahydrofuran and stirred at room temperature for 10 min, then treated by double ended needle with the solution of the alkynylzinc prepared above. This mixture was stirred at room temperature for 18 h, then quenched with 100 ml water. Product was recovered by extraction with 3 times 75 ml ether. Ether fractions were combined and washed with saturated NaCl solutions and dried. Solvent was removed in vacuo and the residue purified by flash chromatography (silica; 5% ethyl acetate in hexane) followed by HPLC (Whatman Partisil M-9 10/50; 4% ethyl acetate in hexane) to give the ethyl 6-[2-(4,4-dimethylthiochroman-6-yl)ethynyl]nicotinate. 2. A solution of 15.4 g (76.2 mmol) of 4,4-dimethyl-6-ethynylthiochroman and 14.0 g (75.5 mmol) of ethyl-6-chloronicotinate in 35 ml of freshly distilled triethylamine was degassed and then treated under nitrogen with a finely powdered mixture of 1 g (5.25 mmol) of high purity cuprous iodide and 2 g (2.85 mmol) of bis(triphenylphosphine) palladium (II) chloride. The mixture was heated under nitrogen at 55°C for 20 h and then cooled to room temperature. The triethylamine was then removed under vacuum and the residue was diluted with 200 ml of a 1:4 mixture of ethyl acetate and hexanes. This mixture was filtered through silica and the filtrate concentrated in vacuo. The resultant residue was purified by flash chromatography (silica gel; 15% ethyl acetate in hexanes) and recrystallized from a mixture of ethyl acetate and hexanes to give the ethyl 6-[2-(4,4-dimethylthiochroman-6yl)ethynyl]nicotinate as a pale yellow solid. References Chandraratna R.A.S.; US Patent No. 5,089,509; Feb. 18, 1992; Assigned: Allergan, Inc., Irvine, Calif.

TAZOBACTAM SODIUM Therapeutic Function: Antibiotic Chemical Name: 4-Thia-1-azabicyclo(3.2.0)heptane-2-carboxylic acid, 3methyl-7-oxo-3-(1H-1,2,3-triazol-1-ylmethyl)-, 4,4-dioxide, (2S,3S,5R)-, sodium salt Common Name: Tazobactam sodium Chemical Abstracts Registry No.: 89785-84-2; 89786-04-9 (Base)

Tazobactam sodium

3147

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

CL-307579

China Pharm Chemical Co., Ltd. Shandong Qilu Medicines Imp. and Exp. Co., Ltd.

China

-

China

-

Tazobactam Sodium Raw Materials

Sodium azide Acetic acid Vinyl acetate

Potassium permanganate Palladium on charcoal Benzhydryl 2-β-chloromethyl-2-α-methylpenam-3α-carboxylate

Manufacturing Process A known β-lactam type antibiotic (for example, benzhydryl 2-β-chloromethyl2-α-methylpenam-3-α-carboxylate) was used for synthesis of new penicillinic derivatives. A solution of 5.00 g of sodium azide in 53 ml of water was added to a solution of benzhydryl 2-β-chloromethyl-2-α-methylpenam-3-α-carboxylate (5.13 g) in dimethylformamide (155 ml). The mixture was stirred at room temperature for 4 h. The resulting reaction mixture was poured into cooled water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over magnesium sulfate and concentrated to provide 4.87 g of the benzhydryl 2-β-azidomethyl-2-α-methylpenam-3-α-carboxylate as oil in 93% yield. To a solution of benzhydryl 2-β-azidomethyl-2-α-methylpenam-3-αcarboxylate (7.03 g) in a mixture of acetic acid (240 ml) and water (40 ml) was added potassium permanganate (6.02 g) over a period of more than 1 h. The mixture was stirred at room temperature for 2.5 h. The resulting reaction mixture was diluted with ice water. The precipitate was collected by filtration, and washed with water. The resulting product was dissolved in ethyl acetate and the solution was washed with an aqueous solution of sodium hydrogen carbonate and dried over magnesium sulfate. Concentration gave 5.48 g of the benzhydryl 2-β-azidomethyl-2-α-methylpenam-3-α-carboxylate-1,1-dioxide in 72% yield. A 200 mg quantity of benzhydryl 2-β-azidomethyl-2-α-methylpenam-3-αcarboxylate-1,1-dioxide was reacted with 10 ml of vinyl acetate in a sealed

3148

Tegafur

reactor at 100° to 110°C for 30 h. The reaction mixture was concentrated at reduced pressure. The residue was crystallized with cooled chloroform. The white crystals of benzhydryl 2-α-methyl-2-β-(1,2,3-triazol-1-yl)methylpenam3-α-carboxylate-1,1-dioxide have a melting point 206°-208°C, dec. Hydrogenation was conducted in 10 ml of ethyl acetate and 10 ml of water at room temperature for 30 min by using 45 mg of benzhydryl 2-α-methyl-2-β(1,2,3-triazol-1-yl)methylpenam-3-α-carboxylate-1,1-dioxide, 15 mg of 10% palladium charcoal and 16 mg of sodium hydrogen carbonate. The aqueous layer was separated from the reaction mixture and washed once with ethyl acetate. The aqueous solution was then purified with an MCl gel, CHP-20P (product of Mitsubishi Kasei Co., Ltd., Japan). After freeze-drying, there was obtained an amorphous product of sodium 2-α-methyl-2-β-(1,2,3-triazol-1yl)methylpenam-3-α-carboxylate-1,1-dioxide with a melting point 170°C, dec. References Micetich R.G. et al.; US Patent No. 4,562,073; Dec. 31, 1985; Assigned: Taiho Pharmaceutical Company Limited, Tokyo, Japan

TEGAFUR Therapeutic Function: Antineoplastic Chemical Name: 1-(Tetrahydro-2-furanyl)-5-fluorouracil Common Name: Ftorafur Structural Formula:

Chemical Abstracts Registry No.: 17902-23-7 Trade Name

Manufacturer

Country

Year Introduced

Futraful

Taiho

Japan

1974

Ftorafur

Gruenenthal

W. Germany

1977

Citofur

Lusofarmaco

Italy

1981

Futraful

Simes

Italy

1981

Coparogin

Nippon Chemiphar

Japan

-

Daiyalose

Daito

Japan

-

Exonal

Toyama

Japan

-

Fental

Kanebo, Ltd.

Japan

-

Tegafur Trade Name F.H. Filacul Flopholin Franroze Ftoral F.T.R. Fulaid Fulfeel Furofluor Furofutran Futraful Zupo Geen Helpa Icalus Lamar Lifril Lunacin Natira Neberk Nitobanil Pharmic Rescrel Richina Riol Sinoflurol Sunfural Tefsiel THF-FU Utefos Videcocan Youfural

Manufacturer Mitsui Torii Tsuruhara Hishiyama Abic Tenyosha Takeda Kyorin Green Cross Taiyo Taiho Tatumi Teikoku Isei Tokyo Tanabe Kissei Pharmaceutical Co., Ltd. Sawai Mohan Fuji Ohta Toyo Nikken Taiyo Toa Eiyo Kaken Toyo Jozo Towa Taiho Almirall Unifa Showa

3149

Country Japan Japan Japan Japan Israel Japan Japan Japan Japan Japan Japan Japan Japan Japan Japan Japan

Year Introduced -

Japan Japan Japan Japan Japan Japan Japan Japan Japan Japan Japan Japan Spain Argentina Japan

-

Raw Materials Ammonia 2-Chlorofuranidin 5-Fluorouracilmercury

2,4-Bis(trimethylsilyl)-5-fluorouracil 2,3-Dihydrofuran

Manufacturing Process One process from US Patent 4,107,162: 27.4 g of 2,4-bis(trimethylsilyl)-5fluorouracil and 7.7 g of 2,3-dihydrofuran are dissolved in 70 ml of acetonitrile, and 30 ml of an acetonitrile solution containing 1.3 g of anhydrous stannic chloride are added thereinto with cooling and stirring. 50 ml of acetonitrile containing 1.3 ml of water dissolved therein are then dropwise added over 15 minutes. After return to room temperature, the reaction is further effected with stirring at 40°C for 5 hours. The reaction mixture is neutralized by adding 1 N aqueous ammonia with cooling and

3150

Telmisartan

stirring (conversion 83%). After the nondissolved substances are removed by filtration, the filtrate is concentrated and dried under reduced pressure. 100 ml of water and 300 ml of dichloromethane are added to the residue to completely dissolve the residue by stirring. The obtained dichloromethane layer is separated. The water layer is subjected to extraction twice with dichloromethane. The thus obtained extracts are combined with the separated dichloromethane layer and the combined extracts, after drying with anhydrous magnesium sulfate, are concentrated and dried. The obtained residue is dissolved in ethanol, and the nondissolved substances are removed by filtration. The filtrate is subjected to recrystallization to give white crystals, followed by further recrystallization of the mother liquor. There are totally obtained 15.6 g of N1-(2'-furanidyl)-5-fluorouracil.Yield: 78% of theory, with respect to 2,4-bis(trimethylsilyl)-5-fluorouracil. An alternative process from US Patent 3,635,946: A vigorously stirred reaction mixture consisting of 32.87 g (0.1 mol) of 5-fluorouracilmercury, 100 ml of dimethylformamide and 50 ml of toluene is dried by azeotropic distillation of toluene. It is then cooled to -40°C in a stream of dry nitrogen, and a solution of 21.3 g (0.2 mol) of 2-chlorofuranidin in 20 ml of dried dimethylformamide is gradually added to the stirred mixture, the temperature being maintained between -40°C and -30°C. After completion of the reaction (which is marked by complete dissolution of the starting 5-fluorouracilmercury) i.e. after about 3 to 4 hours, 60 to 80 ml of the solvent are distilled off in vacuo at a bath temperature not exceeding 35°C. 50 to 70 ml of dry acetone are then added and also vacuum distilled. The residue is easily crystallized. It is collected, washed three times with small quantities of ethanol - 10 ml each - and airdried. 12.2 g of N1-(2'-furanidyl)-5-fluorouracil are obtained in the form of white crystalline solids; melting point 160°C to 162°C. Additional treatment of the mother liquor yields 3.0 g more of the product. Yield: 75% of theory, based on the starting 5-fluorouracilmercury. After recrystallization from ethanol, 14.3 g of N1-(2'-furanidyl)-5fluorouracilare obtained, MP 164°C to 165°C. References Merck Index 8963 Kleeman and Engel p. 855 OCDS Vol. 3 p. 155 (1984) I.N. p. 923 Townsend, L.B., Earl, R.A. and Manning, S.J.; US Patent 3,960,864; June 1, 1976; assigned to The University of Utah Giller, S.A., Zhuk, R.A., Lidak, M.J. and Zidermane, A.A.; US Patent 3,635,946; Jan, 18, 1972 Suzuki, N., Kobayashi, Y., Hiyoshi, Y., Takagi, S., Sone, T., Wakabayashi, M. and Sowa, T.; US Patent 4,107,162; August 15, 1978; assigned to Asahi Kasei Kogyo K.K. (Japan)

TELMISARTAN Therapeutic Function: Antihypertensive

Telmisartan

3151

Chemical Name: 4'-((4-Methyl-6-(1-methyl-2-benzimidazolyl)-2-propyl-1benzimidazolyl)methyl)-2-biphenylcarboxylic acid Common Name: Telmisartan Structural Formula:

Chemical Abstracts Registry No.: 144701-48-4 Trade Name Micardis Pritor Telma Telma 40 Telmisartan

Manufacturer Boehringer Ingelheim Pharma KG Glaxo Wellcome S.P.A. Healtheon (A Div. of Glenmark) Glenmark Boehringer Ingelheim Pharma KG

Country Germany

Year Introduced -

Italy India

-

Germany

-

Raw Materials Butyric acid chloride Trifluoroacetic acid Sodium hydroxide Phosphorus oxychloride Sulfuric acid 2-Methylaminoaniline-dihydrochloride Polyphosphoric acid Potassium t-butoxide Acetic acid Methyl 3,4-diaminobenzoate dihydrochloride t-Butyl 4'-bromomethyl-biphenyl-2-carboxylate Manufacturing Process A solution of 23.9 g (100 mMol) of methyl 3,4-diaminobenzoate dihydrochloride and 11.7 g (110 mMol) of butyric acid chloride in 100 ml of phosphorus oxychloride is refluxed for 2 h. Then about 80 ml of phosphorus oxychloride are distilled off and the residue is mixed with about 150 ml of water. The oily crude product precipitated is extracted three times with 50 ml of ethyl acetate and after evaporation purified by column chromatography (600 g of silica gel; eluant:methylene chloride/methanol (30:1)). Yield of methyl-2-n-propyl-benzimidazole-5-carboxylate: 15.0 g of oil (69%). A solution of 15.0 g (73 mmol) of methyl 2-n-propyl-benzimidazole-5carboxylate and 8 g (200 mMol) of sodium hydroxide in 200 ml of water and 400 ml of ethanol is refluxed for 2 h. Then the alcohol is distilled off, the aqueous solution is acidified with dilute sulphuric acid (pH 4-5) and evaporated using a rotary evaporator. The product crystallising out is suction

3152

Temazepam

filtered, washed with 50 ml of acetone and 50 ml of diethylether and dried. Yield of 2-n-propyl-benzimidazole-5-carboxylic acid-hemisulphate: 9.1 g (61%), melting point: >220°C. A solution of 6.7 g (25 mMol) of 2-n-propyl-benzimidazole-5-carboxylic acidhemisulphate and 4.9 g (25 mMol) of 2-methylaminoaniline dihydrochloride in 200 g of polyphosphoric acid is stirred for 5 h at 150°C, then poured onto 600 ml of water and made alkaline with concentrated ammonia whilst cooling with ice. The resulting solution is extracted three times with 200 ml of ethyl acetate, the crude product thus obtained is purified by column chromatography (300 g of silica gel; eluant:methylene chloride/methanol = 15:1). Yield of 2-n-propy1-5-(1-methylbenzimidazol-2-yl)-benzimidazole: 2.8 g of oil (39%). A solution of 2.0 g (6.9 mMol) of 2-n-propyl-5-(1-methylbenzimidazol-2-yl)benzimidazole and 0.91 g (7.5 mmol) of potassium tert-butoxide in 50 ml of dimethylsulfoxide is stirred for 90 min at room temperature, then 2.6 g (7.5 mMol) of tert-butyl 4'-bromomethyl-biphenyl-2-carboxylate are added and the mixture is stirred for a further 15 h at room temperature. The mixture is then poured onto 300 ml of water and extracted three times with 50 ml of ethyl acetate. The crude product obtained after evaporation of the organic phase is purified by column chromatography (300 g silica gel; eluant:methylene chloride/methanol = 30:1). In this way, 2.7 g (70%) of an isomer mixture are obtained (by NMR spectroscopy), contains about 1.18 g of tert-butyl-4'-[(2-npropyl-5-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]biphenyl-2carboxylate and about 1.52 g of tert-butyl 4'-[(2-n-propyl-6-(1methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate). 2.70 g of the isomer mixture obtained above are dissolved in 100 ml of methylene chloride, mixed with 40 ml of trifluoroacetic acid and stirred for 4 h at room temperature. The mixture is then evaporated to dryness in vacuo, the residue is dissolved in 100 ml of 2 N sodium hydroxide solution, the solution is washed with 50 ml of diethylether and the product mixture is precipitated by acidifying the aqueous phase with acetic acid. By column chromatography (400 g of silica gel, eluant:methylene chloride/methanol = 15:1) of the solid thus obtained 0.9 g (74%) of 4'-[[2-n-propyl-6-(1-methylbenzimidazol-2-yl)benzimidazol-1-yl]methyl]biphenyl-2-carboxylate, melting point 217°-218°C. References Narr B. et al.; US Patent No. 5,587,393; Dec. 24, 1996; Assigned: Dr. Karl Thomae GmbH, Biberach an der Riss, Germany

TEMAZEPAM Therapeutic Function: Tranquilizer Chemical Name: 7-Chloro-1,3-dihydro-3-hydroxy-1-methyl-5-phenyl-2H-1,4benzodiazepin-2-one Common Name: -

Temazepam

3153

Structural Formula:

Chemical Abstracts Registry No.: 846-50-4 Trade Name Levanxol Euhypnos Normison Restoril Planum Normison Euhypnos Normison Planum Mabertin Maeva Signopam

Manufacturer Carlo Erba Montedison Wyeth Sandoz Carlo Erba Wyeth Byla Farmitalia Wyeth Carlo Erba Sidus Ravizza Polfa

Country Italy UK UK US W. Germany France France Switz. Switz. Argentina Italy Poland

Year Introduced 1970 1977 1977 1981 1981 1981 1981 1983 1983 -

Raw Materials 3-Acetoxy-7-chloro-1-methyl-5-phenyl-1,3-dihydro-2H-1,4benzodiazepin-2-one Sodium hydroxide Manufacturing Process According to British Patent 1,022,645 3.4 g of 3-acetoxy-7-chloro-1-methyl-5phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one suspended in 80 ml alcohol was treated with 6 ml of 4 N NaOH. After complete solution had taken place, a solid precipitated; this solid was redissolved by the addition of 80 ml of water. The solution was acidified with acetic acid to give white crystals which were recrystallized from alcohol to yield 7-chloro-3-hydroxy-5-phenyl-1methyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one, MP 119° to 121°C. References Merck Index 8976 Kleeman and Engel p. 856 PDR p. 1591 OCDS Vol. 2 p. 402 (1980) DOT 6 (6) 224 (1970) & 9 (6) 238 (1973) I.N. p. 923 REM p. 1064

3154

Temozolomide

American Home Products Corporation; British Patent 1,022,642; March 16, 1966 American Home Products Corporation; British Patent 1,022,645; March 16, 1966 Bell, S.C.; British Patent 1,057,492; February 1, 1967; assigned to American Home Products Corporation

TEMOZOLOMIDE Therapeutic Function: Antineoplastic Chemical Name: Imidazo(5,1-d)(1,2,3,5)tetrazine-8-carboxamide, 3,4dihydro-3-methyl-4-oxoCommon Name: Methazolastone; Temozolomide Structural Formula:

Chemical Abstracts Registry No.: 85622-93-1 Trade Name Temodal Temodar

Manufacturer Schering Schering

Country -

Year Introduced -

Raw Materials Nitrous acid 1H-Imidazole-4-carboxilic acid amide Methylisocyanate Manufacturing Process Reaction of 1H-imidazole-4-carboxilic acid amide with nitrous acid leads to the diazonium salt (5-diazenyl-1-H-imidazole-4-carboxilic acid amide). Condensation of the diazonium salt with methylisocyanate leads to initial formation of unstable urea which cyclizes under the reaction condition to give 3,4-dihydro-3-methyl-4-oxoimidazo(5,1-d)-1,2,3,5-tetrazine-8-carboxamide (temozolomide).

Teniposide

3155

References Merck Index, Monograph number: 9289, Twelfth edition, 1996, Editor: S. Budavari; Merck and Co., Inc. Stevens M.F.G. et al.; J. Med. Chem., 1984, 27, 196

TENIPOSIDE Therapeutic Function: Antineoplastic Chemical Name: 4'-Demethylepipodophyllotoxin-β-D-thenylidene glucoside Common Name: Structural Formula:

Chemical Abstracts Registry No.: 29767-20-2 Trade Name Vehem Vumon Vumon Vumon

Manufacturer Sandoz Bristol Bristol Bristol

Country France W. Germany Switz. Italy

Year Introduced 1976 1980 1980 1982

Raw Materials Thiophene-2-aldehyde 4'-Demethylepipodophyllotoxin-β-D-glucoside Manufacturing Process 10 ml of pure thiophene-2-aldehyde and 0.25 g of anhydrous zinc chloride are

3156

Tenonitrozole

added to 0.5 g of dried 4'-demethylepipodophyllotoxin-β-D-glucoside and the mixture is shaken on a machine at 20°C in the absence of moisture, whereupon a clear solution is gradually obtained. The course of condensation is checked by thin layer chromatography. After a reaction period of 3 to 4 hours the solution is diluted with chloroform and shaken out with water. The chloroform phase is washed twice more with a small amount of water and then dried over sodium sulfate and concentrated by evaporation. Excess thiophene-2-aldehyde is removed by dissolving the resulting residue in a small amount of acetone and reprecipitation is effected by adding pentane. Reprecipitation from acetone/pentane is repeatedly effected until the condensation product sults in flaky form. Further purification is effected in that the crude product is chromatographed on silica gel. The fractions which are uniform in accordance with thin layer chromatography are combined and yield crystals from absolute alcohol. Pure 4'-demethylepipodophyllotoxin-β-Dthenylidene glucoside has a melting point of 242°C to 246°C (last residue up to 255°C). References Merck Index 8978 Kleeman and Engel p. 857 DOT 12 (11) 465 (1976) & 16 (5) 170 (1980) I.N. p. 924 REM p. 1156 Keller-Juslen, C., Kuhn, M., Renz, J. and von Wartburg, A.; US Patent 3,524,844; Aug. 18, 1970; assigned to Sandoz, Ltd. (Switz.)

TENONITROZOLE Therapeutic Function: Antiprotozoal Chemical Name: 2-Thiophenecarboxamide, N-(5-nitro-2-thiazolyl)Common Name: Tenonitrozole; Thenitrazolum Structural Formula:

Chemical Abstracts Registry No.: 3810-35-3 Trade Name

Manufacturer

Country

Year Introduced

Tenonitrozole

Innotech

-

-

Atrican

Innotech

-

-

Tenonitrozole

ZYF Pharm Chemical

-

-

Tenylidone

3157

Raw Materials 2-Amino-5-nitrothiazole 2-Thienoylchloride Potassium hydroxide Manufacturing Process To a solution of 1 kg (7 moles) of 2-amino-5-nitrothiazole in 5 L of pyridine (dried with potassium hydroxide) was added dropwise for 2-3 hours 8.5 moles of 2-thienoylchloride. N-(5-Nitro-2-thiazolyl)-2-thiophenecarboxamide was prepared as a yellow crystals with melting point 255-256°C. References Henri M., Rene Chantereau, Brevet special de Medicament 835,121; August 5, 1960; Assigned to l'Imperie Nationale, Paris

TENYLIDONE Therapeutic Function: Hepatoprotectant Chemical Name: 2,6-Bis(2-thenylidene)cyclohexanone Common Name: Tenylidone; Vanitile Structural Formula:

Chemical Abstracts Registry No.: 893-01-6 Trade Name

Manufacturer

Country

Year Introduced

Tenylidone

JINGTIAN PORTLINK CO., LTD.

-

-

Raw Materials Cyclohexanone 2-Formylthiophene Manufacturing Process 2,6-Bis(2-thenylidene)cyclohexanone was obtained by condensation of 1 mol cyclohexanone with 2 mol 2-formylthiophene.

3158

Terazosin hydrochloride dihydrate

References Roland M., Blaise R., Brevet Special de Medicament FR 64M; JUL 22, 1960

TERAZOSIN HYDROCHLORIDE DIHYDRATE Therapeutic Function: Antihypertensive Chemical Name: Piperazine, 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4((tetrahydro-2-furanyl)carbonyl)-, monohydrochloride dihydrate Common Name: Terazosin hydrochloride dihydrate Structural Formula:

Chemical Abstracts Registry No.: 70024-40-7 Trade Name

Manufacturer

Country

Year Introduced

Hytrin

Abbott Laboratories

India

-

Terapress

Intas Pharmaceuticals Pvt. Ltd. China Pharm Chemical Co., Ltd.

India

-

China

-

Terazosin Hydrochloride Raw Materials

4-Amino-2-chloro-6,7-dimethoxyquinazoline N-(2-Tetrahydrofuroyl)piperazine Manufacturing Process To a solution of n-butanol (316 ml), water (24 ml) and N-(2tetrahydrofuroyl)piperazine (20 g) were added, while stirring, 4-amino-2chloro-6,7-dimethoxyquinazoline (22.2 g). The reaction mixture was heated to reflux and the reflux was maintained for about 9 h. Then the reaction mixture was cooled to room temperature and stirred at this temperature for about 1012 h. The crystals were collected by filtration, washed with n-BuOH and dried in vacuo at 40-50°C to yield 40.1 g (94%) of the 1-(4-amino-6,7-dimethoxy2-quinazolinyl)-4-(tetrahydrofuroyl)piperazine hydrochloride dihydrate

Terbinafine hydrochloride

3159

(Terazosin HCl dihydrate). References Schwartz E. et al; US Patent No. 6,248,888 B1; June 19, 2001; Assigned: Teva Pharmaceutical Industries Ltd., Petah Tigva (IL)

TERBINAFINE HYDROCHLORIDE Therapeutic Function: Antifungal Chemical Name: 1-Naphthalenemethanamine, N-(6,6-dimethyl-2-hepten-4ynyl)-N-methyl-, (E/Z)-, (2:5), hydrochloride Common Name: Terbinafine hydrochloride Structural Formula:

Chemical Abstracts Registry No.: 78628-80-5; 91161-71-6 (Base) Trade Name Lamisil

Manufacturer Novartis Pharmaceuticals UK

Country UK

Year Introduced -

Lamisil Lamisil Lamisil Lamisil Dermagel

Medley/EMS Sandoz-Wander Genpharm Inc. Novartis Pharma

Switz.

-

Raw Materials Sodium hydroxide Thionyl chloride Epichlorohydrin 3,3-Dimethylbutyne Butyl lithium Boron trifluoride diethyl etherate Triethylamine Methanesulfonyl chloride N-Methyl-1-naphthalenemethylamine hydrochloride

3160

Terbinafine hydrochloride

Manufacturing Process To an ice-cooled solution of N-methyl-1-naphthalenemethylamine hydrochloride (2.1 g) in methanol (40 ml) and water (10 ml) was added sodium hydroxide powder (2 g) followed by dropwise addition of epichlorohydrin (8 ml). The mixture was heated at 60°C for 3 h, then cooled to room temperature. Volatile materials were removed in vacuo and the residue was taken up in ethyl acetate and washed with water. The organic phase was collected, dried over sodium sulfate, filtered and evaporated to dryness. The crude mixture was purified by flash chromatrography on silica gel (grade 9385, Merck, 230-400 mesh, 60 A) using a solvent gradient of a mixture of hexane and ethyl acetate (95:5, 90:10 and 85:15) as eluent, affording the N-methyl-N-naphthylmethyl-2,3-epoxypropane (1.85 g, 81.5%) as an oil. To a solution of 3,3-dimethylbutyne (2.95 ml) in dry THF (50 ml) at -78°C was added a 2.5 M solution of n-BuLi in hexane (10 ml) dropwise. The mixture was allowed to warm to room temperature over 15 min and stirred at that temparature for a further 15 min, then was cooled back to -78°C and BF3OEt2 (3 ml) was added dropwise. The mixture was stirred for 15 min and 1.8 g of N-methyl-N-naphthylmethyl-2,3-epoxypropane, dissolved in THF (10 ml), was added dropwise. After stirring at -78°C for 2 h, saturated sodium bicarbonate solution (15 ml) was added, and the reaction mixture was allowed to warm to room temperature. The mixture was extracted with ethyl acetate (2 times 25 ml), and the combined organic fractions was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatrography on silica gel (grade 9385, Merck, 230-400 mesh, 60 a) using a mixture of hexane and ethyl acetate (85:15) as eluent, thereby affording the N-methyl-N-(1-naphthylmethyl)-2-hydroxy-heptan-4-ynyl-1-amine as an oil (1.95 g, 79%). To an ice-cooled solution of N-methyl-N-(1-naphthylmethyl)-2-hydroxyheptan-4-ynyl-1-amine (155 mg) in THF (10 ml) was added Et3N (0.35 ml) followed by methanesulfonyl chloride (0.075 ml). The resulting mixture was stirred at 0°C for 3 h, then filtered. The filtrate was concentrated in vacuo, dissolved in toluene (10 ml) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.37 ml) was added. The resulting mixture was heated at 80°C for 4 h, cooled to room temperature then poured onto a silica gel column and eluted with hexane (100%) followed by a mixture of hexane and ethyl acetate (95:5). Thus, a mixture of E- and Z-isomers of N-methyl-N-(1naphthylmethyl)-6,6-dimethylhept-2-en-4-ynyl)-1-amine were obtained in a ratio of 2:5 (95 mg, 66%). In practice it is usually used as hydrochloride salt. References Karimian K. et al., US Patent No. 5,817,875; Oct. 6, 1998

Terbutaline

3161

TERBUTALINE Therapeutic Function: Bronchodilator Chemical Name: 1-(3',5'-Dihydroxyphenyl)-2-(t-butylamino)-ethanol Common Name: Structural Formula:

Chemical Abstracts Registry No.: 23031-25-6; 23031-32-5 (Sulfate) Trade Name Bricanyl Bricanyl Bricanyl Bricanyl Bricanyl Brethine Terbasmin Arubendol Brethaire Bricalin Brican Bristurin Filair

Manufacturer Pharma-Stern Astra Lematte/Boinot Astra Fujisawa Ciba Geigy Farmitalia Ankerwerk Ciba Geigy Teva Draco Bristol Riker

Country W. Germany UK France US Japan US Italy E. Germany US Israel Sweden Japan UK

Year Introduced 1971 1971 1973 1974 1974 1975 1976 -

Raw Materials Benzyl-t-butylamine 3,5-Dibenzyloxy-ϖ-bromoacetophenone Hydrogen Manufacturing Process To a solution of 32 g of benzyl-t-butylamine in 300 ml of absolute ethanol at reflux temperature was added 32 g of 3,5-dibenzyloxy-ϖ-bromoacetophenone in 10 ml of dry benzene. The mixture was refluxed for 20 hours and then evaporated. When absolute ether was added to the residue, benzyl-tbutylamine hydrobromide was precipitated. The precipitated compound was filtered off and to the filtrate was added an excess of 2 N sulfuric acid. This caused precipitation of the hydrogen sulfate of 3,5-dibenzyloxy-ϖ-(benzyl-tbutylamino)-acetophenone which was recrystallized from acetone/ether. If the

3162

Terconazole

product is crystallized from different organic solvents, the melting point will vary with the type and amount of solvent of crystallization, but the product can be used directly for hydrogenation. 15 g of 3,5-dibenzyloxy-ϖ-(benzyl-t-butylamino)-acetophenone hydrogen sulfate in 200 ml of glacial acetic acid were hydrogenated in a Parr pressure reaction apparatus in the presence of 1.5 g of 10% palladium charcoal at 50°C and 5 atmospheres pressure. The reaction time was 5 hours. The catalyst was filtered off, the filtrate was evaporated to dryness and the hydrogen sulfate of 1-(3',5'-dihydroxyphenyl)-2-(t-butylamino)-ethanol was received. This compound is hygroscopic, but it can be transformed into a nonhygroscopic sulfate in the following manner. The hydrogen sulfate was dissolved in water and the pH of the solution was adjusted to 5.6 (pH-meter) with 0.1 N sodium hydroxide solution. The water solution was evaporated to dryness and the residue dried with absolute ethanol/benzene and once more evaporated to dryness. The remaining crystal mixture was extracted in a Soxhlet extraction apparatus with absolute methanol. From the methanol phase the sulfate of 1-(3',5'-dihydroxyphenyl)2-(t-butylamino)-ethanol crystallized. Melting point 246°C to 248°C. References Merck Index 8986 Kleeman and Engel p. 858 PDR pp. 889, 987 I.N. p. 925 REM p. 890 Wetterlin, K.Z.L. and Svensson, L.A.; US Patent 3,937,838; February 10, 1976; assigned to A.B. Draco (Sweden)

TERCONAZOLE Therapeutic Function: Antifungal Chemical Name: Piperazine, 1-(4-((2-(2,4-dichlorophenyl)-2-(1H1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl)methoxy)phenyl)-4-(1methylethyl)-, cisCommon Name: Terconazole; Triaconazole Chemical Abstracts Registry No.: 67915-31-5 Trade Name

Manufacturer

Country

Year Introduced

Terazol

Johnson and Johnson Pharmaceutical Research and Development, LLC

-

-

Terazol

Janssen-Ortho Inc.

Belgium

-

Terconazole

3163

Structural Formula:

Raw Materials 1H-1,2,4-Triazole Potassium carbonate Sodium hydride Methanesulfonyl chloride Sodium methanolate 1-(4-Hydroxyphenyl)-4-(1-methylethyl)piperazine cis-2-(Bromomethyl)-2-(2,4-dichlorophenyl)-l,3-dioxolan-4-ylmethyl benzoate Manufacturing Process A mixture of 1.6 parts of 1H-1,2,4-triazole, 54 parts of N.Ndimethylformamide and 45 parts of benzene is stirred and refluxed for 2 h. After cooling, 0.78 parts of sodium hydride dispersion 78% are added and the whole is stirred for 30 min at room temperature. Then there are added 8.9 parts of cis-2-(bromomethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-ylmethyl benzoate and stirring is continued overnight at 150°C. The reaction mixture is cooled and poured onto water. The product is extracted three times with benzene. The combined extracts are washed twice with water, dried, filtered and evaporated, yielding 8.5 parts of cis-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4triazol- 1-ylmethyl)-1,3-dioxolan-4-ylmethyl]benzoate as a residue. A mixture of 289 parts of cis-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1ylmethyl)-1,3-dioxolan-4-ylmethyl]benzoate, 200 parts of sodium hydroxide solution 50%, 1500 parts of 1,4-dioxane and 300 parts of water is stirred and refiuxed for 2 h. The reaction mixture is cooled and poured onto water. The product is extracted with dichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is purified by columnchromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The first fraction is collected and the eluent is evaporated, yielding 89 parts cis-2-(2,4-dichlorophenyl)-2-(1H-1,2,4triazol-1-ylmethyl)-1,3-dioxolane-4-methanol; melting point 138.2°C. A mixture of 30.6 parts of cis-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1ylmethyl)-l,3-dioxolane-4-methanol and 75 parts of pyridine is stirred at room temperature and there are added dropwise 17.2 parts of methanesulfonyl chloride. Upon completion, stirring is continued overnight at room temperature. The reaction mixture is poured onto ice-water and the product is extracted twice with dichloromethane. The combined extracts are washed

3164

Terfenadine

twice with a diluted hydrochloric acid solution and twice with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The first fraction is collected and the eluent is evaporated, yielding 21 parts of cis-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1ylmethyl)-1,3-dioxolan-4-ylmethyl]methanesulfonate; melting point 98°C. A mixture of 1-(4-hydroxyphenyl)-4-(1-methylethyl)piperazine, cis-[2-(2,4dichloro-phenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4ylmethyl]methanesulfonate, potassium carbonate and N,N-dimethylformamide is stirred and heated overnight at 120°C. The reaction mixture is cooled and poured onto water. The product is extracted twice with dichloromethane. The combined extracts are washed twice with a potassium carbonate solution, dried, filtered and evaporated. The residue is taken up in methanol and a sodium methanolate solution 30% are added. The whole is stirred and refluxed for 1 h. The mixture is poured onto water and the layers are separated. The organic phase is dried, filtered and evaporated. The cis-1-(4((2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4yl)methoxy)phenyl)-4-(1-methylethyl)piperazine was obtained, melting point 116.3°C. References Heeres J. et al.; US Patent No. 4,144,346; March 13, 1979; Assigned: Janssen Pharmaceutica N.V., Beerse, Belgium

TERFENADINE Therapeutic Function: Antihistaminic, Bronchodilator Chemical Name: 1-Piperidinebutanol, α-(4-(1,1-dimethylethyl)phenyl)-4(hydroxydiphenylmethyl)Common Name: Terfenadine Structural Formula:

Chemical Abstracts Registry No.: 50679-08-8

Terofenamate Trade Name Histafen Seldane Seldane Terfenadine Terfenadine

Manufacturer Berk Omega Labs. Hoechst Marion Roussel Zenith Labs. Gruppo Lepetit S.p.A.

Country Canada Italy

3165

Year Introduced -

Raw Materials Potassium hydrocarbonate Potassium iodide Sodium methoxide

Potassium borohydride 4'-tert-Butyl-4-chlorobutyrophenone α,α-Diphenyl-4-piperidinemethanol

Manufacturing Process A mixture of 107 g (0.4 mole) of α,α-diphenyl-4-piperidinemethanol, 105 g (0.44 mole) of 4'-tert-butyl-4-chlorobutyrophenone, 70 g (0.7 mole) of potassium bicarbonate, and a small amount of potassium iodide in 600 ml of toluene was refluxed and stirred for 2.5 days then filtered. The filtrate was treated with charcoal, filtered through celite then treated with ethereal HCl. The resulting solid was recrystallized from methanol and isopropyl alcohol to give the 4'-tert-butyl-4-[4-(α-hydroxy-α-phenylbenzyl)piperidino]butyrophenone hydrochloride, melting point 234°-235°C. To a mixture of 4.2 g (0.0083 mole) of 4'-tert-butyl-4-[4-(α-hydroxy-αphenylbenzyl)piperidino]-butyrophenone hydrochloride and 0.54 g (0.01 mole) of sodium methoxide in 25 ml of methanol is added 2.16 g (0.04 mole) of potassium borohydride. The reaction mixture is stirred overnight, diluted with water and the methanol removed under reduced pressure. The remaining material is extracted with chloroform, washed with water, dried over magnesium sulfate and filtered. The filtrate is concentrated, and the residue is recrystallized from acetone-water to give 4-[α-(p-tert-butylphenyl)-αhydroxybenzyl]-α-phenyl-1-piperidinebutanol, melting point 161°-163°C. References Carr A.A., Kinsolving C.R.; US Patent No. 3,941,795; March 2, 1976; Assigned: Richardson-Merrell Inc., Wilton, Conn Carr A.A., Kinsolving C.R.; US Patent No. 3,806,526; April 23, 1974; Assigned: Richardson-Merrell Inc., New York, N.Y.

TEROFENAMATE Therapeutic Function: Antiinflammatory, Analgesic Chemical Name: 2-[(2,6-Dichloro-3-methylphenyl)amino]benzoic acid ethoxymethyl ester Common Name: Etoclofene

3166

Testolactone

Structural Formula:

Chemical Abstracts Registry No.: 29098-15-5 Trade Name Etofen Ilfi

Manufacturer Lusofarmaco

Country Italy

Year Introduced 1980

Raw Materials N-2,6-Dichloro-m-tolylanthranilic acid Chloromethyl ethyl ether Manufacturing Process 10 g sodium salt of N-2,6-dichloro-m-tolylanthranilic acid, 3 ml chloromethyl ethyl ether and 80 ml dry acetone were refluxed for 12 hours on waterbath under stirring. The solid was filtered off, and the solution evaporated to dryness. The residue was dissolved in chloroform, washed with sodium carbonate solution, then with water until neutral. After drying on sodium sulfate, the solution was evaporated to dryness. The obtained product was recrystallized from 95% ethanol. Melting point 73°C to 74°C. References Merck Index 8992 DFU 1 (8) 421 (1976) I.N. p. 927 Manghisi, E.; US Patent 3,642,864; February 15, 1972; assigned to Istituto Luso Farmaco D'Italia S.R.L. (Italy)

TESTOLACTONE Therapeutic Function: Cancer chemotherapy Chemical Name: D-Homo-17-α-oxaandrosta-1,4-diene-3,17-dione Common Name: 1-Dehydrotestololactone Chemical Abstracts Registry No.: 968-93-4

Testolactone

3167

Structural Formula:

Trade Name Fludestrin Teslac

Manufacturer Heyden Squibb

Country W. Germany US

Year Introduced 1968 1969

Raw Materials Bacterium Cylindrocarpon radicola Corn steep liquor Brown sugar Manufacturing Process (a) Fermentation: A medium of the following composition is prepared: 3.0 grams cornsteep liquor solids; 3.0 grams NH4H2PO4; 2.5 grams CaCO3; 2.2 grams soybean oil; 0.5 gram progesterone and distilled water to make 1 liter. The medium is adjusted to pH 7.00.1. Then, 100 ml portions of the medium are distributed in 500 ml Erlenmeyer flasks and the flasks plugged with cotton and sterilized in the usual manner (i.e., by autoclaving for 30 minutes at 120°C). When cool, each of the flasks is inoculated with 5 to 10% of a vegetative inoculum of Cylindrocarpon radicola [the vegetative inoculum being grown from stock cultures (lyophilized vial or agar slant) for 48 to 72 hours in a medium of the following composition: 15 grams cornsteep liquor; 10 grams brown sugar; 6 grams NaNO3; 0.001 gram ZnSO4; 1.5 grams KH2PO4;0.5 gram MgSO47H2O; 5 grams CaCO3; 2 grams lard oil; and distilled water to make 1 liter]. The flasks are then placed on a reciprocating shaker (120 one and one-half inch cycles per minute) and mechanically shaken at 25°C for 3 days. The contents of the flasks are then pooled and, after the pH of the culture is adjusted to about 40.2 with sulfuric acid, filtered through Seitz filter pads to separate the mycelium from the fermented medium. (b) Extraction: 40 liters of the culture filtrate obtained in (a) is extracted with 40 liters chloroform in an extractor (e.g., Podbelniak, US Patent 2,530,886, or improvements thereon) and the filtered chloroform extract is evaporated to dryness in vacuo. The residue (11.1 grams) is taken up in 200 ml of 80% aqueous methanol, and the resulting solution is extracted four times with 100 ml portions of hexane. The 80% aqueous methanol solution is then concentrated in vacuo until crystals appear; and, after cooling at 0°C for several (usually about 3 to 4) hours, the crystals formed are recovered by filtration. About 2.9 grams 1-dehydrotestololactone (MP 217° to 217.5°C) are thus obtained. Concentration of the mother liquors yields additionally about 6.0 grams of the lactone. Recrystallization from acetone yields a purified 1-

3168

Testosterone cypionate

dehydrotestololactone having a melting point of 218° to 219°C. References Merck Index 8999 Kleeman and Engel p. 860 PDR p. 1768 OCDS Vol. 2 p. 160 (1980) I.N. p. 928 REM p. 1000 Fried, J. and Thoma, R.W.; US Patent 2,744,120; May 1, 1956; assigned to Olin Mathieson Chemical Corporation

TESTOSTERONE CYPIONATE Therapeutic Function: Androgen Chemical Name: 17β-(3-Cyclopentyl-1-oxopropoxy)androst-4-en-3-one Common Name: Depo-testosterone Structural Formula:

Chemical Abstracts Registry No.: 58-20-8 Trade Name Depo-Testosterone T-Ionate P.A. Andro-Cyp Andronate Ciclosterone Depostomead Depotest Dep-Test Dep-Testosterone

Manufacturer Upjohn Tutag Keene Pasadena Farmigea Spencer-Mead Blaine Sig Rocky Mtn.

Country US US US US Italy US US US US

Year Introduced 1951 1970 -

Testosterone enanthate Trade Name Durandro Jectatest Malogen Cyp Pertestis Dep. Testomed P.A. Testorit-Dep

Manufacturer Ascher Reid-Provident O'Neal, Jones and Feldman Orma Medics Gallo

Country US US US Italy US Italy

3169

Year Introduced -

Raw Materials β-Cyclopentylpropionic acid Testosterone 3-enol-ethyl ether Acetic anhydride Hydrogen chloride Manufacturing Process 1 g of crude 3-enol-ethyl ether of testosterone dissolved in 3 cc of pyridine is treated with 2 cc of β-cyclopentylpropionic anhydride (obtained from the βcyclopentylpropionic acid and acetic anhydride: boiling point 180°C/2 mm Hg). After standing at room temperature overnight the mixture is diluted with water and extracted with ether, the ethereal layer, washed with water to neutrality and dried, is evaporated by vacuum. The oily residue is taken up in petroleum ether and filtered through a layer of aluminum oxide, which is afterwards washed with a further amount of petroleum ether. The solution so filtered and purified is evaporated to dryness; the crystalline residue is recrystallized from a small amount of methanol containing a trace of pyridine: about 1 g of 3-enol-ethyl-ether of the β-cyclopentyl propionate of testosterone, melting point 86°C to 88°C, is so obtained (by further recrystallization melting point 90°C to 91°C). This product (that may be employed either in the crystalline state, or in the oily one, that is, before the purification by filtration through aluminum oxide) by treatment with a small amount of hydrochloric acid in acetone solution yields the β-cyclopentyl propionate of testosterone, melting point 99°C to 101°C (recrystallized from methanol). References Merck Index 9002 Kleeman and Engel p. 861 PDR pp. 950, 1033, 1841 OCDS Vol. 1 p. 172 (1977) I.N. p. 929 REM p. 1001 Ercoli, A. and de Ruggieri, P.; US Patent 2,742,485; April 17, 1956; assigned to Francesco Vismara Societa per Azioni & A. Ercoli (Italy)

TESTOSTERONE ENANTHATE Therapeutic Function: Androgen

3170

Testosterone enanthate

Chemical Name: 17β-[(1-Oxoheptyl)oxy]androst-4-en-3-one Common Name: Structural Formula:

Chemical Abstracts Registry No.: 315-37-7 Trade Name Delatestryl Reposo-TMD Testate Testostroval PA Androtardyl Andryl Arderone Atlatest Deladumon Delatest Dura-Testate Duratesterone Enarmon Everone Malogen LA Malogex Primoteston Reprosteron Repro Testro Med Retandros Span-Test Tesone Testanate Testinon Testisan Depo Testo-Enant Testone Testrin Testoviron Testrone

Manufacturer Squibb Canfield Savage Tutag S.E.P.P.S. Keene Buring-Arden I.C.I. Squibb Dunhall Ries Myers-Carter Teikoku Zoki Hyrex Fellows-Testagar Stickley Schering Spencer-Mead Medics Rocky Mtn. Scrip Sig Kenyon Mochida I.E. Kimya Evi Geymonat Sud Ortega Pasadena Schering N. Amer. Pharm.

Country US US US US France US US US US US US US Japan US US Canada W. Germany US US US US US US Japan Turkey Italy US US W. Germany US

Year Introduced 1954 1961 1970 1970 -

Tetrabenazine

3171

Raw Materials Oenanthic acid Testosterone Manufacturing Process A mixture of testosterone, pyridine and oenanthic acid anhydride is heated for 1 1/2 hours to 125°C. The cooled reaction mixture is decomposed with water while stirring and cooling. After prolonged standing at a temperature below room temperature, the whole is extracted with ether and the ethereal solution is washed consecutively with dilute sulfuric acid, water, 5% sodium hydroxide solution, and again with water. The crude ester remaining on evaporation of the dried ether solution, after recrystallization from pentane, melts at 36° to 37.5°C. References Merck Index 9003 Kleeman and Engel p. 862 PDR pp. 1033, 1604 I.N. p. 929 REM p. 1001 Junkmann, K., Kathol, J. and Richter, H.; US Patent 2,840,508; June 24, 1958; assigned to Schering AG, Germany

TETRABENAZINE Therapeutic Function: Tranquilizer Chemical Name: 1,3,4,6,7,11b-Hexahydro-9,10-dimethoxy-3-(2methylpropyl)-2H-benzo[a]quinolizin-2-one Common Name: Structural Formula:

Chemical Abstracts Registry No.: 58-46-8 Trade Name

Manufacturer

Country

Year Introduced

Nitoman

Roche

UK

1960

3172

Tetracaine hydrochloride

Raw Materials Paraformaldehyde Sodium Ethanol

Isobutyl malonic acid dimethyl ester Hydrogen chloride 1-Carbethoxymethyl-6,7-dimethoxy-1,2,3,4tetrahydroisoquinoline

Manufacturing Process 280 grams of 1-carbethoxymethyl-6,7-dimethoxy-1,2,3,4tetrahydroisoquinoline, 150 grams of mono-isobutylmalonic acid dimethyl ester and 35 grams of paraformaldehyde were refluxed for 24 hours in 1,000 ml of methanol. Upon cooling, 1-carbethoxymethyl-2-(2,2-dicarbomethoxy-4methyl-n-pentyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline crystallized; MP after recrystallization from methanol, 94° to 96°C. The latter was subjected to Dieckmann cyclization, hydrolysis and decarboxylation in the following manner. 28 grams of sodium was dissolved in 650 ml of absolute ethanol, the solution was concentrated to dryness, and the residue was mixed with 3,600 ml of toluene and 451 grams of the intermediate prepared above. The mixture was heated, and the methanol formed by condensation was distilled off until the boiling point of toluene was reached. The mixture was thereupon refluxed for 2 hours, and then it was concentrated to dryness. The residue was dissolved in 5,200 ml of 3 N hydrochloric acid and heated for 14 hours at 120°C, thereby effecting hydrolysis and decarboxylation. The mixture was cooled, washed with diethyl ether, decolorized with carbon, made alkaline and taken up in diethyl ether. The process yields 2-oxo-3-isobutyl-9,10-dimethoxy1,2,3,4,6,7-hexahydro-11b-benzo[a]quinolizine; MP after recrystallization from diisopropyl ether, 126° to 128°C. References Merck Index 9009 OCDS Vol. 1 p. 350 (1977) I.N. p. 931 Brossi, A., Schnider, O. and Walter, M.; US Patent 2,830,993; April 15, 1958; assigned to Hoffmann-La Roche, Inc.

TETRACAINE HYDROCHLORIDE Therapeutic Function: Local anesthetic Chemical Name: Benzoic acid, 4-(butylamino)-, 2-(dimethylamino)ethyl ester monohydrochloride Common Name: Tetracaine hydrochloride; Amethocaine hydrochloride; Dicaine Chemical Abstracts Registry No.: 136-47-0

Tetracaine hydrochloride

3173

Structural Formula:

Trade Name

Manufacturer

Country

Year Introduced

Anestesia topica

Miro

-

-

Anestol

Continental

-

-

Butylcain

Tanabe

-

-

Medicain

Grunau

-

-

Schleimhautanaestheticum

Tief

-

-

Supracaine

Hoechst-Canada

-

-

Raw Materials n-Butyl bromide 4-Aminobenzoic acid sodium salt Hydrochloric acid Hydrochloride of β-dimethylaminoethanol Manufacturing Process 4-Butylaminobenzoic acid is produced by boiling an aqueous solution of the sodium salt of 4-aminobenzoic acid with n-butyl-bromide. It forms a colorless crystalline powder melting at 153-154°C. Equimolecular quantities of 4-butylaminobenzoic acid and the hydrochloride of β-dimethylaminoethanol are suspended in 10 times their joint weight of toluene. The mixture is saturated with hydrochloric acid gas and heated in an oil bath at about 150°C while a current of hydrochloric acid, gas is slowly passed through the mixture so that toluene slowly distils. Along with toluene the water produced by the esterification distils. After heating for about 10 hours the mixture is cooled and water is added until the salt is dissolved. The layer of toluene is separated and the ester base precipitated from the aqueous solution by means of a solution of sodium carbonate. By dissolving the base in ether, drying the ether solution separated over potassium carbonate and adding alcoholic hydrochloric acid, to the solution until it is neutral to litmus, the monohydrochloride is obtained in the form of a colorless crystalline powder which, when recrystallized from alcohol, melts at 147-148°C. The 4-butylaminobenzoic acid β-di-methylaminoethylester monohydrochloride is a colorless crystalline powder, which is easily soluble in water. The solution may be sterilized by boiling without decomposition having to be feared. The base can be precipitated from the aqueous solution of the salt; it is at first in the form of an oil but soon solidifies, forms colorless crystals and melts at 43°C. The picrate melts at 120°C. When treated with oxalic acid, the base

3174

Tetracycline

forms a neutral oxalate which is easily soluble in water and an acid oxalate which is very difficultly soluble in cold water. In practice it is usually used as hydrochloride salt. References OTTO EISLEB; US Patent No. 1,889,645; Nov. 29, 1932; Assigned to WINTHEOP CHEMICAL COMPANY, IETC., OF NEW YORK, N. Y., A CORPORATION OF NEW YORK

TETRACYCLINE Therapeutic Function: Antibacterial Chemical Name: 4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro3,6,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2naphthacenecarboxamide Common Name: Deschlorobiomycin; Omegamycin Structural Formula:

Chemical Abstracts Registry No.: 60-54-8 Trade Name Tetracyn Achromycin Polycycline Panmycin Cancycline Abricycline Biotetra Copharlan Economycin Mervacycline Mysteclin Pediatetracycline Pervasol

Manufacturer Pfizer Lederle Bristol Upjohn Canfield Farmakhim I.E. Kimya Evi Cophar D.D.S.A. Byk Squibb Theranol Poen

Country US US US US US Bulgaria Turkey Switz. UK Netherlands US France Argentina

Year Introduced 1953 1953 1954 1955 1964 -

Tetracycline Trade Name Sanbiotetra SK-Tetracycline Sumycin Teclinazets Tetra-Co Tetramig Tetra-Proter

Manufacturer Santos SKF Squibb Miluy Coastal Inava Proter

Country Spain US US Spain US France Italy

3175

Year Introduced -

Raw Materials Chlortetracycline Hydrogen Bacterium Streptomyces aureofaciens Manufacturing Process Tetracycline is usually prepared by the catalytic dechlorination of chlortetracycline as described in US Patents 2,699,054 and 3,005,023, or obtained directly by fermentation of Streptomyces aureofaciens or Streptomyces viridifaciens according to US Patents 2,712,517, 2,734,018, 2,886,595 and 3,019,173. The purification of tetracycline produced by either route is described in US Patent 3,301,899. The production of tetracycline by catalytic dechlorination is described in US Patent 2,699,054 as follows: Pure chlortetracycline (4.8 grams) was suspended in 100 ml of methanol and sufficient anhydrous dioxane was added to completely dissolve the product. To the solution was added 0.5 gram of 5% palladium-on-charcoal catalyst. The mixture was placed in a conventional hydrogenation apparatus and subjected to a pressure of 50 psi of hydrogen while being agitated. After the initial drop in pressure due to the absorption of gas by the catalyst and the solvent, there was a steady drop in pressure due to the hydrogenation of the antibiotic. After approximately 1 mol of hydrogen had been absorbed, no further reaction was observed. This occurred after about 2 hours. The catalyst was filtered and washed with boiling methanol and boiling dioxane. The solution gave a positive test for chloride ion when treated with silver nitrate solution. It also possessed a strongly acidic reaction demonstrating the release of the nonionic chlorine in the form of hydrogen chloride. A bioassay of the crude product in solution indicated a potency of approximately 580 µg/mg with oxytetracycline as the standard at a potency of 1,000 µg/mg. The solution was concentrated under vacuum at room temperature and the residual liquid was dried from the frozen state under vacuum. 3.1 grams of bright yellow amorphous tetracycline hydrochloride was obtained. This product may be converted to tetracycline per se by redissolving it in water, carefully neutralizing it to pH 4.5 with dilute sodium hydroxide, and recovering the product by drying the solution.

3176

Tetracycline phosphate complex

References Merck Index 9021 Kleeman and Engel p. 864 PDR pp.996, 1391, 1723, 1752, 1767 OCDS Vol. 1 p. 212 (1977) I.N. p. 932 REM p. 1207 Conover, L.H.; US Patent 2,699,054; January 11, 1955 Gourevitch, A. and Lein, J.; US Patent 2,712,517; July 5, 1955; assigned to Bristol Laboratories Inc. Minieri, P.P., Sokol, H. and Firman, M.C.; US Patent 2,734,018; February 7, 1956; assigned to American Cyanamid Company Heinemann, B. and Hooper, I.R.; US Patent 2,886,595; May 12, 1959; assigned to Bristol Laboratories Inc. Miller, P.A.; US Patent 3,005,023; October 17, 1961; assigned to American Cyanamid Company Arishima, M. and Sekizawa, Y.; US Patent 3,019,173; January 30, 1962; assigned to American Cyanamid Company Kaplan, M.A. and Granatek, A.P.; US Patent 3,301,899; January 31, 1967; assigned to Bristol-Myers Company

TETRACYCLINE PHOSPHATE COMPLEX Therapeutic Function: Antibacterial Chemical Name: Tetracycline phosphate complex Common Name: Structural Formula: See tetracicline for the basic formula Chemical Abstracts Registry No.: 1336-20-5 Trade Name

Manufacturer

Country

Year Introduced

Tetrex Sumycin Panmycin Phos Austrastaph Binicap Biocheclina Bristaciclina Retard Conciclina Devacyclin Fusfosiklin Hexacycline Tetraksilin Tetralet Tetramin

Bristol Squibb Upjohn C.S.L. S.A.M. Wolner Antibioticos Lusofarmaco Deva T.E.M.S. Diamant Atabay Fako Efeyn

US US US Australia Italy Spain Spain Italy Turkey Turkey France Turkey Turkey Spain

1956 1957 1957 -

Tetracycline phosphate complex Trade Name Tetrex Sumycin Panmycin Phos Austrastaph Binicap Biocheclina Bristaciclina Retard Conciclina Devacyclin Fusfosiklin Hexacycline Tetraksilin Tetralet Tetramin

Manufacturer Bristol Squibb Upjohn C.S.L. S.A.M. Wolner Antibioticos Lusofarmaco Deva T.E.M.S. Diamant Atabay Fako Efeyn

Country US US US Australia Italy Spain Spain Italy Turkey Turkey France Turkey Turkey Spain

3177

Year Introduced 1956 1957 1957 -

Raw Materials Tetracycline Phosphorus pentoxide Manufacturing Process In a 500-ml round-bottomed flask equipped with stirrer, condenser and thermometer was placed 7.1 grams (0.05 mol) P2O5 which was immediately covered with 100 ml of chloroform. To the mixture was added with stirring 0.9 ml (0.05 mol) of distilled water. In a few minutes, a lower oily layer appeared, which was believed to be freshly formed metaphosphoric acid resulting from the action of the P2O5 with an equimolar amount of water. To this mixture was added 100 ml of methanol and on continued stirring, the lower oily layer disappeared in the methanol forming a complete pale yellowish-green colored solution. An additional 50 ml of methanol was added to the flask and then 22.2 grams (0.05 mol) of tetracycline, neutral form, was added portionwise intermittently with another 50 ml of methanol. A clear solution was maintained throughout the addition of the tetracycline. After addition of all of the tetracycline, the solution was a deep orange color and the temperature in the reaction flask was 35°C. One hour after addition of the tetracycline, the clear reaction solution was poured into 1,500 ml of chloroform. A yellow product separated and was collected on a coarse sintered glass filter and air dried. The tetracyclinemetaphosphoric acid complex weighed about 10 grams, contained 7.34% of phosphorus and had a bioassay of 634 gammas per milligram. Solubility in water is 750 mg/ml. References Merck Index 9021 I.N. p. 933

3178

Tetrahydrozoline hydrochloride

REM p. 1208 Sieger, G.M. Jr. and Weidenheimer, J.F.; US Patent 3,053,892; September 11, 1962; assigned to American Cyanamid Company

TETRAHYDROZOLINE HYDROCHLORIDE Therapeutic Function: Nasal decongestant, Pharmaceutic aid Chemical Name: 4,5-Dihydro-2-(1,2,3,4-tetrahydro-1-naphthalenyl)-1Himidazole hydrochloride Common Name: Tetryzoline HCl Structural Formula:

Chemical Abstracts Registry No.: 522-48-5; 84-22-0 (Base) Trade Name Tyzine Visine Constrilia Azolin Burnil Collyrium Ischemol Murine Narbel Nasin Oftan-Starine Rhinopront Stilla Tinarhinin Typinal Yxin

Manufacturer Pfizer Leeming P.O.S. Fischer Kurtsan Wyeth Farmila Ross Chugai Abic Star Mack Abic VEB Berlin Chemie Ikapharm Pfizer

Raw Materials 1,2,3,4-Tetrahydro-α-naphthoic acid Ethylenediamine Hydrogen chloride

Country US US France Israel Turkey US Italy US Japan Israel Finland W. Germany Israel E. Germany Israel W. Germany

Year Introduced 1954 1958 1979 -

Tetrazepam

3179

Manufacturing Process A mixture of 540 grams (9.0 mols) of ethylenediamine, 270 grams (1.53 mols) of 1,2,3,4tetrahydro-α-naphthoic acid, and 360 ml (4.32 mols) of concentrated hydrochloric acid was introduced into a two-liter, three-necked flask fitted with a thermometer, stirrer, and distillation takeoff. The mixture was distilled under a pressure of about 20 mm of mercury absolute until the temperature rose to 210°C. Thereafter, heating was continued under atmospheric pressure and when the temperature reached about 260°C, an exothermic reaction was initiated. The heat was then adjusted to maintain a reaction temperature of 275° to 280°C for 45 minutes and the mixture thereafter cooled to room temperature. 900 ml of 4 N hydrochloric acid was added and the aqueous layer stirred with warming until a clear, brown solution resulted. This brown solution was made strongly alkaline with sodium hydroxide. The oil that separated solidified and was collected on a filter leaving filtrate A. The solid was dissolved in 370 ml of alcohol with warming, and the solution was treated with 130 ml of concentrated hydrochloric acid with stirring and cooling. This acidified mixture was diluted with 300 ml of ether and chilled. The solid salt was collected and dried and the filtrate concentrated to approximately 300 ml, diluted with 300 ml of ether and the salt which separated collected and dried. Filtrate A was extracted with ether, dried, acidified with alcoholic hydrogen chloride, and the salt which separated was collected and dried. There was thus obtained, when all the salt had been combined, 250 grams (69.3% of the theoretical yield) of 2-(1,2,3,4-tetrahydro-1-naphthyl)imidazoline hydrochloride, melting at 256° to 257°C. References Merck Index 9042 Kleeman and Engel p. 867 PDR pp.974, 1555, 1945 OCDS Vol. 1 p. 242 (1977) I.N. p. 936 REM p. 890 Synerholm, M.E., Jules, L.H. and Sahyun, M.; US Patent 2,731,471; January 17, 1956; assigned to Sahyun Laboratories Gardocki, J.F., Hutcheon, D.E., Lanbach, G.D. and P'an, S.Y.; US Patent 2,842,478; July 8, 1958; assigned to Chas. Pfizer & Co., Inc.

TETRAZEPAM Therapeutic Function: Muscle relaxant Chemical Name: 7-Chloro-5-(1-cyclohexen-1-yl)-1,3-dihydro-1-methyl-2H1,4-benzodiazepin-2-one Common Name: -

3180

Tetrazepam

Structural Formula:

Chemical Abstracts Registry No.: 10379-14-3 Trade Name Myolastan Musaril

Manufacturer Clin-Comar-Byla Mack-Midy

Country France W. Germany

Year Introduced 1969 1980

Raw Materials Sodium hypochlorite Lithium carbonate Sodium methylate Methyl iodide 7-Chloro-5-cyclohexyl-2-oxo-2,3-dihydro-1H-benzo[f]diazepine-1,4 Manufacturing Process 1,7-Dichloro-5-Cyclohexyl-2-Oxo-2,3-Dihydro-1H-Benzo[f]Diazepine-1,4: (a) Process Using Sodium Hypochlorite - 40 ml of a solution of sodium hypochlorite of 14.5 British chlorometric degrees are added to a suspension of 5.4 grams of 7-chloro-5-cyclohexyl-2-oxo-2,3-dihydro-1H-benzo[f]diazepine1,4 in 80 ml of methylene chloride. The mixture is stirred at room temperature for 15 minutes; the solid dissolves rapidly. The organic layer is decanted, washed with water, dried over anhydrous sodium sulfate and the solvent evaporated under reduced pressure without exceeding a temperature of 30°C. The residue is taken up in a little diisopropyl ether and the crystals which form are dried. They are recrystallized as rapidly as possible from ethyl acetate. Colorless crystals are obtained (3.9 grams; yield, 85%); MP = 163°C, with decomposition. (b) Process Using Tertiary-Butyl Hypochlorite - 1.2 grams of tertiary-butyl hypochlorite are added to a suspension of 2.7 grams of 7-chloro-5-cyclohexyl2-oxo-2,3-dihydro-1H-benzo[f]diazepine-1,4 in 20 ml of methylene chloride and the mixture is stirred and at the same time cooled in a water bath for 30 minutes. The solid dissolves in about 15 minutes. The product is evaporated to dryness under reduced pressure at a temperature below 40°C. The residue is taken up in diisopropyl ether and the crystals which separate are dried. Colorless crystals are obtained (2.8 grams; yield, 98%); MP = 161° to 162°C, with decomposition, according to US Patent 3,551,412. 7-Chloro-5-(1'-Chlorocyclohexyl)-2-Oxo-2,3-Dihydro-1H-Benzo[f]Diazepine1,4: A solution of 117 grams of the compound prepared above in 450 ml ethyl acetate is heated under reflux until a precipitate begins to form. From then onwards reflux is continued until a negative reaction is obtained when the reaction mixture is tested with a solution of sodium iodide in acetone. The

Tetrazepam

3181

reaction mixture is left to cool and the solid which separates is dried. Colorless crystals are obtained (76 grams), MP = 194° to 195°C, with decomposition. A second portion (14 grams) is isolated by concentrating the mother liquor, MPk = 194° to 195°C, with decomposition. The total yield is 77%. The melting point is raised to 196° to 197°C by recrystallization from ethyl acetate. 7-Chloro-5-(1'-Cyclohexenyl)-2-Oxo-2,3-Dihydro-1H-Benzo[f]Diazepine-1,4: 68 grams of 7-chloro-5-(1'-chlorocyclohexyl)-2-oxo-2,3-dihydro-1Hbenzo[f]diazepine-1,4, 34 grams of lithium carbonate and 17 grams of lithium bromide and 340 ml of anhydrous dimethylformamide are placed in a threenecked flask equipped with a mechanical stirrer, immersion thermometer and a reflux condenser connected with a bubble counter. The reaction mixture is gradually heated, with stirring, until evolution of carbon dioxide commences (about 100°C) and the temperature is maintained thereat until the reaction ceases. The temperature is then raised to 110°C and held thereat for 15 minutes. The reaction mixture is allowed to cool and the mineral salts separated and dried. The solvent is evaporated under reduced pressure and the residue dissolved in water. It is allowed to crystallize, dehydrated, dried and then recrystallized from ethyl acetate. The product is yellowish crystals (47.5 grams; yield, 80%); MP = 207° to 208°C. 7-Chloro-5-(1'-Cyclohexenyl)-1-Methyl-2-Oxo-2,3-Dihydro-1HBenzo[f]Diazepine-1,4: 9.7 grams of sodium methylate are added to a solution of 16.5 grams of 7-chloro-5-(1'-cyclohexenyl)-2-oxo-2,3-dihydro-1Hbenzo[f]diazepine-1,4 dissolved in 120 ml of dry dimethylformamide and the mixture stirred for one-half hour. The reaction mixture is cooled in a water bath and a solution of 33.8 grams of methyl iodide dissolved in 35 ml of anhydrous dimethylformamide is then slowly added with stirring. The solution becomes dark brown in color and a precipitate forms. It is stirred for 2 hours, then diluted with a large volume of water and extracted with ethyl acetate. The ethyl acetate solution is washed with water, dried over anhydrous sodium sulfate and the solvent evaporated under reduced pressure. The residue is crystallized from a small volume of ethyl acetate. Brownish yellow crystals are obtained (9 grams; yield, 52%), MP = 144°C. References Merck Index 9065 Kleeman and Engel p. 865 DOT 6 (4) 148 (1970) I.N. p. 936 Berger,