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) 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 Trade Name Manufacturer Country Year Introduced Ziagen GlaxoSmithKline - - Ziagen Glaxo Wellcome - - Ziagenavir Glaxo Wellcome - - 1 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,N- dimethylformamidene (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-1- methanol (IV) in the presence of triethylamine and NaOH gave [2-amino-4- chloro-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 2 Abafungin Trade Name Manufacturer Country Year Introduced Abafungin York Pharma - - 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-(2,4- Dimethylphenoxy)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 Abamectin 3 Trade Name Manufacturer Country Year Introduced Abamectin Yellow River Enterprise Co. (a.k.a Yelori) - - Kraft TM Cheminova - - Abamectin 1.8% LIFES Labo - - Abamectin Ningbo Sega Chemical Company - - Avomec Institutul Pasteur Romania - - Duotin Merial - - Enzec Merck Sharp and Dohme Ltd - - 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. 4 Abamectin 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) Abamectin 5 ABANOQUIL MESYLATE Therapeutic Function: Antiarrhythmic, Coronary vasodilator Chemical Name: 4-Amino, 2-(3,4-dihydro-6,7-dimethoxy-2(1H)-isoquinolyl)- 6,7- dimethoxyquinoline monomethanesulfonate Common Name: Abanoquil mesylate Structural Formula: Chemical Abstracts Registry No.: 118931-00-3; 90402-40-7 (Base) 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-3,4- dihydro-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-2- yl)ethylidineamino]-4,5-dimethoxybenzonitrile: 6 Abanoquil mesylate Trade Name Manufacturer Country Year Introduced Abanquil Onbio Inc. - - To a stirred solution of 1-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2- yl)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]-4,5- dimethoxybenzonitrile as an yellow solid. Synthesis of 2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-6,7- dimethoxyquinolin-4-ylamine hemifumarate hydrate (abanoquil): To a stirred solution of 2-[1-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2- yl)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-(6,7- dimethoxy-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)-6,7- dimethoxyquinolin-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 Abarelix 7 Chemical Name: D-Alaninamide, N-acetyl-3-(2-naphthalenyl)-D-alanyl-4- chloro-D-phenylalanyl-3-(3-pyridinyl)-D-alanyl-L-seryl-N-methyl-L- tyrosyl-D-asparaginyl-L-leucyl-N6-(1-methylethyl)-L-lysyl-L-prolyl- Common Name: Abarelix; PPI-149 Structural Formula: Chemical Abstracts Registry No.: 183552-38-7 Raw Materials Thioanisole Methylbenzyhydramine resin Trifluoroacetic acid Diisopropylethylamine 1-Hydroxybenzotriazole Boc-protected amino acids Dicyclohexylcarbodiimide Silver(I) oxide 2-Iodopropane 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 8 Abarelix Trade Name Manufacturer Country Year Introduced Plenaxis Praecis Pharmaceuticals - -