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The Handbook for Chemical Process Research and Development focuses on developing processes for chemical and pharmaceutical industries. Forty years ago there were few process research and development activities in the pharmaceutical industry, partially due to the simplicity of the drug molecules. However, with the increasing structural complexity, especially the introduction of chiral centers into the drug molecules and strict regulations set by the EMA and FDA, process RD has become one of the critical departments for pharmaceutical companies. This book assists with the key responsibility of process chemists to develop chemical processes for manufacturing pharmaceutical intermediates and final drug substances for clinical studies and commercial production.
Handbook for Chemical Process Research and Development Handbook for Chemical Process Research and Development Wenyi Zhao CRC Press Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487-2742 © 2017 by Wenyi Zhao CRC Press is an imprint of Taylor & Francis Group, an Informa business No claim to original U.S Government works Printed on acid-free paper Version Date: 20160819 International Standard Book Number-13: 978-1-4987-6799-6 (Hardback) This book contains information obtained from authentic and highly regarded sources Reasonable efforts have been made to publish reliable data and information, but the author and publisher cannot assume responsibility for the validity of all materials or the consequences of their use The authors and publishers have attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained If any copyright material has not been acknowledged please write and let us know so we may rectify in any future reprint Except as permitted under U.S Copyright Law, no part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers For permission to photocopy or use material electronically from this work, please access www.copyright.com (http:// www.copyright.com/) or contact the Copyright Clearance Center, Inc (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400 CCC is a not-for-profit organization that provides licenses and registration for a variety of users For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe Library of Congress Cataloging‑in‑Publication Data Names: Zhao, Wenyi (Chemist) Title: Handbook for chemical process research and development / Wenyi Zhao Description: Boca Raton : CRC Press, 2017 | Includes bibliographical references and index Identifiers: LCCN 2016032433 | ISBN 9781498767996 (hardcover : alk paper) Subjects: LCSH: Drugs Research | Drugs Research Methodology | Pharmaceutical industry Classification: LCC RM301.25 Z44 2017 | DDC 615.1/9 dc23 LC record available at https://lccn.loc.gov/2016032433 Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com and the CRC Press Web site at http://www.crcpress.com This book is dedicated to my parents Contents Preface xxix Acknowledgments .xxxix Author xli List of Abbreviations xliii Chapter Modes of Reagent Addition: Control of Impurity Formation 1.1 1.2 Direct Addition 1.1.1 Sonogashira Reaction (I) Problematic “All-In” Conditions .2 (II) Solutions–Semibatch Conditions (DA) 1.1.2 Michael Reaction (I) Problematic Reaction Conditions (RA Mode) (II) Chemistry Diagnosis (III) Solutions .3 1.1.3 Fischer Indole Synthesis .3 (I) Reaction Problems (II) Solutions Procedure 1.1.4 Amide Formation 1.1.4.1 EEDQ-Promoted Amide Formation .5 1.1.4.2 CDI-Promoted Amide Formation 1.1.5 Thioamide Formation (I) Problems (II) Solutions Procedure 1.1.6 C–O Bond Formation 1.1.6.1 SRN1 Reaction .8 1.1.6.2 Mitsunobu Reaction Reverse Addition 10 1.2.1 Grignard Reaction 11 1.2.1.1 Reaction with Alkyl Aryl Ketone 11 1.2.1.2 Grignard Reaction with Aldehydes 12 1.2.1.3 Reaction of Grignard Reagent with Ester 12 1.2.2 Copper-Catalyzed Epoxide Ring-Opening 13 Solutions .14 Procedure 14 1.2.3 Nitration Reaction 14 (I) Problematic Addition Order 14 (II) Chemistry Diagnosis 15 (III) Solutions 15 Procedure 15 1.2.4 Cyclization Reaction 15 Procedure 16 1.2.5 Amide Formation 17 1.2.5.1 CDI-Promoted Amide Formation 17 1.2.5.2 Phenyl Chloroformate–Promoted Urea Formation 18 vii viii Contents 1.2.6 Reduction of Ketone to Hydrocarbon 18 (I) Problematic Addition Order 19 (II) Chemistry Diagnosis 19 (III) Solutions .20 Procedure 20 1.2.7 1,3-Dipole-Involved Reactions 20 1.2.7.1 Addition–Elimination/Cyclization .20 1.2.7.2 [3+2]-Cycloaddition 21 1.3 Other Addition Modes 23 1.3.1 Sequential Addition 23 (I) Problematic Addition Sequence 23 (II) Solutions (to Control the Concentration of CDMT) 23 Procedure 23 1.3.2 Portionwise Addition 24 1.3.2.1 Cyclization 24 1.3.2.2 Dehydrochlorination 25 1.3.3 Slow Release of Starting Material/Reagent .26 1.3.3.1 Synthesis of Urea 26 1.3.3.2 Preparation of Alkylamine 28 1.3.4 Alternate Addition 28 (I) Chemistry Diagnosis 29 (II) Solutions 29 1.3.5 Concurrent Addition 29 1.3.5.1 Bromination Reaction 29 1.3.5.2 Difluoromethylation 31 1.3.5.3 Diels–Alder Reaction 32 Notes 32 Chapter Process Optimization 35 2.1 Addition of Additives 35 2.1.1 Acid Additives 35 2.1.1.1 Hydrochloric Acid 35 2.1.1.2 Sulfuric Acid 38 2.1.1.3 Acetic Acid 41 2.1.1.4 Benzoic Acid as Amine Stabilizer 45 2.1.1.5 Trifluoroacetic Acid 45 2.1.1.6 Toluenesulfonic Acid 46 2.1.2 Base Additives 48 2.1.2.1 Potassium Carbonate 48 2.1.2.2 Sodium Hydrogen Carbonate 49 2.1.2.3 Diisopropylethylamine 50 2.1.2.4 1,4-Diazabicyclo[2.2.2]octane 52 2.1.2.5 Potassium tert-Butoxide 53 2.1.2.6 Sodium Methoxide 55 2.1.2.7 Sodium Acetate 57 2.1.2.8 Sodium Acrylate 60 2.1.3 Inorganic Salts 61 2.1.3.1 Lithium Salts 61 2.1.3.2 Sodium Bromide 62 ix Contents 2.2 2.1.3.3 Magnesium Salts 63 2.1.3.4 Calcium Chloride 67 2.1.3.5 Zinc Chloride 68 2.1.4 Assortment of Scavengers 68 2.1.4.1 Catechol as Methyl Cation Scavenger 68 2.1.4.2 Anisole as Quinone Methide Scavenger 69 2.1.4.3 Carboxylic Esters 70 2.1.4.4 Thionyl Chloride as Water Scavenger 73 2.1.4.5 1-Hexene as HCl Scavenger 74 2.1.4.6 Epoxyhexene as HBr Scavenger 76 2.1.4.7 Acetic Anhydride as Aniline Scavenger 77 2.1.4.8 Amberlite CG50 as Ammonia Scavenger 77 2.1.5 Other Additives 77 2.1.5.1 Imidazole 78 2.1.5.2 Triethylamine Hydrochloride 79 2.1.5.3 Methyl Trioctylammonium Chloride 80 2.1.5.4 TMSCl (or BF3 · Etherate) 81 2.1.5.5 Water 82 2.1.5.6 Hydroquinone 85 2.1.5.7 B(OMe)3 in Borane Reduction of Acid 86 2.1.5.8 Isobutanoic Anhydride 87 2.1.5.9 1,1-Dimethyl-2-Phenylethyl Acetate 87 2.1.5.10 Alcohols 88 2.1.5.11 1,4-Dioxane .92 2.1.5.12 Benzotriazole 93 2.1.5.13 1-Hydroxybenzotriazole 93 2.1.5.14 1,4-Dibromobutane .94 2.1.5.15 Diethanolamine 95 Approaches to Optimize Catalytic Reactions 95 2.2.1 Suzuki–Miyaura Reaction 95 2.2.1.1 Catalyst Poison 97 2.2.1.2 Precipitation of Palladium Catalyst 100 2.2.1.3 Instability of Arylboronic Acids 101 2.2.1.4 Problems Associated with Base 105 2.2.1.5 Dimer Impurity 107 2.2.2 Catalytic Deprotection 109 2.2.2.1 Debenzylation 109 2.2.2.2 Catalytic Removal of Cbz Group 110 2.2.3 Catalytic Hydrogenation 112 2.2.3.1 Reduction of Nitro Group 112 2.2.3.2 Reduction of Pyridine Ring 113 2.2.3.3 Reduction of Cyano Group 114 2.2.3.4 Reduction of Imine Intermediate 114 2.2.3.5 Catalytic Hydrogenation of Azide 115 2.2.4 Other Catalytic Reactions 115 2.2.4.1 Negishi Cross-Coupling Reaction 115 2.2.4.2 Cu(I)-Catalyzed Grignard Reaction 116 2.2.4.3 Decarboxylative Bromination 117 2.2.4.4 Sulfonylation Reaction 118 2.2.4.5 Preparation of Acid Chloride 119 2.2.4.6 Catalytic Dechlorination 120 x Contents 2.3 Temperature and Pressure .120 2.3.1 Temperature Effect 120 2.3.1.1 Metal–Hydrogen/Halogen Exchange 120 2.3.1.2 Cyclization Reactions .123 2.3.1.3 Cross-Coupling Reaction 126 2.3.1.4 Vilsmeier Reaction 127 2.3.1.5 Oxidative Hydrolysis 128 2.3.1.6 Reduction of Ester 128 2.3.1.7 Michael Addition 129 2.3.1.8 Amide Formation 130 2.3.2 Pressure Effect 131 2.3.2.1 Nitrile Reduction 131 2.3.2.2 [3+2]-Cycloaddition 132 2.4 Other Approaches 133 2.4.1 Low Product Yield 133 2.4.1.1 Incomplete Reaction 133 2.4.1.2 Loss of Product during Isolation 136 2.4.1.3 Side Reactions of Starting Materials 137 2.4.1.4 Side Reactions of Intermediates .139 2.4.1.5 Side Reactions of Products .145 2.4.2 Problems Associated with Impurities 151 2.4.2.1 Residual Zn .151 2.4.2.2 Residual MTBE 152 2.4.2.3 Residual Water 153 2.4.2.4 Residual Oxygen .155 2.4.3 Reactions with Poor Selectivity 158 2.4.3.1 CIDR to Improve cis/trans Selectivity .158 2.4.3.2 Two-Step Process to Mitigate Racemization 158 2.4.3.3 Reduction of Carboxylic Acid 159 2.4.3.4 Sacrificial Reagent in Regioselective Acetylation 160 2.4.3.5 Protecting Group 161 2.4.3.6 Functional Group in SNAr Reaction 166 2.4.3.7 Enamine Exchange 167 2.4.3.8 Carryover Approach 169 2.4.4 Miscellaneous Reaction Problems 169 2.4.4.1 Friedel–Crafts Reaction 169 2.4.4.2 Reduction of C–C Double Bond .170 2.4.4.3 Reduction of Nitrile 171 2.4.4.4 Polymerization Issues .172 2.4.4.5 Activation of Functional Groups 175 2.4.4.6 Deactivation of Functional Groups 178 2.4.4.7 Side Reactions with Excess of Reagent 180 2.4.4.8 Optimization of Telescoped Process 181 Notes .184 Chapter Hazardous Reactions 193 3.1 Oxidation Reactions 193 3.1.1 Oxidation of Olefins 193 3.1.1.1 Oxidation with mCPBA 193 3.1.1.2 Oxidation with Sodium Perborate 194