Handbook for Chemical Process Research and Development, Second Edition [2 ed.] 1032259272, 9781032259277

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Handbook for Chemical Process Research and Development, Second Edition

This fully updated second edition reflects the significant changes in process chemistry since the first edition and includes more common process issues such as safety, cost, robustness, and environmental impact. Some areas have made notable progress such as process safety, stereochemistry, new reagents, and reagent surrogates. Forty years ago there were few process research and development activities in the pharmaceutical industry, partly due to the simplicity of drug molecules. With increasing structural complexity especially the introduction of chiral centers into drug molecules and stricter regulations, process research and development (R&D) has become one of the most critical departments for pharmaceutical companies. Features: • This unique volume, now in its second edition, is designed to provide readers with an unprecedented strategy and approach which will help chemists and graduate students develop chemical processes in an efficient manner. • Promotes an industrial mindset concerning safety and commercial viability when developing methods. • The author discusses development strategies with case studies and experimental procedures. • Focuses on mechanism-guided process development which provides readers with practical strategies and approaches. • Addresses more common process issues such as safety, cost, robustness, and environmental impact.

Handbook for Chemical Process Research and Development, Second Edition

Authored By

Wenyi Zhao

Senior Research Scientist Jacobus Pharmaceutical Company, Princeton

Second edition published 2023 by CRC Press 6000 Broken Sound Parkway NW, Suite 300, Boca Raton, FL 33487-2742 and by CRC Press 4 Park Square, Milton Park, Abingdon, Oxon, OX14 4RN ©2023 Wenyi Zhao CRC Press is an imprint of Taylor & Francis Group, LLC 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, access www.copyright.com or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. For works that are not available on CCC please contact [email protected] ​ ​ ​​ Trademark notice: Product or corporate names may be trademarks or registered trademarks and are used only for identification and explanation without intent to infringe. ISBN: 978-1-032-25927-7 (hbk) ISBN: 978-1-032-26461-5 (pbk) ISBN: 978-1-003-28841-1 (ebk) DOI: 10.1201/9781003288411 Typeset in Times by Deanta Global Publishing Services, Chennai, India



Contents Preface...........................................................................................................................................xxix Author Biography........................................................................................................................ xxxiii List of Abbreviations....................................................................................................................xxxv Chapter 1 Reaction Solvent Selection............................................................................................1 1.1

1.2

1.3

1.4 1.5 

Ethereal Solvents................................................................................................3 1.1.1 Cyclopentyl Methyl Ether.....................................................................3 1.1.1.1 Brook Rearrangement............................................................4 1.1.1.2 N-Alkylation Reaction...........................................................4 1.1.2 Tetrahydrofuran.....................................................................................5 1.1.2.1 Grignard Reagent Formation.................................................5 1.1.2.2 Bromination of Ketone.......................................................... 6 1.1.3 2-Methyl Tetrahydrofuran.....................................................................6 1.1.3.1 Control of Impurity Formation..............................................7 1.1.3.2 Enhancing Reaction Rate......................................................7 1.1.3.3 Improving Layer Separation..................................................8 1.1.4 Methyl tert-Butyl Ether.........................................................................9 1.1.4.1 Chlorination Reaction............................................................9 1.1.4.2 Darzens Reaction...................................................................9 1.1.5 Diethoxymethane and Dimethoxyethane............................................ 10 Protic Solvents.................................................................................................. 10 1.2.1 Methanol as a Solvent......................................................................... 10 1.2.1.1 Leak of Palladium Catalyst................................................. 10 1.2.1.2 Side Product Formation....................................................... 11 1.2.1.3 Palladium-Catalyzed Methylation Reaction........................ 11 1.2.2 Ethanol as a Solvent............................................................................ 12 1.2.2.1 Catalytic Reduction of Diaryl Methanol............................. 12 1.2.2.2 SN2 Reaction........................................................................ 12 1.2.3 2-Propanol as a Solvent....................................................................... 12 1.2.3.1 Reaction of Acyl Hydrazine with Trimethylsilyl Isocyanate............................................................................ 12 1.2.3.2 Classical Resolution of Racemic Acid................................. 13 1.2.3.3 Nickel-Catalyzed Addition Reaction................................... 14 1.2.4 1-Pentanol............................................................................................ 14 1.2.5 Ethylene Glycol................................................................................... 15 Water as Reaction Solvent................................................................................ 16 1.3.1 Iodination Reaction............................................................................. 16 1.3.2 Synthesis of Quinazoline-2,4-dione.................................................... 17 1.3.3 Synthesis of Pyrrolocyclohexanone.................................................... 18 1.3.4 Synthesis of Thiourea.......................................................................... 19 1.3.5 Synthesis of Amide............................................................................. 19 1.3.6 Synthesis of 1,3/1,4-Diketones............................................................20 Non-Polar Solvents...........................................................................................20 1.4.1 Condensation of Ketone with tert-Butyl Hydrazine Carboxylate.......20 1.4.2 Acid-Catalyzed Esterification............................................................. 21 Polar Aprotic Solvents...................................................................................... 21 v

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Contents

1.5.1

Acetone as a Solvent............................................................................ 22 1.5.1.1 Michael Addition Reaction with Acetone Cyanohydrin...... 22 1.5.1.2 SN2 Alkylation Reaction...................................................... 22 1.5.1.3 Multi-Component Reactions................................................ 22 1.5.1.4 Amidation Reaction............................................................. 22 1.5.2 Acetonitrile as a Solvent...................................................................... 23 1.5.2.1 Intramolecular Michael Addition Reaction......................... 23 1.5.2.2 Synthesis of Imidazolines.................................................... 23 1.5.2.3 Synthesis of α-Alkylated Ketones.......................................24 1.5.2.4 Chlorosulfonylation Reaction..............................................25 1.5.3 N,N-Dimethylformamide as a Solvent................................................26 1.5.3.1 Preparation of Alkyl Aryl Ether..........................................26 1.5.3.2 Preparation of Bisaryl Ether................................................26 1.6 Halogenated Solvents.......................................................................................26 1.6.1 Dichloromethane.................................................................................26 1.6.1.1 Reaction with Pyridine........................................................26 1.6.1.2 Synthesis of Benzo[d]isothiazolone..................................... 27 1.6.2 1,2-Dichloroethane..............................................................................28 1.6.3 Trifluoroacetic Acid............................................................................. 29 1.6.4 (Trifluoromethyl)benzene.................................................................... 30 1.6.5 Hexafluoroisopropanol........................................................................ 31 1.6.5.1 Selective Oxidation of Sulfide............................................. 31 1.6.5.2 Cycloaddition Reaction........................................................ 32 1.7 Carcinogen Solvent........................................................................................... 32 1.8 Other Solvents.................................................................................................. 32 1.8.1 DW-Therm........................................................................................... 32 1.8.2 Dowtherm A........................................................................................ 33 1.8.2.1 Synthesis of 6-Chlorochromene.......................................... 33 1.8.2.2 Conrad–Limpach Synthesis of Hydroxyl Naphthyridine.........33 1.8.2.3 Conrad–Limpach Synthesis of Quinolone.......................... 34 1.8.3 Polyethylene Glycol.............................................................................34 1.8.4 Propylene Glycol Monomethyl Ether..................................................34 1.8.5 Sulfolane.............................................................................................. 35 1.8.5.1 Bromination/Esterification.................................................. 35 1.8.5.2 Fluorine-Exchange Reaction............................................... 36 1.8.6 Ionic Liquids........................................................................................ 36 1.9 Mixture Of Solvents......................................................................................... 37 1.9.1 Aldol Condensation Reaction.............................................................. 37 1.9.2 Visible-Light Mediated Redox Neutral Reaction................................ 37 1.10 Solvent-Free Reaction....................................................................................... 37 Chapter 2 Reagent Selection........................................................................................................ 43 2.1

Inorganic Base.................................................................................................. 43 2.1.1 Sodium Bicarbonate............................................................................ 43 2.1.2 Potassium Carbonate........................................................................... 43 2.1.2.1 Boc Protection of Amino Group......................................... 43 2.1.2.2 Ring-Opening Iodination.....................................................44 2.1.3 Sodium Hydride..................................................................................44 2.1.3.1 SN2 Reaction........................................................................44 2.1.3.2 Addition/Elimination Reaction........................................... 45 2.1.3.3 Nucleophilic Addition Reaction.......................................... 45

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2.1.4

2.2

2.3

LiOH/H2O2 Combination....................................................................46 2.1.4.1 Hydrolysis of Chiral Pentanoate..........................................46 2.1.4.2 Hydrolysis of Chiral Propanoate.........................................46 2.1.4.3 Hydrolysis of Chiral Amide................................................ 47 Organic Base.................................................................................................... 48 2.2.1 Trialkylamine...................................................................................... 48 2.2.1.1 Diisopropylethylamine........................................................ 48 2.2.1.2 Triethylamine....................................................................... 49 2.2.2 Imidazole............................................................................................. 51 2.2.3 2,6-Dimethylpiperidine....................................................................... 52 2.2.4 2-(N,N-Dimethylamino)pyridine......................................................... 52 2.2.5 Metal Alkoxide Base........................................................................... 53 2.2.5.1 Potassium tert-Pentylate...................................................... 53 2.2.5.2 Lithium tert-Butoxide.......................................................... 55 2.2.5.3 Potassium tert-Butoxide....................................................... 56 2.2.5.4 Potassium Trimethylsilanoate.............................................. 58 2.2.5.5 Combination of Potassium tert-Butoxide with tertButyllithium......................................................................... 59 2.2.5.6 Sodium Methoxide...............................................................60 Reagents For Amide C(O)−N Bond Formation................................................60 2.3.1 CDI-Mediated Amide Formation........................................................60 2.3.1.1 Preparation of Nicotinic Acid Amide..................................60 2.3.1.2 Preparation of Ureas............................................................ 61 2.3.2 Thionyl Chloride-Mediated Amide Formation................................... 62 2.3.2.1 Tetramethylurea-Catalyzed Acid Chloride Formation........ 63 2.3.2.2 N-Sulfinylaniline-Involved Amide Preparation...................64 2.3.3 Boc2O-Mediated Amide Formation....................................................66 2.3.4 Schotten–Baumann Reaction..............................................................66 2.3.5 Other Amide Formation Methods....................................................... 71 2.3.5.1 Copper (II)-Catalyzed Transamidation............................... 71 2.3.5.2 Cross-Coupling between Acyltrifluoroborates and Hydroxylamines................................................................... 71 2.3.5.3 Catalytic Aminolysis of Ester.............................................. 72

Chapter 3 Various Reagent Surrogates........................................................................................ 75 3.1

Ammonia Surrogates........................................................................................ 75 3.1.1 Ammonium Hydroxide....................................................................... 75 3.1.2 Ammonium Acetate............................................................................ 76 3.1.2.1 Condensation with β-Keto Amide....................................... 76 3.1.2.2 Condensation with Cyclohexanones.................................... 77 3.1.2.3 Consecutive Reductive Amination Reactions...................... 78 3.1.3 Ammonium Chloride.......................................................................... 79 3.1.4 Hydroxylamine Hydrochloride............................................................ 79 3.1.4.1 Reductive Amination........................................................... 79 3.1.4.2 Aromatization...................................................................... 79 3.1.5 O-Benzylhydroxylamine.....................................................................80 3.1.6 Hydroxylamine-O-Sulfonic Acid........................................................80 3.1.6.1 SN2 Reaction with Sulfinate.................................................80 3.1.6.2 Reaction with Boronic Acid................................................ 81 3.1.7 Hexamethylene Tetramine................................................................... 81

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Contents

3.2

3.3 3.4

3.5

3.6

3.1.8 Acetonitrile.......................................................................................... 82 3.1.9 Chloroacetonitrile................................................................................ 82 3.1.10 tert-Butyl Carbamate........................................................................... 82 3.1.11 Diphenylmethanimine......................................................................... 83 3.1.12 α-Amino Acids....................................................................................84 3.1.12.1 Glycine Hydrochloride.........................................................84 3.1.12.2 2,2-Diphenylglycine............................................................. 86 3.1.13 Silylated Amines................................................................................. 86 3.1.14 Allylamines......................................................................................... 88 3.1.15 Isoamyl Nitrite..................................................................................... 89 3.1.16 1,2-Benzisoxazole...............................................................................90 Carbon Monoxide Surrogates........................................................................... 91 3.2.1 N-Formylsaccharin.............................................................................. 91 3.2.2 Paraformaldehyde................................................................................92 3.2.3 Molybdenum Carbonyl........................................................................ 93 3.2.4 Phenyl Formate.................................................................................... 93 3.2.5 Benzene-1,3,5-Triyl Triformate (TFBen)............................................94 3.2.6 Formic Acid......................................................................................... 95 Carbon Dioxide Surrogates..............................................................................96 α-Hydroxysulfonates as Aldehyde Surrogates.................................................96 3.4.1 Oxidation of Aldehyde to Acid...........................................................96 3.4.2 Reductive Amination...........................................................................97 3.4.3 Diels–Alder Reaction.......................................................................... 98 3.4.4 Strecker Reaction................................................................................99 3.4.5 Transaminase DKR of Aldehyde........................................................99 3.4.6 Reduction of Aldehyde to Alcohol.................................................... 100 Sulfur Dioxide Surrogate............................................................................... 100 3.5.1 Synthesis of Sulfones........................................................................ 101 3.5.2 Synthesis of Sulfoxides..................................................................... 101 3.5.3 Synthesis of Sulfonamides................................................................ 101 Miscellaneous Surrogates............................................................................... 102 3.6.1 Methyl Iodide Surrogate.................................................................... 102 3.6.2 Cyanide Surrogates........................................................................... 102 3.6.2.1 2-Methyl-2-Phenyl Malononitrile (MPMN)...................... 103 3.6.2.2 2-Cyanoisothiazolidine 1,1-Dioxide.................................. 103 3.6.3 Ethylene Surrogates........................................................................... 103

Chapter 4 Modes of Reagent Addition: Control of Impurity Formation................................... 107 4.1

4.2

Direct Addition............................................................................................... 108 4.1.1 Sonogashira Reaction........................................................................ 108 4.1.2 Michael Reaction............................................................................... 109 4.1.3 Fisher Indole Synthesis..................................................................... 109 4.1.4 Amide Formation.............................................................................. 111 4.1.4.1 EEDQ-Promoted Amide Formation.................................. 111 4.1.4.2 CDI-Promoted Amide Formation...................................... 112 4.1.5 Thioamide Formation........................................................................ 113 4.1.6 C–O Bond Formation........................................................................ 114 4.1.6.1 SRN2 Reaction.................................................................... 114 4.1.6.2 Mitsunobu Reaction........................................................... 115 Reverse Addition............................................................................................ 116 4.2.1 Grignard Reaction............................................................................. 117

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Contents

4.3

4.2.1.1 Reaction with Alkyl Aryl Ketone...................................... 117 4.2.1.2 Grignard Reaction with Aldehydes................................... 118 4.2.1.3 Reaction of Grignard Reagent with Ester.......................... 118 4.2.2 Copper-Catalyzed Epoxide Ring Opening........................................ 119 4.2.3 Nitration Reaction............................................................................. 120 4.2.4 Cyclization Reaction......................................................................... 121 4.2.5 Amide Formation.............................................................................. 122 4.2.5.1 CDI-Promoted Amide Formation...................................... 122 4.2.5.2 Phenyl Chloroformate-Promoted Urea Formation............ 123 4.2.6 Reduction of Ketone to Hydrocarbon............................................... 124 4.2.7 1,3-Dipole-Involved Reactions.......................................................... 126 4.2.7.1 Addition–Elimination/Cyclization.................................... 126 4.2.7.2 [3+2] Cycloaddition........................................................... 127 Other Addition Modes.................................................................................... 128 4.3.1 Sequential Addition........................................................................... 128 4.3.2 Portionwise Addition......................................................................... 129 4.3.2.1 Cyclization......................................................................... 129 4.3.2.2 Deoxychlorination............................................................. 130 4.3.3 Slow Release of Starting Material/Reagent...................................... 131 4.3.3.1 Synthesis of Urea............................................................... 131 4.3.3.2 Preparation of Alkylamine................................................ 133 4.3.4 Alternate Addition............................................................................. 133 4.3.5 Concurrent Addition.......................................................................... 134 4.3.5.1 Bromination Reaction........................................................ 134 4.3.5.2 Difluoromethylation........................................................... 135 4.3.5.3 Diels–Alder Reaction......................................................... 136

Chapter 5 Process Optimization with Additives........................................................................ 141 5.1

5.2

Acid Additives................................................................................................ 141 5.1.1 Hydrochloric Acid............................................................................. 141 5.1.1.1 SNAr Reaction.................................................................... 141 5.1.1.2 Deoxychlorination............................................................. 142 5.1.2 Phosphoric Acid................................................................................ 143 5.1.3 Sulfuric Acid..................................................................................... 144 5.1.3.1 Iodination Reaction............................................................ 144 5.1.3.2 Chlorination Reaction with N-Chlorosuccinimide............ 144 5.1.3.3 Chlorination Reaction with Phosphorus Trichloride......... 145 5.1.3.4 Hydrogenation Reaction.................................................... 147 5.1.4 Methanesulfonic Acid....................................................................... 147 5.1.5 Acetic Acid........................................................................................ 147 5.1.5.1 Condensation Reaction...................................................... 148 5.1.5.2 SN2 Reaction...................................................................... 148 5.1.5.3 Mitsunobu Reaction........................................................... 149 5.1.6 Benzoic Acid..................................................................................... 150 5.1.7 Trifluoroacetic Acid........................................................................... 151 5.1.8 Toluenesulfonic Acid......................................................................... 152 Base Additives................................................................................................ 153 5.2.1 Potassium Carbonate......................................................................... 153 5.2.2 Sodium Hydrogen Carbonate............................................................ 154 5.2.3 Diisopropylethylamine...................................................................... 155

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Contents

5.3

5.4

5.5

5.2.3.1 Neutralizing AcOH/Replacing Ammonia......................... 155 5.2.3.2 Stabilizing Intermediate.................................................... 156 5.2.4 1,4-Diazabicyclo[2.2.2]octane........................................................... 157 5.2.5 N,N’-Dimethylethylenediamine........................................................ 158 5.2.6 Potassium tert-Butoxide.................................................................... 159 5.2.7 Sodium Methoxide............................................................................ 161 5.2.7.1 Increasing Reaction Rate................................................... 161 5.2.7.2 Improving Product Yield................................................... 161 5.2.8 Sodium Acetate................................................................................. 163 5.2.8.1 Trapping Hydrogen Iodide................................................. 163 5.2.8.2 Trapping Hydrogen Chloride............................................. 164 5.2.8.3 Improving Conversion....................................................... 165 5.2.9 Sodium Acrylate................................................................................ 166 Inorganic Salts................................................................................................ 167 5.3.1 Lithium Chloride............................................................................... 167 5.3.1.1 Increasing Reaction Rate................................................... 167 5.3.1.2 Improving Stereoselectivity............................................... 167 5.3.1.3 Improving Conversion....................................................... 168 5.3.2 Lithium Bromide............................................................................... 169 5.3.3 Sodium Bromide............................................................................... 169 5.3.3.1 Lowering Reaction Temperature....................................... 169 5.3.3.2 Improving Product Yield................................................... 169 5.3.4 Magnesium Chloride......................................................................... 170 5.3.5 Magnesium Bromide......................................................................... 171 5.3.6 Calcium Chloride.............................................................................. 173 5.3.6.1 Reaction with NaBH4......................................................... 173 5.3.6.2 Trapping Fluoride.............................................................. 174 5.3.7 Zinc Chloride.................................................................................... 174 5.3.8 Zinc Acetate...................................................................................... 175 Assortment of Scavengers.............................................................................. 175 5.4.1 Catechol as Methyl Cation Scavenger............................................... 175 5.4.2 Anisole as Quinone Methide Scavenger........................................... 176 5.4.3 Ethyl Acetate as Hydroxide Scavenger............................................. 177 5.4.4 Ethyl Trifluoroacetate as Hydroxide Scavenger................................ 178 5.4.5 Ethyl Trifluoroacetate as Benzylamine Scavenger............................ 179 5.4.6 Ethyl Pivalate as Hydroxide Scavenger............................................. 179 5.4.7 Trimethyl Orthoformate as Water Scavenger.................................... 180 5.4.8 Thionyl Chloride as Water Scavenger............................................... 180 5.4.9 1-Hexene............................................................................................ 181 5.4.9.1 As HCl Scavenger.............................................................. 181 5.4.9.2 As Diimide (NH=NH) Scavenger..................................... 183 5.4.10 Epoxyhexene as HBr Scavenger........................................................ 184 5.4.11 Acetic Anhydride as Aniline Scavenger........................................... 184 5.4.12 Amberlite CG50 as Ammonia Scavenger......................................... 185 5.4.13 3-Pentanone as HCN Scavenger........................................................ 185 Other Additives............................................................................................... 186 5.5.1 Imidazole........................................................................................... 186 5.5.2 Triethylamine Hydrochloride............................................................ 187 5.5.3 Methyl Trioctylammonium Chloride................................................ 188 5.5.4 Chlorotrimethylsilane........................................................................ 188 5.5.4.1 Julia Olefination................................................................. 188 5.5.4.2 Michael Addition............................................................... 189

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Contents

5.5.5 Chlorotriethylsilane........................................................................... 190 5.5.6 Bis(trimethylsilyl)acetamide............................................................. 190 5.5.7 Water................................................................................................. 191 5.5.7.1 Wadsworth–Emmons Reaction......................................... 191 5.5.7.2 O-Alkyation....................................................................... 192 5.5.7.3 Methylation Reaction......................................................... 192 5.5.7.4 Enolization Reaction.......................................................... 193 5.5.7.5 Pyrazole Synthesis............................................................. 193 5.5.7.6 Copper-Mediated Intramolecular Cyclization................... 194 5.5.7.7 Crystallization-Induced Dynamic Resolution of Amine........195 5.5.8 Hydroquinone.................................................................................... 195 5.5.8.1 Preclusion of Oxidation..................................................... 195 5.5.8.2 Preclusion of Polymerization............................................. 196 5.5.9 Trimethyl Borate............................................................................... 197 5.5.10 Isobutanoic Anhydride...................................................................... 198 5.5.11 1,1-Dimethyl-2-Phenylethyl Acetate.................................................. 198 5.5.12 Alcohols............................................................................................ 199 5.5.12.1 Ethanol............................................................................... 199 5.5.12.2 2-Propanol......................................................................... 199 5.5.12.3 tert-Butanol........................................................................200 5.5.12.4 Ethylene Glycol.................................................................. 201 5.5.12.5 1,2-Propanediol.................................................................. 201 5.5.12.6 Neopentyl Glycol...............................................................203 5.5.13 1,4-Dioxane.......................................................................................204 5.5.14 Benzotriazole....................................................................................205 5.5.15 1-Hydroxybenzotriazole....................................................................206 5.5.16 1,4-Dibromobutane............................................................................207 5.5.17 Diethanolamine.................................................................................207 5.5.17.1 Improving Selectivity........................................................207 5.5.17.2 Boranate Ester Exchange...................................................208 5.5.18 Trimethyl Phosphite..........................................................................208 5.5.19 Diethyl Phosphite..............................................................................209 5.5.20 4-Trifluoromethyl Benzaldehyde....................................................... 210 Chapter 6 Process Optimization of Catalytic Reactions........................................................... 217 6.1

Suzuki–Miyaura Reaction.............................................................................. 217 6.1.1 Catalyst Poisoning............................................................................. 217 6.1.1.1 Catalyst Poisoning by Sulfhydryl Group........................... 218 6.1.1.2 Catalyst Poisoning by Unknown Impurities...................... 220 6.1.2 Catalyst Precipitation........................................................................ 221 6.1.3 Instability of Arylboronic Acids....................................................... 221 6.1.3.1 Buchwald’s Precatalyst...................................................... 222 6.1.3.2 Tridentate Ligand............................................................... 222 6.1.3.3 Alternative Negishi Coupling Reaction............................. 225 6.1.3.4 Alternative Kumada Coupling Reaction............................ 225 6.1.3.5 Using Protecting Group..................................................... 226 6.1.3.6 Using Trifluoroborate Salt................................................. 227 6.1.4 Problems Associated with Base........................................................ 227 6.1.4.1 Protodeboronation............................................................. 227 6.1.4.2 Formation of Carbamate.................................................... 228 6.1.5 Dimer Impurity................................................................................. 229

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6.2 6.3 6.4 6.5

6.6

6.7

6.1.5.1 Reducing Arylboronic Acid Concentration....................... 229 6.1.5.2 Reducing Free Pd(II) Concentration................................. 229 Negishi Reaction............................................................................................ 231 6.2.1 Poor Product Yield............................................................................ 231 6.2.2 Thick Reaction Mixture.................................................................... 231 Heck Reaction................................................................................................. 232 6.3.1 Enhancing Palladium-Catalyst Stability........................................... 233 6.3.2 Improving Selectivity........................................................................ 233 Sonogashira Reaction..................................................................................... 233 6.4.1 Reducing Palladium-Catalyst Loading............................................. 233 6.4.2 Improving Reactivity......................................................................... 234 Catalytic Deprotection.................................................................................... 234 6.5.1 Debenzylation.................................................................................... 234 6.5.1.1 Catalyst Poisoning............................................................. 234 6.5.1.2 Erosion of Chiral Purity.................................................... 236 6.5.2 Catalytic Removal of Cbz Group...................................................... 237 6.5.2.1 Impurity Formation........................................................... 237 6.5.2.2 Pd(OAc)2 /Charcoal System................................................ 238 Catalytic Hydrogenation................................................................................. 238 6.6.1 Reduction of Nitro Group.................................................................. 239 6.6.1.1 Palladium-Catalyzed Hydrogenation................................. 239 6.6.1.2 Nickel-Catalyzed Hydrogenation.......................................240 6.6.1.3 Platinum-Catalyzed Hydrogenation..................................240 6.6.1.4 Catalytic Transfer Hydrogenation......................................240 6.6.2 Reduction of Pyridine Ring.............................................................. 242 6.6.3 Reduction of α,β-Unsaturated Compounds....................................... 243 6.6.4 Enantioselective Reduction of Quinolines........................................ 243 6.6.5 Reduction of Nitrile...........................................................................244 6.6.6 Reduction of Azide............................................................................ 245 Other Catalytic Reactions.............................................................................. 245 6.7.1 Cu(I)-Catalyzed Reaction.................................................................246 6.7.2 Decarboxylative Bromination...........................................................246 6.7.3 Formation of Acid Chloride.............................................................. 247 6.7.4 Catalytic Dechlorination...................................................................248 6.7.5 Two-Phase Reactions.........................................................................248 6.7.5.1 Enhancement of Reaction Rate..........................................248 6.7.5.2 Suppressing Side Reactions............................................... 249 6.7.5.3 Reducing the Amount of Toxic Sodium Cyanide.............. 250 6.7.5.4 Replacing DMSO Solvent in SNAr Reaction..................... 250 6.7.5.5 Two-Phase Reactions without PTC................................... 251 6.7.6 Deoxybromination............................................................................. 252 6.7.7 Regioselective Chlorination.............................................................. 253 6.7.8 Regioselective Magnesiation............................................................. 254 6.7.9 Amide Preparation............................................................................ 254 6.7.9.1 NaOMe as Catalyst............................................................ 254 6.7.9.2 HOBt as Catalyst............................................................... 255 6.7.10 Synthesis of Indole............................................................................ 256 6.7.11 N-Methylation Reaction.................................................................... 257 6.7.12 Baylis−Hillman Reaction.................................................................. 258 6.7.13 Catalytic Wittig Reaction.................................................................. 258 6.7.14 Palladium-Catalyzed Rearrangement............................................... 259

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Chapter 7 Process Optimization of Problematic Reactions....................................................... 265 7.1

7.2 7.3

7.4

7.5

Temperature Effect......................................................................................... 265 7.1.1 Metal–Halogen/Hydrogen Exchange................................................ 265 7.1.1.1 Magnesium–Bromine Exchange........................................266 7.1.1.2 Lithium–Bromine Exchange.............................................266 7.1.1.3 Lithium–Hydrogen Exchange............................................ 267 7.1.2 Ring Expansion................................................................................. 268 7.1.3 Synthesis of Pyrazole........................................................................ 269 7.1.4 Synthesis of Oxadiazole.................................................................... 270 7.1.5 Cross-Coupling Reaction.................................................................. 270 7.1.6 Vilsmeier Reaction............................................................................ 271 7.1.7 Oxidative Hydrolysis......................................................................... 272 Pressure Effect................................................................................................ 272 7.2.1 Nitrile Reduction............................................................................... 272 7.2.2 [3+2]-Cycloaddition........................................................................... 274 Low Product Yields........................................................................................ 274 7.3.1 Incomplete Reactions........................................................................ 274 7.3.1.1 Poor Mass Transfer............................................................ 274 7.3.1.2 Undesired Physical Properties........................................... 276 7.3.1.3 High Flow Rate of Nitrogen.............................................. 277 7.3.2 Loss of Product During Isolation...................................................... 278 7.3.3 Side Reactions of Starting Materials................................................. 279 7.3.3.1 Decomposition of N-Oxide................................................ 279 7.3.3.2 Decomposition of Hydrazone............................................ 279 7.3.3.3 Hydrolysis of Chlorotriazine.............................................280 7.3.4 Side Reactions of Intermediates........................................................ 281 7.3.4.1 Sandmeyer Reaction.......................................................... 281 7.3.4.2 Hofmann Rearrangement.................................................. 281 7.3.4.3 Tosylation/Amination Reactions........................................ 282 7.3.4.4 Synthesis of Cyclic Sulfimidate......................................... 283 7.3.4.5 Cyclization/Ring Expansion..............................................284 7.3.4.6 Michael Addition............................................................... 286 7.3.5 Side Reactions of Products................................................................ 287 7.3.5.1 Decomposition of Amide................................................... 287 7.3.5.2 Side Reactions of 1,4-Isochromandione............................ 288 7.3.5.3 Side Reactions of Oxirane................................................. 289 Reaction Problems Associated with Impurities.............................................290 7.4.1 Residual MTBE.................................................................................290 7.4.2 Residual Water.................................................................................. 291 7.4.2.1 Bromination Reaction........................................................ 291 7.4.2.2 SNAr Fluorination Reaction............................................... 292 7.4.2.3 Copper-Catalyzed C−N Bond Formation.......................... 292 7.4.3 Residual Oxygen............................................................................... 293 7.4.3.1 Oxidative Dimerization..................................................... 293 7.4.3.2 Oxidation of Phenylenediamine........................................ 294 7.4.4 Residual Zinc..................................................................................... 295 Reactions with Poor Selectivity...................................................................... 295 7.5.1 CIDR to Improve cis/trans Selectivity.............................................. 296 7.5.2 Two-Step Process to Mitigate Racemization.................................... 296 7.5.3 Reduction of Carboxylic Acid........................................................... 297

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7.5.4 Sacrificial Reagent in Regioselective Acetylation............................. 298 7.5.5 Converting Side Product to Product.................................................. 299 7.5.6 Enamine Exchange............................................................................ 299 7.5.7 Carry-Over Approach.......................................................................300 7.5.8 Friedel–Crafts Reaction....................................................................300 7.5.9 Reduction of Carbon–Carbon Double Bond..................................... 301 7.5.10 Reduction of Nitrile...........................................................................302 7.6 Protecting Group............................................................................................ 303 7.6.1 Acetyl Group..................................................................................... 303 7.6.2 Trimethylsilyl Group......................................................................... 303 7.6.2.1 Protection of Terminal Alkyne..........................................304 7.6.2.2 Protection of Enolate......................................................... 305 7.6.2.3 Protection of Hydroxyl Group........................................... 305 7.6.3 Cyanoethyl Group.............................................................................306 7.6.4 Benzhdryl Group...............................................................................307 7.7 Polymerization Issues.....................................................................................308 7.7.1 Polymerization of Chloroacetyl Chloride.........................................309 7.7.2 Polymerization of Acid Chloride......................................................309 7.7.3 Polymerization of Chloroacrylonitrile.............................................. 310 7.7.4 Polymerization of Enone................................................................... 310 7.7.5 Polymerization of Pentasulfide.......................................................... 311 7.8 Activation of Functional Groups.................................................................... 311 7.8.1 Activation of Aniline Nitrogen.......................................................... 311 7.8.2 Activation of Amide.......................................................................... 312 7.8.3 Activation of Lactol........................................................................... 312 7.8.4 C–H Bond Activation........................................................................ 313 7.9 Deactivation of Functional Groups................................................................ 314 7.9.1 Deactivation of Amino Group........................................................... 314 7.9.2 Deactivation of Sulfonyl Chloride..................................................... 314 7.10 Optimization of Telescoped Process.............................................................. 315 Chapter 8 Hazards of Oxidation and Reduction Reactions....................................................... 323 8.1

Oxidation Reactions....................................................................................... 323 8.1.1 Oxidation of Olefins.......................................................................... 323 8.1.1.1 Oxidation with mCPBA..................................................... 323 8.1.1.2 Oxidation with Sodium Perborate..................................... 325 8.1.1.3 Oxidation with Ozone........................................................ 325 8.1.1.4 Oxidation with KMnO4..................................................... 327 8.1.1.5 Oxidation with 9-BBN/H2O2-NaOH................................. 327 8.1.2 Oxidation of Alcohols....................................................................... 328 8.1.2.1 Py·SO3/DMSO System...................................................... 329 8.1.2.2 Ac2O/DMSO System......................................................... 331 8.1.2.3 TFAA/DMSO/TEA System.............................................. 331 8.1.2.4 TEMPO/NaOCl System.................................................... 331 8.1.2.5 RuCl3/NaOCl System........................................................ 333 8.1.2.6 Sulfinimidoyl Chloride...................................................... 334 8.1.2.7 2-Amadamantane N-Oxide/CuCl...................................... 335 8.1.3 Oxidation of Aldehydes to Acids...................................................... 335 8.1.4 Oxidation of Sulfides to Sulfoxides................................................... 336 8.1.5 Oxidation of Sulfides to Sulfones...................................................... 336

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8.2

8.1.5.1 Oxidation with Oxone........................................................ 336 8.1.5.2 Oxidation with Sodium Perborate..................................... 337 8.1.5.3 Oxidation with Sodium Periodate..................................... 338 8.1.5.4 Oxidation with NaOCl....................................................... 338 8.1.5.5 Oxidation with H2O2 /Na2WO4........................................... 339 8.1.5.6 Oxidation with TMSCl/KNO3...........................................340 8.1.6 Other Oxidative Reactions................................................................340 8.1.6.1 Dakin Oxidation................................................................340 8.1.6.2 Hydroxylation.................................................................... 341 8.1.6.3 Oxidation of Phosphite...................................................... 341 Reduction Reactions....................................................................................... 342 8.2.1 Reduction with NaBH4 -Based Agents............................................... 342 8.2.1.1 Reduction of Acids............................................................ 342 8.2.1.2 Reduction of Esters............................................................344 8.2.1.3 Reduction of Amides.........................................................346 8.2.1.4 Reduction of Imine............................................................348 8.2.2 Reduction with Borane...................................................................... 349 8.2.2.1 BH3·THF Complex............................................................. 350 8.2.2.2 BH3·DMS Complex............................................................ 352 8.2.2.3 BH3·Amine Complex......................................................... 353 8.2.3 Reduction with Lithium Aluminum Hydride.................................... 356

Chapter 9 Other Hazardous Reactions....................................................................................... 361 9.1

Catalytic Cross-Coupling Reactions.............................................................. 361 9.1.1 Heck Reaction................................................................................... 361 9.1.2 Negishi Cross-Coupling Reaction..................................................... 362 9.2 Blaise Reaction............................................................................................... 362 9.3 Ritter Reaction................................................................................................ 363 9.4 Hydrogen–Lithium Exchange.........................................................................364 9.5 Halogenation Reactions..................................................................................364 9.5.1 Chlorination Reaction.......................................................................364 9.5.2 Fluorination Reactions...................................................................... 365 9.5.2.1 Deoxyfluorination.............................................................. 365 9.5.2.2 Hydrofluorination of Aziridines........................................ 366 9.5.2.3 Electrophilic Fluorination................................................. 366 9.5.3 Deoxychlorination............................................................................. 367 9.5.3.1 Deoxychlorination of Triazinone....................................... 367 9.5.3.2 Deoxychlorination of Quinazolone.................................... 369 9.5.3.3 Deoxychlorination of Triazine........................................... 369 9.5.3.4 Deoxychlorination of 4,6-Dihydroxypyrimidine............... 370 9.5.3.5 Deoxychlorination of 6,7-D​ihydr​othie​no[3.​2-d]p​yrimi​ dine-​2,4-d​iol...................................................................... 371 9.5.3.6 Deoxychlorination of 6-Chlorophthalazin-1-ol................. 371 9.6 Thiocyanation................................................................................................. 372 9.7 Gas-Involved Reactions.................................................................................. 372 9.7.1 Boc Protection................................................................................... 372 9.7.2 N-Acetylation.................................................................................... 373 9.7.3 Boc Deprotection.............................................................................. 374 9.7.3.1 Selective Deprotection with TFA...................................... 375 9.7.3.2 Deprotection with NaOH................................................... 375

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9.7.4 N-tert-Butylamide Formation............................................................ 375 9.7.5 Deprotection of N-tert-Butyl Group.................................................. 376 9.7.6 Decarboxylative Ethoxide Elimination............................................. 377 9.7.7 Deprotonation.................................................................................... 378 9.7.8 SN2 Reaction...................................................................................... 379 9.7.9 Chlorination Reaction....................................................................... 379 9.8 Darzens Reaction............................................................................................ 380 9.9 Hofmann Rearrangement............................................................................... 380 9.10 Friedel–Crafts Reaction................................................................................. 380 Chapter 10 Hazardous Reagents.................................................................................................. 383 10.1 Diazonium Salts............................................................................................. 383 10.1.1 Hydrolysis of Diazonium Salt........................................................... 383 10.1.2 Diazonium Salt-Involved Cyclization............................................... 384 10.1.3 Nitroindazole Formation................................................................... 384 10.1.4 Synthesis of Trifluoromethyl-Substituted Cyclopropanes................. 386 10.1.5 Sandmeyer Reaction.......................................................................... 386 10.2 Azide Compounds.......................................................................................... 387 10.2.1 Nucleophilic Displacement............................................................... 388 10.2.1.1 Synthesis of 3,4-Dihydropyrrole........................................ 388 10.2.1.2 Synthesis of 3-(1,2-Diarylbutyl) Azide.............................. 388 10.2.1.3 Preparation of Aryl (Alkyl) Azides................................... 389 10.2.2 Nucleophilic Addition....................................................................... 391 10.2.2.1 Synthesis of Tetrazole........................................................ 391 10.2.2.2 Synthesis of Triazole......................................................... 395 10.2.2.3 Synthesis of Carbamate..................................................... 396 10.2.2.4 Curtius Rearrangement...................................................... 398 10.3 Hydrazine.......................................................................................................400 10.3.1 Wolff–Kishner Reduction.................................................................400 10.3.1.1 Reduction of Asymmetric Ketone.....................................400 10.3.1.2 Reduction of Symmetric Ketone....................................... 401 10.3.1.3 Synthesis of Indazole......................................................... 401 10.3.1.4 Synthesis of Pyrazole.........................................................402 10.3.1.5 Preparation of Alkylamine................................................402 10.3.2 Preparation of Aryl (or Alkyl) Hydrazines and Related Reactions........ 403 10.3.2.1 Preparation of 5-Hydrazinoquinoline................................403 10.3.2.2 Synthesis of Aminopyrazole..............................................404 10.3.2.3 Fischer Indole Synthesis....................................................404 10.4 Hydroxylamine...............................................................................................405 10.5 Oxime.............................................................................................................406 10.6 N-Oxide..........................................................................................................407 10.7 Nitro Compounds...........................................................................................408 10.7.1 Preparation of Nitro Compounds by Nitration..................................408 10.7.1.1 NaNO3/TFA/TFAA Nitration System...............................409 10.7.1.2 KNO3/TFA Nitration System............................................ 410 10.7.1.3 Use of Acetyl Nitrate......................................................... 410 10.7.1.4 NaNO3/Py·SO3 System...................................................... 411 10.7.1.5 Stepwise Nitration.............................................................. 412 10.7.1.6 Use of Chlorotrimethylsilane and Nitrate Salt.................. 412 10.7.1.7 Metal-Catalyzed Nitration................................................. 412 10.7.1.8 N-Nitro Intermediate Rearrangement................................ 413

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10.7.2 Hazardous Reactions of Nitro Compounds....................................... 413 10.7.2.1 Unstable Nitrophenate....................................................... 414 10.7.2.2 Accumulation of Reactant................................................. 414 10.8 Volatile Organic Compounds......................................................................... 414 10.8.1 Ethylene Oxide.................................................................................. 414 10.8.2 Acetylene........................................................................................... 415 10.8.3 Halogenated Methyl Ethers............................................................... 416 10.8.3.1 Bis(bromomethyl)ether...................................................... 416 10.8.3.2 Chloromethyl Ethyl Ether.................................................. 416 10.8.4 Methyl Iodide.................................................................................... 417 10.8.4.1 N-Methylation of Heterocycles.......................................... 417 10.8.4.2 N-Methylation of Amide.................................................... 417 10.8.4.3 N-Methylation of 2-Methoxypyridine Derivative.............. 418 10.8.5 Methyl Bromide................................................................................. 419 10.9 High Energy Compounds............................................................................... 419 10.9.1 5-Hydroxybenzofurazan.................................................................... 419 10.9.2 1-Hydroxybenzotriazole (HOBt)....................................................... 420 10.9.2.1 Ethyl Acetate/Water Two-Phase System........................... 420 10.9.2.2 Replacement of HOBt with 2-Hydroxypyridine................ 421 10.9.2.3 Replacement of HOBt with 2-Chloro-4,6-dimethoxy1,3,5-triazine...................................................................... 422 10.10 Toxic Compounds........................................................................................... 422 10.10.1 Zinc Cyanide..................................................................................... 422 10.10.2 Potassium Ferrocyanide.................................................................... 423 10.10.3 Acetone Cyanohydrin........................................................................ 424 10.10.3.1 Epoxide Opening............................................................... 424 10.10.3.2 Michael Addition............................................................... 425 10.11 Corrosive Reagent.......................................................................................... 425 Chapter 11 Grignard Reagent and Related Reactions................................................................. 431 11.1 Preparation Of Grignard Reagents................................................................. 431 11.1.1 Use of Chlorotrimethylsilane............................................................ 431 11.1.1.1 Preparation of 4-Fluoro-2-methylphenylmagnesium Bromide............................................................................. 431 11.1.1.2 Preparation of (4-(2​-(Pyr​rolid​in-1-​yl)et​hoxy)​pheny​l) mag​nesiu​m Bromide.......................................................... 432 11.1.2 Use of Diisobutylaluminum Hydride................................................ 432 11.1.3 Use of Diisobutylaluminum Hydride/Iodine..................................... 433 11.1.4 Use of Grignard Reagents................................................................. 434 11.1.4.1 Use of MeMgCl................................................................. 434 11.1.4.2 Use of EtMgBr................................................................... 435 11.1.4.3 Use of Heel........................................................................ 436 11.1.5 Use of Alkyl Halides......................................................................... 437 11.1.5.1 Use of Iodomethane........................................................... 437 11.1.5.2 Use of 1,2-Dibromoethane................................................. 437 11.1.6 Halogen–Magnesium Exchange........................................................ 437 11.1.6.1 Preparation of Trifluoromethyl Substituted Aryl Grignard Reagents............................................................. 438 11.1.6.2 Preparation of N-Methylpyrazole Grignard Reagent......... 439 11.1.6.3 Preparation of (4-Bromonaphthalen-1-yl)magnesium Chloride............................................................................. 439

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11.1.6.4 Magnesium-ate Complex...................................................440 11.1.6.5 Alkylmagnesium Alkoxides.............................................. 441 11.2 Reactions of Grignard Reagents..................................................................... 441 11.2.1 Reactions with Ketones..................................................................... 441 11.2.1.1 Vinyl Grignard Reagents................................................... 441 11.2.1.2 Aryl Grignard Reagents..................................................... 442 11.2.1.3 Methylmagnesium Bromide.............................................. 443 11.2.2 Reaction with Acid Chloride............................................................. 445 11.2.3 Reaction with Dimethylformamide................................................... 445 11.2.4 Reaction with Weinreb Amide..........................................................446 11.2.5 Michael Addition............................................................................... 447 11.2.6 Reaction with Epoxide......................................................................448 11.2.7 Other Grignard Reagent-Involved Reactions....................................449 11.2.7.1 Ramberg−Bäcklund Reaction............................................449 11.2.7.2 Synthesis of Chiral δ-Ketoamides..................................... 450 11.2.7.3 Access to o-Quinone Methide Intermediates.................... 451 Chapter 12 Challenging Reaction Intermediates......................................................................... 455 12.1 Effect of Intermediates................................................................................... 455 12.1.1 In Telescoping Steps.......................................................................... 455 12.1.2 In Designing Synthetic Route........................................................... 456 12.1.3 In Agitation....................................................................................... 457 12.1.4 In Product Isolations/Purifications....................................................460 12.1.4.1 Pictet–Spengler Reaction...................................................460 12.1.4.2 Imide Reduction................................................................ 461 12.1.5 In Improving Product Yields............................................................. 461 12.1.5.1 Amide Formation............................................................... 461 12.1.5.2 Synthesis of Hydroxybenzisoxazole.................................. 462 12.1.5.3 Synthesis of Vinyl Bromide...............................................464 12.1.6 In Improving Operational Profile......................................................465 12.2 Monitoring Intermediates...............................................................................466 12.2.1 Direct Monitoring Intermediate........................................................466 12.2.2 Indirect Monitoring Intermediates....................................................466 12.2.2.1 Derivatization of Acylimidazolide.................................... 467 12.2.2.2 Derivatization of N-Methylene Bridged Dimer................. 467 Chapter 13 Protecting Groups.....................................................................................................469 13.1 Protection of Hydroxyl Group........................................................................469 13.1.1 Prevention of Side Reactions.............................................................469 13.1.1.1 Friedel–Crafts Alkylation..................................................469 13.1.1.2 Removal of Trifluoromethanesulfonyl Group.................... 470 13.1.1.3 SN2 Reaction...................................................................... 470 13.1.2 Increasing Catalyst Activity.............................................................. 471 13.1.3 Separation of Diol Diastereomers..................................................... 472 13.1.4 Developing Telescoped Process........................................................ 474 13.2 Protection of Amino Group............................................................................ 475 13.2.1 Protection with (4-Nitrophenyl)sulfonyl Group................................ 475 13.2.2 Protection with 2,5-Hexanedione...................................................... 476 13.2.3 Protection with Aldehyde.................................................................. 476 13.2.4 Protection with 4-Methyl-2-Pentanone............................................. 477

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13.3 13.4

13.5 13.6

13.2.5 Protection with Methylene Group..................................................... 477 13.2.6 Protection with tert-Butyloxycarbonyl Group................................... 478 13.2.7 Protection with 2,2,6​,6-Te​trame​thylp​iperi​din-1​-ylox​ycarb​onyl Group................................................................................................. 478 13.2.8 Protection with Trimethylsilyl Group............................................... 479 Protection of Carboxylic Acid........................................................................480 Protection of Aldehydes And Ketones........................................................... 481 13.4.1 Protection of Aldehyde...................................................................... 481 13.4.2 Protection of Ketones........................................................................ 481 13.4.2.1 Protection with Methanol.................................................. 481 13.4.2.2 Protection with Ethylene Glycol........................................ 482 13.4.2.3 Using Internal Protection Approach.................................. 483 Protection of Acetylene.................................................................................. 483 Unusual Protecting Groups............................................................................484 13.6.1 Boron-Containing Protecting Groups...............................................484 13.6.1.1 Borane Complex................................................................484 13.6.1.2 Boronic Acids.................................................................... 485 13.6.2 N-Nitro Protecting Group.................................................................. 486 13.6.2.1 Regioselective Nitration..................................................... 486 13.6.2.2 Activation of Aniline......................................................... 487 13.6.3 Halogen as Protecting Group............................................................ 487 13.6.3.1 Bromine Protecting Group................................................ 487 13.6.3.2 Chlorine Protecting Group................................................ 489

Chapter 14 Telescope Approach.................................................................................................. 493 14.1 Improving Process Safety............................................................................... 493 14.1.1 Chloroketone Intermediate................................................................ 493 14.1.2 Lachrymatory Chloromethacryate Intermediate.............................. 493 14.1.3 Chloromethyl Benzoimidazole.......................................................... 493 14.1.4 Pyridine N-Oxide.............................................................................. 495 14.1.5 Benzyl Bromide................................................................................. 496 14.1.6 Methyl Iodide.................................................................................... 496 14.2 Processing Problematic Intermediates........................................................... 497 14.2.1 Oily Intermediates............................................................................. 497 14.2.2 Hygroscopic Intermediate Solid........................................................ 498 14.2.3 Hygroscopic Amine Salt................................................................... 498 14.2.4 High Water-Soluble Intermediate...................................................... 499 14.2.5 Unstable Intermediates......................................................................500 14.2.5.1 Heteroaryl Chloride...........................................................500 14.2.5.2 Toluenesulfonate Intermediate..........................................500 14.2.5.3 Aldehyde Intermediates.....................................................500 14.2.5.4 Unstable Alkene Intermediates......................................... 501 14.2.5.5 Unstable β-Hydroxyketone................................................504 14.3 Improving Filtration.......................................................................................506 14.3.1 Preparation of Amide........................................................................506 14.3.2 Synthesis of β-Nitrostyrene...............................................................507 14.4 Telescoping Catalytic Reactions..................................................................... 508 14.4.1 Imine Reduction/Debenzylation....................................................... 508 14.4.2 Debromination/Suzuki Cross-Coupling Reaction............................509 14.5 Improving Overall Product Yields................................................................. 510 14.5.1 Synthesis of Spirocyclic Hydantoin.................................................. 510

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14.5.2 Transition Metal-Catalyzed Cross-Coupling Reaction..................... 512 14.6 Reduction In Processing Solvents.................................................................. 512 14.6.1 Toluene as the Common Solvent....................................................... 512 14.6.2 DMF as the Common Solvent........................................................... 513 14.6.3 EtOAc as the Common Solvent......................................................... 514 14.6.4 THF as the Common Solvent............................................................ 514 14.6.5 EtOH/THF as the Common Solvent................................................. 515 14.7 Other Telescope Processes............................................................................. 516 14.7.1 Bromination/Isomerization Reactions.............................................. 516 14.7.2 Fisher Indole Synthesis/Ring Rearrangemet..................................... 517 14.7.3 Ylide Formation/Wittig Reaction/Cycloaddition.............................. 517 14.7.4 Overman Rearrangement.................................................................. 518 14.7.5 Acyla​tion/​Reduc​tion/​O-Alk​ylati​on/Br​omina​tion............................. 518 14.7.6 Synthesis of (–)-Oseltamivir............................................................. 519 14.8 Limitation of the Telescope Approach........................................................... 521 14.8.1 Lack of Purity Control...................................................................... 521 14.8.2 Poor Product Yield............................................................................ 522 14.8.3 Lack of Compatibility....................................................................... 523 Chapter 15 Design of New Synthetic Route................................................................................ 527 15.1 Improving Process Safety............................................................................... 527 15.1.1 Toxic Reagents and Intermediates.................................................... 527 15.1.1.1 Trimethylsilyl Cyanide as Cyanide Source....................... 527 15.1.1.2 CuCN in Sandmeyer Reaction........................................... 527 15.1.1.3 Toxic Reagent (HF)........................................................... 528 15.1.1.4 Toxic Benzyl Halides......................................................... 529 15.1.1.5 Phosphorus Oxychloride.................................................... 531 15.1.1.6 Sulfonyl Chloride Intermediate......................................... 531 15.1.2 High Energy Reagents....................................................................... 532 15.1.2.1 Azide-Involved Cycloaddition........................................... 532 15.1.2.2 Diazonium Salt-Involved Indazole Formation.................. 533 15.1.2.3 Lithium Aluminum Hydride Reduction............................ 534 15.1.3 Undesired Reaction Conditions......................................................... 535 15.1.3.1 Acylation Reaction............................................................. 535 15.1.3.2 SNAr Reaction.................................................................... 535 15.2 Improving Product Yield................................................................................ 536 15.2.1 Cycloaddition Reaction..................................................................... 537 15.2.2 Resolution/Amide Formation/Cyclization........................................ 537 15.2.3 Chlorine Replacement....................................................................... 538 15.2.4 Wittig Reaction..................................................................................540 15.3 Improving Reaction Selectivity...................................................................... 541 15.3.1 Chlorination...................................................................................... 541 15.3.2 Iodination.......................................................................................... 541 15.3.3 N-Alkylation Reaction....................................................................... 542 15.3.4 Formation of Seven-Membered Ring................................................ 542 15.4 Other Route Design Strategies....................................................................... 543 15.4.1 Using Less Expensive Starting Material........................................... 543 15.4.2 Using Convergent Approach............................................................. 543 15.4.2.1 Decarboxylative Cross-Coupling Reaction....................... 543 15.4.2.2 Synthesis of Chiral Amide................................................ 545

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15.4.3 Step-Economy Synthesis................................................................... 547 15.4.3.1 Synthesis of Keto–Sulfone Intermediate........................... 547 15.4.3.2 Synthesis of Bendamustine................................................ 548 15.4.4 Atom-Economy Synthesis................................................................. 548 15.4.4.1 Synthesis of Carboxylic Acid............................................ 549 15.4.4.2 Stereoselective Synthesis of Diol....................................... 549 15.4.5 Alternating Bond-Formation Order.................................................. 550 15.4.6 Minimizing Oxidation Stage Change............................................... 551 15.4.6.1 Minimizing Nitrogen Oxidation Stage Adjustment.......... 551 15.4.6.2 Minimizing Carbon Oxidation Stage Adjustment............. 551 15.4.7 Coupling Reagent-Free Amide Formation........................................ 553 15.4.8 Preventing Etching of Glass Reactor................................................. 553 Chapter 16 Stereochemistry......................................................................................................... 557 16.1 Asymmetric Synthesis.................................................................................... 557 16.1.1 Asymmetric Catalysis....................................................................... 557 16.1.1.1 Desymmetrization of Anhydride....................................... 557 16.1.1.2 Asymmetric Reduction of Enone...................................... 557 16.1.1.3 Sharpless Asymmetric Dihydroxylation............................ 559 16.1.1.4 Enantioselective Alkylation............................................... 560 16.1.1.5 Enantioselective Protonation of Enamines........................ 561 16.1.1.6 CuH-Catalyzed Synthesis of 2,3-Disubstituted Indolines......561 16.1.1.7 CuH-Catalyzed Synthesis of Chiral Amines.................... 562 16.1.2 Chiral Pool Synthesis........................................................................ 562 16.1.2.1 Condensation of Indoline with Benzaldehyde................... 562 16.1.2.2 Claisen Rearrangement...................................................... 563 16.1.3 Use of Chiral Auxiliaries.................................................................. 563 16.1.3.1 Diastereoselective Diels–Alder Reaction.......................... 563 16.1.3.2 Diastereoselective Synthesis of Boronic Acid...................564 16.1.3.3 Synthesis of Chiral (S)-Pyridyl Amine............................. 565 16.1.3.4 Synthesis of L-Carnitine.................................................... 566 16.2 Kinetic Resolution.......................................................................................... 566 16.2.1 Hydrolytic Kinetic Resolution of Epoxide........................................ 566 16.2.2 Resolution of Diol via Stereoselective Esterification........................ 567 16.2.3 Resolution of Phosphine Ligand via Stereoselective Ligand Exchange........................................................................................... 568 16.2.4 Resolution of Diastereomeric Mixture via Salt Formation............... 569 16.3 Enzymatic Resolution..................................................................................... 569 16.3.1 Resolution of Esters........................................................................... 569 16.3.1.1 Resolution of Methyl Piperidine-4-Carboxylate............... 569 16.3.1.2 Resolution of Ethyl α-Amino Acetate............................... 570 16.3.1.3 Resolution of Diazepane Acetate....................................... 570 16.3.2 Resolution of Amino Acids............................................................... 571 16.3.3 Resolution Secondary Alcohols........................................................ 571 16.4 Separation with Chiral Chromatography....................................................... 571 16.5 Classical Resolution........................................................................................ 572 16.5.1 Resolution of Racemic Acid.............................................................. 572 16.5.2 Resolution of Racemic Bases............................................................ 573 16.5.2.1 Use of Optical Pure tert-Leucine Derivative..................... 573 16.5.2.2 Use of di-p-Toluoyl-D-Tartaric Acid.................................. 574

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16.5.2.3 Use of bis((S)-Mandelic Acid)-3-Nitrophthalate............... 575 16.5.3 Resolution of Ketone......................................................................... 575 16.5.4 Resolution of Racemic Ammonium Salt........................................... 575 16.5.5 Diastereomer Salt Break................................................................... 576 16.5.6 Examples of Diastereomeric Salts.................................................... 577 16.6 Dynamic Kinetic Resolution.......................................................................... 577 16.6.1 DKR via Imine Intermediates........................................................... 577 16.6.1.1 3,5-Dichlorosalicylaldehyde Catalyst................................ 577 16.6.1.2 2-Hydroxy-6-(hydroxymethyl)benzaldehyde Catalyst...... 584 16.6.1.3 Picolinaldehyde Catalyst................................................... 585 16.6.1.4 DRK without Catalyst........................................................ 585 16.6.1.5 Iridium-Involved DKR...................................................... 586 16.6.2 DKR via Enolate Intermediates........................................................ 586 16.6.2.1 Enolization with Base........................................................ 586 16.6.2.2 Enolization without Base................................................... 587 16.6.3 DKR via Diastereomeric Salt Formation.......................................... 588 16.6.4 DKR of Six-Membered Ring Systems.............................................. 589 16.6.4.1 Epimerization of cis-Isomer to trans-Isomer.................... 589 16.6.4.2 Isomerization of Cyclohexane Derivative.......................... 590 16.6.4.3 Fischer Indole Synthesis.................................................... 591 16.6.5 DKR via Reversible Bond Formation............................................... 592 16.6.5.1 Reversible C−C Bond Formation....................................... 592 16.6.5.2 Reversible C−N Bond Formation...................................... 592 16.6.5.3 Reversible C−O Bond Formation...................................... 594 16.6.5.4 Reversible C−S Bond Formation....................................... 595 16.6.6 Other DKR Methods......................................................................... 596 16.6.6.1 Bromide-Catalyzed DKR.................................................. 596 16.6.6.2 Resolution of Sulfoxide...................................................... 597 16.6.6.3 Dynamic Kinetic Isomerization via Ir-Catalyzed Internal Redox Transfer Hydrogenation............................ 597 16.6.6.4 Vinylogous Dynamic Kinetic Resolution.......................... 598 16.6.7 Various DKR Examples....................................................................603 Chapter 17 Various Quenching Strategies...................................................................................607 17.1 Acidic Quenching...........................................................................................607 17.1.1 Removal of Magnesium Salts............................................................607 17.1.1.1 Reaction of Grignard Reagent with Weinreb Amide........607 17.1.1.2 Weinreb Amide Formation................................................607 17.1.2 Removal of Zinc................................................................................607 17.2 Basic Quenching.............................................................................................608 17.2.1 Suppressing Thiadiazole Isomerization............................................609 17.2.2 Prevention of Etching Glass Reactor.................................................609 17.2.2.1 Quenching with Sodium Bicarbonate................................609 17.2.2.2 Quenching with Sodium Hydroxide.................................. 610 17.3 Anhydrous Quenching.................................................................................... 610 17.3.1 Removal of Zinc By-Product............................................................. 611 17.3.2 Avoiding Insoluble Organic Mass..................................................... 611 17.3.3 Avoiding Degradation of Product...................................................... 612 17.3.3.1 Use of Ethyl Acetate.......................................................... 612 17.3.3.2 Use of Diisopropylethylamine........................................... 613

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17.3.4 Decomposition of Excess Reagent.................................................... 614 17.3.4.1 Use of Methanol................................................................. 614 17.3.4.2 Use of Silicon Dioxide....................................................... 614 17.4 Oxidative Quenching...................................................................................... 615 17.4.1 Oxidation of Hydrogen Iodide........................................................... 615 17.4.2 Oxidation of Pinacol......................................................................... 616 17.5 Reductive Quenching..................................................................................... 617 17.5.1 Restroying tert-Butyl Hydroperoxide................................................ 617 17.5.2 Destroying Hydrogen Peroxide......................................................... 617 17.5.3 Destroying Oxone.............................................................................. 618 17.5.4 Destroying Halogens......................................................................... 618 17.5.4.1 Use of Ascorbic Acid to Destroy Bromine........................ 619 17.5.4.2 Use of Ascorbic Acid to Destroy Iodine............................ 619 17.6 Disproportionation Quenching....................................................................... 620 17.7 Reverse Quenching......................................................................................... 620 17.7.1 Control of Impurity Formation......................................................... 621 17.7.1.1 Preparation of Ketone........................................................ 621 17.7.1.2 Preparation of Aldehyde.................................................... 621 17.7.1.3 Grignard Reaction............................................................. 622 17.7.2 Removal of Excess Reagent.............................................................. 622 17.7.3 Increase in Conversion...................................................................... 622 17.7.4 Suppressing Product Hydrolysis........................................................ 624 17.7.5 Prevention of Product Decomposition............................................... 625 17.7.6 Prevention of Emulsion..................................................................... 625 17.7.6.1 Copper-Catalyzed Amination............................................ 625 17.7.6.2 Lithium Aluminum Hydride Reduction............................ 625 17.7.7 Prevention of Exothermic Runaway.................................................. 626 17.8 Concurrent Quenching................................................................................... 626 17.9 Double Quenching.......................................................................................... 627 17.9.1 Acetone/HCl Combination................................................................ 627 17.9.1.1 Ketone Reduction.............................................................. 627 17.9.1.2 SNAr Reaction.................................................................... 628 17.9.2 Acetone/Citric Acid Combination..................................................... 629 17.9.3 Acetone/MeOH/H 2O Combination................................................... 629 17.9.4 Ethyl Acetate/Water Combination.................................................... 629 17.9.5 Ethyl Acetate/Tartaric Acid Combination........................................ 630 17.9.6 Ethyl Acetate/Aqueous Sodium Bicarbonate Combination.............. 630 17.9.7 Isopropanol/Citric Acid Combination............................................... 630 17.9.8 Methyl Formate/Aqueous HCl Combination.................................... 631 17.10 Reactive Quenching........................................................................................ 631 Chapter 18 Various Isolation and Purification Strategies............................................................ 635 18.1 Extraction....................................................................................................... 635 18.1.1 Aqueous Extractions......................................................................... 635 18.1.1.1 Use of Methyl tert-Butyl Ether.......................................... 635 18.1.1.2 Use of 2-Methyltetrahydrofuran........................................ 636 18.1.1.3 Use of Ethyl Acetate.......................................................... 637 18.1.1.4 Use of Dodecane................................................................ 637 18.1.1.5 Use of n-Butanol................................................................ 638 18.1.2 Anhydrous Extraction....................................................................... 638

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18.1.2.1 Heptane/Acetonitrile System............................................. 639 18.1.2.2 Heptane–Cyclohexane/N-Methyl-2-pyrrolidone System........639 18.1.3 Double Extraction............................................................................. 639 18.2 Direct Isolation...............................................................................................640 18.2.1 Use of Cooling...................................................................................640 18.2.1.1 Direct Isolation from Isopropanol.....................................640 18.2.1.2 Direct Isolation from Ethyl acetate.................................... 641 18.2.1.3 Direct Isolation from Isopropyl Acetate............................ 641 18.2.1.4 Direct Isolation from Acetonitrile..................................... 642 18.2.2 Use of Anti-Solvent........................................................................... 643 18.2.2.1 Adding Water to Acetic Acid............................................. 643 18.2.2.2 Addition of Water to Dimethylformamide........................ 643 18.2.2.3 Addition of Water to Dimethylacetamide..........................644 18.2.2.4 Addition of Water to Dimethylsulfoxide...........................644 18.2.2.5 Addition of Methanol to Dimethylsulfoxide...................... 645 18.2.3 Use of Cooling and Anti-Solvent...................................................... 645 18.2.3.1 Isolation of Sonogashira Product....................................... 645 18.2.3.2 Isolation of 6-Chlorophthalazin-1-ol.................................646 18.2.3.3 Isolation of SNAr Product.................................................. 647 18.2.4 Use of Neutralization........................................................................ 647 18.2.5 Use of Salt Formation........................................................................648 18.2.6 Other Direct Isolation Approaches................................................... 649 18.2.6.1 Direct Drop Process.......................................................... 649 18.2.6.2 Removal of By-Product by Direct Drop Approach........... 650 18.3 Filtration Problems......................................................................................... 650 18.3.1 Metal-Related Filtration Problems.................................................... 651 18.3.1.1 Copper-Related Filtration Problems.................................. 651 18.3.1.2 TiCl4 -Related Problems..................................................... 653 18.3.2 Small Particle Size............................................................................ 653 18.3.2.1 Addition of Acetic Acid..................................................... 653 18.3.2.2 Addition of Isopropanol..................................................... 655 18.3.2.3 Temperature Control.......................................................... 656 18.3.2.4 Polymorph Transformation................................................ 657 18.3.3 Low-Melting Solid............................................................................ 657 18.4 Purification Strategies.................................................................................... 658 18.4.1 Use of Salt Formation........................................................................ 658 18.4.1.1 Hydrochloric Acid Salts..................................................... 659 18.4.1.2 Acetic Acid Salt................................................................. 662 18.4.1.3 (R)-Mandelate Salt............................................................. 662 18.4.1.4 L-Tartaric Acid Salt........................................................... 663 18.4.1.5 2-Picolinic Acid Salt.......................................................... 663 18.4.1.6 Toluenesulfonic Acid Salts................................................ 665 18.4.1.7 Sodium Salt........................................................................666 18.4.1.8 Potassium Salt.................................................................... 672 18.4.1.9 Magnesium Salt................................................................. 673 18.4.1.10 Dicyclohexylamine Salts................................................... 674 18.4.1.11 Quaternary Salt.................................................................. 676 18.4.2 Derivatization.................................................................................... 678 18.4.2.1 Isolation/Purification of Aldehydes................................... 678 18.4.2.2 Isolation/Purification of Amine......................................... 683 18.4.2.3 Isolation/Purification of Diol............................................. 683 18.4.2.4 Isolation/Purification of Amino Diol................................684

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18.4.3 Various Approaches for Impurity Removal......................................684 18.4.3.1 Removal of Ammonium Chloride.....................................684 18.4.3.2 Removal of 9-BBN............................................................ 686 18.4.3.3 Removal of Acetic Acid..................................................... 686 18.4.3.4 Removal of (1E,3E)-Dienol Phosphate.............................. 687 18.5 Crystallization................................................................................................ 688 18.5.1 Seed-Induced Crystallization............................................................ 689 18.5.1.1 Avoiding Uncontrolled Crystallization..............................690 18.5.1.2 Avoiding Oiling Out.......................................................... 692 18.5.1.3 Control of Exothermic Crystallization.............................. 695 18.5.1.4 Control of Polymorph........................................................ 695 18.5.2 Reactive Crystallization.................................................................... 696 18.5.2.1 Deprotection/Salt Formation............................................. 696 18.5.2.2 Enamine Preparation......................................................... 696 18.5.2.3 Free Acid Formation.......................................................... 697 18.5.2.4 Boc Protection................................................................... 698 18.5.2.5 Limitations of Reactive Crystallization............................. 698 18.5.3 Other Crystallization Approaches..................................................... 699 18.5.3.1 Addition of Water.............................................................. 699 18.5.3.2 Addition of Polymer..........................................................700 18.5.3.3 Crystallization from Extraction Solvent............................ 701 18.5.3.4 Three-Solvent System........................................................ 702 18.5.3.5 Derivatization.................................................................... 703 18.5.3.6 Control of Crystal Size Distribution.................................. 704 18.5.3.7 Cocrystallization................................................................ 704 Chapter 19 Methods for Residual Metal Removal....................................................................... 713 19.1 Removal of Residual Palladium..................................................................... 713 19.1.1 Crystallization................................................................................... 713 19.1.1.1 Crystallization in the Presence of Cysteine....................... 714 19.1.1.2 Crystallization in the Presence of N-Acetylcysteine......... 715 19.1.2 Extraction.......................................................................................... 719 19.1.2.1 Liquid–Liquid Transportation........................................... 719 19.1.2.2 Extractive Precipitation..................................................... 722 19.1.3 Adsorption......................................................................................... 724 19.1.3.1 Activated Carbon............................................................... 724 19.1.3.2 MP–TMT........................................................................... 728 19.1.3.3 Deloxan THP-II................................................................. 728 19.1.3.4 Smopex 110........................................................................ 729 19.1.4 Distillation......................................................................................... 729 19.1.5 Other Methods................................................................................... 730 19.1.5.1 Adsorption–Crystallization............................................... 730 19.1.5.2 Adsorption–TMT Wash..................................................... 731 19.1.5.3 Protecting Group............................................................... 731 19.1.5.4 Salt Formation................................................................... 732 19.1.6 Conclusion......................................................................................... 732 19.2 Removal of Residual Copper.......................................................................... 733 19.2.1 Use of Aqueous Ammonia................................................................ 733 19.2.2 Use of Thiourea................................................................................. 735 19.2.3 Use of 2,4,6-Trimercaptotriazine...................................................... 735

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19.3 Removal of Residual Rhodium....................................................................... 736 19.3.1 Use of Smopex-234............................................................................ 736 19.3.2 Use of Ecosorb C-941........................................................................ 737 19.4 Removal of Residual Ruthenium.................................................................... 737 19.4.1 Use of Activated Carbon................................................................... 737 19.4.2 Use of Supercritical Carbon Dioxide................................................ 738 19.5 Removal of Zinc............................................................................................. 738 19.5.1 Extraction with Trisodium Salt of EDTA......................................... 738 19.5.2 Use of Ethylenediamine.................................................................... 739 19.6 Removal of Magnesium.................................................................................. 740 19.7 Removal of Aluminum................................................................................... 741 19.7.1 Use of Triethanolamine..................................................................... 741 19.7.2 Use of Crystallization........................................................................ 742 19.8 Removal of Iron And Nickel.......................................................................... 742 19.8.1 Removal of Iron................................................................................. 742 19.8.2 Removal of Nickel............................................................................. 743 Chapter 20 Methods for Impurity Removal................................................................................. 747 20.1 Removal of Fluoride....................................................................................... 747 20.1.1 Use of Aqueous Wash....................................................................... 747 20.1.2 Use of CaCl2...................................................................................... 748 20.1.3 Use of CaCO3.................................................................................... 749 20.2 Removal of Iodide.......................................................................................... 750 20.3 Removal of High-Boiling Dipolar Aprotic Solvents...................................... 751 20.3.1 Wash with Aqueous Solution............................................................ 751 20.3.2 Extraction with Heptane.................................................................... 752 20.4 Removal of Triphenylphosphine Oxide.......................................................... 752 20.4.1 Wash with Ethyl Acetate................................................................... 752 20.4.2 Precipitation of Ph3PO with MgCl2................................................... 754 20.4.3 Precipitation of Ph 3PO with ZnCl 2.................................................... 754 20.4.4 Precipitation of Ph 3PO with Heptane................................................ 755 20.5 Use of Sodium Bisulfate................................................................................. 756 20.5.1 Removal of Methacrylic Acid from Acid Product............................ 756 20.5.2 Removal of Alcohol from Aldehyde Product.................................... 757 20.5.3 Removal of Excess Formaldehyde.................................................... 758 20.5.4 Removal of Ketone Intermediate...................................................... 759 20.6 Removal of Excess Reagents.......................................................................... 759 20.6.1 Use of Dimethylamine to Remove Excess Formaldehyde................ 759 20.6.2 Use of N-Methylpiperazine to Remove Boc Anhydride.................... 760 20.6.3 Use of CO2 to Remove Excess Piperazine........................................ 761 20.6.4 Use of Succinic Anhydride to Remove 1-(2-Pyrimidyl)piperazine....... 761 20.6.5 Use of Pivalaldehyde to Remove 4-Chlorobenzylamine.................. 762 20.6.6 Use of DABCO to Remove Benzyl Bromide.................................... 762 20.6.7 Use of Aqueous Ammonia to Remove Diethyl Sulfate..................... 763 20.6.8 Use of Hydrogen Peroxide to Oxidize Ph3P...................................... 764 20.7 Conversion of Impurity To Starting Material................................................. 765 20.8 Conversion of Impurity To Product................................................................ 765 20.8.1 Deoxychlorination............................................................................. 765 20.8.2 Cycloaddition Reaction..................................................................... 766 20.9 Removal of Other Impurities.......................................................................... 767 20.9.1 Removal of Polymeric Material........................................................ 767

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20.9.2 20.9.3 20.9.4 20.9.5

Use of Sodium Periodate to Remove Diol......................................... 768 Use of Phenylboronic Acid to Remove Diol...................................... 769 Use of Sodium Dithionate to Reduce Nitro Group........................... 770 Use of Polymeric Resin to Remove Hydrazide................................. 771

Chapter 21 Pharmaceutical Salts................................................................................................. 775 21.1 Salts of Basic Drug Substances...................................................................... 775 21.1.1 Hydrochloride Salts........................................................................... 775 21.1.2 Hemisulfate Salt................................................................................ 778 21.1.3 Citric Acid Salt.................................................................................. 780 21.1.4 Various Pharmaceutical Salts............................................................ 781 21.2 Salts of Acidic Drug Substances.................................................................... 781 21.2.1 Use of Inorganic Bases...................................................................... 781 21.2.1.1 Sodium Salts...................................................................... 781 21.2.1.2 Potassium Salts.................................................................. 791 21.2.1.3 Calcium Salts..................................................................... 792 21.2.1.4 Various Inorganic Salts...................................................... 793 21.2.2 Use of Organic Bases........................................................................ 793 Chapter 22 Solid Form................................................................................................................. 799 22.1 Polymorphism................................................................................................. 799 22.1.1 Control of Polymorph by Seeding..................................................... 801 22.1.1.1 Use of Direct Addition....................................................... 801 22.1.1.2 Use of Reverse Addition....................................................802 22.1.2 Control of Polymorph by Temperature.............................................802 22.1.3 Control of Polymorph by Slurrying.................................................. 803 22.1.4 Control of Polymorph by Aging........................................................ 803 22.1.5 Control of Polymorph by Adding Polymer.......................................804 22.1.6 Polymorph Transformation...............................................................805 22.2 Cocrystals.......................................................................................................806 22.2.1 Cocrystal with L-Phenylalanine........................................................807 22.2.2 Cocrystal with L-Pyroglutamic Acid................................................807 22.2.3 Cocrystal with Phosphoric Acid........................................................808 22.2.4 Cocrystal with L-Proline...................................................................809 22.2.5 Cocrystal with Adipic Acid............................................................... 810 22.3 Api Particle Size............................................................................................. 810 22.4 Amorphous Solids.......................................................................................... 811 22.4.1 Use of Spray Drying.......................................................................... 811 22.4.2 Use of Solvent-Induced Method........................................................ 812 22.4.3 Use of Hot-Melt Extrusion................................................................ 813 Index............................................................................................................................................... 817

Preface According to the 12 principles of green chemistry, a good chemical process shall satisfy the following key elements: low cost, use available raw materials and reagents, simple workup, robustness, high throughput (fast reaction with high concentration), good product purity, and minimal environmental impact. The scale-up of a chemical process from laboratory to large production scales is by no means a simple linear process. Compared with laboratory-scale reactions, large-scale operations are expected to have an expanded time scale, insufficient mixing, and less-efficient heat transfer, which may potentially lead to runaway reactions. The key responsibility of process chemists is to develop chemical processes that are feasible for manufacturing pharmaceutical intermediates and final drug substances (active pharmaceutical ingredients–APIs) for support of clinical studies and, eventually, for commercial production. Based on the first edition, this new edition continues to address the process issues such as safety, solvent selection, various reagent surrogates, product purification, stereochemistry, solid form, environmental impacts, etc. In addition, this book introduces (a) new reactions, for example, photoredox catalysis for C−C and C−N bond formations, catalytic C−H activations, multicomponent reactions, Grignard regent formation, and its related reactions, (b) new purification techniques to address the challenges in the control of mutagenic impurities, crystallization of low melting solids, and polymorph transformations, (c) design of efficient chemical processes, (d) newly developed reagent surrogates, such as ammonia surrogates, carbon dioxide surrogates, sulfur dioxide surrogates, and cyanide surrogates.

P.1 PROCESS EVALUATION P.1.1 Process Safety Process safety refers to thermal/reactive hazards and health hazards. Thermal or reactive hazards are associated with reactions that are exothermic and/or generating gases or reactions that are involved shock and/or heat sensitive, pyrophoric, flammable, or corrosive materials. Health hazards refer to exposure to toxic chemicals that can cause acute or chronic negative health effects. It is most important to have a hazard assessment for a given process, particularly when using materials or intermediates without available Material Safety Data Sheet (MSDS). Although the advent of flow chemistry has brought much attention recently, most chemical processes in the pharmaceutical industry are developed based on batchwise operations. There are several motivations for developing semibatch processes, such as avoidance of the accumulation of reactive reactants and control of the heat production rate (exothermic reactions). Thus, most exothermic reactions are conducted in a semibatch fashion in order to mitigate the exothermic event and prevent runaway reactions from occurring.

P.1.2 Process Cost Process costs depend largely on the following aspects: materials, labor, equipment, and waste disposal. An economic process will use less expensive, commercially available materials as much as possible. Chromatographic purification is not an ideal process on large scale due to the burden of intensive labor. As per the reduction of process cost, a one-pot process is frequently employed to minimize process wastes, time-consuming isolations, and handling losses. In addition, cryogenic reactions or reactions that require high temperature or pressure should be avoided as much as possible. These reaction conditions usually need special equipment and large amounts of energy, which, in turn, will increase process costs. xxix

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P.1.3 Environmental Impact Green chemistry addresses environmentally benign chemical synthesis, encouraging the design of chemical processes that minimize the use and generation of hazardous substances. An ideal reaction would incorporate all of the atoms of the reactants into the product with limited wastes, which, in turn, effectively reduces environmental pollution and improves efficiency. For instance, the process (shown in Equation P.1) developed by Pfizer uses the Baylis–Hillman reaction in the synthesis of the allyl alcohol, an intermediate for sampatrilat (an inhibitor of the zinc metalloprotease). The inherently environmentally friendly, atom-efficient Baylis–Hillman reaction not only incorporates all the atoms of the two starting materials into the product, but also adds environmental benefit since it allows simple reuse of the 3-quinuclidinol and generated much less waste stream.

P.2 DESIGN OF NEW SYNTHETIC ROUTES At the end of the process evaluation, a decision has to be made on whether the existing process needs to be redesigned. When designing new synthetic routes, a rule of thumb should be followed: • • • • • • •

Use commercially available and less expensive materials. Use catalytic systems. Limit protecting group manipulations. Use convergent routes over linear ones. Use addition reactions. Use multicomponent reactions (MCRs). Use tandem or cascade processes, etc.

A catalytic reaction can be performed at relatively mild conditions, which is desired for large-scale production in terms of process safety and costs. Catalytic reactions are considered environmentally friendly due to the reduced amount of waste generated, as opposed to stoichiometric reactions. Classical olefinations, such as the Wittig reaction and Julia olefination, employ ketones or aldehydes as starting materials which are typically prepared by oxidation of the corresponding alcohols. A direct catalytic olefination of alcohols was realized using the thermal stable Ru-pincer catalyst (Equation P.2). This approach represents a step-economical synthesis, which avoided the alcohol oxidation step. The one-pot process is an economically favorable method by performing a series of bond-formation steps in a single reaction vessel without the isolation of intermediates. The use of one-pot synthesis can greatly improve the process efficiency by minimizing isolation and purification steps. The development of one-pot synthesis is summarized in a review article which highlights various telescoping techniques such as multicomponent reaction (MCR), cascade (or domino) reaction, and tandem reaction.

P.3 PROCESS OPTIMIZATION Prior to scaling up, a number of process parameters need to be identified so that reactions can be carried out under optimal conditions. These parameters include the mode of addition of starting materials/reagents/solvents, temperature, solvent/concentration, pressure (for some cases), agitation rate, etc.

P.3.1 Reaction Temperature A reaction temperature is established based primarily on the reaction rate and impurity profile. Ideally, the reaction temperature shall be within –20 to 100 °C range, too low or too high will

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require additional energy and time at scale, and sometimes, special equipment is needed. Generally, high reaction temperature will lead to poor selectivity thereby the formation of impurities. Large jumps in temperature shall be avoided.

P.3.2 Solvent and Concentration Several solvent evaluation tools are developed as solvent selection guides. Generally, solvents shall be selected and assessed based on three aspects: (a) toxicity (including carcinogencity, mutagenicity, reprotoxicity, and skin absorption/sensitization), (b) process safety (including flammability, emission, electrostatic charge, and potential for peroxide formation), and (c) environmental and regulatory considerations (including ecotoxicity, groundwater contamination, and ozone depletion potential). Class 3 solvents, as proposed in the International Conference on Harmonization (ICH) guidelines, are preferred, especially at the end of the synthesis because of their low toxic potential (see Chapter 1). In general, high-concentration reactions are desired because not only do the reactions at high concentrations afford high throughput, but they also produce less downstream waste. Anhydrous reaction conditions can be reached by using anhydrous reagents and solvents. In addition, azeotropic distillation is the most commonly used technique to remove moisture from a reaction system. In the case of the presence of temperature-sensitive species, a moisture scavenger, such as acetic anhydride, is employed.

P.3.3 Isolation and Purification Direct isolation and extractive workup are two commonly used isolation approaches. Direct isolation is preferred over extractive workup in terms of process wastes, processing times, and costs. An isolated reaction product usually needs to be purified in order to meet the predetermined purity criteria. The purification methods include distillation, crystallization/precipitation, and column chromatography. Owing to the intensive labor requirement, column chromatography is generally not recommended at large scales. Obviously, the product yield and quality, including chemical/chiral purity and solid form (for solid materials), are two important parameters in determining the efficiency of a given process. Generally, reaction product yields of around 100% are considered quantitative, yields between 90 and 100% are considered excellent, yields between 80 and 90% are considered very good, yields between 60 and 80% are considered good, yields between 40 and 50% are considered moderate, and yields below 40% are considered poor. A product failed to meet the predetermined purity criteria may contain impurities such as residual processing solvents, undesired products, or metals (See Chapters 18 to 20 for various isolation/purification strategies).

Author Biography Dr. Wenyi Zhao, Senior Research Scientist (Process Chemistry), Member of the American Chemical Society. 1980–1990: Ph.D., Organic/Physical Organic Chemistry, Nanjing University, China. 1990–1992: Postdoctoral fellow at the Institute of Chemistry, Chinese Academy of Sciences, Beijing. 1992–1995: Associate Professor at the Institute of Photographic Chemistry, Chinese Academy of Sciences, Beijing (now the Institute of Chemistry, Chinese Academy of Sciences, Beijing). 1995–2001: Senior Research Associate in the Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas. Early in 2001, Dr. Zhao moved to the private sector to become a process chemist in the pharmaceutical industry in the United States. He is the author of numerous journal articles and holds several patents.

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List of Abbreviations ACE-Cl: API: ARC: 9-BBN: BCS: BDMAEE: BHT: BINAP: Boc: BOP: BQ BSA: mCBA: mCBPO: Cbz: CDI: CDMT: CIDR: CLD: CMCS: COBC: mCPBA: CPME: CSA: CSD: CSI: CTP: DABCO: DABSO: 1,2-DAP: DAS: DAST: DBDMH: DBH DBN: DBUL DCC: DCE: DCH: DCM: DEA: DEAD: DEAN: DEG: DEM: DEMS:

1-Chloroethyl chloroformate Active pharmaceutical ingredient Accelerating rate calorimeter 9-Borabicyclo[3.3.1]nonane Biopharmaceutics classification system Bis[2-(N,N-dimethylamino)ethyl] ether Butylated hydroxy toluene (2,6-​bis(1​,1-di​methy​lethy​l)-4-​methy​lphen​ol) 2,2′-​Bis(d​iphen​ylpho​sphin​o)-1,​1′-bi​napht​hyl tert-Butyloxycarbonyl (Benz​otria​zol-1​-ylox​y)tri​s-(di​methy​lamin​o)pho​sphon​ium hexafluorophosphate 1,4-Benzoquinone Bis(trimethylsily)acetamide (or TMCS) m-Chlorobenzoic acid m-Chlorobenzoyl peroxide Benzyloxycarbonyl 1,1'-Carbonyldiimidazole 2-Chloro-4,6-dimethoxy-1,3,5-triazine Crystallization-induced dynamic resolution Chord length distribution Chloromethyl chlorosulfate Continuous oscillatory baffled crystallizer m-Chloroperbenzoic acid Cyclopentyl methyl ether Camphorsulfonic acid Crystal size distribution N-Chlorosulfonylisocyanate 4-Chlorothiophenol 1,4-Diazabicyclo[2.2.2]octane 1,4-Diazabicyclo[2.2.2]octane (DABCO)–sulfur dioxide charge-transfer complex 1,2-Diaminopropane Dipolar aprotic solvent Diethylaminosulfur trifluoride Dibromodimethylhydantoin 1,3-Dibromo-5,5-dimethylhydantoin 1,5-Diazabicyclo[4.3.0]non-5-ene 1,8-Diazabicyclo[5.4.0]undec-7-ene Dicyclohexyl carbodiimide Dichloroethane 1,3-Dichloro-5,5-dimethylhydantoin Dichloromethane Diethanolamine Diethyl azodicarboxylate N,N-Diethylaniline Diethylene glycol Diethoxymethane Diethoxy(methyl)silane xxxv

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Deoxo-Fluor: DFI: DHP: DIAD: DIBAL-H: DIC: DIPEA: DIPT: DKR: DMAc: DMAP: DMC: DMCC: DME: DMEDA: DMF: DMI: DMP: 2,2-DMP: DMPU: DMS: DMSO: DPEphos: DPPA: DPPB: DPPE: DPPF: DPPH: DPPP: DSC: DTA: DTAD: DTBP: DTTA: DVS: EDC: EDCI: EDTA: EEDQ: EH&S: EMA: EPA: FBRM: FDA: FTIR: GSK: HATU: HBTU: HDMT: HFIP:

List of Abbreviations

Bis(2-methoxyethyl)aminosulfur trifluoride 2,2-Difluoro-1,3-dimethylimidazolidine 3,4-Dihydro-2H-pyran Diisopropyl azodicarboxylate Diisobutylaluminum hydride 1,3-Diisopropylcarbodiimide Diisopropylethylamine Diisopropyl tartrate Dynamic kinetic resolution Dimethylacetamide 4-Dimethylaminopyridine Dimethyl carbonate Dimethylcarbamoyl chloride Dimethoxyethane N,N-Dimethylethylenediamine Dimethyl formamide Dimethylimidazolidinone Dess–Martin periodinane 2,2-Dimethoxypropane 1,3-Dimethyl tetrahydropyrimidin-2(1H)-one Dimethyl sulfide Dimethyl sulfoxide Bis[(2-diphenylphosphino)phenyl]ether Diphenylphosphoryl azide 1,4-Bis(diphenylphosphino)butane 1,2-Bis(diphenylphosphino)ethane Bis(diphenylphosphino)ferrocene O-(Diphenylphosphinyl)hydroxylamine 1,3-Bis(diphenylphosphino)propane Differential scanning calorimetry Differential thermal analysis Di-tert-butyl azodicarboxylate 2,6-Di-tert-butyl pyridine Di-p-toluoyl-tartaric acid Dynamic vapor sorption 1-Eth​yl-3-​(3-di​methy​lamin​oprop​yl)ca​rbodi​imide​ 1-Eth​yl-3-​(3-di​methy​lamin​oprop​yl)-c​arbod​iimid​e hydrochloride Ethylenediamine tetraacetic acid 2-Eth​oxy-1​-etho​xycar​bonyl​-1,2-​dihyd​roqui​nolin​e Environment, health and safety European Medicines Agency Environmental Protection Agency Focused beam reflectance measurement Food and Drug Administration Fourier transform infrared spectroscopy GlaxoSmithKline Pharmaceuticals 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate 2-Hydroxy-4,6-dimethoxy-1,3,5-triazine Hexafluoro-2-propanol

List of Abbreviations

HKR: HMDS: HMPA: HMTA: HNB: HOAt: HOBt: HOSu: HPLC: HAS: HWE: IBCF: ICH: IMS: INCB: IPA: IPAc: IPE: LAH: LDA: LiHMDS: LiTMP: MCR: MEK: MEMCl: MeTHF: MIBK: MIDA: MP: MPD: MP-TMT: MPMN: MPV: MSA: MSDS: MTBE: MW: NBS: NCP: NCS: NFSI: NIS: NMM: NMO: NMP: NPTC: NSFI: P-BiAA: PBPB: PBS: PCC:

Hydrolytic kinetic resolution Hexamethyldisilazane Hexamethylphosphoramide Hexamethylenetetramine 2-Hydroxy-5-nitrobenzaldehyde 1-Hydroxy-7-azabenzotriazole 1-Hydroxybenzotriazole N-Hydroxysuccinimide High-performance liquid chromatography Hydroxylamine-O-sulfonic acid Horner–Wadsworth–Emmons olefination Isobutyl chloroformate International Conference on Harmonization Industrial methylated spirit International Narcotics Control Board 2-Propanol Isopropyl acetate Diisopropyl ether Lithium aluminum hydride Lithium diisopropylamide Lithium bis(trimethylsilyl)amide Lithium 2,2,6,6-tetramethylpiperidin-1-ide Multicomponent reaction Methyl ethyl ketone 2-Methoxyethoxymethyl chloride 2-Methyl tetrahydrofuran Methyl isobutyl ketone N-Methyl iminodiacetic acid Melting point Mechanism-guided process development Macroporous polystyrene-2,4,6-trimercaptotriazine 2-Methyl-2-phenyl malononitrile Meerwein–Ponndorf–Verley reduction Methanesulfonic acid Material safety data sheet Methyl tert-butyl ether Molecular weight N-Bromosuccinimide N-Chlorophthalimide N-Chlorosuccinimide N-Fluorobenzenesulfonimide N-Iodosuccinimide N-Methylmorpholine N-Methylmorpholine N-oxide N-Methyl-2-pyrrolidone p-Nitrophenol tempo carbonate N-Fluorobenzenesulfonimide Polymer-supported bis(2-aminoethyl)-amine Pyridinium bromide perbromide Phosphate-buffered saline Pyridinium chlorochromate

xxxvii

xxxviii

PCP: P-EDA: L-PGA: PGIs: PGME: PICB: PKA: PLE: PMB: PMP PNB: PPTS: PSD: PTAB: PTC: P-TriAA: PVE: PVM: PYBOP: RCM: R&D: RSST: SAS: SEM: SNAr: SN1: SN2: STAB: T3P: TATP: TBAB: TBACl: TBAF: TBHP: TBS: TCAN: TCCA: TDA: TEA: TEAB: TEAHC: TEBA: TEBAC: TEMP: TEMPO: TFA: TFB: TFBen: TFE: TFFH: TGA:

List of Abbreviations

Purity control point Polymer-supported ethylenediamine L-Pyroglutamic acid Potential genotoxic impurities Propylene glycol monomethyl ether 2-Picoline borane Porcine kidney Pig liver esterase p-Methoxybenzyl p-Methoxyphenyl p-Nitrobenzyl Pyridinium p-toluenesulfonate Particle size distribution Phenyltrimethyl ammonium tribromide Phase-transfer catalyst Polymer-supported tris(2-aminoethyl)-amine Propyl vinyl ether Particle vision measurement (Benz​otria​zol-1​-ylox​y)-tr​ispyr​rolid​inoph​ospho​nium hexafluorophosphate Ring-closing metathesis Research and development Reactive system screening tool Sodium anthraquinone-2-sulfonate Scanning electron microscope Aromatic nucleophilic substitution Nucleophilic unimolecular substitution Nucleophilic two-molecular substitution Sodium triacetoxyborohydride n-Propanephosphonic acid cyclic anhydride Triacetone triperoxide Tetrabutylammonium bromide Tetrabutylammonium chloride Tetrabutylammonium fluoride tert-Butyl hydroperoxide tert-Butyldimethylsilyl Trichloroacetonitrile Trichloroisocyanuric acid Tris(3,6-dioxaheptyl)amine Triethylamine Tetraethylammonium bromide Tetraethylammonium hydrogen carbonate Triethylbenzylammonium chloride Triethylbenzylammonium chloride 2,2,6,6-Tetramethylpiperidine 2,2,6,6-Tetramethyl-1-piperidine-N-oxide Trifluoroacetic acid (Trifluoromethyl)benzene Benzene-1,3,5-triyl triformate Trifluoroethanol N,N,N΄,N΄-Tetramethylfluoroformamidinium hexafluorophosphate Thermogravimetric analysis

List of Abbreviations

THF: THP: TIPS: TMAF: TMCS: TMDS: TMEDA: TMG: TMM: TMP: TMS: TMSCl: TMSCN: TMSI: TMSOK: TMT: TMU: TPPMS: TPPTS: TRIS: p-TSA: UHP: VDKR: VOC: WFE: XRPD: XtalFluor-E: XtalFluor-M:

Tetrahydrofuran Tetrahydropyran Triisopropylsilyl Tetramethylammonium fluoride N,O-Bis(trimethylsilyl)acetamide (or BSA) Tetramethyl disiloxane Tetramethylethylenediamine Tetramethyl guanidine Trimethylenemethane 2,2,6,6-Tetramethylpiperidine Trimethylsilyl Chlorotrimethylsilane Trimethylsilyl cyanide Iodotrimethylsilane Potassium trimethylsilanolate Trimercaptotriazine (or trithiocyanuric acid) Tetramethyl urea Sodium 3-(diphenylphosphino)benzenesulfonate 3,3′,​3″-Ph​ospha​netri​yltri​s(ben​zenes​ulfon​ic acid) trisodium salt Tris(hydroxymethyl)aminomethane para-Toluenesulfonic acid Urea–hydrogen peroxide Vinylogous dynamic kinetic resolution Volatile organic compound Wiped film evaporation X-ray powder diffraction Diethylaminodifluorosulfinium tetrafluoroborate Difluoro(morpholino)sulfonium tetrafluoroborate

xxxix

1

Reaction Solvent Selection

Process chemists face numerous challenges, such as dealing with issues including process safety, waste streams, chemical toxicity, recycling of solvents/catalysts, process economics, and a multitude of engineering/technology considerations. In a chemical process, solvents are employed for multiple purposes: to achieve the desired reaction rate and selectivity and to improve the process safety by efficient mass transfer, taking up heat generated by the reaction, or offering a safety barrier via refluxing. Solvents are also required during product isolations such as extractions and crystallizations. Therefore, the solvent plays a critical role in the synthetic process; the appropriate selection of solvent for processing a drug substance may enhance the yield, allow isolation of a preferred crystal form, or improve product purity. The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use guidance for industry (ICH Q3C) makes recommendations as to what amounts of residual solvents are considered safe in pharmaceuticals and commonly used solvents have been grouped by toxicity under the ICH Q3C guidance. The most toxic solvents (Class 1, Table 1.1) should be avoided in the production of drug substances or excipients unless their use can be strongly justified in a risk-benefit assessment. Solvents with less severe toxicity (Class 2) should be limited in the drug production process in order to protect patients from potential adverse effects. Ideally, less toxic solvents (Class 3) should be used. In general, process solvents cannot be completely removed by practical manufacturing techniques; therefore, besides the reactivity and compatibility, the solvent selection should be also based on the assessment of health hazards, such as carcinogenicity, mutagenicity, skin sensitization, etc.,1 and all residual solvents should be removed from the drug product to the extent possible to meet product specifications or other quality-based requirements. Generally, in addition to ICH Q3C the selection of an appropriate solvent for a given reaction should meet the following criteria: • • • •

be inert to the reaction conditions. be able to dissolve the reactants and reagents. have an appropriate boiling point. be easily removed at the end of the reaction.

In order to help process chemists to choose sustainable solvents, some pharmaceutical companies have elaborated solvent selection guides.2 Figure 1.1 shows the top 10 most frequently used solvents by GlaxoSmithKline Pharmaceuticals (GSK) in 2005 and during the time period of 1990–2000. An indication, from these data, is that there is a trend toward decreasing tetrahydrofuran (THF), toluene, and dichloromethane use. In general, in order to achieve a high material throughput, a solvent with a solubility of 100 mg/mL or greater is preferred. Solvent use is responsible for 60% of the overall energy used in a pharmaceutical process and accounts for 50% of the post-treatment green house gas emissions.3 In addition, 80% of waste generated during the manufacture of a typical active pharmaceutical ingredient (API) is related to solvent use. Given these figures, vigilant solvent selection to maximize efficiency and potential recovery can have a huge impact on the process costs and the environment. In general, a single solvent in a process is preferred because of the simplicity of recycling.

DOI: 10.1201/9781003288411-1

1

2

Handbook for Chemical Process Research and Development

TABLE 1.1 Some Class 1, Class 2, and Class 3 Solventsa Class 1

2

3

a

Solvent Benzene Carbon tetrachloride 1,2-dichloroethane 1,1-dichloroethene 1,1,1-Trichloroethane Acetonitrile Chlorobenzene Chloroform Cyclohexane 1,2-Dichloroethene Dichloromethane Dimethoxyethane N,N-Dimethylacetamide N,N-Dimethylformamide 1,4-Dioxane 2-Ethoxyethanol Ethylene glycol Hexane Methanol 2-Methoxyethanol N-Methyl pyrrolidone Nitromethane Pyridine Sulfolane Tetrahydrofuran Toluene Xylene Acetic acid Acetone Anisole 1-Butanol 2-Butanol Butyl acetate tert-Butyl methyl ether Dimethyl sulfoxide Ethanol Ethyl acetate Formic acid Heptane Isobutyl acetate 1-Propanol 2-Propanol Propyl acetate Triethylamine

Concentration Limit (in ppm) 2 4 5 8 1500 410 360 60 3880 1870 600 100 1090 880 380 160 620 290 3000 50 530 50 200 160 720 890 2170 5000 5000 5000 5000 5000 5000 5000 5000 5000 5000 5000 5000 5000 5000 5000 5000 5000

Cited from: https://www​.fda​.gov​/media​/71737​/download.

Concern Carcinogen Toxic and environmental hazard Toxic Toxic Environmental hazard – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – –

3

Reaction Solvent Selection

1 2

2005

5

7

8

9 2005

2005

8

10 11

1990-2000

1990-2000

12

IPA

EtOAc

MeOH D. EtOH Heptane

THF

Toluene

DCM

AcOH

2005

2005

2005

6

1990-2000

1990-2000

6

14 1990-2000

2005

2005

4

3 1990-2000

3

1990-2000

1990-2000

1990-2000

2005

2

4 5

1990-2000

2005

1

MeCN

FIGURE 1.1  Comparison of solvent use in GSK in 2005 and from 1990–2000 (reprinted with permission from Constable, D.J.C. et al., Org. Process Research & Development, 11, 2007, 133. Copyright 2007 American Chemical Society).

1.1 ETHEREAL SOLVENTS Prudent selection of solvents is important for developing a safe and robust chemical process. It is well-known that solvents with low boiling points and low flash points,4 such as diethyl ether, are not suitable for scaling up. Tetrahydrofuran (THF), 2-methyl tetrahydrofuran (MeTHF), and methyl tert-butyl ether (MTBE) are frequently used as substituents of diethyl ether. Some physical properties of commonly used ether solvents can be found in the literature.5 Notably, the peroxide content in ether solvents is also a process safety concern, as most ethereal solvents have a propensity of forming explosive organic peroxides after storing for a period of time. Therefore, commercially available ether solvents are usually blended with anti-oxidant, 2,6-di-tertbutyl-4-methylphenol (BHT). MeTHF (CAS 96-47-9) and cyclopentyl methyl ether (CPME: CAS 5614-37-9) are being increasingly used6 as alternatives to their analogs such as THF and MTBE. These two solvents offer superior physical (higher flash point, water azeotrope, phase cuts, and lower volatility) and chemical properties (greater acid/base stability). A toxicological assessment of MeTHF and CPME was made7 in support of their use in pharmaceutical chemical process development.

1.1.1 Cyclopentyl Methyl Ether CPME has become available in commercial quantities since late 2005. Compared with other ethereal solvents, CPME has a high boiling point (106 °C), low peroxide level, and relative stability

4

Handbook for Chemical Process Research and Development

under acidic and basic conditions. Having a relatively low water content (the water solubility is 0.3 g per 100 g of CPME) among the ethereal solvents, CPME can be used directly as the solvent for reactions including Grignard reactions, enolate formations, Claisen condensations, reductions, and Pd-mediated transformations. Other characteristics of CPME, such as a low level of peroxides coupled with a narrow explosion range, render CPME a good alternative to other ethereal solvents such as THF, MeTHF, dioxane (carcinogenic), and dimethoxyethane (DME). In addition, relatively low solubility in water and low vaporization energy make the recovery of CPME more efficient. However, the use of solvents such as CPME and MeTHF should be with caution, especially in the last processing steps, as these solvents are not classified for use by ICH guidelines.8 1.1.1.1 Brook Rearrangement CPME shows a unique solvent effect in stabilizing a reactive enolate 2 in Brook rearrangementmediated [4+3] cycloaddition for the stereoselective construction of 2-oxabicyclo[3.3.2]decenone derivatives 4 (Scheme 1.1).9 As the enolate 2 of cycloheptenone is unstable at –80 ºC, replacement of THF with CPME was able to perform this cycloaddition at –98 ºC. As a result, the yields of cycloadducts 4 were improved. O O

NaN(SiMe3)2 CPME, -98 oC

O

ONa

SiMe2tBu R

O

1

O O

Me2(tBu)SiO

3

R R

2

Yield, %

SiMe 3 SiMe2Ph SiMe 2tBu

4

83 73 77

iPr

79

tBu

77

SCHEME 1.1   

REMARKS (a) It was found that enantioselective α-methylation of chiral amides in CPME gave the highest enantiomer excess among other ethereal solvents.10 The asymmetric induction in CPME was assumed to proceed via a mixed aggregate during the chirality transfer from an undeprotonated chiral amide into an achiral enolate. (b) CPME as an additive for the carbenoid chemistry led to a high yield of enynes (Equation 1.1).11



R1

Cl

R2

S(O)Tol

(a) tBuMgCl iPrMgCl THF/CPME, -78 oC (b) Li

R

R

(1.1)

R1 R2

H

1.1.1.2  N-Alkylation Reaction Having a low solubility in water, CPME was chosen as the reaction solvent for the alkylation reaction (Equation 1.2).12 In this CPME/water two-phase reaction system, CPME served as the reaction solvent and the solvent for the extraction during the workup. This would avoid the need for solvent

5

Reaction Solvent Selection

removal as in the case of THF or acetonitrile before extracting the free base into solvents such as DCM or ethyl acetate. Ph Ph



CONH2 NH 5

(a) K2CO3 CPME/H2O

Br

+

(b) aq HBr acetone

O

L-Tartrate

6

Ph Ph

HBr

CONH2

O (1.2)

N 7

Procedure Stage (a) • Charge 404.55 g (2.93 mol, 4.2 equiv) of K2CO3 into a solution of 5 (300 g, 0.7 mol) in a biphasic mixture of water (900 mL) and CPME (1.2 L) at 25–30 ºC. • Stir for 30 min. • Charge 185.17 g (0.82 mol, 1.2 equiv) of 6 at 25–30 ºC. • Heat the batch to 70–75 ºC and stir at that temperature for 12 h. • Cool to 25–30 ºC. • Add CPME (1.2 L) and water (900 mL) and stir for 30 min. • Filter through a bed of hyflow. • Separate layers and extract the aqueous layer with CPME (600 mL). • Wash the combined CPME layers with water. • Distill under reduced pressure. • Add toluene and continue to distill. Stage (b) • Add acetone (1.5 L). • Cool to 0–5 ºC. • Add 117.3 mL of 48% (in water) HBr. • Stir at 0–5 ºC for 2 h and at room temperature for 5 h. • Distill under reduced pressure. • Add acetone (2.4 L) and stir for 4 h. • Filter to give a wet solid. • Dissolve the wet solid in n-butanol (2.1 L) at reflux. • Cool to room temperature and stir for 3 h. • Filter and wash with acetone. • Dry at 50–60 ºC under vacuum. • Yield: 265 g (75%).

1.1.2 Tetrahydrofuran 1.1.2.1 Grignard Reagent Formation Ethereal solvents, such as THF and diether ether, are frequently chosen as solvents for the preparation of Grignard reagents. One of the most common problems in Grignard preparation is the Wurtz-type coupling forming a dimer side product. Attempts to prepare the Grignard reagent from a reaction of benzyl chloride with magnesium metal (Equation 1.3)13 in THF led to the almost exclusive formation of the ethane dimer. Except for diethyl ether, other ethereal solvents failed to give the desired Grignard reagent. Cl R



8

Mg solvent R=H, SMe

MgCl R

9

(1.3)

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Handbook for Chemical Process Research and Development

In order to avoid dimer formation, a protocol of adding the chloride 8 THF solution to Mg (1.5 equiv) in toluene at 3.0 kg of 24 in 89% yield in a safe and environmentally acceptable manner. 1.1.4.2 Darzens Reaction The methyl glycidate intermediate 27 was obtained via Darzens reaction by treating benzophenone 25 with methyl chloroacetate 26 in the presence of sodium methoxide in MTBE (Equation 1.11).24 Although the calorimetric evaluation showed no safety issues and the reaction was carried out successfully on laboratory scales, the first pilot scale synthesis was accompanied by an unwelcome

10

Handbook for Chemical Process Research and Development

surprise. The reaction was initiated very violently, after half of 26 had been added, resulting in most of the MTBE evaporating within seconds. O +



Cl

25

CO2Me

CO2Me

O

NaOMe

(1.11)

solvent

26

27

Investigations found that the poor solubility of NaOMe in MTBE was the cause of the problem, leading to the accumulation of 26. As the reaction produced methanol as the byproduct which helped to dissolve NaOMe, a self-accelerated reaction was thus observed. Therefore, the replacement of MTBE with THF could solve the problem.

1.1.5 Diethoxymethane and Dimethoxyethane Diethoxymethane (DEM) is a useful organic solvent and can be used under basic conditions for a variety of applications,25 including sodium hydride reactions, organolithium chemistry, coppercatalyzed conjugate additions, and phase-transfer reactions. It has unique properties: a moderate boiling point (88 °C), azeotropes with water, and a very low affinity for water. Like DEM, dimethoxyethane (DME) is also used as a reaction solvent. For instance, the SN2 reaction of enolate of 4-fluoroacetopheone 28 gave two products, ketone 30 and aryl vinyl ether 31 (Equation 1.12).26 A significantly solvent effect was observed when conducting the reaction in DME (or THF) compared to in DMSO, indicating that high solvating solvents, such as DMSO, promoted reaction at oxygen, while DME enhanced reaction at carbon. O

O

X Me

28

O

NaH

+

F



N CF3 X=F, Cl 29

N F

30

+ CF3

F

31

N

(1.12) CF3



1.2 PROTIC SOLVENTS Because of their low toxicity, commercial availability, and good solubility for most organic compounds, methanol, ethanol, and 2-propanol are three commonly used solvents in various applications in the pharmaceutical industry.

1.2.1 Methanol as a Solvent Due to their water miscibility and good solubility with most organic compounds, alcoholic solvents are commonly used in catalytic hydrogenations. 1.2.1.1 Leak of Palladium Catalyst When using alcohol solvents, the isolated product may be contaminated with black solids because of the leaching of palladium catalyst from the carbon support or partial digestion of the carbon support. For example, the palladium-catalyzed hydrogenation of nitro acetal 32 in alcohols led to the product amino acetal 33 being contaminated with black solids (Equation 1.13).27 OMe OMe NO2



32

OMe OMe (1.13)

5% Pd/C, H2 toluene

NH2 33

11

Reaction Solvent Selection

To address this issue, toluene was chosen as the reaction solvent to replace alcoholic solvents, ­providing 93.6% of the product 33. 1.2.1.2 Side Product Formation The selection of reaction solvents can impact the product stability, and thus the isolated product yield and purity. For example, using methanol as the solvent for the hydrogenation of nitroindazole 34 resulted in the contamination of the desired product 35 with 30% of deprotected amino indazole 36 (Equation 1.14).28 NO2 N

NH2 (a) 10% Pd/C, H2

N CO2Me

(b) HCl

N

N CO2Me

34

(1.14)

35 NH2 N



N H

36

Ultimately, the use of THF or ethyl acetate as the reaction solvent suppressed the formation of 36. 1.2.1.3 Palladium-Catalyzed Methylation Reaction In addition to being a reaction solvent, methanol was utilized as a surrogate for the methylation reagent in a highly efficient, palladium-catalyzed methylation of nitroarenes (Scheme 1.4).29 Generally, N-methylation can be prepared by either methylation of amines with toxic reagents, such as methyl iodide, dimethyl sulfate, and dimethyl carbonate or reductive methylation with formaldehyde. The use of methanol as an inexpensive reductive methylation reagent requires a challenging, controlled oxidation. A phosphine-based ligand containing a pyridyl moiety activates the O–H bond in methanol, allowing the oxidative addition of Pd(0) to the O–H bond leading to a palladium hydride complex. The subsequent β-hydride elimination would generate formaldehyde and hydrogen in situ. Thus, methanol in this reaction acts as a solvent, hydrogen source, and methylation reagent.

Pd(OAc)2 (1-2 mol%) Ligand (4-8 mol%) KOH (1.25 equiv)

NO2 R

MeOH, 80-110 oC

Me N H

R

N tBu iPr

N

P iPr Pd L

SCHEME 1.4   

L

N H

O CH3

L

Pd

O CH 3 H

O H

H

+

H2

12

Handbook for Chemical Process Research and Development

1.2.2 Ethanol as a Solvent 1.2.2.1 Catalytic Reduction of Diaryl Methanol Solvent selection sometimes has a significant effect on reaction outcomes, for example, the selectivity of the catalytic reduction of diaryl methanol 37 varied drastically when switching alcoholic solvent to a non-protic solvent (Equation 1.15).30 H2, Pd/C H2SO4

OH Cl

N

CO2Et

N

Cl

ZnBr 2 (1 mol%) solvent

OH

CO2Et

(1.15)

OH 38

37

N

CO2Et

OH 39 Solvent



ZnBr2 (mol%)

Conversion (%)

Selectivity (38:39)

EtOH

none

80

3.3:1

EtOH

100

22

40:1

EtOAc

1

99

>200:1

(I) Reaction problems Although a good conversion of diarylmethanol 37 was achieved in acidic ethanol, this reaction suffered poor selectivity, leading to a mixture of the product 38 and a dechlorinated side product 39 in a ratio of 3.3:1 (38:39). (II) Solutions The use of less polar solvents or halide additives can reduce the rate of reductive dehalogenation.31 Thus, using ethyl acetate as the reaction solvent with ZnBr2 as the additive gave a 99% conversion in excellent selectivity (38:39, >200:1). 1.2.2.2 SN2 Reaction Ethanol could replace DMF in the SN2 nucleophilic substitution reaction to synthesize alkyl aryl ether 53 (Equation 1.16).32 OHC

OH +

Br

K2CO3 EtOH, reflux 8 h, 95%

OMe



40

41

OHC

O

(1.16)

OMe 42

Compared with the 84% yield in DMF, the reaction in EtOH gave an excellent yield (95%) of 53 reproducibly on a 10 kg scale.

1.2.3 2-Propanol as a Solvent 1.2.3.1 Reaction of Acyl Hydrazine with Trimethylsilyl Isocyanate An intriguing solvent-related effect during the installation of the urea moiety on the basic nitrogen of acyl hydrazine 43 was observed (Equation 1.17).33 In isopropyl alcohol (IPA) the reaction of

13

Reaction Solvent Selection

43 with trimethylsilyl isocyanate (TMS-NCO) gave the desired product 44 in 81% yield, while in dichloromethane no product was formed.

Me

Me

tBuO2C

O

H N O

TMS-NCO (1.5 equiv)

N H Me

43

solvent, rt, 16 h

H N

Me Me tBuO2C



O

O

44

N

(1.17)

O

NH2

Solvent

Yield, %

DCM IPA

0 81

Me

REMARK Although IPA is frequently used in laboratories and manufacturing plants, the likelihood of peroxide (or triacetone triperoxide) formation in IPA and its associated hazards is overlooked. There have been several reports of explosions occurring during the distillation of IPA that have resulted in injury to researchers. Thus, a research paper34 suggests a few safety practices that should be implemented in the laboratory environment:

1. Store IPA bottles in a flammable cabinet and away from light. 2. Dispose of old bottles of IPA. 3. Take extra caution when distilling IPA. Always check for peroxides before distillation, and do not distill when peroxides are detected. Never distill the solvent to dryness.

1.2.3.2 Classical Resolution of Racemic Acid Solvent selection for classical resolution affects both the yield and optical purity. It was observed that the resolution of racemic hexynoic acid (±)-45 with (1S,2R)-1-amino-2-indanol 46 by forming a diastereomeric salt was solvent dependent, and different yield and optical purity were obtained when using three different solvents (Equation 1.18).35 Me H2N CO2H

+

HO

Conditions

(1.18)

CO2H

HO

HO

HO 45

46 Solvent



H2 N

Me

2-propanol 1-propanol acetonitrile

47

Equiv of 46 1.0 0.55 0.55

Optical Purity ~93% ee (free acid) >98% de 98% de

Yield 28% 28 34% 39 41%

Resolution in 2-propanol gave the chiral hexynoic acid 45 (after the salt break) in 28% yield with ~93% ee, while in 1-propanol or acetonitrile provided the diastereomeric salt 47 in 28–34% yield (>98% de) and 39–41% yield (98% de), respectively.

14

Handbook for Chemical Process Research and Development

REMARK Glycerol is immiscible with hydrocarbons and is considered a biodegradable, inexpensive, and non-toxic solvent. It can form strong hydrogen bonds and dissolve inorganic compounds. Glycerol was used as a solvent in the metal-catalyzed cycloisomerization of (Z)-2-en-4-yn-1-ols into furans.36 1.2.3.3 Nickel-Catalyzed Addition Reaction A nickel-catalyzed addition reaction was developed to access chiral β-hydroxynitriles (Scheme 1.5).37 The reaction proceeded in 2-propanol via an enantioselective addition of acetonitrile to aldehydes in the presence of nickel pincer complex catalyst and potassium tert-butoxide (2 mol%). Although with a high pKa of 31.3 (in DMSO), acetonitrile, being coordinated with the Ni(II) pincer complex, is deprotonated with potassium tert-butoxide. The resulting coordinated cyanocarbanion adds to the aldehyde affording a zwitterionic intermediate. This process features a high atom economy and uses inexpensive acetonitrile as a nitrogen and two-carbon source. O

H

Ar O Ar

+

H

H

cat. (2 mol%) KOtBu (2 mol%)

CN

N

o

H H

Ph

O

MeCN/iPrOH, -20 C 24 h

N

H Ph

Ni

N N

O

OH

N N

23 examples 41-99% yields 65-96% ee

Me Ph

O N

cat. =

N N

N Ni

Ph

CN

Ar

O N N PF6

SCHEME 1.5   

1.2.4 1-Pentanol The debenzylation of dibenzylated amine hydrochloride 48 was carried out under catalytic transfer hydrogenation conditions (Equation 1.19)38 with ammonium formate as the hydrogen source. Ph O

HCl O

N 48

Bn

(a) NaOH, solvent (b) 10% Pd/C, HCO2NH4 (c) succinic acid

Bn

O

O

HO NH2 O

OH

(1.19)

49 Ph O



O Ph

O

NHBn 50

(I) Reaction problems It was observed that the catalytic debenzylation in ethanol at 40–45 ºC was very slow even with 5 equiv of ammonium formate, giving a considerable amount (73%) of mono-benzyl side product 50.

15

Reaction Solvent Selection

(II) Solutions A significant improvement was achieved when switching to 1-pentanol by conducting the reaction in a two-phase system. After 12 h, 100% conversion was achieved. The amount of the mono-benzyl intermediate 50 was reduced to less than 1%. Procedure Stage (a) free base formation • Charge 121.0 g (0.286 mol) of 48 and 405.5 g (500 mL) of 1-pentanol. • Charge 312.0 g of 1 N NaOH. • Heat to 45–50 ºC and stir for 5 min. • Separate layers and cool the organic layer to 20–25 ºC. Stages (b) hydrogenolysis • Charge 24.2 g of 10% Pd/C to another reactor. • Charge the 1-pentanol solution of the free base of 48. • Prepare, in a separate container, an aqueous solution by dissolving 90.2 g (1.43 mol) of ammonium formate in 150 mL of water. • Charge the ammonium formate solution over 30–40 min to the reactor at 45–50 ºC. • Stir at 45–50 ºC for 16 h. • Cool to 20–25 ºC prior to filtration. • Wash the cake with 100 mL of 1-pentanol and 50 mL of water. • Separate the lower aqueous layer from the filtrate. • Wash the organic layer with 2×100 mL of water at 45–50 ºC. • Distill at atmospheric pressure at 102 ºC until ~100 mL of distillate is collected. • Cool to 30 ºC. Stage (c) formation of succinic acid salt • Charge 33.8 g (0.29 mol) of succinic acid. • Heat to 95–100 ºC. • Cool to 20–25 ºC over 2 h and stir at that temperature for ≥90 min. • Add 250 mL of heptane and stir for 1.5 h. • Filter and wash with 150 mL of 1:1 mixture of heptane and 1-pentanol. • Dry at 55–60 ºC under vacuum. • Yield: 77.5 g (80%).

1.2.5 Ethylene Glycol Ethylene glycol is a good solvent for the addition/elimination reaction of ester 51 with 4-chlorobenzylamine 52 (Equation 1.20).39 O N

NH2

O OEt

O

N

51

OH

Cl

O

52 ethylene glycol 132 oC

O

N O

N H N

53

OH

(1.20)

Cl



In ethylene glycol, a homogeneous solution was obtained by heating the slurry of 51 and 52, and the reaction was performed at 132 ºC for 8 h, furnishing the desired amide 53.

16

Handbook for Chemical Process Research and Development

Procedure • Charge 800 g (2.1 mol) of 51 into a 22-L, three-necked flask under nitrogen, followed by adding ethylene glycol (4.8 L) and 755 mL (6.2 mol, 3 equiv) of 52. • Heat the resulting suspension at 132 ºC for 8 h. • Cool to 102 ºC. • Add toluene (2.4 L). • Cool to 75 ºC. • Add MeCN (1.2 L), followed by adding 215 mL (2.1 mol, 1.0 equiv) of pivaldehyde. • Cool to room temperature • Filter, rinse with EtOH (2 L) and MeCN (2×1 L), and dry at 55 ºC under vacuum. • Yield: 1318 g (132%) of crude 53. REMARK During the isolation, 4-chlorobenzylamine readily forms an insoluble carbonate salt. Therefore, the addition of pivaldehyde was used to convert the excess amine to the soluble imine and removed via filtration.

1.3 WATER AS REACTION SOLVENT When designing organic syntheses, the selection of reaction solvents is considered one of the most important aspects, especially at scale. Regarding the negative environmental impact of using volatile organic compounds (VOCs) as solvents, water becomes a highly recommended reaction solvent. Due to its high heat capacity, water is an ideal solvent for exothermic reactions. In addition, the hydrogen-bonding network can influence the reactivity of substrates.40 When conducting a reaction in water, other interesting features of water can be applied, such as adding additives or co-solvents and adjusting pH.

1.3.1 Iodination Reaction Approaches to the synthesis of iodinated molecules include diazotization–iodination reaction and electrophilic iodination using iodine or iodide in combination with an oxidant. Using molecular iodine and hydrogen peroxide in an aqueous medium is one of the most useful protocols,41 which addresses the growing concern over environmental pollution and sustainable development. Water as a reaction solvent was employed in the iodination of N-methylpyrazole 54 with iodine in the presence of hydrogen peroxide (0.6 equiv) (Equation 1.21).42 The 4-iodo-N-methylpyrazole product 55 was conveniently isolated directly by filtration from the reaction mixture in 91% yield (16.2 kg). N



N Me 54

I2 (0.5 equiv) H2O2 (0.6 equiv) H2O

N N Me 55

I

(1.21)

Procedure • Charge, into a 100-L reactor, 7.0 kg (85.3 mol) of 54 and water (30 L) followed by adding 11.0 kg (43.5 mol) of iodine. • Stir for 10 min. • Charge 15 g of 55 (as seeds). • Charge 5.2 L of 30% H2O2 (51.2 mol) over 30 min (the temperature increased from 18 to 32 ºC).

17

Reaction Solvent Selection

• • • • • • •

Stir for 42 h. Cool to 10 ºC. Add 20 L of 10% of NaHSO3 at 95%

N

145

Me

148

146

SCHEME 6.17   

Solutions The moderate product yields were presumably caused by the low nucleophilic reactivity of the Grignard reagent 147. To improve the nucleophilicity of 147, a catalytic amount of CuCl·2LiCl complex was employed to convert 147 into the corresponding organocopper 149 (Equation 6.39). Ultimately, the reaction was optimized by adding 5 mol% of CuCl·2LiCl complex to the reaction mixture, giving an overall isolated product yield of 70%. MeO MgBr

Cl



147

cat. CuCl 2LiCl

MeO Cl

2

CuLi (6.39)

149

DISCUSSIONS Organocopper reagents are mild and selective nucleophiles for addition and substitution reactions. The arylcopper nucleophile 149 was generated in situ via a transmetalation of the Grignard reagent 147 with copper (I) chloride. Procedure (for the preparation of 149): • Add anhydrous THF (50 mL) to a mixture of copper(I) chloride (1.9 g, 19 mmol) and LiCl (1.6 g, 38 mmol). • Stir the mixture for 15 min at rt to give a golden-yellow solution. • Transfer the solution via a cannula to the Grignard solution of 147 at room temperature. • Stir for 5 min prior to mixing with 146.

6.7.2 Decarboxylative Bromination The preparation of pyridone bromide 151 was realized through decarboxylative bromination (Equation 6.40).72

247

Process Optimization of Catalytic Reactions F

F F

N

N



F

NBS

H N

O

THF/H2O, 20 oC

N

CO2H

150

H N

N

O

(6.40)

Br

151

Reaction problems This decarboxylative bromination had the following issues: • Excess of NBS (2–3 equiv) was required to achieve a full conversion in solvents such as MeCN, DMF, N-methyl-2-pyrrolidone (NMP), and AcOH due to the background reaction. • Using THF as the solvent resulted in a slow reaction and low conversion. (II) Solutions The addition of a catalytic amount of lithium acetate73 allowed the reaction to complete with 1.1 equiv of NBS in aqueous THF. The lithium acetate-mediated decarboxylative bromination may proceed through β-lactone intermediate 153 (Scheme 6.18). F

F F

LiOAc 150 N

N

H N

F

NBS O

N

N

H N

151

Br

CO2Li 152

-CO2

O

153

O

O

SCHEME 6.18   

Procedure • Charge 3.32 kg (11.39 mol) of 150 into a dry 60-L jacketed reactor, followed by adding 75.1 g (1.14 mol, 10 mol%) of LiOAc, THF (20 L), and water (1.66 L). • Charge 2.23 kg (12.53 mol, 1.1 equiv) of NBS at 20 °C in four portions over 3 h. • Stir at 20 °C for 2 h. • Heat to 50 °C and stir for 1 h. • Cool to 20 °C. • Add water (33.16 L) over 70 min. • Stir the resulting mixture at 20 °C for 2 h. • Filter, wash the reactor, and the filter cake with water (3×6.63 L), and dry. • Yield: 3.30 kg (89%).

6.7.3 Formation of Acid Chloride Acid chlorides are normally prepared by a reaction of acids with oxalyl chloride in the presence of catalytic amounts of DMF. For example, DMF was used as the catalyst for the preparation of acid chloride 155 on a kilogram scale.74 Although effective at this scale of preparation, this experimental protocol raised concerns due to the potential generation of carcinogenic dimethyl carbamyl chloride 156 (Equation 6.41). Thus, alternative reaction conditions were sought for this transformation by

248

Handbook for Chemical Process Research and Development

evaluating NMP and 4-dimethylaminopyridine (DMAP) as alternative catalysts for this reaction. Ultimately, NMP was chosen as the catalyst to replace DMF. (COCl)2, cat. NC R 154

CO2H

CH2Cl2

(6.41)

NC

COCl R 155

R H, Et, OMe cat.: DMF, NMP, or DMAP O Cl Me2N 156



The optimized reaction conditions were to employ 1.2 mol equiv of oxalyl chloride and 10 mol% of NMP in methylene chloride.

6.7.4 Catalytic Dechlorination A sluggish reaction was encountered during the catalytic dechlorination of 157 with palladium on carbon (Equation 6.42).75 In the absence of a base the reaction was stalled, as the product hydrochloride salt 158 crystallized on the surface of the catalyst. F

F N



OMe N

N H 157

Cl N

N

2 HCl

H2, Pd/C

OMe (6.42)

N N

N H 158

N

N

In the presence of calcium hydroxide as a base, the reaction proceeded readily and completed in 4 h at 55–65 °C under 20 psi of hydrogen.

6.7.5 Two-Phase Reactions The application of phase transfer catalyst (PTC) in organic synthesis is well-documented in the literature. A phase-transfer catalyst is used to facilitate the migration of a reactant from one phase into another phase where the reaction occurs. The use of PTC allows the achieving of faster reactions in higher product yields with fewer side products. PTC-catalyzed reactions are especially desired in the green chemistry perspective as the phase-transfer catalysis process permits the use of water to reduce the organic solvent quantity, thereby minimizing the process waste. Quaternary ammonium and phosphonium salts are commonly utilized as PTC for nucleophilic aliphatic substitution. Typical catalysts include tetrabutylammonium bromide (TBAB), benzyltrimethylammonium chloride, and hexadecyltributylphosphonium bromide. 6.7.5.1 Enhancement of Reaction Rate The major advantage of using PTC is that it increases the reaction rate, which leads to a more efficient process due to a shorter processing cycle time on a larger scale. For instance, the Gabriel reaction (Equation 6.43)76 of bromide 159 with potassium phthalimide 160 required 18 h to complete without PTC, while in the presence of TBAB it is completed within 4 h.

249

Process Optimization of Catalytic Reactions O

F Me

Br

+

NK

I

F Me

TBAB

159

N

DMF

O



O

(6.43)

O

I

160

161

SNAr sulfonylation of halogen-substituted pyridine derivatives 162 with sodium solfinate 163 suffered from a slow reaction rate and low conversion due to the poor solubility of 163 in the reaction media (Equation 6.44).77 X

Y N

+ RSO 2Na 163

X=Cl, Br, I, OTf



TBACl (0.3 equiv)

Y

DMAc, 100 oC, 24 h

SO2R N (6.44) 164

162

Ultimately, the addition of tetrabutylammonium chloride (TBACl) phase transfer catalyst accelerated the reaction rate significantly through the in situ formed n-Bu4NSO2Tol. REMARK Ammonium chloride was found to be able to catalyze the cyclization of arylhydrazides with orthoesters during the synthesis of 1,3,4-oxadiazoles (Equation 6.45).78 O Ar



NHNH2

+

RC(OEt)3

N N

NH4Cl (30 mol%) Ar

EtOH, reflux

R

O

(6.45)

Compared with uncatalyzed cyclization, NH4Cl-catalyzed cyclization was completed in a much shorter time. 6.7.5.2 Suppressing Side Reactions The use of a phase-transfer catalyst can suppress the impurity formation. For instance, the preparation of alkyl aryl ether 167 was achieved by an SN2 reaction of phenol 165 with alkyl chloride 166 (Equation 6.46).79 Under homogeneous reaction media,80 the formation of undesired quaternary ammonium salt 168 was unavoidable. Employing triethylbenzylammonium chloride (TEBAC) (5%) in the presence of 2.2 equiv of 30% sodium hydroxide, 4-bromophenol 165 was converted selectively (>95%) into 167 within 18 h at 30–35 °C. HCl

OH + Cl

Br 165

cat. TEBAC NaOH

N 166

CH2Cl2 /H2O 30-35 oC

O Br

N

(6.46)

167

OH O

N

N

Br



168

A water-miscible organic solvent can be utilized as a non-charged PTC. For instance, acetonitrile was utilized as a PTC to mitigate the formation of side product 172 during the preparation of potassium phosphate 170 (Scheme 6.19).81 Initially, the oxidation of di-tert-butylphosphite 169 with iodine, generated in situ via oxidation of KI with H2O2, in toluene produced a low yield (39%) of the corresponding potassium phosphate

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Handbook for Chemical Process Research and Development

OH P OtBu tBu-O

30% H2O2 KI (cat) toluene/MeCN

169

O tBu-O P OtBu I 171

O tBu-O P OK OtBu 170

O P OtBu tBu-O O OtBu OtBu O P

172

SCHEME 6.19   

170 upon treatment with potassium tert-butoxide. Besides product 170, this reaction generated a significant amount of pyrophosphate 172. It was hypothesized that the low water content (KF Cl. Due to strong C–F bonds, aryl fluorides do not undergo lithium–fluorine exchange. Both the alkyllithium and the resulting aryllithium are highly reactive and unstable under normal reaction conditions, thereby cryogenic temperature is frequently required for such lithium–halogen exchange process. Deprotonation can be a side reaction with enolizable carbonyl compounds, especially with hindered organolithium reagents such as tert-butyllithium. REMARK Due to their high reactivity, organolithium compounds are incompatible with water, oxygen, and carbon dioxide, and must be handled under a protective atmosphere, such as nitrogen or argon. Organolithium compounds are often corrosive and flammable (t-BuLi is pyrophoric). Alkyllithium DOI: 10.1201/9781003288411-7

265

266

Handbook for Chemical Process Research and Development

reagents can also undergo thermal decomposition to form the corresponding alkyl species and lithium hydride. Organolithium reagents are typically stored below 2–8 °C. 7.1.1.1 Magnesium–Bromine Exchange Generally, Grignard reagents are prepared by refluxing a heterogenous mixture of aryl bromides and magnesium metal in THF. However, these reactions frequently suffer from incomplete conversion and hard-to-control exotherm events that may lead to runaway reactions. Magnesium–halogen exchange has emerged as a viable synthetic tool used to generate arylmagnesium in situ. For instance, magnesium–bromine exchange was employed to prepare aryl Grignard reagent 2 from 2-Bromo-4-fluoroanisole 1 (Equation 7.1).1 The protocol used 2.0 equiv of isopropyl magnesium chloride in THF under reflux and the exchange was completed in 1 h. OMe

OMe Br

MgCl

i-PrMgCl

+

THF F

F

1

i-PrBr (7.1)

2

OMe i-Pr OH

F



3

(I) Problems Besides the desired Mg–Br exchange Grignard product 2, a significant amount of side product 3 was also observed under reflux conditions. The formation of 3 may be attributed to the reaction of 2 with THF followed by reacting with isopropyl bromide. (II) Solutions When the Mg–Br exchange was performed at 30 °C, levels of 3 were dramatically reduced from 20.8% to 0.4%. 7.1.1.2 Lithium–Bromine Exchange Due to the high reactivity of organolithium compounds, lithium–halogen exchange is carried out at cryogenic temperature. However, cryogenic reaction conditions are undesired on a large-scale preparation because such conditions will not only generate a viscous reaction mixture that may create agitation problems but also significantly increase the process costs. The synthesis of spironolactone 6 was carried out by treatment of 2-bromobenzoic acid 4 with 2.2 equiv of n-BuLi at –78 °C, followed by the addition of N-benzylpiperidone 5 and acidification (Equation 7.2).2 O Br CO2H

Bn

nBuLi

+

O

N Bn

O

5

4

H CO2H



N

7

6 HO

nBu

N Bn 8

(7.2)

267

Process Optimization of Problematic Reactions

Besides the requirement of costly cryogenic reaction conditions, two side products, benzoic acid 7 and tertiary alcohol 8, were generated. Solutions An approach was developed to overcome the aforementioned issues. The combination of the Grignard reagent with n-BuLi was envisioned to convert the less stable aryllithium 9 to the thermally more stable arylmagnesium 10, and thus could potentially obviate the costly cryogenic conditions (Scheme 7.1). Therefore, the sequential treatment of 2-bromobenzoic acid 4 with n-BuMgCl (0.9 equiv) and n-BuLi (1.3 equiv) at –20 to 0 °C, followed by adding N-benzyl piperidone 5 afforded the spironolactone 6 in 74% yield. Br

Li

(a) nBuMgCl (b) nBuLi

CO2H

MgX

CO2MgX

4

CO2Li

9

10

SCHEME 7.1   

Procedure • Charge 4.5 L of n-BuMgCl (2.0 M in THF, 9.0 mol) slowly to a solution of 4 (2.0 kg, 9.95 mol) in 20 L of THF, followed by adding 8.3 L of n-BuLi (1.56 M in hexane, 12.9 mol) at –15 to –5 °C. • Stir for 0.5 h. • Charge a solution of 5 (2.02 L, 10.9 mol) in 6.0 L of heptane over 1 h. • Stir the mixture for 1 h. • Add 10.0 L of MTBE and 3.14 L (54.8 mol) of AcOH in 20 L of water. • Heat to 35 to 40 °C and stir for 3 h. • Workup. 7.1.1.3 Lithium–Hydrogen Exchange An isolated, apolar C–H bond in a molecule has a very low reactivity owing to the large kinetic barrier associated with the C–H bond cleavage. Therefore, metal–hydrogen exchange typically occurs at the C–H bond adjacent to a heteroatom such as oxygen and nitrogen or at the C–H bond where the hydrogen is relatively acidic. Lithium organic compounds are frequently used in the metalation reaction under cryogenic conditions especially when a reaction involves unstable intermediates. The synthesis of thienopyrimidine carbaldehyde 12 was achieved via a two-step, one-pot process involving lithiation of thienopyrimidine 11 with n-butyllithium at –70 to –50 °C followed by quenching the resulting lithium intermediate 13 with DMF (Equation 7.3).3 Apparently, such cryogenic conditions and instability of the organolithium species 13 should be precluded on large scale. O N S

N Cl

N

H

(b) DMF (1.2 equiv) -70 to 0 C O

11

S

N Cl

(7.3)

N S

N Cl

N 12

N



O

(a) nBuLi (1.2 equiv) -70 to -50 C

N 13

Li

CHO

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Solutions In an effort to address the cryogenic condition and instability of 13, lithium triarylmagnesiate 14 (Figure 7.1) was considered to replace 1ess stable 13. O N S

N Cl

N

MgLi 3

14

FIGURE 7.1  The structure of lithium triarylmagnesiate 14.

Compared with 13, 14 was more stable and could be conveniently prepared with LiMg(nBu)2(iPr) at –10 °C. LiMg(nBu)2(i-Pr) reagent could be generated in situ by a reaction of isopropylmagnesium chloride with n-butyllithium. Ultimately, an operationally simple process was developed and demonstrated on a 20-kg scale, producing the product 12 with 87% yield. Procedure • Charge 20.1 kg (39.1 mol, 0.51 equiv) of 20% solution of i-PrMgCl in THF to a cold (–10 °C) mixture of 11 (19.8 kg, 77.4 mol) in THF (197 L) over 1.5 h. • Charge 32.6 kg (76.3 mol, 0.99 equiv) of 15% solution of n-BuLi in hexanes at ≤–10 °C over 1.5 h. • Stir the resulting mixture at –10 °C for 1 h. • Charge slowly 8.8 kg (120 mol, 1.6 equiv) of anhydrous DMF at –10±5 °C. • Stir the batch for 4 h. • Transfer the batch to a cold mixture of AcOH (58.7 kg), 35% aqueous HCl (21.3 kg), and water (159 kg ) over 1.5 h. • Stir the resulting mixture for 1 h. • Heat to 55 °C over 4 h and stir for 3 h. • Cool to 20–30 °C over 1 h and age for 1 h. • Filter and wash with water (4×25 kg). • Dry at 50 °C under vacuum. • Yield: 19.2 kg (87%).

7.1.2 Ring Expansion The beneficial effect of higher reaction temperature was observed during the ring expansion of hydroxyisoinolinone 15 in the presence of a stoichiometric amount of hydrazine, affording 6-chlorophthalazin-1-ol 16 (Equation 7.4).4 It was found that the reaction at a lower temperature (90 °C) and diluted reaction mixture would suppress the formation of impurity 17. O N-tBu Cl

OH

O

H

NH-tBu Cl

15

O

NH2NH2 Cl

CHO

OH NH-tBu N NH2

- tBuNH2

Cl 16

19

18

N N

18 NH2NH2 O

Cl

NH-tBu N N

17

O

NH-tBu

Cl

SCHEME 7.2   

Procedure • Charge 2.06 kg (8.59 mol) of 15 into a 30-L jacketed reactor under nitrogen, followed by adding glacial AcOH (6.4 L). • Heat the resulting thick slurry to 90 °C. • Charge, dropwise, 0.53 kg (9.0 mol, 1.05 equiv) of 54 wt% hydrazine hydrate (exotherm) while keeping the internal temperature at 90–93 °C over 3 h. • Continue to stir at 90 °C for 1.5 h (until 15 is