CRC Handbook for Chemical Process Research and Development Zhao 2016

The Handbook for Chemical Process Research and Development focuses on developing processes for chemical and pharmaceutical industries. Forty years ago there were few process research and development activities in the pharmaceutical industry, partially due to the simplicity of the drug molecules. However, with the increasing structural complexity, especially the introduction of chiral centers into the drug molecules and strict regulations set by the EMA and FDA, process RD has become one of the critical departments for pharmaceutical companies. This book assists with the key responsibility of process chemists to develop chemical processes for manufacturing pharmaceutical intermediates and final drug substances for clinical studies and commercial production.

Handbook for Chemical Process

Research and Development

Handbook for Chemical Process

Research and Development

Wenyi Zhao

Taylor & Francis Group

6000 Broken Sound Parkway NW, Suite 300

Boca Raton, FL 33487-2742

© 2017 by Wenyi Zhao

CRC Press is an imprint of Taylor & Francis Group, an Informa business

No claim to original U.S Government works

Printed on acid-free paper

Version Date: 20160819

International Standard Book Number-13: 978-1-4987-6799-6 (Hardback)

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Library of Congress Cataloging‑in‑Publication Data

Names: Zhao, Wenyi (Chemist) Title: Handbook for chemical process research and development / Wenyi Zhao.

Description: Boca Raton : CRC Press, 2017 | Includes bibliographical references and index.

Identifiers: LCCN 2016032433 | ISBN 9781498767996 (hardcover : alk paper) Subjects: LCSH: Drugs Research | Drugs Research Methodology | Pharmaceutical industry.

Classification: LCC RM301.25 Z44 2017 | DDC 615.1/9 dc23

LC record available at https://lccn.loc.gov/2016032433

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Contents

Preface xxix

Acknowledgments xxxix

Author xli List of Abbreviations xliii Chapter 1 Modes of Reagent Addition: Control of Impurity Formation 1

1.1 Direct Addition 2

1.1.1 Sonogashira Reaction 2

(I) Problematic “All-In” Conditions 2

(II) Solutions–Semibatch Conditions (DA) 2

1.1.2 Michael Reaction 3

(I) Problematic Reaction Conditions (RA Mode) 3

(II) Chemistry Diagnosis 3

(III) Solutions 3

1.1.3 Fischer Indole Synthesis 3

(I) Reaction Problems 4

(II) Solutions 4

Procedure 4

1.1.4 Amide Formation 5

1.1.4.1 EEDQ-Promoted Amide Formation 5

1.1.4.2 CDI-Promoted Amide Formation 6

1.1.5 Thioamide Formation 6

(I) Problems 7

(II) Solutions 7

Procedure 7

1.1.6 C–O Bond Formation 8

1.1.6.1 SRN1 Reaction 8

1.1.6.2 Mitsunobu Reaction 9

1.2 Reverse Addition 10

1.2.1 Grignard Reaction 11

1.2.1.1 Reaction with Alkyl Aryl Ketone 11

1.2.1.2 Grignard Reaction with Aldehydes 12

1.2.1.3 Reaction of Grignard Reagent with Ester 12

1.2.2 Copper-Catalyzed Epoxide Ring-Opening 13

Solutions 14

Procedure 14

1.2.3 Nitration Reaction 14

(I) Problematic Addition Order 14

(II) Chemistry Diagnosis 15

(III) Solutions 15

Procedure 15

1.2.4 Cyclization Reaction 15

Procedure 16

1.2.5 Amide Formation 17

1.2.5.1 CDI-Promoted Amide Formation 17

1.2.5.2 Phenyl Chloroformate–Promoted Urea Formation 18

1.2.6 Reduction of Ketone to Hydrocarbon 18

(I) Problematic Addition Order 19

(II) Chemistry Diagnosis 19

(III) Solutions 20

Procedure 20

1.2.7 1,3-Dipole-Involved Reactions 20

1.2.7.1 Addition–Elimination/Cyclization 20

1.2.7.2 [3+2]-Cycloaddition 21

1.3 Other Addition Modes 23

1.3.1 Sequential Addition 23

(I) Problematic Addition Sequence 23

(II) Solutions (to Control the Concentration of CDMT) 23

Procedure 23

1.3.2 Portionwise Addition 24

1.3.2.1 Cyclization 24

1.3.2.2 Dehydrochlorination 25

1.3.3 Slow Release of Starting Material/Reagent 26

1.3.3.1 Synthesis of Urea 26

1.3.3.2 Preparation of Alkylamine 28

1.3.4 Alternate Addition 28

(I) Chemistry Diagnosis 29

(II) Solutions 29

1.3.5 Concurrent Addition 29

1.3.5.1 Bromination Reaction 29

1.3.5.2 Difluoromethylation 31

1.3.5.3 Diels–Alder Reaction 32

Notes 32

Chapter 2 Process Optimization 35

2.1 Addition of Additives 35

2.1.1 Acid Additives 35

2.1.1.1 Hydrochloric Acid 35

2.1.1.2 Sulfuric Acid 38

2.1.1.3 Acetic Acid 41

2.1.1.4 Benzoic Acid as Amine Stabilizer 45

2.1.1.5 Trifluoroacetic Acid 45

2.1.1.6 Toluenesulfonic Acid 46

2.1.2 Base Additives 48

2.1.2.1 Potassium Carbonate 48

2.1.2.2 Sodium Hydrogen Carbonate 49

2.1.2.3 Diisopropylethylamine 50

2.1.2.4 1,4-Diazabicyclo[2.2.2]octane 52

2.1.2.5 Potassium tert-Butoxide 53

2.1.2.6 Sodium Methoxide 55

2.1.2.7 Sodium Acetate 57

2.1.2.8 Sodium Acrylate 60

2.1.3 Inorganic Salts 61

2.1.3.1 Lithium Salts 61

2.1.3.2 Sodium Bromide 62

2.1.3.3 Magnesium Salts 63

2.1.3.4 Calcium Chloride 67

2.1.3.5 Zinc Chloride 68

2.1.4 Assortment of Scavengers 68

2.1.4.1 Catechol as Methyl Cation Scavenger 68

2.1.4.2 Anisole as Quinone Methide Scavenger 69

2.1.4.3 Carboxylic Esters 70

2.1.4.4 Thionyl Chloride as Water Scavenger 73

2.1.4.5 1-Hexene as HCl Scavenger 74

2.1.4.6 Epoxyhexene as HBr Scavenger 76

2.1.4.7 Acetic Anhydride as Aniline Scavenger 77

2.1.4.8 Amberlite CG50 as Ammonia Scavenger 77

2.1.5 Other Additives 77

2.1.5.1 Imidazole 78

2.1.5.2 Triethylamine Hydrochloride 79

2.1.5.3 Methyl Trioctylammonium Chloride 80

2.1.5.4 TMSCl (or BF3 · Etherate) 81

2.1.5.5 Water 82

2.1.5.6 Hydroquinone 85

2.1.5.7 B(OMe)3 in Borane Reduction of Acid 86

2.1.5.8 Isobutanoic Anhydride 87

2.1.5.9 1,1-Dimethyl-2-Phenylethyl Acetate 87

2.1.5.10 Alcohols 88

2.1.5.11 1,4-Dioxane 92

2.1.5.12 Benzotriazole 93

2.1.5.13 1-Hydroxybenzotriazole 93

2.1.5.14 1,4-Dibromobutane 94

2.1.5.15 Diethanolamine 95

2.2 Approaches to Optimize Catalytic Reactions 95

2.2.1 Suzuki–Miyaura Reaction 95

2.2.1.1 Catalyst Poison 97

2.2.1.2 Precipitation of Palladium Catalyst 100

2.2.1.3 Instability of Arylboronic Acids 101

2.2.1.4 Problems Associated with Base 105

2.2.1.5 Dimer Impurity 107

2.2.2 Catalytic Deprotection 109

2.2.2.1 Debenzylation 109

2.2.2.2 Catalytic Removal of Cbz Group 110

2.2.3 Catalytic Hydrogenation 112

2.2.3.1 Reduction of Nitro Group 112

2.2.3.2 Reduction of Pyridine Ring 113

2.2.3.3 Reduction of Cyano Group 114

2.2.3.4 Reduction of Imine Intermediate 114

2.2.3.5 Catalytic Hydrogenation of Azide 115

2.2.4 Other Catalytic Reactions 115

2.2.4.1 Negishi Cross-Coupling Reaction 115

2.2.4.2 Cu(I)-Catalyzed Grignard Reaction 116

2.2.4.3 Decarboxylative Bromination 117

2.2.4.4 Sulfonylation Reaction 118

2.2.4.5 Preparation of Acid Chloride 119

2.2.4.6 Catalytic Dechlorination 120

2.3 Temperature and Pressure 120

2.3.1 Temperature Effect 120

2.3.1.1 Metal–Hydrogen/Halogen Exchange 120

2.3.1.2 Cyclization Reactions 123

2.3.1.3 Cross-Coupling Reaction 126

2.3.1.4 Vilsmeier Reaction 127

2.3.1.5 Oxidative Hydrolysis 128

2.3.1.6 Reduction of Ester 128

2.3.1.7 Michael Addition 129

2.3.1.8 Amide Formation 130

2.3.2 Pressure Effect 131

2.3.2.1 Nitrile Reduction 131

2.3.2.2 [3+2]-Cycloaddition 132

2.4 Other Approaches 133

2.4.1 Low Product Yield 133

2.4.1.1 Incomplete Reaction 133

2.4.1.2 Loss of Product during Isolation 136

2.4.1.3 Side Reactions of Starting Materials 137

2.4.1.4 Side Reactions of Intermediates 139

2.4.1.5 Side Reactions of Products 145

2.4.2 Problems Associated with Impurities 151

2.4.2.1 Residual Zn 151

2.4.2.2 Residual MTBE 152

2.4.2.3 Residual Water 153

2.4.2.4 Residual Oxygen 155

2.4.3 Reactions with Poor Selectivity 158

2.4.3.1 CIDR to Improve cis/trans Selectivity 158

2.4.3.2 Two-Step Process to Mitigate Racemization 158

2.4.3.3 Reduction of Carboxylic Acid 159

2.4.3.4 Sacrificial Reagent in Regioselective Acetylation 160

2.4.3.5 Protecting Group 161

2.4.3.6 Functional Group in SNAr Reaction 166

2.4.3.7 Enamine Exchange 167

2.4.3.8 Carryover Approach 169

2.4.4 Miscellaneous Reaction Problems 169

2.4.4.1 Friedel–Crafts Reaction 169

2.4.4.2 Reduction of C–C Double Bond 170

2.4.4.3 Reduction of Nitrile 171

2.4.4.4 Polymerization Issues 172

2.4.4.5 Activation of Functional Groups 175

2.4.4.6 Deactivation of Functional Groups 178

2.4.4.7 Side Reactions with Excess of Reagent 180

2.4.4.8 Optimization of Telescoped Process 181

Notes 184

Chapter 3 Hazardous Reactions 193

3.1 Oxidation Reactions 193

3.1.1 Oxidation of Olefins 193

3.1.1.1 Oxidation with mCPBA 193

3.1.1.2 Oxidation with Sodium Perborate 194

3.1.1.3 Oxidation with Ozone 194

3.1.1.4 Oxidation with KMnO4 197

3.1.2 Oxidation of Alcohols to Aldehydes or Ketones 197

3.1.2.1 SO3 ∙ Py/DMSO System 198

3.1.2.2 Ac2O/DMSO System 200

3.1.2.3 TFAA/DMSO/TEA System 201

3.1.2.4 TEMPO/NaOCl System 201

3.1.2.5 RuCl3/NaOCl System 203

3.1.2.6 Sulfinimidoyl Chloride 204

3.1.3 Oxidation of Aldehydes to Acids 204

Procedure 205

3.1.4 Oxidation of Sulfides to Sulfoxides 205

3.1.5 Oxidation of Sulfides to Sulfones 205

3.1.5.1 Oxidation with Oxone 205

3.1.5.2 Oxidation with Sodium Perborate 206

3.1.5.3 Oxidation with Sodium Periodate 207

3.1.5.4 Oxidation with NaOCl 208

3.1.5.5 Oxidation with H2O2/Na2WO4 208

3.1.5.6 Oxidation with TMSCl/KNO3 209

3.1.6 Other Oxidative Reactions 209

3.1.6.1 Dakin Oxidation 209

3.1.6.2 Hydroxylation 210

3.1.6.3 Oxidative Cyclization 211

3.1.6.4 Oxidation of Phosphite 211

3.2 Reduction Reactions 212

3.2.1 Boron-Based Reductive Reactions 212

3.2.1.1 Reduction with NaBH4 212

3.2.1.2 Reduction with Borane 219

3.2.2 Reduction with Lithium Aluminum Hydride 226

Procedure 226

3.3 Nitrogen-Involved Hazardous Reactions 227

3.3.1 Diazonium Salts 227

3.3.1.1 Hydrolysis of Diazonium Salt 227

3.3.1.2 Diazonium Salt–Involved Cyclization 228

3.3.1.3 Nitroindazole Formation 229

3.3.1.4 Synthesis of Trifluoromethyl-Substituted Cyclopropanes 230

3.3.1.5 Sandmeyer Reaction 230

3.3.2 Azide Compounds 232

3.3.2.1 Nucleophilic Displacement 233

3.3.2.2 Nucleophilic Addition 236

3.3.3 Hydrazine 243

3.3.3.1 Wolff–Kishner Reduction 243

3.3.3.2 Synthesis of Indazole 245

3.3.3.3 Synthesis of Pyrazole 245

3.3.3.4 Synthesis of Triazole 245

3.3.3.5 Preparation of Dihydropyridazinone 246

3.3.3.6 Preparation of Phthalazin-1-ol 246

3.3.3.7 Preparation of Alkylamine 247

3.3.4 Preparation of Aryl (or Alkyl) Hydrazines and Related Reactions 247

3.3.4.1 Preparation of 5-Hydrazinoquinoline 248

3.3.4.2 Synthesis of Aminopyrazole 249

3.3.4.3 Fischer Indole Synthesis 250

3.3.4.4 Preparation of Alkylhydrazine 250

3.3.5 Hydroxylamine 251

3.3.6 Oxime 252

Procedure 252

3.3.7 N-Oxide 253

3.3.8 Nitro Compounds 254

3.3.8.1 Preparation of Nitro Compounds by Nitration 254

3.3.8.2 Hazardous Reactions of Nitro Compounds 259

3.3.9 Ritter Reaction 260

(I) Ritter Reaction Incident 261

(II) Solutions 261

3.4 Other Hazardous Reactions and Reagents 261

3.4.1 Other Hazardous Reactions 261

3.4.1.1 Heck Reaction 261

3.4.1.2 Negishi Cross-Coupling Reaction 262

3.4.1.3 Blaise Reaction 262

3.4.1.4 Hydrogen/Metal Exchange 263

3.4.1.5 Halogenation Reactions 264

3.4.1.6 Dehydrochlorination 266

3.4.1.7 Thiocyanation 270

3.4.1.8 Gas-Involved Reactions 271

3.4.1.9 Darzens Reaction 277

3.4.2 Hazardous Reagents 278

3.4.2.1 Volatile Organic Compounds 278

3.4.2.2 High-Energy Compounds 283

3.4.2.3 Toxic Compounds 286

Notes 289

Chapter 4 Catalytic Reactions 297

4.1 Two-Phase Reactions 297

4.1.1 Nucleophilic Substitution Reactions 297

4.1.1.1 Enhancement of SN2 Reaction Rate 297

4.1.1.2 Replacement of DMSO in SNAr Reaction 298

4.1.1.3 Reduction of Amounts of Toxic Sodium Cyanide 299

4.1.1.4 Controls of Impurity Formation 299

4.1.2 Oxidation of Di-tert-Dutylphosphite 300

4.2 Dehydrobromination 301

Procedure 301

4.3 Regioselective Chlorination 301

Procedure 302

4.4 Regioselective Deprotonation 302

Procedure 302

4.5 Amide Preparation 303

4.5.1 NaOMe as Catalyst 303

Procedure 303

4.5.2 HOBt as Catalyst 304

Procedure 304

4.6 Synthesis of Indole 305

Procedure 305

4.7 N-Methylation Reaction 306

Procedure 306

4.8 Baylis–Hillman Reaction 307

Procedure 307

4.9 Catalytic Wittig Reaction 307

4.10 Negishi Cross-Coupling Reaction 307

4.11 Catalytic Hydrogenations 308

4.11.1 Chemoselective Hydrogenation 308

4.11.1.1 Using P(OPh)3 Additive 309

4.11.1.2 Nickel-Catalyzed Reduction 309

4.11.2 Catalytic Transfer Hydrogenation 310

4.11.2.1 Metal-Catalyzed Reductions 310

4.11.2.2 Organocatalytic Transfer Hydrogenation 312

4.12 Palladium-Catalyzed Rearrangement 313

Procedure 314

Notes 314

Chapter 5 Grignard Reagent and Related Reactions 317

5.1 Preparation of Grignard Reagent 317

5.1.1 Use of Chlorotrimethylsilane 317

5.1.1.1 Preparation of 4-Fluoro-2-Methylphenylmagnesium Bromide 317

5.1.1.2 Preparation of (4-(2-(Pyrrolidin-1-yl)ethoxy)phenyl) magnesium Bromide 318

5.1.2 Use of Diisobutylaluminum Hydride 318

Procedure 319

5.1.3 Use of Diisobutylaluminum Hydride/Iodine 319

Procedure 319

5.1.4 Use of Grignard Reagent 320

5.1.4.1 Use of MeMgCl 320

5.1.4.2 Use of EtMgBr 321

5.1.4.3 Use of Heel 322

5.1.5 Use of Alkyl Halides 323

5.1.5.1 Iodomethane 323

5.1.5.2 1,2-Dibromoethane 323

5.1.6 Halogen–Magnesium Exchange 323

5.1.6.1 Preparation of Trifluoromethyl Substituted Aryl Grignard Reagents 324

5.1.6.2 Preparation of N-Methylpyrazole Grignard Reagent 325

5.1.6.3 Preparation of (4-Bromonaphthalen-1-yl)Magnesium Chloride 325

5.1.6.4 Magnesium-Ate Complex 326

5.2 Reactions of Grignard Reagents 327

5.2.1 Reactions with Ketones 327

5.2.1.1 Vinyl Grignard Reaction 327

5.2.1.2 Aryl Grignard Reaction 328

5.2.1.3 Grignard Reaction of Methylmagnesium Bromide 330

5.2.2 Reaction with Acid Chloride 331

Procedure 331

5.2.3 Reaction with Amide 331

5.2.4 Michael Addition 333

5.2.5 Reaction with Epoxide 333

(I) Chemistry Diagnosis 334

(II) Solutions 334

5.2.6 Cross-Coupling Reactions 334

5.2.6.1 Suzuki Coupling Reaction 334

5.2.6.2 Iron-Catalyzed Coupling Reaction 336

Notes 336

Chapter 6 Challenging Reaction Intermediates 339

6.1 Effect of Intermediates 339

6.1.1 In Telescoping Steps 339

6.1.2 In Designing Synthetic Steps 339

6.2 Intermediate in the Product Isolation 342

6.2.1 Counter Ion Exchange 342

(I) Problems 343

(II) Solutions 343

6.2.2 Pictet–Spengler Condensation 344

Procedure 344

6.2.3 Amide Reduction 345

6.3 Multiple Reaction Stages 346

Procedure 347

6.4 Intermediate in the Process Development 347

6.4.1 Indirect Monitoring of the Intermediate 347

6.4.1.1 Derivatization of Acylimidazolide 347

6.4.1.2 Derivatization of N-Methylene Bridged Dimer 348

6.4.2 Direct Monitoring of the Intermediate 349

Notes 350

Chapter 7 Protecting Groups 351

7.1 Protection of Hydroxyl Group 351

7.1.1 Prevention of Side Reactions 351

7.1.1.1 Friedel–Crafts Alkylation 351

7.1.1.2 Removal of Trifluoromethanesulfonyl Group 352

7.1.2 Increasing Catalyst Activity 352

7.1.3 Selection of Protecting Group 354

7.1.3.1 Protection of Hydroxyphenylboronic Acid 354

7.1.3.2 Protection of Iodobutanol 354

7.1.3.3 Protection of 1-Hydroxypropan-2-yl Methanesulfonate 354

7.1.4 Protection of Diol for Separation of anti- and syn-Diols 356

Procedure 356

7.2 Protection of Amino Group 357

7.2.1 Protection of Indole Nitrogen 357

Procedure 358

7.2.2 Epoxide Ring Opening 358

7.2.3 Formation of Imines 359

7.2.3.1 Protection of Amine with Aryl Aldehyde 359

7.2.3.2 Protection of Amine with 4-Methyl-2-Pentanone 359

7.2.4 Indirect Protection 360

Procedure 361

7.3 Protection of Carboxylic Acid 361

7.4 Protection of Aldehydes and Ketones 362

7.4.1 Protection of Ketone with Dimethyl Ketal 363

7.4.2 Dioxolane 363

7.4.3 Deprotection of Acetal 364

7.5 Protection of Acetylene 364

7.6 Unusual Protecting Groups 365

7.6.1 Boron-Containing Protecting Group 365

7.6.1.1 Borane Complex 365

7.6.1.2 Boronic Acid 366

7.6.2 N-Nitro Protecting Group 367

7.6.2.1 Regioselective Nitration 367

7.6.2.2 Activation of Aniline 368

7.6.3 Halogen as Protecting Group 368

7.6.3.1 Bromine Protecting Group 368

7.6.3.2 Chlorine as Protecting Group 370

7.7 Protecting Group Migration 371

Notes 371

Chapter 8 Reaction Solvents 373

8.1 Ethereal Solvents 373

8.1.1 Cyclopentyl Methyl Ether 374

8.1.1.1 Brook Rearrangement 374

8.1.1.2 N-Alkylation Reaction 375

8.1.2 Tetrahydrofuran 376

8.1.2.1 Grignard Reagent Formation 376

8.1.2.2 Bromination of Ketone 376

8.1.3 2-Methyl Tetrahydrofuran 377

8.1.3.1 Control of Impurity Formation 377

8.1.3.2 Improving Reaction Rate 378

8.1.3.3 Improving Layer Separation 379

8.1.4 Methyl tert-Butyl Ether 380

8.1.4.1 Chlorination Reaction 380

8.1.4.2 Darzens Reaction 381

8.1.5 Diethoxymethane and Dimethoxyethane 381

8.2 Protic Solvents 381

8.2.1 Reaction of Acyl Hydrazine with Trimethylsilyl Isocyanate 381

8.2.2 Amide Formation 382

Procedure 382

8.2.3 Catalytic Reduction of Diaryl Methanol 383

(I) Reaction Problems 383

(II) Solutions 383

8.2.4 Catalytic Debenzylation 383

(I) Reaction Problems 384

(II) Solutions 384

Procedure 384

8.2.5 Catalytic Reduction of Nitro Group 384

8.2.5.1 Leak of Palladium Catalyst 384

8.2.5.2 Side Product Formation 385

8.2.5.3 Classic Resolution of Acid 385

8.2.6 S 2 Reaction 386

8.3 Water as a Reaction Solvent 386

8.3.1 Iodination Reaction 386

Procedure 386

8.3.2 Synthesis of Quinazoline-2,4-Dione 387

Procedure (for Synthesis of 58a) 387

8.3.3 Synthesis of Pyrrolo Cyclohexanone 388

Procedure 388

8.3.4 Synthesis of Thiourea 389

(I) Reaction Problems 389

(II) Solutions 389

8.4 Nonpolar Solvents 389

8.4.1 Condensation of Ketone with tert-Butyl Hydrazine-Carboxylate 390

Procedure 390

8.4.2 Acid-Catalyzed Esterification 390

8.5 Polar Aprotic Solvents 391

8.5.1 Decarboxylative Blaise Reaction 391

8.5.2 Michael Addition Reaction 391

8.5.2.1 Acetone as a Solvent 391

8.5.2.2 Acetonitrile as a Solvent 392

8.5.3 SNAr Reaction 393

8.5.3.1 Preparation of Alkyl Aryl Ether 393

8.5.3.2 Preparation of Bisaryl Ether 393

8.6 Halogenated Solvents 394

8.6.1 Dichloromethane 394

8.6.1.1 Reaction with Pyridine 394

8.6.1.2 Synthesis of Benzo[d]isothiazolone 394

8.6.2 Trifluoroacetic Acid 396

(I) Problems 396

(II) Solutions 396

Procedure 397

8.6.3 (Trifluoromethyl)benzene 397

8.6.4 Hexafluoroisopropanol 398

8.7 Carcinogen Solvent 399

8.8 Other Solvents 399

8.8.1 DW-Therm 399

8.8.2 Dowtherm A 399

8.8.2.1 Synthesis of 6-Chlorochromene 399

8.8.2.2 Conrad–Limpach Synthesis of Hydroxyl Naphthyridine 400

8.8.3 Polyethylene Glycol 400

8.8.4 Propylene Glycol Monomethyl Ether 401

Procedure 401

8.8.5 Sulfolane 401

8.8.6 Ionic Liquid 402

8.9 Solvent-Free Reaction 403

Procedure 403

Notes 403

Chapter 9 Base Reagent Selection 407

9.1 Inorganic Base 407

9.1.1 Sodium Bicarbonate 407

9.1.2 Potassium Carbonate 407

9.1.3 Sodium Hydride 407

9.1.4 Combination of LiOH with H2O2 408

9.1.4.1 Hydrolysis of Chiral Ester 408

9.1.4.2 Hydrolysis of Chiral Amide 410

9.2 Organic Base 410

9.2.1 Trialkylamine 410

9.2.1.1 Diisopropylethylamine 411

9.2.1.2 Triethylamine 412

9.2.2 Imidazole 414

Procedure 414

9.2.3 2,6-Dimethylpiperidine 414

9.2.4 2-(N,N-Dimethylamino)pyridine 415

9.2.5 Metal Alkoxide Base 415

9.2.5.1 Potassium tert-Pentylate 415

9.2.5.2 Lithium tert-Butoxide 418

9.2.5.3 Potassium tert-Butoxide 419

9.2.5.4 Combination of Potassium tert-Butoxide with tert-Butyllithium 421

9.2.5.5 Sodium Methoxide 422

Notes 422

Chapter 10 Reagents for Amide Formation 425

10.1 CDI-Mediated Amide Preparation 425

10.1.1 Preparation of Amide 425

Procedure 426

10.1.2 Preparation of Ureas 426

10.1.2.1 In the Absence of a Base 426

10.1.2.2 Activation via N-Methylation 426

10.2 Thionyl Chloride-Mediated Amide Preparation 426

10.2.1 Preparation of Acid Chloride 426

Procedure 428

10.2.2 N-Sulfinylaniline-Involved Amide Preparation 429

10.3 Boc2O-Mediated Amide Preparation 430

10.4 Schotten–Baumann Reaction 431

Procedure 431

10.5 Other Methods 431

10.5.1 Copper (II)-Catalyzed Transamidation 431

10.5.2 Cross-Coupling between Acyltrifluoroborates and Hydroxylamines 436

Notes 437

Chapter 11 Various Reagent Surrogates 439

11.1 Ammonia Surrogates 439

11.1.1 Ammonium Hydroxide 439

Procedure 440

11.1.2 Ammonium Acetate 440

11.1.2.1 Condensation with Aldehyde 440

11.1.2.2 Condensation with Ketone 440

11.1.3 Ammonium Chloride 442

11.1.4 Hydroxylamine Hydrochloride 442

11.1.4.1 Reaction with Aldehyde 442

11.1.4.2 Reaction with Ketone 442

11.1.5 O-Benzylhydroxylamine 443

11.1.6 Hydroxylamine-O-Sulfonic Acid 443

11.1.6.1 SN2 Reaction of with Sulfinate 443

11.1.6.2 Reaction with Boronic Acid 443

11.1.7 4-Methylbenzenesulfonamide 444

11.1.8 Hexamethylenetetramine 444

11.1.9 Acetonitrile 445

Procedure 446

11.1.10 Chloroacetonitrile 446

11.1.11 tert-Butyl Carbamate 447

11.1.12 Diphenylmethanimine 447

Procedure 447

11.1.13 tert-Butylcarbamidine 448

Procedure 449

11.1.14 Silylated Amines as Ammonia Equivalents 450

Procedure (for the Preparation of 56) 451

11.1.15 Allylamines as Ammonia Equivalents 451

Procedure 452

11.2 Carbon Monoxide Surrogates 453

11.2.1 N-Formylsaccharin 453

11.2.2 Paraformaldehyde 453

11.2.3 Molybdenum Carbonyl 453

11.3 Aldehyde Surrogates 454

11.3.1 Sodium Bisulfite 454

11.3.1.1 Oxidation of Aldehyde to Acid 454

11.3.1.2 Reductive Amination 455

11.3.1.3 Diels–Alder Reaction 456

11.3.1.4 Strecker Reaction 457

11.3.1.5 Transaminase DKR of Aldehyde 457

11.3.2 Sulfur Dioxide Solution 458

Procedure 458

11.4 Sulfur Dioxide Surrogate 459

11.4.1 Synthesis of Alkyl Aryl Sulfones 459

11.4.2 Synthesis of Sulfonamides 459

Notes 459

Chapter 12 Telescope Approach 461

12.1 Hazardous Intermediates and Toxic Reagents 461

12.1.1 Chloroketone Intermediate 461

Procedure 461

12.1.2 Lachrymatory Chloromethacrylate Intermediate 462

12.1.3 Chloromethyl Benzimidazole 462

Procedure 463

12.1.4 Pyridine N-Oxide 464

12.1.5 Benzyl Bromide 465

12.2 Hygroscopic and Oily Intermediate 465

12.2.1 Oily Intermediates 466

Procedure 466

12.2.2 Hygroscopic Solid 467

12.2.3 Amine Hydrochloride Salt 467

Procedure 469

12.2.4 High Water-Soluble Intermediate 469

12.3 Filtration Problem 470

12.3.1 Preparation of Amide 470

12.3.2 Synthesis of β-Nitrostyrene 470

Procedure 471

12.4 Unstable Intermediates 472

12.4.1 Heteroaryl Chlorides 472

Procedure 472

12.4.2 Toluenesulfonate Intermediate 473

12.4.3 Aldehyde Intermediates 474

12.4.3.1 Reduction/Grignard-Type Reaction 474

12.4.3.2 Oxidation/Wittig Reaction 474

12.4.4 Unstable Alkene Intermediates 474

12.4.4.1 Diels–Alder Reaction 474

12.4.4.2 Acrylate Formation/Heck Coupling 476

12.4.4.3 Protection/Heck Reaction/Deprotection 477

12.4.5 Unstable β-Hydroxyketone 478

Procedure 479

12.5 Expensive Catalyst 480

12.5.1 Imine Reduction/Debenzylation 480

Procedure 480

12.5.2 Palladium-Catalyzed Debromination/Suzuki Cross-Coupling Reaction 481

Procedure 482

12.6 Improvement of Overall Yields 482

12.6.1 Synthesis of Spirocyclic Hydantoin 482

Procedure 482

12.6.2 Synthesis of Diaryl Compound 484

12.7 Reduction in Processing Solvents 485

12.7.1 Toluene as the Common Solvent 485

12.7.2 DMF as the Common Solvent 485

Procedure 485

12.7.3 EtOAc as the Common Solvent 486

12.7.3.1 Acid Activation/Hydrazide Formation/Triazolone Formation 486

12.7.3.2 Reduction/Acid Activation/Acylation 488

12.7.4 THF as the Common Solvent 489

Procedure 490

12.7.5 EtOH/THF as the Common Solvent 490

Procedure 490

12.8 Solvent Exchange 491

12.9 Other Telescope Processes 492

12.9.1 Bromination/Isomerization Reactions 492

12.9.2 Fisher Indole Synthesis/Ring Rearrangement 492

12.9.3 Ylide Formation/Wittig Reaction/Cycloaddition 493

Procedure 493

12.9.4 Overman Rearrangement 494

Procedure 495

12.9.5 Nitro Reduction/Reductive Amination/Dehalogenation 495

Procedure 496

12.9.6 Michael Addition/Elimination/Cycloaddition 496

12.9.7 Synthesis of Aryl Bromide 497

12.9.8 Synthesis of Lactam 497

Procedure 497

12.9.9 Synthesis of (–)-Oseltamivir 499

12.10 Limitation of the Telescope Approach 501

12.10.1 Lack of Purity Control 501

12.10.2 Poor Product Yields 501

12.10.3 Lack of Compatibility 503

Notes 504

Chapter 13 Stereochemistry 507

13.1 Asymmetric Synthesis 507

13.1.1 Asymmetric Catalysis 507

13.1.1.1 Desymmetrization of Anhydride 507

13.1.1.2 Asymmetric Reduction of Enone 509

13.1.1.3 Sharpless Asymmetric Dihydroxylation 510

13.1.1.4 Enantioselective Alkylation 511

13.1.1.5 Asymmetric Cross-Benzoin Addition 511

13.1.1.6 CuH-Catalyzed Stereoselective Synthesis of 2,3-Disubstituted Indolines 512

13.1.2 Chiral Pool Synthesis 512

13.1.2.1 Generation of a New Chiral Center 512

13.1.2.2 Transfer of Chiral Center 514

13.1.3 Use of Chiral Auxiliaries 515

13.1.3.1 Diastereoselective Diels–Alder Reaction 515

13.1.3.2 Diastereoselective Synthesis of Boronic Acid 515

13.1.3.3 Synthesis of Chiral (S)-Pyridyl Amine 516

13.2 Kinetic Resolution 517

13.2.1 Classical Resolution 518

13.2.1.1 Resolution of Racemic Acid 518

13.2.1.2 Resolution of Racemic Base 519

13.2.1.3 Enantiomeric Enrichment 522

13.2.1.4 Diastereomer Salt Break 522

13.2.1.5 Examples of Diastereomeric Salts 523

13.2.2 Enzymatic Resolution 523

13.2.2.1 Resolution of Esters 525

13.2.2.2 Resolution of Amino Acids 528

13.2.2.3 Resolution Secondary Alcohols 529

13.2.3 Other Resolution Methods 529

13.2.3.1 Stereoselective Ligand Exchange 529

13.2.3.2 Diastereomer Salt Formation 530

13.2.3.3 Stereoselective Esterification of Racemic Diol 530

13.2.3.4 Chiral Chromatographic Separation 532

13.3 Dynamic Kinetic Resolution 533

13.3.1 Dynamic Kinetic Resolution via Imine Intermediate 533

13.3.1.1 Aldehyde-Catalyzed Dynamic Kinetic Resolution 533

13.3.1.2 Enantioselective Synthesis of Azabicyclic Rings 535

13.3.1.3 Asymmetric Synthesis of Chiral Amines 537

13.3.2 Dynamic Kinetic Resolution via Proton Transfer 537

13.3.2.1 Ketone Reduction 537

13.3.2.2 Racemization of Nitrile 539

13.3.2.3 Formation of Diastereomeric Salt 540

13.3.2.4 Epimerization of cis-Isomer to trans-Isomer 541

13.3.2.5 Isomerization of Cyclohexane Derivative 542

13.3.2.6 Fischer Indole Synthesis 543

13.3.3 Dynamic Kinetic Resolution via Reversible Bond Formation 544

13.3.3.1 Reversible C−C Bond Formation 544

13.3.3.2 Reversible C−N Bond Formation 544

13.3.3.3 Reversible C−O Bond Formation 547

13.3.3.4 Reversible C−S Bond Formation 547

13.3.4 Other Resolution Methods 548

13.3.4.1 Bromide-Catalyzed Dynamic Kinetic Resolution 548

13.3.4.2 Resolution of Sulfoxide 549

13.3.4.3 Resolution of Dihydropyrazole Carboxylate 549

13.3.4.4 Dynamic Kinetic Resolution via C–C σ-Bond Rotation 550

13.3.4.5 Dynamic Kinetic Isomerization via Ir-Catalyzed Internal Redox Transfer Hydrogenation 550

13.3.5 Various Dynamic Kinetic Resolution Examples 550

Notes 555

Chapter 14 Design of New Synthetic Route 561

14.1 Process Safety 561

14.1.1 Toxic Reagents and Products 561

14.1.1.1 Cyanogen Bromide 561

14.1.1.2 Hydrogen Cyanide (HCN) Evolution 561

14.1.1.3 Toxic Reagent–Hg(OAc)2 563

14.1.1.4 Toxic Reagent–PBr3 564

14.1.1.5 Toxic Reagent–Hydrogen Fluoride HF 565

14.1.1.6 Toxic Benzyl Halides 565

14.1.1.7 Lachrymatory 2-(Benzo[d])[1,3]dioxol-5-yl-2-Bromoacetic Acid 566

14.1.1.8 Phosphorus Oxychloride 567

14.1.1.9 Sulfonyl Chloride Intermediate 568

14.1.2 High-Energy Reagents 569

14.1.2.1 Azide-Involved Cycloaddition 569

14.1.2.2 Diazonium Salt-Involved Indazole Formation 570

14.1.2.3 Lithium Aluminum Hydride Reduction 570

14.1.3 Undesired Reaction Conditions 572

14.1.3.1 Acylation Reaction 572

14.2 Process Costs 57414.2.1 Expensive Starting Materials 574

14.2.1.1 Using Fluorine-Free Starting Material 57414.2.1.2 Using Convergent Approach 57514.2.2 Expensive Reagents 577

14.2.2.1 Kumada Coupling 57714.2.2.2 Cross-Coupling Reaction 57814.2.2.3 Chiral Acid in Amide Preparation 57914.3 Low Product Yields 57914.3.1 Cycloaddition Reaction 58014.3.2 Resolution and Grignard Reaction 58014.3.3 Resolution/Amide Formation/Cyclization 58114.3.4 Chlorine Replacement 581

Procedure 58214.4 Convergent Approach 58414.4.1 Decarboxylative Cross-Coupling Reaction 58414.4.2 Synthesis of Chiral Amide 58614.5 Multicomponent Reaction 58714.5.1 Construction of Piperidinone Structure 58714.5.2 Construction of Pyrimidinone Structure 58714.6 Step-Economy Synthesis 58714.6.1 Synthesis of Keto-Sulfone Intermediate 58714.6.2 Synthesis of Bendamustine 58814.7 Atom-Economic Synthesis 58914.7.1 Synthesis of Carboxylic Acid 58914.7.2 Stereoselective Synthesis of Diol 59014.8 Problematic Intermediates 59214.8.1 Unstable Alkyne 59214.8.2 Oily Intermediates 592

14.8.2.1 Alkyl Alcohols 593

14.8.2.2 N-Acylpiperidine Derivatives 593

14.9 Reaction Selectivity 59414.9.1 Iodination 594

14.9.2 N-Alkylation Reaction 595

14.9.3 Formation of Indole Derivative 59514.9.4 Formation of Seven-Membered Ring 59714.10 Residual Metals 59814.10.1 C−N Bond Formation 59814.10.2 C−C Bond Formation 59814.10.3 Formation of C–C/C–N Bonds 598

Reagents and Conditions 60014.11 Minimum Oxidation Stage Change 60014.11.1 Minimizing Nitrogen Oxidation Stage Adjustment 60014.11.2 Minimizing Carbon Oxidation Stage Adjustment 600

14.11.2.1 Synthesis of Carboxylate Ester 60014.11.2.2 Synthesis of Alkyl Chloride 601

14.12 Coupling Reagent–Free Amide Formation 60214.13 Etching of Glass Reactors 603Procedure (Route II, Production of 312) 604Notes 604

Chapter 15 Reaction Workup 607

15.1 Various Quenching Strategies 60715.1.1 Acidic Quenching 60715.1.1.1 Removal of Magnesium Salt 60715.1.1.2 Removal of Zinc By-Products 60815.1.2 Basic Quenching 60915.1.2.1 Prevention of Thiadiazole Isomerization 60915.1.2.2 Prevention of Etching Glass Reactor 61015.1.3 Anhydrous Quenching 61115.1.3.1 Removal of Zinc By-Products 61115.1.3.2 Avoidance of Insoluble Organic Mass 61115.1.3.3 Avoidance of Degradation of Product 61215.1.3.4 Decomposition of Excess Reagent 61415.1.4 Oxidative Quenching 614(I) Problematic Iodine 615(II) Solutions 61515.1.5 Reductive Quenching 61515.1.5.1 Triethylphosphite 61515.1.5.2 Sodium Bisulfite 61615.1.5.3 Ascorbic Acid 61615.1.6 Disproportionation Quenching 617Procedure 61815.1.7 Reverse Quenching 61815.1.7.1 Control of Impurity Formation 61815.1.7.2 Removal of Excess Reagent 62015.1.7.3 Increase in Conversion 62015.1.7.4 Prevention of Product Hydrolysis 62115.1.7.5 Prevention of Product Decomposition 62215.1.7.6 Prevention of Emulsion 62215.1.7.7 Prevention of Exothermic Runaway 62315.1.8 Concurrent Quenching 624(I) Problems 624(II) Solutions 62415.1.9 Double Quenching 62515.1.9.1 Acetone/HCl Combination 62515.1.9.2 Acetone/Citric Acid Combination 626

15.1.9.4 Ethyl Acetate/Water Combination 62815.1.9.5 Ethyl Acetate/Tartaric Acid 62815.1.9.6 Ethyl Acetate/Aqueous Sodium Bicarbonate 62815.1.9.7 Isopropanol/Citric Acid 62915.1.9.8 Methyl Formate/Aqueous HCl 630

15.2 Direct Isolation 63015.2.1 Cooling of Reaction Mixture 63015.2.1.1 Direct Isolation from 2-Propanol 63015.2.1.2 Direct Isolation from Isopropanol Acetate 63115.2.1.3 Direct Isolation from Ethyl Acetate 63115.2.1.4 Direct Isolation from Acetonitrile 63215.2.2 Addition of Antisolvent 63215.2.2.1 Adding Water to Acetic Acid 63215.2.2.2 Addition of Water to DMF 63315.2.2.3 Addition of Water to DMAc 63415.2.2.4 Addition of Water to DMSO 63515.2.2.5 Addition of Methanol to DMSO 63515.2.3 Cooling/Addition of Antisolvent 63615.2.3.1 Isolation of Sonogashira Product 63615.2.3.2 Isolation of 6-Chlorophthalazin-1-ol 637

15.2.3.3 Isolation of

6-(pyridin-2-ylmethoxy)-1H-pyrazolo[3,4-b]pyrazine 637

15.2.4 Neutralization 638Procedure 63815.2.5 Salt Formation 639Procedure 63915.2.6 Miscellaneous Approaches 64015.2.6.1 Direct Drop Process 64015.2.6.2 Direct Removal Approach 64115.3 Purification Strategies 64215.3.1 Extraction 642

15.3.1.1 Methyl tert-Butyl Ether Extraction 642

15.3.1.2 Ethyl Acetate Extraction 64315.3.1.3 Dodecane Extraction 644

15.3.1.4 n-Butanol Extraction 645

15.3.1.5 Anhydrous Extraction 64515.3.1.6 Double Extraction 64615.3.2 Salt Formation 64715.3.2.1 Basic Organic Amines 64715.3.2.2 Organic Acids 65515.3.2.3 Quaternary Salt 66415.3.3 Derivatization 66615.3.3.1 Isolation/Purification of Aldehydes 66615.3.3.2 Isolation/Purification of Diol 67115.3.3.3 Isolation/Purification of Amino Diol 67115.3.3.4 Isolation/Purification of Amine 67115.3.4 Removal of Impurities 67215.3.4.1 Removal of Ammonium Chloride 67215.3.4.2 Removal of 9-BBN 67315.3.4.3 Removal of Acetic Acid 67415.3.4.4 Selective Hydrolysis Approach 67515.4 Crystallization 67615.4.1 Seed-Induced Crystallization 67715.4.1.1 Avoiding Uncontrolled Crystallization 67815.4.1.2 Avoiding Oiling Out 680

15.4.1.3 Control of Exothermic Crystallization 68215.4.1.4 Polymorph Control 68315.4.2 Various Other Crystallization Approaches 68315.4.2.1 Reactive Crystallization 68315.4.2.2 Addition of Water 68715.4.2.3 Crystallization from Extraction Solvent 68815.4.2.4 Three-Solvent System 68915.4.2.5 Derivatization 69015.4.2.6 Control of Crystal Size Distribution 69015.4.2.7 Cocrystallization 69115.5 Filtration Problems 69315.5.1 Metal-Related Filtration Problems 69315.5.1.1 Copper-Related Problems 693

15.5.1.3 Aluminum-Related Problems 69415.5.2 Small Particle Size 69515.5.2.1 Addition of Acetic Acid 69515.5.2.2 Addition of 2-Propanol 69715.5.2.3 Temperature Control 69815.5.2.4 Polymorph Transformation 69915.5.3 Low-Melting Solid 700Procedure 70015.6 Removal of Residual Palladium 70015.6.1 Crystallization 70115.6.1.1 Crystallization of Suzuki Reaction Product 70115.6.1.2 Crystallization in the Presence of Additives 70115.6.2 Extraction 70615.6.2.1 Liquid–Liquid Transportation 70615.6.2.2 Extractive Precipitation 71015.6.3 Adsorption 71215.6.3.1 Activated Carbon 71215.6.3.2 MP-TMT 71315.6.3.3 Deloxan THP-II 71715.6.3.4 Smopex 110 71715.6.4 Distillation 718Procedure 71815.6.5 Miscellaneous Methods 71815.6.5.1 Adsorption–Crystallization 71815.6.5.2 Adsorption and TMT Wash 71915.6.5.3 Protecting Group 71915.6.5.4 Salt Formation 72015.6.6 Conclusion 72115.7 Removal of Other Metals 72115.7.1 Removal of Copper 72115.7.1.1 Aqueous Ammonia 72215.7.1.2 Thiourea 72315.7.1.3 2,4,6-Trimercaptotriazine 72315.7.2 Removal of Rhodium 72515.7.2.1 Smopex-234 72515.7.2.2 Ecosorb C-941 725

15.7.3 Removal of Ruthenium 72615.7.3.1 Activated Carbon 72615.7.3.2 Supercritical Carbon Dioxide 72615.7.4 Removal of Zinc 72615.7.4.1 Extraction with Trisodium Salt of EDTA 72615.7.4.2 Use of Ethylenediamine 72815.7.5 Removal of Magnesium 729Procedure 72915.7.6 Removal of Aluminum 73015.7.6.1 Use of Triethanolamine 73015.7.6.2 Use of Crystallization 73115.7.7 Removal of Iron and Nickel 73115.7.7.1 Removal of Iron 73115.7.7.2 Removal of Nickel 73215.8 Removal of Impurities 73215.8.1 Extractive Wash 73315.8.1.1 Aqueous Wash 73315.8.1.2 Organic Wash 73515.8.2 Precipitation Approach 73715.8.2.1 Precipitation of Product 73715.8.2.2 Precipitation of By-Product 73915.8.3 Use of Additives 740

15.8.3.10 Application of Succinic Anhydride 75115.8.3.11 Application of Pivaldehyde 75115.8.3.12 Application of Benzyltributylammonium Chloride 75315.8.3.13 Application of Sodium Dithionate 75415.8.3.14 Application of Polymeric Resin 75515.8.3.15 Application of Aqueous Ammonia 75615.8.3.16 Application of DABCO 75615.8.4 Transformation of Impurity to Starting Material or Product 75715.8.4.1 Transformation to Starting Material 75715.8.4.2 Transformation to Product 758Notes 760

Chapter 16 Pharmaceutical Salts 769

16.1 Common Acids in the Salt Formation 76916.2 Hydrochloride Salts 770Procedure 77016.3 Various Pharmaceutical Salts 773

16.4 Salts of Acidic Drug Substances 773

16.4.1 Potassium Salts 773

16.4.1.1 Potassium Salt of 1,5-Naphthyridin-4(1H)-one 773

16.4.1.2 Potassium Salt of Amide 780

16.4.2 Calcium Salts 780

16.4.2.1 Salt Exchange from Sodium to Calcium Salt 780

16.4.2.2 Salt Exchange from Ammonium to Calcium Salt 781

16.4.3 Various Inorganic Salts 781

16.4.4 Salts with Organic Bases 781

17.1.2 Control of Polymorph by Temperature 788

17.1.2.1 Hydrolysis of Butyl Ester 788

Preface

Forty years ago, there was little process research and development (R&D) activities in the maceutical industry partially due to the simplicity of the drug molecules Over the past decades, however, considerable attention has been paid to the process R&D of chemical synthesis for large-scale production With increasing structural complexity, especially the introduction of chiral cen-ters into drug molecules and in order to comply with the regulations set by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA), process R&D has become one

phar-of the critical departments for pharmaceutical companies

The scale-up of synthetic organic chemistry from laboratory glassware to large reaction vessels

is by no means a simple linear process Large-scale operations are expected to lead to expanded time scale, poor heat transfer, insufficient mixing, and loss of temperature control, which may potentially result in runaway reactions

Therefore, the process R&D in pharmaceutical industry requires integration of a broad range of disciplines, including, but not limited to, synthetic organic chemistry, physical organic chemistry, analytical chemistry, chemical engineering, regulatory compliance, and plant operation The key responsibility of process chemists is to develop chemical processes that are feasible for manufac-turing pharmaceutical intermediates and final drug substances (active pharmaceutical ingredients [APIs]) for support of clinical studies and, eventually, for commercial production A good chemical process shall meet all key elements: low cost, available raw materials and reagents, simple workup, robustness, high throughput (fast reaction with high concentration), good product purity, and mini-mum environmental impact

P.1.1 P rocess s afety

Among various factors that need to be addressed appropriately during process R&D in laboratories, process safety is the most important aspect in the chemical process development “If a route cannot

be scaled up safely, then it should not be scaled up at all.”1

Process safety refers to (a) thermal and reactive hazards and (b) health hazards The thermal or reactive hazards associated with process and operator safety include reactions with gas evolution and the possibility of thermal runaway and explosion and reactions that involve shock or heat- sensitive and pyrophoric, flammable, or corrosive materials It is important to have a hazard assess-ment for a given process, particularly when using materials or intermediates without an available material safety data sheet (MSDS) Early thermal decomposition data such as differential scanning calorimetry (DSC) can give an indication of operating limits for a particular process For commer-cially available materials, MSDS is a valuable safety data MSDS also provides important informa-tion of chemicals with health hazards

P.1.2 P rocess c ost

Process costs depend largely on the following aspects: materials, labor, equipment, and waste disposal In general, raw materials, intermediates, reagents, and solvents are comprised of 20%–80% of the total cost of a given process An economic process will use less expensive, com-mercially available materials as much as possible Quite often the cost and availability of raw materials can be one of the major considerations in the synthetic route selection (see Chapter 14) Fortunately, due to the development of new synthetic methodologies and catalysis systems, more chemical compounds are available in bulk quantity at affordable prices Therefore, the limita-tion of raw materials has diminished, which gives process chemists more freedom in devising chemical processes Some reagents can be generated in situ, and hydrogen chloride, for example,

is frequently prepared especially when HCl is needed in requisite amount and under dry-reaction conditions.2

Obviously, less labor intense processes are preferred, for example, chromatographic purification

is not an ideal process on a large scale due to the burden of intensive labor As per reduction of cess cost, the one-pot process is frequently employed to minimize process wastes, time-consuming isolations, and handling losses

pro-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

P.1.3 e nvironmental i mPact

Green chemistry addresses environmentally benign chemical synthesis, encouraging the design of chemical processes that minimize the use and generation of hazardous substances Paul Anastas and John Warner developed the 12 green chemistry principles.3 The concept of atom economy4

for organic reactions proposed by Trost addresses that a maximum number of atoms of tants should end up in products Thus, an ideal reaction would incorporate all of the atoms of the reactants with limited wastes, which, in turn, effectively reduces environmental pollution and improves efficiency

reac-Most chemical processes, however, produce products and wastes at the same time These cal wastes will, to a certain extent, have negative environmental impacts Roger Sheldon, Professor Emeritus of Biocatalysis and Organic Chemistry at Delft University of Technology, the Netherlands, developed the concept of environmental factors (E-factors)5 to assess the environmental footprint

chemi-of chemical processes The E-factor is defined as “kg chemi-of total waste”/“kg chemi-of product.” Due to the complexity of the drug substance and tight quality regulations, pharmaceutical companies are more focused on the manufacture of molecules and the quality of the products

Therefore, the pharmaceutical industry faces a great challenge as well as an opportunity to reduce environmental impact Green chemistry encourages the use of more sustainable chemistry and provides some benchmarking data Accordingly, significant improvement has been made For instance, the process (shown in Equation P.1)6 developed by Pfizer uses the Baylis–Hillman reaction in the synthesis of allyl alcohol, an intermediate for sampatrilat (an inhibitor of zinc metalloprotease) The inherently environmentally friendly, atom-efficient Baylis−Hillman reac-tion not only incorporates all the atoms of the two starting materials into the product, but it also adds environmental benefit since it allows the simple reuse of the 3-quinuclidinol and generated much less waste stream

Scheme P.17 demonstrates a highly convergent synthesis of sildenafil citrate, the active ingredient

in Viagra, which was launched in early 1998 In this commercial manufacture route, the molecules,

2 and 3, were put together by a hydrogenation, activation, and acylation sequence in one pot using

ethyl acetate (Class 3 solvent) as solvent The single solvent for the three telescoped steps allows easy solvent recovery

This environmentally benign synthesis of sildenafil citrate has an E-factor of 6, which is cantly less than the industry standard (25–100) Consequently, the amount of waste produced per year is extremely low (just 6 kg of waste per kilogram of the product).8

signifi-P.1.4 c ontrolled s ubstances and l egal i ssues

Any chemicals that can be used for illicit drug refinement are controlled by governments and constantly monitored by the International Narcotics Control Board (INCB) Licenses are often required for the possession, supply, and manufacture of these chemicals For example, (+)-pseudo-ephedrine (Figure P.1) has many applications; it is used as a resolving agent, ligand, and intermedi-ate in organic synthesis (+)-Pseudoephedrine is, however, a regulated chemical in the UK and the United States

International governments also tightly control chemicals that can be used in the production of chemical weapons Notable examples include phosgene and cyanogen chloride

In the development stage, intellectual property (IP) issues should be avoided or resolved as early as possible

OH Me

NHMe

FIGURE P.1 The chemical structure of (+)-pseudoephedrine.

O

S N O O

N

HN

N N

Me O

N Me

Sildenafil citrate

N N Me

Me

H2N

H2N O

(a) CDI/EtOAc

(b) tBuOK

1

4 3

O Me

(c) Citric acid

HO2C

•

H2Pd/C EtOAc

2

CO2H

O S

N

O O

N Me

Me

O2N

N N

Me

H2N O

Me

SCHEME P.1

P.2 DESIGN OF NEW SYNTHETIC ROUTES

At the end of a process evaluation, a decision has to be made 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

P.2.1 m aterials and r eagents

The selection of starting materials and reagents is primarily based on process safety, cost, and mercial availability Introducing atom-economical reagents into a process can potentially reduce costs and downstream wastes For instance, similar reaction profiles were obtained when bromina-

com-tion of aminopyrazole 5 with either N-bromosuccinimide (NBS),

1,3-dibromo-5,5-dimethylhydan-toin (DBH), or N-bromoacetamide (Equation P.2).9

Compared with NBS and DBH, N-bromoacetamide was more expensive and not readily

avail-able on scale DBH was selected as the bromination reagent due to its robust solution stability in dimethyl formamide (DMF)/MeCN It should be noted that both bromine atoms in DBH were uti-lized in this bromination reaction, making the process atom economical

P.2.2 c atalytic s ystems

A catalytic reaction proceeds through a transition state with lower activation energy, resulting in

a higher reaction rate than an uncatalyzed reaction under otherwise the same reaction conditions Thereby a catalytic reaction can be performed at relatively mild conditions, which is desired in large-scale production in terms of process costs and safety Catalytic reactions are considered envi-ronmentally 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 hydes as starting materials that are typically prepared by oxidation of the corresponding alcohols

alde-A direct catalytic olefination of alcohols was realized using the thermally stable Ru-pincer catalyst (Equation P.3).10 This approach represents a step-economical synthesis, which avoids the alcohol oxidation step

catalyst (Equation P.4).11 This new method allows the fluorination reaction to be conducted in

non-polar media (p-xylene/ethylcyclohexane) at room temperature using insoluble Selectfluor as the

fluorine reagent and tolylboronic acid as the in situ directing group

F R΄

O O P O HO

iPr

iPr

iPr iPr

(P.4)

P.2.3 P rotecting g rouPs

Chemoselective transformation via protection of functional groups is one of the standard tools in the total synthesis of natural products, and a large number of protecting groups12 have been devel-oped to fulfill the chemoselective construction of complex molecules The protecting group has

to be stable enough under certain reaction conditions and, at the end, the deprotection has to be selective For instance, the synthesis of natural products, (±)-basiliolide B, involved transforma-

tion of 7 → 8 that contains nine synthetic steps, including cyclopropane ring opening, oxidation,

olefination, Achmatowicz ring expansion, methylation, another olefination, oxidation of ketal to lactone, base-promoted double-bond migration to form 2-pyrone, and Diels–Alder cycloaddition (Scheme P.2).13

While the allylic protecting group in 7 survived in all nine chemical transformations, the removal

of the allylic group in 8 had to be selective without damaging other existing ester functionalities To

that end, a palladium-catalyzed deprotection protocol was adopted

However, these protecting/deprotecting manipulations render processes less efficient Efforts in limiting protection/deprotection operations or protecting group-free synthesis14 led to the develop-ment of various strategies (see Chapter 7)

O

I

OH O

Me

O O

O

O MeO

P.2.4 c onvergent s ynthesis

Convergent synthesis allows the coupling of advanced intermediates at the later stage of synthesis, which not only shortens processing times but also provides a better opportunity to remove impuri-ties For example, a convergent synthesis (Route II, Scheme P.3) of SDZ NKT343, a human NK-1 tachykinin receptor antagonist developed by Novartis, avoided the formation of three impurities

(13–15) generated from the linear synthesis (Route I, Scheme P.3).15 Consequently, this convergent process allowed chromatography-free preparation of the drug substance on a large scale

P.2.5 a ddition and s ubstitution r eactions

In general, addition reactions are preferred over elimination reactions, as additions will build up molecular skeletons while eliminations will lose fragments of molecules that, in most cases, become

H2N

N

O Bn Me

O Bn O

Me HN

H N N

O Bn O

Me N

N H O

O N N H

O

OH

SDZ NKT343 O

O Cl

Me Me

N-benzyldimethylamine toluene, –20°C to –25°C

O O

N N H O

Me

H

O O

N N H

H N N

O Bn O

Me N

O

O Me Me

wastes Addition reactions are limited to compounds that have unsaturated bonds, such as carbon–carbon double bonds, triple bonds, or carbonyl groups.

Most organic transformations can be regarded as substitution reactions, in which X in the tants RX is replaced by Y to form products RY (Equation P.5) Depending on reactants, these substi-tution reactions can generally be classified into nucleophilic substitution, electrophilic substitution, and free-radical substitution Substitution reactions are inherently more balanced transformations, given that the replacement occurs between two compatible pieces in terms of mass

Besides traditional aromatic substitution reactions, transition metal–catalyzed cross-coupling reactions (Equation P.6) are extensively applied in the pharmaceutical industry owing to the recent development on organometallic chemistry

12 provides useful information regarding these telescoping strategies and their application in the chemical process development

P.3 PROCESS OPERATION

Although the advent of flow chemistry has brought much attention recently, most chemical cesses in the pharmaceutical industry are developed based on batchwise operation The way of mixing starting materials, reagents, catalysts, etc., in the presence of a solvent (in most cases) has a direct impact on the outcome of a given reaction As a consequence, it affects not only the product yield and purity but also the thermodynamic behavior and process safety

pro-There are several motivations for developing semibatch processes, such as control of reactant concentration to improve the selectivity of a reaction, avoidance of accumulation of reactants, and control of heat production of reactions (exothermic reactions) Most exothermic reactions are con-ducted in a semibatch fashion in order to mitigate the exothermic event and prevent a runaway reac-tion from occurring

frequently used in the pharmaceutical industry

P.4 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 ing materials/reagents/solvents, temperature, solvent/concentration, pressure (for some cases), agitation rate, etc

start-P.4.1 r eaction t emPerature

A reaction temperature is established based primarily on the reaction rate and impurity profile Ideally, the reaction temperature should be within the −20°C to 100°C range, too low or too high will

require additional energy and time at scale and sometimes special equipment is needed Generally,

a high reaction temperature will lead to poor selectivity, thereby forming impurities Large jumps

in temperature should be avoided

P.4.2 s olvent and c oncentration

Several solvent evaluation tools20 are developed as solvent selection guides Solvents shall be selected and assessed based on three general aspects: (a) toxicity (including carcinogenicity, mutagenicity, reprotoxicity, skin absorption/sensitization), (b) process safety (including flammability, emission, static charge, and potential for peroxide formation), and (c) environmental and regulatory consid-erations (including ecotoxicity, ground water 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 8)

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 wastes

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.4.3 i solation and P urification

Direct isolation and extractive workup are two commonly used isolation approaches Direct tion is preferred over extractive workup in terms of process wastes, processing times, and costs

isola-An isolated reaction product usually needs to be purified in order to meet a predetermined purity criteria The purification methods include distillation, recrystallization/precipitation, and column chromatography Owing to the intensive labor requirement, column chromatography is gen-erally not recommended in large scale

Obviously, the product yield and quality, including chiral and chemical 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.21 A product failing to meet the predetermined purity criteria may contain impurities, such as residual processing solvents, undesired products, or metals (see Chapter 15 for various isolation/purification strategies)

P.5 CONCLUSION

This book is designed to provide readers with unprecedented R&D approaches, which will help process chemists and graduate students who plan to become industrial chemists to develop chemical processes in an efficient manner Based on the mechanism-guided process development (MPD) strategy, this book consists of 17 chapters, and each chapter contains numerous case stud-ies Each case study focuses on a mechanistic diagnosis of reaction problems, giving readers an opportunity of independent thinking and ultimately the ability to solve process problems in the real world

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