Process chemistry in the pharmaceutical industry, volume 2: challenges in an ever changing climate

Process Chemistry in the Pharmaceutical Industry: Challenges in an Ever Changing Climate, Volume 2......Page 2
Dedication......Page 4
Forewords......Page 5
Table of Contents......Page 8
Preface......Page 12
Acknowledgments......Page 13
The Editors......Page 14
Contributors......Page 15
Affiliations......Page 20
Table of Contents......Page 0
1.1 INTRODUCTION......Page 22
1.2.1.1 Small and Large Molecules......Page 23
1.2.3 REGULATORY COMPLIANCE......Page 24
1.4 PRESCRIPTION PHARMACEUTICAL DRUGS......Page 25
1.5.1 CASE STUDIES......Page 26
1.5.3 ENZYMATIC INTERVENTION, CRYSTALLIZATION, AND MORPHOLOGY AND CHEMICAL ENGINEERING......Page 30
REFERENCES AND NOTES......Page 31
2.2 CHANGE......Page 33
2.3.1 AUTOMATION......Page 34
2.3.3 POSTFILING CHANGES......Page 35
2.4.1 GENOTOXIC IMPURITIES......Page 36
2.4.2 PHARMACEUTICAL CGMPS FOR THE 21ST CENTURY......Page 37
2.4.4 RISK MANAGEMENT......Page 38
2.5 EMERGING ASIAN MARKETS......Page 39
2.7 FUTURE TRENDS......Page 40
REFERENCES......Page 41
3.1 OVERVIEW......Page 43
3.3 DISCOVERY SYNTHESIS OF VARENICLINE......Page 44
3.4 EARLY PROCESS CHEMISTRY CAMPAIGNS: THE FEARED BENZYNE-OSMIUM ROUTE TO BENZAZEPINE FROM BENZONORBORNADIENE......Page 46
3.4.1 CRACKING AND STORAGE OF CYCLOPENTADIENE......Page 47
3.4.2 SCALED BENZYNE REACTIONS......Page 49
3.4.4 OSMIUM-CATALYZED DIHYDROXYLATION: A PROCESS PERSPECTIVE......Page 50
3.4.6 PIPERIDINE SYNTHESIS: OXIDATIVE CLEAVAGE/REDUCTIVE AMINATION......Page 51
3.4.8 QUINOXALINE RING: DISCOVERY AND SYNTHESIS: DINITRATION OF TRIFLUOROACETYL–BENZAZEPINE......Page 52
3.4.10 OZONOLYSIS......Page 55
3.5 RETHINKING THE PROBLEM: DEVELOPMENT OF A NEW APPROACH TO BENZAZEPINE......Page 56
3.5.1 1-INDANONE-3-CARBOXYLATE/CYANOHYDRIN ROUTE TO BENZAZEPINE 6 (ROUTE B)......Page 57
3.5.3 NUCLEOPHILIC AROMATIC SUBSTITUTION STRATEGY (ROUTE D)......Page 59
3.5.4 PALLADIUM-CATALYZED CYCLIZATION ROUTE TO BENZAZEPINE (ROUTE E)......Page 77
ACKNOWLEDGMENTS......Page 79
REFERENCES AND NOTES......Page 80
4.1 INTRODUCTION......Page 84
4.3.1 EARLY AMIDATION ROUTE......Page 85
4.4 ROUTE SELECTION......Page 88
4.5 REGULATORY STARTING MATERIAL STRATEGY......Page 89
4.7 COMMERCIAL PROCESS DEVELOPMENT......Page 90
4.7.2 STEP 1B......Page 92
4.8.1 LESSON 1: EFFECT OF CARBON DIOXIDE ON AMIDATION RATE......Page 93
4.8.2 LESSON 2: ACETATE PROMOTED AMINAL FORMATION......Page 95
4.9 CONCLUSIONS......Page 97
REFERENCES......Page 98
5.1 INTRODUCTION......Page 99
5.1.1 MEDICINAL CHEMISTRY......Page 100
5.1.2.1 Piperidine......Page 101
5.1.3 FINAL COUPLING......Page 109
5.2 LONG-TERM ROUTE SELECTION......Page 110
5.2.1 THE AMINE FRAGMENT......Page 111
5.2.2 THE ACID FRAGMENT......Page 113
5.2.2.2 Tert-Butylamine Displacement......Page 114
5.2.2.4 Nitrile Anion Cyclization......Page 116
5.2.2.5 Epimerization/Saponification of Pyrrolidine Nitrile......Page 118
5.3 CONCLUSION......Page 119
REFERENCES......Page 121
6.1 INTRODUCTION......Page 122
6.3 PROCESS EVALUATION......Page 123
6.3.1.1 Route Selection......Page 125
6.3.1.3 Workup Procedure......Page 126
6.3.2.1 Route Selection......Page 127
6.3.2.2 Large-Scale Preparation......Page 129
6.3.3.1 Route Selection......Page 130
6.3.4 OPTICAL RESOLUTION OF RAC-THbetaC......Page 131
6.3.4.1 Issues with Final Salt Preparation......Page 132
6.3.4.2 Pilot-Plant-Scale Resolution (Scheme 6.10)......Page 133
6.3.5.1 Racemization through Oxidation-Reduction......Page 134
6.3.5.2 Racemization under Acid and Basic Conditions......Page 135
6.3.5.2.1 Racemization–Resolution: A Semicontinuous Process......Page 137
6.3.5.2.2 Representative Laboratory-Scale Procedure......Page 138
6.3.6 ASYMMETRIC SYNTHESIS......Page 140
ACKNOWLEDGMENTS......Page 142
REFERENCES AND NOTES......Page 143
7.1 INTRODUCTION: ENTRY INTO THE FIELD OF CNS ACTIVE CHROMANS......Page 144
7.2 AN UPHILL STRUGGLE: THE FIRST ATTEMPT TO PRODUCE MATERIAL AT SCALE......Page 147
7.3 ENVISAGING A NEW ROUTE AND ITS STRATEGIC IMPLICATIONS......Page 150
7.4.1 STEP 3: CONTROLLING THE CLAISEN REARRANGEMENT......Page 152
7.4.2 STEP 7: AN INNOVATIVE CATALYTIC OLEFIN NITRATION......Page 156
7.4.3 COMBINING A NITRO GROUP REDUCTION WITH A RACEMATE RESOLUTION IN ONE STEP......Page 158
7.4.4 THE END GAME: ADDING THE TWO CYCLOBUTYL GROUPS......Page 160
7.5 REACHING THE TARGET: A COMMERCIALLY VIABLE PRODUCTION PROCESS......Page 163
7.6 SMALL MOLECULE—BIG TROUBLE......Page 165
7.7 THE LAST STUMBLING BLOCK: DEALING WITH A LATE-STAGE SAFETY ISSUE......Page 166
ACKNOWLEDGMENTS......Page 167
REFERENCES......Page 168
8.1 INTRODUCTION......Page 169
8.3 DEFINING THE FOCUS—THE CHALLENGING ASPECTS OF alpha-CHIRAL AMINE SYNTHESIS......Page 170
8.5.1 THE METHOD OF ELLMAN......Page 172
8.6.1 CARBANION CHEMISTRY......Page 174
8.6.2 ENANTIOSELECTIVE IMINE REDUCTION......Page 177
8.6.4 REDUCTIVE AMINATION WITH H2......Page 179
8.6.5 N-ACETYLENAMIDES......Page 181
CONCLUSION......Page 184
REFERENCES......Page 186
9.1 INTRODUCTION......Page 189
9.2 RESOLUTIONS......Page 190
9.2.1 DYNAMIC RESOLUTIONS......Page 192
9.3 CHIRAL AUXILIARIES......Page 193
9.4 ASYMMETRIC HYDROGENATIONS......Page 197
9.5 BIOLOGICAL APPROACHES......Page 201
9.5.1 FORMATION OF A STEREOGENIC CENTER......Page 202
9.5.2 DECARBOXYLASES......Page 204
9.5.3 DYNAMIC PROCESSES......Page 205
9.7 SUMMARY......Page 207
REFERENCES......Page 208
10.1 INTRODUCTION......Page 212
10.2 MEDICINAL CHEMISTRY ROUTE......Page 213
10.3 PROCESS ROUTE TO UK-350,926 AND UK-349,862......Page 215
10.4 CONCLUSIONS......Page 220
REFERENCES AND NOTES......Page 221
11.1 INTRODUCTION......Page 222
11.2 OVERVIEW OF SYNTHETIC STRATEGY......Page 223
11.3.1 PRELIMINARY SELECTION OF SUITABLE BLOCKING GROUP......Page 224
11.3.2 PENICILLIN G AND ITS REARRANGEMENT TO 4-THIA-2, 6-DIAZABICYCLO [3.2.0] HEPT-2-ENES......Page 225
11.3.3 OPTICALLY ACTIVE 2-ACETYL-THF......Page 226
11.5 1-AZETIDINEACETIC ACID DERIVATIVES AND INTRODUCTION OF CHIRAL THF SIDE CHAIN......Page 227
11.6 FORMATION OF 2H-DIHYDRO-1, 3-THIAZINE RING......Page 229
11.6.3 DEPROTECTION OF CEPHEM 29 AND FORMATION OF 7-AMINO-CEPHEM 30......Page 230
11.8 USE OF THIOPHOSPHATE ESTER ACTIVATION TO FORM API......Page 232
REFERENCES AND NOTES......Page 234
12.1 INTRODUCTION......Page 236
12.3 LITHIUM–HALOGEN EXCHANGE OF ARYL HALIDES AND VINYL HALIDES......Page 237
12.5 SUMMARY......Page 244
REFERENCES AND NOTES......Page 246
13.1 INTRODUCTION......Page 248
13.2 BACKGROUND......Page 249
13.3 SYNTHESIS OF OXETANES......Page 251
13.4 OXETANES IN DRUG DISCOVERY......Page 252
13.5 SYNTHESIS......Page 253
13.6 APPLICATIONS......Page 256
13.7 CONCLUSION......Page 257
REFERENCES......Page 258
14.1 INTRODUCTION......Page 261
14.2.1 SYNTHESIS......Page 262
14.2.2.1 Suzuki–Miyaura Cross-Coupling Reactions......Page 263
14.2.3 C–N BOND FORMATION REACTIONS......Page 265
14.3.1 SYNTHESIS......Page 267
14.4 SUMMARY......Page 271
REFERENCES AND NOTES......Page 276
15.1 INTRODUCTION......Page 278
15.2 WATER-COMPATIBLE LEWIS ACIDS......Page 279
15.3 LEWIS ACID–SURFACTANT COMBINED CATALYSTS......Page 280
15.4 BRØNSTED ACID–SURFACTANT COMBINED CATALYSTS......Page 283
15.5.1 HYDROXYMETHYLATION......Page 285
15.5.2 EPOXIDE RING OPENING......Page 288
15.5.3 MANNICH-TYPE REACTION......Page 290
15.4 CONCLUSION......Page 291
REFERENCES AND NOTES......Page 292
16.1 INTRODUCTION AND BIOLOGY......Page 295
16.2 DEVELOPMENT OF COMMERCIAL MANUFACTURING ROUTE......Page 297
16.3 ALTERNATIVE ROUTES TO SILDENAFIL......Page 300
16.4 ALTERNATIVE SYNTHESIS OF PYRAZOLE 5......Page 301
16.5 ENVIRONMENTAL PERFORMANCE OF COMMERCIAL ROUTE......Page 303
REFERENCES......Page 304
17.1 INTRODUCTION......Page 306
17.2.1 RESOLUTION WITH ACYLASE......Page 307
17.2.2 PREPARATION OF L-6-HYDROXYNORLEUCINE BY REDUCTIVE AMINATION USING AMINO ACID DEHYDROGENASE......Page 308
17.2.3 PREPARATION OF ALLYSINE ETHYLENE ACETAL BY REDUCTIVE AMINATION USING PHENYLALANINE DEHYDROGENASE......Page 309
17.2.4 USE OF LYSINE-epsilon-AMINOTRANSFERASE......Page 312
17.3 HYDROXYLATION OF MUTILIN......Page 313
17.4 REGIOSELECTIVE AMINOACYLATION OF LOBUCAVIR......Page 314
17.5 SEMISYNTHESIS OF PACLITAXEL......Page 316
REFERENCES......Page 320
CONTENTS......Page 322
18.2 LARGE, COMPLEX, ORGANIC MOLECULES......Page 323
18.3.1 PARTICLE SIZE......Page 324
18.3.3 PURITY......Page 325
18.4.1 DETERMINING SOLUBILITY CURVE......Page 326
18.4.2.1 Monotropy......Page 327
18.4.2.2 Enantiotropy......Page 328
18.5 ROLE OF KINETICS......Page 329
18.6 SALT AND SOLVENT SELECTION......Page 330
18.7 NUCLEATION AND SEEDING......Page 331
18.8.1 COOLING......Page 333
18.8.2 ADDITION OF ANTISOLVENT......Page 334
18.9.1 FILTRATION......Page 335
18.10 TO MILL OR NOT TO MILL?......Page 336
18.12 RECOMMENDATIONS FOR DESIGN OF ROBUST CRYSTALLIZATION PROCESSES......Page 338
REFERENCES......Page 339
19.1 APPLICATIONS AND ADVANTAGES......Page 340
REFERENCES......Page 342
20.1 INTRODUCTION......Page 344
20.2 PROCEDURES......Page 345
REFERENCES AND NOTES......Page 358
21.1 INTRODUCTION......Page 360
21.2 ONE-POT THREE-COMPONENT COUPLING......Page 361
21.3 ACID EFFECTS IN ONE-POT PROCESS......Page 363
21.4 KINETIC STUDIES ON SELF-DECOMPOSITION OF ACYL MELDRUM’S ADDUCT......Page 364
21.5 KINETIC EVIDENCE AGAINST NUCLEOPHILIC ADDITION–ELIMINATION MECHANISM......Page 366
21.6 KINETIC PROFILES IN PROCESS SOLUTION......Page 369
REFERENCES AND NOTES......Page 372
22.1 INTRODUCTION......Page 375
22.2 VINYL ETHER FORMATION......Page 376
22.4 MID-IR LABORATORY DEVELOPMENT......Page 377
22.5 PILOT-PLANT SETUP AND OPERATING PROCEDURES......Page 378
22.6 PILOT-PLANT RESULTS......Page 379
22.7 MID-IR QUANTITATIVE ASSAY DEVELOPMENT......Page 380
22.8 PREPARATION OF DIMETHYLTITANOCENE......Page 381
22.9 DETERMINATION OF WATER LEVELS......Page 384
22.10 CONCLUSION......Page 385
REFERENCES AND NOTES......Page 386
23.1 PART I—CHALLENGES AND OLD PARADIGMS......Page 387
23.1.1 CLASSICAL ORGANIC CHEMISTRY AND TRADITIONAL TESTING......Page 388
23.1.2 GOVERNMENT REGULATIONS......Page 390
23.2.1 RAW MATERIAL APPLICATIONS......Page 393
23.2.3 FILTER-DRYER APPLICATIONS......Page 395
23.2.4 NONREGULATORY IN-PROCESS ANALYSIS......Page 398
23.2.6 STRATEGIC PAT AND PROCESS VALIDATION......Page 405
REFERENCES......Page 406
24.1 INTRODUCTION......Page 408
24.2 PEGYLATION CHEMISTRY......Page 409
24.2.2 EVOLUTION OF PEG STRUCTURE......Page 410
24.2.3.1 Amine Selective Chemistry......Page 411
24.2.3.2 Thiol Selective Chemistry......Page 412
24.3.1 TARGET IDENTIFICATION......Page 413
24.3.2 PEGYLATED PRODUCT GENERATION......Page 414
24.4.1 PROCESS CONSIDERATION......Page 415
24.4.2.1 Kinetic Model......Page 416
24.4.2.2 Rate Constants from Data Fit......Page 417
24.4.2.3 Model Prediction......Page 418
24.4.3 DOWNSTREAM CONSIDERATIONS......Page 419
24.5.1 PEG REAGENTS ANALYSIS......Page 420
24.5.2.3 PEG Moiety Stability......Page 421
24.6 MANUFACTURING CONSIDERATIONS......Page 422
REFERENCES......Page 423
25.1.1 MICROWAVE-ASSISTED ORGANIC SYNTHESIS (MAOS)—AN OVERVIEW......Page 428
25.1.2.2 Dielectric Properties—Solvents and Microwaves......Page 430
25.1.2.3 Microwave versus Classical Heating......Page 432
25.1.3 GETTING STARTED WITH MICROWAVE-ASSISTED ORGANIC SYNTHESIS (MAOS)......Page 433
25.1.3.2 Selecting Solvent......Page 434
25.1.3.3 Working with Gaseous Substrates......Page 435
25.1.3.4 Reaction Optimization......Page 437
25.1.4 MAOS IN PROCESS RESEARCH......Page 438
25.1.5 MAOS AND GREEN CHEMISTRY......Page 439
25.2 MICROWAVE INSTRUMENTATION BASICS: MULTI- AND SINGLE-MODE CAVITIES......Page 440
25.3 EXAMPLES OF PROCESS OPTIMIZATION WITH MAOS......Page 441
25.4.1 SYNTHESIS OF TRIMETHOPRIM......Page 445
25.4.2 SYNTHESIS OF ALBUTEROL......Page 446
25.4.3 SYNTHESIS OF OXAPROZIN......Page 448
25.5 CONCLUSION AND FUTURE TRENDS......Page 449
REFERENCES AND NOTES......Page 450
CONTENTS......Page 452
26.2 STRUCTURE OF MONOCLONAL ANTIBODIES......Page 453
26.3.1 TARGET AND ANTIBODY IDENTIFICATION......Page 457
26.3.2.1 Historic—Hybridoma......Page 458
26.3.2.3 Display Technology......Page 459
26.4.1.1 Expression Systems......Page 460
26.4.1.2 Screening of Cell Lines......Page 461
26.4.2.1 Modes of Upstream Processes......Page 462
26.4.2.2 Medium and Feed Development......Page 463
26.4.2.3 Bioreactor Process Development......Page 464
26.4.2.4 Scalability......Page 465
26.4.3.1.1 Clarification......Page 466
26.4.3.1.4 Anion Exchange Chromatography......Page 467
26.4.3.2 Sample Purification Train for Monoclonal Antibodies......Page 468
26.4.3.3 Downstream Process Scale-Up......Page 469
26.4.4 FORMULATION OF MONOCLONAL ANTIBODIES......Page 470
26.5 MANUFACTURING CONSIDERATIONS......Page 471
26.5.1 MANUFACTURING CAPACITY......Page 472
26.5.2 PRODUCT CHARACTERIZATION AND SPECIFICATIONS......Page 473
26.7 FUTURE DIRECTIONS......Page 474
REFERENCES......Page 476
27.1 INTRODUCTION......Page 479
27.2 KINETIC STUDIES USING IN SITU TOOLS......Page 480
27.3.1 SAME EXCESS [E] EXPERIMENTS......Page 483
27.3.2 DIFFERENT EXCESS [E] EXPERIMENTS......Page 484
27.3.3.2 Different Excess......Page 485
27.4 CAVEATS......Page 487
REFERENCES AND NOTES......Page 488
28.2 ROLE OF CHINA......Page 489
28.3 ROLES OF AGENTS......Page 491
29.1 INTRODUCTION......Page 495
29.3 LAW, LEGAL SYSTEMS, COURTS, AND LAWYERS......Page 497
29.8 HOLIDAYS AND WORK SCHEDULES......Page 498
29.11 EXPORT SHIPPING AND PAPERWORK......Page 499
29.16 WAGES AND PRODUCTIVITY......Page 500
29.18 LANGUAGE AND COMMUNICATIONS......Page 501
29.21 COMMON GOOD MANUFACTURING PRACTICE REGULATIONS AND COMPLIANCE......Page 502
29.23 PROFITABILITY......Page 503