Green Chemistry in the Pharmaceutical Industry

Green Chemistry in the Pharmaceutical Industry......Page 2
Contents......Page 10
Foreword......Page 8
List of Contributors......Page 18
1.1 The Development of Organic Synthesis......Page 22
1.2 The Environmental Factor......Page 25
1.3 The Role of Catalysis......Page 28
1.4 Green Chemistry: Benign by Design......Page 31
1.6 The Question of Solvents: Alternative Reaction Media......Page 32
1.7 Biocatalysis: Green Chemistry Meets White Biotechnology......Page 36
References......Page 39
2.1 Introduction......Page 42
2.2 Measuring Resource Usage......Page 45
2.2.1 Focus on Solvents......Page 47
2.2.2 Focus on Renewables......Page 49
2.3 Life Cycle Assessment (LCA)......Page 51
2.4 Measuring Chemistry and Process Efficiency......Page 55
2.5 Measuring Process Parameters and Emissions......Page 56
2.6.1 Scalability......Page 57
2.6.2 Controllability......Page 58
2.7 Operational Efficiency......Page 59
2.8 Measuring Energy......Page 60
2.9.1 Occupational Exposure Hazard and Risk......Page 61
2.10 Measuring Degradation Potential......Page 64
2.12 Conclusions......Page 66
References......Page 67
3.1.1 Introduction......Page 70
3.1.2 Process Efficiency Metrics......Page 71
3.1.3 Impact Beyond the Plant – Solvent Life Cycle......Page 72
3.1.4 Solvent Utilization......Page 73
3.1.5 Solvents Used in the Pharmaceutical Industry......Page 75
3.1.6 Solvent Use in Process Development......Page 78
3.1.7 Consequences of Excessive Solvent Use......Page 80
3.1.8 Waste Management Practices in the United States......Page 82
3.2.1.1 Greenness Assessment of Pharmaceutical Processes and Technology......Page 85
3.2.1.2 Greenness Scoring Methods for Solvents......Page 87
3.2.1.3 The GSK Solvent Selection Guide......Page 89
3.2.1.4 The Rowan Solvent Greenness Index Method......Page 91
3.3.1 Minimizing Solvent Use......Page 94
3.3.1.2 Biosynthetic Processes......Page 95
3.3.1.4 Telescoping......Page 96
3.3.2.1 Methods to Recover and Reuse Solvents......Page 97
3.3.2.2 Issues with Solvent Recovery and Reuse......Page 100
Acknowledgments......Page 101
References......Page 102
4.1 Historical Perspective......Page 104
4.2.1 Presence......Page 105
4.2.3 Bioaccumulation......Page 107
4.2.4 Ecotoxicology......Page 108
4.3 Environmental Regulations......Page 111
4.3.1 Product Regulations......Page 112
4.3.2.1 Chemicals Control......Page 114
4.3.2.2 Integrated Pollution Control......Page 116
4.3.3 Environmental Quality Regulations......Page 118
4.4 A Look to the Future......Page 119
References......Page 120
5.1 Introduction......Page 122
5.2 First-Generation Route......Page 123
5.3 Sitagliptin through Diastereoselective Hydrogenation of an Enamine. The PGA Enamine-Ester Route......Page 126
5.4 The Triazole Fragment......Page 130
5.5 Direct Preparation of β-Keto Amides......Page 133
5.6 Second-Generation Chiral Auxiliary Route. The PGA Enamine-amide Route......Page 136
5.7 The Asymmetric Hydrogenation Route......Page 137
5.8 Purification and Isolation of Sitagliptin (Pharmaceutical Form)......Page 143
5.9 The Final Manufacturing Route......Page 144
References......Page 146
6.1 Introduction: Biocatalysis......Page 148
6.2 The Relevance of Statins......Page 149
6.3 Biocatalytic Routes to Statin Side Chains......Page 150
6.4.1 Chemical Transformations of the DERA Product Toward Statins......Page 152
6.4.2 Optimization and Scale-Up of the DERA Reaction......Page 154
6.4.2.2 Enzyme Kinetics......Page 157
6.4.2.3 Conclusions and Outlook......Page 159
6.4.3 Improvement of DERA by Directed Evolution......Page 160
6.5 Conclusions......Page 163
References......Page 164
7.1 Introduction......Page 166
7.2 Discovery and Early Development......Page 167
7.3 From Extraction of Taxol® from Pacific Yew Tree Bark to Semi-Synthetic Taxol®......Page 168
7.4 T axol® from Plant Cell Fermentation......Page 171
7.5.1.3 Chemical Synthesis......Page 175
7.5.2.3 Chromatographic Purification of Crude Paclitaxel......Page 176
7.6.2 Solvent Use......Page 177
7.6.3 Energy and Handling Implications......Page 178
Acknowledgments......Page 179
References......Page 180
8.2 Process Routes to Pregabalin......Page 182
8.2.1 Classical Resolution Route......Page 183
8.2.2 Asymmetric Hydrogenation Route to Pregabalin......Page 184
8.3 Biocatalytic Route to Pregabalin......Page 186
8.3.1 Enzyme Screening, Optimization, and Recycling of Undesired Enantiomer......Page 187
8.3.2 Subsequent Chemical Steps to Pregabalin......Page 191
8.4 Green Chemistry Considerations......Page 192
8.4.1 Material Usage......Page 193
8.4.2 Energy Usage......Page 194
References......Page 197
9.2 Green Chemistry Considerations in Peptide-like API Manufacture......Page 200
9.3 Purification Process to Manufacture Amorphous API......Page 203
9.3.1 Cation Exchange Chromatography......Page 205
9.3.2 Extraction......Page 207
9.4 Preparation of Unnatural Amino Acids......Page 208
9.4.1 Crystallization-Induced Diastereomer Transformation......Page 209
9.4.2 Optical Resolution via Diastereomeric Salt Formation......Page 212
References......Page 214
10.1 Introduction......Page 218
10.1.1 Background......Page 219
10.2 Chemistry Process and the Dynamic Kinetic Resolution (DKR)......Page 220
10.2.1 General Description of the Chemistry......Page 222
10.2.3 Route 3......Page 223
10.3 Multicolumn Chromatography–Development of Route 4......Page 227
10.4 Environmental Assessment......Page 233
10.4.1 Life Cycle Metrics......Page 235
10.4.2 Eco-Efficiency Benefits......Page 237
10.5 Summary......Page 238
References......Page 239
11.1 Introduction......Page 242
11.2.1 Laboratory Screening......Page 244
11.2.2 Reaction Scale-up......Page 246
11.2.3 Product Isolation and Waste Treatment......Page 247
11.3 Continuous Process to Prepare Celecoxib......Page 249
11.4 Continuous Oxidation of Alcohols to Aldehydes......Page 253
11.5 Continuous Production of Bromonitromethane......Page 255
11.6 Continuous Production and Use of Diazomethane......Page 256
11.7 A Snapshot of Some Further Continuous Processes Used in the Preparation of Pharmaceutical Agents......Page 259
References......Page 262
12.1 Introduction......Page 264
12.2 Basic Principles of Chromatography......Page 265
12.3 Process Optimization to Reduce Eluent Consumption......Page 267
12.3.1.2 Reducing Cycle Time with Stacked Injections (Case of Isocratic Eluents)......Page 268
12.3.1.3 Reducing Cycle Time Using Gradients......Page 269
12.3.2 Continuous Processes......Page 270
12.4 Use of a Green Solvent: Supercritical Carbon Dioxide......Page 273
12.5 Solvent Recycling Technologies......Page 276
12.5.1 Recycling Devices for Isocratic Chromatography......Page 277
12.5.2 Recycling Devices for Gradient Chromatography......Page 278
12.5.3 Recycling Devices for Supercritical Carbon Dioxide......Page 279
12.6.2 Selection of the Chromatographic Conditions......Page 280
12.6.3 Scale-up on a Pilot SFC Unit......Page 282
12.7 Conclusion: An Environmentally Friendly Solution for Each Separation......Page 285
References......Page 287
13.1.1 Chiral Amine Resolution Processes......Page 290
13.1.2 Homochiral Amine Racemization Processes......Page 293
13.2.1 Dynamic Resolution Processes......Page 297
13.3.1 Asymmetric Transformation of (S)-7-Methoxy-1,2,3,4-tetrahydronaphthalen-2-amine......Page 300
13.3.2 Asymmetric Transformation of (R)-1-tert-butyloxycarbonyl-3-aminopyrrolidine......Page 302
13.3.3 Sertraline......Page 303
13.4 Conclusions......Page 307
References......Page 308
14.1 Introduction......Page 310
14.2 ‘Waste’: Definition and Remedy......Page 313
14.3.1 Carbodiimide and Acid Chloride Mediated Transformation......Page 314
14.3.2.2 Palladium-Catalyzed Amide Synthesis......Page 315
14.3.2.3 Ruthenium-Catalyzed Amide Synthesis......Page 316
14.3.3 N-Heterocyclic Carbene (NHC-Catalyzed Amidation)......Page 317
14.3.4 Amidation Catalyzed by Boric Acid Derivatives......Page 318
14.5.1 Precedented Approach......Page 319
14.5.2 A Greener Approach......Page 320
14.6.1 Established Approach......Page 321
14.7.1 The Classical Approach......Page 322
14.7.3 A Catalytic Approach......Page 323
14.8.1 Current Zafirlukast Bromination Method......Page 325
14.8.3 Waste-Minimized Bromination......Page 326
14.9.1 The Traditional Approach......Page 327
14.10 Conclusions......Page 328
References......Page 329
15.1 Introduction......Page 332
15.2.1 Types of Therapeutic Biologics......Page 333
15.2.2 General Features of Therapeutic Protein Manufacture......Page 335
15.3.1.1 Insulin Production Process......Page 338
15.3.1.2 Production of a Typical Medium-Sized Protein......Page 339
15.3.1.3 Highly Efficient Protein Manufacturing Process......Page 340
15.3.2 Monoclonal Antibodies and Mammalian Cell Culture Processes......Page 342
15.3.2.2 Projected ‘Intensified’ Large-Scale Monoclonal Antibody Manufacturing Process......Page 343
15.4 Overall Comparison......Page 345
15.5 Environmental Indices for Therapeutic Protein Manufacture......Page 346
15.6 Technologies with Potential Environmental Impact......Page 348
15.7 Single-Use Biologics Manufacture......Page 349
15.8 Summary......Page 350
References......Page 351
16.1 Introduction......Page 354
16.2 Waste Minimization in Drug Discovery......Page 355
16.3.1 Synthesis Design and Execution......Page 359
16.3.2 Reduction and Oxidation......Page 360
16.3.3 C–C Bond Formation......Page 361
16.3.5 Biocatalysis Now and Into the Future......Page 362
16.3.6 Application of Technology......Page 364
16.4 Alternative Solvents in the Pharmaceutical Industry......Page 365
16.4.2 Ionic Liquids (ILs)......Page 366
16.4.4 Supercritical CO2(SC-CO2) and Gas-Expanded Liquids (GXL)......Page 367
16.4.5 Molecular Solvents from Renewable Sources......Page 368
16.4.7 The Work-Up......Page 369
16.5 Green Chemistry in Secondary Pharmaceutical Operations......Page 370
16.6.1 The Pharmaceutical Roundtable......Page 372
16.6.3 The Global Impact......Page 373
References......Page 374
Index......Page 378