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 |  موضوع: كتاب Green Techniques for Organic Synthesis and Medicinal Chemistry الإثنين 24 أغسطس 2020, 12:56 am | |
| 
أخوانى فى الله
أحضرت لكم كتاب
Green Techniques for Organic Synthesis and Medicinal Chemistry
Edited by
Wei Zhang
Department of Chemistry
University of Massachusetts–Boston
Massachusetts
USA
Berkeley W. Cue
BWC Pharma Consulting
Nottingham, New Hampshire
USA
Second Edition
و المحتوى كما يلي :
Contents
List of Contributors xvii
Foreword xxi
Preface xxiii
Part I General Topics in Green Chemistry 1
? Green Chemistry Metrics 3
Frank Roschangar and Juan Colberg
1.1 Business Case 3
1.2 Historical Context 3
1.3 Metrics, Awards, and Barriers 4
1.3.1 Mass-Based Metrics 4
1.3.2 Life-Cycle Assessment 6
1.3.3 Green Analytical Chemistry (GAC) 7
1.3.4 Awards 7
1.3.5 Barriers 9
1.4 Metrics Unification Via Green Aspiration Level 9
1.4.1 Standardizing Metrics 10
1.4.2 Defining Analysis Starting Points 10
1.4.3 Considering Drug Manufacturing Complexity 11
1.4.4 Green Aspiration Level (GAL) 11
1.4.5 Relative Process Greenness (RPG) 11
1.5 Green Scorecard 12
1.6 Supply Chain 14
1.7 Outlook and Opportunities 15
1.7.1 Industry-Wide Adaption 15
1.7.2 Integration with LCA 15
1.7.3 Application of GAL to Supply Chain 15
1.7.4 Transformation-Type–Based GAL 15
1.7.5 Opportunities for Government 16
References 17
? Green Solvents 21
Janet L. Scott and Helen F. Sneddon
2.1 Introduction 21
2.1.1 The Need for Greener Alternatives for Chlorinated Solvents 21vi Contents
2.1.2 The Need for Greener Alternatives for Dipolar Aprotic Solvents 23
2.1.3 Scope 23
2.2 Solvent Selection Guides and Tools 23
2.3 Greener Molecular Solvents 24
2.3.1 Carbonates 24
2.3.2 ?-Valerolactone 25
2.3.3 Dimethylisosorbide 27
2.3.4 Butanol 27
2.3.5 Ethyl Lactate and Lactic Acid 28
2.3.6 Glycerol and Glycerol Derivatives 29
2.3.7 Cyrene 31
2.3.8 2-Methyl Tetrahydrofuran 32
2.3.9 Cyclopentyl Methyl Ether 32
2.4 Opportunities, Challenges, and Future Developments 34
References 34
? Green Analytical Chemistry 43
Paul Ferguson and Douglas Raynie
3.1 Introduction 43
3.1.1 Analytical Method Assessment 44
3.1.2 Case Studies 46
3.2 Sample Preparation 47
3.2.1 Sample Preparation Focusing on Liquid Approaches 47
3.2.2 Sample Preparation Using Solid Supports 49
3.3 Techniques and Methods 50
3.3.1 Liquid Chromatography 50
3.3.2 Gas Chromatography 57
3.3.3 Supercritical Fluid Chromatography 58
3.3.4 Spectroscopy 60
3.4 Process Analytical Technology 60
3.5 Biopharmaceutical Analysis 62
3.5.1 Biopharmaceutical Sample Preparation 63
3.5.2 Chromatographic and Electrophoretic Separation 63
3.5.3 PAT for Biopharmaceuticals 65
3.6 Conclusions 65
Acknowledgments 66
References 66
? Green Engineering 71
Christopher L. Kitchens and Lindsay Soh
4.1 Introduction: Green Engineering Misconceptions and Realizations 71
4.2 12 Principles of Green Engineering 72
4.3 Green Chemistry Metrics Applied to Engineering 73
4.3.1 Maleic Anhydride Production Example 74
4.3.2 Level 1 Green Chemistry Metrics 74
4.3.3 Level 2 Green Chemistry Metrics 78
4.3.4 Level 3 Green Chemistry Metrics 80
4.4 Use of Green Solvents in the Chemical Industry 80
4.4.1 Waste Prevention 80Contents vii
4.4.2 Inherently Non-Hazardous 81
4.4.3 Renewable Rather Than Depleting 83
4.4.4 Design for Commercial After-Life 84
4.4.5 Separation and Purification to Minimize Energy Consumption and Materials Use 84
4.4.6 Integration and Interconnectivity with Available Energy and Materials Flows 85
4.4.7 Conserve Complexity 85
4.5 Presidential Green Chemistry Awards 86
4.6 Opportunities and Outlook 87
References 87
? Greening of Consumer Cleaning Products 91
David C. Long
5.1 History of Green Consumer Cleaning Products 91
5.1.1 Cleaning Products Before 1990: Great Cleaners but Not Green 91
5.1.2 The Birth of Green Cleaning Products: Green but Didn’t Clean 92
5.1.3 Early Entries in Green Cleaning 93
5.1.4 Green Cleaning Can Provide Better Cleaning: The Historical Influence of Major Manufacturers 93
5.2 Drivers for Greener Products 94
5.2.1 Consumers 94
5.2.2 Governmental Regulations and Non-Governmental Organizations 95
5.2.3 Environmentally Preferable Purchasing Programs 96
5.2.4 Major Retailers 97
5.3 Development of Green Cleaning Criteria and Eco-Labeling 98
5.3.1 History and Background 98
5.3.2 Green Seal 100
5.3.3 ECOLOGO 100
5.3.4 EPA’s Design for the Environment/Safer Choice 101
5.3.5 GreenList 101
5.4 Development of Greener Ingredients for Cleaners 102
5.4.1 Background 102
5.4.2 Surfactants 102
5.4.3 Solvents 104
5.4.4 Chelants 105
5.4.5 Oxidizers 107
5.4.6 Colorants and Dyes 108
5.4.7 Fragrances 108
5.4.8 Disinfectants and Preservatives 109
5.5 The Future of Green Cleaning 111
Acknowledgments 112
References 112
? Innovation with Non-Covalent Derivatization 117
John C. Warner and Emily Stoler
6.1 Introduction 117
6.2 NCD Overview 118
6.2.1 NCD Definitions 118
6.2.2 NCD Design 118
6.2.3 NCD Preparation 119
6.2.4 NCD Characterization 120viii Contents
6.3 Pharmaceutical NCDs 121
6.3.1 API Solubility 121
6.3.2 API Bioavailability 122
6.3.3 API Stability 122
6.3.4 API Additional Performance Enhancements 122
6.3.5 API NCD Future 123
6.4 Environmental and Green Chemistry Benefits 123
References 123
Part II Green Catalysts 131
? Catalytic C-H Bond Cleavage for Heterocyclic Compounds 133
Zhanxiang Liu and Yuhong Zhang
7.1 Introduction 133
7.2 Synthesis of Nitrogen Heterocycles 133
7.2.1 Synthesis of Five-Membered N-Heterocycles 133
7.2.2 Synthesis of Six-Membered N-Heterocycles 140
7.2.3 Synthesis of Other N-Heterocycles 143
7.3 Synthesis of Oxygen-Containing Heterocycles 144
7.3.1 Synthesis of Furan 144
7.4 Synthesis of Sulfur-Containing Heterocycles 148
7.4.1 Synthesis of Dibenzothiophenes 148
7.5 Medium-Sized Heterocyclic Compounds 150
7.6 Conclusion 152
References 152
? Biocatalysis 161
James Lalonde
8.1 Introduction 161
8.2 Enzymes for Biocatalysis 162
8.2.1 Practical Aspects of Using Enzymes in Drug Manufacture 163
8.3 Advances in Enzyme Engineering and Directed Evolution 164
8.4 Biocatalytic Synthesis of Pharmaceuticals: Case Studies of Highly Efficient Pharmaceutical
Syntheses 165
8.4.1 Atorvastatin 165
8.4.2 Synthesis of Beta-Lactam Antibiotics 168
8.4.3 Pregabalin 169
8.4.4 Sitagliptin, Glasdegib, and Dexamphetamine 170
8.4.5 Simvastatin 172
8.4.6 Sulopenem and Montelukast 173
8.4.7 Boceprevir and Telaprevir 175
8.4.8 Esomeprazole 176
8.4.9 Synthesis of Drug Metabolites 177
8.5 Summary and Future Outlook 178
References 180
? Practical Asymmetric Organocatalysis 185
Wen-Zhao Zhang, Samik Nanda, and Sanzhong Luo
9.1 Introduction 185
9.2 Aminocatalysis 185Contents ix
9.3 Br?nsted Acid Catalysis 191
9.4 Br?nsted Base Catalysis 193
9.5 Hydrogen-Bonding Catalysis 197
9.6 Phase-Transfer Catalysis 202
9.7 Lewis Acid, Lewis Base, and N-Heterocyclic Carbene Catalysis 204
9.8 Large-Scale Reaction (>100-Gram Reaction) 207
9.9 Conclusion 209
References 209
?? Fluorous Catalysis 219
Laszl ´ o T. Mika and Istv ´ an T. Horv ´ ath ´
10.1 Introduction and the Principles of Fluorous Catalysis 219
10.2 Ligands for Fluorous Transition Metal Catalysts 224
10.3 Synthetic Application of Fluorous Catalysis 225
10.3.1 Hydroformylation 225
10.3.2 Hydrogenation 229
10.3.3 Hydrosylilation 232
10.3.4 Cross-Coupling Reactions 236
10.3.5 Hydroboration 243
10.3.6 Oxidation 243
10.3.7 Esterification, Transesterification, and Acetylation 248
10.3.8 Other Metal Catalyzed Carbon-Carbon Bond–Forming Reactions 250
10.4 Fluorous Organocatalysis 256
10.5 Other Applications of Fluorous Catalysis 259
References 259
?? Solid-Supported Catalysis 269
Sukanta Bhattacharyya and Basudeb Basu
11.1 Introduction 269
11.1.1 General Introduction 269
11.1.2 The Impact of Solid-Phase Organic Synthesis on Green Chemistry 269
11.2 Immobilized Palladium Catalysts 270
11.2.1 Suzuki Reactions 270
11.2.2 Mizoroki–Heck Reactions in Water 273
11.2.3 Sonogashira Reactions in Water 274
11.2.4 Tsuji–Trost Reactions in Water 276
11.3 Immobilized Rhodium Catalysts 276
11.3.1 Introduction 276
11.3.2 Rhodium(II) Carbenoid Chemistry 277
11.3.3 Rhodium(I)-Catalyzed Addition Reactions 278
11.3.4 Rhodium-Catalyzed Hydrogenation Reactions 278
11.3.5 Rhodium-Catalyzed Carbonylation Reactions 278
11.4 Immobilized Ruthenium Catalysts 279
11.4.1 Introduction 279
11.4.2 Ruthenium-Catalyzed Metathesis Reactions 279
11.4.3 Ruthenium-Catalyzed Transfer Hydrogenation 280
11.4.4 Ruthenium-Catalyzed Epoxidation 282
11.4.5 Ruthenium-Catalyzed Cyclopropanation Reactions 282
11.4.6 Ruthenium-Catalyzed Halogenation Reactions 283x Contents
11.5 Other Immobilized Catalysts 284
11.5.1 Immobilized Cobalt Catalysts 284
11.5.2 Immobilized Copper Catalysts 285
11.5.3 Immobilized Iridium Catalysts 285
11.6 Conclusions 286
References 287
?? Asymmetric Organocatalysis in Aqueous Media 291
Kartick C. Bhowmick and Tanmoy Chanda
12.1 Introduction 291
12.2 Carbon-Carbon Bond-Formation Reactions 292
12.2.1 Aldol Reactions 292
12.2.2 1,4-Conjugate Addition Reactions 305
12.2.3 Mannich Reactions 310
12.2.4 Diels-Alder Reactions 311
12.2.5 Miscellaneous C-C Bond-Forming Reactions 312
12.3 Reactions Other than C-C Bond Formation 313
12.4 Conclusion 314
References 314
Part III Green Synthetic Techniques 325
?? Solvent-Free Synthesis 327
Kendra Leahy Denlinger and James Mack
13.1 Introduction 327
13.2 Ball Milling 328
13.2.1 Types of Ball Mills 329
13.2.2 Kinetics and Thermodynamics of Solvent-Free Reactions 330
13.2.3 Hard-Soft Acid-Base Theory 333
13.2.4 Stereoselectivity 334
13.2.5 Catalysis 334
13.2.6 Isolation Techniques 336
References 339
?? Ultrasonic Reactions 343
Rodrigo Cella and Helio A. Stefani ´
14.1 Introduction 343
14.2 How Does Cavitation Work? 343
14.3 Aldol/Condensation Reactions 345
14.3.1 Aldol Reaction 345
14.3.2 Mukaiyama Aldol Reaction 345
14.3.3 Knoevenagel Reaction 346
14.3.4 Claisen-Schmidt Reaction 349
14.3.5 Mannich Reaction 350
14.4 1,4-Addition 351
14.4.1 Michael Additions 351
14.4.2 Baylis-Hillman Reaction 353
14.5 Heterocycles Synthesis 353
14.6 Coupling Reactions 356
14.6.1 Heck Cross-Coupling Reaction 356Contents xi
14.6.2 Sonogashira Reaction 357
14.6.3 Stille Cross-Coupling 357
14.6.4 Suzuki Cross-Coupling 359
14.7 Wittig Reaction 361
14.8 Diels-Alder Reaction 362
14.9 Miscellaneous 365
14.10 Conclusions 366
References 366
?? Photochemical Synthesis 373
Stefano Protti, Maurizio Fagnoni, and Angelo Albini
15.1 Introduction 373
15.2 Synthesis and Rearrangement of Open-Chain Compounds 376
15.2.1 Reactions of Olefins 376
15.2.2 Ar-H Functionalization 380
15.2.3 Miscellaneous 380
15.3 Synthesis of Three- and Four-Membered Rings 382
15.3.1 Synthesis of Three-Membered Rings 383
15.3.2 Synthesis of Four-Membered Rings 385
15.4 Synthesis of Five-, Six- (and Larger)-Membered Rings 391
15.4.1 Synthesis of Five-Membered Rings 391
15.4.2 Synthesis of Six-Membered Rings 394
15.4.3 Synthesis of Larger Rings 397
15.5 Oxygenation and Oxidation 398
15.6 Conclusions 400
Acknowledgments 401
References 401
?? Pot Economy Synthesis 407
Wenbin Yi, Xin Zeng, and Song Gao
16.1 Introduction 407
16.2 Multicomponent Reactions 407
16.2.1 The Grieco Reaction 408
16.2.2 The Petasis Reaction 409
16.2.3 The Sonogashira-Type Reaction 410
16.2.4 The Ugi/Knevengagel/Click Reaction 411
16.2.5 MCR involving Aza-Diels-Alder Reaction 412
16.2.6 MCR Involving Fluorination and Trifluoromethylation 412
16.2.7 Other Kinds of Reactions 413
16.3 One-Pot and Multi-Step Reactions 415
16.3.1 Two-Step Reaction Sequences 416
16.3.2 Three-Step Reaction Sequences 418
16.3.3 More Than Three-Step Reaction Sequences 421
16.4 One-Pot Asymmetric Synthesis 424
16.4.1 Transition-Metal Catalysis 424
16.4.2 Organocatalysis 427
16.4.3 Chiral Pool-Based One-Pot Synthesis 431
16.5 Outlook 434
References 434xii Contents
?? Microwave-Assisted Organic Synthesis: Overview of Recent Applications 441
Nandini Sharma, Upendra K. Sharma, and Erik V. Van der Eycken
17.1 Introduction 441
17.1.1 Microwave-Assisted MCR Synthesis of N-Containing Heterocycles 442
17.1.2 Coupling Reactions 445
17.2 C-H Functionalization 449
17.2.1 Metal-Catalyzed C-H Functionalization 449
17.2.2 Metal-free C-H Functionalization 451
17.2.3 Oxidative C-H Functionalization 451
17.3 Insertion Reactions 452
17.3.1 Carbon Dioxide Insertion 452
17.3.2 Carbon Monoxide Insertion 453
17.3.3 Isonitrile Insertion 453
17.4 Reduction 453
17.4.1 Microwave-Assisted Hydrogenation of Alkynes and Alkenes 454
17.4.2 Reduction of Carbonyl Groups 454
17.5 Synthesis of Peptides and Related Fine Chemicals 455
17.6 Newer Developments 459
17.6.1 SiC Reactors and Continuous Flow Synthesis 459
17.6.2 Nanomaterial Synthesis 460
17.7 Summary 461
References 461
?? Solid-Supported Synthesis 469
Indrajeet J. Barve and Chung-Ming Sun
Abbreviations 469
18.1 Introduction 471
18.2 Techniques of Solid-Phase Supported Synthesis 472
18.2.1 Recent Advances in Linkers for Solid-Supported Synthesis 472
18.3 Solid-Phase Supported Heterocyclic Chemistry 476
18.3.1 Solid-Phase Synthesis of Nitrogen Heterocycles 476
18.3.2 Solid-Phase Synthesis of Oxygen Heterocycles 484
18.3.3 Solid-Phase Synthesis of Heterocycles with More Heteroatom 485
18.4 Solid-Supported Synthesis of Natural Products 486
18.5 Solid-Supported Organometallic Chemistry 491
18.6 Solid-Phase Synthesis of Peptides 493
18.7 Solid-Phase Supported Stereoselective Synthesis 494
18.8 Interdisciplinary Solid-Supported Synthesis 499
18.8.1 Microwave-Assisted Solid-Phase Synthesis 499
18.8.2 Solid-Phase Supported Reagents in Organic Synthesis 502
References 505
?? Light Fluorous Synthesis 509
Wei Zhang
19.1 Introduction 509
19.2 “Heavy” Versus “Light” Fluorous Chemistry 509
19.3 The Green Chemistry Aspects of Fluorous Synthesis 510
19.3.1 Fluorous Solid-Phase Extraction (F-SPE) to Reduce Waste 510
19.3.2 Recycling Techniques 510Contents xiii
19.3.3 Monitoring Reactions 510
19.3.4 Fluorous Linker-Facilitated Synthesis 511
19.3.5 Microwave-Assisted Synthesis 511
19.3.6 Multicomponent Reactions 511
19.3.7 Reactions and Separations in Aqueous Media 511
19.4 Fluorous Techniques for Discovery Chemistry 511
19.4.1 Fluorous Ligands for Metal Catalysis 511
19.4.2 Fluorous Organocatalysis 514
19.4.3 Fluorous Reagents 516
19.4.4 Fluorous Scavengers 518
19.4.5 Fluorous Linkers 520
19.4.6 Fluorous Mixture Synthesis (FMS) 528
19.5 Conclusions 533
References 533
Part IV Green Techniques and Strategies in the Pharmaceutical Industry 539
?? Ionic Liquids in Pharmaceutical Industry 541
Julia L. Shamshina, Paula Berton, Hui Wang, Xiaosi Zhou, Gabriela Gurau, and Robin D. Rogers
Abbreviations 541
20.1 Introduction 543
20.2 Finding the Right Role for ILs in the Pharmaceutical Industry 544
20.2.1 Use of ILs as Solvents in the Synthesis of Drugs or Drug Intermediates 544
20.2.2 Use of ILs for Pharmaceutical Crystallization 546
20.2.3 Use of ILs in Pharmaceutical Separations 547
20.2.4 Use of ILs for the Extraction of Drugs From Natural Products 551
20.2.5 Use of ILs for Drug Delivery 552
20.2.6 Use of ILs for Drug Detection 553
20.2.7 ILs as Pharmaceutical Ingredients 554
20.2.8 ILs in Membrane Transport 566
20.3 Conclusions and Prospects 567
References 568
?? Green Technologies and Approaches in the Manufacture of Biologics 579
Sa V. Ho and Kristi L. Budzinski
21.1 Introduction 579
21.2 Characteristics of Biologics 580
21.3 Manufacture of Therapeutic Biologics 581
21.3.1 General Characteristics of Conventional Biologics Manufacturing 581
21.3.2 Process and Analytical Technologies 583
21.3.3 Manufacturing Facilities 586
21.4 Environmental Metrics Development and Impact Analysis 587
21.4.1 Mass-Based Metrics 587
21.4.2 Energy-Based Metrics 589
21.4.3 Life-Cycle Assessment 591
21.5 Some Future Directions 592
21.6 Conclusions 594
Acknowledgments 594
References 594xiv Contents
?? Benchmarking Green Chemistry Adoption by “Big Pharma” and Generics Manufacturers 601
Vesela R. Veleva and Berkeley W. Cue
22.1 Introduction 601
22.2 Literature Review 602
22.3 Pharmaceutical Industry Overview and Green Chemistry Drivers 604
22.3.1 Cost Savings 605
22.3.2 Improved Reputation 605
22.3.3 Environmental Impacts of Pharmaceuticals 605
22.3.4 Legislation 606
22.3.5 Customer Demands 606
22.3.6 Investor Pressures 607
22.3.7 Attracting and Retaining Talent 607
22.4 Benchmarking Industry Adoption of Green Chemistry 607
22.4.1 Methods 607
22.4.2 Innovative Pharmaceutical Companies 608
22.4.3 Generic Pharmaceutical Companies 608
22.5 Results and Discussion 610
22.6 Conclusion 616
References 616
?? Green Process Chemistry in the Pharmaceutical Industry: Case Studies Update (????–????) 621
Joseph M. Fortunak, Ji Zhang, Frederick E. Nytko III, and Tiffany N. Ellison
23.1 Introduction 621
23.2 Pharmaceutical Patents Driving Innovation 622
23.3 A Caution About Drug Manufacturing Costs 623
23.4 Process Evolution by Multiple Route Discovery Efforts—Dolutegravir 624
23.5 The Impact of Competition on Process Evolution—Tenofovir Disoproxil Fumarate 628
23.5.1 Tenofovir Disoproxil Fumarate: The Cumulative Impact of Incremental Process Improvements 632
23.6 Simeprevir (Olysio/Sovriad) and Analogues: Chiral Phase-Transfer Catalyst-Promoted Optical
Alpha-Amino Acid Synthesis: A Metal-free Process 633
23.7 Vaniprevir (MK 7009), Simeprevir (TMC435), and Danoprevir: Ring-Closing Metathesis (RCM)
for Macrocyclic Lactam Synthesis: Now a Commercial Reality 635
23.8 Daclatasvir (BMS-790052, Daklinza), and Ledipasvir (GS-5885): Palladium Catalyzed
Cross-Coupling for Greening a Process 638
23.9 Sitagliptin (Januvia) and Ponatinib (Iclusig): Greening the Process by Telescoping Multiple Steps
Together 639
23.10 Febuxostat (Uloric): Greening the Process via Metal Catalyzed C-H Activation: A Prospect 641
23.11 Conclusions 644
References 644
?? Greener Pharmaceutical Science Through Collaboration: The ACS GCI
Pharmaceutical Roundtable 649
Julie B. Manley and Michael E. Kopach
24.1 Introduction 649
24.2 Establishing Pre-Competitive Collaborations 650
24.2.1 Background 650
24.2.2 Mission and Membership 651
24.2.3 Strategic Priorities 652
24.3 Informing and Influencing the Research Agenda 654Contents xv
24.3.1 Key Research Areas 654
24.3.2 Research Grants 656
24.4 Developing Tools 661
24.4.1 Process Mass Intensity 661
24.4.2 Solvent Guide 662
24.4.3 Reagent Guide 662
24.4.4 Electronic Lab Notebooks 663
24.4.5 Continuous Processing Business Cases 664
24.5 Educating Leaders 666
24.5.1 Articles of Interest 667
24.5.2 Influencing Editorial Policy 667
24.5.3 Future Scientists 667
24.6 Collaborating Globally 668
24.6.1 Internal Collaboration 668
24.6.2 External Collaboration 668
24.7 Future Opportunities 669
24.7.1 Analytical Chemistry 669
24.7.2 Animal Health Products 669
24.7.3 Generic Manufacturing 670
24.7.4 Drug Delivery Formulation 670
24.8 Success Factors 671
24.8.1 Unique Value Proposition 671
24.8.2 Degree of Commonality 671
24.8.3 Critical Mass 671
24.8.4 Financial Investment 672
24.8.5 In-Kind Contribution 672
24.8.6 Leadership 672
References 673
Index 675???
Index
a
Abbreviated New Drug Application (ANDA)
615–616
absorption 22, 45, 79, 82, 373–4, 387, 398, 507, 514,
541, 555, 560, 566
Absorption, Distribution, Metabolism, and Excretion
(ADME) 541, 560
ABT-341 423
accelerated hydrogen peroxide (AHP) 110–11
accidents 603
acesulfamate 558
acesulfame 567
acetaldehyde 167–8, 295, 423, 482, 496–8
acetaminophen 547
acetic acid 29, 38, 45, 57, 81, 92, 105–6, 198, 353, 355,
408–9, 426, 442, 449, 451, 460, 469, 471, 482,
488–9, 496–8, 501
acetone 27, 45, 55, 125, 166, 186, 220, 231, 256, 258–9,
268, 298, 303, 310, 336, 345, 384–7, 394, 428, 510
acetone, aldol reactions of 258
acetonitrile 23, 45, 47, 51–2, 54–5, 59, 68, 235–6, 248,
338, 349, 378, 391, 395, 397–8, 400, 549
acetophenone 238, 384, 454
acetylation 248–50
of 2-phenylethanol 249
acetylcodeine 549
acetylene dicarboxylicesters asdipolarophiles 425
acetylsalicylate 560
acetylsalicylic acid 547, 558
AChE 411
acid–base neutralization 587
acroloylferrocene 352
ACS Green Chemistry Institute Pharmaceutical Round
Table (GCI PR) 23, 586
Actavis plc 611
activation reactions 141, 441
active pharmaceutical ingredients (APIs) 21, 543, 555
additional performance enhancements 122
bioavailability of 122
biocatalytic routes to 162
cocrystals of 122
greenness of 21
liquid salt forms of 556
as NCD 123
solubility of 121–2
“spring and parachute” model of 122
stability of 122
acyclovir 560
acylation 250–1
acyl chloride 477, 486
AD, see adefovir dipivoxil
adamantane 250, 270
based NHC–palladium polymer 271
1,4-addition 351–3
addition reactions 305–6
adefovir dipivoxil (AD) 546, 549
adrenosterone 389
affinity chromatography (AC) 582
Aglaia plant genus 391
agrochemicals 133, 152, 412, 442
AIBN, see 2,2?-azobisazobutyronitrile
albendazole 546–8
alcohol dehydrogenases 173
aldehydes 375
aldolases 163, 167–8
aldol reactions 292, 345
asymmetric, in water 293–303
4-hydroxyproline organocatalysts for 302
linear amino acid based organocatalysts for 305
Mukaiyama 345–6
organocatalysts for 292–305
aliphatic aldehydes 426
Green Techniques for Organic Synthesis and Medicinal Chemistry, Second Edition. Edited by Wei Zhang and Berkeley W. Cue.
 2018 John Wiley & Sons Ltd. Published 2018 by John Wiley & Sons Ltd.??? Index
alkene 375
alkylation 251–3
fluorous-biphase 251
Pd-catalyzed asymmetric allylic 252
alkylbenzenes 356
alkylimidazolium salts 546
alkyl polyglucosides (APGs) 103
allergic reactions 164
allylation 251
allylphenols 378
allyltrimethylsilane 378
alumina 281, 284
supported cobalt catalysts 284
aluminium-trichloride 251
Alzheimer’s disease (AD) 385, 411
American Chemical Society (ACS) 96, 101–2, 601
?-methylstyrene 408
Amgen 417, 586
amino acid 389
Fmoc 482
?-amino acid 334
?-amino-carbonyl 350
Aaminocarbonylation 453
aminocatalysis 185–91
aldol reaction 185–9
chiral aminocatalysts 186, 188, 190
Mannich reaction in 190
of Michael addition 190–1
pathways 186
proline-catalyzed Mannich reaction 189
synthesis of Wieland–Miescher and Hajos–Parrish
189
aminomethylphenol derivatives 409
4-aminophenol 547
aminophenols 409
3-aminopropylated-MCM-48, 273
3-aminopropyl triethoxysilane 279
2-aminopyridines 520
2-aminothiazole 121
aminotris (methylene phosphonic acid) (ATMP)
106
ammonium chloride 110–11, 355
amorphous compounds 555
amoxicillin 161, 168–9
amphiphilic organocatalysts 297, 301–2
ampicillin 168, 565–6
AMVI, see analytical method volume intensity
analgesics 558
analytical method volume intensity (AMVI) 46
Anastas, Paul 96, 601
anesthetics 558–9, 567
anilides 137
anion-exchange method 552–3
anionic antibiotics 565
anionic surfactants 103
anisoles 250–1, 378
anthraquinone 400
antiarrhythmic drugs 558
antibacterials 558
anticancer activity 565
anticrystal engineering 558
anticrystal engineering approach 556–7
antidepressants 548
antifreeze glycopeptides 456
antifungals 418
antihelminthic neotuberostemonines 397
antimalarial compounds 551
Antimycin A3b 489, 491
apigenin 550
API-ILs 556–60
antimicrobial properties of 565
anti-proliferative effects of 565–6
appropriate selection of ions 556–8
design approach 566
examples 557–8
immobilized onto silica 564
modulating ionicity of 560–3
pharmaceutical activity assessment of 564–6
as pharmaceuticals strategies 561
prodrug 563
solubility of a drug through 566
water solubility of 560
API supported ionic liquid phases (API-SILPs) 564
Apotex 612
aprepitant 409
aquatic organisms 27, 92, 103
arene–alkene meta-photocycloaddition reaction 397
Ar-ethynyl-TAA 357
Ar-H functionalization 380
Arkon Consultants and NuPro Technologies, Inc. 87
aromatic aldehydes 186, 246, 258, 295, 297, 299,
345–51, 451
artemisinin 551
arylacetylenes 365
arylalkanoic acids 549
arylation 251–3
of indoles with aryl-halides 252
aryl halides 239, 270, 272Index ???
3-aryl-1,2,3-oxadiazoles 364
arylpiperazinylbutyl derivatives, solid-supported
synthesis of 481
?-arylpropionic acid derivatives, synthesis of 378
aryl stannanes 239
ascaridol 399
Aspen Pharmaceutical 612
Aspergillus 418
aspirin 552, 558
astemizole 178
AstraZeneca 81, 610
asymmetric aldol reactions
asymmetric aldol addition 257
in water 293–300, 303
asymmetric allylic alkylation 251
asymmetric catalysis 204
asymmetric Michael addition reaction 203, 257, 309,
430
catalyzed by Br?nsted base catalyst 195
of cyclic ketones 307
of cyclohexanone 307
of ketones 306
of thioacetic acid, thiophenol, and thiol 198
in water media 306–8
asymmetric Michael/transamination/cyclization
process 429
asymmetric organocatalytic oxidation reactions 257
asymmetric polyene Heck cyclization 425
asymmetric synthesis 161, 256, 424–34
asymmetric transfer hydrogenation 280
atenolol 550
atom economy 73–4, 168, 172, 269, 407, 458, 509, 603
atorvastatin 165–8
chemoenzymatic routes to 166
Pfizer’s process to 167–8
aza-Diels–Alder reaction 363, 412
tetrahydroquinolines, synthesis of 364
azalactones 202
aza-Michael reaction 352
aza-Povarov 363–4
azasugar 395
azepinones, synthesis of 151
azide–alkyne cycloaddition 285, 334–5, 421, 443, 456
azide–alkyne (click reaction) for diastereoselective
synthesis 421
azides 138, 142, 276, 411, 443
2-azidobenzoic acid 477
2-azidoethanol 415
2,2?-azobisazobutyronitrile (AIBN) 282
azodicarboxylate 428
azole antifungals 418
azomethine ylide 394, 421
b
Bacillus megaterium 178
Baeyer–Villiger mono-oxygenase (BVMO) 176
Baeyer–Villiger oxidation 247, 249, 545
ball milling 328–38
diagrams of motion in 332
functionalized polymer resins in 338
types of ball mills 329, 332
Bartoli-indole synthesis 483
batch microwave reactors 443, 459
Baylis-Hillman reactions 353
benchmarking 601–16
benign solvents 59, 445
benzaldehyde 31, 40, 135, 345, 386
benzalkonium 556–9
benzalkonium chloride 104
benzene, benzoylation of 250
benzene 1,2-diamine 520
benzene reaction 74
benzethonium 558–9
benzimidazolinopiperazinones 495
solid-supported synthesis of 482–3
benzo[b]phosphole 415
1,5-benzodiazepinic rings 354
1,3-benzodioxole isocyanide 426
benzofurans 484–5
benzoin esters 384
benzophenone 358, 360, 376–7
benzophenones 358, 360
benzoquinone 363
1,2-benzothiazines 150
benzothiazoles 26, 149
synthesis of 149
benzotriazoles
based activators 456
benzotriazoles, synthesis of 139
benzoxazine 191
benzoxazole 26
benzoylnitromethane 415
1-benzyl-3-methylimidazolium chloride [C7H7mim]Cl
551
beta-lactam antibiotics 168–9
BET bromodomain inhibitor 521
biaryl derivatives 491
biaryl ethenes 360??? Index
biaryl moieties 308
bicalutamide 122
bifunctional organocatalysts 296
Biginelli, Pietro 355
Biginelli reactions 355
big pharma 604, 606, 612–13
Biltricide, see praziquantel
bimetallic catalysts 274
bimetallic copolymers 271
Bim-Oct 552–3
BimSi(OEt)3Cl or OimSi(OEt)3Cl 552–3
BINAP 232
bioaccumulation 46, 55, 78–9
bioaccumulation factor (BAF) 26, 35, 58–9
bioactivation 22
bioactive palominol, synthesis of 393
bioactive triquinane sequiterpene (±)-?9(12)-capnellene
384
bioactivity 580
bio-based glycerol and glycerol derivatives 29–31
acetals and ketals 31
hydrogen-bonding capacity of 30–1
physicochemical properties of 30
range of reactions 30
biocatalysis
biocatalytic routes to API 162
enzymes for 162–4
of pharmaceuticals 165–78
for synthesis of pharmaceutical intermediates
163
biocatalysts, use in chemical manufacturing 164
biodegradation 55, 79
bioethanol 54
biologics 579, 605
characteristics of 580–1
environmental impact considerations for 587–92
future prospects 592–4
manufacturing facilities for 586–7
manufacturing of 579, 581–7
process analytical technology (PAT) for 585–6
process technologies for 583–5
therapeutic 581–7
biopharmaceutical analysis 62–5. See also biologics
chromatographic and electrophoretic separation
63–5
sample preparation 63
Biopharmaceutical benchmarks 2014 579
biopharmaceutical industry 604
bioprocessing 579–81, 585, 587
biosensors 554
biphasic catalysis 509, 511
biphasic systems 219, 545, 551
bipolar disorder 419
bis-butenolide 400
bis(2-methoxyethyl) ammonium
bis(trifluoromethylsulfonyl)imide 551
bis-NHC–palladium polymer 270
bisoprolol 549
[bis(trifluoroacetoxy)iodo]benzene 449
Biyouyanagi (H. chinense L. var. salicifolium) 386
biyouyanagin A 386
B3LYP/6-31+G(d) density functional theory 331
BNCT, see boron neutron capture therapy
Boc 456, 473, 475
boceprevir 175–6
bone marrow 580
borate ester–mediated amidation reactions 33
boronic acid 361, 410
boronic acids 278
boron neutron capture therapy (BNCT) 433
borosilicate 460
BPy-PMO 285–6
breast cancer 110, 579–80
Bbrivudine 546
bromobenzene 270, 357
4-bromobenzyl bromide 361
bromoiodoarene 414
2-bromo-2-nitropropane-1,3-diol (bromopol) 109
Br?nsted acid catalysis 191–3
asymmetric Friedel-Crafts reaction catalyzed by
193
asymmetric Mannich reaction by 193
asymmetric reduction of quinolines by 192
enamides catalyzed by 192
pathway 191
Br?nsted base catalysis 193–6
asymmetric Michael addition catalyst by 194–6
asymmetric Phospha-Michael addition catalyzed by
196
pathway 194
BTPP, see tert-butylimino-tri(pyrrolidino)phosphorane
Buchi, George 374, 390 ¨
Buchwald-Hartwig reactions 449
buspirone 178
butanol 27
butenolide 400
1-butyl-3-methylimidazolium dimethyl phosphate
([C4mim][DMP]) 549Index ???
1-butyl-3-methylimidazolium ibuprofenate
([C4mim][Ibu]) 552
1-butyl-3-methylimidazolium trifluoroacetate
([C4mim][TFA]) 546
?-butyrolactone 26
BVDU (Brivudin, Zostex, Zerpex, Zonavir) 446
BVMO, see Baeyer–Villiger mono-oxygenase
byproducts 377
c
CAE, see coacervative extraction
CALB, see Candida antarctica
California Green Chemistry Initiative 606
camptothecin 391
Candida antarctica (CALB) 335
Candida infections 418
capillary electrophoresis (CE) 65, 549
capillary electrophoresis-enhanced chemiluminescence
(CE-ECL) 549
capillary gel electrophoresis (CGE) 65
capillary zone electrophoresis (CZE) 65, 549–50
Capnella imbricata 384
carbamates 488
carbamazepine 122
carbazoles, synthesis of 138
carbenes 204, 207
carbohydrates 103, 166
carbonates 24–5
cyclic 24
dialkyl 24
dimethyl 24–5
metal mediated reactions 24
carbon-carbon bond-formation reactions 292,
312–13, 392, 422, 445–9
diastereoselective and enantioselective 351
carbon-carbon bond-forming reactions, metal
catalyzed 250–6
carbon-carbon bonds 250–6
carbon dioxide 48–9, 84–5
carbon dioxide insertion chemistry 452
carbon footprint 587, 603, 606, 616
carbon monoxide 225, 452
insertion chemistry 453
carbon tetrachloride 21
carbonyl-alkene cycloaddition 374
?-carboranyl-?-acyloxy-amides 433
carboxylic acid 119–20, 188–9
cascade reaction 407
castanospermine 393
catalysis 334–6
catalyst/product separation 20
catecholborane 243
cationic surfactants 103
cavitation 343–5
Cbz 489, 520
C?CAT catalytic system 453
C-C coupling 237
CE, see capillary electrophoresis
CE-ECL, see capillary electrophoresis-enhanced
chemiluminescence
cellulose 25–6, 31, 59, 549
cephalexin 161, 168–9
cephalosporins 433
cephalotoxine 397
cetylpyridinium 558–9
cetyltrimethylammonium bromide (CTAB) 283
C60 fullerene 362
CGE, see capillary gel electrophoresis
chalcones 349–50
chelants 105–7
chemical engineering 44, 356
chemical processing industry 80
chemoenzymatic processes 169
chemoselectivity 164, 230
ChemSusChem 21
chiral amine-polyoxometalate (CA-POM) hybrids
188
chiral analysis 59
chiral Br?nsted acid catalysts 191, 391
chiral Br?nsted base catalysts 194
chiral dihydropyrones 313
chiral drugs 550
chiral hydrogen-bonding catalysts 197, 201
chiral imidazolidinones 311
chiral ionic liquids (CILs) 314
chiral Lewis acid 206
chiral metal complexes 291
chiral phase-transfer catalysts 203
chiral pool-based one-pot synthesis 431–4
chiral resolution 122, 162
chiral separations 550
chloramphenicol 550
chlorinated hydrocarbon solvents 104
chlorinated solvents 21–2
greener alternatives for 21–2
chlorinated waste 22
chlorine bleach 107, 110
chlorine demand 107??? Index
4?-chloroacetanilide 547
chloroacetic acid 426
2-chloroacrylonitrile 416
chloroform 21–2, 547
6-chlorohexanol 503
4-chloro-3-nitrocoumarin 391
chlorophenols 92, 378
chlorpheniramine 550
cholesterol 166, 172, 297, 380
chromanoid scaffolds 431
chromatographic analysis 46, 549
chromatographic purification 584
chromatography 336
chromium 108
cinacalcet 417
Cinchona alkaloids 193–5, 197–203
cinchonidine 208
cinnamaldehydes 205, 429
cinnarizinne 566
circulating (micro)reactors 374
circulatory disorders 388
13-cis-retinoic acid 379
Claisen-Schmidt reactions 349–50
click chemistry 334
click reactions 285, 411–12
climate change 99, 592
clinoptilolite (CP) 346
Clorox Bleach 94, 107
cloud point extraction (CPE) 48
Cl
2PdL29a catalyst 238
CM, see cross metathesis
[C4mim]Cl-salt aqueous biphasic system 551
CMR, see cross-metathesis reaction
C-N coupling 448–9
coacervates 48
coacervative extraction (CAE) 48
coacervative liquids 48
cobalt catalysts 284–5
cobalt catalysts, immobilized 284–5
cobalt-catalyzed C-H annulation reactions 148
cocrystals 118–20, 122
of API 122
in chiral resolution of APIs 122
of 1:1 danazol:vanillin 122
definition 118
glutaric acid 122
stability to hydration 122
cofactor recycling systems 178
Colawet MA-80, 557–8
Co-L31e catalyst 244
Collaborative Innovation Project Group 110
colloids 555
colorants 108
column chromatography 336
combinatorial chemistry 409, 413, 471
communication 111–12
competitive absorption 374
computational chemistry 112
computational toxicology 112
condensation reactions 345–51
conductor-like screening model for real solvents
(COSMO-RS) 550
1,4-conjugate addition reactions 305–10
conjugate additions 203–5
conjugated dienes 232, 375, 398
consumer pressure 96
Consumer Product Safety Act of 1972 93
continuous chromatography 584
continuous processes 585
copper (I) catalyst 389
copper catalysts, immobilized 285
copper-catalyzed azide–alkyne cycloaddition (CuAAC)
reaction 335, 443, 456
copper-catalyzed 1,7-enyne
trifluoromethylation/bicyclization reaction 416
copper-catalyzed Henry reactions 254–5
copper-free Sonogashira reactions 24
cosmetics 27
COSMO-RS, see conductor-like screening model for
real solvents
cost index (CI) 73
cotton 387
coumarin-3-carboxamides with 1,2,3-triazole moiety,
synthesis of 411
coumarin-pyrrole-isoquinoline-fused pentacyclic
compounds 391
coumarins, synthesis of 146–7
coupling reactions 30–2, 356–61
of amines 490
C-N coupling 448–9
C-S coupling 448
Diels-Alder reaction 362–5
Heck 445–7
Heck and Suzuki 30
Heck cross-coupling reaction 356–7
Hiyama cross-coupling reaction 491
isonitrile insertion/C-O cross-coupling reaction
453Index ???
ligand-free Suzuki 28
microwave-assisted 445–9
palladium-catalyzed carbonylative Negishi
cross-coupling reactions 453
Sonagashira cross-coupling reactions 31
Sonogashira 447–8
Stille cross-coupling 357
Suzuki cross-coupling reaction 359–61
Suzuki reaction 447
Wittig reaction 361–2
CP, see clinoptilolite
CPE, see cloud point extraction
CPME, see cyclopentyl methyl ether
cross-coupling reactions 27, 31–2
cross-linking 282, 461
cross metathesis (CM) 279
cross-metathesis reactions (CMR) 254
cryogenic conditions 167
C-S coupling 448
CTAB, see cetyltrimethylammonium bromide
Cu-catalyzed azide–alkyne Huisgen
[3+2]-cycloaddition reaction 443
Cu-catalyzed Ullmann coupling 449
CuI nanoparticles 357
cumene hydroperoxide 176
?-cuparenone 392
Curie, Jacques 343
Curie, Pierre 343
current manufacturing guidelines (c-GMPs) 612
cyclic carbonates 24
cyclic enones 352
cycloaddition 416
cycloalkane 248
cyclobutane ring, intramolecular formation of 387–9
cyclobutanes 382
cyclodextrin 317, 319
?-cyclodextrin (?-CD) 550
cyclodextrin complexes 357
?-cyclodextrin modified with epichlorohydrin
(?-CDEpi) 554
cycloheptanoindole 398
1,3-cyclohexanedione derivative 393
cyclohexanone 176, 189, 194
cyclohexene 229–30
cyclohexenone 244, 351
cyclooctene 245
cyclopalladated ferrocenylimines 359
cyclopenta[b]benzofurans 391
cyclopentadiene 32, 205–6
cyclopentyl methyl ether (CPME) 32–4, 202
cyclopropanation reactions 277–8, 282–3
cyclopropanes 282, 383–4, 429
CYP102A1 (P450-BM3) 178
CYP3A4 enzymes 178
cyrene 31
cytochrome P450 enzymes 177
cyclopropanation 179
drug metabolites from 177–9
engineered 179
cytotoxic activity 391, 396
cytotoxicity 552, 565
Cytovene 609
CZE, see capillary zone electrophoresis
d
danazol 122
Dane salt 169
D-camphor sulfonic acid (D-CSA) 299–300
DCE, see 1,2-dichloroethane
D-CSA, see D-camphor sulfonic acid
decanoic acid 563
decarboxylative cross-couplings 449
degradation 48, 51, 59, 79, 122
dehydroaminoacids 230
dehydrocavidine 551
7-dehydrocholesterol 380
dendrimers 298–9
density functional theory 331
2-deoxy-D-ribose 5-phosphate aldolase (DERA) 167
DERA, see 2-deoxy-D-ribose 5-phosphate aldolase
dermatitis 111
design for degradation (DfD) 603
Design for the Environment (DfE)/Safer Choice
Program 96, 101
destabilization 375
destruxin E, solid-supported synthesis of 489–92
dexametasone 552
dexamphetamine 161, 170–1
DfE program, see Design for the Environment/Safer
Choice Program
diabetes 170, 395, 418, 423
dialkylethers 220
?,?-diamino acid 195
1,5-diaminoanthraquinones 408
diarylprolinol ether catalyst 313
diazoketones 389, 393
?-diazoketones 393
diazolidinyl urea 109??? Index
diazomethane 168
diazonamide A 398
dibenzo[b,d]azepines 151
dibenzothiophenes, synthesis of 148–9
dichloroethane 334
1,2-dichloroethane (DCE) 334
dichloromethane (DCM) 22, 549
dicyanonaphthalene 395
didecyldimethylammonium 557
Diels-Alder reactions 205–7, 254–6, 292, 311–12,
331, 397
of N-oxides and cycopenta-1,3-diene 255
dienes 232, 256, 345
diethylamine 57
diethylenetriamine penta (methylene phosphonic acid)
(DTPMP)) 106
diethylenetriaminepentaacetic acid (DTPA) 106
diethyl ether 22, 32–4, 389
diethyl malonate 252, 431
diethyl tartrate 176
differential scanning calorimetry (DSC) 120–1
2,6-difluorobenzyl azide 416
1,2-difurylalkene 400
2,3-dihydrobenzo[f][1,2,5]thiadiazepin-4(5H)-one
1,1-dioxides, solid-supported synthesis of 485
3,4-dihydro-2H-pyran 408
dihydrolevoglucosenone, see cyrene
2,3-dihydronaphtho[1,2-b]furans 145
dihydropyrano[2,3-c] pyrazole 475
dihydropyrimidinones 355
2,4-diketones 352
2,5-diketopiperazines 432
dimethyl carbonate 24
dimethylformamide (DMF) HS-GC-MS method
549
dimethylisosorbide (DMI) 27
boiling point of 27
neat 27
solubilizing properties of 27
stability of 27
dimethylol dimethyl (DMDM) hydantoin 109
dimethyl sulfoxide (DMSO) 23, 549
diosgenin-based amphiphilic organocatalyst 297
dioxolane 395
dipeptide 298
dipeptidyl peptidase 4 (DPP-4) 418
diphyllobothrium latum 421
dipolar aprotics 23
disinfectants 110–11
disodium benzophenondisulfonate 377
DISSOLVINE 106
1,4-disubstituted 1,2,3-triazoles 354
1,4-divinyl benzene (DVB) 282
2D-LC 64
DMDM, see dimethylol dimethyl hydantoin
DMI, see dimethylisosorbide
DMSO, see dimethyl sulfoxide
docusate 556–7, 565
1-dodecyl-3-methylimidazolium chloride 565
domino reaction 407
double salt ionic liquids (DSIL) 547
downstream process (DSP) 581
DPP-4, see dipeptidyl peptidase 4
D-proline 345
dragmacidin E 398
drug metabolites, synthesis of 177–8
DSC, see differential scanning calorimetry
DSIL, see double salt ionic liquids
DSP, see downstream process
DTPA, see diethylenetriaminepentaacetic acid
DTPMP, see diethylenetriamine penta (methylene
phosphonic acid)
dual functional liquid salts 559–60
DVB, see 1,4-divinyl benzene
dyes 108
e
(E)-2-(benzo[d]thiazole-2-yl)-3-heteroarylacrylonitriles 349
Eckert, Charles 87
ECL, see electrochemiluminescence sensor
eco-labeling 98–100
eco-label certification 100
ISO 14020/14024 guiding principles 98–9
ECOLOGO program 100–1
Eco Options program, 2006 97
EDTA, see ethylenediaminetetraacetic acid tetra
E-factor 73–5, 78, 80, 587–8, 603, 615
electrochemiluminescence (ECL) sensor 554
electrophilic lactonization reaction, solid-supported
synthesis in 485
electrospray ionisation (ESI) 61
Eli Lilly 586
ELISA, see enzyme-linked immunosorbent assay
antibody based testing
Elliman’s solid-phase organic synthesis 473Index ???
Emergency Planning and Community Right-to-Know
Act (EPCRA) 96
EMLA cream 567
endo/exo isomers 391
energy-based metrics 589–91
enol silyl ether moiety 395
EntrestoTM 123
Environmentally Preferable Purchasing Program, 1999
96–7
Environmental Protection Agency (EPA) 606
EPA method 550, 47
EPA method 610, 47
Safer Chemical Ingredients List 110
“Safer Detergents Stewardship Initiative” 103
Toxic Release Inventory (TRI) 46
enzyme engineering 164–5
enzyme-linked immunosorbent assay (ELISA) antibody
based testing 164
EPA, see Environmental Protection Agency
EPCRA, see Emergency Planning and Community
Right-to-Know Act
epoxidation 282
Eschenmoser-type condensation 418
e-series glycol ethers 104
ESI, see electrospray ionisation
esomeprazole 176
esterification 248–50
in biphasic system 249
ethanol 54
ethyl cyanoacetate 346
ethylenediaminetetraacetic acid tetra (EDTA) 105–6
ethylene glycol ether 105
ethyl glyoxalate 415
ethyl lactate 28–9
melamine-Pd catalyst mediated Suzuki-Miyaura
cross-coupling in 28
as a solvent in Cu-catalyzed oxidative coupling 28
1-ethyl-3-methylimidazolium acetate ([C2mim][OAc])
547
ethyl-S-lactate solvents 105
etodolac 567
Etodolac-Lidocaine Topical Patch 567
etomidate 547
Etter, Margaret 118
Euphorbiaceae plant family 388
excited-state-intramolecular proton transfer (ESIPT)
391
E/Z isomerization, photoinduced 379
f
failure mode and effect analysis (FMEA) 74
fault tree analysis (FTA) 74
FBS, see fluorous-biphase systems
FDASIA, see Food and Drug Administration Safety and
Innovation Act
fenofibrate 547
fexofenadine (Allegra) 177
five-membered rings
formation by ring contraction/enlargement 392–4
synthesis of 391–4
flash chromatography 57
flavanoid scaffold 431
flavonol 391
Flos Genkwa 550
fluoren-9-ylmethyloxycarbonyl (Fmoc) 456
fluorinated cyclohexenones 412
fluorinated dihydroquinolinone 413
fluorinated isoquinolines 413
fluorination 412–13
fluorous benzaldehyde 520
fluorous-biphase allylation 252
fluorous-biphase Prins reaction 251
fluorous-biphase systems (FBS) 220, 246
fluorous bis(oxazolines) 254
fluorous Boc 520
fluorous catalysis
in acetylation 248–50
in esterification 248–50
fluorous-biphase concept in 220–2
fluorous transition metal catalysts 224–5
in hydroboration–oxidation reaction 243
in hydroformylation reaction 225–9
in hydrogenation 229–32
in hydrosilylation reaction 232–6
in oxidation reactions 243–8
principles of 219–24
in transesterification reactions 248–50
in transition metal catalyzed cross-coupling
reactions 236–43
fluorous catalyst 221–3
fluorous distannoxane catalyst 249
fluorous DMSO 518–19
fluorous HPLC (F-HPLC) 528
fluorous ligands for metal catalysis 512–14
fluorous linkers 520–8
fluorous mixture synthesis (FMS) 528–33
fluorous nanoparticles, Pd-based 242??? Index
fluorous organocatalysis 256–9, 514–16
fluorous organocatalysts 256–8, 431–2, 511–16
fluorous phosphines 222–3
ligands of 224
fluorous phosphite ligands 225
fluorous (S)-pyrroldine sulfonamide 256
fluorous reagents 516–18
fluorous reverse-phase silica gels 242
fluorous safety-catch linkers 520
fluorous scavengers 518–20
fluorous (Rf) silyl 528
fluorous synthesis
of an imidazo[1,2-a]pyridine derivative
521
components of a 560-member mappicine library
529
for discovery chemistry 511–33
of drug-like molecules and nature product analogs,
diastereomers, and enantiomers 529–33
fluorous linker-facilitated synthesis 511
fluorous solid-phase extraction (F-SPE) to reduce
waste 510
green chemistry aspects of 510–11
heavy versus light 509–10
monitoring reactions 510
of quinoxalinone 520
recycling techniques 510
fluorous-tagged aryl stannanes 239
fluorous transition metal catalysts 224–5
FMEA, see failure mode and effect analysis
Fmoc-amino acids 482
FMS, see fluorous mixture synthesis
Food and Drug Administration Safety and Innovation
Act (FDASIA) 615
fragrances 108–9
Friedel-Crafts acylations 249–50
with acyl-chloride 250
of veratrole 250
Friedel-Crafts reactions 192, 545
Fritsch Pulverisette 6, 332
frustrated Lewis pairs (FLP)-catalyzed hydrogenations
455
FTA, see fault tree analysis
fumaric esters 352
functionalized polymer resins 337
furan, synthesis of 144–5
furan-2(5H)-one derivatives, solid-supported synthesis
of 485–6
furfural 32
g
GAC, see green analytical chemistry
Ga-catalyzed Mannich reaction 351
gas chromatography 57–8
gastrointestinal stromal tumor (GIST) 417
GC3 Innovation Project Group 111
G-CON Manufacturing 587
GDUFA, see Generic Drug User Fee Amendment
GE Healthcare Life Sciences’ KUBio FlexFactory
platform 587
gem-difluoromethylenes 413
GEN, see Global Ecolabeling Network
Genentech 586
Generally Regarded as Safe (GRAS) List 111, 558
GeneratoR of Agro-based Sustainable Solvents
(GRASS) 29
Generic Drug User Fee Amendment (GDUFA)
615
Generic Pharmaceutical Association (GPhA) 606
generic pharmaceutical industry 604, 608–10
Gewald reaction 419
GHS, see Globally Harmonized System
Gilead Sciences 610
Ginkgo Biloba 388
GIST, see gastrointestinal stromal tumor
glasdegib 162, 171–2
GlaxoSmithKline (GSK) 81, 327, 586, 609
Global Ecolabeling Network (GEN) 98–9
Globally Harmonized System (GHS) 82
glycerol 83
glycerol carbonate 24
glycol ethers 104–5
glycosidases 395
glycyrrhizic acid 551
glyoxal 109
GPhA, see Generic Pharmaceutical Association
Grandisol 387
GRAS, see Generally Regarded as Safe List
GRASS, see GeneratoR of Agro-based Sustainable
Solvents
green analytical chemistry (GAC)
case studies 46–7
comparison of green profiles 46–7
critical review of 44
principles of 43
relative eluting strengths of solvent mixtures 56
sample preparation and analytical measurement
options 44–5, 47–50
techniques and methods 50–60Index ???
green aspiration level (GAL) 9–10, 11
application to supply chain 15
drug manufacturing complexity and 11
green chemistry with 16
Green Scorecard and 13
industry-wide adaption 15
LCA, integration with 15
process starting materials, definition for 10–11
relative process greenness and 11
standardizing metrics 10
transformation-type-based 15
green chemistry 601–2
benchmarking industry adoption of 607–17
cost of implementing 614–15
customer demands 606
literature review 602–4
opportunities 615
principles of 603
green chemistry metrics
awards 7–8
barriers 9
GAC 7
government adoption of 16
Green Scorecard 12
historical context of 3–4
industries and 3, 14
life-cycle assessment 6–7, 15
mass-based 4–5, 6
supply chain 14
unification via green aspiration level 9
Green Chemistry 21
Green Chemistry Institute (ACS/GCI) Green
Chemistry Formulators’ Roundtable 102, 111
green chemistry metrics
components 73
E-factor 75
energy-based metrics 589–91
exposure assessment 79
level 1, 74–8
level 2, 78–80
level 3, 80
maleic anhydride production example 74
mass-based metrics 587–9
reaction mass efficiency (RME) metric 74
risk and hazard assessment 78–9
green chemistry (GC) program 607
green consumer cleaning products
birth of 92
chelants 105–7
chemical selection in consumer cleaning products
96
colorants and dyes 108
consumers and 94–5
Design for the Environment (DfE) Program
101
drivers and 94–7
early products 93–4
eco-labeling 98–100
ECOLOGO program 100–1
fragrances 108–9
future of 111–12
general requirements for chemicals 102
government regulations and non-governmental
organizations, role of 95–6
Greenlist 101
Green Seal standards 100
major retailers of 97–8
oxidants or oxidizers 107
solvents 104–5
surfactants 102–4
green engineering
green chemistry metrics in 73–80
life-cycle considerations for 86
misconceptions and realizations 71–2
principles of 72
greener alternatives
for chlorinated solvents 21–3
for dipolar aprotics 23
greener molecular solvents
bio-based glycerol and glycerol derivatives 29–31
carbonates 24–5
cyclopentyl methyl ether (CPME) 32–4
cyrene 31
dimethylisosorbide (DMI) 27
ethyl lactate 28–9
lactic acid 28–9
2-methyl tetrahydrofuran (2-MeTHF) 32
n-butanol 27
opportunities, challenges, and future developments
34
?-valerolactone 25–7
Greenlist process 94, 101
green procurement programs 97
Green Reaction Conditions, 1998 87
Green Scorecard 12
GAL and 13
rating matrix for RPG for 12
Green Seal standards 100??? Index
green solvents, application of
bio-based products 83
in conserving complexity of a process 85–6
for EHS and life-cycle impacts 81–2
as fertilizers 84
mass/energy integration 85
in reactions and separations processes 81
renewable solvents 83–4
in separations processes 84–5
waste prevention 80–1
Grieco three-component reaction 408–9
Grignard reactions 32, 34
griseofulvin 547
Grubbs catalyst 253
Grubbs-Hoveyda catalysts 253–4, 279–80
GVL, see ?-valerolactone
h
Hajos-Parrish-Eder-Sauer-Wiechert reaction 207, 256
halohydrin dehalogenase (HHDH) 166
hamigerans 396
Hantzsch-type mechanism 443
Hantzsch-type reaction 28
hard-soft acid-base (HSAB) theory 333–4
1H-benzotriazoles 353
HCOOH/KI catalytic system 452
Heck and Suzuki coupling reactions 30
Heck cross-coupling reaction 356–7
Heck isomerization–Fischer indolization–alkylation
(HIFIA) synthesis 443
Heck isomerization–Fischer indolization (HIFI)
synthesis 443
Heck reactions 236–9, 243, 445–7
of 2,3-dihydrofurane and 4-chloropentyl-triflate
238
of iodobenzene and methyl-acrylate 239
palladium complexes for 237
HEDP, see 1-hydroxyethylidene diphosphonic acid
helium 57–8
Henry reactions 254
herbertenolide 392
heterocycles synthesis 353–5
heterogeneous catalysts 446
heterogeneous sonochemistry 344
1-hexadecyl-3-methylimidazolium chloride 565
hexanoic acid 563
hexetidinium 558–9
1-hexyl-2,3-dimethylimidazolium dazolium
dihydrogen phosphate ([bnmim]H2PO4) 346
HIFI, see Heck isomerization–Fischer indolization
synthesis
HIFIA, see Heck isomerization–Fischer
indolization–alkylation synthesis
high performance liquid chromatography (HPLC)
51–2, 586
high through-put (HTP) screening 164–5
Hippophae rhamnoides 550
Hiyama cross-coupling reaction 491
HLB, see hydrophilic-lipophilic balance
HMG-CoA reductase inhibitor 394
Home Depot 97–8
homogeneous catalytic reactions 219
homogeneous sonochemistry 344
Hospira 611
“hot spot” theory 344
HPLC, see high performance liquid chromatography
HSAB, see hard-soft acid-base theory
HTP, see high through-put screening
Huisgen 1,3-dipolar cycloaddition 354
4-hydoxyproline catalysts 300–5
hydrazides 473, 475
hydrazine-derived heterocycles 473
?-hydrazinocarboxylic acids 410
hydroboration 243–4
hydroformylation 225–9
of 1-alkenes 229
catalysts for 228
first fluorous 228
of propylene 225
rhodium-catalyzed, of 1-octene 228–30
hydrogen 58
hydrogenation 229–32
fluorous ligands for 231
of 1-octene 231
of 4-octyne 231
of styrene 232
hydrogen bonding 118–19
hydrogen-bonding catalysis 197–202
asymmetric intramolecular [2+2]
photocycloaddition catalyzed by 202
asymmetric Strecker reaction catalyzed by 198
Michael addition reaction 198–201
pathway of 197
symmetric Michael addition catalyzed by 202
hydrogen peroxide-based bleaches 107
hydrophilic interaction chromatography (HILIC) 54,
59
hydrophilic-lipophilic balance (HLB) 553Index ???
hydroxy and acid group–modified catalysts 303–5
1-hydroxyethylidene diphosphonic acid (HEDP) 106
1-hydroxyethyl-3-methylimidazolium chloride
[C2OHmim]Cl 551
hydroxy group–protected catalysts 300–3
with polymer support 303
hydroxylactams, solid-supported synthesis of 484
4-hydroxy-L-proline 302
5-hydroxy-1,4-naphthoquinone 399
hydroxy-o-quinodimethanes 397
4-hydroxyproline-based catalysts 305–10
ionic liquid–type 309
modified 308–9
modified with polymer support 309
hydroxyquinoline-2-carboxylic acid derivate 429
Hypericum genus 386
i
IBISS, see InBioSynSolv
ibuprofen 381, 556
ibuprofenate 557
ideal recoverable catalyst 219
IFRA, see International Fragrance Association
IL, see ionic liquids
ILs, see ionic liquids
imatinib 417
imidazole 480
imidazolidinyl urea 109
4-imino-?-lactam derivatives, synthesis of 144
immobilized cobalt catalysts 284–5
immobilized copper catalysts 285
immobilized iridium catalysts 285–6
immobilized palladium catalysts 270–6
immobilized rhodium catalysts 276–9
immobilized ruthenium catalysts 279–84
InBioSynSolv (IBISS) 29
indazole, synthesis of 138–9
indole 382
infrared (IR) spectroscopy 60, 120
in silico design strategies 83–4
insulin-regulated aminopeptidase (IRAP) inhibitors
459–60
intermolecular formation of a cyclobutane ring 385–7
International Consortium for Innovation and Quality
in Pharmaceutical Development (IQ) 603
International Fragrance Association (IFRA) 108
intramolecular formation of a cyclobutane ring 387–9
ionic-catalyzed Knoevenagel condensation 346
ionic liquids (ILs) 48
ADME (absorption, distribution, metabolism, and
excretion) for 560
1-allyl-3-ethylimidazolium tetrafluoroborate
([aeim][BF4]) 546
in analysis of separation efficiency 548
of antibacterial quaternary ammonium cations 556
based silica sorbent 551
in chromatographic analysis 549
in chromatographic separations 548–9
for continuous pharma manufacturing 547–50
definition 544
in determination of flavonoids 550
as drug carriers 552–3
for drug detection 553–4
for extraction of drugs from natural products 551
formation of biphasic systems 545
in headspace gas chromatography (HSGC) 549
in high performance liquid chromatography (HPLC)
548–9
in HS-GC analysis of residual solvents 549
hydrophilic 547
hydrophobic 547
IL-APIs 556–60
imidazolium 553
imidazolium-based 546, 549
for isolation of pharmaceutically active shikimic acid
551
as matrix media 549
in membrane transport 566–7
miscible 546–7
for pharmaceutical crystallization 546–7
as pharmaceutical ingredients 554–6
phosphonium and ammonium-based 565
protic (PILs) 551
in purification of several APIs 547
room temperature (RTIL) 545–6
salicylate 558
solubility of model drugs in 546
as solvents in synthesis of drugs or drug
intermediates 544–6
structure 544
sulfonic acid-functionalized 551
in synthesis of 5?-O-monoesters of
1-?-D-arabinofuranosylcytosine 545
tuammoniumheptane salicylate 566
as a tunable hydrophilic–lipophilic carrier 553
ionic liquid–tagged organocatalysts 309
IRAP, see insulin-regulated aminopeptidase inhibitors
iridium catalysts, immobilized 285–6??? Index
isatins, synthesis of 136–7
isobenzofuranones, synthesis of 145–6
isochromenes, synthesis of 147–8
isocoumarins, synthesis of 146–7
ISO Eco-Labels 99
isofagomine 395
isoindolin-1-ones, synthesis of 134
isoniazid 121
isonitrile 520
isonitrile insertion/C-O cross-coupling reaction 453
isopropanol 388, 400
isopropylmyristate (IPM) 552
isoquinoline, synthesis of 140–1
isoquinolinium 412
isoquinolinones, synthesis of 141–2
isorhamnetin 550
itraconazole 547, 566
j
Januvia 170
Johnson & Johnson 586, 609
Jorgensen–Hayashi catalyst 429
Jorgensen–Hayashi organocatalysts 306
Josiphos 170
Juglone 399–400
k
kaempferol 550
?-ketoesters 352
ketone reductase (KRED) 166–7, 173
montelukast 174
reduction 173–5
ketones 375
ketoprofen 549
Knoevenagel condensation 346–9
of ethyl cianoacetate and aromatic aldehydes
347
green protocol for 346
of malonitrile and aromatic aldehydes 348
Knoevenagel–Michael cyclization 355
Knoevenagel/Ugi/click reaction 411–12
KRED, see ketone reductase
l?
-lactam antibiotics 433
lactic acid 28–9
lactones, synthesis of 147
lanthanide(III) bis(perfluorooctansulfonyl)amides
249
large-scale reaction 207–9
of 6-cyanoindole derivatives 209
of Wieland–Miescher and Hajos–Parrish ketones
208
L29e-modified Pd catalyst 238
Lennox-Gastaut syndrome 416
levulinic acid 32
Lewis acid catalysis 204–7
Lewis base catalysis 204–7
Li
2CO3 334
lidocaine 542
lidocainium 557–9
lidocainium acetylsalicylate 558
lidocainium chloride 564
lidocainium salicylate 562
life-cycle assessment (LCA) approach 587, 591–2
ligand-free catalysis 335
ligand-free Suzuki coupling reactions 28
ligands
bipyridine 286
diphenylphosphine 271
exchange of the catalyst species 228
fluorous 511–14
fluorous phosphine 224
fluorous phosphite 225
fluorous-tagged 241
for HIV protease inhibitor 376
N-, O-, S-, and Si-containing 226–7
Phosphine-phosphite 502
linear amino acid catalysts 305
linkers for solid-phase organic synthesis (SPOS)
472–5
linoleic acid 563
Liotta, Charlie 87
lipase hydrolytic ester resolution 170
lipophilic decylsulfate 566
lipopolysaccharides (LPS) 164
Lipshutz, Bruce 87
liquid chromatography 63
acetone as solvent in 55
dichloromethane mixtures in 55
green acids and bases used in 57
methanol as solvent in 55
popularity 50
propylene carbonate-ethanol mixtures in 54–5
reduction in mobile-phase volume 50–1
solvent selection in 52–7
sustainability of 50
temperature, importance of 51–2Index ???
liquid-liquid extraction (LLE) 48
liquiritin 551
low thermal-mass (LTM) chromatography 58
L-proline 299, 345, 428
LUF5771 416
?-Lycorine 428
Lyrica 169
Lysobactin (Katanosin B) 487
m
mAb production, characteristics of 582–3
MacMillan’s imidazolidinone catalyst 190
macrocyclic peptide 495
macrocyclic peptidomimetics, solid-phase parallel
synthesis of 493–4
maleic acid, sunlight-photocatalyzed alkylation of
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