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An updated overview of the rapidly developing field of green techniques for organic synthesis and medicinal chemistry
Green chemistry remains a high priority in modern organic synthesis and pharmaceutical R&D, with important environmental and economic implications. This book presents comprehensive coverage of green chemistry techniques for organic and medicinal chemistry applications, summarizing the available new technologies, analyzing each technique's features and green chemistry characteristics, and providing examples to demonstrate applications for green organic synthesis and medicinal chemistry.
The extensively revised edition of Green Techniques for Organic Synthesis and Medicinal Chemistry includes 7 entirely new chapters on topics including green chemistry and innovation, green chemistry metrics, green chemistry and biological drugs, and the business case for green chemistry in the generic pharmaceutical industry. It is divided into 4 parts. The first part introduces readers to the concepts of green chemistry and green engineering, global environmental regulations, green analytical chemistry, green solvents, and green chemistry metrics. The other three sections cover green catalysis, green synthetic techniques, and green techniques and strategies in the pharmaceutical industry.
Green Techniques for Organic Synthesis and Medicinal Chemistry, Second Edition is an essential resource on green chemistry technologies for academic researchers, R&D professionals, and students working in organic chemistry and medicinal chemistry.
WEI ZHANG, PHD, is Professor of Chemistry and Director of the Center for Green Chemistry at the University of Massachusetts Boston. He is known for research work in organic synthesis, medicinal chemistry, and green chemistry. He received the 2015 International Fluorous Technology Award and is one of the top three most published authors in fluorous chemistry.
BERKELEY W. CUE, PHD, is President and Founder of BWC Pharma Consulting LLC, a consultancy specializing in pharmaceutical sciences and green chemistry, and Adjunct Professor of Chemistry at the University of Massachusetts Boston.
List of Contributors xvii
Foreword xxi
Preface xxiii
Part I General Topics in Green Chemistry 1
Green ChemistryMetrics 3 Frank Roschangar and Juan Colberg
1.1 Business Case 3
1.2 Historical Context 3
1.3 Metrics, Awards, and Barriers 4
1.4 Metrics Unification Via Green Aspiration Level 9
1.5 Green Scorecard 12
1.6 Supply Chain 14
1.7 Outlook and Opportunities 15
References 17
Green Solvents 21 Janet L. Scott and Helen F. Sneddon
2.1 Introduction 21
2.2 Solvent Selection Guides and Tools 23
2.3 Greener Molecular Solvents 24
2.4 Opportunities, Challenges, and Future Developments 34
References 34
Green Analytical Chemistry 43 Paul Ferguson and Douglas Raynie
3.1 Introduction 43
3.2 Sample Preparation 47
3.3 Techniques and Methods 50
3.4 Process Analytical Technology 60
3.5 Biopharmaceutical Analysis 62
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
4.4 Use of Green Solvents in the Chemical Industry 80
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
5.2 Drivers for Greener Products 94
5.3 Development of Green Cleaning Criteria and Eco-Labeling 98
5.4 Development of Greener Ingredients for Cleaners 102
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
6.3 Pharmaceutical NCDs 121
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
7.3 Synthesis of Oxygen-Containing Heterocycles 144
7.4 Synthesis of Sulfur-Containing Heterocycles 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
8.3 Advances in Enzyme Engineering and Directed Evolution 164
8.4 Biocatalytic Synthesis of Pharmaceuticals: Case Studies of Highly Efficient Pharmaceutical Syntheses 165
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 185
9.3 Brønsted Acid Catalysis 191
9.4 Brønsted 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
>100-Gram Reaction) 207
9.9 Conclusion 209
References 209
Fluorous Catalysis 219 L¿aszl¿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
10.4 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
11.2 Immobilized Palladium Catalysts 270
11.3 Immobilized Rhodium Catalysts 276
11.4 Immobilized Ruthenium Catalysts 279
11.5 Other Immobilized Catalysts 284
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
12.3 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 JamesMack
13.1 Introduction 327
13.2 Ball Milling 328
References 339
Ultrasonic Reactions 343 Rodrigo Cella and H¿elio A. Stefani
14.1 Introduction 343
14.2 How Does CavitationWork? 343
14.3 Aldol/Condensation Reactions 345
14.4 1,4-Addition 351
14.5 Heterocycles Synthesis 353
14.6 Coupling Reactions 356
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
15.3 Synthesis of Three- and Four-Membered Rings 382
15.4 Synthesis of Five-, Six- (and Larger)-Membered Rings 391
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
16.3 One-Pot and Multi-Step Reactions 415
16.4 One-Pot Asymmetric Synthesis 424
16.5 Outlook 434
References 434
Microwave-Assisted Organic Synthesis: Overview of Recent Applications 441 Nandini Sharma, Upendra K. Sharma, and Erik V. Van der Eycken
17.1 Introduction 441
17.2 C-H Functionalization 449
17.3 Insertion Reactions 452
17.4 Reduction 453
17.5 Synthesis of Peptides and Related Fine Chemicals 455
17.6 Newer Developments 459
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
18.3 Solid-Phase Supported Heterocyclic Chemistry 476
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
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
19.4 Fluorous Techniques for Discovery Chemistry 511
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, HuiWang, 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
20.3 Conclusions and Prospects 567
References 568
Green Technologies and Approaches in theManufacture 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
21.4 Environmental Metrics Development and Impact Analysis 587
21.5 Some Future Directions 592
21.6 Conclusions 594
Acknowledgments 594
References 594
Benchmarking Green Chemistry Adoption by "Big Pharma"and Generics Manufacturers 601 Vesela R. Veleva and BerkeleyW. Cue
22.1 Introduction 601
22.2 Literature Review 602
22.3 Pharmaceutical Industry Overview and Green Chemistry Drivers 604
22.4 Benchmarking Industry Adoption of Green Chemistry 607
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
23.6 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 andMichael E. Kopach
24.1 Introduction 649
24.2 Establishing Pre-Competitive Collaborations 650
24.3 Informing and Influencing the Research Agenda 654
24.4 Developing Tools 661
24.5 Educating Leaders 666
24.6 Collaborating Globally 668
24.7 Future Opportunities 669
24.8 Success Factors 671
References 673
Index 675
Frank Roschangar1 and Juan Colberg2
1 Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, USA
2 Pfizer Global Research and Development, Pfizer Inc., Groton, Connecticut, USA
Green chemistry is an integral, strategic component for pharmaceutical firms to inspire development of drug manufacturing processes with optimal environmental impact, process safety, and energy consumption, all of which bring about improved economics. Manufacturing contributes a substantial part of industry expenditures that has been estimated at one-third of total costs to one-third of total sales, or about $200 billion worldwide in 2008 [1,2]. This figure includes about 10 billion kg of annual drug manufacturing waste treatment with costs of $20 billion [3]. Therefore, if effectively utilized, green chemistry represents a significant opportunity for industry to increase drug development and manufacturing efficiencies that could translate to trillions of dollars in social value for the public health consumer surplus [4]. This is precisely the reason why industry should optimally utilize green chemistry. In this context, metrics become vital as a reflection of corporate priority, in line with the proven management adage "you can't manage what you don't measure." Unless improvements are defined, quantified, and measured, we cannot establish clear objectives that allow us to estimate manufacturing improvements. We must, therefore, measure green chemistry by carefully choosing metrics that matter. Ideally, those selected metrics are standardized and aligned within the industry, and also leveraged within the firms with key stakeholders, namely company leadership, technical staff, and suppliers, thereby promoting a culture of continuous ambition and improvement. It was not until 23 years after introduction of the E factor [5] that the first standardized and unified green manufacturing goal metric became available that will be detailed vide infra [6,7].
The origins of metrics date back to 1956 when Nobel laureate Woodward questioned how to create the best possible synthesis, and invented the concept of synthetic design [8]: "synthesis must always be carried out by a plan, and the synthetic frontier can be defined only in terms of the degree to which realistic planning is possible, utilizing all of the intellectual and physical tools available." In 1989, Corey leap-frogged the field of synthetic design by introduction of retrosynthesis methodology, in which the chemist starts planning from the product backward via the most efficient bond dissection to arrive at simple and readily available raw materials [9]. For these contributions, he was awarded the 1990 Nobel Prize in Chemistry. The initial considerations for environment in synthetic planning, and thus the first environmental green chemistry metrics, can be traced to Trost and Sheldon who went beyond synthesis design and assessed efficiency through Atom Economy (AE) [10] and Environmental impact factor (E factor) [11] in 1991 and 1992, respectively, with the implied goal to consider waste as a criterion for molecular design and thereby minimize it. AE measures what proportion of the reactants becomes part of the product, and as such addresses a shortcoming of chemical yield (CY). For example, we can have a step with 100% CY that produces more waste than product weight, as was the case with the key step of the first commercial process of phenol via pyrolysis of sodium benzenesulfonate that was developed in Germany in the 1890s (Equation 1.1). Trost received the Presidential Green Chemistry Challenge 1998 Academic Award for development of the AE concept [12].
Equation 1.1 Key step of commercial phenol process.
Unlike AE, the E factor considers CY and selectivity of a process by measuring the amount of waste, excluding water, that is co-produced with 1 kg of the target molecule. A high E factor indicates more waste and greater negative environmental impact. The ideal E factor is 0. Typical E factors for various chemical industries were estimated by Sheldon in 1997 and indicate that pharmaceuticals face substantially elevated waste burden compared to the allied chemical industries (Table 1.1) [13].
Table 1.1 E factors, waste and process complexity across chemical industries.
The primary cause for the high E factors of pharmaceutical manufacturing is the greater molecular complexity of drugs and the resulting larger step number count to produce them. In addition, the industry faces internal and external barriers that may obstruct optimal manufacturing efficiencies as summarized in Table 1.4 vide infra.
Efficiency and productivity metrics conceived after AE and E factor focused on the amount of generated waste with respect to the product, and for simplicity, assumed that all waste had the same environmental impact, independent of its nature. The ACS GCI PR compiled drug manufacturing waste data and showed that solvents and water make up the majority, or 86% of waste for the processes studied, and should therefore be included in comprehensive waste analysis (Figure 1.1) [14,19]. Thus, the Pharmaceutical Roundtable consequently introduced the Process Mass Intensity (PMI) metric that does consider all materials used in the process and workup, including water.
Figure 1.1 Typical pharmaceutical drug manufacturing waste composition.
For a comprehensive overview, we summarize the common mass-based metrics and their consideration for resources in Table 1.2.
Table 1.2 Mass-based environmental process waste metrics.
From the above group of diverse green chemistry mass metrics, both E factor and PMI emerged as the most utilized in industry. Recently, the complete E factor or cEF was introduced, combining the advantages of PMI that is the inclusion of water and solvents in analysis, with E factor that is step mass balance, as a well-suited metric for multi-step manufacturing process analysis [6].
However, while mass-based metrics can measure process improvements and thereby aid route design to a specific drug target, they do not allow for comparison of manufacturing processes between different drugs, and thus by themselves cannot deliver a standardized green process goal.
Accurately measuring the greenness of a manufacturing process unquestionably goes beyond quantifying co-produced waste, and includes assessing sustainability of process inputs such as metals, reagents, and solvents, evaluating overall environmental impact including eco-toxicity and carbon footprint, energy consumption, as well as occupational health and risk factors, all of which are integral part of the comprehensive life-cycle assessment (LCA) (Figure 1.2) [24,25].
Figure 1.2 Comprehensive green metrics categories for life cycle assessment.
LCA methodology encompasses cradle-to-grave impact analysis starting from sources and upstream processes for process inputs, the processes themselves to manufacture intermediates and the drug, including equipment cleaning and waste handling, all the way to pharmaceutical manufacturing, packaging, and eventually drug disposal and recycling over the useful life of the drug. However, there are several hurdles to overcome with LCA [26]. A significant challenge is the lack of life-cycle inventory (LCI) input data and standardization [27], as well as the difficulty to allocate energy consumption to a particular process within pharmaceutical multi-purpose plants. A further barrier is that analysis remains time-consuming, and thereby inhibits widespread use, particular during early phases of drug development where LCA is expected to have the biggest impact during the synthesis design phase, despite efforts to simplify the methodology via fast life-cycle assessment of synthetic chemistry (FLASC)...
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