Green Techniques for Organic Synthesis and Medicinal Chemistry

by Zhang, Wei; Cue, Berkeley

• ISBN13: 9780470711514
• ISBN10: 0470711515
• Format: Hardcover
• Copyright: 2012-07-23
• Publisher: Wiley

Summary

Boasting both environmental and economic benefits, green chemistry is becoming a high priority in modern organic synthesis and pharmaceutical R & D. This book fills a gap in the field, offering the only comprehensive treatment focused on green chemistry applications in organic synthesis, medicinal chemistry, and drug discovery. It covers many innovative and new techniques, along with an assessment of the green chemistry aspects and limiting factors for each technique. Coverage also includes green concepts and catalysis, as well as case studies illustrating practical applications in the pharmaceutical industry.

Table of Contents

List of Contributors	p. xix
Introduction	p. 1
Green Toxicology	p. 3
Introduction	p. 3
History and Scope of Toxicology	p. 4
The need for green toxicology	p. 5
Principles of Toxicology	p. 5
Characteristics of exposure	p. 6
Spectrum of toxic effects	p. 6
The dose-response relationship	p. 7
Disposition of Toxicants in Organisms	p. 8
Absorption	p. 9
Distribution	p. 11
Metabolism	p. 11
Excretion	p. 12
Nonorgan System Toxicity	p. 12
Carcinogenesis	p. 13
Reproductive and developmental toxicity	p. 13
Immunotoxicology	p. 14
Mechanistic Toxicology	p. 15
Quantitative Structure-Activity Relationships	p. 16
Environmental Toxicology	p. 18
Persistence and bioaccumulation	p. 18
Risk Assessment	p. 19
NonCancer risk assessment	p. 20
Cancer risk assessment	p. 21
Conclusions	p. 21
References	p. 22
Green Chemistry and the Pharmaceutical Industry	p. 25
Introduction	p. 25
Green Chemistry versus Sustainable Chemistry	p. 26
Trend: The Ongoing Use of Hazardous Chemistry	p. 27
Myth: To Do Green Chemistry One Must Sacrifice Performance and Cost	p. 28
Green Chemistry and the Future of the Pharmaceutical Industry	p. 29
Green Chemistry in Pharmaceutical Process Development and Manufacturing	p. 30
Conclusions	p. 30
References	p. 31
Green Catalysis	p. 33
Environmental Science and Green Chemistry; Guiding Environmentally Preferred Manufacturing, Materials, and Products	p. 35
Introduction	p. 35
Market Forces	p. 36
Chemicals in the natural and human environment	p. 37
Precautionary decision making	p. 37
Chemical control laws	p. 37
Green chemistry initiatives	p. 38
Drug registration Environmental Risk Assessment (ERA)	p. 39
Extended Producer Responsibility (EPR)	p. 39
Ecosystem valuation	p. 39
Company expectations	p. 39
Public expectations	p. 39
Environmental labeling, standards, and classification	p. 39
Indicators (Attributes) of Environmental Performance	p. 40
Environmental Impact	p. 40
Strategic Approach to Greener Manufacturing Processes and Products	p. 42
Manufacturing Process Improvements	p. 43
Business and Professional Advantages from Manufacturing Process Improvements	p. 44
Product Improvements	p. 45
Environmental Decision Making	p. 46
E-factor	p. 47
Process Mass Intensity (PMI)	p. 47
Life Cycle Assessment (LCA)	p. 47
Individual company initiatives	p. 48
Environmental (Ecological) Risk Assessment (ERA)	p. 49
Alternatives Assessment (AA)/Chemical Alternatives Assessment (CAA)	p. 49
Green Screen	p. 50
iSUSTAINTM Green chemistry index	p. 50
Computational Science and Quantitative Structure-Activity Relationships (QSARs)	p. 51
Tiered testing	p. 52
Databases and lists of chemicals	p. 52
Case Study - Pharmaceuticals/Biologics	p. 53
Pharmaceutical manufacturing	p. 53
Pharmaceutical products	p. 54
Case Study - Nanotechnology	p. 58
Green Credentials and Environmental Standards	p. 59
Inspiring Innovation - Academic and Industry Programs	p. 60
Academic programs	p. 60
Industry programs	p. 60
Conclusions and Recommendations	p. 61
References	p. 64
Direct CH Bond Activation Reactions	p. 69
Introduction	p. 69
Homogeneous CH Activation by Metal Complex Catalysis	p. 70
Pd-catalyzed carbon-carbon bond formations	p. 70
Pd-catalyzed carbon-heteroatom bond formation	p. 73
CH activation by other metals	p. 74
Heterogeneous Catalytic Methods for CH Activation	p. 75
Supported metal complexes	p. 75
Supported metals	p. 78
CH Activation by Organocatalysts	p. 80
Enzymatic CH Activations	p. 83
References	p. 87
Supported Asymmetric Organocatalysis	p. 99
Introduction	p. 99
Polymer-Supported Organocatalysts	p. 99
Polymer-supported chiral amines for enamine and iminiun catalysis	p. 99
Polymer-supported phase transfer catalysts	p. 106
Polymer-supported phosphoric acid catalyst	p. 107
Miscellaneous	p. 108
Solid Acid-Supported Organocatalysis	p. 108
Polyoxometalate-supported chiral amine catalysts	p. 109
Solid sulfonic acid supported chiral amine catalysts	p. 110
Ionic Liquid-Supported Organocatalysts	p. 111
Magnetic Nanoparticle-Supported Organocatalysts	p. 119
Silica-Supported Asymmetric Organocatalysts	p. 119
Silica-supported proline and its derivatives	p. 120
Silica-supported MacMillan catalysts	p. 121
Other silica-supported organocatalysts	p. 122
Clay Entrapped Organocatalysts	p. 123
Miscellaneous	p. 124
Conclusion	p. 126
Acknowledgments	p. 126
References	p. 127
Fluorous Catalysis	p. 137
Introduction and the Principles of Fluorous Catalysis	p. 137
Ligands for Fluorous Transition Metal Catalysts	p. 142
Synthetic Application of Fluorous Catalysis	p. 142
Hydroformylation	p. 142
Hydrogenation	p. 147
Hydrosylilation	p. 150
Cross-coupling reactions	p. 154
Hydroboration	p. 161
Oxidation	p. 163
Esterification, transesterification and acetylation	p. 167
Other metal catalyzed carbon-carbon bond forming reactions	p. 168
Fluorous Organocatalysis	p. 174
References	p. 177
Solid-Supported Catalysis	p. 185
Introduction	p. 185
General Introduction	p. 185
The impact of solid-phase organic synthesis on green chemistry	p. 187
Immobilized Palladium Catalysts for Green Chemistry	p. 188
Introduction	p. 188
Suzuki reactions	p. 189
Heck-Mizoroki reactions in water	p. 193
Sonogashira reactions in water	p. 194
Tsuji-Trost reactions in water	p. 196
Immobilized Rhodium Catalysts for Green Chemistry	p. 197
Introduction	p. 197
Rhodium(II) carbenoid chemistry	p. 197
Rhodium (I)-catalyzed conjugate addition reactions	p. 198
Rhodium-catalyzed hydrogenation reactions	p. 198
Rhodium-catalyzed carbonylation reactions	p. 199
Immobilized Ruthenium Catalysts for Green Chemistry	p. 199
Introduction	p. 199
Ruthenium-catalyzed metathesis reactions	p. 199
Ruthenium-catalyzed transfer hydrogenation	p. 204
Ruthenium-catalyzed opening of epoxides	p. 206
Ruthenium-catalyzed cyclopropanation reactions	p. 206
Ruthenium-catalyzed halogenation reactions	p. 207
Other Immobilized Catalysts for Green Chemistry	p. 208
Immobilized cobalt catalysts	p. 208
Immobilized copper catalysts	p. 208
Immobilized iridium catalysts	p. 209
Conclusions	p. 210
References	p. 210
Biocatalysis	p. 217
Introduction	p. 217
Brief History of Biocatalysis	p. 217
Biocatalysis Toolboxes	p. 218
Enzymatic Synthesis of Pharmaceuticals	p. 218
Synthesis of atorvastatin and rosuvastatin	p. 219
Synthesis of b-lactam antibiotics	p. 222
Synthesis of glycopeptides	p. 225
Synthesis of tyrocidine antibiotics	p. 227
Synthesis of polyketides	p. 230
Synthesis of taxoids and epothilones	p. 231
Synthesis of pregabalin	p. 234
Summary	p. 237
Acknowledgment	p. 237
References	p. 237
Green Synthetic Techniques	p. 241
Green Solvents	p. 243
Introduction	p. 243
Origins of the Neoteric Solvents	p. 244
Ionic liquids	p. 244
Supercritical carbon dioxide	p. 245
Water	p. 245
Perfluorinated solvents	p. 246
Biosolvents	p. 246
Petroleum solvents	p. 247
Application of Green Solvents	p. 248
Synthetic organic chemistry overview	p. 248
Diels-Alder cycloaddition	p. 248
Cross-coupling	p. 250
Ring-closing metathesis	p. 253
Recapitulation and Possible Future Developments	p. 256
References	p. 257
Organic Synthesis in Water	p. 263
Introduction	p. 263
Pericyclic Reactions	p. 264
Passerini and Ugi Reactions	p. 268
Nucleophilic Ring-Opening Reactions	p. 269
Transition Metal Catalyzed Reactions	p. 271
Pericyclic reactions	p. 271
Addition reactions	p. 273
Coupling reactions	p. 274
Transition metal catalyzed reactions of carbenes	p. 279
Oxidations and reductions	p. 280
Organocatalytic Reactions	p. 283
Aldol reaction	p. 283
Michael addition	p. 284
Mannich reaction	p. 285
Cycloaddition reactions	p. 286
Miscellaneous	p. 288
Conclusion	p. 290
References	p. 291
Solvent-Free Synthesis	p. 297
Introduction	p. 297
Alternative Methods to Solution Based Synthesis	p. 300
Mortar and pestle	p. 300
Ball milling	p. 301
Microwave assisted solvent-free synthesis	p. 309
References	p. 318
Microwave Synthesis	p. 325
Introduction	p. 325
The Mechanism of Microwave Heating	p. 326
The Green Properties of Microwave Heating	p. 326
Green solvents	p. 326
Energy reduction	p. 328
Improved reaction outcomes resulting in less purification	p. 328
Microwaves versus Green Chemistry Principles	p. 329
Green Solvents in Microwave Chemistry	p. 329
Water	p. 329
Solventless reactions	p. 330
Ionic liquids	p. 331
Glycerol	p. 332
Catalysis	p. 333
Microwave assisted CH bond activation	p. 333
Microwave assisted carbonylation reactions	p. 334
Microwave Chemistry Scale-Up	p. 334
Flow microwave reactors	p. 335
Energy efficiency of large-scale microwave reactions	p. 336
Large-scale batch microwave reactors	p. 339
Future work in microwave scale-up	p. 340
Summary	p. 340
References	p. 341
Ultrasonic Reactions	p. 343
Introduction	p. 343
How Does Cavitation Work?	p. 344
Condensation Reactions	p. 345
Michael Additions	p. 348
Mannich Reactions	p. 349
Heterocycles Synthesis	p. 350
Coupling Reactions	p. 353
Miscellaneous	p. 358
Conclusions	p. 359
References	p. 359
Photochemical Synthesis	p. 363
Introduction	p. 363
Synthesis and Rearrangement of Open-Chain Compounds	p. 365
Synthesis of Three- and Four-Membered Rings	p. 370
Synthesis of three-membered rings	p. 370
Synthesis of four-membered rings	p. 372
Synthesis of Five-, Six (and Larger)-Membered Rings	p. 378
Synthesis of five-membered rings	p. 379
Synthesis of six-membered rings	p. 381
Synthesis of larger rings	p. 383
Oxygenation and Oxidation	p. 385
Conclusions	p. 387
Acknowledgment	p. 388
References	p. 388
Solid-Supported Organic Synthesis	p. 393
Introduction	p. 393
Techniques of Solid-Supported Synthesis	p. 394
General method of solid-supported synthesis	p. 394
Supports for supported synthesis	p. 395
Linkers for solid-supported synthesis	p. 398
Reaction monitoring	p. 401
Separation techniques	p. 402
Automation technique	p. 404
Split and combine (split and mix) technique	p. 405
Solid-Supported Heterocyclic Chemistry	p. 406
Multicomponent reaction	p. 406
Combinatorial library synthesis	p. 408
Diversity-oriented synthesis	p. 412
Multistep parallel synthesis	p. 412
Solid-Supported Natural Product Synthesis	p. 417
Total synthesis of natural product	p. 418
Synthesis of natural product-like libraries	p. 420
Synthesis of natural product inspired compounds	p. 421
Solid-Supported Synthesis of Peptides and Carbohydrates	p. 422
Solid-supported synthesis of peptides	p. 422
Solid-supported synthesis of carbohydrates	p. 424
Soluble-Supported Synthesis	p. 426
Poly(ethylene glycol)	p. 426
Linear polystyrene (LPS)	p. 427
Ionic liquids	p. 428
Multidisciplinary Synthetic Approaches	p. 429
Solid-supported synthesis and microwave synthesis	p. 429
Solid-supported synthesis under sonication	p. 431
Solid-supported synthesis in green media	p. 433
Solid-supported synthesis and photochemical reactions	p. 433
References	p. 434
Fluorous Synthesis	p. 443
Introduction	p. 443
"Heavy" versus "Light" Fluorous Chemistry	p. 443
Green Aspects of Fluorous Techniques	p. 444
Fluorous solid-phase extraction to reduce the amount of waste solvent	p. 444
Recycling techniques in fluorous synthesis	p. 444
Monitoring fluorous reactions	p. 446
Two-in-one strategy for using fluorous linkers	p. 448
Efficient microwave-assisted fluorous synthesis	p. 448
Atom economic fluorous multicomponent reactions	p. 451
Fluorous reactions and separations in aqueous media	p. 451
Fluorous Techniques for Discovery Chemistry	p. 451
Fluorous ligands for metal catalysis	p. 451
Fluorous organocatalysts for asymmetric synthesis	p. 451
Fluorous reagents	p. 453
Fluorous scavengers	p. 454
Fluorous linkers	p. 454
Conclusions	p. 465
References	p. 465
Reactions in Ionic Liquids	p. 469
Introduction	p. 469
Finding the Right Role for ILs in the Pharmaceutical Industry	p. 470
Use of ILs as solvents in the synthesis of drugs or drug intermediates	p. 470
Use of ILs for pharmaceutical crystallization	p. 472
Use of ILs in pharmaceutical separations	p. 472
Use of ILs for the extraction of drugs from natural products	p. 476
Use of ILs for drug delivery	p. 477
Use of ILs for drug detection	p. 478
ILs as pharmaceutical ingredients	p. 479
Conclusions and Prospects	p. 489
References	p. 490
Multicomponent Reactions	p. 497
Introduction	p. 497
Multicomponent Reactions in Aqueous Medium	p. 498
Multicomponent reactions are accelerated in water	p. 498
Multicomponent reactions "on water"	p. 500
Solventless Multicomponent Reactions	p. 503
Case Studies of Multicomponent Reactions in Drug Synthesis	p. 507
Schistosomiasis drug praziquantel	p. 507
Schizophrenia drug olanzapine	p. 509
Oxytocin antagonist GSK221149A	p. 510
Miscellaneous	p. 511
Perspectives of Multicomponent Reactions in Green Chemistry	p. 512
The union of multicomponent reactions	p. 512
Sustainable synthesis technology by multicomponent reactions	p. 515
Alternative solvents for green chemistry	p. 516
Outlook	p. 518
References	p. 518
Flow Chemistry	p. 523
Introduction	p. 523
Types of Flow Reactors	p. 525
Microreactors	p. 526
Miniaturized tubular reactors	p. 527
Spinning Disk Reactor (SDR)	p. 528
Spinning tube-in-tube reactor	p. 530
Heat exchanger reactors	p. 531
Application of Flow Reactors	p. 532
Prevention of waste and yield improvement	p. 532
Increase energy efficiency and minimize potential for accidents	p. 535
Use of heterogeneous catalysts and atom efficiency	p. 540
Use of supported reagents	p. 543
Photochemistry	p. 543
Conclusion	p. 544
Acknowledgment	p. 544
References	p. 545
Green Chemistry Strategies for Medicinal Chemists	p. 551
Introduction	p. 551
Historical Background: The Evolution of Green Chemistry in the Pharmaceutical Industry	p. 552
Green Chemistry in Process Chemistry, Manufacturing and Medicinal Chemistry and Barriers to Rapid Uptake	p. 553
Green Chemistry Activity Among PhRMA Member Companies	p. 554
Modeling Waste Generation in Pharmaceutical R&D	p. 555
Strategies to Reduce the Use of Solvents	p. 556
Green Reactions for Medicinal Chemistry	p. 558
Modeling Waste Co-Produced During R&D Synthesis	p. 560
Green Chemistry and Drug Design: Benign by Design	p. 562
Green Biology	p. 565
Conclusions and Recommendations	p. 565
References	p. 567
Green Techniques For Medicinal Chemistry	p. 571
The Business of Green Chemistry in the Pharmaceutical Industry	p. 573
Introduction	p. 573
Green Chemistry as a Business Opportunity	p. 574
The Need for Green Chemistry	p. 574
The Business Case for Green Chemistry Principles	p. 576
An Idea whose Time Has Arrived	p. 579
What Green Chemistry Is and What It Is Not	p. 582
Overcoming Obstacles to Green Chemistry	p. 583
Conclusion	p. 586
References	p. 586
Preparative Chromatography	p. 589
Introduction	p. 589
Preparative Chromatography for Intermediates and APIs	p. 590
Early discovery	p. 590
Clinical and commercial scale quantities	p. 590
Chiral separations	p. 591
Chromatography and the 12 Principles of Green Chemistry	p. 592
The 12 principles	p. 592
The metrics	p. 593
The impact of chromatography on the environment	p. 594
Overview of Chromatography Systems	p. 595
Chromatographic separation mechanisms	p. 595
Elution modes: isocratic versus gradient	p. 596
Batch chromatography	p. 596
Continuous chromatography	p. 598
Supercritical fluid chromatography	p. 600
Solvent Recycling	p. 601
Examples of Process Chromatography	p. 602
Early process development	p. 602
Implementation of SMB technology for chiral resolution	p. 603
Global process optimization: combining synthesis and impurity removal	p. 605
Chromatography versus crystallization to remove a genotoxic impurity	p. 607
SMB mining - recover product from waste stream	p. 608
Conclusions	p. 609
References	p. 610
Green Drug-Delivery Formulations	p. 613
Introduction and Summary	p. 613
Application of Green Chemistry in the Pharmaceutical Industry	p. 614
Need for Green Chemistry Technologies to Deliver Low-Solubility Drugs	p. 615
The need	p. 615
Characteristics of low-solubility drugs	p. 616
Low bioavailability	p. 616
SDD Drug-Delivery Platform	p. 617
Technology overview	p. 617
Polymer choice	p. 619
Process description	p. 620
Formulation description	p. 622
Dissolved drug	p. 622
Drug in colloids and micelles	p. 623
SDD efficacy	p. 623
In Vitro testing	p. 624
In Vivo testing	p. 624
Green Chemistry Advantages of SDD Drug-Delivery Platform	p. 625
Modeling	p. 625
Reduction in waste due to efficient screening	p. 626
Reduction of waste during manufacturing	p. 626
Reduction in waste due to nonprogression of candidates	p. 627
Reduction in waste due to lower dose requirements	p. 627
Reduction in amount of drug that enters the environment	p. 627
Calculated impact on waste reduction	p. 627
Conclusions	p. 628
Acknowledgments	p. 628
References	p. 628
Green Process Chemistry in the Pharmaceutical Industry: Recent Case Studies	p. 631
Introduction	p. 631
Sitagliptin: From Green to Greener; from a Catalytic Reaction to a Metal-Free Enzymatic Process	p. 632
Saxagliptin: Elimination of Toxic Chemicals and the Use of a Biocatalytic Approach	p. 637
Armodafinil: From Classical Resolution to Catalytic Asymmetric Oxidation to Maximize the Output	p. 639
Emend: Elimination of the Use of Tebbe Reagent for Pollution Prevention and Utilization of Catalytic Asymmetric Transfer Hydrogenation	p. 642
Greening a Process via One-pot or Telescoped Processing	p. 646
Greening a Process via Salt Formation	p. 651
Metal-free Organocatalysis: Applications of Chiral Phase-transfer Catalysis	p. 652
Conclusions	p. 653
References	p. 657
Green Analytical Chemistry	p. 659
Introduction	p. 659
Method Assessment	p. 660
Solvents and Additives for pH Adjustment	p. 661
Sample Preparation	p. 665
Techniques and Methods	p. 666
Screening methods	p. 666
Liquid chromatography	p. 667
Gas chromatography	p. 676
Supercritical fluid chromatography	p. 678
Chiral analysis	p. 679
Process analytical technology	p. 680
Conclusions	p. 681
Acknowledgments	p. 682
References	p. 682
Green Chemistry for Tropical Disease	p. 685
Introduction	p. 685
Interventions in Drug Dosing	p. 686
Dose reduction through innovative drug formulation	p. 686
Dose optimization: green dose setting	p. 687
Active Pharmaceutical Ingredient Cost Reduction with Green Chemistry	p. 688
Revision of the original manufacturing process	p. 688
Case studies: manufacture of drugs for AntiRetroviral therapy	p. 689
Case studies: Artemisinin combination therapies for malaria treatment	p. 695
Conclusions	p. 698
References	p. 698
Green Engineering in the Pharmaceutical Industry	p. 701
Introduction	p. 701
Green Engineering Principles	p. 702
Optimizing the use of resources	p. 702
Life cycle thinking	p. 706
Minimizing environment, health and safety hazards by design	p. 709
More Challenge Areas for Sustainability in the Pharmaceutical Industry	p. 709
Future Outlook and Challenges	p. 712
References	p. 712
Index
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