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| List of Contributors | |
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| Introduction | |
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| Green Toxicology | |
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| Introduction | |
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| History and Scope of Toxicology | |
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| The need for green toxicology | |
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| Principles of Toxicology | |
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| Characteristics of exposure | |
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| Spectrum of toxic effects | |
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| The dose-response relationship | |
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| Disposition of Toxicants in Organisms | |
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| Absorption | |
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| Distribution | |
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| Metabolism | |
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| Excretion | |
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| Nonorgan System Toxicity | |
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| Carcinogenesis | |
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| Reproductive and developmental toxicity | |
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| Immunotoxicology | |
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| Mechanistic Toxicology | |
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| Quantitative Structure-Activity Relationships | |
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| Environmental Toxicology | |
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| Persistence and bioaccumulation | |
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| Risk Assessment | |
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| NonCancer risk assessment | |
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| Cancer risk assessment | |
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| Conclusions | |
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| References | |
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| Green Chemistry and the Pharmaceutical Industry | |
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| Introduction | |
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| Green Chemistry versus Sustainable Chemistry | |
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| Trend: The Ongoing Use of Hazardous Chemistry | |
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| Myth: To Do Green Chemistry One Must Sacrifice Performance and Cost | |
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| Green Chemistry and the Future of the Pharmaceutical Industry | |
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| Green Chemistry in Pharmaceutical Process Development and Manufacturing | |
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| Conclusions | |
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| References | |
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| Green Catalysis | |
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| Environmental Science and Green Chemistry; Guiding Environmentally Preferred Manufacturing, Materials, and Products | |
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| Introduction | |
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| Market Forces | |
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| Chemicals in the natural and human environment | |
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| Precautionary decision making | |
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| Chemical control laws | |
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| Green chemistry initiatives | |
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| Drug registration Environmental Risk Assessment (ERA) | |
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| Extended Producer Responsibility (EPR) | |
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| Ecosystem valuation | |
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| Company expectations | |
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| Public expectations | |
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| Environmental labeling, standards, and classification | |
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| Indicators (Attributes) of Environmental Performance | |
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| Environmental Impact | |
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| Strategic Approach to Greener Manufacturing Processes and Products | |
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| Manufacturing Process Improvements | |
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| Business and Professional Advantages from Manufacturing Process Improvements | |
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| Product Improvements | |
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| Environmental Decision Making | |
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| E-factor | |
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| Process Mass Intensity (PMI) | |
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| Life Cycle Assessment (LCA) | |
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| Individual company initiatives | |
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| Environmental (Ecological) Risk Assessment (ERA) | |
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| Alternatives Assessment (AA)/Chemical Alternatives Assessment (CAA) | |
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| Green Screen | |
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| iSUSTAINTM Green chemistry index | |
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| Computational Science and Quantitative Structure-Activity Relationships (QSARs) | |
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| Tiered testing | |
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| Databases and lists of chemicals | |
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| Case Study - Pharmaceuticals/Biologics | |
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| Pharmaceutical manufacturing | |
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| Pharmaceutical products | |
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| Case Study - Nanotechnology | |
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| Green Credentials and Environmental Standards | |
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| Inspiring Innovation - Academic and Industry Programs | |
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| Academic programs | |
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| Industry programs | |
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| Conclusions and Recommendations | |
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| References | |
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| Direct CH Bond Activation Reactions | |
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| Introduction | |
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| Homogeneous CH Activation by Metal Complex Catalysis | |
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| Pd-catalyzed carbon-carbon bond formations | |
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| Pd-catalyzed carbon-heteroatom bond formation | |
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| CH activation by other metals | |
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| Heterogeneous Catalytic Methods for CH Activation | |
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| Supported metal complexes | |
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| Supported metals | |
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| CH Activation by Organocatalysts | |
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| Enzymatic CH Activations | |
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| References | |
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| Supported Asymmetric Organocatalysis | |
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| Introduction | |
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| Polymer-Supported Organocatalysts | |
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| Polymer-supported chiral amines for enamine and iminiun catalysis | |
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| Polymer-supported phase transfer catalysts | |
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| Polymer-supported phosphoric acid catalyst | |
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| Miscellaneous | |
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| Solid Acid-Supported Organocatalysis | |
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| Polyoxometalate-supported chiral amine catalysts | |
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| Solid sulfonic acid supported chiral amine catalysts | |
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| Ionic Liquid-Supported Organocatalysts | |
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| Magnetic Nanoparticle-Supported Organocatalysts | |
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| Silica-Supported Asymmetric Organocatalysts | |
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| Silica-supported proline and its derivatives | |
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| Silica-supported MacMillan catalysts | |
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| Other silica-supported organocatalysts | |
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| Clay Entrapped Organocatalysts | |
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| Miscellaneous | |
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| Conclusion | |
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| Acknowledgments | |
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| References | |
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| Fluorous Catalysis | |
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| Introduction and the Principles of Fluorous Catalysis | |
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| Ligands for Fluorous Transition Metal Catalysts | |
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| Synthetic Application of Fluorous Catalysis | |
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| Hydroformylation | |
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| Hydrogenation | |
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| Hydrosylilation | |
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| Cross-coupling reactions | |
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| Hydroboration | |
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| Oxidation | |
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| Esterification, transesterification and acetylation | |
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| Other metal catalyzed carbon-carbon bond forming reactions | |
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| Fluorous Organocatalysis | |
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| References | |
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| Solid-Supported Catalysis | |
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| Introduction | |
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| General Introduction | |
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| The impact of solid-phase organic synthesis on green chemistry | |
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| Immobilized Palladium Catalysts for Green Chemistry | |
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| Introduction | |
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| Suzuki reactions | |
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| Heck-Mizoroki reactions in water | |
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| Sonogashira reactions in water | |
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| Tsuji-Trost reactions in water | |
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| Immobilized Rhodium Catalysts for Green Chemistry | |
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| Introduction | |
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| Rhodium(II) carbenoid chemistry | |
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| Rhodium (I)-catalyzed conjugate addition reactions | |
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| Rhodium-catalyzed hydrogenation reactions | |
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| Rhodium-catalyzed carbonylation reactions | |
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| Immobilized Ruthenium Catalysts for Green Chemistry | |
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| Introduction | |
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| Ruthenium-catalyzed metathesis reactions | |
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| Ruthenium-catalyzed transfer hydrogenation | |
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| Ruthenium-catalyzed opening of epoxides | |
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| Ruthenium-catalyzed cyclopropanation reactions | |
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| Ruthenium-catalyzed halogenation reactions | |
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| Other Immobilized Catalysts for Green Chemistry | |
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| Immobilized cobalt catalysts | |
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| Immobilized copper catalysts | |
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| Immobilized iridium catalysts | |
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| Conclusions | |
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| References | |
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| Biocatalysis | |
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| Introduction | |
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| Brief History of Biocatalysis | |
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| Biocatalysis Toolboxes | |
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| Enzymatic Synthesis of Pharmaceuticals | |
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| Synthesis of atorvastatin and rosuvastatin | |
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| Synthesis of b-lactam antibiotics | |
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| Synthesis of glycopeptides | |
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| Synthesis of tyrocidine antibiotics | |
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| Synthesis of polyketides | |
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| Synthesis of taxoids and epothilones | |
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| Synthesis of pregabalin | |
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| Summary | |
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| Acknowledgment | |
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| References | |
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| Green Synthetic Techniques | |
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| Green Solvents | |
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| Introduction | |
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| Origins of the Neoteric Solvents | |
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| Ionic liquids | |
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| Supercritical carbon dioxide | |
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| Water | |
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| Perfluorinated solvents | |
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| Biosolvents | |
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| Petroleum solvents | |
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| Application of Green Solvents | |
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| Synthetic organic chemistry overview | |
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| Diels-Alder cycloaddition | |
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| Cross-coupling | |
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| Ring-closing metathesis | |
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| Recapitulation and Possible Future Developments | |
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| References | |
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| Organic Synthesis in Water | |
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| Introduction | |
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| Pericyclic Reactions | |
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| Passerini and Ugi Reactions | |
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| Nucleophilic Ring-Opening Reactions | |
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| Transition Metal Catalyzed Reactions | |
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| Pericyclic reactions | |
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| Addition reactions | |
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| Coupling reactions | |
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| Transition metal catalyzed reactions of carbenes | |
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| Oxidations and reductions | |
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| Organocatalytic Reactions | |
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| Aldol reaction | |
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| Michael addition | |
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| Mannich reaction | |
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| Cycloaddition reactions | |
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| Miscellaneous | |
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| Conclusion | |
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| References | |
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| Solvent-Free Synthesis | |
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| Introduction | |
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| Alternative Methods to Solution Based Synthesis | |
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| Mortar and pestle | |
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| Ball milling | |
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| Microwave assisted solvent-free synthesis | |
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| References | |
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| Microwave Synthesis | |
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| Introduction | |
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| The Mechanism of Microwave Heating | |
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| The Green Properties of Microwave Heating | |
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| Green solvents | |
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| Energy reduction | |
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| Improved reaction outcomes resulting in less purification | |
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| Microwaves versus Green Chemistry Principles | |
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| Green Solvents in Microwave Chemistry | |
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| Water | |
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| Solventless reactions | |
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| Ionic liquids | |
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| Glycerol | |
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| Catalysis | |
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| Microwave assisted CH bond activation | |
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| Microwave assisted carbonylation reactions | |
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| Microwave Chemistry Scale-Up | |
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| Flow microwave reactors | |
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| Energy efficiency of large-scale microwave reactions | |
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| Large-scale batch microwave reactors | |
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| Future work in microwave scale-up | |
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| Summary | |
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| References | |
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| Ultrasonic Reactions | |
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| Introduction | |
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| How Does Cavitation Work? | |
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| Condensation Reactions | |
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| Michael Additions | |
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| Mannich Reactions | |
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| Heterocycles Synthesis | |
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| Coupling Reactions | |
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| Miscellaneous | |
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| Conclusions | |
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| References | |
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| Photochemical Synthesis | |
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| Introduction | |
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| Synthesis and Rearrangement of Open-Chain Compounds | |
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| Synthesis of Three- and Four-Membered Rings | |
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| Synthesis of three-membered rings | |
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| Synthesis of four-membered rings | |
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| Synthesis of Five-, Six (and Larger)-Membered Rings | |
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| Synthesis of five-membered rings | |
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| Synthesis of six-membered rings | |
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| Synthesis of larger rings | |
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| Oxygenation and Oxidation | |
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| Conclusions | |
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| Acknowledgment | |
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| References | |
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| Solid-Supported Organic Synthesis | |
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| Introduction | |
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| Techniques of Solid-Supported Synthesis | |
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| General method of solid-supported synthesis | |
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| Supports for supported synthesis | |
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| Linkers for solid-supported synthesis | |
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| Reaction monitoring | |
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| Separation techniques | |
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| Automation technique | |
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| Split and combine (split and mix) technique | |
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| Solid-Supported Heterocyclic Chemistry | |
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| Multicomponent reaction | |
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| Combinatorial library synthesis | |
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| Diversity-oriented synthesis | |
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| Multistep parallel synthesis | |
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| Solid-Supported Natural Product Synthesis | |
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| Total synthesis of natural product | |
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| Synthesis of natural product-like libraries | |
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| Synthesis of natural product inspired compounds | |
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| Solid-Supported Synthesis of Peptides and Carbohydrates | |
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| Solid-supported synthesis of peptides | |
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| Solid-supported synthesis of carbohydrates | |
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| Soluble-Supported Synthesis | |
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| Poly(ethylene glycol) | |
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| Linear polystyrene (LPS) | |
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| Ionic liquids | |
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| Multidisciplinary Synthetic Approaches | |
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| Solid-supported synthesis and microwave synthesis | |
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| Solid-supported synthesis under sonication | |
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| Solid-supported synthesis in green media | |
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| Solid-supported synthesis and photochemical reactions | |
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| References | |
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| Fluorous Synthesis | |
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| Introduction | |
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| "Heavy" versus "Light" Fluorous Chemistry | |
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| Green Aspects of Fluorous Techniques | |
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| Fluorous solid-phase extraction to reduce the amount of waste solvent | |
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| Recycling techniques in fluorous synthesis | |
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| Monitoring fluorous reactions | |
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| Two-in-one strategy for using fluorous linkers | |
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| Efficient microwave-assisted fluorous synthesis | |
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| Atom economic fluorous multicomponent reactions | |
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| Fluorous reactions and separations in aqueous media | |
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| Fluorous Techniques for Discovery Chemistry | |
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| Fluorous ligands for metal catalysis | |
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| Fluorous organocatalysts for asymmetric synthesis | |
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| Fluorous reagents | |
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| Fluorous scavengers | |
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| Fluorous linkers | |
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| Conclusions | |
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| References | |
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| Reactions in Ionic Liquids | |
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| Introduction | |
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| Finding the Right Role for ILs in the Pharmaceutical Industry | |
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| Use of ILs as solvents in the synthesis of drugs or drug intermediates | |
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| Use of ILs for pharmaceutical crystallization | |
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| Use of ILs in pharmaceutical separations | |
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| Use of ILs for the extraction of drugs from natural products | |
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| Use of ILs for drug delivery | |
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| Use of ILs for drug detection | |
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| ILs as pharmaceutical ingredients | |
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| Conclusions and Prospects | |
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| References | |
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| Multicomponent Reactions | |
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| Introduction | |
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| Multicomponent Reactions in Aqueous Medium | |
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| Multicomponent reactions are accelerated in water | |
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| Multicomponent reactions "on water" | |
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| Solventless Multicomponent Reactions | |
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| Case Studies of Multicomponent Reactions in Drug Synthesis | |
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| Schistosomiasis drug praziquantel | |
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| Schizophrenia drug olanzapine | |
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| Oxytocin antagonist GSK221149A | |
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| Miscellaneous | |
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| Perspectives of Multicomponent Reactions in Green Chemistry | |
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| The union of multicomponent reactions | |
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| Sustainable synthesis technology by multicomponent reactions | |
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| Alternative solvents for green chemistry | |
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| Outlook | |
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| References | |
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| Flow Chemistry | |
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| Introduction | |
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| Types of Flow Reactors | |
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| Microreactors | |
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| Miniaturized tubular reactors | |
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| Spinning Disk Reactor (SDR) | |
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| Spinning tube-in-tube reactor | |
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| Heat exchanger reactors | |
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| Application of Flow Reactors | |
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| Prevention of waste and yield improvement | |
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| Increase energy efficiency and minimize potential for accidents | |
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| Use of heterogeneous catalysts and atom efficiency | |
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| Use of supported reagents | |
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| Photochemistry | |
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| Conclusion | |
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| Acknowledgment | |
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| References | |
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| Green Chemistry Strategies for Medicinal Chemists | |
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| Introduction | |
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| Historical Background: The Evolution of Green Chemistry in the Pharmaceutical Industry | |
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| Green Chemistry in Process Chemistry, Manufacturing and Medicinal Chemistry and Barriers to Rapid Uptake | |
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| Green Chemistry Activity Among PhRMA Member Companies | |
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| Modeling Waste Generation in Pharmaceutical R&D | |
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| Strategies to Reduce the Use of Solvents | |
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| Green Reactions for Medicinal Chemistry | |
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| Modeling Waste Co-Produced During R&D Synthesis | |
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| Green Chemistry and Drug Design: Benign by Design | |
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| Green Biology | |
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| Conclusions and Recommendations | |
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| References | |
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| Green Techniques For Medicinal Chemistry | |
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| The Business of Green Chemistry in the Pharmaceutical Industry | |
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| Introduction | |
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| Green Chemistry as a Business Opportunity | |
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| The Need for Green Chemistry | |
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| The Business Case for Green Chemistry Principles | |
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| An Idea whose Time Has Arrived | |
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| What Green Chemistry Is and What It Is Not | |
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| Overcoming Obstacles to Green Chemistry | |
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| Conclusion | |
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| References | |
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| Preparative Chromatography | |
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| Introduction | |
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| Preparative Chromatography for Intermediates and APIs | |
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| Early discovery | |
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| Clinical and commercial scale quantities | |
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| Chiral separations | |
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| Chromatography and the 12 Principles of Green Chemistry | |
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| The 12 principles | |
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| The metrics | |
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| The impact of chromatography on the environment | |
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| Overview of Chromatography Systems | |
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| Chromatographic separation mechanisms | |
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| Elution modes: isocratic versus gradient | |
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| Batch chromatography | |
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| Continuous chromatography | |
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| Supercritical fluid chromatography | |
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| Solvent Recycling | |
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| Examples of Process Chromatography | |
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| Early process development | |
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| Implementation of SMB technology for chiral resolution | |
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| Global process optimization: combining synthesis and impurity removal | |
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| Chromatography versus crystallization to remove a genotoxic impurity | |
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| SMB mining - recover product from waste stream | |
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| Conclusions | |
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| References | |
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| Green Drug-Delivery Formulations | |
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| Introduction and Summary | |
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| Application of Green Chemistry in the Pharmaceutical Industry | |
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| Need for Green Chemistry Technologies to Deliver Low-Solubility Drugs | |
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| The need | |
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| Characteristics of low-solubility drugs | |
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| Low bioavailability | |
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| SDD Drug-Delivery Platform | |
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| Technology overview | |
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| Polymer choice | |
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| Process description | |
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| Formulation description | |
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| Dissolved drug | |
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| Drug in colloids and micelles | |
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| SDD efficacy | |
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| In Vitro testing | |
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| In Vivo testing | |
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| Green Chemistry Advantages of SDD Drug-Delivery Platform | |
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| Modeling | |
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| Reduction in waste due to efficient screening | |
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| Reduction of waste during manufacturing | |
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| Reduction in waste due to nonprogression of candidates | |
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| Reduction in waste due to lower dose requirements | |
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| Reduction in amount of drug that enters the environment | |
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| Calculated impact on waste reduction | |
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| Conclusions | |
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| Acknowledgments | |
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| References | |
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| |
| Green Process Chemistry in the Pharmaceutical Industry: Recent Case Studies | |
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| |
| Introduction | |
| |
| |
| |
| Sitagliptin: From Green to Greener; from a Catalytic Reaction to a Metal-Free Enzymatic Process | |
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| Saxagliptin: Elimination of Toxic Chemicals and the Use of a Biocatalytic Approach | |
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| |
| Armodafinil: From Classical Resolution to Catalytic Asymmetric Oxidation to Maximize the Output | |
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| |
| Emend: Elimination of the Use of Tebbe Reagent for Pollution Prevention and Utilization of Catalytic Asymmetric Transfer Hydrogenation | |
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| |
| Greening a Process via One-pot or Telescoped Processing | |
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| |
| Greening a Process via Salt Formation | |
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| |
| Metal-free Organocatalysis: Applications of Chiral Phase-transfer Catalysis | |
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| |
| |
| Conclusions | |
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| |
| References | |
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| |
| Green Analytical Chemistry | |
| |
| |
| |
| |
| Introduction | |
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| |
| Method Assessment | |
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| |
| Solvents and Additives for pH Adjustment | |
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| |
| Sample Preparation | |
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| |
| Techniques and Methods | |
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| |
| Screening methods | |
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| |
| Liquid chromatography | |
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| |
| Gas chromatography | |
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| |
| |
| Supercritical fluid chromatography | |
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| |
| |
| Chiral analysis | |
| |
| |
| |
| Process analytical technology | |
| |
| |
| |
| Conclusions | |
| |
| |
| Acknowledgments | |
| |
| |
| References | |
| |
| |
| |
| Green Chemistry for Tropical Disease | |
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| |
| |
| |
| Introduction | |
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| |
| |
| Interventions in Drug Dosing | |
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| |
| |
| Dose reduction through innovative drug formulation | |
| |
| |
| |
| Dose optimization: green dose setting | |
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| |
| |
| Active Pharmaceutical Ingredient Cost Reduction with Green Chemistry | |
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| |
| |
| Revision of the original manufacturing process | |
| |
| |
| |
| Case studies: manufacture of drugs for AntiRetroviral therapy | |
| |
| |
| |
| Case studies: Artemisinin combination therapies for malaria treatment | |
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| |
| |
| Conclusions | |
| |
| |
| References | |
| |
| |
| |
| Green Engineering in the Pharmaceutical Industry | |
| |
| |
| |
| |
| Introduction | |
| |
| |
| |
| Green Engineering Principles | |
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| |
| |
| Optimizing the use of resources | |
| |
| |
| |
| Life cycle thinking | |
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| |
| |
| Minimizing environment, health and safety hazards by design | |
| |
| |
| |
| More Challenge Areas for Sustainability in the Pharmaceutical Industry | |
| |
| |
| |
| Future Outlook and Challenges | |
| |
| |
| References | |
| |
| |
| Index | |