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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 | |
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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 | |
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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 | |
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Process analytical technology | |
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Conclusions | |
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Acknowledgments | |
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References | |
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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 | |
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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 | |
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Case studies: manufacture of drugs for AntiRetroviral therapy | |
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Case studies: Artemisinin combination therapies for malaria treatment | |
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Conclusions | |
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References | |
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Green Engineering in the Pharmaceutical Industry | |
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Introduction | |
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Green Engineering Principles | |
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Optimizing the use of resources | |
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Life cycle thinking | |
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Minimizing environment, health and safety hazards by design | |
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More Challenge Areas for Sustainability in the Pharmaceutical Industry | |
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Future Outlook and Challenges | |
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References | |
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Index | |