Asymmetric Catalysis on Industrial Scale

HYDROGENATION OF A 2-ISOPROPYLCINNAMIC ACID DERIVATIVE EN ROUTE TO THE BLOOD PRESSURE-LOWERING AGENT ALISKIRENIntroductionDevelopment of Monodentate Phosphoramidites as Ligands for Asymmetric HydrogenationInstant Ligand Libraries of Monodentate BINOL-Based PhosphoramiditesAliskirenHigh-Throughput Screening in Search of a Cheap Phosphoramidite LigandMixtures of LigandsFurther Screening of ConditionsValidation and Pilot Plant RunInstant Ligand Library Screening to Further Optimize Rate and eeValidationsRecent Developments in the Asymmetric Hydrogenation of 3ConclusionASYMMETRIC PHASE-TRANSFER CATALYSIS FOR THE PRODUCTION OF NON-PROTEINOGENIC ALPHA-AMINO ACIDSBackgroundDesigner's Chiral Phase-Transfer CatalystsCynthesis of the C2-Symmetric Chiral Mono-1,1'-Binaphthyl-Derived CatalystApplication of Enantiomers of 21 to the Industrial Production of NPAAsConclusionDEVELOPMENT OF EFFICIENT TECHNICAL PROCESSES FOR THE PRODUCTION OF ENANTIOPURE AMINO ALCOHOLS IN THE PHARMACEUTICAL INDUSTRYIntroductionPhenylephrineAdrenaline (Epinephrine)LobelineAvailability of the CatalystGeneral Remarks on the Development of Industrial Processes for Asymmetric HydrogenationTHE ASYMMETRIC HYDROGENATION OF ENONES - ACCESS TO A NEW L-MENTHOL SYNTHESISIntroductionScreening of Metal Complexes, Conditions, and LigandsScale-Up and Mechanistic WorkCatalyst Recycling and Continuous ProcessingConclusionELIMINATING BARRIERS IN LARGE-SCALE ASYMMETRIC SYNTHESISIntroductionImprovement of the Synthetic Route to Biaryl LigandsDevelopment of an Efficient Process En Route to Unprotected Beta-Amino AcidsConclusionCATALYTIC ASYMMETRIC RING OPENING: A TRANSFER FROM ACADEMIA TO INDUSTRYIntroductionCatalyst Preparation and Initial OptimizationFurther OptimizationProcess AdaptationProtecting Group AdaptionUse of Benzoate as O-NucleophileChemical ElaborationConclusionASYMMETRIC BAEYER-VILLIGER REACTIONS USING WHOLE-CELL BIOCATALYSTSIntroductionChemistryBiocatalystsProcess Screening and DesignDownstream ProcessingFuture Process DevelopmentsPerspectiveLARGE-SCALE APPLICATIONS OF HYDROLASES IN BIOCATALYTIC ASYMMETRIC SYNTHESISIntroductionChemistryBiocatalystProcess Screening and DesignDownstream Processing and PurificationFuture Process DevelopmentsPerspectivesSCALE-UP STUDIES IN ASYMMETRIC TRANSFER HYDROGENATIONBackgroundReaction ComponentsCase StudiesConclusions2,2',5,5'-TETRAMETHYL-4,4'-BIS(DIPHENYLPHOSHINO)-3,3'-BITHIOPHENE: A VERY EFFICIENT CHIRAL LIGAND FOR RU-CATALYZED ASYMMETRIC HYDROGENATIONS ON THE MULTI-KILOGRAMS SCALEIntroductionCase HistoriesConclusionTHE POWER OF WHOLE-CELL REACTION: EFFICIENT PRODUCTION OF HYDROPYROLINE, SUGAR NUCLEOTIDES, OLIGOSACCHARIDES, AND DIPEPTIDESIntroductionProduction of Hydroxyproline by Asymmetric Hydroxylation of L-ProlineOligosaccharide Production by Bacterial CouplingDipeptide Production SystemsConclusion and PerspectiveENANTIOSELECTIVE KETONE HYDROGENATION: FROM RESEARCH TO PILOT SCALE WITH INDUSTRIALLY VIABLE RU/PHOSPHINE-OXAZOLINE) COMPLEXESIntroductionLigand Screening and Optimization of the Reaction ConditionsQuality RisksHealth and SafetyCatalyst RemovalFinal Process PART III: Processes for New Chemical Entities (NCEs)ENABLING ASYMMETRIC HYDROGENATION FOR THE DESIGN OF EFFICIENT SYNTHESIS OF DRUG SUBSTANCESIntroductionLaropiprantTaranabantSitagliptinConclusions and OutlookSCALE-UP OF A TELESCOPED ENZYMATIC HYDROLYSIS PROCESS FOR AN INTERMEDIATE IN THE SYNTHESIS OF A FACTOR Xa INHIBITORIntroductionThe Discovery Chemistry SynthesisOptimization and Multi-Kilogram Supply of Monoacid (R,R)-2Process Development of the N-Boc ApproachScalable Enzymatic Monohydrolysis of the Diester (R,R)-1Production - Experimental PartEvaluation of an Enzymatic Alternative - The N-Difluoroethyl ApproachDiscussionAN EFFICIENT, ASYMMETRIC SYNTHESIS OF ODANACATIB, A SELECTIVE INHIBITOR OF CATHEPSIN K FOR THE TREATMENT OF OSTEOPOROSIS, USING AN ENZYME-MEDIATED DYNAMIC KINETIC RESOLUTIONIntroductionFluoroleucine Synthesis StrategyFirst-Generation Enzymatic Dynamic Kinetic Resolution: Batch ProcessDevelopment of Enzymatic Dynamic Kinetic Resolution: Towards a Manufacturing ProcessPilot Plant RunsConclusionBIOCATALYTIC ROUTES TO THE GPIIb/IIIa ANTAGONIST LOTRAFIBAN, SB 214857IntroductionThe Medicinal Chemistry Route of SynthesisThe First Biocatalytic Route - A Late-Stage ResolutionEarly-Stage ResolutionCatalase for the Removal of IodideOther Synthetic Strategies to Chiral Lotrafiban IntermediatesThe End GameDISCOVERY AND DEVELOPMENT OF A CATALYTIC ASYMMETRIC CONJUGATE ADDITION TO KETOESTERS TO NITROALKENES AND ITS USE IN THE LARGE-SCALE PREPARATION OF ABT-546IntroductionRetrosynthetic Analysis of ABT-546Early Asymmetric SynthesesSynthesis of the Reaction PartnersDiscovery of the Asymmetric Conjugate Addition ReactionCompletion of the Synthesis of ABT-546Extension to Other Reaction PartnersConclusionTHE KAGAN OXIDATION - INDUSTRIAL-SCALE ASYMMETRIC SULFOXIDATIONS IN THE SYNTHESIS OF TWO RELATED NK1/NK2 ANTAGONISTSIntroductionBackground and Introduction to ZD7944Introduction to the ZD7944 CBz Sulfoxide StageProcess Development of ZD7944 CBz SulfoxideAdditional Investigations in the Development of ZD7944 CBz SulfoxideThe Impact of Other Stages on the ZD7944 CBz Sulfoxide ProcessSummary of ZD7944Background and Introduction to ZD2249Process Development of ZD2249 CBz SulfoxideSummary of ZD2249Comparison and ConclusionLARGE-SCALE APPLICATION OF ASYMMETRIC PHASE-TRANSFER CATALYSIS FOR AMINO ACID SYNTHESISIntroductionInitial StrategySynthesis of 4,4'-Difluorobenzylhydryl BromideInitial Studies and OptimizationScale-Up of the PTC AlkylationConclusionExperimentalAPPLICATION OF PHASE-TRANSFER CATALYSIS IN THE ORGANOCATALYTIC ASYMMETRIC SYNTHESIS OF AN ESTROGEN RECEPTOR BETA-SELECTIVE AGONISTIntroductionMedicinal Chemistry Synthesis and Revised Synthetic PlanPreparation of the Phase-Transfer Substrate 11Asymmetric Phase-Transfer Michael AdditionEther Cleavage, Cyclization, and ChlorinationConclusionASYMMETRIC SYNTHESIS OF HCVAND HPV DRUG CANDIDATES ON SCALE: THE CHOICE BETWEEN ENANTIOSELECTIVE AND DIASTEREOSELECTIVE SYNTHESESIntroductionGSK260983A (1) for the HPVGSK873082X (2) for the HCVConclusion