Transition Metal-Catalyzed Couplings in Process Chemistry

Development Process Optimization Process Scale-up Recent Developments Conclusions COPPER-CATALYZED C - N COUPLING ON LARGE SCALE: AN INDUSTRIAL CASE STUDY Introduction Process Development of the C - N Bond Formation Choice of Catalytic System Choice of Base: Inorganic Versus Organic Choice of Solvent Optimized Conditions for C - N Bond Formation to 1 Purging Residual Copper from 1 Conclusions DEVELOPMENT OF A HIGHLY EFFICIENT REGIO- AND STEREOSELECTIVE HECK REACTION FOR THE LARGE-SCALE MANUFACTURE OF AN A4B2 NNR AGONIST Introduction Process Optimization Conclusions COMMERCIAL DEVELOPMENT OF AXITINIB (AG-013736): OPTIMIZATION OF A CONVERGENT PD-CATALYZED COUPLING ASSEMBLY AND SOLID FORM CHALLENGES Introduction First-Generation Synthesis of Axitinib Early Process Research and Development Commercial Route Development Conclusions LARGE-SCALE SONOGASHIRA COUPLING FOR THE SYNTHESIS OF AN MGLUR5 NEGATIVE ALLOSTERIC MODULATOR Introduction Background Process Development of the Sonogashira CouplingLarge-Scale Sonogashira Coupling and API Purification Conclusions PALLADIUM-CATALYZED BISALLYLATION OF ERYTHROMYCIN DERIVATIVES Introduction Discovery of 6,11-O,O-Bisallylation of Erythromycin DerivativesProcess Development of 6,11-O,O-Bisallylation of Erythromycin Derivatives Discovery and Optimization of 3,6-Bicyclolides Conclusions ROUTE SELECTION AND PROCESS DEVELOPMENT FOR THE VANILLOID RECEPTOR-1 ANTAGONIST AMG 517 Introduction Retrosynthesis and Medicinal Chemistry Route Optimization of Medicinal Chemistry Route Identification of the Process Chemistry Route Optimization of the Suzuki - Miyaura Reaction Postcampaign Improvements Summary TRANSITION METAL-CATALYZED COUPLING REACTIONS IN THE SYNTHESIS OF TARANABANT: FROM INCEPTION TO PILOT IMPLEMENTATIONIntroduction Development of Pd-Catalyzed Cyanations Development of Pd-Catalyzed Amidation ReactionsConclusions RING-CLOSING METATHESIS IN THE LARGE-SCALE SYNTHESIS OF SB-462795 Background The RCM Disconnection The RCM of Diene 5 DEVELOPMENT OF MIGITA COUPLINGS FOR THE MANUFACTURE OF A 5-LIPOXYGENASE INHIBITOR Introduction Evaluation of the Sulfur Source for Initial Migita Coupling Selection of Metal Catalyst and Coupling PartnersDevelopment of a One-Pot, Two-Migita Coupling Process Crystallization of 1 with Polymorph Control Final Commercial Process on Multikilogram Scale Conclusions PREPARATION OF 4-ALLYLISOINDOLINE VIA A KUMADA COUPLING WITH ALLYLMAGNESIUM CHLORIDE IntroductionKumada Coupling of 4-Bromoisoindoline WorkupIsolation ConclusionsMICROWAVE HEATING AND CONTINUOUS-FLOW PROCESSING AS TOOLS FOR METAL-CATALYZED COUPLINGS: PALLADIUM-CATALYZED SUZUKI - MIYAURA, HECK, AND ALKOXYCARBONYLATION REACTIONS Introduction Coupling Reactions Performed Using Microwave Heating or Continuous-Flow Processing ConclusionsAPPLYING THE HYDROPHOBIC EFFECT TO TRANSITION METAL-CATALYZED COUPLINGS IN WATER AT ROOM TEMPERATURE Introduction: the Hydrophobic Effect under Homogeneous and Heterogeneous Conditions Micellar Catalysis Using Designer Surfactants First Generation: PTS Heck Couplings in Water at rt Olefin Metathesis Going Green Adding Ammonia Equivalents onto Aromatic and Heteroaromatic RingsCouplings with Moisture-Sensitive Organometallics in Water A New, Third-Generation Surfactant: 'Nok' Summary, Conclusions, and a Look Forward LARGE-SCALE APPLICATIONS OF TRANSITION METAL REMOVAL TECHNIQUES IN THE MANUFACTURE OF PHARMACEUTICALS Introduction Methods that Precipitate or Capture/Extract the Metal while Maintaining the Coupling Product in SolutionMethods that Precipitate the Coupling Product while Purging the Metal to the FiltratesMiscellaneous Methods Other Methods for Metal Removal Conclusions INDEX