Application of C–H Functionalization in the Development of a Concise and Convergent Route to the Phosphatidylinositol-3-kinase Delta Inhibitor Nemiralisib
Robert N. Bream, Hugh Clark, Dean D. Edney, Antal Harsányi, John Hayler, Alan Ironmonger, Nadine Mc Cleary, Natalie A. Phillips, Catherine Priestley, Alastair J. Roberts, Philip J. Rushworth, Peter Szeto, Michael R. Webb, Katherine M. P. Wheelhouse
Abstract
This paper describes the development of an improved and scalable method for the manufacture of nemiralisib, a phosphatidylinositol-3-kinase delta inhibitor. Incorporation of three consecutive catalytic reactions, including a palladium-catalyzed C–H functionalization and an iridium-catalyzed borylation, significantly simplified and shortened the synthetic sequence. The revised route was successfully implemented in a pilot plant on a multikilogram scale to deliver >100 kg of product.
Topics & Concepts
PhosphatidylinositolCombinatorial chemistrySurface modificationBorylationCatalysisPalladiumIridiumChemistryStereochemistryKinaseOrganic chemistryBiochemistryArylAlkylPhysical chemistryCatalytic C–H Functionalization MethodsSynthesis and Catalytic ReactionsSulfur-Based Synthesis Techniques