Process Optimization of a Noyori Transfer Hydrogenation Utilizing a Quality-by-Design Approach: Development of a Robust Step in the Synthesis of Casdatifan

Abstract A key step in the manufacture of casdatifan involves a Noyori transfer hydrogenation of a stereochemically complex difluorodiketone 4 that establishes three contiguous stereocenters in a single transformation. Herein, we describe a systematic quality-by-design (QbD)-driven optimization of this reaction, involving risk assessment to identify critical process parameters, multivariate design of experiments to evaluate their effects, and targeted one-variable-at-a-time (OVAT) studies to further refine operating conditions. Implementation of the optimized, buffer-free conditions resulted in a robust process delivering 74–75% isolated yield with >99% high-performance liquid chromatography purity.