Manufacturing Process Development for Belzutifan, Part 3: Completing a Streamlined Through-Process with a Safe and Scalable Oxidation

We report the development of a modified Kornblum oxidation mediated by 2-picoline N-oxide for the synthesis of belzutifan that circumvented safety and stench problems associated with the original clinical supply route conditions. A robust quench for the crude bromination stream with 1,3-dimethoxybenzene and 2,6-lutidine enabled a single-solvent through-process that avoided the isolation of a mutagenic intermediate and resulted in a significantly lower process mass intensity. A ternary-solvent, constant-volume distillation was then used to crystallize the ketone product directly from the reaction mixture.