Manufacturing Process Development for Belzutifan, Part 3: Completing a Streamlined Through-Process with a Safe and Scalable Oxidation
Zhiwei Chen, Nastaran Salehi Marzijarani, Scott Quirie, Gregory F. Pirrone, Stephen M. Dalby, Tao Wang, Jungchul Kim, Feng Peng, Adam J. Fine
Abstract
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.