Evolution of a Green and Sustainable Manufacturing Process for Belzutifan: Part 1-Process History and Development Strategy

An improved synthesis has been developed for belzutifan, a novel HIF-2 alpha inhibitor for the treatment of Von Hippel-Lindau (VHL) disease-associated renal cell carcinoma (RCC). The efficiency of previous supply and commercial routes was encumbered by a lengthy 5-step sequence, needed to install a chiral benzylic alcohol by traditional methods. Identification and directed evolution of FoPip4H, an iron/alpha-ketoglutarate dependent hydroxylase, enabled a direct enantioselective C-H hydroxylation of a simple indanone starting material. While this enabling transformation set the stage for a greatly improved synthesis, several other key innovations were made including the development of a base-metal-catalyzed sulfonylation, a KRED-catalyzed dynamic kinetic resolution, and a facile SNAr reaction in water. Together, these improvements resulted in a significantly shorter synthesis (9 steps) versus the supply route (16 steps) and a 75% reduction in process mass intensity (PMI), while also removing the reliance on third-row transition metals and toxic solvents.