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

• DOI: 10.1021/acs.oprd.3c00408
• Publication Date: 2024-02-05T17:28:33Z
• Authors: Daniel A. DiRocco; Yong-Li Zhong; Diane N. Le; Scott D. McCann; J. Caleb Hethcox; Jungchul Kim; Joshua N. Kolev; Birgit Kosjek; Stephen M. Dalby; Jonathan P. McMullen; Rekha Gangam; William J. Morris
• Keywords: Process development; Manufacturing process

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