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

• Published in: Organic process research & development 2024-02, Vol.28 (2), p.404-412
• Main Authors: DiRocco, Daniel A., Zhong, Yong-Li, Le, Diane N., McCann, Scott D., Hethcox, J. Caleb, Kim, Jungchul, Kolev, Joshua N., Kosjek, Birgit, Dalby, Stephen M., McMullen, Jonathan P., Gangam, Rekha, Morris, William J.
• Format: Article
• Language: English
• ISSN: 1083-6160; 1520-586X
• DOI: 10.1021/acs.oprd.3c00408

An improved synthesis has been developed for belzutifan, a novel HIF-2α 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/α-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.