Synthesis of the Hypoxia-Inducible Factor-2 α (HIF-2 α ) Inhibitor, 3-[(1 S ,2 S ,3 R )-2,3-Difluoro-1-hydroxy-7-methylsulfonylindan-4-yl]oxy-5-fluorobenzonitrile (PT2977, Belzutifan); Efficient Replication of Established Approaches.

A concise linear synthesis of hypoxia inducible factor-2 α (HIF-2 α ) inhibitor, belzutifan was achieved by reproducing key components of previous synthetic approaches to this molecule as described in several publications and patents. Belzutifan is an orally bioavailable small-molecule (HIF-2 α ) inhibitor for the treatment of von Hippel-Lindau (VHL) disease-associated renal cell carcinoma (RCC) that received FDA approval in 2021. Herein, we report a 13-step synthesis of PT2977 that proceeded in good overall yield with high diastereoselectivity. Separation of diastereomeric mixtures at two different stages of the synthesis proved advantageous in ease of separation. The X-ray structure of belzutifan was determined.