Synthesis of Belzutifan

Key words

belzutifan - dynamic kinetic resolution - photochemstry - halogenation - flow reaction - asymmetric synthesis

Significance

Belzutifan (MK-6482) is a selective hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor that was approved by the FDA in 2021 as a first-in-class treatment for renal-cell carcinoma. A manufacturing process for belzutifan is described in forensic detail in six back-to-back papers that have been conflated in the single scheme shown above.

Comment

Especially innovative steps in the synthesis are (1) the copper-catalyzed C,S-coupling, leading to sulfone E (Part 1); (2) the continuous-flow photochemical bromination of F under mild conditions (Part 2); (3) a Kornblum oxidation mediated by picoline N-oxide (Part 3); (4) a fluorination–DKR sequence that installs three contiguous stereogenic centers (Part 5).

Publication History

Article published online:
17 May 2022