Peng F,
*,
Tan L.
*
et al.
Merck & Co. Inc., Rahway, USA
Manufacturing Process Development for Belzutifan, Part 1: A Concise Synthesis of the Indanone Starting Material.
Org. Process Res. Dev. 2022;
26: 508-515
DOI:
10.1021/acs.oprd.1c00236
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).
