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Synfacts 2022; 18(06): 0579
DOI: 10.1055/s-0041-1738315
Synthesis of Natural Products and Potential Drugs

Synthesis of Belzutifan

Contributor(s):
Philip Kocienski
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.
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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.


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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).


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Publication History

Article published online:
17 May 2022

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