Belzutifan (MK-6482) is an oral first-in-class selective inhibitor of hypoxia-inducible factor-2α (HIF-2α) from Merck. The original supply route to belzutifan had several drawbacks for long-term manufacturing. Owing to these limitations, we were able to develop a convergent synthesis of belzutifan involving a new API step via an S<sub>n</sub>Ar reaction. Through experimental and mechanistic studies, product inhibition was observed and rationalized. Herein, we describe our efforts toward the development of a green and sustainable manufacturing process for belzutifan.

Development of an ideal manufacturing route to HIF-2α inhibitor MK-6482

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