Belzutifan is a HIF-2α inhibitor used for the treatment of von Hippel-Lindau disease and associated renal cell carcinoma. The previous supply route to belzutifan had several drawbacks for long-term manufacturing. Owing to these limitations, we developed an improved third generation and convergent synthesis of belzutifan involving a new API step via nucleophilic aromatic substitution. The latter process suffered originally from reaction stalling despite the use of superstoichiometric amounts of phenol and prolonged reaction times. Through experimental and mechanistic studies, product inhibition was observed and rationalized. Herein, we describe our efforts to overcome this synthetic challenge and current ongoing efforts toward the synthesis of belzutifan.

Overcoming product inhibition: Synthesis of belzutifan via nucleophilic aromatic substitution

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ACS Fall 2022

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