Manufacturing Process Development for Belzutifan, Part 5: A Streamlined Fluorination–Dynamic Kinetic Resolution Process

Here we report the fluorination–dynamic kinetic resolution (DKR) process for the commercial supply of belzutifan (MK-6482). Key process safety and robustness issues in the Selectfluor fluorination reaction were identified and addressed on the basis of increased mechanistic understanding. Aggressive process optimization enabled a single-pot direct isolation process that allowed delivery of the fluorodiol product with low process mass intensity.