Manufacturing Process Development for Belzutifan, Part 5: A Streamlined Fluorination–Dynamic Kinetic Resolution Process
Tao Wang, Eric M. Phillips, Stephen M. Dalby, E. B. Sirota, Stephanus Axnanda, C. Scott Shultz, Pratiq A. Patel, Jacob H. Waldman, Embarek Alwedi, Xiao Wang, Kerstin Zawatzky, Matthew Chow, Nilusha Padivitage, Mark Weisel, Michael Whittington, Jianjun Duan, Taotao Lu
Abstract
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.
Topics & Concepts
Kinetic resolutionProcess engineeringProcess (computing)SelectfluorBiochemical engineeringProcess developmentChemistryComputer scienceEngineeringOrganic chemistryCatalysisEnantioselective synthesisOperating systemFluorine in Organic ChemistryAnalytical Chemistry and ChromatographyMass Spectrometry Techniques and Applications