Manufacturing Process Development for Belzutifan, Part 2: A Continuous Flow Visible-Light-Induced Benzylic Bromination
Cecilia Bottecchia, François Lévesque, Jonathan P. McMullen, Yining Ji, Mikhail Reibarkh, Feng Peng, Lushi Tan, Glenn Spencer, Jarod Nappi, Dan Lehnherr, Karthik Narsimhan, Michael K. Wismer, Like Chen, Yipeng Lin, Stephen M. Dalby
Abstract
We report the development and scale-up of a continuous flow photochemical benzylic bromination en route to belzutifan (MK-6482), a small molecule for the treatment of renal cell carcinoma associated with Von Hippel–Lindau syndrome. Compared with the clinical supply route, the photochemical approach circumvents the need for azo radical initiators and proceeds at room temperature. Implementation of continuous flow technology allowed tight control of irradiation and residence time, resulting in a robust process with minimized byproduct formation. This method was selected for the manufacturing process for belzutifan and represents the first commercial continuous flow photochemical process in our company, laying the foundation for the utilization of photochemistry in the pharmaceutical industry.