Manufacturing Process Development for Belzutifan, Part 2: A Continuous Flow Visible-Light-Induced Benzylic Bromination

Bottecchia, Cecilia; Lévesque, François; McMullen, Jonathan P.; Ji, Yining; Reibarkh, Mikhail; Peng, Feng; Tan, Lushi; Spencer, Glenn; Nappi, Jarod; Lehnherr, Dan; Narsimhan, Karthik; Wismer, Michael K.; Chen, Like; Lin, Yipeng; Dalby, Stephen M.

Manufacturing Process Development for Belzutifan, Part 2: A Continuous Flow Visible-Light-Induced Benzylic Bromination

By Bottecchia, Cecilia; Lévesque, François; McMullen, Jonathan P.; Ji, Yining; Reibarkh, Mikhail; Peng, Feng; Tan, Lushi; Spencer, Glenn; Nappi, Jarod; Lehnherr, Dan; Narsimhan, Karthik; Wismer, Michael K.; Chen, Like; Lin, Yipeng; Dalby, Stephen M.

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Published on CMKC

23 Jul 2024

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.

Journal

Organic Process Research & Development. Volume 26, 2022, 516–524

DOI

10.1021/acs.oprd.1c00240

Type of publication

Peer-reviewed journal

Affiliations

Merck & Co., Inc.
Shanghai SynTheAll Pharmaceutical Co. Ltd.

Article Classification

Research Article

Classification Areas

Intermediate