Benzylic Photobromination for the Synthesis of Belzutifan: Elucidation of Reaction Mechanisms Using In Situ LED-NMR

A detailed mechanistic understanding of a benzylic photobromination en route to belzutifan (MK-6482, a small molecule for the treatment of renal cell carcinoma associated with von Hippel-Lindau syndrome) has been achieved using in situ LED-NMR spectroscopy in conjunction with kinetic analysis. Two d...

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Bibliographic Details
Published in:Journal of organic chemistry 2022-02, Vol.87 (4), p.2055-2062
Main Authors: Ji, Yining, Bottecchia, Cecilia, Lévesque, François, Narsimhan, Karthik, Lehnherr, Dan, McMullen, Jonathan P, Dalby, Stephen M, Xiao, Kai-Jiong, Reibarkh, Mikhail
Format: Article
Language:English
Subjects:
Carcinoma, Renal Cell - complications
Carcinoma, Renal Cell - pathology
Humans
Kidney Neoplasms - complications
Kidney Neoplasms - pathology
Kinetics
Magnetic Resonance Spectroscopy
von Hippel-Lindau Disease - complications
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Summary:A detailed mechanistic understanding of a benzylic photobromination en route to belzutifan (MK-6482, a small molecule for the treatment of renal cell carcinoma associated with von Hippel-Lindau syndrome) has been achieved using in situ LED-NMR spectroscopy in conjunction with kinetic analysis. Two distinct mechanisms of overbromination, namely, the ionic and radical pathways, have been revealed by this study. The behavior of the major reaction species, including reactants, intermediates, products, and side products, has been elucidated. Comprehensive understanding of both pathways informed and enabled mitigation of a major process risk: a sudden product decomposition. Detailed knowledge of the processes occurring during the reaction and their potential liabilities enabled the development of a robust photochemical continuous flow process implemented for commercial manufacturing.
ISSN:0022-3263
1520-6904
DOI:10.1021/acs.joc.1c01465