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 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.

Automated summary

A detailed mechanistic understanding of the benzylic photobromination reaction has been achieved, revealing both ionic and radical pathways. The behavior of the major reaction species has been elucidated. This knowledge enabled the development of a robust photochemical continuous flow process for commercial manufacturing.