A commercial scale synthesis of the  beta-secretase-1 (BACE-1) inhibitor verubecestat (MK-8931) is described. A key bond disconnection in this manufacturing route is a copper-catalyzed cross coupling reaction between a primary amide and an aromatic bromide. During process development, variability in reaction profile was observed which provided the impetus to  investigate the reaction mechanism. Detailed NMR analysis provided insight into the root cause of the varibility and impurity formation  and led to an improved procedure that improved reaction robustness.

Development of a robust copper-catalyzed cross coupling enabling the synthesis of verubecestat

256th National Meeting (2018)

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