Improved Process for a Copper-Catalyzed C–N Coupling in the Synthesis of Verubecestat

Verubecestat is a β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor which was previously evaluated for the treatment of Alzheimer’s disease. The synthesis of verubecestat relies on a Cu-catalyzed carbon–nitrogen coupling. During process development, observations of impurity formation led to a more robust understanding of the catalyst. The transformation was discovered to be highly dependent on the ratio of ligand to substrate concentration during the course of the reaction. In-depth studies aimed at attaining mechanistic understanding provided an explanation of experimental findings and ultimately led to the identification of conditions that resulted in a more robust process.