Synthesis of Vixotrigine, a Use-Dependent Sodium Channel Blocker. Part 1: Development of Bulk Supply Routes to Enable Proof of Concept

Two syntheses of vixotrigine are reported. Route 1, adapted from the medicinal chemistry route, enabled rapid delivery of drug substance for clinical development. Route 2, which was developed to address many of the limitations of Route 1, was used to manufacture pilot quantities of API. Key features of Routes 1 and 2 are the generation of a chiral ketone intermediate from an (S)-pyroglutamic acid derivative and catalytic reduction to introduce the second stereogenic center into the API with high stereoselectivity. Route 2 was developed to address the purification burden attributable to "benzyne-derived" impurities generated in Route 1. The improved process eliminated the possibility of the formation of these impurities, substantially improved the stereoselectivity in the reduction of the alternate cyclic imine intermediate 22, and gave a pilot plant process with significantly enhanced yield and throughput.