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.

中文翻译：

---

依赖用途的钠通道阻滞剂Vixotrigine的合成。第1部分：开发批量供应路线以实现概念验证

报道了维托三嗪的两种合成。路线1（从药物化学路线改编而来）使得能够快速递送原料药用于临床开发。路线2是为解决​​路线1的许多限制而开发的，用于制造API的中试数量。路线1和2的关键特征是从（S焦谷氨酸衍生物并催化还原，将第二个立体异构中心引入具有高立体选择性的API中。路线2的开发旨在解决由于路线1中产生的“苯并衍生自”杂质而导致的纯化负担。改进的工艺消除了形成这些杂质的可能性，大大提高了在选择性取代环状亚胺中间体22时的立体选择性，并进行了中试工艺，大大提高了产量和产量。