Multigram-Scale Synthesis of the Nav1.7 Inhibitor GDC-0310

This paper describes the development of an improved, practical, and scalable route for the multigram-scale synthesis of , a selective Nav1.7 inhibitor. The route was designed to avoid the carbon monoxide-mediated alkoxycarbonylation step used in the reported early development process and to provide practical access to both key fragments from readily available starting materials. The piperidine fragment was prepared through esterification, regioselective nucleophilic aromatic substitution, Suzuki coupling, and a one-pot deprotection/methyl esterification sequence. The chiral side-chain fragment was obtained from 1-(3,5-dichlorophenyl)ethanone by Corey–Bakshi–Shibata asymmetric reduction followed by mesylation. Key transformations, including Suzuki coupling, stereospecific -alkylation, and final amidation, were optimized to improve conversion, selectivity, and operational practicality. The developed process afforded in 23.5% overall yield with 99.71% purity by high-performance liquid chromatography. The structure of was confirmed by spectroscopic analysis, and selected intermediates were also characterized to support the reliability of the synthetic route.