Versatile Construction of a 4-Substituted Piperidine by Continuous Preparation of a Complex Grignard and Addition to an In Situ Generated Pyridinium Species

Abstract

A robust and enabling synthesis of a sterically encumbered 4-substituted piperidine, a common motif in a novel KRAS G12C inhibitor series, was developed. It was discovered that the critical congested C–C bond could be forged by the regioselective addition of a functionalized Grignard reagent to an N-carbamyl pyridinium species. Kinetic studies demonstrated that the Grignard species was inherently unstable, leading to diminished yields in large-scale batch processes. A semicontinuous reactor train was developed to generate the Grignard continuously using a plug flow reactor, which flowed directly into a stirred reactor containing the preformed pyridinium species. This system was utilized to produce >100 g quantities of the Grignard adduct in a single operation, which could be converted to the desired 4-substituted piperidine in two additional steps. Further studies determined that regioselectivity was governed by the steric environment of the nucleophilic Grignard species.