Implementation of micelle-enabled C(sp²)–C(sp³) cross-electrophile coupling in pharmaceutical synthesis

Abstract

A sustainable C(sp²)-C(sp³) cross-electrophile coupling was developed between readily available 5-bromophthalide and 1-benzyl-4-iodopiperidine under micellar conditions, leading to a key intermediate of one of our development compounds. Copper was found to play a crucial role as a co-catalyst in this dual catalysis system. The chemistry and process were successfully demonstrated in a kilo scale to deliver sufficient drug substance to the clinical campaigns. This is the first reported scale-up of such a challenging cross-electrophilic coupling that uses an aqueous medium, and not undesirable reprotoxic polar aprotic solvents (<i>e.g.</i> DMF, DMAc, and NMP).