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 (e.g. DMF, DMAc, and NMP).
Subject(s)
Micelles , Water , Solvents , CatalysisABSTRACT
A robust and sustainable C(sp2)-C(sp3) cross-electrophile coupling was developed via nickel/copper synergistic catalysis under micellar conditions. This protocol provided a general method to access alkylated arenes with good to excellent yields on a very large scale.
