Large Scale Synthesis of an Ampakine-type Active Pharmaceutical Ingredient Based on a Telescoped Regioselective Double Amidation Reaction

This work describes the process development and manufacture of an ampakine-type active pharmaceutical ingredient in clinical trials. A regioselective CDI-mediated amidation process was optimized for the subsequent couplings of two distinctive amines with a terephthalic acid substrate. Choice of the synthetic route, key scale-up issues, safety calorimetry, and optimization of all steps for multikilogram production are discussed.