Development of a Continuous Flow Synthesis of Ezogabine: Process Optimization and Scale-Up

Ezogabine, a positive allosteric modulator of KCNQ2–5 used to treat epilepsy, was synthesized by a continuous flow hydrogenation process optimized to reduce the overall process and manufacturing mass intensity (PMI/MMI) of the corresponding batch scale procedure. The long reaction time observed in batch mode was streamlined via application of flow chemistry to less than 2 s in 2-MeTHF using Raney-Ni in a Phoenix Flow Reactor system. The continuous flow hydrogenation afforded ezogabine with 99.5% purity by HPLC with significantly reduced PMI (26) and equipment turnover time, thus providing the opportunity for substantial cost reductions relative to batch processing and greater alignment with green chemistry principles.