Continuous Flow Synthesis of ACE Inhibitors From N‐Substituted l‐Alanine Derivatives

A strategy for the continuous flow synthesis of angiotensin converting enzyme (ACE) inhibitors is described. An optimization effort guided by in situ IR analysis resulted in a general amide coupling approach facilitated by N‐carboxyanhydride (NCA) activation that was further characterized by reaction kinetics analysis in batch. The three‐step continuous process was demonstrated by synthesizing 8 different ACE inhibitors in up to 88 % yield with throughputs in the range of ≈0.5 g h−1, all while avoiding both isolation of reactive intermediates and process intensive reaction conditions. The process was further developed by preparing enalapril, a World Health Organization (WHO) essential medicine, in an industrially relevant flow platform that scaled throughput to ≈1 g h−1. An “ACE” in the hole: A range of angiotensin converting enzyme inhibitors were synthesized in continuous flow using a single synthetic approach in good overall yields (see scheme). Utilization of in situ IR analysis facilitated a rapid development process and provided kinetic insight to the key amide coupling step across the set of important active pharmaceutical ingredients.