Continuous Flow Synthesis of ACE Inhibitors From N‐Substituted l‐Alanine Derivatives
Abstract
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Oct 18, 2019
- Source ID
- 10.1002/chem.201904400
Entities
People
- Christopher P. Breen
- Timothy F. Jamison
Organizations
- Defense Advanced Research Projects Agency
- Massachusetts Institute of Technology