Continuous Flow Synthesis of ACE Inhibitors From N-Substituted L-Alanine Derivatives
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Continuous_Flow_Synthesis_of_ACE_Inhibitors_From_N‐Substituted_l‐Alanine_Derivatives.pdf
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1021.55 KB
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Author(s)
Breen, Christopher P.
Jamison, Timothy F
Date Issued
October 18, 2019
Journal
Chemistry - A European Journal
Publisher
Wiley-VCH
Citation
Breenand, Christopher P. and Timothy F. Jamison. “Continuous Flow Synthesis of ACE Inhibitors From N-Substituted L-Alanine Derivatives.” Chemistry - A European Journal, 25, 69 (October 2019) © 2019 The Author(s)
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.
MIT Department
Massachusetts Institute of Technology. Department of Chemistry
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