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 reactio...
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| Format: | Article |
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Wiley-VCH
2020
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| Online Access: | https://hdl.handle.net/1721.1/128240 |
| _version_ | 1811093824526614528 |
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| author | Breen, Christopher P. Jamison, Timothy F |
| author2 | Massachusetts Institute of Technology. Department of Chemistry |
| author_facet | Massachusetts Institute of Technology. Department of Chemistry Breen, Christopher P. Jamison, Timothy F |
| author_sort | Breen, Christopher P. |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T15:51:17Z |
| format | Article |
| id | mit-1721.1/128240 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T15:51:17Z |
| publishDate | 2020 |
| publisher | Wiley-VCH |
| record_format | dspace |
| spelling | mit-1721.1/1282402022-09-29T16:36:52Z Continuous Flow Synthesis of ACE Inhibitors From N-Substituted L-Alanine Derivatives Breen, Christopher P. Jamison, Timothy F Massachusetts Institute of Technology. Department of Chemistry 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. United States. Defense Advanced Research Projects Agency. Make-It Program (ARO W911NF-16-2-0023) 2020-10-29T14:50:22Z 2020-10-29T14:50:22Z 2019-10-18 Article http://purl.org/eprint/type/JournalArticle 0947-6539 https://hdl.handle.net/1721.1/128240 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) 10.1002/chem.201904400 Chemistry - A European Journal Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf Wiley-VCH Prof. Jamison |
| spellingShingle | Breen, Christopher P. Jamison, Timothy F Continuous Flow Synthesis of ACE Inhibitors From N-Substituted L-Alanine Derivatives |
| title | Continuous Flow Synthesis of ACE Inhibitors From N-Substituted L-Alanine Derivatives |
| title_full | Continuous Flow Synthesis of ACE Inhibitors From N-Substituted L-Alanine Derivatives |
| title_fullStr | Continuous Flow Synthesis of ACE Inhibitors From N-Substituted L-Alanine Derivatives |
| title_full_unstemmed | Continuous Flow Synthesis of ACE Inhibitors From N-Substituted L-Alanine Derivatives |
| title_short | Continuous Flow Synthesis of ACE Inhibitors From N-Substituted L-Alanine Derivatives |
| title_sort | continuous flow synthesis of ace inhibitors from n substituted l alanine derivatives |
| url | https://hdl.handle.net/1721.1/128240 |
| work_keys_str_mv | AT breenchristopherp continuousflowsynthesisofaceinhibitorsfromnsubstitutedlalaninederivatives AT jamisontimothyf continuousflowsynthesisofaceinhibitorsfromnsubstitutedlalaninederivatives |