{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T04:34:36Z","timestamp":1783139676034,"version":"3.54.6"},"reference-count":45,"publisher":"Wiley","issue":"64","license":[{"start":{"date-parts":[[2020,10,18]],"date-time":"2020-10-18T00:00:00Z","timestamp":1602979200000},"content-version":"am","delay-in-days":366,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#am"},{"start":{"date-parts":[[2019,10,18]],"date-time":"2019-10-18T00:00:00Z","timestamp":1571356800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000185","name":"Defense Advanced Research Projects Agency","doi-asserted-by":"publisher","award":["ARO W911NF-16-2-0023"],"award-info":[{"award-number":["ARO W911NF-16-2-0023"]}],"id":[{"id":"10.13039\/100000185","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Chemistry A European J"],"published-print":{"date-parts":[[2019,11,18]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>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 <jats:italic>N<\/jats:italic>\u2010carboxyanhydride (NCA) activation that was further characterized by reaction kinetics analysis in batch. The three\u2010step continuous process was demonstrated by synthesizing 8\u2005different ACE inhibitors in up to 88\u2009% yield with throughputs in the range of \u22480.5\u2005g\u2009h<jats:sup>\u22121<\/jats:sup>, 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 \u22481\u2005g\u2009h<jats:sup>\u22121<\/jats:sup>.<\/jats:p>","DOI":"10.1002\/chem.201904400","type":"journal-article","created":{"date-parts":[[2019,10,18]],"date-time":"2019-10-18T06:24:40Z","timestamp":1571379880000},"page":"14527-14531","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Continuous Flow Synthesis of ACE Inhibitors From N\u2010Substituted <scp>l<\/scp>\u2010Alanine Derivatives"],"prefix":"10.1002","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1762-5977","authenticated-orcid":false,"given":"Christopher P.","family":"Breen","sequence":"first","affiliation":[{"name":"Department of Chemistry Massachusetts Institute of Technology  77 Massachusetts Ave. Cambridge MA 02139 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8601-7799","authenticated-orcid":false,"given":"Timothy F.","family":"Jamison","sequence":"additional","affiliation":[{"name":"Department of Chemistry Massachusetts Institute of Technology  77 Massachusetts Ave. Cambridge MA 02139 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,10,18]]},"reference":[{"key":"e_1_2_2_1_1","unstructured":"\u00a0"},{"key":"e_1_2_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(14)61468-9"},{"key":"e_1_2_2_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMcp1613481"},{"key":"e_1_2_2_4_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1712231"},{"key":"e_1_2_2_5_1","unstructured":"S. G.Pal G. H.Madhav N. S.Purushottam(Lupin Ltd.) WO2005037788A1 2005."},{"key":"e_1_2_2_6_1","unstructured":"\u00a0"},{"key":"e_1_2_2_7_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.191908"},{"key":"e_1_2_2_8_2","unstructured":"M. A.Ondetti D. W.Cushman(E.\u2005R. Squibb & Sons Inc.) US4046889 1977;"},{"key":"e_1_2_2_9_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm00345a011"},{"key":"e_1_2_2_10_1","unstructured":"\u00a0"},{"key":"e_1_2_2_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/288280a0"},{"key":"e_1_2_2_12_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm00122a003"},{"key":"e_1_2_2_13_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm00105a066"},{"key":"e_1_2_2_14_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm00401a014"},{"key":"e_1_2_2_15_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm00127a033"},{"key":"e_1_2_2_16_2","first-page":"1399","volume":"34","author":"Teetz V.","year":"1984","journal-title":"Arzneimittelforschung"},{"key":"e_1_2_2_17_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm00389a006"},{"key":"e_1_2_2_18_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm00147a030"},{"key":"e_1_2_2_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0040-4039(00)60190-9"},{"key":"e_1_2_2_20_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm00160a026"},{"key":"e_1_2_2_21_2","first-page":"563","volume":"20","author":"Suh J. T.","year":"1985","journal-title":"Eur. J. Med. Chem."},{"key":"e_1_2_2_22_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm00372a022"},{"key":"e_1_2_2_23_2","doi-asserted-by":"publisher","DOI":"10.1039\/P19860001011"},{"key":"e_1_2_2_24_2","doi-asserted-by":"publisher","DOI":"10.1254\/jjp.48.349"},{"key":"e_1_2_2_25_2","unstructured":"M. A.Ondetti J.Krapcho(E.\u2005R. Squibb & Sons Inc.) US4316906 1982."},{"key":"e_1_2_2_26_1","unstructured":"S. M.Jennings(Warner-Lambert Company LLC) US2004019261A1 2004."},{"key":"e_1_2_2_27_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aax1566"},{"key":"e_1_2_2_28_1","unstructured":"\u00a0"},{"key":"e_1_2_2_29_2","doi-asserted-by":"publisher","DOI":"10.1002\/asia.201801488"},{"key":"e_1_2_2_30_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201807393"},{"key":"e_1_2_2_30_3","doi-asserted-by":"publisher","DOI":"10.1002\/ange.201807393"},{"key":"e_1_2_2_31_1","unstructured":"\u00a0"},{"key":"e_1_2_2_32_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.200600693"},{"key":"e_1_2_2_32_3","doi-asserted-by":"publisher","DOI":"10.1002\/ange.200600693"},{"key":"e_1_2_2_33_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja01566a035"},{"key":"e_1_2_2_34_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201803549"},{"key":"e_1_2_2_34_3","doi-asserted-by":"publisher","DOI":"10.1002\/ange.201803549"},{"key":"e_1_2_2_35_1","unstructured":"\u00a0"},{"key":"e_1_2_2_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ces.2014.04.036"},{"key":"e_1_2_2_37_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.iecr.5b01444"},{"key":"e_1_2_2_38_1","unstructured":"\u00a0"},{"key":"e_1_2_2_39_2","unstructured":"O. P.Goel U.Krolls(Warner-Lambert Company) US4761479 1988;"},{"key":"e_1_2_2_40_2","unstructured":"G.Kretz K.Rossen(Sanofi-Aventis) WO2014202659A1 2014;"},{"key":"e_1_2_2_41_2","unstructured":"G. R.Lalmani K.Sudhakar C. T.Rao T.Rajamannar(Sun Pharmaceuticals Ind. Ltd.) WO200706968 2007;"},{"key":"e_1_2_2_42_2","unstructured":"U.Yasuyoshi K.Koichi M.Tadashi Y.Yoshifumi F.Yoshihide(Kaneka Corp.) US6335453 2002."}],"container-title":["Chemistry \u2013 A European Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/chem.201904400","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/chem.201904400","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/am-pdf\/10.1002\/chem.201904400","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/chem.201904400","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T11:09:31Z","timestamp":1760267371000},"score":1,"resource":{"primary":{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/10.1002\/chem.201904400"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,10,18]]},"references-count":45,"journal-issue":{"issue":"64","published-print":{"date-parts":[[2019,11,18]]}},"alternative-id":["10.1002\/chem.201904400"],"URL":"https:\/\/doi.org\/10.1002\/chem.201904400","archive":["Portico"],"relation":{},"ISSN":["0947-6539","1521-3765"],"issn-type":[{"value":"0947-6539","type":"print"},{"value":"1521-3765","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,10,18]]},"assertion":[{"value":"2019-09-24","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-10-18","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}