{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T12:30:53Z","timestamp":1793449853598,"version":"4.5.0"},"reference-count":43,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2015,12,1]],"date-time":"2015-12-01T00:00:00Z","timestamp":1448928000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005632","name":"The National Centre for Research and Development","doi-asserted-by":"publisher","award":["INNOTECH-K1\/IN1\/14\/159003\/NCBR\/12"],"award-info":[{"award-number":["INNOTECH-K1\/IN1\/14\/159003\/NCBR\/12"]}],"id":[{"id":"10.13039\/501100005632","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>During the process development for multigram-scale synthesis of olmesartan medoxomil (OM), two principal regioisomeric process-related impurities were observed along with the final active pharmaceutical ingredient (API). The impurities were identified as N-1- and N-2-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl derivatives of OM. Both compounds, of which N-2 isomer of olmesartan dimedoxomil is a novel impurity of OM, were synthesized and fully characterized by differential scanning calorimetry (DSC), infrared spectroscopy (IR), nuclear magnetic resonance spectroscopy (NMR) and high-resolution mass spectrometry\/electrospray ionization (HRMS\/ESI). Their 1H, 13C and 15N nuclear magnetic resonance signals were fully assigned. The molecular structures of N-triphenylmethylolmesartan ethyl (N-tritylolmesartan ethyl) and N-tritylolmesartan medoxomil, the key intermediates in OM synthesis, were solved and refined using single-crystal X-ray diffraction (SCXRD). The SCXRD study revealed that N-tritylated intermediates of OM exist exclusively as one of the two possible regioisomers. In molecular structures of these regioisomers, the trityl substituent is attached to the N-2 nitrogen atom of the tetrazole ring, and not to the N-1 nitrogen, as has been widely reported up to the present. This finding indicates that the reported structural formula of N-tritylolmesartan ethyl and N-tritylolmesartan medoxomil, as well as their systematic chemical names, must be revised. The careful analysis of literature spectroscopic data for other sartan intermediates and their analogs with 5-(biphenyl-2-yl)tetrazole moiety showed that they also exist exclusively as N-2-trityl regioisomers.<\/jats:p>","DOI":"10.3390\/molecules201219762","type":"journal-article","created":{"date-parts":[[2015,12,1]],"date-time":"2015-12-01T10:26:58Z","timestamp":1448965618000},"page":"21346-21363","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Synthesis and Physicochemical Characterization of the Process-Related Impurities of Olmesartan Medoxomil. Do 5-(Biphenyl-2-yl)-1-triphenylmethyltetrazole Intermediates in Sartan Syntheses Exist?"],"prefix":"10.3390","volume":"20","author":[{"given":"Iwona","family":"Dams","sequence":"first","affiliation":[{"name":"Pharmaceutical Research Institute, Rydygiera 8, Warsaw 01-793, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Ostaszewska","sequence":"additional","affiliation":[{"name":"Pharmaceutical Research Institute, Rydygiera 8, Warsaw 01-793, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Puchalska","sequence":"additional","affiliation":[{"name":"Pharmaceutical Research Institute, Rydygiera 8, Warsaw 01-793, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justyna","family":"Chmiel","sequence":"additional","affiliation":[{"name":"Pharmaceutical Research Institute, Rydygiera 8, Warsaw 01-793, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8413-9290","authenticated-orcid":false,"given":"Piotr","family":"Cmoch","sequence":"additional","affiliation":[{"name":"Pharmaceutical Research Institute, Rydygiera 8, Warsaw 01-793, Poland"},{"name":"Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44\/52, 01-224 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iwona","family":"Bujak","sequence":"additional","affiliation":[{"name":"Pharmaceutical Research Institute, Rydygiera 8, Warsaw 01-793, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agata","family":"Bia\u0142o\u0144ska","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry, University of Wroc\u0142aw, Joliot-Curie 14, 50-383 Wroc\u0142aw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wojciech","family":"Szczepek","sequence":"additional","affiliation":[{"name":"Pharmaceutical Research Institute, Rydygiera 8, Warsaw 01-793, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2015,12,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1513","DOI":"10.1016\/S0140-6736(08)60655-8","article-title":"Global burden of blood-pressure-related disease, 2001","volume":"371","author":"Lawes","year":"2008","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1016\/S0140-6736(07)61299-9","article-title":"Essential hypertension","volume":"370","author":"Messerli","year":"2007","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"150S","DOI":"10.1016\/S0895-7061(99)00218-6","article-title":"Angiotensin II receptor blockade and end-organ protection","volume":"12","author":"Chung","year":"1999","journal-title":"Am. 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