{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T22:31:12Z","timestamp":1777329072367,"version":"3.51.4"},"reference-count":35,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2017,8,15]],"date-time":"2017-08-15T00:00:00Z","timestamp":1502755200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Two unknown impurities were observed during the process development for multigram-scale synthesis of eplerenone (Inspra\u00ae). The new process-related impurities were identified and fully characterized as the corresponding (7\u03b2,11\u03b1,17\u03b1)-11-hydroxy- and (7\u03b1,11\u03b2,17\u03b1)-9,11-dichloroeplerenone derivatives 12a and 13. Seven other known but poorly described in the literature eplerenone impurities, including four impurities A, B, C and E listed in the European Pharmacopoeia 8.4 were also detected, identified and fully characterized. All these contaminants result from side reactions taking place on the steroid ring C of the starting 11\u03b1-hydroxy-7\u03b1-(methoxycarbonyl)-3-oxo-17\u03b1-pregn-4-ene-21,17-carbolactone (12) and the key intermediate (7\u03b1,17\u03b1)-9(11)-enester 7, including epimerization of the C-7 asymmetric center, oxidation, dehydration, chlorination and lactonization. The impurities were isolated and\/or synthesized and fully characterized by infrared spectroscopy (IR), nuclear magnetic resonance spectroscopy (NMR) and high-resolution mass spectrometry\/electrospray ionization (HRMS\/ESI). Their 1H- and 13C-NMR signals were fully assigned. The molecular structures of the eight impurities, including the new (7\u03b2,11\u03b1,17\u03b1)-11-hydroxy- and (7\u03b1,11\u03b2,17\u03b1)-9,11-dichloroeplerenone related substances 12a and 13, were solved and refined using single-crystal X-ray diffraction (SCXRD). The full identification and characterization of these impurities should be useful for the quality control and the validation of the analytical methods in the manufacture of eplerenone.<\/jats:p>","DOI":"10.3390\/molecules22081354","type":"journal-article","created":{"date-parts":[[2017,8,15]],"date-time":"2017-08-15T14:35:00Z","timestamp":1502807700000},"page":"1354","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Synthesis and Physicochemical Characterization of the Process-Related Impurities of Eplerenone, an Antihypertensive Drug"],"prefix":"10.3390","volume":"22","author":[{"given":"Iwona","family":"Dams","sequence":"first","affiliation":[{"name":"R&D Chemistry Department, Pharmaceutical Research Institute, Rydygiera 8, 01-793 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"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":[{"role":"author","vocabulary":"crossref"}]},{"given":"Piotr","family":"Cmoch","sequence":"additional","affiliation":[{"name":"R&D Chemistry Department, Pharmaceutical Research Institute, Rydygiera 8, 01-793 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ma\u0142gorzata","family":"Krupa","sequence":"additional","affiliation":[{"name":"R&D Chemistry Department, Pharmaceutical Research Institute, Rydygiera 8, 01-793 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anita","family":"Pietraszek","sequence":"additional","affiliation":[{"name":"R&D Chemistry Department, Pharmaceutical Research Institute, Rydygiera 8, 01-793 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Ostaszewska","sequence":"additional","affiliation":[{"name":"R&D Chemistry Department, Pharmaceutical Research Institute, Rydygiera 8, 01-793 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Micha\u0142","family":"Chody\u0144ski","sequence":"additional","affiliation":[{"name":"R&D Chemistry Department, Pharmaceutical Research Institute, Rydygiera 8, 01-793 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2017,8,15]]},"reference":[{"key":"ref_1","first-page":"488","article-title":"Eplerenone","volume":"24","author":"Rabasseda","year":"1999","journal-title":"Drugs Future"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1016\/S0022-3565(25)22580-0","article-title":"Three new epoxy-spirolactone derivatives: Characterization in vivo and in vitro","volume":"240","author":"Joss","year":"1987","journal-title":"J. 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