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Molecules 2017, 22(8), 1354; doi:10.3390/molecules22081354

Synthesis and Physicochemical Characterization of the Process-Related Impurities of Eplerenone, an Antihypertensive Drug

1
R&D Chemistry Department, Pharmaceutical Research Institute, Rydygiera 8, 01-793 Warsaw, Poland
2
Faculty of Chemistry, University of Wrocław, Joliot-Curie 14, 50-383 Wrocław, Poland
*
Author to whom correspondence should be addressed.
Received: 28 July 2017 / Accepted: 11 August 2017 / Published: 15 August 2017
(This article belongs to the Special Issue Medicinal Chemistry in Europe)

Abstract

Two unknown impurities were observed during the process development for multigram-scale synthesis of eplerenone (Inspra®). The new process-related impurities were identified and fully characterized as the corresponding (7β,11α,17α)-11-hydroxy- and (7α,11β,17α)-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 11α-hydroxy-7α-(methoxycarbonyl)-3-oxo-17α-pregn-4-ene-21,17-carbolactone (12) and the key intermediate (7α,17α)-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 (7β,11α,17α)-11-hydroxy- and (7α,11β,17α)-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. View Full-Text
Keywords: selective aldosterone blocker; hypertension; steroids; eplerenone; impurities; spectroscopic methods; crystal structure selective aldosterone blocker; hypertension; steroids; eplerenone; impurities; spectroscopic methods; crystal structure
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Dams, I.; Białońska, A.; Cmoch, P.; Krupa, M.; Pietraszek, A.; Ostaszewska, A.; Chodyński, M. Synthesis and Physicochemical Characterization of the Process-Related Impurities of Eplerenone, an Antihypertensive Drug. Molecules 2017, 22, 1354.

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