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

molecules Article Synthesis and Physicochemical Characterization of the Process-Related Impurities of Eplerenone, an Antihypertensive Drug Iwona Dams 1,*, Agata Biało ńska 2, Piotr Cmoch 1, Małgorzata Krupa 1, Anita Pietraszek 1, Anna Ostaszewska 1 and Michał Chody ński 1 1 R&D Chemistry Department, Pharmaceutical Research Institute, Rydygiera 8, 01-793 Warsaw, Poland; [email protected] (P.C.); [email protected] (M.K.); [email protected] (A.P.); [email protected] (A.O.); [email protected] (M.C.) 2 Faculty of Chemistry, University of Wrocław, Joliot-Curie 14, 50-383 Wrocław, Poland; [email protected] * Correspondence: [email protected]; Tel.: +48-22-456-3929; Fax: +48-22-456-3838 Received: 28 July 2017; Accepted: 11 August 2017; Published: 15 August 2017 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. Keywords: selective aldosterone blocker; hypertension; steroids; eplerenone; impurities; spectroscopic methods; crystal structure 1. Introduction Eplerenone (2, Figure1) is a cardiovascular drug indicated for the treatment of essential hypertension and congestive heart failure that, in contrast to its predecessor spironolactone 1 (Figure1) demonstrates a high degree of selectivity for the aldosterone receptor and a low-binding affinity for progesterone and androgen receptors [1–8]. As a result of the presence of a 9,11-epoxide group in the eplerenone structure, its selectivity for the aldosterone receptor is enhanced and the drug minimizes the risk of adverse hormonal effects and provides important clinical benefits not previously available with spironolactone 1. Treatment with eplerenone is associated with reductions in blood pressure and improved survival (15% reduction in total mortality) for patients with heart failure who are in stable condition after a myocardial infarction. The product was originally developed by scientists at Molecules 2017, 22, 1354; doi:10.3390/molecules22081354 www.mdpi.com/journal/molecules Molecules 2017, 22, 1354 2 of 26 Molecules 2017, 22, 1354 2 of 26 Molecules 2017, 22, 1354 2 of 26 originally developed by scientists at Ciba-Geigy AG (Basel, Switzerland) and launched in the US in ® originally2003 by Pharmacia developed (Sandwich, by scientists Kent, at Ciba-GeigyUK) under theAG trade (Basel, name Switzerland) Inspra . and launched in the US in Ciba-Geigy AG (Basel, Switzerland) and launched in the US in 2003 by Pharmacia (Sandwich, Kent, 2003 by Pharmacia (Sandwich, Kent, UK) under the trade name Inspra®. UK) under the trade name Inspra®. Figure 1. Chemical structures of the aldosterone receptor antagonists spironolactone (Aldactone®, 1) Figureand eplerenone 1. Chemical (Inspra structures®, 2). of the aldosterone receptor antagonists spironolactone (Aldactone®, 1) Figure 1. Chemical structures of the aldosterone receptor antagonists spironolactone (Aldactone®, 1) and eplerenone (Inspra®, 2). and eplerenone (Inspra®, 2). Eplerenone contains sensitive 9,11α-epoxide, 17α-γ-lactone and 7α-carbomethoxy moieties that, Eplerenonedepending contains containson the sensitive sensitiveconditions, 9,11 9,11 αmay-epoxide,α-epoxide, hydrol 17 αyze17-γα-lactone -γor-lactone epimerize and and 7α-carbomethoxy 7toα -carbomethoxyafford degradation moieties moieties that, or dependingthat,epimerization depending on theproducts on conditions, the [9–13].conditions, may The hydrolyze SCXRDmay hydrol orstru epimerizectureyze orof toepimerizeeplerenone afford degradation toconfirms afford ordegradationthe epimerization relative cisor productsepimerizationconfiguration [9–13 ].productsof The the SCXRD 9[9–13].α,11 structureα-epoxide The SCXRD of ring eplerenone struandcture the confirms of7 αeplerenone-carbomethoxy the relative confirmscis substituentconfiguration the relative [14–17]. of thecis 9configurationManufactureα,11α-epoxide ofof ringeplerenone the and 9α the,11 is 7αα -epoxidealways-carbomethoxy accompaniedring and substituent theby side7α [14-carbomethoxy –reactions17]. 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[[17,18]17 of,18 the] fromfrom 11α Ciba-Geigy-hydroxyCiba-Geigy group AGAG accomplishedaccomplished[1,9,16–21]. thethe firstfirst synthesissynthesis ofof eplerenoneeplerenone 9(11) byby employingemployingIn 1984, Grob NagataNagata et al. hydrocyanationhydrocyanation [17,18] from Ciba-Geigy ofof DΔ9(11)-canrenone-canrenone AG accomplished ( (33)) as as the the the key first step synthesis (Scheme of 11), ),eplerenone butbut withwith moderatebymoderate employing stereoselectivitystereoselectivity Nagata hydrocyanation inin thethe 7 7αα-cyano-cyano of derivativeΔ derivative9(11)-canrenone4 4formation formation (3) as (7the (7α/7α key/7ββ≈ ≈step 4:1) (Scheme necessitating 1), but tedious with columnmoderatecolumn chromatographicchromatographic stereoselectivity in separations.separations. the 7α-cyano The The derivative original original 4EP EP formation 122232 122232 B1(7 B1α /7patent β ≈ 4:1) does necessitating not disclose tedious any informationcolumninformation chromatographic withwith respect respect to theseparations. to purity the of thepurityThe material original of obtained,the EP material122232 its purification B1 obtained, patent todoes pharmaceutical-gradeits notpurification disclose anyto orinformationpharmaceutical-grade the removal with of impurities. respect or the removalto the ofpurity impurities. of the material obtained, its purification to pharmaceutical-grade or the removal of

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