Wydział Chemii

Iwona Dams

Agata Białońska

Piotr Cmoch

Małgorzata Krupa

Anita Pietraszek

Anna Ostaszewska

Michał Chodyński

2017

Molecules

22

1354/1-1354/26

10.3390/molecules22081354

Naukowa

Angielski

Artykuł

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.

selective aldosterone blocker, hypertension, steroids, eplerenone, impurities, spectroscopic methods, crystal structure

CC-BY

http://dx.doi.org/10.3390/molecules22081354

http://www.mdpi.com/journal/metals