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Molecules 2015, 20(12), 21346-21363; doi:10.3390/molecules201219762

Synthesis and Physicochemical Characterization of the Process-Related Impurities of Olmesartan Medoxomil. Do 5-(Biphenyl-2-yl)-1-triphenylmethyltetrazole Intermediates in Sartan Syntheses Exist?

1
Pharmaceutical Research Institute, Rydygiera 8, Warsaw 01-793, Poland
2
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
3
Faculty of Chemistry, University of Wrocław, Joliot-Curie 14, 50-383 Wrocław, Poland
*
Author to whom correspondence should be addressed.
Academic Editor: Jean Jacques Vanden Eynde
Received: 23 October 2015 / Revised: 18 November 2015 / Accepted: 19 November 2015 / Published: 1 December 2015
(This article belongs to the Special Issue Prodrugs)
View Full-Text   |   Download PDF [2595 KB, uploaded 1 December 2015]   |  

Abstract

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. View Full-Text
Keywords: crystal structure; impurities; medoxomil; NMR spectroscopy; olmesartan; prodrugs; regioisomers; sartans; structure; synthesis crystal structure; impurities; medoxomil; NMR spectroscopy; olmesartan; prodrugs; regioisomers; sartans; structure; synthesis
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MDPI and ACS Style

Dams, I.; Ostaszewska, A.; Puchalska, M.; Chmiel, J.; Cmoch, P.; Bujak, I.; Białońska, A.; Szczepek, W.J. Synthesis and Physicochemical Characterization of the Process-Related Impurities of Olmesartan Medoxomil. Do 5-(Biphenyl-2-yl)-1-triphenylmethyltetrazole Intermediates in Sartan Syntheses Exist? Molecules 2015, 20, 21346-21363.

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