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

Iwona Dams¹  Anna Ostaszewska¹  Maria Puchalska¹  Justyna Chmiel¹  Piotr Cmoch¹  Iwona Bujak¹  Agata Białońska²  Wojciech J. Szczepek¹ 

[1] Pharmaceutical Research Institute, Rydygiera 8, Warsaw 01-793, Poland;Faculty of Chemistry, University of Wrocław, Joliot-Curie 14, 50-383 Wrocław, Poland;

关键词: crystal structure;    impurities;    medoxomil;    NMR spectroscopy;    olmesartan;    prodrugs;    regioisomers;    sartans;    structure;    synthesis;   

DOI  :  10.3390/molecules201219762

来源: mdpi

【 摘 要 】

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.

【 授权许可】

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