title: Synthesis and Physicochemical Characterization of the Process-Related Impurities of Olmesartan Medoxomil. Do 5-(Biphenyl-2-yl)-1-triphenylmethyltetrazole Intermediates in Sartan Syntheses Exist?
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, (13)C and (15)N 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.
authors.affiliation: Pharmaceutical Research Institute, Rydygiera 8, Warsaw 01-793, Poland. i.dams@ifarm.eu.
authors.forename: Iwona
authors.initials: I
authors.lastname: Dams
authors.affiliation: Pharmaceutical Research Institute, Rydygiera 8, Warsaw 01-793, Poland. a.ostaszewska@ifarm.eu.
authors.forename: Anna
authors.initials: A
authors.lastname: Ostaszewska
authors.affiliation: Pharmaceutical Research Institute, Rydygiera 8, Warsaw 01-793, Poland. m.puchalska@ifarm.eu.
authors.forename: Maria
authors.initials: M
authors.lastname: Puchalska
authors.affiliation: Pharmaceutical Research Institute, Rydygiera 8, Warsaw 01-793, Poland. j.chmiel@ifarm.eu.
authors.forename: Justyna
authors.initials: J
authors.lastname: Chmiel
authors.affiliation: Pharmaceutical Research Institute, Rydygiera 8, Warsaw 01-793, Poland. piotr.cmoch@icho.edu.pl.|Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland. piotr.cmoch@icho.edu.pl.
authors.forename: Piotr
authors.initials: P
authors.lastname: Cmoch
authors.affiliation: Pharmaceutical Research Institute, Rydygiera 8, Warsaw 01-793, Poland. i.bujak@ifarm.eu.
authors.forename: Iwona
authors.initials: I
authors.lastname: Bujak
authors.affiliation: Faculty of Chemistry, University of Wrocław, Joliot-Curie 14, 50-383 Wrocław, Poland. agata.bialonska@chem.uni.wroc.pl.
authors.forename: Agata
authors.initials: A
authors.lastname: Białońska
authors.affiliation: Pharmaceutical Research Institute, Rydygiera 8, Warsaw 01-793, Poland. w.szczepek@ifarm.eu.
authors.forename: Wojciech J
authors.initials: WJ
authors.lastname: Szczepek
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000032:analysis* / Q000138:chemical synthesis*; D002851:Chromatography, High Pressure Liquid; D004340:Drug Contamination; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D000068557:Olmesartan Medoxomil / Q000032:analysis* / Q000138:chemical synthesis*; D021241:Spectrometry, Mass, Electrospray Ionization; D013055:Spectrophotometry, Infrared; D013777:Tetrazoles / Q000737:chemistry*; D014961:X-Ray Diffraction
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D013777:Tetrazoles; D000068557:Olmesartan Medoxomil
keywords: NMR spectroscopy; crystal structure; impurities; medoxomil; olmesartan; prodrugs; regioisomers; sartans; structure; synthesis