Four process-related potential new impurities in ticagrelor: Identification, isolation, characterization using HPLC, LC/ESI–MSn, NMR and their synthesis

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Graphical abstractHighlightsFour unknown process-related impurities in ticagrelor were detected by HPLC method.The structures of impurities were proposed by means of LC–MSn studies.The impurities were isolated by column chromatography and preparative HPLC.The proposed structures has been confirmed by MS, 1D&2D NMR and IR data.Prospects for impurities formation and their synthesis are first discussed.Five process-related impurities were detected in the range of 0.08-0.22% in ticagrelor laboratory batches by HPLC and LC–MS methods. These impurities were named as TIC Imp-I, -II, -III, -IV and -V. Four of these impurities, TIC Imp-I to -IV were unknown and have not been reported previously. Based on LC–ESI/MSn study, the chemical structures of new impurities were presumed as (1S,2S,3S,5S)-3-(2-hydroxyethoxy)-5-(7-amino-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d] pyrimidin-3-yl)cyclopentane-1,2-diol (TIC Imp-I), (1S,2S,3S,5S)-3-(7-((1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylsulfinyl)-3H-[1,2,3]triazolo [4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol (TIC Imp-II), (1S,2R,3S,4S)-4-(7-((1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)cyclopentane-1,2,3-triol (TIC Imp-III) and (3S,5S)-3-(7-((1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol (TIC Imp-IV). The unknown impurities were isolated from enriched crude sample by column chromatography and preparative HPLC. The complete spectral analysis, MS, 1D NMR (1H, 13C and DEPT), 2D NMR (HSQC and HMBC) and IR confirmed the proposed chemical structures of impurities. Identification, isolation, structural characterization, prospects for the formation of impurities and their synthesis were first reported in this paper.

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