Identification, isolation, and synthesis of seven novel impurities of anti‐diabetic drug Repaglinide

Seven unknown impurities in Repaglinide bulk drug batches at below 0.1% (ranging from 0.05 to 0.10%) were detected by an ultra‐performance liquid chromatographic (UPLC) method. These impurities were isolated from the crude sample of Repaglinide using preparative high performance liquid chromatography (prep‐HPLC). Based on liquid chromatography‐electrospray ionization‐mass spectrometry (LC‐ESI/MS) study, the chemical structures of seven new impurities (8, 9, 10, 11, 13, 14, and 16) were presumed and characterized as 4‐(cyanomethyl)‐2‐ethoxybenzoic acid (8), 4‐(cyanomethyl)‐2‐ethoxy‐N‐(3‐methyl‐1‐(2‐(piperidin‐1‐yl)phenyl)butyl)benzamide (9), 4‐(2‐amino‐2‐oxoethyl)‐2‐ethoxy‐N‐(3‐methyl‐1‐(2‐(piperidin‐1‐yl)phenyl)butyl) benzamide (10) and 2‐(3‐ethoxy‐4‐((3‐methyl‐1‐(2‐(piperidin‐1‐yl)phenyl)butyl) carbamoyl) phenyl) acetic acid (11) and 4‐(cyanomethyl)‐N‐cyclohexyl‐2‐ethoxybenzamide (13), 2‐(4‐(cyclohexylcarbamoyl)‐3‐ethoxyphenyl) acetic acid (14) and N‐cyclohexyl‐4‐(2‐(cyclohexylamino)‐2‐oxoethyl)‐2‐ethoxybenzamide (16). The complete spectral analysis, proton nuclear magnetic resonance (1H NMR), 13C NMR, MS, and infrared (IR) confirmed the proposed chemical structures of impurities. Identification, structural characterization, formation, and their synthesis was first reported in this study. The impurity 11 was crystallized and structure was solved by single crystal X‐ray diffraction. Copyright © 2017 John Wiley & Sons, Ltd. Seven unknown impurities in repaglinide 1 bulk drug batches at below 0.1 level were detected by an ultra performance liquid chromatographic (UPLC) method. The spectral analysis e.g. 1H NMR, 13C NMR, MS and IR confirmed the proposed chemical structures of impurities. Identification, complete characterization data and their synthesis were reported for the first time.