Structural elucidation of impurities in 5-n-butyl-4-{4-[2-(1H-tetrazole-5-yl)-1H-pyrrol-1-yl]phenylmethyl}-2,4-dihydro-2-(2,6-dichlorophenyl)-3H-1,2,4-triazol-3-one (Ib), a novel nonpeptide angiotensin AT1 receptor antagonist

5-n-butyl-4-{4-[2-(1H-tetrazole-5-yl)-1H-pyrrol-1-yl]phenylmethyl}-2,4-dihydro-2-(2,6-dichlorophenyl)-3H-1,2,4-triazol-3-one (Ib), a new nonpeptide angiotensin AT1-receptor antagonist, has been observed to play a positive role in the treatment of hypertension in preclinical tests. Four process impurities of Ib were detected by LC-UV and LC/ESI-MS, and the impurities isolated by preparative HPLC chromatography were characterized by LC-MS/MS, high resolution MS (HRMS), NMR and IR analyses. The structures of impurities were confirmed as 5-n-butyl-4-{4-[2-chloro-5-(1H-tetrazole5-yl)-1H-pyrrol-1-y]phenylmethyl}-2,4-dihydro-2-(2,6-dichlorophenyl)-3H-1,2,4-triazol-3-one (I), 5-n-butyl-4-{4-[2-bromo-5-(1H-tetrazole-5-yl)-1H-pyrrol-1-yl]phenylmethyl}-2,4-dihydro-2-(2,6-dichlorophenyl)-3H-1,2,4-triazol-3-one (II), 5-n-butyl-4-{4-[4-chloro-2-(1H-tetrazole-5-yl)-1H-pyrrol-1-yl]phenylmethyl}-2,4-dihydro-2-(2,6-dichlorophenyl)-3H-1,2,4-triazol-3-one (III) and 5-n-butyl-4-{4-[4-bromo-2-(1H-tetrazole-5-yl)-1H-pyrrol-1-yl]phenylmethyl}-2,4-dihydro-2-(2,6-dichlorophenyl)-3H-1,2,4-triazol-3-one (IV), respectively. All of the four impurities were produced as the by-products of the bromination reaction by NBS (N-bromosuccinimide) in the synthesis of Ib. (C) 2012 Elsevier B.V. All rights reserved.