Synthesis and characterization of related substances of Azilsartan Kamedoxomil

Azilsartan Kamedoxomil is an AT1-subtype angiotensin II receptor blocker (ARB). During the laboratory synthesis of Azilsartan Kamedoxomil, four related substances of Azilsartan Kamedoxomil were observed and identified. These were 2-Ethoxy-3-[[4-[2- [4-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl]-5-oxo-1,2,4-oxadiazol-3-yl]phenyl]phenyl] methyl] benzimidazole-4-carboxylic acid (azilsartan N-medoxomil, 9), (5-methyl-2-oxo- 1,3-dioxol-4-yl)methyl 2-ethoxy-3-[[4-[2-[4-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl]-5- oxo-1,2,4-oxadiazol-3-yl]phenyl]phenyl] methyl] benzimidazole-4-carboxylate (azilsartan dimedoxomil, 10), (5-methyl-2-oxo-1,3-dioxo-4-yl)methyl 1-[2’-(4,5-dihydro-5-oxo-4H- 1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-2-methoxy-1H-benzimidazole-7-carboxylate (methoxy analogue of azilsartan medoxomil, 11), Methyl 1-((2’-amidobiphenyl-4-yl) methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylate (amide methyl ester, 12). The present work describes the origin, synthesis and characterization of these related substances.