Synthesis Of Organic Impurities Of Anti-hypertensive Olmesartan Medoxomil

Olmesartan medoxomil is a new type of angiotensin II receptor antagonist approved by the FDA for the treatment of hypertension, which shows a very good therapeutic effect on the different style of hypertension diseases. However, some residual impurities can occur during the process of production and storage, which will directly or indirectly affect the purity and quality of this drug. Thereby, it must conduct qualitative and quantitative research on impurities of olmesartan medoxomil in order to ensure the safety of drug quality and patient. The main project of this work is to synthesize three known organic impurities of olmesartan medoxomil, namely: 4-(1-hydroxy-l-methylethyl)-2-propyl-l-[[2’-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-imidazole-5-carboxylic acid (Impurity A); 6,6-dimethyl-2-propyl-3-[[2’-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-3,6-dihydro-4H-furo[3,4-d]imidazol-4-one(Impu-rityB);(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl4-(1-methylethenyl)-2-propyl-1-[[2’-(1 H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-imidazole-5-carboxylate(Impurity C), that are used for drug quality control.In this work, impurity A, B and C have been successfully prepared by exploring and optimizing the literature synthetic routes. Impurity A was obtained directly by acidic removal of trityl protecting group. Impurity B was afforded by lactone cyclization followed by reaction with 4-[2-(1-trityl tetrazol-5-yl)phenyl] benzyl bromide involving N-alkylation. Impurity C was resulted by dehydration of tertiary alcohol and subsequent deprotection of trityl group. The target structures of three synthesized compounds have been unambiguously confirmed by comprehensive micro-analytical methods including IR, ESI-MS, NMR and HPLC etc.