Study On The Process Of Large-scale Production Of Olmesartan Medoxomil And Its Important Intermediates

This thesis includes two parts,the study on the large-scale production process of olmesartan medoxomil which is used in the treatment of hypertensions and improvement research on synthetic process of intermediate ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylate.First,comparing the current process of olmesartan medoxomil,olmesartan medoxomil was synthesized using the ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylate and 4-[2-(tri Phenyltetrazol-5-yl)phenyl] benzyl bromide as the starting material via "one-pot" method,in the acetone water system low temperature N-deprotection reaction.After purification with acetone,the purity of olmesartan medoxomil is more than 99%,the single impurity is less than 0.1%,the quality is better than EP standard,the total yield is more than 60%.The large-scale production process with stable product quality and yield was obtained by the optimization of the reaction conditions and the purification methods of the final product.Secondly,comparing the current process of ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylate,diethyl tartrate as starting material,1,3-Dibromo-5,5-dimethylhydantoin as oxidizing agent,ethyl(1-hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylate was obtained by oxidative reaction,cyclization reaction and grignard reaction,the total yield is more than 50%.Optimization of the synthesis reaction conditions make the reaction more moderate and reduce the generation of "three wastes".The improved post-treatment process makes the quality and yield of product greatly improved and the product HPLC purity is greater than 99%,which meets the production of olmesartan medoxomil quality requirements.