The Synthesis Of A Novel Antihypertensive Drug Olmesartan Medoxomil

Objective To study methods of synthesis and efficient purification, which had a lower cost, a higher yield and a shorter production cycle, by the mothed of synthesize antihypertensive drug olmesartan medoxomil mildly and easily.Methods After screening of existing technologies, a suitable process route has been selected investigated and optimized. Taking the diaminomaleonitrile as the starting material, the olmesartan medoxomil was synthesized by the nine-step reaction, which contained dealcoholization, closed-loop, hydrolysis, esterification, Grignard reaction, N-alkylation, Alkaline hydrolyzation, O-alkylation and Acid hydrolyzation. The multi-step synthesis of olmesartan medoxomil intermediates has been improved. Taking 2, 3-diamino-maleic nitrile as the starting material, 2-propyl-imidazole-4, 5 - dicarboxylic acid (4) was synthesized by one- pot method that contained diaminomaleonitrile, closed-loop and hydrolysis. During the preparation, N, N-dimethylformamide (DMF) was used to as the solvent instead of acetonitrile and p-xylene. After the reaction completed, removed the DMF by vacuum distillation, and the hydrolysis has been done directly. The method above did not only simplify the technic, but also reduce the costs. It was alkaline hydrolysis reaction of synthesizing 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(1H-tetrazol-5-yl) phenyl ] phenyl } methyl imidazol-5-Carboxylic acid. The reaction conditions were optimized by single factor experiment. The results showed that it was an deal condition that the reactants reacted in the 10% sodium hydroxide solution at 40℃for 3 hours and reacted at room temperature for 10 ~12 hours. Under the conditions, the ester was hydrolyzed completely and the triphenylmethyl was removed infrequently. 4-[2-(trityl tetrazol-5-yl)phenyl]benzene methyl bromide took 4'-methyl-2-cyano biphenyl changed into tetrazole ring by the effect of Triethylamine hydrochloride and sodium azide, while a cycloaddition reaction occurred. The product reacted with 3-phenyl methyl bromide as a substitution reaction. Finally the target product has been synthesized by a bromination reaction with N-bromosuccinimide (NBS).The olmesartan medoxomil and intermediates were purified and refined by the methods of crystallization and recrystallization. the purity of the intermediates were assured. Results The olmesartan medoxomil was synthesized successfully, the synthesis of each intermediate has been optimized and improved. The yield is 42.0% (30.7% in references). The purity of olmesartan medoxomil, detected by HPLC, was 99.6%. There was only one impurity which percentage content was more than 0.1% (0.16%). The structures was identified by the data of IR,UV,1H-NMR,13C-NMR,MS,Organic elemental analysis and X-ray diffraction.Conclusions The mildly and easily synthesis process, which had a lower cost, a higher yield and a shorter production cycle, has been worked out. This synthesis process has huge value and suit for the industrial production.