奥美沙坦酯合成新方法研究

Study on the new synthetic process for Olmesartan Medoxomil

目的研究血管紧张素Ⅱ受体拮抗剂奥美沙坦酯的合成方法。方法以二氨基马来腈(2)和原丁酸三甲酯为起始原料,经环合、水解、酯化、格氏反应,制得中间体4-(2-羟基-2-甲基乙基)-2-丙基-1H-咪唑-5-羧酸乙酯(6)。化合物6与N-三苯甲基-5-(4′-溴甲基联苯基-2-基)四氮唑(7)缩合后经水解、取代、脱保护3步反应制得目标化合物奥美沙坦酯。结果优化并确定了奥美沙坦酯的合成路线,总收率为34.9%(以二氨基马来腈计,文献中其收率为25.0%),纯度99.5%(采用高效液相色谱法的归一法检测),其结构经核磁共振氢谱和质谱等确证。结论该合成路线成本较低、操作简便、条件温和、收率高,具有工业化生产的潜力。

Objective To study the synthesis methods of angiotensin Ⅱ receptor antagonist olmesartan medoxomil.Methods Taking diaminomaleonitrile(2) and trimethyl orthobutyrate as starting materials to obtain intermediate Ethyl4-(1-hydroxy-1-methylethyl)-2-propyl-imidazole-5-carboxylate(6) through cyclization, hydrolysis, esterification and Grignard reaction. Then target compound olmesartan medoxomil was obtained through condensation between compound6 and N-(Triphenylmethyl)-5-(4′-Methylbiphenyl-2-yl)Tetrazole(7) which followed by three steps including hydrolysis, substitution and deprotection. Results Optimized and confirmed the synthesis routes of olmesartan medoxomil, the total yield was 34.9%(calculated by diaminomaleonitrile, the reported yield in literature was 25.0%) and the purity was99.5%(Normalization method of high performance liquid chromatography was used for detection). The chemical structure was characterized by nuclear magnetic resonance spectrometry and mass spectrometry. Conclusion The synthetic route has the advantages of low cost, simple operations, mild conditions and high yields, which make it more suitable for industrial production.