奥美沙坦酯合成新方法研究
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摘要
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.
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.
引文
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[14]Hedvati L,Pilarsky G.Preparation of Olmesartan Medoxomil:WO,2006 029056[P].2006-03-16.
[15]Willam H,John R.Methods for triazole synthesis:US,20140171658[P].2012-06-19.
[16]Shigeo Y.Method for producing Olmesartan Medoxomil:US,8933241[P].2015-01-13.
[17]Philip K.Synthesis of Olmesartan Medoxomil[J].Synfacts,2015,11(12):1235.
[18]王鹏,曾苏.奥美沙坦酯的工艺改进[J].中国现代应用药学,2016,33(7):889-891.
[19]马其胜,李保琴,孙鹏.一种奥美沙坦酯关键中间体及奥美沙坦酯的制备方法:中国,105418593A[P].2015-11-25.
[20]樊珊珊,赵琳,张勇.奥美沙坦酯有关物质的合成[J].中国医药工业杂志,2014,45(11):1016-1018.
[21]Iwona D,Anna O,Maria P,et al.Synthesis and Physicochemical Characterization of the Process-Related Impurities of Olmesartan Medoxomil Do 5-(Biphenyl-2-yl)-1-triphenylmethyltetrazole Intermediates in Sartan Syntheses Exist?[J].Molecules,2015,20(12):21 346-21 363.
[2]Siragy HM.Angiotensin receptor blockers:how important is selectivity?[J].Am J Hypertens,2002,15(11):1006-1014.
[3]Zhuang R,Jin W,Wang X,et al.Identification and characterization of the druggable kinase targets of olmesartan and its analogues from a systematic kinase-chemical interaction profile in atherosclerosis[J].J Mol Graph Model,2018,80:211-216.
[4]Takai S,Jin D,Ikeda H,et al.Significance of angiotensinⅡreceptor blockers with high affinityto angiotensinⅡtype1 receptors for vascular protection in rats[J].Hypertens Res,2009,32(10):853-860.
[5]Schwocho L,Masonson H.Pharmacokinetics of CS-866,a new angiotensinⅡreceptor blocker,in healthy subjects[J].J Clin Pharmacol,2001,41(5):515-527.
[6]甘喜.奥美沙坦酯治疗轻中度原发性高血压的疗效及安全性研究[J].当代医学,2015,21(15):123-124.
[7]王秀菊.奥美沙坦酯治疗中度原发性高血压的效果研究[J].中西医结合心血管病杂志:电子版,2016,4(32):65-66.
[8]Kakio Y,Uchida H,Umebayashi R,et al.Practical efficacy of olmesartan versus azilsartan in patients with hypertension:a multicenter randomized-controlled trial(MUS-CAT-4 study)[J].Blood Pressure Monit,2017,22(2):59-67.
[9]Gorain B,Choudhury H,Tekade R,et al.Comparative biodistribution and safety profiling of olmesartan medoxomil oilin-water oral nanoemulsion[J].Regul Toxicol Pharmacol,2016,82:20-31.
[10]Yanagisawa H,Amemiya Y,Kanazaki T,et al.Nompeptide angiotensinⅡreceptor antagonists:synthesis,biological activities and structure-activity relationships o imidazlol-5-carboxylic acids bearing alkenyl,and hydroxyalkyl substituents at the 4-position and their related compound[J].J Med Chem,1996,39(1):323-338.
[11]Razzetti,Gabriele.A process for the preparation of phenyltetrazole compounds:EP,1905770[P].2008-02-04.
[12]Hedvati L,Pilarsky G.Process for the preparation of olmesartan Medoxomil:US,7528258[P].2012-05-05.
[13]石立平,傅志贤,尹晓龙,等.一种取代的四氮唑类化合物的制备方法:中国,102911129A[P].2013-02-06.
[14]Hedvati L,Pilarsky G.Preparation of Olmesartan Medoxomil:WO,2006 029056[P].2006-03-16.
[15]Willam H,John R.Methods for triazole synthesis:US,20140171658[P].2012-06-19.
[16]Shigeo Y.Method for producing Olmesartan Medoxomil:US,8933241[P].2015-01-13.
[17]Philip K.Synthesis of Olmesartan Medoxomil[J].Synfacts,2015,11(12):1235.
[18]王鹏,曾苏.奥美沙坦酯的工艺改进[J].中国现代应用药学,2016,33(7):889-891.
[19]马其胜,李保琴,孙鹏.一种奥美沙坦酯关键中间体及奥美沙坦酯的制备方法:中国,105418593A[P].2015-11-25.
[20]樊珊珊,赵琳,张勇.奥美沙坦酯有关物质的合成[J].中国医药工业杂志,2014,45(11):1016-1018.
[21]Iwona D,Anna O,Maria P,et al.Synthesis and Physicochemical Characterization of the Process-Related Impurities of Olmesartan Medoxomil Do 5-(Biphenyl-2-yl)-1-triphenylmethyltetrazole Intermediates in Sartan Syntheses Exist?[J].Molecules,2015,20(12):21 346-21 363.