新型降压药替米沙坦合成的研究论文论文.pdf

沈阳药科大学硕士学位论文新型降压药替米沙坦的合成研究姓名:刘辉申请学位级别:硕士专业:药物化学指导教师:陈玉彬 20040501 沈阳药科大学硕士学位论文摘要摘要替米沙坦(Telmisartan,商品名:Micardis)为新一代苯并眯唑类血管紧张素Ⅱ受体拮抗剂,由德国Boehdnger Ingetheim公司研制,经美国FDA批准用于治疗原发性高血压。该药具有长效(每日一次)、耐受性好、受体选择性高等优点。本文重点对替米沙坦的合成进行了研究,并结合国内的原料供应情况, 对其合成工艺进行了考察和改进,-,经16步反应制得替米沙坦(1),其结构经1H-NMR、MS确证。该合成路线较适于工业化生产。由3·-氨基苯甲酸甲酯(6)(8),将缩环、水解两步反应“一勺烩”。本文所使用的工艺未见文献报道。在制各(6)的过程中对其后处理方法进行了改进。由(5)至(8)总收率(%)较文献报道收率(%)%。将制备中间体(9)的反应时间由20小时缩短为12小时。由中间体4。。(14)(16’),收率(92%)较文献制备4’.溴甲基联苯-(16) 收率(75%)提高17%,且简化了工艺,降低了生产成本。以中间体(16t)代替(16)制得目标产物替米沙坦(1),并对工艺方法进行改进,终产品(1)的粗品收率(%)较文献报道的最高收率(%) %。关键词:降压药;替米沙坦;血管紧张素1I受体拮抗剂;合成沈阳药科大学珂i士学位论文Abstract Abstract Telmisartan,as a new benzimidazol angiotensin II receptor antagonist,was developed byBoehringer Ingelheim ratified by FDA forantihypertensive,with thecharacterstics of10ng—lasting,good tolerance and high receptor—selectivity. Theproject aims to study synthesis acid and 3-methyl一4一nitrobenzoic acid as the starting material s, telmisartan was synthesized essfully via afifteen—step route with overall yields %.Its structure was identified by the data of1H-NMR and MS. Theintermediate(5)as the starting material,(8)was prepared by one—step reaction with the yield of %.This method has not been reported by prepare the intermediate(6),the procedure was improved and the yields was raised. To prepare theintermediate(9),we reduced the reaction time from 20h to 12h with the same yield. (16’)was made from(14)via two new method was simple and the yield was raised from 75%to 92%.Andtheintermediate(16’)as the starting material,telmisartan was yield of crude product was raised from %to %. Key words:Antihypertensive drug:Telmisartan; Angiotensin II receptor antagonists:Synthesis 2 沈阳药科大学硕士学位论文第一章绪论第一章绪论 。据统计,全世界约有十亿人患有高血压病。%,