【作者】 何永梁；

【导师】 高仁孝；

【作者基本信息】 西安建筑科技大学 ， 应用化学， 2009， 硕士

【摘要】 高血压是世界各国最常见的心血管疾病,目前全世界约有十亿人患有高血压病,我国是世界上高血压患者最多的国家。高血压病不仅是一个独立的疾病,同时可导致心、脑、肾、血管、眼底的结构和功能发生改变和损害,引起相关的疾病。高血压引起的并发症具有高度的致死率和致残率,给患者及其家人带来沉重的精神负担和经济负担。目前高血压病的治疗以药物治疗为主要手段,治疗高血压的药物分为六大类,其特点各异。其中,血管紧张素Ⅱ受体拮抗剂以其降压作用确切,不良反应轻微,具有广阔的应用前景。而血管紧张素Ⅱ受体拮抗剂中的厄贝沙坦其生物利用度最高,血浆半衰期长,是可以实现1日1次的长效抗高血压药物,而且没有活性代谢物,并能有效预防和逆转高血压所致的左心室肥厚,具有较大的研究意义。传统的合成厄贝沙坦的方法需使用有剧毒的氰化物,危害环境,不易大规模生产。而且在合成中间体2-丁基-1,3-二氮杂螺[4,4]壬-1-烯-4-酮时会产生其异构体2-丁基-1,3-二氮杂螺[4,4]壬-1-烯-8-酮,该物质参与下一步反应,形成杂质不易去除,影响产物纯度。本文提出了新的合成方法合成厄贝沙坦,本文提出的合成路线分两个阶段,第一阶段以甘氨酸为起始原料,经酯化、酰胺化、脱水、闭环,水解制得环亮氨酸盐酸盐。第二阶段以环亮氨酸盐酸盐为起始原料,经酰胺化、脱水缩合、偶联、与叠氮化钠反应制得厄贝沙坦。本文的合成方法避免了使用氰化物,且原料易得,单步反应收率高,产物易纯化。此外,在制备中间体2-丁基-1,3-二氮杂螺[4,4]壬-1-烯-4-酮时采用间接闭环,避免了异构体产生,反应条件温和,极大的缩短了闭环反应的时间。本文路线的总收率为17.22%,第一阶段制备环亮氨酸盐酸盐总收率为54.16%,若环亮氨酸盐酸盐能工业化生产,那么以环亮氨酸盐酸盐为起始原料制备厄贝沙坦总收率可达31.81%。更多还原

【Abstract】 Hypertension is a commonly and frequently encountered disease that severely endangered human health nowadays.There are about one billion people of the whole world suffering from this kind of disease and the number is increasing year by year. There are the most patients in our country.Hypertension is not only an independent disease,but also it can lead to the changes of structure and function in heart,brain, kidney,blood vessels,which could cause some related diseases.High rates of death and disability caused by complications of hypertension,which made patients and their families a heavy burden of spirit and financial.At present,the drug therapy is a primary means in the treatment of hypertension,which include six different kinds of drug categories.Because of its role in the exact step-down,minor adverse reactions, angiotensinⅡreceptor antagonist have broad application prospects.Irbesartan is the one of angiotensinⅡreceptor antagonist.It owns highest bioavailability,long plasma half-life,which can realize one time a day.There is no active metabolite and to be effective in preventing and reversal of hypertension-induced left ventricular hypertrophy,which has important practical significance.In the traditional method,it required the use of cyanide in the synthesis of Irbesartan.Cyanide is highly toxic,hazardous to the environment and not mass production.In the mean time,2-(n-Butyl) -1,3-diazaspiro[4,4]ono-1-ene-8-one would be produced,which is the isomer of 2-(n-Butyl) -1,3- diazaspiro[4,4]ono -1-ene-4-one.This by-product involved in the next step,which was difficult to be removed.This paper puts forward a new method of synthesis of irbesartan.The process includes two stages:first,glycine as the starting material,cycloleucine hydrochlorate was obtained by esterification,amidation,dehydration,a closed-loop and hydrolysis.And then,cycloleucine hydrochlorate as the starting material,the irbesartan was obtained by amidation,dehydration condensation,and coupled with the sodium azide.In this paper,the new synthesis method,it can not only avoid the use of cyanide,easy to get raw materials,high-yield of single-step reaction and easily purified,but also avoid the production of isomer,the mild rection conditions which can greatly shorten the time the cyclization reaction.In this paper,the total yield is 17.22%.The yield of first stage is 54.16%.If cycloleucine hydrochlorate could realize industrial production,the yield of Irbesartan will up to 31.81%.更多还原