【作者】 赵飞；

【导师】 朱锦桃； 江银枝；

【作者基本信息】 浙江理工大学 ， 有机化学， 2019， 硕士

【摘要】 随着生活水平的日趋提高,糖尿病的发病率不断上升,正逐渐成为导致人们死亡的主要杀手之一。目前有效的治疗手段主要依赖于口服药物,一些具有优良特性的新型降糖药物逐渐走进人们的视野。其中,利格列汀以其降糖效果好、不良反应少和肝肾功能不全患者也可正常服用等优点在降糖药市场中占有重要地位,其合成方法也引起了广大化学工作者的关注。其基础专利将于2023年到期。现有文献报道中的合成方法存在一些缺点和不足,因此有必要开发出更简便、更合理的适于工业化生产的合成工艺。本论文以合成利格列汀过程中涉及到的两个重要中间体2-氯甲基-4-甲基喹唑啉和8-溴-7-(2-丁炔基)-3,7-二氢-3-甲基-1H-嘌呤-2,6-二酮为出发点,对已有工艺进行了探讨改进并设计了新的合成路线,同时对每步的反应条件进行了优化,然后在此基础上完成对目标产物的合成工艺探究并优化反应条件。首先,以甲基脲为原料,与氰乙酸乙酯发生缩合环化,然后经亚硝化、还原、成环得到中间产物3-甲基黄嘌呤,最后经溴代、取代得到中间体8-溴-7-(2-丁炔基)-3,7-二氢-3-甲基-1H-嘌呤-2,6-二酮,六步总收率约41.2%。其次,以邻硝基苯甲酸为原料,经酰氯化、取代、水解、还原得到邻氨基苯乙酮,最后经成环反应得到中间体2-氯甲基-4-甲基喹唑啉,五步总收率约42.9%。此外,还重点对由邻硝基苯甲酸制备邻硝基苯乙酮的方法进行了深入的探究,改进后的收率显著提高;该方法具有一定的底物普适性,可用于制备许多不易得的苯乙酮类化合物。最后,将两个中间体进行取代反应,再经(R)-3-Boc-氨基哌啶取代,最后脱保护得到目标产物利格列汀,三步总收率约44.2%。目标产物以及所涉及的各种中间产物通过~1H NMR、IR以及MS进行了确证,所得谱图数据均符合相关化合物的结构特征。更多还原

【Abstract】 With the improvement of living standards,the incidence of diabetes is rising,and it is becoming one of the main killers leading to people’s death.At present,effective treatment methods mainly depend on oral medicines.Some new hypoglycemic drugs with excellent characteristics are gradually coming into people’s vision.Linagliptin plays an important role in the market of hypoglycemic drugs because of its good hypoglycemic effect,less adverse reactions and normal use of patients with liver and kidney dysfunction.The synthetic method of linagliptin has also attracted the attention of chemical workers.Its basic patent will expire in2023.There are some shortcomings in the synthetic methods reported in the literature,so it is necessary to develop a more simple and reasonable synthetic process suitable for industrial production.In this paper,starting from the synthesis of 2-chloromethyl-4-methylquinazoline and 8-bromo-7-(2-butyn-1-yl)-3,7-dihydro-3-methyl-1H-Purine-2,6-dione is a useful synthetic intermediate,two important intermediates involved in the synthesis of linagliptin.The existing process was improved and a new synthetic route was designed.At the same time,the reaction conditions of each step were optimized.And on this basis,the synthesis process of the target product was explored and the reaction conditions were optimized.Firstly,methyl urea was used as raw material to condensate and cyclize with ethyl cyanoacetate,then 3-methylxanthine was obtained by nitrification,reduction and cyclization.Finally,8-bromo-7-(2-butyn-1-yl)-3,7-dihydro-3-methyl-1H-Purine-2,6-dione was obtained by bromination and substitution.The total yield of six steps is about 41.2%.Secondly,o-aminoacetophenonewas synthesized from o-nitrobenzoic acid by acyl chlorination,substitution,hydrolysis and reduction.Finally,2-chloromethyl-4-methylquinazoline was synthesized by cyclization.The total yield of five steps is about 42.9%.In addition,the method of preparing o-nitroacetophenone from o-nitrobenzoic acid has been deeply explored.The yield of the improved method has been significantly improved.The method has certain substrate universality and can be used for preparing many acetophenone compounds which are not easy to obtain.Finally,the two intermediates were subjected to a substitution reaction,followed by substitution with(R)-3-Boc-aminopiperidine,and the target product linagliptin was obtained.The total yield of three steps is about 44.2%.The target products and the intermediates involved were confirmed by~1H NMR,IR and MS.The obtained spectra were consistent with the structural characteristics of the related compounds.更多还原