新型苯并咪唑衍生物的合成研究

发布时间：2018-05-20 11:59

  本文选题：苯并咪唑 + 达比加群　； 参考：《长春工业大学》2017年硕士论文

【摘要】：苯并咪唑是一类含氮芳香杂环化合物,由苯环和咪唑环稠合而成,是一种重要的药效基团。苯并咪唑及其衍生物具有良好的生物活性和反应活性,在抗菌、抗癌、抗糖尿病、抗溃疡、抗高血压等方面均有广泛的应用,其合成研究具有深远的意义。最近的研究表明苯并咪唑及其衍生物具有良好的抗凝血活性,而其中达比加群酯作为新型凝血酶抑制剂具有抗凝效果可以预测、口服给药、无需临床检测、药物相互作用少等特点,应用前景广阔。然而,达比加群酯的口服生物利用度仅有7.2%,同时也存在出血、便秘、发热、恶心等不良反应。因此,对达比加群酯的合成方法及结构进行深入研究具有重要的研究价值。本论文以廉价且来源方便的4-甲氨基-3硝基苯甲酸为原料,改进了达比加群的合成工艺,并制备了三种苯并咪唑衍生物,深入探讨了每条合成路线的反应机理、成败原因,对各步中间体及产物的结构进行了核磁氢谱、核磁碳谱等表征。主要工作如下:1.4--31.以廉价且来源方便的4-甲氨基-3硝基苯甲酸为原料,通过酯化、还原、酰胺化、成环、成脒等反应对达比加群(N)的合成工艺进行了改进,使产率由文献中的12.5%提高到57.1%,同时反应具有条件温和、易操作等特点。2.以对氨基苯腈和4-甲氨基-3硝基苯甲酸为原料,通过酯化、还原、成环等反应合成了苯并咪唑衍生物2-(((4-氰基-苯基)氨基)甲基)-1-甲基-1H-苯并咪唑-5-甲酸乙酯(Ⅰ)。3.以达比加群关键中间体3-[(3-氨基-4-甲胺基苯甲酰基)(吡啶-2-基)氨基]丙酸乙酯(G)为原料合成苯并咪唑衍生物3-[[[2-(己氧基)羰基]氨基]甲基]-1-甲基-1H-苯并咪唑-5-基]羰基](吡啶-2-基)氨基]丙酸乙酯(Ⅱ),采用传统的酸高温回流条件没有成功,尝试微波催化关环的条件同样失败,探讨其反应机理。4.以达比加群和白藜芦醇为原料进行拼合来制备苯并咪唑衍生物(Ⅲ、Ⅳ),通过筛选连接基(丁二酸酐、丁二酸和对苯二甲酸等)进行模型反应,最终确定丁二酸酐为拼合反应连接基。
[Abstract]:Benzimidazole is a kind of nitrogen-containing aromatic heterocyclic compounds, which is composed of benzene ring and imidazole ring. Benzimidazole and its derivatives have been widely used in antibacterial, anti-cancer, anti-diabetes, anti-ulcer, anti-hypertension and so on. Recent studies have shown that benzimidazole and its derivatives have good anticoagulant activity, and the anticoagulant effect of dapidazole plus group ester as a new type of thrombin inhibitor can be predicted by oral administration without clinical detection. The drug interaction is less, so it has a wide application prospect. However, the oral bioavailability of Dabiganate was only 7.2, and there were also adverse reactions such as bleeding, constipation, fever, nausea and so on. Therefore, it is of great value to study the synthesis method and structure of Darby-group ester. In this paper, 4-methylamino -3 nitrobenzoic acid was used as raw material to improve the synthesis process of Darby addition group, and three kinds of benzimidazole derivatives were prepared. The reaction mechanism of each synthesis route and the reasons for success or failure were discussed. The structures of the intermediates and their products were characterized by nuclear magnetic hydrogen spectroscopy, nuclear magnetic carbon spectrum and so on. The main work is as follows: 1.4--31. In this paper, the synthetic process of 4-methylamino -3 nitrobenzoic acid was improved by esterification, reduction, amidation, cyclization, amidine formation, and so on, using cheap and convenient source of 4-methylamino -3 nitrobenzoic acid as raw material. The yield was increased from 12.5% in the literature to 57.1%, and the reaction was characterized by mild conditions and easy operation. Using p-aminobenzonitrile and 4-methylamino -3 nitrobenzoic acid as raw materials, the benzimidazole derivative 2-butadiene-4-cyano-phenyl) amino acid was synthesized by esterification, reduction and ring formation. Ethyl ester (鈪，

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