發(fā)布時(shí)間：2018-05-20 11:59

  本文選題：苯并咪唑 + 達(dá)比加群��； 參考：《長(zhǎng)春工業(yè)大學(xué)》2017年碩士論文

【摘要】：苯并咪唑是一類含氮芳香雜環(huán)化合物,由苯環(huán)和咪唑環(huán)稠合而成,是一種重要的藥效基團(tuán)。苯并咪唑及其衍生物具有良好的生物活性和反應(yīng)活性,在抗菌、抗癌、抗糖尿病、抗?jié)�、抗高血壓等方面均有廣泛的應(yīng)用,其合成研究具有深遠(yuǎn)的意義。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,而其中達(dá)比加群酯作為新型凝血酶抑制劑具有抗凝效果可以預(yù)測(cè)、口服給藥、無需臨床檢測(cè)、藥物相互作用少等特點(diǎn),應(yīng)用前景廣闊。然而,達(dá)比加群酯的口服生物利用度僅有7.2%,同時(shí)也存在出血、便秘、發(fā)熱、惡心等不良反應(yīng)。因此,對(duì)達(dá)比加群酯的合成方法及結(jié)構(gòu)進(jìn)行深入研究具有重要的研究?jī)r(jià)值。本論文以廉價(jià)且來源方便的4-甲氨基-3硝基苯甲酸為原料,改進(jìn)了達(dá)比加群的合成工藝,并制備了三種苯并咪唑衍生物,深入探討了每條合成路線的反應(yīng)機(jī)理、成敗原因,對(duì)各步中間體及產(chǎn)物的結(jié)構(gòu)進(jìn)行了核磁氫譜、核磁碳譜等表征。主要工作如下:1.4--31.以廉價(jià)且來源方便的4-甲氨基-3硝基苯甲酸為原料,通過酯化、還原、酰胺化、成環(huán)、成脒等反應(yīng)對(duì)達(dá)比加群(N)的合成工藝進(jìn)行了改進(jìn),使產(chǎn)率由文獻(xiàn)中的12.5%提高到57.1%,同時(shí)反應(yīng)具有條件溫和、易操作等特點(diǎn)。2.以對(duì)氨基苯腈和4-甲氨基-3硝基苯甲酸為原料,通過酯化、還原、成環(huán)等反應(yīng)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.以達(dá)比加群關(guān)鍵中間體3-[(3-氨基-4-甲胺基苯甲�；�)(吡啶-2-基)氨基]丙酸乙酯(G)為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),采用傳統(tǒng)的酸高溫回流條件沒有成功,嘗試微波催化關(guān)環(huán)的條件同樣失敗,探討其反應(yīng)機(jī)理。4.以達(dá)比加群和白藜蘆醇為原料進(jìn)行拼合來制備苯并咪唑衍生物(Ⅲ、Ⅳ),通過篩選連接基(丁二酸酐、丁二酸和對(duì)苯二甲酸等)進(jìn)行模型反應(yīng),最終確定丁二酸酐為拼合反應(yīng)連接基。
[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，

本文編號(hào)：1914539