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摘要：达比加群酯是最前沿的新一代口服抗凝药物直接凝血酶抑制剂(DTIs)，针对急性和慢性血栓栓塞性疾病的预防及治疗这一急需满足的临床需求。3-[[[2-[[(4-氰基苯基)氨基]甲基]-1-甲基-1H-苯并咪唑-5-基]羰基](吡啶-2-基)氨基]丙酸乙酯是达比加群酯的重要中间体，本论文对该中间体的合成进行了研究。本文第一步先通过氨基酸制备成酰氯，然后与A1（4-甲胺基-3-硝基苯甲酸）反应，得到A2 (3-[(4-甲胺基-3-硝基苯甲酰基)(吡啶-2-基)氨基]丙酸乙酯），产率为78%，进行优化选取50℃的反应温度，使用三乙胺做反应缚酸剂，反应时间为48 h。第二步以A2为原料，通过在高压釜中加入乙酸乙酯、钯碳(Pd/C)，得到A3（3-[(3-氨基-4-甲胺基苯甲酰基)(吡啶-2-基)氨基] 丙酸乙酯），产率为82%，优化选择了70℃为反应温度，氢气压力为0.3 MPa，并使用全新的钯碳。第三步以A3与B1(2-((4-苯腈)氨基)乙酸)为原料，进行反应，得到最终产物达比加群酯中间体AB（3-[[[2-[[(4-氰基苯基)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），产率为77%，优化选择了60℃的反应温度，N,N'-羰基二咪唑(CDI)当量为1.8。三步反应总产率为49%，产物经HPLC检测，纯度为99.4%。27753
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毕业论文关键词：达比加群酯；中间体；合成
Synthesis of dabigatran intermediates
Abstract：Dabigatran etexilate is the latest generation of oral anticoagulants direct thrombin inhibitor(DTIs), clinical needs of acute and chronic thromboembolic disease prevention and treatment of the urgent need. 3 - [[[2 - [[(4-cyanophenyl) amino] methyl] -1-methyl -1H- benzimidazol-5-yl] carbonyl] (pyridin-2-yl) amino] propionic ethyl are important intermediates of dabigatran etexilate. In this paper, the synthetic intermediates were studied. The first step is to synthesize chloride by amino acid. And then reacted with A1 (4- methylamino-3-nitrobenzoic acid) to give A2 (3 - [(4- methylamino-3-nitrobenzoyl) (pyridin-2-yl) amino] propanoate). The yield was 78%. The reaction temperature is at 50℃ and use the triethylamine to do the acid binding agent. The reaction time is reach in 48 h and the thionyl chloride is added over 1 h. A2 as a raw material in the second step, by adding ethyl acetate and Pd / C in an autoclave and to give A3 (3 - [(3- amino-4-methylamino-benzoyl) (pyridin-2-yl) amino] propanoate). The yield was 82%. The reaction temperature is at 70℃ and the hydrogen pressure of 0.3 MPa with Pd/C. The third step is the A3 and B1 (2 - ((4- benzonitrile) amino) acetic acid) as starting material in the reaction. Then to give the condensation product AB (3 - [[[2 - [[(4- cyanophenyl) amino] methyl] -1-methyl -1H- benzimidazol-5-yl] carbonyl] (pyridin-2-yl) amino] propanoate). The yield was 77%. The reaction temperature is at 60℃ and CDI equivalent to 1.8. The total yield in three steps is 49%. The product has been tested and purity of 99.4% by HPLC.
KeyWords: Dabigatran etexilate; Intermediates; synthesis
目录
1绪论 1
1.1本课题研究背景及意义 1
1.1.1血栓栓塞的概念 1
1.1.2达比加群酯 2
1.2 课题研究现状及目的 6
1.2.1达比加群酯的合成路线 6
1.2.2本课题的研究目的与意义 8
2 达比加群酯中间体的合成实验 11
2.1合成路线设计思路 11
2.2使用的材料试剂、仪器设备 11
2.2.1 主要化学原料与试剂 11
2.2.2 仪器设备 12
2.3 3-[(4-甲胺基-3-硝基苯甲酰基)(吡啶-2-基)氨基]丙酸乙酯的合成 13
2.3.1 反应方程式 13
2.3.2 物料表 13
2.3.3 实验步骤 13