盐酸噻氯匹啶的合成

【作者】 郭海昌；

【导师】 陈志荣；

【作者基本信息】 浙江大学 ， 应用化学， 2004， 硕士

【摘要】 盐酸噻氯匹啶是一种血小板聚集抑制剂。本文以噻吩为原料，经氯甲基化、氰化、催化加氢制得关键中间体2-噻吩乙胺，再经亚胺化、环合制得主环4,5,6,7-四氢噻吩并[3,2-C]吡啶，与邻氯氯苄缩合成盐后得到盐酸噻氯匹啶。 本文运用质谱、红外及核磁等分析方法确认了各步反应产物的结构，并结合反应机理对各步反应的工艺条件进行了改进和优化。氯甲基化反应时通过单因素实验确立了反应温度为-5℃，噻吩和甲醛的摩尔比为0.9～1.1的最佳反应条件；通过单因素实验及正交实验得到氰化反应的最佳反应条件为：反应温度35～60℃，2-氯甲基噻吩粗品(90.0g)滴加时间30min，粉末氰化钠44g，非水极性溶剂A150ml；催化加氢反应时的最佳反应条件是：2-噻吩乙腈50g(溶剂B500ml)，氨压0.25MPa(50℃)，反应温度90℃；亚胺化和环合反应时通过单因素实验得到了反应温度50～60℃、氯化氢和原料的摩尔比等于2的最佳反应条件；缩合反应时通过单因素实验确立了邻氯氯苄和4,5,6,7-四氢噻吩并[3,2-C]吡啶盐酸盐的摩尔比等于1.04的最佳投料比。采用上述最佳工艺条件，盐酸噻氯匹啶的总收率为21％。更多还原

【Abstract】 Ticlopidine hydrochloride is a potent blood platelet aggregation inhibitors. The synthesis of ticlopidine hydrochloride is studied in this paper which consists of chlormethylation, cyanidation and catalytic hydrogenation of thiophene, formimination and cyclization of 2-(2-Thienyl)ethylamine, and condensation and acidification of 4,5,6,7-tetrahydrothieno[3,2-C]pyridine with o-chlorobenzyl chloride.Products of every step are identified by MS, IR and NMR and the process is optimized in this paper. During the chlormethylation, the yield is highest when reaction temperature is -5℃ and the mole ratio of thiophene to formaldehyde is 1.04. The yield of cyanidation is highest when reaction temperature is 35~60℃, dropping time of 2-chloromethylthiophene(90g) is 30min, pulverous NaCN is 44g and solvent A is 150ml. The optimum hydrogenation conditions are as follows: 2-thiopheneacetonitrile is 50g(solvent B 500ml), pressure of NH3 is 0.25 MPa(50℃) and reaction temperature is 90℃. In the formimination and cyclization, reaction temperature of 50~60℃ and mole ratio of HC1 to material of 2 give the best yield. In the condensation, the optimum mole ratio of o-chlorobenzyl chloride to 4,5,6,7-tetrahydrothieno [3,2-C]pyridine is 1.04. According to above results of optimization, the overall yield of ticlopidine hydrochloride is 21%.更多还原