度洛西汀中间体的合成

【作者】 赵贵财；

【导师】 杨立荣；

【作者基本信息】 浙江大学 ， 化学工程， 2005， 硕士

【摘要】 度洛西汀,化学名为（S）-N-甲基-3-（1-萘氧基）-3-（2-噻吩）-1-丙胺,是一种对5-羟色胺和去甲肾上腺素的再吸收有双重抑制作用的抗抑郁药。 3-甲胺-1-（2-噻吩）-丙醇是度洛西汀合成中最主要的中间体。按照起始原料的不同,通过三条路线可以合成3-甲胺-1-（2-噻吩）-丙醇。本文选取了以噻吩为起始原料的路线进行了详细的研究,通过傅克酰基化、还原反应、碘代反应、胺解反应四步反应制备3-甲胺-1-（2-噻吩）-丙醇。 本文着重研究了以傅克酰基化为主的合成路线。噻吩和3-氯丙酰氯在氯化铝的催化作用下,发生酰基化反应合成了3-氯-1-（2-噻吩）-丙酮。通过大量实验,我们优化了这一步的反应条件:即在0℃,CH₂Cl₂为溶剂,反应2小时,摩尔比AlCl₃:3-氯丙酰氯:噻吩=1.5:1:1。特别是在后处理上,我们的创新之处在于:将上述产物通入HCl进行加成反应,促使副产物向产物转化,极大提高了产物收率,收率达87%,高于文献报道的39%的收率,并且不用纯化,直接用于下一步反应。我们也对其他反应步骤进行优化,得到了最佳的反应条件。 为了降低成本,避开碘代反应,我们采取了在反应釜内直接进行胺解反应的方法。最后的总收率略高于上述的路线。与原来的路线比较,这个方法降低成本,操作简化,易于实现工业化。更多还原

【Abstract】 Duloxetine, （s）-N-methyl-3-（l-naphthalenyloxy）-3-（2-thienyl）-l-propanamine, is used as an antidpresssant by inhibiting the reuptake of norepinephrine and serotonin.3-methylamino-l-（2-thienyl）-propanol is the most important intermediate during synthesis of Duloxetine. According to start material, there are three synthesis routines. Primary work has been done to the routine which start from thiophene. Starting from thiophene and 3-chloropropinylchloride, 3-methylamino-l-（2-thienyl） -propanol was prepared by Friedel-crafts acylation, reduction, iodization and aminelysisKey study focused on routine starting from Friedel-crafts acylation of thiophene. Catalyzed by Aluminium trichloride, 3-chloro-l-（2-thienyl）-propanone was prepared through the acylation between thiophene and 3-chloropropinylchloride. After practice, optimized conditions achieved: at 0℃, react 2 hr, CH₂Cl₂ as solvent , more rate AlCl₃: 3-chloropropionyl chloride: thiophene=1.5:l:l. After the addition of hydrochloric gas, improvement has obtained greatly in Yield, because of transformation of by-product to main product. Finally, the Yield is 87%, higher than the original reported literature. The product will go to next reaction without any purification. We still study on other reaction steps and achieve optimized conditions.Aminelysis in high pressure reactor was taken for avoid iodization and cut cost. The overall Yield is higher than the routine mentioned above. Compared to original routine, this method not only reduce cost, but also simplify the operation, therefore it was suitable for industrialize use.更多还原