SalenCo（Ⅲ）手性催化剂及氟西汀对映体的中间体的不对称合成

【作者】 杨润升；

【导师】 郝金库；

【作者基本信息】 天津师范大学 ， 物理化学， 2006， 硕士

【摘要】 氟西汀是目前临床广泛使用的一种非三环类抗抑郁药，除用于治疗抑郁症以外，氟西汀对临床常见的强迫症、贪食症、惊恐发作、经前期焦虑障碍等也有很好的疗效。药物手性化合物异构体在生理活性、药效、代谢行为等方面存在着明显差异，因此其对映体的不对称合成就得到了越来越多的关注。外消旋体拆分、不对称化学催化和酶催化都是制备氟西汀对映体的高效、简便的合成方法。我们尝试通过Salen Co(Ⅲ)手性催化剂与外消旋未端环氧化合物的水解动力学拆分反应去合成制备氟西汀的重要中间体手性R-苯基环氧乙烷，再经过一系列反应最终旨在合成手性药物氟西汀。 1、在综合各类文献资料的基础上，我们设计出一条未见诸国内外文献报道的新的合成氟西汀的路线，利用Salen Co(Ⅲ)手性催化剂与外消旋未端环氧化合物的水解动力学拆分反应去合成制备氟西汀的重要中间体手性R-苯基环氧乙烷，再经过一系列反应最终旨在合成手性药物氟西汀。 2、对外消旋化合物(±)-1，2-二苯基乙二胺的合成与拆分，本文以成本低廉、易得的苯甲醛为起始原料经过三步反应得到，在制备主要产物过程中，我们对合成的线路及反应条件从温度、时间进行了比较和研究，总结出制备目标产物的最佳线路和条件。 3、在合成在手性(Salen)Co(Ⅲ)催化剂中，本文对制备2-叔丁基-4-甲基苯酚，通过比较选取了最佳的合成路线，并对其从温度和物料配比进行了研究，得出了最好反应温度及物料配比，后续反应中从时间、温度等方面进行了摸索。 4、利用手性(Salen)Co(Ⅲ)催化末端环氧水解动力学拆分反应得到R-苯基环氧乙烷，并对其合成工艺进行了优化和改进，得到了最佳的反应温度、时间及物料配比。实验操作简单，反应时间短，化学产率及纯度都较理想。产物经过了柱层析分离提纯。 5、整个实验过程中，本文对各步主要反应产物进行了元素分析、红外光谱、核磁共振氢谱分析等表征，并与文献值相对照，来确定产物正确性，基本一致。更多还原

【Abstract】 Fluoxetine is a potent and selective inhibitor of neural serotonin-reuptake. It is effective not only as an antidepression, but also for treatment of anxiety, alcoholism, chronic pain, and eating disorder such as obesity and bulimia. It is very popular on market because of its effectivity and less side-effects. Because the individual enantiomers display different pharmacological activities and different metabolic behaviour, the preparation of the enantiomers of the drugs has attracted considerable attention. Resolution, enzymatic catalysts, chemical catalysts are all the effective and convenient approaches for preparing enantiomers of Fluoxetine. In our experiment, we attempt to apply chiral (Salen)Co(III)-catalyzed Hydrolytic kinetic resolution of racemic terminal epoxides to the syntheses of R- phenyloxiran of the important intermediate of preparing enantiomers of Fluoxetine .1. Basing on all kinds of literature, we worked out a new way of synthesis of fluoxetine which has not been used home and abroad, applying chiral (Salen)Co(III)-catalyzed Hydrolytic kinetic resolution of racemic terminal epoxides to the syntheses of R- phenyloxiran of the important intermediate of preparing enantiomers of Fluoxetine .2. For the synthesis and resolution of (±)-1,2-diphenylethanediamine,we gained the target product by three steps using benzaldehyde, a low-cost and easy-to-get chemical, as one of the original materials. During preparing all staples, we carefully compared and studied synthetical line and condition of reaction from temperature and time, and found the best way to obtain target product.3. During synthesis of chiral (Salen) Co(III)-catalyzed , we found the best way to prepare 2- butyl-4-methyl phenol by comparing all other ways and got the best reactive temperature and proportion of the involved materials. In the follow-up experiment of reactions, we made further exploration in terms of reactive temperature and time.4. In order to get R-phenyloxiran, we made full use of Chiral (Salen) Co-更多还原