节点文献
3-（1-萘氧基）-1，2-环氧丙烷水解动力学拆分及其应用的研究
【作者】 张国安；
【导师】 夏敏；
【作者基本信息】 浙江理工大学 ， 有机化学， 2011， 硕士
【摘要】 手性末端环氧化合物是有机合成的重要砌块,在生物活性化合物制备中的地位与需求日益突出。尽管目前以不对称合成的方法来获得高光学纯度的末端环氧化合物的研究已取得了巨大的进展,但从成本、效率、可控性及环境友好等角度出发,Jacobson研究小组创建的水解动力学拆分的方法依然具有一定的优势。3-(1-萘氧基)-1,2-环氧丙烷的水解动力学拆分的产物之一是合成抗高血压和心血管疾病的重要药物(S)-萘哌地尔的关键中间体。本文以手性Salen Co(Ⅲ)络合物为催化剂,探讨了该末端环氧化合物水解动力学拆分的各种影响因素及拆分产物在(S)-萘哌地尔制备中的应用。主要研究内容和结果如下：(1)以标准化的水解动力学拆分反应处理3-(1-萘氧基)-1,2-环氧丙烷,在建立反应转化率及产物光学纯度定量分析方法的基础上,进而详细研究了催化剂种类与用量、反应时间与温度、水的用量、溶剂种类等对上述两因素的影响,确定了该末端环氧化合物水解动力学拆分的最佳条件,即：四氢呋喃做溶剂,水的用量为0.55eq,以手性1,2-环己二胺为配体的催化剂用量为0.75mo1%,室温下反应40h,以49%的收率与100%的ee值,得到(S)-3-(1-萘氧基)-1,2-环氧丙烷。(2)参考文献的合成路线,将拆分的产物(S)-3-(1-萘氧基)-1,2-环氧丙烷用于(S)-萘哌地尔类似物的制备。在制备中采用超声波促进的方法以实现(S)-3-(1-萘氧基)-1,2-环氧丙烷与N-取代哌嗪的反应,使原来在常规加热条件下需要高温回流反应30小时左右的反应在室温下超声辐射5小时即可完成,大大提高了反应的效率。此法证明对含有脂肪、芳香、杂芳香及杂环取代的哌嗪均有效,都能获得良好的反应产率。我们对制备的(S)-萘哌地尔类似物进行了包括熔点、比旋光值、红外、质谱、氢核磁共振以及碳核磁共振等详细的表征,为快速高效获得(S)-萘哌地尔及其类似物提供了新的制备途径。
【Abstract】 Chiral terminal epoxides are important building blocks in organic synthesis, the status and needs of which is increasingly prominent in the preparation of bioactive compounds. Although the asymmetric synthesis method to obtain high optical purity of terminal epoxides has made tremendous progress, from the perspective of cost, efficiency and environment-friendly, the method of hydrolytic kinetic resolution created by Jacobson’s group still has certain advantages.One of the product of the hydrolytic kinetic resolution for 3-(1-naphthyloxy)-1,2-epoxypropane is the key intermediate for (S)-naftopidil, which is the important drug for treatment of arterial hypertension and cardiovascular disease. We explored the various factors of hydrolytic kinetic resolution of terminal epoxides by chiral Salen(III) complex and applied the split product for the preparation of (S)-naftopidil. The major research and result was as followings:(1) 3-(1-naphthyloxy)-1,2-epoxypropane was treated by the standardized reaction of hydrolytic kinetic resolution. Based on the quantitative analysis method of the conversion rate and the optical purity, further detailed study of the type and amount of catalyst, reaction time, temperature, the amount of water, solvents how to affect these aforesaid factors, we obtained the optimized reaction condition:the solvent was tetrahydrofuran, the water was 0.55 euqivalent, the amount of catalyst was 0.75mol% that was prepared by the chiral ligand 1,2-diaminocyclohexane, the temperature was at room temperature, reaction time was 40 hours. Under the reaction condition, we acquired 49% yield and 100% ee for (S)-3-(1-naphthyloxy)-1,2-epoxypropane.(2) Based on some synthetic route reported, we applied the split product (S)-3-(1-naphthyloxy)-1,2-epoxypropane to synthesize the (S)-naftopidil analogues. We adopted ultrasound-promoted method to achieve the reaction between 3-(1-naphthyloxy)-1,2-epoxypropane and N-substituted piperazine derivatives. While the reaction under conventional condition required high-temperature refluxing for 30 hours, under ultrasound-assisted condition it finished at room temperature for 5 hours, significantly improving the efficiency. The method proved to contain aliphatic, aromatic, heteroaromatic and heterocyclic substituted piperazine derivatives were effective and could obtain good yield. The prepared (S)-naftopidil analogues were characterized by melting point, specific rotation, IR,1H NMR,13C NMR and MS in detail. It fast and efficiently provided a new way for acquiring (S)-naftopidil analogues.