(R)-2-羟基-4-苯基丁酸乙酯的合成

制药工程论文编号:ZY116    论文字数:9042,页数:23

 
目  录
中文摘要...................................................................Ⅰ
英文摘要...................................................................Ⅱ
目录.......................................................................Ⅲ
1.绪论......................................................................1
    1.1 前言................................................................1
 1.2 概述................................................................2
        1.2.1拆分法.........................................................2
        1.2.2合成法.........................................................3
 1.3 本章小结............................................................4
2.实验部分..................................................................6
 2.1 实验仪器与试剂......................................................7
           2.1.1实验仪器.....................................................7     
 2.2.2分析检测仪器.................................................7
         2.1.3实验试剂.....................................................7
 2.2 反应路线............................................................7
 2.3 2,4-二氧代苯基丁酸乙酯的合成........................................7
 2.4 (R)-2-羟基4-氧代苯基丁酸乙酯的合成..................................8
 2.5 (R)-2-羟基4-苯基丁酸乙酯的合成......................................8
 2.6 本章小结............................................................8
3.结果与讨论................................................................9
    3.1 对合成2,4-二氧代苯基丁酸乙酯的各因素的探讨..........................9
 3.1.1不同催化剂对收率的影响........................................9
 3.1.2不同反应物摩尔比对收率的影响..................................10
 3.1.3不同反应温度对收率的影响......................................11
 3.1.4不同反应溶剂对收率的影响......................................11
 3.2 对合成(R)-2-羟基-4-氧代苯基丁酸乙酯的反应条件的探讨................13
 3.2.1收率与e.e%的两者关系探讨.....................................13
 3.2.2修饰剂用量对不对称加氢的影响.................................14
 3.3 合成(R)-2-羟基-4-苯基丁酸乙酯的收率及表征..........................14
   3.4 本章小结...........................................................15
4．总结与展望..............................................................16
致谢.......................................................................17
参考文献...................................................................18

摘 要：(R)-2-羟基-4-苯基丁酸乙酯是合成众多血管紧张素转化酶抑制剂(ACEI)类治疗高血压和充血性心力衰竭药物的关键手性中间体。本文阐述了以苯乙酮、草酸二乙酯为原料最终合成（R）-2-羟基-4-苯基丁酸乙酯的合成路线。并对合成2,4-二氧代苯基丁酸乙酯的反应条件作了优化探讨,最终发现当以甲苯为溶剂,乙醇钠为催化剂,反应温度为30℃，反应时间为2小时，转化率可达到39.1%。而且对本实验中的Raney Ni催化加氢步骤也作了研究；修饰剂的用量，反应时间，氢气压力对于合成对映体的量有很大的影响。最终发现，当修饰剂用量为7mg,反应时间为150min，其转化率、不对称选择效果可达到最大值。不对称选择性效果并不随着反应时间的增加而增大，反而会随着反应时间的增大而减小。本文为工业化生产制备该类药物提供了一些可行的方法和途径。

关键字：加氢； (R)-2-羟基-4-苯基丁酸乙酯；修饰剂；

Abstract: A synthesis route to produce ethyl (R)-2-hydroxy-4-phenylbutyrate, an important intermediate for several ACE inhibitors is described starting from acetophenone and diethyl oxalate. Ethyl 2,4-dioxo-phenylbutyrate is synthesized from acetophenone and diethyl oxalate by using different conditions，the optimal condition is founded. The reaction was run in aqueous toluene at 30℃ for 2h under the catalysis of Sodium ethoxide. The yield is 39.1%. Also the condition of the hydrogenation of ethyl 2,4-dioxo-4-phenylbutyrate catalyzed by a heterogeneous Raney Ni catalyst is studied . The effects of modifier amount, reaction time, hydrogen pressure and temperature on enantiometric excess are investigated to synthesize ethyl (R)-2-hydroxy-4-
phenylbutyrate. It is found that conversation and enantioselectivity showed a maximum in the condition of modifier amount is 7mg for 150min. The conversation increased with the increase of reaction time，which almost had no effect on the enantioselectivity, but it had adverse influence on enantiomeric excess. The study provides a practicable method for industrial production of this remedy．

Keywords: Hydrogenolysis; Ethyl (R)-2-hydroxy-4-phenylbutyrate; Modifier;