(R)-2-羥基-4-苯基丁酸乙酯的合成

制藥工程論文編號:ZY116    論文字?jǐn)?shù):9042,頁數(shù):23

 
目  錄
中文摘要...................................................................Ⅰ
英文摘要...................................................................Ⅱ
目錄.......................................................................Ⅲ
1.緒論......................................................................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 本章小結(jié)............................................................4
2.實驗部分..................................................................6
 2.1 實驗儀器與試劑......................................................7
           2.1.1實驗儀器.....................................................7     
 2.2.2分析檢測儀器.................................................7
         2.1.3實驗試劑.....................................................7
 2.2 反應(yīng)路線............................................................7
 2.3 2,4-二氧代苯基丁酸乙酯的合成........................................7
 2.4 (R)-2-羥基4-氧代苯基丁酸乙酯的合成..................................8
 2.5 (R)-2-羥基4-苯基丁酸乙酯的合成......................................8
 2.6 本章小結(jié)............................................................8
3.結(jié)果與討論................................................................9
    3.1 對合成2,4-二氧代苯基丁酸乙酯的各因素的探討..........................9
 3.1.1不同催化劑對收率的影響........................................9
 3.1.2不同反應(yīng)物摩爾比對收率的影響..................................10
 3.1.3不同反應(yīng)溫度對收率的影響......................................11
 3.1.4不同反應(yīng)溶劑對收率的影響......................................11
 3.2 對合成(R)-2-羥基-4-氧代苯基丁酸乙酯的反應(yīng)條件的探討................13
 3.2.1收率與e.e%的兩者關(guān)系探討.....................................13
 3.2.2修飾劑用量對不對稱加氫的影響.................................14
 3.3 合成(R)-2-羥基-4-苯基丁酸乙酯的收率及表征..........................14
   3.4 本章小結(jié)...........................................................15
4．總結(jié)與展望..............................................................16
致謝.......................................................................17
參考文獻(xiàn)...................................................................18

摘 要：(R)-2-羥基-4-苯基丁酸乙酯是合成眾多血管緊張素轉(zhuǎn)化酶抑制劑(ACEI)類治療高血壓和充血性心力衰竭藥物的關(guān)鍵手性中間體。本文闡述了以苯乙酮、草酸二乙酯為原料最終合成（R）-2-羥基-4-苯基丁酸乙酯的合成路線。并對合成2,4-二氧代苯基丁酸乙酯的反應(yīng)條件作了優(yōu)化探討,最終發(fā)現(xiàn)當(dāng)以甲苯為溶劑,乙醇鈉為催化劑,反應(yīng)溫度為30℃，反應(yīng)時間為2小時，轉(zhuǎn)化率可達(dá)到39.1%。而且對本實驗中的Raney Ni催化加氫步驟也作了研究；修飾劑的用量，反應(yīng)時間，氫氣壓力對于合成對映體的量有很大的影響。最終發(fā)現(xiàn)，當(dāng)修飾劑用量為7mg,反應(yīng)時間為150min，其轉(zhuǎn)化率、不對稱選擇效果可達(dá)到最大值。不對稱選擇性效果并不隨著反應(yīng)時間的增加而增大，反而會隨著反應(yīng)時間的增大而減小。本文為工業(yè)化生產(chǎn)制備該類藥物提供了一些可行的方法和途徑。

關(guān)鍵字：加氫； (R)-2-羥基-4-苯基丁酸乙酯；修飾劑；

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;