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摘要：盐酸左布比卡因是布比卡因的一个光学纯异构体的盐酸盐。盐酸布比卡因属于长效酰胺类局麻药，多用于神经阻滞、硬膜外阻滞。但是在临床应用的时候发现，布比卡因的右旋体毒性较强，而其左旋体几乎没有毒性。因而为了更高的的安全性需要进行手性拆分，获得纯度较高的左旋布比卡因。主要的合成方法是将2,6-二甲基苯胺和2-哌啶甲酸酰化后，与1-溴代正丁烷经烷基化反应合成布比卡因，再经拆分、成盐得成品。本实验在酰胺合成部分主要尝试以HATU为反应条件使2,6-二甲基苯胺和2-哌啶甲酸完成酰化合成中间体，而在光学异构的拆分时，则用D-酒石酸将左右旋光体分开。本次试验在各类合成文献的先例之上，尝试设计出一种适用于实验室制备的更为简便、产物更单一明确的实验路线。23933
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毕业论文关键词：布比卡因；盐酸左布比卡因；酰胺；手性拆分
The Synthesis of Levobupivacaine Hydrochloride
Abstract：Hydrochloride levobupivacaine is the hydrochloride of bupivacaine’s Optical pure isomer. Bupivacaine belongs to long-term Local anesthetics of amide derivatives, mostly used for nerve block and epidural block. However, Chiral resolution has to be conducted because of the dextroisomer of bupivacaine has a higher toxicity, whilst high purity of Levobupivacaine can be acquired. After the acylation reaction between 2, 6-dimethylaniline and 2-piperidine formic acid, the intermediate and 1 - bromine generation of n-butane alkylated to bupivacaine as well as obtaining the finished product through resolving and salifying which is the main compounding method. The experiment use HATU as reaction condition to complete the acylation between 2, 6 - dimethylaniline and 2 - piperidine formic acid, while resolving the optical isomers, the experience use the D-tartaric acid to separate them. This experiment is trying to design an exprimental method with simpler operation and definite outcome which is suitable for experimental preparation based on various documents in regard to compound.
Key word： Bupivacaine; Levobupivacaine Hydrochloride; Amide; Chiral resolution
目 录
1 前言 1
1.1 局部麻醉药概述 1
1.1.1 局部麻醉药的发展史 1
1.1.2 局部麻醉药的构效关系 1
1.2 盐酸左布比卡因概述 2
1.2.1 盐酸左布比卡因的临床实验 2
1.2.2 盐酸左布比卡因的药代动力学 3
1.2.3 盐酸左布比卡因的药效动力学 4
1.2.4 盐酸左布比卡因的毒性 4
1.2.5 盐酸左布比卡因用药的注意事项 5
2 盐酸左布比卡因的合成方法确定 6
2.1 盐酸左布比卡因的合成 6
2.1.1 中间体N-（2’，6’-二甲基苯基）-2-哌啶酰胺的合成方法 6
2.1.2 布比卡因的拆分 8
2.1.3 盐酸左布比卡因合成小结 9
2.2 盐酸左布比卡因的鉴定 9
2.2.1 盐酸左布比卡因的理化性质鉴定 9
2.2.2 盐酸左布比卡因的右旋体含量测定 10
3 实验部分 11
3.1 实验仪器设备以及试剂 11
3.1.1 实验仪器及设备 11
3.1.2 实验试剂 11
3.2 实验步骤 12
3.2.1 N-(2,6-二甲苯基)-2-哌啶甲酰胺的合成 12
3.2.2 盐酸左布比卡因的制备 12
3.2.3 盐酸左布比卡因的鉴别 12
3.3 实验记录 13
3.3 实验小结 18