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摘要：吡喹酮(Praziquantel)，化学名称为2-环己基甲酰基-1,2,3,6,7,11b-优尔氢-4H-吡嗪并[2,1-a]异喹啉-4-酮，是广谱抗寄生虫药物，对各类血吸虫均有杀灭作用。因其具有疗效高、疗程短、毒性小等优点，目前是世界上治疗血吸虫病的首选药物。但是，我国现行的吡喹酮生产工艺中存在着严重的安全和环保问题，制约了吡喹酮的大规模生产。本课题的研究目的是摸索出一条今后能用于工业化大生产的合成路线，因此要求原料来源充足，反应条件温和，合成步骤少，成本低，环境污染少等。本课题是以甘氨酸乙酯盐酸盐和溴代乙醛缩二乙醇为原料，经过N-烃化反应、N-酰化反应和Pictet-Spengler缩合反应合成出产物吡喹酮。通过工艺条件对照实验，本文优化了这几步反应的实验过程，增强了各步反应的稳定性和重复性，提高了产物收率和纯度，降低了实验成本，为今后工业化生产摸索出了一条相对可行的工艺路线。32048
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毕业论文关键词：吡喹酮；抗血吸虫药物；甘氨酸乙酯盐酸盐；溴代乙醛缩二乙醇；合成
Study on New Synthetic Method of Praziquantel
Abstract: Praziquantel, chemical name 2-cyclohexylcarbonyl-1,2,3,6,7,11b-hexahydro-4H-
pyrazino[2,1-a]isoquinolin-4-one, is a broad spectrum antiparasitic drug and has remarkable activity against all species of schistosomas. At present, it is the first choice drug for the treatment of schistosomiasis in the world because of excellent efficacy, short course of treatment and low toxicity. It can’t be produced on a large scale in our country because of serious problem on safety and environment in current process. The topic is aimed at finding a synthetic process which can be applied for major industrial production in the future, with abundant raw materials, mild reaction condition, few synthetic steps, low cost and less environmental pollution. Praziquantel is synthesized by N-alkylation reaction, N-acylation reaction and Pictet-Spengler reaction steps based on glycine ethyl ester hydrochloride and bromoacetaldehyde diethyl acetal as the starting materials. Through the contrast experiment, we optimize experiment condition, enhance stability and reproducibility of each reaction, improve the productivity and purity of product, reduce production cost and determine a relatively feasible process which can be applied for major industrial production in the future.
Key Words: Praziquantel; Antischistosomal; Glycine ethyl ester hydrochloride; Bromoacetal-dehyde diethyl acetal; Synthesis
目 录
1 前言1
1.1 吡喹酮的简介 •• 1
1.2 吡喹酮的药理学研究 1
1.3 吡喹酮的药代动力学及毒副作用研究••2
1.4 吡喹酮的市场•2
2 文献综述与方案论证•4
2.1 文献综述 •4
2.2 方案论证••9
2.3 确定实验路线10
3 实验部分•12
3.1 试剂及仪器 •12
3.1.1 试剂••12
3.1.2 仪器••13
3.2 实验方法 13
3.2.1 N-(2,2-二乙氧基乙基)甘氨酸乙酯的合成••13
3.2.2 N-(环己基羰基)- N-(2,2-二乙氧基乙基)甘氨酸乙酯的合成••15
3.2.3 吡喹酮的合成18
4 实验讨论•21
4.1 N-(2,2-二乙氧基乙基)甘氨酸乙酯的合成••21
4.1.1溶剂对反应收率的影响•21
4.1.2催化剂用量对反应收率的影响•21
4.1.3缚酸剂对反应收率的影响••22
4.1.4反应终点的确定•23
4.2 N-(环己基羰基)- N-(2,2-二乙氧基乙基)甘氨酸乙酯的合成••24
4.2.1反应温度对反应收率的影响24
4.2.2反应终点的确定•24
4.3 吡喹酮的合成25
4.3.1酸催化剂对反应收率的影响25
4.3.2反应终点的确定•26
5 结论••28
致谢•29