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摘要：阿托伐他汀钙，化学名称为[R-(R*,R*)]-2-(4-氟苯基)-β,δ-二羟基-5-(1-甲基乙基)-3-苯基-4-[(苯胺基)-羰基]-1氢-吡咯-1-庚酸钙三水合物，为治疗高胆固醇血症和混合型高脂血症有效的他汀类药物，市场前景非常广阔，但目前国内还不能大规模生产。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M-4 2-[2-(4-氟苯基)-2-氧代-1-苯基乙基]-4-甲基-3-氧代-N-苯基戊酰胺和阿托伐他汀中间体ATS-9 (4R-cis)-6-氨乙基-2,2-二甲基-1,3-二氧优尔环-4-乙酸叔丁酯等为原料，经关环反应、缩酮水解反应、酯的水解反应得到产物阿托伐他汀钙。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。38472
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毕业论文关键词：阿托伐他汀钙；[R-(R*,R*)]-2-(4-氟苯基)-β,δ-二羟基-5-(1-甲基乙基)-3-苯基-4-[(苯胺基)-羰基]-1氢-吡咯-1-庚酸钙三水合物；M-4 2-[2-(4-氟苯基)-2-氧代-1-苯基乙基]-4-甲基-3-氧代-N-苯基戊酰胺；ATS-9 (4R-cis)-6-氨乙基-2,2-二甲基-1,3-二氧优尔环-4-乙酸叔丁酯；合成
The Research on Synthesis of Atorvastatin Calcium
Abstract: Atorvastatin calcium, chemical name [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy -5-(1-methylethyl)-3-phenyl-4-[(phenylamino)-carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt, is an effective statin drugs which is used for treating hypercholesterolemia and mixed hyperlipidemia, and has very broad market prospects. At present, it can’t be produced on a large scale in our country. 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. Atorvastatin calcium is synthesized by ring-closing reaction, acetal hydrolysis reaction and ester hydrolysis reaction steps based on M-4 2-[2-(4-fluorophenyl)-2-oxo-1-phenyl-ethyl]-4-methyl-3-oxo-pentanoic acid phenylamide and ATS-9 (4R,6R)-t-butyl-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate as the starting material. 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: Atorvastatin Calcium; [R-(R*,R*)]-2-(4-Fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)-carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt; 2-[2-(4-Fluorophenyl)-2-oxo-1-phenyl-ethyl]-4-methyl-3-oxo-pentanoic acid phenylamide; (4R,6R)-t-Butyl-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate; Synthesis
目 录
1 前言•1
1.1 阿托伐他汀钙的简介••1
1.2 阿托伐他汀钙的药理学研究••1
1.3 阿托伐他汀钙的药代学特征••2
1.4 药物相互作用••2
1.5 不良反应2
1.6 阿托伐他汀钙的市场情况•3
2 文献综述与方案论证••4
2.1 文献综述 •• 4
2.1.1 Paal-Knorr合成法•4
2.1.2 手性拆分法 5
2.1.3 不对称合成法• 7
2.2 方案论证9
2.3 确定实验路线••9
2.3.1 L-1的合成10
2.3.2 阿托伐他汀钙的合成•11