摘要：阿托伐他汀钙是一种是一种用于治疗心血管疾病的畅销药物,作用于3-羟基-3-甲基辅酶A（HMG-CoA）还原酶，对胆固醇的合成有着强烈的抑制作用。该酶是胆固醇合成的关键限速酶，可以抑制胆固醇的合成。6-氰基-3R-5R-二羟基己酸叔丁酯是阿托伐他汀钙的双手性药效基。传统的（3R-5R-2）化学合成过程需要深冷条件（反应温度低于-60℃），且反应副产物多、产物光学纯度低，同时存在能量和溶剂消耗大等缺陷。目前，对其手性侧链的合成工艺的改进的开发引起了各界的关注。鉴于传统的化学合成工艺存在许多问题，比如：对环境污染严重，反应条件十分苛刻，反应成本高无法大规模生产等，因此利用生物法合成阿托伐他汀钙已经成为了近年来的研究热点。利用克鲁斯假丝酵母的羰基还原酶不对称还原6-氰基-3R-5R-二羟基己酸叔丁酯相较于化学合成法与酶法具有着许多的优势。本实验通过利用优良天然菌株，在底物浓度高的反应体系中仍可以高效的催化不对称还原反应合成6-氰基-3R-5R-二羟基己酸叔丁酯，并且该催化过程中不需要加入价格昂贵的辅酶NAD(P)H，能有效降低生物催化的成本，具有较好应用前景。71503

毕业论文关键词：6-氰基-3R-5R-二羟基己酸叔丁酯；克鲁斯假丝酵母；生物酶法；不对称还原 

Abstract: Atorvastatin calcium is an efficient drug used to reduce the blood lipids. It can affect   the limit key enzyme of cholesterol synthesis, 3 - hydroxy -3-methyl coenzyme A.Thus, it is an important drug in treatment of cardiovascular disease. 6-cyano-3R-5R- dihydroxy caproic acid tert-butyl ester is the bis-chiral groups of atorvastatin calcium. The traditional chemical synthesis for (3R-5R-2) needs for cryogenic conditions (reaction temperature is lower than -60℃), and optical purity of the product is low. Also, there are many defects, such as energy and solvent consumption. At present, the improvement of synthesis process, especially the development of chiral side chain has aroused the concerns. The traditional chemical synthesis process has some problems, such as harsh reaction conditions and serious environmental pollution,so in recent years the synthesis of atorvastatin side chain intermediates by biological enzyme method has become a hot research topic.Using ketoreductases to asymmetric reducte 6-cyano–3R -5R-dihydroxy caproic acid tert-butyl ester has many technical advantages. It is of great significance to select excellent natural bacterial strains for the efficient catalytic asymmetric synthesis of 6-cyano-3R-5R-dihydroxy caproic acid tert-butyl ester.And in the system, there is no need to add expensive coenzyme NAD (P) H, which can effectively reduce the cost of biological catalysis.

Key words: 6- cyano-3R-5R- two hydroxy caproic acid tert butyl ester; Candida Cruise; Biological enzyme method；Asymmetric reduction 

目   录

1. 前 言 4

1.1 阿托伐他汀合成技术的重要性 4

1.2化学合成法 4

1.3生物转化与催化法 4

2．材料与方法 5

2.1 实验仪器 5

2.2 实验材料 5

2.3实验方法 6

2.3.1 转化反应方法 6

2.3.2反应体系对菌株转化效率的影响 7

2.3.3温度对菌株转化效率的影响 7

2.3.4 PH对菌株转化效率的影响 7

3. 结果与分析