【作者】 孙丰来；

【导师】 杨立荣；

【作者基本信息】 浙江大学 ， 生物化工， 2007， 博士

【摘要】 他汀药物是一类新型,最畅销的降血脂药物。它通过对人体胆固醇合成过程中的限速酶,3-羟基-3-甲基辅酶A（HMG-CoA）还原酶的抑制作用,减少细胞内游离胆固醇生成,最终降低血清中总胆固醇和低密度胆固醇水平。本文重点研究了几个关键手性中间体合成方法和工艺。主要内容包括:（1）优化了（S）-6-氯-5-羟基-3-羰基己酸叔丁酯和（R）-6-氰基-5-羟基-3-羰基己酸叔丁酯的合成工艺。通过对反应机理分析和各种条件实验,确定了较优的反应条件。改进了（R）-4-氰基-3-羟基丁酸乙酯的合成工艺,确定了以反应溶剂EtOH/H₂O,反应温度35℃,四丁基溴化铵为催化剂的反应体系。该反应工艺生产成本低,反应条件温和,产物纯度和收率高,适合工业化生产。（2）提出了化学酶法合成（S）-6-苄氧基-5-羟基-3-羰基己酸叔丁酯的新路线。并探讨了在有机相中,脂肪酶催化转酯化拆分4-芳甲氧基-3-羟基-丁腈。以4-苯甲氧基-3-羟基-丁腈做为模板化合物,通过酶和溶剂筛选,选择了脂肪酶Artgribacter sp.,确定了混合溶剂（乙腈/正庚烷=1:1）作为反应体系。并用该方法对不同取代基的4-芳甲氧基-3-羟基-丁腈进行了研究,发现脂肪酶Artgribactersp.对底物的反应选择性,随着芳环上取代基数量的增加而增大。（3）提出了化学法合成（3R,5S）-6-羟基-3,5-氧-异亚丙基-3,5-二羟基己酸叔丁酯的新路线。采用（R）-环氧氯丙烷为原料,经过几步条件温和的反应合成了目标化合物（3R,5S）-6-羟基-3,5-氧-异亚丙基-3,5-二羟基己酸叔丁酯。在第一步反应中,使用三氟化硼作为催化剂,高光学选择性的引入手性羟基;在制备化合物（S）-3-羟基-4-苄氧基丁腈过程中,比较两条不同的路径,确定了最佳反应途径;（S）-3-羟基-4-苄氧基丁腈经过羟基保护,与溴乙酸叔丁酯缩合,三乙基硼手性诱导还原,经过二羟基保护,最后催化加氢脱去对甲苄基得到目标产物。与以前报道工艺相比,本工艺具有反应条件比较温和,反应试剂便宜、易得等优点。（4）提出了酶法和化学法拆分制备（3R,5S）-6-羟基-3,5-氧-异亚丙基-3,5-二羟基己酸叔丁酯的新方法。其手性中心C-5通过脂肪酶转酯拆分得到,手性中心C-3通过化学法拆分得到。在酶法制备手性中心C-5的过程中,探讨了在有机相中脂肪酶催化转酯化拆分1-芳基-3-氯-2-丙醇。以1-苯甲氧基-3-氯-2-丙醇做为模板化合物,通过酶和溶剂的筛选,确定了脂肪酶Alcaligenes sp.为反应用酶,混合溶液（乙腈/正己烷,1:3,v/v）作为反应溶剂。并用该体系对不同取代基的1-芳甲氧基-3-氯-2-丙醇反应进行了研究,确定酶选择性最佳底物1-（4-甲基苯甲氧基）-3-氯-2-丙醇为合成手性C-5的反应底物。为了得到手性中心C-3,探讨了溶剂对硼氢化钠选择性还原（5S）-6-对甲基苄氧基-5-羟基-3-羰基已酸叔丁酯的影响,在异丙醇水溶液中,产物（5S）-6-对甲基苄氧基-3,5-二羟基已酸叔丁酯中顺式和反氏的比例达到了4.0:1。酸水解拆分（5S）-6-对甲基苄氧基-3,5-氧-异亚丙基-3,5-二羟基己酸叔丁酯高选择性的得到顺式（3R,5S）-6-对甲基苄氧基-3,5-氧-异亚丙基-3,5-二羟基己酸叔丁酯,de值为98%,收率65%。（5）对（4R-cis）6-氰（氯）基-2,2-二甲基-1,3-二氧六环-4-乙酸叔丁酯的合成工艺进行了优化。以（S）-环氧氯丙烷为原料,经过与NaCN加成,羟基保护,与溴乙酸叔丁酯缩合得到了（S）-6-氯基-5-羟基-3-羰基已酸叔丁酯。（S）-6-氯基-5-羟基-3-羰基已酸叔丁酯经过氰基取代后,经三乙基硼诱导还原,二羟基保护得到（4R-cis）-6-氰基-2,2-二甲基-1,3-二氧六环-4-乙酸叔丁酯。本工艺具有简单,环境友好,生产成本低等优点。更多还原

【Abstract】 Statin is one of new and best-selling medicines which is used as an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme-A reductase（HMG-CoA）,the rate limiting enzyme in cholesterol biosynthesis.This medicine can reduce the forming of dissociated cholesterol in cells and thus lower plasma an low density lipoprotein cholesterol in blood.In this dissertation,some new synthetic methods and technologies to its key structures are emphatically described.The main contents of this work are as follows:（1）The synthetic technology for the construction of tert-butyl（S）-6-chloro-5-hydroxyl-3-oxohexanoatewas optimized.Through analysis of reaction mechanism and operation of different experiments,the optimum reaction condition was obtained. Meanwhile,synthetic technology for the synthesis of ethyl（R）-4-cyano-3-hydroxybutanaote was improved,and the good reaction condition was that EtOH/H₂O,35℃and tetrabutylammonium bromide were selected as the reaction solvent,temperature and catalyzer,respectively.The synthetic technology were suitable for industrial production for its low manufacturing cost,mild reaction conditions,high purities and good yields.（2）A chemoenzymatie synthesis of tert-butyl（S）-6-benzyloxy-5-hydroxy-3-oxo-hexanoate was described.The kinetic resolution of 4-arylmethoxy-3-hydroxybutane-nitriles was investigated by lipase-catalyzed transesterification in organic solvent.High enantioselectivity was obtained by reaction with vinyl acetate in mixed solvent（n-heptane/acetonitrile 1:1）,which was catalyzed by the lipase from Artgribacter sp.Better selectivity was demonstrated with the number of substituents on the aryl ring increasing.（3）A new synthetic method of（4R,6S）-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetic acid,1,1-dimethylethyl ester was accomplished.The target compound was successfully prepared via several mild reaction processes by using R-epichlorohydrin,which is an easily available starting material.Through comparing with three different synthetic methods,the best route was obtained.Dihydroxy ester was synthesized by a syn-selective triethylborane reduction with de value of 97%. After acid-catalyzed protection of dihydroxy ester and hydrogenolysis of the benzyl protecting group,the objective was obtained with high enantiomeric and diastereomeric purity.（4）A facile route to synthesis tert-butyl（3R,5S）-6-hydroxy-3,5-O-isopropylidene-3,5-dihydroxyhexanoate by a chemoenzymatic approach was described.To get the hydroxyl stereocenter at C5,the kinetic resolution of 1-arylmethoxy -3-chloro-2-propanols was investigated by lipase-catalyzed esterification in organic solvents.High enantioselectivity was obtained by reaction with vinyl acetate in mixed solvent（n-hexane/acetonitrile 3:1）,which was catalyzed by the lipase from Alcaligenes sp.1-（4-methylbenzyloxy）-3-chloro-2-propanol was enantioselectively resolved by lipase from Alcaligenes sp.with excellent enantioselectivity（E≥200）and chosen as the optimum subtrate.Another hydroxyl stereocenter at C3 was built by a three-step method,first sodium borohydride reduction of tert-butyl（S）-6-（4-methybenzyloxy）-5-hydroxy-3-oxohexanoate in aqueous isopropyl alcohol with a high disastereomeric ratio(dr_s:a= 4.0:1),then acetonide protection,followed by hydrolysis of tert-butyl （5S）-6-（4-methybenzyloxy）-3,5-O-isopropylidene-3,5-dihydroxyhexanoate with acid solutions.The compound tert-butyl（3R,5S）-6-（4-methybenzyloxy）-3,5-O-isopropylidene-3, 5-dihydroxyhexanoate was obtained in 65%yield and 98.0%de.（5）A new synthesis method of tert-butyl（4R-cis）-6-cyanoxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate was achieved,which started from（S）-epichiorohydrin, followed by addition with sodium cyanide,hydroxyl-group protection, condensation,substitution,syn-selective reduction and dihydroxyl-group protection. This route was suitable for large-scale preparation for its high yields,mild reaction conditions,easily available materials and facile purification of products.更多还原