阿托伐他汀钙的合成研究  

Synthesis of Atorvastatin Calcium

作　　者：王珣 张耀光 丁利红 杜如阳 肖艳华 WANG Xun;ZHANG Yaoguang;DING Lihong;DU Ruyang;XIAO Yanhua(Hubei Key Laboratory of Novel Reactor and Green Chemical Technology,Key Laboratory of Green Chemical Process of Ministry of Education,School of Chemical Engineering and Pharmacy,Wuhan Institute of Technology,Wuhan 430074,China)

机构地区：[1]武汉工程大学化工与制药学院绿色化工过程教育部重点实验室湖北省新型反应器与绿色化学工艺重点实验室,湖北武汉430074

出　　处：《化学与生物工程》2023年第8期35-37,41,共4页Chemistry & Bioengineering

基　　金：绿色化工过程教育部重点实验室开放基金项目(GCP20190208)。

摘　　要：以1-(4-氟苯基)-5-甲基-2-苯基-1,4-己二酮(Ⅱ)、(4R-cis)-6-氨乙基-2,2-二甲基-1,3-二氧戊环-己酸叔丁酯(Ⅲ)为起始原料,经帕尔-克诺尔(Paal-Knorr)反应得到多取代的吡咯环化合物2-[(4 R,6R)-2-(4-氟苯基)-5-异丙基-3-苯基-1 H-吡咯]-1-(2,2-二甲基-1,3-二氧代环氧己烷)-4-己酸叔丁酯(Ⅳ),再与苯异氰酸酯反应得到化合物2-[(4 R,6R)-2-(4-氟苯基)-5-异丙基-4-苯胺甲酰基-3-苯基-1 H-吡咯]-1-(2,2-二甲基-1,3-二氧代环氧己烷)-4-己酸叔丁酯(Ⅴ),化合物Ⅴ在酸性条件下脱异丙酮基,并在碱性条件下水解后与醋酸钙成盐得到阿托伐他汀钙(Ⅰ),3步反应总收率35.6%。经1HNMR鉴定,各中间体、产物与目标物均一致。Taking 1-(4-fluorophenyl)-5-methyl-2-phenyl-1,4-hexanedione(Ⅱ)and(4R-cis)-6-aminoethyl-2,2-dimethyl-1,3-dioxopentyclo-tert-butyl caproate(Ⅲ)as starting materials,we firstly obtained polysubstituted pyrrole ring compound 2-((4 R,6R)-2-(4-fluorophenyl)-5-isopropyl-3-phenyl-1 H-pyrrole)-1-(2,2-dimethyl-1,3-dioxo hexane oxide)-4-tert-butyl ester(Ⅳ)by Paal-Knorr reaction,and then obtained compound 2-((4 R,6R)-2-(4-fluorophenyl)-5-isopropyl-4-anilamoyl-3-phenyl-1 H-pyrrole)-1-(2,2-dimethyl-1,3-dioxoepoxyhexane)-4-tert-butyl ester(Ⅴ)through the reaction of compoundⅣwith phenylisocyanate.Finally,we obtained Atorvastatin calcium(Ⅰ)after the removal of isopropyl of compoundⅤunder acidic conditions,hydrolysis under alkaline conditions,and salt formation with calcium acetate.The total yield of there-step reaction is 35.6%.All the intermediates and the product are consistent with the target compounds by 1HNMR identification.

关 键 词：阿托伐他汀钙 羟甲基戊二酰辅酶A还原酶抑制剂 合成 优化 

分 类 号：TQ460[化学工程—制药化工]