阿托伐他汀钙的合成研究

Synthesis of Atorvastatin Calcium

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.