降血脂药立普妥的合成路线优化

发布时间：2018-04-08 17:26

本文选题：立普妥　切入点：HMG-CoA还原酶抑制剂　出处：《复旦大学》2014年硕士论文

【摘要】：立普妥是一种他汀类药物,其通过抑制肝组织中,对合成胆固醇起关键作用的第一限速酶---3-羟基-3-甲基戊二酰酶A (HMG-CoA)的活性,使LDL粒子、血清胆固醇、LDL胆固醇水平下降从而有效治疗、预防高胆固醇血症和混合型高脂血症。本文主要进行了立普妥合成路线的优化,其关键步骤是在Pd-NHC的催化下,通过筛选溶剂,碱,反应时间,反应温度等实现了由碘代物(4R-cis)-6-[2-[2-(4-氟苯基)-5-(、1-异丙基)-3-苯基-4-碘-1H-吡咯-1-基]乙基]-2,2---甲基-1,3-二氧戊环-4-乙酸叔丁酯(化合物13)插羰反应直接构建(4R-cis)-6-[2-[2-(4-氟苯基)-5-(1-异丙基)-3-苯基-4-[(苯胺)羟基]-1H-吡咯-1-基]乙基]-2,2--甲基-1,3-二氧戊环-4-乙酸叔丁酯(化合物14)的酰胺键,收率为46.9%。同时我们优化了立普妥合成路线的前两步反应：Knoevenagel缩合反应和stetter反应。通过我们的优化,Knoevenagel缩合反应得收率提高到了95.4%,stetter反应的收率提高到了56.3%,即这两步的总收率提高到了53.7%,大大提高了前两步的总收率。
[Abstract]:Lipitor is a kind of statins that make LDL particles by inhibiting the activity of the first rate-limiting enzyme, 3-hydroxy-3-methyl-glutamylase A (HMG-CoA), which plays a key role in the synthesis of cholesterol in liver tissue.The decrease of serum cholesterol cholesterol level leads to effective treatment and prevention of hypercholesterolemia and mixed hyperlipidemia.In this paper, the synthesis route of Lipitor is optimized. The key step is to screen solvent, alkali and reaction time under the catalysis of Pd-NHC.Amide-bond of -4- [(aniline) hydroxyl] -1H-pyrrole -1- ethyl] -2O2-methyl-1- (3-dioxopentyl-3-dioxopentyl-4-acetate) tert-butyl ester (compound 14),The yield is 46.9%.At the same time, we optimized the first two steps of Lipitor synthesis: Knoevenagel condensation reaction and stetter reaction.Through our optimized Knoevenagel condensation reaction, the yield was increased to 56.3%, that is, the total yield of the two steps was increased to 53.7%, which greatly improved the total yield of the first two steps.
【学位授予单位】：复旦大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914.5

【共引文献】