依则替米贝的合成工艺改进

Improved synthesis of ezetimibe

目的改进降血脂药依则替米贝的合成工艺。方法以对羟基苯甲醛为起始原料,经羟基保护、缩合、环合3步反应制得中间体trans-1-(4-氟苯基)-3-(2-氯甲基)-4-(4-苄氧基苯基)-2-氮杂环丁酮(4);以对氟扁桃酸为起始原料,经还原、溴代、羟基保护3步反应得到中间体(R)-α-三甲基硅氧基-4-氟苯基溴乙烷(7);中间体4和7经偶联反应得到目标产物依则替米贝。结果与结论中间体和目标物的结构经质谱、核磁共振氢谱确证,总收率为3.4%(以对羟基苯甲醛计)。新合成路线起始原料价格低廉、操作简便、收率高、反应条件温和,适合工业化生产。

Ezetimibe, whose chemical name is 1 - （ 4-fluorophenyl ） -3 （ R ） - [ 3 （ S ） -hydroxy-3- （ 4-fluorophe- nyl ） -propyl ] -4 （S） - （ 2,4-dihydroxyphenyl ） -2-azetidinone, has recently been commercialized as an effective acyl-CoA cholesterol acyltransferase inhibitor for lowering cholesterol levels. It was synthesized starting from 4-hydroxybenzaldehyde via 9 steps. The intermediate 4 was synthesized from 4-hydroxybenzaldehyde via al- kylation, condensation and cyclization. Another key intermediate 7 was prepared from 4-fluoromandelic acid via reduction,halogenation and protection. Compound 7 was coupled with 4 to afford ezetimibe after depro- tection and resolution. The overall yield of the target compound was 3.4% （ calculated by 4-hydroxybenzal- dehyde）, and its structure was confirmed by ~H-NMR and MS analysis. The developed method has some ad- vantages such as simple starting materials, mild reaction conditions, ease operations and high yield.