胆固醇吸收抑制剂Ezetimibe合成工艺研究

Study on the Synthesis of Ezetimibe

目的合成胆固醇吸收抑制剂Ezetimibe。方法以戊二酸酐和氟苯为始原料,经傅克反应、酯化、羰基还原、水解、内酯化得到(6S)-6-(4-氟苯基)四氢-2H-吡喃-2-酮,(6S)-6-(4-氟苯基)四氢-2H-吡喃-2-酮与4-苄氧基苯亚甲基-4-氟苯胺反应得到反1-(4-氟苯基)-3-[3(S)-(4-氟苯基-3-羟基丙基)-4-(4-苄氧基苯基)2-氮杂环丁酮,反1-(4-氟苯基)-3-[3(S)-(4-氟苯基-3-羟基丙基)-4-(4-苄氧基苯基)2-氮杂环丁酮再经脱苄、拆分后得到Ezetimibe。结果与结论目标化合物的结构经1H-NMR、MS谱等确证,总收率为18.6%。经改进,步骤中的酯化、还原、成环、脱苄步骤均得到有效优化,较大的降低了合成难度。

:OBJECTIVE To synthesize ezetimibe.METHODS Starting from dihydro-2H-pyran-2,6(3H)-dione and fluorobenzene,(S)-6-(4-fluorophenyl)tetrahydro-2H-pyran-2-one was obtained by Friedel-Crafts acylation,esterification,carbonyl reduction,hydrolysis and lactonization.The obtained pyran coupled with(E)-N-(4-(benzyloxy)benzylidene)-4-fluoroaniline to give 4-(4-(benzyloxy)phenyl)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)azetidin-2-one.And then it was followed by debenzylation and resolution of the racemates to yield the target compound ezetimibe.RESULTS and CONCLUISON The overall yield of this method is 18.6%.The esterification,carbonyl reduction,annelation and debenzylation in the process were optimized well.