依折麦布关键中间体的合成工艺优化

Optimization on synthesis of key intermediate for ezetimibe

分别使用三甲基氯硅烷和N,O-双三甲基甲硅烷基乙酰胺对(4S)-3-[(5S)-5-(4-氟苯基)-5-羟基戊酰基]-4-苯基-1,3-氧氮杂环戊烷-2-酮(Ⅱ)和4-{[(4-氟苯基)亚胺]甲基}-苯酚(Ⅲ)的羟基进行保护,然后以TiCl_(4)为催化剂、二氯甲烷为溶剂,经类Mannich反应得依折麦布关键中间体(S)-3-{(2R,5S)-5-(4-氟苯基)-2-((S)-[(4-氟苯基)氨基]{4-[(三甲基硅基)氧基]苯基}甲基)-5-[(三甲基硅基)氧基]戊酰基}-4-苯基噁唑烷-2-酮(Ⅰ)。用^(1)HNMR、^(13)CNMR、MS、FTIR及旋光仪对产物结构进行了表征。采用单因素法考察了反应物物质的量比及反应温度对Ⅰ收率的影响,得到的最佳工艺条件为:n(Ⅱ)∶n(Ⅲ)∶n(TiCl_(4))=1.0∶1.5∶1.2,反应时间为4.0 h,反应温度为–30~–25℃。在此条件下产物Ⅰ收率可达63.17%(以Ⅱ物质的量计),产物HPLC纯度达97.28%;一次精制后纯度达98.96%。

Hydroxyl groups in(4 S)-3-[(5 S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyl-1,3-oxazolidin-2-one(Ⅱ)and 4-{[(4-fluorophenyl)imino]methyl}phenol(Ⅲ)were protected by chlorotrimethylsilane and N,O-bis(trimethylsilyl)acetamide,respectively.Then key intermediate of ezetimibe,(S)-3-{(2 R,5 S)-5-(4-fluorophenyl)-2-((S)-[(4-fluorophenyl)amino]{4-[(trimethylsilyl)oxy]phenyl}methyl)-5-[(trimethylsilyl)oxy]pentanoyl}-4-phenyloxazolidin-2-one(Ⅰ)was obtained by Mannich-like reaction with TiCl_(4) as catalyst and dichloromethane as solvent.The structure of product was characterized by ^(1)HNMR,^(13)CNMR,MS,FTIR and polarimeter.The effects of molar ratio of reactants and reaction temperature on the yield of productⅠwere investigated by single factor method.The optimum conditions were obtained as follows:n(Ⅱ)∶n(Ⅲ)∶n(TiCl_(4))=1.0∶1.5∶1.2,reaction time of 4.0 h,reaction temperature between–30 and–25℃.Under the above conditions,productⅠhad a yield of 63.17%and HPLC purity of 97.28%.The purity ofⅠcould be improved to 98.96%after one refination.