依折麦布关键中间体的合成工艺优化  

Optimization on synthesis of key intermediate for ezetimibe

作　　者：柯浩 杨汉跃 闫显光 李树亮 张珍明 李润莱 KE Hao;YANG Hanyue;YAN Xianguang;LI Shuliang;ZHANG Zhenming;LI Runlai(School of Pharmacy,Jiangsu Ocean University,Lianyungang 222005,Jiangsu,China;Jiangsu Deyuan Pharmaceutical Co.,Ltd.,Lianyungang 222047,Jiangsu,China;College of Polymer Science and Engineering,Sichuan University,Chengdu 610065,Sichuan,China;School of Environmental and Chemical Engineering,Jiangsu Ocean University,Lianyungang 222005,Jiangsu,China)

机构地区：[1]江苏海洋大学药学院,江苏连云港222005 [2]江苏德源药业股份有限公司,江苏连云港222047 [3]四川大学高分子科学与工程学院,四川成都610065 [4]江苏海洋大学环境与化学工程学院,江苏连云港222005

出　　处：《精细化工》2022年第2期426-432,共7页Fine Chemicals

基　　金：国家自然科学基金青年基金项目(52103042);江苏省苏北科技专项(SZ-LYG202017);江苏海洋大学博士启动基金(KQ16001);连云港市“花果山英才计划”科技副总项目资助(201953);江苏省研究生科研与实践创新计划(SJCX20_1229,KYCX20_2958,KYCX20_2960,SJCX20_1218,SJCX20_1219,SJCX20_1227);江苏省大学生创新项目(SY202111641637002,SZ202111641640001,SY202111641637005,SY202111641637006)。

摘　　要：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.

关 键 词：依折麦布中间体 羟基保护 工艺优化 类Mannich反应 精细化工中间体 

分 类 号：TQ460.6[化学工程—制药化工]