降脂药非诺贝特的合成工艺改进  

Improved synthesis of fenofibrate as lipid-lowering drug

作　　者：满莉莉 李树亮 杨汉跃 闫显光 董淑波 张珍明 MAN Lili;LI Shuliang;YANG Hanyue;YAN Xianguang;DONG Shubo;ZHANG Zhenming(School of Pharmacy,Jiangsu Ocean University,Lianyungang 222005,Jiangsu,China;Jiangsu Deyuan Pharmaceutical Co.,Ltd.,Lianyungang 222047,Jiangsu,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]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》2023年第7期1505-1512,共8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);连云港市“花果山英才计划科技副总项目资助”(2019.12);江苏省大学生创新项目(SZ202111641640001)。

摘　　要：首先,FeCl3催化苯甲醚和对氯苯甲酰氯发生Friedel-Crafts酰基化反应生成4-氯-4’-甲氧基二苯甲酮(Ⅰ);接着,中间体Ⅰ水解生成4-氯-4’-羟基二苯甲酮(Ⅱ);然后,化合物Ⅱ与丙酮、氯仿缩合得到非诺贝特酸(Ⅲ);最后,中间体Ⅲ与异丙醇酯化生成产物非诺贝特(Ⅳ),进一步纯化后制备非诺贝特晶体。采用MS、FTIR、XRD、1HNMR和13CNMR对产物进行了表征;并用XRD解析了非诺贝特晶体结构。考察了反应条件对中间体及非诺贝特收率的影响。结果表明,合成中间体Ⅰ的优化条件为:n(苯甲醚)∶n(FeCl3)∶n(对氯苯甲酰氯)=4.0∶0.0125∶1.0,145~155℃反应6 h;合成中间体Ⅲ的优化条件为:n(氯仿)∶n(Ⅱ)=2.5∶1.0,析晶温度为10℃,析晶溶剂为甲苯;合成非诺贝特的优化条件为:n(Ⅲ)∶n(异丙醇)∶n(浓硫酸)=1.0∶3.0∶2.0,用异丙醇精制得到非诺贝特晶体。非诺贝特的总收率可达56.17%(以对氯苯甲酰氯计),产物HPLC纯度达99.93%。Intermediate 4-chloro-4'-methoxybenzophenone(I)was firstly synthesized from Friedel-Crafts acylation of anisole and p-chlorobenzoyl chloride catalyzed by FeCl3,and hydrolyzed to produce 4-chloro-4'-hydroxybenzophenone(II),which was further used to synthesize was fenofibrate acid(II)via condensation reaction with acetone and chloroform.Finally,target product fenofibrate was obtained by esterification between intermediate II and isopropanol,and purified to produce fenofibrate crystals.The product was characterized by MS,FTIR,XRD,'HNMR and 13CNMR,and the crystal structure was analyzed by XRD.The influence of reaction conditions on the yields of intermediates and final product were also investigated.The results showed that the optimum conditions for the synthesis of intermediate I were obtained as follows:n(anisole):n(FeCl3):n(4-chlorobenzoyl chloride)-4.0:0.0125:1.0,reaction temperature of 145~155°C,and reaction time of 6 h,while that of intermediate II were n(CHCl3):n(II)-2.5:1.0,and crystallization with toluene as solvent at 10 C.Under the optimized conditions for fenofibrate(IV)synthesis of n(II):n(isopropyl alcohol):n(H2SO4)=1.0:3.0:2.0 and purification with isopropyl alcohol,the total yield(based on p-chlorobenzoyl chloride)and HPLC purity of fenofibrate obtained were 56.17%and 99.93%,respectively.

关 键 词：非诺贝特 非诺贝特酸 工艺优化 酰基化 晶体制备 医药原料 

分 类 号：TQ460.6[化学工程—制药化工]