降脂药非诺贝特的工艺改进

Improved synthesis of fenofibrate as the lipid-lowering drug

摘要:

摘要：以对氯苯甲酰氯为原料，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，继而水解生成4-氯-4'-羟基二苯甲酮，4-氯-4'-羟基二苯甲酮再与丙酮、氯仿缩合得到非诺贝特酸；非诺贝特酸再和异丙醇酯化生成非诺贝特，进一步纯化后制备非诺贝特晶体。采用MS、FTIR、X 单晶衍射、1HNMR和13CNMR对产物结构进行表征；并用X射线单晶衍射仪解析了非诺贝特晶体结构。考察了投料量、反应温度以及精制溶剂等因素对非诺贝特中间体及非诺贝特收率的影响。结果表明，合成4-氯-4'-甲氧基二苯甲酮的优化条件为：n(苯甲醚)∶n(三氯化铁)∶n(对氯苯甲酰氯)=4.0∶0.0125∶1.0，145~155 ℃反应6 h；合成非诺贝特酸的优化条件为：n(氯仿)∶n(4-氯-4'-羟基二苯甲酮)=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(非诺贝特酸)∶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%。

Abstract:

Abstract: Using p-chlorobenzyl chloride as raw material, Friedel-Crafts acylation of anisole and p-chlorobenzoyl chloride was catalyzed by FeCl3, followed by hydrolysis to produce 4-chloro-4 '- hydroxybenzophenone, which reacted with acetone and chloroform by condensation to obtain fenofibrate acid. And then fenofibrate was synthesized by esterification with fenofibrate acid and isopropanol and further purification to prepare fenofibrate crystals. The structure of the product was characterized by MS, FTIR, X-ray diffraction, 1HNMR and 13CNMR. The crystal structure of fenofibrate was analyzed by X-ray crystal structure analysis. The effects of feed rate, reaction temperature and refining solvent on the yield were investigated. The optimum conditions for the synthesis of 4-chloro-4'- methoxy benzophenone are as follows: n(anisole):n(FeCl3):n(4-chlorobenzoyl chloride)=4.0:0.0125:1.0, acylation under 145~155 ℃ for 6h. The optimized conditions for synthesis of fenofibrate acid were as follows: n(CHCl3):n(4-chloro-4'-hydroxybenzophenone)=2.5:1.0, and crystallization with toluene at 10 ℃. The optimized conditions for synthesis of fenofibrate were as follows: n(fenofibrate acid):n(isopropyl alcohol):n(H2SO4)=1.0:3.0:2.0, purification with isopropyl alcohol to obtain crystals. The total yield and content of fenofibrate were 56.17% and 99.93%, respectively.