碘催化芳基重排法合成2-(4-溴甲基苯基)丙酸

Synthesis of 2-(4-Bromomethylphenyl)propionic Acid via Iodine-catalyzed Aryl Rearrangement

对洛索洛芬钠的关键中间体2-(4-溴甲基苯基)丙酸的合成工艺进行了改进研究。甲苯与丙酰氯经Friedel-Crafts反应生成1-(4-甲基苯基)-1-丙酮,收率87.8%;1-(4-甲基苯基)-1-丙酮与碘和原甲酸三乙酯进行芳基重排反应,生成2-(4-甲基苯基)丙酸乙酯,收率88%;2-(4-甲基苯基)丙酸乙酯在氢氧化钾-甲醇-水体系中水解生成2-(4-甲基苯基)丙酸,收率93%;2-(4-甲基苯基)丙酸在偶氮双异丁腈引发下于四氯化碳-石油醚二元溶剂体系中,用N-溴代琥珀酰亚胺溴化,收率72.9%,四步反应总收率58.6%。反应步骤少、操作简便、原料易得。

improved synthesis of 2-（ 4-bromomethylphenyl ）propionic acid, the key intermediate for loxoprofen sodium, was investigated. Toluene reacted with propionyl chloride to give 1-（ 4- methylphenyl）-1-propanone in 87.8% yield, which was treated with iodine and triethyl orthoformate to give ethyl 2-（4-methylphenyl） propionate in 88% yield. Ethyl 2-（4-methyl phenyl） propionate was hydrolysed in KOH-MeOH-H2O to afford 2-（4-methylphenyl）propionic acid in 93% yield followed by bromination with NBS and AIBN in CCl4-petroleum ether to give 2-（4-bromomethylphenyl） propionic acid in 72.9% yield. The total yield was 58.6%. This is an efficient synthetic route of only few steps and convenient operations with readily available reagents.