依托度酸的合成工艺优化  

Improved Synthetic Process of Etodolac

作　　者：张乃华 鲍广龙 聂建兵 王伟 张贵民 ZHANG Naihua;BAO Guanglong;NIE Jianbing;WANG Wei;ZHANG Guimin(National Engineering and Technology Research Center of Chirality Pharmaceutical,Shandong New Time Pharmaceutical Co.,Ltd.,Linyi 273400)

机构地区：[1]国家手性制药工程技术研究中心,山东新时代药业有限公司,山东临沂273400

出　　处：《中国医药工业杂志》2021年第4期495-498,共4页Chinese Journal of Pharmaceuticals

摘　　要：本研究改进了依托度酸(1)的合成工艺。以邻乙基溴苯(3)为起始原料,经水合肼肼解后成盐精制制得邻乙基苯肼盐酸盐(4),4在碱性条件下游离后经Amberlyst 15树脂催化与2,3-二氢呋喃(5)反应生成7-乙基色醇(2),2不经分离与3-氧代戊酸甲酯(6)缩合环化得依托度酸甲酯(7),最后水解制得目标产品1,纯度99.91%,总收率68%(以5计)。其中由3制备2的方法未见文献报道,改进后的工艺操作简便,缩短了生产周期,已经公斤级放大验证,适合工业化生产。The synthetic process of etodolac(1)was improved.o-Ethyl phenylhydrazine hydrochloride(4)was obtained from o-ethyl bromobenzene(3)by hydrazinolysis of hydrazine hydrate and salification,and then free 4 in alkaline condition reacted with 2,3-dihydrofuran(5)on exposure to Amberlyst 15 ion-exchange resin to afford 7-ethyltryptophol(2).Without separation,2 was condensed with methyl 3-oxovanoate(6)to obtain methyl etodolate(7),and followed by hydrolysis to get the target compound 1 with a total yield of 68%(based on 5)and a purity of 99.91%.The synthetic method for 2 from 3 has not yet been found in literature.The optimized process had simple operation,and shortened production cycle,which has been verified by kilogram scale-up and was suitable for industrial production.

关 键 词：依托度酸 非甾体抗炎药 合成工艺 

分 类 号：R914.5[医药卫生—药物化学] R971.1[医药卫生—药学]