盐酸厄洛替尼的合成  

Synthesis of Erlotinib Hydrochloride

作　　者：陈宁 CHEN Ning(Hainan Jianke Pharmaceutical Co.,Ltd.,Hainan Haikou 571200,China)

机构地区：[1]海南建科药业有限公司,海南海口571200

出　　处：《广州化工》2023年第10期44-47,共4页GuangZhou Chemical Industry

摘　　要：通过对盐酸厄洛替尼的合成研究,确定了盐酸厄洛替尼的合成路线,并可以用于工业化生产。该工艺条件与其他路线比较,具有起始原料易得、反应条件温和、产品收率高、操作简便等优点。即以盐酸厄洛替尼的合成以2-硝基-4,5-二-甲氧乙氧基苯甲腈(ErSM1)为起始原料,先通过保险粉(Na_(2)S_(2) O_(4) )还原,乙酸乙酯/正己烷重结晶纯化得到2-胺基-4,5-二-甲氧乙氧基苯甲腈(ErM1),然后2-胺基-4,5-二-甲氧乙氧基苯甲腈(ErM1)与DMF-DMA高温下反应,减压蒸馏后得到ErM2,ErM2与3-氨基苯乙炔以冰醋酸为溶剂高温下反应得到粗品ErM3,后重结晶纯化得到ErM3,ErM3在甲醇中滴加盐酸得到盐酸厄洛替尼粗品,经过重结晶生成盐酸厄洛替尼成品,结构经1 H-NMR确认,总收率55%,含量大于99.9%,产品质量符合2020版药典要求。Through the research on the synthesis of erlotinib hydrochloride,the synthetic route of erlotinib hydrochloride was determined,and it could be used for industrial production.Compared with other routes,the process conditions had the advantages of easy availability of starting materials,mild reaction conditions,high product yield,and simple operation.That was,the synthesis of erlotinib hydrochloride took 2-nitro-4,5-di-methoxyethoxybenzonitrile(ErSM1)as the starting material,first reduced it by sodium hydrosulfite(Na_(2) S_(2) O_(4) ),ethyl acetate/recrystallization and purification of n-hexane gave 2-amino-4,5-di-methoxyethoxybenzonitrile(ErM1),then 2-amino-4,5-di-methoxyethoxybenzonitrile(ErM1)reacted with DMF-DMA at high temperature,obtained ErM2 after vacuum distillation,ErM2 and 3-aminophenylacetylene were reacted with glacial acetic acid at high temperature to obtain crude product ErM3,then recrystallized and purified to obtain ErM3,ErM3 was added dropwise hydrochloric acid in methanol.The crude erlotinib hydrochloride was obtained,which was recrystallized to generate the finished erlotinib hydrochloride.The structure was confirmed by 1H-NMR.The total yield was 55%,and the content was greater than 99.9%.The product quality met the requirements of the 2020 edition of the Pharmacopoeia.

关 键 词：盐酸厄洛替尼 合成 工艺研究 

分 类 号：R972[医药卫生—药品]