摘要
本研究改进了艾曲波帕的关键中间体 3’-氨基-2’-羟基联苯-3-羧酸(1)的合成工艺。2-溴-6-硝基苯酚(2)经硫酸二甲酯保护羟基后得1-溴-2-甲氧基-3-硝基苯(3),再和3-羧基苯硼酸(4)经Suzuki偶联得2’-甲氧基-3’-硝基联苯-3-羧酸(5),5在氢溴酸和乙酸体系中回流得2’-羟基-3’-硝基联苯-3-羧酸(6),6经雷尼镍/氢气还原得1,纯度达99.82%,总收率84%(以2计)。本工艺在还原6的硝基时采用雷尼镍/氢气体系常压下即可进行,避免了高压操作。该路线条件温和,操作简单,产品纯度高,适合工业化生产。
The synthetic process of 3’-amino-2’-hydroxybiphenyl-3-carboxylic acid(1),a key intermediate of eltrombopag,was improved in this report.2-Bromo-6-nitrophenol(2) was subjected to hydroxyl protection to give 1-bromo-2-methoxy-3-nitrobenzene(3),which was further treated with 3-carboxyphenylboronic acid(4) to afford 2’-methoxy-3’-nitrobiphenyl-3-carboxylic acid(5) via Suzuki coupling reaction.Compound 5 was refluxing in the mixed solution of hydrobromic acid and acetic acid to obtain 2’-hydroxy-3’-nitrobiphenyl-3-carboxylic acid(6),then followed by reduction with Raney nickel/hydrogen to give 1 with a purity of 99.82% and a total yield of 84%(based on 2).In this process,Raney nickel/hydrogen system was used to the redution of 6 under normal pressure condition,thus avoiding high pressure operation.This synthetic route had some advantages of mild reaction condition,simple operation and high purity of the product,which were more suitable for industrial production.
作者
高纪
王国瑞
臧超
张贵民
GAO Ji;WANG Guorui;ZANG Chao;ZHANG Guimin(National Engineering and Technology Research Center of Chirality Pharmaceutical,Lunan Pharmaceutical Co.,Ltd.,Linyi 273400)
出处
《中国医药工业杂志》
CAS
CSCD
北大核心
2020年第9期1147-1149,共3页
Chinese Journal of Pharmaceuticals
