3’-氨基-2’-羟基联苯-3-羧酸的合成工艺改进

Improved Synthetic Process of 3’-Amino-2’-hydroxybiphenyl-3-carboxylic Acid

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.