2-羟基-3-氟-4-三氟甲基吡啶的合成工艺改进

Improved Synthetic Process of 2-Hydroxy-3-Fluoro-4-(Trifluoromethyl)pyridine

报道了多拉韦林(doravirine MK-1439)的关键中间体2-羟基-3-氟-4-三氟甲基吡啶(HFTP-1)的新合成工艺。以3-氨基吡啶为起始原料,首先利用双氧水-盐酸体系对氨基邻位进行氯代反应得2-氯-3-氨基吡啶,其次采用改进的Balz-Schiemann反应得2-氯-3-氟吡啶,然后在二异丙胺基锂拔氢后碘取代得2-氯-3-氟-4-碘吡啶,最后由三氟甲基取代碘后再水解等一系列反应合成了目标化合物2-羟基-3-氟-4-三氟甲基吡啶,总收率48.6%(以3-氨基吡啶计)。该路线与目前报道的路线相比,起始原料廉价易得,工艺操作简便,产品收率高,质量稳定,非常适合工业化生产。

The synthetic process of 2-hydroxy-3-fluoro-4-(trifluoromethyl)pyridine(HFTP-1),a key intermediate of doravirine,was reported in this paper.Taking 3-aminopyridine as the starting material,chlorination reaction of amino ortho was carried out with H 2O 2-HCl system,2-chloro-3-fluoropyridine was obtained by improved Balz-schiemann reaction,and then trifluoromethyl was introduced after iodine substitution.Finally,(HFTP-1)was synthesized by hydrolysis of chlorine atoms,total yield of 48.6%(based on 3-aminopyridine).Compared with the reported route,this synthetic process was simple to operate,higher yield,and stable of the quality,which was more suitable for industrial production.