步骤:在-70℃下,将正丁基锂(2.4M in THF,55.5mL)缓慢滴加至二异丙胺(24.64g)的THF(100mL)溶液中,滴加过程中确保反应体系温度不超过-70℃;滴加完毕后,缓慢升温至-10℃,随后再次冷却至-70℃;在-70℃下,向反应体系中加入2-溴-5-氟吡啶(19.48g)的THF(100mL)溶液,保持温度在-70℃并搅拌2小时;随后,缓慢滴加N,N-二甲基甲酰胺(16.3g),保持温度在-70℃并继续搅拌2小时;缓慢加入4M盐酸-二恶烷溶液(111mL),滴加过程中确保反应体系温度不超过-70℃;反应完成后,用乙酸乙酯稀释反应混合物,依次用水和饱和盐水溶液洗涤;分离有机相,用无水硫酸钠干燥,过滤后减压浓缩滤液;最后,通过硅胶柱色谱纯化残余物,得到目标产物2-溴-5-氟-4-吡啶甲醛(20.28g)。
收率:20.28g
条件:Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran at -70 - -10℃; for 2 h; Stage #2: at -70℃; for 2 h;
参考文献:[1] Patent: WO2009/10801, 2009, A1. Location in patent: Page/Page column 69-70 [2] Patent: WO2016/128529, 2016, A1. Location in patent: Paragraph 0732; 0733; 0734 [3] Patent: WO2018/15410, 2018, A1. Location in patent: Paragraph 0185-0188 [4] Patent: CN108003161, 2018, A. Location in patent: Paragraph 0700; 0702-0704