卤代酮的合成.docVIP

经典化学合成反应标准操作 α-卤代酮的合成 编者：齐志奇 药明康德新药开发有限公司化学合成部 目 录 1．前言 2 2. 直接卤化 2 3．经重氮酮制备 4 4．从weinreb 酰胺制备 6 5．傅克酰基化合成卤代酮 7 6 其他合成α-卤代酮的方法 9 1．前言’-卤代酮的混合物。由于酮卤代的决定步骤是酮的烯醇化，因此，易形成烯醇的方向优先卤代。 例 2-甲基环己酮与亚硫酰氯作用， 多取代的α-氢优先氯代。 若利用双（二甲基乙酰胺基）三溴化氢做溴化剂，可使不对称酮在少取代一边溴代。 若将不对称酮首先转变成为一定构型的烯醇盐，继而卤代，是区域定向卤代的新方法。 另外，甲基酮可用甲基格式试剂与相应的Weinreb 酰胺来制备， 如下例即是先合成甲基酮，后溴化来合成α-溴代酮的。 合成实例一 A suspension of ketone 2A (700 mg, 2.17 mmol) in acetic acid (15 ml) was heated to 70℃, followed by addition of bromine (347 mg, 2.17 mmol). After the mixture was stirred at 70℃ for 3h, the solvent was evaporated and the residue was purified by column chromatography to give the compound 2B (591 mg, 68%). 合成实例二 Bromine (7.99 g, 50 mmol) in CHCl3 (20 ml) was added in a dropwise manner to a stirred solution of 2, 5-dimethoxy-4-bromoacetophenone 2C (12.95 g, 40 mmol) in CHCl3 (100 ml) at 5℃. After the addition was completed, the reaction mixture was allowed to warm to room temperature and stirred for an additional 2 h. The mixture was poured onto crushed ice, the organic portion was separated and washed with water, saturated NaHCO3 solution, and again with water. The solution was dried MgSO4, and evaporated to dryness under reduced pressure to give a crude product. The product was recrystallized from MeOH to yield 14.70 g (87%) of the desired bromoacetophenone 2D as a white solid. 合成实例三 To a solution of 1-(2-aminopyrimidin-4yl) ethanone (412 mg, 3 mmol) in glacial acetic acid (1 mL) and 48% aq. HBr (0.3 mL), bromine (0.153 mL) in acetic acid (0.4 mL) was added and the resulting orange solution was stirred at RT for1.5 hours. After diluting with ethyl acetate (15 mL), the precipitate was filtered and washed with ethl acetate thus affording the target compound as a whitish solid (580 mg, 65%). 合成实例四 Benzyltrimethylammonium tribromide (4.17 g, 10.7 mmol) was added to a solution of Compound 2E (4.00 g, 10.7 mmol) in CH2Cl2-MeOH (5:2, 25 mL). The mixture was stirred at RT for 3 h. At this time the reaction mixture