杂环酚羟基卤代-060114.docVIP

经典化学合成反应标准操作 杂环的酚羟基或醚的烷氧基卤代反应 编者： 李金鹏 药明康德新药开发有限公司化学合成部 目 录 ………………………………………………………………2 氯代………………………………………………………………2 2.1杂环的酚羟基的用三氯氧磷氯代反应示例……………………………2 2.2杂环的酚羟基用三氯氧磷与五氯化磷混合处理氯代反应示例………3 2.3杂环的酚醚甲氧基用三氯氧磷氯代反应示例………………………3 溴代………………………………………………………………4 3.1杂环的酚羟基用 POBr3溴代反应示例（一）………………………4 3.2杂环的酚羟基用 POBr3溴代反应示例（二）……………………………4 3.3杂环的酚羟基用四丁基溴化胺法溴代反应示例………………………5 3.4杂环的甲氧基用PBr3溴代反应示例………………………………5 参考文献…………………………………………………………6 1．前言 杂环的酚羟基的通常较易被卤代，其也是杂环一种常见的官能团的转换方式之一，卤代反应常见的有氯代、溴代反应。另外，在存在吸电子基的杂环上，不仅酚羟基容易被卤代，而且烷氧基（甲氧基，乙氧基等）也很容易被卤代。因此其也是合成的一种策略。经常有文献首先将杂环卤代物用甲氧基取代后，利用甲氧基推电子效应完成一系列转化后，再将甲氧基卤代回来。 2. 氯代 杂环的酚羟基的氯代一般用三氯氧磷1,2,3或三氯氧磷与五氯化磷混合4,5处理。使用五氯化磷的条件更强，用于难以发生的杂环的酚羟基的氯代反应。杂环烷氧基的氯代也可用三氯氧磷直接处理6. 2.1 杂环的酚羟基的用三氯氧磷氯代反应示例1 2-Hydroxy-3-iodo-5-nitropyridine 1 (70.5 g, 0.27 mol) was added to quinoline (16 mL, 0.133 mol). The reaction flask was cooled to 5 degree and phosphoryl chloride (25 mL, 0.27 mol) was added dropwise. The mixture was blanketed with argon and heated to 120 degree for 2 h. Upon complete consumption of the precursor, as indicated by TLC, the mixture was cooled to room temperature and 100 mL of H2O was added. The mixture was then cooled to 0 degree, and the resulting brown solid was filtered. Recrystallization from ethanol gave sand-color crystals 2 (60 g, 0.21mol, 78% yield). 2.2 杂环的酚羟基用三氯氧磷与五氯化磷混合处理氯代反应示例5 To a solution of 10.5 g of 1 in 16 mL of phosphorus oxychloride was heated to reflux and added 20 g of phosphorus pentachloride in small portions over a period of 1.5 hr. The oil bath temperature was then raised to 165 degree and kept there for 1 hr. The phosphorus oxychloride was removed under reduced pressure, 50 g of ice then added, and the mixture made strongly basic by adding a concentrated KOH solution. When this was steam distilled, a colorless heavy oil was obtained, which was separated by two extractions with 100-mL portions of ether. The ether was dried and removed, and the residue distilled, giving a colorless oil (4.0 g, 34%). 2.3 杂环的酚醚甲氧基用三氯氧