杂环的酚羟基的卤代

1、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1 前言22 氯代22.1杂环的酚羟基的用三氯氧磷氯代反应示例22.2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32.3杂环的酚醚甲氧基用三氯氧磷氯代反应示例33 溴代43.1杂环的酚羟基用 POBr3溴代反应示例（一）43.2杂环的酚羟基用 POBr3溴代反应示例（二）43.3杂环的酚羟基用四丁基溴化胺法溴代反应示例53.4杂环的甲氧基用PBr3溴代反应示例54 参考文献61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

2、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12-Hydroxy-3-iodo-5-nitropyridine 1 (70.5 g, 0.27 mol) was added

3、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 r

4、oom 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 o

5、xychloride 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

6、 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

7、的酚醚甲氧基用三氯氧磷氯代反应示例6A mixture of 1 (10 mmol) and phosphoryl chloride (20 mL) was refluxed for 0.5 hr. Then the excess of phosphoryl chloride was evaporated in vacuo. The residue was carefully poured onto ice (30 g) and neutralized with conc. ammonia at 0-5 degree. The solid was filtered off, washed wi

8、th water and air-dried. The product was purified by crystallized from ethanol to give 86-94% yields.3溴代杂环的酚羟基的溴代常见的方法有用三溴氧磷7,8或四丁基溴化胺9。杂环烷氧基的溴代也可用三溴氧磷处理10.3.1 杂环的酚羟基用 POBr3溴代反应示例一7A stirred mixture of 1 (0.8 g, 4.25 mmol) and freshly prepared POBr3 (8.0 g, 28 mmol) in anisole (8.0 mL) was heated at

9、145 degree for 2 days. After cooling, the reaction mixture was poured into ice water (300 mL) and basified with saturated sodium carbonate solution until the PH was 8-9. The mixture was extracted with CH2Cl2 (3 x 300 mL); the combined extracts were dried over anhydrous sodium sulfate and evaporated

10、in vacuo. Purification of the residue by flash chromatography (silica gel, 1:1 CH2Cl2: Et2O) and recrystallization from ethanol gave bromide 2 (0.831 g, 60%) as colorless, fine needles.3.2 杂环的酚羟基用 POBr3溴代反应示例二8Phosphorus oxybromide (25.0 g, 87.2 mmol) was added to toluene (55 mL) at room temperature

11、. Next, 1 (21.1 g, 79.3 mmol) and quinoline (9.5 mL) were added consecutively to mechanically stirred reaction mixture to 90-100 degree. The vigorous reaction was monitored by TLC (ethyl acetate/hexane 5:15). After reaction completion, the toluene layer was separated. The remaining brownish solid wa

12、s extracted with boiling toluene (3 x 260 mL). The combined toluene solutions were washed with 5% aqueous NaHCO3, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation. Flash column chromatography (95:5 hexane/ethyl acetate) workup gave 2 (21.1 g, 81.1%) as a yellow solid.3.3 杂

13、环的酚羟基用四丁基溴化胺法溴代反应示例91 (177 g, 1.01 mol), phosporus pentoxide (300 g, 1.06 mol) and tetrabutyl ammonium bromide (391 g, 1.21 mol) was mixed in toluene (2 L) and heated to reflux for 4 h. The mixture was cooled to room temperature and water (1 L) was added carefully with stirring and cooling. The mixt

14、ure was stirred for 2 h and then filtered through a pad of Celite, and the layers were separated. The toluene layer was washed with brine and concentrated in vacuo. The product was passed through a pad of silica gel (50 g) and eluted with ethyl acetate:hexane (10:1) to give 202 g (84% yield) of 2 as

15、 a clear yellow oil.3.4 杂环的甲氧基用PBr3溴代反应示例10Phosphorus tribromide (3 mL) was added to a solution of 1 (1.3 g) in DMF (30 mL) in an ice bath. The reaction was further stirred for 2 hr at 80 degree and then poured into ice-water. The aqueous mixture was made alkaline with NaOH and extracted with CH2Cl2

16、. The extract was washed with brine, dried and evaporated. The residue was chromatographed on silica gel using CH2Cl2acetone (50:1) as an eluent to give product 2 (1.04 g, 65%). 参考文献：1. J. Med. Chem.; 45; 13; 2002; 2841-2849.2. J. Org. Chem.; 68; 18; 2003; 6919-6927.3. J. Med. Chem.; 43; 22; 2000; 4288-4312.4. J. Amer. Chem. Soc.; 70; 1948; 1494-1497.5. J. Amer.