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1、经典合成反应标准操作腈的合成 药明康德新药开发有限公司经典化学合成反应标准操作腈的合成编者： 江志赶药明康德新药开发有限公司化学合成部目 录1 前言42 酰胺的脱水42.1用P2O5为脱水剂的反应实例42.2用POCl3为脱水剂的反应实例52.3用SOCl2为脱水剂的反应实例52.4用PCl5为脱水剂的反应实例62.5用Bugess 试剂为脱水剂的反应实例62.6用TFAA-NEt3为脱水剂的反应实例72.7用(COCl) 2-NEt3-DMSO为脱水剂的反应实例72.8用CH3SO2Cl为脱水剂的反应实例82.9用TiCl4为脱水剂的反应实例82.10 叔丁酰胺脱水为腈 93 脂肪卤代烃或磺
2、酸酯的反应 103.1脂肪卤代烃的氰基取代的反应示例113.2磺酸酯的氰基取代的反应示例114. 用TMSCN转化羟基到腈 124.1 TMSCN双芳基甲醇氰化反应示例124.2 TMSCN单芳基甲醇氰化反应示例125. 用TosMIC直接从酮转化为氰基 136. 用2,4,6-三异丙基磺酰肼-KCN将酮转化为氰基147.芳香卤代烃在金属催化作用下的腈化反应147.1 钯催化下芳香卤代烃或（TfO-）氰基取代反应 147.2 Cu催化下芳香卤代烃或（TfO-）和K4Fe(CN)6反应氰基取代167.3 微波反应芳卤氰基化168. 肟脱水生成腈171. 前言腈类化合物是很多药物的合成中间体，而腈
3、的合成是有机合成中非常重要的一部分，它一般经由如下几种方法制备：1. 酰胺的脱水2. 脂肪卤代烃或磺酸酯的反应3芳香卤代烃的氰基取代4其他羟基或肟到腈的转化下面分别进行阐述。2. 酰胺的脱水反应酰胺的脱水反应可在P2O5、POCl3、SOCl2、PCl5等脱水剂存在下进行脱水反应生成腈，此为实验室合成腈的方法之一。将酰胺与P2O5的混合物加热，反应毕将生成的腈蒸出可得到良好的收率。SOCl2最适宜于处理高级的酰胺，这是由于副产物均为气体，易于除去，因而减少精制腈的困难。同时，以上这些脱水试剂多在酸性条件下反应，对于酸敏感的底物是不实用的，因此人们也开发了许多更加温和的方法用于酰胺的脱水，如：B
4、urgess reagent Et3N+SO2N-COOMe，三氟醋酸酐(TFAA)三乙胺，(COCl)2-NEt3-DMSO等条件可以在低温和几乎中性的条件下反应。还有甲烷磺酰氯(CH3SO2Cl)，四氯化钛(TiCl4) 等等。2.1 用P2O5为脱水剂的反应实例A solution of 35g (0.16 mol) of 2-(2-ethyl-3-benzofuranyl)-propionamide in 500ml of toluene was refuxed for 18 hours in the presence of P2O5. The organic phase was de
5、canted off and the residue was carefully decomposed with ice-water and extracted with ether. The organic phase was washed with water, dried over sodium sulphate and added to the toluenic phase. The solvent was evaporated off under reduced pressure and the residue was fractionated to give 23.8g of 2-
6、(2-ethyl-3-benzofuranyl)-propionitrile (yield 74.4%, boiling point: 105.deg. C. at0.2 mmHg).Reference: US4124710 A1 (1978/11/07)2.2 用POCl3为脱水剂的反应实例 A mixture of 2-chloro-1,3,4-thiadiazole-5-carboxamide (1.4 g) in 17 ml of POCl3 is heated at reflux for 18 hours. The reaction mixture is concentrated a
7、nd the residue is suspended in 25 ml of ethyl acetate. The suspension is cooled in an ice bath and neutralized with saturated, aqueous NaHCO3 (to pH 7). The phases are separated and the aqueous phase is extracted with 20 ml of ethyl acetate. The combined organic phases are dried over MgSO4, filtered
8、 and concentrated. The residue is purified by column chromatography (using 30 percent ethyl acetate / hexane as eluent) to afford 0.832 g of 2-cyano-5-chloro-1,3,4-thiadiazole. MP: 65-67. deg.CReference: Patent; EP883611 B1 (2002/07/31) 2.3 用SOCl2为脱水剂的反应实例A solution of thionyl chloride (7.70 g, 0.06
9、5 mol) in dry DMF (10 ml) was added dropwise to a stirred solution of compound 13 (4.20 g, 0.013 mol) in dry DMF (25 ml) at room temperature. The stirred mixture was heated at 120C for 3 h and poured into icewater. The product was extracted into ether (twice) and the combined ethereal extracts were
10、washed with water, saturated sodium hydrogen carbonate solution, water, and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by column chromatography (silica gellight petroleum (bp 4060 8C) with the gradual introduction of dichloromethane) to yield a colourless solid. Yie
11、ld 2.88 g (68%);Reference: J. Chem. Soc., Perkin Trans. 1, 1998, 347934842.4 用PCl5为脱水剂的反应实例4-Oxo-4H-9-oxa-1,4a-diaza-fluorene-3-carboxylic acid amide (4.58 g, 20 mmol) was suspended in 150 ml of anhydrous DMF, PC15 (5.0 g, 24 mmol) was added, and the mixture was stirred for 2 h at 40-50 oC. The reac
12、tion mixture was poured into 600 ml ice-water to yield a solid, which was collected by filtration. The solid was washed thoroughly (first with saturated aqueous NaHCO3, then with water) and dried to give 4-oxo-4H-9-oxa-1,4a-diaza- fluorene-3-carbonitrile.Ref: J . Med. Chem. 1983, 26, 608-6112.5 用Bug
13、ess试剂为脱水剂的反应实例To a solution of 2-tetrazol-1-yl-benzamide (1.5 g, 7.9 mmol) in tetrahydrofuran (50 ml) was added Et3N+SO2N-COOMe (2.8 g, 11.8 mmol) in three portions over 1.5 h.Water was added and the reaction mixture was extracted with ethyl acetate. The combined organic layers were washed with brin
14、e and water. After drying and filtration, the solvent was evaporated to give 2-tetrazol-1-yl-benzonitrile.Reference: J. Med. Chem. 47, 12, 2004, 2995-3008.Preparation of Bugess reagent:将无水甲醇19.2g (0.6 mol) 和无水苯40mL的混合物在30-40分钟内，滴入ClSO2NCO85g (52.3 mL, 0.6 mol)和无水苯200mL的混合物中，控温10-15。加毕，室温搅拌2小时。然后加入1000mL无水苯稀释后，小心滴入190mL无水三乙胺和250mL无水苯的混合物中，控温10-15，约40分钟左右加完。加毕，室温搅拌2小时，析出大量固体。反应毕，过滤，固体用无水苯200mL、无水THF200mL洗后，滤液浓缩后，（控温
