腈的合成-060303讲解

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 (4)

2．酰胺的脱水 (4)

2.1用P2O5为脱水剂的反应实例 (4)

2.2用POCl3为脱水剂的反应实例 (5)

2.3用SOCl2为脱水剂的反应实例 (5)

2.4用PCl5为脱水剂的反应实例 (6)

2.5用B u ge s s试剂为脱水剂的反应实例 (6)

2.6用TFAA-NEt3为脱水剂的反应实例 (7)

2.7用(COCl)2-NEt3-DMSO为脱水剂的反应实例 (7)

2.8用CH3SO2Cl为脱水剂的反应实例 (8)

2.9用TiCl4为脱水剂的反应实例 (8)

2.10 叔丁酰胺脱水为腈 (9)

3．脂肪卤代烃或磺酸酯的反应 (10)

3.1脂肪卤代烃的氰基取代的反应示例 (11)

3.2磺酸酯的氰基取代的反应示例 (11)

4. 用TMSCN转化羟基到腈 (12)

4.1 TMSCN双芳基甲醇氰化反应示例 (12)

4.2 TMSCN单芳基甲醇氰化反应示例 (12)

5. 用TosMIC直接从酮转化为氰基 (13)

6. 用2,4,6-三异丙基磺酰肼-KCN将酮转化为氰基 (14)

7.芳香卤代烃在金属催化作用下的腈化反应 (14)

7.1 钯催化下芳香卤代烃或（TfO-）氰基取代反应 (14)

7.2 Cu催化下芳香卤代烃或（TfO-）和K4[Fe(CN)6]反应氰基取代 (16)

7.3 微波反应芳卤氰基化 (16)

8. 肟脱水生成腈 (17)

1. 前言

腈类化合物是很多药物的合成中间体，而腈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P 2O 5、POCl 3、SOCl 2、PCl 5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。

R C O

NH

2

R

C OH N H -H 2O R C N

将酰胺与P 2O 5的混合物加热，反应毕将生成的腈蒸出可得到良好的收率。SOCl 2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：Burgess reagent

[Et 3N +SO 2N -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(CH 3SO 2Cl)，四氯化钛(TiCl 4) 等等。

2.1 用P 2O 5为脱水剂的反应实例

O

H 2N

O P 2O 5

N O

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 P 2O 5. The organic phase was decanted

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-(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

S N O

H 2Cl POCl S N N Cl

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 and 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 MgSO 4, filtered 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.C

Reference : Patent; EP883611 B1 (2002/07/31)

2.3 用SOCl 2为脱水剂的反应实例

O F

Br H 2N

O SOCl DMF N F

Br

A solution of thionyl chloride (7.70 g, 0.065 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 ice –water. The product was extracted into ether (twice) and the combined ethereal extracts were 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