常用制备腈的方法有：酰胺可在P2O5、POCl3、SOCl2、PCl5等脱水剂存在下进行脱水反应生成腈，另外温和的方法用于酰胺的脱水，如：Burgess 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。脂肪卤代烃或磺酸酯与金属氰化物的亲核取代合成腈也经常用到，但要用到剧毒的氰化物是其明显的缺点。芳香卤代烃也可以在过渡金属催化下制备芳香腈，应用也很广泛。

下面介绍几种种不是很常规的制备腈的方法，苄位的羟基可以直接利用TMSCN转化为腈，还有利用TosMIC 和2,4,6-三异丙基苯磺酰肼-KCN直接从酮转化为氰基。

1、TMSCN 双芳基甲醇氰化反应

Thionyl chloride (50 ml) was added to bis(4-fluorophenyl)methanol (24.2 g) at 0 deg C and after stirring for 30 min, the mixture was poured into 2N hydrochloric acid (500 ml). The mixture was extracted with ethyl acetate and the organic layer was dried over calcium chloride and concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane (200 ml) and after addition of trimethylsilylcyanide (16.4 ml), titanium tetrachloride (13.4 ml) was added dropwise at 0 degC. The mixture was stirred for 50 min. Methanol (5 ml) was added to the reaction mixture and the mixture was poured into saturated

aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (21.8 g) oil.

Ref: EP1219294 A1 (2002/07/03)

2、TMSCN 单芳基苄醇氰化反应

To solution of 4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)-4-hydroxy-cyclohexane

carboxylic acid ethyl ester (13.5 g, 33.9 mmol) in CH2Cl2 (135 mL) cooled to 0 °C was added trimethylsilyl cyanide (22.6 mL, 169 mmol) followed by a slow addition of SnCl4 (13.6mL of a 1.0 M solution in CH2Cl2, 13.6 mmol). The reaction mixture was allowed to warm to room temperature overnight. K2CO3 (18.7 g, 136 mmol) and KF .2H2O (12.8 g, 136 mmol) were added, followed by dropwise addition of H2O (4.30 mL, 239 mmol). The reaction mixture was stirred vigorously for 90 min, after which silica gel (25 g) was added. The mixture was filtered and washed thoroughly with CH2Cl2. The filtrate was washed with saturated aqueous NaHCO3 (250 mL), dried over MgSO4, filtered, and concentrated to yield 13.2 g oily product of (96% recovery) cyano-4-(1-cyclohexyl-3-ethyl- 1H-indazol-6-yl)cyclohexanecarboxylic acid ethyl ester as a mixture of diastereoisomers. For characterization purposes, a sample of each diastereoisomer was obtained by chromatographic purification on silica gel eluting with 4:1 hexanes/EtOAc.

Reference: : Organic Process Research & Development 2001, 5, 587-592

3、用 TosMIC 直接从酮转化为氰基

To a 250 mL round-bottomed flask equipped with condenser and nitrogen inlet were added 4.34 g (23.49 mmol) N-carboethoxyperhydroazepin-4-one (prepared according to the procedure given by Z. G. Finney and T. N. Riley, J. Med. Chem., 23, 895, 1980), 10.53 g (54.02 mmol) tosylmethylisocyanide and 117 mL 1,2-dimethoxyethane. The solution was cooled to 0 deg C and 2.48 mL (54.02 mmol) ethanol and 9.21 g (82.2 mmol) potassium t-butoxide were added. The mixture was heated at 60 deg C for 18 hours, cooled and concentrated. The residue was taken up in ethyl acetate, washed with brine, dried over sodium sulfate and concentrated to give an oil. The oil was purified by chromatography on

silica gel using hexane/ethyl acetate as eluent to afford 4.6 g (100percent) of oil.

Reference: 72800; Patent; Pfizer Inc.; Publ.: US5373003 A1 (1994/12/13)

4、用2,4,6-三异丙基苯磺酰肼-KCN将酮转化为氰基

3-Quinuclidinone (24.2 g, 0.19 mol) and 2,4,6-triisopropylbenzenesulphonohydrazide (72 g, 0.24 mol) were stirred together in anhydrous MeOH (250 mL) for 3 h. Potassium cyanide (33.8 g, 0.51 mol) was added and the mixture was heated under reflux for 5 h. The residue after evaporation of the solvent was partitioned between water and CH2C12. The organic phase was dried and evaporated and the residue was fractionally distilled under reduced pressure to give 3-cyanoquinuclidine (32, 6.1 g).

Reference: J. Med. Chem. 1990, 33, 1128-1138

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