FFONO2HNOHNONFO

FNO2N

A 5 L round bottom flask was charged with N,N'-di-tert-butyl-5-(2,3-difluoro-6-nitro- phenoxy)-isophthalamide (21; 564 g) and 1.3 L of phosphorus oxychloride. The mixture was heated to between 90 deg C. ~ 100.deg. C. for 2 h, after which approximately 1/2 of the POCl3was removed by distillation. Toluene was added (1 L) and additional liquid was

distilled. After cooling the mixture overnight, a crude was obtained by filtration. Additional material was obtained by recovery from the mother liquid. The combined solids were stirred in MeOH (0.7 L) for between 1 and 3 h, filtered and dried in a vacuum oven between 50~80 degC. at 25 Torr with a nitrogen bleed to afford 339 g of 22 (90percent theory).

Reference: US2005/234236

2.10.3叔丁酰胺脱水为腈示例三

OONNONHNOONN

At ice-water bath, oxalyl chloride (0.345 ml) was added dropwise to a solution of 1.0 g of ethyl

1-{4-[2-(t-butylaminocarbonyl)phenyl]phenyl}methyl-4-(1-hydroxy-1-methylethyl)-

2-propylimidazole-5-carboxylate in 10 ml of methylene chloride. The mixture was stirred at the same temperature for 2 hours. The reaction mixture was diluted with an aqueous solution of sodium hydrogencarbonate and ethyl acetate, and the ethyl acetate layer was separated, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by silica gel column chromatography, using 1:1 EtOAc/hex (v/v) as the eluent, to give 0.69 g of the title compound as crystals. Reference: US5616599

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3. 脂肪卤代烃或磺酸酯与金属氰化物的亲核取代反应

脂肪体系中的亲核取代反应是最受有机化学家注意的单元反应之一，其中脂肪卤代烃或磺酸酯与金属氰化物的亲核取代合成腈得到了广泛的应用：

R-X+CN-R-CN+X-X is I- Br- Cl- or MsO- or TsO-

在转化合成过程中最有用的是在直接取代机理方面有反应活性的底物。即伯类及未受阻碍的仲类脂肪卤代烷或磺酸酯。在叔烷基体系中发生消去反应的倾向是相当显著的，从而在涉及这些体系的转化合成方面限制了亲核取代反应的应用。有时侯，当非碘代的卤代烃反应活性不够时，需要在反应体系中加入KI或NaI 增加卤代烃反应活性，或者假如氧离子络合剂，如18冠6等; 有不少文献报道用相转移催化方法完成这一取代。

脂肪卤代烃可由相应醇经卤代反应制备，而磺酸酯可由相应醇经与甲烷磺酰氯或对甲苯磺酰氯反应得来。

3.1 烷基卤代物的氰基取代反应示例

NaCNBr KIN

To a stirring solution of sodium cyanide (1.62 g, 33 mmol) and potassium iodide (66 mg, 0.4 mmol) in dimethyl sulfoxide (20 ml) at 40 deg C., was slowly added 1-bromo-2-ethylbutane over 30 min. The reaction mixture was stirred at 80 deg C for 12 h, then at 110 deg C for 4 h. The reaction mixture was cooled and partitioned between Et2O and water. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to yield 2.9 g (87percent yield) of 1-cyano-2-ethylbutane as an amber oil.

1

H NMR (300 MHz, CDCl3): ?2.34 (d, 2 H), 1.58(m, 1 H), 1.46(m, 4 H), 0.92(t, 6 H).

Reference: : Bioorg. Med. Chem. 11, 18, 2003, 4093-4102.

3.2 磺酸酯的氰基取代反应示例

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ClCl

NNHOOOSONaCNNDMFNHON

A mixture of 1-[(4-butylphenyl)methyl]-3-(4-chloro-2-methylphenyl)-1-[6-

[(methylsulfonyl)oxyl]-hexyl]urea (2.0 g) in a few mL of DMF was added to a cooled stirring suspension of anhydrous sodium cyanide (0.50 g) in 3 mL of dry DMSO. The mixture was heated overnight at 80 oC. Then it was poured into water (100 mL) and the product was extracted with dichloromethane. The combined extracts were washed water, dried (MgSO4) and

concentrated

to

give

1-[(4-butylphenyl)methyl]-3-(4-chloro-2-methylphenyl)-

1-(6-cyanohexyl)urea. Ref: US 4623662 A1

4. 用TMSCN转化羟基到腈

对于芳基苄位的羟基，可以用TMSCN直接转化为腈，反应的好坏与邻位的碳上是否有烷基的氢质子有关。

4.1 TMSCN双芳基甲醇氰化反应示例一

OHTMSCNFFFF

NThionyl 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

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sulfate and concentrated under reduced pressure to give the title compound (21.8 g) oil. Ref: EP1219294 A1 (2002/07/03)

4.2 TMSCN单芳基苄醇氰化反应示例二

OHNN TMSCNSnCl2 / CH2Cl2CNNEtOOCNEtOOC 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 (13.6 mL 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 KFa2H2O (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

5. 用TosMIC直接从酮转化为氰基

ONOO tosylmethylisocyanideNNOO

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

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