杏耀几年

由羧酸合成酰胺

反应实例1

反应说明：该反应是羧酸与胺反应生成酰胺的反应

反应机理

A：首先形成混合酸酐

B：氰基与混合酸酐反应形成酰腈

反应实例2

反应说明：该反应是首先邻氨基苯甲酸与亚硝酸酯反应形成苯炔，然后异苯腈与苯炔发生，最后用水后处理生成酰胺的反应

反应机理

A：苯胺与亚硝酸酯形成重氮盐

B：消去一分子二氧化碳和一分子氮气形成苯炔

C：异腈亲核加成到苯炔上

D：水加成到腈鎓离子上得到产物

逆向思维：

如何通过酰胺水解合成羧酸

酰胺的活性比羧酸差，因此酰胺的水解一般需要强酸或强碱参与并在加热的条件下进行。酰胺水解也有碱水解和酸水解两种情况，在有些情况下，加入亚硝酸钠可以促进酰胺水解。

由于酰胺直接水解较为强烈，对于一些复杂的分子无法使用，因此对氮上有活泼氢的酰胺可将其衍生化后水解，一般衍生化的方法是用引入Boc，其反应如下：

以上方法也可用于保护氨基的酰胺键，得到相应的Boc保护的胺：

酰胺直接酸水解示例 

A suspension of2-(5-oxo-10,11-dihydrodibenzo[a,d]cyclohepten-2-yl)propionamide (15 g, 53.7mmol) in a mixture of sulphuric acid (d = 1.36, 50 mL) and water (60 mL) washeated with vigorous stirring for 3 hours at 110°C. After cooling, the product whichprecipitated was filtered off and then added to 2 N sodium hydroxide solution(55 mL). The alkaline solution, clarified by filtration, was acidified byadding 2 N hydrochloric acid (60 mL). The product which precipitated was filtered off, driedand then recrystallized from CCl4 (170 mL) to give2-(5-oxo-10,11-dihydrodibenzo[a,d]cyclohepten2-yl)propionic acid (7.4 g, 49.2%)melting at 122°C.

Reference:  US3933905

酰胺直接碱水解示例 

A solution of 4-(1,1-diphenylpropyl)-picolinamide (3.8 g,0.012 mol) in ethanol (50 mL) was added 10% aqueous potassium hydroxide (100mL) and the resulting mixture was heated at reflux overnight。 The solvent was removed under reduced pressure and theresidue was added water then adjusted to about pH 5 with 10% aqueoushydrochloric acid. The resulting solid was filtered and recrystallized fromethanol to obtain the desired compound of this example (1.6 g, 42.0%) melting at 191~193°C.

Reference:  US4138488

亚硝酸钠促进的酰胺酸水解法示例   

To a solution of 4-carbamoyl-3-methoxyisothiazole (7.9 g, 0.05 mole)in 90 mL of 80% sulfuric acid at 10~15°C was added slowly beneath the surface of the liquid a solution ofsodium nitrite (9.5 g, 0.137 mol) in water (13 mL). When the addition wascomplete the solution was allowed to come to 25°C and then was heated to 60°C for several minutes. After cooling to 25°C the reaction solution waspoured onto ice to afford 4-carboxy-3-methoxyisothiazole (3.64 g, 46%) as awhite solid melting at 182~185°C.

Reference:  US3957808

酰胺的间接水解法示例   

To a 0.5 M solution of (R)-N-Methyl-3-phenylbutanamide(194 mg, 1.09 mmol) in methylene chloride was added triethylamine (0.15 ml,1.09mmol), di-tert-butyl dicarbonate (0.5 ml, 2.18 mmol) and4-(dimethylamino)pyridine (150 mg, 1.11 mmol). The solution was stirred for 8 hat room temperature. The volatiles were removed and the residue was purified byflash chromatogramphy (1/20 (v/v) EtOAc/hexane) to afford the desired (R)-N-Boc-N-Methyl-3-phenylbutanamide(210 mg, 70%).

A 0.2 M solution of (R)-N-Boc-N-Methyl-3-phenylbutanamide(175 mg, 0.63 mmol) in THF (4 ml), under N2 atmosphere, was cooledto 0°C. To this solutionwas added 1 N lithium hydroxide (2.0 ml, 2.0 mmol). The reaction mixture wasallowed to stir for 6 h. After removal of THF in vacuo, the basicresidue was acidified with 5% HCl and extracted with ether (3× 15 ml). The combined ether layers weredried over anhydrous MgSO4, filtered and concentrated under reducedpressure. The residue was purified by bulb-to-bulb distillation (110~120°C/1.2mmHg) to give the desired (R)-3-phenylbutyricacid (85 mg, 85%).

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