酰胺水解制備羧酸

酰胺的活性比羧酸差，因此酰胺的水解一般需要強酸或強堿參與并在加熱的條件下進行。酰胺水解也有堿水解和酸水解兩種情況，酸水解時，加入亞硝酸鈉可以促進酰胺水解。

由于酰胺直接水解條件較為強烈，對于一些復雜的分子無法使用，因此對氮上有活潑氫的酰胺可將其衍生化后水解，一般衍生化的方法是用引入Boc，其反應如下：

以上方法也可用于保護氨基的酰胺鍵，得到相應的Boc 保護的胺：

反應實例

1、酰胺直接酸水解

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

【US3933905】

2 、酰胺直接堿水解示例

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

【US4138488】

3、 亞硝酸鈉促進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 of sodium nitrite (9.5 g, 0.137 mol) in water (13 mL). When the addition was complete 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 was poured onto ice to afford 4-carboxy-3-methoxyisothiazole (3.64 g, 46%) as a white solid melting at 182~185°C.

【US3957808】

4 、酰胺的間接水解法示例

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) and 4-(dimethylamino)pyridine (150 mg, 1.11 mmol). The solution was stirred for 8 h at room temperature. The volatiles were removed and the residue was purified by flash 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 cooled to 0°C. To this solution was added 1 N lithium hydroxide (2.0 ml, 2.0 mmol). The reaction mixture was allowed to stir for 6 h. After removal of THF in vacuo, the basic residue was acidified with 5% HCl and extracted with ether (3 ×15 ml). The combined ether layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by bulb-to-bulb distillation

(110~120°C/1.2 mmHg) to give the desired (R)-3-phenylbutyric acid (85 mg, 85%).

【J. Org. Chem., 1996, 61, 4542-4554】

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