水解法合成羧酸——酰胺的水解

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    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 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 CCl 4 (170 mL) to give 2-(5-oxo-10,11-dihydrodibenzo[a,d]cyclohepten2-yl)propionic acid (7.4 g, 49.2%) melting at 22°C.

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 (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.

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 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.

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, 2.18mmol) 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 N 2 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 MgSO 4 , 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%).


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