酯交换为酰胺-060123.docVIP

经典合成反应标准操作—酯交换为酰胺 药明康德新药开发有限公司 PAGE Page PAGE 5 of NUMPAGES 8 药明康德内部保密资料 药明康德内部保密资料 经典化学合成反应标准操作 酯交换为酰胺 编者： 杜晓行 药明康德新药开发有限公司化学合成部 目 录 前言…………………………………………………………………2 酯交换为酰胺…………………………………………………………2 酯交换为N-取代酰胺…………………………………………………2 1．前言 酯和氨水反应可以很方便地得到酰胺。N-取代酰胺一般可以利用相应的胺与酯直接反应得到，在有些条件下，需要有铝试剂的存在反应才能够顺利进行。 2．酯与氨交换 一般酯的氨解通过氨的醇溶液或氨水来进行。氨的醇溶剂氨解反应可通过加入适量的甲醇钠和氰化钠来催化。用氨水直接氨解一般需要加热（当该反应温度到100度时，一定要用高压釜做这一反应），这类反应一般可以通过硫酸铜来进行催化。反应的条件选择主要看酯的活性程度，一般脂肪酸酯的交换要比芳香羧酸酯来得容易，甲酯要比乙酯来得快。对脂肪酸酯，α位的位阻大小也决定了反应的快慢。 酯通过甲酰胺在乙醇钠的存在下，高温也可得到相应的酰胺。这一方法对各类的酯都比较有效，只是产品的分离比直接氨解稍微麻烦一些，但反应较快。 另外近年来，AlMe3-NH4Cl或Me2AlNH2在多官能团及复杂化合物的合成中用的较多，该方法条件较强，各类酯都能很快的氨解。其缺点是AlMe3易自燃，操作不是太方便。 氨水用于脂肪羧酸酯氨解示例[1] To ethyl 5-ethoxycarbonylmethyl-3-methylisoxazole-4-carboxylate (1.00 g, 4.15 mmol) was added an excess of conc. aqueous ammonia (d = 0.88 kg·dm-3, 5.0 cm3) and EtOH (3.0 cm3), and the suspension was stirred vigorously at room temperature for 14 h. After this period a white solid had precipitated which was filtered and recrystallized (EtOAc) to yield the desired product as a white solid (0.81 g, 92%). Prepared as described above for ethyl 5-carbamoylmethyl-3-methylisoxazole-4-carboxylate but using methyl-5-ethoxycarbonyl- 3-methylisoxazole-4-carboxylate (1.00 g, 4.15 mmol) and methylamine in toluene (30% w/v, 10.0 cm3), to yield the desired product as a white solid (0.93 g, 99%). 氨甲醇氨解脂肪羧酸酯示例[2] [3] The ester (4.11 g, 14 mmol) was dissolved in absol. methanolic ammonia (100 ml, 20 % NH3), and the solution was allowed to stand at temperature for 3 days, the solvent was then evaporated, and the resulting crystalline was purified by recrystallization. 氨水用于芳香羧酸酯氨解示例[4] To an autoclave, was added methyl 6-methylniconate (500 g, 3.31 mol), sat. aq. NH4OH (500 ml) and ethanol (500 ml). After sealing, the reaction was heated to 80℃ for 2 days. The cooled reaction mixture was filtrated, and the filter cake was recrystallized to affor