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
1． 前言⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯
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2． 酯交换为酰胺
⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯ 酯交换为 N-取代酰胺
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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， AlMe 3-NH 4Cl 或 Me2AlNH 2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 AlMe 3易自燃，操作不是太方 便。
2.1 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 ocf onc. 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%).
O O N O
H
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%).
2.2 氨甲醇氨解脂肪羧酸酯示例 [2] [3]
O
O NH COOEt
MeNH 2 / MeOH
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.
2.3 氨水用于芳香羧酸酯氨解示例 [4]
NH 4OH
To an autoclave, was added methyl 6-methylniconate (500 g, 3.31 mol)s, at. 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 afford white solid (247 g, 54.8%)。
2.4 HCONH 2-NaOEt 体系用于酯氨解示例 [5]
COOEt
Boc N
NaOEt, HCONH 2 DMF, 100 oC, 2 h
70%
tert-Butyl 4-(3-ethoxycarbonylpropyl)piperidine-1-carboxylate (0.60 g, 2.0 mmol, the product of Production example 43-1) and formamide (0.27 ml, 6.7 mmol) were dissolved in N,N-dimethylformamide (1.0 ml); sodium ethoxide (0.095 g, 1.4 mmol) was added thereto while stirred and heated at 100 .deg.C; the reaction mixture was stirred for 2 hours under
nitrogen atmosphere.After cooled to room temperature, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent; hexane-ethyl acetate = 95:5 to 85:15). The title compound was obtained as a colorless oil (0.38 g, 1.4 mmol, 70percent).
2.5 NH4Cl-AlMe 3 体系用于酯氨解示例 [6]
COOEt
CONH 2
100%
A stirred suspension of ammonium chloride (963 mg, 3 equiv. ) in toluene at 5.deg.C is treated with trimethylaluminium (9 mL of 2 M solution in toluene, 3 equiv.), stirred at room temperature for 2 h, treated with a solution of ethyl 1-(thieno[2,3- b]pyrrol-4-yl) acetate (1.25 g, 6 MMOL, 1 equiv.) in toluene, heated at 50.deg.C for 16 h, cooled to room temperature, quenched with water and extracted with EtOAc. The extracts are combined, dried over MgS40 and
concentrated in vacuo to give the title product as a tan oil, 1. 1g (quantitative yield), identified by liquid chromatography and mass spectral analyses.
3．酯与脂肪伯胺的交换
酯与脂肪伯胺的交换一般直接用无溶剂的方法加热进行， 对于低沸点的伯按胺直接 用其作溶剂回流即可。 有时两个反应底物物都是固体无法混溶时，将两者溶解到某一 溶剂后再浓缩干即可混合均匀，一般的无溶剂加热反应最好一边抽真空一边反应。有时 胺的位阻较大时，也不好交换，一般也可仲胺交换反应条件来进行。
在此有一点需要指出的，当我们用 LAH 还原酰胺和腈到胺时，最后的产物为胺的 铝盐，如果我们用酯去淬灭反应时常常得到的是相应的酰胺，如用乙酸乙酯淬灭即得到 相应的乙酰胺。
3. 1 脂肪胺氨解芳香酸酯示例
[7] [8]
n-Bu
COOMe
nBuNH 2
Br
A solution of 50 mg (0.10 mmol) of 5-n-butyl-2-(5-carbomethoxy-2-chlorophenyl)-2, 3-dihydro-4-(2-fluoro-4-bromobanzyl)-1,2,4-triazol-3-one in 1 ml of n-butylamine was stirred overnight at 65 \"C. After being cooled to room temperature, volatiles were evaporated in vacuo. The residue was flash chromatographed (gradient elution with 1-5% MeOH in CH2C12) to yield 41 mg (76%) of a colorless, glassy solid.
4．酯与脂肪仲胺的交换 [9~13] 酯与脂肪仲胺的交换一般直接交换是不行的，但其
可通过相应的氨的负离子来反 应，如通过正丁基锂作碱，同样三甲基铝可用于这类交换反应。
5．酯与芳胺的交换 [14~18] 由于芳香胺的亲核性不是太强，因而与酯直接交换不太
容易，一般需要
200 度的高
温才能交换。但如果通过强碱将芳胺变为相应的负离子，其亲核能力大大加强，可以发 生相应的酯交换反应。 目前常用的碱为 NaHMDS, NaOEt, BuLi, EtMgBr 等。有文献报道 在微波下，用 KOtBu 作碱在没溶剂的情况下可一分钟内完成胺交换反应。通过
AlMe3
也可顺利地将芳胺和酯进行交换。以上多见于芳香的伯胺，很少有文献报道芳香的仲胺 参与酯的交换反应的。但有文献报道二氢吲哚与三甲基铝的复合物无可与酯进行交换。
5. 1 脂肪胺氨解芳香酸酯示例
[19]
S
N
N COOEt H
CN of trimethyl aluminium in hexane (1.9 mL) was added dropwise to a cold
A 2M solution
(0 ℃) solution of 4-amino-benzonitrile (0.29 g, 2.46 mmol) in anhydrous dichloromethane (30
ml) under argon atmosphere. The mixture was warmed to room temperature
and stirred at room temperature for 30 min. A solution of 4-methyl-3- (4- pyridin-4-yl-thiazol-2-ylamino) -benzoic acid methyl ester (0.80 g, 2.46 mmol) in anhydrous dichloromethane (30 mL) and added slowly, and the resulting mixture was heated at reflux for 5h. The mixture was cooled to 0.deg.C and quenched by dropwise addition of a 4N aqueous sodium hydroxide solution (3 mL). The mixture was extracted with dichloromethane (3x20 mL). The combined organic layers were washed with brine (3x20 mL) and dried over anhydrous MgS04. N- (4-Cyano-phenyl)-4-methyl-3- (4- pyridin-4-yl-thiazol-2-ylamino) -benzamide is obtained in 98percent after trituration of the crude product in methanol.
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WO2005/73225
The End
