酰胺的合成讲解

经典化学合成反应标准操作酰胺及酰亚胺的合成目录1. 前言 (3)2. 羧酸与胺的缩合酰化反应 (3)2.1活性酯法 (3)2.1.1应用氯甲酸乙酯或异丁酯活性酯法合成酰胺示例 (5)2.1.2应用氯甲酸乙酯或异丁酯活性酯法合成伯酰胺示例 (5)2.1.3应用羰基二咪唑合成Weinreb酰胺示例 (6)2.1.4应用的磺酰氯合成酰胺示例 (6)2.1.5应用Boc酸酐合成伯酰胺示例 (7)2.2碳二亚胺类缩合剂法 (7)2.2.1应用DCC缩合法合成酰胺示例 (9)2.2.2应用DIC缩合法合成酰胺示例 (10)2.2.3应用EDC缩合法合成酰胺示例一（二氯甲烷为溶剂） (10)2.2.4应用EDC缩合法合成酰胺示例二（DMF为溶剂） (11)2.3 鎓盐类的缩合剂法 (11)2.3.1应用HATU/TBTU为缩合剂合成酰胺示例 (13)2.3.2应用BOP为缩合剂合成酰胺示例 (14)2.3.3应用PyBOP为缩合剂合成酰胺示例一（常规） (14)2.3.4应用PyBOP为缩合剂合成酰胺示例二（用于合成伯酰胺） (15)2.4 有机磷类缩合剂 (15)2.4.1应用DPP-Cl为缩合剂合成酰胺示例 (16)2.4.2应用DPPA为缩合剂合成酰胺示例 (16)2.4.3应用BOP-Cl为缩合剂合成酰胺示例 (17)2.5.1应用三苯基磷-多卤代甲烷合成酰胺示例 (18)2.5.2应用三苯基磷-六氯丙酮合成酰胺示例 (18)2.5.3应用三苯基磷-NBS合成酰胺示例 (19)3. 氨或胺与酰卤的酰化反应 (19)3.1酰卤的制备示例 (20)3.5.1应用二氯亚砜合成酰氯示例 (20)3.5.2用草酰氯合成酰氯示例 (21)3.5.3用三氯均三嗪合成酰氯示例 (21)3.5.4用三氟均三嗪合成酰氟示例 (22)3.1应用酰卤的合成酰胺 (22)3.5.1应用酰氯合成酰胺示例（有机碱） (22)3.5.2应用酰氯合成酰胺示例（无机碱） (22)3.5.3应用酰氟合成酰胺示例 (24)4. 氨或胺与酸酐的酰化反应 (24)4.2酸酐合成酰胺示例 (25)5. 其他缩合方法 (25)1. 前言酰胺化是有机合成中最基本，也是最重要的合成方法之一。

合成酰胺的通用方法是先活化羧基，然后再与胺反应得到酰胺。

ROHO R XO X = Activating GroupR NH O R 1R 1NH 22. 羧酸与胺的缩合酰化反应羧酸与胺的反应是合成酰胺的重要方法。

由于这一反应是一个平衡反应，因此采用过量的反应物之一或除去反应中生成的水， 均有利于平衡向产物方向转移。

除去水的方法通常是在反应物中加入苯或甲苯进行共沸蒸馏。

例如将α-羟基乙酸及苄胺于90℃共热， 并蒸出生成的水及过量的苄胺，则生成α-羟基乙酰基苄胺1。

HOCH 2COOH+PhCH 2NH 2HOCH 22Ph O2.1活性酯法活性酯法早期主要应用酸与氯甲酸乙酯或异丁酯反应生成混合酸酐，而后再与胺反应得到相应的酰胺，这一反应如果酸的α-位位阻大或者连有吸电子基团，有时会停留在混合酸酐这一步，但加热可以促使其反应；这一反应也可用于无取代酰胺的合成2。

COOHPhCHCl 3, -20~5C, 1.5hPhNH 291%应用羰基二咪唑(CDI)与羧酸反应得到活性较高的酰基咪唑，许多酰基咪唑有一定的稳定性，有时可以分离出来，但一般来说其不用分离，反应液直接与胺一锅反应制备相应的酰胺；有文献报道羰基二咪唑与三氟甲磺酸甲酯反应得到的二甲基化的三氟甲磺酸盐(CBMIT)的缩合性能更好。

该类反应由于过量的CDI 或CBMIT 会和胺反应得到脲的副产物，因此其用量一定要严格控制在1当量。

最近我们发现应用CDI 合成Weinreb 酰胺是一个较好的方法。

O ORCOOHRO NNON HO OR=Tetrahedron 1994, 50, 11113NNONNCH 3NO 2, 10CNN ONN-OTf2Chem. Pharma. Bull. 1982, 30, 4242CBMIT另一类常用的方法是羧酸和磺酰氯生成羧酸-磺酸的混合酸酐，其与胺反应得到相应的酰胺。

常用的磺酰氯有甲烷磺酰氯（MsCl ），对甲苯磺酰氯（TsCl ）和对硝基苯磺酰氯（NsCl ）, 对硝基苯磺酰氯由于其吸电子性，其与酸反应生成活性更高的混合酸酐，一般二级胺和三级胺，甚至位阻很大的胺都能顺利反应3。

2N O PhO O SO ONO COOHOH O O SOO OHNNNHO NSynthesis 1989, 745通过酸与Boc 酸酐反应得到的混合酸酐与氨反应可得到相应的伯酰胺。

CbzHNCOOHCbzHNO OOO NH CbzHNNH 2O Tetrahedron Lett. 1995, 36, 7115上述的这些缩合方法一般都是分步进行，其主要因为胺极易与这些活性酯反应得到相应的酰化产物。

2.1.1应用氯甲酸乙酯或异丁酯活性酯法合成酰胺示例OHNOOHOOHNOOOOOOHNONHOC5H115112NMM, DMF12J. Med. Chem. 2004, 47, 2110-2122J. Med. Chem. 2002, 45, 713-720.A solution of acid 1 and 4-methylmorpholine (NMM, 0.54 mL, 4.92 mmol) in DMF (10 mL) was treated at room temperature with isobutyl chloroformate (0.64 mL, 4.92 mmol). After 30 min, pentylamine (0.57 mL, 4.92 mmol) was added. The reaction mixture was stirred for 12 h. The solvent was evaporated, and the residue was partitioned between ethyl acetate (25 mL) and water (25 mL). The ethyl acetate layer was washed with 5% NaHCO3 (10 mL) and brine (20 mL), dried over Na2SO4, and evaporated. The residue was chromatographed on silica gel eluting with hexane and ethyl acetate (2:1) to give 0.33 g (33%) of tert-butoxycarbonylated amino amide (2).2.1.2应用氯甲酸乙酯或异丁酯活性酯法合成伯酰胺示例332 ClCOOC H, TEA, THF, then NH (g)-20'C to rt.34Synth. Commun., Vol. 34, No. 1, pp. 159-170, 2004To a cooled (-20℃) solution of compound 3 (4.8 g, 18 mmol) in anhydrous THF (50 mL) was added Et3N (2.5 mL, 18 mmol) during 20 min. After 10 min ethyl chloroformate (1.7 mL, 18mmol) was added at the same temperature during 10 min and stirred for an additional 20 min. The resulting mixture was saturated with NH3 gas and kept at r.t. overnight. The mixture was concentrated at reduced pressure, the residue was diluted with H2O (10 mL) and extracted with EtOAc (4 *10 mL). The combined organic phases were dried (Na2SO4), filtered and concentrated to afford a white solid. It was recrystallized from petroleum ether and ethyl acetate to afford pure product 4 as white crystal (3.1 g, 65%).2.1.3应用羰基二咪唑合成Weinreb 酰胺示例41. CDI, CH 2Cl 22. HN(OMe)Me. HCl56To acid 5 (4.0 g, 14.1 mmol) in CH 2Cl 2 (70 mL) at 23℃ was added 1, 1’-carbonyldiimidazole (3.65 g, 22.5 mmol) in equal portions over 15 min. After the final addition, stirring was continued for 10 min, then N,O -dimethylhydroxylamine • HCl (3.43 g, 35.16 mmol) was added in one portion. The reaction was allowed to stir at 23℃ for 3 h. Et 2O was added (50 mL) and the reaction mixture was filtered. The filtrate was evaporated, diluted with Et 2O (125 mL), washed with 5% aq. citric acid (2 x 50 mL) and brine (50 mL), and dried over MgSO 4. The crude product was purified by flash chromatography (3:1 hexanes: EtOAc) to afford Weinreb amide 6 (4.29 g, 93% yield) as a colorless oil. R f 0.42 (2:1 hexanes:EtOAc);1H NMR (300 MHz, CDCl 3): δ 5.43 (m, 1H), 4.72 (s, 1H), 4.17-4.11 (m, 1H), 3.71 (s, 3H),3.22 (s, 3H), 2.59-2.24 (comp. m, 3H), 2.03 (dd, J = 14.6 Hz, 4.1 Hz, 1H), 1.75-1.71 (m, 3H), 0.86 (s, 9H), 0.11 (s, 3H), 0.09 (s, 3H).2.1.4应用的磺酰氯合成酰胺示例SO 2ClK 2CO 3, benzeneOHO H 2NOEtOO OSO O reflux, 40 minN HO OEt 78A mixture of the benzoic acid (10 mmol), 4-methylbenzene-1-sulfonyl chloride (10 mmol), K 2CO 3 (5.52 g, 40 mmol) and TEBAC (0.23 g, 1mmol) in 60 mL of benzene is stirred at reflux for 40 min. Then ethyl 2-aminoacetate (10 mmol) is added and stirring is continued for 10 min at reflux temperature. The precipitate is filtered off, and the filtrate is evaporated under reduced pressure. The carboxamide 8 thus obtained is crystallized from MeOH to afford the pure product (yield 82%).2.1.5应用Boc 酸酐合成伯酰胺示例RCOOH. Py + (Boc)2ORO OOO43RO NH 2+ BuOH + CO 2Tetrahedron Lett. 1995, 36, 7115910Bull. Chem. Soc. Jap. 1988, 61, 2647Typical procedure:To a stirred solution of N -protected amino acid 9 (10 mmol), pyridine (0.5 ml) and Boc 2O (3 g, 13 mmol) in an appropriate solvent (such as dioxane, DMF and CH 3CN, 10-15 ml), ammonium hydrogencarbonate (1 g, 12.6 mmol) was added and the mixture was stirred for 4-16 h. Ethyl acetate was added and after washings with water and 5% H 2SO 4, the solution was dried, the solvent was evaporated and the product was triturated with ether. In another variant the reaction mixture was diluted with water (30-40 ml), stirred until crystallization was completed, a residue was then collected by filtration, washed by water, dried and recrystallized as necessary.2.2碳二亚胺类缩合剂法利用碳二亚胺类缩合剂缩合制备酰胺在药物合成中应用极为广泛，目前常用的缩合剂主要有三种：二环己基碳二亚胺(DCC )、二异丙基碳二亚胺(DIC )和1-(3-二甲胺基丙基)-3-乙基碳二亚胺(EDCI )。