活性酯法合成酰胺主要包括羧酸的混合酸酐和羧酸的酰基咪唑与胺反应制备相应的酰胺。其中混合酸酐主要有以下三类：

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-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。

示例1：氯甲酸乙酯合成酰胺操作示例：

3-Methyl-2-nitrobenzenecarboxamide To a solution of 3-methyl-2-nitrobenzoic acid (13.2 g) in tetrahydrofuran (150 ml) was added slowly at ambient temperature triethylamine (11.0 ml). After stirring for 30 minutes, the solution was cooled in an ice bath and ethyl chloroformate (7.6 ml) was added dropwise. Following the addition the thick mixture was stirred for 1 hour while maintaining the temperature at about 0°. Next, gaseous ammonia was bubbled through the well stirred mixture until it was well saturated (about 15 minutes). The cooling bath was removed and the mixture was allowed to warm slowly to ambient temperature with stirring for 2 hours. The mixture was partitioned between ethyl acetate and water; some gentle warming was required to solubilize all of the solid material. The layers were separated; the organic phase was washed with brine, dried over Na₂ SO₄ and concentrated to leave a white solid. Trituration with ether/hexane followed by filtration afforded the carboxamide (12.5 g, 95%); m.p. 189°-191°; tlc, R_f =0.08, silica gel, ethyl acetate:hexane (1:1).

示例二：氯甲酸异丁酯合成酰胺操作示例：

A solution of 3-methyl-2-nitrobenzoic acid (50.00 g, 276 mmol) in dichloromethane (500 mL) and triethylamine (41 .83 g, 414 mmol) was cooled to 0 °C. Isopropyl chloroformate (50.74 g, 414 mmol) was added drop-wise and the reaction was stirred for 1 hour at 0 °C. Concentrated aqueous ammonium hydroxide (300 mL) was then added to the reaction, which was stirred for an additional 30 minutes at 0 °C. Filtration afforded C19 as a white solid. Yield: 41 .6 g, 231 mmol, 84%. ¹H NMR (400 MHz, DMSO-c/₆) δ 2.28 (s, 3H), 7.53-7.61 (m, 3H), 7.71 (br s, 1 H), 8.21 (br s, 1 H).

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。

示例3：羧酸-甲磺酸混合酸酐合成酰胺操作示例

Preparation of (R)-alpha-ethyl-2-oxo-l -pyrrolidineacetamide from (R)-alpha-ethyl-2- oxo-1-pyrrolidineacetic acid; A suspension of (S)-alpha-ethyl-2-oxo-l-pyrrolidineacetic acid (35 g, 0.20 mol) in methylene chloride (225 ml) was cooled to 0⁰C and triethylamine (41 g, 0.40 mol) and methanesulfonyl chloride (29 g, 0.26 mol) were added dropwise. The mixture was stirred at O⁰C for 30 min., then a stream of ammonia was purged in the solution at O⁰C for 2 hours. The insoluble solids were filtered and the filtrate was concentrated. The product was recrystallized from m ethyl isobutyl k etone to g ive 27.5g (78 %) of (R)- alpha-ethyl-2-oxo- 1 -pyrrolidineacetamide.

示例4：羧酸-对甲苯磺酸混合酸酐合成酰胺操作示例

Methylene chloride (6000 mL), trans-4-isopropylcyclohexane (200 g) followed by para toluene sulfonyl chloride (208.38 g) and triethyl amine (409 mL) were added in a round bottom flask at 25-30⁰C. The contents were maintained for 8 hours. D-Phenylalanine (150 g) was added to the above reaction mass over 30 minutes at 25-30⁰C. The contents were maintained for 18 hours. 778 mL of 10% HCL solution was added to the reaction mass and stirred for 30 minutes. Methylene dichloride layer was taken and 1500 mL DM water was added and the mixture was stirred for 30 minutes repeatedly twice. The organic layer was dried with sodium sulphate (5 g), filtered and distilled off completely at 35- 40⁰C. Methylene chloride (400 mL) and 1600 mL of cyclohexane was added into above crude at 25-30⁰C. The contents were heated to 60-65⁰C (minimum 3 to 4 hours), and then maintained the contents for 1 hour at 0-5⁰C. Filtered, washed with chilled cyclohexane (200 mL) and dried under vacuum for 8-10 hours at 50-55⁰C to get the title compound (216 g, 75%).

4- (N,N-dimethylamino)pyridine (36.6 g, 0.3 mol) was added to a stirred suspension of 5- chlorothiophene-2-carboxylic acid (16.25 g, 0.1 mol) in dichloromethane ( 162 ml) at 0- 5°C and the resulting solution was stirred for 10 minutes. A mixture of p-toluenesulfonyl chloride ( 19.05 g, 0.1 mol) and dichloromethane (50 ml) was added to the above solution at -5°C. The resulting solution was stirred for 1 hour at -5°C to produce a reaction mass containing the sulfonyl ester intermediate, followed by portion wise addition of 4-[4-[(5S)- 5- (aminomethyl)-2-oxo- l ,3-oxazolidin-3-yl]phenyl] morpholine-3-one (29.1 g, 0.1 mol, chiral purity: 99.9%). The reaction mixture was stirred for 2 hours at 25-30°C, followed by the addition of water ( 1 62 ml) and then stirring for 15 minutes. The separated solid was filtered, washed with dichloromethane (50 ml) and water ( 100 ml), and the resulting wet material was dried at 80-85°C for 3 to 5 hours to produce 37.3 g of pure rivaroxaban as a white crystalline solid (Theoretical Yield: 85.6%; Purity by HPLC: 99.9%; and Chiral Purity by HPLC: 99.9%). )

应用羰基二咪唑(CDI)与羧酸反应得到活性较高的酰基咪唑，一般生成的酰基咪唑稳定性较差，反应过程不需要分离，反应液直接与胺一锅反应制备相应的酰胺；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。

应用羰基二咪唑(CDI)合成酰胺反应操作示例

To acid 5 (4.0 g, 14.1 mmol) in CH2Cl2 (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. Et2O was added (50 mL) and the reaction mixture was filtered. The filtrate was evaporated, diluted with Et2O (125 mL), washed with 5% aq. citric acid (2 x 50 mL) and brine (50 mL), and dried over MgSO4. 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. Rf 0.42 (2:1 hexanes:EtOAc); 1H NMR (300 MHz, CDCl3): 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).

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。

操作示例：

To a strirred solution of 2chloro3nitro5(trifluoromethyl)benzoic acid (2.7 g, 10 mmol, 1.0 equiv.), pyridine (0.50 ml,6.2 mmol, 0.62 equiv.), and Boc2O(2.8 g, 13.0 mmol, 1.3 equiv.)in 1,4-dioxane (10 ml) at room temperature was added ammonium bicarbonate (1.00 g, 12.6 mmol, 1.26 equiv.). The reaction was stirred overnight at room temperature and then partitioned between EtOAc (50 ml) and H2O (50 ml). The organic layer was separated, washed consecutively with water 50 ml) and 0.6 N aqueous HCl (50 ml), dried (Mg2SO4), and filtered. The filtrate was concentrated under reduced pressure to provide 2 as a white solid [yield 2.42 g, 90%; m.p. 190-193 C; literature (Welch et al., 1969) 195-197 C]. 1H NMR and MS data are consistent with previously reported spectra(Cooper et al., 2013).