酰胺的合成.docx

1、酰胺的合成经典化学合成反应标准操作酰胺及酰亚胺的合成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。 2. 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-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-羟基乙酰基苄胺。2.1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

2、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。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。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

3、，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。 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。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A solution of acid 1 and 4-methylmorpholine (NMM, 0.54 mL, 4.92 mmol) in DMF (1

4、0 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). Th

5、e 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To a coo

6、led (-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

7、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

8、 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

9、 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) an

10、d 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): 5.43 (m, 1H), 4.72 (s, 1H), 4.17-4.11 (m, 1H), 3.71 (s, 3H), 3.22

11、 (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A mixture of the benzoic acid (10 mmol), 4-methylbenzene-1-sulfonyl chloride (10 mmol), K2CO3 (5.52 g, 40 mmol) and TEBAC (0.23 g, 1mmol) in 60 mL of be

12、nzene 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

13、the pure product (yield 82%). 2.1.5应用Boc酸酐合成伯酰胺示例Typical procedure: To a stirred solution of N-protected amino acid 9 (10 mmol), pyridine (0.5 ml) and Boc2O (3 g, 13 mmol) in an appropriate solvent (such as dioxane, DMF and CH3CN, 10-15 ml), ammonium hydrogencarbonate (1 g, 12.6 mmol) was added and

14、the mixture was stirred for 4-16 h. Ethyl acetate was added and after washings with water and 5% H2SO4, 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 crystallizati

15、on 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)。使用该类的缩合剂一般需要加入酰化催化剂或活化剂，如4-N,N-二甲基吡啶（DMAP）、1-羟基苯并三氮唑(HOBt)等等，其主要由于在反应的第一

16、阶段酸对碳二亚胺的加成中间体其并不稳定，若不用酰化催化剂转化为相应的活性酯或活性酰胺，其自身会通过重排成相应的稳定的脲的副产物 (Path b).常用的缩合活化剂有以下几种，目前4-N,N-二甲基吡啶（DMAP）已被广泛应用于催化各种酰化反应。有时在用DMAP催化效果不好时，可采用4-PPY，据相关文献报道其催化能力要比DMAP高千倍左右。在三个常用的缩合剂DCC、DIC和EDCI中， DCC和DIC的价格较为便宜，一般DCC和DMAP合用，使用DCC有一个最大的缺点就是反应的另一产物二环己基脲在一般的有机相溶解度很小但又都有一些微溶，因此通过一些常用的纯化方法，重结晶，柱层析等等很难将其除得很彻底；由于二环己基脲在乙醚中的溶解度相对要比其他溶剂小， 因此处理这类反应一般蒸掉反应溶剂后加入乙醚，滤掉大部分的二环己基脲后再进一步处理。DIC由于其产生的二