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)。 摄像头识别
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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由于其产⽣的⼆异丙基脲在有⼀般的有机溶剂中溶解度较好，因此⼀般在组合化学的固相合成中⽤的较多。
⽬前，在药物化学中⽤的最多的还是EDCI，其⼀个主要的特点就是其反应后的⽣成的脲是⽔溶性的，很容易被洗掉，⼀般EDCI与HOBt合⽤（注意: 这⼀反应HOBt⼀般是缺不了的，否则有可能导致缩合产率太低）。有时如果酸的a-位位阻⼤或者连有吸电⼦基团，反应会停留在活性酯这⼀步（这⼀活性酯的质谱信号较强，可通过MS或LC-MS检测到）。由于HOBt也是⽔溶性的，其使得反应的处理和纯
化相对要容易。⼀般在这⼀缩合中要加⼊碱，特别当⽤胺或氨基酸的盐酸盐等缩合，常⽤的是加2-3当量的N-甲基啉或⼆异丙基⼄胺（DIEA,Hunig base）, 缩合时以⼆氯甲烷为溶剂，若底物的溶解度不好，可⽤DMF作反应溶剂，再使⽤该⽅法进⾏。
在使⽤该⽅法进⾏氨基酸缩合时，⼀般投料必须在零下20~30℃下进⾏，并在此温度下搅拌近⼀⼩时后再室温搅拌，否则其会引起氨基酸的消旋化。
1、DCC缩合法合成酰胺⽰例
To a solution of compound11(4.06 g, 10 mmol) in DMF (150 mL) wasadded N-hydroxybenzotriazole (HOBt, 5.64 g, 42 mmol), followed by dicyclohexylcarbodiimide (DCC; 8.60 g, 42 mmol). After stirring for l h,a solution of di-tert-butyl 4-amino-4-[2-(tert-butoxycarbonyl)ethyl]heptanedioate5(17.34 g, 41.7 mmol)in DMF (60 mL) was added and the solution stirred at 25℃for 23 h. The crystals were filtered and washed on thefilter with DMF (25 mL). The solvent wasdistilled at 50℃/1mm, and the residual oil was dissolved in ether (600mL). Crystals were filtered, the ethereal solutionwas washed successi
卧式金属带锯床vely with 10% HCl (2 x100 mL), saturated NaHCO3(2 x 100 mL), and brine (2 x 50 mL), then dried (Na2SO4). The ether solution was filtered throughcelite and solvent was then removed in vacuoto afford 19.0 g of crude product, which waspurified on a silica column eluting with toluene/EtOAc (1:1) to furnish (60%)the white, non-crystalline ester 12:14.0 g; mp 55-60℃. 1HNMR δ 1.43 (s, CH3, 108H), 1.94-2.28 (m, CH2CH2,64H), 5.87 (s, NH, 4H), 6.17 (s, CH=CH, 2H); 13C NMR (DMSO-d6) δ28.3 (CH3), 29.3 (CH2CH2),56.8 (CNH), 69.0 (CSO2), 171.1 (CO), 171.4 (CO).
2、DIC缩合法合成酰胺⽰例
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To a solution of amine 13 (106 mg, 0.3 mmol),Fmoc-Phe-OH (116 mg, 0.3 mmol), and HOBt (44.8 mg, 0.33 mmol) in anhydrous DMF(2 mL) was added DIC (56 µL, 0.36 mmol). The resulting mixture was stirred at roomtemperature overnight, and DMF was then evaporated under high vacuum. The residue was dissolved in ethyl acetate (10mL), washed sequentially with saturated aqueous NaHCO3 and brine,and then dried over Na2SO4. The evaporation of the solvent gave the crudeprod
uct that was directly submitted for the Fmoc removal without purification. The crude product was dissolved in DMF (8 mL),piperidine (2.0 mL) was added, and the resulting solution was stirred at roomtemperature for 1 h. Following thesolvent evaporation, the residue was purified by silica gel chromatography (50%ethyl acetate in hexanes to 10% methanol in chloroform) to provide product 14(128 mg) in 85% yield as a mixture of two diastereomers. 1H NMR (CDCl3, 400MHz) ‰ 8.12-8.00 (2H, m), 7.90-7.80 (2H, m), 7.70-7.54 (2H, m), 7.42(2H, m), 7.35-7.20 (2H, m), 6.97-6.83 (3H, m), 5.32 (1H, m), 4.32 (1H, m),4.20-4.03 (2H, m), 3.96-3.80 (2H, m), 3.60 (1H, m), 2.98 (3H, m), 2.88 (2H, s),2.60 (1H, s), 2.00 (1H, m), 1.85 (2H, m), 1.77-1.55 (3H, m); MS (ES+) m/z) 501.4 (M + 1).
3、应⽤EDC缩合法合成酰胺⽰例⼀（⼆氯甲烷为溶剂）
To a solution of amine16(0.284 mg, 1.19 mmol) and 5-hexenoic acid 15(0.136 g,1.19 mmol) in CH2Cl2 (12.0 ml) at 0℃were added HOBt (0.177 g,1.31 mmol) and EDC (0.251 g,1.31 mmol). The reaction mixture was stirredat room temperature for 10 h, then washed with 5% aqueous HCl (3×15.
0 ml), 5% aqueous NaHCO3 (20 .0 ml),H2O (20.0 ml), and brine (20.0 ml), and dried (Na2SO4). Purification by flash chromatography(CH3Cl/MeOH, 10%, Rf = 0.43) afforded amidoalkene 17in 99%yield as a brown oil.
4、应⽤EDC缩合法合成酰胺⽰例⼆（DMF为溶剂）
A DMF solution (10 mL) containing HOBt (103 mg, 0.76mmol), EDC (192 mg, 1.0 mmol), and Boc-D-Ile (172 mg, 0.76 mmol) was stirred atroom temperature for 20 h. A solution ofthe amino ketal 18 (0.41 g,0.76 mmol) and 4-methylmorpholine (0.17 mL, 1.5 mmol) dissolved in 10 mL of DMFwas then added to the reaction mixture. After4 h the reaction mixture was partitioned between EtOAc and H2O. The organic layer was washed with H2O,dried over MgSO4, and concentrated under reduced pressure. Flash chromatography (4:1 EtOAc/hexanes)afforded the Boc ketal 19 (0.44 g,0.59 mmol, 78%).
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