碳二亚胺类缩合剂制备酰胺

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-甲基吗啡啉或二异丙基乙胺（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 compound 11 (4.06 g, 10 mmol) in DMF (150 mL) was added 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-butxycaronyl)

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 the filter with DMF (25 mL).  The solvent was distilled at 50^oC/1mm, and the residual oil was dissolved in ether (600mL).  Crystals were filtered, the ethereal solution was washed successively 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 through celite and solvent was then removed in vacuum to afford 19.0 g of crude product, which was purified 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

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 room temperature 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 crude product 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 room temperature for 1 h.  Following the solvent 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 stirred at 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 17 in 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 at room temperature for 20 h.  A solution of the amino ketal 18 (0.41 g, 0.76 mmol) and 4-methylmorpholine (0.17 mL, 1.5 mmol) dissolved in 10 mL of DMF was 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%).

本文内容来源于网络，版权归原作者所有