近年来,许多盐缩合剂被相继开发出来用于酰胺的缩合反应,从盐的种类来分,主要有两类,一类是碳 盐,目前常用的为O-(7-氮杂苯并三氮唑-1-基)-二(二甲胺基)碳鎓六氟磷酸盐(HATU)、O-(苯并三氮唑-1-基)-二(二甲胺基)碳鎓六氟磷酸盐(HBTU)、O-(5-氯苯并三氮唑-1-基)-二(二甲胺基)碳鎓六氟磷酸盐(HCTU)、O-(苯并三氮唑-1-基)-二(二甲胺基)碳鎓四氟硼酸盐(TBTU)、O-(N-丁二酰亚胺基)-二(二甲胺基)碳鎓四氟硼酸盐(TSTU)、O-(N-endo-5-降莰烯-2,3-二碳二酰亚胺)-二(二甲胺基)碳鎓四氟硼酸盐(TNTU)等。

这些试剂性能及应用有一些区别:HATU 是活性最高的碳鎓盐类缩合剂,但由于它价格昂贵很少用于工业化生产,而且经常是在其它缩合剂效果不好时才用到它。HBTU 相对来说要经济的多,而且可以用于大多数缩合反应,然而其利较低的收率是限制用于大量生产的主要原因。HCTU活性较高,可以代替HATU用于工业化生产,其高活性要归功于有更好活性的Cl-HOBt 中间体。TSTU TNTU 可以用于含水溶剂的酰胺化反应。若将HATUHBTU的二甲胺基变为四氢吡咯基可以得到活性比它们更高的O-(7-氮杂苯并三氮唑-1-)-二(四氢吡咯基)碳六氟磷酸盐(HAPyU)、O-(苯并三氮唑-1-)-二(四氢吡咯基)碳六氟磷酸盐(HBPyU,但这些试剂的价格极其昂贵。

另一类为鏻鎓盐,最早的为苯并三氮唑-1-基氧-三(二甲胺基)鏻鎓六氟磷酸盐BOP)试剂,该试剂由于产生致癌的六甲基磷酰胺(HMPA)副产物,因而近年来被活性更好的,不产生致癌的副产物的苯并三氮唑-1-基氧-三(四氢吡咯基)鏻鎓六氟磷酸盐PyBOP)所代替。

鏻鎓盐类的缩合剂中PyBOP的是一个较为强的缩合剂,一般其他缩合剂缩合不好时常常用PyBOP可以得到更好的结果。比如PyBOP可用于将氨基酸与氯化铵缩合得到相应的氨基酰胺。最近有报道PyAOP的缩合剂具有更强的活性。

使用碳盐缩合剂进行酰胺缩合,主要是通过分子内的转移,一步得到相应的活性酯,以下以HATU的缩合反应为例,说明其反应机理。

吡啶环作为分子内的碱使中间体的活性更高。

1、利用HATU/TBTU为缩合剂合成酰胺示例

The generalprocedure:

The carboxyl acid (10mmol), amine (10.4 mmol)and triethylamine (20 mmol) are dissolved in MeCN (20 mL), and HBTU or HATU (10.4mmol) is added to the solution. After 15-30min the reaction is completed. 100-200 mL of a saturated NaCl solution isthen added and the product extracted with EtOAc (3×50 mL). The combined organics are washed with 2N HCl, H2O, 5% NaHCO3, and then H2O. The organics are dried over MgSO4, filtered, and concentrated in vacuo to give the amide(90-100% yield).

2 、应用BOP为缩合剂合成酰胺示例

A solution of tert -butyloxycarbonyl threonine 20(2.19 g,10 mmol) and phenylalanine methyl ester hydrochloride 21(2.16 g,10 mmol) in 150 mL CH 3 CN is stirred at R.T. while the BOP-reagent (4.42 g, 10 mmol) is added, followed bythe addition of triethylamine (2.2 g,2.8 mL, 20 mmol). The reaction isstirred at R.T. for 1.5 hr. 100 mL of asaturated NaCl solution is added and the product extracted with EtOAc. The combined organics are washed with 2 N HCl, H 2O, 5% NaHCO3, and then H2O. The organics are dried over MgSO4, filtered, and concentrated in vacuo to give the dipeptide (3.74g, 98%).

3、应用PyBOP为缩合剂合成酰胺示例一 (常规)

Morpholine(0.17 mL, 0.58 mmol) and PyBOP (0.56 g, 0.32 mmol) were added to the solutionof N -methylmorpholine (0.22 mL, 0.58mmol) and carboxylic acid 23(0.50 g, 0.29 mmol) in dimethylformamide (5mL). The mixture was stirred at roomtemperature for 3 days. The mixture was quenchedwith water and the aqueous solution was extracted with dichloromethane. The organic layer was washed with water, driedover Na 2 SO 4 and concentrated in vacuo. The crude product was purified by silica gelcolumn chromatography eluting with dichloromethane/ethanol (9/1) to give morpholide 24as a white solid (109 mg, 65%). Mp 92–94 .

4、应用PyBOP为缩合剂合成酰胺示例二(用于合成伯酰胺)

A solution of2-(4-(2-amino-4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)phenyl)acetic acid (65mg, 0.17 mmol) in anhydrous DMF (1.2 mL) was treated with PyBOP (125 mg, 0.24mmol) and HOBt (32 mg, 0.24 mmol) followed by DIPEA (60 mL, 0.35 mmol) and NH 4 Cl(19 mg, 0.35 mmol). After stirring atroom temperature for 20 min, the mixture was concentrated under vacuum and theresidue partitioned between EtOAc and saturated aq. NaHCO 3 solution. The EtOAc phase was washed with brine, dried(MgSO 4 ) and concentrated in vacuo. The product was purified by flash column chromatography on SiO 2 elutingwith 0-8% of MeOH/CH 2 Cl 2 to give the title compound 26(40 mg, 62percent) as an ambercolored oil. 1 H NMR (DMSO-d 6 ) d 8.23 (dd, 1H, J=10.7, 2.5Hz), 8.05 (d, 1H, J=9.2 Hz), 7.93 (d, 1H, J=6.1 Hz), 7.42-7.32 (m, 2H),7.33-7.25 (m, 4H), 6.92 (s, 1H), 6.25 (d, 1H, J=5.6 Hz), 5.64 (s, 2H), 3.36 (s,2H); MS (ESI + ): m/z 383.17 (M+H) + .

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