3  、鎓盐类的缩合剂法 

      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，一类是碳鎓盐，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 和 TNTU 可以用于含水溶剂的酰胺化 反应。若将 HATU 和 HBTU 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-基)-二（四氢吡咯基）碳鎓六氟磷酸盐（HAPyU）、O-（苯并三 氮唑-1-基)-二（四氢吡咯基）碳鎓六氟磷酸盐（HBPyU）,但这些试剂的价格极其昂贵。

      另一类为鏻鎓盐，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。 

       在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5。近有报道PyAOP的缩合剂具有更强的活性。 

       使用碳鎓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。 

3.1 应用HATU/TBTU为缩合剂合成酰胺示例 

    The general procedure: 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 is then 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).

3.2 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 CH3CN is stirred at R.T. while the BOP-reagent (4.42 g, 10 mmol) is added, followed by the addition of triethylamine (2.2 g, 2.8 mL, 20 mmol).  The reaction is stirred at R.T. for 1.5 hr.  100 mL of a saturated NaCl solution is added and the product extracted with EtOAc.  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 dipeptide (3.74g, 98%).

3.3 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 solution of N-methylmorpholine (0.22 mL, 0.58 mmol) and carboxylic acid 23 (0.50 g, 0.29 mmol) in dimethylformamide (5 mL).  The mixture was stirred at room temperature for 3 days.  The mixture was quenched with water and the aqueous solution was extracted with dichloromethane.  The organic layer was washed with water, dried over Na2SO4 and concentrated in vacuo.  The crude product was purified by silica gel column chromatography eluting with dichloromethane/ethanol (9/1) to give morpholide 24 as a white solid (109 mg, 65%).  Mp 92–94℃.  1H NMR d 7.56 (s, 1H, H9), 6.99 (s, 1H, H7), 7.16–7.12 (m, 3H, 3Har), 7.11 (d, 2H, J=8.5 Hz, 2H’ar), 6.87 (d, 2H, J=8.5 Hz, 2H’ar), 4.01–3.97 (m, 2H, H4), 3.74 (s, 3H, OCH3), 3.65–3.61 (m, 2H, CH2 morph.), 3.60–3.57 (m, 2H, CH2 morph.), 3.00– 2.96 (m, 2H, H6), 2.88–2.84 (m, 4H, CH2), 2.68–2.66 (m, 2H, CH2), 2.50–2.46 (m, 2H, CH2), 2.39 (s, 6H, CH3), 2.16– 2.12 (m, 2H, H5), 1.52–1.48 (m, 4H, CH2).  MS-ES+ (MeOH): m/z 581 (M + H+, 100%). 

3.4 应用PyBOP为缩合剂合成酰胺示例二（用于合成伯酰胺） 

    A solution of 2-(4-(2-amino-4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)phenyl)acetic acid (65 mg, 0.17 mmol) in anhydrous DMF (1.2 mL) was treated with PyBOP (125 mg, 0.24 mmol) and HOBt (32 mg, 0.24 mmol) followed by DIPEA (60 mL, 0.35 mmol) and NH4Cl (19 mg, 0.35 mmol).  After stirring at room temperature for 20 min, the mixture was concentrated under vacuum and the residue partitioned between EtOAc and saturated aq. NaHCO3 solution.  The EtOAc phase was washed with brine, dried (MgSO4) and concentrated in vacuo.  The product was purified by flash column chromatography on SiO2 eluting with 0-8% of MeOH/CH2Cl2 to give the title compound 26 (40 mg, 62percent) as an amber colored oil. 1H NMR (DMSO-d6) d 8.23 (dd, 1H, J=10.7, 2.5 Hz), 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)+.