近年來，許多鹽縮合劑被相繼開發(fā)出來用于酰胺的縮合反應(yīng)，從鹽的種類來分，主要有兩類，一類是碳鎓鹽，目前常用的為O-(7-氮雜苯并三氮唑-1-基)-二（二甲胺基）碳鎓六氟磷酸鹽（HATU）、O-（苯并三氮唑-1-基)-二（二甲胺基）碳鎓六氟磷酸鹽（HBTU）、O-(5-氯苯并三氮唑-1-基)-二（二甲胺基）碳鎓六氟磷酸鹽（HCTU）、O-（苯并三氮唑-1-基)-二（二甲胺基）碳鎓四氟硼酸鹽（TBTU）、O-(N-丁二酰亞胺基)-二（二甲胺基）碳鎓四氟硼酸鹽（TSTU）、O-(N-endo-5-降莰烯-2,3-二碳二酰亞胺)-二（二甲胺基）碳鎓四氟硼酸鹽（TNTU）等。

這些試劑性能及應(yīng)用有一些區(qū)別：HATU 是活性最高的碳鎓鹽類縮合劑，但由于它價格昂貴很少用于工業(yè)化生產(chǎn)，而且經(jīng)常是在其它縮合劑效果不好時才用到它。 HBTU 相對來說要經(jīng)濟的多，而且可以用于大多數(shù)縮合反應(yīng)，然而其利較低的收率是限制用于大量生產(chǎn)的主要原因。HCTU活性較高，可以代替HATU用于工業(yè)化生產(chǎn)，其高活性要歸功于有更好活性的Cl-HOBt 中間體。TSTU 和 TNTU 可以用于含水溶劑的酰胺化反應(yīng)。若將HATU和HBTU的二甲胺基變?yōu)樗臍溥量┗梢缘玫交钚员人鼈兏叩?/span>O-(7-氮雜苯并三氮唑-1-基)-二（四氫吡咯基）碳鎓六氟磷酸鹽（HAPyU）、O-（苯并三氮唑-1-基)-二（四氫吡咯基）碳鎓六氟磷酸鹽（HBPyU）,但這些試劑的價格極其昂貴。

另一類為鏻鎓鹽，最早的為苯并三氮唑-1-基氧-三（二甲胺基）鏻鎓六氟磷酸鹽（BOP）試劑，該試劑由于產(chǎn)生致癌的六甲基磷酰胺（HMPA）副產(chǎn)物，因而近年來被活性更好的，不產(chǎn)生致癌的副產(chǎn)物的苯并三氮唑-1-基氧-三（四氫吡咯基）鏻鎓六氟磷酸鹽（PyBOP）所代替。

在鏻鎓鹽類的縮合劑中PyBOP的是一個較為強的縮合劑，一般其他縮合劑縮合不好時常常用PyBOP可以得到更好的結(jié)果。比如PyBOP可用于將氨基酸與氯化銨縮合得到相應(yīng)的氨基酰胺。最近有報道PyAOP的縮合劑具有更強的活性。

使用碳鎓鹽縮合劑進行酰胺縮合，主要是通過分子內(nèi)的轉(zhuǎn)移，一步得到相應(yīng)的活性酯，以下以HATU的縮合反應(yīng)為例，說明其反應(yīng)機理。

吡啶環(huán)作為分子內(nèi)的堿使中間體的活性更高。

1、利用HATU/TBTU為縮合劑合成酰胺示例

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 、應(yīng)用BOP為縮合劑合成酰胺示例

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 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 2NHCl, 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、應(yīng)用PyBOP為縮合劑合成酰胺示例一（常規(guī)）

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 Na₂SO₄ and concentrated in vacuo. The crude product was purified by silica gelcolumn chromatography eluting with dichloromethane/ethanol (9/1) to give morpholide24 as a white solid (109 mg, 65%). Mp 92–94℃.

4、應(yīng)用PyBOP為縮合劑合成酰胺示例二（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 NH₄Cl(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. NaHCO₃solution. The EtOAc phase was washed with brine, dried(MgSO₄) and concentrated in vacuo. The product was purified by flash column chromatography on SiO₂elutingwith 0-8% of MeOH/CH₂Cl₂to give the title compound 26 (40 mg, 62percent) as an ambercolored oil. ¹H NMR (DMSO-d₆) 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)⁺.