利用有機磷類縮合劑製備醯胺
1972年，Shioiri, T.等人首先報導了利用DPPA通過羧酸-磷酸混酐進行醯胺化【J. Am. Chem. Soc.1972, 94, 6203.】。但是還沒有利用此方法進行大量合成的報導，可能與此試劑相對昂貴，易爆和高毒有關。
多種磷酸酯和磷醯胺類縮合劑也被廣泛應用於醯胺的縮合。如二苯基磷醯氯（DPP-Cl）、氰代磷酸二乙酯（DECP）、疊氮化磷酸二苯酯（DPPA）、硫代二甲基磷醯基疊氮（MPTA）、二（2-氧-3-唑烷基）磷醯氯（BOP-Cl）等。
在這些磷酸酯和磷醯胺類縮合劑中，DECP常用於小量的多肽的合成， BOP-Cl特別適合與胺基酸的合成，其收率高、不易消旋，但其缺點是，當胺的反應活性低時，常常得到醯化的唑烷。
另外，BOP-Cl的溶解性較差，導致反應時間較長，有時會長達四五天，常用DMF做反應溶劑。
另外有更加適合放大的製備羧酸-磷酸混酐的試劑被發現，如正丙基膦酸酐（T3P）和乙基甲基次膦酸酐（EMPA），下面作詳細介紹。
正丙膦酸酐，通常被稱為T3P，是在1980年作為肽偶聯劑被開發出來的【Angew. Chem., Int. Ed. Engl.1980, 19, 133.】。在過去的十年中，這種試劑已經實現了大規模製備醯胺(a)Synthesis2013, 45, 1569. (b)Synlett2000, 1369. (c)Synlett2007, 1328.】。
反應實例
一、DPPCl為縮合劑合成醯胺示例
以下反應用DCC只有15%的收率, 但用DPP-Cl可以得到94%收率。
二、DPPA為縮合劑合成醯胺示例
To solution of this free amine 30 (0.270 g, 0.96 mmol) was added DMF (5 mL),(2-phthalimidoethoxy)acetic acid 29 (0.237 g, 0.96 mmol), DPPA (0.25 mL, 1.15mmol) and Et3N (0.29 mL, 2.11 mmol) at 0℃ while stirring. The ice bath was removed after two hours and the reaction was stirred at R.T. overnight. EtOAc (70 mL) was added and the solution was extracted successively with 10% citric acid, H2O, saturated NaHCO3solution, H2O, and saturated NaCl solution (20 mL each), dried (anhydrous MgSO4) and finally evaporated in vacuum. The oily residue was purified by column chromatography on silica gel, eluting with 7:1 CHCl3-MeOH to give the desired product 31 as a white solid. Yield: 81% (two steps)。
三、BOP-Cl為縮合劑合成醯胺示例
To a solution of the acid 33 in dry CH2Cl2 (5 ml / mmol) was added diisopropyl ethylamine (DIEA, 1 equiv) under nitrogen, and the mixture was stirred for 10 min. Then, BOP-Cl (1 equiv), amine 32 (1.1 equiv) and again DIPEA (2 equiv) were added. After it was stirred overnight, most of the DCM was removed under reduced pressure and ethyl acetate (100 ml) was added. The solution was washed three times with 5% NaHCO3 solution and once consecutively with water, 2M HCl solution, water and saturated brine (50 ml each). The organic layer was dried over Na2SO4, and the solvent was evaporated to give the desired amide34.
四、T3P為縮合劑合成醯胺示例
T3P was dosed to a mixture of acid, amine, and pyridine in 2:1 v/v MeCN/EtOAc. This solvent ratio, upon quenching with 0.5 M aqueous HCl, provided the direct-drop crystallization of free base amide 112 (34.1 kg, 88% yield) with high purity (>99% achiral, 0.5% ent-112) and purging of pyridine, excess aminonicotinate 111, andT3P byproducts to the mother liquor。
【Org. Process Res. Dev.2012, 16, 1635】
【Org. Process Res.Dev. 2009, 13, 900】
其它縮合劑
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