利用有机磷类缩合剂制备酰胺

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  多种磷酸酯和磷酰胺类缩合剂也被广泛应用于酰胺的缩合。如二苯基磷酰氯(DPP-Cl)、氰代磷酸二乙酯(DECP)、叠氮化磷酸二苯酯(DPPA、硫代二甲基磷酰基叠氮(MPTA)、二(2--3-唑烷基)磷酰氯(BOP-Cl),2,4,6-三丙基-1,3,5,2,4,6-三氧三磷酸-2,4,6-三氧化物(T3P)等。


在这些磷酸酯和磷酰胺类缩合剂中,DECP常用于小量的多肽的合成, BOP-Cl特别适合与氨基酸的合成,其收率高、不易消旋,但其缺点是,当胺的反应活性低时,常常得到酰化的唑烷。

另外,BOP-Cl的溶解性较差,导致反应时间较长,有时会长达四五天,常用DMF做反应溶剂。

         以下反应用DCC只有15%的收率, 但用DPP-Cl可以得到94%收率。

反应实例

一、DPPA为缩合剂合成酰胺示例

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 wasextracted successively with 10% citric acid, H2O, saturated NaHCO3solution, H2O, and saturated NaCl solution (20 mL each), dried(anhydrous MgSO4) and finnaly evaporated in vacuo.  The oily residue was purified by columnchromatography on silica gel, eluting with 7:1 CHCl3-MeOH to givethe desired product 31 as a white solid. Yield: 81% (two steps)。


二、BOP-Cl为缩合剂合成酰胺示例

To a solution of theacid 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) wereadded.  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 threetimes with 5% NaHCO3 solution and once consecutively with water, 2M HCl solution, water and saturatedbrine (50 ml each).  The organic layerwas dried over Na2SO4, and the solvent was evaporated to give the desired amide34.


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