酰卤(酰氯、酰溴和酰氟)与氨或胺作用是合成酰胺的最简便的方法。通过酰氯、酰溴与脂肪族、芳香族胺均可迅速酰化，以较高的产率生成酰胺。酰氟对水和其他亲核试剂较为稳定。其可通过三氟均三嗪在吡啶的存在下制备(Tetrahedron lett. 1991,32（10)，1303)。并可以通过层析分离出来。一般酰氯、酰溴与胺反应是放热的，有时甚至极为激烈，因此通常在冰冷却下进行反应，亦可使用一定量的溶剂以减缓反应速度。常用溶剂为二氯乙烷、乙醚、四氯化碳、甲苯等。由于反应中生成的卤化氢，因此需要用碱除去卤化氢，以防止其与胺成盐。有机碱和无机碱均可用于此类反应，常用的有机碱有三乙胺、吡啶等，常用的无机碱有 Na2CO3,NaHCO3,  K2CO3,NaOH, KOH等。在研究中我们发现，许多反应用无机碱反应更干净且容易处理。

反应实例

一、酰氯合成酰胺示例（有机碱）

To a solution of 47 (1.09 g, 3.00 mmol) was added pyridine (1.50 g, 18.96 mmol), followed by dropwiseaddition of phenylacetyl chloride (0.93 g, 6.00 mmol) in CH2Cl2 (20 mL).  The solution was stirred for 2h. at 25°C, then it was washed successivelywith 10% HCl, 10% NaHCO3 andwater, dried (MgSO4), filtered andthe solvent was then evaporated to give the impure amide which was recrystallizedfrom ethanol to give N-(α-carboethoxy-β-phenylethyl)-3-phenylacetylamino-4-styryl-2-azetidinone(48, 3.86g,80%)。

二、酰氯合成酰胺示例（无机碱）

A mixture containing 8.21 g of phenylalanine, 5.565 g of Na2CO3 in40 mL of water and 20 mL of tetrahydrofuran (THF) was stirred at roomtemperature.  benzoyl chloride (7.73 g), dissolved in 20 mL of anhydrousTHF, was added gradually over a period of 45 minutes with continued stirring atroom temperature.  Stirring was allowedto continue for an additional hour, at which time the reaction mixture wastransferred to a rotary evaporator at 30℃to remove the THF.  An excess of waterwas then added and the reaction mixture extracted four times with ethylacetate.  The aqueous phase was thentitrated to PH 2 with 3N HCl.  A whitecrystalline precipitate formed which was recovered by filtration, washed threetimes with cold dilute HCl and three times with cold water, and dried in avacuum oven over P2O5 at about 50℃.  The product was recrystallized from aqueousethanol, yielding 8.37 g,m.p. 183℃.-184℃., which migrated as a singlecompound on thin layer chromatography in five separate solvent systems.  In this reaction sequence the racemate isobtained.

If a NaOH solution is used in place of the Na2CO3 in this example and the procedure setforth in Carter, H. E. et al, J. Biol. Chem. 138, 627 (1941) is substantiallyfollowed, optical activity is maintained.  Thus, if L-Phe or D-Phe is the startingmaterial, N-alpha-benzoyl-L-phe, or N-alpha-benzoyl-D-Phe, respectively, isproduced.  Similarly, when benzoylN-hydroxysuccinimide ester is used in place of benzoyl chloride in this exampleand the same procedure is followed, the optical activity of D-Phe or D-Phe ismaintained in the N-alpha-benzoyl derivative.

A solution of 6-nitro-1,2-dihydro-3-spiro-1’-cyclopropyl-1H-indole (1.3 g) in CH2Cl2 (100 mL) was suspendedwith NaHCO3 (5 g), andacetyl chloride (720 mg) was added dropwise with vigorous stirring.  After the addition, the reaction was stirredfor 1 h.  the mixture was filtered andthe filtrate was concentrated in vacuo, and then purified via flashchlomatography on silica (EtOAc:hexanes=3:1 to 4:1) to give the title compound.MS (ESI, pos. ion) m/z: 233 (M + 1).

3.5.3应用酰氟合成酰胺示例

Method A:

The N-protected amino acid fluoride (1 mmol) isreacted with the chlorhydrate of and a-amino ester (1.1 mmol) andN-methylmorpholine (2.2 mmol) in acetonitrile (10 ml) untile the acyl fluorideis consumed (approximately 4 h at 25℃).  The reaction is then worked up as usual.

Method B:

A solution of the acylfluoride (1.2 mmol) in CH2Cl2 (5 ml) and a 10%NaHCO3 aqueous solution (10 ml)are added simultaneously to a stirred solution of the ester (1 mmol) in CH2Cl2(5 ml) at room temperature.  Aftercompletion of the reaction (generally 1 to 2 hours), the mixture is worked upas usual. 

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