Reaction #1909785

Reaction equation

water

N-tert-butoxycarbonyl-L-phenylalanine methyl ester

acetamide oxime

sodium hydride

→

N-tert-butoxycarbonyl-1-(3-methyl-1,2,4-oxadiazol-5-yl)-2-phenylethylamine

Yield 48.7%

Solvents

THF

THF

Conditions

Workup

1. 1
   Temperaturethe mixture was refluxed
2. 2
   Temperatureunder heating for 1 hour
3. 3
   Temperatureto cool
4. 4
   TemperatureThe mixture was refluxed
5. 5
   Temperatureunder heating for 20 minutes
6. 6
   Temperatureto cool
7. 7
   Concentrationwhich was followed by concentration under reduced pressure
8. 8
   workup.ADDITIONA 10% aqueous citric acid solution was added to the residue
9. 9
   Extractionthe mixture was extracted with ethyl acetate
10. 10
    WashThe organic layer was washed with saturated brine
11. 11
    Dryingdried over anhydrous sodium sulfate
12. 12
    Concentrationconcentrated under reduced pressure
13. 13
    OtherThe residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=3/1 v/v)

Procedure

To a solution of acetamide oxime [2.67 g, J. Saunders et al., J. Med. Chem., 33, 1128 (1990)] in THF (125 ml) was added 60% sodium hydride (1.44 g) in oil, and the mixture was refluxed under heating for 1 hour. Then, the reaction mixture was allowed to cool, and a solution of N-tert-butoxycarbonyl-L-phenylalanine methyl ester (8.38 g) in THF (40 ml) was added at room temperature. The mixture was refluxed under heating for 20 minutes. The mixture was allowed to cool, and water (10 ml) was added, which was followed by concentration under reduced pressure. A 10% aqueous citric acid solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=3/1 v/v) to give 4.43 g of N-tert-butoxycarbonyl-1-(3-methyl-1,2,4-oxadiazol-5-yl)-2-phenylethylamine. This compound was added to a 4N hydrogen chloride-dioxane solution (50 ml), and the mixture was stirred at room temperature for 2 hours. Toluene was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Ether was added to the residue for crystallization to give the title compound (3.25 g, yield 47%).

Source