Reacción #1742467

Ecuación de reacción

isobutyl chloroformate

(S)-2-t-butoxycarbonylamino-3-(biphenyl-4-yl)-propionic acid

N-methylmorpholine

→

(S)-3-t-Butoxycarbonylamino-4-(biphenyl-4-yl)-butyric acid methyl ester

Disolventes

triethylamine

THF

Condiciones de reacción

Tratamiento posterior

1. 1
   Filtraciónfiltered
2. 2
   LavadoThe precipitate is washed with dry ether (5 mL)
3. 3
   workup.ADDITIONA saturated solution of diazomethane in ether is added at 0° until persistence of a yellow color
4. 4
   workup.STIRRINGAfter stirring for 1 hour at 0° and 1 hour at room temperature
5. 5
   Concentraciónthe solution is concentrated in vacuo
6. 6
   workup.STIRRINGThe dark solution is stirred at room temperature for 30 minutes
7. 7
   Filtraciónfiltered through Celite
8. 8
   ConcentraciónThe filtrate is concentrated under reduced pressure
9. 9
   workup.DISSOLUTIONthe residue is redissolved in ethyl acetate (20 mL)
10. 10
    LavadoThe organic layer is washed successively with water (10 mL), saturated sodium bicarbonate (10 mL) and 1N hydrochloric acid (10 mL)
11. 11
    Secadobefore being dried over anhydrous sodium sulfate
12. 12
    Filtraciónfiltered
13. 13
    OtroAfter evaporation of the solvent in vacuo
14. 14
    Otrothe residue is purified by flash-chromatography on silica gel
15. 15
    Lavadoeluting with 25% ethyl acetate in hexane

Procedimiento

Similarly to a method reported in J. Med. Chem., 1988, 31, 2199, to a stirred solution of (S)-2-t-butoxycarbonylamino-3-(biphenyl-4-yl)-propionic acid (J. Org. Chem., 1992, 57, 379; 1 g, 2.93 mmol) in THF (10 mL) at 0° is added N-methylmorpholine (0.35 mL, 3.18 mmol), followed by isobutyl chloroformate (0.39 mL, 3.0 mmol). The suspension is stirred for 1 hour, then filtered. The precipitate is washed with dry ether (5 mL). A saturated solution of diazomethane in ether is added at 0° until persistence of a yellow color. After stirring for 1 hour at 0° and 1 hour at room temperature, the solution is concentrated in vacuo to yeild the intermediate diazoketone as a beige solid (m.p. 128°-129°). The solid is suspended in methanol (10 mL). A solution of silver benzoate (150 mg, 0.65 mmol) in triethylamine (3 mL) is added dropwise. The dark solution is stirred at room temperature for 30 minutes, then filtered through Celite. The filtrate is concentrated under reduced pressure and the residue is redissolved in ethyl acetate (20 mL). The organic layer is washed successively with water (10 mL), saturated sodium bicarbonate (10 mL) and 1N hydrochloric acid (10 mL) before being dried over anhydrous sodium sulfate and filtered. After evaporation of the solvent in vacuo, the residue is purified by flash-chromatography on silica gel, eluting with 25% ethyl acetate in hexane. (S)-3-t-Butoxycarbonylamino-4-(biphenyl-4-yl)-butyric acid methyl ester is obtained as a solid, m.p. 86°-87°.

Fuente