Reacción #47621

Ecuación de reacción

2-amino-3-(2,6-dichloro-phenyl)-propionic acid methyl ester hydrochloride salt

N,N-diisopropylethylamine

4-bromo-3-(2,6-difluoro-phenoxy)-but-2-enoic acid ethyl ester

(S)-3-cyclohexyl-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide

N,N-diisopropylethylamine

→

3-(2,6-dichloro-phenyl)-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester

Rendimiento 13.1%

Disolventes

acetonitrile

acetonitrile

Condiciones de reacción

Tratamiento posterior

1. 1
   OtroIn a flask was placed
2. 2
   Temperaturacooled to 25° C
3. 3
   Temperaturaheated at 80° C.
4. 4
   TemperaturaThe mixture was heated at 100° C. for 16 h
5. 5
   Otroplaced in a sealed microwave tube
6. 6
   Temperaturaheated at 140° C. for 1 h in the microwave
7. 7
   ConcentraciónThe mixture was then concentrated in vacuo with silica gel (2 g)
8. 8
   OtroPurification by Biotage flash chromatography (40S column, 10% ethyl acetate/hexanes to 100% ethyl acetate)

Procedimiento

In a flask was placed 2-amino-3-(2,6-dichloro-phenyl)-propionic acid methyl ester hydrochloride salt (313 mg, 1.10 mmol), acetonitrile (5 mL) and N,N-diisopropylethylamine (200 μL, 1.23 mmol). This mixture was stirred at 60° C. for 1 h and then cooled to 25° C. The mixture was then treated with N,N-diisopropylethylamine (200 μL, 1.23 mmol) and heated at 80° C. and a solution of 4-bromo-3-(2,6-difluoro-phenoxy)-but-2-enoic acid ethyl ester (prepared as in Example 36, 321 mg, 1.00 mmol) in acetonitrile (1 mL) was added slowly. The mixture was heated at 100° C. for 16 h and then placed in a sealed microwave tube and heated at 140° C. for 1 h in the microwave. The mixture was then concentrated in vacuo with silica gel (2 g). Purification by Biotage flash chromatography (40S column, 10% ethyl acetate/hexanes to 100% ethyl acetate) afforded 3-(2,6-dichloro-phenyl)-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (58 mg, 12%) as a gold oil: HR-ES-MS m/z calculated for C20H15NO4Cl2F2 [M+H]+ 442.0419, observed 442.0420.

Fuente