Reacción #47623

Ecuación de reacción

oxalyl chloride

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

1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol

(S)-2-[4-(2,3-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide hydrochloride

2,6-lutidine

→

3-(2,6-dichloro-phenyl)-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

Rendimiento 36.0%

Disolventes

dichloromethane

dichloromethane

dichloromethane

Condiciones de reacción

Tratamiento posterior

1. 1
   OtroIn a round bottom flask under argon was placed
2. 2
   Otroat 25° C
3. 3
   Otroresulted in gas evolution
4. 4
   Concentraciónconcentrated in vacuo
5. 5
   workup.ADDITIONadded dropwise into a flask
6. 6
   workup.STIRRINGThe mixture was then stirred for 1 h at 25° C.
7. 7
   Otroquenched with methanol
8. 8
   workup.ADDITIONdiluted with dichloromethane
9. 9
   LavadoThis mixture was then washed with a 1N aqueous hydrochloric acid solution
10. 10
    Secadodried over sodium sulfate
11. 11
    Concentraciónconcentrated in vacuo with silica gel (2 g)
12. 12
    OtroPurification by Biotage flash chromatography (25% ethyl acetate/hexanes)

Procedimiento

In a round bottom flask under argon was placed 3-(2,6-dichloro-phenyl)-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (38 mg, 0.089 mmol) in dichloromethane (3 mL) and N,N-dimethylformamide (3 drops) at 25° C. To this mixture was then added a 2.0M solution of oxalyl chloride in dichloromethane (50 μL, 0.10 mmol) dropwise which resulted in gas evolution. The mixture was then stirred for 15 min at 25° C. and concentrated in vacuo. The residue was taken up in dichloromethane (3 mL) and added dropwise into a flask containing a solution of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared as in US20080021032, Example 80, 17 mg, 0.107 mmol), dichloromethane (3 mL) and 2,6-lutidine (50 μL, 0.18 mmol) at 25° C. The mixture was then stirred for 1 h at 25° C. and then quenched with methanol and diluted with dichloromethane. This mixture was then washed with a 1N aqueous hydrochloric acid solution, dried over sodium sulfate and concentrated in vacuo with silica gel (2 g). Purification by Biotage flash chromatography (25% ethyl acetate/hexanes) afforded 3-(2,6-dichloro-phenyl)-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 (18 mg, 36%) as a light amber foam: HR-ES-MS m/z calculated for C26H24N4O4Cl2F2 [M+H]+ 565.1216, observed 565.1216; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.04 (s, 3H), 1.05 (s, 3H), 3.34-3.51 (m, 2H), 3.88 (s, 2H), 4.19 (d, J=18.3 Hz, 1H), 4.55 (d, J=18.3 Hz, 1H), 4.66 (s, 1H), 4.98 (s, 1H), 5.03 (dd, J=8.2, 6.0 Hz, 1H), 6.50 (d, J=2.1 Hz, 1H), 7.27 (dd, J=8.2, 7.7 Hz, 1H), 7.35 (t, J=8.7 Hz, 2H), 7.38-7.48 (m, 3H), 7.54 (d, J=2.1 Hz, 1H), 10.68 (s, 1H).

Fuente