Réaction #47302

Équation de réaction

(S)-3-cyclohexyl-2-[2-oxo-4-(2-trifluoromethyl-phenoxy)-2,5-dihydro-pyrrol-1-yl]-propionic acid

oxalyl chloride

1-methyl-1H-pyrazol-3-ylamine

triethylamine

→

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

Solvants

dichloromethane

dichloromethane

ethyl acetate

Conditions de réaction

Traitement

1. 1
   Autresolvents were evaporated
2. 2
   workup.DISSOLUTIONThe residue was dissolved in dichloromethane (4 mL)
3. 3
   workup.STIRRINGThe reaction mixture was stirred for 4 h at 25° C., under nitrogen
4. 4
   Lavagewashed with saturated ammonium chloride solution, water, saturated sodium chloride solution
5. 5
   Séchagedried over sodium sulfate
6. 6
   ConcentrationThe organic layer was concentrated
7. 7
   Autrethe crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g, 30% to 100% ethyl acetate/hexanes)

Mode opératoire

A solution of (S)-3-cyclohexyl-2-[2-oxo-4-(2-trifluoromethyl-phenoxy)-2,5-dihydro-pyrrol-1-yl]-propionic acid (prepared as in Example 32, 100 mg, 0.25 mmol) in dichloromethane (4 mL) was treated with a dichloromethane solution of oxalyl chloride (2 M, 0.25 mL) and one drop of N,N-dimethylformamide. The mixture was stirred for 45 min and solvents were evaporated. The residue was dissolved in dichloromethane (4 mL) and treated with 1-methyl-1H-pyrazol-3-ylamine (30 mg, 0.30 mmol), and triethylamine (50 mg, 0.5 mmol). The reaction mixture was stirred for 4 h at 25° C., under nitrogen. The reaction mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution, water, saturated sodium chloride solution and dried over sodium sulfate. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g, 30% to 100% ethyl acetate/hexanes) to afford (S)-3-cyclohexyl-N-(1-methyl-1H-pyrazol-3-yl)-2-[2-oxo-4-(2-trifluoromethyl-phenoxy)-2,5-dihydro-pyrrol-1-yl]-propionamide. This material was dissolved in dichloromethane (4 mL) and treated with 1M hydrogen chloride in diethyl ether (2 mL). Solvents were evaporated and the residue was triturated with diethyl ether and filtered to give (S)-3-cyclohexyl-N-(1-methyl-1H-pyrazol-3-yl)-2-[2-oxo-4-(2-trifluoromethyl-phenoxy)-2,5-dihydro-pyrrol-1-yl]-propionamide hydrochloride (20 mg, 16%) as a tan solid: LR-ES-MS m/z calculated for C24H27F3N4O3 [M]+ 476, observed [M+H]+ 477; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.78-1.32 (m, 6H) 1.51-1.87 (m, 7H) 3.73 (s, 3H) 4.19 (d, J=18.7 Hz, 1H) 4.58 (d, J=18.7 Hz, 1H) 4.86-4.94 (m, 1H) 4.96 (s, 1H) 6.40 (d, J=2.1 Hz, 1H) 7.47-7.58 (m, 2H) 7.65 (d, J=7.8 Hz, 1H) 7.74-7.90 (m, 2H) 10.72 (s, 1H).

Source