Реакция #47302

Уравнение реакции

(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

Растворители

dichloromethane

dichloromethane

ethyl acetate

Условия реакции

Обработка

1. 1
   Другоеsolvents 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
   Промывкаwashed with saturated ammonium chloride solution, water, saturated sodium chloride solution
5. 5
   Сушкаdried over sodium sulfate
6. 6
   КонцентрированиеThe organic layer was concentrated
7. 7
   Другоеthe crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g, 30% to 100% ethyl acetate/hexanes)

Методика

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).

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