反応 #47290
ord-686fdfc287d049b0970fc285f0c556d5
反応方程式
反応物
試薬
反応条件
後処理
- 1洗浄washed with saturated ammonium chloride, water
- 2乾燥a saturated sodium chloride solution and dried over sodium sulfate
- 3濃縮The organic layer was concentrated
- 4その他the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g, 20% to 90% ethyl acetate/hexanes)
実験手順
A solution of (S)-2-[4-(3-chloro-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionic acid (prepared as in Example 72, 160 mg, 0.40 mmol) in N,N-dimethylformamide (3 mL) was treated with 1-methyl-1H-pyrazol-3-ylamine (50 mg, 0.51 mmol), benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (450 mg, 1.01 mmol) and N,N-diisopropylethylamine (130 mg, 1.01 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, water, a 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, 20% to 90% ethyl acetate/hexanes) to afford (S)-2-[4-(3-chloro-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-N-(1-methyl-1H-pyrazol-3-yl)-propionamide as a waxy material. This material was dissolved in dichloromethane (4 mL) and treated with hydrogen chloride in diethyl ether (1 M, 4 mL). Solvents were evaporated and the residue was triturated with diethyl ether. The resulting mixture was filtered to give (S)-2-[4-(3-chloro-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-N-(1-methyl-1H-pyrazol-3-yl)-propionamide hydrochloride (75 mg, 36%) as a tan solid: LR-ES-MS m/z calculated for C23H25ClF2N4O3 [M]+ 478, observed 479 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.65-1.30 (m, 6H) 1.42-1.83 (m, 7H) 3.71 (s, 3H) 4.27 (d, J=18.7 Hz, 1H) 4.61 (d, J=18.7 Hz, 1H) 4.87 (dd, J=10.3, 5.1 Hz, 1H) 5.22 (s, 1H) 6.38 (d, J=2.1 Hz, 1H) 7.43 (td, J=9.0, 1.7 Hz, 1H) 7.53 (d, J=2.1 Hz, 1H) 7.66 (td, J=9.0, 5.4 Hz, 1H) 10.72 (s, 1H).