Diisopropylethylamine → (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

Temperatur

25 °C

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).

1. washwashed with saturated ammonium chloride, water
2. dry with materiala saturated sodium chloride solution and dried over sodium sulfate
3. concentrationThe organic layer was concentrated
4. customthe crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g, 20% to 90% ethyl acetate/hexanes)

ORD-Eintrag

ord-686fdfc287d049b0970fc285f0c556d5

Quelldatensatz

uspto-grants-2010_06

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US07741327B2