Reaction Steps
To a solution of (S)-2-[4-(2,6-difluoro-3-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (0.200 g, 0.56 mmol) in N,N-dimethylformamide (7 mL) was added 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 0.139 g, 0.70 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.374 g, 0.85 mmol). The mixture was stirred at 0° C. and N,N-diisopropylethylamine (0.193 g, 1.49 mmol) was added. The mixture was stirred at room temperature overnight and the solvents were evaporated. The residue was treated with ethyl acetate and ammonium chloride solution, and the organic layer separated. The organic layer was washed with brine and dried over sodium sulfate. The solvents were evaporated and the residue was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 40 g, 50% to 90% ethyl acetate/hexanes) which afforded (S)-2-[4-(2,6-difluoro-3-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.193 g, 64%) as a pale brown solid: HR-ES-MS m/z calculated for C26H32F2N4O6 [M+H]+ 535.2363, observed 535.2363, 1H NMR (300 MHz, DMSO-d6) δ ppm 1.00 0.90 (d, J=6.3 Hz, 3H), 0.93 (d, J=6.3 Hz, 3H), 1.25 (s, 3H), 1.30 (s, 3 H), 1.36-1.50 (m, 1H), 1.50-1.65 (m, 1H), 1.69-1.84 (m, 1H), 3.73 (dd, J=8.4, 5.7 Hz, 1H), 3.87 (s, 3H), 4.00 (dd, J=8.4, 6.5 Hz, 1H), 4.11 (t, J=5.4 Hz, 2H), 4.27 (d, J=18.7 Hz, 1H), 4.35 (t, J=5.7 Hz, 1H), 4.62 (d, J=18.7 Hz, 1H), 4.88 (dd, J=10.6, 4.8 Hz, 1H), 5.06 (s, 1H), 6.43 (d, J=2.1 Hz, 1H), 7.18 (td, J=9.3, 5.1 Hz, 1H), 7.30 (td, J=9.5, 1.8 Hz, 1H), 7.60 (d, J=2.1 Hz, 1H), 10.82 (s, 1H).
