Reaction Steps
A solution of (S)-2-[4-(2,5-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (0.36 g, 1.10 mmol) in N,N-dimethylformamide (4.25 mL) at 25° C. was treated with N,N-diisopropylethylamine (0.54 mL, 3.31 mmol), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (0.73 g, 1.65 mmol) and a solution of 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 0.22 g, 1.16 mmol) in N,N-dimethylformamide (0.5 mL). The reaction was stirred at 25° C. overnight. At this time, the reaction was diluted with ethyl acetate (100 mL) and was washed with a saturated aqueous sodium bicarbonate solution (1×150 mL) and a saturated aqueous sodium chloride solution (1×150 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 50-70% ethyl acetate/hexanes) afforded (S)-2-[4-(2,5-difluoro-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 (0.36 g, 64%) as a red/orange foam: HR-ES-MS m/z calculated for C25H30N4O5F2 [M+H]− 505.2257, observed 505.2254; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90 (d, J=6.4 Hz, 3H), 0.94 (d, J=6.4 Hz, 3H), 1.25 (s, 3H), 1.30 (s, 3H), 1.36-1.64 (m, 2H), 1.68-1.85 (m, 1H), 3.73 (dd, J=8.5, 5.7 Hz, 1H), 3.95-4.14 (m, 3H), 4.22 (d, J=18.6 Hz, 1H), 4.29-4.42 (m, 1H), 4.60 (d, J=18.6 Hz, 1H), 4.89 (dd, J=10.6, 4.5 Hz, 1H), 5.03 (s, 1H), 6.43 (d, J=2.1 Hz, 1H), 7.12-7.32 (m, 1H), 7.43-7.59 (m, 2H), 7.60 (d, J=2.1 Hz, 1H), 10.81 (s, 1H).
