Reaction Steps
A solution of (S)-2-[4-(2,4-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (0.49 g, 1.53 mmol) in N,N-dimethylformamide (5.9 mL) at 25° C. was treated with N,N-diisopropylethylamine (0.76 mL, 4.59 mmol), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (1.01 g, 2.29 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, 0.31 g, 1.60 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, 50-75% ethyl acetate/hexanes) afforded (S)-2-[4-(2,4-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 (0.63 g, 81%) as a light orange foam: HR-ES-MS m/z calculated for C25H30N4O5F2 [M+H]+ 505.2257, observed 505.2257; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.88 (d, J=6.4 Hz, 3H), 0.91 (d, J=6.4 Hz, 3H), 1.23 (s, 3H), 1.28 (s, 3H), 1.43 (br. s., 1H), 1.48-1.63 (m, 1H), 1.66-1.81 (m, 1H), 3.71 (dd, J=8.5, 5.7 Hz, 1H), 3.94-4.13 (m, 3H), 4.19 (d, J=18.4 Hz, 1H), 4.27-4.38 (m, 1H), 4.57 (d, J=18.4 Hz, 1H), 4.86 (dd, J=10.9, 4.8 Hz, 1H), 4.90 (s, 1H), 6.41 (d, J=2.1 Hz, 1H), 7.12-7.23 (m, 1H), 7.48-7.62 (m, 3H), 10.79 (s, 1H).
