Diisopropylethylamine → (S)-3-cyclopentyl-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide

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A solution of (S)-3-cyclopentyl-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (109 mg, 0.31 mmol) in N,N-dimethylformamide (4 mL) was treated with 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 62 mg, 0.40 mmol), benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (354 mg, 0.8 mmol) and N,N-diisopropylethylamine (103 mg, 0.8 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, 10% to 80% ethyl acetate/hexanes) to afford (S)-3-cyclopentyl-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (52 mg, 34%): HR-ES-MS m/z calculated for C25H30F2N4O4 [M+H]+ 489.2308 observed 489.2308; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.05 (br. s., 3H) 1.06 (br. s., 3H) 1.09-1.98 (m, 11H) 3.89 (s, 2H) 4.30 (d, J=18.7 Hz, 1H) 4.61 (d, J=18.7 Hz, 1H) 4.68 (s, 1H) 4.82 (dd, J=10.1, 4.4 Hz, 1H) 5.03 (s, 1H) 6.45 (d, J=2.1 Hz, 1H) 7.26-7.50 (m, 3H) 7.54 (d, J=2.1 Hz, 1H) 10.82 (s, 1H).

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