Reaction Steps
A solution of (S)-2-[4-(2-ethoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (130 mg, 0.4 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, 75 mg, 0.46 mmol), benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (353 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, 30% to 100% ethyl acetate/hexanes) to afford (S)-2-[4-(2-ethoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide as a fluffy material. This material was dissolved in diethyl ether (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 solid was filtered to give (S)-2-[4-(2-ethoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide hydrochloride (45 mg, 23%): HR-ES-MS m/z calculated for C25H34N4O5 [M+H]+ 471.2602, observed 471.2603; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.89 (d, J=6.6 Hz, 3H), 0.92 (d, J=6.6 Hz, 3H), 1.04 (br. s., 3H), 1.06 (br. s., 3H), 1.26 (t, J=6.8 Hz, 3H), 1.32-1.64 (m, 2H), 1.64-1.82 (m, 1H), 3.89 (s, 2H), 4.00-4.13 (m, 3H), 4.35-4.62 (m, 2H), 4.74 (s, 1H), 4.89 (dd, J=10.9, 4.5 Hz, 1H), 6.43 (d, J=2.1 Hz, 1H), 6.99 (t, J=6.9 Hz, 1H), 7.15-7.22 (m, 1H), 7.22-7.32 (m, 2H), 7.53 (d, J=2.1 Hz, 1H), 10.77 (s, 1H).
