Diisopropylethylamine → (S)-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]-3-(tetrahydro-pyran-2-yl)-propionamide

Participants

Reaction Steps

(S)-2-amino-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(tetrahydropyran-2-yl)-propionamide hydrochloride (prepared as in Example 92, 300 mg, 0.78 mmol) was dissolved in methanol (5 mL) and N,N-diisopropylethylamine (0.5 mL) was added. The mixture was evaporated to dryness. The residue was dissolved acetonitrile (8 mL). To this solution was added (E)-4-bromo-3-(2,6-difluoro-phenoxy)-but-2-enoic acid ethyl ester (prepared as in Example 36, 296 mg, 0.92 mmol). The mixture was refluxed for 40 h. The mixture was evaporated and the residue was treated with ethyl acetate and water. The layers were separated and the organic layer was dried and concentrated. The crude material was purified through reverse phase preparative HPLC (acetonitrile in water, 25% to 100% linear gradient) to afford (S)-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]-3-(tetrahydro-pyran-2-yl)-propionamide (114 mg, 29%): HR-ES-MS m/z calculated for C25H30N4O5F2 [M+H]+ 505.2257, observed 505.2260; 1H NMR (300 MHz, CDCl3) δ ppm 1.16 (s, 6H), 1.24-1.70 (m, 5H), 1.74-1.97 (m, 2H), 2.17-2.30 (m, 1H), 3.29-3.52 (m, 2H), 3.92-4.05 (m, 1H), 3.95 (s, 3H), 4.25 (d, J=17.8 Hz, 1H), 4.43 (d, J=17.8 Hz, 1H), 4.95 (s, 1H), 5.10 (dd, J=8.6, 6.5 Hz, 1H), 6.69 (s, 1H), 6.97-7.10 (m, 2H), 7.14-7.25 (m, 1H), 7.30 (s, 1H), 8.77 (br. s., 1H).

Provenance & Evidence