反应详情

To a stirring solution of 1-(4-cyano-3-fluorophenyl)-6-oxo-4-(piperidin-4-yloxy)-1,6-dihydropyridazine-3-carbonitrile HCl salt (Example 36, step A) (19 mg, 0.05 mmol) in DCM (3 mL) at room temperature under argon was added TEA (0.014 mL, 0.10 mmol) and isopropyl carbonochloridate (12 mg, 0.10 mmol). The reaction mixture was stirred at room temperature overnight. Solvent was removed in vacuo and the crude product was dissolved in a small amount of DCM (˜2 ml) and loaded onto a 40 g ISCO silica gel column which was eluted with a 20 min gradient from 0% to 100% EtOAc/Hexanes. 15 mg (43%) of isopropyl 4-(3-cyano-1-(4-cyano-3-fluorophenyl)-6-oxo-1,6-dihydropyridazin-4-yloxy)piperidine-1-carboxylate was obtained as white solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.72-7.81 (1H, m), 7.56-7.72 (2H, m), 6.30 (1H, s), 4.82-5.04 (1H, m, J=6.6, 6.3, 6.2, 6.2 Hz), 4.65 (1H, ddd, J=7.0, 3.4, 3.3 Hz), 3.65-3.84 (2H, m), 3.37-3.61 (2H, m), 1.96-2.12 (2H, m), 1.81-1.96 (2H, m), 1.13-1.33 (6H, m). MS (ESI) 426 (M+H).

1. customSolvent was removed in vacuo
2. dissolutionthe crude product was dissolved in a small amount of DCM (˜2 ml)
3. washwas eluted with a 20 min gradient from 0% to 100% EtOAc/Hexanes