Maleic Acid → HCID 178495260, compound

Participants

Reaction Steps

A solution of trans-4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenol (0.100 g, 0.245 mmol) in dimethylformamide (25 mL), was treated with 2-fluoro-6-[(2-methoxyethyl)amino]benzonitrile (0.128 g, 0.613 mmol) and potassium carbonate (0.068, 0.49 mmol). The reaction mixture was stirred at 120° C. over night under a nitrogen atmosphere. Ethyl acetate and 1 N sodium hydroxide solution were added to the reaction mixture. The organic layer was washed with 1 N sodium hydroxide solution (1 L). The layers were partitioned and the organic layer was washed with water and brine (500 mL each), dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel using 10% methanol in dichloromethane as eluent, to afford 71 mg (48%) of trans-2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)-6-[(3-methoxypropyl)amino]benzonitrile. A warm solution of trans-2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)-6-[(3-methoxypropyl)amino]benzonitrile (0.071 g, 0.119 mmol) in ethyl acetate was treated with a warm solution of maleic acid (0.042 g, 0.358 mmol) in ethyl acetate. The precipitate was filtered under nitrogen and dried under high vacuum to give trans-2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)-6-[(3-methoxypropyl)amino]benzonitrile tris-maleate. 1H NMR (DMSO-d6, 400 MHz) δ 8.23 (s, 1H), 7.69-7.67 (d, 2H, J=8 Hz), 7.37-7.33 (m, 1H), 7.25-7.23 (d, 2H, J=8 Hz), 6.53-6.51 (d, 1H, J=8 Hz), 6.30-6.29 (m, 1H), 6.19-6.17 (d, 1H, J=8 Hz), 6.17 (s, 6H), 4.65-4.64 (m, 1H), 3.45-3.42 (m, 2H), 3.27 (s, 3H), 2.55-2.50 (m, 4H), 2.50-2.30 (m, 5H), 2.33 (br, s, 3H), 2.01-1.96 (m, 8 Hz), 1.84-1.80 (m, 2H), 1.49-1.46 (m, 2H); HPLC Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 μm, 2.1×50 mm; 5%-95% acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rt 5.181 min (95%).

Provenance & Evidence