Ethanol → HCID 49764010, compound

Participants

Reaction Steps

A 250 ml round-bottomed flask equipped with a magnetic stirrer and with a septum having a top-mounted argon intake is charged with 992 mg of 5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-1H-pyrazolo[4,3-c]isoquinoline-7-carbonitrile trifluoroacetate, 63 ml of ethanol, 30 ml of THF and 10 ml of 9.3N sodium hydroxide. After 3 h at reflux, the mixture is cooled and poured into 250 ml of a 1M aqueous solution of potassium dihydrogen phosphate. The mixture is extracted with AcOEt, washed with saturated aqueous NaCl solution, dried over MgSO4, filtered and concentrated to dryness under RP. The crude solid is dissolved in 20 ml of DMF, and then 1 g of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluoride (BOP), 323 mg of 1-hydroxybenzotriazole (HOBT), 170 mg of ammonium chloride and 1 ml of N,N-diisopropylethylamine (DIPEA) are added. After 2 h of stirring at RT, the reaction mixture is poured into water, extracted with AcOEt, washed with a 1M aqueous solution of potassium dihydrogen phosphate and then with saturated aqueous NaCl solution. Drying over MgSO4, filtering and concentration under RP are followed by purification by flash chromatography on silica gel (40-63 μm), eluting with a mixture of DCM, methanol and 4N methanolic ammonia (90/10/1 by vol.), to give 321 mg of 5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-1H-pyrazolo[4,3-c]isoquinoline-7-carboxamide (lemon yellow solid). MS (E/I): m/z=500 (M+); 1H NMR: 1.68 (m, 2H); 2.11 (m, 2H); 2.88 (s, 3H); 2.90 (m, 2H); 3.56 (m, 2H); 3.80 (m, 1H); 6.09 (d, J=8.0 Hz, 1H); 7.33 (t, J=8.0 Hz, 2H); 7.57 (broad s, 1H); 7.69 (m, 1H); 8.17 (broad s, 1H); 8.23 (broad s, 1H); 8.36 (broad d, J=8.5 Hz, 1H); 8.45 (d, J=8.5 Hz, 1H); 12.85 (s, 1H).

Provenance & Evidence