Methylamine → N4-Methyl-6-{2-(methylamino)-6-[(3R)-3-methyl-4-morpholinyl]-4-pyrimidinyl}-1H-indazole-3,4-diamine

Participants

Reaction Steps

To a 20-mL vial was added 2,6-difluoro-4-{2-(methylamino)-6-[(3R)-3-methyl-4-morpholinyl]-4-pyrimidinyl}benzonitrile (100 mg, 0.290 mmol), DMF (1 mL), and methylamine (2 M in THF, 0.174 mL, 0.347 mmol). The reaction was stirred overnight at room temperature. An additional 0.6 equiv of methylamine solution (2 M in THF) was added and the reaction stirred at room temperature for 3 days over the weekend. The reaction mixture was concentrated in vacuo, and the residue was dissolved in ethanol (1.5 mL), and hydrazine (0.101 mL, 1.737 mmol) and Hunig's base (0.152 mL, 0.869 mmol) were added. The reaction was heated at 150° C. for 60 minutes in a microwave reactor. The reaction mixture was concentrated, and the residue dissolved in DMSO and purified by RPHPLC. The product fractions were combined, basified with NaHCO3 and extracted with EtOAc. The organics were combined, dried and concentrated to afford the title compound (40.5 mg) as a brown solid. LC-MS (ES) m/z=369 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.18 (d, J=6.8 Hz, 3H), 2.73-2.91 (m, 6H), 3.03-3.15 (m, 1H), 3.39-3.52 (m, 1H), 3.62 (d, J=2.5 Hz, 1H), 3.67-3.78 (m, 1H), 3.87-3.98 (m, 1H), 4.01-4.15 (m, 1H), 4.41-4.55 (m, 1H), 5.07 (s, 2H), 5.59-5.74 (m, 1H), 6.26-6.62 (m, 3H), 7.14 (br. s., 1H), 11.35 (s, 1H).

Provenance & Evidence