Methanol → 6-{2-(Methylamino)-6-[(3R)-3-methyl-4-morpholinyl]-4-pyrimidinyl}-4-(methyloxy)-1H-indazol-3-amine

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Reaction Steps

A 100 mL RBF was charged with sodium hydride (73.1 mg, 2.90 mmol), placed under a nitrogen atmosphere and cooled to 0° C. Then CH3OH (10 mL) was added dropwise via syringe, and the resulting mixture was stirred at this temperature for 10 minutes. Then the mixture was warmed to room temperature for 10 minutes to give a cloudy solution of sodium methoxide in CH3OH. To a 4-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 1.2 mL of the solution of sodium methoxide in CH3OH (1.2 equiv). The reaction was stirred for 2 hours at room temperature, then was poured into EtOAc (10 mL). The aqueous was extracted with EtOAc (2×10 mL) and the combined organics were dried over Na2SO4, and then concentrated. The residue was transferred to a 2-mL microwave vial, and ethanol (1.5 mL), Hunig's base (0.152 mL, 0.869 mmol) and hydrazine hydrate (0.101 mL, 1.74 mmol) were added. The resulting mixture was heated at 150° C. for 30 minutes in a microwave reactor. The reaction mixture was concentrated, and the residue purified by RP-HPLC (0-30% CH3CN in H2O, 0.1% TFA). The product fractions were combined, basified with Na2CO3 and extracted into EtOAc. The organic layer was concentrated and the residue lyophilized to afford the title compound (41.7 mg) as an off-white solid. LC-MS (ES) m/z=370 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.19 (d, J=6.6 Hz, 3H), 2.83 (d, J=4.0 Hz, 3H), 3.05-3.22 (m, 1H), 3.46 (d, J=2.5 Hz, 1H), 3.62 (d, J=2.8 Hz, 1H), 3.67-3.79 (m, 1H), 3.85-4.01 (m, 4H), 4.04-4.22 (m, 1H), 4.41-4.62 (m, 1H), 5.03 (s, 2H), 6.37-6.68 (m, 2H), 6.95 (s, 1H), 7.53 (bs, 1H), 11.53 (s, 1H).

Provenance & Evidence