Ethanol → 4-(Ethyloxy)-6-{2-(methylamino)-6-[(3R)-3-(1-methylethyl)-4-morpholinyl]-4-pyrimidinyl}-1H-indazol-3-amine

Participants

Reaction Conditions

Reaction Steps

To a solution of 2-(ethyloxy)-6-fluoro-4-{2-(methylamino)-6-[(3R)-3-(1-methylethyl)-4-morpholinyl]-4-pyrimidinyl}benzonitrile (315 mg, 0.79 mmol) in ethanol (10 mL) was added hydrazine monohydrate (2.5 mL) in one portion. The mixture was heated at 100° C. for 20 hours, cooled to room temperature and concentrated in vacuo. The residue was taken up in water (10 mL) as a suspension. The solids were collected by filtration and washed with water (3×2 mL). Further purification was carried out by silica gel column chromatography using gradient elution of 1% A in CHCl3 to 75% A in CHCl3 (where A was a mixture of 800/80/3200 CH3OH/NH4OH/CHCl3). The fraction containing the desired product were combined and concentrated. The resulting residue was dissolved in a solution of 5% CH3OH in CHCl3 (15 mL) and filtered. The filtrate was concentrated in vacuo, and azeotroped with 10 mL of ethanol. The resulting residue was taken up in 10 mL of water, and sonicated. A suspension formed and was filtered. The solids collected were dried under vacuum at room temperature over P2O5 for 18 hours, and then washed with hexane (3×2 mL). Further drying under vacuum at 65° C. for 20 hours gave the title compound (231 mg) as a cream-colored solid. LC-MS (ES) m/z=412 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 0.89 (d, J=6.8 Hz, 3H), 1.11 (d, J=6.6 Hz, 3H), 1.55 (t, J=7.0 Hz, 3H), 2.45-2.55 (m, 1H), 2.96 (s, 3H), 3.25-3.35 (m, 1H), 3.53-3.61 (m, 2H), 3.94 (dd, J=11.1, 3.5 Hz, 1H), 4.11 (d, J=11.6 Hz, 1H), 4.30 (q, J=7.0 Hz, 2H), 6.37 (s, 1H), 6.86 (s, 1H), 7.33 (s, 1H).

Provenance & Evidence