Hydrazine hydrate (1:1) → HCID 46214960, compound

Participants

Reaction Steps

A stock solution of sodium isopropoxide in isopropanol was generated by the addition of isopropanol (40 mL) to NaH (254 mg, 10.56 mmol) at 0° C., followed by stirring at room temperature for 30 minutes, then at 40° C. for 30 minutes. The clear, colorless solution was allowed to cool to room temperature. To a 20-mL microwave vial was added 4-{2-amino-6-[(3R)-3-methyl-4-morpholinyl]-4-pyrimidinyl}-2,6-difluorobenzonitrile (700 mg, 2.11 mmol), DMF (2 mL) and isopropanol (3 mL). The reaction was cooled to 0° C., and a solution of sodium isopropoxide in isopropanol (8.80 mL, 2.324 mmol) was added dropwise. The reaction was stirred overnight. Then an additional portion of DMF (2 mL) was added, and the reaction was allowed to stir overnight at room temperature. At this time, an additional 0.4 equiv of sodium isopropoxide in isopropanol (3.2 mL) was added, and the reaction was stirred for 3 days over the weekend. The reaction mixture was concentrated, and the resulting residue was dissolved in ethanol (10 mL). Hydrazine hydrate (0.73 mL, 12.7 mmol) and Hunig's base (1.11 mL, 6.34 mmol) were added, and the reaction mixture was heated in a microwave reactor for 90 minutes at 150° C. The reaction was allowed to cool to room temperature, whereupon a precipitate formed. The precipitate was collected by filtration, washed with ethanol and dried in vacuo to afford the title compound (600 mg) as a white solid. LC-MS (ES) m/z=384 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.18 (d, J=6.8 Hz, 3H), 1.38 (d, J=5.8, 3H), 1.37 (d, J=5.8, 3H), 3.03-3.19 (m, 1H), 3.40-3.50 (m, 1H), 3.53-3.65 (m, 1H), 3.66-3.79 (m, 1H), 3.92 (dd, J=11.1, 3.0 Hz, 1H), 4.08 (d, J=12.6 Hz, 1H), 4.45-4.55 (d, J=5.1 Hz, 1H), 4.78-4.94 (m, 1H), 4.99 (s, 2H), 6.09 (s, 2H), 6.47 (s, 1H), 6.94 (s, 1H), 7.45 (s, 1H), 11.50 (s, 1H).

Provenance & Evidence