Dimethylformamide → Ammonium Hydroxide

Participants

Reaction Conditions

Reaction Steps

4-{2-Amino-6-[(3R)-3-methyl-4-morpholinyl]-4-pyrimidinyl}-2,6-difluorobenzonitrile (500 mg, 1.509 mmol) was suspended in CH3OH (7 mL) with stirring in a 50 mL round bottom flask under nitrogen, and a solution of sodium methoxide in methanol (freshly prepared from sodium (41.6 mg, 1.811 mmol) and methanol (3 mL)) was added. The mixture was stirred at room temperature monitoring it by HPLC. After 4 hours, the reaction was not changing and seemed to stop. Since it was a suspension and solubility was poor, DMF (3 mL) was added to give a clear yellow solution. After another hour (5 hours total), HPLC showed some progression, so the reaction was left of stir overnight. HPLC indicated complete conversion. Acetic acid (5 drops) was added to quench any leftover methoxide, and the mixture was evaporated to dryness. The residue was suspended in ethanol (8 mL), and hydrazine monohydrate (1.464 mL, 30.2 mmol) was added. The mixture was refluxed under nitrogen in a 100° C. oil bath overnight. HPLC showed complete conversion to product. After concentrating to dryness, purification by silica gel chromatograpy (Analogix SF25-40 g cartridge) eluting with a gradient of CHCl3 to 90:10:1 CHCl3:CH3OH: NH4OH gave the title compound (491 mg) as a pale yellow solid. LC-MS (ES) m/z=356 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.18 (d, J=6.6 Hz, 3H), 3.11 (td, J=12.8, 3.7 Hz, 1H), 3.44 (td, J=11.8, 2.9 Hz, 1H), 3.53-3.66 (m, 1H), 3.66-3.79 (m, 1H), 3.84-4.01 (m, 4H), 4.08 (d, J=12.6 Hz, 1H), 4.42-4.55 (m, 1H), 5.03 (s, 2H), 6.11 (s, 2H), 6.50 (s, 1H), 6.92 (s, 1H), 7.49 (s, 1H), 11.54 (s, 1H).

Provenance & Evidence