Methanol → 4-[6-[(3r)-3-Ethyl-4-morpholinyl]-2-(methylamino)-4-pyrimidinyl]-2-fluoro-6-(methyloxy)benzonitrile

Participants

Reaction Steps

CH3OH (10 mL) was added dropwise to a 100 mL RBF at 0° C. charged with sodium hydride (66.8 mg, 2.78 mmol). The mixture was stirred for 10 minutes and then allowed to warm to room temperature for 10 minutes. To a 4 mL vial were added 4-[6-[(3R)-3-ethyl-4-morpholinyl]-2-(methylamino)-4-pyrimidinyl]-2,6-difluorobenzonitrile (100 mg, 0.278 mmol), DMF (1 mL) and 1.2 mL of sodium methoxide solution (1.2 eq). The reaction was stirred at room temperature overnight. An extra 0.5 eq of sodium methoxide was added to the reaction and it was heated to 40° C. for 3 hours. The reaction mixture was then poured into EtOAc (10 mL). The organics were washed with H2O (2×) and then dried over Na2SO4 and concentrated to afford 4-[6-[(3R)-3-ethyl-4-morpholinyl]-2-(methylamino)-4-pyrimidinyl]-2-fluoro-6-(methyloxy)benzonitrile. This material was taken up in CH3CN (1 mL) and added to a 5 mL microwave vial followed by the addition of hydrazine (0.035 mL, 1.113 mmol) and Hunig's base (0.39 mL, 2.23 mmol). The reaction was irradiated at 150° C. for 90 minutes. The reaction mixture was then concentrated and purified via reverse phase HPLC (10-30% CH3CN/H2O, 0.1% TFA). Fractions were combined and diluted with EtOAc. The organics were washed with saturated NaHCO3 solution that was back extracted with EtOAc (×1). The organics were combined and dried over Na2SO4. The product was taken up in 2 mL H2O and lyophilized to afford the title compound (34.8 mg) as a white fluffy powder. LC-MS (ES) m/z=384 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.88 (t, 3H), 1.59-1.82 (m, 2H), 2.82 (d, J=3.8 Hz, 3H), 3.07-3.18 (m, 1H), 3.39-3.49 (m, 1H), 3.50-3.56 (m, 1H), 3.82-3.87 (m, 1H), 3.87-3.92 (m, 1H), 3.94 (s, 3H), 4.10-4.23 (m, 1H), 4.27-4.39 (m, 1H), 5.02 (s, 2H), 6.45-6.57 (m, 1H), 6.94 (bs, 1H), 7.52 (bs, 1H), 8.30-8.34 (bs, 1H), 11.53 (bs, 1H).

Provenance & Evidence