Toluene → 2-Fluoro-4-{2-(methylamino)-6-[(3R)-3-(1-methylethyl)-4-morpholinyl]-4-pyrimidinyl}-6-(methyloxy)benzonitrile

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Reaction Steps

2,6-Difluoro-4-{2-(methylamino)-6-[(3R)-3-(1-methylethyl)-4-morpholinyl]-4-pyrimidinyl}benzonitrile (360 mg, 0.96 mmol) was azeotroped with toluene (2×12 mL). The resulting residue was taken up in 7.5 mL of CH3OH as a suspension. NaH (260 mg, 60% wt in mineral oil, 6.5 mmol) was added to a chilled (ice bath) solution of CH3OH (12.5 mL) under nitrogen portion-wise. After completion of addition, the ice bath was removed. The resulting mixture was stirred at ambient temperature for 10 minutes (concentration of CH3ONa was assumed to be 0.52 mmol/mL). A 2.25 mL portion (1.17 mmol, 1.2 equiv) of this mixture was added to the above suspension at room temperature in one portion. The resulting suspension was stirred at room temperature for 2 hours. LCMS showed no conversion. After another 1 h, 5 mL of DMF was added to the mixture, which became milky. The mixture was stirred at room temperature for another 16 hours, upon which time, it became a clear solution. LCMS showed conversion complete. The mixture was concentrated in vacuo. The residue was taken up in water (20 mL) as a suspension, which was sonicated briefly, and then filtered. The solids collected were dried under house vacuum at room temperature for 1 hour. Purification by silica gel column chromatography using gradient elution of 1% EtOAc in CHCl3 to 100% EtOAc gave the title compound (350 mg) as a foam. LC-MS (ES) m/z=386 [M+H]+.

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