[Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.C([O-])(O)=O.[Na+].[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>C1COCC1.CCO.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:19][C:18]2[CH:20]=[CH:21][C:15]([F:14])=[CH:16][CH:17]=2)[CH:5]=[CH:4][N:3]=1
To a solution of 2,4-dichloropyrimidine (260 g, 1.75 mol) in THF (780 mL) and EtOH (3100 mL) is added NaHCO3 (244 g, 2.91 mol). To the slurry which results is added 4-fluoroaniline (162 g, 1.46 mol) in one portion and the resulting mixture allowed to warm to 65° C. and held at this temperature for 10 hours. The reaction if not completed in a single day can be cooled over night. Re-heating the next day to 70° C. for an additional 10 hours is usually sufficient for completion of the reaction. The reaction solution is diluted with EtOAc (4.5 L) and washed with water (3×2 L). The combined aqueous layers are extracted with EtOAc (3 L). The combined organic layers are dried over MgSO4 and filtered. The filter cake is washed with acetone (2×1 L) then with 5% MeOH/acetone (2×500 mL). The filtrate is concentrated until a thick slurry is obtained (ca. 1 L volume), hexane (3.5 L) is added and the solution cooled to about 4° C. for 16 hours. The thick slurry is collected by filtration, washed with hexane (2×500 mL), and dried (20 mmHg, room temperature) to afford 99.43 g (79.3% yield) of the desired product as a white solid. 1H NMR (300 MHz, CD3OD) δ 8.06 (d, J=6.0 Hz, 1H), 7.59 (m, 2H), 7.11 (m, 2H), 6.64 (d, J=6.0 Hz, 1H); MS (ESI) m/z 224 (M+1).
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