The general procedure for the synthesis of 2,6-dichloropyrimidine-4-carboxamides from 2,6-dichloropyrimidine-4-carbonyl chloride is as follows:
Scheme 3 Synthesis of 2,6-dichloropyrimidine-4-carboxamide: To a solution of ether (Et2O, 500 mL) containing 2,6-dichloropyrimidine-4-carbonyl chloride (26.13 g, 123.6 mmol), a 0.5 M solution of ammonia dioxane (250 mL, 125 mmol) and diisopropylethylamine (iPr2NEt, 22 mL, 126 mmol), and the titration time was about 50 minutes. The reaction mixture was stirred overnight at room temperature. Subsequently, the reaction solution was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography with the eluent being a hexane solution of 10-50% ethyl acetate (EtOAc). The fraction containing the target product was collected and the solid residue was obtained after evaporating the solvent under reduced pressure. The solid residue was ground with 10 mL of 10% EtOAc/hexane solution and filtered to afford 2,6-dichloropyrimidine-4-carboxamide as an orange crystalline solid (9.743 g, 50.74 mmol, 41% yield).
Product characterization: LC/MS: m/z = 192.2 [M + H]+; 1H NMR (400 MHz, DMSO-d6): δ 8.40 (1H, br s), 8.16 (1H, br s), 8.10 (1H, s).
