The general procedure for the synthesis of 2,4-dichloro-5-fluoro-6-methylpyrimidines from methylmagnesium bromide and 2,4-dichloro-5-fluoropyrimidines is as follows (adapted from the literature methodology: M. Butters, J. Ebbs, S.P. Green, J. MacRae, M.C. Morland, C.W. Murtiashaw and A.J. Pettman, Organic Process Research & Development 2001, 5, 28-36): to a solution of 3.0 M methylmagnesium bromide in tetrahydrofuran (20 mL) in ether (15 mL, 45 mmol, 1.5 eq.) was added 2,4-dichloro-5-fluoropyrimidine (5 g, 30 mmol, 1 equivalent) in 1,2-dimethoxyethane, keeping the temperature below 15 °C while maintaining a volume of 20 mL. The resulting solution was stirred at 15 °C for 1 h and then cooled to 0 °C. The reaction mixture was then cooled to 0 °C. A solution of triethylamine (4.17 mL, 30 mmol, 1 eq.) in tetrahydrofuran (10 mL) was slowly added to the reaction mixture, maintaining an internal temperature of about 5 °C, followed by a solution of iodine (30 mmol, 1 eq.) in tetrahydrofuran (10 mL). The reaction mixture was quenched with water, warmed to room temperature, extracted with ethyl acetate and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane/hexane) to afford 2,4-dichloro-5-fluoro-6-methylpyrimidine in 74% yield.
