General procedure for the synthesis of ethyl 2-chloro-4,6-dimethylpyrimidine-5-carboxylate from ethyl 4,6-dimethyl-2-oxo-1,2-dihydropyrimidine-5-carboxylate: to a stirred ethyl trichlorophosphate (POCl3, 10.42 mL, 122 mmol) and N,N-diisopropylethylamine (DIEA, 33 mL, 189 mmol) in a nitrogen protected Ethyl 4,6-dimethyl-2-oxo-1,2-dihydropyrimidine-5-carboxylate (2.4 g, 12.23 mmol) was slowly added to the mixed solution. The reaction mixture was stirred at 80 °C for 2 hours. After completion of the reaction, the solution was concentrated and partitioned between ethyl acetate (EA) and saturated sodium bicarbonate (NaHCO3) solution. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10:1). All fractions containing the product were collected and detected by thin layer chromatography (TLC, petroleum ether/ethyl acetate, 10:1, Rf 0.7), combined and concentrated to afford ethyl 2-chloro-4,6-dimethylpyrimidine-5-carboxylate (1.6 g, 7.45 mmol, 60.9% yield) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 4.43 (q, J = 6.8 Hz, 2H), 2.54 (s, 6H), 1.40 (t, J = 7.1 Hz, 3H); ES-LCMS m/z 215.1 (M + H).
