General procedure for the synthesis of 2-chloro-5-fluoro-3-methoxypyridine from 2-chloro-3-methoxy-5-aminopyridine: To a suspension of 2-chloro-3-methoxy-5-aminopyridine (2.14 g, 13.50 mmol) in 4M aqueous HCl (10.12 mL, 40.50 mmol) under ice-bath cooling conditions was slowly added dropwise sodium nitrite ( 1.02 g, 14.84 mmol) dissolved in water (7 mL) was slowly added dropwise for 5 min. After the dropwise addition, the reaction mixture was stirred vigorously at 5 °C for 30 min. Subsequently, a solution of sodium tetrafluoroborate (2.67 g, 24.29 mmol) dissolved in water (17 mL) was added dropwise to the reaction mixture at 5 °C. Upon completion of the reaction, the resulting thick suspension was collected by filtration, washed sequentially with cold water and a small amount of cold ethanol, and then dried under reduced pressure at 55 °C for 8 hours. The resulting black solid was dissolved in xylene (25 mL) and refluxed for 1 hour. After completion of the reaction, the solvent was removed by evaporation under reduced pressure and the residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic phase was separated, dried with anhydrous sodium sulfate, filtered and the solvent was removed in vacuum. Finally, the black oily material obtained was purified by silica gel fast chromatography (Biotage SP4 25M, cyclohexane/ethyl acetate 95/5) to afford 2-chloro-5-fluoro-3-methoxypyridine (0.11 g, 0.69 mmol, 5% yield) as a light yellow solid.1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.03 ( d, 1H), 7.70 (dd, 1H), 3.92 (s, 3H).
