(1) Synthesis of 3-bromo-2-chloro-4-methylpyridine
3-Amino-2-chloro-4-methylpyridine (2 g) was dissolved in a solvent mixture of 48% aqueous hydrogen bromide solution (17 mL) and water (12 mL). Sodium nitrite (2.5 g) was added to the solution in batches at 0 °C. Subsequently, bromine (22 mL) was added slowly and dropwise. The reaction mixture was gradually warmed to room temperature and stirred continuously for 12 hours. Upon completion of the reaction, the pH was adjusted to neutral with 5N aqueous sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration to remove the drying agent, the filtrate was concentrated under reduced pressure to afford the target product 3-bromo-2-chloro-4-methylpyridine (1.7 g). The product was characterized by 1H-NMR (400 MHz, CDCl3): δ 2.51 (s, 3H), 7.01-7.24 (m, 1H), 8.06-8.35 (m, 1H).
