General procedure for the synthesis of 2-amino-3-methoxy-5-bromopyridine from 2-amino-3-methoxypyridine: To a 2000 mL Erlenmeyer flask was added 10% sulfuric acid solution (800 mL). 2-Amino-3-methoxypyridine (25.80 g, 206 mmol) was added at room temperature while stirring. After the solution was clarified, it was cooled to about 3°C in an ice/water bath. Subsequently, bromine (10.8 mL, 210 mmol) was slowly added to the mixture in acetic acid at 0°C. Upon completion of the reaction, the solid product was collected by filtration, washed twice (30 mL each) with cold water and dried to give 39.0 g of crude product. The crude product was suspended in ethyl acetate (500 mL) with vigorous stirring for 0.5 h and then filtered through Celite. The black solid was washed twice with ethyl acetate, and the filtrates were combined and washed sequentially with 10% sodium thiosulfate solution (100 mL) and saturated brine, and finally dried over anhydrous sodium sulfate. The mixture was concentrated to give 29.0 g (68.3% yield) of 2-amino-3-methoxy-5-bromopyridine as a yellow solid. The product was confirmed by 1H NMR (300 MHz, CDCl3): δ 7.71 (d, J = 2.1 Hz, 1H), 7.01 (d, J = 2.1 Hz, 1H), 4.69 (br s, 2H), 3.84 (s, 3H).LC-MS (m/z): 204.9 ([M+H]+).
