Synthesis
General procedure for the synthesis of 5-bromo-4-chloro-2-methoxypyridine from 4-chloro-2-methoxypyridine: 5.76 g (40.1 mmol) of 4-chloro-2-methoxypyridine was dissolved in 20 mL of dimethylformamide, and 8.01 g (44.1 mmol, 98%) of N-bromosuccinimide was added dropwise to the solution in dimethylformamide (20 mL) slowly with a dropwise time was 30 minutes. After the reaction mixture was stirred at room temperature for 2 days, unreacted feedstock was identified by TLC, followed by the addition of 2.85 g (16 mmol, 98%) of N-bromosuccinimide, and stirring was continued at room temperature for 3 days. Upon completion of the reaction, the mixture was poured into 250 mL of water and extracted three times with ether (100 mL each time). The organic layers were combined, washed sequentially with water (100 mL), aqueous sodium thiosulfate (100 mL) and saturated sodium chloride solution (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography to afford 7.10 g (yield: 80%) of the target compound 5-bromo-4-chloro-2-methoxypyridine.1H-NMR (CDCl3, 400 MHz) data were as follows: δ 3.91 (s, 3H), 6.89 (s, 1H), 8.28 (s, 1H).
References
[1] Patent: EP1679003, 2006, A1. Location in patent: Page/Page column 14-15
[2] Patent: WO2015/153683, 2015, A1. Location in patent: Paragraph 0847
