Synthesis
General procedure for the synthesis of 2-methoxy-3-bromo-5-chloropyridine from 2-methoxy-5-chloropyridine:
1. Glacial acetic acid solution of bromine was prepared by slowly adding bromine (1.5 mL, 29.28 mmol) to glacial acetic acid (7 mL).
2. 5-chloro-2-methoxypyridine (2.1 g, 14.63 mmol) and sodium acetate (1.2 g, 14.63 mmol) were dissolved in glacial acetic acid (7 mL) to form a mixture.
3. The bromine solution prepared in step 1 was slowly added to the mixture in step 2.
4. The resulting reaction mixture was stirred at 80 °C for 6 hours.
5. Upon completion of the reaction, the mixture was allowed to cool to room temperature.
6. Add ether and water to the cooled reaction mixture and extract.
7. The organic layer was separated and washed sequentially with 1N aqueous sodium hydroxide solution and 4% aqueous sodium bisulfite solution.
8. The organic layer was dried with magnesium sulfate and then the solvent was removed under reduced pressure.
9. The residue was purified by fast chromatography (100% hexane as eluent) to afford 2-methoxy-3-bromo-5-chloropyridine (2.1 g, 64% yield) as a white solid.
1H-NMR (300MHz, CDCl3) δ: 3.99 (s, 3H), 7.81 (d, 1H), 8.05 (d, 1H).
References
[1] Journal of Heterocyclic Chemistry, 1985, vol. 22, p. 1583 - 1592
[2] Journal of Medicinal Chemistry, 1986, vol. 29, # 9, p. 1590 - 1595
[3] Patent: WO2012/69202, 2012, A1. Location in patent: Page/Page column 53
[4] Patent: EP2463289, 2012, A1. Location in patent: Page/Page column 21
[5] Patent: US5512575, 1996, A
