Synthesis
General procedure for the synthesis of 5-bromo-2-chloro-6-methylpyridine from 2-amino-5-bromo-6-methylpyridine: dichloromethane (900 mL) was added to a 2L three-necked round-bottomed flask, followed by the addition of 2-amino-6-methyl-5-bromopyridine (74.23 g, 0.39 mol), pyridine hydrochloride (139 g, 1.2 mol), sodium nitrite (83.26 g, 1.2 mol) and cuprous chloride (3.76 g, 5% w/w relative to the feedstock). The reaction mixture was cooled to 0-10 °C in an ice water bath. Hydrochloric acid (4.5 mL, 6% v/w vs. feedstock) was added slowly and stirred at 0-10 °C for 30 min. The cooling bath was removed and the mixture was continued to stir at room temperature for 1 hour. Upon completion of the reaction, the reaction was quenched with saturated aqueous sodium bicarbonate (400 mL) and the organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane (100 mL). The organic layers were combined and concentrated to dryness. Hexane (750 mL) was added to the residue and stirred. The solid was collected by filtration, washed with hexane, and the filtrate was concentrated to dryness to afford the pure product 5-bromo-2-chloro-6-methylpyridine (61 g, 70% yield) in light yellow crystalline form.
References
[1] Patent: WO2007/22371, 2007, A2. Location in patent: Page/Page column 49
[2] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 2, p. 273 - 276
[3] Journal of Heterocyclic Chemistry, 2004, vol. 41, # 4, p. 569 - 574
[4] Patent: US2005/192310, 2005, A1. Location in patent: Page/Page column 36
[5] Patent: WO2011/28395, 2011, A1. Location in patent: Page/Page column 16
