5-broMo-2-chloro-4,6-diMethylpyridine

Synthesis

The general procedure for the synthesis of 2-chloro-5-bromo-4,6-dimethylpyridine from 2-amino-5-bromo-4,6-dimethylpyridine was as follows: 1. 5-bromo-4,6-dimethylpyridin-2-amine (CAS No. 89856-44-0; Aldrich) (4.00 g) was added to a mixed solution of concentrated hydrochloric acid (24 mL) and water (24 mL). 2. The reaction solution was cooled to 0 °C, followed by the addition of sodium nitrite (3.57 g) and stirred at the same temperature for 10 min. 3. Copper(I) chloride (5.91 g) was added to the reaction system and the mixture was stirred at 0°C for 5 minutes, followed by continued stirring at room temperature for 4 hours and 15 minutes. 4. The reaction mixture was again cooled to 0 °C and the reaction mixture was adjusted to alkaline by slowly adding 5 N aqueous sodium hydroxide solution. 5. The reaction mixture was extracted by adding ethyl acetate to the reaction mixture, followed by filtration. 6. The organic layer in the filtrate was separated and the aqueous layer was further extracted with ethyl acetate. 7. All organic layers were combined and concentrated under reduced pressure to remove the solvent. 8. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-heptane, 5%) to afford the target product 2-chloro-5-bromo-4,6-dimethylpyridine (1.79 g). Product characterization: 1H-NMR (400 MHz, CDCl3) δ (ppm): 2.39 (s, 3H), 2.65 (s, 3H), 7.06 (s, 1H).

References

[1] Organic Process Research and Development, 2012, vol. 16, # 1, p. 109 - 116
[2] Organic and Biomolecular Chemistry, 2010, vol. 8, # 21, p. 4815 - 4818
[3] Patent: WO2012/58187, 2012, A1. Location in patent: Page/Page column 66; 67
[4] Patent: US2013/143907, 2013, A1. Location in patent: Paragraph 0388; 0389; 0390
[5] Patent: WO2014/22528, 2014, A1. Location in patent: Page/Page column 92