Hydrochloric Acid → 3-Bromo-6-chloro-2,4-dimethylpyridine

Temperature

-10 °C

A stirred solution of 2-amino-5-bromo-4,6-dimethylpyridine (65 g, 323 mmol) in 37% hydrochloric acid (780 ml) was cooled to −10° C. Sodium nitrite (66.9 g, 970 mmol) was added in small portions over 10 min. The reaction was stirred for 15 min at −10° C. and then warmed to room temperature. After stirring for 1 hour at r.t., the reaction was quenched by pouring into ice/water (4 L). The mixture was stirred for 5 minutes and then extracted with EtOAc (4 L). The organic extract was washed with water (4 L) and brine (2 L). The organic layer was dried over Na2SO4, filtered, and concentrated. The resulting white solid was dissolved in CH2Cl2 (200 mL) and heptanes (700 mL) were added. The solution was stirred for 20 minutes and then filtered to remove solids. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel with 0 to 15% EtOAc/heptanes to afford 3-bromo-6-chloro-2,4-dimethylpyridine. LCMS=219.9 and 221.9 (M+H)+ 1H NMR (CDCl3, 500 MHz) δ 7.05 (s, 1H), 2.65 (s, 3H), 2.39 (s, 3H).

1. temperaturewarmed to room temperature
2. stirringAfter stirring for 1 hour at r.t.
3. customthe reaction was quenched
4. additionby pouring into ice/water (4 L)
5. stirringThe mixture was stirred for 5 minutes
6. extractionextracted with EtOAc (4 L)
7. extractionThe organic extract
8. washwas washed with water (4 L) and brine (2 L)
9. dry with materialThe organic layer was dried over Na2SO4
10. filtrationfiltered
11. concentrationconcentrated
12. dissolutionThe resulting white solid was dissolved in CH2Cl2 (200 mL)
13. additionheptanes (700 mL) were added
14. stirringThe solution was stirred for 20 minutes
15. filtrationfiltered
16. customto remove solids
17. concentrationThe filtrate was concentrated
18. customthe residue was purified by flash chromatography on silica gel with 0 to 15% EtOAc/heptanes

ORD record

ord-5129883f4eda480696359eb974556235

Source dataset

uspto-grants-2015_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09221834B2