Preparation of 2,6-dichloro-4-methoxypyridine_Industrial additives

Preparation background and overview of 2,6-dichloro-4-methoxypyridine

2,6-Dichloro-4-methoxypyridine is an organic intermediate that can be prepared from 2-chloro-4-methoxypyridine nitrogen oxide in two steps or from 2,6-dichloro Generation-4-nitropyridine was prepared in one step.

Preparation of 2,6-dichloro-4-methoxypyridine

Preparation Report 1 of 2,6-dichloro-4-methoxypyridine,

Sodium carbonate

Step 1: 2-Chloropropylene ethyl carbonate-4-methoxypyridine nitrogen oxide

Dissolve 2-chloro-4-nitropyridine nitrogen oxide (5.12g, 30mmol) in anhydrous methanol (50mL), add sodium methoxide (1.78g, 33mmol), and reflux the reaction solution for 2 hours. The solvent was spun dry and 2-chloro-4-methoxypyridine nitrogen oxide (3.35g) was obtained by silica gel column chromatography, yield: 70%. MS m/z[ESI]: 160.0[M+1]. ¹H-NMR (MHz, CDCl₃): δ=8.312 (d, J=7.6Hz, 1H), 7.473 (d, J=3.2Hz, 1H) ,7.066(m,1H),3.849(s,3H).

Step 2: 2,6-dichloro-4-methoxypyridine

Add 2-chloro-4-methoxypyridine nitrogen oxide (3.35g, 21mmol) to toluene (50mL), add phosphorus oxychloride (20mL) dropwise, and reflux for 8 hours. After cooling, pour into crushed ice, adjust the pH value to 8-9 with sodium hydroxide solution in an ice bath, extract with ethyl acetate, dry, concentrate and separate by silica gel column chromatography to obtain 2,6-dichloro-4-methoxy. Pyridine (1.12g), yield: 30%. MSm/z[ESI]: 178.0[M+1]. ¹H-NMR (MHz, CDCl₃): δ=7.264 (s, 1H), 6.796 (s, 1H), 3.875 (s, 3H).

Preparation report 2 of 2,6-dichloro-4-methoxypyridine,

Heat a mixture of 2,6-dichloro-4-nitropyridine (1.0 equiv.), potassium carbonate (3 equiv.) and methanol (20 equiv.) in the microwave to 70°C for 25 min. The reaction mixture was diluted with methanol and decanted from the remaining solid. After concentration, the mixture was partitioned between water and EtOAc. The organic phase was washed with brine and dried over sodium sulfate. The solution was concentrated and dried under vacuum to obtain 2,6-dichloro-4-methoxypyridine in 88% yield. LCMS (m/z) (M+H)=177.9/179.9, Rt=0.72min.

References

[1] [Invented in China] CN201310051825.1 Substituted 2-aminopyridine protein kinase inhibitor

[2] [Invented in China] CN201810126023.5 Biarylamide compounds as kinase inhibitors