Acetic Anhydride → Methyl 6-aminopyridine-2-carboxylate

Temperature

75 °C

A solution of 6-methylpyridin-2-amine (25 g, 231 mmol) and acetic anhydride (44 mL, 465 mmol) in tetrahydrofuran (188 mL) was heated under reflux for 12 hr. The solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. This was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. Water (350 mL) was added to the obtained crystals, and the mixture was heated to 75° C., and potassium permanganate (87.1 g, 551 mmol) was gradually added over 45 min. The mixture was stirred for 3 hr, and filtered through celite, and the filtrate was concentrated. Hydrochloric acid/methanol solution (Tokyo Chemical Industry Co., Ltd., 350 mL) was added, and the mixture was heated under reflux for 24 hr. The reaction solution was concentrated, diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted with ethyl acetate. The obtained organic layers were mixed, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (6.28 g, yield 18%).

1. temperatureunder reflux for 12 hr
2. customThe solvent was evaporated under reduced pressure
3. additionthe residue was diluted with ethyl acetate
4. washwashed with saturated aqueous sodium hydrogen carbonate solution and saturated brine
5. dry with materialThis was dried over anhydrous sodium sulfate
6. customthe solvent was evaporated under reduced pressure
7. additionWater (350 mL) was added to the obtained crystals
8. filtrationfiltered through celite
9. concentrationthe filtrate was concentrated
10. additionHydrochloric acid/methanol solution (Tokyo Chemical Industry Co., Ltd., 350 mL) was added
11. temperaturethe mixture was heated
12. temperatureunder reflux for 24 hr
13. concentrationThe reaction solution was concentrated
14. additiondiluted with ethyl acetate
15. washwashed with saturated aqueous sodium hydrogen carbonate solution
16. extractionThe aqueous layer was extracted with ethyl acetate
17. additionThe obtained organic layers were mixed
18. washwashed with saturated brine
19. dry with materialdried over anhydrous sodium sulfate
20. customThe solvent was evaporated under reduced pressure
21. customthe residue was purified by silica gel column chromatography

ORD record

ord-4bd0fbb8332e4e6785c00e4fb0912eed

Source dataset

uspto-grants-2012_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08247429B2