Hydrochloric Acid → 4-(Tert-butyl)-2-((tert-butylamino)methyl)-6-(5-methylpyridin-2-yl)phenol dihydrochloride

A mixture of paraformaldehyde (661 mg, 22.0 mmol) and tert-butylamine (2.32 mL, 22.0 mmol) in isopropanol (10 mL) was gently refluxed under nitrogen for 1 hour. A solution of 4-(tert-butyl)-2-(5-methylpyridin-2-yl)phenol (1.062 g, 4.4 mmol) in isopropanol (5 mL) was added and the reaction mixture refluxed for 6 days. The cooled reaction mixture was then concentrated under reduced pressure and the residue partitioned between ethyl acetate (80 mL) and 1.0 M aqueous sodium hydroxide solution (80 mL). The organic phase was separated, washed with water (80 mL) and saturated brine (80 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give a yellow syrup. The crude 3,4-dihydro-2H-benzo[e][1,3]oxazine was dissolved in absolute ethanol (90 mL), 1.0 M aqueous hydrochloric acid solution (30 mL) added and the reaction mixture stirred at room temperature for 9 days. The reaction mixture was concentrated under reduced pressure to remove ethanol, the resulting aqueous solution diluted to 50 mL with 1.0 M aqueous hydrochloric acid solution and washed with ethyl acetate (50 mL). The aqueous phase was basified to pH 7-8 by the addition of solid sodium carbonate and the resulting milky suspension extracted with ethyl acetate (80 mL). The organic phase was separated, washed with half saturated brine (80 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give a yellow syrup. The product was dissolved in absolute ethanol (50 mL), hydrogen chloride-ethanol solution (1.25 M, 18.44 mL, 23.05 mmol) added, the mixture stood for 20 minutes then concentrated under reduced pressure to give a cream solid. Diethyl ether (50 mL) and absolute ethanol (15 mL) were added and the resulting suspension stirred vigorously overnight then filtered to give 4-(tert-butyl)-2-((tert-butylamino)methyl)-6-(5-methylpyridin-2-yl)phenol dihydrochloride (1.466 g, 83% yield) as a hygroscopic white solid.

1. temperaturewas gently refluxed under nitrogen for 1 hour
2. temperaturethe reaction mixture refluxed for 6 days
3. customThe cooled reaction mixture
4. concentrationwas then concentrated under reduced pressure
5. customthe residue partitioned between ethyl acetate (80 mL) and 1.0 M aqueous sodium hydroxide solution (80 mL)
6. customThe organic phase was separated
7. washwashed with water (80 mL) and saturated brine (80 mL)
8. dry with materialdried (MgSO4)
9. filtrationfiltered
10. concentrationconcentrated under reduced pressure
11. customto give a yellow syrup
12. concentrationThe reaction mixture was concentrated under reduced pressure
13. customto remove ethanol
14. additionthe resulting aqueous solution diluted to 50 mL with 1.0 M aqueous hydrochloric acid solution
15. washwashed with ethyl acetate (50 mL)
16. additionThe aqueous phase was basified to pH 7-8 by the addition of solid sodium carbonate
17. extractionthe resulting milky suspension extracted with ethyl acetate (80 mL)
18. customThe organic phase was separated
19. washwashed with half saturated brine (80 mL)
20. dry with materialdried (MgSO4)
21. filtrationfiltered
22. concentrationconcentrated under reduced pressure
23. customto give a yellow syrup
24. waitthe mixture stood for 20 minutes
25. concentrationthen concentrated under reduced pressure
26. customto give a cream solid
27. stirringthe resulting suspension stirred vigorously overnight
28. filtrationthen filtered

ORD record

ord-c87d875a38dc42d78db3f12624ba2c94

Source dataset

uspto-grants-2016_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09409893B2