Chlorobenzene → 9-Hydroxy-3-(2-hydroxyethyl)-2-methylpyrido[1,2-a]pyrimidin-4-one

Temperature

125 °C

In a reaction vessel equipped with a dropping funnel and a reverse water-separator, 2-amino-3-hydroxypyridine (110.12 g; 1 mol) was added to chlorobenzene (1500 ml) at room temperature. 2-Acetylbutyrolactone (134.53 g; 1.05 mol) was added dropwise to this mixture from the dropping funnel while stirring. The dropping funnel was rinsed with chlorobenzene (250 ml) and the resulting solution was added dropwise to the previously obtained mixture. Next, p-toluenesulfonic acid monohydrate (5.7 g; 0.03 mol) was added, and the resulting mixture was heated to reflux temperature (refluxing starting at 125° C.). The reaction mixture was refluxed for 19 hours, while the water liberated during the course of the reaction was collected in the reverse water-separator. The mixture was allowed to cool to about 80° C. and then there were added 2-propanol (250 ml), activated carbon (Norit A™ supra, 25 g) and filter agent (dicalite speed plus; 2.5 g). The mixture was heated to reflux (100° C.) during 30 minutes. The reaction mixture was filtered at a temperature of 90 to 95° C. and the filter cake was washed with chlorobenzene (100 ml; 80° C.). The combined filtrate was allowed to cool to room temperature. Crystallization of the reaction product started at about 40-45° C. and was left to continue for 18 hours at room temperature. The crystals were collected and washed with chlorobenzene (100 ml) and dried in vacuo at 50-60° C. for 24 hours, yielding 164.2 g (73.6%) 9-hydroxy-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one; mp 150° C.; purity >97% (LC % w/w); residual 2-amino-3-hydropyridine: 0.85%; sum of other impurities <0.52%; residual 2-acetylbutyrolactone was 0% (GC % w/w).

1. customIn a reaction vessel equipped with a dropping funnel
2. washThe dropping funnel was rinsed with chlorobenzene (250 ml)
3. additionthe resulting solution was added dropwise to the previously obtained mixture
4. temperaturethe resulting mixture was heated
5. temperatureto reflux
6. customwas collected in the reverse water-separator
7. temperatureto cool to about 80° C.
8. additionthere were added 2-propanol (250 ml), activated carbon (Norit A™ supra, 25 g) and
9. filtrationfilter agent (dicalite speed plus; 2.5 g)
10. temperatureThe mixture was heated
11. temperatureto reflux (100° C.) during 30 minutes
12. filtrationThe reaction mixture was filtered at a temperature of 90 to 95° C.
13. washthe filter cake was washed with chlorobenzene (100 ml; 80° C.)
14. temperatureto cool to room temperature
15. customCrystallization of the reaction product
16. customstarted at about 40-45° C.
17. waitwas left
18. customThe crystals were collected
19. washwashed with chlorobenzene (100 ml)
20. customdried in vacuo at 50-60° C. for 24 hours

ORD record

ord-0849e0cf90ab481296a3b6847f207164

Source dataset

uspto-grants-2010_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07723518B2