2-Acetylbutyrolactone → 3-(2-Chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one

Temperature

75 °C

To a solution of 2-Amino-3-benzyloxypyridine (formula-2) (20 grams) in toluene (40 ml) added 2-acetyl gammabutyro lactone (formula-3) (16.6 grams), stirred for 15 min and added phosphorus oxychloride (0.27 ml). The reaction mixture was refluxed for 12 hours and water was removed azeotropically. Then the reaction mixture was cooled to 70-80° C., added phosphorus oxychloride (11.9 ml) and then heated to 90-95° C. and stirred for 8 hr. The solvent was distilled off under reduced pressure and concentrated hydrochloric acid (70 ml) was added to the reaction mixture followed by toluene (100 ml) and stirred at 65-70° C. for 9 hours. The reaction mixture was cooled to 0-5° C. and the solid formed was filtered, washed with toluene and acetic acid. The wet solid was taken in autoclave along with acetic acid (110 ml), added Pd/C and applied 3.0-3.5 kg/cm2 hydrogen pressure. The reaction mixture was heated to 50-60° C., stirred for 8 hrs, then cooled to 25° C. and quenched with water. The reaction mixture was filtered and the pH of the filtrate was adjusted to 11 using aqueous sodium hydroxide solution. Extracted the reaction mixture with ethyl acetate. The ethyl acetate layer was treated with basic carbon, filtered and distilled off under reduced pressure. The solid formed was taken in cyclohexane (45 ml) and stirred for 60 min at 25° C. The solid was filtered, washed with cyclohexane and dried to provide the title compound.

1. temperatureThe reaction mixture was refluxed for 12 hours
2. customwater was removed azeotropically
3. additionadded phosphorus oxychloride (11.9 ml)
4. temperatureheated to 90-95° C.
5. stirringstirred for 8 hr
6. distillationThe solvent was distilled off under reduced pressure and concentrated hydrochloric acid (70 ml)
7. additionwas added to the reaction mixture
8. stirringstirred at 65-70° C. for 9 hours
9. temperatureThe reaction mixture was cooled to 0-5° C.
10. customthe solid formed
11. filtrationwas filtered
12. washwashed with toluene and acetic acid
13. additionadded Pd/C
14. temperatureThe reaction mixture was heated to 50-60° C.
15. stirringstirred for 8 hrs
16. temperaturecooled to 25° C.
17. customquenched with water
18. filtrationThe reaction mixture was filtered
19. extractionExtracted the reaction mixture with ethyl acetate
20. additionThe ethyl acetate layer was treated with basic carbon
21. filtrationfiltered
22. distillationdistilled off under reduced pressure
23. customThe solid formed
24. stirringstirred for 60 min at 25° C
25. filtrationThe solid was filtered
26. washwashed with cyclohexane
27. customdried

ORD record

ord-c4aba4cc6c7143fcb55b83c32b368394

Source dataset

uspto-grants-2013_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08481729B2