反应详情

温度

1.7000000476837158 °C

A solution of (S)-3-(4-(4-methoxybenzoyl)piperidin-1-yl)pyrrolidin-2-one (25.66 g, 85 mmol) in THF (283 mL) was cooled to −1.7° C. and to this was slowly added NaH (10.18 g, 255 mmol) and 2-chloromethyl-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (89 mmol, 17.88 g) maintaining the temperature below 5° C. The reaction vessel was immersed into an ice-water bath and allowed bath to expire overnight. When reaction was complete by LCMS (approximately 15 h), the reaction was cooled to 1.7° C. and saturated NH4Cl was slowly added, keeping the internal temperature below 10° C. The mixture was diluted with dichloromethane (500 mL) and 1 N NaOH (500 mL) and split into two batches that were processed identically. Additional 1 N NaOH (500 mL) was added and the aqueous layer was washed with dichloromethane (2×500 mL). The aqueous layer was adjusted to pH 7 using approximately 250 mL 3 N HCl and extracted with dichloromethane (4×500 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude material was taken up in dichloromethane (500 mL) and ethyl acetate (500 mL) was added. The resulting solution was concentrated to an approximate volume of 300 mL and seeded with pure title compound and concentrated further in vacuo. To this stirred solution was added ethyl acetate (500 mL) and a seed of pure title compound. Filtration of the suspension provided the title compound as a white solid (32.87 g, 70.5 mmol).

1. temperaturemaintaining the temperature below 5° C
2. customThe reaction vessel was immersed into an ice-water bath
3. customWhen reaction
4. customwas complete by LCMS (approximately 15 h)
5. customthe internal temperature below 10° C
6. customsplit into two batches that
7. additionAdditional 1 N NaOH (500 mL) was added
8. washthe aqueous layer was washed with dichloromethane (2×500 mL)
9. extractionextracted with dichloromethane (4×500 mL)
10. dry with materialdried over Na2SO4
11. filtrationfiltered
12. concentrationconcentrated in vacuo
13. additionethyl acetate (500 mL) was added
14. concentrationThe resulting solution was concentrated to an approximate volume of 300 mL
15. concentrationconcentrated further in vacuo
16. additionTo this stirred solution was added ethyl acetate (500 mL)
17. filtrationFiltration of the suspension