反应详情

Charge 4-(1-(2-(Pyrrolidin-1-yl)ethyl)-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl)piperidine trihydrochloride (300 g, 1.0 equiv), (R)-4-Chloro-5-methyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (146.2 g, 1.0 equiv) and n-propanol (3.0 L) to a 12-L reaction flask. Stir the reaction mixture and add 1,8-diazabicyclo[5.4.0]undec-7-ene (394.3 g, 3.5 equiv) over ten minutes. Heat the reaction to 90° C. for 8 hours, and allow to cool to room temperature over 12 hours. Displace the n-propanol with n-butyl acetate to a total volume of 3-L and a residual n-propanol content of 11% (w/w). Heat the organic solution to 50-60° C. and wash with brine (2.25 L). Back-extract the aqueous phase with nButyl acetate (1.5 L) and combine the organic layers. Wash the combined organic layers with water (2×450 mL) at 50-60° C. Separate the organic layer and add activated charcoal (75 g, 0.25 equiv) and stir at 50-60° C. for 30 min. Filter the slurry and rinse the solids with n butyl acetate (1.5 L). Wash with water (1 L), separate the organic phase and azeotropically dry the organic phase to remove water. At 50-60° C., add heptanes (3.0 L) cool to 40° C. and add seed crystals. Allow the slurry to cool to room temperature over ˜12 h. Cool to 0-5° C., filter the slurry and wash with heptanes (2×900 mL). Dry in vacuo and isolate (R)-5-Methyl-4-(4-(1-(2-(pyrrolidin-1-yl)ethyl)-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one as a white solid (365.3 g, 64%). MS (ES) m/z=494 [M]+.

1. temperatureHeat
2. customthe reaction to 90° C. for 8 hours
3. temperatureHeat the organic solution to 50-60° C.
4. washwash with brine (2.25 L)
5. extractionBack-extract the aqueous phase with nButyl acetate (1.5 L)
6. washWash the combined organic layers with water (2×450 mL) at 50-60° C
7. customSeparate the organic layer
8. stirringstir at 50-60° C. for 30 min
9. filtrationFilter the slurry
10. washrinse the solids with n butyl acetate (1.5 L)
11. washWash with water (1 L)
12. customseparate the organic phase
13. customazeotropically dry the organic phase
14. customto remove water
15. additionAt 50-60° C., add heptanes (3.0 L)
16. temperaturecool to 40° C.
17. additionadd seed crystals
18. temperatureAllow the slurry to cool to room temperature over ˜12 h
19. temperatureCool to 0-5° C.
20. filtrationfilter the slurry
21. washwash with heptanes (2×900 mL)
22. customDry in vacuo