反应详情

To a solution of 4-fluoro-N-[(3R,4S)-3-hydroxy-6-[4-(oxetan-3-yl)piperazin-1-yl]chroman-4-yl]benzamide (72.0 g, 168 mmol) in THF (648 mL) add 1,1′-carbonyldiimidazole (35.5 g, 219 mmol) and stir the solution at room temperature overnight. Cool the mixture to 5° C. and add a solution of 2 M methylamine in THF (210 mL, 421 mmol, 2.5 eq) dropwise over a period of 15 min. Stir for 30 min. and pour over a mixture of water (720 mL) and methyl tert-butyl ether (216 mL). Stir the mixture for 30 min. and decant the phases. Extract the aqueous phase with dichloromethane (3×216 mL). Wash the combined organic phases with brine (3×100 mL), dry over anhydrous sodium sulfate, and concentrate in vacuo. Suspend the residue in ethyl acetate (720 mL), heat at reflux for 2 hr. and cool to 10° C. Collect the solid by filtration and dry under vacuum overnight to obtain the title compound (64.0 g, 78%) as a white solid. LC-ES/MS m/z 485 [M+H]+.

1. temperatureCool the mixture to 5° C.
2. stirringStir for 30 min.
3. stirringStir the mixture for 30 min.
4. customdecant the phases
5. extractionExtract the aqueous phase with dichloromethane (3×216 mL)
6. washWash the combined organic phases with brine (3×100 mL)
7. dry with materialdry over anhydrous sodium sulfate
8. concentrationconcentrate in vacuo
9. temperatureheat
10. temperatureat reflux for 2 hr
11. temperatureand cool to 10° C
12. customCollect the solid
13. filtrationby filtration
14. customdry under vacuum overnight