反应详情

A solution of methyl 1-{[2-amino-2-(3,5-difluorophenyl)propyl]amino}cyclohexanecarboxylate from Step F (205 mg, 0.628 mmol), and AcOH (0.36 mL, 6.28 mmol) in xylenes (5 mL) was heated at 80° C. for 3 h, allowed to cool, then poured into saturated aqueous NaHCO3 (5 mL). The resulting mixture was extracted with EtOAc (2×10 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of EtOAc:MeOH—100:0 to 92:8, to give the racemic product. The enantiomers were separated by HPLC, using a ChiralPak AD column and eluting with hexane:EtOH:Et2NH—40:60:0.1. The first major peak to elute was (3R)-3-(3,5-difluorophenyl)-3-methyl-1,4-diazaspiro[5.5]undecan-5-one, the title compound, and the second major peak to elute was (3S)-3-(3,5-difluorophenyl)-3-methyl-1,4-diazaspiro[5.5]undecan-5-one. MS: m/z=295 (M+1).

1. temperatureto cool
2. extractionThe resulting mixture was extracted with EtOAc (2×10 mL)
3. dry with materialThe combined organic extracts were dried over Na2SO4
4. filtrationfiltered
5. concentrationconcentrated under reduced pressure
6. customThe crude product was purified by silica gel chromatography
7. washeluting with a gradient of EtOAc
8. customMeOH—100:0 to 92:8, to give the racemic product
9. customThe enantiomers were separated by HPLC
10. washeluting with hexane
11. washThe first major peak to elute
12. washthe title compound, and the second major peak to elute