Hydrochloric Acid → (6S)-6-(3,5-difluorophenyl)-3,3,6-trimethylpiperidin-2-one

Temperature

110 °C

To a solution of methyl (5S)-5-[(tert-butylsulfinyl)amino]-5-(3,5-difluorophenyl)-2,2-dimethylhexanoate (1.14 g, 2.93 mmol) in MeOH (60 mL), cooled to 0° C., was added anhydrous HCl gas for 1 minute. The reaction was sealed and allowed to sit at 0° C. for fifteen minutes at which point the reaction was complete by LCMS analysis. Nitrogen was bubbled through the reaction for twenty minutes. The reaction was concentrated in vacuo. Additional MeOH (50 mL) was added and it was again concentrated in vacuo. This was repeated with another addition of MeOH and triethylamine (1.18 g, 11.7 mmol). To the resulting residue was added toluene (50 mL) and triethylamine (1.18 g, 11.7 mmol). A reflux condenser was attached and the mixture stirred at 110° C. After five days of stirring at reflux, the reaction was judged to be complete by LCMS. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was diluted with diethyl ether (75 mL) and washed individually with 30 mL of each of the following aqueous solutions: 1M HCl (twice), water, saturated brine. The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo to give a residue that was purified by silica gel chromatography, eluting with a gradient of MeOH:CH2Cl2—1:99 to 5.5:94.5, to give the title compound. MS: m/z=254 (M+1).

1. customThe reaction was sealed
2. waitto sit at 0° C. for fifteen minutes at which
3. customNitrogen was bubbled through the reaction for twenty minutes
4. concentrationThe reaction was concentrated in vacuo
5. additionAdditional MeOH (50 mL) was added
6. concentrationit was again concentrated in vacuo
7. customA reflux condenser was attached
8. stirringAfter five days of stirring
9. temperatureat reflux
10. temperatureThe mixture was cooled to ambient temperature
11. concentrationconcentrated in vacuo
12. additionThe residue was diluted with diethyl ether (75 mL)
13. washwashed individually with 30 mL of each of the following aqueous solutions
14. dry with materialThe organic layer was then dried over sodium sulfate
15. filtrationfiltered
16. concentrationconcentrated in vacuo
17. customto give a residue that
18. customwas purified by silica gel chromatography
19. washeluting with a gradient of MeOH

ORD record

ord-cfb6bd2941c0442dafb057b19d573262

Source dataset

uspto-grants-2011_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07893079B2