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 relux, 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 at relux
9. temperatureThe mixture was cooled to ambient temperature
10. concentrationconcentrated in vacuo
11. additionThe residue was diluted with diethyl ether (75 mL)
12. washwashed individually with 30 mL of each of the following aqueous solutions
13. dry with materialThe organic layer was then dried over sodium sulfate
14. filtrationfiltered
15. concentrationconcentrated in vacuo
16. customto give a residue that
17. customwas purified by silica gel chromatography
18. washeluting with a gradient of MeOH

ORD record

ord-96887a9aed324ef6a99a32886e41be3a

Source dataset

uspto-grants-2009_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07625901B2