Trifluoroacetic acid → (3S,6R)-6-(5-amino-2-fluorophenyl)-3,5,5-trifluoro-3,6-dimethylpiperidine-2-thione

Temperature

0 °C

tert-butyl (4-fluoro-3-((2R,5S)-3,3,5-trifluoro-2,5-dimethyl-6-thioxopiperidin-2-yl)phenyl)carbamate (1.15 g, 2.83 mmol) was dissolved in dichloromethane (13 ml). The solution was cooled to 0° C. and TFA (6.5 ml, 84 mmol) was added. The solution was stirred at 0° C. for 1 h 20 min. The reaction was diluted with toluene (25 mL) and concentrated to approx 10 mL under reduced pressure. The residue was diluted with ethyl acetate (50 mL) and washed with saturated aqueous NaHCO3 (25 mL). The phases were separated and the aqueous layer was extracted with ethyl acetate (2×25 mL). The combined organics were dried over MgSO4, filtered, and concentrated under reduced pressure to afford (3S,6R)-6-(5-amino-2-fluorophenyl)-3,5,5-trifluoro-3,6-dimethylpiperidine-2-thione (548 mg (70% purity), 63.2% yield). The crude product was used in the next reaction step without further purification. LC-MS (m/z) 307.2 (MH+) tR=0.49 minutes (Method B) 1H NMR (600 MHz, CDCl3) δ 7.93 (bs, 1H), 6.93-6.88 (m, 1H), 6.66-6.61 (m, 1H), 6.59-6.55 (m, 1H), 2.62-2.57 (m, 2H), 1.90 (s, 3H), 1.86 (d, J=22.4 Hz, 3H) [α]D20=−211° (589 nm, c=0.1 g/100 mL, MeOH

1. concentrationconcentrated to approx 10 mL under reduced pressure
2. additionThe residue was diluted with ethyl acetate (50 mL)
3. washwashed with saturated aqueous NaHCO3 (25 mL)
4. customThe phases were separated
5. extractionthe aqueous layer was extracted with ethyl acetate (2×25 mL)
6. dry with materialThe combined organics were dried over MgSO4
7. filtrationfiltered
8. concentrationconcentrated under reduced pressure

ORD record

ord-09d99aff9fc3464e8ab3c0e76ecc253a

Source dataset

uspto-grants-2016_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09353084B2