Ammonia → N-(3-((2R,5S)-6-amino-3,3,5-trifluoro-2,5-dimethyl-2,3,4,5-tetrahydropyridin-2-yl)-4-fluorophenyl)-5-fluoropico linamide

5-fluoropicolinic acid (269 mg, 1.906 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo-[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) (797 mg, 2.10 mmol) were placed in a round bottom flask, dissolved in DMF (5.2 mL), and stirred at room temperature for 5 min. (3S,6R)-6-(5-amino-2-fluorophenyl)-3,5,5-trifluoro-3,6-dimethylpiperidine-2-thione (292 mg, 0.953 mmol) was added followed by N,N-diisopropylethylamine (830 μl, 4.77 mmol) and the reaction was stirred at room temperature for 5 min. The reaction was diluted with ethyl acetate (50 mL) and washed with a mixture of water (25 mL) and saturated aqueous NH4Cl (25 mL). The phases were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organics were dried over MgSO4, filtered, and concentrated under reduced pressure. The intermediate 5-fluoro-N-(4-fluoro-3-((2R,5S)-3,3,5-trifluoro-2,5-dimethyl-6-thioxopiperidin-2-yl)phenyl)picolinamide was purified using a CombiFlash system (40 g SiO2, gradient elution; heptanes:ethyl acetate 100:0→60:40). The intermediate (225 mg, 0.523 mmol) was split in two equal portions and placed in two separate reaction vials. Ammonia (14.6 mL, 102 mmol, 7 M in methanol) was also split in two equal portions and added to the two vials. The vials were capped and heated to 65° C. using an oil bath. After 6 h stirring at this temperature the reactions were allowed to cool to room temperature, the mixtures were combined and concentrated under reduced pressure. The crude material was subjected to silica-gel chromatography (eluent; heptane:ethyl acetate=50:50→0:100) to afford N-(3-((2R,5S)-6-amino-3,3,5-trifluoro-2,5-dimethyl-2,3,4,5-tetrahydropyridin-2-yl)-4-fluorophenyl)-5-fluoropico linamide (124 mg, 57% yield).

1. additionwas added
2. washwashed with a mixture of water (25 mL) and saturated aqueous NH4Cl (25 mL)
3. customThe phases were separated
4. extractionthe aqueous layer was extracted with ethyl acetate (2×50 mL)
5. dry with materialThe combined organics were dried over MgSO4
6. filtrationfiltered
7. concentrationconcentrated under reduced pressure
8. customThe intermediate 5-fluoro-N-(4-fluoro-3-((2R,5S)-3,3,5-trifluoro-2,5-dimethyl-6-thioxopiperidin-2-yl)phenyl)picolinamide was purified
9. washa CombiFlash system (40 g SiO2, gradient elution; heptanes:ethyl acetate 100:0→60:40)
10. customseparate
11. customreaction vials
12. additionadded to the two vials
13. customThe vials were capped
14. temperatureheated to 65° C.
15. stirringAfter 6 h stirring at this temperature the reactions
16. temperatureto cool to room temperature
17. concentrationconcentrated under reduced pressure

ORD-Eintrag

ord-17a86bf2ed7e4ae2b0d4cd303805c0eb

Quelldatensatz

uspto-grants-2016_05

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US09353084B2