Trifluoromethanesulfonic anhydride → (6S)-3-(1,1-Difluoro-2-(((3S,5S,6R)-6-methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl)amino)ethyl)-1'((2-(trimethylsilyl)ethoxy)methyl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridin]-2'(1'H)-one

Trifluoromethanesulfonic anhydride (0.056 mL, 0.335 mmol) was added to a cooled solution of (S)-3-(1,1-difluoro-2-hydroxyethyl)-1′-((2-(trimethylsilyl)ethoxy)methyl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (described in Intermediate 10) (0.100 g, 0.223 mmol) and 2,6-di-tert-butyl-4-methylpyridine (0.070 g, 0.335 mmol) in CH2Cl2 (3 mL) at −78° C. The resulting mixture was warmed slowly to ambient temperature and stirred for 18 h. The reaction was diluted with EtOAc (100 mL), filtered through a pad of Celite®, washing with EtOAc, and concentrated to dryness in vacuo. The crude product dissolved in CH2Cl2 (3 mL) at ambient temperature. To this solution was added (3S,5S,6R)-3-amino-6-methyl-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-2-one HCl salt (described in Intermediate 11) (0.033 g, 0.104 mmol) and N,N-diisopropylethylamine (0.033 mL, 0.190 mmol). The resulting mixture was stirred at ambient temperature for 18 h before being partitioned between water (20 mL) and EtOAc (100 mL). The organic layer was removed and the aqueous phase was extracted further with EtOAc (30 mL). The combined organic extracts were washed with brine, then dried over sodium sulfate, filtered, and concentrated to dryness in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc—80:20 to 0:100, to give the title compound MS: m/z=716.3 (M+1).

1. filtrationfiltered through a pad of Celite®
2. washwashing with EtOAc
3. concentrationconcentrated to dryness in vacuo
4. dissolutionThe crude product dissolved in CH2Cl2 (3 mL) at ambient temperature
5. stirringThe resulting mixture was stirred at ambient temperature for 18 h
6. custombefore being partitioned between water (20 mL) and EtOAc (100 mL)
7. customThe organic layer was removed
8. extractionthe aqueous phase was extracted further with EtOAc (30 mL)
9. washThe combined organic extracts were washed with brine
10. dry with materialdried over sodium sulfate
11. filtrationfiltered
12. concentrationconcentrated to dryness in vacuo
13. customThe crude product was purified by silica gel chromatography
14. washeluting with a gradient of hexanes

ORD-Eintrag

ord-7d1fff9c5f804780a7ad377652fd47b3

Quelldatensatz

uspto-grants-2016_01

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US09227972B2