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

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Reaction Steps

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).

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