Reaction Steps
Triethylamine (146 μL, 1.044 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (69 mg, 0.358 mmol), and 1-hydroxy-7-azabenzotriazole (41 mg, 0.298 mmol) were added to a solution of the hydrochloride salt of [6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-9-yl]acetic acid (127 mg, 0.298 mmol) and 2-oxo-1-piperidinium-4-yl-2,3-dihydro-1H-imidazo[4,5-b]pyridin-4-ium dichloride (87 mg, 0.298 mmol) in acetonitrile (3 mL) and N,N-dimethylformamide (1 mL). After 4 h, the reaction mixture was diluted with ethyl acetate and saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate, washed with saturated brine, dried with sodium sulfate, filtered and concentrated to give the title compound. Purification by reverse phase HPLC (100% water→100% acetonitrile with 0.1% trifluoroacetic acid) gave racemic cis compounds 1-(1-{[(6S,9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-9-yl]acetyl}piperidin-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one and 1-(1-{[(6R,9S)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-9-yl]acetyl}piperidin-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; MS 590.2299 (M+1), and racemic trans compounds 1-(1-{[(6S,9S)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-9-yl]acetyl}piperidin-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one and 1-(1-{[(6R,9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-9-yl]acetyl}piperidin-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; MS 590.2293 (M+1). The trans enantiomers were separated by Chiralpak OD column (2×35 cm), 60% hexanes (0.1% diethylamine)/ethanol at 6 mL/min.
