Diisopropylethylamine → (6S)-N-[(5S,6S,9R)-5-Azido-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl]-2'-oxo-1',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridine]-3-carboxamide

Participants

Reaction Steps

To a solution of (5S,6S,9R)-5-azido-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-amine (the mixture of diastereomers described in Intermediate 11) (90 mg, 0.28 mmol), (6S)-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxylic acid (described in Intermediate 4) (85 mg, 0.30 mmol) and HATU (2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (160 mg, 0.43 mmol) in DMF (3.0 mL) was added N,N-diisopropylethylamine (0.15 mL, 0.86 mmol), and the resulting mixture was stirred at ambient temperature for 16 h. The reaction mixture was partially purified by reversed-phase HPLC on a C-18 column, eluting with a gradient of H2O:CH3CN:TFA-100:0:0.1 to 0:100:0.1. Product-containing fractions were combined and neutralized with saturated aqueous sodium carbonate and the acetonitrile was removed by evaporation under reduced pressure. The resulting mixture was extracted with ethyl acetate (50 mL) and dichloromethane (2×50 mL) and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a mixture of four diastereomers. Separation of the diastereomers was achieved by SFC on a ChiralCel OJ-H column, eluting with CO2:MeOH-80:20, to give four diastereomers in approximately a 2:1:2:5 ratio:

Provenance & Evidence