Sodium Bicarbonate → (5S,6S,9R)-6-(2,3-difluorophenyl)-5-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate

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Reaction Steps

(5R,6S,9R)-6-(2,3-difluorophenyl)-5-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (example 5); and (5S,6R,9R)-6-(2,3-difluorophenyl)-5-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate. In a 100 mL round-bottom flask was dissolved (9R)-6-(2,3-difluorophenyl)-5-oxo-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (44.4 mg, 0.083 mmol) (example 2) in methanol (1 mL) to give a colorless solution. Sodium borohydride (6.30 mg, 0.166 mmol) was added, and the mixture was stirred at room temperature for 30 min. LCMS indicated complete conversion to three components (presumably diastereomers), all with desired MW (M+H=536). The mixture was concentrated and directly purified by prep-HPLC (0.1% TFA-methanol-water system) to afford three compounds (order of elution: example 4>5>6, only pure fractions collected). Direct concentration (acidic solution) under high vacuum gave some decomposition (by LCMS and NMRs). They were individually treated with sodium bicarbonate and concentrated to dryness. The residues were repeatedly washed with methylene chloride to obtain the individual free bases. They were then individually purified by FCC (a gradient up to 10% methanol/methylene chloride) to afford the products example 4 (6.7 mg, 14%), example 5 (5.5 mg, 12%), and example 6 (3.0 mg, 6%) as white solids. The relative stereochemistry was not strictly assigned.

Provenance & Evidence