8-Hydroxyquinoline → 1-(4-Methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo(3,4-c)pyridine-3-carboxylic acid

Participants

Reaction Conditions

Reaction Steps

A solution of 1-(4-methoxy-phenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (50, 2.0 g, 6.4 mmol), 1-(4-iodo-phenyl)-piperidin-2-one (60, 2.5 g, 8.3 mmol, 1.3 equiv), and K2CO3 (325 mesh powder, 1.80 g, 12.8 mmol, 2.0 equiv) in DMSO (35 mL) was degassed three times under a steady nitrogen stream before being treated with CuI (244 mg, 1.3 mmol, 20% equiv) and 8-hydroxyquinoline (189 mg, 1.3 mmol, 20% equiv) under N2. The resulting reaction mixture was subsequently degassed three times again before being warmed up to 125° C. for 10 h. When HPLC showed the coupling reaction was complete, the reaction mixture was cooled down to 5-10° C. before being treated with 14% NH4OH aqueous solution (30 mL) and ethyl acetate (30 mL) at 5-10° C. with good stirring. The mixture was stirred for an additional 1 h at 5-10° C. The mixture was filtered through a Celite® bed and the Celite® bed was washed with water (2×10 mL). The two layers of the filtrates were separated, and the aqueous layer was acidified by 1 N aqueous HCl solution to pH=4. The mixture was subsequently stirred at 5-10° C. for an additional 1 h. The solids were collected by filtration, washed with water (2×5 mL), and dried in vacuo at 40-45° C. for 12 h to afford the crude desired 1-(4-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (61, 2.0 g, 2.95 g theoretical, 68%), which was found to be pure enough to do the following reaction without further purification. For 61, CIMS m/z 461 (M++H, C25H24N4O5).

Provenance & Evidence