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

HRID 896813Notes

Reaction equation

HRID 896813 reaction equation
C([O:3][C:4]([C:6]1[C:14]2[CH2:13][CH2:12][NH:11][C:10](=[O:15])[C:9]=2[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[N:7]=1)=[O:5])C.I[C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][C:32]2=[O:37])=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+].OC1C=CC=C2C=1N=CC=C2.[NH4+].[OH-]>CS(C)=O.[Cu]I.C(OCC)(=O)C>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([N:8]2[C:9]3[C:10](=[O:15])[N:11]([C:25]4[CH:30]=[CH:29][C:28]([N:31]5[CH2:36][CH2:35][CH2:34][CH2:33][C:32]5=[O:37])=[CH:27][CH:26]=4)[CH2:12][CH2:13][C:14]=3[C:6]([C:4]([OH:3])=[O:5])=[N:7]2)=[CH:21][CH:20]=1

Participants

9

Reactant 5

HCID 19238-HydroxyquinolineHCID 11430Potassium CarbonateHCID 14923Ammonium HydroxideHCID 22240468Ethyl 1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylateHCID 223522321-(4-Iodophenyl)piperidin-2-one

Product 1

HCID 222404401-(4-Methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo(3,4-c)pyridine-3-carboxylic acidYield 68%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 679Dimethyl SulfoxideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
125 °C

Procedure

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).

Workup

  1. customThe resulting reaction mixture
  2. customwas subsequently degassed three times again
  3. customthe coupling reaction
  4. temperaturethe reaction mixture was cooled down to 5-10° C.
  5. filtrationThe mixture was filtered through a Celite® bed
  6. washthe Celite® bed was washed with water (2×10 mL)
  7. customThe two layers of the filtrates were separated
  8. stirringThe mixture was subsequently stirred at 5-10° C. for an additional 1 h
  9. filtrationThe solids were collected by filtration
  10. washwashed with water (2×5 mL)
  11. customdried in vacuo at 40-45° C. for 12 h

Sources & evidence

ORD record
ord-808bf34e04004ca2b660d9d7795ef9c9
Source dataset
uspto-grants-2005_07
Patent number
US06919451B2

Reaction notes

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