8-Hydroxyquinoline → 2-{2-[2-(4-Cyclobutylpiperazin-1-Yl)-2-Oxoethyl]-1,2,3,4-Tetrahydroiso-Quinolin-6-Yl}Pyridazin-3(2H)-One

HRID 1713101Notes

Reaction equation

HRID 1713101 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([CH2:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([CH:21]3[CH2:24][CH2:23][CH2:22]3)[CH2:17][CH2:16]1)=[O:14])[CH2:6][CH2:5]2.[N:25]1[NH:26][C:27](=[O:31])[CH:28]=[CH:29][CH:30]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>Cl[Cu].CN(C=O)C>[CH:21]1([N:18]2[CH2:17][CH2:16][N:15]([C:13](=[O:14])[CH2:12][N:7]3[CH2:6][CH2:5][C:4]4[C:9](=[CH:10][CH:11]=[C:2]([N:26]5[C:27](=[O:31])[CH:28]=[CH:29][CH:30]=[N:25]5)[CH:3]=4)[CH2:8]3)[CH2:20][CH2:19]2)[CH2:22][CH2:23][CH2:24]1

Participants

7

Reactant 4

HCID 19238-HydroxyquinolineHCID 11430Potassium CarbonateHCID 681533(2H)-PyridazinoneHCID 574205706-Bromo-2-[2-(4-cyclobutylpiperazin-1-yl)-2-oxoethyl]-1,2,3,4-tetrahydroisoquinoline

Product 1

HCID 247515092-{2-[2-(4-Cyclobutylpiperazin-1-Yl)-2-Oxoethyl]-1,2,3,4-Tetrahydroiso-Quinolin-6-Yl}Pyridazin-3(2H)-One

Reagents, catalysts & solvents 2

HCID 62652Cuprous chlorideCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
140 °C

Procedure

To a sealed tube charged with 6-bromo-2-[2-(4-cyclobutylpiperazin-1-yl)-2-oxoethyl]-1,2,3,4-tetrahydroisoquinoline (128 mg, 0.326 mmol), CuCl (3.2 mg, 0.0163 mmol, 0.05 eq.), pyridazin-3(2H)-one (47 mg, 0.489 mmol, 1.5 eq.), 8-hydroxyquinoline (9.5 mg, 0.0326 mmol, 0.1 eq.) and K2CO3 (90 mg, 0.652 mmol, 2.0 eq.) is added anhydrous DMF (3 ml). The mixture is degassed with nitrogen for 5 min. The tube is sealed and heated at 140° C. overnight. The mixture is cooled to rt and filtered through Celite. The Celite bed is washed with EtOAc, the combined organics are concentrated, and 5N HCl (30 mL) is added. The mixture is extracted with EtOAc (2×30 mL). The aqueous layer is basified with 10N NaOH, and extracted with DCM (3×40 mL), and the combined organics are dried and concentrated. The crude reaction mixture is purified by preparatory LC/MS to yield the title compound. 1H NMR (300 MHz, CDCl3) δ 7.87 (1H, dd), 7.32 (2H, m), 7.24 (1H, d), 7.12 (1H, d), 7.04 (1H, d), 3.72 (2H, s), 3.67-3.63 (4H, m), 3.36 (2H, s), 2.94 (2H, t), 2.81 (2H, t), 2.69 (1H, m), 2.27 (4H, m), 1.66-2.08 (6H); MS (+VE) m/z 408.14 (M++1).

Workup

  1. customThe mixture is degassed with nitrogen for 5 min
  2. customThe tube is sealed
  3. temperatureThe mixture is cooled to rt
  4. filtrationfiltered through Celite
  5. washThe Celite bed is washed with EtOAc
  6. concentrationthe combined organics are concentrated
  7. addition5N HCl (30 mL) is added
  8. extractionThe mixture is extracted with EtOAc (2×30 mL)
  9. extractionextracted with DCM (3×40 mL)
  10. customthe combined organics are dried
  11. concentrationconcentrated
  12. customThe crude reaction mixture
  13. customis purified by preparatory LC/MS

Sources & evidence

ORD record
ord-31a619f9877542739862a240346d83d7
Source dataset
uspto-grants-2010_09
Patent number
US07795262B2

Reaction notes

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