8-Hydroxyquinoline → 4-(Benzyloxy)-1-(1-(2,2-dimethoxyethyl)-1H-indazol-5-yl)pyridin-2(1H)-one

HRID 2387500Notes

Reaction equation

HRID 2387500 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH:12]([O:15][CH3:16])[O:13][CH3:14])[N:6]=[CH:5]2.[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][NH:28][C:27](=[O:31])[CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+].OC1C=CC=C2C=1N=CC=C2>CS(C)=O.[Cu]I>[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][N:28]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH2:11][CH:12]([O:15][CH3:16])[O:13][CH3:14])[N:6]=[CH:5]3)[C:27](=[O:31])[CH:26]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1

Participants

7

Reactant 4

HCID 19238-HydroxyquinolineHCID 11430Potassium CarbonateHCID 36077244-Benzyloxy-2(1H)-pyridoneHCID 592933985-Bromo-1-(2,2-dimethoxyethyl)-1H-indazole

Product 1

HCID 592933874-(Benzyloxy)-1-(1-(2,2-dimethoxyethyl)-1H-indazol-5-yl)pyridin-2(1H)-oneYield 87.4%

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 679Dimethyl SulfoxideSolvent

Conditions

Temperature
130 °C

Procedure

A suspension of 5-bromo-1-(2,2-dimethoxyethyl)-1H-indazole (4.0, 14 mmol), 4-(benzyloxy)pyridin-2(1H)-one (3.1 g, 16 mmol), K2CO3 (2.1 g, 16 mmol), 8-hydroxyquinoline (310 mg, 2.1 mmol) and CuI (3.1 g, 16 mmol) in DMSO (20 mL) was evacuated for 30 minutes under high vacuum then backfilled with nitrogen. The mixture was stirred under nitrogen at 130° C. for 20 h and then allowed to cool. The mixture was diluted with 20% MeOH/NH4OH (10:1) in CH2Cl2 (200 mL), stirred for 15 min, and then loaded onto a silica plug. The material was eluted through the plug with 20% MeOH/NH4OH (10:1) in CH2Cl2 (400 ml) and then concentrated. The residue was dissolved in CH2Cl2, washed with LiCl (4×100 mL) and brine (1×100 mL), dried over Na2SO4, filtered and concentrated to dryness. Purification by flash column chromatography (120 g ISCO column eluting with methylene chloride and a methanol/ammonia mixture (10:1); gradient 100% methylene chloride to 80% methylene chloride over 60 min at 40 mL/min) gave the title compound (4.96 g, 85%) as a light orange solid 1H NMR (300 MHz, CDCl3) δ 8.04 (s, 1H), 7.66 (d, J=1.6 Hz, 1H), 7.56 (d, J===8.9 Hz, 1H), 7.45-7.33 (m, 6H), 7.27 (d, J===2.9 Hz, 1H), 6.12-6.04 (m, 2H), 5.05 (s, 2H), 4.76 (t, J=5.3 Hz, 1H), 4.59 (d, J=5.3 Hz, 2H), 3.37 (s, 6H).

Workup

  1. customwas evacuated for 30 minutes under high vacuum
  2. temperatureto cool
  3. additionThe mixture was diluted with 20% MeOH/NH4OH (10:1) in CH2Cl2 (200 mL)
  4. stirringstirred for 15 min
  5. washThe material was eluted through the plug with 20% MeOH/NH4OH (10:1) in CH2Cl2 (400 ml)
  6. concentrationconcentrated
  7. dissolutionThe residue was dissolved in CH2Cl2
  8. washwashed with LiCl (4×100 mL) and brine (1×100 mL)
  9. dry with materialdried over Na2SO4
  10. filtrationfiltered
  11. concentrationconcentrated to dryness
  12. customPurification by flash column chromatography (120 g ISCO column
  13. washeluting with methylene chloride

Sources & evidence

ORD record
ord-3b0478bdc72644c6bed7866b1dcf5986
Source dataset
uspto-grants-2012_09
Patent number
US08268868B2

Reaction notes

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