Tetrahydrofuran → 2,4-dimethoxy-7-(4-methoxy-3,5-dimethylphenyl)-1,6-naphthyridin-5(6H)-one

HRID 555512

Reaction equation

HRID 555512 reaction equation
[CH3:1][O:2][C:3]1[C:8]([C:9]([NH2:11])=[O:10])=[C:7]([CH3:12])[N:6]=[C:5]([O:13][CH3:14])[CH:4]=1.C([Li])CCC.CO[C:22]1C=[CH:28][C:25]([C:26]#N)=[CH:24][CH:23]=1.[CH2:30]1[CH2:34][O:33][CH2:32][CH2:31]1>>[CH3:14][O:13][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:8]2[C:9](=[O:10])[NH:11][C:28]([C:25]3[CH:24]=[C:23]([CH3:22])[C:34]([O:33][CH3:32])=[C:30]([CH3:31])[CH:26]=3)=[CH:12][C:7]=2[N:6]=1

Participants

5

Reactant 4

HCID 8028Tetrahydrofuran2×HCID 701294-MethoxybenzonitrileHCID 666614724,6-Dimethoxy-2-methyl-nicotinamideHCID 178418339Butyllithium

Product 1

HCID 249597052,4-dimethoxy-7-(4-methoxy-3,5-dimethylphenyl)-1,6-naphthyridin-5(6H)-oneYield 12%

Conditions

Temperature
0 °C

Procedure

To a solution of 4,6-dimethoxy-2-methyl nicotinamide (2.0 g, 10.2 mmol) in THF (80 mL), n-butyl lithium (19.12 mL, 30.6 mmol, 1.6 M solution in hexane) was added slowly under nitrogen at −78° C. After completion of addition the mixture was stirred for 1 h at 0° C. Then cooled to −78° C. and a solution of 4-methoxy benzonitrile (1.65 g, 10.2 mmol) in THF (10 mL) was added quickly. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature and stirred for 16 h at room temperature. Saturated NH4Cl solution was added with cooling. The organic layer was washed with water, brine, dried over Na2SO4 and concentrated to give crude product. The crude product was purified by chromatography using 50% ethyl acetate in hexane and then 2% methanol in ethyl acetate to give 2,4-dimethoxy-7-(4-methoxy-3,5-dimethylphenyl)-1,6-naphthyridin-5(6H)-one (410 mg, 12%), as a yellow solid. Selected data: MS (ES) m/z: 341.1; mp 262-263° C. (at decomposition).

Workup

  1. additionAfter completion of addition the mixture
  2. temperatureThen cooled to −78° C.
  3. customThe cooling bath was removed
  4. temperatureto warm to room temperature
  5. stirringstirred for 16 h at room temperature
  6. additionSaturated NH4Cl solution was added
  7. temperaturewith cooling
  8. washThe organic layer was washed with water, brine
  9. dry with materialdried over Na2SO4
  10. concentrationconcentrated
  11. customto give crude product
  12. customThe crude product was purified by chromatography

Sources & evidence

ORD record
ord-82bc7110afba4889a0cbc09ebee336fc
Source dataset
uspto-grants-2011_11
Patent number
US08053440B2

Linked notes

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