Methanol → 4-Oxo-2-(3-(trifluoromethyl)phenyl)-1,4-dihydro-1,6-naphthyridine-8-carboxylic acid

HRID 520472Notes

Reaction equation

HRID 520472 reaction equation
Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)=[C:8](C(OCC)=O)[C:7]2=[O:27].[Cu]C#N.[C:31](=O)([O-:33])[O-:32].[Na+].[Na+].CO>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[O:27]=[C:7]1[C:6]2[C:11](=[C:2]([C:31]([OH:33])=[O:32])[CH:3]=[N:4][CH:5]=2)[NH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:21])[F:20])[CH:13]=2)=[CH:8]1

Participants

8

Reactant 4

HCID 887MethanolHCID 10340Sodium CarbonateHCID 58552956Ethyl 8-bromo-4-oxo-2-(3-(trifluoromethyl)phenyl)-1,4-dihydro-1,6-naphthyridine-3-carboxylateHCID 178418546HCID 178418546, compound

Product 1

HCID 585528604-Oxo-2-(3-(trifluoromethyl)phenyl)-1,4-dihydro-1,6-naphthyridine-8-carboxylic acidYield 58.1%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
120 °C

Procedure

A mixture of ethyl 8-bromo-4-oxo-2-(3-(trifluoromethyl)phenyl)-1,4-dihydro-1,6-naphthyridine-3-carboxylate 48 (910 mg, 2.06 mmol), palladium acetate (22.4 mg, 0.100 mmol), XPhos (48.8 mg, 0.102 mmol), copper (I) cyanide (450 mg, 5.02 mmol), and sodium carbonate (636 mg, 6.00 mmol) in DMF (7.0 mL) was heated at 120° C. for 16 h. After cooling to room temperature, the mixture was poured into methanol (100 mL), filtered through celite, and concentrated in vacuo. The crude residue was dissolved in dioxane (10 mL) and 1N HCl (5 mL). The reaction mixture was heated at 190° C. for 50 min in a microwave reactor. The volatiles were removed in vacuo and the residue was redissolved in methanol (10 mL) and 1N NaOH (5 mL). This solution was heated in a microwave reactor at 160° C. for 1.5 h, after which 6N HCl (5 mL) was added. The resulting precipitate was collected by filtration, rinsed with H2O and dried under vacuum to give 49 (400 mg, 58% yield.)

Workup

  1. temperatureAfter cooling to room temperature
  2. filtrationfiltered through celite
  3. concentrationconcentrated in vacuo
  4. dissolutionThe crude residue was dissolved in dioxane (10 mL)
  5. temperatureThe reaction mixture was heated at 190° C. for 50 min in a microwave reactor
  6. customThe volatiles were removed in vacuo
  7. dissolutionthe residue was redissolved in methanol (10 mL)
  8. temperatureThis solution was heated in a microwave reactor at 160° C. for 1.5 h
  9. additionafter which 6N HCl (5 mL) was added
  10. filtrationThe resulting precipitate was collected by filtration
  11. washrinsed with H2O
  12. customdried under vacuum

Sources & evidence

ORD record
ord-6e92ed77f03b46bf8ea2f5d8630d955f
Source dataset
uspto-grants-2016_05
Patent number
US09326986B2

Reaction notes

Loading…