Hydrochloric Acid → Ethyl 1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-7-hydroxy-4-oxo-1,8-naphthyridine-3-carboxylate

HRID 232481Notes

Reaction equation

HRID 232481 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:23]=[C:22]([OH:24])[C:21]([F:25])=[CH:20][C:11]=1[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:13].[C:26](OC(=O)C)(=O)C.C([O-])([O-])OCC.C(=O)([O-])[O-].[Na+].[Na+].Cl>O1CCOCC1.C(OCC)C.O.C(OCC)(=O)C.CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:10]2[C:11](=[CH:20][C:21]([F:25])=[C:22]([OH:24])[N:23]=2)[C:12](=[O:13])[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:26]1

Participants

11

Reactant 5

HCID 313Hydrochloric AcidHCID 7918Acetic AnhydrideHCID 10340Sodium CarbonateHCID 53630039EthylorthoformateHCID 178472175Ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-hydroxynicotinoyl]acetate

Product 1

HCID 178469556Ethyl 1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-7-hydroxy-4-oxo-1,8-naphthyridine-3-carboxylateYield 52.3%

Reagents, catalysts & solvents 5

HCID 887MethanolSolventHCID 962WaterSolvent2×HCID 3283Diethyl EtherSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Procedure

In 1 ml of dioxane were dissolved 80 mg of ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-hydroxynicotinoyl]acetate, 46 mg of acetic anhydride and 50 mg of ethyl ortho-formate, and the resulting solution was subjected to reaction under reflux for 7 hours, after which the solvent was removed by distillation under reduced pressure. The residue thus obtained was dissolved 10 ml of methanol and 5 ml of water, and the pH thereof was adjusted to 8.5 with a 10% by weight aqueous sodium carbonate solution. The resulting mixture was subjected to reaction at room temperature for 30 minutes, and the pH of the reaction mixture was adjusted to 2.0 with 2N hydrochloric acid, after which 20 ml of ethyl acetate and 10 ml of water were added thereto. The organic layer was separated, washed successively with 15 ml of water and 15 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and to the residue thus obtained was added 1 ml of diethyl ether, after which the crystals thus deposited were collected by filtration to obtain 43 mg (yield 52.3%) of ethyl 1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-7-hydroxy-4-oxo-1,8-naphthyridine-3-carboxylate. The physical properties of this compound were identical with those of the compound obtained in Example 40.

Workup

  1. customthe resulting solution was subjected to reaction
  2. temperatureunder reflux for 7 hours
  3. customafter which the solvent was removed by distillation under reduced pressure
  4. customThe residue thus obtained
  5. customThe resulting mixture was subjected to reaction at room temperature for 30 minutes
  6. customThe organic layer was separated
  7. washwashed successively with 15 ml of water and 15 ml of saturated aqueous sodium chloride solution
  8. dry with materialdried over anhydrous magnesium sulfate
  9. customThe solvent was removed by distillation under reduced pressure
  10. customto the residue thus obtained
  11. filtrationafter which the crystals thus deposited were collected by filtration

Sources & evidence

ORD record
ord-d131123deb1044aea830b5f96f9fcfed
Source dataset
uspto-grants-1989_07
Patent number
US04851535

Reaction notes

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