Acetic Acid → 7-Chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid

HRID 2104109Notes

Reaction equation

HRID 2104109 reaction equation
Cl[C:2]1[C:7]([C:8](=[O:15])[CH2:9][C:10]([O:12]CC)=[O:11])=[CH:6][C:5]([F:16])=[C:4]([Cl:17])[N:3]=1.[C:18](O)(=O)C.[CH:22]1([NH2:25])[CH2:24][CH2:23]1>C1(C)C=CC=CC=1>[Cl:17][C:4]1[N:3]=[C:2]2[C:7]([C:8](=[O:15])[C:9]([C:10]([OH:12])=[O:11])=[CH:18][N:25]2[CH:22]2[CH2:24][CH2:23]2)=[CH:6][C:5]=1[F:16]

Participants

5

Reactant 3

HCID 176Acetic AcidHCID 69828CyclopropylamineHCID 2733708Ethyl 2,6-dichloro-5-fluoro-beta-oxo-3-pyridinepropionate2×

Product 1

HCID 110551427-Chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acidYield 358.8%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Procedure

To a stirred solution of 3-(2,6-Dichloro-5-fluoropyridin-3-yl)-3 -oxo-propanoic acid ethyl ester (compound (1): 85.0 kg, 303 mol) in toluene (808 kg)was added Me2 NCH(OMe)2 (40.8 kg ) and acetic acid (4.56 kg). The mixture was stirred at room temperature for 50 minutes. Cyclopropylamine (22.53 kg) was added to the reaction mixture, and the mixture was stirred at 25 to 35° C. for 50 minutes. The reaction mixture was washed with 10% aqueous citric acid solution, and then water. After layer separation, the aqueous layer was discarded, and tetrabutylammonium bromide (4.88 kg) and 25% aqueous sodium hydroxide solution (53 kg) were added to the separated organic layer. The resulting mixture was stirred for 2 hours. 35% aqueous hydrochloric acid solution (142 kg) was added, and the resulting mixture was heated at reflux. After about 8 hours, the reaction mixture was cooled, and water (about 50 kg) was added thereto, and then the aqueous layer was separated off. The reaction solution was washed with water, and the solid compound present in the separated organic layer was filtered, and washed with isopropanol, water, and isopropanol in sequence. The resulting solid was dried under vacuum to give the title compound (77 kg) as a white crystal.

Workup

  1. stirringthe mixture was stirred at 25 to 35° C. for 50 minutes
  2. washThe reaction mixture was washed with 10% aqueous citric acid solution
  3. customAfter layer separation
  4. additiontetrabutylammonium bromide (4.88 kg) and 25% aqueous sodium hydroxide solution (53 kg) were added to the separated organic layer
  5. stirringThe resulting mixture was stirred for 2 hours
  6. addition35% aqueous hydrochloric acid solution (142 kg) was added
  7. temperaturethe resulting mixture was heated
  8. temperatureat reflux
  9. waitAfter about 8 hours
  10. temperaturethe reaction mixture was cooled
  11. additionwater (about 50 kg) was added
  12. customthe aqueous layer was separated off
  13. washThe reaction solution was washed with water
  14. filtrationthe solid compound present in the separated organic layer was filtered
  15. washwashed with isopropanol, water, and isopropanol in sequence
  16. customThe resulting solid was dried under vacuum

Sources & evidence

ORD record
ord-55048556ca2d4344a19165aa29f84289
Source dataset
uspto-grants-2009_08
Patent number
US07576214B2

Reaction notes

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