Triethylamine → 7-(1-Amino-3-azabicyclo[3.2.0]hept-3-yl)-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

HRID 1457976Notes

Reaction equation

HRID 1457976 reaction equation
C(OC([C:8]12[CH2:14][CH2:13][CH:12]1[CH2:11][NH:10][CH2:9]2)=O)(C)(C)C.[F:15][C@H:16]1[CH2:18][C@H:17]1[N:19]1[C:28]2[C:23](=[CH:24][C:25]([F:32])=[C:26](F)[C:27]=2[O:29][CH3:30])[C:22](=[O:33])[C:21]([C:34]([OH:36])=[O:35])=[CH:20]1.C([N:39](CC)CC)C>CS(C)=O>[NH2:39][C:8]12[CH2:14][CH2:13][CH:12]1[CH2:11][N:10]([C:26]1[C:27]([O:29][CH3:30])=[C:28]3[C:23]([C:22](=[O:33])[C:21]([C:34]([OH:36])=[O:35])=[CH:20][N:19]3[C@@H:17]3[CH2:18][C@@H:16]3[F:15])=[CH:24][C:25]=1[F:32])[CH2:9]2

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 120946186,7-difluoro-1,4-dihydro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methoxy-4-oxo-3-quinolinecarboxylic acidHCID 221005211-Tert-butoxycarbonyl-3-azabicyclo[3.2.0]heptane

Product 1

HCID 129727587-(1-Amino-3-azabicyclo[3.2.0]hept-3-yl)-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Procedure

To a solution of 1-tert-butoxycarbonyl-3-azabicyclo[3.2.0]heptane (1.02 mmol) in dimethyl sulfoxide (1.5 ml) were added 180 mg (0.5 mmol) of difluoroboric acid ester of 1-[2-(S)-fluoro-1-(R)-cyclopropyl]-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 0.5 ml of triethylamine, followed by 110 hours of stirring at room temperature. After evaporation of triethylamine, the resulting residue was mixed with water, and the thus precipitated crystals were collected by filtration. To the thus collected crystals were added 15 ml of 90% methanol and 3 ml of triethylamine, subsequently carrying out 4 hours of reflux. This was cooled to room temperature and then concentrated. The resulting residue was mixed with 10% citric acid and extracted with chloroform. The organic layer was washed with water and saturated brine and dried on anhydrous sodium sulfate, subsequently evaporating the solvent. To the thus obtained residue dissolved in dichloromethane (5 ml) and cooled in an ice bath was added trifluoroacetic acid (5 ml), followed by 1 hour of stirring at room temperature. After concentration, the resulting residue was mixed with concentrated hydrochloric acid and washed with chloroform. The resulting solution was adjusted to pH 7.5 with concentrated sodium hydroxide aqueous solution and then extracted with chloroform. The extract was dried over anhydrous sodium sulfate, subsequently evaporating the solvent. By recrystallizing the resulting residue from ethanol, 75.9 mg of the title compound was obtained.

Workup

  1. customAfter evaporation of triethylamine
  2. additionthe resulting residue was mixed with water
  3. filtrationthe thus precipitated crystals were collected by filtration
  4. additionTo the thus collected crystals were added 15 ml of 90% methanol and 3 ml of triethylamine
  5. waitsubsequently carrying out 4 hours
  6. temperatureof reflux
  7. temperatureThis was cooled to room temperature
  8. concentrationconcentrated
  9. additionThe resulting residue was mixed with 10% citric acid
  10. extractionextracted with chloroform
  11. washThe organic layer was washed with water and saturated brine
  12. dry with materialdried on anhydrous sodium sulfate
  13. customsubsequently evaporating the solvent
  14. dissolutionTo the thus obtained residue dissolved in dichloromethane (5 ml)
  15. temperaturecooled in an ice bath
  16. additionwas added trifluoroacetic acid (5 ml)
  17. waitfollowed by 1 hour
  18. stirringof stirring at room temperature
  19. concentrationAfter concentration
  20. additionthe resulting residue was mixed with concentrated hydrochloric acid
  21. washwashed with chloroform
  22. extractionextracted with chloroform
  23. dry with materialThe extract was dried over anhydrous sodium sulfate
  24. customsubsequently evaporating the solvent
  25. customBy recrystallizing the resulting residue from ethanol

Sources & evidence

ORD record
ord-1faa3d3544754de09cd627eddf168641
Source dataset
uspto-grants-1998_12
Patent number
US05849757

Reaction notes

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