Triethylamine → 5-Amino-7-[1-amino-5-azaspiro[2.4]heptan-5-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic Acid

HRID 992441Notes

Reaction equation

HRID 992441 reaction equation
C(O[C:9]([N:11]1[CH2:25][CH2:24][C:13]2([CH:15]([NH:16]C(OC(C)(C)C)=O)[CH2:14]2)[CH2:12]1)=O)C1C=CC=CC=1.[NH2:26][C:27]1[C:36]([F:37])=[C:35](F)[C:34](C)=[C:33]2[C:28]=1[C:29](=[O:47])[C:30]([C:44]([OH:46])=[O:45])=[CH:31][N:32]2[C@@H:40]1[CH2:42][C@@H:41]1[F:43].C(N(CC)CC)C>C(O)C.[C].[Pd]>[NH2:26][C:27]1[C:36]([F:37])=[C:9]([N:11]2[CH2:25][CH2:24][C:13]3([CH:15]([NH2:16])[CH2:14]3)[CH2:12]2)[C:34]([CH3:35])=[C:33]2[C:28]=1[C:29](=[O:47])[C:30]([C:44]([OH:46])=[O:45])=[CH:31][N:32]2[C@@H:40]1[CH2:42][C@@H:41]1[F:43]

Participants

6

Reactant 3

HCID 8471TriethylamineHCID 110233625-amino-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acidHCID 184122455-Benzyloxycarbonyl-1-tert-butoxycarbonylamino-5-azaspiro[2.4]heptane

Product 1

HCID 228883385-Amino-7-[1-amino-5-azaspiro[2.4]heptan-5-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic AcidYield 35%

Reagents, catalysts & solvents 2

HCID 178418390HCID 178418390, compoundCatalyst2×HCID 702EthanolSolvent

Conditions

Temperature
155 °C

Procedure

A 693 mg (2.00 mmol) portion of 5-benzyloxycarbonyl-1-tert-butoxycarbonylamino-5-azaspiro[2.4]heptane (1-a) was dissolved in 60 ml of ethanol, and the solution was mixed with 600 mg of 10% palladium-carbon and subjected to 2 hours of hydrogenation under atmospheric pressure. After completion of the reaction, 10% palladium-carbon was removed by filtration and ethanol was evaporated. The thus obtained residue was suspended in 6 ml of dimethyl sulfoxide, and the suspension was mixed with 312 mg (1.00 mmol) of 5-amino-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 2.00 ml (14.35 mmol) of triethylamine, and heated at 150 to 160° C. for 19 hours in a stream of nitrogen. After evaporation of the solvent, the thus obtained residue was mixed with chloroform, washed with water, 10% citric acid aqueous solution and saturated brine in that order, and then dried over anhydrous sodium sulfate, subsequently evaporating the solvent. The thus obtained tert-butylcarbamate compound was mixed with 5 ml of concentrated hydrochloric acid, stirred at room temperature for 20 minutes, washed with chloroform (50 ml×3), adjusted to pH 7.4 with sodium hydroxide aqueous solution and then extracted with chloroform, and the extract was dried over anhydrous sodium sulfate. After evaporation of the solvent, the resulting residue was purified by a preparative TLC (developed by the lower layer of chloroform:methanol:water 7:3:1) and recrystallized from ethanol-ether to yield 142 mg (35%) of the title compound.

Workup

  1. customwas removed by filtration and ethanol
  2. customwas evaporated
  3. customAfter evaporation of the solvent
  4. additionthe thus obtained residue was mixed with chloroform
  5. washwashed with water, 10% citric acid aqueous solution and saturated brine in that order
  6. dry with materialdried over anhydrous sodium sulfate
  7. customsubsequently evaporating the solvent
  8. additionThe thus obtained tert-butylcarbamate compound was mixed with 5 ml of concentrated hydrochloric acid
  9. washwashed with chloroform (50 ml×3)
  10. extractionextracted with chloroform
  11. dry with materialthe extract was dried over anhydrous sodium sulfate
  12. customAfter evaporation of the solvent
  13. customthe resulting residue was purified by a preparative TLC (
  14. customrecrystallized from ethanol-ether

Sources & evidence

ORD record
ord-31c7ab5a6ee14767ade02961990c1b8a
Source dataset
uspto-grants-2002_10
Patent number
US06469023B1

Reaction notes

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