Hydrochloric Acid → 5-(Cyclopropylamino)-9-fluorobenzo[c]-2,6-naphthyridin-1(2H)-one

HRID 1802453Notes

Reaction equation

HRID 1802453 reaction equation
Cl[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:5]=1[N:6]=[C:7]2Cl.[CH:18]1([NH2:21])[CH2:20][CH2:19]1.Cl.C(=O)([O-])[OH:24].[Na+]>CC(N(C)C)=O.C1COCC1.C(OCC)(=O)C>[CH:18]1([NH:21][C:7]2[C:8]3[CH:9]=[CH:10][NH:11][C:2](=[O:24])[C:3]=3[C:4]3[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:5]=3[N:6]=2)[CH2:20][CH2:19]1

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 69828CyclopropylamineHCID 516892Sodium BicarbonateHCID 594361181,5-Dichloro-9-fluorobenzo[c]-2,6-naphthyridine

Product 1

HCID 251954875-(Cyclopropylamino)-9-fluorobenzo[c]-2,6-naphthyridin-1(2H)-one

Reagents, catalysts & solvents 3

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolventHCID 31374DimethylacetamideSolvent

Conditions

Temperature
100 °C

Procedure

To a solution of 1,5-dichloro-9-fluorobenzo[c]-2,6-naphthyridine (40 mg, 0.15 mmol) in DMA (1.5 mL) was added cyclopropylamine (42.2 μl, 0.60 mmol) and the solution was heated to 100° C. for 30 min. The reaction mixture was cooled to room temperature and added to ethyl acetate (50 mL). The organic layer was washed with aqueous sodium hydrogen carbonate (saturated, 50 mL) and brine (50 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to afford the crude mixture as a yellow oil. The oil was dissolved in THF followed by the addition of hydrochloric acid (2 mL, 12.0 mmol, 6.0 M). The mixture was then refluxed at 100° C. for 3 hr. After cooling to room temperature, the reaction mixture was added to aqueous sodium hydrogen carbonate (saturated, 50 mL). The aqueous layer was extracted with dichloromethane (2×50 mL). The combined organic extracts were washed with brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in water and DMSO and purified by preparative HPLC Reverse phase (C-18; eluting with acetonitrile/water+0.05% TFA), which afforded the title compound as a yellow solid.

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. washThe organic layer was washed with aqueous sodium hydrogen carbonate (saturated, 50 mL) and brine (50 mL)
  3. dry with materialThe combined organic extracts were dried over sodium sulfate
  4. concentrationconcentrated under reduced pressure
  5. customto afford the crude mixture as a yellow oil
  6. temperatureThe mixture was then refluxed at 100° C. for 3 hr
  7. temperatureAfter cooling to room temperature
  8. extractionThe aqueous layer was extracted with dichloromethane (2×50 mL)
  9. washThe combined organic extracts were washed with brine (50 mL)
  10. dry with materialdried over sodium sulfate
  11. concentrationconcentrated under reduced pressure
  12. dissolutionThe residue was dissolved in water
  13. customDMSO and purified by preparative HPLC Reverse phase (C-18; eluting with acetonitrile/water+0.05% TFA), which

Sources & evidence

ORD record
ord-7fb1efb0027140f3a739573166101bcb
Source dataset
uspto-grants-2013_01
Patent number
US08349865B2

Reaction notes

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