Hydrochloric Acid → 8-Fluoro-7-methoxy-2-methylquinoline

HRID 338995Notes

Reaction equation

HRID 338995 reaction equation
[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:10][C:11](=O)OC(C)(C)C.Cl.[CH:19](=O)/[CH:20]=C/C.[OH-].[NH4+].[CH3:26]O>O1CCOCC1.CCCCO>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]2[C:3]=1[N:10]=[C:11]([CH3:26])[CH:20]=[CH:19]2

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 887MethanolHCID 14923Ammonium HydroxideHCID 447466CrotonaldehydeHCID 44203148Tert-butyl (2-fluoro-3-methoxyphenyl)carbamate

Product 1

HCID 867075048-Fluoro-7-methoxy-2-methylquinolineYield 67%

Reagents, catalysts & solvents 2

HCID 2631-ButanolSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
106 °C

Procedure

A solution of tert-butyl 2-fluoro-3-methoxyphenylcarbamate (2.27 g, 9.41 mmol) in methanol (5 mL) was treated with 4N HCl in 1,4-dioxane (30 mL) for 2 hours. The solvent was removed under reduced pressure and the residue stirred in aqueous 6N HCl (20 mL) at 106° C. A solution of crotonaldehyde (1.56 mL, 18.8 mmol) in n-BuOH (2 mL) was added dropwise from an addition funnel over 20 minutes and the resulting mixture was heated at reflux for an additional 2 hours. The reaction was cooled to ambient temperature and the mixture carefully pH adjusted to 9 with ammonium hydroxide. The mixture was extracted with dichloromethane and the combined dichloromethane extracts were dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Biotage 40M; 10% ethyl acetate/hexanes) to afford 8-fluoro-7-methoxy-2-methylquinoline (1.20 g, 6.28 mmol, 67%).

Workup

  1. customThe solvent was removed under reduced pressure
  2. temperaturethe resulting mixture was heated
  3. temperatureat reflux for an additional 2 hours
  4. temperatureThe reaction was cooled to ambient temperature
  5. extractionThe mixture was extracted with dichloromethane
  6. dry with materialthe combined dichloromethane extracts were dried (MgSO4)
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure
  9. customThe residue was purified by column chromatography (Biotage 40M; 10% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-d8fc74233e31472b90878d2e35ee20f3
Source dataset
uspto-grants-2014_11
Patent number
US08889704B2

Reaction notes

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