Hydrochloric Acid → 5-Bromo-6-fluoro-2-methylquinoline

HRID 1199128Notes

Reaction equation

HRID 1199128 reaction equation
[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2.[Cl-].[Al+3].[Cl-].[Cl-].[Br:17]Br.Cl>ClCCCl.O>[Br:17][C:3]1[C:2]([F:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([CH3:12])=[N:8]2

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 24408BromineHCID 707846-Fluoro-2-methylquinolineHCID 6451240Aluminum(III) Chloride

Product 1

HCID 130353135-Bromo-6-fluoro-2-methylquinolineYield 99.2%

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolvent2×HCID 962WaterSolvent

Conditions

Temperature
75 °C

Procedure

A solution of 12.1 kg (75 mole) of 6-fluoro-2-methylquinoline in 33 liters of 1,2-dichloroethane was chilled to 5° C., and 15.0 kg (113 mole) of aluminum chloride was added thereto in portions over 15 minutes. The mixture was purged with nitrogen and then heated to 75° C. A solution of 13.2 kg (82.6 mole) of bromine in 2 liters of 1,2-dichloroethane was added over a period of 5.5 hours. The reaction was maintained at 75° C. during the addition and for an additional 15 minutes after the addition was completed. The reaction was stirred at 70° C. for 23 hours and was then cooled to 10° C. and slowly added to a mixture of 8 kg of 30% hydrochloric acid, 41 liters of water and 31.75 kg of ice. The mixture warmed to 50° C. during the addition. The mixture was heated in reflux and the 1,2-dichloroethane was removed by azeotropic distillation. The remaining aqueous solution was cooled to 60° C. and 12 kg of 10% hydrochloric acid was added. The solution was treated with Celite® (available from Johns-Manville Corp.) and filtered. The filtrate was cooled to 25° C. and 18 kg of 30% hydrochloric acid and 10.22 kg of zinc chloride were added. The resulting slurry was chilled to 5° C. and allowed to stir for several days. The solid was collected and then reslurried with 10 gallons of water. The slurry was chilled to 5° C. and 22 kg of chilled ammonium hydroxide was added. The resulting slurry (pH 10-11) was diluted with 25 gallons of water and the solid was collected, rinsed with water and dried in vacuo at 60° C. to give crude 5-bromo-6-fluoro-2-methylquinoline (84.5% pure by gas chromatography analysis). The material was recrystallized from hexane to give 99.2% pure 5-bromo-6-fluoro-2-methylquinoline.

Workup

  1. customThe mixture was purged with nitrogen
  2. temperatureThe reaction was maintained at 75° C. during the addition and for an additional 15 minutes
  3. additionafter the addition
  4. temperaturewas then cooled to 10° C.
  5. temperatureThe mixture warmed to 50° C. during the addition
  6. temperatureThe mixture was heated
  7. temperaturein reflux
  8. customthe 1,2-dichloroethane was removed by azeotropic distillation
  9. temperatureThe remaining aqueous solution was cooled to 60° C.
  10. addition12 kg of 10% hydrochloric acid was added
  11. additionThe solution was treated with Celite® (available from Johns-Manville Corp.)
  12. filtrationfiltered
  13. temperatureThe filtrate was cooled to 25° C.
  14. addition18 kg of 30% hydrochloric acid and 10.22 kg of zinc chloride were added
  15. temperatureThe resulting slurry was chilled to 5° C.
  16. stirringto stir for several days
  17. customThe solid was collected
  18. temperatureThe slurry was chilled to 5° C.
  19. addition22 kg of chilled ammonium hydroxide was added
  20. additionThe resulting slurry (pH 10-11) was diluted with 25 gallons of water
  21. customthe solid was collected
  22. washrinsed with water
  23. customdried in vacuo at 60° C.
  24. customto give crude 5-bromo-6-fluoro-2-methylquinoline (84.5% pure by gas chromatography analysis)
  25. customThe material was recrystallized from hexane

Sources & evidence

ORD record
ord-e1feac8d15e447438166d4d3bf7c7d90
Source dataset
uspto-grants-1990_02
Patent number
US04898945

Reaction notes

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