Carbon Dioxide → 3-Bromo-6-chloro-2-fluorobenzoic acid

HRID 1270735Notes

Reaction equation

HRID 1270735 reaction equation
[Li].[Li]CCCC.C(NC(C)C)(C)C.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[F:22].[C:23](=[O:25])=[O:24]>C1COCC1.C(=O)=O.CC(C)=O.CCOCC.Cl>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([Br:14])=[C:16]([F:22])[C:17]=1[C:23]([OH:25])=[O:24]

Participants

10

Reactant 5

HCID 280Carbon DioxideHCID 7912DiisopropylamineHCID 1372751-Bromo-4-chloro-2-fluorobenzeneHCID 3028194LithiumHCID 178418339Butyllithium

Product 1

HCID 217423273-Bromo-6-chloro-2-fluorobenzoic acid

Reagents, catalysts & solvents 4

HCID 313Hydrochloric AcidSolventHCID 3283Diethyl EtherSolventHCID 8028TetrahydrofuranSolventHCID 18522661Acetone cardiceSolvent

Conditions

Temperature
-70 °C

Procedure

A solution of lithium diiosopropyl amide is generated by adding n-BuLi (360 mL of 2 M solution in THF) to diisopropylamine (73 g, 0.722 mol) in 500 mL of anhydrous THF while a reaction temperature of −60° C. is maintained by cooling in dry-ice acetone bath. After stirring for 30 minutes, 1-bromo-4-chloro-2-fluorobenzene (75 g, 0.36 mol) is added and stirring maintained at −70° C. for 2 hours. The cold solution is then transferred, via a cannula, under an inert atmosphere to a suspension of solid CO2 (100 g, excess) in anhydrous Et2O. The mixture is allowed to warm to room temperature with stirring and then the solvent removed by rotary evaporator. The residual solid is treated with 1 N HCl solution until pH=3.0 and the mixture is filtered. The white solid that is obtained is suspended in 1000 mL of 2 N HCl solution and stirred for an additional 1 hour. The suspension is filtered to collect a white solid which is air dried, suspended in 100 mL of hexanes and collected to give 2-chloro-5-bromo-6-fluorobenzoic acid.

Workup

  1. temperatureis maintained
  2. stirringstirring
  3. temperatureto warm to room temperature
  4. stirringwith stirring
  5. customthe solvent removed by rotary evaporator
  6. additionThe residual solid is treated with 1 N HCl solution until pH=3.0
  7. filtrationthe mixture is filtered
  8. customThe white solid that is obtained
  9. stirringstirred for an additional 1 hour
  10. filtrationThe suspension is filtered
  11. customto collect a white solid which
  12. customdried
  13. customcollected

Sources & evidence

ORD record
ord-6c9ea5fcd81343a7acbd50557642ace7
Source dataset
uspto-grants-2007_04
Patent number
US07202364B2

Reaction notes

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