Benzyl Chloride → 4-(Benzyloxy)-2-fluorobenzoic acid

HRID 2231803Notes

Reaction equation

HRID 2231803 reaction equation
[CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]1[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13].[OH-].[K+]>C(O)C>[F:9][C:10]1[CH:18]=[C:17]([O:19][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]

Participants

5

Reactant 3

HCID 7503Benzyl ChlorideHCID 14797Potassium HydroxideHCID 27833982-Fluoro-4-hydroxybenzoic Acid

Product 1

HCID 223145024-(Benzyloxy)-2-fluorobenzoic acidYield 85.1%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Conditions

Temperature
60 °C

Procedure

62 g of benzyl chloride was added to a mixture of 73 g of 2-fluoro-4-hydroxy-benzoic acid, 55 g of potassium hydroxide and 300 ml of ethanol, and the resulting mixture was heated with stirring at 60° C. for 4 hours. 250 ml of the ethanol was distilled away, and 200 ml of water and 25 g of sodium hydroxide were added to the residue. The resulting mixture was stirred for 1 hour at 60° C. The reaction mixture was allowed to cool, and after addition of 200 ml of concentrated hydrochloric acid, it was further cooled. Solids formed were collected, filtered with heating using 600 ml of acetic acid, and then recrystallized as it is to obtain 98 g of 2-fluoro-4-benzyloxybenzoic acid having a clearing point of 167 to 169° C. A mixture of 59 g of 2-fluoro-4-benzyloxybenzoic acid and 70 ml of thionyl chloride was heated for 6 hours on a water bath maintained at 50° C. Excessive thionyl chloride was distilled away under reduced pressure. On cooling with water, solids were formed. These solids were dispersed in hexane and then filtered to obtain 61 g of solid. This was 2-fluoro-4-benzyloxybenzoic acid chloride. 36 g of 2-fluoro-4-benzyloxybenzoic acid chloride and 27 g of R-(-)-2-octanol were heated with stirring for 3 hours in an atmosphere of nitrogen. The reaction mixture was allowed to cool and then 200 ml of toluene was added. An organic layer was washed with saturated saline water, with 6 N hydrochloric acid, with saturated saline water, with a 2 N sodium hydroxide aqueous solution and then with saturated saline water to make it neutral. The organic layer was dried over anhydrous magnesium sulfate and concentrated to obtain 1'-methylheptyl 2-fluoro-4-benzyloxy-benzoate. The total of 1'-methylheptyl 2-fluoro-4-benzyloxybenzoate was subjected to hydrogenalysis in ethyl acetate by the use of a 2% palladium-carbon catalyst to obtain R-1'-methylheptyl 2-fluoro-4-hydroxy-benzoate.

Workup

  1. temperaturethe resulting mixture was heated
  2. distillation250 ml of the ethanol was distilled away
  3. addition200 ml of water and 25 g of sodium hydroxide were added to the residue
  4. stirringThe resulting mixture was stirred for 1 hour at 60° C
  5. temperatureto cool
  6. additionafter addition of 200 ml of concentrated hydrochloric acid, it
  7. temperaturewas further cooled
  8. customSolids formed
  9. customwere collected
  10. filtrationfiltered
  11. temperaturewith heating
  12. customrecrystallized as it

Sources & evidence

ORD record
ord-015e8e655fd04d55b28e79ad7960192a
Source dataset
uspto-grants-1988_11
Patent number
US04784791

Reaction notes

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