Tetrahydrofuran → 2-(2-(4-Fluorobenzyl)phenyl)acetic acid

HRID 2378496Notes

Reaction equation

HRID 2378496 reaction equation
[F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13]Cl)=[CH:4][CH:3]=1.C1COCC1.C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:51]([O-:54])(=[O:53])C.[Na+]>CC([O-])=O.CC([O-])=O.[Pd+2].O>[F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13][C:51]([OH:54])=[O:53])=[CH:4][CH:3]=1

Participants

7

Reactant 4

HCID 8028TetrahydrofuranHCID 812191,3-Bis(diphenylphosphino)propaneHCID 517045Sodium AcetateHCID 16656029[2-(4-Fluoro-benzyl)-phenyl]-chloromethane

Product 1

HCID 112302882-(2-(4-Fluorobenzyl)phenyl)acetic acidYield 91%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolvent

Conditions

Temperature
80 °C

Procedure

[2-(4-fluoro-benzyl)-phenyl]-chloromethane (1 eq.), THF (1 L/mol), water (0.7 L/mol), Pd(OAc)2 (1.3 mol %), dppp (2.6 mol %) and sodium acetate (2.5 eq.) were placed in a inertized reactor. The reaction mixture is placed under a CO pressure of 4 bars and allowed to stir at 80° C. for 20 hours. The organic layer is separated and evaporated under pressure. Toluene (0.75 L/mol) is added to the residue and the carboxylic acid is extracted with a 2 N solution of sodium hydroxide (0.75 L/mol). The black particles of palladium are removed by filtration over Celite. The water layer is placed in a flask and acetic acid (0.9 L/mol) is added. The mixture is warmed up to 80° C. then allowed to spontaneously cool down. The crystallisation starts around 50° C. The crystals are filtered off at room temperature, washed with water and dried to give black [2-(4-fluoro-benzyl)-phenyl]-acetic acid (91%). Treatment of 5 g of black [2-(4-fluoro-benzyl)-phenyl]-acetic acid with charcoal in 25 ml of a mixture of acetic acid and water (7/3) allows the isolation of pure white crystals of [2-(4-fluoro-benzyl)-phenyl]-acetic acid. This step can be performed before the first addition of acetic acid.

Workup

  1. customThe organic layer is separated
  2. customevaporated under pressure
  3. additionToluene (0.75 L/mol) is added to the residue
  4. extractionthe carboxylic acid is extracted with a 2 N solution of sodium hydroxide (0.75 L/mol)
  5. customThe black particles of palladium are removed by filtration over Celite
  6. customThe water layer is placed in a flask
  7. additionacetic acid (0.9 L/mol) is added
  8. temperatureThe mixture is warmed up to 80° C.
  9. temperatureto spontaneously cool down
  10. customThe crystallisation
  11. customstarts around 50° C
  12. filtrationThe crystals are filtered off at room temperature
  13. washwashed with water
  14. customdried

Sources & evidence

ORD record
ord-2be0482995274fff861e0a3dc8110627
Source dataset
uspto-grants-2008_12
Patent number
US07470809B2

Reaction notes

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