Hydroxyphenylacetic acid → 2-((4-Carboxymethylphenoxy)methyl)benzoic acid

HRID 2247131Notes

Reaction equation

HRID 2247131 reaction equation
[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[C:12]1([C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][O:14]1)=[O:13].C[O-].[Na+].Cl>CN(C=O)C.O.CO>[C:12]([C:21]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:15][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1)([OH:14])=[O:13]

Participants

8

Reactant 4

HCID 127Hydroxyphenylacetic acidHCID 313Hydrochloric AcidHCID 6885Phthalide2×HCID 10942334Sodium Methoxide

Product 1

HCID 122923092-((4-Carboxymethylphenoxy)methyl)benzoic acidYield 82.8%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
130 °C

Procedure

A solution of 4-hydroxyphenylacetic acid (90.0 g, 0.58 mol; assay >98%) and phthalide (85.07 g, 0.63 mol) in DMF (323 g) was heated to an internal temperature of 130° C. The pressure was reduced to 800 mbar and sodium methoxide (224.6 g, 1.25 mol, assay: 30% methanolic solution) was added slowly to the mixture maintaining the internal temperature above 100° C. During the addition methanol was distilled off, and after the addition the distillation was continued under normal pressure until the internal temperature increased to 130° C. again (260 g distillate). After stirring at this temperature for 6.5 h, phthalide (8.5 g, 0.06 mol) was added and the mixture was stirred overnight (16 h). Afterwards the mixture was cooled to 100° C. and hydrolyzed with water (1040 g). After cooling to <10° C., the pH of the mixture was adjusted to pH 1 with hydrochloric acid (163.5 g, 1.43 mol; assay: 32%). The product was filtered off, washed with water (700 g) and dried under vacuum for 15 hours at 60° C. to give crude 4-(2-carboxybenzyloxy)phenylacetic acid (Olo-IM1) (yield: 174.6 g, 0.48 mol, 82.1%; HPLC assay: 78.0%).

Workup

  1. additionwas added slowly to the mixture
  2. temperaturemaintaining the internal temperature above 100° C
  3. distillationwas distilled off
  4. additionafter the addition
  5. distillationthe distillation
  6. stirringthe mixture was stirred overnight (16 h)
  7. temperatureAfter cooling to <10° C.
  8. filtrationThe product was filtered off
  9. washwashed with water (700 g)
  10. customdried under vacuum for 15 hours at 60° C.

Sources & evidence

ORD record
ord-5b7301c466c7472a8459a2f6c20e78a3
Source dataset
uspto-grants-2010_03
Patent number
US07687646B2

Reaction notes

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