Citric Acid → 3-[3-(4-Acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenylamino]-benzoic acid methyl ester

HRID 2267030Notes

Reaction equation

HRID 2267030 reaction equation
[NH2:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([OH:16])[C:8]=1[CH2:17][CH2:18][CH3:19].[CH3:23][O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28](Br)[CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:23][O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:1][C:2]2[CH:22]=[CH:21][CH:20]=[C:4]([CH2:5][O:6][C:7]3[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([OH:16])[C:8]=3[CH2:17][CH2:18][CH3:19])[CH:3]=2)[CH:27]=1

Participants

8

Reactant 5

HCID 311Citric AcidHCID 10796Cesium carbonateHCID 12070Methyl 3-bromobenzoateHCID 634876Binap, (A+-)-HCID 145235601-{4-[(3-Aminophenyl)methoxy]-2-hydroxy-3-propylphenyl}ethan-1-one

Product 1

HCID 685331563-[3-(4-Acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenylamino]-benzoic acid methyl esterYield 43%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

Combine 1-[4-(3-amino-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanone (500 mg, 1.67 mmol), 3-bromo-benzoic acid methyl ester (326 mg, 1.52 mmol) and cesium carbonate (693 mg, 2.13 mmol) in toluene (25 mL) and stir. Purge reaction vessel with argon. Add BINAP [rac-2,2′-Bis(diphenyl-phosphino)-1,1′-binaphthyl] (142 mg, 0.228 mmol), and palladium acetate (34 mg, 0.152 mmol). Purge reaction vessel with argon. Heat to 100° C. After 18 hours, cool to ambient temperature. Add 10% aqueous citric acid, and extract with ethyl acetate. Combine the organic layers, dry with sodium sulfate, filter and concentrate to dryness. Purify the resulting residue by flash chromatography eluting with ethyl acetate:hexanes to yield the title compound as a white solid (280 mg, 43%): 1H NMR (DMSO-d6) δ 0.81 (t, 3H), 1.46 (sextet, 2H), 2.57 (m, 5H), 3.82 (s, 3H), 5.23 (s, 2H), 6.71 (d, 1H), 6.95 (d, 1H), 7.01 (d, 1H), 7.19 (m, 1H), 7.28-7.41 (m, 4H), 7.65 (m, 1H), 7.81 (d, 1H), 8.49 (bs, 1H), 12.84 (s, 1H).

Workup

  1. customPurge
  2. customreaction vessel with argon
  3. customPurge
  4. customreaction vessel with argon
  5. temperaturecool to ambient temperature
  6. extractionextract with ethyl acetate
  7. dry with materialdry with sodium sulfate
  8. filtrationfilter
  9. concentrationconcentrate to dryness
  10. customPurify the resulting residue by flash chromatography
  11. washeluting with ethyl acetate

Sources & evidence

ORD record
ord-6c06be35bed947ebb3538c518dcb61e0
Source dataset
uspto-grants-2010_12
Patent number
US07858646B2

Reaction notes

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