Citric Acid → 3-[3-(4-Acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenylamino]-benzonitrile

HRID 2267036Notes

Reaction equation

HRID 2267036 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].Br[C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[C:27]#[N:28].C(=O)([O-])[O-].[Cs+].[Cs+].C1OCCOCCOCCOCCOCCOC1.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>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]2[CH:3]=[C:2]([NH:1][C:24]3[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=3)[C:27]#[N:28])[CH:22]=[CH:21][CH:20]=2)=[C:8]([CH2:17][CH2:18][CH3:19])[C:9]=1[OH:16])(=[O:15])[CH3:14]

Participants

9

Reactant 6

HCID 311Citric AcidHCID 10796Cesium carbonateHCID 233813-BromobenzonitrileHCID 2855718-Crown-6HCID 634876Binap, (A+-)-HCID 145235601-{4-[(3-Aminophenyl)methoxy]-2-hydroxy-3-propylphenyl}ethan-1-one

Product 1

HCID 685391703-[3-(4-Acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenylamino]-benzonitrileYield 68%

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 (1.65 g, 5.51 mmol), 3-bromo-benzonitrile (912 mg, 5.01 mmol), cesium carbonate (2.29 g, 7.01 mmol), and 18-crown-6 (132 mg, 0.501 mmol) in toluene (25 mL) and stir. Purge reaction vessel with argon. Add BINAP [rac-2,2′-bis(diphenyl-phosphino)-1,1′-binaphthyl] (468 mg, 0.752 mmol), and palladium acetate (112 mg, 0.501 mmol). Purge reaction vessel with argon. Heat to 100° C. for 18 hours and 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 30% ethyl acetate:hexanes to yield a yellow oil (1.36 g, 68%): 1H NMR (CDCl3) δ 0.92 (t, 3H), 1.56 (sextet, 2H), 2.56 (s, 3H), 2.69 (t, 2H), 5.15 (s, 2H), 5.86 (bs, 1H), 6.49 (d, 1H), 7.06 (m, 2H), 7.15-7.21 (m, 3H), 7.27-7.37 (m, 3H), 7.59 (d, 1H), 12.75 (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 30% ethyl acetate

Sources & evidence

ORD record
ord-5051ca7edf344e9f96764c7df29e2d30
Source dataset
uspto-grants-2010_12
Patent number
US07858646B2

Reaction notes

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