Citric Acid → 5-[3-(4-Acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenylamino]-nicotinic acid methyl ester

HRID 2267031Notes

Reaction equation

HRID 2267031 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]=[C:30](Br)[CH:29]=[N:28][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]=[C:30]([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:29]=[N:28][CH:27]=1

Participants

8

Reactant 5

HCID 311Citric AcidHCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 699336Methyl 5-bromopyridine-3-carboxylateHCID 145235601-{4-[(3-Aminophenyl)methoxy]-2-hydroxy-3-propylphenyl}ethan-1-one

Product 1

HCID 685357025-[3-(4-Acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenylamino]-nicotinic acid methyl esterYield 38%

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), 5-bromo-nicotinic acid methyl ester (328 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 yield a residue. Purify the residue by flash chromatography eluting with ethyl acetate:hexanes to yield a yellow solid (250 mg, 38%):1H NMR (DMSO-d6) δ 0.81 (t, 3H), 1.46 (sextet, 2H), 2.57 (m, 5H), 3.86 (s, 3H), 5.25 (s, 2H), 6.72 (d, 1H), 7.03 (d, 1H), 7.08 (d, 1H), 7.24 (bs, 1H), 7.35 (t, 1H), 8.54 (dd, 1H), 8.69 (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
  10. customto yield a residue
  11. customPurify the residue by flash chromatography
  12. washeluting with ethyl acetate

Sources & evidence

ORD record
ord-7a8221713a3945f9b5aa700c2b9e0557
Source dataset
uspto-grants-2010_12
Patent number
US07858646B2

Reaction notes

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