1,1'-Carbonyldiimidazole → Hydroxy-bis-(3-methoxy-phenyl)-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester

HRID 660072Notes

Reaction equation

HRID 660072 reaction equation
[OH:1][C:2]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1)[C:3]([OH:5])=[O:4].C1N=CN(C(N2C=NC=C2)=O)C=1.[N:34]12[CH2:41][CH2:40][CH:37]([CH2:38][CH2:39]1)[C@@H:36](O)[CH2:35]2>C1COCC1.C(OCC)(=O)C>[N:34]12[CH2:41][CH2:40][CH:37]([CH2:38][CH2:39]1)[C@@H:36]([O:4][C:3](=[O:5])[C:2]([OH:1])([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)[CH2:35]2

Participants

6

Reactant 3

HCID 682631,1'-CarbonyldiimidazoleHCID 914043-Quinuclidinol, (-)-HCID 585026Hydroxy-bis-(3-methoxyphenyl)acetic acid2×

Product 1

HCID 86627867Hydroxy-bis-(3-methoxy-phenyl)-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a stirred solution of hydroxy-bis-(3-methoxy-phenyl)-acetic acid (Intermediate J) (1.384 g, 4.8 mmol) in dry THF (2.0 ml) is added CDI (0.870 g, 5.3 mmol) and the mixture is heated to reflux for 90 minutes. (R)-1-aza-bicyclo[2.2.2]octan-3-ol (0.67 g, 5.3 mmol) is then added. After refluxing for 16 hours, the reaction mixture is diluted with ethyl acetate and washed with water. The organic layer is then extracted with 2M HCl and the aqueous portion is treated with potassium carbonate to basify the solution. The aqueous portion is re-extracted with ethyl acetate. The organic portions are combined, dried over MgSO4 and concentrated in vacuo to yield a crude residue which is purified using C-18 reverse phase column chromatography (eluent: water-acetonitrile), to afford the titled compound.

Workup

  1. temperaturethe mixture is heated
  2. temperatureto reflux for 90 minutes
  3. temperatureAfter refluxing for 16 hours
  4. washwashed with water
  5. extractionThe organic layer is then extracted with 2M HCl
  6. additionthe aqueous portion is treated with potassium carbonate
  7. extractionThe aqueous portion is re-extracted with ethyl acetate
  8. dry with materialdried over MgSO4
  9. concentrationconcentrated in vacuo
  10. customto yield a crude residue which
  11. customis purified

Sources & evidence

ORD record
ord-98ff7986f7d846c1a0ebaac6d465d72c
Source dataset
uspto-grants-2011_12
Patent number
US08084463B2

Reaction notes

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