Sodium Iodide → 4-[2',4'-Dichloro-3'-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-4-yloxy]-butyric acid

HRID 2235284Notes

Reaction equation

HRID 2235284 reaction equation
[CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([CH2:12][C:13]3[C:14]([Cl:27])=[C:15]([C:20]4[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=4)[CH:16]=[CH:17][C:18]=3[Cl:19])[C:8]2=[O:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[I-].[Na+].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:38][CH2:39][CH2:40][C:41]([O:43]C(C)(C)C)=[O:42]>C1COCC1>[Cl:27][C:14]1[C:13]([CH2:12][CH:9]2[CH2:10][CH2:11][N:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:8]2=[O:28])=[C:18]([Cl:19])[CH:17]=[CH:16][C:15]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[CH:22][CH:21]=1

Participants

6

Reactant 4

HCID 5238Sodium IodideHCID 10796Cesium carbonateHCID 2757253tert-Butyl 4-bromobutanoateHCID 592993283-(3-(4-Hydroxyphenyl)-2,6-dichlorobenzyl)-1-cyclohexylpyrrolidin-2-one

Product 1

HCID 592994774-[2',4'-Dichloro-3'-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-4-yloxy]-butyric acidYield 66%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

Place 1-cyclohexyl-3-(2,4-dichloro-4′-hydroxy-biphenyl-3-ylmethyl)-pyrrolidin-2-one (Example 113) (200 mg, 0.5 mmol), sodium iodide (72 mg, 0.5 mmol), and cesium carbonate (1.25 g, 3.8 mmol) in THF (10 mL). Add tert-butyl 4-bromobutanoate (213 mg, 1.0 mmol) and stir at room temperature for 3 hours. Add dichloromethane and wash with water. Dry over sodium sulfate, filter, and concentrate. Dissolve residue in dichloromethane (5 mL) and TFA (5 mL) and stir for 30 minutes. Remove solvent and dissolve product in IM NaOH. The deprotonated carboxylic acid does not go into the aqueous layer. Bring the pH ˜2 with 6M HCl and extract with dichloromethane. Dry over sodium sulfate, filter, and concentrate. Purify by silica gel (dichloromethane-5% methanol in dichloromethane) affords 158 mg (66%) the title compound as a brown solid: Mass spectrum (apci) m/z=504.2 (M+H).

Workup

  1. washAdd dichloromethane and wash with water
  2. dry with materialDry over sodium sulfate
  3. filtrationfilter
  4. concentrationconcentrate
  5. dissolutionRemove solvent and dissolve product in IM NaOH
  6. extractionBring the pH ˜2 with 6M HCl and extract with dichloromethane
  7. dry with materialDry over sodium sulfate
  8. filtrationfilter
  9. concentrationconcentrate
  10. customPurify by silica gel (dichloromethane-5% methanol in dichloromethane)

Sources & evidence

ORD record
ord-fbd7fd4b9ac64fbabde67780d8f8566e
Source dataset
uspto-grants-2010_05
Patent number
US07713979B2

Reaction notes

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