Cesium carbonate → 3-((3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-2,4-dioxoimidazolidin-1-yl)methyl)benzoic acid

HRID 1770511Notes

Reaction equation

HRID 1770511 reaction equation
[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:19]COC4C=CC=CC=4)[C:14]3=[O:28])[CH:10]=[N:9]2)=[C:5]([CH3:29])[O:4][N:3]=1.BrC[C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=1)[C:35]([O:37]C)=[O:36].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.Cl>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:19][C:32]4[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=4)[C:35]([OH:37])=[O:36])[C:14]3=[O:28])[CH:10]=[N:9]2)=[C:5]([CH3:29])[O:4][N:3]=1

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 517981Methyl 3-(bromomethyl)benzoateHCID 574224263-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1-(2-phenoxyethyl)imidazolidine-2,4-dione

Product 1

HCID 574224293-((3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-2,4-dioxoimidazolidin-1-yl)methyl)benzoic acidYield 83%

Reagents, catalysts & solvents 2

HCID 313Hydrochloric AcidSolventHCID 6228DimethylformamideSolvent

Procedure

3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (500 mg, 1.8 mmol) (example 10-5), methyl 3-(bromomethyl)benzoate (456 mg, 2 mmol), and cesium carbonate (650 mg, 2 mmol) were stirred in DMF (4 mL) in the microwave reactor at 85° C. for 20 minutes. The reaction was cooled, diluted with 1N aqueous HCl (100 mL) and extracted with ethyl acetate (3×, 75 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The crude ester was dissolved in methanol (5 mL) and aqueous NaOH (50 mL, 10% by wt) was added and the mixture was stirred at ambient temperature for 2 hours. The reaction was acidified with 1N HCl (150 mL) and extracted with ethyl acetate (3×, 75 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated on the rotovap. The free acid was triturated with ethyl acetate/hexanes (1/9) and dried under vacuum to afford 3-((3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-2,4-dioxoimidazolidin-1-yl)methyl)benzoic acid (610.mg, 83%) as a white solid. 1H NMR (DMSO-d6, 400 2.13 (s, 3H), 2.29 (s, 3H), 4.00 (s, 2H), 4.59 (s, 2H), 5.18 (s, 2H), MHz): δ 7.46-7.59 (m, 2H), 7.78 (s, 1H), 7.85-7.88 (m, 2H), 8.18 (s, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 1.8 μM.

Workup

  1. temperatureThe reaction was cooled
  2. extractionextracted with ethyl acetate (3×, 75 mL)
  3. dry with materialThe combined organic extracts were dried over sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated
  6. dissolutionThe crude ester was dissolved in methanol (5 mL)
  7. additionaqueous NaOH (50 mL, 10% by wt) was added
  8. extractionextracted with ethyl acetate (3×, 75 mL)
  9. dry with materialThe combined organic extracts were dried over sodium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated on the rotovap
  12. customThe free acid was triturated with ethyl acetate/hexanes (1/9)
  13. customdried under vacuum

Sources & evidence

ORD record
ord-952e8d15c49248f9aec211b58e1c47f5
Source dataset
uspto-grants-2016_02
Patent number
US09247759B2

Reaction notes

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