Methyl iodide → 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1-(3-(methoxymethyl)benzyl)-5,5-dimethylimidazolidine-2,4-dione

HRID 2095077Notes

Reaction equation

HRID 2095077 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])[C:16]([CH3:20])([CH3:19])[N:15]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][OH:29])[CH:23]=4)[C:14]3=[O:30])[CH:10]=[N:9]2)=[C:5]([CH3:31])[O:4][N:3]=1.[H-].[Na+].I[CH3:35]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[N:15]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][O:29][CH3:35])[CH:23]=4)[C:14]3=[O:30])[CH:10]=[N:9]2)=[C:5]([CH3:31])[O:4][N:3]=1

Participants

6

Reactant 3

HCID 6328Methyl iodideHCID 24758Sodium hydrideHCID 533739613-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1-(3-(hydroxymethyl)benzyl)-5,5-dimethylimidazolidine-2,4-dione

Product 1

HCID 533737453-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1-(3-(methoxymethyl)benzyl)-5,5-dimethylimidazolidine-2,4-dioneYield 36%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1-(3-(hydroxymethyl)benzyl)-5,5-dimethylimidazolidine-2,4-dione (Example 12-34) (559 mg, 1.32 mmol) in anhydrous dimethylformamide (10 mL) at 0° C., was added sodium hydride (53 mg, 1.32 mmol), followed by iodomethane (99 ul, 1.58 mmol). The reaction was allowed to warm to room temperature and stirred for about 4 hours. The resulting mixture was diluted with ethyl acetate (40 mL) and ice water (10 mL), The organic phase was collected, dried over anhydrous MgSO4, filtered and then concentrated on the rotovap. The residue was purified by reverse phase HPLC (gradient 10% to 100% methanol/water) and further purified by column chromatography (60% EtOAc in hexane). Yield 36%, colorless gel. 1H NMR (DMSO-d6, 400 MHz): δ1.29 (s, 6H), 2.14 (s, 3H), 2.40 (s, 3H), 3.25 (s, 3H), 4.37 (s, 2H), 4.55 (s, 2H), 5.18 (s, 2H), 7.19 (t, 1H) 7.30 (d, 2H), 7.32 (s, 1H), 7.82 (s, 1H) 8.20 (s, 1H). MS 438 (MH+). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.13 μM.

Workup

  1. customThe organic phase was collected
  2. dry with materialdried over anhydrous MgSO4
  3. filtrationfiltered
  4. concentrationconcentrated on the rotovap
  5. customThe residue was purified by reverse phase HPLC (gradient 10% to 100% methanol/water)
  6. customfurther purified by column chromatography (60% EtOAc in hexane)

Sources & evidence

ORD record
ord-a7157302f8ab4a1b8e09ca116c85989a
Source dataset
uspto-grants-2013_05
Patent number
US08445692B2

Reaction notes

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