반응 #635320

반응 방정식

1-(3-(bromomethyl)benzyl)-3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione

dimethylamine

sodium hydride

3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione

1,3-bis(bromomethyl)benzene

cesium carbonate

→

1-(3-((dimethylamino)methyl)benzyl)-3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione

수율 13.0%

용매

ethanol

THF

DMF

반응 조건

후처리

1. 1
   기타irradiated in the microwave reactor at 165° C. for 5 minutes
2. 2
   기타salt precipitate was removed by filtration
3. 3
   workup.ADDITIONThe clear solution containing crude product
4. 4
   농축was concentrated
5. 5
   workup.DISSOLUTIONredissolved in ethyl acetate
6. 6
   세척The organic solution was washed with water
7. 7
   건조The organic layer was dried over sodium sulfate
8. 8
   기타evaporated
9. 9
   기타to give the crude product which
10. 10
    기타was carried forward to the next step without further purification or characterization
11. 11
    기타was purified by HPLC (10-95% Acetonitrile/Water, 25 minutes)

실험 절차

3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) (275 mg, 1 mmol) 1,3-bis(bromomethyl)benzene (263 mg, 1 mmol), and cesium carbonate (325 mg, 1 mmol) were dissolved in 2 mL DMF and irradiated in the microwave reactor at 165° C. for 5 minutes. The reaction was cooled to room temperature, and salt precipitate was removed by filtration. The clear solution containing crude product was concentrated and redissolved in ethyl acetate. The organic solution was washed with water twice followed by brine. The organic layer was dried over sodium sulfate and evaporated to give the crude product which was carried forward to the next step without further purification or characterization. 1-(3-(bromomethyl)benzyl)-3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 42a) (152 mg, 0.3 mmol), dimethylamine (2 M solution in THF) (1.5 mL, 3 mmol), and sodium hydride (9 mg, 0.36 mmol) were dissolved in 1 mL anhydrous THF. The reaction was placed in a microwave reactor for 5 minutes at 120° C. The crude product was redissolved in 2 mL ethanol and was purified by HPLC (10-95% Acetonitrile/Water, 25 minutes) to afford 1-(3-((dimethylamino)methyl)benzyl)-3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (16 mg, 13%). MS M+H calculated 423.1; found 423.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 1.2 uM.

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