反应详情

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.

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