反应详情

温度

80 °C

1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine-hydrochloride (100 mg, 0.44 mmol), 2-(bromomethyl)benzonitrile (115 mg, 0.6 mmol), and triethylamine (0.5 mL, 3.5 mmol) in DMF (3 mL) were irradiated and stirred in the microwave reactor at 80° C. for 10 minutes. The reaction was cooled, diluted with H2O (50 mL) and extracted with ethyl acetate (3×, 30 mL). The combined organic extracts were dried over sodium sulfate and concentrated on the rotovap. The residue was dissolved in ethanol (70 mL), H2O (3 mL) and acetic acid (1 mL) and the mixture was refluxed for 2 hours. The solution was concentrated on the rotovap, taken up in methanol (3 mL) and purified by reversed phase HPLC in 3-1 mL aliquots (5 to 95% acetonitrile in H2O: 16 minute gradient). The pure fractions were combined and concentrated on the rotovap. The residue was triturated with ethyl acetate/hexanes (1/9) to afford 2-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)isoindolin-1-one (85 mg, 61%) as a pure white solid. 1H NMR (DMSO-d6, 400 MHz): δ2.18 (s, 3H), 2.43 (s, 3H), 4.97 (s, 2H), 5.18 (s, 2H), 7.58-7.68 (m, 3H), 7.77 (s, 1H), 8.10 (d, J=8 Hz, 1H), 8.27 (s, 1H), 9.19 (bs, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 value greater than 30 μM.

1. temperatureThe reaction was cooled
2. extractionextracted with ethyl acetate (3×, 30 mL)
3. dry with materialThe combined organic extracts were dried over sodium sulfate
4. concentrationconcentrated on the rotovap
5. dissolutionThe residue was dissolved in ethanol (70 mL)
6. temperatureH2O (3 mL) and acetic acid (1 mL) and the mixture was refluxed for 2 hours
7. concentrationThe solution was concentrated on the rotovap
8. custompurified by reversed phase HPLC in 3-1 mL aliquots (5 to 95% acetonitrile in H2O: 16 minute gradient)
9. concentrationconcentrated on the rotovap
10. customThe residue was triturated with ethyl acetate/hexanes (1/9)