反应详情

温度

0 °C

To a suspension of 3-(8-(2-chlorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazin-3-yl)-4-methylbenzoic acid (100 mg, 0.25 mmol; prepared by the general method shown in scheme 2) in DCM at 0° C. was added oxalyl chloride (43.7 μl, 0.49 mmol) followed by a drop of DMF. The reaction was stirred at 0° C. for 15 min then warmed to RT for 1 h. The volatile solvents were removed under reduced pressure and the residue was dissolved in DCM. To the reaction mixture was added 3-aminoisoxazole (54.6 μl, 0.74 mmol) and N,N-diisopropylethylamine (42.9 μl, 0.25 mmol). After the reaction mixture was stirred at RT for 3 h, the solvent was then removed in vacuo. The residual crude material was purified with Reverse phase-HPLC [elution gradient of 10-50% of (0.1% TFA in acetonitrile) in (0.1% of TFA) in water] and the fractions containing the product were combined and concentrated in vacuo. The remaining crude mixture was stirred with EtOAc and sat. Na2CO3. The organic layer was separated and washed with brine, separated, then dried with sodium sulfate and concentrated to give 3-(8-(2-chlorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazin-3-yl)-N-(isoxazol-3-yl)-4-methylbenzamide (33.0 mg) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.43 (1H, s), 9.48 (1H, s), 8.81 (1H, s), 8.24 (1H, s), 7.95-8.10 (2H, m), 7.76-7.86 (1H, m), 7.56-7.74 (3H, m), 7.46 (1H, d, J=8.0 Hz), 7.05 (1H, s), 3.12 (3H, s), 2.24 (3H, s); Mass Found: LC-MS (ESI): m/e=472/474

1. customprepared by the general method
2. customat 0° C.
3. temperaturethen warmed to RT for 1 h
4. customThe volatile solvents were removed under reduced pressure
5. dissolutionthe residue was dissolved in DCM
6. stirringAfter the reaction mixture was stirred at RT for 3 h
7. customthe solvent was then removed in vacuo
8. customThe residual crude material was purified with Reverse phase-HPLC [elution gradient of 10-50% of (0.1% TFA in acetonitrile) in (0.1% of TFA) in water]
9. additionthe fractions containing the product
10. concentrationconcentrated in vacuo
11. stirringThe remaining crude mixture was stirred with EtOAc and sat. Na2CO3
12. customThe organic layer was separated
13. washwashed with brine
14. customseparated
15. dry with materialdried with sodium sulfate
16. concentrationconcentrated