反应详情

温度

70 °C

To a suspension of 4-(5-(4-chlorophenyl)-3-oxo-2,3-dihydropyridazin-4-yl)benzonitrile (2.21 gm, 7.2 mmol) in 30 ml of methanol at rt was added LiOH monohydrate (0.45, 10.8 mmol). The resulting mixture was heated to 70° C. and stirred at this temperature for 15 min. Br2 (2.3 g, 14.4 mmol) was then carefully added dropwise to the reaction mixture. After addition was complete, the color of Br2 disappeared after 2 minutes. HPLC indicated that the reaction had proceeded to 40% completion. Additional Br2 (˜0.8 g, 5 mmol) was then added followed by additional LiOH monohydrate (0.21 g, 5 mmol). The Br2 was consumed within 2 minutes after addition. The reaction was then cooled to rt and the solvent was removed under reduced pressure. The resulting residue was reconcentrated from acetone (2×20 ml). To the resulting light brown residue was added 20 mL DMF, followed by addition of LiOH monohydrate (0.612 g, 14.40 mmol) and 3-(chloromethyl)-2-methyl-6-(trifluoromethyl)pyridine (1.65 gm, 7.91 mmol) at rt under Ar. The reaction mixture was heated to 70° C. and stirred at this temperature for 1 hr. After this time, the solution was cooled to rt and diluted with water (50 ml) and EtOAc (50 ml) and stirred for 10 minutes. The layers were separated and organic phase was washed with saturated aqueous NaCl (100 mL). The organic layer was then slurried with MgSO4 to remove excess water, filtered and concentrated to give the crude product. The crude product was purified using an automated column chromatography system (ISCO, 120 gm silica gel) eluting with a gradient of 20%-80% EtOAc/Hex to give product as off-white solid (3.27 gm, 81% yield). HPLC retention time (method B) 3.91 min; LCMS (M+H)=561.0.

1. additionAfter addition
2. customThe Br2 was consumed within 2 minutes
3. additionafter addition
4. temperatureThe reaction was then cooled to rt
5. customthe solvent was removed under reduced pressure
6. additionTo the resulting light brown residue was added 20 mL DMF
7. temperatureThe reaction mixture was heated to 70° C.
8. stirringstirred at this temperature for 1 hr
9. temperatureAfter this time, the solution was cooled to rt
10. stirringstirred for 10 minutes
11. customThe layers were separated
12. washorganic phase was washed with saturated aqueous NaCl (100 mL)
13. customto remove excess water
14. filtrationfiltered
15. concentrationconcentrated
16. customto give the crude product
17. customThe crude product was purified
18. washeluting with a gradient of 20%-80% EtOAc/Hex