反応 #2286326

反応方程式

phthalic anhydride

3,6-dichloro-4-isopropyl-pyridazine

sodium chloride

sodium acetate

4-amino-2,6-dichloro-phenol

potassium tert-butoxide

→

2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-isoindole-1,3-dione

収率 68.0%

溶媒

water

methyl tert-butyl ether

N,N-dimethylacetamide

water

反応条件

後処理

1. 1
   温度The reaction was heated at 90° C. for 17 h
2. 2
   その他The organic layer was separated
3. 3
   洗浄washed with water (2×400 mL)
4. 4
   濃縮concentrated to a volume of ˜200 mL
5. 5
   workup.ADDITIONThis solution was diluted with toluene (800 mL)
6. 6
   workup.DISTILLATIONdistilled
7. 7
   その他to remove ˜300 mL of solvent
8. 8
   温度The remaining solution was cooled to 80° C.
9. 9
   温度This mixture was heated
10. 10
    workup.DISTILLATIONwas distilled azeotropically
11. 11
    濃縮At this time, the reaction was concentrated under vacuum to ˜200 mL
12. 12
    workup.ADDITIONdiluted with glacial acetic acid (800 mL)
13. 13
    濃縮concentrated
14. 14
    その他to remove ˜300 mL of solvent
15. 15
    温度heated
16. 16
    温度to reflux for 6 h
17. 17
    温度At this time, the reaction was cooled to room temperature
18. 18
    温度This mixture was warmed to 60° C.
19. 19
    温度cooled to room temperature
20. 20
    ろ過The resulting solid was collected by filtration
21. 21
    洗浄washed with a 1:1 mixture of glacial acetic acid
22. 22
    その他dried under house vacuum
23. 23
    その他dried at 55° C. in a vacuum oven overnight

実験手順

A mixture of 4-amino-2,6-dichloro-phenol (50 g, 280.8 mmol) and potassium tert-butoxide (33.16 g, 280.8 mmol) in N,N-dimethylacetamide (200 mL) was heated to 90° C. The resulting solution was then treated with 3,6-dichloro-4-isopropyl-pyridazine (55.31 g, 280.8 mmol). The reaction was heated at 90° C. for 17 h. At this time, the reaction was diluted with methyl tert-butyl ether (700 mL) and a saturated aqueous sodium chloride solution (800 mL). The organic layer was separated, washed with water (2×400 mL) and concentrated to a volume of ˜200 mL. This solution was diluted with toluene (800 mL) and then distilled to remove ˜300 mL of solvent. The remaining solution was cooled to 80° C. and was treated with phthalic anhydride (42.01 g, 280.8 mmol). This mixture was heated to reflux for 4 h while water was distilled azeotropically. At this time, the reaction was concentrated under vacuum to ˜200 mL, diluted with glacial acetic acid (800 mL) and then concentrated to remove ˜300 mL of solvent. The reaction was treated with sodium acetate (46.06 g, 561.6 mmol) and heated to reflux for 6 h. At this time, the reaction was cooled to room temperature and diluted with water (500 mL). This mixture was warmed to 60° C., stirred for 30 min and then cooled to room temperature. The resulting solid was collected by filtration, washed with a 1:1 mixture of glacial acetic acid:water (300 mL) followed by water (150 mL), dried under house vacuum and then dried at 55° C. in a vacuum oven overnight to afford 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-isoindole-1,3-dione (84.8 g, 68%) as an off-white solid; ES(+)-LRMS for C21H15Cl2N3O4 (M+H)+ at m/z=444. Exact Mass=443.0440; Molecular Weight=444.28.

出典