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

Temperature

90 °C

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.

1. temperatureThe reaction was heated at 90° C. for 17 h
2. customThe organic layer was separated
3. washwashed with water (2×400 mL)
4. concentrationconcentrated to a volume of ˜200 mL
5. additionThis solution was diluted with toluene (800 mL)
6. distillationdistilled
7. customto remove ˜300 mL of solvent
8. temperatureThe remaining solution was cooled to 80° C.
9. temperatureThis mixture was heated
10. distillationwas distilled azeotropically
11. concentrationAt this time, the reaction was concentrated under vacuum to ˜200 mL
12. additiondiluted with glacial acetic acid (800 mL)
13. concentrationconcentrated
14. customto remove ˜300 mL of solvent
15. temperatureheated
16. temperatureto reflux for 6 h
17. temperatureAt this time, the reaction was cooled to room temperature
18. temperatureThis mixture was warmed to 60° C.
19. temperaturecooled to room temperature
20. filtrationThe resulting solid was collected by filtration
21. washwashed with a 1:1 mixture of glacial acetic acid
22. customdried under house vacuum
23. customdried at 55° C. in a vacuum oven overnight

ORD record

ord-cc1e025224c6453ebcc807d9c5da30a3

Source dataset

uspto-grants-2016_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

USRE046024E1