Reaction #2286324

Reaction equation

hydrochloric acid

hydrochloric acid

(6-chloro-5-isopropyl-pyridazin-3-yl)-[2,6-dibromo-4-(tetrahydro-pyran-2-yloxymethyl)-phenyl]-acetonitrile

sodium acetate

→

6-(2,6-dibromo-4-chloromethyl-benzyl)-4-isopropyl-pyridazin-3-one

Yield 36.0%

6-(2,6-Dibromo-4-chloromethyl-benzyl)-4-isopropyl-pyridazin-3-one

Yield 36.0%

Solvents

acetic acid

ethyl acetate

acetic acid

Conditions

Workup

1. 1
   Temperaturewas heated
2. 2
   Temperatureto reflux for 2.5 h
3. 3
   Temperatureheated
4. 4
   Temperatureto reflux for 18 h
5. 5
   Temperatureheated
6. 6
   Temperatureto reflux for an additional 24 h
7. 7
   WashThis solution was washed with a saturated aqueous sodium chloride solution (2×50 mL)
8. 8
   Dryinga saturated aqueous sodium carbonate solution (1×100 mL), dried with magnesium sulfate
9. 9
   Filtrationfiltered
10. 10
    Concentrationconcentrated under vacuum
11. 11
    workup.ADDITIONThe resulting brown oil was treated with glacial acetic acid (1.0 mL) and concentrated hydrochloric acid (6.0 mL)
12. 12
    Temperaturewas heated
13. 13
    Temperatureto reflux for 3 d
14. 14
    TemperatureAt this time, the reaction was cooled to 25° C.
15. 15
    workup.ADDITIONdiluted with ethyl acetate (150 mL)
16. 16
    WashThis solution was washed with a saturated aqueous sodium chloride solution (2×50 mL)
17. 17
    Dryinga saturated aqueous sodium carbonate solution (1×100 mL), dried with magnesium sulfate
18. 18
    Filtrationfiltered
19. 19
    Concentrationconcentrated under vacuum

Procedure

A mixture of (6-chloro-5-isopropyl-pyridazin-3-yl)-[2,6-dibromo-4-(tetrahydro-pyran-2-yloxymethyl)-phenyl]-acetonitrile (61) (332.8 mg, 0.61 mmol) and sodium acetate (103.8 mg, 1.26 mmol) in glacial acetic acid (2.7 mL) was heated to reflux for 2.5 h. The reaction was then treated with concentrated hydrochloric acid (2.0 mL) and heated to reflux for 18 h. At this time, the reaction was treated with more concentrated hydrochloric acid (6.0 mL) and additional glacial acetic acid (3.0 mL) and heated to reflux for an additional 24 h. The reaction was then cooled to 25° C. and diluted with ethyl acetate (150 mL). This solution was washed with a saturated aqueous sodium chloride solution (2×50 mL) and a saturated aqueous sodium carbonate solution (1×100 mL), dried with magnesium sulfate, filtered, and concentrated under vacuum. The resulting brown oil was treated with glacial acetic acid (1.0 mL) and concentrated hydrochloric acid (6.0 mL) and was heated to reflux for 3 d. At this time, the reaction was cooled to 25° C. and diluted with ethyl acetate (150 mL). This solution was washed with a saturated aqueous sodium chloride solution (2×50 mL) and a saturated aqueous sodium carbonate solution (1×100 mL), dried with magnesium sulfate, filtered, and concentrated under vacuum. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 2/1 hexanes/ethyl acetate) afforded 6-(2,6-dibromo-4-chloromethyl-benzyl)-4-isopropyl-pyridazin-3-one (62) (96.3 mg, 36%) as an off-white solid; LRMS for C15H15Br2ClN2O (M+H) at m/z=433. Molecular Weight=434.5606; Exact Mass=431.9240

Source