Réaction #1244405

Équation de réaction

2,6-dibromo-4-(3-hydroxy-propyl)-phenol

2,6-Dibromo-4-(3-hydroxy-propyl)-phenol

potassium tert-butoxide

3,6-Dichloro-4-isopropyl pyridazine

3,6-dichloro-4-isopropyl pyridazine

→

3-[3,5-dibromo-4-(6-chloro-5-isopropyl-pyridazin-3-yloxy)-phenyl]-propan-1-ol

Rendement 24.7%

3-[3,5-Dibromo-4-(6-chloro-5-isopropyl-pyridazin-3-yloxy)-phenyl]-propan-1-ol

Rendement 24.7%

Solvants

N,N-dimethyl acetamide

water

Conditions de réaction

Traitement

1. 1
   TempératureThe reaction was cooled to room temperature
2. 2
   Extractionextracted with ethyl acetate (3×100 mL)
3. 3
   Lavagewere washed with a 1N aqueous sodium hydroxide solution (1×150 mL)
4. 4
   SéchageThe organic layer was dried with sodium sulfate
5. 5
   Filtrationfiltered
6. 6
   Concentrationconcentrated
7. 7
   AutreThe resulting residue was purified by flash chromatography (Biotage 40M)
8. 8
   Lavageeluted with 15% ethyl acetate in hexanes
9. 9
   AutreThe desired fractions were collected
10. 10
    Concentrationconcentrated under vacuum
11. 11
    Filtrationfiltered
12. 12
    workup.ADDITIONThe solid was then diluted with a 1:1 mixture of isopropyl acetate
13. 13
    TempératureThe mixture was heated
14. 14
    Températureto reflux
15. 15
    Températurecooled to room temperature
16. 16
    AutreThe solvent was decanted
17. 17
    Filtrationfiltered
18. 18
    Autredried under high vacuum overnight
19. 19
    ConcentrationThe filtrate was concentrated
20. 20
    workup.ADDITIONThe resulting solid was then diluted with a 1:1 mixture of isopropyl acetate
21. 21
    TempératureThe mixture was heated
22. 22
    Températureto reflux
23. 23
    Températurecooled to room temperature
24. 24
    AutreThe solvent was decanted
25. 25
    Filtrationfiltered
26. 26
    Autreto afford a second crop of solid which
27. 27
    Autrewas dried under high vacuum overnight

Mode opératoire

A mixture of 2,6-dibromo-4-(3-hydroxy-propyl)-phenol (20) (5.0 g, 16.3 mmol) in N,N-dimethyl acetamide (8 mL) was treated with potassium tert-butoxide (1.74 g, 15.48 mmol) under nitrogen at room temperature. The suspension was heated to 100° C. for 15 min and turned brown in color. 3,6-Dichloro-4-isopropyl pyridazine (7) (2.47 g, 12.9 mmol) was added to the suspension and the reaction was stirred at 140° C. for 24 h. The reaction was cooled to room temperature, diluted with water (180 mL) and extracted with ethyl acetate (3×100 mL). The organic layers were combined and were washed with a 1N aqueous sodium hydroxide solution (1×150 mL), followed by a saturated aqueous sodium chloride solution (1×150 mL). The organic layer was dried with sodium sulfate, filtered and concentrated. The resulting residue was purified by flash chromatography (Biotage 40M) eluted with 15% ethyl acetate in hexanes, followed by 25% ethyl acetate in hexanes, followed by 50% ethyl acetate in hexanes. The desired fractions were collected and concentrated under vacuum. The resulting solid was slurried in cold acetonitrile and filtered. The solid was then diluted with a 1:1 mixture of isopropyl acetate:methyl tert-butyl ether (20 mL). The mixture was heated to reflux and then cooled to room temperature. The solvent was decanted. The solid was slurried in heptane, filtered and dried under high vacuum overnight. The filtrate was concentrated. The resulting solid was then diluted with a 1:1 mixture of isopropyl acetate: methyl tert-butyl ether (20 mL). The mixture was heated to reflux and then cooled to room temperature. The solvent was decanted and the solid was slurried in heptane and filtered to afford a second crop of solid which was dried under high vacuum overnight. The solids were combined to afford 3-[3,5-dibromo-4-(6-chloro-5-isopropyl-pyridazin-3-yloxy)-phenyl]-propan-1-ol (21) (1.48 g, 20%) as a white solid; LRMS for C16H17Br2ClN2O2 (M+H) m/z=465. Molecular Weight=464.5871; Exact Mass=461.9345

Source