반응 #2286297

반응 방정식

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

수율 24.7%

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

수율 24.7%

용매

N,N-dimethyl acetamide

water

반응 조건

후처리

1. 1
   온도The reaction was cooled to room temperature
2. 2
   추출extracted with ethyl acetate (3×100 mL)
3. 3
   세척were washed with a 1N aqueous sodium hydroxide solution (1×150 mL)
4. 4
   건조The organic layer was dried with sodium sulfate
5. 5
   여과filtered
6. 6
   농축concentrated
7. 7
   기타The resulting residue was purified by flash chromatography (Biotage 40M)
8. 8
   세척eluted with 15% ethyl acetate in hexanes
9. 9
   기타The desired fractions were collected
10. 10
    농축concentrated under vacuum
11. 11
    여과filtered
12. 12
    workup.ADDITIONThe solid was then diluted with a 1:1 mixture of isopropyl acetate
13. 13
    온도The mixture was heated
14. 14
    온도to reflux
15. 15
    온도cooled to room temperature
16. 16
    기타The solvent was decanted
17. 17
    여과filtered
18. 18
    기타dried under high vacuum overnight
19. 19
    농축The filtrate was concentrated
20. 20
    workup.ADDITIONThe resulting solid was then diluted with a 1:1 mixture of isopropyl acetate
21. 21
    온도The mixture was heated
22. 22
    온도to reflux
23. 23
    온도cooled to room temperature
24. 24
    기타The solvent was decanted
25. 25
    여과filtered
26. 26
    기타to afford a second crop of solid which
27. 27
    기타was dried under high vacuum overnight

실험 절차

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

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