反応 #2286297

反応方程式

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

収率 24.7%

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

収率 24.7%

溶媒

N,N-dimethyl acetamide

water

反応条件

後処理

1. 1
   温度The reaction was cooled to room temperature
2. 2
   抽出extracted with ethyl acetate (3×100 mL)
3. 3
   洗浄were washed with a 1N aqueous sodium hydroxide solution (1×150 mL)
4. 4
   乾燥The organic layer was dried with sodium sulfate
5. 5
   ろ過filtered
6. 6
   濃縮concentrated
7. 7
   その他The resulting residue was purified by flash chromatography (Biotage 40M)
8. 8
   洗浄eluted with 15% ethyl acetate in hexanes
9. 9
   その他The desired fractions were collected
10. 10
    濃縮concentrated under vacuum
11. 11
    ろ過filtered
12. 12
    workup.ADDITIONThe solid was then diluted with a 1:1 mixture of isopropyl acetate
13. 13
    温度The mixture was heated
14. 14
    温度to reflux
15. 15
    温度cooled to room temperature
16. 16
    その他The solvent was decanted
17. 17
    ろ過filtered
18. 18
    その他dried under high vacuum overnight
19. 19
    濃縮The filtrate was concentrated
20. 20
    workup.ADDITIONThe resulting solid was then diluted with a 1:1 mixture of isopropyl acetate
21. 21
    温度The mixture was heated
22. 22
    温度to reflux
23. 23
    温度cooled to room temperature
24. 24
    その他The solvent was decanted
25. 25
    ろ過filtered
26. 26
    その他to afford a second crop of solid which
27. 27
    その他was dried under high vacuum overnight

実験手順

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

出典