反应 #2286297

反应方程式

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

收率 24.7%

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

收率 24.7%

溶剂

N,N-dimethyl acetamide

water

反应条件

后处理

1. 1
   温度The reaction was cooled to room temperature
2. 2
   萃取extracted with ethyl acetate (3×100 mL)
3. 3
   洗涤were washed with a 1N aqueous sodium hydroxide solution (1×150 mL)
4. 4
   干燥The organic layer was dried with sodium sulfate
5. 5
   过滤filtered
6. 6
   浓缩concentrated
7. 7
   其他The resulting residue was purified by flash chromatography (Biotage 40M)
8. 8
   洗涤eluted with 15% ethyl acetate in hexanes
9. 9
   其他The desired fractions were collected
10. 10
    浓缩concentrated under vacuum
11. 11
    过滤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
    其他The solvent was decanted
17. 17
    过滤filtered
18. 18
    其他dried under high vacuum overnight
19. 19
    浓缩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
    其他The solvent was decanted
25. 25
    过滤filtered
26. 26
    其他to afford a second crop of solid which
27. 27
    其他was dried under high vacuum overnight

实验过程

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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