Реакция #2286297

Уравнение реакции

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

Выход 24.7%

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

Выход 24.7%

Растворители

N,N-dimethyl acetamide

water

Условия реакции

Обработка

1. 1
   ТемператураThe reaction was cooled to room temperature
2. 2
   Экстракцияextracted with ethyl acetate (3×100 mL)
3. 3
   Промывкаwere washed with a 1N aqueous sodium hydroxide solution (1×150 mL)
4. 4
   СушкаThe organic layer was dried with sodium sulfate
5. 5
   Фильтрацияfiltered
6. 6
   Концентрированиеconcentrated
7. 7
   ДругоеThe resulting residue was purified by flash chromatography (Biotage 40M)
8. 8
   Промывкаeluted with 15% ethyl acetate in hexanes
9. 9
   ДругоеThe desired fractions were collected
10. 10
    Концентрированиеconcentrated under vacuum
11. 11
    Фильтрацияfiltered
12. 12
    workup.ADDITIONThe solid was then diluted with a 1:1 mixture of isopropyl acetate
13. 13
    ТемператураThe mixture was heated
14. 14
    Температураto reflux
15. 15
    Температураcooled to room temperature
16. 16
    ДругоеThe solvent was decanted
17. 17
    Фильтрацияfiltered
18. 18
    Другоеdried under high vacuum overnight
19. 19
    КонцентрированиеThe filtrate was concentrated
20. 20
    workup.ADDITIONThe resulting solid was then diluted with a 1:1 mixture of isopropyl acetate
21. 21
    ТемператураThe mixture was heated
22. 22
    Температураto reflux
23. 23
    Температураcooled to room temperature
24. 24
    ДругоеThe solvent was decanted
25. 25
    Фильтрацияfiltered
26. 26
    Другоеto afford a second crop of solid which
27. 27
    Другоеwas dried under high vacuum overnight

Методика

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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