反应详情

To a stirred solution of 3-amino-5-fluoro-4-methyl-benzoic acid methyl ester (Preparation 1e, 34.7 g) in THF (300 mL) at room temperature was added N,N-diisopropylethylamine (61.2 mL) followed by bromoacetonitrile (24.41 mL). The mixture was heated at reflux for 16 h, further bromoacetonitrile (4.8 mL) and N,N-diisopropylethylamine (12.5 mL) were added and heating was continued for 6 h. The reaction was cooled to room temperature and concentrated. 1N HCl (600 mL) and dichloromethane (800 mL) were added. This gave some solid precipitate which did not dissolve. Water (300 mL) was added to help identify layers. The lower organic layer containing solid and a bit of water was separated and this organic fraction was washed with 1M HCl/brine (400 mL of 1:1 mixture) before being dried (MgSO4). A second drying (Na2SO4) was needed. After the drying agent was filtered off (washed through with 400 ml dichloromethane) the filtrate was concentrated (˜60 g). This was azeotroped with toluene (400 mL) and final solvent removal gave subtitle compound (39.4 g).

1. temperatureThe mixture was heated
2. temperatureat reflux for 16 h
3. temperatureheating
4. concentrationconcentrated
5. addition1N HCl (600 mL) and dichloromethane (800 mL) were added
6. customThis gave some solid precipitate which
7. dissolutiondid not dissolve
8. additionThe lower organic layer containing solid
9. customa bit of water was separated
10. washthis organic fraction was washed with 1M HCl/brine (400 mL of 1:1 mixture)
11. dry with materialbefore being dried (MgSO4)
12. dry with materialA second drying (Na2SO4)
13. filtrationAfter the drying agent was filtered off
14. wash(washed through with 400 ml dichloromethane) the filtrate
15. concentrationwas concentrated (˜60 g)
16. customThis was azeotroped with toluene (400 mL) and final solvent removal