反应详情

温度

80 °C

Magnesium (733 mg), ethanol (3 mg) and carbon tetrachloride (0.1 ml) were stirred at room temperature in a three necked flask to activate them. A solution of ethyl malonate (4.5 ml) in tetrahydrofuran (20 ml) was slowly added dropwise to the activated mixture, followed by stirring at 80° C. for 4 hours. After the reaction mixture was cooled back to room temperature, it was chilled to -40° C. Oxalyl chloride (2.5 ml) and N,N-dimethylformamide (3 drops) were added to a solution of 2,5-difluoro-3-methyl-4-nitrobenzoic acid (6.1 g) in methylene chloride (10 ml). After the mixture was stirred at room temperature for 2 hours, the solvent was distilled off under reduced pressure. Toluene was added to the residue to conduct azeotropic distillation. The residue wets dissolved in tetrahydrofuran (15 ml), and the solution was slowly added dropwise at -40° C. to the reaction mixture obtained previously. After completion of the addition, the temperature of the reaction mixture was given back to room temperature to conduct stirring overnight. After the solvent was distilled off under reduced pressure, concentrated hydrochloric acid (5 ml) was added to the residue to keep its pH at about 2. The residue was then extracted with chloroform, and the solvent was distilled off under reduced pressure. Water (20 ml) and p-toluenesulfonic acid monohydrate (250 mg) were added to the resultant residue, and the mixture was heated under reflux for 5.5 hours. After the reaction mixture was cooled back to room temperature, water was added to the reaction mixture to conduct extraction with chloroform. After an organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography on silica gel (eluent; ethyl acetate:hexane=1:7) to obtain the title compound (6.0 g) as a red oil.

1. temperatureAfter the reaction mixture was cooled back to room temperature
2. temperatureit was chilled to -40° C
3. stirringAfter the mixture was stirred at room temperature for 2 hours
4. distillationthe solvent was distilled off under reduced pressure
5. additionToluene was added to the residue
6. distillationdistillation
7. dissolutionThe residue wets dissolved in tetrahydrofuran (15 ml)
8. additionthe solution was slowly added dropwise at -40° C. to the reaction mixture
9. customobtained previously
10. additionAfter completion of the addition
11. customwas given back to room temperature
12. stirringto conduct stirring overnight
13. distillationAfter the solvent was distilled off under reduced pressure, concentrated hydrochloric acid (5 ml)
14. additionwas added to the residue
15. extractionThe residue was then extracted with chloroform
16. distillationthe solvent was distilled off under reduced pressure
17. additionWater (20 ml) and p-toluenesulfonic acid monohydrate (250 mg) were added to the resultant residue
18. temperaturethe mixture was heated
19. temperatureunder reflux for 5.5 hours
20. temperatureAfter the reaction mixture was cooled back to room temperature
21. additionwater was added to the reaction mixture
22. extractionextraction with chloroform
23. dry with materialAfter an organic layer was dried over anhydrous magnesium sulfate
24. distillationthe solvent was distilled off under reduced pressure