反应详情

To a solution (1.25M) of diethyl acetamidomalonate (5.17 g, 23.80 mmol) in N-methyl-2-pyrrolidone (18.2 mL) was added potassium t-butoxide (2.77 g, 24.69 mmol), and the mixture was stirred for 1 hour at room temperature. A solution (21.79 g) of bis(4-fluorophenyl)methylene chloride (4.54 g, 19.02 mmol) in toluene and potassium iodide (3.19 g, 19.10 mol) were added, and the mixture was stirred at 70° C. for 6 hours. After completion of the reaction, 2M aqueous sodium hydroxide solution (45 mL) was added to the reaction mixture, and the mixture was stirred at 60° C. for 5 hours. After cooling to room temperature, the mixture was partitioned. The aqueous layer was adjusted to pH 7.0 with concentrated hydrochloric acid (4.4 mL), ethyl acetate (30 mL) and then concentrated hydrochloric acid (6.9 mL) were added, and the aqueous layer was extracted. The aqueous layer was further extracted with ethyl acetate (6 mL). The organic layers were combined, and the content of the title compound was examined by HPLC. As a result, it was found that 5.678 g of the title compound was contained in the organic solvent. The organic layer was washed 3 times with 2M hydrochloric acid (9 mL), washed with saturated brine (4.5 mL), and concentrated. Toluene (13.5 mL) was added to the concentrate, and the mixture was concentrated at 50° C. Toluene (13.5 mL) was added to the concentrate, and the mixture was stirred for 30 minutes. The mixture was cooled to 0° C. over 5 hours to allow precipitation of white crystals. The crystals were collected by filtration to give wet crystals. The powder X-ray (Cu—Kα ray) of the wet crystals showed characteristic peaks at 17.1°, 17.6°, 18.8°, 20.7°, 21.8°, 22.0°, 22.7°, 23.1°, and 25.4°. The wet crystals were dried under reduced pressure to give the title compound as dry crystals (5.39 g). The powder X-ray (Cu—Kα ray) of the dry crystals showed characteristic peaks at 17.1°, 21.8° 22.0°, 22.7°, 23.1°, and 25.4°. melting point 187° C.

1. stirringthe mixture was stirred at 70° C. for 6 hours
2. additionwas added to the reaction mixture
3. stirringthe mixture was stirred at 60° C. for 5 hours
4. temperatureAfter cooling to room temperature
5. customthe mixture was partitioned
6. additionconcentrated hydrochloric acid (6.9 mL) were added
7. extractionthe aqueous layer was extracted
8. extractionThe aqueous layer was further extracted with ethyl acetate (6 mL)
9. washThe organic layer was washed 3 times with 2M hydrochloric acid (9 mL)
10. washwashed with saturated brine (4.5 mL)
11. concentrationconcentrated
12. additionToluene (13.5 mL) was added to the concentrate
13. concentrationthe mixture was concentrated at 50° C
14. additionToluene (13.5 mL) was added to the concentrate
15. stirringthe mixture was stirred for 30 minutes
16. temperatureThe mixture was cooled to 0° C. over 5 hours
17. customprecipitation of white crystals
18. filtrationThe crystals were collected by filtration
19. customto give wet crystals
20. customat 17.1°
21. custom17.6°, 18.8°, 20.7°, 21.8°, 22.0°, 22.7°, 23.1°, and 25.4°
22. customThe wet crystals were dried under reduced pressure