反应详情

To a suspension of NaH (11.3 g, 60% oil dispersion, 282 mmol) in tetrahydrofuran (THF) (35 mL) in an ice-bath was added a solution of diethyl malonate (45.2 g, 42.9 mL, 282 mmol) in THF (70 mL) over a period of an hour so that the reaction temperature was kept below 20° C. Some white solid precipitated during the addition. To the above reaction mixture was added a solution of 1,2,3-trifluoro-4-nitrobenzene (25.0 g, 141 mmol) in THF (35 mL) over a period of 1 hour so that the reaction temperature was kept below 10° C. The ice-bath was removed and the mixture was stirred at ambient temperature for 2 hours. Acetic acid (18 mL) was added to the reaction solution, and THF was evaporated under reduced pressure. Chloroform (200 mL), H2O (250 mL), and concentrated HCl (18 mL) were added. The organic layer was separated, concentrated, mixed with 4N HCl (45 mL) and acetic acid (35 mL), and refluxed for 14 hours. The reaction mixture was allowed to cool to room temperature. The solid precipitated upon cooling was filtered off, washed with diisopropyl ether, and dissolved in MeOH (70 mL). After treating with active carbon, the solvent was evaporated, and the crystalline residue washed with isopropyl ether, and filtered off to give the title compound (17.6 g, 58% yield) as a white solid. 1H-NMR (400 MHz, CDCl3) δ 8.05-8.01 (m, 1H), 7.47 (dd, J=17.4, 8.9 Hz, 1H), 4.10 (s, 2H).

1. customwas kept below 20° C
2. customSome white solid precipitated during the addition
3. customwas kept below 10° C
4. customThe ice-bath was removed
5. additionAcetic acid (18 mL) was added to the reaction solution, and THF
6. customwas evaporated under reduced pressure
7. additionChloroform (200 mL), H2O (250 mL), and concentrated HCl (18 mL) were added
8. customThe organic layer was separated
9. concentrationconcentrated
10. additionmixed with 4N HCl (45 mL) and acetic acid (35 mL)
11. temperaturerefluxed for 14 hours
12. temperatureto cool to room temperature
13. customThe solid precipitated
14. temperatureupon cooling
15. filtrationwas filtered off
16. washwashed with diisopropyl ether
17. dissolutiondissolved in MeOH (70 mL)
18. additionAfter treating with active carbon
19. customthe solvent was evaporated
20. washthe crystalline residue washed with isopropyl ether
21. filtrationfiltered off