反应详情

温度

80 °C

A 3 L 4-necked round-bottomed flask equipped with addition funnel, mechanical stirrer, nitrogen inlet, heating mantle and thermocouple was charged with [carbamoyl-(5-chloro-benzo[b]thiophen-3-yl)-methyl]-methyl-phosphinic acid ethyl ester (10.5 g, 0.03 mol), K2CO3 (8.0 g, 0.03 mol), N,N-dimethylacetamide (DMA) (40 mL, anhydrous 99.8%), N,N′-dimethyl-ethylenediamine (1.6 g, 0.018 mol) and copper (I) iodide (1.14 g, 0.006 mol) and the resulting mixture heated to about 80° C. under nitrogen. To the resulting mixture was then added 4-(2-bromo-vinyl)-1,2-difluoro-benzene (7.9 g, 0.036 mol) slowly, over a about 20 minutes, at 80° C. and the resulting mixture stirred at this temperature for about 5 hours. The resulting mixture was then quenched while hot with H2O (60 mL), and diluted with EtOAc (70 mL), added slowly through an addition funnel. The resulting biphasic mixture was cooled to 50-55° C. and at this temperature the layers were separated. The organic layer was washed with H2O (50 mL), 0.5N HCl aq. solution (50 mL) and brine (50 mL), then filtered and concentrated under reduced pressure to about half the original volume (35-40 mL). The concentrated solution was heated to slow reflux and then heptane (25 mL) was added slowly at this temperature. The resulting suspension was cooled to 5-10° C. over a period of 1 hr, diluted with additional heptane (10 mL) and aged at this temperature for about 2 hrs. The resulting solid precipitate was filtered, rinsed with cold heptane/EtOAc (4/1) solvent mixture (10 ml), and dried 55° C. in a vacuum oven overnight, to yield the title compound as a white solid.

1. customA 3 L 4-necked round-bottomed flask equipped with addition funnel, mechanical stirrer, nitrogen inlet
2. temperatureheating mantle
3. customThe resulting mixture was then quenched while hot with H2O (60 mL)
4. additiondiluted with EtOAc (70 mL)
5. additionadded slowly through an addition funnel
6. temperatureThe resulting biphasic mixture was cooled to 50-55° C. and at this temperature the layers
7. customwere separated
8. washThe organic layer was washed with H2O (50 mL), 0.5N HCl aq. solution (50 mL) and brine (50 mL)
9. filtrationfiltered
10. concentrationconcentrated under reduced pressure to about half the original volume (35-40 mL)
11. temperatureThe concentrated solution was heated
12. temperatureto slow reflux
13. additionheptane (25 mL) was added slowly at this temperature
14. temperatureThe resulting suspension was cooled to 5-10° C. over a period of 1 hr
15. additiondiluted with additional heptane (10 mL)
16. waitaged at this temperature for about 2 hrs
17. filtrationThe resulting solid precipitate was filtered
18. washrinsed with cold heptane/EtOAc (4/1) solvent mixture (10 ml)
19. customdried 55° C. in a vacuum oven overnight