反应详情

[Carbamoyl-(5-chloro-benzo[b]thiophen-3-yl)-methyl]-methyl-phosphinic acid ethyl ester (60.0 g, 181 mmol) was placed in a reactor under nitrogen, followed by addition of cesium carbonate (35.3 g, 108 mmol) and copper iodide (6.90 g, 36.2 mmol) and the resulting mixture was stirred at ambient temperature. DMA (123 g) and N,N′-dimethylethylenediame (6.36 g, 72.1 mmol) (with the addition flask washed with DMA (30 g)) were added and the resulting mixture heated to 70-75° C. with about 30-60 minutes, over which time a thin blue suspension was observed to form. To the resulting mixture was then added 4-(2-bromo-vinyl)-1,2-difluoro-benzene (47.6 g, 217 mmol) over about 10-30 minutes (with the addition flask washed with DMA (30 g)), then stirred for 5 to 7 hours at 75-85° C., with the progress of the reaction monitored by HPLC. When the reaction was deemed complete, the reaction mixture was cooled to 60-78° C., ethyl acetate (345 g) was added followed by addition of water (303 g), and the mixture stirred for 10-30 minutes. The resulting phases were separated. To the organic phase was added a solution of NaCl (30 g in 270 g H2O), followed by stirring for 10-30 min at a temperature of 55-65° C. The resulting phases were separated, to the organic phase was added again a solution of NaCl (30 g in 270 g H2O), followed by stirring for 10-30 min at a temperature of 55-65° C. The resulting phases were separated and treated a third time with addition of a solution of NaCl (30 g in 270 g H2O), followed by stirring for 10-30 min at a temperature of 55-65° C. The resulting phases were separated, the organic phase heated to distill off 107-139 g of solvent (at 50-65° C.). To the resulting residue, cyclohexane (280 g) was added over 20-40 minutes and the resulting mixture cooled to 10-15° C., then stirred at this temperature for 2-3 hours, over which time a thick suspension was observed to form. The resulting suspension was filtered, the filtercake washed with a mixture of cyclohexane (135 g) and ethyl acetate (45 g), then dried at 55-60° C., under vacuum to yield the title compound as a solid.

1. washDMA (123 g) and N,N′-dimethylethylenediame (6.36 g, 72.1 mmol) (with the addition flask washed with DMA (30 g))
2. additionwere added
3. temperaturethe resulting mixture heated to 70-75° C. with about 30-60 minutes, over which time a thin blue suspension
4. customto form
5. stirringthen stirred for 5 to 7 hours at 75-85° C., with the progress of the reaction
6. temperaturethe reaction mixture was cooled to 60-78° C.
7. stirringthe mixture stirred for 10-30 minutes
8. customThe resulting phases were separated
9. additionTo the organic phase was added a solution of NaCl (30 g in 270 g H2O)
10. stirringby stirring for 10-30 min at a temperature of 55-65° C
11. customThe resulting phases were separated, to the organic phase
12. additionwas added again a solution of NaCl (30 g in 270 g H2O)
13. stirringby stirring for 10-30 min at a temperature of 55-65° C
14. customThe resulting phases were separated
15. additiontreated a third time
16. additionwith addition of a solution of NaCl (30 g in 270 g H2O)
17. stirringby stirring for 10-30 min at a temperature of 55-65° C
18. customThe resulting phases were separated
19. temperaturethe organic phase heated
20. distillationto distill off 107-139 g of solvent (at 50-65° C.)
21. additionTo the resulting residue, cyclohexane (280 g) was added over 20-40 minutes
22. temperaturethe resulting mixture cooled to 10-15° C.
23. stirringstirred at this temperature for 2-3 hours, over which time a thick suspension
24. customto form
25. filtrationThe resulting suspension was filtered
26. washthe filtercake washed with a mixture of cyclohexane (135 g) and ethyl acetate (45 g)
27. customdried at 55-60° C., under vacuum