反应详情

Under nitrogen, stirred dioxane (20 ml) at 80° C. was charged with 6-fluoro-2-iodo-3,4-dimethoxybenzonitrile from Example 1(a) (1.0 g, 3.3 mmol), tetrakis(triphenyl-phosphine) palladium(0) (0.19 g, 0.16 mmol), the pyridyl boronate from Example 1(b) (1.22 g, estimated to be 7.1 mmol), copper(I)iodide (0.25 g, 1.3 mmol), sodium carbonate (0.69 g, 6.5 mmol) and triphenylphosphine (0.17 g, 0.65 mmol) and the resulting brown slurry heated to reflux. Further portions of the pyridyl boronate were added at the following times after the reaction had reached reflux: 0.61 g after 30 mins; 0.61 g after 1 hour; 0.61 g after 1 hour 30 mins; 0.61 g after 2 hours 30 mins; 0.61 g after 3 hours; and 0.30 g after 4 hours. After a total of 5 hours at reflux the reaction was allowed to cool to room temperature, water (10 ml) and ethyl acetate (20 ml) were added and the resulting mixture allowed to stir for 15 mins. After this time, the mixture was filtered through Arbocel™ filter aid and the pad washed with ethyl acetate (20 ml). The phases were separated and the aqueous phase extracted with ethyl acetate (20 ml). The organic phases were combined and evaporated to a brown oil. Acetonitrile was added, the mixture warmed to reflux and left to cool to room temperature overnight. The resulting suspension was filtered to give a cream solid that was dried in vacuo overnight at 45° C. to give 0.42 g of the title product (49%).

1. temperaturehad reached reflux
2. wait0.61 g after 1 hour
3. wait0.61 g after 1 hour 30 mins
4. wait0.61 g after 2 hours 30 mins
5. wait0.61 g after 3 hours
6. waitand 0.30 g after 4 hours
7. temperatureAfter a total of 5 hours at reflux the reaction
8. filtrationAfter this time, the mixture was filtered through Arbocel™
9. filtrationfilter aid
10. washthe pad washed with ethyl acetate (20 ml)
11. customThe phases were separated
12. extractionthe aqueous phase extracted with ethyl acetate (20 ml)
13. customevaporated to a brown oil
14. additionAcetonitrile was added
15. temperaturethe mixture warmed
16. temperatureto reflux
17. waitleft
18. temperatureto cool to room temperature overnight
19. filtrationThe resulting suspension was filtered
20. customto give a cream solid
21. customthat was dried in vacuo overnight at 45° C.