反应详情

4-(Bromomethyl)-2,5-difluoro-N-(methylsulfonyl)benzamide (Preparation 164, 100 mg, 0.27 mmol), (4-chloro-2-methoxyphenyl)boronic acid (55 mg, 0.295 mmol), tetrakis(triphenylphosphine)palladium (31 mg, 0.027 mmol), aqueous potassium carbonate solution (1.8 M, 0.45 mL, 0.804 mmol) and tetrahydrofuran (15 mL) were combined and stirred under nitrogen at reflux for 6 hours. After cooling, the mixture was filtered through Celite™ and the filtrate evaporated. The residue was dissolved in water (20 mL) and acidified with aqueous potassium hydrogen sulphate solution (0.5 M) to pH 2 and the mixture extracted with ethyl acetate (1×30 mL). The organic layer was separated and back-washed with brine (2×20 mL). The organic layer was separated, dried over sodium sulphate, filtered and evaporated to give an orange oil. The oil was purified using silica gel column chromatography eluting with heptane to ethyl acetate:heptane 1:1 to give a solid. The solid was further purified by reverse phase HPLC to give the title compound (38 mg, 36%) as a white solid.

1. temperatureat reflux for 6 hours
2. temperatureAfter cooling
3. filtrationthe mixture was filtered through Celite™
4. customthe filtrate evaporated
5. dissolutionThe residue was dissolved in water (20 mL)
6. extractionthe mixture extracted with ethyl acetate (1×30 mL)
7. customThe organic layer was separated
8. washback-washed with brine (2×20 mL)
9. customThe organic layer was separated
10. dry with materialdried over sodium sulphate
11. filtrationfiltered
12. customevaporated
13. customto give an orange oil
14. customThe oil was purified
15. washeluting with heptane to ethyl acetate:heptane 1:1
16. customto give a solid
17. customThe solid was further purified by reverse phase HPLC