反应详情

Add (2-bromo-5-fluoro-phenyl)-carbamic acid tert-butyl ester (1.06 g, 3.67 mmol), bis(pinacolato)diboron (1.03 g, 4.04 mmol), palladium(II) acetate (0.062 g, 0.28 mmol), tricyclohexylphosphine (0.103 g, 0.37 mmol) and acetonitrile (40 mL) to a round bottom flask. Stir at ambient temperature for approximately 5 minutes to dissolve most of the reagents. Add cesium fluoride (2.10 g, 13.82 mmol), place the flask in a 90° C. oil bath, and stir for 30-45 minutes. Remove the oil bath and allow the reaction mixture to cool to ambient temperature. To this mixture, add trifluoromethanesulfonic acid 6-benzyloxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (0.75 g, 1.22 mmol), palladium(II) acetate (0.062 g, 0.28 mmol), tricyclohexylphosphine (0.103 g, 0.37 mmol) and place the reaction in a 90° C. oil bath. Stir the reaction for 4 hours at 90° C. Cool the reaction to ambient temperature, filter it through a pad of Celite and rinse the pad with ample, hot ethyl acetate. Wash the filtrate with 50% aqueous sodium carbonate, saturated aqueous ammonium chloride, H2O and brine; then dry (sodium sulfate) and evaporate it in vacuo. Load the resulting material onto an SCX column. Wash with dichloromethane, 50% dichloro-methane/methanol, elute with ammonia solution (2N NH3 in methanol) and remove solvent under vacuum. Purify the resulting residue by flash chromatography (silica gel; 1%-5% methanol gradient in dichloromethane: followed by a second chromatography 2% of 2N NH3 in methanol/25% THF/hexanes: followed by purification on a Chromatotron; 2% MeOH/dichloromethane) to provide 0.300 g (36%) of the title compound: mass spectrum (ion spray) m/z=675 (M+H).

1. dissolutionto dissolve most of the reagents
2. customRemove the oil bath
3. temperatureto cool to ambient temperature
4. customthe reaction in a 90° C. oil bath
5. stirringStir
6. customthe reaction for 4 hours at 90° C
7. temperatureCool
8. customthe reaction to ambient temperature
9. filtrationfilter it through a pad of Celite
10. washrinse the pad with ample, hot ethyl acetate
11. washWash the filtrate with 50% aqueous sodium carbonate, saturated aqueous ammonium chloride, H2O and brine
12. dry with materialthen dry (sodium sulfate)
13. customevaporate it in vacuo
14. washWash with dichloromethane, 50% dichloro-methane/methanol
15. washelute with ammonia solution (2N NH3 in methanol)
16. customremove solvent under vacuum
17. customPurify the resulting residue by flash chromatography (silica gel
18. customfollowed by purification on a Chromatotron