反应详情

A 1 L, 3-neck round bottom flask, equipped with magnetic stirring bar, thermometer, nitrogen gas inlet, and addition funnel was charged with Zn dust (66 g, 1.01 mol, 3 eq). The flask was evacuated and filled with nitrogen three times. On the third evacuation the flask was thoroughly heated with a heat gun, and then allowed to cool to room temperature. Anhydrous THF (120 mL) and 1,2-dibromoethane (19.7 g, 104.8 mmol, 0.3 eq) were charged and the mixture stirred under nitrogen at 65° C. for 10 min. The reaction was cooled to room temperature, and chlorotrimethylsilane (2.6 g, 23.7 mmol, 0.07 eq) was added and the reaction stirred at room temperature for 45 min. A solution of tert-butyl 3-(iodomethyl)piperidine-1-carboxylate (Preparation 69, 110 g, 338.2 mmol, 1 eq) in THF (60 mL and 20 mL to wash the flask) was added through an addition funnel and the mixture was stirred at room temperature for 45 min (NOTE: fast exothermic reaction which, if necessary, can be controlled by means of an ice/water bath). Then a solution of 2-chloropyrimidine (32.5 g, 284 mmol, 0.84 eq) in THF (80 mL+20 mL to wash the flask) was added followed by bis(dibenzylidene acetone) palladium (0) (9.3 g, 10 mmol, 0.03 eq), and tri-o-tolylphosphine (4.1 g, 13.5 mmol, 0.04 eq) and the reaction mixture was heated at 65° C. for 2 h then allowed to cool to room temperature and stirring was continued at room temperature for 17 h. The reaction mixture was diluted with ethyl acetate (1.2 L) and filtered through Celite. The Celite cake was thoroughly washed with ethyl acetate until the filtrate was no longer ultra-violet absorbent, the organic filtrates were combined and washed with a 10% solution of ammonium chloride (2×250 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford a brown residue that was purified through flash chromatography (Biotage). The fractions eluted with ethyl acetate:hexanes (40:60 v/v) were combined and concentrated in vacuo to title compound as a slightly yellow solid (27.3 g, 98.4 mmol, 34.6%).

1. customA 1 L, 3-neck round bottom flask, equipped with magnetic stirring bar
2. additionthermometer, nitrogen gas inlet, and addition funnel
3. customThe flask was evacuated
4. additionfilled with nitrogen three times
5. temperatureOn the third evacuation the flask was thoroughly heated with a heat gun
6. temperatureThe reaction was cooled to room temperature
7. stirringthe reaction stirred at room temperature for 45 min
8. additionwas added through an addition funnel
9. stirringthe mixture was stirred at room temperature for 45 min (NOTE
10. customfast exothermic reaction which
11. customif necessary, can be controlled by means of an ice/water bath
12. additionwas added
13. temperaturethe reaction mixture was heated at 65° C. for 2 h
14. temperatureto cool to room temperature
15. stirringstirring
16. waitwas continued at room temperature for 17 h
17. filtrationfiltered through Celite
18. washThe Celite cake was thoroughly washed with ethyl acetate until the filtrate
19. washwashed with a 10% solution of ammonium chloride (2×250 mL)
20. dry with materialdried over sodium sulfate
21. filtrationfiltered
22. concentrationconcentrated under reduced pressure
23. customto afford a brown residue that
24. customwas purified through flash chromatography (Biotage)
25. washThe fractions eluted with ethyl acetate:hexanes (40:60 v/v)