反应详情

A solution of 4-fluorobenzotrifluoride (25 g, 0.152M) in anhydrous THF (300 ml) was cooled to −60° C. (IPA/CO2 bath) and treated with n-butyl lithium (84 mL of a 2.0M solution in Hexane, 0.168M-1.1 eq) with a maximum rate so not to exceed −60° C. The reaction was stirred for 3 hours (temperature maintained) and then treated with a solution of 4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (51.86 g, 0.190M-1.25 eq, in 130 mL of anhydrous THF) with a maximum rate so as not to exceed −55° C. The mixture was stirred for a further two hours before allowing to warm to room temperature and stirred for 0.5 hours. The reaction was quenched with saturated ammonium chloride solution (75 mL) and the THF removed under reduced pressure. The residue was dissolved in ethylacetate (800 mL), washed with 1N Hydrochloric acid (400 ml), 5% aq NaHCO3 (400 mL), water (400 mL) and brine (400 mL) successively. The organics were dried over MgSO4, filtered and concentrated to give a brown oil, which on triturating in ethyl acetate gave a white solid 27.6 g (48%).

1. customto exceed −60° C
2. temperature(temperature maintained)
3. customto exceed −55° C
4. stirringThe mixture was stirred for a further two hours
5. stirringstirred for 0.5 hours
6. customThe reaction was quenched with saturated ammonium chloride solution (75 mL)
7. customthe THF removed under reduced pressure
8. dissolutionThe residue was dissolved in ethylacetate (800 mL)
9. washwashed with 1N Hydrochloric acid (400 ml), 5% aq NaHCO3 (400 mL), water (400 mL) and brine (400 mL) successively
10. dry with materialThe organics were dried over MgSO4
11. filtrationfiltered
12. concentrationconcentrated
13. customto give a brown oil, which
14. customon triturating in ethyl acetate