反应详情

温度

-15 °C

A 1 L flask equipped with mechanical stirrer, thermometer well, and pressure equalizing addition funnel was charged with 500 mL of tetrahydrofuran and 49 ml (0.38 mol) veratrole under a nitrogen atmosphere. The solution was cooled to −15° C. and 160 mL (2.5M, 0.42 mol) of n-butyllithium was placed in the addition funnel. The n-butyllithium solution was added to the reaction mixture over a 25 minute period while maintaining the reaction temperature below −10° C. After complete addition, the pale green solution was held at 0° C. for one hour and then room temperature for 2 hours resulting in a very thick slurry. A 3 L Morton flask containing 82.3 g (0.32 mol) 4-[(methoxymethylamino)carbonyl]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (15) in 300 mL of tetrahydrofuran under nitrogen atmosphere was cooled to −15° C. while the lithiated veratrole slurry was cooled to 0° C. The lithiated veratrole slurry was added to the 4-[(methoxymethylamino)carbonyl]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester solution over a 15 minute period while keeping the temperature below −10° C. The resulting pale green slurry was stirred an additional 15 minutes at −15° C. and then allowed to warm to room temperature, causing the reaction mixture to become clear. The reaction mixture was stirred for 20 hours at room temperature then quenched with 500 mL of saturated ammonium chloride solution. The aqueous phase was extracted with toluene (2×250 mL) which was then combined with the tetrahydrofuran solution. The organic solution was washed with brine (2×25 mL) and dried over sodium sulfate. The solution was filtered and then concentrated by rotary evaporator to give 140 g of an orange oil. The crude oil was quickly run through 350 g of silica gel using 20% ethyl acetate in toluene as eluant. Solvent evaporation then gave 88.9 g of an orange oil. The orange oil was then placed in a kugelrohr for three hours (80° C., 1 mm Hg) to remove most of the veratrole, giving the title compound (7) remaining in the pot as an orange syrup (55.9 g, 50%).

1. customA 1 L flask equipped with mechanical stirrer
2. additionaddition funnel
3. temperaturewhile maintaining the reaction temperature below −10° C
4. additionAfter complete addition
5. customroom temperature for 2 hours resulting in a very thick slurry
6. temperaturewas cooled to 0° C
7. customthe temperature below −10° C
8. temperatureto warm to room temperature
9. stirringThe reaction mixture was stirred for 20 hours at room temperature
10. customthen quenched with 500 mL of saturated ammonium chloride solution
11. extractionThe aqueous phase was extracted with toluene (2×250 mL) which
12. washThe organic solution was washed with brine (2×25 mL)
13. dry with materialdried over sodium sulfate
14. filtrationThe solution was filtered
15. concentrationconcentrated by rotary evaporator