反应详情

温度

0 °C

In a 5 L, 4-necked round bottom flask, immersed in ice-cold ethanol-isopropanol (isopropanol 13%, −15° C.) bath, to a solution of 2,6-bis[(2,2-dimethylpropanoyl)amino]pyridine (J. Am. Chem. Soc. 1986, 108, 3310–3318, 126 g, 454 mmol) in anhydrous tetrahydrofuran (1.5 L) was added 2.66 M solution of n-buthyllithium in hexane (598 mL) dropwise from a dropping funnel (1 L) during the period of 6 h under nitrogen atmosphere (internal temperature was maintained at −15° C.˜−5° C.). The resulting solution was stirred at 0° C. (internal temperature) for 12 h under nitrogen atmosphere. The formation of yellowish precipitate was noticed. Then the suspension was cooled to −15° C., dimethyl carbonate (194 mL, 2.3 mmol) was added in one portion. The reaction solution was stirred at 0° C. for 1 h, quenched with 1.5 L of 1 N aqueous hydrochloric acid, pH value was controlled to ˜4.5 by adding 1 N aqueous hydrochloric acid, then 600 mL of ethyl acetate was added. After the layers were separated, the organic layer was washed with 1 L of 0.2 N aqueous NaOH (1 L) and brine (500 mL). Each aqueous layer was extracted with ethyl acetate (300 mL) twice. Combined organic layer was dried over sodium sulfate (˜300 g) and concentrated. The residue was diluted with diisopropylether (300 mL) and the solution was evaoprated to remove the residual ethyl acetate azeotropically. The residue was dissolved with diisopropylether (360 mL) at 60° C. with gentle stirring, and then the small portion of the crystalline of the desired product (˜5 mg) was added as seed. The formation of a pale yellow precipitate was noticed. The resulting suspension was cooled to room temperature (during the period of 2 h), and stirred at room temperature for 2 h. The suspension was filtered through paper filter, then the cake was washed with diisopropylether (80 mL). The solid was dried under reduced pressure at room temperature for 1 day to give the title compound (120 g, 358 mmol, 79%) as a pale yellow solid.

1. temperature(internal temperature was maintained at −15° C.˜−5° C.)
2. temperatureThen the suspension was cooled to −15° C.
3. stirringThe reaction solution was stirred at 0° C. for 1 h
4. customquenched with 1.5 L of 1 N aqueous hydrochloric acid
5. additionby adding 1 N aqueous hydrochloric acid
6. addition600 mL of ethyl acetate was added
7. customAfter the layers were separated
8. washthe organic layer was washed with 1 L of 0.2 N aqueous NaOH (1 L) and brine (500 mL)
9. extractionEach aqueous layer was extracted with ethyl acetate (300 mL) twice
10. dry with materialCombined organic layer was dried over sodium sulfate (˜300 g)
11. concentrationconcentrated
12. additionThe residue was diluted with diisopropylether (300 mL)
13. customto remove the residual ethyl acetate azeotropically
14. dissolutionThe residue was dissolved with diisopropylether (360 mL) at 60° C. with gentle stirring
15. additionthe small portion of the crystalline of the desired product (˜5 mg) was added as seed
16. temperatureThe resulting suspension was cooled to room temperature (during the period of 2 h), and
17. stirringstirred at room temperature for 2 h
18. filtrationThe suspension was filtered through paper
19. filtrationfilter
20. washthe cake was washed with diisopropylether (80 mL)
21. customThe solid was dried under reduced pressure at room temperature for 1 day