反应详情

A solution of tert-butyl 4-[(3S)-4-benzyl-3-methylpiperazin-1-yl]-4-cyanopiperidine-1-carboxylate (242 g, 0.605 mol) in tetrahydrofuran (1.5 L) in a 5 L flask was cooled down to −40° C. using dry ice/acetonitrile. Methylmagnesium bromide (3.0 M in tetrahydrofuran, 800 mL) was slowly added. After the addition, the reaction mixture was slowly warmed up to room temperature and stirred overnight. After cooling down to −40° C. using dry ice/acetonitrile, celite (200 g), and then ethyl acetate (500 mL) were carefully added. After the addition, the mixture was stirred for 4 hours while the temperature slowly rose to room temperature. The reaction mixture was cooled back down to −40° C. again, and water (200 mL), and then methanol (1.5 L) were added. After being stirred at room temperature overnight, the mixture was filtered through a thin layer of sand. The cake was taken back into a 5 L flask and stirred with methanol (2 L) for 5 hours. Insoluble solid was filtered off. The combined filtrates were concentrated to dryness. Methylene chloride (3.5 L) was added. Insoluble solid was filtered off. The filtrate was dried with magnesium sulfate. After the solvent was removed, 436 g (92.6%) of product was obtained as a white sticky solid. The crude product was essentially pure and used directly for next step. MS (EI) 388.3 (M+1).

1. additionAfter the addition
2. temperatureAfter cooling down to −40° C.
3. additionAfter the addition
4. stirringthe mixture was stirred for 4 hours while the temperature
5. customslowly rose to room temperature
6. temperatureThe reaction mixture was cooled back down to −40° C. again
7. stirringAfter being stirred at room temperature overnight
8. filtrationthe mixture was filtered through a thin layer of sand
9. customThe cake was taken back into a 5 L flask
10. stirringstirred with methanol (2 L) for 5 hours
11. filtrationInsoluble solid was filtered off
12. concentrationThe combined filtrates were concentrated to dryness
13. additionMethylene chloride (3.5 L) was added
14. filtrationInsoluble solid was filtered off
15. dry with materialThe filtrate was dried with magnesium sulfate
16. customAfter the solvent was removed