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.

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