反应详情

Toluene (36 L, 6 vol), L-pyroglutaminol (6.0 Kg, 1.0 eq), benzaldehyde (8.3 Kg, 1.5 eq) and p-toluenesulfonic acid (134 g, 1.5% mol) were charged to a reactor. The resulting mixture was heated to reflux and the water formed during the reaction was separated out by using Dean-Stark condenser. The completion of the reaction was monitored by HPLC until L-pyroglutaminol was ≦0.1%. It was cooled to 15˜20° C., added aqueous 5% NaHCO3 (3 vol), agitated for 15 min and separated the layers. 20% aqueous NaHSO3 (6 vol) was charged to the organic phase, upon stirring for 30 min, filtered through Celite and washed the cake with toluene. Separated the organic phase (this step could be skipped if there was no solid), and filtered the organic phase through a thin pad of silica gel (1.0 wt/wt) and washed the silica gel with toluene three times. Combined the organic phase and monitored by HPLC. If impurity (RRT=1.5)>1.5%, repeated the silica gel filtration procedures until the impurity (RRT=1.5)≦1.5%. Dried the filtrate with anhydrous Na2SO4 for at least 2 hrs, filtered and washed the cake with toluene for twice. Concentrated below 55° C. (bath temp) under vacuum to afford 8.30 kg (78.6% yield) of the title compound with 94.6% HPLC purity. ESI MS m/z (M+H)+ 204.11.

1. temperatureThe resulting mixture was heated
2. temperatureto reflux
3. customwas separated out
4. temperatureIt was cooled to 15˜20° C.
5. additionadded aqueous 5% NaHCO3 (3 vol)
6. customseparated the layers
7. addition20% aqueous NaHSO3 (6 vol) was charged to the organic phase
8. stirringupon stirring for 30 min
9. filtrationfiltered through Celite
10. washwashed the cake with toluene
11. customSeparated the organic phase (this step
12. filtrationfiltered the organic phase through a thin pad of silica gel (1.0 wt/wt)
13. washwashed the silica gel with toluene three times
14. filtrationthe silica gel filtration procedures until the impurity (RRT=1.5)≦1.5%
15. dry with materialDried the filtrate with anhydrous Na2SO4 for at least 2 hrs
16. filtrationfiltered
17. washwashed the cake with toluene for twice
18. concentrationConcentrated below 55° C. (bath temp) under vacuum