반응 #88820

반응 방정식

toluene

carbonate

di-isopropyl ethyl amine

L-tert-leucine

hydrochloric acid

→

VII

(S)-2-((((1R,2R)-2-allylcyclopropoxy)carbonyl)amino)-3,3-dimethylbutanoic acid (S)-1-Phenylethan-1-amine Salt

반응 조건

후처리

1. 1
   기타in the reaction
2. 2
   기타reaction volume up to 60 mL
3. 3
   온도The reaction was then cooled to room temperature
4. 4
   workup.STIRRINGThe biphasic mixture was agitated for about 30 min at room temperature
5. 5
   기타the phases were split
6. 6
   농축The organic rich stream was then concentrated to approximately 20 mL by rotary evaporation
7. 7
   workup.ADDITION80 mL of acetonitrile was added
8. 8
   농축Concentration down to 20 mL
9. 9
   온도heated to about 50° C
10. 10
    온도The mixture is then heated to about 50° C.
11. 11
    workup.ADDITION(S)-phenethylamine (6.0 g, 49.7 mmol as a solution in 30 mL of acetonitrile at 50° C.) was charged
12. 12
    workup.WAITthe thin slurry was aged for 1 h at 50° C
13. 13
    온도The mixture was then cooled down to room temperature over about 3 h
14. 14
    기타was aged for at least about 12 h
15. 15
    여과The solids were collected by filtration
16. 16
    세척the cake was washed with about 20 mL of acetonitrile
17. 17
    기타The final wet cake was dried in the oven at about 40° C. under vacuum

실험 절차

To a reaction vessel was charged a toluene solution of carbonate O (the amount of solution charged was determined by obtaining a wt % by 1H NMR of the carbonate in solution and then charging the amount necessary to have 9.9 g, 41.4 mmol of carbonate O in the reaction.). Additional toluene was charged to the reaction to bring the final reaction volume up to 60 mL. To this solution was charged di-isopropyl ethyl amine (10.7 g, 82.8 mmol) and L-tert-leucine (6.0 g, 45.52 mmol). The reaction mixture was heated to about 45° C. and agitated at this temperature for about 6 h. The reaction was then cooled to room temperature and hydrochloric acid (60 mL of a 3N aqueous solution) was charged. The biphasic mixture was agitated for about 30 min at room temperature and then the phases were split. The organic rich stream was then concentrated to approximately 20 mL by rotary evaporation and then 80 mL of acetonitrile was added. Concentration down to 20 mL and then recharging of acetonitrile was continued until the amount of toluene is about <5% v/v. The final stream is adjusted to a volume of 80 mL using acetonitrile and heated to about 50° C. The mixture is then heated to about 50° C. and (S)-phenethylamine (6.0 g, 49.7 mmol as a solution in 30 mL of acetonitrile at 50° C.) was charged. The reaction mixture was seeded with 0.5 wt % seeds of VII (0.05 g) and the thin slurry was aged for 1 h at 50° C. The mixture was then cooled down to room temperature over about 3 h and the resulting slurry was aged for at least about 12 h. The solids were collected by filtration and the cake was washed with about 20 mL of acetonitrile. The final wet cake was dried in the oven at about 40° C. under vacuum to afford VII.

출처