反应详情

温度

70 °C

In a 500 ml RBF was added a solution of 4-[(1R,2S)-2-(2-hydroxyethyl)cyclopropyl]piperidine-1-carbonitrile (from Step B, Intermediate 7; 7.5 g, 40 mmol) in 1:1 THF:EtOAc (150 ml). To this solution was added N-hydroxy-2-methoxyethanimidamide (5 g, 45 mmol) as a solid and the resulting mixture was stirred to yield a clear solution. An addition funnel was added to the flask and the whole set up was set under nitrogen atmosphere. The solution was placed in an oil bath heated to 70° C. A 0.5M solution of zinc chloride (100 ml, 50 mmol) in THF was placed in the addition funnel and added over a 5 minute period to the reaction mixture. Upon complete addition, the resulting mixture was stirred at 70° C. for 2 hours. After 30 minutes the clear solution became cloudy. After 1 hour at 70° C., a thick white precipitate formed. TLC indicates consumption of the all starting material. The mixture was cooled to RT and the white solid was filtered off and washed with 1:1 THF:EtOAc (200 mL) and dried. The white solid in the fritted funnel was dissolved in 50 mL of DMF and drawn through by vacuum into a 250 ml RBF. To this solution was then added Tosic Acid (4 g, 20 mmol) and the resulting mixture stirred at 80° C. overnight. The mixture was allow to cool to room temperature and then was diluted with 150 mL of ethyl acetate. The mixture was placed in a separatory funnel and washed with sat'd sodium bicarbonate solution (150 mL). The aqueous was extracted once with ethyl acetate (100 mL) and the organics were combined. The organics were washed with 1M Na2CO3 (50 mL), followed by water (2×100 mL), and then brine (100 mL). The organics were dried over sodium sulfate, filtered, and the filtrate concentrated to dryness under reduced pressure. The residue was taken up in 50 mL DCM and loaded onto a Flash 75 system (silica gel column). Biotage Flash 75 purification was done eluting with 40-80% ethyl acetate/hexane for 4 column volumes followed by 80% ethyl acetate for 4 column volumes (total solvent 16 L). The fractions containing the product were collected and concentrated under reduced pressure to afford the pure product. LC/MS (m/z): 282 (M+H)+.

1. customto yield a clear solution
2. additionAn addition funnel was added to the flask
3. customThe solution was placed in an oil bath
4. additionadded over a 5 minute period to the reaction mixture
5. additionUpon complete addition
6. stirringthe resulting mixture was stirred at 70° C. for 2 hours
7. waitAfter 1 hour at 70° C.
8. customa thick white precipitate formed
9. customconsumption of the all starting material
10. temperatureThe mixture was cooled to RT
11. filtrationthe white solid was filtered off
12. washwashed with 1:1 THF
13. dry with materialEtOAc (200 mL) and dried
14. dissolutionThe white solid in the fritted funnel was dissolved in 50 mL of DMF
15. temperatureto cool to room temperature
16. customThe mixture was placed in a separatory funnel
17. washwashed with sat'd sodium bicarbonate solution (150 mL)
18. extractionThe aqueous was extracted once with ethyl acetate (100 mL)
19. washThe organics were washed with 1M Na2CO3 (50 mL)
20. dry with materialThe organics were dried over sodium sulfate
21. filtrationfiltered
22. concentrationthe filtrate concentrated to dryness under reduced pressure
23. customBiotage Flash 75 purification
24. washwas done eluting with 40-80% ethyl acetate/hexane for 4 column volumes
25. additionThe fractions containing the product
26. customwere collected
27. concentrationconcentrated under reduced pressure
28. customto afford the pure product