반응 #617462

반응 방정식

ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate

(R)-Ethyl 3-((R)-1,1-dimethylethylsulfinamido)-2,2-difluoro-3-(2-fluorophenyl)butanoate

DIBAL-H

N,N-diisopropylethylamine

Lithium chloride

→

(R)-ethyl 5-((R)-1,1-dimethylethylsulfinamido)-2,4,4-trifluoro-5-(2-fluorophenyl)hex-2-enoate

수율 60.0%

용매

acetonitrile

toluene

반응 조건

후처리

1. 1
   기타transferred to a dry round bottom flask
2. 2
   workup.ADDITIONpump (addition rate 1 mL/min)
3. 3
   workup.ADDITIONUpon complete addition the reaction
4. 4
   기타The reaction was quenched at −78° C. by addition of 10 mL of ethyl acetate
5. 5
   workup.ADDITIONfollowed by addition of 150 mL of a saturated aqueous solution of sodium potassium tartrate
6. 6
   workup.ADDITIONUpon complete addition the cooling
7. 7
   기타was removed
8. 8
   온도to warm to room temperature
9. 9
   workup.STIRRINGstirred at this temperature for 1 h
10. 10
    workup.ADDITIONThe mixture was diluted with ethyl acetate (200 mL)
11. 11
    여과filtered through a plug of celite
12. 12
    세척for elution
13. 13
    기타The filtrate was transferred to a separation funnel
14. 14
    기타the organic layer was isolated
15. 15
    추출The aqueous phase was extracted with ethyl acetate (2×100 mL)
16. 16
    세척the combined organics were washed with brine (100 mL)
17. 17
    건조dried over MgSO4
18. 18
    여과filtered
19. 19
    농축concentrated under reduced pressure
20. 20
    기타to afford an intermediate
21. 21
    기타The intermediate was used immediately in the subsequent step without further purification
22. 22
    기타dried under vacuum
23. 23
    온도with heating
24. 24
    온도to cool to room temperature under vacuum
25. 25
    workup.ADDITIONAcetonitrile (87 mL) was added
26. 26
    온도The solution was cooled to 0° C.
27. 27
    workup.STIRRINGAfter 10 min stirring at this temperature a solution of the intermediate
28. 28
    workup.ADDITIONwas added
29. 29
    workup.ADDITIONUpon complete addition the cooling
30. 30
    기타was removed
31. 31
    workup.STIRRINGthe reaction was stirred overnight at room temperature
32. 32
    농축The reaction mixture was concentrated to approximately 50 mL (under vacuum), ethyl acetate (250 mL), water (50 mL) and saturated aqueous NH4Cl (50 mL)
33. 33
    workup.ADDITIONwere added
34. 34
    기타The phases were separated
35. 35
    추출the aqueous layer was extracted with ethyl acetate (2×100 mL)
36. 36
    건조The combined organics were dried over MgSO4
37. 37
    여과filtered
38. 38
    농축concentrated under reduced pressure
39. 39
    기타The crude material was purified
40. 40
    세척a CombiFlash system (220 g SiO2, gradient elution; heptanes:ethyl acetate 100:0→60:40)

실험 절차

(R)-Ethyl 3-((R)-1,1-dimethylethylsulfinamido)-2,2-difluoro-3-(2-fluorophenyl)butanoate (7.6 g, 20.8 mmol) was dissolved in toluene (100 ml) (dried over 4 Å MS) and transferred to a dry round bottom flask. The solution was cooled to −78° C. using a dry ice/acetone bath. DIBAL-H (41.6 ml, 41.6 mmol, 1 M in toluene) was added in a dropwise manner using a syringe pump (addition rate 1 mL/min) Upon complete addition the reaction was stirred at −78° C. for an additional 1 h 20 min. The reaction was quenched at −78° C. by addition of 10 mL of ethyl acetate followed by addition of 150 mL of a saturated aqueous solution of sodium potassium tartrate. Upon complete addition the cooling was removed, the reaction allowed to warm to room temperature and stirred at this temperature for 1 h. The mixture was diluted with ethyl acetate (200 mL) and filtered through a plug of celite using ethyl acetate for elution. The filtrate was transferred to a separation funnel and the organic layer was isolated. The aqueous phase was extracted with ethyl acetate (2×100 mL), the combined organics were washed with brine (100 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to afford an intermediate. The intermediate was used immediately in the subsequent step without further purification. Lithium chloride (2.20 g, 52.0 mmol) was placed in a round bottom flask, dried under vacuum with heating and allowed to cool to room temperature under vacuum. Acetonitrile (87 mL) was added followed by ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate (5.79 g, 23.9 mmol). The solution was cooled to 0° C. using an ice/water bath and N,N-diisopropylethylamine (4.03 g, 5.5 ml, 31.2 mmol) was added. After 10 min stirring at this temperature a solution of the intermediate mentioned above in acetonitrile (33 ml) was added. Upon complete addition the cooling was removed and the reaction was stirred overnight at room temperature. The reaction mixture was concentrated to approximately 50 mL (under vacuum), ethyl acetate (250 mL), water (50 mL) and saturated aqueous NH4Cl (50 mL) were added. The phases were separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organics were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified using a CombiFlash system (220 g SiO2, gradient elution; heptanes:ethyl acetate 100:0→60:40) to afford (R)-ethyl 5-((R)-1,1-dimethylethylsulfinamido)-2,4,4-trifluoro-5-(2-fluorophenyl)hex-2-enoate (5.1 g, 60% yield). 1H NMR (600 MHz, CDCl3) δ 7.45 (tt, J=4.3, 2.2 Hz, 1H), 7.40-7.33 (m, 1H), 7.16 (tt, J=5.4, 2.7 Hz, 1H), 7.09 (ddd, J=13.2, 8.2, 1.2 Hz, 1H), 6.00 (dt, J=20.3, 14.5 Hz, 1H), 4.98 (d, J=4.1 Hz, 1H), 4.30 (q, J=7.1 Hz, 2H), 2.03 (s, 3H), 1.32 (t, J=7.2 Hz, 3H), 1.24 (s, 9H).

출처