반응 #8618

반응 방정식

acetic acid

lithium t-butoxide

[4-(3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]carbamic acid 2-methylpropyl ester

(S)—N-[2-(acetyloxy)-3-chloropropyl]acetamide

→

title compound

수율 78.5%

(S)—N-[[3-[4-(3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide

수율 78.5%

용매

—

isooctanes

methanol

methanol

N,N-dimethylformamide

toluene

반응 조건

후처리

1. 1
   온도The mixture is cooled to 0° C.
2. 2
   온도The mixture is warmed to 21° C.
3. 3
   기타The phases are separated
4. 4
   세척the upper washed twice with a mixture of methanol (29 ml) and water (9 ml)
5. 5
   workup.ADDITIONis added water (69 ml) and methylene chloride (69 ml)
6. 6
   기타The phases are separated
7. 7
   세척the upper phase washed twice with methylene chloride (29 ml)
8. 8
   농축are concentrated under reduced pressure to 112 ml total volume
9. 9
   workup.ADDITIONMethanol (69 ml) is added
10. 10
    농축the mixture concentrated to 112 ml
11. 11
    workup.ADDITIONMethanol (69 ml) is added
12. 12
    농축the mixture concentrated to 75 ml
13. 13
    workup.ADDITIONtoluene (65 ml) is added
14. 14
    workup.ADDITIONWater (65 ml) is added over ½ h
15. 15
    온도while maintaining 19 to 30° C
16. 16
    온도The mixture is cooled to 9° C.
17. 17
    workup.ADDITIONisooctanes (56 ml) added
18. 18
    온도The slurry is cooled to 0° C.
19. 19
    여과the precipitate collected by vacuum filtration
20. 20
    세척washed with water (22 ml) and isooctanes (22 ml)
21. 21
    기타dried in a nitrogen stream

실험 절차

To a mixture of [4-(3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]carbamic acid 2-methylpropyl ester (17.89 g, 57.83 mmol), (S)—N-[2-(acetyloxy)-3-chloropropyl]acetamide (22.35 g, 115.42 mmol, 2.00 eq), methanol (3.66 g, 114 mmol, 1.97 eq), 2,6-di-tert-butyl-4-methylphenol (0.1365 g, 0.6194 mmol, 0.0107 eq), toluene (52 ml), isooctanes (49 ml), and N,N-dimethylformamide (34.3 ml) is added a solution of lithium t-butoxide (13.94 g, 174.1 mmol, 3.01 eq) in isooctanes (130 ml) over 1.6 h while maintaining 15° C. Isooctanes (20 ml) is added and the mixture stirred at 15 to 19° C. for 17 h. The mixture is cooled to 0° C. and acetic acid (6.7 ml, 117 mmol, 2.02 eq) added. The mixture is warmed to 21° C. and methanol (29 ml) added. The phases are separated and the upper washed twice with a mixture of methanol (29 ml) and water (9 ml). To the combined lower phases is added water (69 ml) and methylene chloride (69 ml). The phases are separated and the upper phase washed twice with methylene chloride (29 ml). The combined lower phases are concentrated under reduced pressure to 112 ml total volume. Methanol (69 ml) is added and the mixture concentrated to 112 ml. Methanol (69 ml) is added and the mixture concentrated to 75 ml then toluene (65 ml) is added. Water (65 ml) is added over ½ h while maintaining 19 to 30° C. The mixture is cooled to 9° C. and isooctanes (56 ml) added. The slurry is cooled to 0° C. and the precipitate collected by vacuum filtration, washed with water (22 ml) and isooctanes (22 ml) and dried in a nitrogen stream to give the title compound (15.909 g, 78.5%): HPLC retention time=2.77 min (column=Phenomenex Luna 5.0 micron C-8(12) 150×4.6 mm, flow rate=2.0 ml/min, gradient elution from 40:60 A:B to 73.3:26.7 A:B over 15 minutes; A=acetonitrile; B=water).

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