تفاعل #8618

معادلة التفاعل

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

المردود 78.5%

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

المردود 78.5%

المذيبات

—

isooctanes

methanol

methanol

N,N-dimethylformamide

toluene

ظروف التفاعل

المعالجة

1. 1
   درجة الحرارةThe mixture is cooled to 0° C.
2. 2
   درجة الحرارةThe mixture is warmed to 21° C.
3. 3
   أخرىThe phases are separated
4. 4
   غسيلthe 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
   أخرىThe phases are separated
7. 7
   غسيلthe upper phase washed twice with methylene chloride (29 ml)
8. 8
   تركيزare concentrated under reduced pressure to 112 ml total volume
9. 9
   workup.ADDITIONMethanol (69 ml) is added
10. 10
    تركيزthe mixture concentrated to 112 ml
11. 11
    workup.ADDITIONMethanol (69 ml) is added
12. 12
    تركيزthe 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
    درجة الحرارةwhile maintaining 19 to 30° C
16. 16
    درجة الحرارةThe mixture is cooled to 9° C.
17. 17
    workup.ADDITIONisooctanes (56 ml) added
18. 18
    درجة الحرارةThe slurry is cooled to 0° C.
19. 19
    ترشيحthe precipitate collected by vacuum filtration
20. 20
    غسيلwashed with water (22 ml) and isooctanes (22 ml)
21. 21
    أخرىdried in a nitrogen stream

الإجراء التجريبي

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).

المصدر