반응 #8620

반응 방정식

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

Isobutyl 4-(1,1-dioxido-4-thiomorpholinyl)-3,5-difluorophenylcarbamate

lithium t-butoxide

methanol

acetic acid

→

lithium t-butoxide

title compound

수율 73.0%

N-[[(5S)-3-[4-(1,1-Dioxido-4-thiomorpholinyl)-3,5-difluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide

수율 73.0%

용매

THF

THF

Water

THF

반응 조건

후처리

1. 1
   온도while maintaining less than 20° C
2. 2
   workup.ADDITIONadded to the reaction mixture over 1 h
3. 3
   온도while maintaining the reaction temperature between 15 and 17° C
4. 4
   workup.STIRRINGThe cloudy light yellow/brown solution is stirred at 15 to 16° C. for 16 h
5. 5
   온도while maintaining less than 20° C
6. 6
   기타The phases are separated
7. 7
   세척the organic phase washed with water (20 ml)
8. 8
   농축The organic phase is concentrated to approximately 200 ml total volume
9. 9
   workup.ADDITIONIsopropanol (300 ml) is added slowly to the stirred orange solution via syringe pump at a rate of 2 ml/min
10. 10
    workup.STIRRINGstirred for 30 min
11. 11
    여과The product is collected by vacuum filtration
12. 12
    세척washed with cold isopropanol (2×100 ml)
13. 13
    기타dried in vacuo at 60° C. overnight

실험 절차

A slurry of lithium t-butoxide (18.0 g, 223.5 mmol, 3.00 eq) in THF (100 ml) is prepared. Isobutyl 4-(1,1-dioxido-4-thiomorpholinyl)-3,5-difluorophenylcarbamate (27.0 g, 74.5 mmol) is dissolved in THF (180 ml) then added to the lithium t-butoxide slurry while maintaining less than 20° C. The mixture is stirred for 15 min then methanol (6.1 ml, 149 mmol, 2.0 eq) is added. (S)—N-[2-(acetyloxy)-3-chloropropyl]acetamide (28.9 g, 149 mmol, 2.0 eq) is dissolved in THF (100 mL) and added to the reaction mixture over 1 h while maintaining the reaction temperature between 15 and 17° C. The cloudy light yellow/brown solution is stirred at 15 to 16° C. for 16 h. The reaction is then quenched with concentrated acetic acid (8.6 ml, 149 mmol, 2.0 eq) while maintaining less than 20° C. Water (75 ml) is added via addition funnel over 3 min. The phases are separated and the organic phase washed with water (20 ml). The organic phase is concentrated to approximately 200 ml total volume. Isopropanol (300 ml) is added slowly to the stirred orange solution via syringe pump at a rate of 2 ml/min. The yellow slurry is then cooled to approximately 5 to 10° C. and stirred for 30 min. The product is collected by vacuum filtration, washed with cold isopropanol (2×100 ml) and dried in vacuo at 60° C. overnight to give the title compound (22.0 g, 73%): HPLC retention time=3.0 min (99.8 area %); HPLC procedure: Inertsil ODS-2 5.0 micron 150×4.6 mm, flow rate=1.0 ml/min, detection at 254 nm, isocratic elution solvent: 479.5 g buffer (1 l water, 1.57 g ammonium formate, formic acid to pH=3.2) and 409.1 g acetonitrile.

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