Reaktion #61113

Reaktionsgleichung

2-{(2S,3S)-2-[2-tert-Butoxycarbonylamino-2-(4-methylsulfanyl-phenyl)-acetylamino]-3-phenyl-butyrylamino}-thiazole-4-carboxylic acid methyl ester

diisopropyl ethyl amine

diphosgene

→

2-{(2S,3S)-2-[4-(4-methylsulfanyl-phenyl)-2,5-dioxo-imidazolidin-1-yl]-3-phenyl-butyrylamino}-thiazole-4-carboxylic acid methyl ester

Lösungsmittel

—

solution

trifluoroacetic acid

dichloromethane

dichloromethane

dichloromethane

Reaktionsbedingungen

Aufarbeitung

1. 1
   SonstigeAfter 2.5 hours the reaction mixture was partitioned between ethyl acetate and aqueous saturated sodium bicarbonate
2. 2
   workup.ADDITIONThe aqueous layer was adjusted to pH=8 by the addition of solid sodium bicarbonate
3. 3
   Extraktionextracted twice with ethyl acetate
4. 4
   TrocknenThe combined organic layers were dried over sodium sulfate
5. 5
   Filtrationfiltered
6. 6
   Einengenconcentrated to an off white solid
7. 7
   workup.ADDITIONthe resulting solution was added in a dropwise manner to a 0° C.
8. 8
   Sonstigepartitioned between dichloromethane and water
9. 9
   TrocknenThe organic layer was dried over sodium sulfate
10. 10
    Filtrationfiltered
11. 11
    Einengenconcentrated to the crude product
12. 12
    SonstigeAfter purification by chromatography over silica gel gradient
13. 13
    Wascheneluted up to 3:2 ethyl acetate/hexanes and precipitation of the material

Vorschrift

2-{(2S,3S)-2-[2-tert-Butoxycarbonylamino-2-(4-methylsulfanyl-phenyl)-acetylamino]-3-phenyl-butyrylamino}-thiazole-4-carboxylic acid methyl ester (110 mg, 0.18 mmol) was dissolved at 0° C. in a 30% solution of trifluoroacetic acid in dichloromethane. After 2.5 hours the reaction mixture was partitioned between ethyl acetate and aqueous saturated sodium bicarbonate. The aqueous layer was adjusted to pH=8 by the addition of solid sodium bicarbonate and then extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated to an off white solid. The solid was dissolved in a solution of diisopropyl ethyl amine (0.16 mL, 0.92 mmol) in dichloromethane (5 mL) and the resulting solution was added in a dropwise manner to a 0° C. mixture of diphosgene (16 μL, 0.13 mmol) in dichloromethane (5 mL). The mixture was stirred for 20 minutes and then partitioned between dichloromethane and water. The organic layer was dried over sodium sulfate, filtered and concentrated to the crude product. After purification by chromatography over silica gel gradient eluted up to 3:2 ethyl acetate/hexanes and precipitation of the material obtained from chromatography from dichloromethane with excess hexanes, 2-{(2S,3S)-2-[4-(4-methylsulfanyl-phenyl)-2,5-dioxo-imidazolidin-1-yl]-3-phenyl-butyrylamino}-thiazole-4-carboxylic acid methyl ester, was isolated as a white amorphous solid (45 mg, 46%).

Quelle