반응 #61113

반응 방정식

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

용매

—

solution

trifluoroacetic acid

dichloromethane

dichloromethane

dichloromethane

반응 조건

후처리

1. 1
   기타After 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
   추출extracted twice with ethyl acetate
4. 4
   건조The combined organic layers were dried over sodium sulfate
5. 5
   여과filtered
6. 6
   농축concentrated to an off white solid
7. 7
   workup.ADDITIONthe resulting solution was added in a dropwise manner to a 0° C.
8. 8
   기타partitioned between dichloromethane and water
9. 9
   건조The organic layer was dried over sodium sulfate
10. 10
    여과filtered
11. 11
    농축concentrated to the crude product
12. 12
    기타After purification by chromatography over silica gel gradient
13. 13
    세척eluted up to 3:2 ethyl acetate/hexanes and precipitation of the material

실험 절차

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%).

출처