反应详情

To a 100 ml round bottom flask containing 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-benzyl-pyrrolidin-3-yl)-amide (530 mg, 0.88 mmol) and proton sponge (132 mg, 0.62 mmol) was added 1,2 dichloroethane (20 ml). The clear solution was stirred under nitrogen and cooled in an ice bath for 10 min. To this was added 1-chloroethyl chloroformate (0.19 ml, 1.77 mmol). The reaction was stirred in the ice bath for 5 min, the bath removed and the reaction warmed to room temperature for 20 min. The reaction was placed in an oil bath and heated at 85° C. for 4 h then allowed to cool to room temperature overnight and concentrated. The residue was suspended in methanol (20 ml) and heated at reflux for 3 h then removed from the heat and allowed to cool to room temperature. Some product precipitated during cooling and was filtered off and washed with methanol. The remaining product was recovered from the mother liquor. The liquid was concentrated, suspended in ethyl acetate and washed with aqueous sodium bicarbonate. The aqueous solution with solids was extracted four times with dichloromethane. The organic layers were combined and washed with brine (100 ml), dried over magnesium sulfate, filtered, concentrated, and dried from a mixture of ethyl acetate and hexanes. The crude was suspended in boiling ethyl acetate (20 ml), cooled, filtered and washed with ethyl acetate and hexanes to afford 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (R)-pyrrolidin-3-ylamide as a white solid. This material was combined with the product that precipitated from the reaction and was used without further purification. LC-MS: (M+H)+=510.

1. temperaturecooled in an ice bath for 10 min
2. customthe bath removed
3. customThe reaction was placed in an oil bath
4. temperatureheated at 85° C. for 4 h
5. temperatureto cool to room temperature overnight
6. concentrationconcentrated
7. temperatureheated
8. temperatureat reflux for 3 h
9. customthen removed from the
10. temperatureheat
11. temperatureto cool to room temperature
12. customSome product precipitated
13. temperatureduring cooling
14. filtrationwas filtered off
15. washwashed with methanol
16. customThe remaining product was recovered from the mother liquor
17. concentrationThe liquid was concentrated
18. washwashed with aqueous sodium bicarbonate
19. extractionThe aqueous solution with solids was extracted four times with dichloromethane
20. washwashed with brine (100 ml)
21. dry with materialdried over magnesium sulfate
22. filtrationfiltered
23. concentrationconcentrated
24. dry with materialdried from a mixture of ethyl acetate and hexanes
25. temperaturecooled
26. filtrationfiltered
27. washwashed with ethyl acetate and hexanes