反应详情

温度

100 °C

3-[3-[[1-[2-(2-Chloroethoxy)phenyl]-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl-benzamide (Example 198e, 17.5 g) in dioxane (50 mL) was treated with 40% Methylamine solution (50 ml) under nitrogen. The resulting suspension was heated in a sealed system at 100° C. for 4 h. After cooling to room temperature, the solution was evaporated to dryness. The crude product was purified by flash chromatography (SiO2, eluent 10% methanol in dichloromethane and 1% triethylamine). Evaporation of the relevant fractions to dryness and trituration of the residue in diethyl ether gave a solid which was filtered off. The filtrate was collected and evaporated. This residue was purified by preparative HPLC (Waters X-Terra column using a 95-5% gradient of aqueous 0.2% ammonia in acetonitrile as eluent). The fractions containing the desired compound were evaporated to dryness. Further purification by preparative HPLC (phenomenex column, aqueous 0.2% ammonia in acetonitrile as eluent) and freeze-drying of the relevant fractions gave a solid. This freeze dried material readily dissolved in ethyl acetate (30 mL) at room temperature and after stirring for 1 h some solid precipitated. The mixture was then heated to at 85° C. for 1 h to effect dissolution and then cooled and stirred at room temperature for 1 week. The solid was filtered off and dried in vacuo at 40° C. to afford the title compound (2.20 g).

1. temperatureAfter cooling to room temperature
2. customthe solution was evaporated to dryness
3. customThe crude product was purified by flash chromatography (SiO2, eluent 10% methanol in dichloromethane and 1% triethylamine)
4. customEvaporation of the relevant fractions to dryness and trituration of the residue in diethyl ether
5. customgave a solid which
6. filtrationwas filtered off
7. customThe filtrate was collected
8. customevaporated
9. customThis residue was purified by preparative HPLC (Waters X-Terra column
10. additionThe fractions containing the desired compound
11. customwere evaporated to dryness
12. customFurther purification by preparative HPLC (phenomenex column, aqueous 0.2% ammonia in acetonitrile as eluent)
13. customfreeze-drying of the relevant fractions
14. customgave a solid
15. customprecipitated
16. temperatureThe mixture was then heated to at 85° C. for 1 h
17. dissolutiondissolution
18. temperaturecooled
19. stirringstirred at room temperature for 1 week
20. filtrationThe solid was filtered off
21. customdried in vacuo at 40° C.