反应详情

温度

65 °C

Potassium (E)-2-chloro-3-ethoxy-3-oxoprop-1-en-1-olate (Preparation E; 41.32 g, 219.0 mmol) was suspended (through vigorous magnetic stirring) in anhydrous ether (365 mL) and 6N sulfuric acid (18.25 mL, 109.5 mmol) was added. Water (100 mL) was added to aid in phase separation. When the pH of the bottom (aqueous) phase, dropped below 3, the ether layer was separated. The aqueous phase was further extracted with ether (400 mL). The combined ether phases were dried over sodium sulfate and magnesium sulfate for 10 minutes. The solution was filtered and concentrated under reduced pressure, with the temperature of the water bath not exceeding 20° C. A residual oil was obtained, which crystallized upon drying under high vacuum overnight. This residue was dissolved in absolute EtOH (360 mL). 4-(2-(4-Isopropylpiperazin-1-yl)ethoxy)pyridin-2-amine (Preparation G; 28.95 g, 109.5 mmol) was added, and the mixture was heated under nitrogen at 65° C. for 18 hours. After allowing the mixture to cool, the resulting suspension was evaporated to dryness. The resulting solids were shaken with THF and collected by filtration, then dried under vacuum. This material (HCl salt) was mixed with water (400 mL) and ethanol (200 mL). Sodium bicarbonate (20 g) was added and the mixture was stirred for 16 hours (some effervescence occurred). The suspension was evaporated to dryness under vacuum. The solids were shaken in EtOAc/THF and filtered. These solids were washed with a large volume of ethyl acetate and THF. The organic solution was further dried with sodium sulfate and magnesium sulfate, filtered and evaporated under vacuum to give an amber gum. This material was triturated with 2:1 ether-hexanes, and the resulting solids were collected by filtration to afford ethyl 7-(2-(4-isopropylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (23.46 g, 59% yield) as beige solids.

1. additionWhen the pH of the bottom (aqueous) phase, dropped below 3
2. customthe ether layer was separated
3. extractionThe aqueous phase was further extracted with ether (400 mL)
4. dry with materialThe combined ether phases were dried over sodium sulfate and magnesium sulfate for 10 minutes
5. filtrationThe solution was filtered
6. concentrationconcentrated under reduced pressure, with the temperature of the water bath not
7. customexceeding 20° C
8. customA residual oil was obtained
9. customwhich crystallized
10. customupon drying under high vacuum overnight
11. dissolutionThis residue was dissolved in absolute EtOH (360 mL)
12. temperatureto cool
13. customthe resulting suspension was evaporated to dryness
14. filtrationcollected by filtration
15. customdried under vacuum
16. additionThis material (HCl salt) was mixed with water (400 mL) and ethanol (200 mL)
17. additionSodium bicarbonate (20 g) was added
18. stirringthe mixture was stirred for 16 hours (some effervescence
19. customThe suspension was evaporated to dryness under vacuum
20. stirringThe solids were shaken in EtOAc/THF
21. filtrationfiltered
22. washThese solids were washed with a large volume of ethyl acetate and THF
23. dry with materialThe organic solution was further dried with sodium sulfate and magnesium sulfate
24. filtrationfiltered
25. customevaporated under vacuum
26. customto give an amber gum
27. customThis material was triturated with 2:1 ether-hexanes
28. filtrationthe resulting solids were collected by filtration