反应详情

温度

60 °C

To a solution of 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methoxy)-3-nitroquinoline (for a preparation see intermediate 18, 7 g) in acetonitrile (100 ml) was added (2-pyridinylmethyl)amine (6.8 g) and the resulting mixture was heated at 60° C. for 1 h. The reaction mixture was then hydrolysed, extracted with DCM and the combined organic phases were dried (Na2SO4), filtered and evaporated to dryness. A portion of this material (2 g) was dissolved in Ethanol (80 ml) and HCl (1 ml, conc.). Tin (II) chloride dihydrate (1 g) was then added in two portions and the reaction mixture was stirred for 2 h at room temperature. The reaction mixture was hydrolysed using a saturated solution of sodium hydrogen carbonate. The m was extracted with DCM and the combined organic layers were filtered over Celite. The filtrate was dried (Na2SO4), filtered and concentrated to dryness to give, after chromatography, 3 g of material. The latter was dissolved in DCM (100 ml) and to this mixture were added HATU (3.65 g) and tetrahydro-2H-pyran-4-carboxylic acid (1.25 g). The resulting reaction mixture was stirred overnight at room temperature and hydrolysed by adding a solution of sodium hydrogen carbonate. The reaction mixture was extracted with DCM, dried (Na2SO4), filtered and concentrated to dryness to give the crude intermediate (2.9 g). This was dissolved on acetic acid (30 ml) and the resulting mixture was heated to 90° C. for 6 h. The reaction mixture was concentrated to dryness. A saturated aqueous solution of Sodium hydrogen carbonate was added and the mixture was extracted with DCM, dried (Na2SO4), filtered and concentrated to dryness. The crude compound was purified by chromatography on silica gel, eluting with DCM/methanol (95:5), then recrystallised from ethanol and was dried under vacuum to give 7-(3,5-dimethyl-4-isoxazolyl)-8-(methyloxy)-1-(2-pyridinylmethyl)-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]quinoline as a beige powder (1.88 g).

1. extractionhydrolysed, extracted with DCM
2. dry with materialthe combined organic phases were dried (Na2SO4)
3. filtrationfiltered
4. customevaporated to dryness
5. dissolutionA portion of this material (2 g) was dissolved in Ethanol (80 ml)
6. additionTin (II) chloride dihydrate (1 g) was then added in two portions
7. extractionThe m was extracted with DCM
8. filtrationthe combined organic layers were filtered over Celite
9. dry with materialThe filtrate was dried (Na2SO4)
10. filtrationfiltered
11. concentrationconcentrated to dryness
12. customto give
13. customThe resulting reaction mixture
14. stirringwas stirred overnight at room temperature
15. extractionThe reaction mixture was extracted with DCM
16. dry with materialdried (Na2SO4)
17. filtrationfiltered
18. concentrationconcentrated to dryness
19. customto give the crude intermediate (2.9 g)
20. dissolutionThis was dissolved on acetic acid (30 ml)
21. temperaturethe resulting mixture was heated to 90° C. for 6 h
22. concentrationThe reaction mixture was concentrated to dryness
23. additionA saturated aqueous solution of Sodium hydrogen carbonate was added
24. extractionthe mixture was extracted with DCM
25. dry with materialdried (Na2SO4)
26. filtrationfiltered
27. concentrationconcentrated to dryness
28. customThe crude compound was purified by chromatography on silica gel
29. washeluting with DCM/methanol (95:5)
30. customrecrystallised from ethanol
31. customwas dried under vacuum