反应详情

温度

80 °C

To a suspension of 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-oxo-2-butyn-1-yl)quinazoline (IV) (786 mg) and tert-buthyl (S)-2-aminoxymethyl-morpholine-4-carboxylate (614 mg) in 1,4-dioxane (31 mL) was added 2 mol/L methanesulfonic acid aq. solution (2.21 mL) and stirred for 22 hr at 80° C. 2 mol/L methanesulfonic acid aq. solution (1.32 mL) was added and stirred for additional 5.5 hr. After the reaction was completed, the mixture was poured into ice-sodium hydrogen carbonate aq. solution and extracted with ethyl acetate. After the aqueous layer was extracted again with ethylacetate, all the organic layers were combined, washed with water and dried over anhydrous magnesium sulfate. The filtrate was concentrated and the residue was purified by silicagel column chromatography (eluted with chloroform:methanol=9:1) to give yellow oil. A solution of this oil in ethyl acetate (50 mL) was filtered and 4 mol/L hydrochloric acid-ethyl acetate (0.95 mL) was added under stirring and stirred for 1 hr at room temperature. The precipitate was filtered and washed with ethyl acetate and then hexane. The precipitate was recrystallized from methanol-ethyl acetate to give 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-((S)-morpholine-2-yl-methoxyimino)-2-butyn-1-yl)quinazoline.2HCl (VI-1) (839 mg) as yellow crystalline.

1. stirringstirred for additional 5.5 hr
2. extractionextracted with ethyl acetate
3. extractionAfter the aqueous layer was extracted again with ethylacetate, all the organic layers
4. washwashed with water
5. dry with materialdried over anhydrous magnesium sulfate
6. concentrationThe filtrate was concentrated
7. customthe residue was purified by silicagel column chromatography (eluted with chloroform:methanol=9:1)
8. customto give yellow oil
9. filtrationA solution of this oil in ethyl acetate (50 mL) was filtered
10. addition4 mol/L hydrochloric acid-ethyl acetate (0.95 mL) was added
11. stirringunder stirring
12. stirringstirred for 1 hr at room temperature
13. filtrationThe precipitate was filtered
14. washwashed with ethyl acetate
15. customThe precipitate was recrystallized from methanol-ethyl acetate