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 (VII-4, 786 mg) and 614 mg of (S)-2-aminooxymethyl-morpholine-4-carboxylic acid tert-butyl ester in 31 ml of 1,4-dioxane was added 2.21 ml of 2 mol/L methanesulfonic acid aqueous solution, followed by stirring at 80° C. for 22 hours. And, 1.32 ml of 2 mol/L methanesulfonic acid aqueous solution was additionally added, followed by further stirring for 5.5 hours. After completion of the reaction, the reaction mixture was poured into aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate. After an aqueous layer was re-extracted with ethyl acetate, all organic layers were combined, washed with water, and dried over anhydrous magnesium sulfate. After the filtrate was concentrated, the residue was purified by silica gel column chromatography (eluting with chloroform:methanol=9:1) to obtain a yellow oil. This oil was dissolved in 50 ml of ethyl acetate, and filtered, and 0.95 ml of 4 mol/L hydrochloric acid-ethyl acetate solution was added with stirring, followed by stirring at room temperature for 1 hour. A precipitate was filtered, and washed with ethyl acetate and hexane in this order. A substance collected by filtration was recrystallized with methanol-ethyl acetate to obtain 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-((S)-morpholin-2-ylmethoxyimino)-2-butyn-1-yl)quinazoline dihydrochloride (VIII-32, 839 mg) as a yellow crystal.

1. stirringby further stirring for 5.5 hours
2. customAfter completion of the reaction
3. extractionfollowed by extraction with ethyl acetate
4. extractionAfter an aqueous layer was re-extracted with ethyl acetate
5. washwashed with water
6. dry with materialdried over anhydrous magnesium sulfate
7. concentrationAfter the filtrate was concentrated
8. customthe residue was purified by silica gel column chromatography (eluting with chloroform:methanol=9:1)
9. customto obtain a yellow oil
10. filtrationfiltered
11. addition0.95 ml of 4 mol/L hydrochloric acid-ethyl acetate solution was added
12. stirringwith stirring
13. stirringby stirring at room temperature for 1 hour
14. filtrationA precipitate was filtered
15. washwashed with ethyl acetate and hexane in this order
16. filtrationA substance collected by filtration
17. customwas recrystallized with methanol-ethyl acetate