反应详情

The hydrochloride salt of N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine (30.0 g, 69.79 mmol), dichloromethane (1125 mL) and water (300 mL) were mixed together using mechanical agitation and then treated with saturated sodium bicarbonate solution (300 mL). The mixture was allowed to settle and separate into two cloudy liquid phases. The aqueous phase was removed and further extracted with dichloromethane (300 mL) The organic layers were combined and washed with saturated sodium bicarbonate solution (300 mL), separated and dried by treatment with dried magnesium sulfate (50 g) and then filtered to give a clear organic layer which was concentrated by evaporation to a volume of about 300 mL. The resultant solution was treated with isopropanol (450 mL) and concentrated by evaporation to 300 mL giving a slurry mixture. The slurry mixture was treated slowly with methanesulfonic acid (4.5 mL, 69.79 mmol) to give a pale yellow solution which on cooling to room temperature gave a gum. Addition of seed crystals of polymorph B as prepared in example 4 eventually resulted in formation of a crystal slurry. The crystal slurry was granulated for 24 hours at ambient temperature overnight, the crystals were isolated by filtration, washed with isopropanol (50 mL) and dried under vacuum at 45° C. to give polymorph B, 23.43 g, yield 69%, as a white crystalline solid mp 142-144° C.

1. customseparate into two cloudy liquid phases
2. customThe aqueous phase was removed
3. extractionfurther extracted with dichloromethane (300 mL) The organic layers
4. washwashed with saturated sodium bicarbonate solution (300 mL)
5. customseparated
6. dry with materialdried by treatment with dried magnesium sulfate (50 g)
7. filtrationfiltered
8. customto give a clear organic layer which
9. concentrationwas concentrated by evaporation to a volume of about 300 mL
10. additionThe resultant solution was treated with isopropanol (450 mL)
11. concentrationconcentrated by evaporation to 300 mL
12. customgiving a slurry mixture
13. customto give a pale yellow solution which
14. customgave a gum
15. additionAddition of seed crystals of polymorph B
16. customas prepared in example 4
17. customeventually resulted in formation of a crystal slurry
18. customthe crystals were isolated by filtration
19. washwashed with isopropanol (50 mL)
20. customdried under vacuum at 45° C.
21. customto give polymorph B, 23.43 g, yield 69%