反应详情

温度

42.5 °C

The hydrochloride salt of N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine (100.0 g, 0.223 mole), ethyl acetate (2000 mL) and water (500 mL) were mixed together using mechanical agitation and then warmed to 40-45° C. The stirred mixture was treated portionwise with 50% aqueous sodium hydroxide (40 mL) so that the pH of the aqueous phase was in the range 8-9. The mixture was allowed to settle and separate into two clear liquid phases. The aqueous phase was removed and organic phase washed with water (300 mL). The resultant pale yellow organic solution was filtered to obtain a clear solution which was concentrated by distillation at atmospheric pressure to remove 1 L of solvent. Isopropanol (2 L) was added to the concentrate and a further 1 L of solvents were removed by distillation at atmospheric pressure. The resultant concentrate was cooled to 40° C. and treated with methanesulfonic acid (15.1 mL, 0.233 mole) and allowed to crystallize. The crystal slurry was warmed to 62° C. for 18 hours. Monitoring with near-infrared spectroscopy after the method of Norris, Aldridge and Sekulic, Analyst, 1997, 122, 549, indicated that no conversion to polymorph C had occurred. The temperature was raised to 70° C., after a period of 16 hours, near-infrared monitoring as described indicated the conversion was complete. The heat source was removed and the mixture cooled to 0-5° C. and granulated for a period of 1 hour. The crystalline product was isolated by filtration, washed with isopropanol (50 mL) and dried under vacuum at 33° C. to give polymorph C, 105.63 g, yield 93%, as a white crystalline solid mp 153-156° C.

1. customseparate into two clear liquid phases
2. customThe aqueous phase was removed
3. washorganic phase washed with water (300 mL)
4. filtrationThe resultant pale yellow organic solution was filtered
5. customto obtain a clear solution which
6. concentrationwas concentrated by distillation at atmospheric pressure
7. customto remove 1 L of solvent
8. additionIsopropanol (2 L) was added to the
9. concentrationconcentrate
10. customa further 1 L of solvents were removed by distillation at atmospheric pressure
11. concentrationThe resultant concentrate
12. temperaturewas cooled to 40° C.
13. customto crystallize
14. temperatureThe crystal slurry was warmed to 62° C. for 18 hours
15. temperatureThe temperature was raised to 70° C., after a period of 16 hours
16. customThe heat source was removed
17. temperaturethe mixture cooled to 0-5° C.
18. customThe crystalline product was isolated by filtration
19. washwashed with isopropanol (50 mL)
20. customdried under vacuum at 33° C.
21. customto give polymorph C, 105.63 g, yield 93%