反应详情

温度

60 °C

6-Acetoxy-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline hydrochloride from step 1 (33.5 kg, 69.6 mol) was suspended in methanol (198 kg). To the stirred suspension at 25° C. was added water (86 kg) and sodium hydroxide (31.5 kg, 32%). The resulting solution was stirred at 60° C. for 4.5 hours and then cooled to 25° C. Acetic acid (approximately 16.0 kg) was added until a pH of 5.5-6.0 was achieved at which point the product precipitates from solution. After the addition of further methanol (5.5 kg) the suspension was stirred for 90 minutes. The product was filtered then washed with 25% aqueous methanol (39.0 kg MeOH+17.0 kg Water) and then methanol (55.5 kg). The crude solid was dried under vacuum at 40° C. The crude solid was slurried with water (145 kg) and stirred for 2 hours at 65° C. The slurry was cooled to 20° C. and filtered. The filter cake was washed with methanol (2×21.5 kg), then dried under vacuum at 40° C. to give a the title product as a light brown solid (21.85 kg, 98%); 1H NMR: 3.95 (s, 3H), 7.19 (s, 1H), 7.23 (dd, 1H), 7.42 (dd, 1H), 7.50 (dd, 1H), 7.64 (s, 1H), 8.32 (s, 1H), 9.43 (s, 1H), 9.67 (br.s, 1H); Mass Spectrum: 320.4, 322.4.

1. temperaturecooled to 25° C
2. customprecipitates from solution
3. additionAfter the addition of further methanol (5.5 kg) the suspension
4. stirringwas stirred for 90 minutes
5. filtrationThe product was filtered
6. washthen washed with 25% aqueous methanol (39.0 kg MeOH+17.0 kg Water)
7. customThe crude solid was dried under vacuum at 40° C
8. stirringstirred for 2 hours at 65° C
9. temperatureThe slurry was cooled to 20° C.
10. filtrationfiltered
11. washThe filter cake was washed with methanol (2×21.5 kg)
12. customdried under vacuum at 40° C.