Formaldehyde → Vandetanib

Temperature

81 °C

7-(1-tert-butoxycarbonyl)piperidine-4-ylmethoxy)-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline (40 g), water (16 ml), formic acid (43 ml) and aqueous formaldehyde (37% w/w, 33 ml) were added to a vessel equipped with overhead stirrer, reflux condenser and thermometer. The reaction mixture was heated to 81° C. and stirred at this temperature for 5 hours. The reaction mixture was cooled to 60° C. and tetrahydrofuran (178 ml) was added. The temperature of the reaction mixture was adjusted to 40° C. and potassium hydroxide (49% w/w, 84 ml) was added, followed by water (22 ml). The aqueous phase was separated and discarded. The organic phase was adjusted to 60° C. and water (107 ml) and butyl acetate (107 ml) were added. The aqueous phase was separated and discarded. The organic phase was filtered, following through with tetrahydrofuran (18 ml) wash. The temperature of the filtrates was adjusted to 60° C. and butyl acetate (107 ml) was added. The reaction mixture was set for distillation at ambient pressure. The distillation was stopped when the contents temperature reached 106° C. The slurry was cooled to 65° C. and tetrahydrofuran (107 ml) was added. The slurry was cooled to 0-5° C. and held for 1 hour before isolating the product by filtration. The product was washed with ethyl acetate (72 ml) and dried at 50° C. Yield: 24.82 g, 80.3%.

1. customequipped with overhead stirrer
2. temperaturereflux condenser
3. temperatureThe reaction mixture was cooled to 60° C.
4. customwas adjusted to 40° C.
5. customThe aqueous phase was separated
6. customwas adjusted to 60° C.
7. additionwater (107 ml) and butyl acetate (107 ml) were added
8. customThe aqueous phase was separated
9. filtrationThe organic phase was filtered
10. washwash
11. customwas adjusted to 60° C.
12. additionbutyl acetate (107 ml) was added
13. distillationThe reaction mixture was set for distillation at ambient pressure
14. distillationThe distillation
15. customreached 106° C
16. temperatureThe slurry was cooled to 65° C.
17. additiontetrahydrofuran (107 ml) was added
18. temperatureThe slurry was cooled to 0-5° C.
19. waitheld for 1 hour
20. custombefore isolating the product
21. filtrationby filtration
22. washThe product was washed with ethyl acetate (72 ml)
23. customdried at 50° C

ORD record

ord-8ce5b1fe291c41b5b2d47387804b7a43

Source dataset

uspto-grants-2014_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08865899B2