反应详情

温度

15 °C

7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (28 kg) and triethylamine hydrochloride (2.7 kg) were added to anisole (244 kg). N,N-Diisopropylethylamine (19.2 kg) was added, followed by a line wash of anisole (20 kg). The mixture was cooled to 15° C. and phosphorus oxychloride (19.8 kg) added over 5 minutes, followed by a line wash of anisole (13.9 kg). After stirring for 15 minutes the mixture was heated to 80° C. over 90 minutes and held at 80° C. for 1 hour. When the reaction was complete the batch was transferred to a new reactor, followed by a line wash of anisole (39.7 kg). The mixture was cooled to 40° C. and 16.19% w/w aqueous sodium hydroxide solution (132 kg) added over 15 minutes, allowing the temperature to rise to 50° C., followed by a line wash of water (5 kg). The mixture was held at 50° C. for 30 minutes, then heated to 80° C. The batch was filtered through a Gaf filter, followed by a line-wash of anisole (10 kg). The lower aqueous layer was separated and the upper organic layer washed at 80° C. with 20.9% w/w aqueous sodium chloride solution (98.2 kg). The mixture was distilled under reduced pressure (80 mbar) to leave a residual volume of 224 l. 1-Methyl-2-pyrrolidinone (28.9) was added and the mixture heated to 80° C. to give a solution of 7-(benzyloxy)-4-chloro-6-methoxyquinazoline.

1. washwash of anisole (20 kg)
2. additionphosphorus oxychloride (19.8 kg) added over 5 minutes
3. washwash of anisole (13.9 kg)
4. temperaturewas heated to 80° C. over 90 minutes
5. waitheld at 80° C. for 1 hour
6. customwas transferred to a new reactor
7. washwash of anisole (39.7 kg)
8. temperatureThe mixture was cooled to 40° C.
9. addition16.19% w/w aqueous sodium hydroxide solution (132 kg) added over 15 minutes
10. customto rise to 50° C.
11. washwash of water (5 kg)
12. waitThe mixture was held at 50° C. for 30 minutes
13. temperatureheated to 80° C
14. filtrationThe batch was filtered through a Gaf
15. filtrationfilter
16. washa line-wash of anisole (10 kg)
17. customThe lower aqueous layer was separated
18. washthe upper organic layer washed at 80° C. with 20.9% w/w aqueous sodium chloride solution (98.2 kg)
19. distillationThe mixture was distilled under reduced pressure (80 mbar)
20. customto leave a residual volume of 224 l
21. temperaturethe mixture heated to 80° C.