Phosphorus oxychloride → 2,6-Dichloroquinoline

Phosphorus oxychloride (16.72 Kg) was charged to a vessel containing 6-chloroquinolin-2(1H)-one (12.50 Kg) (Prepared according to method of Johnston K. M. et al., J. Chem. Soc. Perkin Trans. 1, 1972, 1648 and references therein), benzyltrimethylammonium chloride (1.575 Kg) and 1,2-dimethoxyethane (87.8 Kg) at 70° C. 1,2-dimethoxyethane (22.5 Kg) was charged as a line rinse. The reaction was stirred at 70° C. to 75° C. for ca. 6 hours before the batch was concentrated to ca. 44 L by vacuum distillation (<40° C.). The concentrate was diluted with dichloromethane (253.1 Kg), adjusted to 38° C. to 45° C. and quenched by the addition of water (37.5 Kg) whilst maintaining the temperature at 38° C. to 45° C. After 70 minutes the batch was cooled to 25° C. to 30° C. and treated with Celite (1.30 Kg) for 40 minutes. The slurry was pressure filtered via a 1 μm filter membrane and the filtrates diluted with dichloromethane (87.5 Kg). The phases were separated and the aqueous phase extracted twice with dichloromethane (82 Kg). The combined organic extracts were washed sequentially with 5% w/w sodium hydrogen carbonate solution (37 L), water (37 Kg) and then concentrated to ca. 75 L at 25° C. to 40° C. Isopropanol (96.5 Kg) was charged and the batch then concentrated to ca. 75 L at 25° C. to 40° C. Isopropanol (95.4 Kg) was charged and the batch then concentrated to ca. 75 L at 25° C. to 40° C. The resultant slurry was stirred at 16° C. to 18° C. for 2 hours and then filtered. The filter cake was washed with isopropanol (19.7 Kg) at ca. 20° C. and then dried at up to 50° C. in vacuo to provide the subtitle compound as an off white solid (12.04 Kg).

1. customPrepared
2. customat 70° C
3. washrinse
4. concentrationwas concentrated to ca. 44 L by vacuum distillation (<40° C.)
5. additionThe concentrate was diluted with dichloromethane (253.1 Kg)
6. customadjusted to 38° C. to 45° C.
7. customquenched by the addition of water (37.5 Kg)
8. temperaturewhilst maintaining the temperature at 38° C. to 45° C
9. temperatureAfter 70 minutes the batch was cooled to 25° C. to 30° C.
10. additiontreated with Celite (1.30 Kg) for 40 minutes
11. filtrationfiltered via a 1 μm
12. filtrationfilter membrane
13. additionthe filtrates diluted with dichloromethane (87.5 Kg)
14. customThe phases were separated
15. extractionthe aqueous phase extracted twice with dichloromethane (82 Kg)
16. washThe combined organic extracts were washed sequentially with 5% w/w sodium hydrogen carbonate solution (37 L), water (37 Kg)
17. concentrationconcentrated to ca. 75 L at 25° C. to 40° C
18. additionIsopropanol (96.5 Kg) was charged
19. concentrationthe batch then concentrated to ca. 75 L at 25° C. to 40° C
20. additionIsopropanol (95.4 Kg) was charged
21. concentrationthe batch then concentrated to ca. 75 L at 25° C. to 40° C
22. stirringThe resultant slurry was stirred at 16° C. to 18° C. for 2 hours
23. filtrationfiltered
24. washThe filter cake was washed with isopropanol (19.7 Kg) at ca. 20° C.
25. customdried at up to 50° C. in vacuo

ORD record

ord-6b102cb2e2d3490b9d7aa24af3e6f054

Source dataset

uspto-grants-2011_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07964616B2