反应详情

An nitrogen-purged 22 L 5-necked flask was charged with DMF (9 L) followed by slow addition of 2-aminopyridin-3-ol (250.0 g, 2270 mmol) and stirred with mechanical overhead agitator at ambient temperature for 30 minutes to dissolve material. 60% Sodium hydride (87.17 g, 2180 mmol) was added in portions with vigorous stirring and a nitrogen sweep of the reaction vessel. The pot temperature rose from 16° C. to 25° C. during the NaH addition. After the addition was complete, the reaction was stirred at ambient temperature for 60 minutes to ensure all NaH was consumed. 2,4-Dibromo-1-fluorobenzene (225.3 mL, 1816 mmol) was added and heated to 110° C. under nitrogen for 24 hours. The reaction was cooled to 60° C. and transferred to a 20 L flask and the majority of the DMF removed. The resultant sludge was diluted with 1N NaOH (8 L) and EtOAc (8 L) and the mixture was passed through a plug of celite and washed with EtOAc. The layers were separated and the aqueous was extracted with EtOAc (4 L). The combined organic layers were washed with 1 N NaOH (4 L) and 50% saturated brine (4 L), water (2 L) and concentrated until solids started to form. Hexanes (4 L) were added slowly and the mixture was concentrated to around 2 L volume. Hexanes (4 L) were added and the mixture was stirred for 1 hour to allow to cool to ambient temperature. The resulting slurry was filtered, dried on the filter and then dried under high vacuum overnight to afford 3-(2,4-dibromophenoxy)pyridin-2-amine (277.3 g, 44.4% yield).

1. customAn nitrogen-purged 22 L 5-necked flask
2. additionwas charged with DMF (9 L)
3. dissolutionto dissolve material
4. stirringwith vigorous stirring
5. additionAfter the addition
6. stirringthe reaction was stirred at ambient temperature for 60 minutes
7. customwas consumed
8. temperatureheated to 110° C. under nitrogen for 24 hours
9. temperatureThe reaction was cooled to 60° C.
10. customtransferred to a 20 L flask
11. customthe majority of the DMF removed
12. additionThe resultant sludge was diluted with 1N NaOH (8 L) and EtOAc (8 L)
13. washwashed with EtOAc
14. customThe layers were separated
15. extractionthe aqueous was extracted with EtOAc (4 L)
16. washThe combined organic layers were washed with 1 N NaOH (4 L) and 50% saturated brine (4 L), water (2 L)
17. concentrationconcentrated until solids
18. customto form
19. concentrationthe mixture was concentrated to around 2 L volume
20. additionHexanes (4 L) were added
21. stirringthe mixture was stirred for 1 hour
22. temperatureto cool to ambient temperature
23. filtrationThe resulting slurry was filtered
24. customdried on the
25. filtrationfilter
26. customdried under high vacuum overnight