Sodium Chloride → 4-(2-(4-Methylpiperazin-1-yl)ethoxy)pyridin-2-amine

Temperature

40 °C

Sodium hydride (60% in mineral oil; 43.56 g; 1089 mmol) was added to a 3 L reaction flask under nitrogen. A mechanical stirrer and thermocouple was attached. Dry diglyme (400 mL) was added. A solution of 2-(4-methylpiperazin-1-yl)ethanol (157 g; 1089 mmol) in diglyme (450 mL) was added slowly with stirring. The mixture was stirred with warming to 40° C. for 1 hour. 4-Chloropyridin-2-amine (70.0 g; 544.5 mmol) was added as a solid. The mixture was heated to 80° C. with stirring until effervescence had ceased. The temperature was increased to 157° C. for 16 hours. The mixture was allowed to cool and diluted with water (500 mL). THF (1000 mL) was added followed by sodium chloride (sufficient to saturate the aqueous phase). The phases were separated and the aqueous phase was further extracted with THF (3×800 mL). Additional water was added as required to aid in phase separation. The combined organic phases were dried with sodium sulfate (1000 g) for 16 hours and filtered. The solvent was removed under vacuum to remove the majority of the THF. The solution was filtered through Celite® to remove fine particulates rinsing with diglyme. The diglyme was removed under vacuum (10 mm Hg vacuum, with the bath temperature increased to 60° C.). The residue was placed under high vacuum for 1 hour and then triturated with ether (400 mL). The resulting solids were collected by filtration, washed with ether and dried under vacuum to give the product (100.4 g) as an off white solid.

1. customA mechanical stirrer and thermocouple was attached
2. stirringThe mixture was stirred
3. temperatureThe mixture was heated to 80° C.
4. stirringwith stirring until effervescence
5. temperatureThe temperature was increased to 157° C. for 16 hours
6. temperatureto cool
7. concentrationto saturate the aqueous phase)
8. customThe phases were separated
9. extractionthe aqueous phase was further extracted with THF (3×800 mL)
10. additionAdditional water was added
11. customto aid in phase separation
12. dry with materialThe combined organic phases were dried with sodium sulfate (1000 g) for 16 hours
13. filtrationfiltered
14. customThe solvent was removed under vacuum
15. customto remove the majority of the THF
16. filtrationThe solution was filtered through Celite®
17. customto remove fine particulates
18. washrinsing with diglyme
19. customThe diglyme was removed under vacuum (10 mm Hg vacuum
20. temperaturewith the bath temperature increased to 60° C.)
21. customtriturated with ether (400 mL)
22. filtrationThe resulting solids were collected by filtration
23. washwashed with ether
24. customdried under vacuum

ORD record

ord-589c2a4719c74912b8f9bbfb1adbf7c3

Source dataset

uspto-grants-2014_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08841455B2