Potassium Carbonate → 6-(4-(cyclopropylamino)furo[3,2-d]pyrimidin-2-ylamino)-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one

Temperature

85 °C

To a flask was added 2-chloro-N-cyclopropylfuro[3,2-d]pyrimidin-4-amine (7.82 g, 37.3 mmol), 6-amino-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one (8.60 g, 44.7 mmol, Example #3, Step C), K2CO3 (6.18 g, 44.7 mmol) and t-BuOH (249 mL). To the mixture was added Pd2dba3 (2.05 g, 2.24 mmol) and X-Phos (2.13 g, 4.47 mmol). The flask was de-gassed and vented with N2 three times. The mixture was heated to about 85° C. and stirred overnight. The mixture was diluted with EtOAc (700 mL) and washed with water (700 mL). The aqueous layer was extracted with EtOAc (2×300 mL). The combined organic layers were dried with MgSO4, filtered through a pad of Celite® and concentrated in vacuo. The material was purified by column chromatography (300 g silica gel) using a gradient of 30 to 100% EtOAc/DCM. The material was suspended in 30% EtOAc/DCM (150 mL) and heated to about 77° C. with stirring. MeOH (20 mL) was added gradually to the hot solution until a clear solution resulted. The mixture was allowed to stir for about 1 h and then cooled to rt. The precipitate formed was collected by filtration to give a solid. The mother liquor was kept in the refrigerator overnight and the resulting precipitate was collected by filtration to yield a second batch of the product. The two solids were combined. The material was then suspended in DCM and filtered. The precipitate was dried in a vacuum oven at about 70° C. for about 18 h. The material was then pulverized using a mortar and pestle and dried in the vacuum oven at about 80° C. for about 16 h. The material was taken up in IPA (200 mL) and the suspension was heated to about 50° C. with stirring for about 2 h. The mixture was brought to rt and filtered. The precipitate was dried in a vacuum oven at about 80° C. for about 16 h. The material was dissolved in MeOH (200 mL) and evaporated under reduced pressure. The residue was dried in a vacuum oven at about 80° C. for about 16 h. The material was suspended in water (200 mL) and sonicated for about 10 min then stirred vigorously for about 1 h. The mixture was filtered and the precipitate was dried in a vacuum oven at about 80° C. for about 20 h to provide 6-(4-(cyclopropylamino)furo[3,2-d]pyrimidin-2-ylamino)-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one (5.0 g, 37%): LC/MS (Table 2, Method c) Rt=1.87 min.; MS m/z: 366 (M+H)+. Syk IC50=A

1. customThe flask was de-gassed
2. additionThe mixture was diluted with EtOAc (700 mL)
3. washwashed with water (700 mL)
4. extractionThe aqueous layer was extracted with EtOAc (2×300 mL)
5. dry with materialThe combined organic layers were dried with MgSO4
6. filtrationfiltered through a pad of Celite®
7. concentrationconcentrated in vacuo
8. customThe material was purified by column chromatography (300 g silica gel)
9. temperatureheated to about 77° C.
10. stirringwith stirring
11. additionMeOH (20 mL) was added gradually to the hot solution until a clear solution
12. customresulted
13. stirringto stir for about 1 h
14. temperaturecooled to rt
15. customThe precipitate formed
16. filtrationwas collected by filtration
17. customto give a solid
18. customwas kept in the refrigerator overnight
19. filtrationthe resulting precipitate was collected by filtration
20. customto yield a second batch of the product
21. filtrationfiltered
22. customThe precipitate was dried in a vacuum oven at about 70° C. for about 18 h
23. customdried in the vacuum oven at about 80° C. for about 16 h
24. temperaturethe suspension was heated to about 50° C.
25. stirringwith stirring for about 2 h
26. customwas brought to rt
27. filtrationfiltered
28. customThe precipitate was dried in a vacuum oven at about 80° C. for about 16 h
29. dissolutionThe material was dissolved in MeOH (200 mL)
30. customevaporated under reduced pressure
31. customThe residue was dried in a vacuum oven at about 80° C. for about 16 h
32. customsonicated for about 10 min
33. stirringthen stirred vigorously for about 1 h
34. filtrationThe mixture was filtered
35. customthe precipitate was dried in a vacuum oven at about 80° C. for about 20 h

ORD record

ord-f3d98f7b643a446c8e1b7340c62b3c39

Source dataset

uspto-grants-2013_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08551981B2