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

Participants

Reaction Conditions

Reaction Steps

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

Provenance & Evidence