Potassium Carbonate → 7-(4-(cyclopropylamino)furo[3,2-d]pyrimidin-2-ylamino)-3,4-dihydroquinolin-2(1H)-one

Participants

Reaction Conditions

Reaction Steps

A flask was charged with 2-methyl-2-butanol (140 mL) and the solvent was sparged with N2 for about 15 min. To the solvent were added 2-chloro-N-cyclopropylfuro[3,2-d]pyrimidin-4-amine (6.5 g, 31 mmol, Example #3, Step C), 7-amino-3,4-dihydroquinolin-2(1H)-one (5.03 g, 31.0 mmol, Astatech), and K2CO3 (8.57 g, 62.0 mmol). The flask was purged with N2 (3×) followed by the addition of X-Phos (2.07 g, 4.34 mmol) and Pd2dba3 (1.99 g, 2.17 mmol). The flask was again purged with N2 (2×) and the mixture was heated to about 78° C. for about 24 h. The mixture was cooled to rt and filtered through a pad of Celite®. The filter pad was washed with DCM (˜900 mL) and the combined filtrates were concentrated under reduced pressure to about ½ the initial volume. The mixture was dissolved in DCM (200 mL) and washed with water (100 mL). The layers were separated and the organic solution was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to about ⅕ volume. Additional DCM/MeOH (3:1, 100 mL) was added along with silica gel (˜25 g, 200-400 Mesh, 60 Å) and the solvents were removed under reduced pressure. The crude material was purified by silica gel chromatography (220 g) eluting with 0.5 to 2.5% MeOH in DCM over about 20 min, 2.5 to 3.5% MeOH in DCM over 15 min, and isocratic at 3.5% MeOH in DCM for about 25 min. The product containing fractions were combined and concentrated under reduced pressure to give a solid that was triturated with MeOH (˜30 mL). The solid was collected by vacuum filtration to give 7-(4-(cyclopropylamino)furo[3,2-d]pyrimidin-2-ylamino)-3,4-dihydroquinolin-2(1H)-one (3.2 g, 31%): LC/MS (Table 2, Method c) Rt=1.71 min; MS m/z: 336 (M+H)+. Syk IC50=A

Provenance & Evidence