Cesium carbonate → 4-amino-8-((5-chloro-3-(2-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)pyrido[2,3-d]pyrimidin-5(8H)-one

Participants

Reaction Conditions

Reaction Steps

To a mixture of 4-aminopyrido[2,3-d]pyrimidin-5(8H)-one (0.1 g, 0.616 mmol), Cs2CO3 (0.3013 g, 0.925 mmol, 1.5 eq), and KI (0.0102 g, 0.0616 mmol, 0.1 eq) in DMF (2 mL) was added 5-chloro-2-(chloromethyl)-3-(2-methoxyphenyl)quinazolin-4(3H)-one (0.2273 g, 0.678 mmol, 1.1 eq) and the mixture was stirred at 100° C. for 1 h. The mixture was concentrated under reduced pressure. The crude product was purified by column chromatography on a 40 g of Redi-Sep™ column using 0 to 100% gradient of :MeOH:NH4OH (89:9:1) in CH2Cl2 over 14 min as eluent to provide 4-amino-8-((5-chloro-3-(2-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)pyrido[2,3-d]pyrimidin-5(8H)-one as yellow solid (0.1707 g, 60%). The yellow solid was triturated with MeOH and filtered to provide 4-amino-8-((5-chloro-3-(2-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)pyrido[2,3-d]pyrimidin-5(8H)-one [PI3Kδ IC50=13 nM] as yellow solid. 1H NMR (DMSO-d6) δ ppm 9.53 (1 H, d, J=4.7 Hz), 8.20 (1 H, s), 8.14 (1H, d, J=4.7 Hz), 7.88 (1 H, d, J=7.8 Hz), 7.65-7.72 (1 H, m), 7.49-7.59 (3 H, m), 7.37 (1 H, dd, J=8.2, 1.2 Hz), 7.31 (1 H, dd, J=8.6, 1.2 Hz), 7.15-7.21 (1 H, m), 6.20 (1 H, d, J=8.2 Hz), 4.91-5.13 (2 H, m), 3.85 (3 H, s). Mass Spectrum (ESI) m/e=461.0 (M+1).

Provenance & Evidence