1015474-32-4

1015474-86-8

1015474-32-4

General procedure for the synthesis of 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione from RSYY (niraparib intermediate)-14: To a stirred mixture of 2-amino-6-nitrobenzoic acid (25-1) (1 g, 5.49 mmol) and imidazole (1.2 equiv) in acetonitrile (10 mL) was added acetyl chloride (25-2) (469 μL) and then the reaction mixture was stirred overnight. 3-Aminopiperidine-2,6-dione hydrochloride (903 mg, 5.49 mmol) was then added and supplemented with the addition of the remaining base to bring the total imidazole amount to 1.34 g (19.7 mmol). Triphenyl phosphite (1.72 mL, 6.58 mmol) was then added and the reaction mixture was refluxed for two days. After cooling to room temperature, 40 mL of water was added to slowly form a suspension, which was filtered and washed sequentially with water and EtOAc. The solid product 3-(2-methyl-5-nitro-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione (1-2) was obtained by isolation (953 mg, 3.01 mmol, 55.0% yield). lc/ms (es+): m/z 317 [M+H]+. 3-(2-methyl-5-nitro-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione (25-3) (690 mg, 2.18 mmol) was dissolved in 10 mL of anhydrous DMF, carbon-loaded dihydroxypalladium (306 mg, 0.218 mmol) at 50% humidity was added, and the mixture was purged with nitrogen for 15 min, followed by three cycles of replacement with hydrogen at a 1 atm hydrogen pressure for overnight reaction. Upon completion of the reaction, the palladium catalyst was removed by filtration through a diatomaceous earth pad, and the filtrate was concentrated and purified by an ISCO system using a MeOH/DCM solvent mixture to afford the target product, 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione (25-4) (498 mg, 1.73 mmol, 79.8% yield), as an off-white solid.LC/MS (ES+): m/z 287 [M+H]+.