Potassium Phosphate, Tribasic → 2-(tert-butylamino)-8-(2-(2,4-dimethoxybenzyl)-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl)-3-methylquinazolin-4(3H)-one

Participants

Reaction Conditions

Reaction Steps

A mixture of Pd(dppf)Cl2 DCM adduct (4.0 mg), 2-(tert-butylamino)-8-iodo-3-methylquinazolin-4(3H)-one (701) (37 mg, 0.10 mmol), (BPin)2 (39.5 mg, 0.155 mmol) and KOAc (22 mg, 0.22 mmol) in 0.5 mL of DMF was heated in a microwave at 110° C. for 40 min. It was diluted with 15 mL of EtOAc and filtered through a pad of Celite. The filtrate was washed with 2 mL of water followed by 2 mL of brine. The organic solution was dried over Na2SO4 and concentrated. The dark residue containing (2-(tert-butylamino)-3-methyl-4-oxo-3,4-dihydroquinazolin-8-yl)boronic acid (714) was used in next step without purification. m/z (ESI, +ve) 276.1 (M+H)+. A 5 mL glass microwave reaction tube was charged with the crude (2-(tert-butylamino)-3-methyl-4-oxo-3,4-dihydroquinazolin-8-yl)boronic acid (714), dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (2.86 mg, 6.00 μmol), Pd2(dba)3 (2.75 mg, 3.00 μmol), 7-bromo-2-(2,4-dimethoxybenzyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one (36.5 mg, 0.10 mmol) and K3PO4 (63 mg, 0.30 mmol). The tube was purged with argon, and the contents were suspended in Dioxane (2 mL) and Water (0.50 mL). The reaction mixture was heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc.) at 130° C. for 45 min. Additional X-Phos (3 mg) and Pd2(dba)3 (3 mg) were added and the resulting mixture was heated again in a microwave at 140° C. for 25 min. It was diluted with 10 mL of EtOAc, washed with 2 mL of 0.5 N NaOH followed by 2 mL of brine. The organic solution was concentrated and the residue was purified by silica gel chromatography (eluted with 40-65% EtOAc in Hexanes) to give 2-(tert-butylamino)-8-(2-(2,4-dimethoxybenzyl)-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl)-3-methylquinazolin-4(3H)-one (449a; 10 mg, 19% yield) as a brown amorphous solid. m/z (ESI, +ve) 516.2 (M+H)+.

Provenance & Evidence