反应详情

温度

110 °C

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)+.

1. filtrationfiltered through a pad of Celite
2. washThe filtrate was washed with 2 mL of water
3. dry with materialThe organic solution was dried over Na2SO4
4. concentrationconcentrated
5. additionThe dark residue containing (2-(tert-butylamino)-3-methyl-4-oxo-3,4-dihydroquinazolin-8-yl)boronic acid (714)
6. customwas used in next step without purification
7. customA 5 mL glass microwave reaction tube
8. customThe tube was purged with argon
9. temperatureThe reaction mixture was heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc.) at 130° C. for 45 min
10. additionAdditional X-Phos (3 mg) and Pd2(dba)3 (3 mg) were added
11. temperaturethe resulting mixture was heated again in a microwave at 140° C. for 25 min
12. additionIt was diluted with 10 mL of EtOAc
13. washwashed with 2 mL of 0.5 N NaOH
14. concentrationThe organic solution was concentrated
15. customthe residue was purified by silica gel chromatography (eluted with 40-65% EtOAc in Hexanes)