反应详情

A solution of crude 9-bromomethyl-3-methylbenzo[f]quinazolin-1(2H)-one (4.32 g), (S)-diethyl 2-(5-amino-1-oxo-2-isoindolinyl)glutarate (4.0 g, 12 mmol), and NaHCO3 (2.0 g, 24 mmol) in DMF (30 ml) was stirred under nitrogen at 105° C. for 1.5 hours. After cooling, acetic acid (1 ml, 17 mmol) was added, the reaction mixture transferred to a larger round bottom flask with ethanol, and then concentrated in vacuo onto silica gel (30 g). The absorbed material was purified by chromatography on silica gel eluting with methanol:methylene chloride (1:24) and then precipitation of the solid from methylene chloride (~20 ml) with ethyl acetate (~45 ml) and methanol (~5 ml). The white solid was filtered under nitrogen and dried under high vacuum to give diethyl (S)-2-(5-(((1,2-dihydro-3-methyl-1-oxobenzo[f]-quinazolin-9-yl)methyl)amino)-1-oxo-2-isoindolinyl)glutarate (3.27 g). 1H NMR (DMSO-d6, 300 MHz, δ: 1.10 (t, J=7 Hz, 3H, ester CH3), 1.15 (t, J=7 Hz, 3H, ester CH3), 1.93-2.33 (m, 4H, glu CH2CH2), 2.43 (s, 3H, C3 -CH3) 3.87-4.03 (m, 2H, ester CH2), 4.09 (q, J=7 Hz, 2H, ester CH2), 4.25 (very strongly coupled AB pair, 2H, glu NCH2Ar), 4.58 (d, J=6 Hz, 2H, C9 -CH2N), 4.74-4.83 (m, 1H, glu CH), 6.71 (br d, J=2 Hz, 1H, Ar), 6.74 (dd, J=8,2 Hz, 1H, Ar), 7.20 (t, J=6 Hz, 1H, ArNH), 7.37 (d, J=8 Hz, 1H Ar), 7.59 (d, J=9 Hz, 1H, Ar), 7.63 (dd, J=8,2 Hz, 1H, Ar), 8.00 (d, J=8 Hz, 1H, Ar), 8.21 (d, J=9 Hz, 1H, Ar), 9.87 (s, 1H, Ar), 12.54 (s, 1H, N2H). Mass spectrum (CI-CH4) 557 (M+1, 100%). Anal. Calculated for C31H32N4O6 : C, 66.89; H, 5.79; N, 10.07. Found: C, 66.80; H, 5.82; N, 10.10.

1. temperatureAfter cooling
2. concentrationconcentrated in vacuo onto silica gel (30 g)
3. customThe absorbed material was purified by chromatography on silica gel eluting with methanol:methylene chloride (1:24)
4. customprecipitation of the solid from methylene chloride (~20 ml) with ethyl acetate (~45 ml) and methanol (~5 ml)
5. filtrationThe white solid was filtered under nitrogen
6. customdried under high vacuum