反应详情

A solution of 1.72 g of 2-(2-amino-4-fluoro-phenylamino)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide, prepared as in Part C, (5.20 mmol) in 15 mL of tetrahydrofuran is transferred to an addition funnel. A solution of 0.506 mL of malonyl dichloride (5.20 mmol, 1.0 equiv) in 15 mL tetrahydrofuran is transferred to a separate addition funnel. Each solution of each reagent is simultaneously added dropwise over 30 min. to 100 mL of tetrahydrofuran at ambient temperature under nitrogen with vigorous agitation. After stirring for 20 min. at ambient temperature, an additional 0.506 mL of malonyl dichloride (5.20 mmol, 0.1 equiv) is added in a single portion. The reaction is allowed to stir an additional 2.5 hrs. and then evaporated in vacuo to a residue. The residue is purified on flash grade silica gel with 1:3 ethyl acetate/hexane followed by 3:1 ethyl acetate/hexane. The appropriate fractions were combined, evaporated in vacuo to a residue and triturated with hexane. The hexane is removed in vacuo and the residual solid is dried under high vacuum to provide 1.06 g of 2-(7-Fluoro-2,4-dioxo-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide as a tan solid: 1H NMR (300 MHz, CDCl3) δ8.14 (s, br, 1H), 7.45 (dd, 1H, J=5.5. 9.2), 7.29 (m, 1H), 7.05 (m, 1H), 6.94 (m, 3H), 6.78 (m, 1H), 4.99 (m, 1H), 4.37 (d, 1H, J=16.4), 3.82 (s, 3H), 3.69 (d, 1H, J=16.0), 3.40 (m, 2H), 1.09 (d, 6H, J=6.8); low resolution MS (FAB)m/e 400 (MH+).

1. customis transferred to an addition funnel
2. stirringto stir an additional 2.5 hrs
3. customand then evaporated in vacuo to a residue
4. customThe residue is purified on flash grade silica gel with 1:3 ethyl acetate/hexane
5. customevaporated in vacuo to a residue
6. customtriturated with hexane
7. customThe hexane is removed in vacuo
8. customthe residual solid is dried under high vacuum