反应详情

To a suspension N-(4-fluorobenzyl)-3-hydroxy-4-oxo-10-((oxo(1-piperazinyl)acetyl)amino)-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxamide (0.024 g, 0.038 mmol) in dichloromethane (1 mL) was added diisopropyl ethylamine (0.027 mL, 0.153 mmol). After stirring for 5 min, 5-methylisoxazole-3-carbonyl chloride (0.011 g, 0.077 mmol) was added and the solution stirred at room temperature for 1 h. Dimethylamine (0.192 mL, 0.383 mmol) (2 M in methanol) was added and the solution stirred at room temperature for 1 h then concentrated. The residue was purified by preparative HPLC: Solvent A=10% methanol/90% H2O/0.1% trifluoroacetic acid; Solvent B=90% methanol/10% H2O/0.1% trifluoroacetic acid; Start % B=10; Final % B=100; Gradient time=20 min; Stop time=25 min; Column=XTERRA® 19×50 mm, C18, 5 μm (product elutes at 12.6 min) to give the title compound as a pale lavender solid (12.1 mg, 49% yield). 1H NMR (500 MHz, CDCl3) δ: 12.00 (1 H, brs), 8.51 (1 H, d, J=5.80 Hz), 8.40 (1 H, d, J=5.19 Hz), 7.28-7.50 (2 H, m), 6.88-7.12 (2 H, m), 6.33 (1 H, d, J=2.14 Hz), 4.55 (2 H, t, J=6.26 Hz), 4.16 (2 H, brs), 4.02-4.14 (2 H, m), 3.89-4.00 (2 H, m), 3.80 (2 H, dt, J=18.08, 5.00 Hz), 3.50-3.68 (2 H, m), 2.53-2.77 (2 H, m), 2.48 (4 H, d, J=7.93 Hz), 1.87-2.15 (4 H, m), 1.72 (2 H, brs). LCMS (M+H) calcd for C30H33FN7O7: 622.24; found: 622.78.

1. stirringthe solution stirred at room temperature for 1 h
2. stirringthe solution stirred at room temperature for 1 h
3. concentrationthen concentrated
4. customThe residue was purified by preparative HPLC
5. customGradient time=20 min
6. customtime=25 min