反应详情

温度

120 °C

A mixture of 9-bromo-8-fluoro-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene from Example 8 (300 mg, 0.738 mmol), 1-isopropylpiperidine-4-thiol (176 mg, 1.107 mmol), Pd2(dba)3 (34 mg, 5 mol %), XantPhos (43 mg, 10 mol %) and DIPEA (0.52 mL, 2.95 mmol) in dioxane (10 mL) was purged with nitrogen and then heated at 120° C. for 1 h using microwave irradiation. The crude reaction mixture was diluted with DCM (100 mL) and purified by column chromatography (Si-PCC, gradient 0-10% MeOH in DCM followed by C18, gradient 20-55% MeOH in 0.5% TFA/H2O). The product containing fractions were combined and concentrated in vacuo and the resulting residue was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 0.5M NH3 in MeOH affording 209 as a white solid (217 mg, 61%). LCMS: RT 3.12 min [M+H]+ 485.1. 1H NMR (DMSO, 400 MHz): δ 8.49 (1H, d, J=8.69 Hz), 7.89 (1H, s), 7.01 (1H, d, J=10.14 Hz), 5.78-5.66 (1H, m), 4.57-4.46 (4H, m), 3.10-3.00 (1H, m), 2.78-2.69 (2H, m), 2.67-2.57 (1H, m), 2.24 (3H, s), 2.15 (2H, bt, J=10.98 Hz), 1.89 (2H, bd, J=12.50 Hz), 1.52-1.39 (8H, m), 0.90 (6H, d, J=6.56 Hz)

1. customwas purged with nitrogen
2. custommicrowave irradiation
3. customThe crude reaction mixture
4. custompurified by column chromatography (Si-PCC, gradient 0-10% MeOH in DCM followed by C18, gradient 20-55% MeOH in 0.5% TFA/H2O)
5. additionThe product containing fractions
6. concentrationconcentrated in vacuo
7. washThe cartridge was washed with MeOH
8. washthe product eluted with 0.5M NH3 in MeOH affording 209 as a white solid (217 mg, 61%)