反应详情

A mixture of 2-[4-(4-morpholin-4-yl-2-(tributylstannanyl)thieno[3,2-d]pyrimidin-6-ylmethyl)piperazin-1-yl]isobutyramide (0.35 g, 0.51 mmol), 5-bromoimidazo[1,2-a]pyridine (0.11 g, 0.56 mmol), copper(I) 2-thiophene carboxylate (0.019 g, 0.1 mmol) and Pd(PPh3)4 (0.059 g, 0.05 mmol) in dioxane (5 mL) was subjected to microwave irradiation at 140° C. for 20 min. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH. The eluent was concentrated in vacuo and the residue was purified by flash chromatography (Si—PPC, MEOH:DCM, gradient 0:100 to 10:90). The residue was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH. The solution was concentrated in vacuo and the residue was purified by reverse phase HPLC (Phenomenex Gemini 5u C 18, 20 mM triethylamine in water on a gradient of acetonitrile 75:25 to 2:98) to give 697 as a white powder (0.117 g, 45%). LCMS: RT=4.35 min, [M+H]+ 521.2. 1H NMR (400 MHz, DMSO-d6): δ 9.33 (d, J=1.1 Hz, 1 H); 8.04 (dd, J=7.5, 1.2 Hz, 1 H); 7.78 (dd, J=8.9, 1.1 Hz, 1 H); 7.74 (d, J=1.2 Hz, 1 H); 7.54 (s, 1 H); 7.41 (dd, J=8.9, 7.5 Hz, 1 H); 7.07 (d, J=3.5 Hz, 1 H); 6.95 (d, J=3.5 Hz, 1 H); 4.00 (t, J=4.7 Hz, 4 H); 3.89 (s, 2 H); 3.82 (t, J=4.7 Hz, 4 H); 2.56-2.54 (m, 4 H); 2.49-2.44 (m, 4 H); 1.08 (s, 6 H)

1. customirradiation at 140° C. for 20 min
2. washThe cartridge was washed with MeOH
3. washthe desired product was eluted
4. concentrationThe eluent was concentrated in vacuo
5. customthe residue was purified by flash chromatography (Si—PPC, MEOH:DCM, gradient 0:100 to 10:90)
6. washThe cartridge was washed with MeOH
7. washthe desired product was eluted
8. concentrationThe solution was concentrated in vacuo
9. customthe residue was purified by reverse phase HPLC (Phenomenex Gemini 5u C 18, 20 mM triethylamine in water on a gradient of acetonitrile 75:25 to 2:98)