反应详情

温度

90 °C

To a mixture of 2-fluoro-N-methyl-4-(3-(piperidin-4-yl)pyrazin-2-yl)benzamide trihydrochloride (315 mg, 0.743 mmol), 2,7-dichloroquinoline (192 mg, 0.969 mmol), cesium carbonate (1211 mg, 3.72 mmol), dioxane (4 mL), and bis(tri-t-butylphosphine)palladium(0) (89 mg, 0.174 mmol). The solution was stirred at 90° C. After stirring for 5 h, the reaction was allowed to cool to room temperature and filtered. The solids were washed with EtOAc. The filtrate was concentrated to ½ it's orginal volume and purified by reverse-phase preparative HPLC (Shimadzu) on a Phenomenex Gemini column (10 micron, C18, 110 Å, Axia, 100×50 mm) eluting at 90 mL/min with a linear gradient of 10-60% MeCN (0.1% TFA) in water (0.1% TFA) over 20 min. The desired fractions were poured into 10% Na2CO3 and extracted with dichloromethane (DCM) (8×10 mL). The combined DCM layers were dried over MgSO4 and concentrated in vacuo to give 4-(3-(1-(7-chloroquinolin-2-yl)piperidin-4-yl)pyrazin-2-yl)-2-fluoro-N-methylbenzamide (135 mg, 0.284 mmol, 38.2% yield), as an off white solid. m/z=476 (M+1). 1H NMR (300 MHz, CDCl3) δ 8.54 (d, J=2.34 Hz, 1H), 8.49 (d, J=2.34 Hz, 1H), 8.27 (t, J=8.04 Hz, 1H), 7.83 (d, J=9.35 Hz, 1H), 7.67 (d, J=2.05 Hz, 1H), 7.49 (d, J=8.62 Hz, 1H), 7.44 (dd, J=1.46, 8.04 Hz, 1H), 7.35 (dd, J=1.46, 12.42 Hz, 1H), 7.15 (dd, J=2.05, 8.48 Hz, 1H), 6.98 (d, J=9.35 Hz, 1H), 6.79 (d, J=6.28 Hz, 1H), 4.68 (d, J=13.30 Hz, 2H), 3.16-3.31 (m, 1H), 3.09 (dd, J=0.80, 4.75 Hz, 3H), 2.86-3.02 (m, 2H), 2.01-2.19 (m, 2H), 1.82 (d, J=11.55 Hz, 2H).

1. stirringAfter stirring for 5 h
2. temperatureto cool to room temperature
3. filtrationfiltered
4. washThe solids were washed with EtOAc
5. concentrationThe filtrate was concentrated
6. custompurified by reverse-phase preparative HPLC (Shimadzu) on a Phenomenex Gemini column (10 micron, C18, 110 Å, Axia, 100×50 mm)
7. washeluting at 90 mL/min with a linear gradient of 10-60% MeCN (0.1% TFA) in water (0.1% TFA) over 20 min
8. additionThe desired fractions were poured into 10% Na2CO3
9. extractionextracted with dichloromethane (DCM) (8×10 mL)
10. dry with materialThe combined DCM layers were dried over MgSO4
11. concentrationconcentrated in vacuo