反应详情

温度

130 °C

A mixture of 1-(4-bromo-2-methoxyphenoxy)-2-methylpropan-2-ol (157 mg, 0.571 mmol), 2-(4-chlorophenyl)thieno[2,3-d]pyridazin-7(6H)-one (150 mg, 0.571 mmol), (1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (24.36 mg, 0.171 mmol), K3PO4 (0.142 ml, 1.713 mmol) and cupric oxide (24.51 mg, 0.171 mmol) in dioxane (4 ml) was stirred at 130° C. under N2 in a sealed tube for 24 hours. Since LC-MS analysis revealed no product, another portion of cupric oxide (24.51 mg, 0.171 mmol) was added to the mixture which was then was stirred at 130° C. under N2 in a sealed tube for another 24 hours. Since LC-MS analysis indicated only 25% conversion to product, another equivalent of copper (I) oxide and dimethylcyclohexane-1,2-diamine was added. The mixture was stirred at 150° C. under N2 in a seal tube for 8 hours. After cooling to RT, LC-MS analysis showed the conversion was 45% to product. The mixture was diluted with CH2Cl2 (40 ml) prior to removal of the inorganic solid by filtration. The CH2Cl2 filtrate was washed with a solution of saturated NaHCO3 (3×40 ml), dried over Na2SO4 and concentrated. The crude product was purified by ISCO chromatography on two silica gel column (2×4.0 g) employing a 10 min gradient ranging from hexane to 100% ethyl acetate to elute partially pure product. After titration with MeOH, 2-(4-chlorophenyl)-6-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)thieno[2,3-d]pyridazin-7(6H)-one (101 mg, 0.221 mmol, 38.7% yield) was obtained as light brown solid. LC MS at t=2.52 min. (m+H=457) PHENOMENEX® S5 C18 4.6X30 mm column/water-MeOH-TFA 90:10:0.1 to 10:90:0.1 gradient over 2 min at 5 mL/min with 1 min hold at the end of the gradient. 1H NMR (400 MHz, CDCl3) 8 ppm 1.36 (s, 6H), 3.89 (d, J=3.78 Hz, 5H), 7.00 (d, J=8.56 Hz, 1H), 7.17-7.24 (m, 2H), 7.42-7.54 (m, 3H), 7.66 (d, J=8.31 Hz, 2H), 8.31 (s, 1H).

1. stirringwas then was stirred at 130° C. under N2 in a sealed tube for another 24 hours
2. stirringThe mixture was stirred at 150° C. under N2 in a seal tube for 8 hours
3. temperatureAfter cooling to RT
4. customto removal of the inorganic solid
5. filtrationby filtration
6. washThe CH2Cl2 filtrate was washed with a solution of saturated NaHCO3 (3×40 ml)
7. dry with materialdried over Na2SO4
8. concentrationconcentrated
9. customThe crude product was purified by ISCO chromatography on two silica gel column (2×4.0 g)
10. waitemploying a 10 min
11. washto elute partially pure product