| 12.4% |
In lithium hydroxide monohydrate; isopropanol at 95℃; for 5h; |
5.3 3. Synthesis of 7-chloroimidazo[1,2-b]pyridazine (10-4)
Into a 250-mL round-bottom flask, was placed 5-chloropyridazin-3-amine (5-1, 15.00 mL), chloroacetaldehyde (17.5 mL), H2O (17.5 mL), i-PrOH (25 mL). The resulting solution was stirred for 5 hr at 95 °C in an oil bath. The resulting mixture was concentrated. The pH value of the solution was adjusted to 9 with NaOH. The resulting solution was extracted with 3x50 mL of ethyl acetate, the organic layer was washed with 3 x50 ml of brine. The organic phase was collected and dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (2:3). This resulted in 2.2 g (12.4%) of 7- chloroimidazo[1,2-b]pyridazine (10-4) as yellow oil. |
| 12.4% |
In lithium hydroxide monohydrate; isopropanol at 95℃; for 5h; |
5.3 3. Synthesis of 7-chloroimidazo[1,2-b]pyridazine (10-4)
Into a 250-mL round-bottom flask, was placed 5-chloropyridazin-3-amine (5-1, 15.00 mL), chloroacetaldehyde (17.5 mL), H2O (17.5 mL), i-PrOH (25 mL). The resulting solution was stirred for 5 hr at 95 °C in an oil bath. The resulting mixture was concentrated. The pH value of the solution was adjusted to 9 with NaOH. The resulting solution was extracted with 3x50 mL of ethyl acetate, the organic layer was washed with 3 x50 ml of brine. The organic phase was collected and dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (2:3). This resulted in 2.2 g (12.4%) of 7- chloroimidazo[1,2-b]pyridazine (10-4) as yellow oil. |
|
In isopropanol at 90℃; for 5h; |
30.1
A mixture of 3,5-dichloropyridazine (1.49 g, 10.0 mmol, Maybridge, MO08501), benzophenone imine (2.01 g, 11.1 mmol, Aldrich, Cat. No. 293733), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (208 mg, 0.360 mmol), tris(dibenzylideneacetone)dipalladium(0) (165 mg, 0.180 mmol) and 1,4-dioxane (30 mL) was degassed and recharged with nitrogen for three times, and was heated and stirred at 90° C. overnight. After cooling, the mixture was filtered through a pad of silica gel, and washed with THF. [LCMS (M+H)+: m/z=294.1/296.0 corresponds to 5-chloro-N-(diphenylmethylene)pyridazin-3-amine]. The filtrate was treated with 3 N HCl aq. (6 ml) at RT and stirred for 30 min. The mixture was adjusted with NaOH (2 N) to pH=7. The resulting mixture was concentrated under reduced pressure to about the volume of 30 mL. [LCMS (M+H)+: m/z=130.1/132.0 corresponds to 5-chloropyridazin-3-amine]. Isopropanol (50 mL) and chloroacetaldehyde (10.0 mL, 78.7 mmol) was added to the solution. The mixture was heated and stirred at 90° C. for 5 h. After cooling, the mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate, and extracted with water. The combined aqueous layers were adjusted to about pH=9 with 1 N NaOH aq. Solution. The resulting solution was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford the desired product (0.988 g, 64.3%) which was directly used in next step reaction without further purification. LCMS (M+H)+: m/z=153.9/155.9. |
|
With Sodium hydrogenocarbonate In ethanol at 80℃; for 4h; |
15.C Step C.7-chloroimidazo[1,2-b]pyridazine
To a solution of 5-chloropyridazin-3-amine (1.30 g, 10.0 mmol) and sodium bicarbonate (1.69 g, 20.07 mmol) in ethanol (20 mL) was added 2-chloroacetaldehyde (14.07 g, 71.70 mmol, 11.53 mL, 40% purity). The resulting reaction mixture was stirred at 80 °C for 4 hours, and was then cooled to room temperature and concentrated under reduced pressure. The resulting residue was diluted with water (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel (0 - 40% ethyl acetate in petroleum ether) to provide the title compound: LCMS m/z 154.0 [M+H]+. |
|
With Sodium hydrogenocarbonate In ethanol at 80℃; for 4h; |
15.C Step C.7-chloroimidazo[1,2-b]pyridazine
To a solution of 5-chloropyridazin-3-amine (1.30 g, 10.0 mmol) and sodium bicarbonate (1.69 g, 20.07 mmol) in ethanol (20 mL) was added 2-chloroacetaldehyde (14.07 g, 71.70 mmol, 11.53 mL, 40% purity). The resulting reaction mixture was stirred at 80 °C for 4 hours, and was then cooled to room temperature and concentrated under reduced pressure. The resulting residue was diluted with water (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel (0 - 40% ethyl acetate in petroleum ether) to provide the title compound: LCMS m/z 154.0 [M+H]+. |
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