With the rapid development and complex challenges of chemical substances, new drug synthesis pathways are usually the most effective.6082-66-2,3,4,6-Trichloropyridazine,as a common compound, the synthetic route is as follows.
Step 1: 4,6-dichloropyridazin-3(2H)-one and 5,6-dichloropyridazin-3(2H)-one A solution of 3,4,6-trichloropyridazine (20.0 g, 109.04 mmol) in HOAc (100 mL) was heated at 100 C for 12 h, at which time TLC indicated the reaction had gone to completion. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (petroleum ether : Ethyl acetate = 1 : 1 ) to give the title compounds (11.2 g, 63% yield) (1 : 1 ratio of regioisomers) as a white solid. LCMS M/Z (M+H) 165. Step 2: 4,6-dichloro-2-methylpyridazin-3-(2H)-one and 5,6-dichloro-2-methylpyridazin-3-(2H)-one To a suspension of 4,6-dichloropyridazin-3(2H)-one and 5,6-dichloropyridazin-3(2H)-one (11.2 g, 67.89 mmol), and Cs2CO3 (33.2 g, 101.83 mmol) in DMF (100 mL) was added CH3I (10.6 g, (0355) 74.68 mmol). The resulting mixture was stirred at 25 C for 15 h, at which time TLC indicated the reaction had gone to completion. The reaction mixture was quenched by addition of a saturated aqueous solution of ammonium chloride (100 mL), and then extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether : ethyl acetate = 1 : 1 ) to give the title compounds (7.5 g, 62% yield) (1 : 1 ratio of regioisomers) as white solids. LCMS M/Z (M+H) 179. Step 3: 4-amino-6-chloro-2-methylpyridazin-3-(2H)-one A mixture of 4,6-dichloro-2-methylpyridazin-3(2H)-one (7.5 g, 41.90 mmol, mixture with 5,6- dichloro-2-methylpyridazin-3(2H)-one) in ammonium hydroxide (48%, 50 mL) was heated at 120 C for 15 h in a sealed tube, at which time LCMS indicated that the reaction had gone to completion. After cooled, the product was collected by filtration. The crude solid was washed with water and dried under reduced pressure to give a mixture of two regioisomers (3.8 g, 57%, 1 : 1 ratio) as white solids. LCMS M/Z (M+H) 160. Step 4: 4-amino-6-chloro-5-iodo-2-methylpyridazin-3-(2H)-one To a solution of 4-amino-6-chloro-2-methylpyridazin-3(2H)-one (3.8 g, 23.81 mmol, mixture with regio- isomers) in acetonitrile (60 mL) was added l -iodopyrrolidine-2,5-dione (5.4 g, 23.81 mmol). The reaction mixture was heated to reflux for 3 h, at which time LCMS indicated that the reaction had gone to completion. After cooled, the reaction was quenched by addition of a saturated aqueous solution of ammonium chloride (20 mL), and then extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether : ethyl acetate = 1 :3) to give a mixture of regioisomers with a 1 : 1 ratio (2.5 g, 37% yield) as yellow solids. LCMS M/Z (M+H) 286.
The synthetic route of 6082-66-2 has been constantly updated, and we look forward to future research findings.
Reference£º
Patent; GENENTECH, INC.; CONSTELLATION PHARMACEUTICALS, INC.; ALBRECHT, Brian, K.; COTE, Alexandre; CRAWFORD, Terry; DUPLESSIS, Martin; GOOD, Andrew, Charles; LEBLANC, Yves; MAGNUSON, Steven; NASVESCHUK, Christopher, G.; PASTOR, Richard; ROMERO, F. Anthony; TAYLOR, Alexander, M.; (179 pag.)WO2016/36954; (2016); A1;,
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