With the rapid development and complex challenges of chemical substances, new drug synthesis pathways are usually the most effective.19064-67-6,6-Chloro-3-hydroxypyridazine,as a common compound, the synthetic route is as follows.
General procedure: A suspension of 3,6-dichloropyridazine (25.50 g, 171.2 mmol) in 100 mL of water was treated with NaOH (15.06 g, 376.6 mmol) and heated at 80 C for 2 h. The resulting red solution was allowed to cool to rt and was then acidified to pH 1 with concentrated HCl (aq). The off-white solid was washed with water and Et2O and then dried under vacuum overnight to afford 6-chloropyridazin-3(2H)-one (4, 19.13 g,85% yield). A mixture of 4 (2.55 g, 19.54 mmol) and EtI (1.88 mL, 23.44 mmol) in 10 mL of DMF at rt was treated with K2CO3 (8.10 g, 58.61 mmol). The reaction mixture stirred 48 h at rt and then H2O was added and the mixture was extracted with EtOAc. The combined organic layers were washed with water, dried over Na2SO4, filtered and concentrated to give 6-chloro-2-ethylpyridazin-3(2H)-one (5, 2.70 g, 87% yield). A solution of 5 (2.70 g, 17.03 mmol) in hydrazine hydrate (4.14 mL, 85.13 mmol) was heated at 70 C. After 2 h, the reaction mixture was loaded directly on to a silica gel column and eluted with 0-10% MeOH in CH2Cl2 to afford 2-ethyl-6-hydrazinylpyridazin-3(2H)-one (6, 1.26 g, 48% yield) as a light-yellow solid. A mixture of 6 (163 mg, 1.06 mmol) and 2-chloro-6-fluorobenzaldehyde (168 mg, 1.06 mmol) in 8 mL of EtOH was heated to reflux. After 1 h, the reaction mixture was concentrated, the solid wasresuspended in THF (8 mL) and chloramine T-hydrate (265 mg, 1.16 mmol) was added. The mixture was heated at 65 C for 4 h. The reaction mixture was allowed to cool to rt and H2O was added. The mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4,filtered and concentrated. The crude material was purified by silica gel chromatography (0-50% EtOAc in hexanes) to afford 3-(2-chloro-6-fluorophenyl)-5-ethyl-[1,2,4]triazolo[4,3-b]pyridazin-6(5H)-one (7, 222 mg, 72% yield). A mixture of 7 (222 mg, 0.76 mmol) and Br2 (0.19 mL, 3.79 mmol) in 3 mL of acetic acid was heated at 80 C for 2 h. The reaction was cooled to rt, water was added and the mixture was extracted with EtOAc. The combined organic layers were washed with H2O and saturated NaHCO3 (aq) and then dried over anhydrous Na2SO4, filtered and concentrated to afford 7,8-dibromo-3-(2-chloro-6-fluorophenyl)-5-ethyl-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6(5H)-one (8, 285 mg, 83% yield) as a yellow oil. A solution of 8 (285 mg, 0.63 mmol) in 3 mL of THF at rt was treated with NEt3 (0.26 mL, 1.89 mmol). After 1 h, H2O was added and the mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give 7-bromo-3-(2-chloro-6-fluorophenyl)-5-ethyl-[1,2,4]triazolo[4,3-b]pyridazin-6(5H)-one (9, 194 mg, 83% yield) as a yellow oil. In a microwave tube was placed 9 (194 mg, 0.52 mmol), 10 (190 mg, 0.63 mmol), PdCl2(PPh3)2 (18 mg, 0.026 mmol) and 2 M Na2CO3 (aq, 1.3 mL, 2.6 mmol) and 2.5 mL of dioxane. The mixture was heated in a microwave at 120 C for 25 min. After cooling to rt, H2O was added and the mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude material was purified by HPLC (Phenomenex 150 x 30 mm Luna column) eluting with 5-100% CH3CN in water with 0.1% TFA at 35 mL/min over 15 min to afford 3-(3-(2-chloro-6-fluorophenyl)-5-ethyl-6-oxo-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-7-yl)-N-cyclopropyl-4-methylbenzamide (3j, 69 mg, 28% yield) as an off-white solid.
19064-67-6, 19064-67-6 6-Chloro-3-hydroxypyridazine 252828, apyridazine compound, is more and more widely used in various fields.
Reference£º
Article; Herberich, Brad; Jackson, Claire; Wurz, Ryan P.; Pettus, Liping H.; Sherman, Lisa; Liu, Qiurong; Henkle, Bradley; Saris, Christiaan J.M.; Wong, Lu Min; Chmait, Samer; Lee, Matthew R.; Mohr, Christopher; Hsieh, Faye; Tasker, Andrew S.; Bioorganic and Medicinal Chemistry Letters; vol. 22; 2; (2012); p. 1226 – 1229;,
Pyridazine – Wikipedia
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