Pyridazinone compound, preparation method of pyridazinone compound, pharmaceutical composition and application
A compound, pyridazinone technology, applied in the field of its preparation, pyridazinone compounds or their pharmaceutically acceptable salts, can solve the problems of many adverse reactions, poor interferon tolerance, drug resistance and side effects
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Embodiment 1
[0082]
[0083] step 1:
[0084] Add 5g of 4-fluoroacetophenone to 3.76ml of pyruvic acid, stir at 120°C for 10h, then cool to room temperature, add ammonia water to adjust the pH to 8-9 in an ice bath, extract the unreacted aqueous layer with ethyl acetate of 4-fluoroacetophenone. After adding 4ml of hydrazine hydrate (85%) to the aqueous layer, it was refluxed overnight at 100°C. The next day, the reaction solution was cooled, and a solid was precipitated at this time, and 5.2 g of a white solid (compound 2) was obtained by suction filtration (72% yield). 1 H NMR (300MHz, CDCl 3 )δ11.39(s,1H),7.86–7.71(m,2H),7.57(s,1H),7.15(t,J=8.7Hz,2H),2.32(s,3H).
[0085] Step 2:
[0086] Dissolve 100mg of intermediate compound 2 in 30ml of N,N-dimethylformamide (DMF), then add 94mg of p-chlorobenzyl chloride and 190mg of cesium carbonate, react the reaction solution at 50°C for 5-6 hours, TLC shows the bottom compound disappeared completely, stopped the reaction and cooled the re...
Embodiment 2
[0094]
[0095] step 1:
[0096] Dissolve 10g of 3,6-dichloro-4-methylpyridazine in 100ml of acetic acid, reflux at 120°C for 4h, TLC shows that the substrate completely disappears, stop the reaction and cool the reaction solution to room temperature, evaporate the acetic acid under reduced pressure to obtain a solid. 200ml of ethyl acetate was added, and the insoluble solid was filtered, and the obtained white solid was intermediate compound 7 (3g, yield 33%). 1 H NMR (300MHz, DMSO) δ13.02(s, 1H), 6.89(s, 1H), 2.16(s, 3H).
[0097] The filtrate was dried, concentrated, and column chromatography gave a white solid as intermediate compound 6 (4 g, yield 44%). 1 H NMR (300MHz, DMSO) δ13.03(s, 1H), 7.43(d, J=1.3Hz, 1H), 2.04(d, J=1.2Hz, 3H).
[0098] Step 2:
[0099] Dissolve 500mg of intermediate compound 7 in 50ml of N,N-dimethylformamide (DMF), then add 670mg of p-chlorobenzyl chloride and 1.35g of cesium carbonate, and react the reaction solution at 50°C for 5-6 hours, ...
Embodiment 3
[0103]
[0104] step 1:
[0105] 500mg of intermediate 6 (prepared in Example 2) was dissolved in 50ml of DMF, then 670mg of p-chlorobenzyl chloride and 1.35g of cesium carbonate were added, and the reaction solution was reacted at 50° C. for 5-6 hours, and TLC showed that the substrate disappeared completely. The reaction was stopped and the reaction solution was cooled to room temperature, the reaction solution was extracted with ethyl acetate, the organic layer was washed 3 times, dried with anhydrous sodium sulfate, concentrated, and column chromatography gave 700 mg of white solid (compound 8b) (yield 75%) . 1 H NMR (300MHz, CDCl 3 )δ7.41(s,1H),7.38(s,1H),7.30(d,J=8.5Hz,2H),7.06(d,J=1.2Hz,1H),5.20(s,2H),2.20( d,J=1.2Hz,3H).
[0106] Step 2:
[0107] Dissolve 100mg of compound 8b in 30ml of DMF and 3ml of water, add 93mg of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- base)-1H-pyrazole, 30mg Pd(dppf) 2 Cl 2 ([1,1'-bis(diphenylphosphino)ferrocene]palladi...
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