Pyridine compound as well as preparation method and pharmaceutical application thereof
A compound and pharmaceutical technology, applied in the field of medicine, can solve problems such as poor selectivity and unstable pharmacokinetic properties
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Embodiment 1
[0035] Embodiment 1: the preparation of compound 1
[0036]
[0037] (1) Synthesis of (E)-3-(3-bromopyridin-4-yl) ethyl acrylate
[0038] Weigh sodium hydride (content 60%, 520 mg) and place it in a dry round bottom flask, add 5 mL of anhydrous tetrahydrofuran, and slowly add phosphonotriethyl ester (2.912 g, 13 mmol) dissolved in 20 mL of anhydrous tetrahydrofuran dropwise under ice bath , After the dropwise addition was completed, the stirring reaction was continued for 1h under ice bath. To the above reaction system, 3-bromo-4-formylpyridine (1.86 g, 10 mmol) diluted with 25 mL of tetrahydrofuran was continued to be added dropwise, and the reaction was stirred at room temperature for about 3 h after the addition was completed. After the reaction was completed, the solvent was evaporated, extracted with ethyl acetate and saturated brine, the organic layers were combined and concentrated to obtain a light yellow oil, and a white solid (1.8g , 70% yield).
[0039] (2) Sy...
Embodiment 2
[0041] Embodiment 2: the preparation of compound 2
[0042]
[0043] (1) Synthesis of (E)-3-(3-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyridin-4-yl)ethyl acrylate
[0044] (E)-3-(3-bromopyridin-4-yl) ethyl acrylate (512mg, 2mmol), p-piperazinylaniline (420mg, 2.2mmol), X-phos (95mg, 0.2mmol), Pd 2 (dba) 3 (92 mg, 0.1 mmol), sodium tert-butoxide (269 mg, 2.8 mmol) were placed in a round bottom flask, and 10 mL of toluene was added. The reaction system was purged with nitrogen for 5 minutes, and then heated to reflux for about 8 hours under the protection of nitrogen. After the reaction was completed, the reaction was cooled to room temperature, the solvent was evaporated, extracted with saturated brine and ethyl acetate, the organic layer was concentrated and concentrated to obtain a crude product, and a solid (366 mg, yield 50%) was obtained through silica gel column chromatography.
[0045] (2) Synthesis of (E)-3-(3-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyridin-4-yl...
Embodiment 3
[0047] Embodiment 3: the preparation of compound 3
[0048]
[0049] (1) Synthesis of (E)-3-(3-((4-fluorophenyl)amino)pyridin-4-yl)ethyl acrylate
[0050] (E)-3-(3-bromopyridin-4-yl) ethyl acrylate (512mg, 2mmol), p-fluoroaniline (244mg, 2.2mmol), X-phos (95mg, 0.2mmol), Pd 2 (dba) 3 (92 mg, 0.1 mmol), sodium tert-butoxide (269 mg, 2.8 mmol) were placed in a round bottom flask, and 10 mL of toluene was added. The reaction system was purged with nitrogen for 5 minutes, and then heated to reflux for about 8 hours under the protection of nitrogen. After the reaction was completed, the reaction was cooled to room temperature, the solvent was evaporated, extracted with saturated brine and ethyl acetate, the organic layer was concentrated and concentrated to obtain a crude product, and a solid (300 mg, yield 50%) was obtained through silica gel column chromatography.
[0051] (2) Synthesis of (E)-3-(3-((4-fluorophenyl)amino)pyridin-4-yl)acrylamide
[0052] (E)-Ethyl 3-(3-((4-...
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