Aromatic ethylene compound, and preparation method, intermediate, pharmaceutical composition and application thereof
A technology of aromatic ethylene and compounds, applied in the direction of drug combination, organic chemical method, acyclic/carbocyclic compound isotope introduction, etc., to achieve the best drug peak concentration, alleviate or treat cancer
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Embodiment 1
[0246] (S,E)-1-(4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-3-trifluoromethylbenzyl)piperidine -2-Formic acid (compound 1)
[0247]
[0248] Synthesis of compound 1-c
[0249] To a solution of 2-bromo-6-chlorobenzonitrile (2.16 g, 10.0 mmol) and phenylboronic acid (1.33 g, 11.0 mmol) in 1,4-dioxane (40 mL) was added water (4 mL), [1, 1'-Bis(diphenylphosphino)ferrocene]palladium dichloride (365 mg, 0.5 mmol) and sodium carbonate (2.65 g, 25.0 mmol). The reaction mixture was heated to 80°C and stirred under nitrogen for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 6:1) to obtain compound 1-c (1.55 g, yield: 72%).
[0250] Synthesis of compound 1-b
[0251] Add water (8 mL), palladium acetate to compound 1-c (1.50 g, 7.0 mmol) and vinyl pinacol borate (2.13 g, 8.4 mmol) in 1,4-dioxane (80 mL) solution (78mg, 0.35mmol), 2-...
Embodiment 2
[0261] (S,E)-1-(3-chloro-4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)benzyl)piperidine-2- Formic acid (compound 2)
[0262]
[0263] Synthesis of compound 2-a
[0264] Compound 1-b (205.0mg, 1.0mmol) and 4-bromo-3-chlorobenzaldehyde (240.9mg, 1.1mmol) were dissolved in toluene solution (30mL), and N,N'-diisopropylethylamine was added (387 mg, 3.0 mmol) and bis(tri-tert-butylphosphine)palladium (51.1 mg, 0.1 mmol). The reaction solution was replaced with nitrogen three times at room temperature, heated to 90° C., and stirred for 10 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate (100 mL), washed with water (100 mL×3) and saturated brine (100 mL) successively, the obtained organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was washed with Purification by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1-5:1) gave compound 2-a (270 mg, yield: 78%).
[0265] S...
Embodiment 3
[0270](S,E)-1-(3-chloro-4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)benzyl)piperidine-2- Formic acid (compound 3)
[0271]
[0272] Synthesis of compound 3-c
[0273] Phenylboronic acid (1.626g, 13.34mmol) and 2,6-dibromotoluene (5.0g, 20.0mmol) were dissolved in a mixed solution of 1,4-dioxane (60mL) and water (3mL), and added to [ 1,1'-Bis(diphenylphosphino)ferrocene]palladium dichloride (1.154 g, 1.334 mmol) and sodium carbonate (3.535 g, 33.35 mmol). After the reaction system was replaced with nitrogen three times, it was heated to 80° C. and stirred for 16 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate (100 mL), washed with water (100 mL×3) and saturated brine (100 mL) successively, the obtained organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was washed with Purify by silica gel column chromatography (petroleum ether) to obtain compound 3-c (1.9 g, yield: 57.2%).
[0...
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