Pyridoazepine derivatives, pharmaceutical compositions and applications thereof
A compound, pharmaceutical technology, applied in the direction of drug combinations, active ingredients of heterocyclic compounds, antipyretics, etc.
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Embodiment 1
[0125] Embodiment 1: the synthesis of compound 1.8
[0126]
[0127] Step 1: Under ice-bath conditions, drop into a tetrahydrofuran (400 mL) solution of 2-amino-6-chloropyridine (40.0 g, 311 mmol) and lithium bistrimethylsilylamide (685 mL, 685 mmol, 1M tetrahydrofuran solution) Add di-tert-butyl dicarbonate (74.7 g, 342 mmol). The reaction system was stirred overnight at room temperature and then concentrated, diluted with ethyl acetate (400 mL), the organic phase was washed with hydrochloric acid solution (1M), saturated aqueous sodium bicarbonate solution and saturated brine, and the organic phase was separated with anhydrous sulfuric acid Sodium-dried, filtered and concentrated, the obtained residue was recrystallized from ethanol, filtered, and the filter cake was dried to obtain compound 1.1 (39.5 g, yield: 56%) as a yellow solid.
[0128] Step 2: Under nitrogen protection, a solution of compound 1.1 (39.5g, 173mmol) and N,N,N',N'-tetramethylethylenediamine (74.4g, 4...
Embodiment 2
[0135] Embodiment 2: the synthesis of compound 2.11
[0136]
[0137] Step 1: 3-bromo-2-chloro-6-methyl-5-nitropyridine (9.0g, 35.8mmol) and stannous chloride (27.2g, 143mmol) were added to ethanol (300mL), and the reaction system The temperature was raised to 80°C and stirred for 3 hours. Concentrate the reaction solution under reduced pressure, dilute with ethyl acetate (400mL), wash the organic phase with aqueous sodium hydroxide solution (1M), filter, extract the filtrate with ethyl acetate (4×100mL), combine the organic phases and wash with saturated brine Wash, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain compound 2.1 (7.3 g, yield: 92%) as a yellow solid.
[0138] Step 2: Compound 2.1 (7.3 g, 33.0 mmol) was added into a mixed solution of acetic anhydride (40 mL) and glacial acetic acid (20 mL), and stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure to obtain compound 2....
Embodiment 3
[0148] Embodiment 3: the synthesis of compound 3.2
[0149]
[0150] Step 1: N, The N-dimethylformamide (10mL) solution was stirred at 50°C for 5 hours, the reaction system was cooled to room temperature and poured into water, the solid was collected by filtration, the filter cake was washed with water and petroleum ether, and dried under reduced pressure to obtain compound 3.1 ( 0.84 g, Yield: 78%) as a yellow solid.
[0151] Step 2: Under the protection of nitrogen, compound 3.1 (500mg, 1.63mmol), potassium acetate (481mg, 4.9mmol), biboronic acid pinacol ester (622mg, 2.45mmol) and Pd(dppf) 2 Cl 2 (11.9 mg, 0.02 mmol) in 1,4-dioxane (10 mL) was stirred at 80°C for 4 hours. The reaction system was cooled to room temperature, filtered with diatomaceous earth, rinsed with ethyl acetate solution, the filtrate was concentrated, the obtained residue was slurried with ethanol, the solid was collected by filtration, and dried under reduced pressure to obtain compound 3.2 (528...
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