Benzoate of 3-(3-aminopiperidine-1-yl)-5-oxo-1,2,4-triazine derivative, and preparation method and pharmaceutical composition thereof
A technology of triazine derivatives and aminopiperidine, applied in the field of medicine, can solve the problems of easy oxidation, instability, poor stability and the like, and achieve the effects of good stability, guaranteed quality and good bioavailability
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Embodiment 1
[0038] Example 1 Preparation of 1-bromo-4-fluoro-2-(methyl isothiocyanate)benzene (2)
[0039] To 1-bromo-2-(bromomethyl)-4-fluorobenzene (1,5.36g, 20.0mmol) in DMF (20ml), add sodium iodide (1.20g, 8.00mmol) and potassium thiocyanate (3.88g, 40.0mmol). The mixture was heated to 80° C. for 12 h under a nitrogen atmosphere, cooled to room temperature, 100 ml of water was added thereto, and extracted with ethyl acetate (50 mL×2), the combined organic layers were washed with saturated brine, and dried over anhydrous magnesium sulfate. The crude product was concentrated by suction filtration, and the residue was purified by silica gel column chromatography (eluent: petroleum ether) to obtain 1-bromo-4-fluoro-2-(methylisothiocyanate)benzene (2).
Embodiment 2
[0040] Example 2 Preparation of N-(2-bromo-5-fluorobenzyl)hydrazine thioformamide (3)
[0041] Hydrazine hydrate (80%, 2.22g, 35.5mmol) in 1,4-dioxane solution (20ml) was cooled to 0°C, and 1-bromo-4-fluoro-2-(methylisothiocyanate A solution of benzene (2,3.16g, 12.8mmol) in 1,4-dioxane (5ml). The mixture was stirred at room temperature for 2 hours, 100ml of ice water was added to it, and a solid precipitated out, filtered with suction, washed with water, and dried overnight with phosphorus pentoxide to obtain N-(2-bromo-5-fluorobenzyl)hydrazinothiomethyl Amide (3). MS: m / z, 278 (100%, M+1), 280 (100%), 300 (10%, M+23), 302 (10%).
Embodiment 3
[0042] Example 3 Preparation of methyl 2-(2-(2-bromo-5-fluorobenzylaminothiocarboxamide)hydrazino)propionate (4)
[0043] To a solution of pyruvic acid (352mg, 4.00mmol) in methanol (15mL) was added successively N-(2-bromo-5-fluorobenzyl)hydrazinothiocarboxamide (3, 1.112g, 4.00mmol), and concentrated Add 5 drops of sulfuric acid, heat the mixture to reflux for 7 hours, evaporate most of the solvent, extract the residue with ethyl acetate (150ml), wash the organic layer with water, saturated sodium bicarbonate solution, saturated brine, and anhydrous magnesium sulfate Dry and concentrate by suction to obtain methyl 2-(2-(2-bromo-5-fluorobenzylaminothiocarboxamide)hydrazino)propionate (4). MS: m / z, 362 (100%, M+1), 364 (100%), 384 (60%, M+23), 386 (60%).
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