Nitric oxide donating hypoglycemic compound, its preparation method and use
A technology of compounds and intermediates, applied in the field of hypoglycemic compounds and their preparation, and the preparation of hypoglycemic drugs, which can solve the problems of large gastrointestinal damage, indigestion, poor tolerance drug interactions, etc., and achieve obvious inhibitory effect Effect
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Embodiment 1
[0073] 2-(3-(3-(piperidin-1-ylmethyl)phenoxy)propylamino)-2-oxoethyl nitrate (compound Ⅰ-1)
[0074]
[0075] Add intermediate V-1 (3.2g, 0.01mol) in the reaction flask equipped with stirring, condenser and thermometer, dissolve in anhydrous acetonitrile (20m1), add anhydrous acetonitrile solution of silver nitrate (2.0g, 0.012mol) (10m1), refluxed for 5h under stirring in the dark, TLC showed that the reaction was complete and cooled to room temperature, and the solvent was evaporated to dryness under reduced pressure. Dichloromethane (20ml) was added to the residue, stirred for 10min, filtered, and the filtrate was evaporated to dryness under reduced pressure. Add absolute ethanol (30ml), decolorize with activated carbon, evaporate to dryness under reduced pressure, and dry under reduced pressure at room temperature overnight to obtain light yellow transparent oil I-1 (3.1g, yield 90%), purity 98.2% (HPLC method). MS (m / z): 351.
[0076] Referring to the method of Examp...
Embodiment 2
[0079] 2-(3-(3-(piperidin-1-ylmethyl)phenoxy)propylamino)ethyl nitrate (compound Ⅰ-4)
[0080]
[0081] Mix 6.5ml of fuming nitric acid and 19.5ml of acetic anhydride in a reaction flask equipped with stirring, condenser, and thermometer, control the temperature at -15°C, and add intermediate VI-1 (2.9g, 0.01mol) dropwise Tetrahydrofuran solution 100mL, after dropping, slowly rise to room temperature, react for 4h, add dropwise ice water to stop the reaction. The reaction mixture was dissolved in 200ml of ethyl acetate, washed successively with 200ml of water, 200ml of saturated sodium bicarbonate solution, and then washed with 200ml of water and 200ml of saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate. Concentrated under reduced pressure, the crude product was purified by column chromatography (v (petroleum ether): v (ethyl acetate) = 1:1] to obtain 1.9 g of yellow oil with a yield of 58% and a purity of 99.1%. MS (m / z ): ...
Embodiment 3
[0085] Compound Ⅰ-2 into hydrochloride: Take 1.5 g of compound Ⅰ-2 yellow oil and dissolve it in 10 mL of absolute ethanol. Cool in an ice-water bath to 5°C, add 11.1% ethanol hydrochloric acid solution dropwise until the pH is 2, and continue stirring for about 1 h in an ice-water bath. Filter and dry in vacuo to obtain a yellow solid.
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