Amino modified cyclodextrin based artemisinin prodrug and its preparation method
A technology of cyclodextrin and artemisinin, which is used in pharmaceutical formulations, medical preparations without active ingredients, and medical preparations containing active ingredients, etc. It can improve the target bioavailability, reduce the toxic and side effects of drugs, and achieve mild reaction conditions.
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Embodiment 1
[0057] Example 1: Preparation of mono-[6-(ethylenediamino)-6-deoxy]-β-cyclodextrin-artesunate linkage
[0058] Dissolve 2.61g (2mmol) of mono-[6-(ethylenediamino)-6-deoxy]-β-cyclodextrin in anhydrous N,N-dimethylamide (50mL) and cool to about 0°C . Add 1.2 g of dicyclohexylcarbodiimide (DCC) and 0.9 g of 1-hydroxybenzotriazole (HOBT) to the solution, add 2.77 g (6 mmol) of artesunate after stirring in an ice bath for 5 h, and the reaction solution is Stir at 0°C for 20 hours, and at 25°C for 10 hours (using TCL tracking detection, the developer is methanol: ethyl acetate: water = 7:7:1). The reaction solution was evaporated to dryness under reduced pressure at 60°C, the residue was fully dissolved in water, filtered, the filtrate was concentrated, extracted by adding 100 mL of chloroform dropwise, filtered, the precipitate was collected, and vacuum-dried at 50°C for 24 hours to obtain mono-[6-(ethylenediamine )-6-deoxy]-β-cyclodextrin-artesunate linkage, the yield was 65%; t...
Embodiment 2
[0060] Example 2: Preparation of mono-[6-(monoamino)-6-deoxy]-β-cyclodextrin-artesunate linkage
[0061] Dissolve 2.56g (2mmol) mono-[6-(monoamino)-6-deoxy]-β-cyclodextrin in anhydrous N,N-diethylamide (50mL) and cool to about -10°C . Add 1.2 g of dicyclohexylcarbodiimide (DCC) to the solution, stir in an ice bath for 0.5 h, then add 5.54 g (12 mmol) of artesunate, and stir the reaction solution at 10° C. for 6 h and 45° C. for 4 h. The reaction solution was evaporated to dryness at 60°C under reduced pressure, the residue was fully dissolved in water, filtered, the filtrate was concentrated, extracted by adding 100 mL of tetrahydrofuran dropwise, filtered, the precipitate was collected, and vacuum-dried at 50°C for 24 hours to obtain mono-[6-(monoamino) -6-deoxy]-β-cyclodextrin-artesunate linkage, the yield was 58%; the solubility of the product in water at 25°C was 45 mg / mL.
Embodiment 3
[0062] Example 3: Preparation of mono-[3-(diethylenetriamine)-6-deoxy]-α-cyclodextrin-artesunate linkage
[0063] Dissolve 2.04 g (2 mmol) of mono-[3-(diethylenetriamine)-6-deoxy]-α-cyclodextrin in anhydrous dimethyl sulfoxide (50 mL), and cool to about -5°C. Add 1.2 g of dicyclohexylcarbodiimide (DCC) and 0.9 g of 1-hydroxybenzotriazole (HOBT) to the solution, stir in an ice bath for 2.5 h, then add 13.86 g (30 mmol) of artesunate, and the reaction solution Stir at 0°C for 12h and at 25°C for 24h. The reaction solution was evaporated to dryness under reduced pressure at 60°C, the residue was fully dissolved in water, filtered, the filtrate was concentrated, 100 mL of isopropanol was added dropwise, filtered, the precipitate was collected, and vacuum-dried at 50°C for 24 hours to obtain mono-[3-(diethylenetri Amino)-6-deoxy]-α-cyclodextrin-artesunate linkage, the yield was 56%; the solubility of the product in water at 25°C was 78mg / mL.
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