3-methyluridine and 4-methylcytidine nucleoside compounds, synthesis method and pharmaceutical use thereof
A technology of methyluridines and compounds, applied in chemical instruments and methods, medical preparations containing active ingredients, sugar derivatives, etc. Solve problems such as the synthesis of glycoside nucleoside analogues, achieve the effect of simple synthesis method and good application prospect
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Embodiment 1
[0031] Synthesis of Compound 2: Compound 1 (40.0g, 79.4mmol) was dissolved in dichloromethane (400mL), hydrobromic acetic acid (45%v / v, 80mL, 433.6mmol) was added dropwise at 0°C, and it was raised to room temperature Stir overnight, after the reaction is complete, wash with saturated sodium bicarbonate solution (3×200 mL), dry over anhydrous sodium sulfate, and concentrate to dryness under reduced pressure to obtain 2 as a yellow syrup, which can be directly used in the next reaction. 525(M+H) + ,547(M+Na) + .
[0032] Synthesis of compound 3: uracil (25.3g, 226.0mmol) and ammonium sulfate (3.1g, 237.8mmol) were dissolved in hexamethyldisilazane (200mL) and stirred under reflux until the reaction was clear. After cooling to room temperature, the above Step syrup 2 was dissolved in anhydrous chloroform (400mL) and added to the above reaction solution, heated to reflux, continued to stir and react overnight, and after cooling to room temperature, the reaction solution was direc...
Embodiment 2
[0049] Synthesis of Compound 23: Compound 21 (30.0g, 64.7mmol) was dissolved in dichloromethane (300mL), and HBr / AcOH (45%v / v, 60mL, 325.2mmol) was added dropwise at 0°C, stirred at room temperature overnight , after the reaction was complete, it was washed with saturated sodium bicarbonate solution (3×200 mL), dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain 22 as a yellow syrup, which was directly used in the next reaction. MS:423(M+H) + ,445(M+Na) + .
[0050] Uracil (19.0g, 169.5mmol) and ammonium sulfate (2.4g, 178.4mmol) were dissolved in hexamethyldisilazane (150mL) and stirred under reflux to react until clarified. After cooling to room temperature, dissolve the previous step syrup 22 Add it to the above reaction solution in anhydrous chloroform (300 mL), raise the temperature to reflux, continue to stir the reaction overnight, cool to room temperature, and directly introduce the reaction solution into the ice-water mi...
Embodiment 3
[0062] Synthesis of compound 18: weigh triazole (0.33g, 4.8mmol), dissolve in dichloromethane (10ml), add phosphorus oxychloride (0.13mL, 1.44mmol) dropwise under nitrogen protection, gradually Triethylamine (0.84ml, 4.8mmol) was added dropwise, compound 16 (0.2g, 0.48mmol) was added to the above reaction solution, and after stirring at room temperature for 2 hours, triethylamine (1.0mL) and water (0.25mL) were added Stir for a while to terminate the reaction, add dichloromethane (100mL) and saturated sodium bicarbonate solution (100mL), separate the organic phase, dry over anhydrous sodium sulfate, concentrate to dryness under reduced pressure, add 1,4-dioxane ( 10mL) and concentrated ammonia water (2mL), stirred and reacted at room temperature for 8 hours, the above reaction solution was evaporated to dryness under reduced pressure to obtain compound 18 in the form of yellow syrup, which can be directly carried out to the next step without further treatment. MS:414(M+H) + ,...
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