Preparation and use of 6-hydroxydideoxyguanosine phosphate
A dideoxy and triphosphate technology, applied in the field of drug research, can solve the problems of poor fat solubility, poor liver targeting, poor affinity, etc., and achieve the effect of increasing concentration and increasing fat solubility
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Embodiment 1
[0177] Example 1 Preparation of compound (III)
[0178] Add dry DMF (60ml) into a 500mL three-neck flask, start stirring and add compound II (26.77g, content 99%, 0.10mol), Cbz-Cl (17.06g, 0.10mol). Cool to 10°C under stirring, keep in the range of 0 to 10°C, add pyridine (15.82g, 0.20mol) dropwise, and let it rise to room temperature for 1 hour after the dropwise reaction. 240 mL of purified water was added to the reaction liquid, followed by extraction with 120 mL of dichloromethane while stirring. Liquid extraction was carried out, and the aqueous layer was extracted once with 120 mL of dichloromethane. The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate (100 g). After filtration, the filtrate was concentrated under reduced pressure to recover dichloromethane to obtain 37.81 g of oily liquid with a yield of 94.1%. ESI-MS ( m / z ): 402.7 [M+H] + ; HPLC purity: 98.6%.
Embodiment 2
[0179] Embodiment 2 Preparation of compound (Ⅳ)
[0180] Add compound III (36.16 g, content 98.6%, 0.090 mol), benzyl chloride (11.40 g, 0.090 mol) and DMF (80 mL) into a 500 mL three-necked flask. Silver oxide (0.5 g) was added with stirring, and the reaction was maintained at 25°C for 6 hours. Add 320 mL of purified water, filter, and discard the filter residue. The pH of the filtrate was adjusted to neutral with sodium hydroxide while stirring. 120 mL of ethyl acetate was added for liquid separation extraction, and the aqueous layer was extracted once with 120 mL of fresh ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate (120 g). After filtration, the filtrate was concentrated under reduced pressure to recover ethyl acetate to obtain 36.90 g of oily liquid with a yield of 83.3%. ESI-MS ( m / z ): 493.0 [M+H] + ; HPLC purity: 97.5%.
Embodiment 3
[0181] The preparation of embodiment 3 compound (Ⅴ)
[0182] Compound IV (35.42 g, 0.072 mol), the product of Example 2, was added into a 500 mL three-necked flask, and 180 mL of anhydrous methanol was added, and dissolved completely under stirring. Add 10% sodium hydroxide (60.0 g, 0.15 mol) and heat to reflux for 2 hours. Sampling for TLC analysis. After the reaction was completed, the temperature was lowered to room temperature, and extracted with 120 ml of dichloromethane. The aqueous layer was extracted again with 120 ml of dichloromethane, and the combined organic layers were dried by adding anhydrous magnesium sulfate (80 g). After filtration, the filtrate was concentrated under reduced pressure, and dichloromethane was recovered to obtain 22.40 g of light yellow solid with a yield of 91.7%. ESI-MS ( m / z ): 340.3 [M+H] + ; HPLC purity: 97.2%.
[0183] TLC development conditions: ethyl acetate / petroleum ether=1:2 (V / V)
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