Antiviral nucleoside analogues
A technology of nucleosides and nucleosides, applied in the field of purine nucleosides, can solve problems such as poor pharmacokinetic properties and achieve the effect of good curative effect
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Embodiment 1
[0120] 2-(R,S)-Benzoyloxymethyl-1,3-dioxolane-4-(R)-carboxylic acid methyl ester At 80°C, 2,3-O-isopropylidene-D-methyl glycerate (Fluka Company, catalog No. 59449) (9.76g, 60.9mmol, 1eq.) and benzoyloxyacetaldehyde ( 10g, 60.9mmol, 1eq.) were added p-toluenesulfonic acid (460mg, 2.4mmol, 4mol%) in the toluene (20ml) solution, and the reaction flask remained in vacuum for 1 hour, and distillate was collected during this time (80-85°C). The residue was cooled to room temperature and subjected to column chromatography using silica gel as a solid support and hexane / ethyl acetate as eluent to yield 13.2 g (81%) of the title compound. The compound is a mixture with a 3:1 ratio of cis isomer to trans isomer.
[0121] Cis isomer:
[0122] 1 H-NMR (CDCl 3 ): δ (ppm): 3.75 (s, 3H, CH3); 4.15 (dd, 1H,
[0123] C 5 -CH), 4.30 (dd, 1H, C 5 -CH); 4.5(m,2H,CH 2 -O-CO-C 6 h 5 ); 4.7
[0124] (m, 1H, C 4 -CH); 5.4(t, 1H, C 2 -CH); 7.45-8.1 (m, 5H, Ar-CH
[0125] ).
[0126] tra...
Embodiment 2
[0132] (2R,4R)-2-benzoyloxymethyl-1,3-dioxolane-4-carboxylic acid;
[0133] (2S,4R)-2-benzoyloxymethyl-1,3-dioxolane-4-carboxylic acid; In 2-(R,S)-benzoyloxymethyl-1,3-dioxolane-4-(R)-carboxylic acid methyl ester (411g, 1.54mmol, 1eq., cis and trans isomer ratio of 2:1 mixture) in tetrahydrofuran-water solution (THF and water ratio is 1:1) was added lithium hydroxide (64.8g, 1.54moles, 1eq.) (lithium hydroxide in 30 minutes Gradually added), the temperature of the reaction flask was kept below 30°C. After 90 minutes, THF was removed under vacuum, and 30% (w / w) sulfuric acid was added dropwise to acidify the aqueous solution to pH 2.5-3.2. It was then extracted with dichloromethane (4 x 400ml). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated to give 380 g of a dark oil. The isomer mixture was subjected to column chromatography using silica gel as a solid phase carrier and 2% acetic acid in dichloromethane to obtain 220 g of ci...
Embodiment 3
[0144] (2R)-2-Benzoyloxymethyl-4-(R,S)-acetoxy-1,3-dioxolane To (2R,4R)-2-benzoyloxymethyl-1,3-dioxolane-4-carboxylic acid (130g, 0.515moles, 1eq.) and pyridine (60ml, 0.741moles, 1.44eq. ) in acetonitrile solution (4° C.), gradually add lead tetraacetate (analytical value: 95%, 300 g, 0.678 moles, 1.25 eq.) in 20 minutes. The reaction mixture was stirred continuously at room temperature for 18 hours. Filter to remove inorganic matter, pour the filtrate into 2 liters of saturated sodium bicarbonate solution and then add solid sodium bicarbonate (pH7-8). The organic phase was separated, and the aqueous phase was extracted three times with 400 ml of ethyl acetate. In this way, the organic phases were combined and concentrated. Column chromatography using silica gel as a solid support and hexane / ethyl acetate as eluent gave 93.5 g (68%) of the title compound. This is a mixture in which the ratio of cis and trans isomers is 2:1. The resulting mixture was used in the next ste...
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