2',2'-dihalo nucleoside analogs for treatment of the flaviviridae family of viruses and cancer
A compound and composition technology, which can be used in antiviral agents, drug combinations, sugar derivatives, etc., can solve the problems of pigmentation and edema, leukocyte thrombocytopenia, etc.
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[0277] Specific compounds representative of this invention were prepared according to the following examples and reaction sequences; the examples and schematic diagrams describing the reaction sequences are provided as illustrations to aid in the understanding of the invention, but are not to be construed as limiting in any way the ensuing claims The invention described in. Compounds of the invention can also be used as intermediates in subsequent examples to produce additional compounds of the invention. No attempt was made to optimize the yield obtained in any reaction. Those skilled in the art will know how to increase such yields by routine changes in reaction times, temperatures, solvents and / or reagents.
[0278] Anhydrous solvents were purchased from Aldrich Chemical Company (Milwaukee, WI) and EMD Chemicals (Gibbstown, NJ). Reagents were purchased from commercial sources. Unless otherwise indicated, materials used in the examples were obtained from readily available...
Embodiment 1
[0280] Preparation of 2,2-Dichlororibolactol (14)
[0281]
[0282] 2-Deoxy-3,5-di-O-(tert-butyldimethylsilyl)-D-ribonolactone (12).
[0283] To a solution of 2-deoxy-D-ribose (10.0 g, 74.6 mmol) in 60 mL of water was added Br 2 (20mL). The flask was sealed and the contents were stirred at room temperature for 5 days. Quench with sodium thiosulfate in a rotary evaporator collection flask and evaporate excess Br under reduced pressure 2 . The resulting pale yellow mixture was neutralized until pH 7 by adding silver carbonate. The mixture was filtered and washed with water. After removal of water, the crude product was filtered through a pad of silica gel and eluted with ethyl acetate. The filtrate was concentrated under reduced pressure. To a solution of crude 2-deoxyribonolactone in 300 mL of anhydrous DMF was added imidazole (12.7 g, 186 mmol) and tert-butyldimethylsilyl chloride (27.0 g, 178 mmol). The reaction was stirred at ambient temperature for 24 h, and the ...
Embodiment 2
[0289] Preparation of nucleoside analog 18
[0290]
[0291]1-(4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-3,3-dichlorotetrahydrofuran-2 -yl)pyrimidine-2,4(1H,3H)-dione (15 and 16).
[0292] A solution of uracil (942 mg, 8.40 mmol) and BSA (6.15 mL, 24.8 mmol) in ACN (57 mL) was stirred at 60 °C for 15 minutes, then compound 19 (3.00 g, 5.61 mmol) and TMSOTf (3.03 mL , 16.7 mmol). The reaction vessel was then placed in the cavity of a microwave reactor (CEM Discover) and irradiated at 130° C. for 6 minutes. at 0 °C by adding saturated NaHCO 3 Aqueous solution (100 mL) quenched the reaction. The aqueous layer was extracted with ethyl acetate (50 mL×3), and the combined organic layers were washed with brine. Dilute the solution with Na 2 SO 4 Dry and concentrate in vacuo. The residue was purified by flash chromatography (hexane / ethyl acetate 4:1) to afford 15 (245 mg, 0.47 mmol, 8.4% yield) and 16 (737 mg, 1.40 mmol, 25% yield).
[0293]...
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