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Deuterated Sofosbuvir and use thereof

A deuterated, deuterated alkyl technology, applied in the field of viral hepatitis C treatment drugs, can solve the problem of undisclosed chemical structure

Inactive Publication Date: 2015-06-03
中科云和(北京)生物医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] IDX21437, which is being developed by Idenix Pharmaceuticals for the treatment of hepatitis C, is also a uracil nucleotide prodrug NS5B inhibitor, and its chemical structure has not been disclosed so far

Method used

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  • Deuterated Sofosbuvir and use thereof
  • Deuterated Sofosbuvir and use thereof
  • Deuterated Sofosbuvir and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0084]

[0085]

[0086] 1-[(2R,3R,4R,5R)-4-(tert-butyldimethylsilyloxy)-3-fluoro-5-hydroxymethyl-3-methyltetrahydrofuran-2-yl]pyrimidine— 2,4(1H,3H)-Diketone (212)

[0087]

[0088] Pyridine (30 mL) and dichloromethane (30 mL) were added to 211 (5.0 g, 19.21 mmol), and the solution was cooled to 0 °C. To the solution was added 4,4'-dimethoxytrityl chloride (7.16 g, 21.14 mmol), and the mixture was stirred at 0°C overnight. Methanol (5 mL) was added to quench the reaction, the reaction solution was concentrated to dryness under reduced pressure, and ethyl acetate (300 mL) and water (30 mL) were added to the residue. The organic layer was washed with brine (40 mL), dried over sodium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in dichloromethane (100 mL). To the solution was added imidazole (3.92 g, 57.5 mmol) and tert-butyldimethylsilyl chloride (4.34 g, 28.8 mmol). After the reaction mixture was stirred overnight at room ...

Embodiment 2

[0113]

[0114] Compound 217 (3 g) was dissolved in heavy water (30 mL), then deuterated Raney nickel (6 mL) was added and the reaction solution was stirred at 110° C. for 8 days. The reaction solution was cooled to room temperature, filtered through a thin layer of diatomaceous earth, and the oil obtained after the filtrate was concentrated was the product 218 (2.7 g, 90%).

[0115]

[0116] The dry compound 218 (2.7g) was dissolved in pyridine-dichloromethane (2:1, 40mL), benzoyl chloride (10mL) was slowly added at 0°C, and the reaction solution was then stirred at 0-4°C for reaction 4 After 1 hour, the reaction was quenched by pouring ice water, and the reaction mixture was concentrated under reduced pressure. The residue was partitioned between chloroform and saturated aqueous sodium bicarbonate solution, and the organic phase was washed with brine and dried. The crude product obtained after concentration was purified by column chromatography (hexane:ethyl acetate=4:...

Embodiment 3

[0126]

[0127] The mixture of 224 (930mg, 2.5mmol) and THF (13mL) was cooled to 0°C, and deuterated lithium borohydride (70mg, 2.71mmol) was added, then reacted at 0°C for 40 minutes, slowly raised to room temperature and continued stirring for one hour . After cooling to 0 °C, deuterated methanol was added to quench the reaction. The solvent was evaporated under reduced pressure, ethyl acetate (90mL) and water (10mL) were added to the residue, and the organic layer was washed with 1N hydrochloric acid solution (10mL), saturated sodium bicarbonate solution (20mL) and saturated brine (30mL), respectively. Dry over sodium sulfate and distill off the solvent under reduced pressure. Add 15 mL of dichloromethane to the obtained oily crude product and cool to 0°C, add triethylamine (0.68 mL, 5 mmol), slowly add MsCl (0.23 mL, 3.0 mmol) dropwise, slowly warm to room temperature and continue stirring for two hours. The reaction was quenched by adding 60 mL of dichloromethane and...

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Abstract

The invention discloses deuterated Sofosbuvir and application thereof. Deuterated Sofosbuvir is a nucleoside phosphoramidate compound shown in the formula I or II, or stereisomer, salt, hydrate, solvate or crystal of the nucleoside phosphoramidate compound. The compound and the composition are used for treating flaviviridae viruses, and particularly used for treating infection of hepatitis c virus (HCV); and the deuterated Sofosbuvir has good HCV resistance.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a new class of deuterated nucleoside phosphoramidate compounds, compositions containing the deuterated nucleoside phosphoramidate compounds, and the compounds or compositions as drugs for treating viral infectious diseases purposes, especially as a drug for the treatment of viral hepatitis C. Background technique [0002] Hepatitis C virus (HCV) infection is a worldwide epidemic disease, the global chronic infection has exceeded 200 million, the chronic infection rate is 15% in Egypt, 4.8% in Pakistan, and 3.2% in China, ranking the top three in the world. The clinical manifestations of hepatitis C virus infection are diverse, ranging from mild inflammation to severe liver cirrhosis and liver cancer. Chronic hepatitis C can also be complicated by certain extrahepatic manifestations, including rheumatoid arthritis, conjunctival keratitis sicca, lichen planus, glomer...

Claims

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Application Information

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IPC IPC(8): C07H19/06C07H19/10C07H1/00C07B59/00A61K31/7072A61P31/14
CPCA61K31/7072C07B59/005C07H1/00C07H19/06C07H19/067C07H19/10
Inventor 王彩琴冯汝宏周守明汤律进
Owner 中科云和(北京)生物医药科技有限公司
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