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Beta-2'-deoxygenation-ramification of nucleotide, synthetic method and application of medication

A technology of derivatives and nucleosides, applied in the field of new nucleoside derivatives, can solve problems that have not been seen yet, and achieve the effects of small toxic and side effects, high anti-HBV activity, and high yield

Inactive Publication Date: 2007-05-16
QUALITY TEST & ANALYTIC MEASUREMENT RES CENT HENAN ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

A few days ago, patients with hepatitis B and AIDS are in urgent need of specific drugs for the treatment of such diseases. For this reason, we have synthesized a new type of β-L-2'-deoxy-nucleoside compound. In the existing literature, no compound of the present invention and its Related reports for anti-HBV

Method used

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  • Beta-2'-deoxygenation-ramification of nucleotide, synthetic method and application of medication
  • Beta-2'-deoxygenation-ramification of nucleotide, synthetic method and application of medication
  • Beta-2'-deoxygenation-ramification of nucleotide, synthetic method and application of medication

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] (A) Synthesis of 3',5'-dibenzoyloxy-2'-deoxy-β-L-uridine (2)

[0031] 2'-deoxy-β-L-uridine (1) (1g, 4.4mmol) was dissolved in anhydrous pyridine (20mL), and N 2 Benzoyl chloride (2 mL) was slowly added dropwise under protection. After completion, the reaction at room temperature was carried out for 6 hours. TLC detected that the starting point disappeared, and the compound 21.88 g (98.4%) was obtained by column separation, m.p.218-220°C.

[0032] 1 H NMR (CDCl 3 ): δppm 2.20-2.40 (1H, m), 2.60-2.80 (1H, m), 4.40-4.60 (3H, m), 5.62 (2H, m), 6.41 (1H, q), 7.48-8.10 (11H, m), 9.20 (1H, s, br).

[0033] (B) Synthesis of 3', 5'-dibenzoyloxy-2'-deoxy-β-L-4-thio-uridine (3)

[0034] Compound 2 (220mg, 0.5mmol) and Lawesson's reagent (408mg, 1.0mmol) were put into 1,2-dichloroethane (20mL), heated to reflux for 20h, TLC detected that the raw material point disappeared, cooled to room temperature, washed with water, concentrated and dried , column separation to obtain c...

Embodiment 2

[0042] (A) Synthesis of 3',5'-dibenzoyloxy-2'-deoxy-5-iodo-β-L-uridine (6)

[0043] Compound 4 (1g, 2.40mmol), I 2 (0.8g), cesium ammonium nitrate (CAN) (0.7g), dissolved in acetonitrile (30mL), stirred and reacted at 85°C for 5h, TLC detected that the raw material point disappeared, and cooled to room temperature to precipitate 60.9g (69.8%) of compound, m.p. 190-192°C.

[0044] 1 H NMR (CDCl 3 )δppm: 2.31 (1H, m), 2.61-2.72 (1H, m), 4.47-4.52 (1H, m), 4.68-4.71 (2H, m), 5.58 (1H, m), 6.35 (1H, q) , 7.31-8.21 (11H, m), 9.21 (1H, s).

[0045] (B) Synthesis of 3',5'-dibenzoyloxy-2'-deoxy-3-N-toluoyl-β-L-thymidine (8)

[0046] Compound 6 (1.0g, 1.78mmol) was dissolved in anhydrous pyridine (20mL), then ethyldiisopropylammonium (DIEA) (0.7mL) was added, and p-toluoyl chloride (0.8mL ), complete and then react at room temperature for 3h, TLC detects that the raw material point disappears, add a small amount of water to stop the reaction, and use CH 2 Cl 2 Extraction, w...

Embodiment 3

[0059] (A) Synthesis of 3,'5'-dibenzoyloxy-2'-deoxy-5-fluoro-β-L-uridine (13)

[0060] Carry out the same method as Example 1, except that compound 12 is used instead of compound 1 for the reaction, and the product is determined to be 3',5'-dibenzoyloxy-2'-deoxy-5-fluoro-β-L - Uridine (13), yield 96.8%, m.p. 171-173°C.

[0061] 1 H NMR (CDCl 3 )δppm: 2.31-2.42 (1H, m), 2.59-2.80 (1H, m), 4.72-4.84 (3H, m), 5.73 (1H, m), 6.28 (1H, q), 7.35-8.08 (11H, m), 9.45 (1H, s, br).

[0062] (B) Synthesis of 3',5'-dibenzoyloxy-2'-deoxy-5-fluoro-β-L-uridine (14)

[0063] Carry out the same method as Example 1, except that compound 13 is used instead of compound 2 for the reaction, and the product is determined to be 3', 5'-dibenzoyloxy-2'-deoxy-5-fluoro-β-L- 4-Thio-uridine (14), yield 98.9%, m.p.168-169°C.

[0064] 1 H NMR (CDCl 3 )δppm: 2.33-2.44 (1H, m), 2.60-2.79 (1H, m), 4.73-4.83 (3H, m), 5.81 (1H, m), 6.32 (1H, q), 7.31-8.07 (11H, m), 9.48 (1H, s, br).

[0065] (C) Synt...

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Abstract

A beta-L-2'-deoxyl-nucleoside derivative used for treating the diseases associated with HBV and HIV is prepared from beta-L-2'-deoxy-uracil nucleoside through etherifying, sulfurizing, and reducing. Its advantages are high curative activity and low toxic by-effect.

Description

technical field [0001] The present invention relates to a novel nucleoside derivative, its synthesis method and its application, in particular to a β-L-2-deoxy-nucleoside derivative, its synthesis method and its medicinal application. Background technique [0002] At present, hepatitis B patients and AIDS patients are increasing worldwide. Most of the drugs for treating hepatitis B, such as bifendate (DDB), lamivudine (3TC) (US-5539116), FTC (W092 / 15308), L -FMAU (US5587362), L-FddC (WO92 / 18517), β-L-dT, β-L-dC (US6566344B1) have good effects, but once the patients stop taking the medicine, they all have different degrees of rebound phenomenon . A few days ago, patients with hepatitis B and AIDS are in urgent need of specific drugs for the treatment of such diseases. For this reason, we have synthesized a new type of β-L-2'-deoxy-nucleoside compound. In the existing literature, no compound of the present invention and its Related reports for anti-HBV. Contents of the inv...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H19/073C07H19/10A61K31/7068A61P31/12
Inventor 常俊标余学军王利敏王强祁秀香董春红
Owner QUALITY TEST & ANALYTIC MEASUREMENT RES CENT HENAN ACAD OF SCI
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