(2R,5R)-5-phosphoryl methoxy-2-(2-substituted adenine-9-yl)-2,5-dihydrofuran nucleoside analog as well as preparation method and application thereof

A dihydrofuran nucleoside and phosphoryl methoxy technology, applied in the field of nucleotide chemistry and medicinal chemistry, can solve the problems of complex nucleoside synthesis process and no reports

Inactive Publication Date: 2014-05-14
ZHENGZHOU UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But because the nucleoside synthetic process is complicated, a little change of base or sugar ring all can cause

Method used

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  • (2R,5R)-5-phosphoryl methoxy-2-(2-substituted adenine-9-yl)-2,5-dihydrofuran nucleoside analog as well as preparation method and application thereof
  • (2R,5R)-5-phosphoryl methoxy-2-(2-substituted adenine-9-yl)-2,5-dihydrofuran nucleoside analog as well as preparation method and application thereof
  • (2R,5R)-5-phosphoryl methoxy-2-(2-substituted adenine-9-yl)-2,5-dihydrofuran nucleoside analog as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] Example 1: Preparation of compound II

[0062] Dissolve 3,5-di-O-p-methylbenzoyl-2-deoxy-D-riboside (I, 7.7 g, 20 mmol) in 15 ml of glacial acetic acid, and pass through dry HCl gas at 0°C , after the solid was no longer precipitated, it was suction filtered, and the filter cake was washed with acetone to obtain 7.0 g (90%) of compound II as a white solid.

[0063] Experimental data:

[0064] white solid, 1 H NMR (400 MHz, CDCl 3 ) δ 8.02 (d, J = 8.2 Hz, 1H, Ar-H), 7.92 (d, J = 8.2 Hz, 1H, Ar-H), 7.28 (dd, J = 11.7, 7.0 Hz, 4H, Ar-H), 6.50 (d, J = 5.0 Hz, 1H, H-1'), 5.59 (dd, J = 7.0, 2.6 Hz, 1H, H-3'), 4.88 (dd, J = 6.8, 3.2 Hz, 1H, H-4'), 4.71 (dd, J = 12.1, 3.1 Hz, 1H, H-5'a), 4.62 (dd, J = 12.1, 4.2 Hz, 1H, H-5'b), 2.89 (ddd, J = 15.1, 7.4, 5.2 Hz, 1H, H-2'a), 2.77 (d, J = 15.1 Hz, 1H, H-2'b), 2.45 (s, 1H, -CH 3 ), 2.44 (s, 1H, -CH 3 ). 13 C NMR (101 MHz, CDCl 3 ) δ 166.4 (C=O), 166.1 (C=O), 144.3, 144.1, 129.9, 129.7, 129.3, 129.2, 126.8...

Embodiment 2

[0065] Example 2 : Preparation of Compound III

[0066] Dissolve 1.15 g (6 mmol) of 2,6-dichloropurine in 12 ml of anhydrous tetrahydrofuran. After it is completely dissolved, add it to 10 ml of acetonitrile solution containing 240 mg of sodium hydride under nitrogen protection. After no more gas was generated, 1.95 g (5 mmol) of compound II was added in portions at 25°C. The reaction progress was monitored by thin-layer chromatography. After the reaction was completed, it was filtered with suction, the filter cake was washed with ethyl acetate, the filtrate was concentrated under reduced pressure, and separated by silica gel column chromatography to obtain 2.1 g of compound III (yield 78%).

[0067] Experimental data:

[0068] White solid, 1 H NMR (400 MHz, CDCl 3 ): δ 8.32 (s, 1H, H-8), 7.99 (d, J = 8.1 Hz, 2H, Ar-H), 7.84 (d, J = 8.1 Hz, 2H, Ar-H), 7.31 (d, J = 8.1 Hz, 2H, Ar-H), 7.22 (d, J = 8.1 Hz, 2H), 6.57 (t, J = 6.9 Hz, 1H, H-1'), 5.81 (m, 1H, H-3'), 4...

Embodiment 3

[0069] Example 3: Preparation of compound Ⅳ

[0070] Suspend 1.2g (2.2 mmol) of compound III in 50ml of anhydrous methanol, add 375mg (7 mmol) of sodium methoxide, and stir the reaction at 25°C. The reaction progress was monitored by thin-layer chromatography. After the reaction, glacial acetic acid was added to adjust the pH to 7. The reaction solution was concentrated and separated by silica gel column chromatography to obtain 500 mg of compound IV (yield 75%).

[0071] Experimental data:

[0072] Goo. 1 H NMR (400 MHz, CDCl 3 ) δ 8.14 (s, 1H, H-8), 6.38 (dd, J = 8.3, 5.9 Hz, 1H, H-1'), 4.80 (d, J = 5.1 Hz, 1H, H-3'), 4.20 (s, 4H, H-4', -OCH 3 ), 3.99 (dd, J = 12.7, 1.5 Hz, 1H, H-5'a), 3.84 (dd, J = 12.6, 1.8 Hz, 1H, H-5'b), 2.91 (ddd, J = 13.7, 8.4, 5.6 Hz, 1H, H-2'a), 2.43 (m, 1H, H-2'b). 13 C NMR (101 MHz, CDCl 3) δ 161.6 (C-2), 153.0 (C-4), 151.8 (C-6), 142.2 (C-8), 121.6 (C-5), 89.0 (C-4'), 86.9 (C-1 '), 72.4 (C-3'), 62.9 (C-5'), 55.3 (-OCH 3 ), 40.9 (C-2...

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Abstract

The invention discloses a novel beta-furan phosphonate purine nucleoside analog, and in particular relates to a (2R,5R)-5-phosphoryl methoxy-2-(2-substituted adenine-9-yl)-2,5-dihydrofuran nucleoside analog as well as a preparation method and an application thereof, which belongs to the field of nucleoside chemicals and pharmaceutical chemistry. The analog has a structure as shown in the formula (1) in the specification, wherein R1 represents C1, NH2, OCH3, SCH3, NHCH3 or NHNH2; R2 represents NH2, OCH3 and NHCH3; R' represents H, Na or K. Chlorinated sugar with high activity is formed through chlorination of 3.5-di-O-p-methyl benzoyl-2-deoxidation-D-ribose glucoside, the chlorinated sugar is subsequently reacted with alkali, and a novel beta-D-dihydrofuran phosphonate adenine nucleoside analog is formed through selective oxidation, decarboxylation, addition, elimination, functional group conversion and ethyl removal. The analog has anti-virus activity and good development prospect.

Description

technical field [0001] The invention belongs to the fields of nucleotide chemistry and medicinal chemistry, and in particular relates to a novel phosphonate furan nucleoside analogue and a preparation method thereof. Background technique [0002] Non-natural nucleoside drugs are the main therapeutic drugs for viral diseases, and they are also a very important class of anti-tumor drugs. Most biologically active nucleoside analogs are activated by phosphorylation into mononucleotides under the action of nucleoside kinases in cells, and mononucleotides are then converted into 5'-trinucleotides through two-step phosphorylation reactions. Nucleoside phosphates can act as substrates for RNA or DNA polymerases to exert antiviral effects, that is, nucleoside analogs are only prodrugs of antiviral drugs. The first step phosphorylation is a slow or rate-limiting reaction in most cases, which directly restricts its antiviral activity. By directly synthesizing monophosphorylated deriv...

Claims

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Application Information

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IPC IPC(8): C07H19/207C07H1/00A61K31/7076A61P31/20
Inventor 刘丰五徐锐钢刘飞刘应举
Owner ZHENGZHOU UNIV
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