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Preparation method of adenine derivative

A technology of adenine and derivatives, applied in the field of preparation of adenine derivatives, can solve the problems of low yield and low purity, and achieve the effect of high product purity and simple operation process

Active Publication Date: 2006-06-14
ZHEJIANG CHARIOTEER PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In order to overcome the shortcomings of low yield and low purity in the prior art, the present invention provides a method for preparing adenine derivatives such as formula (I), more particularly provides a kind of adefovir dipivoxil intermediate Preparation

Method used

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  • Preparation method of adenine derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Example 1 Preparation of 9-(2-diethoxyphosphonomethoxyethyl)adenine

[0021] Throw 54g of adenine, 115g of potassium carbonate, 1g of sodium methoxide, and 600ml of DMF into a 1000ml reaction flask, raise the temperature to 100°C, add 103g of substituted phosphonate such as formula (IV) dropwise, and react at 120°C for 18 Hour. During the reaction, TLC (chloroform:methanol=7:1) was used to track and determine the end point. After the reaction was finished, potassium carbonate was removed by filtration, and the filter cake was washed with an appropriate amount of DMF, and the filter cake was discarded. DMF was recovered under reduced pressure until the material became a paste, 300 g of acetone was added and stirred for 24 hours, the condensate was obtained by filtration, and dried to obtain 118 g of the product with a yield of 89.6%. The obtained product was quantitatively analyzed by high performance liquid chromatography, and the content of 9-(2-diethoxyphosphonometh...

Embodiment 2

[0032]Throw 54g of adenine, 115g of potassium carbonate, 1g of sodium ethoxide, and 600ml of DMF into a 1000ml reaction flask, raise the temperature to 100°C, add 150g of substituted phosphonate such as formula (IV) dropwise, and react at 120°C for 18 Hour. The process was followed by TLC (chloroform:methanol=7:1) and the end point was determined. After the reaction was finished, potassium carbonate was removed by filtration, and the filter cake was washed with an appropriate amount of DMF, and the filter cake was discarded. DMF was recovered under reduced pressure until the material became a paste, 300 g of acetone was added and stirred for 24 hours, the condensate was obtained by filtration, and dried to obtain 100 g of the product with a yield of 76.0%. The chromatographic conditions described in Example 1 were used for quantitative analysis of the obtained product, and the content of 9-(2-diethoxyphosphonomethoxyethyl)adenine was 94%.

Embodiment 3

[0033] Example 3 Preparation of 9-(2-diethoxyphosphonomethoxyethyl)adenine

[0034] Throw 54g of adenine, 150g of potassium carbonate, 2g of sodium methoxide, and 800ml of DMSO into a 1500ml reaction bottle, heat up to 100°C, add 120g of substituted phosphonate as in formula (IV) dropwise, and react at 120°C for 24 Hour. During the reaction, TLC (chloroform:methanol=7:1) was used to track and determine the end point. After the reaction was finished, potassium carbonate was removed by filtration and the filter cake was washed with an appropriate amount of DMSO, and the filter cake was discarded. DMSO was recovered under reduced pressure until the material became a paste, 300 g of acetone was added and stirred for 24 hours, the condensate was obtained by filtration, and dried to obtain 120 g of the product with a yield of 91.1%. The chromatographic conditions described in Example 1 were used for quantitative analysis of the obtained product, and the content of 9-(2-diethoxypho...

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Abstract

The present invention relates to a preparation method of adenine derivative. Said method includes the following steps: in non-protonic polar solvent, under the action of catalyst making adenine and phosphonate ester react at 50-150deg.C, then making after-treatment so as to obtain the invented product. The described catalyst at least contains one inorganic alkali and one organic alkali, the described inorganic alkali is selected from carbonate of alkali metal or sodium hydride, and the described organic alkali is selected from alcohol sodium or alcohol potassium of C1-C5.

Description

(1) Technical field [0001] The invention relates to a preparation method of adenine derivatives. (2) Background technology [0002] Hepatitis B is a disease that seriously endangers human health caused by hepatitis B virus (HBV). Elimination of HBV with antiviral therapy is the fundamental treatment. Anti-HBV drugs include interferon, nucleoside analogs and immunomodulators. The antiviral treatment of viral hepatitis currently has problems such as unsatisfactory curative effect, high recurrence rate, drug resistance, high toxicity of some drugs, and high drug price. [0003] Nucleoside drugs are the focus of anti-HBV drug research in recent years, and the progress is rapid. Adefovir dipivaloyloxymethyl ester (1) (abbreviation: adefovir dipivaloyloxymethyl ester, also known as adefovir dipivaloyloxymethyl ester) is a new type of nucleoside anti-inflammatory drug developed by Gilead Science Company of the United States. As a hepatitis B drug, adefovir dipivoxil is decompos...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6561
Inventor 蒲通王乃星范一张飞飞李丰庭万定建陈恬陈世干
Owner ZHEJIANG CHARIOTEER PHARMA
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