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Method for synthesizing adefovir serving as anti-hepatitis B virus medicine

A synthetic method and anti-hepatitis B technology, applied in the fields of chemical instruments and methods, compounds of group 5/15 elements of the periodic table, organic chemistry, etc., can solve the problems of low synthesis process yield, many side reactions, unsuitable for industrial production, etc. , to achieve good selectivity, improved reaction selectivity, and reduced side reactions

Inactive Publication Date: 2011-11-23
扬州三友合成化工有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0021] The purpose of the present invention is to provide a kind of preparation method of adefovir type with high yield, strong controllability and low cost, to solve the low yield of the synthesis process of adefovir and its intermediates in the prior art , many side reactions and many other problems that are not suitable for industrial production

Method used

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  • Method for synthesizing adefovir serving as anti-hepatitis B virus medicine
  • Method for synthesizing adefovir serving as anti-hepatitis B virus medicine
  • Method for synthesizing adefovir serving as anti-hepatitis B virus medicine

Examples

Experimental program
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Effect test

Embodiment 1

[0041] Synthesis of 9-(2-hydroxyethyl)adenine:

[0042] At room temperature and under nitrogen protection, 27 g (0.200 mol) of adenine, 100 mL of DMF, and 0.3 g of sodium hydroxide were put into a 250 mL reaction flask. Then ethylene oxide gas was passed through the system, and detected by TLC and HPLC until the adenine disappeared. DMF was distilled off under reduced pressure, 80 mL of absolute ethanol was added, refluxed for 2 h, and filtered to obtain 33.3 g of 9-(2-hydroxyethyl)adenine as a white solid with a yield of 94% and a purity of more than 99% by HPLC.

[0043] Synthesis of 9-(2-(diethylphosphonomethoxy)ethyl)adenine:

[0044] At 80°C, add 10.0 g (0.056 mol) of 9-(2-hydroxyethyl)adenine into 50 mL of DMF, then add 4.8 g (0.028 mol) of magnesium tert-butoxide, and react for 0.5-1 h. Add 18.0 g (0.056 mol) of diethyl p-toluenesulfonyloxymethylphosphonite, react for 7~8 h, add acetic acid to neutralize the excess alkali to neutral, evaporate DMF, and use ethyl aceta...

Embodiment 2

[0048] Synthesis of 9-(2-hydroxyethyl)adenine:

[0049] At room temperature and under the protection of nitrogen, 54.0 g (0.400 mol) of adenine, 150 mL of DMF, and 0.6 g of sodium hydroxide were added at one time. Then ethylene oxide gas was passed through the system, and detected by TLC and HPLC until the adenine disappeared. DMF was distilled off under reduced pressure, and recrystallized using ethanol-water system (V:V=2:8) to obtain 62.3 g of white solid 9-(2-hydroxyethyl)adenine, with a yield of 87% and a purity of more than 99% by HPLC.

[0050] Synthesis of 9-(2-(diethoxyphosphonomethoxy)ethyl)adenine:

[0051] At 80°C, add 17.9 g (0.100 mol) of 9-(2-hydroxyethyl) adenine into 50 mL of DMF, then add 8.5 g (0.050 mol) of magnesium tert-butoxide, and react for 0.5-1 h , add 32.2 g (0.100 mol) of diethyl p-toluenesulfonyloxymethylphosphonite, react for 7~8 h, add p-toluenesulfonic acid to neutralize excess alkali to neutral, distill DMF, and use ethyl acetate ( 300 mL ×...

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Abstract

The invention discloses a method for synthesizing adefovir serving as anti-hepatitis B virus medicine, which belongs to the field of antiviral chemical medicines. In the method, adefovir is obtained by using adenine as a starting raw material and by three nucleophilic substitution reactions. In the invention, the reaction conditions are mild, the method is simple, easy to implement, efficient and high in selectivity, fewer byproducts are produced, and the yield and purity of the product are high.

Description

technical field [0001] The invention belongs to the field of antiviral chemical drugs, and in particular relates to a preparation method of an anti-hepatitis B virus (HBV) drug adefovir (9-(2-(phosphorylmethoxy)ethyl)adenine). Background technique [0002] Viral hepatitis B is a worldwide disease caused by the hepatitis B virus (HBV). The incidence rate is high in developing countries. According to statistics, there are more than 350 million asymptomatic hepatitis B virus carriers in the world, and my country accounts for about 130 million. Most of them are asymptomatic, and 1 / 3 of them have clinical manifestations of liver damage. At present, there are about 30 million hepatitis B patients in my country. [0003] Adefovir is a nucleotide analogue of adenosine monophosphate, which is phosphorylated into active adefovir diphosphate by cellular kinases in vivo. Adefovir diphosphate inhibits the NDA polymerase or reverse transcriptase of HBV. After oral administration of ad...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6561
Inventor 张瑞龙魏开举周莉李明成张扬张众笑
Owner 扬州三友合成化工有限公司
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