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Polysubstituted purine derivatives as well as preparation method and application thereof

A technology of purines and derivatives, applied in the medical field, can solve unseen problems and achieve the effect of reducing by-products, complete reaction, and high antiviral activity

Inactive Publication Date: 2018-07-24
RIZHAO PUDA PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Based on the good anti-HBV activity of benzimidazole analogues, the present invention uses the bioelectronic isostere purine ring to replace the benzimidazole ring, and designs and synthesizes a series of substituted purine derivatives. No such compounds and their derivatives have been seen in the prior art. application

Method used

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  • Polysubstituted purine derivatives as well as preparation method and application thereof
  • Polysubstituted purine derivatives as well as preparation method and application thereof
  • Polysubstituted purine derivatives as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Synthesis of [2-[(2-nitro-4-hydroxy-5-yl)pyrimidine]-4-pyridine]purin-8-yl-carboxylic acid (D).

[0041] Structural formula:

[0042] .

[0043] (2-Chloro-6-pyridine)purin-8-ylcarboxylic acid (B) (5g, 1.8mol) and (2-nitro-4-hydroxy)pyrimidin-5-yl-boronic acid dimethyl ester (C) ( 5.8g, 2.3mol) into the reaction vessel, in the presence of the organic solvent dichloromethane (50ml) and sodium carbonate (0.8g), add the catalyst 1,1'-bis(diphenylphosphino)ferrocene chloride Palladium (0.32g), heated to 85°C in a water bath and kept stirring, TLC detected that the reaction was complete, generating [2-[(2-nitro-4-hydroxy-5-yl)pyrimidine]-4-pyridine]purine-8- Dimethyl-formic acid (D) (9.69g, 2.4mol).

[0044] Synthesis of [2-[(2-nitro-4-hydroxy-5-yl)pyrimidine]-4-pyridine]purin-8-yl-formyl chloride (E).

[0045] Structural formula:

[0046] .

[0047] The [2-[(2-nitro-4-hydroxy-5-yl)pyrimidine]-4-pyridine]purin-8-yl-formic acid (D) (9.69g, 2.4mol) generated above was...

Embodiment 2-4

[0054] The catalyst in Example 1 was changed, and other operations were unchanged, and the operation steps of Example 1 were repeated to obtain Examples 2-4, and the results are shown in the following table.

[0055]

[0056] In conjunction with embodiment 1 and embodiment 2~4, catalyzer has important influence to the synthesis of the present invention, uses 1,1'-two (diphenylphosphino) ferrocene palladium chloride to make catalyst and has good catalytic effect, does not Using a catalyst or using palladium as a catalyst or using 1,1'-bis(di-phenylphosphino)ferrocene as a catalyst, the final yield is 10.58% or 60.12% or 48.77%, which seriously affects [2-[( Yield of 2-nitro-4-hydroxy-5-yl)pyrimidin]-4-pyridine]purin-8-yl-formic acid-(2-chloro-4-methyl)phenyl ester (A).

Embodiment 5

[0058] The alkali in Example 1 was removed, and other operations were unchanged, and the operation steps of Example 1 were repeated to obtain Example 5. The results are shown in the table below.

[0059]

[0060] In combination with Example 1 and Example 5, in the absence of alkali, the final [2-[(2-nitro-4-hydroxy-5-yl)pyrimidine]-4-pyridine]purin-8-yl-formic acid-( The yield of 2-chloro-4-methyl)phenyl ester (A) is greatly reduced, so the base plays an important role in the reaction of the present invention.

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Abstract

The invention provides polysubstituted purine derivatives as well as a preparation method and application thereof. According to the preparation method, the acyl chloride with more lively properties isfirstly prepared by using thionyl chloride, so that the production of by-products is reduced, the by-products are only sulfur dioxide and hydrogen chloride which are gases, and purification is facilitated; the acyl chloride and phenol are then enabled to be subjected to an esterification reaction, so that the reaction is promoted to be smoothly and thoroughly carried out, and the yield of the final product is greatly increased; in addition, the action sites and modes of the polysubstituted purine derivatives provided by the invention are unique; the polysubstituted purine derivatives have very high antiviral activity, especially anti-hepatitis b virus (HBV) activity, can meet space requirement of a special drug action target, have better biocompatibility, and have a good therapeutic effect on respiratory virus infection, viral hepatitis, polio and influenza virus diseases.

Description

Technical field [0001] The invention relates to the field of medical technology, in particular, the invention relates to a multi-radical substituted purine derivative and its preparation method and application. Background technique [0002] Viral infectious diseases are a large class of diseases that seriously endanger human life and health. Hepatitis B virus (HBV) is the main pathogen of hepatitis B. Although the current hepatitis B vaccine has been successfully developed and widely promoted, the hepatitis B virus is still extremely harmful to society due to its strong infectivity and pathogenicity. In addition, the implementation of interferon and nucleoside drugs is a major breakthrough in the treatment of hepatitis B, but the emergence of drug resistance and the toxicity of long-term medication have greatly limited the application of this therapy. The research and development of the anti-hepatitis B drug of mechanism is urgent. [0003] Heterocyclic compounds have a w...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/00C07D473/34C07D519/00A61K31/52A61P31/12A61P31/20A61P11/00A61P31/16
CPCC07D473/00C07D473/34C07D519/00Y02A50/30
Inventor 不公告发明人
Owner RIZHAO PUDA PHARMA TECH CO LTD
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