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Diarylpyrimido pyridone derivative, preparation method and application thereof

A technology for diarylpyrimidine-pyridone and its derivatives, which is applied in the field of derivatives and their preparation, diarylpyrimidine-pyridone derivatives and their preparation, and can solve the problems of poor oral availability and side effects

Active Publication Date: 2020-10-30
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among them, the marketed drugs etravirine and rilpivirine, as typical representatives of the second-generation NNRTIs, have received extensive attention. However, due to the poor oral availability or side effects of these two drugs, further research is needed. Structural modifications to overcome the above problems

Method used

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  • Diarylpyrimido pyridone derivative, preparation method and application thereof
  • Diarylpyrimido pyridone derivative, preparation method and application thereof
  • Diarylpyrimido pyridone derivative, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0083] Example 1: Preparation of 4-methoxy-2-(methylthio)-5-pyrimidinecarboxylic acid (IVA-2)

[0084] Weigh ethyl 4-chloro-2-methylthio-5-pyrimidinecarboxylate (2 g, 8.6 mmol) into a 100 mL eggplant-shaped flask, and add 30 mL of MeOH and 10 mL of 2N NaOH solution in sequence. After stirring at room temperature for 3 hours, most of the methanol was evaporated to dryness. The resulting solution was acidified with 2N dilute hydrochloric acid solution to pH 4-5, filtered to obtain a pure white solid, and dried in vacuo overnight. It was directly submitted to the next step without further purification.

Embodiment 2

[0085] Example 2: Preparation of 3-(4-methoxy-2-methylsulfanylpyrimidin-5-yl)-3-oxopropionic acid ethyl ester (IVA-3)

[0086] 4-Methoxy-2-(methylthio)-5-pyrimidinecarboxylic acid (1.6g, 8mmol) was dispersed in dichloromethane (30mL) and cooled in an ice bath, then added dropwise to One drop of DMF and oxalyl chloride (2.3 mL, 25.8 mmol). Stirring was continued at room temperature for 4 hours after the addition was complete. The reaction solvent was evaporated to give a pure white solid, which was used in the next step without further purification.

[0087] Under nitrogen protection, add methylmagnesium bromide ether solution (3M, 14.3mL, 42.9mmol) dropwise to a solution of monoethyl malonate (2.3mL, 21.4mmol) in anhydrous THF (15mL) in an ice bath . After the dropwise reaction was continued for 20 minutes, a THF (30 mL) solution of the above acid chloride was added dropwise to the reaction system. After stirring at room temperature for 3 hours, the reaction solution was p...

Embodiment 3

[0088] Embodiment 3: IVA-4 preparation general method

[0089] Potassium carbonate method: the above-mentioned 3-(4-methoxy-2-methylsulfanylpyrimidin-5-yl)-3-oxopropionic acid ethyl ester (1.0g, 3.7mmol), acetic anhydride (1.0 mL, 10mmol) and triethyl orthoformate (1.0mL, 6mmol) were heated to reflux at 130°C for 4h, then concentrated under reduced pressure to obtain a brown oil. Add THF 15mL to the above oil, add aniline or mesitylene or 4-amino-3,5-dimethylbenzonitrile (4.1mmol) under stirring condition, room temperature overnight. The reaction solution was evaporated to dryness, 15 mL of anhydrous DMF and potassium carbonate (0.6 g, 4.1 mmol) were added, and heated at 105° C. for 8 h under nitrogen protection. After the reaction, most of the DMF was evaporated to dryness under reduced pressure, 50 mL of water was added, extracted with dichloromethane (3*20 mL), the organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate. The organ...

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Abstract

The invention provides a diarylpyrimido pyridone derivative. The diarylpyrimido pyridone derivative has a structure shown as general formula I in the specification. The invention also relates to a preparation method of the derivative and application of the derivative as an HIV inhibitor in preparation of anti-AIDS drugs.

Description

technical field [0001] The invention relates to a derivative and its preparation method and application, in particular to a diarylpyrimidine-pipyridone derivative and its preparation method and application, belonging to the technical field of medicine. Background technique [0002] AIDS, also known as acquired immunodeficiency syndrome (Acquired immunodeficiency syndrome, AIDS), is an infectious disease mainly caused by the pathogen of AIDS, human immunodeficiency virus (Human immunodeficiency virus, HIV), mainly T cell immune function deficiency . Since its discovery in the 1980s, AIDS has become one of the major infectious diseases that seriously endanger human health. At present, the most commonly used clinical method for preventing and treating AIDS is highly active antiretroviral therapy (Highly Active Antiretroviral Therapy, HAART). Although the implementation of this therapy has greatly improved the suppression efficiency of HIV virus, but because HIV virus is very e...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61P31/18A61K31/5377A61K31/519
CPCA61P31/18C07D471/04
Inventor 刘新泳高萍展鹏宋淑孙彦莹
Owner SHANDONG UNIV
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