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Substituted pyrimidine derivatives, and preparation method and application thereof

A technology of derivatives and pyrimidines, applied in the treatment of human immunodeficiency virus, replacing the field of pyrimidine derivatives, can solve the problem of slow attenuation

Active Publication Date: 2020-05-22
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although there are very few latently infected cells in the patient's body, the attenuation rate is extremely slow, so it is difficult to completely cure AIDS only by relying on the current HAART

Method used

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  • Substituted pyrimidine derivatives, and preparation method and application thereof
  • Substituted pyrimidine derivatives, and preparation method and application thereof
  • Substituted pyrimidine derivatives, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] Example 1: Preparation of 4-((6-chloro-2-((4-cyanophenyl)amino)pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile (3)

[0066] Weigh 2,4,6-trichloropyrimidine (2.0g, 10.9mmol), 4-hydroxyl-3,5-dimethylbenzonitrile (1.6g, 10.9mmol) and N,-diisopropylethylamine ( 3.6ml, 21.8mmol) in 25mL of 1,4-dioxane solution, stirred at 70°C for 2h. TLC detects that the reaction is complete. After the reaction solution is cooled, 100 mL of water is slowly added thereto, continued to stir for 30 min, filtered, and dried in a vacuum oven to obtain a white solid that is compound 4-((2,6-dichloropyrimidin-4-yl )oxy)-3,5-dimethylbenzonitrile (2), yield 91.8%. 1 H NMR (400MHz, DMSO-d 6 , ppm) δ: 7.76 (2H, s, Ph–H), 7.64 (1H, s, pyrimidine-H), 2.12 (6H, s, CH 3 ).ESI–MS: m / z 294.28(M+1).C 13 h 9 Cl 2 N 3 O(293.01), mp:207–209℃.

[0067] Intermediate 2 (2.0g, 6.8mmol) and 4-aminobenzonitrile (0.8g, 6.8mmol) were dissolved in N-methylpyrrolidone (10mL) at 0–5°C, then tert-butanol was added in ...

Embodiment 2

[0068] Example 2: n=2,5-((6-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)pyrimidin-4-yl ) amino) valeric acid (LTb2) preparation

[0069] Intermediate 3 (1.0g, 2.66mmol) and 5-aminovaleric acid (0.55g, 5.32mmol) were dissolved in N-methylpyrrolidone (5mL), and reacted at 130°C for 20min under microwave conditions. After the reaction was completed, the reaction solution was dropped into 50 ml of ice water, and a white solid was precipitated, filtered, vacuum-dried, and then flash column chromatographed to obtain the intermediate LTb2 with a yield of 52.5%.

Embodiment 3

[0070] Example 3: n=2,5-((6-(4-cyano-2,6-dimethylphenoxy)-2-(((4-cyanophenyl)amino)pyrimidine-4- base) amino)-N-hydroxypentanamide (IA-1-2) preparation

[0071]1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.10g, 0.54mmol) and 1-hydroxybenzotriazole (0.15g, 0.54mmol) were dissolved in 5ml DMF , stirred in an ice bath for 30 min, and then the intermediate LTb2 (0.20 g, 0.45 mmol) and O-(tetrahydropyran-2-yl) hydroxylamine (0.064 g, 0.54 mmol) were added to the reaction solution, and the stirring was continued at room temperature for 8 h . After the reaction was completed, it was extracted with ethyl acetate (3×20ml), washed with saturated sodium chloride solution, and the organic layer was separated and dried over anhydrous sodium sulfate. Then flash column chromatography was carried out to obtain a white solid which is the intermediate LTb2a. Intermediate LTb2a (0.10g, 0.18mmol) was dissolved in 5ml of anhydrous methanol, p-toluenesulfonic acid (0.032g, 0.18mmo...

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Abstract

The invention discloses substituted pyrimidine compounds as shown in general formulas I-VI which are described in the specification, preparation methods of the substituted pyrimidine compounds, and application of compositions containing one or more of the compounds in preparation of medicines for treating and preventing human immunodeficiency viruses (HIV).

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a substituted pyrimidine derivative. The invention also relates to a preparation method of the derivative and its application in treating human immunodeficiency virus (HIV). Background technique [0002] AIDS, also known as acquired immunodeficiency syndrome. Since AIDS was first discovered, some 35 million people have died from the disease. The current clinical treatment of AIDS is mainly highly active antiretroviral therapy (Highly Active Antiretroviral Therapy, HAART), which can effectively control the replication of HIV, and then control the virus to a range that cannot be detected by conventional methods. Infected people can live a normal life without symptoms. HAART has provided hope for a cure for AIDS for a long time. Unfortunately, once the drug is stopped, the viral load will quickly rebound to the pre-treatment level, and the patient must take the drug ...

Claims

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Application Information

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IPC IPC(8): C07D239/48C07D239/47C07D401/12A61K31/506A61K31/505A61P31/18
CPCA61P31/18C07D239/47C07D239/48C07D401/12
Inventor 刘新泳周忠霞展鹏
Owner SHANDONG UNIV