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Substituted diarylpyrimidine derivative as well as preparation method and application thereof

A derivative, dimethylformamide technology, applied in the field of medicine, can solve the problems of low bioavailability, poor membrane permeability, cross-resistance, etc.

Active Publication Date: 2017-06-13
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

As a new generation of NNRTIs, they have high inhibitory activity against a variety of drug-resistant strains, but their low water solubility and poor membrane permeability lead to low bioavailability, increased oral doses, causing toxic side effects and crossover Drug resistance and other issues
For example, etravirine requires multiple daily doses and is associated with severe allergic skin reactions
The pharmacokinetic properties of rilpivirine have improved, but there are still toxic and side effects such as depression, insomnia, acute respiratory distress syndrome, headache and rash, which limit its wide application

Method used

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  • Substituted diarylpyrimidine derivative as well as preparation method and application thereof
  • Substituted diarylpyrimidine derivative as well as preparation method and application thereof
  • Substituted diarylpyrimidine derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] Embodiment 1: the preparation of intermediate 4-((4-chloropyrimidin-2-yl) amino) benzonitrile

[0062] Preparation of 4-((4-oxo-1,6-dihydropyrimidin-2-yl)amino)benzonitrile (2)

[0063] Weigh 2-(methylthio)pyrimidin-4(3H)-one (3g, 21mmol) and 4-aminobenzonitrile (2.99g, 25mmol) in a 50mL round-bottom flask, nitrogen protection, and slowly heat up to 180°C, Reaction 8h. After the reaction was cooled, 20 mL of acetonitrile was added for sonication, filtered, the filter cake was washed with acetonitrile, no 4-aminobenzonitrile residue was detected by TLC, and the filter cake was dried to obtain a pale yellow solid which was 4-((4-oxo-1,6 -Dihydropyrimidin-2-yl)amino)benzonitrile, yield 73.6%, ESI-MS: m / z 213.3[M+H] + ,C 11 h 8 N 4 O(212.12).

[0064] Preparation of intermediate 4-((4-chloropyrimidin-2-yl)amino)benzonitrile

[0065] Accurately weigh 4-((4-oxo-1,6-dihydropyrimidin-2-yl)amino)benzonitrile (0.80g, 3.8mmol), add 5mL phosphorus oxychloride, stir and reflu...

Embodiment 2

[0066] Embodiment 2: the preparation of target compound

[0067] Preparation of 4-((3-aminophenyl)ethynyl)-2,6-dimethylphenol

[0068] Weigh 3-aminophenylacetylene (0.1g, 0.85mmol), 4-iodo-2,6-dimethylphenol (0.254g, 1.0mmol), bistriphenylphosphine dichloride palladium (0.0359g, 0.51mmol ), cuprous iodide (0.0195g, 1.0mmol), triethylamine (0.06g, 0.6mol) were dissolved in anhydrous tetrahydrofuran, under nitrogen protection, reacted at 60°C for 10h, after the TLC detection reaction was completed, the reaction solution was diatom After soil filtration, evaporate to dryness under reduced pressure, add 30 mL ethyl acetate to the residual substrate, wash with saturated saline solution 3 times, 10 mL each time, separate the organic layer, dry over anhydrous sodium sulfate, filter and concentrate. The intermediate 4-((3-aminophenyl)ethynyl)-2,6-dimethylphenol was separated by flash column chromatography.

[0069] Preparation of 4-((4-(4-((3-aminophenyl)ethynyl)-2,6-dimethylphenoxy...

Embodiment 3

[0106] Embodiment 3: the preparation of target compound

[0107] Preparation of 2,6-dimethyl-4-styrylphenol

[0108] Weigh styrene (0.177g, 1.5mmol), 4-iodo-2,6-dimethylphenol (0.248g, 1.0mmol), palladium acetate (0.0224g, 0.1mmol), Tol 3 P (0.091g, 0.3mmol), sodium ethoxide (0.184g, 2.3mmol) in a double-neck flask, add N,N-dimethylacetamide dropwise with a constant pressure dropping funnel under nitrogen protection, and heat up to 60°C , reacted for 10 h, after the reaction, the solvent was evaporated to dryness, and the crude product of intermediate 5 was obtained by flash column separation.

[0109] (E)-4-((4-(2,6-Dimethyl-4-styrylphenoxy)pyrimidin-2-yl)amino)benzonitrile

[0110] The operation is the same as the preparation of IB-1-1, except that 2,6-dimethyl-4-styrylphenol is used.

[0111]

[0112] The product is white crystals, yield: 38%, melting point: 222-224°C.

[0113] 1 H NMR (400MHz, DMSO-d 6 )δ10.15(s,1H,NH),8.47(d,J=5.6Hz,1H,C6-pyrimidine-H),7.69-7.59(...

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Abstract

The invention discloses a substituted diarylpyrimidine derivative as well as a preparation method and application thereof. The substituted diarylpyrimidine derivative or a pharmaceutically acceptable salt or predrug of the substituted diarylpyrimidine derivative has a structure represented by the following general formula I or II (shown in the description). The invention further discloses a preparation method of the substituted diarylpyrimidine derivative and application of a composition containing one or more compounds in preparation of drugs for treating and preventing human immunodeficiency virus (HIV). The formulae I and II are as shown in the specification.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a substituted diarylpyrimidine derivative, and also relates to a preparation method of the derivative and the application of the anti-human immunodeficiency virus (HIV) inhibitor. Background technique [0002] AIDS (AIDS) is a disease that destroys the human immune system and seriously endangers human life and health. It is caused by HIV infection. Among anti-AIDS drugs, HIV-1 non-nucleoside reverse transcriptase inhibitors (Non-nucleoside Reverse Transcriptase Inhibitors, NNRTIs) play a key role because of their strong selectivity, high activity, low toxicity and other advantages. However, due to the high variability of HIV-1 virus, the frequent emergence of drug-resistant strains has become a major problem in clinical treatment. In addition, the problems of poor drug resistance, strong side effects and poor pharmacokinetics of NNRTIs in clinical drug therapy limit...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/47C07D401/12A61K31/505A61K31/506A61P31/18
CPCY02P20/55C07D239/47C07D401/12
Inventor 刘新泳周忠霞展鹏
Owner SHANDONG UNIV
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