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Diarylpyrimidine HIV-1 reverse transcriptase inhibitor containing trans-double bonds, and preparation method and application thereof

A technology of diarylpyrimidines and reverse transcriptase inhibition, which is applied in the fields of organic compound synthesis and medical application, can solve the problems of low bioavailability, poor water solubility, cross-resistance and the like, and achieves the effect of high application value

Active Publication Date: 2020-09-18
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the disadvantages of poor water solubility and poor membrane permeability caused by its own rigid structure, its bioavailability is low, and the oral dose is increased, which in turn causes problems such as toxic side effects and cross-drug resistance.

Method used

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  • Diarylpyrimidine HIV-1 reverse transcriptase inhibitor containing trans-double bonds, and preparation method and application thereof
  • Diarylpyrimidine HIV-1 reverse transcriptase inhibitor containing trans-double bonds, and preparation method and application thereof
  • Diarylpyrimidine HIV-1 reverse transcriptase inhibitor containing trans-double bonds, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Example 1: Ethyl (E)-3-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)pyrimidine-5- base) preparation of ethyl acrylate (Z1)

[0042]

[0043] Dissolve 2,4-dichloropyrimidine (0.10g, 0.67mmol) and 4-hydroxy-3,5-dimethylbenzonitrile (0.12g, 0.8mmol) in 30mL DMF, add K 2 CO 3 (0.11g, 0.8mmol), stirred at room temperature for 6h, and detected the reaction by TLC. After the reaction, extract with dichloromethane (10mL×3), combine several layers, wash with saturated brine (30mL) once, anhydrous Na 2 SO 4 Dry for 5h, filter and mix the sample. Column separation and recrystallization from ethyl acetate / petroleum ether gave white solid I-2. Yield: 80%; melting point 126-128°C.

[0044] Palladium acetate (0.004g, 0.0019mmmol) and 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (0.009g, 0.0019mmol) were dissolved in dioxane (15mL), room temperature After stirring and activating for 15 min, compound I-2 (0.1 g, 0.38 mmol) and cesium carbonate (4.89 g, 0.49 mmol) ...

Embodiment 2

[0049] Example 2: (E)-3-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)pyrimidin-5-yl) Preparation of acrylamide (Z2)

[0050]

[0051] Dissolve I-6 (0.15g, 0.36mmol) in dichloromethane (10mL), add oxalyl chloride (100μL, 1.16mmol), add a drop of DMF as catalyst, stir overnight at room temperature, evaporate to dryness under reduced pressure, add 30mL ammonia water , heated to reflux at 50°C for 6h, and the reaction was detected by TLC. After the reaction, the filter residue was obtained by filtration and dried. Dissolve the dried product (0.2g) in 10mL of dichloromethane, add 10mL of ammonia water, reflux at 45°C for 6h, mix the sample, separate by column, and recrystallize from ethyl acetate / petroleum ether to obtain the final product (E)-3-(4- (4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)pyrimidin-5-yl)acrylamide.

[0052] The product is a white solid, yield 50.1%, melting point: 226-228°C.

[0053] 1 H NMR (400MHz, DMSO-d 6 ):δ10.40(s,1H,NH),8.7...

Embodiment 3

[0054] Embodiment 3: the preparation of target compound (Z3~Z10, Z20, Z21)

[0055] I-5 (0.1g, 0.24mmol) and 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.11g, 0.288mmol) Dissolve in DMF (10mL), activate in ice bath for 15min, add N,N-diisopropylethylamine (121μL, 0.72mmol) and cyclopropylamine (20μL, 0.288mmol) to continue activation for 15min, stir at room temperature for 6h, TLC detection reaction . After the reaction was complete, it was concentrated and evaporated to dryness. Add 40mL of water, extract with dichloromethane (20mL×3), combine several layers, wash with saturated brine (30mL) once, anhydrous Na 2 SO 4 Dry for 5h, filter, concentrate, and mix samples. After column separation and ethyl acetate / petroleum ether recrystallization, the target compound Z3 was obtained.

[0056]

[0057] The product is a white solid, yield 78.6%, melting point: 254-255°C.

[0058] 1 H NMR (400MHz, DMSO-d 6 ):δ10.41(s,1H,NH),8.75(s,1H,C 6 -p...

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Abstract

The invention relates to a diarylpyrimidine HIV-1 reverse transcriptase inhibitor containing trans-double bonds, and a preparation method and application thereof. The compound has a structure represented by formula I in the specification. The invention also relates to a pharmaceutical composition containing the compound with the structure represented by the formula I. The invention also provides application of the compound and the composition containing one or more compounds in preparation of drugs for treating and preventing human immunodeficiency virus (HIV).

Description

technical field [0001] The invention belongs to the technical field of organic compound synthesis and medical application, and specifically relates to a diaryl pyrimidine HIV-1 reverse transcriptase inhibitor containing a trans double bond and a preparation method and application thereof. Background technique [0002] AIDS, the full name of Acquired Immunodeficiency Syndrome (AIDS), is a very harmful infectious disease caused by human immunodeficiency virus (Human immunodeficiency virus, HIV), HIV-1 is the main pathogen. In the process of HIV-1 virus replication, the role of reverse transcriptase (Reversetranscriptase, RT) is crucial, so it is an important target for the design of anti-AIDS drugs. In particular, nonnucleoside RT inhibitors (NNRTIs) have the advantages of high efficiency, high specificity and low toxicity, and play an important role in the current highly active antiretroviral therapy (HAART). However, the antiviral efficacy of NNRTIs is reduced due to the ra...

Claims

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Application Information

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IPC IPC(8): C07D239/47C07D403/12C07D401/12A61K31/505A61K31/506A61K31/5377A61P31/18
CPCA61P31/18C07D239/47C07D401/12C07D403/12
Inventor 展鹏左晓芳刘新泳霍志鹏康东伟
Owner SHANDONG UNIV
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