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2,4,5-trisubstituted pyrimidine compound taking HIV-1 reverse transcriptase as target spot as well as preparation method and application thereof

A compound and pyrimidine technology, applied in the field of 2,4,5-trisubstituted pyrimidine compounds and their preparation, can solve the problems of poor solubility and poor bioavailability, and achieve the effect of high application value

Active Publication Date: 2020-06-16
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the previous research work of the applicant, a number of compounds with high resistance to HIV-1 wild strains and mutant strains were found, such as K-5a2 and 25a, but the two were the same as the marketed drugs etravirine and rilpivirine same, but they all have poor solubility, which leads to the problem of poor bioavailability

Method used

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  • 2,4,5-trisubstituted pyrimidine compound taking HIV-1 reverse transcriptase as target spot as well as preparation method and application thereof
  • 2,4,5-trisubstituted pyrimidine compound taking HIV-1 reverse transcriptase as target spot as well as preparation method and application thereof
  • 2,4,5-trisubstituted pyrimidine compound taking HIV-1 reverse transcriptase as target spot as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Synthesis of Example 1.4-((5-iodo-2-(piperidin-4-ylamino)pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile (E1)

[0039] Weigh 4-hydroxy-3,5-dimethylbenzonitrile (1.50g, 10mmol) and potassium carbonate (1.70g, 12mmol) in 30mL of N,N-dimethylformamide (DMF) solution, stir at room temperature After 15 minutes, 2,4-dichloropyrimidine (A, 1.47 g, 10 mmol) was added and the mixture was stirred at room temperature for 5 h (reaction completed by TLC). At this time, a large amount of white solids were generated, to which 25mL ice water was slowly added, filtered, and dried in a vacuum oven to obtain a white solid which was the compound 4-((2-chloropyrimidin-4-yl)oxy)-3 , 5-Dimethylbenzonitrile B1, yield 96%. ESI-MS: m / z 260.3[M+1] + .C 13 h 10 ClN 3 O(259.05).

[0040]Weigh compound B1 (0.26g, 1.0mmol), N-Boc-4-aminopiperidine (0.24g, 1.2mmol) and potassium carbonate (0.28g, 2.0mmol) in 5mL of N,N-dimethylformamide In the reaction at 120°C for 8h. After the reaction was cool...

Embodiment 2

[0043] Embodiment 2. Synthesis of compound F1

[0044] Weigh compound E1 (0.45g, 1.0mmol) in 10mL DMF, stir and dissolve at room temperature, add anhydrous potassium carbonate (0.28g, 2.0mmol) and substituted benzyl (1.2mmol), stir at room temperature for 7h (TLC detection reaction is complete). Add 40 mL of water to the reaction solution, then add 20 mL of ethyl acetate to extract three times, dry over anhydrous sodium sulfate, filter and concentrate. The target compound was separated by flash column chromatography, and then recrystallized in an ethyl acetate-petroleum ether system to obtain the target compound F1.

[0045] With different substituted benzyl and 4-((5-iodo-2-(piperidin-4-ylamino)pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile E1 using the above method respectively Compounds F1-1~F1-3 were obtained, the results are as follows:

[0046]

[0047] The operation is the same as above, except that 4-bromomethylbenzenesulfonamide is used, and the product is a white...

Embodiment 3

[0052] Example 3. Synthesis of Compound G

[0053] Weigh compound F1 (1.0mmol), substituted boronic acid pinacolate Ar (1.0mmol), tetrakistriphenylphosphine palladium (0.12g, 0.1mmol), cesium carbonate (0.33g, 1.0mmol) in 10mL DMF, under nitrogen Reaction was carried out at 120° C. for 6-10 h under protected conditions (the reaction was completed as detected by TLC). After the reaction solution was cooled to room temperature, the reaction solution was obtained by suction filtration. Then 40 mL of water was added to the reaction solution, and then 20 mL of ethyl acetate was added to extract 3 times, dried over anhydrous sodium sulfate, filtered and concentrated. The target compound was separated by flash column chromatography, and then recrystallized in ethyl acetate-petroleum ether system to obtain the target compound G.

[0054] With different starting materials F1 and different substituted boronic acid pinacidate Ar, compound G1-15 was prepared respectively by the above me...

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PUM

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Abstract

The invention discloses a 2,4,5-trisubstituted pyrimidine compound taking HIV-1 reverse transcriptase as a target spot as well as a preparation method and application thereof. The compound has a structure as shown in a general formula I in the specification. The invention also relates to a pharmaceutical composition containing the compound with the structure shown in the formula I. Activity screening experiments show that the compound provided by the invention has good anti-HIV-1 activity, so that the invention also provides application of the compound in preparation of anti-AIDS drugs.

Description

technical field [0001] The invention belongs to the technical field of organic compound synthesis and medical application, and specifically relates to a class of 2,4,5-trisubstituted pyrimidine compounds targeting HIV-1 reverse transcriptase, a preparation method and application thereof. Background technique [0002] AIDS (Acquired Immune Deficiency Syndrome, AIDS) is mainly caused by human immunodeficiency virus type 1 (HIV-1) infection, and is one of the major diseases that seriously endanger human health. In the life cycle of HIV-1, reverse transcriptase (RT) is responsible for the reverse transcription of single-stranded RNA carrying the genetic information of the virus into double-stranded DNA, which is a key target for the design of anti-AIDS drugs. HIV-1 reverse transcriptase inhibitors (NNRTIs) have the advantages of high efficiency, low toxicity, and strong specificity, and are an important part of Highly Active Antiretroviral Therapy (HAART) therapy. Although the ...

Claims

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Application Information

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IPC IPC(8): C07D409/14C07D405/14C07D401/12C07D401/14A61K31/506A61P31/18
CPCA61P31/18C07D401/12C07D401/14C07D405/14C07D409/14
Inventor 刘新泳康东伟展鹏封达孙彦颖
Owner SHANDONG UNIV
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