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Monoaromatic miazine HIV-1 reverse transcriptase inhibitor containing triazole rings and preparation method and application thereof

A technology for reverse transcriptase inhibition and HIV-1, applied to medical preparations containing active ingredients, chemical instruments and methods, compounds containing elements of group 3/13 of the periodic table, etc., can solve toxic side effects, poor solubility, etc. problem, to achieve the effect of high application value

Inactive Publication Date: 2019-07-30
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, with the clinical application of NNRTIs, problems such as drug resistance, poor solubility, and toxic side effects of these inhibitors have gradually attracted people's attention.

Method used

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  • Monoaromatic miazine HIV-1 reverse transcriptase inhibitor containing triazole rings and preparation method and application thereof
  • Monoaromatic miazine HIV-1 reverse transcriptase inhibitor containing triazole rings and preparation method and application thereof
  • Monoaromatic miazine HIV-1 reverse transcriptase inhibitor containing triazole rings and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Example 1: Preparation of 4-((2-chloropyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile (7)

[0045]

[0046] Starting materials 2,4-dichloropyrimidine (13.42mmol, 2.00g), 3,5-dimethyl-4-hydroxybenzonitrile (14.76mmol, 2.18g) and potassium carbonate (16.10mmol, 2.22g) were added to 20mL N,N-dimethylformamide (DMF) solution, stirred at room temperature, and reacted for 8-12h. The reaction was monitored by TLC. After the reaction was completed, 40 mL of aqueous solution was added to the reaction solution and stirring was continued for 20-30 min, and a white solid, Intermediate 7, was obtained by filtration. 1 H NMR (400MHz, DMSO-d 6 )δ8.70(d, J=5.7Hz, 1H), 7.75(s, 2H), 7.32(d, J=5.7Hz, 1H), 2.10(s, 6H); ESI-MS: m / z 259.97( M+H) + ,C 13 h 10 ClN 3 O(259.05).

Embodiment 2

[0047] Example 2: Preparation of 4-((2-chloropyrimidin-4-yl)amino)-3,5-dimethylbenzaldehyde (11)

[0048]

[0049] The operation steps are the same as the preparation of intermediate 7, the difference is that 3,5-dimethyl-4-hydroxy-benzaldehyde is used to replace 3,5-dimethyl-4-hydroxybenzonitrile in the preparation process of 7 to obtain white solid. 1 H NMR (400MHz, DMSO-d 6 )δ9.97(s,1H),8.70(d,J=5.7Hz,1H),7.77(s,2H),7.30(d,J=5.7Hz,1H),2.15(s,6H); ESI- MS:m / z263.10(M+H) + ,C 13 h 11 ClN 2 o 2 (262.05).

Embodiment 3

[0050] Example 3: Preparation of (E)-3-(4-((2-chloropyrimidin-4-yl)amino)-3,5-dimethylphenyl)acrylonitrile (12)

[0051]

[0052] Under ice-bath conditions, diethyl cyanomethylphosphate (11.40mmol, 2.02g) was added to 10mL of a mixed solution of tetrahydrofuran and dichloromethane (v:v=1:1), and after thorough mixing, the Potassium tert-butoxide (11.40 mmol, 1.28 g) was added. Then, intermediate 11 (3.81 mmol, 1.00 g) dissolved in 5 mL of tetrahydrofuran was slowly added dropwise to the above mixed solution. After the dropwise addition was completed, the ice bath was removed and the reaction was carried out at room temperature. After the reaction was completed, the solvent was removed under reduced pressure, dissolved in 20 mL of DMF, and then 60-80 mL of aqueous solution was added to precipitate a white solid. Filtrate, wash the filter cake with water, and recrystallize from chloroform to obtain intermediate (E)-3-(4-((2-chloropyrimidin-4-yl)amino)-3,5-dimethylphenyl)acry...

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Abstract

The invention relates to a monoaromatic miazine HIV-1 reverse transcriptase inhibitor containing triazole rings and a preparation method and application thereof. The compound has the structure shown as the formula I or II. The invention further relates to a drug composition containing the compound of the formula I or II. The compound and the application of the composition containing one or more compounds of this kind in preparation of anti-AIDS drugs are further provided.

Description

technical field [0001] The invention belongs to the technical field of organic compound synthesis and medical application, and specifically relates to a monoaryl pyrimidine HIV-1 reverse transcriptase inhibitor containing a triazole ring, a preparation method and application thereof. Background technique [0002] AIDS (Acquired Immune Deficiency Syndrome, AIDS), abbreviated as Acquired Immunodeficiency Syndrome, is a chronic infectious disease caused by Human Immunodeficiency Virus (Human Immunodeficiency Virus, HIV) that destroys the human immune system. Since AIDS was discovered in 1981, people have actively explored related treatment methods. The combined application of various marketed anti-AIDS drugs can control the HIV-1 viral load of AIDS patients below the detection limit. Even so, the situation of global AIDS prevention and control is still grim. According to statistics from the World Health Organization (WHO) in 2018, by the end of 2017, there were about 36.9 mill...

Claims

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Application Information

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IPC IPC(8): C07D403/12C07D401/14C07F5/02A61K31/506A61K31/5377A61K31/69A61P31/18
CPCA61P31/18C07D401/14C07D403/12C07F5/025
Inventor 展鹏武高禅刘新泳康东伟左晓芳荆兰兰姜向毅
Owner SHANDONG UNIV
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