Diaryl pyrimidine HIV-1 reverse transcriptase inhibitor containing six-membered non-aromatic ring as well as preparation method and application of diaryl pyrimidine HIV-1 reverse transcriptase inhibitor

A technology of diarylpyrimidines and reverse transcriptase inhibition, applied in the field of medicine, can solve the problems of large oral dose, low oral bioavailability, toxic and side effects and the like

Active Publication Date: 2021-11-16
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the water solubility and oral bioavailability of this type of compound are very low, and the oral dose is large, which easily causes serious toxic and side effects in clinical use.

Method used

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  • Diaryl pyrimidine HIV-1 reverse transcriptase inhibitor containing six-membered non-aromatic ring as well as preparation method and application of diaryl pyrimidine HIV-1 reverse transcriptase inhibitor
  • Diaryl pyrimidine HIV-1 reverse transcriptase inhibitor containing six-membered non-aromatic ring as well as preparation method and application of diaryl pyrimidine HIV-1 reverse transcriptase inhibitor
  • Diaryl pyrimidine HIV-1 reverse transcriptase inhibitor containing six-membered non-aromatic ring as well as preparation method and application of diaryl pyrimidine HIV-1 reverse transcriptase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Example 1: Preparation of 4-((2-chloropyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile (2)

[0041]

[0042] 2,4-Dichloropyrimidine 1 (1.49 g, 0.01 mol) and potassium carbonate (1.66 g, 0.012 mol) were dissolved in dimethylformamide (20 mL), and 4-hydroxy-3,5 - Dimethylbenzonitrile (1.47 g, 0.01 mol) and stirred at 50 °C for 4 h until the reaction was complete. Ice water (200 mL) was added and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with saturated brine, anhydrous Na 2 SO 4 Drying, filtration and concentration under reduced pressure and finally recrystallization using ethyl acetate and petroleum ether afforded the pure intermediate 4-((2-chloropyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile 2. White solid, yield: 88.4%. 1 H NMR (400MHz, DMSO-d 6 )δ8.70(d, J=5.7Hz, 1H, pyrimidine-H), 7.75(s, 2H, Ph-H), 7.32(d, J=5.7Hz, 1H, pyrimidine-H), 2.10(s, 6H, Ph-CH 3 ×2). ESI-MS:m / z 259.97(M+H) + ,C 13 h 10 ClN 3 O(259.05).

Embodiment 2

[0043] Example 2: Preparation of 4-((2-chloropyrimidin-4-yl)oxy)-3,5-dimethylbenzaldehyde (3)

[0044]

[0045] The preparation method is the same as in Example 1, except that the raw material 4-hydroxyl-3,5-dimethylbenzonitrile (1.47g, 0.01mol) is replaced by 4-hydroxyl-3,5-dimethylbenzaldehyde ( 1.50 g, 0.01 mol). White solid, yield: 81.4%. 1 HNMR (400MHz, DMSO-d 6 )δ9.97(s,1H,CHO),8.70(d,J=5.7Hz,1H,pyrimidine-H,Ph-H),7.77(s,2H),7.30(d,J=5.7Hz,1H, pyrimidine-H),2.15(s,6H,Ph-CH 3 ×2).ESI-MS:m / z263.10(M+H) + ,C 13 h 11 ClN 2 o 2 (262.69).

Embodiment 3

[0046] Example 3: Preparation of (E)-3-(4-((2-chloropyrimidin-4-yl)oxy)-3,5-dimethylphenyl)acrylonitrile (4)

[0047]

[0048] Dissolve diethyl cyanomethylphosphate (0.092mL, 0.57mmol) in 5mL of tetrahydrofuran, add potassium tert-butoxide (0.0064g, 0.57mmol) under ice-cooling conditions, and activate for 30min, the 4-((2-chloro Pyrimidin-4-yl)oxy)-3,5-dimethylbenzaldehyde 3 (0.10 g, 0.38 mmol) in tetrahydrofuran (3 mL) was slowly added dropwise to the reaction liquid, and reacted at room temperature for 4 h. The solvent was evaporated under reduced pressure, the residue was added with 30 mL of water, extracted with ethyl acetate (3×10 mL), the organic phases were combined, washed with saturated sodium chloride solution (3×20 mL), dried over anhydrous sodium sulfate; filtered and concentrated under reduced pressure, Finally recrystallization using ethyl acetate and petroleum ether afforded pure intermediate (E)-3-(4-((2-chloropyrimidin-4-yl)oxy)-3,5-dimethylphenyl)propene ...

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PUM

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Abstract

The invention discloses a diaryl pyrimidine HIV-1 reverse transcriptase inhibitor containing a six-membered non-aromatic ring as well as a preparation method and application of the diaryl pyrimidine HIV-1 reverse transcriptase inhibitor. The compound has a structure as shown in a general formula I. The invention also relates to a pharmaceutical composition containing the compound with the structure as shown in the formula I. An activity screening experiment shows that the compound disclosed by the invention has good anti-HIV-1 activity, so that the invention also provides application of the compound in preparation of an anti-AIDS medicine.

Description

technical field [0001] The invention relates to a derivative and its preparation method and application, in particular to a diaryl pyrimidine HIV-1 reverse transcriptase inhibitor containing a six-membered non-aromatic ring, its preparation method and application, and belongs to the technical field of medicine. Background technique [0002] AIDS (Acquired Immune Deficiency Syndrome, AIDS) is mainly caused by Human Immunodeficiency Virus Type 1 (Human Immunodeficiency Virus Type 1, HIV-1), a serious infectious disease that destroys the human immune system. 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. Non-nucleoside reverse transcriptase inhibitors (Non-nucleoside Reverse Transcriptase Inhibitors, NNRTIs), as an important part of HAART, have the advantages of high activity,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12C07D239/47A61K31/506A61K31/5377A61K31/541A61P31/18
CPCC07D401/12C07D239/47A61P31/18
Inventor 刘新泳姜向毅展鹏李敬季相凯黄伯世
Owner SHANDONG UNIV
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