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Diarylpyrimidine derivative containing six-membered nitrogen heterocyclic ring as well as preparation method and application of diarylpyrimidine derivative

A technology of diarylpyrimidine and nitrogen heterocycle, which is applied in the directions of medical preparations containing active ingredients, organic chemistry, pharmaceutical formulations, etc., can solve the problems of large oral dose, low oral bioavailability, toxic and side effects, etc.

Active Publication Date: 2020-12-04
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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  • Diarylpyrimidine derivative containing six-membered nitrogen heterocyclic ring as well as preparation method and application of diarylpyrimidine derivative
  • Diarylpyrimidine derivative containing six-membered nitrogen heterocyclic ring as well as preparation method and application of diarylpyrimidine derivative
  • Diarylpyrimidine derivative containing six-membered nitrogen heterocyclic ring as well as preparation method and application of diarylpyrimidine derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Embodiment 1: Preparation of 4-(4-nitrobenzyl)thiomorpholine (B)

[0030]

[0031] 4-Nitrobenzyl bromide A (2.16g, 0.01mol) and thiomorpholine (1.03g, 0.01mol) were dissolved in dichloromethane (20mL), and triethylamine (1.21g, 0.012mol). The resulting mixture was stirred at room temperature until completion as monitored by TLC. Quench the reaction with 30 mL of water, then wash with saturated brine, separate the organic layer, and use anhydrous Na 2 SO 4 Dry on celite, filter, and concentrate under reduced pressure. The residue was recrystallized from ethyl acetate / petroleum ether to obtain intermediate B. Pale yellow solid, yield: 92.1%. 1 H NMR (400MHz, DMSO-d 6 )δ8.19(d, J=8.6Hz, 2H, Ph-H), 7.59(d, J=8.6Hz, 2H, Ph-H), 3.64(s, 2H, CH 2 ), 2.67–2.60 (m, 8H, thiomorpholine-H). ESI-MS:m / z 239.08(M+H) + ,C 11 h 14 N 2 o 2 S(238.08).

Embodiment 2

[0032] Embodiment 2: the preparation of 4-(thiomorpholine methyl) aniline (C)

[0033]

[0034] The intermediate 4-(4-nitrobenzyl)thiomorpholine B (1.0 g) was dissolved in 20 ml of absolute ethanol, then stannous chloride dihydrate (5.0 g) was added. The reaction mixture was stirred at room temperature under nitrogen until complete as monitored by TLC. 2 mol / L NaOH was added to the mixture to adjust the pH to 7. The resulting white solid was filtered and washed with ethyl acetate. The filtrate was added with saturated sodium chloride solution and ethyl acetate. Use anhydrous Na 2 SO 4The organic layer was dried, filtered, concentrated under reduced pressure, and dried in vacuo to finally obtain the intermediate 4-(thiomorpholinemethyl)aniline C. Used directly in the next step without further purification. Yellow solid, yield: 52.2%. ESI-MS:m / z 208.95(M+H) + ,241.03(M+H) + , C 11 h 16 N 2 S(208.10).

Embodiment 3

[0035] Example 3: Preparation of 4-((2-chloropyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile (E1)

[0036]

[0037] 2,4-Dichloropyrimidine D (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 the mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with saturated brine, using 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 E1. 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...

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PUM

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Abstract

The invention discloses a diarylpyrimidine compound containing a six-membered nitrogen heterocyclic ring as well as a preparation method and application of the diarylpyrimidine compound. The compoundhas 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-HIV1 activity, so that the invention also provides application of the compound in preparation of anti-AIDS drugs.

Description

technical field [0001] The invention relates to a derivative and its preparation method and application, in particular to a diaryl pyrimidine derivative containing a six-membered nitrogen heterocycle and its preparation method and application, belonging to the technical field of medicine. Background technique [0002] AIDS (Acquired Immune Deficiency Syndrome, AIDS) is a serious infectious disease mainly caused by Human Immunodeficiency Virus Type 1 (Human Immunodeficiency Virus Type 1, HIV-1) 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, strong selectivity, and...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/47A61P31/18A61K31/541
CPCA61P31/18C07D239/47
Inventor 刘新泳姜向毅展鹏李敬黄伯世
Owner SHANDONG UNIV
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