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4-(1,2,3-triazole substituted anilino)-pyridyl pyrimidinone derivatives and preparation method and application thereof

A technology of pyridyl-pyrimidinone and its derivatives, which can be used in pharmaceutical formulations, medical preparations containing active ingredients, organic chemistry, etc., and can solve problems such as drug resistance

Active Publication Date: 2017-06-23
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The integrase inhibitors Raltegravir (RAL), Elvitegravir (EVG), and Dolutegravir (DTG) currently used in clinical practice all have drug resistance problems

Method used

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  • 4-(1,2,3-triazole substituted anilino)-pyridyl pyrimidinone derivatives and preparation method and application thereof
  • 4-(1,2,3-triazole substituted anilino)-pyridyl pyrimidinone derivatives and preparation method and application thereof
  • 4-(1,2,3-triazole substituted anilino)-pyridyl pyrimidinone derivatives and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Embodiment 1: Preparation of intermediate methyl 2-(benzyloxyamino)nicotinate (2)

[0045] Methyl 2-fluoronicotinate (1.32g, 8.51mmol, 1.05eq), O-benzylhydroxylamine (1.00g, 8.12mmol, 1eq) and diisopropylethylamine (DIPEA, 12mL, 68.7mmol, 8.09eq ) into the reaction bottle, microwave reaction at 140°C for 120min (reaction in three times). After the reaction was completed, excess diisopropylethylamine was distilled off under reduced pressure, and the resulting crude product was separated and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate=10:1) to obtain the intermediate 2-(benzyl Oxyamino) nicotinate (2, yield: 34.3%), yellow oil.

[0046] Product spectral analysis data:

[0047] ESI-MS: m / z 259.0(M+1),281.3(M+23).C 14 h 14 N 2 o 3 [258.27].

Embodiment 2

[0048] Example 2: Preparation of Intermediate 1-(Bianoxy)pyridine-[2,3-d]pyrimidine-2,4(1H,3H)-dione (3)

[0049] To a solution of 2-(benzyloxyamino)nicotinate (2, 0.18g, 0.70mmol, 1eq) in dichloroethane (9.79mL) was added trichloroacetylisocyanate (0.28g, 1.49mmol, 2.1eq ) in dichloroethane (1.89mL), stirred at room temperature for 50min, added triethylamine (204μL, 1.47mmol, 2.1eq), after 30min, evaporated the excess solvent under reduced pressure. Add a methanol solution of sodium methoxide (25% mass solubility, 760 μL, 3.5 mmol, 5 eq) into the reaction flask, stir at room temperature for 5 min, add 5 mL of methanol and continue the reaction for 3 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the pH of the reaction mixture was adjusted to 3 with 1N hydrochloric acid solution. The obtained suspension was extracted three times with ethyl acetate, and the organic phases were combined. The combined organic phases were washed wi...

Embodiment 3

[0052] Example 3: Intermediates 1-(benzyloxy)-4-(2-ethynylanilino)pyridinium[2,3-d]pyrimidin-2(1H)-one (5a) and 1-(benzyl Preparation of oxy)-4-(3-ethynylanilino)pyridinium[2,3-d]pyrimidin-2(1H)-one (5b)

[0053] Add phosphorus oxychloride (5eq) dropwise to the solution of intermediate 3 (1eq) in diisopropylethylamine (5eq). After completion, the reaction temperature rose to 100°C. After 45min, the excess solvent was evaporated under reduced pressure to obtain black Oil (interm. 4). Dissolve the crude product of intermediate 4 in N,N-dimethylformamide immediately, then add the corresponding alkynyl-substituted aniline (1.6eq) in N,N-dimethylformamide solution to the above mixed solution, and stir at room temperature Reaction 50min ~ 2h. After the reaction was completed, the reaction solution was poured into water and extracted three times with ethyl acetate. The insoluble matter was filtered and collected, and the combined organic phase was dried with anhydrous magnesium su...

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Abstract

The invention provides a 4-(1,2,3-triazole substituted anilino)-pyridinopyrimidinones derivative. The structure of the 4-(1,2,3-triazole substituted anilino)-pyridinopyrimidinones derivative is shown in the general formula I, wherein 1,2,3-triazole loop is aniline ortho-substituted and meta-substituted, and R is 4-fluorobenzyl or 4-methylbenzyl or phenethyl or phenylpropyl or 1-naphthyl or anilino acyl methyl or 4-fluoro- anilino acyl methyl or 4-fluoro-phenacyl or 4-trifluoromethyl-anilino acyl methyl. The invention further relates to a preparation method of the 4-(1,2,3-triazole substituted anilino)-pyridinopyrimidinones derivative and application of the 4-(1,2,3-triazole substituted anilino)-pyridinopyrimidinones derivative as an HIV inhibitor for preparing anti-AIDS medicine.

Description

technical field [0001] The present invention relates to a derivative and a preparation method thereof, in particular to the preparation of a 4-(1,2,3-triazole substituted anilino)-pyridyl pyrimidinone derivative and its application in the field of anti-HIV drugs. It belongs to the technical field of organic synthesis and medical application. Background technique [0002] AIDS, also known as acquired immunodeficiency syndrome (Acquired Immunodeficiency Syndrome, AIDS), is a major global infectious disease that seriously threatens human life and health. -1). Due to the integrated characteristics and high variability of HIV genetic material, the treatment of HIV infection has been a major problem in the field of global medicinal chemistry since it was first found to be prevalent in human society in the 1980s. Since the 1990s, the application of highly active antiretroviral therapy (HAART), which is a combination of multiple anti-HIV drugs, has greatly reduced the morbidity an...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04A61K31/519A61P31/18
CPCC07D471/04
Inventor 刘新泳张凌子展鹏孙林高萍
Owner SHANDONG UNIV
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