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8-amino-7-methyl formate-pyrazine pyridone derivatives and preparation method and use thereof

A technology of pyrazine pyridone and methyl formate, which is used in the preparation of 8-amino-7-methyl formate-pyrazine pyridone derivatives, the application in the field of anti-HIV drugs, the field of derivatives and their preparation

Active Publication Date: 2018-07-20
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In order to discover a new generation of HIV inhibitors, the present invention discloses a new class of 8-amino-7-formic acid methyl ester-pyrazine-pyridone HIV-1RNase H-IN dual-target inhibitors. No related reports

Method used

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  • 8-amino-7-methyl formate-pyrazine pyridone derivatives and preparation method and use thereof
  • 8-amino-7-methyl formate-pyrazine pyridone derivatives and preparation method and use thereof
  • 8-amino-7-methyl formate-pyrazine pyridone derivatives and preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Embodiment 1: Preparation of intermediate 3-((benzyloxy)amino)pyrazine-2-carboxylate methyl ester (2)

[0049] Methyl 3-chloropyrazine-2-carboxylate (504mg, 2.9mmol, 1eq.), O-benzylhydroxylamine (1073mg, 8.72mmol, 3eq.), dimethylsulfoxide (3mL) and N,N - Diisopropylethylamine (1.44mL, 8.72mmol, 3eq.) was added to a microwave reaction tube, and microwaved at 100°C for one hour. After the reaction is complete, transfer the reaction solution into a separatory funnel, add 30 mL of ethyl acetate and 30 mL of saturated sodium chloride solution, separate the organic phase, extract the water layer twice with ethyl acetate, combine the organic phases, and add anhydrous magnesium sulfate to dry. Filtrate, concentrate the filtrate, mix the sample with 100-200 mesh silica gel, separate and purify by 200-300 mesh silica gel column chromatography (eluent EA:PE=1:4) to obtain the crude intermediate 2, and use petroleum ether / n-hexane for the crude product Recrystallization of alkane ...

Embodiment 2

[0052] Embodiment 2: Preparation of intermediate 3-(N-(benzyloxy)-3-methoxy-3-oxopropionamido)pyrazine-2-carboxylic acid methyl ester (3)

[0053] Intermediate 2 (1897mg, 7.29mmol, 1eq.), triethylamine (2.02mL, 14.59mmol, 2eq.) and 40mL of methylene chloride were added to a 100mL eggplant-shaped bottle, and placed in an ice bath to stir . Under ice bath, malonate monomethyl chloride (3.12 mL, 29.18 mmol, 4 eq.) was slowly added dropwise into the reaction flask. After 30 min, the ice bath was removed, and the reaction was transferred to a 45° C. oil bath under reflux and stirred. After 24 hours, the reaction was completed, the reaction solution was transferred to a separatory funnel, 30 mL of dichloromethane was added, 30 mL of saturated sodium chloride solution was extracted, the aqueous phase was extracted twice with dichloromethane, the organic phases were combined, dried by adding anhydrous magnesium sulfate, Filtrate, concentrate the filtrate, mix the sample with 100-200...

Embodiment 3

[0056] Example 3: Intermediate 5-(benzyloxy)-8-hydroxyl-6-oxo-5,6-dihydropyrido[2,3-b]pyrazine-7-carboxylic acid methyl ester (4) preparation

[0057] Intermediate 3 (212mg, 0.557mmol, 1eq.), sodium methoxide (74mg, 1.376mmol, 2.47eq.) and 9.8mL of methanol were added into a 50mL eggplant-shaped bottle, stirred at room temperature overnight. After the reaction is completed, 4N HCl solution is added dropwise to the reaction system to adjust the pH to 3-4. During this process, flocculent white insoluble matter is formed, filtered by suction, and after the filter cake is dried, the intermediate 5-(benzyloxy) -8-Hydroxy-6-oxo-5,6-dihydropyrido[2,3-b]pyrazine-7-carboxylic acid methyl ester (4, yield: 66%), white solid, melting point: 195- 197°C.

[0058] Spectral data:

[0059] 1 H NMR (400MHz, DMSO-d 6)δ8.88 (d, J=2.3Hz, 1H, pyrazine-H), 8.70 (d, J=2.3Hz, 1H, pyrazine-H), 7.64-7.62 (m, 2H, Ph-H), 7.46- 7.39(m,3H,Ph-H),5.17(s,2H,CH 2 ),3.84(s,3H,CH 3 ). 13 C NMR (100MHz, D...

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Abstract

The invention provides 8-amino-7-methyl formate-pyrazine pyridone derivatives and a preparation method and use thereof. The 8-amino-7-methyl formate-pyrazine pyridone derivatives have a structure shown in the following general formula I, wherein R is 4'-cyano-[1,1'-biphenyl]-4-yl, 4'-cyano-[1,1'-biphenyl]-3-yl, 3'-cyano-[1,1'-biphenyl]-4-yl, 4-(pyrimidin-5-yl)phenyl, 3-(pyrimidin-5-yl)phenyl, 3',4'-dimethoxy- 1,1'-biphenyl]-4-yl, 3',4'-dimethoxy-[1,1'-biphenyl]-3-yl, naphthalene-1-yl and [1,1'-biphenyl]-4-yl. The invention also relates to a process for the preparation of such derivatives and their use as HIV inhibitors in the preparation of anti-AIDS drugs.

Description

technical field [0001] The present invention relates to a derivative and its preparation method, in particular to the preparation of 8-amino-7-methyl carboxylate-pyrazine-pyridone derivative and its application in the field of anti-HIV drugs, belonging to organic synthesis and medical application technology field. Background technique [0002] AIDS, also known as Acquired Immunodeficiency Syndrome (AIDS), is a major infectious disease that seriously threatens human life and health. Its main pathogen is Human Immunodeficiency Virus Type I (HIV-1 ). Due to the integrated nature 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 discovered in the 1980s. Since the 1990s, the application of Highly Active Antiretroviral Therapy (HAART), a combination of multiple anti-HIV drugs, has greatly reduced the morbidity and mortality caused by HIV-1 infection. However, with th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/4985A61K31/506A61P31/18
Inventor 刘新泳孙林展鹏高萍程锡强李艳琦王学顺
Owner SHANDONG UNIV
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