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Bis(3,2-hydroxy-pyridone) derivative, and preparation method and application thereof

A technology of hydroxypyridones and derivatives, which is applied in the direction of drug combinations, pharmaceutical formulas, medical preparations containing active ingredients, etc., can solve the problems of toxic and side effects, and achieve the effect of low toxicity and good water solubility

Inactive Publication Date: 2017-05-31
INST OF NUCLEAR PHYSICS & CHEM CHINA ACADEMY OF
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are still some shortcomings in the current research on HOPO that need to be resolved urgently, such as the toxic and side effects of this type of chemical on the organism, the balance between water solubility and fat solubility, etc.

Method used

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  • Bis(3,2-hydroxy-pyridone) derivative, and preparation method and application thereof
  • Bis(3,2-hydroxy-pyridone) derivative, and preparation method and application thereof
  • Bis(3,2-hydroxy-pyridone) derivative, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] 1) Preparation of HOPO-1-1

[0044] Dissolve 10 parts of diethyl oxalate sodium salt in 100 mL of tetrahydrofuran, then add 5 parts of chloroacetone, bubbling in ammonia gas and react for 4 hours, then slowly add 0.5 part of aluminum chloride, and react for 5 days at room temperature. Stop the reaction, filter with suction, dissolve the filter cake in 700mL HCl, and adjust the pH <3, stir for 0.5h, filter with suction, wash the filter cake with water, collect the filter cake, recrystallize it with absolute ethanol, and dry the filter cake at 40°C to obtain a grayish gray solid, the yield: 31.2%.

[0045] 2) Preparation of HOPO-1-2

[0046] Add 10 parts of dichloromethane, 0.2 parts of benzyl bromide, and 0.2 parts of cetylpyridinium chloride to 0.2 parts of the intermediate product HOPO-1-1 and 0.8 parts of potassium carbonate aqueous solution, and react at 40°C for 24 hours. The reaction was stopped, the two phases were separated, extracted with dichloromethane, and the orga...

Embodiment 2

[0056] 1) Preparation of HOPO-1-1

[0057] Dissolve 50 parts of diethyl oxalate sodium salt in 500 mL of tetrahydrofuran, then add 25 parts of chloroacetone, bubbling in ammonia gas and react for 4 hours, then slowly add 3.25 parts of aluminum chloride, and react for 5 days at room temperature. Stop the reaction, filter with suction, dissolve the filter cake in 700mL HCl, and adjust the pH <3, stirring for 1 hour, suction filtration, washing the filter cake with water, collecting the filter cake, recrystallizing with absolute ethanol, suction filtration, drying at 40°C to obtain a grayish gray solid, yield: 30.5%.

[0058] 2) Preparation of HOPO-1-2

[0059] Add 50 mL of dichloromethane, 0.9 part of benzyl bromide, and 0.9 part of cetylpyridinium chloride to 1 part of the intermediate product HOPO-1-1 and 1 part of potassium carbonate aqueous solution, and react at 40°C for 24 hours. The reaction was stopped, the two phases were separated, extracted with dichloromethane, and the org...

Embodiment 3

[0069] 1) Preparation of HOPO-1-1

[0070] Dissolve 100 parts of diethyl oxalate sodium salt in 1000 mL of tetrahydrofuran, then add 50 parts of chloroacetone, bubbling in ammonia gas and react for 4 hours, then slowly add 6.5 parts of aluminum chloride, and react for 5 days at room temperature. Stop the reaction, filter with suction, dissolve the filter cake in 700mL HCl, and adjust the pH <3, stirring for 1h, suction filtration, washing with water, recrystallization of the filter cake with absolute ethanol, suction filtration, and drying at 40°C to obtain an earthy gray solid, yield: 30.9%.

[0071] 2) Preparation of HOPO-1-2

[0072] 100 mL of dichloromethane, 1.8 parts of benzyl bromide, and 1.8 parts of cetylpyridinium chloride were added to 2 parts of intermediate product HOPO-1-1 and 2 parts of potassium carbonate aqueous solution, and reacted at 40°C for 24 hours. The reaction was stopped, the two phases were separated, extracted with dichloromethane, and the organic phases ...

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Abstract

The invention discloses bis(3,2-hydroxy-pyridone) derivative, and a preparation method and application thereof. The preparation method is characterized by comprising the following steps: performing Michael addition and amidation reaction for chloroacetone, oxalacetic acid sodium salt derivatives and ammonia gas under the catalysis of Lewis acid, building 2,3-hydroxy-pyridone fragments, protecting the fragments by virtue of benzyl, hydrolyzing ethyl ester to obtain four carboxylic acids by virtue of saponification under a strong alkaline condition, then performing amidation reaction for lysine and the activated 3,2-hydroxy-pyridone derivative to obtain a target product precursor protected by benzyl, and finally removing the benzyl by virtue of Pd / C under the condition of H2 to obtain the target bis(3,2-hydroxy-pyridone) derivative. A compound of the invention has the structural characteristics that bi-hydroxyl pyridone has a unique toothed structure; by introducing the lysine group, the bis(3,2-hydroxyl-pyridone) derivative can form a stable complex with metal ions so as to be used as a potential chelating agent in the field such as metal chelating in living bodies and the like.

Description

Technical field [0001] The invention belongs to the technical field of compound artificial synthesis, and specifically relates to a bis-3,2-hydroxypyridone derivative and a preparation method and application thereof. The bis 3,2-hydroxypyridone derivatives can be used as an excretion promoting agent to promote metal excretion in organisms. Background technique [0002] With the increasing application of heavy metals, while benefiting mankind, heavy metals also bring many potential hazards to people. Heavy metals have strong chemical toxicity and can enter the human body through respiratory tract, digestive tract, skin contact, etc. Once the content of heavy metals in the body exceeds the standard, they will combine with the organic ligands in the body to form metal complexes, which will cause the body to lose its original physiological and biochemical functions and cause heavy metal poisoning. The best way to solve heavy metal poisoning is to take or inject metal excretion prom...

Claims

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Application Information

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IPC IPC(8): C07D213/81A61K31/444A61P39/04
CPCC07D213/81
Inventor 谢翔卓连刚马宗平黄曾何遥刘飞张锐陈琪萍牟婉君李兴亮魏洪源蹇源张佳强王定林党宇峰王博刘超
Owner INST OF NUCLEAR PHYSICS & CHEM CHINA ACADEMY OF
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