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A kind of double 3,2-hydroxypyridone derivatives and preparation method and use thereof

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

Inactive Publication Date: 2019-06-18
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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  • A kind of double 3,2-hydroxypyridone derivatives and preparation method and use thereof
  • A kind of double 3,2-hydroxypyridone derivatives and preparation method and use thereof
  • A kind of double 3,2-hydroxypyridone derivatives and preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

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

[0044] Dissolve 10 parts of diethyl oxalacetate sodium salt in 100 mL of tetrahydrofuran, then add 5 parts of chloroacetone, pass through ammonia gas for 4 hours, then slowly add 0.5 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, make the pH<3, stir for 0.5h, filter with suction, wash the filter cake with water, collect the filter cake, recrystallize with absolute ethanol, and dry the filter cake at 40°C to obtain Earth gray solid, 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 hexadecyl pyridinium chloride to an aqueous solution of 0.2 parts of the intermediate product HOPO-1-1 and 0.8 parts of potassium carbonate, and react at 40°C for 24 hours. Stop the reaction, separate the two phases, extract with dichloromethane, combine the organic phases, an...

Embodiment 2

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

[0057] Dissolve 50 parts of diethyl oxalacetate sodium salt in 500 mL of tetrahydrofuran, then add 25 parts of chloroacetone, pass through ammonia gas 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, make the pH<3, stir for 1h, filter with suction, wash the filter cake with water, collect the filter cake, recrystallize with absolute ethanol, filter with suction, and dry at 40°C. An earthy gray solid was obtained, yield: 30.5%.

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

[0059] Add 50mL of dichloromethane, 0.9 parts of benzyl bromide, and 0.9 parts of hexadecyl pyridinium chloride to an aqueous solution of 1 part of intermediate product HOPO-1-1 and 1 part of potassium carbonate, and react at 40°C for 24 hours. Stop the reaction, separate the two phases, extract with dichloromethane, combine the organic phases, and...

Embodiment 3

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

[0070] Dissolve 100 parts of diethyl oxalacetate sodium salt in 1000 mL of tetrahydrofuran, then add 50 parts of chloroacetone, pass through ammonia gas 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, make the pH<3, stir for 1h, filter with suction, wash with water, recrystallize the filter cake with absolute ethanol, filter with suction, and dry at 40°C to obtain a gray solid. Yield: 30.9%.

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

[0072] Add 100mL of dichloromethane, 1.8 parts of benzyl bromide, and 1.8 parts of hexadecyl pyridinium chloride to the aqueous solution of 2 parts of intermediate product HOPO-1-1 and 2 parts of potassium carbonate, and react at 40°C for 24h. Stop the reaction, separate the two phases, extract with dichloromethane, combine the organic phases, and rotary evaporate to obtain a light y...

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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 synthesis, and in particular relates to a bis-3,2-hydroxypyridone derivative and its preparation method and application. The bis 3,2-hydroxypyridone derivatives can be used as an excretion enhancer for metal excretion in organisms. Background technique [0002] With the increasing application of heavy metals, heavy metals not only benefit human beings, but also bring many potential harms to people. Heavy metals have strong chemical toxicity and can enter the human body through the respiratory tract, digestive tract, and skin contact. Once the content of heavy metals in the body exceeds the standard, they will combine with 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 enhancers, which can co...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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