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Synthesis technology of 2,5-dihydroxymethyl-3,6-dimethylpyrazine

A technology of dimethylpyrazine and dimethylol, which is applied in the field of drug synthesis, can solve the problems of complicated separation and purification work, complicated separation and purification, and complicated operation steps, and achieves high product purity, simple operation and optimized process. The effect of the condition

Inactive Publication Date: 2018-03-23
NANJING UNIVERSITY OF TRADITIONAL CHINESE MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] The problems of the above synthesis method are that the operation steps are cumbersome, the reaction time is long, the reaction consumes more energy, the separation and purification work is complicated, the yield is low, and the cost is high.
[0008] This synthesis method can obtain the product in one step reaction, but due to the complicated separation and purification, the yield is low and the cost is high

Method used

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  • Synthesis technology of 2,5-dihydroxymethyl-3,6-dimethylpyrazine
  • Synthesis technology of 2,5-dihydroxymethyl-3,6-dimethylpyrazine
  • Synthesis technology of 2,5-dihydroxymethyl-3,6-dimethylpyrazine

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Effect test

Embodiment 1

[0028] (1) Synthesis of ethyl 2-hydroxyiminoacetoacetate

[0029] Into a 500ml three-necked flask, put ethyl acetoacetate (65g, 0.5mol) and glacial acetic acid (33g, 0.55mol). Cool to below 5°C, slowly add the prepared 16% sodium nitrite aqueous solution (sodium nitrite 37.9g, 0.55mol, water 237ml) dropwise, keep the temperature below 5°C, continue to stir for half an hour, let it stand, and separate the organic layer , the aqueous layer was extracted with ethyl acetate (2×50ml), the organic layers were combined, washed with 100ml saturated sodium bicarbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain ethyl 2-hydroxyiminoacetoacetate, the yield was 79.6 %.

[0030] (2) Synthesis of 3,6-dimethylpyrazine-2,5-diethyl carboxylate

[0031] Add ethyl 2-hydroxyiminoacetoacetate (3.6g, 22.6mmol), 10%Pd / C (0.2g), ethanol (40ml) and triethylamine (2.29g, 22.6mmol) in the autoclave, After replacing with hydrogen for three times, feed hydrog...

Embodiment 2

[0035] (1) Synthesis of ethyl 2-hydroxyiminoacetoacetate

[0036] In a 500ml three-necked flask, put ethyl acetoacetate (65g, 0.5mol) and glacial acetic acid (39g, 0.65mol). Under the condition of ice bath, cool to below 5°C, slowly add the prepared 16% sodium nitrite aqueous solution (sodium nitrite 44.7g, 0.65mol, water 280ml) dropwise, always control the reaction temperature below 5°C. After the dropwise addition was completed, the reaction was continued for half an hour. Stand the reaction solution, separate the organic layer, extract the aqueous layer with ethyl acetate (2 × 50ml), combine the organic layers, wash the organic layer with 100ml saturated sodium bicarbonate, let stand, separate the organic layer, and wash the aqueous layer with ethyl acetate Ester extraction (4×100ml), combined organic layers, dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain 82.4g light yellow oil, HPLC detection and calculation yield was 83.8%, cooling cry...

Embodiment 3

[0042] (1) Synthesis of ethyl 2-hydroxyiminoacetoacetate

[0043] Into a 500ml three-necked flask, put ethyl acetoacetate (65g, 0.5mol) and glacial acetic acid (45g, 0.75mol). Under the condition of ice bath, cool to below 5°C, slowly add the prepared 16% sodium nitrite aqueous solution (sodium nitrite 51.5g, 0.75mol, water 322ml) dropwise, always control the reaction temperature below 5°C. After the dropwise addition was completed, the reaction was continued for half an hour. Stand the reaction solution, separate the organic layer, extract the aqueous layer with ethyl acetate (2 × 50ml), combine the organic layers, wash the organic layer with 100ml saturated sodium bicarbonate, let stand, separate the organic layer, and wash the aqueous layer with ethyl acetate Ester extraction (4×100ml), combined organic layers, dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain 82.6g of light yellow oil, HPLC detection and calculation yield was 80.0%, coolin...

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Abstract

The invention discloses a synthesis technology of 2,5-dihydroxymethyl-3,6-dimethylpyrazine (liguzinediol). According to the method, ethyl acetoacetate which is used as a raw material undergoes a nitrosation reaction to generate 2-hydroximinoethyl acetoacetate; through palladium-carbon catalytic reduction, condensation and aromatization, 3,6-dimethylpyrazine-2,5-dicarboxylic acid diethyl ester is generated; and finally through reduction, liguzinediol is obtained. The technology has advantages as follows: raw materials are easily available; reaction is mild; operation is simple; separation and purification are easy; and cost is low. The technology is suitable for industrial production.

Description

technical field [0001] The invention relates to a synthesis process of 2,5-dimethylol-3,6-dimethylpyrazine (Liguzinediol), which belongs to the pharmaceutical synthesis technology Background technique [0002] 2,5-dimethylol-3,6-dimethylpyrazine (liguzinediol) is a monomeric compound obtained by modifying the structure of ligustrazine, which has a positive inotropic effect on the heart of normal SD rats , and no adverse reactions such as arrhythmia; the study of the mechanism of action shows that liguzinediol exerts a positive inotropic effect by acting on the SERCA2a target in cardiomyocytes; in addition, through pharmacokinetic studies, the metabolites of liguzinediol in SD rats and bioavailability have also been established. A series of studies have shown that liguzinediol is a potential drug for treating heart failure. [0003] The synthesis method of liguzinediol disclosed in Chinese patent (ZL200810157140.4), US patent (US8,158,630B2) and Australian patent (AU2010200...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D241/12
CPCC07D241/12
Inventor 李伟
Owner NANJING UNIVERSITY OF TRADITIONAL CHINESE MEDICINE