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Process for removing nifuratel cyclization impurities

A technology for nifuratel ring and impurities, which is applied in the field of removal technology of nifuratel ring impurities, can solve the problems of low efficiency, no suitable treatment method, high cost and the like

Inactive Publication Date: 2018-08-10
BEIJING JINCHENG TAIER PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Patent application number CN102391259A uses a preparative chromatographic column to purify and concentrate to prepare nifuratel. This method can indeed produce nifuratel with higher purity, but its cost is high, the efficiency is low, and it is difficult to industrialize production
[0007] In the production process of the patent CN105693709A, the cyclization process only distills the cyclization solvent diethyl carbonate, and does not separate other impurities in the remaining mother liquor from the cyclization product, and it produces 3-methylthio-2-hydroxy-propylhydrazine There is no effective impurity removal process in the process, resulting in a great quality risk
[0008] In summary, the process of producing nifuratel with 3-methylthio-2-hydroxy-propylhydrazine as the starting material for cyclization is the process with the best yield and quality, and is also the most environmentally friendly process. In some processes, there is no effective treatment of the cyclization impurities and the impurities produced during the production of 3-methylthio-2-hydroxy-propylhydrazine, and the next step is directly processed, and there is no suitable treatment method, which makes the product quality Without a better guarantee, in order to make the product quality more excellent, it is very necessary to completely remove all impurities

Method used

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  • Process for removing nifuratel cyclization impurities
  • Process for removing nifuratel cyclization impurities

Examples

Experimental program
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Effect test

Embodiment 1

[0031] Add 41.6g of 3-methylthio-2-hydroxy-propylhydrazine and 80.0g of diethyl carbonate into a 500ml reaction flask and stir evenly, add 100g of 28% liquid sodium methoxide, heat and reflux for 3 hours, and the reaction is complete , lower the temperature to 25°C to filter the insoluble matter, pass the cyclization mother liquor through a packing column of 800g macroporous resin DA-201, circulate at 10°C for about 5 hours, and collect the macroporous resin adsorbing the cyclization product for later use.

[0032] Take 97.2 g of nitrofurfural diethyl ester, 310.0 g of ethanol, and 36.0 g of hydrochloric acid, heat and reflux for 1 hour, and obtain the hydrolyzate of nitrofurfural diethyl ester after cooling down, put it into the dropping funnel for standby.

[0033] Put the macroporous resin that adsorbs the cyclization product into a 1000ml reaction bottle, add 300ml of ethanol, and add the hydrolyzate of nitrofurfural diethyl ester dropwise at 10°C. The dropping time is cont...

Embodiment 2

[0036] Add 41.6g of 3-methylthio-2-hydroxy-propylhydrazine and 80.0g of diethyl carbonate into a 500ml reaction flask and stir evenly, add 100g of 28% liquid sodium methoxide, heat and reflux for 3 hours, and the reaction is complete , lower the temperature to 25°C to filter the insoluble matter, pass the cyclization mother liquor through a packed column of 600g macroporous resin DM-301, circulate at 20°C for about 7 hours, and collect the macroporous resin that adsorbs the cyclization product for later use.

[0037] Take 97.2 g of nitrofurfural diethyl ester, 310.0 g of ethanol, and 36.0 g of hydrochloric acid, heat and reflux for 1.5 hours, and obtain the hydrolyzate of nitrofurfural diethyl ester after cooling down, put it into the dropping funnel for later use.

[0038] Put the macroporous resin that adsorbs the cyclization product into a 1000ml reaction bottle, add 300ml of ethanol, and add the hydrolyzate of nitrofurfural diethyl ester dropwise at 8°C. The dropping time i...

Embodiment 3

[0041] Add 41.6g of 3-methylthio-2-hydroxy-propylhydrazine and 80.0g of diethyl carbonate into a 500ml reaction flask and stir evenly, add 100g of 28% liquid sodium methoxide, heat and reflux for 3 hours, and the reaction is complete , lower the temperature to 25°C to filter the insoluble matter, pass the cyclization mother liquor through a packed column of 1000g macroporous resin HPD-100, circulate at 30°C for about 20 hours, and collect the macroporous resin adsorbing the cyclization product for later use.

[0042] Take 97.2 g of nitrofurfural diethyl ester, 310.0 g of ethanol, and 36.0 g of hydrochloric acid, heat and reflux for 1 hour, and obtain the hydrolyzate of nitrofurfural diethyl ester after cooling down, put it into the dropping funnel for standby.

[0043] Put the macroporous resin that adsorbs the cyclization product into a 1000ml reaction bottle, add 300ml of ethanol, and add the hydrolyzate of nitrofurfural diethyl ester dropwise at 8°C. The dropping time is con...

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Abstract

The invention relates to nifuratel, in particular to a process for removing nifuratel cyclization impurities. The process for removing the nifuratel cyclization impurities comprises the step of preparing a hydrazinolysis product, namely 3-methyl thio-2-hydroxyl-propyl hydrazine and is characterized in that the 3-methyl thio-2-hydroxyl-propyl hydrazine, diethyl carbonate and sodium methoxide are mixed, then cyclized and filtered to obtain cyclization mother liquor, and the cyclization mother liquor is subjected to adsorption treatment through a macro-porous resin packing column, then is condensed with 5-nitro furfural and is re-crystallized to obtain nifuratel. The process provided by the invention has the beneficial effects that through performing treatment on the cyclization mother liquorthrough the macro-porous resin packing column, a cyclized product is completely separated from cyclized impurities and other impurities. The invention overcomes the defect that an existing process cannot completely remove the cyclized impurities and the other impurities and finds a simple, effective, safe and environment-friendly method suitable for industrialization.

Description

technical field [0001] The invention relates to nifuratel, in particular to a process for removing the cyclized impurities of nifuratel. Background technique [0002] Nifuratel, chemical name 5-[(methylthio)methyl]-3-[[(5-nitro-2-furyl methylene]amino]-2-oxazolidinone, Chinese alias: Ni Mozole, nifuratel, English name Nifuratel, molecular weight: 285.276, is a nitrofuran derivative, a broad-spectrum antibiotic, nifuratel is effective against bacteria, trichomonas and candida that cause women's reproductive system infections. This product mainly inhibits the growth of bacteria by interfering with its enzyme system, it is difficult to pass through the placenta, and has no teratogenic effect. [0003] Carrying out cyclization with 3-methylthio-2-hydroxyl-propylhydrazine is a common step in the nifuratel process, and 3-methylthio-2-hydroxyl-propylhydrazine is also a necessary substance, such as patents CN100516063C and CN103232445A Both use 3-methylthio-2-hydroxyl-propylhydraz...

Claims

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Application Information

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IPC IPC(8): C07D413/12
CPCC07D413/12
Inventor 孙滨徐小翠张彤王萌王坤李宗奇
Owner BEIJING JINCHENG TAIER PHARMA CO LTD