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Novel method for refining aztreonam

A technology of aztreonam and refining method, applied in the direction of organic chemistry, etc., can solve the problem of low purity of aztreonam

Inactive Publication Date: 2011-06-08
HAINAN LINGKANG PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] In order to overcome the defects of the above-mentioned prior art, especially the defect of low purity of aztreonam prepared by the prior art, the invention provides a method for refining aztreonam compound

Method used

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  • Novel method for refining aztreonam

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0078] Under stirring, add 20ml of ethanol to 10g of aztreonam with a purity of 95% prepared according to US4775670A, then add an ethanol solution of 1mol / L sodium ethylate at 30°C, slowly heat to 60°C, and process for 2 hours with stirring. Then adjust the pH value to 1.5 with hydrochloric acid, cool down to room temperature, and precipitate aztreonam. At this time, the speckle detected by TLC (developer=acetonitrile:water=4:1) was 2.5%.

[0079] Add the solution containing aztreonam into the fixed bed filled with D201 macroporous strongly basic styrene-based anion exchange resin, and continue the exchange until the pH value is adjusted to 5.2. Then elution was carried out with aqueous sodium hydroxide as the eluent, and the eluate was collected and concentrated under reduced pressure. At this time, the speckle detected by TLC (developer=acetonitrile:water=4:1) was 0.8%.

[0080] Then use 0.5mol / L p-fluorobenzenesulfonic acid aqueous solution to adjust the pH value to 1.2, ...

Embodiment 2

[0085] Under stirring, add 20ml dimethyl sulfoxide to 10g of aztreonam crude drug with a purity of 97%, then add a methanol solution of 1mol / L sodium methoxide at room temperature, slowly heat to 50°C, and process under stirring for 2.5 hours. Then adjust the pH value to 1.8 with p-fluorobenzenesulfonic acid, cool down to room temperature, and precipitate aztreonam. At this time, the speckle detected by TLC (developer=acetonitrile:water=4:1) was 1.5%.

[0086] Add the solution containing aztreonam into the fixed bed filled with D201 macroporous strongly basic styrene-based anion exchange resin, and continue the exchange until the pH value is adjusted to 5.5. Then elute with sodium hydroxide ethanol solution as eluent, collect the eluate, and concentrate under reduced pressure. At this time, the speckle detected by TLC (developer=acetonitrile:water=4:1) was 0.7%.

[0087] Then use 0.5mol / L formic acid to adjust the pH value to 1.5, let it stand still, and start to precipitate...

Embodiment 3

[0092] Under stirring, add 20 ml of tetrahydrofuran to 10 g of crude aztreonam with a purity of 96% prepared according to CN 1681812A, then add 1 mol / L ethanol solution of potassium ethylate at 40°C, slowly heat to 65°C, and stir for 1 hour . Then adjust the pH value to 2.0 with formic acid, cool down to room temperature, and precipitate aztreonam. At this time, the speckle detected by TLC (developer=acetonitrile:water=4:1) was 2.0%.

[0093] Add the solution containing aztreonam to the filled In the reaction tank of IRA-900 anion exchange resin, through CO 2 Gas facilitates the exchange until the pH is adjusted to 5.8. Then, potassium hydroxide ethanol solution was used as eluent for elution, and the eluate was collected and concentrated under reduced pressure. At this time, the speckle detected by TLC (developer=acetonitrile:water=4:1) was 0.8%.

[0094] Then use 0.8mol / L benzenesulfonic acid to adjust the pH value to 1.5, let it stand, and start to precipitate solids....

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Abstract

The invention relates to a method for refining aztreonam, comprising the following processing steps: 1) in the presence of an appropriate solvent or solvent mixture, processing raw material aztreonam by using alkali metal or alkaline-earth metal oxide under the condition of heating, regulating the pH value with proper acid, cooling, separating out aztreonam precipitate so as to obtain the primarily purified aztreonam; 2) absorbing the aztreonam with strong alkaline ion-exchange resin, then eluting, collecting eluent, and concentrating at reduced pressure, so as to obtain secondary purified aztreonam; and 3) regulating the pH value with proper acid, crystallizing, centrifugally washing precipitated crystals, and drying, thus three-stage purified aztreonam is obtained. The purity of the refined aztreonam obtained by the method is not less than 99.2%, the purity of most refined aztreonam is not less than 99.5%, flaming residues are few, and the content of heavy metal is extremely low.

Description

technical field [0001] The invention relates to a new preparation method of aztreonam, which belongs to the technical field of medicine. Background technique [0002] Aztreonam (Aztreonam) is a monobactam antibiotic, the chemical name is [2S-[2α,3β(Z)]]-2-[[[1-(2-amino-4-thiazolyl)-2 -[(2-Methyl-4-oxo-1-sulfo-3-azetidinyl)amino]-2-oxoethylene]amino]oxo]-2-methylpropionic acid , the molecular formula is C 13 h 17 N 5 o 8 S 2 , the molecular weight is 435.44, and the structural formula is: [0003] [0004] Aztreonam is an atypical β-lactam antibiotic developed by Bristol-Myers Squibb, which can be synthesized artificially. It was launched in Italy in 1984. It has high antibacterial activity against most aerobic Gram-negative bacteria, including Escherichia coli, Klebsiella pneumoniae and Oxitoella sp., Bacillus aerogenes, Bacillus cloacae, Proteus sp., Serratia sp. Genus, Citrobacter, Shigella and other Enterobacteriaceae bacteria, as well as influenza bacillus, Ne...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/12
CPCC07D417/12C07D501/36
Inventor 陶灵刚
Owner HAINAN LINGKANG PHARMA CO LTD
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