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Method for preparing intermediate of cefetamet pivoxil hydrochloride

A technology of ceftamet pivoxil hydrochloride and ceftametexil acid, which is applied in the field of preparation of ceftametexil pivoxil hydrochloride intermediates, can solve the ceftametexil acid synthesis process that has not been reported, increased water and ethanol consumption, and crystallization conditions requirements Harsh and other problems, to achieve the effect of industrial production, avoid energy waste, and reduce production costs

Active Publication Date: 2010-05-26
鲁南新时代生物技术有限公司
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AI Technical Summary

Problems solved by technology

However, the crystallization of cefetametic acid needs to be carried out at 0-5°C, and the wet product needs to be washed with water and ethanol respectively, and the product cefetametic acid is substituted relative to the starting material 3-methyl-7-amino-8-oxo - The molar yield of 5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (7-ADCA) was only 79.4%
It can be seen that the crystallization conditions of this synthesis method are relatively harsh, the washing of wet products increases the consumption of water and ethanol, industrialization is difficult to operate, and the product yield is low
[0012] An Liya also discloses a kind of synthetic method of ceftamet pivoxil hydrochloride intermediate ceftametexil acid in "Research on New Method of Cefetamet Acid" (Hebei Chemical Industry, 2005, Volume 28, No. 3, No. 3, page 35). The content of the final product ceftametexil acid obtained is 95%, but there are more impurities in the product, which leads to more residues of impurities in the final product of the subsequent synthesis of ceftazime pivoxil hydrochloride
[0013] At present, there are many reports on the laboratory synthesis of cefetaxime acid, but there is no report on the synthesis process of cefetaxime acid on a scale of more than 200 kg as the starting material 7-ADCA

Method used

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  • Method for preparing intermediate of cefetamet pivoxil hydrochloride

Examples

Experimental program
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Effect test

Embodiment 1

[0052] Take 214.25g (1mol) of 3-methyl-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (7-ADCA) , 500ml of acetone, and 125ml of pure water were added to a 2000ml three-neck flask, fully stirred and cooled to 20°C, slowly added dropwise 101.19g (1mol) of triethylamine, cooled while stirring, cooled to 20°C after fully stirring, and 367.5g (1.05mol) of 2-methoxyimino-2-(2-amino-4-thiazolyl)-(z)-thioxoacetate (AE active ester) was added to the above-mentioned 7- Add 2.9g of N,N-dimethylformamide to the mixed solution of ADCA as a catalyst. After fully stirring, incubate and react at 20°C for 2.5h. After the reaction is completed, extract with 50ml of water and 50ml of dichloromethane. , the organic phase was discarded, and the water phase part was distilled off under reduced pressure to remove acetone and dichloromethane, and the acetone and dichloromethane gases were condensed into liquids by a condenser and then recovered. Then in the aqueous solution that...

Embodiment 2

[0054] Take 214.25g (1mol) of 3-methyl-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (7-ADCA) , 500ml of acetone, and 100ml of pure water were added to a 2000ml three-necked flask, fully stirred and cooled to 20°C, slowly added dropwise 121.43g (1.2mol) of triethylamine, cooled while stirring, and cooled to 20°C after fully stirring, Add 353.5 g (1.01 mol) of 2-methoxyimino-2-(2-amino-4-thiazolyl)-(z)-dihydrazolylthioacetate (AE active ester) to the above-mentioned mixture containing 7 -ADCA mixed solution, and add 8.52g N,N-dimethylbenzamide as a catalyst, after fully stirring, keep warm at 18°C ​​for 1h, extract with 50ml water and 50ml dichloromethane after the reaction, and divide statically phase, the organic phase was discarded, and the water phase part was distilled off under reduced pressure to remove acetone and dichloromethane, and the acetone and dichloromethane gases were condensed into liquids by the condenser and recovered. Then in the aque...

Embodiment 3

[0056] Get 214.25g (1mol) of 3-methyl-7-amino-8-oxo-5-thia-1azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (7-ADCA), Add 300ml of acetone and 300ml of pure water into a 2000ml three-neck flask, stir fully and cool down to 20°C, slowly add 106.25g (1.05mol) of triethylamine dropwise, cool down while stirring, and cool down to 20°C after fully stirring. 381.5g (1.09mol) of 2-methoxyimino-2-(2-amino-4-thiazolyl)-(z)-thiophenhydrazine thioacetate (AE active ester) was added to the above-mentioned 7- Add 6.44g of N,N-dimethylacetamide as a catalyst to the mixed solution of ADCA, and after fully stirring, incubate and react at 22°C for 4h. The organic phase was discarded, and the water phase part was distilled off under reduced pressure to remove acetone and dichloromethane, and the acetone and dichloromethane gases were condensed into liquids by a condenser and then recovered. Then in the aqueous solution that removes acetone and dichloromethane, add medicinal active carbon, the add...

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Abstract

The invention belongs to the field of chemistry, which in particular relates to a method for preparing cefetamet which is an intermediate of cefetamet pivoxil hydrochloride. By optimizing the process, especially improving the synthesis ratio of raw materials and a crystal growing process, the invention enhances the yield and the purity of a product. The method for preparing the cefetamet, which is provided by the invention, has the advantages of mild reaction conditions and little discharge of three wastes, also has stable process and is suitable for industrial large-scale production.

Description

technical field [0001] The invention belongs to the field of chemistry, and in particular relates to a preparation method of an intermediate of ceftazidime hydrochloride. Background technique [0002] Ceftazime pivoxil hydrochloride is the oral prodrug of ceftazime, chemical name: (6R, 7R)-3-methyl-7-[(Z)-2-(2-amino-4-thiazolyl)-2- (Methoxyimino)-acetylamino}-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid pivaloyloxymethyl ester hydrochloride Salt, the chemical formula is as follows: [0003] [0004] The product was developed by Roche (Ro15-8075) and developed by Japan's Takeda Pharmaceutical Company, and a national-scale research was organized in Japan in 1987. Since its listing in 1992, it has been applied in countries all over the world. As an oral anti-infection drug, ceftazidime pivoxil hydrochloride is a newly listed third-generation oral cephalosporin prodrug, which is a leading product of cephalosporins. The most unique advantage of this product is...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/22C07D501/06
Inventor 赵志全张帅
Owner 鲁南新时代生物技术有限公司
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