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Synthesis method of cefalexin impurity

A synthesis method, the technology of cephalexin, is applied in the direction of organic chemistry, etc., to achieve the effects of high content of synthetic products, reduction of the generation of by-products, and simple operation of the reaction process

Inactive Publication Date: 2019-06-04
HEBEI UNIVERSITY OF SCIENCE AND TECHNOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But because this cephalexin impurity is specific impurity, and also rarely sell this impurity on the market, therefore have important value to the quality control of cephalexin drug, safety assessment based on this specific impurity, so researching the synthesis of this cephalexin impurity just has very important practical significance

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  • Synthesis method of cefalexin impurity
  • Synthesis method of cefalexin impurity
  • Synthesis method of cefalexin impurity

Examples

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preparation example Construction

[0029] This example relates to the synthesis method of cephalexin impurity, the cephalexin impurity is specifically (6R,7R)-7-[(2,2-dimethyl-1-oxopropyl)amino]-3-methyl- 8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, and the synthetic method comprises:

[0030] Step a, at 0-10°C, react 7-aminodesacetoxycephalosporanic acid with a molar ratio of 1:(1-1.5) and tetramethylguanidine for 0.5-1 hour to obtain 7-aminodesacetoxy Cephalosporanate.

[0031] Step b, at 0-25°C, react 7-aminodesacetoxycephalosporanate with a molar ratio of 1:(0.5-1.5) and pivaloyl chloride for 2-5 hours to obtain (6R,7R)- 7-[(2,2-Dimethyl-1-oxopropyl)amino]-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]octane-2 -ene-2-carboxylates.

[0032] Step c, at 15-40°C, fully mix dilute hydrochloric acid with a mass concentration of 1%-15% and the product obtained in step b, carry out a hydrolysis reaction at 25-35°C for 10-60 minutes, and statically Set the layers, remove the lower organic phase and ev...

preparation example 1

[0038] The synthesis of the cephalexin impurity of present example comprises the following steps.

[0039] Step a, in a dry and clean reaction flask, add 40ml of dichloromethane and 5g of 7-aminodesacetoxy cephalosporanic acid, cool to 0°C, add 2.8g of tetramethylguanidine in the reaction flask, control the reaction temperature Above 10°C, react for 30 minutes to obtain 7-aminodesacetoxycephalosporanic acid salt solution.

[0040] Step b. Add 3 g of pivaloyl chloride to the reaction flask under temperature control not exceeding 10° C. After the addition, control the temperature at 0° C. and react for 4 hours.

[0041] Step c, add 70ml of hydrochloric acid with a mass concentration of 5.64% to the hydrolysis reaction bottle, adjust the temperature to 30°C, pour the product after the reaction in step b into the hydrolysis reaction bottle and stir for 30 minutes, let it stand for 30 minutes, and remove the lower layer Organic phase, the organic phase was evaporated and crystalli...

preparation example 2

[0044] The synthesis of the cephalexin impurity of present example comprises the following steps.

[0045] Step a, in a dry and clean reaction flask, add 10ml of dichloromethane, 30ml of chloroform and 5g of 7-aminodesacetoxycephalosporanic acid, cool to 4°C, add 3.2g of tetramethylguanidine into the reaction flask, Control the reaction temperature not to be higher than 10° C., and react for 40 minutes to obtain a 7-aminodesacetoxycephalosporanic acid salt solution.

[0046] Step b. Add 2 g of pivaloyl chloride to the reaction flask under temperature control not exceeding 10° C. After the addition, control the temperature at 4° C. and react for 3 hours.

[0047] Step c, add 70ml of hydrochloric acid with a mass concentration of 2.84% to the hydrolysis reaction bottle, adjust the temperature to 35°C, pour the product after the reaction in step b into the hydrolysis reaction bottle and stir for 40 minutes, let it stand for 30 minutes, and remove the lower layer Organic phase, t...

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Abstract

The invention provides a synthesis method of a cefalexin impurity. The method comprises the following steps: a, reacting 7-amino deacetoxy cephalosporanic acid with tetramethyl guanidine to obtain a 7-amino deacetoxyl cephalosporanic acid salt; b, carrying out reaction on the 7-amino deacetoxyl cephalosporanic acid salt and pivaloyl chloride to obtain (6R,7R)-7-[(2, 2-dimethyl-1-oxopropyl) amino ]-3-methyl-8-oxo-5-thio-1-azadicyclo [4.2.0] octyl-2-ene 2-carboxylic acid salt; and c, fully mixing dilute hydrochloric acid with a product obtained in the step b to carry out a hydrolysis reaction, standing for layering after the reaction is ended, taking an organic phase at the lower layer, and evaporating and crystallizing the obtained organic phase under reduced pressure so as to obtain the cefalexin impurity. The synthesis method can be used for synthesizing the cefalexin impurity, and has a great promotion effect on deeper and wider researches on cefalexin-related application safety, reliability and stability and quality control in the production process.

Description

technical field [0001] The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing cephalexin impurities. Background technique [0002] Cephalexin is the first generation of cephalosporin antibiotics that can be used orally. It was researched and developed by Eli Lilly and Company of the United States in 1967 and was first put on the market in 1970. Cefalexin mainly inhibits the synthesis of cell walls, so that the cell contents grow and swell to rupture, leading to the leakage of cell contents and killing bacteria. It has the advantages of broad antibacterial spectrum, strong bactericidal power, acid resistance, and good gastrointestinal absorption. It is well distributed after oral administration, and the peak blood concentration can be reached in one hour. The drug is mainly used to treat respiratory tract infections, urinary tract infections and skin and soft tissue infections. [0003] The quality of drugs is an import...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/22C07D501/04
Inventor 刘宝树韩玮凯孙华张军立
Owner HEBEI UNIVERSITY OF SCIENCE AND TECHNOLOGY
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