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Preparation method of 7-amino-3-ethenyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

An azabicycle and vinyl technology, applied in the field of medicine, can solve the problems of high impurity content, dark color and the like, and achieve the effects of low impurity content, light color and environmental protection

Active Publication Date: 2013-04-24
GUANGZHOU BAIYUNSHAN PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the inventors found that the 7-amino-3-vinyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid thus obtained had an impurity content of The problem of high and deep color, the color of the product is generally greater than yellow No. 7, and the total amount of impurities is greater than 1.0%. Use such 7-amino-3-vinyl-8-oxo-5-thia-1-aza Cefixime or cefdinir prepared from bicyclo[4.2.0]oct-2-ene-2-carboxylic acid tends to be darker in color, with a light yellow to yellow appearance and high impurity content

Method used

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  • Preparation method of 7-amino-3-ethenyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
  • Preparation method of 7-amino-3-ethenyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Step 1: In a 250ml reaction flask, add 20 grams of 7-phenylacetamido-3-vinyl-4-cephalosporanic acid p-methoxybenzyl ester and 60 grams of phenol, and react at a temperature of 48-50°C for 6 hour, add 200ml ethyl acetate, extract and separate layers, add 200ml×2 water to the organic layer and extract twice, combine the water layer, then add 200ml ethyl acetate to wash the water layer, then add 2 grams of activated carbon to the water layer for decolorization, filter , wash the carbon cake with 40ml of water, combine the filtrate and lotion, add 20 grams of penicillin acylase, raise the temperature to 30-32°C, add 5wt% ammonia water dropwise to adjust the pH=7.5-8.0, and maintain the pH value for 5 hours after the reaction, Filter out the enzyme, wash the enzyme with 60ml of water, combine the filtrate and washings, that is, 7-amino-3-vinyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2- Alkene-2-carboxylic acid basic salt solution.

[0027] Step 2: To the basic salt of 7-amino-3...

Embodiment 2

[0029] Step 1: with embodiment 1, just used ammoniacal liquor changes into 6wt% sodium carbonate aqueous solution.

[0030] Step 2: To the basicity of 7-amino-3-vinyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid obtained in step 1 In the saline solution, add 15ml methanol and cool down to 10-20°C, add 5wt% sulfuric acid, 7-amino-3-vinyl-8-oxo-5-thia-1-azabicyclo[4.2.0]octane -2-ene-2-carboxylic acid solid gradually precipitated, continue to add 5wt% sulfuric acid, 7-amino-3-vinyl-8-oxo-5-thia-1-azabicyclo[4.2.0]octyl- After a large amount of precipitation, 2-ene-2-carboxylic acid is converted into 7-amino-3-vinyl-8-oxo-5-thia-1-azabicyclo[4.2.0] with the continuous addition of acid Oct-2-ene-2-carboxylic acid sulfate gradually dissolves to give 7-amino-3-vinyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene -2-Carboxylic acid sulfate solution; Then, add 0.1 g of activated carbon to the solution, stir and decolorize for 20 minutes, filter out the activated carbon and...

Embodiment 3

[0032] Step 1: with embodiment 1, just used ammoniacal liquor is changed into 5wt% sodium bicarbonate aqueous solution.

[0033] Step 2: To the basicity of 7-amino-3-vinyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid obtained in step 1 Add 75ml of ethanol to the saline solution, keep the temperature at 20-30°C, add formic acid, 7-amino-3-vinyl-8-oxo-5-thia-1-azabicyclo[4.2.0]octane- 2-ene-2-carboxylic acid solid gradually precipitated, continue to add formic acid, 7-amino-3-vinyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene -2-Carboxylic acid is converted into 7-amino-3-vinyl-8-oxo-5-thia-1-azabicyclo[4.2.0]octane-2 with the continuous addition of acid after a large amount of precipitation -ene-2-carboxylic acid formate gradually dissolved to give 7-amino-3-vinyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2 -Carboxylic acid formate solution; Then, add 0.5 gram of active carbon in this solution, stir and decolorize for 20 minutes, filter out active carbon and wash ...

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Abstract

The invention relates to a preparation method of 7-amino-3-ethenyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. The method comprises the following steps: step 1, removing a 4th site carboxyl protector of GVNE under effect of phenol, and removing a 7th site amino protective group in the presence of penicillin acylase to obtain a water solution containing 7-amino-3-ethenyl-8-oxo-5-thia-1-azabicyclo [4.2.0]oct-2-ene-2-carboxylic acid basic salt; and step 2, adding acid into the water solution obtained in the step 1 to precipitate 7-amino-3-ethenyl-8-oxo-5-thia-1-azabicyclo [4.2.0]oct-2-ene-2-carboxylic acid solid and then dissolve the solid, so as to obtain a solution containing 7-amino-3-ethenyl-8-oxo-5-thia-1-azabicyclo [4.2.0]oct-2-ene-2-carboxylic acid acid salt; and extracting the solution by an organic solvent, and adding alkali into the water phase to precipitate the 7-amino-3-ethenyl-8-oxo-5-thia-1-azabicyclo [4.2.0]oct-2-ene-2-carboxylic acid, so as to obtain 7-amino-3-ethenyl-8-oxo-5-thia-1-azabicyclo [4.2.0]oct-2-ene-2-carboxylic acid with light color and low impurity content.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a preparation method of a cephalosporin antibiotic intermediate, more specifically, to 7-amino-3-vinyl-8-oxo-5-thia-1-azabicyclo[4.2 .0] Process for the preparation of oct-2-ene-2-carboxylic acid. Background technique [0002] Cephalosporin antibiotics are a class of broad-spectrum semi-synthetic antibiotics. The first cephalosporin antibiotics came out in the 1960s. At present, there are more than 60 varieties on the market, and the output accounts for more than 60% of the antibiotic production in the world. Compared with penicillin, cephalosporin antibiotic has the advantages of wider antibacterial spectrum, resistance to penicillinase, high curative effect, low toxicity, and less allergic reaction, and occupies a very important position in anti-infection treatment. [0003] The preparation of cephalosporin antibiotics generally adopts a semi-synthetic method, using the mother ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P35/02
Inventor 刘丹青冯胜昔梁少娟朱艺基王妙英金国有
Owner GUANGZHOU BAIYUNSHAN PHARM CO LTD
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