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Method for preparing 7-aminocephalosporanic acid via enzymic method

An aminocephalosporanic acid and enzymatic preparation technology, which is applied in the field of preparation of cephalosporanic acid, can solve the problems of low purity, high impurities, fine particles and the like, and achieve the effect of reducing the content of impurities

Active Publication Date: 2013-04-03
华北制药河北莱欣药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The purpose of the present invention is to provide a new two-step enzymatic method for preparing 7-ACA to solve the problems of fine 7-ACA crystal particles, low purity and high impurities in the prior art

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] The concentration of 5000L is that 3% cephalosporin C solution is joined in the reaction tank that 20MU oxidase is housed, with 30m 3 Oxygen is introduced at a flow rate of / h, and the pressure in the tank is controlled at 0.1Mpa, the temperature in the tank is controlled at 18-20°C, and the pH=7.2 is controlled with 3mol / L ammonia water; the pH fluctuation becomes small, and samples are taken for HPLC analysis. When the chromatographic content of residual cephalosporin C is less than 3%, the oxidation is terminated to obtain an oxidized solution containing glutaryl-7-ACA. Filter the oxidized solution, add the obtained filtrate into a reaction tank equipped with 25MU acylase, control the temperature in the tank at 18-20°C, and control the pH=8.3 with 3mol / L ammonia water; when the pH fluctuation becomes small, take a sample for HPLC analysis, When the chromatographic content of the residual glutaryl-7-ACA in the solution is less than 3%, the acylation is terminated and ...

Embodiment 2

[0030] The concentration of 5000L is that 3% cephalosporin C solution is joined in the reaction tank that 20MU oxidase is housed, with 30m 3 Oxygen is introduced at a flow rate of / h, and the pressure in the tank is controlled at 0.1Mpa, the temperature in the tank is controlled at 18-20°C, and the pH=7.2 is controlled with 3mol / L ammonia water; the pH fluctuation becomes small, and samples are taken for HPLC analysis. When the chromatographic content of residual cephalosporin C is less than 3%, the oxidation is terminated to obtain an oxidized solution containing glutaryl-7-ACA. Filter the oxidized solution, add the obtained filtrate into a reaction tank equipped with 25MU acylase, control the temperature in the tank at 18-20°C, and control the pH=8.3 with 3mol / L ammonia water; when the pH fluctuation becomes small, take a sample for HPLC analysis, When the chromatographic content of the residual glutaryl-7-ACA in the solution is less than 3%, the acylation is terminated and ...

Embodiment 3

[0033] The concentration of 5000L is that 3% cephalosporin C solution is joined in the reaction tank that 20MU oxidase is housed, with 30m 3 Oxygen is introduced at a flow rate of / h, and the pressure in the tank is controlled at 0.1Mpa, the temperature in the tank is controlled at 18-20°C, and the pH=7.2 is controlled with 3mol / L ammonia water; the pH fluctuation becomes small, and samples are taken for HPLC analysis. When the chromatographic content of residual cephalosporin C is less than 3%, the oxidation is terminated to obtain an oxidized solution containing glutaryl-7-ACA. Filter the oxidized solution, add the obtained filtrate into a reaction tank equipped with 25MU acylase, control the temperature in the tank at 18-20°C, and control the pH=8.3 with 3mol / L ammonia water; when the pH fluctuation becomes small, take a sample for HPLC analysis, When the chromatographic content of the residual glutaryl-7-ACA in the solution is less than 3%, the acylation is terminated and ...

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Abstract

The invention discloses a high-purity crystallizing method for preparing 7-ACA (aminocephalosporanic acid) via an enzymic method. The method comprises the following preparation processes: oxidizing cephalosporin C solution via oxidase and acylating cephalosporin C solution via acylase to obtain a 7-ACA crystallization solution; absorbing and separating the obtained 7-ACA crystallization solution via an adsorbent, carrying out membrane separation via an ultra-filtration membrane or a micro-filtration membrane, extracting and separating via an extracting agent in turn to obtain a purified 7-ACA crystallization solution; adding a crystallization accessory ingredient into the purified crystallization solution, adjusting PH via hydrochloric acid and crystallizing, then filtering, washing and drying to obtain high-purity 7-ACA crystallization particles. The invention can effectively reduce the impurity content in the 7-ACA crystal; the content of the impurity protein in the obtained 7-ACA crystal is less than 0.2% and the minimum content reaches 0.02%; and the endotoxin content is less than or equal to 0.5EU / mg and the minimum content reaches 0.01EU / mg.

Description

technical field [0001] The present invention relates to the synthetic method of compound, specifically relates to the preparation method of cephalosporanic acid. Background technique [0002] 7-aminocephalosporanic acid, chemical name: 7-amino-3-[(acetyloxy)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2 -ene-2-carboxylic acid, English name: 7-Aminocephalosporanic acid, abbreviation: 7-ACA, is a white crystalline powder, insoluble in water and general organic solvents. 7-ACA is a pharmaceutical intermediate and the starting material for many semi-synthetic cephalosporins, such as ceftriaxone sodium. There are three ways for its synthesis route: chemical cleavage method, fermentation method and enzymatic method, wherein the enzymatic method includes one-step enzymatic method and two-step enzymatic method. The one-step enzymatic method directly acts on the side chain of cephalosporin C (CPC) to generate 7-ACA. This method has simple process and low cost, but at present, this k...

Claims

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Application Information

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IPC IPC(8): C12P35/02C07D501/18C07D501/12
Inventor 段志钢程俊山闫峰郭文仿张伟谷中芝张苗静杨洪先尹科科刘海莲杨立婷赵华
Owner 华北制药河北莱欣药业有限公司
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