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Enzymatic technology for compounding cefquinome sulfate

A technology of cefquinome sulfate and cefquinome sulfate, which is applied in the field of enzymatic process of cefquinome sulfate raw material drug for animals, can solve the problems of many reaction steps, harsh reaction conditions and low reaction temperature, and achieve mild reaction conditions , Product quality is stable, and the effect of reducing side reactions

Inactive Publication Date: 2017-01-25
AMICOGEN CHINA BIOPHARM CO LTD
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0005] The chemical method requires more organic chemical raw materials (such as solvent dichloromethane, pyridine, xyleneamine), and the reaction conditions are harsh. If anhydrous conditions are required, the reaction temperature is low (some need to be as low as minus 90°C), and there are many reaction steps. , producing a large amount of three wastes to be treated

Method used

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  • Enzymatic technology for compounding cefquinome sulfate

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] In the enzyme reactor, add 20000 u of immobilized enzyme and 1 L of deionized water, and start stirring. Add 0.5 mol of 7-aminocefotaxime and 0.65 mol of AE active ester. Add 1 mol / L hydrochloric acid solution dropwise to adjust the pH value to 5.5. The reaction temperature was controlled to be 20°C. The reaction was carried out for 3 hours until 0.05% of 7-aminocefotaxime remained as detected by HPLC. The reaction liquid is separated through a screen to obtain the cefquinome mother liquid, and the immobilized enzyme is collected and recycled. Extract the obtained cefquinome mother liquor with 500 ml of ethyl acetate, adjust the pH to 1.5 with 1 mol / L sulfuric acid solution in the water phase, add 1 L of acetone, stir until crystals are precipitated, grow crystals at 0-5°C for 1 hour, and then filter with suction. After washing with acetone and vacuum drying at 55° C., 289 g of cefquinoxime sulfate was obtained with a yield of 89.6% (the maximum single impurity detec...

Embodiment 2

[0027] In the enzyme reactor, add 30000 u of immobilized enzyme and 1 L of deionized water, and start stirring. Add 0.5 mol of 7-aminocefotaxime and 0.6 mol of AE active ester. Add dropwise 1mol / L hydrochloric acid solution to adjust the pH value to 6. The reaction temperature was controlled to be 25°C. The reaction was carried out for 3 h until 0.09% of 7-aminocefotaxime remained as detected by HPLC. Separating the reaction solution through a sieve to obtain the cefquinome mother liquor, extracting the obtained cefquinome mother liquor with 500ml ethyl acetate, adjusting the pH to 1.1 with 1mol / L sulfuric acid solution in the water phase, adding 1L of acetone, and stirring until crystals are precipitated , after crystal growth at 0-5° C. for 1 h, suction filtration, washing with acetone, and vacuum drying at 55° C., 291 g of cefquinome sulfate was obtained with a yield of 90.3% (the maximum single impurity detected by HPLC was 0.08%, and the total impurity was 0.39%).

Embodiment 3

[0029] In the enzyme reactor, add 10000 u of immobilized enzyme and 1 L of deionized water, and start stirring. Add 0.5 mol of 7-aminocefotaxime and 0.55 mol of AE active ester. Add dropwise 1mol / L hydrochloric acid solution to adjust the pH value to 5. The reaction temperature was controlled to be 15°C. React for 3 hours until the residual 7-aminocefotaxime detected by HPLC is less than 0.1%. Separating the reaction solution through a sieve to obtain cefquinome mother liquor, extracting the obtained cefquinome mother liquor with 500ml ethyl acetate, adjusting the pH to 1.3 with 1mol / L sulfuric acid solution in the water phase, adding 1L acetone, and stirring until crystals precipitated , after crystal growth at 0-5° C. for 1 h, suction filtration, washing with acetone, and vacuum drying at 55° C. to obtain 297 g of cefquinoxime sulfate with a yield of 92.1% (maximum single impurity 0.09% detected by HPLC, total impurity 0.51%).

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Abstract

The invention relates to an enzymatic technology for compounding an antibiotic bulk drug-cefquinome sulfate special for animals. The enzymatic technology comprises the following steps: enabling an AE (Active Ester) to react with 7-amino cefquinome under a catalytic action of enzyme, thus generating cefquinome; filtering and separating a mother solution containing the cefquinome by using a screen; salifying and crystallizing, thus obtaining the cefquinome sulfate. The enzymatic technology disclosed by the invention adopts an enzymatic method to compound the cefquinome sulfate. Compared with an existing chemical technology, firstly, in aspect of catalytic synthesis, the selectivity of the enzyme is higher, side effects are less, generated impurities are relatively less, and the product quality is high; secondly, the enzymatic technology uses water as a reaction solvent, low-toxicity reagents are used in a technological process, the generation of waste is particularly reduced, and the enzymatic technology has obvious advantages in environment protection and is beneficial for environment protection; in addition, the enzymatic technology has the characteristics of strong parameter controllability, moderate reaction conditions, stable product quality and the like; since the enzyme can be recycled, the cost of the enzymatic technology is obviously lower than that of the chemical method, and the enzymatic technology is suitable for promotion and industrial production.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to an enzymatic process for cefquinome sulfate, an animal-specific antibiotic raw material drug. [0002] technical background [0003] Cefquinoxime sulfate is the fourth-generation animal-specific cephalosporin antibiotic developed by the German Hoechst company in the 1980s. It was first approved for listing in Germany in 1993, and British Intervet (Intervet) was also listed in 1994. Cefquinome sulfate has the characteristics of broad antibacterial spectrum, strong antibacterial activity, fast absorption, low toxicity, and low residue. It has excellent antibacterial activity against Gram-positive bacteria, Gram-negative bacteria, anaerobic bacteria, and Pseudomonas aeruginosa. , especially for Gram-negative bacteria. Cefquinome sulfate has fast absorption, short time to peak, high bioavailability, large area under the drug-time curve, and large volume of distribution. Cefquinome h...

Claims

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Application Information

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IPC IPC(8): C12P35/04C12N11/02C07D501/46C07D501/12
CPCC12P35/04C07D501/12C07D501/46C12N11/02
Inventor 张永志杨申永王玲李建国
Owner AMICOGEN CHINA BIOPHARM CO LTD
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