Cefradine preparing process

A technology of cephradine and polyethylene glycol, applied in the field of biopharmaceuticals, can solve the problems that the catalytic performance is easily affected by pH value, temperature, ionic strength and organic solvents, the catalyst performance cannot be maximized, and the cost of biocatalysts is expensive. , to achieve the effects of continuous and automatic control, easy separation, and improved conversion rate

Active Publication Date: 2009-07-29
ZHEJIANG ANGLIKANG PHARMA
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  • Abstract
  • Description
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  • Application Information

AI Technical Summary

Problems solved by technology

[0003] At present, the production of cephradine raw materials is mainly in China and India, and the production process mainly adopts chemical synthesis. However, due to the large amount of industrial wastewater produced in the chemical synthesis process of β-lactam antibiotics, the treatment cost is high, and it also causes certain damage to the environment. pressure
For this reason, European and Japanese producers are adopting enzymatic transformation process step by step, as the preparation method of a kind of cephradine of CN200480018394.8 as application number, adopt under the effect of enzyme, make 7-amino deacetoxy cephalosporanic acid ( Be called for short 7-ADCA) and D-dihydrophenylglycine (being called for short DHa) reaction of activated form obtains cephradine, this method has avoided environmental pollution, but biocatalyst is not only expensive, and catalytic performance is susceptible to pH value, temperature, ionic strength and organic solvents; at the same time, there are products and by-products that inhibit the reaction during the reaction, so that the performance of the catalyst cannot be maximized
In addition, since the molecular structures of the reaction substrate and product are usually relatively close, some of their physical and chemical properties are very similar, which brings certain difficulties to the downstream separation and extraction.

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0032] Dissolve dihydrophenylglycine methyl ester and 7-ADCA in a reaction vessel equipped with a two-phase aqueous system at a ratio of 1:1, add 4mol / L sulfuric acid to adjust the pH of the system to 5.0, and use a temperature control device to control the reaction liquid The temperature is controlled at T=5℃, and the immobilized penicillin acylase (carrier is polypropylene fiber, acetate fiber, amino silica gel, resin, diatomaceous earth) and nitrile hydratase are added for about 1 hour, and they are carried out under the following conditions Acylation: temperature T=15°C, PH=6.5, continuous reaction for about 3 hours, proofing analysis result is that 65% of 7-ADCA has been converted into cefradine. At this stage, samples are taken from the upper and lower phases every half an hour, and the concentration of reactants and products are analyzed by HPLC. After the final detection, the centrifuge device is rotated to separate the upper and lower phases again, and the upper phase sol...

Embodiment 2

[0034] Dissolve dihydrophenylglycine methyl ester and 7-ADCA in a reaction vessel equipped with a two-phase aqueous system at a ratio of 1:1, add 4mol / L sulfuric acid to adjust the pH of the system to 6.5, and use a temperature control device to control the reaction liquid The temperature is controlled at T=20℃, and the immobilized penicillin acylase (carrier is polypropylene fiber, acetate fiber, amino silica gel, resin, diatomaceous earth) and nitrile hydratase are added for about 1 hour, and they are carried out under the following conditions Acylation: temperature T=15°C, PH=6.5, continuous reaction for about 3 hours, proofing analysis result shows that 70% of 7-ADCA has been converted into cefradine. At this stage, samples are taken from the upper and lower phases every half an hour, and the concentration of reactants and products are analyzed by HPLC. After the final detection, the centrifuge device is rotated to separate the upper and lower phases again, and the upper phase...

Embodiment 3

[0036] Dissolve dihydrophenylglycine methyl ester and 7-ADCA in a reaction vessel equipped with a two-phase aqueous system at a ratio of 1.5:1, add 4mol / L sulfuric acid to adjust the pH of the system to 6.5, and use a temperature control device to control the reaction liquid The temperature is controlled at T=10℃, and the immobilized penicillin acylase (carrier is polypropylene fiber, cellulose acetate, amino silica gel, resin, diatomaceous earth) and nitrile hydratase are added for about 1 hour, and they are carried out under the following conditions Acylation: temperature T=15°C, PH=6.5, continuous reaction for about 3 hours, proofing analysis result shows that 75% of 7-ADCA has been converted into cefradine. At this stage, samples are taken from the upper and lower phases every half an hour, and the concentration of reactants and products are analyzed by HPLC. After the final detection, the centrifuge device is rotated to separate the upper and lower phases again, and the upper...

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Abstract

The invention discloses a method for preparing cephradine. Under the catalysis of enzymes, 7-ADCA and dihydrophenylglycine methyl ester are reacted in an enzyme-catalyzed reactor equipped with a two-phase system to form cephradine. The lower phase is separated and filtered to remove cephradine, and the mother liquor is returned to the enzyme-catalyzed reactor for circular reaction. The present invention adopts enzymatic method to synthesize cephradine, less solvent is used, the pollution to the environment is reduced, the two-phase system is adopted, the products inhibiting the reaction and some by-products can be separated in time during the reaction process, and the synthesis reaction and the product can be realized The separation cycle is carried out, thereby greatly improving the conversion rate of the reaction.

Description

Technical field [0001] The invention relates to a preparation method of cefradine and belongs to the technical field of biopharmaceuticals. Background technique [0002] Cefradine is the first-generation cephalosporin, a semi-synthetic broad-spectrum cephalosporin. It is mainly used for acute pharyngitis, tonsillitis, otitis media, bronchitis, pneumonia and other respiratory infections, genitourinary infections and skin and soft tissue infections caused by cefradine-sensitive bacteria. treatment. [0003] At present, the production of cefradine raw materials is mainly based in China and India, and the production process mainly adopts chemical synthesis. However, due to the large amount of industrial wastewater generated during the chemical synthesis of β-lactam antibiotics, the treatment cost is high, and it causes certain environmental problems. pressure. For this reason, European and Japanese manufacturers are gradually adopting enzyme conversion technology. For example, a prep...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D501/06C07D501/22C12P17/18C12P35/04
Inventor 叶树祥徐成苗马海岭
Owner ZHEJIANG ANGLIKANG PHARMA
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