Cefradine preparing process

A cephradine and reaction technology, 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 performance of the catalyst cannot be maximized, and the price of the biocatalyst is expensive. Effects of separation, less solvent, and reduced sewage discharge

Active Publication Date: 2007-06-27
ZHEJIANG ANGLIKANG PHARMA
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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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  • Cefradine preparing process

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Effect test

Embodiment 1

[0032] Dissolve dihydrophenylglycine methyl ester and 7-ADCA in a ratio of 1:1 in a reaction vessel equipped with a two-phase system, add 4mol / L sulfuric acid to adjust the pH value of the system to 5.0, and use a temperature control device to cool the reaction solution The temperature is controlled at T=5°C, and 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, the results of sample analysis showed that 65% of 7-ADCA had been converted into cephradine. At this stage, samples are taken from the upper and lower phases every half hour, and the concentrations of reactants and products are analyzed by HPLC. After the last detection, the centrifugal device is rotated to separate the upper and lower phases again, and the upper...

Embodiment 2

[0034] Dissolve dihydrophenylglycine methyl ester and 7-ADCA in a ratio of 1:1 in a reaction vessel equipped with a two-phase system, add 4mol / L sulfuric acid to adjust the pH value of the system to 6.5, and use a temperature control device to cool the reaction solution The temperature is controlled at T=20°C, and 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, the results of sample analysis showed that 70% of 7-ADCA had been converted into cephradine. At this stage, samples are taken from the upper and lower phases every half hour, and the concentrations of reactants and products are analyzed by HPLC. After the last detection, the centrifugal device is rotated to separate the upper and lower phases again, and the uppe...

Embodiment 3

[0036] Dissolve dihydrophenylglycine methyl ester and 7-ADCA in a ratio of 1.5:1 in a reaction vessel equipped with a two-phase system, add 4mol / L sulfuric acid to adjust the pH value of the system to 6.5, and use a temperature control device to cool the reaction solution The temperature is controlled at T=10°C, and 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, the results of sample analysis showed that 75% of 7-ADCA had been converted into cephradine. At this stage, samples are taken from the upper and lower phases every half hour, and the concentrations of reactants and products are analyzed by HPLC. After the last detection, the centrifugal device is rotated to separate the upper and lower phases again, and the up...

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Abstract

The present invention discloses cefradine preparing process. Under the catalysis of enzyme, 7-ADCA and methyl dihydrogen benzene glycinate are reacted in a double water phase system inside an enzyme catalyzed reactor to form cefradine. Cefradine is obtained through separating the upper phase and the lower phase and filtering, and the mother liquid is returned to the enzyme catalyzed reactor for circular reaction. The enzyme catalyzed cefradine synthesizing process has low solvent consumption, reduced environmental pollution, timely separation of the reaction product from side product and high reaction conversion rate.

Description

technical field [0001] The invention relates to a preparation method of cefradine, which belongs to the technical field of biopharmaceuticals. Background technique [0002] Cephradine is the first-generation cephalosporin, which is a semi-synthetic broad-spectrum cephalosporin. It is mainly used for acute pharyngitis, tonsillitis, otitis media, bronchitis, pneumonia and other respiratory tract infections, genitourinary infections, and skin and soft tissue infections caused by cephradine-sensitive bacteria. treat. [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 ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P17/18
Inventor 叶树祥徐成苗马海岭
Owner ZHEJIANG ANGLIKANG PHARMA
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