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Method of synthesizing cefadroxil by enzyme process

A technology of cefadroxil and cefadroxil complex, which is applied in the field of enzymatic synthesis of cefadroxil, can solve the problems of high cost, harsh reaction conditions, and large pollution, and achieve the effects of simple operation, increased yield, and high purity

Inactive Publication Date: 2017-08-18
苏州盛达药业有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are many raw materials and auxiliary materials used in the preparation process, and a large amount of solvents such as dichloromethane, DMF, acetone and other auxiliary materials such as hexamethyldisilazane, ethyl chloroformate or methyl chloroformate, tetramethylguanidine, etc. are used. The reaction conditions are relatively harsh, and cryogenic temperatures as low as -50°C are required, resulting in high cost and high pollution

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] In the enzyme reactor, put 5 kg of 7-ADCA, 5 kg of D-hydroxyphenylglycine methyl ester, 30 kg of purified water, and 4 kg of penicillin acylase, and react at a temperature of 15°C~20°C. -ADCA residues should be less than 3mg / mL. After passing the test, separate penicillin acylase and cefadroxil crude product mixture through 100-mesh sieve, cefadroxil crude product mixture is centrifuged, centrifuged to obtain centrifuged mother liquor and cephalosporin The centrifuged mother liquid is recycled to the reactor to wash the enzyme for the crude product of amoxicillin, separated and centrifuged in multiple cycles until the washing liquid is clear, and the penicillin acylase and enzyme reaction mother liquid are obtained. The enzyme reaction mother liquor is transferred into a 100L kettle to recover the complex.

[0031] Add the obtained cefadroxil crude product into another 100L kettle, add 40L of purified water, adjust the pH value to 0.5 with concentrated hydrochloric acid...

Embodiment 2

[0035] In the enzyme reactor, put 5kg of 7-ADCA, 5.5kg of D-hydroxyphenylglycine ethyl ester, 30kg of purified water, 4kg of penicillin acylase, react at a temperature of 15°C~20°C, and take samples for 5h to measure the residue of 7-ADCA. If it is less than 3mg / mL, if it is qualified, the mixture of penicillin acylase and cefadroxil crude product is obtained by separation through a 120-mesh sieve. The enzyme is washed in the reactor, separated and centrifuged in multiple cycles until the washing liquid is clear, and the penicillin acylase and enzyme reaction mother liquid are obtained.

[0036] The obtained cefadroxil crude product was put into another 100L kettle, 40L of purified water was added, the pH value was adjusted to 0.5 with concentrated hydrochloric acid, dissolved, and the temperature was controlled at 10°C to 15°C to obtain the cefadroxil crude product solution.

[0037] Add 2.2 kg of the cefadroxil 2,7-dihydroxynaphthalene complex obtained in Example 1, 10 L of ...

Embodiment 3

[0040]In the enzyme reactor, put 5kg of 7-ADCA, 5.5kg of D-hydroxyphenylglycine ethyl ester, 30kg of purified water, 5kg of penicillin acylase, react at a temperature of 15°C~20°C, and take samples for 5h to measure the residue of 7-ADCA. If it is less than 3mg / mL, if it is qualified, the mixture of penicillin acylase and cefadroxil crude product is obtained by separation through a 120-mesh sieve. The enzyme is washed in the reactor, separated and centrifuged in multiple cycles until the washing liquid is clear, and the penicillin acylase and enzyme reaction mother liquid are obtained.

[0041] The obtained cefadroxil crude product was put into another 100L kettle, 40L of purified water was added, the pH value was adjusted to 0.5 with concentrated hydrochloric acid, dissolved, and the temperature was controlled at 10°C to 15°C to obtain the cefadroxil crude product solution.

[0042] Add 2 kg of β-naphthol to the mother liquor of the enzyme reaction, control the temperature at...

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Abstract

The invention relates to a method of synthesizing cefadroxil by an enzyme process. The method comprises the following steps of: by taking 7-ADCA as an initial raw material, performing a reaction on D-tyrosine methyl ester or D-p-hydroxyl phenylglycine ethyl ester and 7-ADCA in water by directly inputting the solid in the presence of penicillin acylase at 10-25 DEG C; after reaction, separating a cefadroxil coarse product and enzyme reaction mother liquor; further purifying the cefadroxil coarse product to obtain a white cefadroxil product; and adding beta-naphthol or 2,7-dioxynaphthalene into the enzyme reaction mother liquor to obtain a cefadroxil compound. Cefadroxil can be further treated and recovered from the cefadroxil compound, so that the recovery rate of cefadroxil is increased. The product obtained by the method is high in yield and purity. The product is white in appearance, multi-step reaction of a chemical process and various solvents and auxiliary materials are not needed, and green synthesis of cefadroxil is realized.

Description

technical field [0001] The invention belongs to the technical field of original medicines, and in particular relates to a method for enzymatically synthesizing cefadroxil. Background technique [0002] Cefadroxil (Cefadroxil) is the first generation of oral cephalosporin antibiotics, with strong activity, broad antibacterial spectrum, good oral absorption, low side effects and stable in vivo. It is widely used clinically in the treatment of various infections. The synthesis method of cefadroxil before 2010 is mainly the synthesis of chemical method, generally through the mother nucleus 7-ADCA as the starting material, in dichloromethane, after silanization protection, with D-p-hydroxyphenylglycine Deng salt and chlorine The mixed anhydride formed by ethyl formate is condensed under cryogenic conditions to form a DMF complex, which is crystallized in water to obtain cefadroxil. There are many raw materials and auxiliary materials used in the preparation process, and a large...

Claims

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Application Information

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IPC IPC(8): C12P35/04
CPCC12P35/04
Inventor 周自金罗新祖陈锋黄军豪张波刘要武
Owner 苏州盛达药业有限公司
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