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Preparation method of cefadroxil

A technology for cefadroxil and fadroxil, which is applied in the field of medicine and can solve the problems of the decrease in the catalytic activity of penicillin acylase, the harm to the ecological environment caused by the volatile organic solvent, and the low yield of the target product.

Active Publication Date: 2019-06-07
NINGXIA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Although the use of organic reagent solvents can inhibit the hydrolysis reaction to a certain extent, the catalytic activity of penicillin acylase in organic solvents capable of dissolving substrates has declined significantly, resulting in low yields of target products; and the volatility of organic solvents Harmful to the ecological environment

Method used

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  • Preparation method of cefadroxil
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  • Preparation method of cefadroxil

Examples

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preparation example Construction

[0028] The method for preparing cefadroxil provided by the present invention includes the following steps: adding a predetermined volume of ionic liquid and a phosphate buffer solution to form a co-solvent in a water bath thermostat; adding a predetermined molar ratio of D to the co-solvent -HPGM and 7-ADCA are stirred and the molar ratio of D-HPGM to 7-ADCA is 1:1~1:2.0; the concentration of 7-ADCA is 0.1~1.0 mol / L; D-HPGM and 7-ADCA are added to Add magnetic immobilized penicillin G acylase to the ADCA co-solvent, and the mass ratio of magnetic immobilized penicillin G acylase to 7-ADCA is 1:10~1:50. Continue stirring to make the magnetic immobilized penicillin G acylase Fully contact with D-HPGM and 7-ADCA until the end of the reaction, where the stirring speed is controlled to be 150-250r / min; the reaction system liquid at the end of the reaction is allowed to stand in layers to make the upper phosphate buffer with cefadroxil dissolved The solution is layered with the lower...

Embodiment 1

[0036] Example 1. Add 60 mL of ionic liquid 1-butyl-3-methylimidazole bistrifluoromethanesulfonimide salt and 40 mL of sodium phosphate buffer solution (0.10mol / L, pH 7.0) into the reactor, and mix well. Add 0.1mol 7-ADCA and 0.15molD-HPGM, at this time the concentration of 7-ADCA is 214g / L. Then add 0.42g magnetic immobilized penicillin G acylase, at this time the mass ratio of immobilized enzyme to 7-ADCA is 1:50, the temperature of the water bath is controlled at 30℃, the stirring speed is controlled to 150r / min, the reaction is 10 hours, magnetic force The immobilized enzyme is isolated under the action. Adjust the pH value of the upper layer solution of the separated reaction system to 5.2, and obtain cefadroxil crystals by crystallization. The reactor can be a batch reactor commonly used in industry.

Embodiment 2

[0037] In Example 2, 60mL of ionic liquid 1-butyl-3-methylimidazole hexafluorophosphate and 40mL of sodium phosphate buffer solution (0.10mol / L, pH 7.0) were added to the reactor, and 0.1mol 7- ADCA and 0.15mol D-HPGM, at this time the concentration of 7-ADCA is 214g / L. Then add 0.42g magnetic immobilized penicillin G acylase, at this time the mass ratio of immobilized enzyme to 7-ADCA is 1:50, the temperature of the water bath is controlled at 30℃, the stirring speed is controlled to 150r / min, the reaction is 10 hours, and the magnetic force acts Isolate the immobilized enzyme under. Adjust the pH value of the upper layer solution of the separated reaction system to 5.0, and obtain cefadroxil crystals by crystallization.

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Abstract

The invention relates to a preparation method of cefadroxil. The preparation method comprises the following steps of adding preset volume of a cosolvent consisting of ionic liquid and a thiophosphatesalt buffer solution to a reactor with constant-temperature water bath; adding preset molar ratio of D-HPGM and 7-ADCA to the cosolvent, wherein the molar ratio of the D-HPGM to the 7-ADCA is (1 to 1)to (1 to 2.0), and the concentration of the 7-ADCA is 0.1-1.0mol / L; adding magnetic fossilized penicillin G acylase to the cosolvent of the D-HPGM and the 7-ADCA,and continuing performing stirring toenable the magnetic fossilized penicillin G acylase to be in sufficient contact with the D-HPGM and the 7-ADCA until the reaction is finished; performing layered standing on the reaction system liquid after the reaction is finished, so that an upper-layer thiophosphate salt buffer solution and lower-layer ionic liquid in which the cefadroxil dissolves to be subjected to layering; and regulating the pH of the separated thiophosphate salt buffer solution to 4.0-5.5, so that the cefadroxil is separated out and dried.

Description

Technical field [0001] The invention relates to the technical field of medicine, in particular to a preparation method of sporadroxil. Background technique [0002] Cefadroxil (cefadroxil) is an important semi-synthetic β-lactam antibiotic widely used clinically. It has the advantages of strong activity, good oral absorption, low side effects and broad antibacterial spectrum. At present, the domestic production of cefadroxil generally adopts the mixed acid anhydride method (such as CN201310227621.9). The steps are cumbersome. The group protection process in the process needs to be carried out at a low temperature of -30°C, and a large amount of toxic reagents are used, resulting in a large amount of waste. Serious harm to the ecological environment. The enzymatic method uses penicillin G acylase (EC 3.5.1.11, referred to as PGA) to catalyze 7-amino-3-deacetoxycephalosporanic acid (7-ADCA) and D-p-hydroxyphenylglycine methyl The ester (D-HPGM) reaction to synthesize cefadroxil, ...

Claims

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Application Information

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IPC IPC(8): C12P35/04C12N11/14C12N11/08C12N9/84
CPCY02P20/54
Inventor 薛屏张玮玮史可人李鹏郑庆忠杨金会胡春苗
Owner NINGXIA UNIVERSITY
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