Preparation method for cefotaxime acid

A technology of cefotaxime acid and 7-ACA, which is applied in the field of medicine, can solve the problems of difficult control of the crystallization process, low product quality, unfavorable large-scale production, etc., to avoid ring opening and gelation of β-lactam, improve quality and yield Efficiency and purity, avoiding the effect of product color difference

Inactive Publication Date: 2016-04-20
HENAN KANGDA PHARMA
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Problems solved by technology

[0003] At present, the most commonly used synthetic method of cefotaxime acid is to dissolve 7-ACA by mixing THF with water, and then react with AE-active ester under the action of a catalyst to generate cefotaxime acid, but on the one hand, THF has strong activity and is industrialized There is a large safety hazard in production, which is not conducive to large-scale production; on the other hand, the crystallization process is not easy to control, and it is easy to coalesce into a gel phenomenon, and the prepared cefotaxime acid has small crystal particle size, uneven particle size distribution, and high purity. Lower and other deficiencies, resulting in increased production costs and lower product quality

Method used

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  • Preparation method for cefotaxime acid

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Effect test

Embodiment 1

[0025] A preparation method of cefotaxime acid includes the following steps:

[0026] (A) In a clean glass kettle, first mix 12L of dichloromethane, 0.2L of ethanol with a mass concentration of 90%, 0.2kg of purified water and 0.5L of isopropanol, and then add 1kg7-ACA, 1.2kgAE-activity Dissolve ester and 0.05kg sodium bisulfite to obtain a mixed solution;

[0027] (B) Add 0.5 kg of triethylamine dropwise to the mixed solution of step (a) within 2 to 3 hours to react. The reaction temperature is 5°C, the pH value is maintained between 7.0 and 8.0, and the residue of 7-ACA is detected by HPLC the amount When <1%, the reaction is deemed complete;

[0028] (C) After the reaction, add 15 kg of 2% sodium bicarbonate aqueous solution for extraction, remove the organic phase, transfer the aqueous phase to another reaction vessel, remove the dichloromethane by vacuum filtration, add 0.02L acetone Mix, at a temperature of 10℃, dropwise add 20% hydrochloric acid until the solution is turbid ...

Embodiment 2

[0031] A preparation method of cefotaxime acid includes the following steps:

[0032] (A) In a clean glass kettle, first mix 13L of dichloromethane, 0.3L of ethanol with a mass concentration of 90%, 0.2kg of purified water and 0.6L of isopropanol, and then add 1kg7-ACA, 1.2kgAE-active Dissolve the ester and 0.07kg sodium bisulfite to obtain a mixed solution;

[0033] (B) Add 0.5 kg of triethylamine dropwise to the mixed solution of step (a) within 2 to 3 hours to react. The reaction temperature is 7°C, the pH value is maintained between 7.0 and 8.0, and the residue of 7-ACA is detected by HPLC the amount When <1%, the reaction is deemed complete;

[0034] (C) After the reaction, add 15 kg of 2% sodium bicarbonate aqueous solution for extraction, remove the organic phase, transfer the aqueous phase to another reaction vessel, remove the dichloromethane by vacuum filtration, add 0.02L acetone Mix, at a temperature of 15℃, dropwise add hydrochloric acid with a mass concentration of 20...

Embodiment 3

[0037] A preparation method of cefotaxime acid includes the following steps:

[0038] (A) In a clean glass kettle, first mix 12L of dichloromethane, 0.2L of ethanol with a mass concentration of 90%, 0.3kg of purified water and 0.5L of isopropanol, and then add 1kg7-ACA, 1.2kgAE-activity Dissolve ester and 0.05kg sodium bisulfite to obtain a mixed solution;

[0039] (B) Add 0.5 kg of triethylamine dropwise to the mixed solution of step (a) within 2 to 3 hours to react. The reaction temperature is 5°C, the pH value is maintained between 7.0 and 8.0, and the residue of 7-ACA is detected by HPLC the amount When <1%, the reaction is deemed complete;

[0040] (C) After the reaction, add 17kg of 2% sodium bicarbonate aqueous solution for extraction, remove the organic phase, transfer the water phase to another reaction vessel, remove dichloromethane by vacuum filtration, add 0.02L acetone Mix, at a temperature of 10℃, dropwise add 20% hydrochloric acid until the solution is turbid and gro...

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Abstract

The invention discloses a preparation method for cefotaxime acid, and belongs to the technical field of medicine. The preparation method comprises the following steps: firstly mixing dichloromethane with ethanol, purified water and isopropyl alcohol, and then adding 7-ACA (aminocephalosporanic acid), AE-active ester and antioxygen to obtain mixed liquor; dropwise adding triethylamine into the mixed liquor in 2 to 3 hours for a reaction, and when HPLC (high performance liquid chromatography) is adopted to detect that 7-ACA residual amount is less than 1 percent, regarding as a complete reaction; adding sodium bicarbonate aqueous solution of which the mass concentration is 1 percent to 5 percent for extraction, after reduced pressure suction filtration on an aqueous phase, adding acetone and mixing, dropwise adding hydrochloric acid of which the mass concentration is 10 percent to 25 percent under temperature of 10 to 15 DEG C until a pH (potential of hydrogen)value is 2.5 to 3.0, and cultivating crystals for 1 to 3 hours; centrifuging, spin-drying, leaching, and drying after spin-drying to obtain the cefotaxime acid. The cefotaxime acid prepared by the invention has uniform particle size distribution and stable performance; mass yield reaches more than 170 percent, and product purity can reach more than 99 percent.

Description

Technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to a preparation method of cefotaxime acid. Background technique [0002] Cefotaxime acid (Cefotaximaacid), chemical name: 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyimino]-acetamido-3 -Cephalosporin-4-carboxylic acid, a semi-synthetic oxime-type cephalosporin, is the third generation cephalosporin, has strong antibacterial effect on gram-negative bacteria and enterobacteria, mainly used for the treatment of sensitive bacteria Cause respiratory infections, urinary system infections, biliary and intestinal infections, skin and soft tissue infections, burns and bone and joint infections. [0003] At present, the most commonly used synthesis method of cefotaxime acid is to mix tetrahydrofuran and water to dissolve 7-ACA, and then react with AE-active ester under the action of a catalyst to produce cefotaxime acid. On the one hand, tetrahydrofuran has strong activity and ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/34C07D501/04C07D501/12
CPCC07D501/34C07D501/04C07D501/12
Inventor 李红德高德瀛李文杰李志军孙津鸽刘红坤韩新正
Owner HENAN KANGDA PHARMA
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