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Preparation process of high-purity fluoxefom sodium

A kind of fluoxefom sodium, the technology of preparation technology, is applied in the field of preparation technology of high-purity fluoxefom sodium, can solve the problems such as the high impurity content of final product, complicated preparation process of flumoxef sodium, etc., achieves effective control of product quality, product quality The effect of high yield and easy drying

Active Publication Date: 2016-09-28
NORTH CHINA PHARMA HEBEI HUAMIN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The purpose of the present invention is to provide a kind of preparation method of high-purity flumoxef sodium, to solve the problem that the preparation process of flumoxef sodium product is complex, and the impurity content of final product is high

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] (1) Acid formation reaction: Add 30kg m-cresol and 30kg dichloromethane to the reaction tank under the protection of nitrogen, stir uniformly and cool to -10℃, add 5kg fluoxefone intermediate, and after dissolving, add 0.4kg hydrochloric acid to adjust Start the reaction at pH 2.5 and react for 3 hours to obtain a reaction solution containing fluoxefic acid;

[0031] The reaction formula is as follows:

[0032] ,

[0033] In the formula, (I) is the intermediate of fluoxef and (II) is fluoxefic acid.

[0034] (2) After the acid-forming reaction, under the condition of controlling the temperature at 10℃, add 40kg of ethyl acetate and sodium bicarbonate aqueous solution to the resulting reaction solution at the same time, adjust the pH=6, extract the phases, and make the material (ie fluoxycephalosporin ) Extract into the water phase and recover the water phase; add 20kg of ethyl acetate and hydrochloric acid to the water phase, adjust the pH=1.6, extract the phases, extract the...

Embodiment 2

[0043] (1) Acid formation reaction: Add 30kg anisole and 30kg acetone to the reaction tank under the protection of nitrogen, stir evenly and cool to -15℃, add 5kg fluoxefone intermediate, and after dissolving, add 0.9kg trifluoroacetic acid to adjust The reaction was started when the pH reached 1.2, and the reaction was carried out for 3 hours to obtain a reaction solution containing fluoxefic acid.

[0044] (2) After the acid-forming reaction is completed, under the condition of controlling the temperature at 20℃, add 40 kg of ethyl acetate and sodium bicarbonate aqueous solution to the resulting reaction solution at the same time, adjust the pH=5.8, extract the phases, and make the material (ie fluoxycephalosporic acid) ) Extract into the water phase and recover the water phase; add 20 kg of methyl ethyl ketone and hydrochloric acid to the water phase, adjust the pH=1.0, extract the phases, extract the material (ie fluoxefic acid) into the methyl ethyl ketone phase, and recover ...

Embodiment 3

[0050] (1) Acid formation reaction: Add 30kg N,N-dimethylacetamide and 30kg methyl isopropyl ether to the reaction tank under the protection of nitrogen, stir uniformly and cool to -5°C, then add 5kg of fluoxefone intermediate After the solution was cleared, 0.9kg of trifluoroacetic acid was added to adjust the pH to 1.1 to start the reaction, and reacted for 3 hours to obtain a reaction solution containing fluorooxcephalosporic acid.

[0051] (2) After the acid-forming reaction is completed, under the condition of controlling the temperature -5°C, add 40 kg of ethyl acetate and sodium bicarbonate aqueous solution to the resulting reaction solution at the same time, adjust the pH=4.5, extract the phases, and make the material (ie fluoxef Acid) is extracted into the water phase, and the water phase is recovered; add 20 kg of butyl acetate and hydrochloric acid to the water phase, adjust pH=1.0, extract the phases, and extract the material (i.e. fluoxefic acid) into the butyl acetat...

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PUM

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Abstract

The invention discloses a preparation technology of high-purity flomoxef sodium. The preparation technology includes following steps: on the basis of a flomoxef intermediate, performing an acidifying reaction to obtain a reaction liquid; performing a water washing process, an extraction process, an aseptic filtration process and the like to the reaction liquid; and performing a solventing-out crystallization step through a one-step crystallization process to obtain a flomoxef sodium product with a purity being higher than 99.90%, wherein key points in the solventing-out crystallization step are selection and proportion of a solventing agent and dropwise addition of a salifying agent and the solventing agent at the same time with crystal growing. The preparation technology overcomes problems which are difficult to control during the solventing-out crystallization step of the flomoxef sodium. The flomoxef sodium is prepared in one step with the flomoxef intermediate as a raw material and the purity of the product of the flomoxef sodium reaches higher than 99.90% just through one crystallization step, which is cannot be achieved through a freeze-drying method or a common solventing-out crystallization process in the prior art. Quality of the product is in conformity with or even exceeds a standard in japanese pharmacopoeia JP16. The preparation technology has a more wide application prospect.

Description

Technical field [0001] The invention relates to a production process of fluoxef sodium, in particular to a preparation process of high-purity fluoxef sodium. Background technique [0002] Flomoxef sodium (Flomoxef sodium) is a broad-spectrum antibiotic developed by Shionoyoshi Pharmaceutical Co., Ltd. of Japan in 1988. The finished product is a sodium salt in the form of injections. Its molecular formula C 15 H 17 F 2 N 6 NaO 7 S 2 , Molecular weight: 518.45, molecular structure is as follows: [0003] . [0004] Fluoxef sodium has good antibacterial activity against gram-negative bacteria and anaerobic bacteria, especially against methicillin-resistant Staphylococcus aureus (MRSA). As a medicinal active ingredient, the impurity content of its product directly affects drug safety. Patent CN103524534A discloses a method for preparing fluoxefox sodium by freeze-drying process. The preparation method includes the following steps: under stirring and a temperature of 0-10°C, adding so...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D501/57C07D501/04C07D501/12
CPCC07D505/06C07D505/20
Inventor 魏青杰刘树林张锁庆贾全魏宝军田洪年马亚松张文胜张立斌王欠张娴张映雪高智伟
Owner NORTH CHINA PHARMA HEBEI HUAMIN PHARMA
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