Preparation technology of high-purity flomoxef sodium

A technology of sodium fluoxefac and a preparation process, which is applied in the field of preparation technology of high-purity sodium fluoxefate, can solve the problems of high impurity content in the final product, complicated preparation process of sodium fluoxafen, etc., and achieves effective control of product quality. The effect of high yield and high purity

Active Publication Date: 2015-02-04
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-forming reaction: Add 30kg m-cresol and 30kg methylene chloride to the reaction tank under nitrogen protection, stir evenly and cool down to -10°C, add 5kg of fluoxefem intermediate, after dissolving, add 0.4kg hydrochloric acid to adjust Start the reaction when the pH reaches 2.5, and react for 3 hours to obtain a reaction solution containing fluoxetal acid;

[0031] The reaction formula is as follows:

[0032] ,

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

[0034] (2) After the acid forming reaction is completed, under the condition of temperature control at 10°C, add 40 kg of ethyl acetate and aqueous sodium bicarbonate solution to the obtained reaction solution at the same time, adjust the pH=6, extract and separate the phases, and make the material (that is, fluoxetal acid ) into the water phase, reclaim the water phase; add 20kg of ethyl acetate and hydrochloric acid to the water phase, adjust the pH=1.6, ...

Embodiment 2

[0043] (1) Acid-forming reaction: Add 30kg of anisole and 30kg of acetone to the reaction tank under the protection of nitrogen, stir evenly and cool down to -15°C, add 5kg of fluoxefem intermediate, after dissolving, add 0.9kg of 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 fluoxetal acid.

[0044] (2) After the acid forming reaction is completed, under the condition of temperature control at 20°C, add 40 kg of ethyl acetate and aqueous sodium bicarbonate solution to the obtained reaction solution at the same time, adjust the pH=5.8, extract and separate the phases, and make the material (that is, fluoxetal acid ) into the water phase, reclaim the water phase; add butanone 20kg and hydrochloric acid to the water phase, adjust the pH=1.0, extract and separate the phases, so that the material (ie fluoxetal acid) is extracted into the butanone phase, and recla...

Embodiment 3

[0050] (1) Acid-forming reaction: add 30kg N,N-dimethylacetamide and 30kg methyl isopropyl ether to the reaction tank under the protection of nitrogen, stir evenly and cool down to -5°C, then add 5kg of fluoxetal intermediate , After dissolving, add 0.9kg trifluoroacetic acid to adjust the pH to 1.1 to start the reaction, and react for 3 hours to obtain a reaction solution containing fluoxetal.

[0051] (2) After the acid forming reaction is completed, under the condition of temperature control at -5°C, add 40 kg of ethyl acetate and aqueous sodium bicarbonate solution to the obtained reaction solution at the same time, adjust the pH = 4.5, extract and separate the phases, and make the material (i.e. fluoxefem acid) into the water phase, reclaim the water phase; add 20kg of butyl acetate and hydrochloric acid to the water phase, adjust the pH=1.0, extract and separate the phases, so that the material (ie fluoxetal acid) is extracted into the butyl acetate phase, Recover the bu...

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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 flumoxefin sodium, in particular to a preparation process of high-purity flumoxefin sodium. Background technique [0002] Flomoxef sodium (Flomoxef sodium) is a broad-spectrum oxacephin antibiotic developed and marketed by Shionogi Pharmaceutical Co., Ltd. in Japan in 1988. The finished product is made into an injection in the form of sodium salt. Its formula C 15 h 17 f 2 N 6 NaO 7 S 2 , molecular weight: 518.45, molecular structure formula is as follows: [0003] . [0004] Fluoxefor sodium has good antibacterial activity against Gram-negative positive bacteria and anaerobic bacteria, especially against methicillin-resistant Staphylococcus aureus (MRSA). As a medicinal active ingredient, the impurity content of its product directly affects the safety of medication. Patent CN103524534A discloses a method for preparing fluoxetal sodium by freeze-drying process, the preparation method includes ...

Claims

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Application Information

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Patent Type & Authority Applications(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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