CN102010426B - Method for preparing ceftizoxime sodium - Google Patents
Method for preparing ceftizoxime sodium Download PDFInfo
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- CN102010426B CN102010426B CN2010105702981A CN201010570298A CN102010426B CN 102010426 B CN102010426 B CN 102010426B CN 2010105702981 A CN2010105702981 A CN 2010105702981A CN 201010570298 A CN201010570298 A CN 201010570298A CN 102010426 B CN102010426 B CN 102010426B
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Abstract
The invention relates to synthetic ceftizoxime acid and a method for preparing ceftizoxime sodium from the synthetic ceftizoxime acid. The preparation process comprises the following steps: slowly adding a crystallization solvent in a crystallization liquid until the crystallization liquid becomes slightly turbid, stopping adding the solvent, slowly stirring and growing crystals for 0.5 hour, continuously adding the residual solvent, and stirring and growing the crystals for 1 hour after the residual solvent is completely added. The product prepared by the optimized process in the invention has remarkably improved quality although the yield is lowered by 1.0-1.5%; and the product crystallization state is obviously improved and the product quality problem of clarity stability in the period of validity is solved.
Description
Technical field
The invention belongs to medical technical field, particularly, relate to a kind of synthetic ceftizoxime acid and prepare the method for SKF-88373 by it.
Background technology
SKF-88373 complex-specturm anti-microbial effect; Wide spectrum β-Nei Xiananmei to multiple gram positive organism and gram-negative bacteria generation is stable; The processing parameter that current technology adopted not is the optimum process parameter, and factors such as Tc, solvent rate of addition, stirring velocity exert an influence to the crystal formation of finished product.
SKF-88373 is developed by Japanese Fujisawa Pharmaceutical Co., Ltd the earliest; And at first go on the market in Japan in nineteen eighty-two; Trade(brand)name epocelin (spocelin), these article belong to the 3rd generation cephalosporin antibiotics, have wide spectrum, efficient, anti-enzyme, low toxicity and can be through the characteristics of hemato encephalic barrier.It has extraordinary result of treatment to septicemia, respiratory system infection, uropoiesis and diseases such as genital system infection, pleuritis, peritonitis, cholecystitis, uterine cavity infection, appendagitis, meningitis, wound and burn due to the sensitive bacterial.Be widely used in clinically the treatment various in, severe infection.
Synthesizing of relevant SKF-88373, prior art has disclosed two synthetic routes.Article one, be to be raw material to methoxybenzyl ester,, make SKF-88373 with salt forming agent again through repeatedly sloughing blocking group with 7-phenylacetylamino-3-cephalosporin-4-carboxyl acid.This route reaction step is long, has increased schedule of operation and production cost.Another is to be raw material and the direct condensation of cefotaxime acetate with 7-amino-3-demethyl-3-Cephalosporanic acid (7-ANCA), and then salify, and this route side reaction is more, and products therefrom needs through column chromatography purification.
Described synthetic ceftizoxime acid respectively in " SKF-88373 synthetic " document of people such as people's such as Liu Bing " about discussion of the synthesis technique of SKF-88373 " and Zhang Fengxia, prepared the method for SKF-88373 again by ceftizoxime acid by 7-ANCA.
Summary of the invention
The inventor is through discover for a long time in earnest; Synthesis step of the prior art is changed, adopt hydrochloric acid to regulate specific pH value, select suitable dispersion agent for use; And specific crystallisation process; Unexpectedly can obtain quality significantly improves has remarkable improvement with the product crystalline state sodium salt, further solve the interior clarity stability problem of effect phase that quality product exists, thereby accomplished the present invention.
The purpose of this invention is to provide a kind of preparation quality significantly improve with the product crystalline state have remarkable improvement the method for SKF-88373.
The present invention provides following technical scheme:
In one embodiment, the invention provides a kind of method for preparing ceftizoxime acid, it may further comprise the steps:
(1) adds 7-ANCA in appropriate amount of organic I and the purified water; Stirring and dissolving; Be cooled to-5 ~ 5 ℃, add the organic bases dissolving again, add AE active ester (2-(2-amino-4-thiazolyl)-2-methoxy imino-acetyl-benzothiazole thioesters) then; Keep temperature of reaction-5 ~ 5 ℃, stirring reaction 5 hours;
(2) add purified water and stir extraction, add organic solvent II washing 2-5 time to aqueous phase; Add 0.01mol/l hydrochloric acid to aqueous phase earlier, transfer pH value 5.5-6.0, add gac and aluminium sesquioxide stirring decolouring respectively to aqueous phase again, stirred 20 minutes;
(3) filter respectively successively after, add the organic alcohol of C1-4 and do dispersion agent, the dripping hydrochloric acid aqueous solution to mass crystallization is separated out, and drips the terminal point pH value and reaches 2.0-2.5, stirs growing the grain 1 hour, after the filtering and washing, wet article vacuum-drying obtains ceftizoxime acid.
Said organic solvent I and organic solvent II can be selected identical or different, are selected from: the mixture of one or both in methylene dichloride, the Virahol; Be preferably methylene dichloride.
The preparation of SKF-88373:
In another embodiment, the invention provides a kind of method for preparing SKF-88373, it may further comprise the steps:
(1) get the above-mentioned ceftizoxime acid that makes, add purified water, the control aqueous temperature adds inorganic sodium class alkali to solution and clarifies below 25 ℃ under stirring, add gac and stir decolouring, the de-carbon filtration;
(2) feed liquid is behind the degerming membrane filtration, adds to carry out solvent crystal through the organic alcohol of the C1-6 of membrane filtration degerming, when crystal solution occurs little when muddy; Stop adding solvent; Slowly stir growing the grain 0.5 hour, and continued to add remaining solvent, finish back restir growing the grain 1 hour; After the blowing filtering and washing, wet article vacuum-drying obtains aseptic SKF-88373.
Said inorganic sodium class alkali is selected from one or more the mixture in yellow soda ash, sodium hydroxide, sodium phosphate, the sodium acetate, is preferably sodium acetate.
In this manual, if not explanation especially, the device that is adopted, equipment, instrument, technology, technology, raw material, method, step etc. all are the own knowledges of art technology, and perhaps those skilled in the art can obtain according to known technology.
Compared with prior art, the method for the present invention's employing has following advantage:
1, in the preparation process of ceftizoxime acid, add 0.01mol/l hydrochloric acid earlier, regulate pH value 5.5-6.0, intermediates content (HPLC method) contrast on average improves more than 2%.
2, in the selection of dispersion agent; Add the organic alcohol of C1-4 and do dispersion agent, add THF with former technology and relatively reduced the kind of introducing the use solvent in the technological process, and alcoholic solvent toxicity is low as dispersion agent; The environmental protection that more becomes is beneficial to the protection of healthy and environment.
3, in the preparation process of SKF-88373, adopt new crystallization method, quality is significantly increased: the product crystalline state has remarkable improvement, has solved the interior clarity stability problem of effect phase that quality product exists.
Embodiment
To further set forth the present invention with reference to specific embodiment below, should be appreciated that these embodiment only are the explanations to preferred version of the present invention, and also limit protection scope of the present invention never in any form.
embodiment 1.
I. the preparation of ceftizoxime acid:
Methylene dichloride 1000L; Purified water 5L; Add 7-ANCA (7-amino-3-H-cephem-4-carboxylic acid) 100Kg, stirring and dissolving is cooled to-5/5 ℃ and adds organic bases triethylamine 68Kg dissolving; Add AE active ester (2-(2-amino-4-thiazolyl)-2-methoxy imino-acetyl-benzothiazole thioesters) 195 kg, kept temperature of reaction-5/5 ℃ stirring reaction 5 hours.Add purified water 530L and stir extraction, add methylene dichloride 500L washed twice, add 0.01mol/l hydrochloric acid in the aqueous phase liquid to aqueous phase; After transferring pH value 5.5-6.0, aqueous phase adds 303 type gac 5.0Kg and aluminium sesquioxide (model is XFA-75150, granularity 150 orders >=90%) 20.0Kg respectively; Stir decolouring 20 minutes, after filtering respectively successively, add dispersion agent medicinal alcohol 350L; Drip 3mol/l aqueous hydrochloric acid to mass crystallization and separate out, drip the terminal point pH value and reach 2.0-2.5, stirred growing the grain 1 hour; Suction filtration, and after draining with the 400L washing with acetone, wet article vacuum-drying obtains the sour 169Kg of ceftizoxime.
II. the preparation of SKF-88373:
Get ceftizoxime acid 150Kg, add purified water 300L, the control aqueous temperature stirs adding inorganic salt sodium acetate 41.0 Kg down below 25 ℃; Be stirred to the solution clarification, pH value adds 767 type gac 4.5Kg and stirs decolouring 30 minutes between 9.5-9.8, and de-carbon filters; Feed liquid adds and to carry out solvent crystal through the absolute ethyl alcohol 7000L of membrane filtration degerming behind the degerming membrane filtration, when crystal solution occurs littlely when muddy, stops adding solvent; Slowly stir growing the grain 0.5 hour, and continued to add remaining solvent, finish back restir growing the grain 1 hour; The blowing suction filtration, and after draining with the 1000L washing with acetone, wet article vacuum-drying obtains aseptic SKF-88373 128Kg.
embodiment 2.
Hydrochloric acid is regulated the influence of pH value for product content
When the preparation ceftizoxime is sour in the prior art; Usually adopting hydrochloric acid to regulate pH value is 2.0-2.5, and the present invention is in the preparation process of ceftizoxime acid, and aqueous phase liquid is before adding activated carbon decolorizing; Add 0.01mol/l hydrochloric acid earlier; Regulate pH value 5.5-6.0, intermediates ceftizoxime acid content (HPLC method) contrast on average improves more than 2%, and testing laboratory confirms contrast effect data such as following table (parallel each 6 batches):
embodiment 3.
In the preparation process of SKF-88373, former technology solvent crystal operation adopts certain speed to add the crystallization solvent continuously; Though product yield is high, crystal grain is tiny, the crystal formation heterogeneity; Product stability is relatively poor relatively; The situation of exceeding standard appears in clarity in certain batch of effect phase, and aseptic former powder branch loads operation simultaneously has feedback, and certain batch is difficult for packing.
Preparing method of the present invention is: add crystallization solvent to crystal solution slowly and occur littlely when muddy, stop to add solvent, stirred growing the grain slowly 0.5 hour, continue then to add remaining solvent, added back restir growing the grain 1 hour.Though the handicraft product yield of optimizing reduces 1.0-1.5%, quality significantly improves: the product crystalline state has remarkable improvement, has solved the interior clarity stability problem of effect phase that quality product exists.
Former technology and novel process clarity test control batch are respectively got 50 batches, and branch is filled to the cillin bottle sealing and does the investigation that keeps sample for a long time respectively, and sample clarity mass term statistical conditions are following:
Claims (6)
1. method for preparing SKF-88373 is characterized in that may further comprise the steps:
(1) adds 7-amino-3-H-cephem-4-carboxylic acid in appropriate amount of organic I and the purified water; Stirring and dissolving; Be cooled to-5 ~ 5 ℃, add the organic bases dissolving again, add 2-(2-amino-4-thiazolyl)-2-methoxy imino-acetyl-benzothiazole thioesters then; Keep temperature of reaction-5 ~ 5 ℃, stirring reaction 5 hours;
(2) add purified water and stir extraction, add organic solvent II washing 2-5 time to aqueous phase; Add 0.01mol/l hydrochloric acid to aqueous phase earlier, adjust pH 5.5-6.0 adds gac and aluminium sesquioxide stirring decolouring respectively to aqueous phase again, stirs 20 minutes;
(3) filter respectively successively after, add the organic alcohol of C1-4 and do dispersion agent, the dripping hydrochloric acid aqueous solution to mass crystallization is separated out, and drips endpoint pH and reaches 2.0-2.5, stirs growing the grain 1 hour, after the filtering and washing, wet article vacuum-drying obtains ceftizoxime acid;
(4) get the above-mentioned ceftizoxime acid that makes, add purified water, the control aqueous temperature adds inorganic sodium class alkali to solution and clarifies below 25 ℃ under stirring, add gac and stir decolouring, the de-carbon filtration;
(5) feed liquid is behind the degerming membrane filtration, adds to carry out solvent crystal through the organic alcohol of the C1-6 of membrane filtration degerming, when crystal solution occurs little when muddy; Stop adding solvent; Slowly stir growing the grain 0.5 hour, and continued to add remaining solvent, finish back restir growing the grain 1 hour; After the blowing filtering and washing, wet article vacuum-drying obtains aseptic SKF-88373.
2. according to the method for preparing SKF-88373 of claim 1, it is characterized in that said organic solvent I and organic solvent II can select identical or differently, and be selected from: the mixture of one or both in methylene dichloride, the Virahol.
3. according to the method for preparing SKF-88373 of claim 1 or 2, it is characterized in that said organic bases is selected from triethylamine, diethylamine, ammoniacal liquor.
4. according to the method for preparing SKF-88373 of claim 1, it is characterized in that said inorganic sodium class alkali is selected from one or more the mixture in yellow soda ash, sodium hydroxide, sodium phosphate, the sodium acetate.
5. according to the method for preparing SKF-88373 of claim 1 or 4, it is characterized in that the organic alcohol of said C1-6 is selected from methyl alcohol, ethanol, propyl alcohol, Virahol, the mixture of one or more in the propyl carbinol.
6. a method for preparing SKF-88373 is characterized in that may further comprise the steps: methylene dichloride 1000l, purified water 5l, adding 7-amino-3-H-cephem-4-carboxylic acid 100kg; Stirring and dissolving is cooled to-5/5 ℃ and adds organic bases triethylamine 68kg dissolving, adds 2-(2-amino-4-thiazolyl)-2-methoxy imino-acetyl-benzothiazole thioesters 180-200kg; Kept temperature of reaction-5/5 ℃ stirring reaction 5 hours, and added purified water 530l and stir extraction, add methylene dichloride 500l washed twice to aqueous phase; Add 0.01mol/l hydrochloric acid in the aqueous phase liquid, behind the adjust pH 5.5-6.0, aqueous phase adds 303 type gac 5.0kg and aluminium sesquioxide 20.0kg respectively; Stir decolouring 20 minutes, after filtering respectively successively, add dispersion agent medicinal alcohol 350l; Drip 3mol/l aqueous hydrochloric acid to mass crystallization and separate out, drip endpoint pH and reach 2.0-2.5, stirred growing the grain 1 hour; Suction filtration, and after draining with the 400l washing with acetone, wet article vacuum-drying obtains the sour 160-170kg of ceftizoxime; With the above-mentioned ceftizoxime acid 150kg that makes, add purified water 300l, the control aqueous temperature stirs adding inorganic salt sodium acetate 40.0-42.5kg down below 25 ℃; Be stirred to the solution clarification, the pH value adds 767 type gac 4.5kg and stirs decolouring 30 minutes between 9.5-9.8, and de-carbon filters; Feed liquid adds and to carry out solvent crystal through the absolute ethyl alcohol 7000l of membrane filtration degerming behind the degerming membrane filtration, when crystal solution occurs littlely when muddy, stops adding solvent; Slowly stir growing the grain 0.5 hour, and continued to add remaining solvent, finish back restir growing the grain 1 hour; The blowing suction filtration, and after draining with the 1000l washing with acetone, wet article vacuum-drying obtains aseptic SKF-88373 110-130kg.
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Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102329328B (en) * | 2011-07-15 | 2012-09-26 | 海南灵康制药有限公司 | Novel method for purifying ceftizoxime sodium compound |
| CN102702229A (en) * | 2011-08-04 | 2012-10-03 | 重庆天地药业有限责任公司 | Preparation of ceftizoxime sodium key intermediate and preparation of high-content ceftizoxime sodium |
| CN102351883A (en) * | 2011-08-21 | 2012-02-15 | 苏州二叶制药有限公司 | Detection method and production process for ceftizoxime sodium preparation |
| CN102603771A (en) * | 2012-02-23 | 2012-07-25 | 苏州中联化学制药有限公司 | Preparation method of ceftizoxime sodium |
| CN102603772B (en) * | 2012-03-08 | 2014-10-22 | 哈药集团制药总厂 | Method for preparing sterile cefmenoxime hydrochloride compound |
| CN102936254B (en) * | 2012-11-14 | 2014-11-05 | 罗诚 | Drug composition containing ceftizoxime sodium compound |
| CN102977121A (en) * | 2012-12-25 | 2013-03-20 | 菏泽睿智科技开发有限公司 | Synthetic method of ceftizoxime acid |
| CN103910750B (en) * | 2014-04-18 | 2016-05-11 | 悦康药业集团有限公司 | A kind of Ceftizoxime sodium compound |
| CN105622634A (en) * | 2016-03-04 | 2016-06-01 | 中山福运生物科技有限公司 | Method for producing ceftizoxime acid |
| CN105622635B (en) * | 2016-03-10 | 2017-03-15 | 重庆福安药业集团庆余堂制药有限公司 | One kind reduces anaphylactoid ceftizoxime sodium novel crystal form and its preparation |
| CN109553626B (en) * | 2018-12-29 | 2021-02-26 | 山东罗欣药业集团股份有限公司 | Refining method of ceftizoxime sodium |
| CN109503629B (en) * | 2018-12-29 | 2021-02-26 | 山东罗欣药业集团股份有限公司 | Synthesis method of ceftizoxime acid |
| CN111548357B (en) * | 2020-04-16 | 2021-07-13 | 华北制药河北华民药业有限责任公司 | High-purity cefazolin sodium and preparation method of pharmaceutical preparation thereof |
| CN111777625B (en) * | 2020-06-05 | 2021-06-29 | 华北制药河北华民药业有限责任公司 | Preparation method of ceftizoxime sodium for injection |
| CN112321607B (en) * | 2020-12-04 | 2023-05-02 | 苏州盛达药业有限公司 | Method for synthesizing ceftizoxime acid by one-pot method |
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| CN101671348B (en) * | 2009-08-28 | 2011-07-06 | 海南美大制药有限公司 | Ceftizoxime sosium compound of new way |
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Effective date of registration: 20221028 Address after: No. 68, Limin West 4th Street, Limin Development Zone, Harbin, Heilongjiang 150500 Patentee after: HARBIN PHARMACEUTICAL GROUP HOLDING Co.,Ltd. Patentee after: MEDSHINE DISCOVERY Inc. Address before: No.109 Xuefu Road, Nangang District, Harbin, Heilongjiang 150046 Patentee before: MEDSHINE DISCOVERY Inc. |