CN100484943C - Novel method for preparing clavulanate - Google Patents
Novel method for preparing clavulanate Download PDFInfo
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- CN100484943C CN100484943C CNB2008100164167A CN200810016416A CN100484943C CN 100484943 C CN100484943 C CN 100484943C CN B2008100164167 A CNB2008100164167 A CN B2008100164167A CN 200810016416 A CN200810016416 A CN 200810016416A CN 100484943 C CN100484943 C CN 100484943C
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- Prior art keywords
- clavulanic acid
- clavulanic
- solvent
- clavulanate
- aqueous solution
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Abstract
The invention relates to biological medicine field and in particular relates to a new method to prepare pharmaceutically acceptable salt from fermentation broth of streptomyces sp. The method directly uses alkali carbonate and bicarbonate to prepare clavulanate potassium or other pharmaceutically acceptable salt without producing intermediate compound clavulanic acid. The invention is simple in process and is suitable for industrial production.
Description
Technical field
The invention belongs to biomedicine field, be specifically related to the novel method of preparation pharmacy acceptable salt from Streptomyces sp. fermented liquid.
Background technology
Clavulanic acid be following formula (Z)-popular name of 3-(2-hydroxy ethylene)-7-oxo-4-oxa--1-azabicyclic [3.2.0] heptane-2-carboxylic acid, structural formula is as follows for 2R, 5R:
Its an alkali metal salt is more stable activated beta-lactamase inhibitor, has only its sylvite listing in the market.Clavulanic Potassium is except the effect that suppresses β-Nei Xiananmei, and it and penicillins and cephalosporin β-Nei Xiananleikangshengsu share also has synergy, can prevent the resistance problem of β-Nei Xiananleikangshengsu.
Because Clavulanic Potassium to thermally labile, adopts conventional extraction process can make the Clavulanic Potassium inactivation.Known clavulanic acid an alkali metal salt manufacture method was divided into for three steps: at first remove mycelium in the fermented liquid, most of protein, other solid particulate with methods such as centrifugal, filtrations, obtain the aqueous solution of clavulanic acid; Second step formed the intermediate amine salt of stable clavulanic acid with primary amine, secondary amine or tertiary amine; The 3rd step was changed the intermediate amine salt into needed an alkali metal salt.This approach need use organic amine, form the clavulanic acid amine salt, but these organic amines is all toxic and volatility, simultaneously this technology more complicated.
In patent WO95/34194 patent, narrated a kind of solution that the alkyl acid an alkali metal salt is dissolved in ketone or the alkyl alcohol solvent and joined in the clavulanic acid acetic acid ethyl acetate extract,, directly prepared the method for clavulanic acid sylvite without the amine salt intermediate.But this method uses the ketone or the alcoholic solution of alkyl acid an alkali metal salt directly to add in the ethyl acetate, can cause two or more organic solvents to mix, and has increased the difficulty of solvent recuperation.
Summary of the invention
The present inventor successfully finds the intermediate that it(?) can not need form clavulanic acid by lot of experiments, and directly prepares the novel method of Clavulanic Potassium or pharmaceutically acceptable other salt with alkaline carbonate or supercarbonate.
The inventor finds, K
2CO
3And KHCO
3The clavulanic acid reaction that can be used as in salt forming agent and the organic solvent generates Clavulanic Potassium, and transfers in the aqueous solution.K
2CO
3Or KHCO
3Consumption and the mol ratio of clavulanic acid amount be 1.0～1.2, can be with K
2CO
3Or KHCO
3Be mixed with concentration and be 30～60% the aqueous solution, slowly stream adds then, and vigorous stirring, guarantees and fully the contacting of clavulanic acid, and adds the carrying out of fast response.Temperature of reaction is preferably carried out between 0～5 ℃, and in order to obtain better result, clavulanic acid should contain 200mg/ml at least in the preceding aqueous solution of crystallization, preferably is higher than 400mg/ml.
Can select corresponding salt forming agent such as Na when in like manner, preparing clavulanic acid sodium, clavulanic acid lithium
2CO
3, NaHCO
3Or Li
2CO
3
The clavulanic acid aqueous solutions of potassium is collected through standing demix or centrifugal mode, adds the alcoholic solvent or the ketones solvent of 30 times of volumes, stirs 2 hours.Temperature of reaction is preferably carried out between 0～5 ℃.Filter with filtration unit, use washing with acetone again, collect crystal with vacuum drier about 2 hours of 30 ℃ of dryings, can obtain Clavulanic Potassium.
Be used for the crystalline alcoholic solvent and can select Virahol and propyl carbinol; Ketones solvent can be selected acetone.Wherein Virahol is a preferred solvent.
The present invention compared with prior art has following obvious improvement:
1. process for purification provided by the invention, by in the organic extracting solution of clavulanic acid, adding the aqueous solution of carbonate or supercarbonate, thereby clavulanic acid is formed sylvite transfer to aqueous phase from organic solvent, this has been avoided multiple organic solvent to mix and the solvent recuperation difficult problem brought to a great extent.
2. because Clavulanic Potassium is very easily water-soluble, can reduce aqueous solution volume by improving the strength of solution of clavulanic acid an alkali metal salt before the crystallization, reduce the consumption of alcohols or organic solvent of ketone, thereby reduce the consumption of organic solvent, for industrial production has been saved cost.
3. utilize the product of method provided by the invention preparation, through 3 months accelerated test, and light, humidity, High-Temperature Strengthening condition test, find that product stability is good.
4. use preparation technology provided by the invention, can make the yield of Clavulanate bring up to 82%, than the yield of prior art (WO95/34194) 74%, the present invention has obvious improvement.
5. that process for refining of the present invention has is easy and simple to handle, the cycle is short, yield is high, can improve the stability of heat-sensitive substance, reduces energy consumption.The process for refining that the present invention relates to is applicable to suitability for industrialized production.
Embodiment
Embodiment 1
The acetic acid ethyl acetate extract of clavulanic acid is through dehydration, decolouring.K
2CO
3(1.0 equivalent) is dissolved in the pure water, is made into 60% solution (m/v), slowly joins in the said extracted liquid, and mixture stirred standing demix 45 minutes at 5 ℃.Collection contains the water-soluble liquid phase of clavulanic acid, slowly adds the Virahol of 30 times of volumes, and mixture stirred 120 minutes at 5 ℃.Crystallized product filters, and uses the washing with acetone crystal.Crystal in vacuum drier (30 ℃) dry about 2 hours obtains 240g Clavulanic Potassium (yield 78%).
Embodiment 2
The methyl acetate extracting solution of clavulanic acid is through dehydration, decolouring.KHCO3 (1.1 equivalent) is dissolved in the pure water, is made into 30% solution (m/v), slowly adds said extracted liquid, and mixture stirred standing demix 45 minutes at 5 ℃.Collect water, contain the aqueous solution of clavulanic acid, slowly add the Virahol of 30 times of volumes, mixture stirred 120 minutes at 5 ℃.Crystallized product filters, and uses the washing with acetone crystal.Crystal in vacuum drier (30 ℃) dry about 2 hours obtains 218g Clavulanic Potassium (yield 71%).
Embodiment 3
The methyl ethyl ketone extracting solution of clavulanic acid is through dehydration, decolouring.K
2CO3 (1.2 equivalent) is dissolved in the pure water, is made into 50% solution (m/v), slowly adds said extracted liquid, and mixture stirred standing demix 45 minutes at 5 ℃.Collect water, contain the aqueous solution of clavulanic acid, slowly add the Virahol of 35 times of volumes, mixture stirred 120 minutes at 5 ℃.Crystallized product filters, and uses the washing with acetone crystal.Crystal in vacuum drier (30 ℃) dry about 2 hours obtains 250g Clavulanic Potassium (yield 82%).
Claims (7)
1. method for preparing Clavulanate, this method comprises the reaction of clavulanic acid and alkaline carbonate or supercarbonate, generates Clavulanate and separates, and adds alcoholic solvent or ketones solvent crystallization then, collects crystal;
Described alkaline carbonate or supercarbonate are K
2CO
3Or KHCO
3
Described alkaline carbonate or supercarbonate are its aqueous solution, and concentration is 30～60%.
2. the method for claim 1 is characterized in that, described K
2CO
3Or KHCO
3Consumption and the mol ratio of clavulanic acid amount be 1.0～1.2.
3. the method for claim 1 is characterized in that, the temperature of reaction of clavulanic acid and alkaline carbonate or supercarbonate is controlled between 0～5 ℃.
4. the method for claim 1 is characterized in that, the clavulanic acid potassium content is controlled at more than the 200mg/ml in the preceding aqueous solution of crystallization.
5. the method for claim 1 is characterized in that, the clavulanic acid potassium content is controlled at more than the 400mg/ml in the preceding aqueous solution of crystallization.
6. the method for claim 1 is characterized in that, adds the alcoholic solvent or the ketones solvent of 30 times of volumes during crystallization, stirs 2 hours, and temperature of reaction is between 0～5 ℃.
7. method as claimed in claim 6 is characterized in that, described alcoholic solvent is Virahol and propyl carbinol, and ketones solvent is an acetone.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2008100164167A CN100484943C (en) | 2008-05-29 | 2008-05-29 | Novel method for preparing clavulanate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2008100164167A CN100484943C (en) | 2008-05-29 | 2008-05-29 | Novel method for preparing clavulanate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101279982A CN101279982A (en) | 2008-10-08 |
| CN100484943C true CN100484943C (en) | 2009-05-06 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2008100164167A Active CN100484943C (en) | 2008-05-29 | 2008-05-29 | Novel method for preparing clavulanate |
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Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105030769A (en) * | 2015-05-28 | 2015-11-11 | 浙江长典医药有限公司 | Child type amoxicillin and clavulanate potassium and low-sodium carrier pharmaceutical composition |
| CN105384758B (en) * | 2015-12-01 | 2018-05-01 | 国药集团威奇达药业有限公司 | The preparation method of clavulanic acid amine salt |
-
2008
- 2008-05-29 CN CNB2008100164167A patent/CN100484943C/en active Active
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| CN101279982A (en) | 2008-10-08 |
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| EE01 | Entry into force of recordation of patent licensing contract |
Assignee: Shandong Xinshidai Pharmaceutical Industry Co., Ltd. Assignor: Lunan Pharmaceutical Group Co., Ltd. Contract record no.: 2010370000510 Denomination of invention: Novel method for preparing clavulanate Granted publication date: 20090506 License type: Exclusive License Open date: 20081008 Record date: 20100908 |
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| EC01 | Cancellation of recordation of patent licensing contract |
Assignee: Shandong Xinshidai Pharmaceutical Industry Co., Ltd. Assignor: Lunan Pharmaceutical Group Co., Ltd. Contract record no.: 2010370000510 Date of cancellation: 20121226 |
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Application publication date: 20081008 Assignee: Shandong Xinshidai Pharmaceutical Industry Co., Ltd. Assignor: Lunan Pharmaceutical Group Co., Ltd. Contract record no.: 2013370000264 Denomination of invention: Novel method for preparing clavulanate Granted publication date: 20090506 License type: Exclusive License Record date: 20131210 |
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| LICC | Enforcement, change and cancellation of record of contracts on the licence for exploitation of a patent or utility model |