CN108822134A - The preparation method of clavulanic acid tert-butylamine salt - Google Patents
The preparation method of clavulanic acid tert-butylamine salt Download PDFInfo
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- CN108822134A CN108822134A CN201810378902.7A CN201810378902A CN108822134A CN 108822134 A CN108822134 A CN 108822134A CN 201810378902 A CN201810378902 A CN 201810378902A CN 108822134 A CN108822134 A CN 108822134A
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- clavulanic acid
- butylamine salt
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D503/00—Heterocyclic compounds containing 4-oxa-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxapenicillins, clavulanic acid derivatives; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D503/10—Heterocyclic compounds containing 4-oxa-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxapenicillins, clavulanic acid derivatives; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D503/12—Heterocyclic compounds containing 4-oxa-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxapenicillins, clavulanic acid derivatives; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 unsubstituted in position 6
- C07D503/14—Heterocyclic compounds containing 4-oxa-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxapenicillins, clavulanic acid derivatives; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 unsubstituted in position 6 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, other than a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, attached in position 3
- C07D503/16—Radicals substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical
- C07D503/18—Radicals substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical by oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D503/00—Heterocyclic compounds containing 4-oxa-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxapenicillins, clavulanic acid derivatives; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D503/02—Preparation
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Abstract
The present invention relates to a kind of preparation methods of clavulanic acid tert-butylamine salt.The preparation method includes：After the acidified processing of the aqueous solution of clavulanic acid, clavulanic acid is extracted from clavulanic acid aqueous solution using organic solvent unmixing with water, obtains clavulanic acid extract liquor；Later by clavulanic acid extract liquor and organic amine donor tert-butylamine hybrid reaction at salt, stratification collects heavy phase, obtains the clavulanic acid tert-butylamine salt solution of high concentration；Cosolvent is finally added in clavulanic acid tert-butylamine salt solution, and through antisolvent crystallisation, be filtered, washed and dried, clavulanic acid tert-butylamine salt can be obtained.The preparation method of clavulanic acid tert-butylamine salt of the invention, easy to operate, low energy consumption, can reduce preparation cost and product quality is high.
Description
Technical field
The invention belongs to pharmaceutical technology fields, more specifically, are related to a kind of preparation method of clavulanic acid tert-butylamine salt.
Background technique
Potassium clavulanate is current clinical widely used beta-lactamase inhibitor, and clavulanic acid tert-butylamine salt is to most
The quality of synthesis potassium clavulanate product has vital influence eventually.Preparation method generally comprises at present：Utilize rodlike chain
Mold fermentation and prepare clavulanic acid fermentation liquid, then using the methods of sheet frame, ceramic membrane, ultrafiltration membrane remove fermentation liquid in bacterium
Then filament, most of protein and pigment impurity obtain clavulanic acid aqueous solution after nanofiltration membrane or reverse osmosis membrane concentration；Its
It is secondary, it uses extract clavulanic acid from clavulanic acid aqueous solution with the immiscible solvent of water in acid condition, extract liquor is through subtracting
Pressure is concentrated by evaporation film nanofiltration concentration (such as the CN105384758A of (such as method disclosed in CN1185158A) or organic solvent-resistant
Disclosed method) after, it reacts to form stable clavulanic acid tert-butylamine salt with tert-butylamine.
It is had certain problems in above-mentioned preparation process, as the power of enrichment process is evaporated under reduced pressure in clavulanic acid extract liquor
With high costs, evaporator local temperature is excessively high to easily lead to clavulanic acid degradation, and impurity E significantly increases and influences final products matter
Amount；And use the wound membrane nanofiltration of organic solvent-resistant that clavulanic acid extract liquor is concentrated, each of concentration is evaporated under reduced pressure although can be avoided
Kind defect, but since organic solvent-resistant wound membrane is expensive, the producer for being able to produce this film is few, and service life
It is short, therefore the preparation cost of clavulanic acid tert-butylamine salt is not substantially reduced.Therefore work is prepared based on clavulanic acid tert-butylamine salt
Innovation, the optimization of skill still have great importance.
Summary of the invention
Technical problem
Therefore, the purpose of the present invention is to provide it is a kind of it is easy to operate, low energy consumption, can reduce preparation cost and product product
The preparation method of the high clavulanic acid tert-butylamine salt of matter.
Technical solution
In order to achieve the object of the present invention, the technical scheme adopted by the invention is as follows：Using film process known in the art
Clavulanic acid aqueous solution isolated from clavulanic acid fermentation liquid is concentrated in mode, that is, film filtering and film, using unmixing with water
Organic solvent extract clavulanic acid from clavulanic acid aqueous solution, obtain clavulanic acid extract liquor；Clavulanic acid is extracted later
Take liquid and organic amine donor tert-butylamine hybrid reaction at salt, stratification collects heavy phase, obtains the tertiary fourth of clavulanic acid of high concentration
Amine salt solution；Cosolvent is finally added in clavulanic acid tert-butylamine salt solution, and through antisolvent crystallisation, be filtered, washed and do
It is dry, clavulanic acid tert-butylamine salt can be obtained.
According to the present invention, the preparation method of clavulanic acid tert-butylamine salt provided by the invention, includes the following steps：
(1) extraction of clavulanic acid aqueous solution
After the acidified processing of the aqueous solution of clavulanic acid, using organic solvent unmixing with water from clavulanic acid aqueous solution
Middle extraction clavulanic acid, obtains clavulanic acid extract liquor；
(2) synthesis of clavulanic acid tert-butylamine salt
The clavulanic acid extract liquor that above-mentioned steps (1) obtain is mixed with tert-butylamine, stratification simultaneously collects heavy phase；So
Afterwards, water is added in light phase, stirs, stratification simultaneously collects heavy phase, merges heavy phase to get the clavulanic acid tert-butylamine of high concentration
Salting liquid；
(3) crystallization of clavulanic acid tert-butylamine salt
Cosolvent is added in the clavulanic acid tert-butylamine salt solution that above-mentioned steps (2) obtain, it is and anti-molten after stirring and evenly mixing
Agent mixing is filtered, washed and dried drying so that the crystallization of clavulanic acid tert-butylamine salt is precipitated, and it is brilliant to obtain clavulanic acid tert-butylamine salt
Body.
Beneficial effect
In the present invention, the preparation method for innovatively developing a kind of clavulanic acid tert-butylamine salt, with the prior art
Extract liquor disclosed in CN1185158A be evaporated under reduced pressure concentration method compare, avoid power required for decompression, distillation and
Local temperature is excessively high；Compared with the method for the film nanofiltration concentration of the organic solvent-resistant disclosed in the prior art CN105384758A, keep away
The high cost of the film of organic solvent-resistant is exempted from.
In the present invention, first by using the clavulanic acid extract liquor of low concentration is directly translated into amine salt and separates receipts
The mode of collection heavy phase realizes the highly concentrated of clavulanic acid tert-butylamine salt, reduces the degradation of clavulanic acid, improves product
Yield and quality；It secondly, can be effective by the addition of cosolvent and anti-solvent in clavulanic acid tert-butylamine salt crystallization process
Impurity content in final clavulanic acid tert-butylamine salt product is reduced, product quality is improved.Therefore, using prepared by the method for the present invention
The impurity E of clavulanic acid tert-butylamine salt, impurity G, single miscellaneous and total miscellaneous index be significantly lower than the clavulanic acid uncle of common process
Butylamine salt；The product is used for the preparation of alkali metal salt, the alkali metal salt of available high-quality, medication
It is safer.
Specific embodiment
In the following, further illustrating the preparation method of clavulanic acid tert-butylamine salt of the invention.
It, first will be at the aqueous solution acidification of clavulanic acid in the extraction process of the step (1) clavulanic acid aqueous solution
After reason, clavulanic acid is extracted from clavulanic acid aqueous solution using organic solvent unmixing with water, obtains clavulanic acid extraction
Liquid.
In the art, it is concentrated using film process mode known in the art, that is, film filtering and film from clavulanic acid fermentation liquid
In isolated clavulanic acid aqueous solution, wherein the content of clavulanic acid is generally 15.0~20.0mg/mL, preferably 18.0~
20.0mg/mL, pH are generally 5.00~5.20.For example, flux can be selected big ceramic membrane (molecular cut off 10KD~
100KD) and ultrafiltration membrane (molecular cut off 5KD~10KD) is filtered to remove biomass and other solid matters, it is then possible to select
Nanofiltration membrane (molecular cut off 150D~300D) concentrate solution.
The acidification of the clavulanic acid aqueous solution can carry out acidification to it using acid known in the art,
Such as concentration is 15%~30% (v/v) sulfuric acid, the clavulanic acid aqueous solution pH after acidification is generally 1.00~3.00, excellent
Selecting pH is 1.30~1.60.
The organic solvent unmixing with water can be for example selected from methyl acetate, ethyl acetate, propyl acetate, second
One of acid butyl ester is a variety of, the ethyl acetate in these organic solvents.
Extraction process can preferably temperature control at 0~5 DEG C, for example, into the clavulanic acid aqueous solution of acidified processing plus
Enter the one or more of above-mentioned organic solvent, the additional amount of organic solvent is the clavulanic acid aqueous solution of 4~5 times of volumes, sufficiently
It stirs, the isolated extract liquor containing clavulanic acid after stratification.Clavulanic acid potency in extract liquor is generally 3~
4mg/mL。
In the synthesis process of the step (2) clavulanic acid tert-butylamine salt, clavulanic acid that above-mentioned steps (1) are obtained
Extract liquor is mixed with organic amine donor tert-butylamine, and heavy phase is collected after stratification；Then, water is added in light phase, stirs, stands
It is layered and is collected heavy phase, merges heavy phase to get the clavulanic acid tert-butylamine salt solution of high concentration.
The tert-butylamine is configured to solution form addition using the dicyandiamide solution in clavulanic acid extract liquor, and prepares dense
Degree is preferably between 20%~30% (v/v), and the molar ratio of clavulanic acid and tert-butylamine is preferably between in mixed process
1：1.05~1：Between 1.20, the molar ratio of more preferable clavulanic acid and tert-butylamine is preferably between 1：1.10~1：Between 1.15.
Tert-butylamine solution was added rapidly in the clavulanic acid extract liquor in 10~15 minutes, meeting during tert-butylamine stream adds
Generate apparent white opacity thing but dissolution rapidly immediately.This is because the clavulanic acid tert-butylamine salt that reaction generates is extracting
Solubility in dicyandiamide solution is very small, so precipitate crystal, but since clavulanic acid tert-butylamine salt hydrophily is very strong, and
And solubility is very big, therefore it is dissolved in the micro water of extractant system, and then generates subsequent noted phase separation phenomena.
Stratification and collect heavy phase after tert-butylamine stream adds, then using water for example purify water washing light phase once or
Secondary, purified water usage amount is the 0.3%~0.6% of clavulanic acid extract liquor, and stratification simultaneously collects heavy phase, merges heavy phase,
Obtain clavulanic acid tert-butylamine salt solution.Mixing salification process carries out under the conditions of being typically chosen in 0~5 DEG C.In clavulanic acid uncle
The concentration of clavulanic acid is generally 200~300mg/mL in butylamine salting liquid.
In the crystallization process of the step (3) clavulanic acid tert-butylamine salt, in the clavulanic acid that above-mentioned steps (2) obtain
Cosolvent is added in tert-butylamine salt solution, after stirring and evenly mixing, is mixed with anti-solvent, so that the crystallization analysis of clavulanic acid tert-butylamine salt
Out, it is filtered, washed and dried drying, obtains clavulanic acid tert-butylamine salt crystal.
Wherein, the cosolvent can be or mixtures thereof alcohol, such as methanol, ethyl alcohol, isopropanol, preferably methanol.Institute
The additional amount for stating cosolvent is 3%~5% of clavulanic acid total amount in clavulanic acid tert-butylamine salt solution.
The anti-solvent can choose acetone, and additional amount is 15~30 times of clavulanic acid tert-butylamine salt liquor capacity,
It is preferred that 20~25 times, the yield of the clavulanic acid tert-butylamine salt in solution and quality are higher under this condition.
The hybrid mode of the clavulanic acid tert-butylamine salt solution and anti-solvent acetone, which can choose, is slowly added to acetone
Into clavulanic acid tert-butylamine salt solution, also may be selected for clavulanic acid tert-butylamine salt solution to be slowly added into acetone, preferably
Clavulanic acid tert-butylamine salt solution is slowly added into acetone, which can effectively avoid clavulanic acid tert-butylamine salt
The crystallization behavior of wall built-up, the quality and yield of product are all more excellent.It is preferably 60~120 minutes between the stream added-time of anti-solvent acetone,
Or preferably 30~60 minutes between the stream added-time of clavulanic acid tert-butylamine salt solution.For example, can first by cosolvent and gram
Clavulanic acid tert-butylamine salt solution is added in reaction vessel, is uniformly mixed, then by acetone within 60~120 minutes periods
Be added thereto, with the addition of acetone, clavulanic acid tert-butylamine salt crystal is gradually precipitated, stream add finish after growing the grain 60~120
Minute；Acetone can also be added in reaction vessel, then be uniformly mixed cosolvent and clavulanic acid tert-butylamine salt solution
Be slowly added into acetone within 30~60 minutes periods afterwards, stream add finish after growing the grain 60~120 minutes.Step (3)
It is preferred that 0~5 DEG C at a temperature of implement.Isolated clavulanic acid tert-butylamine salt crystal is washed according to methods known in the art
Wash and can be obtained after drying the standard compliant clavulanic acid tert-butylamine salt product of quality.
In the following, further illustrating the present invention by embodiment, but protection scope of the present invention is not limited to these implementations
In example.
Embodiment 1
It takes clavulanic acid aqueous solution 3L (concentration 18.7mg/mL, pH 5.09), 5 DEG C of temperature is controlled, with 25% sulfuric acid tune
PH to 1.45 is saved, 15L ethyl acetate is added, mixes well, light phase 14.70L (clavulanic acid concentration is collected after stratification
3.7mg/mL).Then, the tert-butylamine ethyl acetate that 20% (v/v) is at the uniform velocity added dropwise into clavulanic acid extract liquor in 15min is molten
Liquid 172mL can generate apparent white opacity thing but dissolution rapidly immediately during tert-butylamine stream adds；In tert-butylamine second
Acetate solution stream stands 10min layering after adding, collection obtains heavy phase 164mL；Then add in light phase ethyl acetate phase
Enter 72mL purified water, 10min layering is stood after stirring washing, collection obtains heavy phase 54mL, and merging obtains heavy phase 218mL.
Under the conditions of 5 DEG C, heavy phase mixed liquor 218mL (clavulanic acid concentration 245.7mg/mL) is mixed with 2.68g methanol
After uniformly and be added in 4.36L acetone in 60 minutes, growing the grain filtering crystals after sixty minutes, after washing is dry clavulanic acid
Tert-butylamine salt 67.6g, clavulanic acid content are 72.91%, and impurity E 0.008%, impurity G is 0.006%, and list is miscellaneous to be
0.008%, always miscellaneous is 0.026%, light transmittance 98.6%, clavulanic acid yield 87.9%.
Embodiment 2
Clavulanic acid aqueous solution 3L (concentration 19.1mg/mL, pH 5.14) is taken, 5 DEG C of temperature are controlled, with 25% sulfuric acid tune
PH to 1.49 is saved, 15L ethyl acetate is added, mixes well, light phase 14.67L (clavulanic acid concentration is collected after stratification
3.8mg/mL)。
Then, the tert-butylamine ethyl acetate solution of 20% (v/v) is at the uniform velocity added dropwise into clavulanic acid extract liquor in 15min
169mL can generate apparent white opacity thing but dissolution rapidly immediately during tert-butylamine stream adds；In tert-butylamine acetic acid
Ethyl ester solution stream stands 10min layering after adding, collection obtains heavy phase 160mL；Then it is added in light phase ethyl acetate phase
73mL purified water stands 10min layering after stirring washing, collection obtains heavy phase 55mL, and merging obtains heavy phase 215mL.
Under the conditions of 5 DEG C, heavy phase mixed liquor 215mL (clavulanic acid concentration 255.4mg/mL) is mixed with 2.75g methanol
It is added in 5.38L acetone after uniformly and in 60 minutes, filtering crystals after growing the grain 60min, obtains clavulanic acid after washing is dry
Tert-butylamine salt 70.5g, clavulanic acid content are 72.85%, and impurity E 0.008%, impurity G is 0.007%, and list is miscellaneous to be
0.009%, always miscellaneous is 0.029%, light transmittance 98.2%, clavulanic acid yield 89.6%.
Embodiment 3
It takes clavulanic acid aqueous solution 3L (concentration 18.4mg/mL, pH 5.11), 5 DEG C of temperature is controlled, with 25% sulfuric acid tune
PH to 1.46 is saved, 15L ethyl acetate is added, mixes well, light phase 14.72L (clavulanic acid concentration is collected after stratification
3.7mg/mL)。
Then, the tert-butylamine ethyl acetate solution of 20% (v/v) is at the uniform velocity added dropwise into clavulanic acid extract liquor in 15min
165mL can generate apparent white opacity thing but dissolution rapidly immediately during tert-butylamine stream adds；In tert-butylamine acetic acid
Ethyl ester solution stream stands 10min layering after adding, collection obtains heavy phase 158mL；Then it is added in light phase ethyl acetate phase
72mL purified water stands 10min layering after stirring washing, collection obtains heavy phase 54mL, and merging obtains heavy phase 212mL.
Under the conditions of 5 DEG C, heavy phase mixed liquor 212mL (clavulanic acid concentration 251.9mg/mL) is mixed with 2.67g methanol
It is added in 4.24L acetone after uniformly and in 60 minutes, filtering crystals after growing the grain 60min, obtains clavulanic acid after washing is dry
Tert-butylamine salt 67.0g, clavulanic acid content are 72.90%, and impurity E 0.008%, impurity G is 0.007%, and list is miscellaneous to be
0.008%, always miscellaneous is 0.028%, light transmittance 98.7%, clavulanic acid yield 88.5%.
Claims (10)
1. a kind of preparation method of clavulanic acid tert-butylamine salt, includes the following steps：
(1) extraction of clavulanic acid aqueous solution
After the acidified processing of the aqueous solution of clavulanic acid, extracted from clavulanic acid aqueous solution using organic solvent unmixing with water
Clavulanic acid is taken, clavulanic acid extract liquor is obtained；
(2) synthesis of clavulanic acid tert-butylamine salt
The clavulanic acid extract liquor that above-mentioned steps (1) obtain is mixed with tert-butylamine, stratification simultaneously collects heavy phase；Then, exist
Water is added in light phase, stirs, stratification simultaneously collects heavy phase, and it is molten to get the clavulanic acid tert-butylamine salt of high concentration to merge heavy phase
Liquid；
(3) crystallization of clavulanic acid tert-butylamine salt
Cosolvent is added in the clavulanic acid tert-butylamine salt solution that above-mentioned steps (2) obtain, it is mixed with anti-solvent after stirring and evenly mixing
It closes, so that the crystallization of clavulanic acid tert-butylamine salt is precipitated, is filtered, washed and dried drying, obtains clavulanic acid tert-butylamine salt crystal.
2. the preparation method of clavulanic acid tert-butylamine salt according to claim 1, characterized in that the water of the clavulanic acid
The content of clavulanic acid is 15.0~20.0mg/mL in solution, and pH is 5.00~5.20.
3. the preparation method of clavulanic acid tert-butylamine salt according to claim 1, characterized in that in the step (1) gram
In the extraction process of clavulanic acid aqueous solution, the acidification carries out acidification using sulfuric acid, the carat dimension after acidification
Aqueous acid pH is 1.00~3.00, and preferably pH is 1.30~1.60.
4. the preparation method of clavulanic acid tert-butylamine salt according to claim 1, characterized in that in the step (1) gram
In the extraction process of clavulanic acid aqueous solution, the organic solvent unmixing with water is selected from methyl acetate, ethyl acetate, acetic acid
One of propyl ester and butyl acetate are a variety of；Extraction process temperature control is at 0~5 DEG C, to the clavulanic acid water of acidified processing
The one or more of above-mentioned organic solvent are added in solution, the additional amount of organic solvent is that the clavulanic acid of 4~5 times of volumes is water-soluble
Liquid is sufficiently stirred, the isolated extract liquor containing clavulanic acid after stratification, and the clavulanic acid potency in extract liquor is 3
~4mg/mL.
5. the preparation method of clavulanic acid tert-butylamine salt according to claim 1, characterized in that in the step (2) gram
In the synthesis process of clavulanic acid tert-butylamine salt, the tert-butylamine is configured to solution using the dicyandiamide solution in clavulanic acid extract liquor
Form is added, and the concentration prepared is between 20%~30% (v/v), and clavulanic acid and tert-butylamine in mixed process
Molar ratio is between 1：1.05~1：Between 1.20.
6. the preparation method of clavulanic acid tert-butylamine salt according to claim 1, characterized in that in the step (2) gram
It in the synthesis process of clavulanic acid tert-butylamine salt, is mixed with tert-butylamine in clavulanic acid extract liquor, stratification and after collecting heavy phase,
Primary or secondary using purifying water washing light phase, purified water usage amount is the 0.3%~0.6% of clavulanic acid extract liquor, is stood
It is layered and is collected heavy phase, merges heavy phase, obtains clavulanic acid tert-butylamine salt solution, and in the clavulanic acid tert-butylamine salt solution
The concentration of clavulanic acid is 200~300mg/mL.
7. the preparation method of clavulanic acid tert-butylamine salt according to claim 1, characterized in that in the step (3) gram
In the crystallization process of clavulanic acid tert-butylamine salt, the cosolvent is or mixtures thereof methanol, ethyl alcohol, isopropanol；The cosolvent
Additional amount be clavulanic acid tert-butylamine salt solution in clavulanic acid total amount 3%~5%.
8. the preparation method of clavulanic acid tert-butylamine salt according to claim 1, characterized in that in the step (3) gram
In the crystallization process of clavulanic acid tert-butylamine salt, the anti-solvent is acetone, and additional amount is clavulanic acid tert-butylamine salt solution body
Long-pending 15~30 times.
9. the preparation method of clavulanic acid tert-butylamine salt according to claim 8, characterized in that in the step (3) gram
In the crystallization process of clavulanic acid tert-butylamine salt, 0~5 DEG C at a temperature of, cosolvent and clavulanic acid tert-butylamine salt solution are added
Enter into reaction vessel, is uniformly mixed, was then added thereto acetone within 60~120 minutes periods, with acetone
Be added, clavulanic acid tert-butylamine salt crystal is gradually precipitated, stream adds finish after growing the grain 60~120 minutes.
10. the preparation method of clavulanic acid tert-butylamine salt according to claim 8, characterized in that in the step (3) gram
In the crystallization process of clavulanic acid tert-butylamine salt, 0~5 DEG C at a temperature of, acetone is added in reaction vessel, then will altogether it is molten
Agent and clavulanic acid tert-butylamine salt solution were slowly added into acetone within 30~60 minutes periods after mixing, carat
It ties up sour tert-butylamine salt crystal to be gradually precipitated, growing the grain 60~120 minutes after stream adds and finishes.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0026044A1 (en) * | 1979-08-24 | 1981-04-01 | Beecham Group Plc | Amine salt of clavulanic acid, its preparation and use |
| CN1144528A (en) * | 1994-02-02 | 1997-03-05 | 史密丝克莱恩比彻姆有限公司 | Process for preparation of salt of clavulanic acid |
| CN105384758A (en) * | 2015-12-01 | 2016-03-09 | 国药集团威奇达药业有限公司 | Preparation method of clavulanic acid amine salt |
-
2018
- 2018-04-25 CN CN201810378902.7A patent/CN108822134B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0026044A1 (en) * | 1979-08-24 | 1981-04-01 | Beecham Group Plc | Amine salt of clavulanic acid, its preparation and use |
| CN1144528A (en) * | 1994-02-02 | 1997-03-05 | 史密丝克莱恩比彻姆有限公司 | Process for preparation of salt of clavulanic acid |
| CN105384758A (en) * | 2015-12-01 | 2016-03-09 | 国药集团威奇达药业有限公司 | Preparation method of clavulanic acid amine salt |
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