CN108822134B - Preparation method of clavulanic acid tert-butylamine salt - Google Patents
Preparation method of clavulanic acid tert-butylamine salt Download PDFInfo
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- CN108822134B CN108822134B CN201810378902.7A CN201810378902A CN108822134B CN 108822134 B CN108822134 B CN 108822134B CN 201810378902 A CN201810378902 A CN 201810378902A CN 108822134 B CN108822134 B CN 108822134B
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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
Abstract
The invention relates to a preparation method of clavulanic acid tert-butylamine salt. The preparation method comprises the following steps: after the aqueous solution of the clavulanic acid is acidified, extracting the clavulanic acid from the aqueous solution of the clavulanic acid by using an organic solvent which is immiscible with water to obtain a clavulanic acid extract; mixing the clavulanic acid extract with organic amine donor tert-butylamine, reacting to form a salt, standing for layering, and collecting a heavy phase to obtain a high-concentration clavulanate tert-butylamine salt solution; and finally, adding a cosolvent into the clavulanic acid tert-butylamine salt solution, and crystallizing, filtering, washing and drying the clavulanic acid tert-butylamine salt solution through an anti-solvent to obtain the clavulanic acid tert-butylamine salt. The preparation method of the clavulanic acid tert-butylamine salt is simple and convenient to operate, low in energy consumption, capable of reducing the preparation cost and high in product quality.
Description
Technical Field
The invention belongs to the technical field of pharmacy, and particularly relates to a preparation method of tert-butylamine clavulanate.
Background
Potassium clavulanate is a beta-lactamase inhibitor which is widely used clinically at present, and the clavulanic acid tert-butylamine salt has a crucial influence on the quality of a finally synthesized potassium clavulanate product. The preparation method generally comprises the following steps: preparing clavulanic acid fermentation liquor by utilizing streptomyces clavuligerus fermentation, removing mycelium, most of protein and pigment impurities in the fermentation liquor by using methods such as plate and frame, ceramic membrane, ultrafiltration membrane and the like, and concentrating by using a nanofiltration membrane or reverse osmosis membrane to obtain a clavulanic acid aqueous solution; secondly, clavulanic acid is extracted from an aqueous solution of clavulanic acid under acidic conditions using a water immiscible solvent, and the extract is concentrated by evaporation under reduced pressure (e.g. the method disclosed in CN 1185158A) or by nanofiltration through an organic solvent resistant membrane (e.g. the method disclosed in CN 105384758A) and then reacted with tert-butylamine to form stable tert-butylamine salt of clavulanic acid.
The preparation process has certain problems, such as high power cost of a clavulanic acid extraction liquid reduced pressure evaporation concentration process, easy degradation of the clavulanic acid caused by overhigh local temperature of an evaporator, obvious increase of impurities E and influence on the quality of a final product; the clavulanic acid extract liquid is concentrated by nanofiltration of the rolling membrane resistant to the organic solvent, various defects of reduced pressure evaporation and concentration can be avoided, but the rolling membrane resistant to the organic solvent is expensive, so that a few manufacturers can produce the membrane, and the service cycle is short, so that the preparation cost of the clavulanic acid tert-butylamine salt is not obviously reduced. Therefore, the innovation and optimization of the preparation process based on the clavulanic acid tert-butylamine salt still have important significance.
Disclosure of Invention
Technical problem
Therefore, the invention aims to provide the preparation method of the clavulanic acid tert-butylamine salt, which is simple and convenient to operate, low in energy consumption, capable of reducing the preparation cost and high in product quality.
Technical scheme
In order to realize the purpose of the invention, the technical scheme adopted by the invention is as follows: extracting clavulanic acid from the aqueous clavulanic acid solution by membrane treatment means known in the art, namely membrane filtration and membrane concentration, using a water-immiscible organic solvent to obtain a clavulanic acid extract; mixing the clavulanic acid extract with organic amine donor tert-butylamine, reacting to form a salt, standing for layering, and collecting a heavy phase to obtain a high-concentration clavulanate tert-butylamine salt solution; and finally, adding a cosolvent into the clavulanic acid tert-butylamine salt solution, and crystallizing, filtering, washing and drying the clavulanic acid tert-butylamine salt solution through an anti-solvent to obtain the clavulanic acid tert-butylamine salt.
According to the invention, the preparation method of the tert-butylamine clavulanate provided by the invention comprises the following steps:
(1) extraction of aqueous clavulanic acid
After the aqueous solution of the clavulanic acid is acidified, extracting the clavulanic acid from the aqueous solution of the clavulanic acid by using an organic solvent which is immiscible with water to obtain a clavulanic acid extract;
(2) synthesis of tert-butylamine clavulanate
Mixing the clavulanic acid extract obtained in the step (1) with tert-butylamine, standing for layering and collecting a heavy phase; then, adding water into the light phase, stirring, standing for layering, collecting the heavy phase, and combining the heavy phases to obtain a high-concentration clavulanate tert-butylamine solution;
(3) crystals of tert-butylamine clavulanate
Adding a cosolvent into the clavulanic acid tert-butylamine salt solution obtained in the step (2), uniformly stirring, mixing with an anti-solvent to crystallize and separate out clavulanic acid tert-butylamine salt, and filtering, washing and drying to obtain clavulanic acid tert-butylamine salt crystals.
Advantageous effects
In the invention, a preparation method of the clavulanic acid tert-butylamine salt is innovatively developed, and compared with a method for evaporating and concentrating extract under reduced pressure disclosed in the prior art CN1185158A, the method avoids the power required by reduced pressure and distillation and overhigh local temperature; compared with the method for nanofiltration concentration of the organic solvent resistant membrane disclosed in the prior art CN105384758A, the high cost of the organic solvent resistant membrane is avoided.
In the invention, the high concentration of the clavulanic acid tert-butylamine salt is realized by directly converting the low-concentration clavulanic acid extract into amine salt and separating and collecting heavy phase, thereby reducing the degradation of the clavulanic acid and improving the yield and quality of the product; and secondly, in the process of crystallizing the clavulanic acid tert-butylamine salt, the impurity content in the final clavulanic acid tert-butylamine salt product can be effectively reduced by adding the cosolvent and the anti-solvent, and the product quality is improved. Therefore, the indexes of the impurity E, the impurity G, the single impurity and the total impurity of the clavulanic acid tert-butylamine salt prepared by the method are obviously lower than those of the clavulanic acid tert-butylamine salt prepared by the conventional process; the product is used for preparing the clavulanic acid alkali metal salt, can obtain the high-quality clavulanic acid alkali metal salt, and is safer to use.
Detailed Description
The process for the preparation of the tert-butylamine salt of clavulanic acid according to the invention is described in more detail below.
In the extraction process of the clavulanic acid aqueous solution in the step (1), after the clavulanic acid aqueous solution is firstly acidified, the clavulanic acid is extracted from the clavulanic acid aqueous solution by using the water-immiscible organic solvent, and a clavulanic acid extract is obtained.
In the field, the clavulanic acid aqueous solution is separated from the clavulanic acid fermentation liquor by adopting membrane treatment modes known in the field, namely membrane filtration and membrane concentration, wherein the content of the clavulanic acid is generally 15.0-20.0 mg/mL, preferably 18.0-20.0 mg/mL, and the pH is generally 5.00-5.20. For example, a ceramic membrane (with a molecular weight cut-off of 10 KD-100 KD) and an ultrafiltration membrane (with a molecular weight cut-off of 5 KD-10 KD) with large flux can be selected for filtering and removing biomass and other solid substances, and then a nanofiltration membrane (with a molecular weight cut-off of 150D-300D) can be selected for concentrating the feed liquid.
The acidification treatment of the clavulanic acid aqueous solution can be carried out by using acid known in the field, for example, sulfuric acid with the concentration of 15-30% (v/v), and the pH value of the clavulanic acid aqueous solution after the acidification treatment is generally 1.00-3.00, preferably 1.30-1.60.
The water-immiscible organic solvent may be, for example, one or more selected from methyl acetate, ethyl acetate, propyl acetate, butyl acetate, among which ethyl acetate is preferred.
The temperature in the extraction process can be controlled to be 0-5 ℃, for example, one or more of the organic solvents are added into the acidified clavulanic acid aqueous solution, the addition amount of the organic solvent is 4-5 times of the volume of the clavulanic acid aqueous solution, the clavulanic acid aqueous solution is fully stirred, and the clavulanic acid-containing extract is obtained after standing, layering and separation. The titer of the clavulanic acid in the extract liquid is generally 3-4 mg/mL.
In the synthesis process of the clavulanic acid tert-butylamine salt in the step (2), mixing the clavulanic acid extract obtained in the step (1) with organic amine donor tert-butylamine, standing for layering, and collecting a heavy phase; then, adding water into the light phase, stirring, standing for layering, collecting the heavy phase, and combining the heavy phases to obtain the high-concentration clavulanate tert-butylamine solution.
The tert-butylamine is added in the form of a solution prepared by adopting a solvent system in a clavulanic acid extraction liquid, the prepared concentration is preferably between 20% and 30% (v/v), and the molar ratio of the clavulanic acid to the tert-butylamine in the mixing process is preferably between 1: 1.05-1: 1.20, more preferably the molar ratio of clavulanic acid to t-butylamine is preferably between 1: 1.10-1: 1.15. The tert-butylamine solution is added to the clavulanic acid extract rapidly within 10-15 minutes, and during the tert-butylamine feeding process, a clear white turbidity is generated but then is dissolved rapidly. The reason is that the solubility of the produced clavulanic acid tert-butylamine salt in the extraction solvent system is very small, so crystals are precipitated, but the clavulanic acid tert-butylamine salt is very hydrophilic and very high in solubility, so the clavulanic acid tert-butylamine salt is quickly dissolved in a trace amount of water in the extraction solvent system, and further the subsequent phase separation phenomenon is generated.
Standing for layering and collecting a heavy phase after the tert-butylamine is fed completely, washing the light phase once or twice by using water such as purified water, wherein the using amount of the purified water is 0.3-0.6% of the clavulanic acid extraction liquid, standing for layering and collecting the heavy phase, and combining the heavy phases to obtain the clavulanic acid tert-butylamine salt solution. The mixing and salifying process is generally carried out at 0-5 ℃. The concentration of clavulanic acid in the clavulanic acid tert-butylamine solution is generally 200-300 mg/mL.
In the crystallization process of the clavulanic acid tert-butylamine salt in the step (3), adding a cosolvent into the clavulanic acid tert-butylamine salt solution obtained in the step (2), uniformly stirring, mixing with an anti-solvent to separate out crystals of the clavulanic acid tert-butylamine salt, and filtering, washing and drying to obtain the clavulanic acid tert-butylamine salt crystals.
Wherein the co-solvent may be an alcohol, such as methanol, ethanol, isopropanol or a mixture thereof, preferably methanol. The addition amount of the cosolvent is 3% -5% of the total amount of clavulanic acid in the clavulanic acid tert-butylamine solution.
The anti-solvent can be acetone, the adding amount of the acetone is 15-30 times, preferably 20-25 times of the volume of the clavulanic acid tert-butylamine salt solution, and the yield and the quality of the clavulanic acid tert-butylamine salt in the solution are high under the condition.
The mixing mode of the clavulanic acid tert-butylamine salt solution and the anti-solvent acetone can be that acetone is slowly added into the clavulanic acid tert-butylamine salt solution, also can be that clavulanic acid tert-butylamine salt solution is slowly added into the acetone, and preferably the clavulanic acid tert-butylamine salt solution is slowly added into the acetone. The feeding time of the anti-solvent acetone is preferably 60-120 minutes, or the feeding time of the clavulanic acid tert-butylamine salt solution is preferably 30-60 minutes. For example, the cosolvent and the clavulanate tert-butylamine solution are added into a reaction container, uniformly mixed, then acetone is added into the reaction container within a period of 60-120 minutes, crystals of the clavulanate tert-butylamine salt are gradually separated out along with the addition of the acetone, and the crystals are grown for 60-120 minutes after the feeding is finished; or adding acetone into a reaction container, then uniformly mixing the cosolvent and the clavulanic acid tert-butylamine solution, slowly adding the mixture into the acetone within a period of 30-60 minutes, and growing the crystals for 60-120 minutes after the feeding is finished. The step (3) is preferably carried out at a temperature of 0 to 5 ℃. The separated tert-butylamine clavulanate salt crystal is washed and dried according to the method known in the field, and the tert-butylamine salt of clavulanic acid with the quality meeting the standard can be obtained.
The present invention will be described more specifically with reference to the following examples, but the scope of the present invention is not limited to these examples.
Example 1
Taking 3L of clavulanic acid aqueous solution (the concentration is 18.7mg/mL, the pH is 5.09), controlling the temperature to be 5 ℃, adjusting the pH to be 1.45 by using 25% sulfuric acid, adding 15L of ethyl acetate, fully mixing, standing for layering, and collecting 14.70L of light phase (the concentration of the clavulanic acid is 3.7 mg/mL). Then, 172mL of 20% (v/v) ethyl tert-butylamine acetate solution is uniformly dripped into the clavulanic acid extraction liquid within 15min, and obvious white turbid matters are generated in the process of feeding tert-butylamine but are quickly dissolved; standing for 10min for layering after the tert-butylamine ethyl acetate solution is added, and collecting to obtain 164mL of heavy phase; then 72mL of purified water is added into the light phase ethyl acetate phase, the mixture is stirred and washed with water, and then is kept stand for 10min for layering, 54mL of heavy phase is obtained after collection, and 218mL of heavy phase is obtained after combination.
Under the condition of 5 ℃, 218mL (the concentration of the clavulanic acid is 245.7mg/mL) of heavy phase mixed solution and 2.68G of methanol are uniformly mixed and added into 4.36L of acetone within 60 minutes, crystals are filtered after the crystals are grown for 60 minutes, and 67.6G of tert-butylamine salt of the clavulanic acid is obtained after washing and drying, the content of the clavulanic acid is 72.91%, the content of the impurity E is 0.008%, the content of the impurity G is 0.006%, the content of single impurities is 0.008%, the content of total impurities is 0.026%, the light transmittance is 98.6%, and the yield of the clavulanic acid is 87.9%.
Example 2
Taking 3L of clavulanic acid aqueous solution (the concentration is 19.1mg/mL, the pH is 5.14), controlling the temperature to 5 ℃, adjusting the pH to 1.49 by using 25% sulfuric acid, adding 15L of ethyl acetate, fully mixing, standing for layering, and collecting 14.67L of light phase (the concentration of the clavulanic acid is 3.8 mg/mL).
Then, 169mL of 20% (v/v) ethyl tert-butylamine acetate solution is uniformly dropped into the clavulanic acid extraction liquid within 15min, and obvious white turbid matters are generated in the process of feeding tert-butylamine but are quickly dissolved; standing for 10min for layering after the tert-butylamine ethyl acetate solution is added, and collecting 160mL of heavy phase; then 73mL of purified water is added into the light phase ethyl acetate phase, the mixture is stirred and washed with water, and then is kept stand for 10min for layering, 55mL of heavy phase is obtained after collection, and 215mL of heavy phase is obtained after combination.
Under the condition of 5 ℃, 215mL (the clavulanic acid concentration is 255.4mg/mL) of heavy phase mixed liquid and 2.75G of methanol are uniformly mixed and added into 5.38L of acetone within 60 minutes, crystals are filtered after the crystals are grown for 60 minutes, and 70.5G of clavulanic acid tert-butylamine salt is obtained after washing and drying, the content of the clavulanic acid is 72.85%, the content of the impurity E is 0.008%, the content of the impurity G is 0.007%, the content of single impurity is 0.009%, the content of total impurity is 0.029%, the light transmittance is 98.2%, and the yield of the clavulanic acid is 89.6%.
Example 3
Taking 3L of clavulanic acid aqueous solution (the concentration is 18.4mg/mL, the pH is 5.11), controlling the temperature to be 5 ℃, adjusting the pH to be 1.46 by using 25% sulfuric acid, adding 15L of ethyl acetate, fully mixing, standing for layering, and collecting 14.72L of light phase (the concentration of the clavulanic acid is 3.7 mg/mL).
Then, adding 165mL of 20% (v/v) ethyl tert-butylamine acetate solution dropwise into the clavulanic acid extraction liquid at a constant speed within 15min, wherein obvious white turbid matters are generated in the process of adding tert-butylamine in a flowing manner but are quickly dissolved; standing for 10min for layering after the tert-butylamine ethyl acetate solution is added, and collecting 158mL of heavy phase; then 72mL of purified water is added into the light phase ethyl acetate phase, the mixture is stirred and washed with water, and then is kept stand for 10min for layering, 54mL of heavy phase is obtained after collection, and 212mL of heavy phase is obtained after combination.
Under the condition of 5 ℃, 212mL (clavulanic acid concentration is 251.9mg/mL) of heavy phase mixed solution and 2.67G of methanol are uniformly mixed and added into 4.24L of acetone within 60 minutes, crystals are filtered after the crystals are grown for 60 minutes, and 67.0G of tert-butylamine salt of the clavulanic acid is obtained after washing and drying, the content of the clavulanic acid is 72.90%, the content of the impurity E is 0.008%, the content of the impurity G is 0.007%, the content of single impurity is 0.008%, the content of total impurity is 0.028%, the light transmittance is 98.7%, and the yield of the clavulanic acid is 88.5%.
Claims (5)
1. A preparation method of clavulanic acid tert-butylamine salt comprises the following steps:
(1) extraction of aqueous clavulanic acid
After the aqueous solution of the clavulanic acid is acidified, extracting the clavulanic acid from the aqueous solution of the clavulanic acid by using an organic solvent which is immiscible with water to obtain a clavulanic acid extract;
wherein the content of the clavulanic acid in the clavulanic acid water solution is 15.0-20.0 mg/mL, and the pH value is 5.00-5.20;
the acidification treatment is carried out by adopting sulfuric acid, and the pH value of the clavulanic acid aqueous solution after the acidification treatment is 1.00-3.00;
the water-immiscible organic solvent is ethyl acetate; controlling the temperature in the extraction process at 0-5 ℃, adding ethyl acetate into the acidified clavulanic acid aqueous solution, fully stirring the clavulanic acid aqueous solution with the addition of the ethyl acetate being 4-5 times of the volume of the clavulanic acid aqueous solution, standing for layering, and separating to obtain an extract liquid containing the clavulanic acid, wherein the titer of the clavulanic acid in the extract liquid is 3-4 mg/mL;
(2) synthesis of tert-butylamine clavulanate
Mixing the clavulanic acid extract obtained in the step (1) with tert-butylamine, standing for layering and collecting a heavy phase; then, washing the light phase once or twice by using purified water, wherein the usage amount of the purified water is 0.3-0.6 percent of the clavulanic acid extract, stirring, standing for layering, collecting the heavy phase, and combining the heavy phases to obtain the high-concentration clavulanic acid tert-butylamine solution;
wherein, the tert-butylamine is added in a form of solution prepared by adopting a solvent system in the clavulanic acid extraction liquid, and the prepared concentration is between 20 and 30 percent, and the concentration is calculated by volume percentage;
and the concentration of clavulanic acid in the clavulanic acid tert-butylamine solution is 200-300 mg/mL;
(3) crystals of tert-butylamine clavulanate
Adding a cosolvent into the clavulanic acid tert-butylamine salt solution obtained in the step (2), uniformly stirring, mixing with an antisolvent to crystallize and separate out clavulanic acid tert-butylamine salt, filtering, washing and drying to obtain clavulanic acid tert-butylamine salt crystals,
wherein the co-solvent is methanol, ethanol, isopropanol or a mixture thereof; the addition amount of the cosolvent is 3% -5% of the total amount of the clavulanic acid in the clavulanic acid tert-butylamine solution; the anti-solvent is acetone, and the addition amount of the anti-solvent is 15-30 times of the volume of the clavulanate tert-butylamine salt solution.
2. The method for preparing a tert-butylamine salt of clavulanic acid according to claim 1, wherein in the step (1) of extracting the aqueous solution of clavulanic acid, the pH of the acidified aqueous solution of clavulanic acid is 1.30 to 1.60.
3. The method for preparing the tert-butylamine salt of clavulanic acid according to claim 1, wherein in the synthesis of the tert-butylamine salt of clavulanic acid of step (2), the molar ratio of clavulanic acid to tert-butylamine is between 1: 1.05 and 1: 1.20 during the mixing process.
4. The preparation method of the clavulanic acid tert-butylamine salt according to claim 1, wherein in the step (3) of crystallizing the clavulanic acid tert-butylamine salt, the cosolvent and the clavulanic acid tert-butylamine salt solution are added into a reaction vessel at the temperature of 0-5 ℃, are uniformly mixed, then the acetone is added into the reaction vessel within the time period of 60-120 minutes, with the addition of the acetone, crystals of the clavulanic acid tert-butylamine salt are gradually separated out, and after the feeding is finished, the crystals are crystallized for 60-120 minutes.
5. The preparation method of the clavulanic acid tert-butylamine salt according to claim 1, wherein in the step (3) of crystallizing the clavulanic acid tert-butylamine salt, acetone is added into a reaction vessel at a temperature of 0-5 ℃, then a cosolvent and a clavulanic acid tert-butylamine salt solution are uniformly mixed and then added into the acetone within a period of 30-60 minutes, crystals of the clavulanic acid tert-butylamine salt are gradually precipitated, and the crystals are crystallized for 60-120 minutes after the flow addition is completed.
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| EP0026044B1 (en) * | 1979-08-24 | 1983-06-08 | Beecham Group Plc | Amine salt of clavulanic acid, its preparation and use |
| GB9401969D0 (en) * | 1994-02-02 | 1994-03-30 | Smithkline Beecham Plc | Process |
| 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 |
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