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The preparation method of clavulanic acid amine salt

A technology of clavulanate amine salt and clavulanic acid, which is applied in the field of preparation of clavulanate amine salt, can solve the problems of deepening the color of the material liquid, consumption of heat source, consumption of cold source, etc., so as to minimize the degree of degradation and improve product quality , the effect of improving product yield

Active Publication Date: 2018-05-01
SHANXI WEIQIDA PHARMA IND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the direct potassium salt method reported in a large number of documents and patents does not need to form clavulanic acid amine salt, and clavulanic acid is directly converted into clavulanic acid alkali metal salt. This method does not have the protective effect of amine molecules due to potassium ions , and lacks the intermediate crystallization and purification process of clavulanic acid amine salt, the formed potassium clavulanate product has low purity, poor quality, instability, and easy inactivation, so the industrialization of the one-step salt formation method is extremely difficult
[0004] At present, there are still some problems in the preparation process of clavulanic acid amine salt. For example, in order to achieve a certain evaporation efficiency in the process of vacuum evaporation and concentration of the extract containing clavulanic acid, the extract needs to be heated, and at the same time, in order to ensure that the system has The high vacuum also requires the use of a cooling system to collect the solvent. This process consumes both heat and cold sources, and the energy consumption is very high. In addition, due to the high local temperature of the evaporator, part of the clavulanic acid in the extract is degraded, not only The content of the related substance E and other impurities in the extraction concentrate increases significantly, which affects the quality of the final product, and the color of the feed liquid is also greatly deepened after concentration under reduced pressure, resulting in the need for decolorization treatment with activated carbon in the subsequent steps, which affects the yield of the final product

Method used

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Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0026] In the preparation of the clavulanic acid amine salt in the step (2), the clavulanic acid extraction concentrate obtained in the above step (1) is mixed with an organic amine donor and a co-solvent to obtain an insoluble clavulanic acid amine salt, which is filtered and drying to obtain clavulanic acid amine salt crystals.

[0027] Wherein, the co-solvent may be alcohol, such as methanol, ethanol, isopropanol or a mixture thereof, preferably methanol. During the mixing process in step (2), the volume ratio of the co-solvent to the clavulanic acid extraction concentrate is greater than or equal to 0.05 and less than or equal to 0.1.

[0028]The organic amine donor may be selected from n-butylamine, tert-butylamine, n-octylamine and tert-octylamine, preferably from tert-butylamine and tert-octylamine, and most preferably tert-butylamine. The organic amine donor is added in the form of a solution in any appropriate solvent system, preferably in the form of a solution in t...

Embodiment 1

[0031] Take 3 L of clavulanic acid aqueous solution (concentration 18.5 mg / mL, pH 5.10), control the temperature at 5 °C, adjust the pH to 1.60 with 25% sulfuric acid, add 19.8 g of ammonium sulfate, and after fully dissolving, add 2 times the volume of ethyl acetate ester, mixed well, and separated the light phase after standing to separate layers to obtain 5.9L of extract containing clavulanic acid (concentration 9.2mg / mL); then use organic solvent-resistant polyimide roll film (2,2 -Bis(3,4-dicarboxylic acid phenyl)hexafluoropropane dianhydride (6FDA), pyromellitic dianhydride (PMDA) and 4,4'-diaminodiphenyl ether (ODA) at a molar ratio of 0.5: 0.5:1 copolymer, the molecular weight cut-off is 600 Daltons) and concentrate the extract by nanofiltration to obtain clavulanic acid extract concentrate 0.82L (concentration 65.2mg / mL, color grade Y2);

[0032] At 5 °C, 41 mL of anhydrous methanol and the above clavulanic acid extract concentrate were added to a crystallization vess...

Embodiment 2

[0034] Take 3 L of clavulanic acid aqueous solution (concentration 19.7 mg / mL, pH 5.19), control the temperature at 5°C, adjust the pH to 1.30 with 25% sulfuric acid, add 19.8 g of ammonium sulfate, and after fully dissolving, add 3 times the volume of ethyl acetate ester, mixed thoroughly, and separated the light phase after standing to separate layers to obtain 8.8L of clavulanic acid extract (concentration 6.5mg / mL); then use an organic solvent-resistant roll film ( S600) Concentrate the extract by nanofiltration to obtain 0.8 L of clavulanic acid extract concentrate (concentration 71.5 mg / mL, color grade Y3);

[0035] At 5 °C, 80 mL of anhydrous methanol and the above clavulanic acid extract concentrate were added to a crystallization vessel, 359 mL of a 1M solution of tert-butylamine in ethyl acetate was added within 60 min, and the mixture was stirred at 5 °C for an additional 60 min. Minutes, the crystals were filtered, washed and dried to obtain white crystals with a ...

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Abstract

The invention belongs to the technical field of pharmacy, and relates to a preparation method of clavulanic acid amine salt. The method comprises the following steps: (1) extraction of a clavulanic acid aqueous solution and concentration of extract liquor: acidizing the clavulanic acid aqueous solution, then adding a salting-out agent, and extracting by an organic solvent, thus obtaining the extract liquor containing clavulanic acid; nano-filtering and concentrating by using an organic solvent-resistant film, thus obtaining a clavulanic acid extraction concentrated solution; (2) preparation of the clavulanic acid amine salt: mixing the clavulanic acid extraction concentrated solution with an organic amine donor and a cosolvent, thus obtaining clavulanic acid amine salt crystals. The salting-out agent is introduced, and the extraction rate of the clavulanic acid is increased; the organic solvent-resistant roll film is innovatively adopted for nano-filtering and concentrating, so the energy consumption is lowered; the addition of the cosolvent can effectively reduce the content of various impurities in a final clavulanic acid amine salt product. Therefore, in the quality parameter aspects of the content, the impurities, light transmittance and the like, the clavulanic acid amine salt prepared by the preparation method is remarkably superior to clavulanic acid amine salt prepared by a conventional process.

Description

technical field [0001] The invention belongs to the technical field of pharmacy, and more specifically relates to a preparation method of clavulanic acid amine salt. Background technique [0002] Clavulanic acid, whose chemical name is (2R,5R,Z)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0]heptane -2-Carboxylic acid is the first β-lactamase inhibitor with clinical value discovered by British Beecham Company from Streptomyces clavulosa in 1976. Its alkali metal salt is relatively stable and can be combined with multiple drug resistance The serine active site of β-lactamase produced by bacteria is irreversibly bound, thereby inhibiting the decomposition of β-lactam antibiotics by bacteria and restoring the resistance of penicillins and cephalosporins to β-lactamase antibacterial activity of bacteria. [0003] The industrial preparation method of clavulanic acid alkali metal salt is divided into three steps: firstly, the mycelium, most of the protein and other solid...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D503/18C07D503/02C07C209/00C07C211/07
CPCC07B2200/13C07D503/02C07D503/18
Inventor 刘君臣张俊波白延峰李树有
Owner SHANXI WEIQIDA PHARMA IND
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