Preparation method of clavulanic acid tert-butylamine salt

Abstract

The invention relates to a preparation method of a clavulanic acid tert-butylamine salt. The preparation method comprises the steps: acidifying a water solution of clavulanic acid, and then, extracting clavulanic acid from the water solution of clavulanic acid by using an organic solvent unmixed with water to obtain a clavulanic acid extracting solution; then, carrying out a mixed reaction on theclavulanic acid extracting solution and tert-butylamine serving as an organic amine donor to form a salt, carrying out standing for layering, and collecting a heavy phase to obtain a clavulanic acid tert-butylamine salt solution with high concentration; and finally, adding a cosolvent into the clavulanic acid tert-butylamine salt solution, and carrying out anti-solvent crystallization, filtration,washing and drying to obtain the clavulanic acid tert-butylamine salt. The preparation method of the clavulanic acid tert-butylamine salt disclosed by the invention is simple and convenient to operate, low in energy consumption and capable of reducing the preparation cost, and the quality of a product is high.

Description

technical field

[0001] The invention belongs to the technical field of pharmacy, and more specifically relates to a preparation method of clavulanic acid tert-butylamine salt. Background technique

[0002] Potassium clavulanate is a β-lactamase inhibitor widely used clinically, and tert-butylamine clavulanate has a crucial influence on the quality of the final synthetic potassium clavulanate product. At present, its preparation method generally includes: using Streptomyces clavulanic acid fermentation to prepare clavulanic acid fermentation liquid, and then using plate frame, ceramic membrane, ultrafiltration membrane and other methods to remove mycelium, most of the protein and pigment impurities in the fermentation liquid, and then Obtain clavulanic acid aqueous solution after nanofiltration membrane or reverse osmosis membrane concentration; Secondly, use under acidic conditions and water-immiscible solvent to extract clavulanic acid from clavulanic acid aqueous solution,...

Examples

Embodiment 1

[0033] Take 3L clavulanic acid aqueous solution (concentration 18.7mg / mL, pH 5.09), control the temperature at 5°C, adjust the pH to 1.45 with 25% sulfuric acid, add 15L ethyl acetate, mix well, and collect after standing and separating Light phase 14.70L (clavulanic acid concentration 3.7mg / mL). Then, 172mL of ethyl tert-butylamine acetate solution of 20% (v / v) was added dropwise at a uniform speed in the clavulanic acid extract within 15min, and obvious white turbidity would be produced in the process of tert-butylamine flowing but dissolved immediately; in tert-butylamine After the addition of the ethyl acetate solution, let stand for 10 minutes to separate the layers, collect and obtain 164 mL of the heavy phase; then add 72 mL of purified water to the light phase of the ethyl acetate phase, stir and wash with water, then stand for 10 minutes to separate the layers, collect and obtain 54 mL of the heavy phase, combine 218 mL of the heavy phase was obtained.

[0034] At 5°C,...

Embodiment 2

[0036] Take 3L clavulanic acid aqueous solution (concentration 19.1mg / mL, pH 5.14), control the temperature at 5°C, adjust the pH to 1.49 with 25% sulfuric acid, add 15L ethyl acetate, mix well, and collect after standing and separating Light phase 14.67L (clavulanic acid concentration 3.8mg / mL).

[0037] Then, 169mL of ethyl tert-butylamine acetate solution of 20% (v / v) was added dropwise at a uniform speed in the clavulanic acid extract within 15min, and obvious white turbidity would be produced in the process of tert-butylamine flowing but dissolved immediately; in tert-butylamine After the addition of the ethyl acetate solution, let stand for 10 minutes to separate the layers, collect and obtain 160 mL of the heavy phase; then add 73 mL of purified water to the light phase of the ethyl acetate phase, stir and wash with water and let stand for 10 minutes to separate the layers, collect and obtain 55 mL of the heavy phase, combine 215 mL of the heavy phase was obtained.

[...

Embodiment 3

[0040] Take 3L clavulanic acid aqueous solution (concentration 18.4mg / mL, pH 5.11), control the temperature at 5°C, adjust the pH to 1.46 with 25% sulfuric acid, add 15L ethyl acetate, mix well, and collect after standing and separating Light phase 14.72L (clavulanic acid concentration 3.7mg / mL).

[0041] Then, 165mL of ethyl tert-butylamine acetate solution of 20% (v / v) was added dropwise at a uniform speed in the clavulanic acid extract within 15min, and obvious white turbidity would be produced in the process of tert-butylamine flowing but dissolved immediately; in tert-butylamine After the addition of the ethyl acetate solution, let stand for 10 minutes to separate layers, collect and obtain 158 mL of the heavy phase; then add 72 mL of purified water to the light phase of ethyl acetate, stir and wash with water, then stand for 10 minutes to separate the layers, collect and obtain 54 mL of the heavy phase, combine 212 mL of the heavy phase was obtained.

[0042] At 5°C, mi...

technical field

[0001] The invention belongs to the technical field of pharmacy, and more specifically relates to a preparation method of clavulanic acid tert-butylamine salt. Background technique

[0002] Potassium clavulanate is a β-lactamase inhibitor widely used clinically, and tert-butylamine clavulanate has a crucial influence on the quality of the final synthetic potassium clavulanate product. At present, its preparation method generally includes: using Streptomyces clavulanic acid fermentation to prepare clavulanic acid fermentation liquid, and then using plate frame, ceramic membrane, ultrafiltration membrane and other methods to remove mycelium, most of the protein and pigment impurities in the fermentation liquid, and then Obtain clavulanic acid aqueous solution after nanofiltration membrane or reverse osmosis membrane concentration; Secondly, use under acidic conditions and water-immiscible solvent to extract clavulanic acid from clavulanic acid aqueous solution,...

Examples

Embodiment 1

[0033] Take 3L clavulanic acid aqueous solution (concentration 18.7mg / mL, pH 5.09), control the temperature at 5°C, adjust the pH to 1.45 with 25% sulfuric acid, add 15L ethyl acetate, mix well, and collect after standing and separating Light phase 14.70L (clavulanic acid concentration 3.7mg / mL). Then, 172mL of ethyl tert-butylamine acetate solution of 20% (v / v) was added dropwise at a uniform speed in the clavulanic acid extract within 15min, and obvious white turbidity would be produced in the process of tert-butylamine flowing but dissolved immediately; in tert-butylamine After the addition of the ethyl acetate solution, let stand for 10 minutes to separate the layers, collect and obtain 164 mL of the heavy phase; then add 72 mL of purified water to the light phase of the ethyl acetate phase, stir and wash with water, then stand for 10 minutes to separate the layers, collect and obtain 54 mL of the heavy phase, combine 218 mL of the heavy phase was obtained.

[0034] At 5°C,...

Embodiment 2

[0036] Take 3L clavulanic acid aqueous solution (concentration 19.1mg / mL, pH 5.14), control the temperature at 5°C, adjust the pH to 1.49 with 25% sulfuric acid, add 15L ethyl acetate, mix well, and collect after standing and separating Light phase 14.67L (clavulanic acid concentration 3.8mg / mL).

[0037] Then, 169mL of ethyl tert-butylamine acetate solution of 20% (v / v) was added dropwise at a uniform speed in the clavulanic acid extract within 15min, and obvious white turbidity would be produced in the process of tert-butylamine flowing but dissolved immediately; in tert-butylamine After the addition of the ethyl acetate solution, let stand for 10 minutes to separate the layers, collect and obtain 160 mL of the heavy phase; then add 73 mL of purified water to the light phase of the ethyl acetate phase, stir and wash with water and let stand for 10 minutes to separate the layers, collect and obtain 55 mL of the heavy phase, combine 215 mL of the heavy phase was obtained.

[...

Embodiment 3

[0040] Take 3L clavulanic acid aqueous solution (concentration 18.4mg / mL, pH 5.11), control the temperature at 5°C, adjust the pH to 1.46 with 25% sulfuric acid, add 15L ethyl acetate, mix well, and collect after standing and separating Light phase 14.72L (clavulanic acid concentration 3.7mg / mL).

[0041] Then, 165mL of ethyl tert-butylamine acetate solution of 20% (v / v) was added dropwise at a uniform speed in the clavulanic acid extract within 15min, and obvious white turbidity would be produced in the process of tert-butylamine flowing but dissolved immediately; in tert-butylamine After the addition of the ethyl acetate solution, let stand for 10 minutes to separate layers, collect and obtain 158 mL of the heavy phase; then add 72 mL of purified water to the light phase of ethyl acetate, stir and wash with water, then stand for 10 minutes to separate the layers, collect and obtain 54 mL of the heavy phase, combine 212 mL of the heavy phase was obtained.

[0042] At 5°C, mi...