Method for refining cefoperazone sodium by one step

Abstract

This invention belongs to the field of pharmaceutical synthesis technology, specifically relating to a one-step method for purifying latamoxef sodium. The method includes the following steps: dissolving crude latamoxef sodium in a mixture of ethyl acetate and purified water as a solvent; then adding acid to the crude latamoxef sodium solution for acidification, followed by multiple extractions, dehydration and decolorization, and finally crystallization using a sodium carboxylate solution to obtain the purified latamoxef sodium. This method has advantages such as simple operation, short reaction time, readily available and simple solvents and equipment, and high product purity and yield. It can effectively control impurity content and is of great significance for improving the quality and safety of latamoxef sodium.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis technology, specifically relating to a one-step method for purifying latamoxef sodium. Background Technology

[0002] Latamoxef sodium is a novel semi-synthetic β-lactam broad-spectrum antibiotic, with the structural formula shown in Formula I. Latamoxef sodium is extremely stable against β-lactam enzymes and exhibits potent antibacterial activity against Gram-positive bacteria and anhydrous bacteria. Its mechanism of action involves binding to target proteins on the cell membrane, preventing bacteria from maintaining normal morphology and reproduction, ultimately leading to lysis and death. Clinically, latamoxef sodium is primarily used to treat meningitis, bacteremia, and infections of the respiratory tract, urinary tract, skin and soft tissues, intra-abdominal and endometrial tissues, as well as other gynecological infections caused by susceptible bacteria.

[0003]

[0004] Due to the numerous processing steps involved in the synthesis of latamoxef sodium, the intermediate products exhibit extremely poor stability, making it prone to impurities during production. Therefore, the purification step of crude latamoxef sodium is crucial in its synthesis. Extensive research has been conducted in this field on the purification of latamoxef sodium. For example, invention patent GB2153823A discloses a method using resin column treatment to purify latamoxef sodium. However, the recovery rate using resin treatment in this invention is unstable, sometimes as low as around 70%, and most individual impurities after resin treatment are difficult to reduce below 0.1%. Furthermore, the low concentration of the raw material when using resin column treatment makes subsequent concentration and freeze-drying more difficult, and the prolonged operation time can lead to larger impurities and potentially the formation of new impurities.

[0005] Patent CN101857601B discloses a purification method for latamoxef sodium, comprising reacting impure latamoxef sodium with acid to adjust the pH to 2-2.5, producing insoluble latamoxef, filtering and drying, dissolving the latamoxef in solvents such as ether, adding activated carbon for adsorption purification, stirring at room temperature for 20-30 minutes, filtering to remove carbon, and then adding sodium hydroxide and the purified latamoxef to react and adjust the pH to 8-10 to generate latamoxef sodium. However, this purification method requires two solid precipitation and drying processes, resulting in high crystallization loss and some product remaining in the solvent, leading to a reduced product yield; furthermore, the purification process is carried out in two steps, with multiple centrifugation and drying processes increasing the difficulty and time required for operation; and the subsequent adjustment of alkali with sodium hydroxide will damage the product and reduce the purity of latamoxef sodium.

[0006] Chinese patent application CN102260280A discloses a method for preparing latamoxef sodium. This invention involves eluting latamoxefic acid sequentially with HP-20 adsorption resin, purified water, and methanol to obtain purified latamoxefic acid. Latamoxefic acid is reacted with sodium carboxylate to obtain latamoxef sodium. To meet clinical drug standards, crude latamoxef sodium is prepared as a 0.11%–0.19% dilute solution and passed through an adsorption resin. It is then purified by elution with a methanol / water or acetone / water mixture. The eluent is concentrated under reduced pressure, neutralized with sodium hydroxide, and then freeze-dried to obtain purified latamoxef sodium. However, this method has several drawbacks: 1) To obtain high-purity latamoxefic acid, desalting purification using adsorption resin is required; 2) To remove the eluent methanol (or acetone) and water, not only is low-temperature vacuum distillation necessary to recover methanol or acetone, but also membrane concentration is required to remove water to reduce the degradation of latamoxefic acid, which increases both the processing steps and equipment investment; 3) When latamoxefic acid is neutralized with sodium hydroxide in the aqueous phase to obtain latamoxef sodium, the alkali will damage latamoxef, reducing the purity of latamoxef sodium. Furthermore, latamoxef sodium is hygroscopic, which will affect the quality of the latamoxef sodium product.

[0007] Therefore, there is an urgent need to find new purification methods for latamoxef sodium in order to obtain latamoxef sodium with higher purity and better quality. Summary of the Invention

[0008] In view of this, one of the objectives of the present invention is to provide a one-step method for refining latamoxef sodium. The present invention achieves the refining and purification of latamoxef sodium by adding acid to the latamoxef sodium solution, followed by acid reabsorption, decolorization and crystallization after multiple extractions, thereby realizing the refining and purification of latamoxef sodium in a convenient and simple manner, and completing all refining operations in one step.

[0009] To achieve the above objectives, the present invention adopts the following technical solution:

[0010] A one-step method for refining latamoxef sodium involves sequentially dissolving crude latamoxef sodium, adding acid for acidification, extraction, dehydration, decolorization, and crystallization to obtain refined latamoxef sodium.

[0011] Furthermore, the method includes the following steps:

[0012] (1) Adding acid to cause acid backflow: After dissolving crude cefazolin sodium, add acid to dissolve it, let it stand and separate the liquid to obtain the lower aqueous phase and the upper organic phase;

[0013] (2) Extraction: The mixture of butanone and ethyl acetate was used as the extraction solution, and sodium chloride aqueous solution was used as the washing solution; the lower aqueous phase obtained in step (1) was extracted once, and the upper organic phase obtained in step (1) was washed twice and the resulting aqueous phase was extracted once each; finally, the organic phases were combined.

[0014] (3) The organic phase obtained in step (2) is dehydrated and decolorized, and sodium carboxylate solution is added for crystallization to obtain refined ceftriaxone sodium.

[0015] Furthermore, in step (1), the dissolution temperature is 5-10°C; the solvent is a mixture of ethyl acetate and purified water, wherein the volume ratio of ethyl acetate to purified water is 2-3:1, more preferably 9:4.

[0016] Furthermore, in step (1), the mass-to-volume ratio of crude cefoperazone sodium to solvent is 1g:10-20mL, preferably 1g:13mL.

[0017] Furthermore, in step (1), acid is added to adjust the pH to 1-2; the acid includes organic acids and / or inorganic acids.

[0018] Preferably, in step (1), the acid is hydrochloric acid; more preferably, it is hydrochloric acid with a concentration of 6.6%.

[0019] Furthermore, step (2) specifically includes:

[0020] 1) Take the lower aqueous phase obtained in step (1), add the extract, stir and let stand to separate the liquid, and retain the organic phase;

[0021] 2) Take the upper organic phase obtained in step (1), add the washing solution, stir and let stand to separate the liquid to obtain the aqueous phase and the organic phase;

[0022] 3) Add the aqueous phase obtained in step 2) to the organic phase obtained in step 1), stir, let stand, and separate the liquids, retaining the organic phase;

[0023] 4) Repeat steps 2) to 3) and combine the organic phases.

[0024] Furthermore, in the extract, the volume ratio of butanone to ethyl acetate is 1:1-10, more preferably 1:2.

[0025] Furthermore, the washing solution is preferably a sodium chloride aqueous solution with a concentration of 0.15%.

[0026] Furthermore, in step (3), the dehydrating agent is anhydrous sodium sulfate.

[0027] Furthermore, in step (3), the decolorization process includes decolorization using activated carbon; in the decolorization process, the rinsing solution is a mixture of butanone and ethyl acetate, wherein the volume ratio of butanone to ethyl acetate is 1:1-5, preferably 1:1.5.

[0028] Furthermore, in step (3), the sodium carboxylate solution includes any one or more of sodium isooctanoate solution and sodium hydroxide solution.

[0029] Preferably, the sodium carboxylate solution is a sodium isooctanoate solution.

[0030] Furthermore, the crystallization process includes: adding sodium carboxylate solution, culturing crystals for 1-5 hours, filtering, and drying at 25-50°C to obtain refined cefoperazone sodium.

[0031] Preferably, the crystal growth time is 1.5-3 hours; the drying temperature is 30-40℃.

[0032] As a preferred embodiment, the method includes the following steps:

[0033] (1) A mixture of ethyl acetate and purified water was used as a solvent to dissolve crude cefazolin sodium; hydrochloric acid was added to dissolve the solution, and the mixture was allowed to stand and separated to obtain a lower aqueous phase A and an upper organic phase A.

[0034] (2) Take the lower aqueous phase obtained in step (1) and add a mixture of butanone and ethyl acetate. Stir, let stand, and separate the liquid to obtain the upper organic phase B.

[0035] (3) Take the upper organic phase A obtained in step (1), add sodium chloride aqueous solution, stir and let stand to separate the liquid to obtain the lower aqueous phase C and the upper organic phase C.

[0036] (4) Add the lower aqueous phase C obtained in step (3) to the organic phase B obtained in step (2), stir, let stand and separate the liquid to obtain the upper organic phase D;

[0037] (5) Repeat steps (3) to (4) to combine the organic phases;

[0038] (6) After dehydrating and decolorizing the organic phase combined in step (5), sodium carboxylate solution is added to crystallize the product to obtain purified ceftriaxone sodium.

[0039] The beneficial effects of this invention are as follows:

[0040] 1. This invention achieves the purification of latamoxef sodium by adding acid to a latamoxef sodium solution, followed by repeated extraction, dehydration, decolorization, and crystallization. Compared to known latamoxef sodium purification methods, this process is simpler to operate, has a shorter reaction time, requires readily available solvents and equipment, and completes all purification operations in one step without using other complex operations or forming intermediate products.

[0041] 2. Existing methods for purifying latamoxef sodium can affect the purity of some degradation impurities after purification. This process effectively controls impurity generation, achieving an HPLC purity of 99.5% and a molar yield of 94% after purification. Purification using this invention maximizes the retention yield, resulting in latamoxef sodium with fewer impurities and higher purity, thus optimizing product quality and ensuring medication safety. Detailed Implementation

[0042] The technical solution of the present invention will be described more clearly and completely below with reference to specific embodiments. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of them. Therefore, based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the protection scope of the present invention.

[0043] Example 1

[0044] (1) Add 450 mL of ethyl acetate and 200 mL of purified water to a 1000 mL three-necked flask, control the temperature to 10 °C, add 50 g of crude cefoperazone sodium, add 6.6% hydrochloric acid dropwise until pH = 2, and let stand to separate the contents.

[0045] (2) Add 50 mL of butanone and 100 mL of ethyl acetate mixture to the lower aqueous phase, stir and let stand to separate the layers.

[0046] (3) Add 200 mL of 0.15% sodium chloride solution to the organic phase in step (1), stir and let stand to separate the liquid.

[0047] (4) The lower aqueous phase is separated into the organic phase of step (2), stirred and allowed to stand for separation.

[0048] (5) Repeat steps (3) to (4) to combine the organic phases.

[0049] (6) Add 40g of anhydrous magnesium sulfate to dehydrate for 30min, filter and rinse with a mixture of 20mL butanone and 30mL ethyl acetate, and store the wash water temporarily.

[0050] (7) After dehydration, the liquid obtained in step (6) is decolorized with 5g of activated carbon for 30min, filtered, and the activated carbon is washed with the wash water from step (6). The wash water is then combined with the organic phase.

[0051] (8) 100 mL of 5% sodium hydroxide solution was added dropwise to the organic phase to induce crystallization. After crystallization for 3 hours, the mixture was filtered and dried at 40 °C to obtain 32.33 g of purified ceftriaxone sodium, with a molar yield of approximately 92.43% and an HPLC purity of 99.1%.

[0052] Example 2

[0053] (1) Add 450 mL of ethyl acetate and 200 mL of purified water to a 1000 mL three-necked flask, control the temperature to 10 °C, add 50 g of crude cefoperazone sodium, add 6.6% hydrochloric acid dropwise until pH = 2, and let stand to separate the contents.

[0054] (2) Add 50 mL of butanone and 100 mL of ethyl acetate mixture to the lower aqueous phase, stir and let stand to separate the layers.

[0055] (3) Add 200 mL of 0.15% sodium chloride solution to the organic phase in step (1), stir and let stand to separate the liquid.

[0056] (4) The lower aqueous phase is separated into the organic phase of step (2), stirred and allowed to stand for separation.

[0057] (5) Repeat steps (3) to (4) to combine the organic phases.

[0058] (6) Add 40g of anhydrous magnesium sulfate to dehydrate for 30min, filter and rinse with a mixture of 20mL butanone and 30mL ethyl acetate, and store the wash water temporarily.

[0059] (7) After dehydration, the liquid obtained in step (6) is decolorized with 5g of activated carbon for 30min, filtered, and the activated carbon is washed with the wash water from step (6). The wash water is then combined with the organic phase.

[0060] 8) 70 mL of 40% sodium isooctanoate solution was added dropwise to the organic phase to induce crystallization. After crystallization for 1.5 h, the solution was filtered and dried at 30 °C to obtain 32.95 g of purified cefoperazone sodium, with a molar yield of approximately 94.20% and an HPLC purity of 99.5%.

Claims

1. A one-step method for refining latamoxef sodium, characterized in that, Includes the following steps: (1) Adding acid and then acidifying: After dissolving crude cefazolin sodium, add acid to adjust the pH to 1-2, dissolve it completely, let it stand and separate the liquid to obtain the lower aqueous phase and the upper organic phase; the dissolution temperature is 5-10℃; the solvent is a mixture of ethyl acetate and purified water, and the volume ratio of ethyl acetate to purified water is 2-3:1; (2) Extraction: 1) Take the lower aqueous phase obtained in step (1), add the extract, stir and let stand to separate the liquid, and retain the organic phase; 2) Take the upper organic phase obtained in step (1), add washing solution, stir and let stand to separate the liquid to obtain the aqueous phase and the organic phase; 3) Add the aqueous phase obtained in step 2) to the organic phase obtained in step 1), stir, let stand, and separate the liquids, retaining the organic phase; 4) Repeat steps 2) to 3), and combine the organic phases; The extract is a mixture of butanone and ethyl acetate, and the washing solution is an aqueous solution of sodium chloride. (3) The organic phase obtained in step (2) is dehydrated and decolorized, and sodium isooctanoate solution is added to crystallize, so as to obtain the refined sodium latamoxef sodium product.

2. The method of claim 1, wherein, In step (1), the mass-to-volume ratio of crude cefoperazone sodium to solvent is 1g:10-20mL.

3. The method of claim 1, wherein, In step (1), the acid is an organic acid and / or an inorganic acid.

4. The method of claim 3, wherein, The acid is hydrochloric acid.

5. The method of claim 1, wherein, In the extract, the volume ratio of butanone to ethyl acetate is 1:1-10.

6. The method of claim 1, wherein, In step (3), the dehydrating agent is anhydrous sodium sulfate.

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