Synthesis method of ceftiofur sodium

Abstract

The present invention provides a kind of synthetic method of ceftiofur sodium, belongs to the field of drug synthesis technology, including: 7-ACF and AE active ester are provided, and amidation reaction is carried out in dichloromethane solvent; A hydrolysis solvent is provided, and a hydrolysis solvent is used for hydrolysis extraction of the reaction system of amidation reaction; An extraction solvent is provided, and an extraction solvent is used for removing impurities from the aqueous phase obtained by hydrolysis extraction, and cooling centrifugation is carried out to the obtained extraction system to obtain a thiofuran intermediate; And, a salt-forming agent is provided, and after the thiofuran intermediate and the salt-forming agent carry out salt-forming reaction, after filtration and drying, a ceftiofur sodium product is obtained. The method can reduce the amount of by-product generation in the amidation reaction, and the thiofuran intermediate is subjected to the refining operation of multiple extractions and cooling centrifugation, and the quality and yield of the thiofuran intermediate are improved, so as to improve the content and purity of the ceftiofur sodium product, reduce the impurity content, and the product yield is high, and the stability is good.

Description

Technical Field

[0001] The invention relates to the technical field of drug synthesis, and in particular to a method for synthesizing ceftiofur sodium. Background Art

[0002] Ceftiofur sodium, chemical name: [6R-[6α,7β(Z)]]-7-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-3-[[(2-furancarbonyl)thio]methyl]-8-oxo-5-thia-1-aminobicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt, is a white or yellow powder and can be used as a compound preparation for bactericidal, anti-inflammatory, antipyretic and analgesic effects. Ceftiofur sodium is a third-generation cephalosporin antibiotic used exclusively in veterinary clinics. It has a broad-spectrum and highly effective bactericidal effect. It has a strong killing effect on Gram+ bacteria, Gram- bacteria, including β-lactamase-producing mold strains. Its mechanism of action is to act on bacterial transpeptidase to block the synthesis of cell walls, showing a bactericidal effect. It is used to treat and control bacterial intestinal and respiratory infections in livestock, especially for common clinical livestock and poultry diseases such as swine plague, porcine actinomycetemcomitum pleuropneumonia, swine streptococcosis, and piglet yellow and white diarrhea. It has a good therapeutic effect.

[0003] At present, the main synthesis route of ceftiofur sodium in China is to react the intermediate 7-ACF with AE active ester to generate a thiofuran intermediate, and then react the thiofuran intermediate with sodium isooctanoate to generate ceftiofur sodium. However, most synthesis methods generate a large amount of by-products, resulting in poor quality of the thiofuran intermediate. Ceftiofur sodium is affected by the quality of the thiofuran intermediate, resulting in low product yield, low content, high impurity content, and poor product stability. Summary of the invention

[0004] The invention provides a synthesis method of ceftiofur sodium, which is used to solve the problems of high by-product generation, low product yield and content, high impurity content and poor product stability caused by poor quality of ceftiofur intermediates in the existing synthesis method.

[0005] To achieve the above-mentioned purpose, the present invention provides a synthesis method of ceftiofur sodium, comprising: providing 7-ACF and AE active ester, and performing an amidation reaction in a dichloromethane solvent; providing a hydrolysis solvent, which is used for hydrolyzing and extracting the reaction system of the amidation reaction; providing an extraction solvent, which is used for removing impurities from the aqueous phase obtained by the hydrolysis and extraction, and cooling and centrifuging the obtained extraction system to obtain a thiofuran intermediate; and providing a salt-forming agent, after the thiofuran intermediate and the salt-forming agent undergo a salt-forming reaction, filtering and drying to obtain a ceftiofur sodium product; the hydrolysis solvent is a mixed solution of ethyl acetate and water, and the extraction solvent is a mixed solution of dichloromethane and ethyl acetate; the salt-forming agent is sodium isooctanoate; during the cooling and centrifuging treatment, the extraction system is cooled to 0-5°C.

[0006] The method can control the pH and temperature of the system in the amidation reaction, reduce the amount of by-products generated, and the generated thiofuran intermediate is subjected to multiple extraction and cooling centrifugation purification operations, thereby improving the quality and yield of the thiofuran intermediate, thereby improving the content and purity of the ceftiofur sodium product, reducing the impurity content, and having a high product yield and good stability. The synthetic route simplifies the purification operations of the thiofuran intermediate and the ceftiofur sodium product, thereby reducing the production cost.

[0007] Preferably, the amidation reaction conditions are: heat preservation reaction, the reaction temperature is 5-10° C., and the reaction time is 4-5 h.

[0008] Preferably, during the amidation reaction, the pH value of the reaction system is controlled at 7.5-8.0 by an alkaline reagent.

[0009] Preferably, the alkaline agent is at least one of triethylamine, sodium bicarbonate, sodium carbonate and sodium hydroxide.

[0010] Preferably, the weight ratio of 7-ACF to AE active ester is 1:(1.05-1.5).

[0011] Preferably, the amidation reaction step is: taking 7-ACF and AE active ester, placing them in a dichloromethane solvent, mixing them and performing an amidation reaction, and during the reaction, the pH value of the reaction system is controlled at 7.5-8.0 by an alkaline reagent.

[0012] The amidation reaction controls the system pH and temperature during the reaction so that the reaction raw materials are fully dissolved in the system and the contact probability is increased, thereby accelerating the reaction speed, promoting the forward reaction, and making the reaction proceed in the direction of the formation of the thiofuran intermediate. At the same time, the formation of by-products (such as ceftriaxone or ceftiofur) can be reduced by strictly controlling the operating condition parameters, thereby reducing the difficulty of refining the thiofuran intermediate and the ceftiofur sodium product and reducing the refining operation steps, reducing the production cost, and reducing the impurity content in the ceftiofur sodium product, which is beneficial to improving the purity and yield of the ceftiofur sodium product, so that the total impurity content in the ceftiofur sodium product is less than 1.0%.

[0013] Preferably, the volume ratio of ethyl acetate to water in the hydrolysis solvent is 1:(1-1.3).

[0014] Preferably, the hydrolysis extraction step is: after the amidation reaction is completed, a hydrolysis solvent is added to the reaction system, mixed evenly, and then allowed to stand for stratification, and the aqueous phase is taken for standby use. After the reaction is completed, the thiofuran intermediate formed by the amidation reaction is extracted from the organic phase of the reaction system into the aqueous phase solvent using a hydrolysis solvent formed by a mixture of ethyl acetate and water, while the unreacted raw materials and by-products remain in the organic phase. The thiofuran intermediate can be decontaminated by hydrolysis extraction, which is beneficial to reducing the impurity content in the ceftiofur sodium product synthesized later.

[0015] Preferably, the volume ratio of dichloromethane to ethyl acetate in the extraction solvent is 1:(1.3-2.0).

[0016] Preferably, the organic extraction step is: the aqueous phase is extracted with an extraction solvent, and the obtained extraction system is used for standby. After the extraction solvent enters the aqueous phase, the impurities in the aqueous phase are extracted and removed again, which is conducive to improving the purity of the product. It can be seen that the impurities in the thiofuran intermediate are further reduced by organic extraction, which can improve the content and yield of the ceftiofur sodium product.

[0017] Preferably, the cooling and centrifugation step is: cooling the extraction system to 0-5°C, and then centrifuging to obtain the thiofuran intermediate. The extraction system is cooled, and different substances have different solubilities at different temperatures. After cooling, the thiofuran intermediate will form crystals that are easier to separate. The cooling operation effectively promotes the crystallization process of the thiofuran intermediate. At the same time, the impurity content in the aqueous phase is reduced by the use of the extraction solvent, which can avoid the thiofuran intermediate from being entrained during the crystallization process. After centrifugation in the later stage, the impurity content in the thiofuran intermediate is reduced, and after multiple extractions and purifications, the thiofuran intermediate can also be prevented from being removed by entrainment, thereby improving the yield of the thiofuran intermediate, thereby helping to improve the yield and purity of the ceftiofur sodium product.

[0018] In the present invention, hydrolysis extraction, organic extraction and cooling centrifugation operations are coordinated with each other, and the thiofuran intermediate is crystallized and separated from the amidation reaction system in a state of high purity and yield without vacuum decompression concentration, thereby simplifying the purification operation of the thiofuran intermediate and reducing the production cost. During the process, impurities are removed by repeated extraction, and the operation of cooling crystallization is coordinated to avoid impurities being contained in the thiofuran intermediate crystals, thereby reducing the impurity content in the ceftiofur sodium product synthesized in the later stage, helping to improve the yield and purity of the ceftiofur sodium product, and the product quality is good. The method is also more suitable for large-scale industrial production.

[0019] Preferably, the salt-forming reaction conditions are: heat preservation reaction, the reaction temperature is 20-25° C., and the reaction time is 1.5-2 h.

[0020] Preferably, in the salt-forming reaction, the mass ratio of 7-ACF to the salt-forming agent is 1:(0.5-1.0) based on 7-ACF.

[0021] Preferably, the salt-forming reaction step is: taking the thiofuran intermediate and the salt-forming agent sodium isooctanoate, placing them in an organic solvent, mixing them and carrying out a salt-forming reaction, and after the reaction is completed, filtering to obtain a wet product, and drying to obtain the ceftiofur sodium product.

[0022] Preferably, the organic solvent is at least one of tetrahydrofuran, acetone and methanol.

[0023] Preferably, the yield of the ceftiofur sodium product can reach a mass yield of 1.36 or more based on 7-ACF. By controlling the amidation reaction process and improving the yield and purity of the thiofuran intermediate, the salt-forming reaction of the ceftiofur sodium product is significantly promoted, thereby improving the conversion rate of the reaction raw materials and further improving the yield of the ceftiofur sodium product.

[0024] Preferably, the purity of the ceftiofur sodium product is above 98.5% by HPLC analysis, the content is above 90%, and the total impurity content is less than 1.0%. Preferably, the purity of the ceftiofur sodium product is above 99.0% by HPLC analysis. The content of the ceftiofur sodium product in the present invention is a relative content compared with the standard product. The ceftiofur sodium product has a high content and a high purity, which significantly enhances the property stability and safety of the ceftiofur sodium product. The low impurity content of the ceftiofur sodium product is also beneficial to reducing the adverse reactions of the drug and improving the market competitiveness of the ceftiofur sodium product.

[0025] The synthesis method of ceftiofur sodium provided by the present invention controls the pH and temperature of the system during the amidation reaction, promotes the reaction to proceed in the direction of generating a thiofuran intermediate, reduces the amount of by-products generated, thereby reducing the difficulty of refining the thiofuran intermediate and the ceftiofur sodium product and reducing the refining operation steps, reducing the production cost, and also reducing the impurity content in the ceftiofur sodium product.

[0026] In the present invention, the hydrolysis extraction, organic extraction and cooling centrifugation operations are coordinated with each other to separate the thiofuran intermediate from the amidation reaction system in a state of high purity and yield through crystallization, thereby simplifying the purification operation of the thiofuran intermediate and reducing the production cost. During the process, impurities are removed by repeated extraction, and the operation of cooling crystallization is coordinated to avoid impurities being contained in the thiofuran intermediate crystals, thereby reducing the impurity content in the ceftiofur sodium product synthesized in the later stage, improving the yield and purity of the ceftiofur sodium product, and significantly enhancing the property stability and safety of the ceftiofur sodium product.

[0027] The reaction conditions of each step of the present invention are mild, the operation control conditions are simple, the solvent can be fully recovered and recycled, the product yield is high, the content is high, the utilization rate and conversion rate of the reaction raw materials are high, the by-products are few and easy to remove, the refining and purification operations are simplified, the production cost is reduced, and the process is suitable for industrial production applications. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0029] Figure 1 The present invention provides a flow chart of a method for synthesizing ceftiofur sodium according to one embodiment of the present invention. DETAILED DESCRIPTION

[0030] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution in the embodiments of the present invention is clearly and completely described below. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work also fall within the scope of protection of the present invention.

[0031] The following examples use conventional instruments and equipment in the art. Unless otherwise specified, the test materials and reagents used in the following examples can be obtained from commercial sources, and their specifications are conventional specifications in the art. If no specific techniques or conditions are specified in the following examples, they can be carried out according to the techniques or conditions described in the literature in the art or according to the product instructions.

[0032] It should be noted that, in the present invention and the following embodiments, concentrations, ratios, etc. not otherwise specified are all weight concentrations, weight ratios, etc., "%" means weight percentage, and "parts" means parts by weight, which are common writing habits used by those skilled in the art and will not be described in detail in the present invention.

[0033] like Figure 1 As shown, as an embodiment, the present invention provides a method for synthesizing ceftiofur sodium, which specifically comprises the following steps:

[0034] 1) Amidation reaction: 7-ACF and AE active ester are mixed in a dichloromethane solvent and subjected to an amidation reaction. During the reaction, the pH value of the reaction system is controlled at 7.5-8.0 by an alkaline reagent.

[0035] Preferably, the amidation reaction conditions are: heat preservation reaction, reaction temperature is 5-10°C, time is 4-5h. The weight ratio of 7-ACF to AE active ester is 1:(1.05-1.5). The alkaline reagent is at least one of triethylamine, sodium bicarbonate, sodium carbonate, and sodium hydroxide.

[0036] Preferably, the weight ratio of 7-ACF to dichloromethane solvent is 1:(5-15).

[0037] 2) Hydrolysis extraction: After the amidation reaction is completed, add the hydrolysis solvent to the reaction system, mix evenly, let it stand to separate the layers, and take the aqueous phase for later use.

[0038] Preferably, the hydrolysis solvent is a mixed solution of ethyl acetate and water, wherein the volume ratio of ethyl acetate to water is 1:(1-1.3).

[0039] Preferably, the amount of the hydrolysis solvent added is 1-5 times the weight of the reaction system.

[0040] 3) Organic extraction: The aqueous phase is extracted with an extraction solvent, and the obtained extraction system is set aside.

[0041] Preferably, the extraction solvent is a mixed solution of dichloromethane and ethyl acetate, wherein the volume ratio of dichloromethane to ethyl acetate is 1:(1.3-2.0).

[0042] Preferably, the volume ratio of the aqueous phase to the extraction solvent is 1:(5-10).

[0043] 4) Cooling and centrifugation: Cool the extraction system to 0-5°C and then centrifuge to obtain the thiofuran intermediate.

[0044] 5) Salt-forming reaction: The thiofuran intermediate and the salt-forming agent sodium isooctanoate are mixed in an organic solvent and subjected to a salt-forming reaction. After the reaction is completed, the wet product is filtered and dried to obtain the ceftiofur sodium product.

[0045] Preferably, the salt-forming reaction conditions are: heat preservation reaction, reaction temperature is 20-25° C., and time is 1.5-2 hours. In the salt-forming reaction, the mass ratio of 7-ACF to the salt-forming agent is 1:(0.5-1.0) based on 7-ACF. The organic solvent is at least one of tetrahydrofuran, acetone, and methanol.

[0046] Preferably, the amount of organic solvent added is 3-10 times the weight of the thiofuran intermediate.

[0047] It should be noted that the usage or addition amount of various solvents (such as dichloromethane solvent, hydrolysis solvent, extraction solvent, organic solvent, etc.) in each step of the present invention is not limited by the numerical value or ratio in the embodiments of the present invention. In actual production, those skilled in the art can select the usage amount according to the production situation. The usage amount in the embodiments of the present invention and the examples serves as an illustrative example.

[0048] The present invention is further described in detail below in conjunction with the examples. However, it should be understood that the examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

[0049] Embodiment 1:

[0050] A method for synthesizing ceftiofur sodium comprises the following steps:

[0051] 1) Amidation reaction: 12.0 g of 7-ACF and 12.7 g of AE active ester were mixed in 65 g of dichloromethane solvent, and the amidation reaction was carried out at a reaction temperature of 5° C. for 4 h. During the reaction, the pH value of the reaction system was controlled at 7.5-8.0 by an alkaline reagent-sodium bicarbonate.

[0052] 2) Hydrolysis extraction: After the amidation reaction is completed, add 1.5 times the weight of the hydrolysis solvent to the reaction system, mix evenly, let stand to separate the layers, and take the water phase for use. The hydrolysis solvent is a mixed solution of ethyl acetate and water, wherein the volume ratio of ethyl acetate to water is 1:1.

[0053] 3) Organic extraction: The aqueous phase is extracted with an extraction solvent, and the obtained extraction system is used for standby. The extraction solvent is a mixed solution of dichloromethane and ethyl acetate, wherein the volume ratio of dichloromethane to ethyl acetate is 1:1.3. The volume ratio of the aqueous phase to the extraction solvent is 1:5.

[0054] 4) Cooling and centrifugation: Cool the extraction system to 0°C and then centrifuge to obtain the thiofuran intermediate.

[0055] 5) Salt-forming reaction: The thiofuran intermediate and 6.0 g of the salt-forming agent sodium isooctanoate were mixed in an organic solvent-tetrahydrofuran, and the salt-forming reaction was carried out for 1.5 h at a reaction temperature of 20°C. After the reaction, the wet product was filtered and dried to obtain 16.33 g of ceftiofur sodium product, and the mass yield of the ceftiofur sodium product was 1.361 (based on 7-ACF). The amount of the above organic solvent added was 3 times the weight of the thiofuran intermediate.

[0056] Embodiment 2:

[0057] A method for synthesizing ceftiofur sodium comprises the following steps:

[0058] 1) Amidation reaction: 15.0 g of 7-ACF and 22.3 g of AE active ester were mixed in 200 g of dichloromethane solvent, and the amidation reaction was carried out at a reaction temperature of 10° C. for 5 h. During the reaction, the pH value of the reaction system was controlled at 7.5-8.0 by an alkaline reagent-sodium carbonate.

[0059] 2) Hydrolysis extraction: After the amidation reaction is completed, add 5 times the weight of the hydrolysis solvent to the reaction system, mix evenly, let stand to separate the layers, and take the water phase for use. The hydrolysis solvent is a mixed solution of ethyl acetate and water, wherein the volume ratio of ethyl acetate to water is 1:1.3.

[0060] 3) Organic extraction: The aqueous phase is extracted with an extraction solvent, and the obtained extraction system is used for standby. The extraction solvent is a mixed solution of dichloromethane and ethyl acetate, wherein the volume ratio of dichloromethane to ethyl acetate is 1:2.0. The volume ratio of the aqueous phase to the extraction solvent is 1:10.

[0061] 4) Cooling and centrifugation: Cool the extraction system to 5°C and then centrifuge to obtain the thiofuran intermediate.

[0062] 5) Salt-forming reaction: The thiofuran intermediate and 14.5 g of sodium isooctanoate, a salt-forming agent, were mixed in an organic solvent-methanol, and the salt-forming reaction was carried out for 2 h at a reaction temperature of 25°C. After the reaction, the wet product was filtered and dried to obtain 20.64 g of ceftiofur sodium product, and the mass yield of the ceftiofur sodium product was 1.376 (based on 7-ACF). The amount of the above organic solvent added was 10 times the weight of the thiofuran intermediate.

[0063] Embodiment 3:

[0064] A method for synthesizing ceftiofur sodium comprises the following steps:

[0065] 1) Amidation reaction: 10.0 g of 7-ACF and 11.0 g of AE active ester were mixed in 100 g of dichloromethane solvent, and the amidation reaction was carried out at a reaction temperature of 5° C. for 4 h. During the reaction, the pH value of the reaction system was controlled at 7.5-8.0 by using an alkaline reagent - triethylamine.

[0066] 2) Hydrolysis extraction: After the amidation reaction is completed, add 3 times the weight of the hydrolysis solvent to the reaction system, mix evenly, let stand to separate the layers, and take the water phase for use. The hydrolysis solvent is a mixed solution of ethyl acetate and water, wherein the volume ratio of ethyl acetate to water is 1:1.

[0067] 3) Organic extraction: The aqueous phase is extracted with an extraction solvent, and the obtained extraction system is used for standby. The extraction solvent is a mixed solution of dichloromethane and ethyl acetate, wherein the volume ratio of dichloromethane to ethyl acetate is 1:1.5. The volume ratio of the aqueous phase to the extraction solvent is 1:7.

[0068] 4) Cooling and centrifugation: Cool the extraction system to 0°C and then centrifuge to obtain the thiofuran intermediate.

[0069] 5) Salt-forming reaction: The thiofuran intermediate and 6.0 g of sodium isooctanoate, a salt-forming agent, were mixed in an organic solvent-acetone, and the salt-forming reaction was carried out for 1.5 h at a reaction temperature of 25°C. After the reaction, the wet product was filtered and dried to obtain 13.84 g of ceftiofur sodium product, and the mass yield of the ceftiofur sodium product was 1.384 (based on 7-ACF). The amount of the above organic solvent added was 6 times the weight of the thiofuran intermediate.

[0070] Comparative Example 1:

[0071] A method for synthesizing ceftiofur sodium, which is a commonly used method at present, comprises the following steps:

[0072] 10.0 g of 7-ACF and 11.0 g of AE active ester were placed in 100 g of dichloromethane solvent and mixed, and 10.0 g of triethylamine was added, and then the amidation reaction was carried out at a reaction temperature of 5°C for 4 hours. After the reaction, an aqueous solution containing 6.0 g of sodium isooctanoate was added, and the salt-forming reaction was carried out at a reaction temperature of 25°C for 1.5 hours. The layers were stirred and separated, and the aqueous phase was separated. The organic phase was washed 3 times with distilled water and the aqueous phase was combined. Acetone was added dropwise until the crystal precipitation no longer increased. The wet product was obtained by filtration and dried to obtain 8.27 g of ceftiofur sodium product. The mass yield of the ceftiofur sodium product was 0.827 (based on 7-ACF).

[0073] Comparative Example 2:

[0074] A method for synthesizing ceftiofur sodium comprises the following steps:

[0075] 1) Amidation reaction: 10.0 g of 7-ACF and 11.0 g of AE active ester were mixed in 100 g of dichloromethane solvent, and the amidation reaction was carried out at a reaction temperature of 5° C. for 4 h. During the reaction, the pH value of the reaction system was controlled at 7.5-8.0 by using an alkaline reagent - triethylamine.

[0076] 2) Hydrolysis extraction: After the amidation reaction is completed, add 3 times the weight of the hydrolysis solvent to the reaction system, mix evenly, let stand to separate the layers, and take the water phase for use. The hydrolysis solvent is a mixed solution of ethyl acetate and water, wherein the volume ratio of ethyl acetate to water is 1:1.

[0077] 3) Salt-forming reaction: 6.0 g of the salt-forming agent sodium isooctanoate was added to the above aqueous phase, and the salt-forming reaction was carried out at a reaction temperature of 25° C. for 1.5 h. After the reaction, acetone was added dropwise until the crystal precipitation no longer increased. The wet product was filtered and dried to obtain 10.31 g of ceftiofur sodium product. The mass yield of the ceftiofur sodium product was 1.031 (based on 7-ACF).

[0078] Comparative Example 3:

[0079] A method for synthesizing ceftiofur sodium comprises the following steps:

[0080] 1) Amidation reaction: 10.0 g of 7-ACF and 11.0 g of AE active ester were mixed in 100 g of dichloromethane solvent, and the amidation reaction was carried out at a reaction temperature of 5° C. for 4 h. During the reaction, the pH value of the reaction system was controlled at 7.5-8.0 by using an alkaline reagent - triethylamine.

[0081] 2) Hydrolysis extraction: After the amidation reaction is completed, add 3 times the weight of the hydrolysis solvent to the reaction system, mix evenly, let stand to separate the layers, and take the water phase for use. The hydrolysis solvent is a mixed solution of ethyl acetate and water, wherein the volume ratio of ethyl acetate to water is 1:1.

[0082] 3) Organic extraction: The aqueous phase is extracted with an extraction solvent, and the obtained extraction system is used for standby. The extraction solvent is a mixed solution of dichloromethane and ethyl acetate, wherein the volume ratio of dichloromethane to ethyl acetate is 1:1.5. The volume ratio of the aqueous phase to the extraction solvent is 1:7.

[0083] 4) Salt-forming reaction: 6.0 g of the salt-forming agent sodium isooctanoate was added to the extraction system, and the salt-forming reaction was carried out at a reaction temperature of 25° C. for 1.5 h. After the reaction, acetone was added dropwise until the crystal precipitation no longer increased. The wet product was filtered and dried to obtain 11.34 g of ceftiofur sodium product. The mass yield of the ceftiofur sodium product was 1.134 (based on 7-ACF).

[0084] The content and purity of the ceftiofur sodium products prepared in Examples 1 to 3 were detected by high performance liquid chromatography, and the contents of other components were detected at the same time, and their properties were observed and recorded, and the results are summarized in Table 1. Among them, the content of the wet product was detected, and the standard substance used for content detection was: ceftiofur sodium purchased from the China Standard Material Information Network, product number DZP25430, HPLC≥97%. Each test example was set up with 3 parallels, and the average value was taken.

[0085] Table 1

[0086]

[0087] Similarly, the content and purity of the ceftiofur sodium products obtained in Comparative Examples 1 to 3 were tested by high performance liquid chromatography, and the contents of other components were also tested, and the content of the wet product was also tested. The results are summarized in Table 2.

[0088] Table 2

[0089]

[0090] It can be seen from the data in Table 1 and Table 2 that the test results of the ceftiofur sodium products obtained in the present invention and the examples all meet the quality index requirements in the national veterinary drug product quality standards.

[0091] As in Comparative Example 1, the pH of the system was not regulated for the amidation reaction, and the salt-forming reaction was directly carried out in the same reactor without multiple extractions and cooling and centrifugation operations, resulting in a large amount of by-products and impurities in the salt-forming system, resulting in a high impurity content in the ceftiofur sodium product, which reduced the content and purity of the ceftiofur sodium product and also affected the yield of the ceftiofur sodium product.

[0092] As in Comparative Example 2, although hydrolysis extraction was performed for preliminary impurity removal, organic extraction and cooling centrifugation were not performed. This method synthesizes ceftiofur sodium in an aqueous phase. Since the aqueous solution of ceftiofur sodium is unstable and easily hydrolyzed to generate impurities, it is easy to cause the content and purity of the ceftiofur sodium product to decrease, and also affects the yield of the ceftiofur sodium product.

[0093] As in Comparative Example 3, although multiple extraction steps were performed, cooling and centrifugation were not performed to separate and purify the obtained thiofuran intermediate, and the extraction system contained a large amount of aqueous phase, which was also likely to cause hydrolysis of ceftiofur sodium, and the impurity removal efficiency was obviously not as good as in the embodiment, therefore, it was easy to cause the content and purity of the ceftiofur sodium product to be reduced, and also affected the yield of the ceftiofur sodium product.

[0094] It should be noted that in the present invention, the detailed steps of some operations are not described in detail, but belong to the prior art known to those skilled in the art, so they will not be repeated here. In addition, in the present invention, all features such as values, quantities, contents and concentrations defined in the form of numerical ranges or percentage ranges are only for simplicity and convenience. Accordingly, the description of numerical ranges or percentage ranges should be deemed to have covered and specifically disclosed all possible secondary ranges and individual values ​​within the range (including integers and fractions).

[0095] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit them. In the present invention, not all possible combinations of the various technical features in the various embodiments or embodiments are described. As long as there is no contradiction in the combination of these technical features, the various technical features in the various embodiments or embodiments can be arbitrarily combined, and all possible combinations should be considered to be within the scope of this specification. Although the present invention has been described in detail with reference to the aforementioned embodiments, a person of ordinary skill in the art should understand that the technical solutions described in the aforementioned embodiments can still be modified, or some or all of the technical features therein can be replaced by equivalents; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for synthesizing ceftiofur sodium, It is characterized in that include: Providing 7-ACF and AE active ester, and performing an amidation reaction in a dichloromethane solvent; during the amidation reaction, the pH value of the reaction system is controlled at 7.5-8.0 by an alkaline reagent; the alkaline reagent is at least one of triethylamine, sodium bicarbonate, sodium carbonate, and sodium hydroxide; Providing a hydrolysis solvent, wherein the hydrolysis solvent is used to perform hydrolysis extraction on the reaction system of the amidation reaction; Providing an extraction solvent, the extraction solvent is used to remove impurities from the aqueous phase obtained by the hydrolysis extraction, and cooling and centrifuging the obtained extraction system to obtain a thiofuran intermediate; and, Providing a salt-forming agent, the thiofuran intermediate and the salt-forming agent undergo a salt-forming reaction, followed by filtering and drying to obtain a ceftiofur sodium product; The yield of the ceftiofur sodium product, calculated as 7-ACF, can reach a mass yield of 1.36 or more; the purity of the ceftiofur sodium product is above 98.5% and the content is above 90% after HPLC analysis, and the total impurity content is less than 1.0%; The hydrolysis solvent is a mixed solution of ethyl acetate and water, the extraction solvent is a mixed solution of dichloromethane and ethyl acetate; the salt-forming agent is sodium isooctanoate; The hydrolysis extraction step comprises: after the amidation reaction is completed, adding a hydrolysis solvent to the reaction system, mixing evenly, standing to separate layers, and taking the aqueous phase for later use; The organic extraction step is as follows: extracting the aqueous phase with an extraction solvent, and the obtained extraction system is ready for use; The cooling and centrifugation step comprises: cooling the extraction system to 0-5°C, and then centrifuging to obtain the thiofuran intermediate.

2. The method for synthesizing ceftiofur sodium according to claim 1, It is characterized in that The amidation reaction conditions are: heat preservation reaction, reaction temperature is 5-10° C., and time is 4-5 h.

3. The method for synthesizing ceftiofur sodium according to claim 1, It is characterized in that The weight ratio of the 7-ACF to the AE active ester is 1:(1.05-1.5).

4. The method for synthesizing ceftiofur sodium according to claim 1, It is characterized in that The volume ratio of ethyl acetate to water in the hydrolysis solvent is 1:(1-1.3).

5. The method for synthesizing ceftiofur sodium according to claim 1, It is characterized in that The volume ratio of dichloromethane to ethyl acetate in the extraction solvent is 1:(1.3-2.0).

6. The method for synthesizing ceftiofur sodium according to claim 1, It is characterized in that The salt-forming reaction conditions are: heat preservation reaction, reaction temperature is 20-25° C., and time is 1.5-2 h.

7. The method for synthesizing ceftiofur sodium according to claim 1, It is characterized in that In the salt-forming reaction, the mass ratio of 7-ACF to the salt-forming agent is 1:(0.5-1.0) based on 7-ACF.

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