A preparation method of cefotaxime

Abstract

This application relates to the technical field of pharmaceutical compounds, specifically disclosing a method for preparing cefotaxime. The preparation method includes the following steps: dissolving 7-ACA in organic solvent A, then adding porous silica spheres, mixing for 90-120 min, washing, and drying to obtain 7-ACA loaded with porous silica spheres; then uniformly dispersing the 7-ACA, AE-active ester, antioxidant, and triethylamine loaded with porous silica spheres in organic solvent B, reacting at 10-25°C for 60-90 min, followed by solid-liquid separation, extraction, acidification, crystallization, washing, and drying to obtain cefotaxime; wherein organic solvent B includes dichloroethane and isopropanol. The cefotaxime obtained in this application has good yield and purity.

Description

Technical Field

[0001] The present application relates to the technical field of pharmaceutical compounds, and in particular to a method for preparing cefotaxime. Background Art

[0002] Cefotaxime is a β-lactam antibiotic that exerts its antibacterial effect mainly by inhibiting the synthesis of bacterial cell walls. This bactericidal mechanism is more effective for growing and multiplying bacteria, because growing bacteria need to continuously synthesize new cell walls to complete cell division and growth, and cefotaxime just blocks this key process. It can also effectively curb the deterioration of the disease when used in the early stages of infection. The demand for it in the medical field and other related fields is increasing day by day, and it has gradually grown into the backbone of domestic cephalosporin drugs. However, the quality of existing cefotaxime products needs to be improved. Therefore, it is necessary to further study and explore the synthesis process of cefotaxime.

[0003] The patent application document with publication number CN101560217A discloses a preparation process of cefotaxime, which comprises adding 7-ACA and AE-active ester reactants into a solvent, and then adding an organic base and an alcohol catalyst to carry out a synthesis reaction. After the reaction is completed, an acidifier is directly added for acidification and then crystallization is performed to obtain the cefotaxime. The solvent is dichloromethane or dichloroethane, the organic base is triethylamine or pyridine, the alcohol is methanol, ethanol or isopropanol, and the acidifier is hydrochloric acid, formic acid or acetic acid.

[0004] The color of the product produced in this patent application document ranges from 3Y (-) to 5Y (-). Although the document mentions that the color meets the company's internal control requirements, the darker color may indicate the presence of some impurities in the product, affecting the appearance and purity of the product. Although the yield is high, there may be problems with the purity. Summary of the invention

[0005] In order to improve the purity of cefotaxime, the present application provides a method for preparing cefotaxime.

[0006] The present application provides a method for preparing cefotaxime, which adopts the following technical scheme: A method for preparing cefotaxime, comprising the following steps:

[0007] 7-ACA is dissolved in an organic solvent A, and then porous silica balls are added, mixed for 90 to 120 minutes, washed, and dried to obtain 7-ACA loaded on the porous silica balls; then 7-ACA loaded on the porous silica balls, AE-active ester, antioxidant, and triethylamine are uniformly dispersed in an organic solvent B, reacted at 10 to 25° C. for 60 to 90 minutes, and solid-liquid separation, extraction, acidification, crystallization, washing, and drying are performed to obtain cefotaxime;

[0008] The organic solvent B includes ethylene dichloride and isopropanol, and the mass volume ratio of the 7-ACA to the AE-active ester, triethylamine, ethylene dichloride, and isopropanol is 1g: (1.1-1.4)g: (0.7-0.9)ml: (8-10)ml: (0.3-0.5)ml.

[0009] Preferably, the organic solvent A is any one of dichloroethane, acetone and ethanol; the mass volume ratio of the 7-ACA to the organic solvent A is 1 g: (4-5) ml.

[0010] Preferably, the mass ratio of the 7-ACA to the antioxidant is 1:0.05-0.1.

[0011] Preferably, the antioxidant is any one of sodium sulfite and sodium bisulfite.

[0012] By adopting the above technical scheme, firstly, after 7-ACA is loaded on porous silica gel balls, more dispersion sites are provided for 7-ACA, the utilization rate and stability of 7-ACA are improved, and the chance of collision with AE-active ester is increased, thereby increasing the reaction probability, which is beneficial to increasing the yield of cefotaxime; secondly, 7-ACA is loaded on porous silica gel balls, and the reaction environment is relatively fixed, which reduces the probability of unnecessary side reactions between 7-ACA molecules and other impurities, and the reaction path is relatively more specific, thereby improving the purity of cefotaxime.

[0013] Preferably, the method for preparing the porous silica gel balls comprises the following steps:

[0014] S11: dispersing polystyrene microspheres in ethanol to obtain a polystyrene microsphere dispersion, then subjecting the polystyrene microsphere dispersion to plasma treatment for 4 to 6 minutes, washing, and drying to obtain pretreated polystyrene microspheres;

[0015] S12: taking a hydrogen peroxide solution, adding ethylenediaminetetraacetic acid and mixing evenly, adjusting the pH to 4.5-5.0, and then adding polystyrene microspheres, mixing for 90-120 minutes, solid-liquid separation, washing, and drying to obtain hydroxylated polystyrene microspheres;

[0016] S13: dispersing hydroxylated polystyrene microspheres in an ethanol aqueous solution, adjusting the pH to 7.5-8.5, heating to 40-60°C, then adding ethyl orthosilicate, keeping the temperature for 2-4 hours, cooling, washing, and drying to obtain silica gel balls;

[0017] S14: sintering at 450-550°C for 2-4 hours under an inert atmosphere, raising the temperature to 470-570°C, keeping the temperature for 40-60 minutes, and cooling to obtain porous silica gel balls;

[0018] The mass ratio of the polystyrene microspheres to tetraethyl orthosilicate is about 1:2-6.

[0019] Preferably, in step S13, the mass volume ratio of the tetraethyl orthosilicate to the ethanol aqueous solution is (2-6) g: (14-20) ml.

[0020] Preferably, the particle size distribution of the polystyrene microspheres is 5-50 nm.

[0021] Preferably, the mass ratio of the porous silica balls to 7-ACA is 1:0.3-0.5.

[0022] Preferably, the mass fraction of the hydrogen peroxide solution is 10% to 20%, and the mass volume ratio of the polystyrene microspheres to the hydrogen peroxide solution is 1 g: (10 to 12) ml.

[0023] Preferably, the amount of EDTA used is 0.05% to 0.12% of the mass of the polystyrene microspheres.

[0024] By adopting the above technical solution, the polystyrene microspheres are pretreated with plasma and hydrogen peroxide, and the hydroxyl groups on the polystyrene microspheres can interact with the silica precursor, which not only improves the crosslinking degree and structural tightness of the silica gel, making it have higher mechanical strength, but also guides the formation of silica gel during the hydrolysis and polycondensation reaction, making the pore structure of the silica gel balls richer, thereby improving the porosity. In addition, the hydroxyl groups on the polystyrene microspheres also make the porous silica gel balls have a certain alkaline buffering capacity, making the alkaline environment of the system milder, reducing the ring opening of cefotaxime due to excessive alkalinity, thereby improving the purity and yield of cefotaxime.

[0025] At the same time, the hydroxyl groups on the polystyrene microspheres will introduce a large number of hydroxyl groups on the surface and inside of the porous silica gel balls, increasing the hydrophilicity and activity of the surface and inside of the porous silica gel balls. The reactant molecules are more likely to gather and collide on the surface of the hydrophilic silica gel balls, thereby accelerating the reaction and helping to increase the yield of cefotaxime. The increase in hydrophilicity can adsorb some polar impurities (such as 2-mercaptobenzothiazole) and separate them from the product, thereby improving the purity of cefotaxime.

[0026] Preferably, the 7-ACA is modified 7-ACA, and the preparation method of the modified 7-ACA comprises the following steps: uniformly mixing an organic solvent A and triethylamine, adding di-tert-butyl dicarbonate and 7-ACA, and stirring and mixing for 1 to 3 hours to obtain modified 7-ACA;

[0027] The mass volume ratio of the 7-ACA to di-tert-butyl dicarbonate, the organic solvent A, and triethylamine is 1 g: (0.9-1) g: (4-5) ml: (0.1-0.15) ml.

[0028] By adopting the above technical scheme, the modified 7-ACA is more stable during the reaction process. It can not only participate in the reaction efficiently and improve the yield of cefotaxime, but also avoid unnecessary reactions with other reactants or solvents, thereby reducing the generation of impurities and further improving the purity of cefotaxime.

[0029] 7-ACA with amino protection loaded on porous silica balls can be deprotected by acidification in the subsequent process, which simplifies the operation process, reduces the processing steps, helps to reduce the risk of impurities introduced during the operation, and further improves the purity of cefotaxime.

[0030] In summary, this application has the following beneficial effects:

[0031] The present application uses porous silica gel balls to load 7-ACA, which can not only reduce the generation of impurities during the reaction and improve the purity of cefotaxime, but also make 7-ACA more evenly and stably dispersed in the reaction system, which can increase the reaction rate and the utilization rate of 7-ACA, thereby further improving the yield of cefotaxime. 2. In the present application, di-tert-butyl dicarbonate is preferably used to modify 7-ACA, which further improves the stability of 7-ACA and further reduces the generation of impurities, thereby improving the purity and yield of cefotaxime. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 is the infrared spectrum of ceftriaxone in Example 1 of the present application;

[0033] Figure 2 is the HPLC liquid phase spectrum of ceftriaxone in Example 1 of the present application;

[0034] Figure 3 is the HPLC liquid phase spectrum of ceftriaxone in Example 2 of the present application;

[0035] Figure 4 This is the HPLC liquid phase spectrum of ceftriaxone in Example 3 of the present application. DETAILED DESCRIPTION

[0036] The present application is further described in detail below with reference to embodiments.

[0037] Unless otherwise specified, the raw materials used in the examples and comparative examples of the present application are all commercially available.

[0038] In the following examples and preparations:

[0039] 7-ACA is 7-aminocephalosporanic acid, with a purity of 99%, purchased from Wuhan Smack Biotechnology Co., Ltd.;

[0040] AE-active ester is 2-methoxyimino-2-(2-amino-4-thiazolyl)-(z)-thioacetic acid phenylhydrazine thiazolyl ester, with a purity of 99%, purchased from Wuhan Smack Biotechnology Co., Ltd.;

[0041] Polystyrene microspheres, purity 99%, were purchased from Zhongke Leiming (Beijing) Technology Co., Ltd.

[0042] Preparation Examples 1-3 Preparation of Porous Silica Gel Balls

[0043] Preparation Example 1

[0044] S11: After 10 g of polystyrene microspheres were stirred and mixed with 100 ml of ethanol, the mixture was stirred at a stirring speed of 400 rpm for 20 min, and then the stirring speed was adjusted to 800 rpm and stirred for 40 min to obtain a polystyrene microsphere dispersion, and then the polystyrene microsphere dispersion was treated with a mixed gas atmospheric pressure plasma jet device at a power of 120 W, a temperature of 60° C., and a distance of 2 to 3 cm. During the treatment, the stirring speed was 120 rpm and the treatment time was 4 min. The mixture was filtered, washed with pure water twice the volume of the polystyrene microspheres and filtered twice, first dried at 50° C. under vacuum at -0.05 MPa for 1.5 h, and then dried at 50° C. for 1 h under the blowing of high-purity nitrogen to obtain pretreated polystyrene microspheres;

[0045] S12: Take 120 ml of 10% hydrogen peroxide aqueous solution, then add 5 mg of ethylenediaminetetraacetic acid, stir for 10 minutes, the stirring speed is 100 rpm, then use 5% acetic acid solution to adjust the pH to 4.5, then add the pretreated polystyrene microspheres three times, stirring while adding, after the addition is completed, use intermittent stirring for 120 minutes, stir for 25 minutes, pause for 5 minutes, and then continue stirring at a stirring speed of 200 rpm, filter, wash with 10% ethanol aqueous solution with a mass fraction of 2 times the volume of the polystyrene microspheres and filter once, then use 5% sodium bicarbonate aqueous solution with a mass fraction of 2 times the volume of the polystyrene microspheres and filter once, then use pure water with a volume of 2 times the volume of the polystyrene microspheres and wash and filter twice, then dry at 50°C for 3 hours under the blowing action of high-purity nitrogen (preheated to about 45°C before the high-purity nitrogen is introduced) to obtain modified polystyrene microspheres;

[0046] S13: slowly add the modified polystyrene microspheres into 140 ml of 50% ethanol aqueous solution, stir and mix for 20 min at a stirring speed of 200 rpm, adjust the pH to 7.5 with 5% ammonia water, heat to 40°C, then slowly drop 20.8 g of tetraethyl orthosilicate, stir while dropping, at a stirring speed of 200 rpm, after the dropwise addition is completed, adjust the stirring speed to 100 rpm, keep warm for 4 h, wash with pure water until neutral, then wash with 2 times the volume of anhydrous ethanol, let stand for 5 min and filter, cycle twice, wherein 100 mg of ethylenediaminetetraacetic acid is uniformly dispersed in every 500 ml of anhydrous ethanol, filter, and then dry at 50°C for 3 h under the blowing action of high-purity nitrogen (preheated to about 45°C before the high-purity nitrogen is introduced) to obtain silica gel balls;

[0047] S14: In a high-purity nitrogen atmosphere, the silica gel balls were placed in a sintering furnace, and the temperature was increased to 450°C at 2°C / min, and sintered for 4 hours. Then, the temperature was increased to 470°C at 1°C / min, and after sintering for 60 minutes, the silica gel balls were cooled in the furnace to obtain porous silica gel balls.

[0048] Wherein, the mixed gas is 95% argon and 5% oxygen;

[0049] The particle size distribution of polystyrene microspheres is 5~20nm.

[0050] Preparation Example 2

[0051] S11: After 10 g of polystyrene microspheres were stirred and mixed with 100 ml of ethanol, the mixture was stirred at a stirring speed of 400 rpm for 20 min, and then the stirring speed was adjusted to 800 rpm and stirred for 40 min to obtain a polystyrene microsphere dispersion, and then the polystyrene microsphere dispersion was treated with a mixed gas atmospheric pressure plasma jet device at a power of 120 W, a temperature of 60° C., and a distance of 2 to 3 cm. During the treatment, the stirring speed was 120 rpm, and the treatment time was 5 min. The mixture was filtered, washed with pure water twice the volume of the polystyrene microspheres and filtered twice, first dried at 50° C. under vacuum at -0.05 MPa for 1.5 h, and then dried at 50° C. for 1 h under the blowing of high-purity nitrogen to obtain pretreated polystyrene microspheres;

[0052] S12: Take 110 ml of 15% hydrogen peroxide aqueous solution, then add 8 mg of ethylenediaminetetraacetic acid, stir for 10 minutes, stirring at a speed of 100 rpm, then use 5% acetic acid solution to adjust the pH to 5.0, then add the pretreated polystyrene microspheres three times, stirring while adding, after the addition is completed, use intermittent stirring for 120 minutes, stirring for 25 minutes, pausing for 5 minutes, and then continue stirring at a stirring speed of 200 rpm, filter, wash with 10% ethanol aqueous solution with a mass fraction of 2 times the volume of the polystyrene microspheres and filter once, then use 5% sodium bicarbonate aqueous solution with a mass fraction of 2 times the volume of the polystyrene microspheres and filter once, then use pure water with a volume of 2 times the volume of the polystyrene microspheres and wash and filter twice, then dry at 50°C for 3 hours under the blowing action of high-purity nitrogen (preheated to about 45°C before the high-purity nitrogen is introduced) to obtain modified polystyrene microspheres;

[0053] S13: slowly add the modified polystyrene microspheres into 180 ml of 50% ethanol aqueous solution, stir and mix for 20 min, stir at a speed of 200 rpm, adjust the pH to 8.0 with 5% ammonia water, heat to 50°C, then slowly drop 41.6 g of tetraethyl orthosilicate, stir while dropping, stir at a speed of 200 rpm, after the dropwise addition is completed, adjust the stirring speed to 100 rpm, keep warm for 3 h, wash with pure water until neutral, then wash with 2 times the volume of anhydrous ethanol, let stand for 5 min and filter, cycle twice, wherein 100 mg of ethylenediaminetetraacetic acid is uniformly dispersed in every 500 ml of anhydrous ethanol, filter, and then dry at 50°C for 5 h under the blowing action of high-purity nitrogen (preheated to about 45°C before the high-purity nitrogen is introduced), to obtain silica gel balls;

[0054] S14: In a high-purity nitrogen atmosphere, the silica gel balls were placed in a sintering furnace, and the temperature was increased to 500°C at 2°C / min, and sintered for 3 hours. Then, the temperature was increased to 520°C at 1°C / min, and after sintering for 50 minutes, the silica gel balls were cooled in the furnace to obtain porous silica gel balls.

[0055] Wherein, the mixed gas is 95% argon and 5% oxygen;

[0056] The particle size distribution of polystyrene microspheres is 20~30nm.

[0057] Preparation Example 3

[0058] S11: After 10 g of polystyrene microspheres were stirred and mixed with 100 ml of ethanol, the mixture was stirred at a stirring speed of 400 rpm for 20 min, and then the stirring speed was adjusted to 800 rpm and stirred for 40 min to obtain a polystyrene microsphere dispersion, and then the polystyrene microsphere dispersion was treated with a mixed gas atmospheric pressure plasma jet device at a power of 120 W, a temperature of 60° C., and a distance of 2 to 3 cm. During the treatment, the stirring speed was 120 rpm, and the treatment time was 6 min. The mixture was filtered, washed with pure water twice the volume of the polystyrene microspheres and filtered twice, first vacuum dried at 50° C. for 1.5 h at -0.05 MPa, and then dried at 50° C. for 1 h under the blowing of high-purity nitrogen to obtain pretreated polystyrene microspheres;

[0059] S12: Take 100 ml of 20% hydrogen peroxide aqueous solution, then add 12 mg of ethylenediaminetetraacetic acid, stir for 10 minutes, the stirring speed is 100 rpm, then use 5% acetic acid solution to adjust the pH to 5.0, then add the pretreated polystyrene microspheres three times, stirring while adding, after the addition is completed, use intermittent stirring for 90 minutes, stirring for 25 minutes, pausing for 5 minutes, and then continue stirring at a stirring speed of 200 rpm, filter, wash with 10% ethanol aqueous solution with a mass fraction of 2 times the volume of the polystyrene microspheres and filter once, then use 5% sodium bicarbonate aqueous solution with a mass fraction of 2 times the volume of the polystyrene microspheres and filter once, then use pure water with a volume of 2 times the volume of the polystyrene microspheres and wash and filter twice, then dry at 50°C for 3 hours under the blowing action of high-purity nitrogen (preheated to about 45°C before the high-purity nitrogen is introduced) to obtain modified polystyrene microspheres;

[0060] S13: slowly add the modified polystyrene microspheres into 200 ml of 50% ethanol aqueous solution, stir and mix for 20 min, stir at a speed of 200 rpm, adjust the pH to 8.5 with 5% ammonia water, heat to 60°C, then slowly drop 62.4 g of tetraethyl orthosilicate, stir while dropping, stir at a speed of 200 rpm, after the dropwise addition is completed, adjust the stirring speed to 100 rpm, keep warm for 2 h, wash with pure water until neutral, then wash with 2 times the volume of anhydrous ethanol, let stand for 5 min and filter, cycle twice, wherein 100 mg of ethylenediaminetetraacetic acid is uniformly dispersed in every 500 ml of anhydrous ethanol, filter, and then dry at 50°C for 7 h under the blowing action of high-purity nitrogen (preheated to about 45°C before the high-purity nitrogen is introduced), to obtain silica gel balls;

[0061] S14: In a high-purity nitrogen atmosphere, the silica gel balls were placed in a sintering furnace, and the temperature was raised to 550°C at 3°C / min, and sintered for 2 hours. Then, the temperature was raised to 570°C at 2°C / min, and after sintering for 40 minutes, the silica gel balls were cooled in the furnace to obtain porous silica gel balls.

[0062] Wherein, the mixed gas is 95% argon and 5% oxygen;

[0063] The particle size distribution of polystyrene microspheres is 30~50nm.

[0064] Comparative Preparation Example 1

[0065] S11: After 10 g of polystyrene microspheres were stirred and mixed with 100 ml of ethanol, the mixture was stirred at a stirring speed of 400 rpm for 20 min, and then the stirring speed was adjusted to 800 rpm and stirred for 40 min to obtain a polystyrene microsphere dispersion, and then the polystyrene microsphere dispersion was treated with a mixed gas atmospheric pressure plasma jet device at a power of 120 W, a temperature of 60° C., and a distance of 2 to 3 cm. During the treatment, the stirring speed was 120 rpm and the treatment time was 4 min. The mixture was filtered, washed with pure water twice the volume of the polystyrene microspheres and filtered twice, first dried at 50° C. under vacuum at -0.05 MPa for 1.5 h, and then dried at 50° C. for 1 h under the blowing of high-purity nitrogen to obtain pretreated polystyrene microspheres;

[0066] S12: Slowly add the pretreated polystyrene microspheres to 200 ml of 50% ethanol aqueous solution, stir and mix for 20 min at a stirring speed of 200 rpm, use 5% acetic acid to adjust the pH to 4.5, heat to 70°C, then slowly drop 20.8 g of tetraethyl orthosilicate, stir while dropping, and stir at a stirring speed of 200 rpm. After the dropwise addition is completed, adjust the stirring speed to 100 rpm, keep warm for 4 h, wash with pure water until neutral, then wash with 2 times the volume of anhydrous ethanol, let stand for 5 min and filter, cycle twice, wherein 100 mg of ethylenediaminetetraacetic acid is uniformly dispersed in every 500 ml of anhydrous ethanol, filter, and then dry at 60°C for 3 h under the blowing action of high-purity nitrogen (preheated to about 55°C before the high-purity nitrogen is introduced) to obtain silica gel balls;

[0067] S13: In a high-purity nitrogen atmosphere, the silica gel balls were placed in a sintering furnace, and the temperature was increased to 450°C at 2°C / min, and sintered for 4 hours. Then, the temperature was increased to 470°C at 1°C / min, and after sintering for 60 minutes, the silica gel balls were cooled in the furnace to obtain porous silica gel balls.

[0068] Wherein, the mixed gas is 95% argon and 5% oxygen;

[0069] The particle size distribution of polystyrene microspheres is 5~15nm.

[0070] Example 1

[0071] This embodiment provides a method for preparing cefotaxime, comprising the following steps:

[0072] S1: At 20°C, add 100 ml of dichloromethane to a dry reaction vessel equipped with effective ventilation and protection devices, then slowly add 20 g of 7-ACA, continue stirring at 120 rpm for 60 min, adjust the stirring speed to 60 rpm, then add 65 g of porous silica gel balls, stir for 15 min, then adjust the stirring speed to 80 rpm, continue stirring for 15 min, then adjust the stirring speed to 150 rpm, stir for 60 min, take samples regularly (30 min) during this period, and detect the content of 7-ACA in the solution by high performance liquid chromatography. The content is less than 0.5%, then let it stand for 1 hour, the system is separated into layers, filtered, and washed twice with dichloromethane, each time with an amount of dichloromethane of 200 ml. Stir gently for 5 minutes, filter, wash once with 400 ml of pure water, then wash twice with anhydrous ethanol, each time using 300 ml of ethanol, filter, and then evenly spread on a freeze-drying tray with a thickness not exceeding 2 cm, then transfer to a freeze dryer precooled to -40°C ~ -50°C, freeze for 3 hours, then turn on the vacuum pump of the freeze dryer, evacuate to between 6~10Pa, slowly heat to -10°C, control the heating rate at 0.5~1°C / min, dry for 12 hours, slowly pass dry high-purity nitrogen, return to normal pressure, take out, put in a desiccator, equilibrate at room temperature for 2 hours, and obtain 7-ACA loaded with porous silica gel balls, then transfer to a sealed container, and store in a dry and cool place;

[0073] S2: Cool the dry reaction vessel at 8°C using a low temperature bath, then add 200 ml of dichloromethane (water content not higher than 0.2%) and 6 ml of isopropanol, then slowly add 7-ACA and 1 g of sodium sulfite loaded on the porous silica gel balls in step S1, stir and mix for 10 min, slowly drop 22 g of AE-active ester and 14 ml of triethylamine, the dropping time is controlled at 30 min, stir and mix at a stirring speed of 80 rpm for 30 min, then heat to 15°C, the heating rate is controlled at 1°C / min, react for 60 min, filter, stand for 1 h to separate layers, extract with pure water three times, each time with 200 ml, combine the organic phases, and then add 4 g of active Carbon, slowly heat to 25 ° C, stir and decolorize for 30 minutes, then filter to remove activated carbon, add 120 ml of acetone to the filtrate, add 10% hydrochloric acid solution by mass, stir continuously at 40 rpm during titration, adjust the pH to about 3.0, slowly cool to 5 ° C at a cooling rate of 1 ° C / min, stir continuously at 40 rpm for 30 minutes to allow cefotaxime to fully crystallize, filter, wash the filter cake with pure water 3 times, each time with 100 ml, drain and then wash with acetone twice, each time with 50 ml, drain and dry in a vacuum drying oven at 40 ° C to constant weight, to obtain cefotaxime, the yield is 90.2%, the high pressure liquid purity is 98.1%, and the color is off-white.

[0074] Among them, the activated carbon is in powder form with a particle size distribution of 2~6nm. Before use, it is washed with 5% by mass dilute hydrochloric acid for 60 minutes, then washed with pure water until neutral, and then transferred to a drying oven at 105°C for 2 hours for use.

[0075] The porous silica gel spheres are obtained from Preparation Example 1.

[0076] Example 2

[0077] The difference between this embodiment and embodiment 1 is that:

[0078] In step S1, the amount of porous silica gel balls used is 50 g, and the porous silica gel balls come from Preparation Example 2;

[0079] The obtained cefotaxime has a yield of 92.1%, a high pressure liquid phase purity of 98.6%, and is off-white in color.

[0080] The rest is the same as in Example 1.

[0081] Example 3

[0082] The difference between this embodiment and embodiment 1 is that:

[0083] In step S1, the amount of porous silica gel balls used is 45 g, and the porous silica gel balls come from Preparation Example 3;

[0084] The obtained cefotaxime has a yield of 90.5%, a high pressure liquid phase purity of 98.3%, and is off-white in color.

[0085] The rest is the same as in Example 1.

[0086] Example 4

[0087] This embodiment provides a method for preparing cefotaxime, comprising the following steps:

[0088] S1: At 20°C, add 80 ml of dichloromethane to a dry reaction vessel equipped with effective ventilation and protection devices, then slowly add 20 g of 7-ACA, continue stirring at 120 rpm for 60 min, adjust the stirring speed to 60 rpm, then add 50 g of porous silica gel balls, stir for 15 min, then adjust the stirring speed to 80 rpm, continue stirring for 15 min, then adjust the stirring speed to 150 rpm, stir for 60 min, take samples regularly (30 min) during this period, and detect the content of 7-ACA in the solution by high performance liquid chromatography. The content is less than 0.5%, then stand for 1 hour, the system is separated into layers, filtered, and washed twice with dichloromethane, each time with 200 ml of dichloromethane, and gently Stir gently for 5 minutes, filter, wash once with 400 ml of pure water, then wash twice with anhydrous ethanol, each time using 300 ml of ethanol, filter, and then evenly spread on a freeze-drying tray with a thickness not exceeding 2 cm, then transfer to a freeze dryer precooled to -40°C ~ -50°C, freeze for 3 hours, then turn on the vacuum pump of the freeze dryer, evacuate to between 6~10Pa, slowly heat to -10°C, control the heating rate at 0.5~1°C / min, dry for 12 hours, slowly pass dry high-purity nitrogen, return to normal pressure, take out, put in a desiccator, equilibrate at room temperature for 2 hours, and obtain 7-ACA loaded with porous silica gel balls, then transfer to a sealed container, and store in a dry and cool place;

[0089] S2: Cool the dry reaction vessel at 5°C using a low temperature bath, then add 180 ml of ethylene dichloride (water content not higher than 0.2%) and 8 ml of isopropanol, then slowly add 7-ACA and 2 g of sodium sulfite loaded on the porous silica gel balls in step S1, stir and mix for 10 min, slowly drop 24 g of AE-active ester and 16 ml of triethylamine, the dropping time is controlled at 40 min, stir and mix at a stirring speed of 80 rpm for 30 min, then heat to 10°C, control the heating rate at 1°C / min, react for 90 min, filter, stand for 1 h to separate layers, extract with pure water three times, each time with 200 ml, combine the organic phases, and then add 5 g of active Carbon, slowly heat to 25 ° C, stir and decolorize for 30 minutes, then filter to remove activated carbon, add 120 ml of acetone to the filtrate, add 10% hydrochloric acid solution by mass fraction, keep stirring at 40 rpm during titration, adjust the pH to about 2.5, slowly cool to 5 ° C at a cooling rate of 1 ° C / min, keep stirring at 40 rpm for 30 minutes to make cefotaxime fully crystallize, filter, wash the filter cake with pure water for 3 times, each time with 100 ml, drain and wash twice with acetone, each time with 50 ml, drain and dry in a vacuum drying oven at 40 ° C to constant weight, to obtain cefotaxime, the yield is 92.5%, the high pressure liquid purity is 98.8%, and the color is off-white.

[0090] Among them, the activated carbon is in powder form with a particle size distribution of 2~6nm. Before use, it is washed with 5% by mass dilute hydrochloric acid for 60 minutes, then washed with pure water until neutral, and then transferred to a drying oven at 105°C for 2 hours for use.

[0091] The porous silica spheres are obtained from Preparation Example 2.

[0092] Example 5

[0093] This embodiment provides a method for preparing cefotaxime, comprising the following steps:

[0094] S1: At 25°C, add 80 ml of dichloroethane to a dry reaction vessel equipped with effective ventilation and protection devices, then slowly add 2 ml of triethylamine, stir and mix at 80 rpm for 20 min, then slowly add 17.7 g of di-tert-butyl dicarbonate and 20 g of 7-ACA under stirring at 80 rpm, adjust the stirring speed to 100 rpm, stir and mix for 2 h to obtain modified 7-ACA; cool to 20°C, adjust the stirring speed to 60 rpm, then add 50 g of porous silica gel balls, stir for 15 min, then adjust the stirring speed to 80 rpm, continue stirring for 15 min, then adjust the stirring speed to 150 rpm, stir for 60 min, take samples regularly (30 min) during this period, and detect the content of 7-ACA in the solution by high performance liquid chromatography. The content is less than 0.5%, then let it stand for 1 h, and the system Layering, filtering, washing with dichloromethane twice, each time with 200 ml of dichloromethane, stirring gently for 5 minutes, filtering, washing once with 400 ml of pure water, and then washing twice with anhydrous ethanol, each time with 300 ml of ethanol, filtering, and then evenly spreading on a freeze-drying tray with a thickness not exceeding 2 cm, and then transferred to a freeze dryer precooled to -40°C ~ -50°C, freezing for 3 hours, and then turning on the vacuum pump of the freeze dryer, evacuating to between 6~10Pa, slowly heating to -10°C, and controlling the heating rate at 0.5~1°C / min, drying for 12 hours, slowly passing dry high-purity nitrogen, returning to normal pressure, taking out, putting in a desiccator, equilibrate at room temperature for 2 hours, and obtaining 7-ACA loaded with porous silica gel balls, and then transferring to a sealed container, and storing in a dry and cool place;

[0095] S2: Cool the dry reaction vessel at 8°C using a low-temperature bath, then add 180 ml of dichloromethane (water content not higher than 0.2%) and 10 ml of isopropanol, then slowly add 7-ACA and 2 g of sodium bisulfite loaded on the porous silica gel balls in step S1, stir and mix for 10 min, slowly drop 24 g of AE-active ester and 16 ml of triethylamine, the dropping time is controlled at 40 min, stir and mix at a stirring speed of 80 rpm for 30 min, then heat to 25°C, control the heating rate at 1°C / min, react for 90 min, filter, stand for 1 h to separate layers, extract with pure water three times, each time with 200 ml, combine the organic phases, and then add 5 g Activated carbon, slowly heat to 25 ° C, stir and decolorize for 30 minutes, then filter to remove the activated carbon, add 120 ml of acetone to the filtrate, add 10% hydrochloric acid solution by mass, stir continuously at 40 rpm during titration, adjust the pH to about 2.5, slowly cool to 5 ° C at a cooling rate of 1 ° C / min, stir continuously at 40 rpm for 30 minutes to allow cefotaxime to fully crystallize, filter, wash the filter cake with pure water 3 times, each time with 100 ml, drain and then wash with acetone 2 times, each time with 50 ml, drain and dry in a vacuum drying oven at 40 ° C to constant weight to obtain cefotaxime with a yield of 93.6%, a high pressure liquid purity of 99.1%, and a white color.

[0096] Among them, the activated carbon is in powder form with a particle size distribution of 2~6nm. Before use, it is washed with 5% by mass dilute hydrochloric acid for 60 minutes, then washed with pure water until neutral, and then transferred to a drying oven at 105°C for 2 hours for use.

[0097] The porous silica spheres are obtained from Preparation Example 2.

[0098] Example 6

[0099] This embodiment provides a method for preparing cefotaxime, comprising the following steps:

[0100] S1: At 25°C, add 90 ml of acetone to a dry reaction vessel equipped with effective ventilation and protection devices, then slowly add 2.5 ml of triethylamine, stir and mix at 80 rpm for 20 min, then slowly add 19.4 g of di-tert-butyl dicarbonate and 20 g of 7-ACA under stirring at 80 rpm, adjust the stirring speed to 100 rpm, stir and mix for 2 h to obtain modified 7-ACA; cool to 20°C, adjust the stirring speed to 60 rpm, then add 45 g of porous silica gel balls, stir for 15 min, then adjust the stirring speed to 80 rpm, continue stirring for 15 min, then adjust the stirring speed to 150 rpm, stir for 60 min, take samples regularly (30 min) during this period, and detect the content of 7-ACA in the solution by high performance liquid chromatography. The content is less than 0.5%, then let it stand for 1 h, and the system Layering, filtering, washing with dichloromethane twice, each time with 200 ml of dichloromethane, stirring gently for 5 minutes, filtering, washing once with 400 ml of pure water, and then washing twice with anhydrous ethanol, each time with 300 ml of ethanol, filtering, and then evenly spreading on a freeze-drying tray with a thickness not exceeding 2 cm, and then transferred to a freeze dryer precooled to -40°C ~ -50°C, freezing for 3 hours, and then turning on the vacuum pump of the freeze dryer, evacuating to between 6~10Pa, slowly heating to -10°C, and controlling the heating rate at 0.5~1°C / min, drying for 12 hours, slowly passing dry high-purity nitrogen, returning to normal pressure, taking out, putting in a desiccator, equilibrate at room temperature for 2 hours, and obtaining 7-ACA loaded with porous silica gel balls, and then transferring to a sealed container, and storing in a dry and cool place;

[0101] S2: Cool the dry reaction vessel at 8°C using a low temperature bath, then add 160 ml of dichloromethane (water content not higher than 0.2%) and 8 ml of isopropanol, then slowly add 7-ACA and 2 g of sodium bisulfite loaded on the porous silica gel balls in step S1, stir and mix for 10 min, slowly drop 26 g of AE-active ester and 18 ml of triethylamine, the dropping time is controlled at 40 min, stir and mix at a stirring speed of 80 rpm for 30 min, then heat to 15°C, the heating rate is controlled at 1°C / min, react for 90 min, filter, stand for 1 h to separate layers, extract with pure water three times, each time with 200 ml, combine the organic phases, and then add 6 g of active The mixture was stirred for 30 minutes and then filtered to remove the activated carbon. 120 ml of acetone was added to the filtrate. A 10% hydrochloric acid solution was added dropwise. The pH was adjusted to about 2.5 at a temperature drop rate of 1 °C / min. The mixture was slowly cooled to 5 °C and stirred for 30 minutes at 40 rpm to allow the cefotaxime to fully crystallize. The mixture was filtered and the filter cake was washed with pure water for 3 times, each time with 100 ml of water. After being drained, the mixture was washed with acetone for 2 times, each time with 50 ml of water. After being drained, the mixture was dried in a vacuum drying oven at 40 °C to constant weight to obtain cefotaxime with a yield of 94.1%, a high pressure liquid purity of 99.3%, and a white color.

[0102] Among them, the activated carbon is in powder form with a particle size distribution of 2~6nm. Before use, it is washed with 5% by mass dilute hydrochloric acid for 60 minutes, then washed with pure water until neutral, and then transferred to a drying oven at 105°C for 2 hours for use.

[0103] The porous silica spheres are obtained from Preparation Example 3.

[0104] Example 7

[0105] This embodiment provides a method for preparing cefotaxime, comprising the following steps:

[0106] S1: At 25°C, add 100 ml of ethanol to a dry reaction vessel equipped with effective ventilation and protection devices, then slowly add 3 ml of triethylamine, stir and mix at 80 rpm for 20 min, then slowly add 21.0 g of di-tert-butyl dicarbonate and 20 g of 7-ACA under stirring at 80 rpm, adjust the stirring speed to 100 rpm, stir and mix for 2 h to obtain modified 7-ACA; cool to 20°C, adjust the stirring speed to 60 rpm, then add 50 g of porous silica gel balls, stir for 15 min, then adjust the stirring speed to 80 rpm, continue stirring for 15 min, then adjust the stirring speed to 150 rpm, stir for 60 min, take samples regularly (30 min) during this period, and detect the content of 7-ACA in the solution by high performance liquid chromatography. The content is less than 0.5%, then let it stand for 1 h, and the system is separated. layer, filter, wash twice with dichloromethane, each time with 200 ml of dichloromethane, gently stir for 5 minutes, filter, wash once with 400 ml of pure water, then wash twice with anhydrous ethanol, each time with 300 ml of ethanol, filter, and then evenly spread on a freeze-drying tray with a thickness not exceeding 2 cm, then transfer to a freeze dryer precooled to -40℃~-50℃, freeze for 3 hours, then turn on the vacuum pump of the freeze dryer, evacuate to between 6~10Pa, slowly heat to -10℃, control the heating rate at 0.5~1℃ / min, dry for 12 hours, slowly pass dry high-purity nitrogen, return to normal pressure, take out, put in a desiccator, equilibrate at room temperature for 2 hours, and obtain 7-ACA loaded with porous silica gel balls, then transfer to a sealed container, and store in a dry and cool place;

[0107] S2: Cool the dry reaction vessel at 8°C using a low temperature bath, then add 160 ml of dichloromethane (water content not higher than 0.2%) and 8 ml of isopropanol, then slowly add 7-ACA and 2 g of sodium bisulfite loaded on the porous silica gel balls in step S1, stir and mix for 10 min, slowly drop 28 g of AE-active ester and 18 ml of triethylamine, the dropping time is controlled at 40 min, stir and mix at a stirring speed of 80 rpm for 30 min, then heat to 15°C, the heating rate is controlled at 1°C / min, react for 90 min, filter, stand for 1 h to separate layers, extract with pure water three times, each time with 200 ml, combine the organic phases, and then add 6 g of active The mixture was stirred for 30 minutes and then filtered to remove the activated carbon. 120 ml of acetone was added to the filtrate. A 10% hydrochloric acid solution was added dropwise. The pH was adjusted to about 2.5 at a temperature drop rate of 1 °C / min. The mixture was slowly cooled to 5 °C at a temperature drop rate of 1 °C / min. The mixture was stirred for 30 minutes at 40 rpm to allow the cefotaxime to fully crystallize. The mixture was filtered and the filter cake was washed with pure water for 3 times with 100 ml of water each time. After being drained, the mixture was washed with acetone for 2 times with 50 ml of water each time. After being drained, the mixture was dried in a vacuum drying oven at 40 °C to constant weight to obtain cefotaxime with a yield of 94.3%, a high pressure liquid purity of 98.9%, and a color off-white.

[0108] Among them, the activated carbon is in powder form with a particle size distribution of 2~6nm. Before use, it is washed with 5% by mass dilute hydrochloric acid for 60 minutes, then washed with pure water until neutral, and then transferred to a drying oven at 105°C for 2 hours for use.

[0109] The porous silica spheres are obtained from Preparation Example 2.

[0110] Comparative Example 1

[0111] This comparative example provides a method for preparing ceftriaxone, comprising the following steps:

[0112] S1: Cool the dry reaction vessel at 8°C using a low temperature bath, then add 200 ml of dichloromethane (water content not higher than 0.2%) and 6 ml of isopropanol, then slowly add 20 g of 7-ACA and 1 g of sodium sulfite, stir and mix for 10 min, slowly drop 22 g of AE-active ester and 14 ml of triethylamine, the dropping time is controlled at 30 min, stir and mix at a stirring speed of 80 rpm for 30 min, then heat to 15°C, the heating rate is controlled at 1°C / min, react for 60 min, filter, stand for 1 h to separate layers, extract with pure water three times, each time with 200 ml, combine the organic phases, then add 4 g of activated carbon, slowly rise to 15°C, and heat to 15°C. Warm to 25°C, stir and decolorize for 30 minutes, then filter to remove activated carbon, add 120 ml of acetone to the filtrate, add 10% hydrochloric acid solution by mass, stir continuously at 40 rpm during titration, adjust pH to about 3.0, slowly cool to 5°C at a cooling rate of 1°C / min, stir continuously at 40 rpm for 30 minutes to allow cefotaxime to fully crystallize, filter, wash the filter cake with pure water 3 times, each time with 100 ml, drain and wash twice with acetone, each time with 50 ml, drain and dry in a vacuum drying oven at 40°C to constant weight to obtain cefotaxime with a yield of 84.1%, a high pressure liquid purity of 94.6%, and a slightly yellowish color.

[0113] Among them, the activated carbon is in powder form with a particle size distribution of 2~6nm. Before use, it is washed with 5% by mass dilute hydrochloric acid for 60 minutes, then washed with pure water until neutral, and then transferred to a drying oven at 105°C for 2 hours for use.

[0114] Comparative Example 2

[0115] The difference between this comparative example and Example 1 is:

[0116] The porous silica gel spheres are derived from Comparative Preparation Example 1.

[0117] The prepared cefotaxime has a yield of 88.6%, a high pressure liquid phase purity of 97.2%, and is off-white in color.

[0118] The rest is the same as in Example 1.

[0119] Comparative analysis of Example 1 and Comparative Examples 1-2 shows that the use of porous silica gel balls to load 7-ACA significantly improves the purity and yield of cefotaxime. This is because: first, the dispersibility and stability of 7-ACA in the reaction system are improved, the collision opportunities with AE-active ester and triethylamine are increased, and the reaction environment is relatively fixed, which reduces the probability of unnecessary side reactions between 7-ACA and other impurity molecules, and the reaction path is relatively more specific, thereby improving the yield and purity of cefotaxime.

[0120] Secondly, by hydroxylating the polystyrene microspheres, not only the contact probability between 7-ACA, AE-active ester and triethylamine is increased, but also the porous silica gel balls have a certain alkaline buffering capacity, making the alkaline environment of the system milder, reducing the ring opening of cefotaxime due to excessive alkalinity, thereby further improving the purity and yield of cefotaxime.

[0121] Comparative analysis of Examples 1 to 3 shows that as the pore size of the porous silica gel ball increases, the yield of the prepared cefotaxime gradually increases, but the purity shows a trend of first increasing and then decreasing. This is because as the pore size of the porous silica gel ball increases, it is easier for AE-active ester, triethylamine and solvent molecules to enter the pores of the silica gel ball, thereby improving the contact efficiency between 7-ACA, AE-active ester and triethylamine, thereby accelerating the reaction rate, and gradually increasing the yield of cefotaxime.

[0122] In the early stage of pore size increase, the pore structure of the porous silica sphere may be more conducive to the formation of the target product cefotaxime, and the inhibitory effect on side reactions is enhanced, thereby improving the purity of the product. However, when the pore size increases to a certain extent, the pore structure may become too open, which may make some side reactions more likely to occur, and these side reactions may produce impurities, thereby reducing the purity of cefotaxime.

[0123] Comparative analysis of Example 2 and Example 4 shows that the yield and purity of the prepared cefotaxime are improved by appropriately increasing the amount of AE-active ester. This is because: appropriately increasing the amount of AE-active ester can, on the one hand, ensure a more complete reaction and reduce unreacted 7-ACA, thereby increasing the yield; on the other hand, it can make the main reaction more dominant, thereby reducing the occurrence of side reactions, which is beneficial to improving the purity of cefotaxime.

[0124] Comparative analysis of Examples 4 to 7 shows that the purity and yield of cefotaxime obtained after 7-ACA was modified with di-tert-butyl dicarbonate were improved. This is because: 7-ACA was modified with di-tert-butyl dicarbonate and then loaded onto the porous silica gel ball, which not only avoided the occurrence of multiple side reactions between the active amino group on 7-ACA and other reactants, but also enabled 7-ACA to effectively participate in the reaction, thereby improving the efficiency of the reaction, and increasing the yield and purity.

[0125] In addition, after 7-ACA is modified with di-tert-butyl dicarbonate, the molecular structure becomes larger. After the pore size of the porous silica gel ball is appropriately increased, 7-ACA is evenly distributed on the surface and inside of the silica gel ball, which is beneficial to reduce the formation of by-products; at the same time, it also helps the product to diffuse out from the inside of the silica gel ball, which is beneficial to improve the conversion rate of the reaction, and then improve the yield and purity of cefotaxime.

[0126] Spectrum detection and analysis

[0127] (1) Detection 1

[0128] Take about 2 mg of cefotaxime prepared in Example 1 and 180 mg of potassium bromide, grind and mix them evenly, press them into transparent sheets in a mold, and then perform Fourier transform infrared spectroscopy detection. Figure 1 .

[0129] (2) Test 2

[0130] Instrument: High performance liquid chromatograph, chromatographic column, octadecylsilane bonded silica gel as filler, specification 3.9mm×150mm×5μm, ultraviolet absorption detector.

[0131] Phosphate buffer: Take 60 mg of potassium dihydrogen phosphate and 1.2 g of disodium hydrogen phosphate, add water to dilute to 1000 ml, take 890 ml to a 1000 ml beaker, add 110 ml of methanol, mix well, and then adjust the pH to 6.25 with 5% phosphoric acid; methanol: phosphate buffer = 11:89.

[0132] Detection wavelength: 235nm

[0133] Column temperature: 30°C

[0134] Flow rate: 1.0ml / min

[0135] Injection volume: 20 μl

[0136] Cefotaxime solution: Take 20 mg of each cefotaxime in Examples 1 to 3, accurately weigh them, place them in 50 ml volumetric flasks, dissolve them in water and dilute them to the 50 ml mark, shake them well, accurately pipette 5 ml of each, place them in 100 ml volumetric flasks, dilute them to the 100 ml mark with water, shake them well to obtain sample 1 (cefotaxime solution from Example 1), sample 2 (cefotaxime solution from Example 2) and sample 3 (cefotaxime solution from Example 3), then inject samples 1 to 3 into liquid chromatograph for analysis, and the specific results are shown in Figure 2~Figure 4 and Table 1~Table 2.

[0137] Table 1 Figure 3 Data of HPLC spectrum of ceftriaxone

[0138]

[0139] Table 2 Figure 4 Data of HPLC spectrum of ceftriaxone

[0140]

[0141] analyze Figure 1It can be seen that a careful comparison of the infrared spectrum of Example 1 with the infrared spectrum of standard cefotaxime shows that the product prepared in Example 1 is cefotaxime.

[0142] analyze Figure 2~Figure 4 From Table 1 to Table 2, we can see that:

[0143] First, compared with Example 1 and Example 3, in Example 2, the peak area and peak area ratio of some impurities in the prepared cefotaxime are slightly reduced, and the peak area and main peak area ratio of cefotaxime are slightly increased, indicating that the optimization of the pore size of the porous silica gel helps to remove impurities. Although the types of impurities remain unchanged, the total amount of impurities is reduced, thereby improving the purity of cefotaxime to a certain extent.

[0144] At the same time, the retention time and tailing factor of some impurities and cefotaxime increased, which may be due to the fact that in the process of preparing cefotaxime in Example 2, the reaction was more complete, so that the content of the target product cefotaxime in the product increased, thereby improving the purity and yield. In addition, it may also be due to the reduction in the content of certain impurities, resulting in changes in the physical and chemical properties of the product, thereby affecting its retention behavior on the chromatographic column, so that the retention time and tailing factor are increased.

[0145] Secondly, compared with Example 1 and Example 3, in Example 2, the peak area of ​​cefotaxime and the proportion of the main peak area of ​​cefotaxime in the prepared cefotaxime are slightly increased, indicating that optimizing the pore size of the porous silica gel increases the yield of cefotaxime. This may be due to the suitable pore size of the porous silica gel, which enhances the adsorption of the reactants and the diffusion effect of the products, selectively promotes the synthesis path of cefotaxime, inhibits the occurrence of side reactions, and increases the synthesis probability of cefotaxime, thereby increasing the yield.

[0146] Finally, combined with the results of three liquid phase chromatogram tests, it can be seen that ceftriaxone in Example 2 has a large peak area and a high concentration, which indicates that it has a high content and high purity in the sample and has a good chromatographic separation effect. The impurities A / B / C / D / E / F / G that have been identified are helpful for a more comprehensive assessment of the quality of the sample.

Claims

1. A method for preparing cefotaxime, characterized in that: The steps include: 7-ACA is dissolved in an organic solvent A, and then porous silica balls are added, mixed for 90 to 120 minutes, washed, and dried to obtain 7-ACA loaded on the porous silica balls; then 7-ACA loaded on the porous silica balls, AE-active ester, antioxidant, and triethylamine are uniformly dispersed in an organic solvent B, reacted at 10 to 25° C. for 60 to 90 minutes, solid-liquid separation, extraction, acidification, crystallization, washing, and drying are performed to obtain cefotaxime; The organic solvent B includes ethylene dichloride and isopropanol, and the mass volume ratio of the 7-ACA to the AE-active ester, triethylamine, ethylene dichloride, and isopropanol is 1g: (1.1-1.4)g: (0.7-0.9)ml: (8-10)ml: (0.3-0.5)ml; The method for preparing the porous silica gel ball comprises the following steps: S11: dispersing polystyrene microspheres in ethanol to obtain a polystyrene microsphere dispersion, then subjecting the polystyrene microsphere dispersion to plasma treatment for 4 to 6 minutes, washing, and drying to obtain pretreated polystyrene microspheres; S12: taking a hydrogen peroxide solution, adding ethylenediaminetetraacetic acid and mixing evenly, adjusting the pH to 4.5-5.0, and then adding polystyrene microspheres, mixing for 90-120 minutes, solid-liquid separation, washing, and drying to obtain hydroxylated polystyrene microspheres; S13: dispersing hydroxylated polystyrene microspheres in an ethanol aqueous solution, adjusting the pH to 7.5-8.5, heating to 40-60°C, then adding ethyl orthosilicate, keeping the temperature for 2-4 hours, cooling, washing, and drying to obtain silica gel balls; S14: sintering at 450-550°C for 2-4 hours under an inert atmosphere, raising the temperature to 470-570°C, keeping the temperature for 40-60 minutes, and cooling to obtain porous silica gel balls; The mass ratio of the polystyrene microspheres to tetraethyl orthosilicate is about 1:2-6; The particle size distribution of the polystyrene microspheres is 5-50 nm.

2. The method for preparing cefotaxime according to claim 1, characterized in that: The mass ratio of the porous silica gel balls to 7-ACA is 1:0.3-0.

5.

3. The method for preparing cefotaxime according to claim 2, characterized in that: The mass fraction of the hydrogen peroxide solution is 10%-20%, and the mass volume ratio of the polystyrene microspheres to the hydrogen peroxide solution is 1g:(10-12)ml.

4. The method for preparing cefotaxime according to claim 3, characterized in that: The 7-ACA is modified 7-ACA. The preparation method of the modified 7-ACA comprises the following steps: uniformly mixing an organic solvent A and triethylamine, adding di-tert-butyl dicarbonate and 7-ACA, and stirring and mixing for 1 to 3 hours to obtain modified 7-ACA; The mass volume ratio of the 7-ACA to di-tert-butyl dicarbonate, the organic solvent A, and triethylamine is 1 g: (0.9-1) g: (4-5) ml: (0.1-0.15) ml.

5. The method for preparing cefotaxime according to claim 4, characterized in that: The organic solvent A is any one of ethylene dichloride, acetone and ethanol.

6. The method for preparing cefotaxime according to claim 5, characterized in that: The amount of EDTA used is 0.05% to 0.12% of the mass of the polystyrene microspheres.

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