Method for preparing high-purity ceftaroline fosamil sodium salt and ceftaroline fosamil through nanofiltration

Abstract

The invention belongs to the technical field of medical chemistry, and particularly relates to a method for preparing high-purity ceftaroline fosamil sodium salt and ceftaroline fosamil through nanofiltration. The method for preparing the high-purity ceftaroline fosamil sodium salt through nanofiltration comprises the following steps: firstly, purifying a ceftaroline fosamil sodium salt crude product to obtain a collection solution; then carrying out nanofiltration concentration on the collected liquid by using a 200D-500D nanofiltration membrane to obtain a concentrated solution; and finally, crystallizing the concentrated solution. The method for preparing high-purity ceftaroline fosamil through nanofiltration comprises the following steps: dissolving prepared ceftaroline fosamil sodium salt in water, and then adding acetic acid; stirring and dissolving the system, and filtering; dropwise adding sulfuric acid until the pH value is 0.5-2; and filtering, washing a filter cake, and drying to obtain the ceftaroline fosamil. By controlling nanofiltration parameters, the product purity is not obviously changed in the nanofiltration concentration process, and the stable yield is ensured; and the system after nanofiltration is relatively stable, so that the product cannot be degraded after being placed for a long time during production. The scheme is large in batch and suitable for continuous batch production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemistry, specifically relating to a method for preparing high-purity cefuroxime sodium salt and cefuroxime by nanofiltration. Background Technology

[0002] Ceftaroline fosamil (Formula 1) belongs to the latest fifth-generation cephalosporin antibiotics. It is used to treat community-acquired bacterial enteritis (CABP) and acute bacterial skin and skin tissue infections (ABSSSI) in adults, including methicillin-resistant Staphylococcus aureus (MRSA) infections. Developed by Takeda Pharmaceutical Company of Japan, this antibiotic entered the US market in 2010 under the brand name "Teflaro" and the European Union in 2012 under the brand name "Zinforo". MRSA often develops resistance to certain antibiotics, including methicillin and many other commonly used antibiotics such as penicillin, oxacillin, and amoxicillin. Therefore, new, more potent, and resistant antibacterial drugs are needed to ensure patient health and safety. Ceftaroline fosamil injection has strong antibacterial activity against most Gram-negative bacteria, Gram-negative anaerobes, and Gram-positive anaerobes, and its adverse reactions are milder and its safety profile is better compared to other cephalosporins, making it an ideal alternative antibacterial drug. This antibiotic is not yet available in China.

[0003]

[0004] Formula 1: Cefuroxime The original research was reported in 2003 by Takeda Pharmaceutical Company of Japan in patent CN1462275A, which describes a method for synthesizing cefuroxime aspirin. First, crude sodium salt is synthesized using two commercially available fragments. This crude sodium salt is then purified by column chromatography using a polymer resin packing material SP-207 to obtain a pure sodium salt solution (CN1462275A, Reference Example 25). The low-concentration, qualified fraction after column chromatography is then concentrated by vacuum distillation to obtain the pure sodium salt, as shown in Route 1 below.

[0005]

[0006] Route 1 This method is currently the main industrial method; patent CN110872322 directly uses activated carbon for decolorization and then adds ethanol for crystallization, which is a similar method in the original research, and the experimental example (24) in the literature (Bioorganic & Medicinal Chemistry 11 (2003) 2427–2437) also uses the method of adding ethanol to the separated aqueous phase to precipitate solids; the inventors later tried to use activated carbon or resin adsorption, although they were able to control the impurities to <0.5%, but far from meeting the requirement of <0.15%.

[0007] According to the original research process, the product deteriorates significantly during vacuum distillation concentration, leading to reduced yield and increased costs. Furthermore, because cephalosporin compounds contain unstable β-lactam structures, and these structures become even more complex and less stable after modification, the product deteriorates even during room temperature concentration of the aqueous solution. Additionally, in industrial production, low-temperature (<20°C) concentration of the aqueous solution is difficult and slow, consuming a considerable amount of time and hindering large-scale production. Therefore, developing an industrially viable production method for high-purity cefuroxime alim is of significant commercial and social value. Summary of the Invention

[0008] To address the shortcomings of existing technologies, this invention provides a method for preparing high-purity cefuroxime sodium salt and cefuroxime by nanofiltration.

[0009] To achieve the objectives of this invention, the following technical solution is adopted: A method for preparing high-purity cefuroxime sodium salt by nanofiltration, characterized by comprising the following steps: (1) The crude cefuroxime sodium salt was purified to obtain the collected solution; (2) The collected liquid is concentrated by nanofiltration using a 200D-500D nanofiltration membrane to obtain a concentrated liquid; (3) The concentrate is crystallized to obtain the product.

[0010] Preferably, the nanofiltration membrane in step (2) has a molecular weight cutoff of 400D.

[0011] Preferably, in step (2), the temperature of the collected liquid is adjusted to 2-15℃.

[0012] Preferably, in step (2), the temperature of the collected liquid is adjusted to 2-8℃.

[0013] Preferably, the nanofiltration concentration in step (2) is at 0.4 M 2 Under the given membrane size conditions, the pump speed is 30-80 r / s, the system pressure is 0.5 MPa to 2.5 MPa, and the outlet flow rate is 50-150 mL / min.

[0014] Preferably, the nanofiltration concentration pump in step (2) has a rotation speed of 40-60 r / s, a system pressure of 1.5 MPa-2.0 MPa, and an outlet flow rate of 50-70 mL / min.

[0015] Preferably, the concentration of cefuroxime sodium salt in the concentrate in step (2) is 6%-10%.

[0016] Preferably, the purification in step (1) is to purify the crude product by polymer resin column chromatography, wherein the polymer resin is selected from SP-207 and LX-2210; the particle size of the polymer resin is 50-150 μm.

[0017] Preferably, the crystallization in step (3) includes adding sodium chloride and sodium acetate to the concentrate, adding solvent, and crystallizing at 10-25°C for 2-8 hours.

[0018] Preferably, in step (1), the preparation of the crude product is described in accordance with the original patent CN1462275A, and with reference to Example 22 and Example 25.

[0019] Preferably, the concentration of the buffer salt phase in step (1) purification process is 0.10~0.20 mol / L sodium acetate, preferably 0.15 mol / L; the pH range of the buffer salt phase in this process is 6.5~8.5, preferably 7.0-8.0; the organic phase in this process is an alcohol solvent, such as methanol, ethanol or isopropanol.

[0020] Preferably, the percentage content of cefuroxime sodium salt in the collected solution in step (2) is less than 2.0%.

[0021] Preferably, the nanofiltration temperature is 2-8°C; Preferably, the nanofiltration endpoint is a cefuroxime sodium salt content between 7% and 9%.

[0022] In step (3), sodium chloride is added to the concentrate at a weight of 0.1-0.3 equivalents relative to the crude product, preferably 0.2 equivalents; sodium acetate is added to the nanofiltration solution at a weight of 0.1-0.3 equivalents, preferably 0.2 equivalents.

[0023] Step (3): The crystallization temperature is preferably 10-15℃; the amount of undesirable solvent alcohol added is 1 to 3 times the volume of the remaining liquid after nanofiltration, preferably 2 times the volume; the stirring time after crystallization is 2-8 h, preferably 3-5 h.

[0024] Ethanol is preferred as a poor solvent.

[0025] The second objective of this invention is to provide a method for preparing high-purity cefuroxime ester by nanofiltration. The method involves dissolving the sodium salt of cefuroxime ester obtained by crystallization in water, then adding acetic acid; stirring and dissolving the system and filtering; then controlling the temperature at 10-30℃ and adding sulfuric acid dropwise until the pH is between 0.5-2; filtering, washing the filter cake, and vacuum drying at 10-20℃ to constant weight to obtain cefuroxime ester.

[0026] Preferably, the crystallized solid is dissolved in 3-6 times its volume of purified water, and then 3-6 times its volume of acetic acid is added; the system is stirred and dissolved, and then filtered; 3M sulfuric acid is added dropwise at a temperature controlled at 10-30℃, preferably 15-20℃, until the pH is between 1-1.5. Then, the mixture is stirred at a temperature controlled at 10-30℃, preferably 15-20℃, for 10-24 h, preferably 15-20 h. After filtration, the filter cake is washed with a mixed solvent of acetic acid / H2O; the volume ratio of acetic acid / water is between 1:1 and 3:1, preferably 2:1; the product is vacuum dried at 10-20℃ to constant weight to obtain cefuroxime azoxystrobin.

[0027] Compared with the prior art, the beneficial effects of the present invention are as follows: (1) Nanofiltration membranes are semi-permeable membranes with asymmetric microporous structures, which can separate mixtures of molecules with different particle sizes at the molecular level, achieving selective separation. Pressure and flow rate are provided by a material pump, causing the material to flow at high speed on the membrane surface with sufficient pressure; the material undergoes dynamic cross-flow filtration on the membrane surface, and the separation of substances is achieved through the asymmetric microporous membrane layer of the membrane itself, so that large molecules are retained by the membrane, while water and solutes permeate through the membrane layer; after filtration, the concentrated large molecule liquid is returned to the material tank for continuous circulation filtration. This invention can achieve rapid concentration under mild conditions by controlling the pressure, flow rate, nanofiltration temperature and concentration provided by the material pump, realizing a high-purity and high-efficiency nanofiltration process, thus providing a convenient method for the industrial production of cefuroxime ester.

[0028] (2) By controlling the nanofiltration parameters, the present invention ensures that the purity of the product does not change significantly during the nanofiltration concentration process, thus guaranteeing a stable yield; while the vacuum distillation concentration process used in the existing original patents significantly reduces the purity of the product, resulting in a lower yield.

[0029] (3) Nanofiltration is easy to operate, suitable for industrial scale-up, and highly efficient. In the production process, only the area of ​​the nanofiltration membrane needs to be linearly increased to achieve a concentration of 10 t within 8 hours, which is significantly faster than vacuum distillation for water concentration.

[0030] (4) The nanofiltration system of the present invention is relatively stable, ensuring that the production process will not degrade after long-term storage.

[0031] (5) The final product, cefuroxime aspirin, is of good quality. It can ensure that the U4 impurity is within the range of <0.10% (actually <0.05%). This method is suitable for large-scale continuous batch production. Detailed Implementation

[0032] The present invention will be further described below with reference to specific embodiments. All the following raw materials are commercially available conventional raw materials; Preparation of crude cefuroxime azoxystrobin sodium salt:

[0033] To a 2 L three-necked flask, add intermediate 1 (130 g, 0.271 mol), purified water (800 mL), and a 3M sodium acetate aqueous solution (181 mL, 0.542 mol). Then add triethylamine (200 mL, 1.44 mol). Cool the system to 0–10 °C in an ice-water bath. To another 500 mL three-necked flask, add intermediate 2 (114.4 g, 325 mmol) and tetrahydrofuran (310 mL); cool the 500 mL mixture to -10 °C, and then slowly add it dropwise to the 2 L reaction flask containing intermediate 1. Maintain the internal temperature of the 2 L reaction flask at 15–25 °C during the dropwise addition. After 2 h of reaction, add a 3M sodium acetate aqueous solution (578 mL, 1.74 mol) and ethyl acetate (650 mL) to the system. The aqueous phase was separated, and then ethanol (3 L) was added to the aqueous phase at 0-10℃. The system was stirred for 30 min and then filtered. The filter cake was dried with nitrogen to obtain 138 g of crude product, with a yield of 70%.

[0034] Following the above method for preparing the crude product, intermediate 1 (141.3 g) and intermediate 2 (123.6 g) were fed to obtain 152.4 g of crude product, with a yield of 71%.

[0035] Example 1 1.1 Preparation of high-purity cefuroxime azoxystrobin sodium salt The crude product (138 g) was dissolved in a 150 mmol / L sodium acetate aqueous solution. The pH of the system was adjusted to 7.0 using acetic acid, and the solution was filtered before column purification. Glass column specifications: 49 mm (ID) * 460 mm (L); UV wavelength: 350 nm (preferred); flow rate: 100 mL / min; mobile phase A: 0.15 M NaOAc aqueous solution; mobile phase B: ethanol. The combined qualified solution yielded 6279 g, with a purity of 2.0% (yield 91%, containing 125.6 g of product) and a purity of 96.11%.

[0036] A qualified low-concentration dilute solution (2.0% concentration, 6279 g) was added to the nanofiltration tank, and then the internal temperature was lowered to 2°C. The nanofiltration membrane was replaced with a 300D 0.4 M membrane. 2Membrane setup; adjust rotation speed to 50 rpm; adjust pressure to 1.5 MPa, begin nanofiltration; nanofiltration flow rate approximately 60 mL / min. After approximately 1 hour, the concentration is detected to be approximately 7.0%, reaching the endpoint of nanofiltration, and nanofiltration is stopped. Then, the concentrated solution after nanofiltration is discharged, and the nanofiltration pipeline is rinsed with 50 mL of purified water; the rinsing solution is combined with the nanofiltrate. Sodium chloride (25 g) and sodium acetate (25 g) are added to the nanofiltrate, stirred until dissolved, and the system is cooled to 10-15℃. Then, ethanol (1840 mL) is added dropwise to the system. The mixture is stirred at 10-15℃ for 2 hours, filtered, and dried under nitrogen to obtain 119.3 g of nanofiltration solid pure sodium salt, yield 95%; purity 99.23%.

[0037] 1.2 Preparation of high-purity cefuroxime azoxystrobin Add purified water (520 mL) to a 2 L three-necked flask and cool to 10-15 °C. Add the solid from Example 1 (119 g) and stir for 30 min until dissolved. Then add acetic acid (598 mL) and stir for 15 min. Filter into another 2 L three-necked flask. Maintain the temperature of the 2 L three-necked flask at 10 °C and begin adding 2 M H₂SO₄ aqueous solution dropwise until the pH of the system reaches 1.5. Maintain the temperature of the system at 15 °C and stir overnight. Filter by suction, wash the filter cake with a mixed solvent of acetic acid / water (1:1) (150 mL), and then dry the filter cake at 25 °C with a nitrogen stream to obtain 93.3 g of off-white solid, yield 75%, purity 99.53%.

[0038] Comparative Example 1 1.1 The preparation of high-purity cefuroxime azoxystrobin sodium salt is as follows: The crude product (152.4 g) was dissolved in a 150 mmol / L sodium acetate aqueous solution, and the pH of the system was adjusted to 7.0 using acetic acid. After filtration, it was used for column purification. Glass column specifications: 49 mm (ID) * 460 mm (L); flow rate: 100 mL / min; mobile phase A: 0.15 M NaOAc aqueous solution; mobile phase B: ethanol. UV wavelength: 350 nm; the total amount of qualified solution after mixing was 6858 g, with a purity of 2.1% (137.2 g, yield 90%).

[0039] The qualified solution was concentrated to approximately 2 L by distillation under reduced pressure (-0.095 MPa, 25-30 °C). Sodium chloride (25 g) and sodium acetate (25 g) were added to the concentrate, and after stirring until dissolved, the system was cooled to 10-15 °C. Then, ethanol (2000 mL) was slowly added dropwise. The mixture was stirred at 10-15 °C for 2 h, filtered, and the filter cake was dried under a nitrogen stream to constant weight to obtain 71.3 g of pure sodium salt after nanofiltration, with a yield of 52% and a purity of 87.41%.

[0040] The comparison between this comparative example and Example 1 illustrates that the sodium salt yield obtained by vacuum concentration is 52%, significantly lower than the 95% yield of Example 1. The purity of the sodium salt obtained by vacuum concentration (87.41%) is significantly lower than the purity of the sodium salt obtained by nanofiltration (99.23%). This demonstrates the significant advantages of nanofiltration concentration.

[0041] 1.2 The preparation of cefuroxime axetil is as follows: Add purified water (300 mL) to a 2 L three-necked flask and cool to 15 °C. Add the solid from the previous step (68.6 g, purity 87.4%) and stir for 30 min until dissolved. Then add acetic acid (344 mL) and stir for 15 min, then filter into another 2 L three-necked flask. Maintain the temperature in the 2 L three-necked flask at 15 °C and begin adding 2 M H2SO4 aqueous solution dropwise until the pH of the system reaches 1.5. Maintain the temperature at 10-15 °C and stir overnight. Filter by suction, wash the filter cake with a mixed solvent of acetic acid / water = 1:1 (86 mL), then dry the filter cake under a nitrogen stream at 25 °C to obtain 43.8 g of off-white solid, purity 92.0%, yield 61%.

[0042] The comparison between the comparative example and Example 1 illustrates that the purity of cefuroxime ester obtained by vacuum concentration and salt formation (92.0%) is significantly lower than the purity of cefuroxime ester obtained by nanofiltration (99.5%). This indicates that nanofiltration can maintain purity and avoid degradation, thus yielding high-purity cefuroxime ester. Vacuum concentration, due to degradation, results in low purity sodium salt, leading to a final cefuroxime ester purity of only 92.0%, far lower than that obtained by nanofiltration.

[0043] Example 2 2.1 Preparation of high-purity cefuroxime azoxystrobin sodium salt The crude product (138 g) was dissolved in a 150 mmol / L sodium acetate aqueous solution. The pH of the system was adjusted to 7.0 using acetic acid, and the solution was filtered before column purification. Glass column specifications: 49 mm (ID) * 460 mm (L); UV wavelength: 350 nm (preferred); flow rate: 100 mL / min; mobile phase A: 0.15 M NaOAc aqueous solution; mobile phase B: ethanol. The combined qualified solution yielded 6190 g, with a purity of 2.1% (94% yield, containing 130.0 g of product) and a purity of 95.85%.

[0044] A qualified low-concentration dilute solution (2.1% concentration, 6190 g) was added to the nanofiltration tank, and then the internal temperature was lowered to 15°C. The nanofiltration membrane was replaced with a 500D 0.4 M membrane. 2Membrane setup; adjust rotation speed to 30 rpm; adjust pressure to 1.0 MPa, begin nanofiltration; nanofiltration flow rate 100 mL / min. After approximately 1 hour, the concentration is detected to be approximately 7.0%, reaching the endpoint of nanofiltration, and nanofiltration is stopped. Then, the concentrated solution after nanofiltration is discharged, and the nanofiltration pipeline is rinsed with 50 mL of purified water, and the rinsing solution is combined with the nanofiltrate. Sodium chloride (25 g) and sodium acetate (25 g) are added to the nanofiltrate, stirred until dissolved, and the system is cooled to 10-15℃. Then, ethanol (1840 mL) is added dropwise to the system. The mixture is stirred at 15℃ for 2 hours, filtered, and dried under a nitrogen stream to obtain the nanofiltration solid pure sodium salt.

[0045] 2.2 The preparation of high-purity cefuroxime azoxystrobin is as follows: Add purified water (520 mL) to a 2 L three-necked flask and cool to 10-15 °C. Add the solid from Example 2 (119 g) and stir for 30 min until dissolved. Then add acetic acid (598 mL) and stir for 15 min. Filter into another 2 L three-necked flask. Maintain the temperature of the 2 L three-necked flask at 15 °C and begin adding 2 M H2SO4 aqueous solution dropwise until the pH of the system reaches 1.5. Maintain the temperature of the system at 10 °C and stir overnight. Filter by suction, wash the filter cake with a mixed solvent of acetic acid / water (1:1) (150 mL), and then dry the filter cake at 15 °C with a nitrogen stream to obtain an off-white solid.

[0046] Example 3 3.1 Preparation of high-purity cefuroxime azoxystrobin sodium salt The crude product (138 g) was dissolved in a 150 mmol / L sodium acetate aqueous solution. The pH of the system was adjusted to 7.0 using acetic acid, and the solution was filtered before column purification. Glass column specifications: 49 mm (ID) * 460 mm (L); UV wavelength: 350 nm (preferred); flow rate: 100 mL / min; mobile phase A: 0.15 M NaOAc aqueous solution; mobile phase B: ethanol. The combined qualified solution yielded 6425 g, with a purity of 2.0% (yield 93%, containing 128.5 g of product) and a purity of 97.05%.

[0047] A qualified low-concentration dilute solution (2% concentration, 6425 g) was added to the nanofiltration tank, and then the internal temperature was lowered to 8°C. The nanofiltration membrane was replaced with a 400D 0.4 M membrane. 2Membrane setup; adjust rotation speed to 60 rpm; adjust pressure to 2.0 MPa, begin nanofiltration; nanofiltration flow rate approximately 70 mL / min. After approximately 1 hour, the concentration is measured to be approximately 7.0%, reaching the endpoint of nanofiltration, and nanofiltration is stopped. Then, the concentrated solution after nanofiltration is discharged, and the nanofiltration pipeline is rinsed with 50 mL of purified water; the rinsing solution is combined with the nanofiltrate. Sodium chloride (25 g) and sodium acetate (25 g) are added to the nanofiltrate, stirred until dissolved, and the system is cooled to 15°C. Then, ethanol (1840 mL) is added dropwise to the system. The mixture is stirred at 10°C for 2 hours, filtered, and dried under a nitrogen stream to obtain the nanofiltration solid pure sodium salt.

[0048] 3.2 Preparation of high-purity cefuroxime azoxystrobin Add purified water (520 mL) to a 2 L three-necked flask and cool to 10 °C. Add the solid from Example 3 (119 g) and stir for 30 min until dissolved. Then add acetic acid (598 mL) and stir for 15 min. Filter the solution into another 2 L three-necked flask. Maintain the temperature of the 2 L three-necked flask at 10 °C and begin adding 2 M H₂SO₄ aqueous solution dropwise until the pH of the system reaches 1.5. Maintain the temperature of the system at 15 °C and stir overnight. Filter the solution, wash the filter cake with a mixed solvent of acetic acid / water (1:1) (150 mL), and then dry the filter cake at 15 °C with a nitrogen stream to obtain an off-white solid.

[0049] The purity of the solid sodium salt crystals after nanofiltration in Examples 2 and 3, and the purity of the solid sodium salt crystals after vacuum concentration of the crude product are compared in Table 1 below.

[0050] Table 1

[0051] The comparison between the two batches shows that the purity of the solid precipitated after nanofiltration did not change significantly; however, the purity of the solid precipitated after vacuum concentration decreased significantly. This indicates that nanofiltration has a clear advantage in maintaining purity, thereby ensuring the purity of the subsequent cefuroxime azoxystrobin API.

[0052] Comparative Example 2 The difference between this comparative example and Example 1 is that the molecular weight cutoff of the nanofiltration membrane is different, specifically 1000 Daltons; otherwise, it is the same as Example 1. The purity of the solid obtained after crystallization is 89.6%.

[0053] Comparative Example 3 The difference between this comparative example and Example 1 is that sodium chloride (25 g) and sodium acetate (25 g) were not added to the nanofiltration solution obtained after nanofiltration; instead, ethanol was directly added for the subsequent crystallization step. The purity of the solid obtained after crystallization was 92.5%.

[0054] The above detailed description is a specific description of one of the feasible embodiments of the present invention. This embodiment is not intended to limit the patent scope of the present invention. All equivalent implementations or modifications that do not depart from the present invention should be included within the scope of the technical solution of the present invention.

Claims

1. A method for preparing high-purity cefuroxime azoxystrobin sodium salt by nanofiltration, characterized in that, Includes the following steps: (1) The crude cefuroxime sodium salt was purified to obtain the collected solution; (2) The collected liquid is concentrated by nanofiltration using a 200D-500D nanofiltration membrane to obtain a concentrated liquid; (3) The concentrate is crystallized to obtain the product.

2. The method according to claim 1, characterized in that, The nanofiltration membrane described in step (2) has a molecular weight cutoff of 400D.

3. The method according to claim 1, characterized in that, In step (2), the temperature of the collected liquid is adjusted to 2-15℃.

4. The method according to claim 1, characterized in that, In step (2), the temperature of the collected liquid is adjusted to 2-8℃.

5. The method according to claim 1, characterized in that, The nanofiltration concentration described in step (2) is carried out at 0.4 M 2 Under the given membrane size conditions, the pump speed is 30-80 rpm, the system pressure is 0.5 MPa to 2.5 MPa, and the outlet flow rate is 50-150 mL / min.

6. The method according to claim 1, characterized in that, The nanofiltration concentration pump mentioned in step (2) has a rotation speed of 40-60 r / s, a system pressure of 1.5 MPa-2.0 MPa, and an outlet flow rate of 50-70 mL / min.

7. The method according to claim 1, characterized in that, The concentration of cefuroxime sodium salt in the concentrate described in step (2) is 6%-10%.

8. The method according to claim 1, characterized in that, The purification in step (1) involves purifying the crude product by polymer resin column chromatography. The polymer resin is selected from SP-207 and LX-2210. The particle size of the polymer resin is 50-150 μm.

9. The method according to claim 1, characterized in that, The crystallization in step (3) involves adding sodium chloride and sodium acetate in the concentrate at a weight of 0.1-0.3 equivalents relative to the crude product, adding alcohol as a poor solvent, and crystallizing at 10-25°C for 2-8 hours.

10. A method for preparing high-purity cefuroxime azoxystrobin using nanofiltration, characterized in that, The sodium salt of cefuroxime prepared by the method according to any one of claims 1-9 is dissolved in water, and then acetic acid is added; the system is stirred and dissolved and then filtered; then, the temperature is controlled at 10-30℃, and sulfuric acid is added dropwise until the pH is between 0.5-2; the mixture is filtered, the filter cake is washed, and vacuum dried at 10-20℃ to constant weight to obtain cefuroxime.

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