Cephalosporin intermediate 7-ATCA reference substance and preparation method thereof

Abstract

The invention belongs to the field of preparation of medical intermediate reference substances, and particularly relates to a cephalosporin intermediate 7-ATCA reference substance and a preparation method thereof. The method comprises the following steps: (1) adding a 7-ATCA crude product into purified water, and adding diluted hydrochloric acid to adjust the pH value to 1.0-1.2 under a rapid stirring condition to obtain a 7-ATCA mixed solution; (2) adding activated carbon, sodium pyrosulfite and EDTA (Ethylene Diamine Tetraacetic Acid) into the 7-ATCA mixed solution, performing vacuum filtration, and mixing filtrate with purified water to obtain a 7-ATCA solution to be crystallized; (3) taking out a part of the 7-ATCA to-be-crystallized liquid, and mixing with an acetone aqueous solution to prepare a 7-ATCA seed crystal mixed liquid; and (4) adding the residual 7-ATCA liquid to be crystallized and the acetone acetonitrile solution into the 7-ATCA seed crystal mixed liquid in a manner of adding at different flow velocity sections, growing the crystal, filtering, washing and drying to obtain the intermediate 7-ATCA reference substance. The 7-ATCA product prepared by the method disclosed by the invention is high in content and purity, few in impurities and good in stability, and can be used as a 7-ATCA working reference substance.

Description

Technical Field

[0001] The present invention belongs to the field of preparation of reference substances for pharmaceutical intermediates, and particularly relates to a reference substance of cephalosporin intermediate 7-ATCA and a preparation method thereof. Background Art

[0002] 7-ATCA, chemically named (6R,7R)-7-amino-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid, and in Chinese named: (6R,7R)-7-amino-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid, and its structural formula is shown as Formula I: 。

[0003] Formula I 7-ATCA is an important pharmaceutical intermediate and can be used to synthesize a series of cephalosporin antibiotics such as cefoperazone, cefpiramide, cefamandole, cefmenoxime, etc. Most of these cephalosporins use 7-ATCA as a raw material and introduce different 7-side chains to obtain a series of cephalosporin antibiotics. Therefore, the quality of 7-ATCA products will directly affect the quality of these cephalosporin antibiotic finished products, such as performance indicators such as the color, content, and impurities of the finished products.

[0004] As a working reference substance, 7-ATCA is required to have high purity, few impurities, and good stability. The existing preparation method of 7-ATCA is: using 7-ACA as a nucleus and reacting with a side chain to produce 7-ACTA. After post-treatment, crystallization, washing, and drying are carried out to obtain the 7-ACTA product. The 7-ATCA prepared by this method has many impurities, low content, and poor stability, and cannot meet the requirements as a reference substance. And since 7-ATCA is an intermediate, a reference standard cannot be purchased from the market. Therefore, self-developing a 7-ATCA working reference substance as a reference standard for product quality detection is of great significance for ensuring the quality of 7-ATCA products. Summary of the Invention

[0005] The purpose of the present invention is to provide a reference substance of cephalosporin intermediate 7-ATCA and a preparation method thereof. The 7-ATCA product prepared by this method has high content and purity, few impurities, and good stability, and can be used as a 7-ATCA working reference substance.

[0006] To achieve the above purpose, the present invention adopts the following technical solutions: A reference substance of cephalosporin intermediate 7-ATCA, with the total impurity content being 0.21% - 0.23%.

[0007] The preparation method of the above-mentioned reference substance of cephalosporin intermediate 7-ATCA includes the following steps: (1) Add the crude 7-ATCA to purified water. Under the condition of rapid stirring, add dilute hydrochloric acid to adjust the pH to 1.0 - 1.2 to obtain a 7-ATCA mixed solution; (2) Add activated carbon, sodium metabisulfite, and ethylenediaminetetraacetic acid (EDTA) to the 7-ATCA mixed solution. After stirring for 30 - 60 minutes, perform vacuum filtration, and mix the filtrate with purified water to obtain a 7-ATCA solution to be crystallized; (3) Take out a part of the 7-ATCA solution to be crystallized and mix it evenly with an aqueous acetone solution. Under the condition of stirring, quickly add ammonia water to adjust the pH to 2.5 - 3.0 to obtain a 7-ATCA seed crystal mixed solution; (4) Under the condition of stirring, add the remaining 7-ATCA solution to be crystallized and an acetone - acetonitrile solution to the 7-ATCA seed crystal mixed solution in a split - flow rate section. After the feeding is completed, carry out crystal cultivation; successively through filtration, washing, and drying, the reference substance of intermediate 7-ATCA is obtained.

[0008] Furthermore, the mass - to - volume ratio of the 7-ATCA in step (1) to the purified water is 1 g∶4 ml.

[0009] Furthermore, the concentration of the dilute hydrochloric acid in step (1) is 10% - 20%.

[0010] Furthermore, the concentration of the 7-ATCA solution to be crystallized in step (2) is 120 - 160 g / mL.

[0011] Furthermore, the mass ratio of the activated carbon, sodium metabisulfite, EDTA to the crude 7-ATCA in step (2) is 3 - 5∶4 - 6∶2 - 4∶200.

[0012] Furthermore, when preparing the 7-ATCA seed crystal mixed solution in step (3), the volume ratio of the 7-ATCA solution to be crystallized to the aqueous acetone solution is 1∶4 - 6, and the volume of the 7-ATCA seed crystal mixed solution is based on the reach of the stirring device.

[0013] Furthermore, in step (4), the volume ratio and the feeding rate of the acetone - acetonitrile solution to the remaining 7-ATCA solution to be crystallized are both 1:1; for every 50 g of the crude 7-ATCA, the feeding rate of the 7-ATCA solution to be crystallized in different time periods is as follows: .

[0014] Further, the stirring speed in steps (1) and (3) is 320 - 400 r / min; the stirring speed in step (4) is 100 - 400 r / min.

[0015] Further, during the feeding process in step (4), the pH is controlled at 2.5 - 3.0 with 10% - 20% ammonia water all the time; after the feeding is completed, the crystal is aged for 30 - 60 min.

[0016] Further, in the aqueous acetone solution in step (3), the volume ratio of acetone to water is 1∶0.8 - 1.2.

[0017] Further, the concentration of the ammonia water in step (3) is 10% - 20%.

[0018] Further, in the acetone - acetonitrile solution in step (4), the volume ratio of acetone to acetonitrile is 1∶0.9 - 1.1.

[0019] Further, the temperature is controlled at 0 - 10 °C in steps (1) - (4).

[0020] Advantages of the present invention: (1) In the present invention, the crude 7 - ATCA is first mixed with purified water in a specific ratio and the 7 - ATCA mixed solution is prepared under the condition of a specific pH of 1.0 - 1.2, which can ensure that the degradation of the crude 7 - ATCA is minimized under this condition, and at the same time has a certain solubility, making the product content higher; (2) After the vacuum filtration of the 7 - ATCA saturated solution, the filtrate is mixed with purified water to obtain a 7 - ATCA crystallization - waiting solution with a concentration lower than the saturation degree. In this way, the crystallization of the 7 - ATCA crystallization - waiting solution can be effectively controlled. At the same time, by controlling the concentration of the crystallization - waiting solution, the crystallization process parameters can be accurately determined to ensure the product quality; (3) In the present invention, an aqueous acetone solution is used to prepare crystal seeds under the condition of pH 2.5 - 3.0, rather than using the conventional 7 - ATCA crystal seeds, which can effectively control the number of crystal formation and the number of crystal nuclei; (4) During crystallization, the present invention adopts the method of adding the 7 - ATCA crystallization - waiting solution and the acetone - acetonitrile solution to the crystal - seed mixed solution in a way of "slow, relatively fast, slow, fast" split - flow rate segments. On the one hand, mixing acetone and the acetonitrile solution and adding them to the crystal - seed mixed solution in the form of an acetone - acetonitrile mixed solution can reduce the precipitation of impurities during the crystallization process and control the directional growth of crystals. On the other hand, adding the 7 - ATCA crystallization - waiting solution and the acetone - acetonitrile solution to the crystal - seed mixed solution in a way of specific split - flow rate segments can ensure that the supersaturation of the solution during the crystallization process is in a relatively low and stable state, enabling the crystals to grow uniformly and directionally, and avoiding problems such as secondary crystallization or crystal aggregation and impurity encapsulation.

[0021] The 7-ATCA product prepared by the method of the present invention has high purity, few impurities and good stability. When stored for 12 months, the content can still be as high as 99.2%, the purity reaches 99.1%, and the total impurity content is 0.23% - 0.26%. The present invention will provide a working reference substance for the detection of industrial 7-ATCA products and provide a basis for product quality control. Detailed implementation mode

[0022] In order to make the objectives, technical solutions and advantages of the present invention clearer and more understandable, the following further describes the present invention in detail with reference to embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0023] Example 1 (1) Control the temperature at 0 - 5°C. Add 50 g of 7-ATCA crude product and 200 ml of water to a 2000 ml four-necked flask. While stirring at 320 - 400 r / min, add 20% hydrochloric acid to adjust the pH value to 1.0, and continue stirring for 30 min to prepare a 7-ATCA mixed solution; (2) Control the temperature at 0 - 3°C. Add 1 g of activated carbon, 1.25 g of sodium metabisulfite, and 0.5 g of EDTA to the 7-ATCA mixed solution. After stirring for 30 min, perform vacuum filtration through a suction flask; the filtrate enters a 2000 ml suction flask containing 20 ml of water to obtain a 7-ATCA solution to be crystallized; (3) Control the temperature at 0 - 10°C. Take 10 ml of the 7-ATCA solution to be crystallized and add it to a 3000 ml crystallizer. Add 50 ml of an acetone aqueous solution (the volume ratio of acetone to water is 1:1). After stirring evenly, quickly add 20% ammonia water while stirring at 320 - 400 r / min to adjust the pH to 2.9 - 3.0, and continue stirring for 10 - 20 min. Obtain a 7-ATCA seed crystal mixed solution; (4) Control the temperature at 0 - 10°C. Control the stirring speed of the crystallizer at 100 r / min. While stirring, add an acetone acetonitrile solution (the volume ratio of acetone to acetonitrile is 1:1) and the remaining 7-ATCA solution to be crystallized to the 7-ATCA seed crystal mixed solution at the following speed. During the feeding process, always control the pH at 2.9 - 3.0 with ammonia water; after the feeding is completed, age the crystals for 60 min, and after filtration, washing and drying, obtain a 7-ATCA working reference substance.

[0024] Among them, the feeding volume and feeding rate ratio of the acetone acetonitrile solution and the remaining 7-ATCA solution to be crystallized are both 1:1. At different times, the feeding rate of the 7-ATCA solution to be crystallized is as follows: .

[0025] Perform liquid chromatography analysis on the 7-ATCA working reference standard. At day 0, the content was 99.6%, the purity was 99.5%, and the total impurity content was 0.21%; at 12 months, the content was 99.2%, the purity was 99.0%, and the total impurity content was 0.23%. The quality of the 7-ATCA working reference standard met the quality requirements for a reference standard.

[0026] Example 2 (1) Control the temperature at 4 - 7°C. Add 150 g of 7-ATCA crude product and 600 ml of water to a 2000 ml four-necked flask. While stirring at 320 - 400 r / min, add 20% hydrochloric acid to adjust the pH value to 1.0, and continue stirring for 20 min to prepare a 7-ATCA mixed solution; (2) Control the temperature at 4 - 7°C. Add 3 g of activated carbon, 3.75 g of sodium metabisulfite, and 3 g of EDTA to the 7-ATCA mixed solution. After stirring for 45 min, perform vacuum filtration through a suction flask; the filtrate enters a 2000 ml suction flask containing 75 ml of water to obtain a 7-ATCA solution to be crystallized; (3) Control the temperature at 0 - 10°C. Take 10 ml of the 7-ATCA solution to be crystallized and add it to a 3000 ml crystallizer. Add 60 ml of an acetone aqueous solution (volume ratio of acetone to water is 1:0.8). After stirring evenly, quickly add 20% ammonia water while stirring at 320 - 400 r / min to adjust the pH to 2.7 - 2.8, and continue stirring for 10 - 20 min. Obtain a 7-ATCA seed crystal mixed solution; (4) Control the stirring speed of the crystallizer at 400 r / min. While stirring, add an acetone acetonitrile solution (volume ratio of acetone to acetonitrile is 1:0.9) and the remaining 7-ATCA solution to be crystallized to the 7-ATCA seed crystal mixed solution at the following speed. During the feeding process, always control the pH at 2.7 - 2.8 with ammonia water; after the feeding is completed, age the crystals for 45 min, and obtain the 7-ATCA working reference standard through filtration, washing, and drying.

[0027] Among them, the feeding volume and feeding rate ratio of the acetone acetonitrile solution and the remaining 7-ATCA solution to be crystallized are both 1:1. At different times, the feeding rate of the 7-ATCA solution to be crystallized is as follows: .

[0028] Perform liquid chromatography analysis on the 7-ATCA working reference standard. At day 0, the content was 99.6%, the purity was 99.3%, and the total impurity content was 0.22%; at 12 months, the content was 98.9%, the purity was 99.1%, and the total impurity content was 0.26%. The quality of the 7-ATCA working reference standard met the quality requirements for a reference standard.

[0029] Example 3 (1) Control the temperature at 8 - 10°C. Add 200.0 g of crude 7-ATCA and 800 ml of water into a 2000 ml four-necked flask. While stirring at 320 - 400 r / min, add 20% hydrochloric acid to adjust the pH value to 1.2, and continue stirring for 15 min to prepare a 7-ATCA mixed solution. (2) Control the temperature at 0 - 3°C. Add 5 g of activated carbon, 6 g of sodium metabisulfite, and 4 g of EDTA to the 7-ATCA mixed solution. After stirring for 30 min, perform vacuum filtration through a Buchner flask. The filtrate enters a 2000 ml Buchner flask containing 100 ml of water to obtain a 7-ATCA solution to be crystallized. (3) Control the temperature at 8 - 10°C. Take 10 ml of the 7-ATCA solution to be crystallized and add it into a 3000 ml crystallizer. Add 40 ml of an acetone aqueous solution (the volume ratio of acetone to water is 1∶1.2). After stirring evenly, quickly add 20% ammonia water under stirring at 320 - 400 r / min to adjust the pH to 2.5 - 2.7, and continue stirring for 10 - 20 min to obtain a 7-ATCA seed crystal mixed solution. (4) Control the stirring speed of the crystallizer at 200 - 300 r / min. Under stirring conditions, add an acetone acetonitrile solution (the volume ratio of acetone to acetonitrile is 1∶1.1) and the remaining 7-ATCA solution to be crystallized to the 7-ATCA seed crystal mixed solution at the following speed. During the feeding process, always control the pH at 2.5 - 2.7 with ammonia water. After the feeding is completed, carry out crystal aging for 30 min, and after filtration, washing, and drying, obtain a 7-ATCA working reference standard.

[0030] Among them, the feeding volume and feeding rate ratio of the acetone acetonitrile solution and the remaining 7-ATCA solution to be crystallized are both 1:1. At different times, the feeding rate of the 7-ATCA solution to be crystallized is as follows: 。

[0031] Perform liquid chromatography analysis on the 7-ATCA working reference standard. At day 0, the content is 99.5%, the purity is 99.2%, and the total impurity content is 0.23%. At 12 months, the content is 99.0%, the purity is 98.8%, and the total impurity content is 0.26%. The quality of the 7-ATCA working reference standard meets the standard quality requirements for a reference standard.

[0032] Comparative Example 1 As a control for Example 3, the feeding rate of the 7-ATCA solution to be crystallized in this comparative example is as shown in the following table, and the other steps are the same as those in Example 3: 。

[0033] The obtained 7-ATCA product was analyzed by liquid chromatography. At 0 days, the content was 98.6%, the purity was 98.5%, and the total impurity content was 0.45%; at 12 months, the content was 97.2%, the purity was 97.5%, and the total impurity content was 0.63%. The quality and stability of this product did not meet the quality requirements for a 7-ATCA working reference standard.

[0034] Comparative Example 2 (1) Control the temperature at 8 - 10°C. Add 200.0 g of 7-ATCA crude product and 800 ml of water to a 2000 ml four-necked flask. While stirring at 320 - 400 r / min, add 20% lye to adjust the pH value to 8, and continue stirring for 15 min to prepare a 7-ATCA mixed solution.

[0035] (2) Control the temperature at 8 - 10°C. Add 5 g of activated carbon, 6 g of sodium metabisulfite, and 4 g of EDTA to the 7-ATCA mixed solution. After stirring for 30 min, perform vacuum filtration through a suction flask; the filtrate enters a 2000 ml suction flask containing 100 ml of water to obtain a 7-ATCA solution to be crystallized. (3) Control the temperature at 8 - 10°C. Take 10 ml of the 7-ATCA solution to be crystallized and add it to a 3000 ml crystallizer. Add 40 ml of an acetone aqueous solution (the volume ratio of acetone to water is 1:1.2). After stirring evenly, quickly add 20% hydrochloric acid while stirring at 320 - 400 r / min to adjust the pH to 2.5 - 2.7, and continue stirring for 10 - 20 min to obtain a 7-ATCA seed crystal mixed solution. (4) Control the stirring speed of the crystallizer at 200 - 300 r / min. While stirring, add an acetone acetonitrile solution (the volume ratio of acetone to acetonitrile is 1:1.1) and the remaining 7-ATCA solution to be crystallized to the 7-ATCA seed crystal mixed solution at the following speed. During the feeding process, always control the pH at 2.5 - 2.7 with hydrochloric acid solution; after the feeding is completed, age the crystals for 30 min, and then obtain the 7-ATCA working reference standard through filtration, washing, and drying.

[0036] Among them, the feeding volume and feeding rate ratio of the acetone acetonitrile solution and the remaining 7-ATCA solution to be crystallized are both 1:1. At different times, the feeding rate of the 7-ATCA solution to be crystallized is as follows: 。

[0037] The obtained 7-ATCA product was analyzed by liquid chromatography. At 0 days, the content was 97.3%, the purity was 97.8, and the total impurity content was 0.63%; at 12 months, the content was 94.5%, the purity was 94.1%, and the total impurity content was 2.37%. The quality and stability of this product did not meet the quality requirements for a 7-ATCA working reference standard.

[0038] Comparative Example 3 (1)Control the temperature at 0 - 5°C. Add 200.0 g of 7-ATCA crude product and 800 ml of water into a 2000 ml four-necked flask. While stirring at 320 - 400 r / min, add 20% hydrochloric acid to adjust the pH value to 1.5, and continue stirring for 30 min to prepare a 7-ATCA mixed solution; (2)Control the temperature at 3 - 5°C. Add 5 g of activated carbon, 6 g of sodium metabisulfite, and 4 g of EDTA to the 7-ATCA mixed solution. After stirring for 30 min, perform vacuum filtration through a suction flask to obtain a 7-ATCA solution to be crystallized; (3)Control the temperature at 3 - 5°C. Take 10 ml of the 7-ATCA solution to be crystallized and add it into a 3000 ml crystallizer. Add 150 ml of an acetone aqueous solution (the volume ratio of acetone to water is 1:1). After stirring evenly, quickly add 20% ammonia water under the stirring condition of 320 - 400 r / min to adjust the pH to 2.9 - 3.0, and continue stirring for 10 - 20 min. Obtain a 7-ATCA seed crystal mixed solution; (4)Control the stirring speed of the crystallizer at 200 - 300 r / min. Under the stirring condition, add an acetone acetonitrile solution (the volume ratio of acetone to acetonitrile is 1:1) and the remaining 7-ATCA solution to be crystallized to the 7-ATCA seed crystal mixed solution at the following feeding rate. During the feeding process, always control the pH at 2.9 - 3.0 with ammonia water; after the feeding is completed, carry out crystal aging for 60 min, and after filtration, washing, and drying, obtain a 7-ATCA product.

[0039] Among them, the feeding volume and feeding rate ratio of the acetone acetonitrile solution and the remaining 7-ATCA solution to be crystallized are both 1:1. At different times, the feeding rate of the 7-ATCA solution to be crystallized is as follows: 。

[0040] Perform liquid chromatography analysis on the 7-ATCA product. At 0 day, the content is 98.9%, the purity is 99.0%, and the total impurity content is 0.29%; at 12 months, the content is 98.1%, the purity is 98.3%, and the total impurity content is 0.43%. The quality and stability of this product do not meet the quality requirements for a 7-ATCA working reference substance.

[0041] Comparative Example 4 (1)Control the temperature at 0 - 5°C. Add 200.0 g of 7-ATCA crude product and 800 ml of water into a 2000 ml four-necked flask. While stirring at 320 - 400 r / min, add 20% hydrochloric acid to adjust the pH value to 1.0, and continue stirring for 30 min to prepare a 7-ATCA mixed solution; (2)Control the temperature at 0 - 3°C, add 4 g of activated carbon, 5 g of sodium metabisulfite, and 2 g of EDTA to the 7-ATCA mixture, stir for 30 min, and then perform vacuum filtration through a suction flask; the filtrate enters a 2000-ml suction flask containing 100 ml of water to obtain the 7-ATCA crystallization solution to be crystallized; (3)At 0 - 5°C, control the stirring speed of the crystallizer at 320 - 400 r / min. Under stirring conditions, add 20% ammonia water, adjust the pH to 1.2 - 1.5, stop adding ammonia water when crystals appear, stir for 30 min at 160 - 250 r / min for crystal cultivation, and continue to slowly add 20% ammonia water until the pH is adjusted to 2.5 - 3.0; after the feeding is completed, carry out crystal cultivation for 60 min, and obtain the 7-ATCA product through filtration, washing, and drying.

[0042] Perform liquid chromatography analysis on the 7-ATCA product. At day 0, the content is 97.6%, the purity is 98.5%, and the total impurity content is 0.52%; at 12 months, the content is 95.2%, the purity is 96.0%, and the total impurity content is 1.02%. The quality and stability of this product do not meet the quality requirements for a 7-ATCA working reference substance.

[0043] Comparative Example 5 (1)Control the temperature at 0 - 5°C, add 80.0 g of 7-ATCA crude product and 800 ml of water to a 2000-ml four-necked flask. Under stirring at 320 - 400 r / min, add 20% hydrochloric acid to adjust the pH value to 1.0, and continue stirring for 30 min to prepare a 7-ATCA solution; (2)Control the temperature at 0 - 3°C, add 4 g of activated carbon, 5 g of sodium metabisulfite, and 2 g of EDTA to the 7-ATCA solution, stir for 30 min, and then perform vacuum filtration through a suction flask to obtain the 7-ATCA crystallization solution to be crystallized; (3)At 0 - 5°C, control the stirring speed of the crystallizer at 350 - 400 r / min. Under stirring conditions, add 20% ammonia water, adjust the pH to 1.5 - 2.0, stop adding ammonia water when crystals appear, stir for 30 min at 150 - 220 r / min for crystal cultivation, and continue to slowly add 20% ammonia water until the pH is adjusted to 2.9 - 3.0; after the feeding is completed, carry out crystal cultivation for 60 min, and obtain the 7-ATCA product through filtration, washing, and drying.

[0044] Perform liquid chromatography analysis on the 7-ATCA. At day 0, the content is 98.6%, the purity is 98.9%, and the total impurity content is 0.43%; at 12 months, the content is 96.1%, the purity is 96.6%, and the total impurity content is 0.79%. The quality and stability of this product do not meet the quality requirements for a 7-ATCA working reference substance.

Claims

1. A cephalosporin intermediate 7-ATCA reference substance, characterized in that: The cephalosporin intermediate 7-ATCA reference substance has a total impurity content of 0.21% to 0.23%.

2. The method for preparing the cephalosporin intermediate 7-ATCA reference substance according to claim 1, characterized in that: The following steps are involved: (1) Add the crude 7-ATCA to purified water, and add dilute hydrochloric acid to adjust the pH to 1.0-1.2 under rapid stirring to obtain a 7-ATCA mixed solution; (2) adding activated carbon, sodium metabisulfite and EDTA to the 7-ATCA mixed solution, vacuum filtering, and mixing the filtrate with purified water to obtain a 7-ATCA solution to be crystallized; (3) taking out a portion of the 7-ATCA crystallization solution and mixing it evenly with the acetone aqueous solution, and then rapidly adding ammonia water under stirring to adjust the pH to 2.5-3.0 to obtain a 7-ATCA seed crystal mixture; (4) Under stirring conditions, the remaining 7-ATCA solution to be crystallized and the acetone-acetonitrile solution are added to the 7-ATCA seed solution in a split flow rate manner. After the addition is completed, the crystals are grown; and the cephalosporin intermediate 7-ATCA reference substance is obtained by filtering, washing, and drying.

3. The preparation method according to claim 2, characterized in that: The volume ratio of the crude 7-ATCA product in step (1) to purified water is 1 g: 4 ml.

4. The preparation method according to claim 2, characterized in that: The concentration of the 7-ATCA crystallization solution in step (2) is 120-160 g / mL; the mass ratio of the activated carbon, sodium pyrosulfite, EDTA and 7-ATCA crude product is 3-5:4-6:2-4:

200.

5. The preparation method according to claim 2, characterized in that: When preparing the 7-ATCA seed crystal mixture in step (3), the volume ratio of the 7-ATCA solution to be crystallized to the acetone aqueous solution is 1:4-6, and the volume of the 7-ATCA seed crystal mixture is based on the volume that can be touched by the stirring device.

6. The preparation method according to claim 2, characterized in that: In step (4), the volume ratio of the acetone-acetonitrile solution to the remaining 7-ATCA solution to be crystallized and the feeding rate are both 1:1; for every 50 g of crude 7-ATCA, the feeding rate of the 7-ATCA solution to be crystallized in different time periods is as follows: 。 7. The preparation method according to claim 2, characterized in that: The stirring speed of step (1) and step (3) is 320-400 r / min; the stirring speed of step (4) is 100-400 r / min.

8. The preparation method according to claim 2, characterized in that: In the acetone aqueous solution of step (3), the volume ratio of acetone to water is 1:0.8-1.2; in the acetone acetonitrile solution of step (4), the volume ratio of acetone to acetonitrile is 1:0.9-1.

1.

9. The preparation method according to claim 2, characterized in that: During the addition process in step (4), the pH value is always controlled at 2.5-3.0 using 10%-20% ammonia water. After the addition is completed, the crystal is grown for 30-60 minutes.

10. The preparation method according to claim 1, characterized in that: The concentration of the dilute hydrochloric acid in step (1) is 10% to 20%; the concentration of the ammonia water in step (3) is 10% to 20%; and the temperature in steps (1) to (4) is controlled at 0 to 10°C.

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