A preparation method of cefotaxime sodium

Abstract

The present invention provides a method for preparing cefotaxime sodium, which comprises reacting cefotaxime acid with a salifying agent in a first organic solvent, crystallizing after the reaction is completed, filtering after the crystallization is completed to obtain wet cefotaxime sodium powder, subjecting the wet cefotaxime sodium powder to crystal transformation in a mixed system composed of a second organic solvent and water, and then filtering and drying in vacuum to obtain cefotaxime sodium. By subjecting the wet cefotaxime sodium powder to crystal transformation in a mixed system composed of an organic solvent and water, the present invention can significantly reduce the solvent residue in cefotaxime sodium, and the prepared cefotaxime sodium has high purity and good stability.

Description

Technical Field

[0001] The present invention relates to a preparation method of cefotaxime sodium. Background Art

[0002] Cefotaxime sodium is a commonly used carbapenem antibiotic, belonging to the third-generation semi-synthetic cephalosporin. It has a broader antibacterial spectrum than cefuroxime, stronger effects on Gram-negative bacteria, and its antibacterial spectrum includes Haemophilus influenzae, Escherichia coli, Escherichia coli, Salmonella Klebsiella aerogenes, Proteus mirabilis, Neisseria, Staphylococcus, Streptococcus pneumoniae, Streptococcus, Klebsiella and Salmonella and other Enterobacteriaceae bacteria, etc. Cefotaxime sodium has no antibacterial activity against Pseudomonas aeruginosa and Alcaligenes faecalis, has poor antibacterial activity against Staphylococcus aureus, has strong activity against Gram-positive cocci such as Streptococcus hemolyticus and Streptococcus pneumoniae, and Enterococcus (Enterobacter cloacae, Enterobacter aerogenes) is resistant to this product. Currently, it is mainly used clinically for pneumonia and other lower respiratory tract infections, urinary tract infections, meningitis, septicemia, abdominal infections, pelvic infections, skin and soft tissue infections, genital tract infections, bone and joint infections, etc. caused by various sensitive bacteria.

[0003] Cefotaxime sodium can be prepared by reacting cefotaxime acid with a salt-forming agent. Patent CN 112480145 A discloses a preparation method of cefotaxime sodium, which performs a first salting reaction by reacting cefotaxime acid and a first soluble sodium salt-forming agent in a first benign organic solvent to obtain a first salting reaction solution; performs a second salting reaction by reacting the first salting reaction solution and a second soluble sodium salt-forming agent in a second benign organic solvent to obtain a second salting reaction solution; and mixes the second salting reaction solution with a poor organic solvent to obtain the cefotaxime sodium. In actual research, it is found that the cefotaxime sodium prepared by this method has a large amount of solvent residue, and the prepared product is unstable. As time goes by, the impurity content in the product will increase significantly. Summary of the Invention

[0004] The purpose of the present invention is to provide a preparation method of cefotaxime sodium, which can significantly reduce the solvent residue in cefotaxime sodium, and the prepared cefotaxime sodium has high purity and good stability.

[0005] To achieve the above purpose, the technical solution adopted by the present invention is:

[0006] A preparation method of cefotaxime sodium, reacting cefotaxime acid with a salt-forming agent in a first organic solvent, crystallizing after the reaction ends, filtering after the crystallization ends to obtain wet cefotaxime sodium powder, subjecting the wet cefotaxime sodium powder to crystal transformation in a mixed system composed of a second organic solvent and water, and then filtering and vacuum drying to obtain the cefotaxime sodium.

[0007] Preferably, the mass ratio of the second organic solvent to water in the feed is 100:(1-5), such as 100:1, 100:2, 100:3, 100:4, 100:5, etc.

[0008] Preferably, the mass ratio of cefotaxime acid to water in the feed is 1:(0.5-1.5), such as 1:0.5, 1:0.7, 1:0.9, 1:1.1, 1:1.3, 1:1.5, etc.

[0009] Preferably, the crystal transformation is carried out under stirring, the temperature of the crystal transformation is 20-30 °C, such as 20 °C, 22 °C, 24 °C, 26 °C, 28 °C, 30 °C, etc.; the time is 40-80 min, such as 40 min, 45 min, 50 min, 55 min, 60 min, 65 min, 70 min, 75 min, 80 min, etc.

[0010] Preferably, the second organic solvent includes one or more of ethyl acetate, methyl acetate, and acetone.

[0011] Preferably, the salt-forming agent includes one or more of sodium carbonate, sodium acetate trihydrate, anhydrous sodium acetate, and sodium bicarbonate.

[0012] Preferably, the molar ratio of the salt-forming agent to cefotaxime acid in the feed is (0.85-1.05):1, such as 0.85:1, 0.9:1, 0.95:1, 1:1, 1:1.05, etc.

[0013] Preferably, the preparation method includes reacting cefotaxime acid with the salt-forming agent at a first temperature, crystallizing at a second temperature after the reaction ends, and then adding a third organic solvent for secondary crystallization, and the first temperature is not higher than the second temperature.

[0014] More preferably, the first temperature is -10-10 °C, such as -10 °C, -5 °C, 0 °C, 5 °C, 10 °C, etc.; the reaction time is 40-80 min, such as 40 min, 50 min, 60 min, 70 min, 80 min, etc.

[0015] More preferably, the second temperature is 0-10 °C, such as 0 °C, 5 °C, 10 °C, etc.; the crystallization time at the second temperature is 100-140 min, such as 100 min, 110 min, 120 min, 130 min, 140 min, etc.

[0016] Preferably, the mass ratio of the third organic solvent to cefotaxime acid in the feed is (45-60):1, such as 45:1, 48:1, 50:1, 53:1, 55:1, 58:1, 60:1, etc.

[0017] Preferably, the third organic solvent is fed in a dropwise manner and filtered after the dropping is completed.

[0018] Preferably, the third solvent includes one or more of ethyl acetate, methyl acetate, isopropyl alcohol, and acetone.

[0019] More preferably, the third solvent is the same as the second solvent.

[0020] Preferably, the first organic solvent includes one or more of methanol, ethanol, isopropyl alcohol, and acetonitrile.

[0021] Preferably, the mass ratio of the first organic solvent to the cefotaxime acid fed is (20-35):1, such as 20:1, 23:1, 25:1, 28:1, 30:1, 33:1, 35:1, etc.

[0022] Due to the application of the above technical solution, the present invention has the following advantages compared with the prior art:

[0023] By subjecting the cefotaxime sodium wet powder to crystal transformation in a mixed system composed of an organic solvent and water, the present invention can significantly reduce the solvent residue in cefotaxime sodium, and the prepared cefotaxime sodium has high purity and good stability. Detailed Embodiments

[0024] Currently, the commonly used preparation method of cefotaxime sodium is to react cefotaxime acid with a salt-forming agent. After the reaction is completed, an organic solvent is added to the reaction solution for crystallization to obtain cefotaxime sodium. The inventor of the present invention found that although cefotaxime sodium with relatively high purity can be obtained to a certain extent by using an organic solvent for crystallization, it will lead to a large amount of solvent residue in cefotaxime sodium, affecting the quality of cefotaxime sodium. The inventor of the present invention also found that the cefotaxime sodium prepared by the above method has poor stability and will deteriorate after being stored for a certain period of time. After long-term and extensive experimental research, the inventor of the present invention proposed the solution of the present invention. The solution of the present invention is further described below.

[0025] A preparation method of cefotaxime sodium, which comprises reacting cefotaxime acid with a salt-forming agent in a first organic solvent, crystallizing after the reaction is completed, filtering after the crystallization is completed to obtain cefotaxime sodium wet powder, subjecting the cefotaxime sodium wet powder to crystal transformation in a mixed system composed of a second organic solvent and water, and then filtering and vacuum drying to obtain cefotaxime sodium.

[0026] The present invention performs crystal transformation by using a mixed system composed of a second organic solvent and water. On the one hand, it can effectively remove the residual solvent in the product; on the other hand, since the reaction of cefotaxime acid with the salifying agent generates not only cefotaxime sodium but also a weak acid (for example, acetic acid is generated when reacting with acetate), there is a large amount of residual weak acid in the cefotaxime sodium prepared by the methods in the prior art and it cannot be effectively removed. By using the mixed system for crystal transformation, the residual weak acid in the system can be effectively removed.

[0027] According to some preferred embodiments, a method for preparing cefotaxime sodium includes the following steps:

[0028] (1) React cefotaxime acid with a salifying agent in a first organic solvent at a first temperature, and perform crystallization at a second temperature after the reaction ends, where the first temperature is not higher than the second temperature;

[0029] (2) After the crystallization ends, add a third organic solvent dropwise for secondary crystallization. After the addition ends, filter and wash the wet cake of cefotaxime sodium with the third organic solvent;

[0030] (3) Subject the wet cake of cefotaxime sodium to crystal transformation in a mixed system composed of a second organic solvent and water. After the crystal transformation ends, filter and vacuum dry to obtain cefotaxime sodium, where the mass ratio of the second organic solvent to water in the feed is 100:(1 - 5).

[0031] The solution of the present invention has at least the following advantages:

[0032] 1. By subjecting the wet cake of cefotaxime sodium to crystal transformation in a mixed system composed of an organic solvent and water, the present invention can significantly reduce the residual amounts of the solvent and the acid generated by the reaction in cefotaxime sodium.

[0033] 2. The cefotaxime sodium prepared by the present invention has a high purity, reaching over 99.5%; the solvent residue is low, less than 0.5%; it has good stability, and even after a 10-day accelerated experiment at 60°C, its purity is higher than 99%; and the color grade is small.

[0034] The present invention will be further described below in conjunction with embodiments. However, the present invention is not limited to the following embodiments. The implementation conditions adopted in the embodiments can be further adjusted according to different specific requirements, and the implementation conditions not specified are the conventional conditions in the industry. The technical features involved in each embodiment of the present invention can be combined with each other as long as they do not conflict with each other.

[0035] Example 1

[0036] 500 g of methanol and 18 g (0.2194 mol) of anhydrous sodium acetate were charged into a reaction flask and cooled to -10°C. 100 g (0.2196 mol) of cefotaxime acid was added, and the reaction was carried out at -10°C to 0°C for 60 minutes. After the reaction, the temperature was raised to 0°C to 10°C for crystallization for 120 minutes. After crystallization, 1000 g of ethyl acetate was added dropwise. After the addition, filtration was carried out, and the filter cake was washed with ethyl acetate to obtain wet cefotaxime sodium powder. The wet powder was put into a mixture of 500 g of ethyl acetate and 20 g of water and stirred at room temperature (20°C to 30°C) for 60 minutes. After stirring, filtration and suction drying were carried out, and vacuum drying was carried out at 40°C to 50°C to obtain 94 g of cefotaxime sodium, and the molar yield was 89.67%.

[0037] Example 2

[0038] 500 g of methanol and 18 g (0.2194 mol) of anhydrous sodium acetate were charged into a reaction flask and cooled to -10°C. 100 g (0.2196 mol) of cefotaxime acid was added, and the reaction was carried out at -10°C to 0°C for 60 minutes. After the reaction, the temperature was raised to 0°C to 10°C for crystallization for 120 minutes. After crystallization, 1000 g of methyl acetate was added dropwise. After the addition, filtration was carried out, and the filter cake was washed with methyl acetate to obtain wet cefotaxime sodium powder. The wet powder was put into a mixture of 400 g of methyl acetate and 12 g of water and stirred at room temperature for 60 minutes. After stirring, filtration and suction drying were carried out, and vacuum drying was carried out at 40°C to 50°C to obtain 97 g of cefotaxime sodium, and the molar yield was 92.53%.

[0039] Comparative Example 1

[0040] 500 g of methanol and 18 g (0.2194 mol) of anhydrous sodium acetate were charged into a reaction flask and cooled to -10°C. 100 g (0.2196 mol) of cefotaxime acid was added, and the reaction was carried out at -10°C to 0°C for 60 minutes. After the reaction, the temperature was raised to 0°C to 10°C for crystallization for 120 minutes. After crystallization, 1000 g of ethyl acetate was added dropwise. After the addition, filtration was carried out, and the wet powder was put into 500 g of ethyl acetate and stirred at room temperature for 60 minutes. After stirring, filtration and suction drying were carried out, and vacuum drying was carried out at 40°C to 50°C to obtain 98 g of cefotaxime sodium, and the molar yield was 93.49%.

[0041] Comparative Example 2

[0042] 500 g of methanol and 30 g (0.2205 mol) of sodium acetate trihydrate were charged into a reaction flask and cooled to -10°C. 100 g (0.2196 mol) of cefotaxime acid was added, and the reaction was carried out at -10°C to 0°C for 60 minutes. After the reaction, the temperature was raised to 0°C to 10°C for crystallization for 120 minutes. After crystallization, 1000 g of acetone was added dropwise. After the addition, filtration was carried out, and the wet powder was put into 500 g of acetone and stirred at room temperature for 60 minutes. After stirring, filtration and suction drying were carried out, and vacuum drying was carried out at 40°C to 50°C to obtain 94 g of cefotaxime sodium, and the molar yield was 89.67%.

[0043] Comparative Example 3

[0044] Into the reaction flask, add 500 g of methanol and 18 g (0.2194 mol) of anhydrous sodium acetate. Cool the temperature to -10°C, add 100 g (0.2196 mol) of cefotaxime acid, and react at -10°C to 0°C for 60 minutes. After the reaction is completed, raise the temperature to 0 - 10°C for crystallization for 120 minutes. After the crystallization is completed, add 1000 g of methyl acetate dropwise. After the dropwise addition is completed, filter. Put the wet powder into 500 g of methyl acetate and stir at room temperature for 60 minutes. After the stirring is completed, filter and drain. Dry under vacuum at 40 - 50°C to obtain 97 g of cefotaxime sodium, with a molar yield of 92.53%.

[0045] Examples 1 and 2 and Comparative Examples 1 to 3 were determined according to the residual solvent determination method (General Rule 0861, Method 1), and the data are shown in Table 1 below.

[0046] Table 1

[0047] Serial number Acetic acid Acetone Ethyl acetate Methyl acetate Methanol Example 1 0.18 NA 0.20 0.01 0.01 Example 2 0.09 NA 0.01 0.08 0.01 Comparative example 1 0.39 NA 0.40 0.02 0.03 Comparative example 2 0.38 0.29 NA NA 0.02 Comparative example 3 0.37 NA NA 0.10 NA

[0048] The ethyl acetate used in the above examples is industrial ethyl acetate, which contains a small amount of methyl acetate. Therefore, when ethyl acetate is used, there will be residual methyl acetate in the product. Similarly, methyl acetate also contains a small amount of ethyl acetate. Therefore, when methyl acetate is used, there will also be residual ethyl acetate in the product.

[0049] The related substances of the cefotaxime sodium prepared in Examples 1 and 2 and Comparative Examples 1 to 3 were detected by the EP10.0 HPLC method. Among them, the experimental data on day 0 and the experimental data after acceleration at 60°C for 10 days are shown in Tables 2 and 3 respectively.

[0050] Table 2 Experimental data on day 0

[0051] Serial number Impurity A Impurity B Impurity F Other maximum single impurity % Total impurity % Color grade Example 1 0.09 0.17 0.08 0.06 0.42 ＜Y1 Example 2 0.10 0.15 0.07 0.07 0.41 ＜Y1 Comparative example 1 0.08 0.18 0.30 0.08 0.66 ＜Y2 Comparative example 2 0.10 0.18 0.32 0.10 0.63 ＜Y2 Comparative example 3 0.09 0.19 0.34 0.08 0.70 ＜Y2

[0052] Table 3 Experimental data of acceleration at 60°C for 10 days

[0053] Serial number Impurity A Impurity B Impurity F Other maximum single impurity % Total impurity % Color grade Example 1 0.15 0.25 0.49 0.07 0.98 ＜Y2 Example 2 0.15 0.20 0.40 0.07 0.84 ＜Y2 Comparative example 1 0.17 0.43 1.12 0.34 2.30 ＜Y3 Comparative example 2 0.20 0.45 1.34 0.35 2.60 ＜Y3 Comparative example 3 0.17 0.44 1.47 0.37 2.76 ＜Y4

[0054] Among them, impurity A, impurity B, and impurity F in Tables 2 and 3 above are all impurity codes in the EP10.0 standard.

[0055] Unless otherwise specified, "<Y2" in the above tables means greater than Y1 and between Y1 and Y2; "<Y3" means greater than Y2 and between Y2 and Y3; "<Y4" means greater than Y3 and between Y3 and Y4.

[0056] In the post-treatment stage of the present invention, by using a second organic solvent and purified water to carry out crystal transformation on the wet powder, the solvent residue and impurity content in the product are effectively reduced, and the stability of the product is improved.

[0057] The above has described the present invention in detail. The purpose is to enable those skilled in the art to understand the content of the present invention and implement it. However, it should not be used to limit the protection scope of the present invention. Any equivalent changes or modifications made according to the spirit and essence of the present invention should be covered within the protection scope of the present invention.

Claims

1. A preparation method of cefotaxime sodium, characterized in that, It includes the following steps: (1) React cefotaxime acid with a salt-forming agent in a first organic solvent at a first temperature, and crystallize at a second temperature after the reaction ends. The molar ratio of the salt-forming agent to cefotaxime acid in the feed is (0.85 - 1.05):

1. The first organic solvent includes one or more of methanol, ethanol, isopropanol, and acetonitrile. The mass ratio of the first organic solvent to cefotaxime acid in the feed is (20 - 35):

1. The first temperature is not higher than the second temperature. The first temperature is -10 to 10°C. The reaction time is 40 to 80 min. The second temperature is 0 to 10°C. The crystallization time at the second temperature is 100 to 140 min; (2) Add a third organic solvent to the system of step (1) for secondary crystallization, and filter after the crystallization ends to obtain wet cefotaxime sodium powder. The mass ratio of the third organic solvent to cefotaxime acid in the feed is (45 - 60):

1. The third solvent includes one or more of ethyl acetate, methyl acetate, isopropanol, and acetone; (3) Subject the wet cefotaxime sodium powder to crystal transformation in a mixed system composed of a second organic solvent and water, then filter and vacuum dry to obtain cefotaxime sodium. The second organic solvent includes one or more of ethyl acetate, methyl acetate, and acetone. The mass ratio of the second organic solvent to water in the feed is 100:(1 - 5). The mass ratio of cefotaxime acid to water in the feed is 1:(0.5 - 1.5). The temperature for crystal transformation is 20 to 30°C, and the time is 40 to 80 min.

2. The preparation method of cefotaxime sodium according to claim 1, characterized in that: The crystal transformation is carried out under stirring.

3. The preparation method of cefotaxime sodium according to claim 1, characterized in that: The salt-forming agent includes one or more of sodium carbonate, sodium acetate trihydrate, anhydrous sodium acetate, and sodium bicarbonate.

4. The preparation method of cefotaxime sodium according to claim 1, characterized in that: The third organic solvent is fed in a dropwise manner, and filtration is carried out after the dropwise addition ends.