Cefoperazone sodium polymer degradation impurity and preparation process thereof
By acylation reaction of cefoperazone sodium with 7-TMCA and process optimization, the problem of efficient preparation of cefoperazone sodium polymer impurities was solved, achieving high purity and high yield of impurity preparation, meeting the requirements of drug quality control.
Patent Information
- Application Number
- CN202511516686.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-10-23
- Publication Date
- 2025-11-28
AI Technical Summary
Existing technologies make it difficult to efficiently prepare cefoperazone sodium polymer degradation impurities, resulting in high separation and purification difficulties, high costs, long cycles, and a wide variety of impurities, which affect drug purity and safety.
Using cefoperazone sodium as a raw material, the cefoperazone sodium polymer was prepared by reacting with 7-TMCA via acylation reaction to degrade impurities. This included the dropwise addition of pentanoyl chloride and triethylamine at a specific temperature, combined with extraction and crystallization steps, and the optimization of reaction conditions to improve purity and yield.
This method achieves high purity (95.21-99.88%) and high yield (45-50%) of impurities from cefoperazone sodium polymer degradation, simplifies the process, reduces preparation difficulty and cost, and is suitable for drug quality control.
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Figure CN121021544A_ABST
Abstract
Description
TECHNICAL FIELD
[0001] The application relates to the field of chemical drug impurities, in particular to a cefoperazone sodium polymer degradation impurity and a preparation process thereof. BACKGROUND
[0002] In the development and production of chemical drugs, the quality control of drug impurities is a key link to ensure the safety and effectiveness of drugs. Drug impurities may come from raw materials, synthesis process, storage conditions and other aspects. Among them, polymer impurities, due to their special chemical properties and potential biological activity, have become the focus of attention and strict control in the development of cephalosporin antibiotics and other drugs. The existence of these impurities not only may affect the purity of the drug, but also may adversely affect the health of patients.
[0003] Chemical drug impurities provide a reference for drug impurity quality research, control the safety limit of impurities, and improve drug quality and drug safety. Therefore, developing an efficient and reliable impurity preparation method is of great significance for drug quality control.
[0004] At present, for the preparation of impurities in chemical drugs, most chemical impurities do not have ready-made preparation routes and process routes. Especially the preparation of polymer impurities mainly depends on direct separation and purification from raw drugs. However, the content of most chemical impurities in raw drugs is very low, usually between 0.1-0.3%, which directly leads to increased difficulty in separation and purification, high cost, and difficulty in large-scale preparation. Moreover, due to the presence of multiple unstable structures and activated groups in the structure, the generated impurities are of multiple isomers and tautomers, making the direct separation and purification process from the raw material difficult, long and complex.
[0005] Therefore, it is important to provide a new synthesis method of cefoperazone sodium polymer degradation impurity for the research of polymer impurities in cephalosporin antibiotics, and further as a control for drug quality control. SUMMARY
[0006] In order to provide a new synthesis method of cefoperazone sodium polymer degradation impurity with higher purity and easy to mass production, the application provides a cefoperazone sodium polymer degradation impurity and a preparation process thereof.
[0007] In the first aspect, the application provides a cefoperazone sodium polymer degradation impurity, which adopts the following technical scheme: A cefoperazone sodium polymer degradation impurity, the chemical structural formula is shown as formula I: Formula I.
[0008] In formula I, the molecular formula of the cefoperazone sodium polymer degradation impurity is C 35 H 37N 15 O 10 S4, molecular weight is 956.01600.
[0009] In a second aspect, the application provides a preparation process of cefoperazone sodium polymer degradation impurity, which adopts the following technical scheme: A preparation process of cefoperazone sodium polymer degradation impurity takes cefoperazone sodium as raw material, first acylates with pivaloyl chloride, then reacts the acylated product with 7-TMCA (3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-aminocephalosporanic acid, alias cefmetazole mother nucleus) to obtain cefoperazone sodium polymer degradation impurity, and the specific route is as follows: .
[0010] By adopting the above technical scheme, the cefoperazone sodium polymer degradation impurity is about the impurity produced in the actual production and storage of cefoperazone antibiotics, and as a polymer impurity, it is an impurity that is focused on research and control in cefoperazone antibiotics, so preparing the impurity as a control sample is crucial for drug quality control.
[0011] The application realizes that cefoperazone sodium polymer degradation impurity is prepared by a synthesis method taking cefoperazone sodium as raw material, the content is higher, the synthesized components are purer, it is beneficial to crystallization and purification, the target product with higher purity is prepared, and the process is simplified, the period is short, the operation is easier, and it is easy to prepare in large quantities.
[0012] Optionally, the preparation process of cefoperazone sodium polymer degradation impurity specifically includes the following steps: S1, dissolving cefoperazone sodium in dichloromethane, adding pyridine and cooling to -15-(-10)℃, then adding pivaloyl chloride dropwise, reacting to prepare reaction liquid A; S2, dissolving 7-TMCA in dichloromethane, adding triethylamine and tetramethyl guanidine, stirring to prepare solution A; S3, adding solution A to reaction liquid A, obtaining a crude solution after reaction, adding water to the crude solution, extracting and crystallizing, filtering and drying to obtain cefoperazone sodium polymer degradation impurity.
[0013] By adopting the above technical scheme, the purity of cefoperazone sodium polymer degradation impurity prepared by the method provided in the application reaches 95.21-99.88%, and the yield is 45-50%, which meets the needs of drug quality control.
[0014] Optionally, the specific operation after obtaining the crude solution in step S3 is: Firstly, water is added to the crude product solution, then sodium bicarbonate is added to adjust the pH to 7-7.5, extraction is performed, the water layer is taken out, and then the temperature is adjusted to 5-10℃, then hydrochloric acid is added to adjust the pH to 3-4, then the product is crystallized at 3-5℃ for 1-1.5h, and then a white solid is obtained after filtration and drying, thereby obtaining the cefoperazone sodium polymer degradation impurity.
[0015] Optionally, the addition ratio of cefoperazone sodium and pivaloyl chloride is 10g:2.0-2.5mL.
[0016] Optionally, the addition amount of 7-TMCA is 1.0-1.5molar equivalents of cefoperazone sodium.
[0017] Optionally, the addition ratio of cefoperazone sodium and pyridine is 10g:(0.4-0.6)mL.
[0018] Optionally, the volume ratio of triethylamine and tetramethyl guanidine is (2-2.2):1, and the addition ratio of cefoperazone sodium and tetramethyl guanidine is 10g:1.8-2.5mL.
[0019] Optionally, the reaction time in step S1 is 1.5-2.5h.
[0020] Optionally, the reaction time in step S3 is 50-70min.
[0021] In summary, the present application has the following beneficial effects: 1. The present application realizes that cefoperazone sodium polymer degradation impurity is prepared by a synthesis method using cefoperazone sodium as a raw material, the content is higher, the synthesized components are purer, which is beneficial to crystallization and purification, and the target product with higher purity is prepared, and the process is simplified, the period is short, the operation is easier, and mass production is easy. 2. The purity of cefoperazone sodium polymer degradation impurity prepared by the method provided in the present application reaches 95.21-99.88%, and the yield is 45-50%, which meets the needs of drug quality control. BRIEF DESCRIPTION OF DRAWINGS
[0022] Figure 1 is the LC-MS graph of cefoperazone sodium polymer degradation impurity prepared in Example 1 of the present application; Figure 2 is the LC-MS graph of cefoperazone sodium polymer degradation impurity prepared without adding triethylamine in Example 4 of the present application; Figure 3 is the LC-MS graph of cefoperazone sodium polymer degradation impurity prepared using DMF as a solvent in Example 5 of the present application; Figure 4 is the chromatogram of the HPLC detection spectrum of cefoperazone sodium polymer degradation impurity prepared in Example 1 of the present application; Figure 5 is the integral result chart of the HPLC detection spectrum of the cefoperazone sodium polymer degradation impurity prepared in Example 1 of the present application; Figure 6 is the chromatogram of the HPLC detection spectrum of the blank control; Figure 7 is the integral result chart of the HPLC detection spectrum of the blank control; Figure 8 is the HRMS detection high-resolution mass spectrum chart of the cefoperazone sodium polymer degradation impurity prepared in Example 1 of the present application; Figure 9 is the NMR detection hydrogen spectrum chart of the cefoperazone sodium polymer degradation impurity prepared in Example 1 of the present application; Figure 10 is the NMR detection carbon spectrum chart of the cefoperazone sodium polymer degradation impurity prepared in Example 1 of the present application. DETAILED DESCRIPTION
[0023] The present application will be further described in detail below in conjunction with examples, and it is particularly pointed out that: in the following examples, the specific conditions not specified are carried out according to the conventional conditions or the conditions recommended by the manufacturer, and the raw materials used in the following examples can be sourced from ordinary market sales unless otherwise specified.
[0024] Example 1
[0025] A preparation process of a cefoperazone sodium polymer degradation impurity, the reaction path of which is as follows: Specifically comprising the following steps: S1, at room temperature, 10 g of cefoperazone sodium and 100 mL of dichloromethane were added to a 1 L bottle, ultrasonic dissolution was carried out until it was clear and transparent, the ultrasonic power was 100 W, so that the cefoperazone sodium was dissolved in dichloromethane, then 0.5 mL of pyridine was added, the temperature was lowered to -10°C, and then 2.2 mL of tert-butyl chloride was added, and the reaction was carried out at -10°C for 2 h to obtain reaction liquid A for standby; S2, 4.92 g of 7-TMCA (3- (1-methyl-1H-tetrazole-5-yl) thiomethyl-7-aminocephalosporanic acid, alias cefmetazole mother nucleus) was added to a 250 mL bottle, then 50 mL of dichloromethane was added, after stirring, 4.14 mL of triethylamine and 2 mL of tetramethylguanidine were added, and stirring was carried out until it was clear to prepare solution A; S3, solution A prepared in step S2 was added to reaction liquid A prepared in step S1, and stirring was carried out at -10°C for 1 h to obtain a crude solution; Then 200 mL of water was added to the crude product solution, and a 5 wt% sodium bicarbonate solution was added to adjust the pH to 7.5. Extraction was performed, and the aqueous layer was obtained. The aqueous layer was then cooled to 5°C, and 1M hydrochloric acid was added to adjust the pH to 3.5. Crystallization was performed at 5°C for 1h. A white solid was obtained after filtration and drying, and 6.5 g of cefoperazone sodium polymer degradation impurities were obtained with a purity of 96.65% and a yield of 45.4%.
[0026] Example 2
[0027] A preparation process of cefoperazone sodium polymer degradation impurities, which has the same reaction path as that of Example 1, specifically includes the following steps: S1, at room temperature, 10 g of cefoperazone sodium and 100 mL of dichloromethane were added to a 1L bottle, and ultrasonic dissolution was performed until it was clear and transparent, with an ultrasonic power of 100 W, so that the cefoperazone sodium was dissolved in dichloromethane. Then 0.6 mL of pyridine was added, and the temperature was lowered to -10°C. Then 2.5 mL of tert-butyl chloride was added dropwise, and the reaction was performed at -10°C for 2.5 h to obtain reaction liquid A for standby; S2, 5.14 g of 7-TMCA (3- (1-methyl-1H-tetrazole-5-yl) thiomethyl-7-aminocephalosporanic acid, alias cefmetazole mother nucleus) was added to a 250 mL bottle, followed by the addition of 50 mL of dichloromethane. After stirring, 5.0 mL of triethylamine and 2.5 mL of tetramethylguanidine were added, and stirring was performed until it was clear to obtain solution A; S3, solution A prepared in step S2 was added to reaction liquid A prepared in step S1, and stirring was performed at -10°C for 70 min to obtain a crude product solution; Then 200 mL of water was added to the crude product solution, and a 5 wt% sodium bicarbonate solution was added to adjust the pH to 7.5. Extraction was performed, and the aqueous layer was obtained. The aqueous layer was then cooled to 10°C, and 1M hydrochloric acid was added to adjust the pH to 4. Crystallization was performed at 5°C for 1h. A white solid was obtained after filtration and drying, and 6.8 g of cefoperazone sodium polymer degradation impurities were obtained with a purity of 96.5% and a yield of 47.3%.
[0028] Example 3
[0029] A preparation process of cefoperazone sodium polymer degradation impurities, which has the same reaction path as that of Example 1, specifically includes the following steps: S1, at room temperature, 10 g of cefoperazone sodium and 100 mL of dichloromethane were added to a 1L bottle, and ultrasonic dissolution was performed until it was clear and transparent, with an ultrasonic power of 100 W, so that the cefoperazone sodium was dissolved in dichloromethane. Then 0.6 mL of pyridine was added, and the temperature was lowered to -10°C. Then 2.5 mL of tert-butyl chloride was added dropwise, and the reaction was performed at -10°C for 2.5 h to obtain reaction liquid A for standby; S2, 3.43 g of 7-TMCA (3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-aminodesacetoxycephalosporanic acid, alias cefmetoxime mother nucleus) was added into a 250 mL bottle, then 50 mL of dichloromethane was added, after stirring, 3.96 mL of triethylamine and 1.8 mL of tetramethylguanidine were added, and the solution A was prepared after stirring to be clear; S3, the solution A prepared in step S2 was added into the reaction solution A prepared in step S1, and stirred at -10℃ for 50 min to obtain a crude solution; Then 200 mL of water was added to the crude solution, and 5 wt% sodium bicarbonate solution was added to adjust the pH to 7, and then extracted, and the water layer was taken and cooled to 5℃, then 1M hydrochloric acid was added to adjust the pH to 3, and the crystal was precipitated at 5℃ for 1.5h, then filtered to obtain a white solid, and dried to obtain 6.2 g of cefoperazone sodium polymer degradation impurities with a purity of 95.8% and a yield of 43.2%.
[0030] Example 4
[0031] A preparation process of cefoperazone sodium polymer degradation impurities was carried out according to the method in Example 1, except that no triethylamine was added in step S2, and the purity was 40% and the yield was 32.3%.
[0032] Example 5
[0033] A preparation process of cefoperazone sodium polymer degradation impurities was carried out according to the method in Example 1, except that the dichloromethane in steps S1 and S2 was replaced by an equal amount of N,N-dimethylformamide, and the purity was 35% and the yield was 21.5%.
[0034] The cefoperazone sodium polymer degradation impurities in the above Examples 1, 4 and 5 were detected by liquid chromatography-mass spectrometry, and the LC-MS graphs were as shown in Figures 1-3 .
[0035] Figure 1 is the LC-MS graph of the cefoperazone sodium polymer degradation impurities in Example 1, and Figure 1 The upper graph in the attached figure is the total ion current graph, the horizontal coordinate is time (Time), unit: minute (min), and the vertical coordinate represents relative abundance (Relative Abundance), and the lower graph is the mass chromatogram, the horizontal coordinate is mass-to-charge ratio (m / z), and the vertical coordinate represents relative abundance (Relative Abundance); and Figures 2-3 Similar. It can be seen that when triethylamine is added and dichloromethane is used as the solvent, the relative abundance of the target product is high, and the relative abundance of the impurity peak is low, and combined with Figure 2is the case when triethylamine is not added in Example 4, there are multiple impurity peaks (such as impurity peaks with RT 9.74 min, 11.71 min, 11.93 min) in addition to the target product peak. The absence of triethylamine will lead to a decrease in reaction selectivity, generating more by-products and affecting the purity of the target product.
[0036] In combination with Figure 3 As can be seen after using DMF instead of dichloromethane as the solvent in Example 5, the relative abundance of the target product peak is significantly reduced, while the relative abundance of the impurity peak is high. Using DMF as the solvent will affect the reaction results, leading to a decrease in the yield of the target product. As can be seen, the use of triethylamine as a catalyst in Example 1 promotes condensation and promotes double bond transfer, improves reaction selectivity, reduces by-product generation, Figure 1 In Example 1, the purity is high, while in Example 4, triethylamine is not added, and the impurity peaks are more and distributed, and in Example 5, DMF is used as the solvent, which may cause the polarity or solubility of the reaction system to change, leading to a decrease in the yield of the target product, and the impurity peaks are more and significant.
[0037] In addition, the cefoperazone sodium polymer degradation impurities prepared in Example 1 of the present application were detected by HPLC liquid chromatography, and the liquid chromatography conditions were as follows: The chromatographic column was a C18 chromatographic column with a particle size of 5 μm, an inner diameter of 4.6 mm, and a length of 250 mm. The mobile phase was 0.1 wt% formic acid water for mobile phase A and acetonitrile for mobile phase B.
[0038] The gradient elution program is shown in Table 1 below: Table 1:
[0039] The detection wavelength was 254 nm, the column temperature was 30°C, the flow rate was 1.0 mL / min, and the injection volume was 5 μL.
[0040] The HPLC detection spectrum of the cefoperazone sodium polymer degradation impurities obtained in Example 1 is shown in Figure 4 and 5 The HPLC detection spectrum of the blank control is shown in Figure 6 and 7 The HPLC detection spectrum of the blank control is shown in Figure 4 The horizontal axis is time (min) and the vertical axis is absorbance (mAU), Figure 6 Similarly. In addition, the cefoperazone sodium polymer degradation impurities prepared in the examples were identified by hydrogen spectrum, carbon spectrum and mass spectrum, respectively as shown in Figures 8-10 Figure 6 The middle horizontal coordinate represents the mass-to-charge ratio (m / z), and the vertical coordinate represents the relative abundance (Relative Abundance). The structure of the final product cefoperazone sodium polymer degradation impurity is as follows:
[0041] The structure analysis thereof combined with mass spectrometry and hydrogen spectrum is shown in Table 2.
[0042] Table 2:
[0043] In summary, the preparation process provided in the present application realizes the synthesis of cefoperazone sodium polymer degradation impurities, and the yield of the prepared cefoperazone sodium polymer degradation impurities is 45-50%, and the purity is more than 95%, which can be used as a reference substance for cefoperazone sodium polymer degradation impurities, thereby improving the qualitative analysis of cefoperazone sodium polymer degradation impurities, facilitating the control of the impurities, and thus ensuring the safety and effectiveness of the drug.
[0044] In order to further improve the yield of cefoperazone sodium polymer degradation impurities, the reaction conditions of the present application are explored. By adding triethylamine in stages, 2 / 3 of the total amount is added when preparing solution A in step S2, and the amino group of 7-TMCA is activated together with tetramethyl guanidine to form a stable ammonium salt intermediate. The remaining triethylamine is added after 0.5 h of condensation reaction in step S3. At this time, the intermediate after acylation reaction in step S1 has been partially condensed with 7-TMCA, and the additional addition of triethylamine can further catalyze the double bond transfer and promote the generation of the target product.
[0045] Example 6
[0046] A preparation process for cefoperazone sodium polymer degradation impurities is carried out according to the method in Example 1, except that the amount of triethylamine added in step S2 is 2.76 mL, and solution A is prepared; In step S3, after solution A is added to reaction solution A and stirred at -10°C for 0.5 h, 1.38 mL of triethylamine is added, and then the stirring reaction is continued for 0.5 h to obtain a crude solution. The remaining operations are the same as in Example 1. Finally, the purity of the cefoperazone sodium polymer degradation impurity is 98.12, and the yield is 49.8%.
[0047] Example 7
[0048] A preparation process of cefoperazone sodium polymer degradation impurities is carried out according to the method in Example 1, except that in step S3, when hydrochloric acid is used to adjust the pH value, 0.5M hydrochloric acid is first added dropwise to adjust the pH to 5.0, and after stirring for 30 min, filtration is performed, and then 1M hydrochloric acid is continuously added dropwise to 3.5 in the filtrate, and then crystallization treatment is performed. The rest is the same as in Example 1. In this example, the purity of cefoperazone sodium polymer degradation impurities is 98.26%, and the yield is 46.8%.
[0049] In this example, the pH is adjusted in stages. First, the pH is adjusted to 5, so that the product is partially dissolved in the form of a zwitterion, and unreacted 7-TMCA and other impurities are preferentially precipitated and removed by filtration. Then, hydrochloric acid is continuously added dropwise to allow the product to precipitate stably, reduce impurity wrapping, and reduce yield loss due to impurity adsorption.
[0050] Example 8
[0051] A preparation process of cefoperazone sodium polymer degradation impurities is carried out according to the method in Example 1, except that in step S2, after stirring with triethylamine and tetramethylguanidine, 0.8 mL of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) is added, and the solution A is prepared after stirring to clarify; the rest is the same as in Example 1. Finally, the purity of cefoperazone sodium polymer degradation impurities is 96.82, and the yield is 49.3%.
[0052] Example 9
[0053] A preparation process of cefoperazone sodium polymer degradation impurities is carried out according to the method in Example 1, except that in step S2, after stirring with triethylamine and tetramethylguanidine, 1.0 mL of tetrabutylammonium bromide is added, and the solution A is prepared after stirring to clarify; the rest is the same as in Example 1. Finally, the purity of cefoperazone sodium polymer degradation impurities is 96.74, and the yield is 48.1%.
[0054] Example 10
[0055] A preparation process of cefoperazone sodium polymer degradation impurities is carried out according to the method in Example 1, except that in step S2, after stirring with triethylamine and tetramethylguanidine, 0.5 mL of tetrabutylammonium bromide is added, and the solution A is prepared after stirring to clarify; the rest is the same as in Example 1. Finally, the purity of cefoperazone sodium polymer degradation impurities is 96.88, and the yield is 47.2%.
[0056] It can be seen that when triethylamine is added in step S2, the addition of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) can accelerate the reaction rate, reduce side reactions, promote the stability of acylation reaction intermediates, and help subsequent reactions. In addition, although low-temperature reaction can inhibit side reactions at high temperature, low temperature also causes the catalytic activity of triethylamine to decrease slightly. The addition of DBU in combination with triethylamine in the present application can better improve the yield of the product.
[0057] The specific embodiments are merely illustrative of the present application, and are not intended to limit the present application. Those skilled in the art can make modifications to the embodiments without creative contribution after reading the specification, as long as the modifications are within the scope of the claims of the present application.
Claims
1. A method for polymerizing impurities in cefoperazone sodium, characterized in that, The chemical structural formula of the impurities degraded by cefoperazone sodium polymer is as follows: 。 2. The preparation process for the degradation of impurities by cefoperazone sodium polymer as described in claim 1, characterized in that, Using cefoperazone sodium as a raw material, it first undergoes an acylation reaction with pentanoyl chloride, and then the acylation product is reacted with 7-TMCA to obtain cefoperazone sodium polymer degradation impurities. The specific route is as follows: 。 3. The preparation process for cefoperazone sodium polymer degradation of impurities according to claim 2, characterized in that: The preparation process of cefoperazone sodium polymer degradation impurities specifically includes the following steps: S1. Dissolve cefoperazone sodium in dichloromethane, add pyridine, cool to -15-(-10)℃, then add pentanoyl chloride dropwise, react, and prepare reaction solution A; S2. Dissolve 7-TMCA in dichloromethane, add triethylamine and tetramethylguanidine, and stir to obtain solution A; S3. Add solution A to reaction solution A. After the reaction, a crude solution is obtained. Add water to the crude solution, extract and crystallize. Filter and dry to obtain cefoperazone sodium polymer degradation impurities.
4. The preparation process for the degradation of impurities by cefoperazone sodium polymer according to claim 3, characterized in that: The specific procedures after obtaining the crude solution in step S3 are as follows: First, water is added to the crude product solution, then the pH is adjusted to 7-7.5, extraction is performed, the aqueous layer is collected, the temperature is adjusted to 5-10℃, then the pH is adjusted to 3-4, crystallization is carried out at 3-5℃ for 1-1.5 hours, and after filtration, a white solid is obtained, which is dried to obtain cefoperazone sodium polymer degradation impurities.
5. The preparation process of cefoperazone sodium polymer degradation impurities according to claim 2, characterized in that: The addition ratio of cefoperazone sodium to tervastatin chloride is 10g: 2.0-2.5mL.
6. The preparation process for cefoperazone sodium polymer degradation of impurities according to claim 2, characterized in that: The amount of 7-TMCA added is 1.0-1.5 molar equivalents of cefoperazone sodium.
7. The preparation process for the degradation of impurities by cefoperazone sodium polymer according to claim 3, characterized in that: The ratio of cefoperazone sodium to pyridine is 10g: (0.4-0.6)mL.
8. The preparation process for cefoperazone sodium polymer degradation of impurities according to claim 3, characterized in that: The volume ratio of triethylamine to tetramethylguanidine added is (2-2.2):1, and the ratio of cefoperazone sodium to tetramethylguanidine added is 10g:1.8-2.5mL.
9. The preparation process for cefoperazone sodium polymer degradation of impurities according to claim 3, characterized in that: The reaction time in step S1 is 1.5-2.5 hours.
10. The preparation process for the degradation of impurities by cefoperazone sodium polymer according to claim 3, characterized in that: The reaction time in step S3 is 50-70 min.