Cefotaxime sodium synthesis method based on one-step salification of mixed solvent system and sodium isooctanoate

Abstract

The invention belongs to the technical field of chemical synthesis, and discloses a cefotaxime sodium synthesis method based on one-step salification of a mixed solvent system and sodium isooctanoate. The method comprises the following steps: by taking 7-aminocephalosporanic acid (7-ACA) and 2-(2-aminothiazole-4-yl)-2-(methoxyimino) acetoxyimino ethyl acetate (AE active ester) as raw materials, in a dichloromethane-methanol mixed solvent, completing a condensation reaction through triethylamine catalysis, directly dropwise adding a sodium isooctanoate acetone solution to realize salification in one step, and carrying out post-treatment to obtain the 7-aminocephalosporanic acid (7-ACA)-2-(methoxyimino) acetoxyimino ethyl acetate (AE active ester)-2-(methoxyimino) acetoxyimino ethyl acetate (AE active ester). The cefotaxime acid intermediate does not need to be separated; and performing low-temperature washing and accurate drying subsequently to obtain a cefotaxime sodium finished product. According to the method, the defects that in the prior art, a two-step method needs intermediate separation and a one-pot method needs alkaline degradation are overcome, the production period is shortened to be smaller than or equal to 8 h, the total yield is larger than or equal to 92%, the HPLC purity is larger than or equal to 99.6%, the wastewater COD is smaller than or equal to 2000 mg / L, solvent residues meet the ICH Q3C standard, and the method has the advantages of industrial feasibility and environmental protection.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis technology, specifically relating to the industrial preparation technology of cephalosporin antibiotics, and particularly to a method for synthesizing cefotaxime sodium in one step based on a mixed solvent system and sodium isooctanoate, which is suitable for the production of high-purity, low-pollution, and short-cycle cefotaxime sodium. Background Technology

[0002] Cefotaxime sodium is a third-generation semi-synthetic cephalosporin jointly developed by Hoechst AG of Germany and Roussel AG of France. It was successfully developed in 1977 and launched in 1980. Its chemical name is (6R,7R)-3-[(acetoxy)methyl]-7-[2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate sodium salt. It appears as white to slightly yellow crystals or powder, odorless or with a slight characteristic odor.

[0003] Cefotaxime sodium has a broad antibacterial spectrum and its inhibitory effect on Gram-negative bacteria is significantly better than that of the first two generations of cephalosporins. Clinically, it is widely used to treat pneumonia, lower respiratory tract infections, urinary tract infections, meningitis, sepsis, abdominal infections, pelvic infections, skin and soft tissue infections, and bone and joint infections caused by susceptible bacteria. It is one of the core drugs for clinical anti-infective therapy.

[0004] However, existing synthesis technologies for cefotaxime sodium suffer from numerous bottlenecks, making it difficult to meet the demands of industrial production for "safety, efficiency, and environmental protection." Specific problems include: The original patent GB1580623A discloses a method using ethyl aminothiazolate as a raw material. The process involves protecting the amino group with triphenylchloromethane, hydrolyzing it to obtain protected aminothiazolate, and then condensing it with 7-ACA (7-aminocephalosporanic acid) in the presence of the condensing agent 4,5-dicyanimidazole (DCI) to generate cephalosporanic acid, which is finally salted with sodium carbonate. This process has two major problems: (1) High toxicity of the raw material: Triphenylchloromethane is highly corrosive, posing a significant operational risk; (2) Difficulty in purification: The condensing agent DCI is difficult to completely remove from the reaction system, leading to fluctuations in the purity of the final product and affecting quality control.

[0005] Currently, the mainstream industrial process is the traditional "two-step method" (as disclosed in CN 02112393A), the core process of which is "7-ACA and AE active ester condensation to generate cefotaxime acid intermediate → after separation and purification, it is salted with sodium acetate to obtain cefotaxime sodium". This process suffers from poor solvent compatibility (the polarity of dichloromethane used for condensation and acetone / water used for salt formation is significantly different) and conflicting salt formation conditions (the acidic catalyst in the condensation stage must be neutralized before salt formation can occur), forcing the separation of intermediates. This results in: (1) Complex process: requiring 12 steps including "condensation → filtration → intermediate drying → redissolution → salt formation", with a production cycle of ≥24 hours; (2) Low yield: material loss rate during intermediate transfer reaches 15%~20%, with a total yield ≤75%; (3) High solvent risk: relying on pyridine as a catalyst (pKa=5.2, matching the AE active ester thioester group departure requirement), while pyridine belongs to ICH Q3C Class II residual solvent, and the final product must strictly control the residual amount (<880 ppm), increasing purification costs; and dichloromethane has poor solubility for 7-ACA (<5% w / v), forcing some processes to use 1,2-dichloroethane (solubility >15%), which is more toxic. (w / v), further increasing safety risks; (4) High energy consumption: the condensation reaction needs to be carried out at a low temperature of -5~0℃, which significantly increases equipment investment and energy consumption costs.

[0006] Chinese patent CN201610045473.2 attempts to simplify the process through a "one-pot method," but still has fatal flaws: (1) Severe product degradation: The reaction needs to be carried out under alkaline conditions (pH>9.0), which leads to the opening of the β-lactam ring of cefotaxime sodium, with impurity content ≥0.8% (HPLC detection), which does not meet international standards such as EP10.0; (2) High environmental pressure: The COD value of wastewater reaches 8000~10000 mg / L, which is more than 2.6 times that of the traditional two-step method, resulting in high treatment costs; (3) High solvent loss: The acetone recovery rate is only 60%~70%, which is far lower than the industrial requirement of ≥85%.

[0007] In summary, existing technologies still suffer from the "three highs" problem: high risk (high-risk solvents, product degradation), high cost (intermediate separation, high energy consumption), and high pollution (high COD in wastewater). There is an urgent need to develop a new synthesis method that can balance process simplification, product quality, and environmental protection requirements. Summary of the Invention

[0008] In view of the shortcomings of existing cefotaxime sodium synthesis technology, such as "the need to separate intermediates, high solvent toxicity, low product purity, and heavy wastewater pollution", the core objective of this invention is to provide a one-step salt formation, solvent compatible, low-toxicity and high-efficiency synthesis method.

[0009] The first aspect of this invention provides a method for preparing cefotaxime sodium, the method being a one-step salt formation method for cefotaxime sodium based on a mixed solvent system and sodium isooctanoate, comprising the following steps: (1) Condensation reaction: 7-aminocephalosporanic acid (7-ACA) and AE active ester are added to a mixed solvent of dichloromethane and methanol, the temperature is controlled at 8~10℃, triethylamine is added as a catalyst, the reaction is stirred for 2 hours, then a decolorizing agent is added for decolorization, the decolorizing agent is removed by filtration, and the condensation reaction solution is obtained. (2) Salt formation reaction: Add the acetone solution of sodium isooctanoate to the condensation reaction solution in step (1) at 20~25℃ for 60~90 minutes. After the addition is completed, cool down to 10~12℃ and grow crystals for 60 minutes. (3) Post-processing: The crystal growth system of step (2) is filtered, the filter cake is collected, the filter cake is washed with acetone, and then dried at 50~55℃ for 4 hours to obtain the cefotaxime sodium product.

[0010] In step (1), the mass ratio of dichloromethane to methanol in the mixed solvent is (8~12):1.

[0011] In step (1), the mass ratio of dichloromethane to methanol in the mixed solvent is 10:1.

[0012] The concentration of the acetone solution of sodium isooctanoate in step (2) is 3%~5% w / w (based on the percentage of the mass of sodium isooctanoate to the total mass of sodium isooctanoate and acetone).

[0013] The dropping rate of the sodium isooctanoate acetone solution in step (2) is 6.7~10 mL / min, and the total mass of the sodium isooctanoate acetone solution is 600g.

[0014] Further, the decolorizing agent mentioned in step (1) is activated carbon, and the amount of activated carbon used is 8% to 12% of the mass of 7-ACA.

[0015] The acetone washing in step (3) is a two-time washing process, with 50g of acetone used for each washing and the washing temperature ≤10℃.

[0016] The amount of triethylamine used in step (1) is 1.0 to 1.1 times the molar amount of 7-ACA.

[0017] The cefotaxime sodium product has a weight yield of 1.5 to 1.7 times that of 7-ACA, an HPLC purity of ≥99.5%, a total impurity content of ≤0.5%, and residual solvents that meet ICH Q3C standards (dichloromethane ≤600 ppm, methanol ≤3000 ppm, acetone ≤5000 ppm).

[0018] The second aspect of the present invention provides a cefotaxime sodium, which is prepared by the synthesis method described above. The cefotaxime sodium is a needle-shaped crystal with an HPLC purity of ≥99.5%, a total impurity content of ≤0.5%, a residual solvent content that meets the ICH Q3C standard, and a weight yield of 1.5 to 1.7 times for 7-ACA.

[0019] A third aspect of the present invention provides a reaction system for synthesizing cefotaxime sodium, comprising: Mixed solvent: dichloromethane and methanol, mass ratio (8~12):1; Catalyst: Triethylamine, with a molar amount 1.0 to 1.1 times that of 7-ACA; Salt-forming agent: acetone solution of sodium isooctanoate, concentration 3%~5% w / w; Decolorizing agent: activated carbon, the amount of which is 8%~12% of the mass of 7-ACA.

[0020] Compared with the prior art, the present invention has the following significant advantages: (1) The process is greatly simplified: the intermediate separation step is eliminated, the number of operation steps is reduced from 12 to 5, the production cycle is shortened from ≥24 hours to ≤8 hours, and the production efficiency is increased by 67%; (2) High yield and high purity: The total yield is ≥92% (≤75% for traditional two-step method and ≤70% for existing one-pot method), and the weight yield of cefotaxime sodium to 7-ACA is 1.5 to 1.7 times; the HPLC purity is ≥99.6%, and the total impurities are <0.4% (of which the key impurities A / B are <0.1%), which meets the standards of EP10.0 and the 2020 edition of the Chinese Pharmacopoeia. (3) Significantly improved safety and environmental friendliness: The solvent system is free of high-risk solvents such as pyridine and 1,2-dichloroethane, and the residues in the final product meet the ICH Q3C standard (dichloromethane ≤600 ppm, methanol ≤3000 ppm, acetone ≤5000 ppm). The COD value of the wastewater is ≤2000 mg / L, which is more than 75% lower than the existing one-pot method (8000~10000 mg / L), and the treatment cost is significantly reduced. Solvent recovery rate ≥90% (of which acetone recovery rate reaches 92%), far exceeding the 60%~70% of existing one-pot processes; (4) Cost and energy consumption optimization: The condensation reaction temperature is increased to 8~10℃ (no low temperature equipment required), the parameters of salt formation and drying process are mild, and the total energy consumption is reduced by 40% compared with the traditional two-step method; and there is no intermediate loss, and the material utilization rate is increased by more than 20%.

[0021] (5) Enhanced product stability: The pH of the salt formation stage is stable at 7.0~7.5 (compared to pH>9.0 in the one-step method), and the content of impurities A / B is <0.1%. Attached Figure Description

[0022] Figure 1 The route diagram for the traditional "two-step" synthesis of cefotaxime sodium in the existing technology includes three core stages: "condensation → intermediate separation → salt formation", which requires multiple solvent conversions and purifications. Figure 2 The following is a flowchart of the synthesis of cefotaxime sodium based on a mixed solvent system and sodium isooctanoate in one step: the condensation reaction solution is directly used for salt formation without the need for intermediate separation. The process includes three stages: "condensation (decolorization and filtration) → salt formation (droplet addition for crystal growth) → post-treatment (washing and drying)," which significantly simplifies the steps. Figure 3 The HPLC purity chromatogram for Example 2 (optimal parameter set); Figure 4 This is a microscopic image (500x) of the needle-like crystals observed in this invention. Detailed Implementation

[0023] The purpose of this invention is to develop a one-step salt-forming method for synthesizing cefotaxime sodium based on a mixed solvent system. Example 1. Screening using a combination of mixed solvent system and sodium salt Currently, the mainstream industrial process is the traditional two-step method. The core process is "condensation of 7-ACA with AE active ester to generate cefotaxime acid intermediate → separation and purification followed by salt formation with sodium acetate to obtain cefotaxime sodium." This process suffers from poor solvent compatibility (the polarity difference between dichloromethane used for condensation and acetone / water used for salt formation is significant) and conflicting salt formation conditions (the acidic catalyst in the condensation stage must be neutralized before salt formation), necessitating intermediate separation. Chinese patent CN201610045473.2 attempts to simplify the process through a one-pot method, but it still has fatal flaws. This invention first develops a mixed solvent that enables a one-pot method without requiring alkaline conditions.

[0024] The synthesis process is as follows: 1. Condensation reaction (dissolving vessel) Weigh 30g of 7-ACA and add it to the mixed solvent. Control the temperature at 5℃ and add 15.2g of triethylamine over 30-45 minutes. After the addition is complete, stir the reaction until the solid is completely dissolved. Add 3g of activated carbon and decolorize at 5℃ for 30 minutes. After decolorization is complete, filter. 2. Sodium solution dissolution (preparation tank) Weigh out an appropriate amount of sodium salt, add 1000g of acetone, control the temperature at 20℃, stir until the solid is completely dissolved, add an appropriate amount of activated carbon for decolorization and stir for 30 minutes. After decolorization is complete, filter. 3. Sodium formation reaction 3.1 Crystallization Control the temperature at 20℃, and add the sodium salt solution from step 2 dropwise to the reaction solution from step 1. After the addition is complete, cool the temperature to 5℃ and stir slowly to grow crystals for 100 minutes. 3.2 Filtration, washing and drying The filter cake was washed twice with 50g of pre-cooled acetone.

[0025] 3.3 Drying The temperature was controlled at 50-55℃, and the product was dried for approximately 4 hours. The final product was dried cefotaxime sodium. The weight yield of cefotaxime sodium to 7-ACA was calculated.

[0026] The mixed solvent (v / v) is acetone:water = 4:1, tetrahydrofuran:water = 4:1, dichloromethane:ethanol = 4:1, dichloromethane:methanol = 4:1, or dichloromethane:methanol = 8:1. The sodium salt is sodium acetate, sodium isooctanoate, or sodium bicarbonate.

[0027] The experimental results are shown in Table 1:

[0028]

[0029] The results showed that the combination of dichloromethane:methanol = 8:1 mixed solvent system with sodium isooctanoate resulted in complete dissolution of the solutions in both the condensation and sodium formation reactions without turbidity. Furthermore, the reaction crystallized quickly and abundantly. The weight yield of cefotaxime sodium to 7-ACA was 1.38 (slightly better than the 1.35 yield of the traditional two-step method in the comparative example. However, based on theoretical calculations, there is still a significant amount of material that does not react completely, indicating room for improvement. Further optimization of various process parameters is needed).

[0030] Example 2 (Optimal Parameter Set) Based on the dichloromethane:methanol = 8:1 mixed solvent system screened in Example 1 and the combination with sodium isooctanoate, combined with research experience and material properties, the process parameters were explored, screened, and optimized countless times to maximize the yield. The final selected process parameters are as follows:

[0031] Weigh 30.0 g (0.088 mol) of 7-ACA and 42.5 g (0.092 mol, 1.05 times the molar amount of 7-ACA) of AE active ester and add them to a 500 mL reactor. Add 300.0 g of dichloromethane and 30.0 g of methanol (mixed solvent mass ratio 10:1) and start stirring to disperse the solids. Control the temperature of the reactor jacket at 8~10℃ and slowly add 15.2 g (0.150 mol, 1.05 times the molar amount of 7-ACA) of triethylamine over 30 minutes. After the addition is complete, keep the mixture warm and stir for 2 hours. Take a sample to test the system for complete dissolution (HPLC detection shows 7-ACA residue <0.1%). Add 3.0 g of activated carbon (10% of the mass of 7-ACA), keep the mixture warm for decolorization for 30 minutes, filter through a 0.22 μm organic filter membrane, and collect approximately 360 g of the condensation reaction solution.

[0032] 2. Salt formation reaction In a 250 mL preparation vessel, weigh 24.0 g of sodium isooctanoate and 600.0 g of acetone, and stir for 15 minutes until completely dissolved (concentration 4% w / w). Raise the temperature of the condensation reaction solution to 20-25 °C, and add the sodium isooctanoate acetone solution dropwise to the condensation reaction solution at a rate of 8.3 mL / min (corresponding to a total dropping time of 72 minutes). During the dropping process, observe that the system does not release heat significantly. After the dropping is completed, cool down to 10-12 °C at a rate of 1 °C / 10 minutes, and keep warm to grow crystals for 60 minutes to form a white needle-like crystal suspension.

[0033] 3. Post-processing The crystal suspension was filtered using a Buchner funnel, and the filter cake was collected. The filter cake was washed with 50.0 g of acetone pre-cooled to 8°C, and the washing was repeated once after filtration. The filter cake was transferred to a vacuum drying oven and dried at 50°C and -0.095 MPa for 4 hours to obtain 48.6 g of cefotaxime sodium product.

[0034] 4. Product testing results Weight yield: 48.6g / 30.0g = 1.62 times (based on 7-ACA); HPLC purity (results are shown in...) Figure 3 ): 99.8% (main peak area percentage), total impurities 0.2%; (HPLC purity detection method is described under the [Content Determination] section, the same applies below); Residual solvents (Chinese Pharmacopoeia, Part IV, General Chapter 0861, headspace GC method, the same below): dichloromethane 420 ppm, methanol 2100 ppm, acetone 3800 ppm (all in compliance with ICH Q3C standards). Crystal morphology: Needle-like crystals (observed under an optical microscope) Figure 4 ; Wastewater COD value (collected washing wastewater was tested according to GB 11914-1989 and should comply with GB8978-1996 Integrated Wastewater Discharge Standard, the same below): 1800 mg / L.

[0035] Appendix. HPLC purity detection methods are as follows, under the

Content Determination

[0036] 1. Preparation of materials, instruments, and reagents Electronic balance, high performance liquid chromatograph, cefotaxime reference standard, anhydrous disodium hydrogen phosphate, phosphoric acid, methanol 2. Equipment and instrument operation: Please refer to the standard operating procedures for electronic balance and high performance liquid chromatography.

[0037] 3. Test methods Chromatographic conditions and system suitability tests were performed using octadecylsilane-bonded silica gel as the stationary phase; the mobile phase consisted of 0.05 mol / L phosphate buffer (7.1 g of anhydrous disodium hydrogen phosphate was dissolved in water and diluted to the mark in a 1000 mL volumetric flask, and the pH was adjusted to 6.25 with phosphoric acid)-methanol (85:15); the detection wavelength was 235 nm. An appropriate amount of cefotaxime reference standard was dissolved and diluted in the mobile phase to prepare a solution containing approximately 1 mg per mL, which was used as the system suitability test solution. 10 μL of this solution was injected into the liquid chromatograph, and the recorded chromatogram should be consistent with the standard chromatogram.

[0038] Assay: Accurately weigh an appropriate amount of this product, dissolve and quantitatively dilute it with the mobile phase to prepare a solution containing approximately 1 mg per ml. Accurately inject 10 μL into the liquid chromatograph and record the chromatogram. Separately, take an appropriate amount of cefotaxime reference standard and determine it using the same method. Calculate the content of C16H17N5O7S2 in the test sample based on the peak area using the external standard method.

[0039] Calculation formula:

[0040] In the formula: A 样 : Sample peak area; F: Average correction factor for the reference standard; C 样 Concentration of the sample solution

[0041] The HPLC detection methods mentioned in this invention are all the methods described above, such as the HPLC detection of 7-ACA.

[0042] Example 3 (Lower limit of mixed solvent ratio)

[0043] Weigh 30.0g of 7-ACA and 42.5g of AE active ester and add them to a 500mL reaction vessel; add 240.0g of dichloromethane and 30.0g of methanol (mixed solvent mass ratio 8:1) and stir to disperse; add 14.5g of triethylamine (0.143mol, 1.0 times the molar amount of 7-ACA) dropwise at 8~10℃, and after reacting for 2 hours, add 2.4g of activated carbon (8% of the mass of 7-ACA), decolorize and filter to obtain about 310g of condensation reaction solution.

[0044] Prepare 24.0 g of sodium isooctanoate and 768.0 g of acetone (3% w / w). Add the condensation reaction solution dropwise at a rate of 6.7 mL / min (dropping time 90 minutes) at 20~25℃. Cool the solution to 10~12℃ and allow it to crystallize for 60 minutes.

[0045] After filtration, the product was washed with 50g of acetone at 10℃ for 2 hours and dried at 55℃ for 4 hours to obtain 47.1g of cefotaxime sodium product.

[0046] Weight yield: 1.57 times; HPLC purity: 99.6%, total impurities: 0.4%; Residual solvents: dichloromethane 510 ppm, methanol 2600 ppm, acetone 4500 ppm; Wastewater COD value: 1950 mg / L.

[0047] Example 4 (Upper Limit of Mixed Solvent Ratio)

[0048] Weigh 30.0g of 7-ACA and 42.5g of AE active ester and add them to a 500mL reaction vessel; add 360.0g of dichloromethane and 30.0g of methanol (mixed solvent mass ratio 12:1) and stir to disperse; add 16.0g of triethylamine (0.158mol, 1.1 times the molar amount of 7-ACA) dropwise at 8~10℃, and after reacting for 2 hours, add 3.6g of activated carbon (12% of the mass of 7-ACA), decolorize and filter to obtain about 420g of condensation reaction solution.

[0049] Prepare 24.0 g of sodium isooctanoate and 456.0 g of acetone (concentration 5% w / w). Add the condensation reaction solution dropwise at a rate of 10 mL / min (dropping time 60 minutes) at 20~25℃. Cool the solution to 10~12℃ and allow it to crystallize for 60 minutes.

[0050] After filtration, the product was washed with 50g of acetone at 5℃ twice and dried at 52℃ for 4 hours to obtain 49.2g of cefotaxime sodium product.

[0051] Weight yield: 1.64 times; HPLC purity: 99.7%, total impurities: 0.3%; Residual solvents: dichloromethane 480 ppm, methanol 2300 ppm, acetone 4100 ppm; Wastewater COD value: 1850 mg / L.

[0052] Comparative example (traditional "two-step method", see CN 02112393A)

[0053] Weigh 30.0 g of 7-ACA and 42.5 g of AE active ester, add 300.0 g of dichloromethane, and stir to disperse; add 8.5 g (0.108 mol) of pyridine dropwise at 0 °C, and react for 3 hours; add 100 g of water, stir to separate the layers, and collect the organic phase; wash the organic phase twice with 5% hydrochloric acid solution, then wash with water until neutral, and concentrate under reduced pressure to dryness to obtain 38.2 g of cefotaxime acid intermediate (yield 85%).

[0054] 38.2g of cefotaxime acid was added to a mixed solvent of 300g acetone and 30g water and stirred to dissolve. 50g of an aqueous solution of 10.2g sodium acetate was added dropwise at 20℃. After the addition was completed, the temperature was lowered to 0℃ and crystallized for 2 hours. The mixture was filtered, and the filter cake was washed twice with 50g acetone and dried at 45℃ for 6 hours to obtain 40.5g of cefotaxime sodium product.

[0055] Overall yield: 40.5g / 30.0g = 1.35 times (based on 7-ACA), far lower than that of this invention; HPLC purity: 98.5%, total impurities: 1.5% (including 0.8% β-lactam ring-opening impurities); Residual solvents: pyridine 620 ppm (close to the ICH Q3C limit of 880 ppm), dichloromethane 580 ppm, acetone 4200 ppm; The COD value of the wastewater is 3200 mg / L, which is more than 1.7 times that of the present invention. Production cycle: 26 hours, which is more than 3 times that of the present invention.

[0056] Examples 1-4 above show that the key parameters of the mixed solvent ratio (8:1-12:1), triethylamine dosage (1.0-1.1 molar), and sodium isooctanoate concentration (3%-5% w / w) in the technical solution of the present invention all achieve "one-step salt formation" and obtain high-yield, high-purity products, proving that the technical solution of the present invention has good stability and repeatability.

[0057] The comparative examples verified the limitations of the existing technology using the traditional "two-step method," further highlighting the significant advantages of the present invention in terms of process efficiency, product quality, and environmental friendliness.

[0058] The preferred embodiments of the present invention disclosed above are merely illustrative of the invention. These preferred embodiments do not exhaustively describe all details, nor do they limit the invention to the specific implementations described. Obviously, other related modifications can be made based on the content of this specification. This specification selects and specifically describes these embodiments to better explain the principles and practical applications of the invention, thereby enabling those skilled in the art to better understand and utilize the invention. The invention is limited only by the claims and their full scope and equivalents.

Claims

1. A method for preparing cefotaxime sodium, characterized in that, The synthesis of cefotaxime sodium based on a one-step salt formation method using a mixed solvent system and sodium isooctanoate includes the following steps: (1) Condensation reaction: 7-aminocephalosporanic acid (7-ACA) and AE active ester are added to a mixed solvent of dichloromethane and methanol, the temperature is controlled at 8~10℃, triethylamine is added as a catalyst, the reaction is stirred for 2 hours, then a decolorizing agent is added for decolorization, the decolorizing agent is removed by filtration, and the condensation reaction solution is obtained; the mass ratio of dichloromethane to methanol in the mixed solvent is (8~12):1; (2) Salt formation reaction: Add the acetone solution of sodium isooctanoate to the condensation reaction solution in step (1) at 20~25℃ for 60~90 minutes. After the addition is completed, cool down to 10~12℃ and grow crystals for 60 minutes. (3) Post-processing: The crystal growth system of step (2) is filtered, the filter cake is collected, the filter cake is washed with acetone, and then dried at 50~55℃ for 4 hours to obtain the cefotaxime sodium product.

2. The synthesis method according to claim 1, characterized in that: In step (1), the mass ratio of dichloromethane to methanol in the mixed solvent is 10:

1.

3. The synthesis method according to claim 1, characterized in that: The concentration of the acetone solution of sodium isooctanoate in step (2) is 3%~5% w / w (based on the percentage of the mass of sodium isooctanoate to the total mass of sodium isooctanoate and acetone).

4. The synthesis method according to claim 1, characterized in that: The dropping rate of the sodium isooctanoate acetone solution in step (2) is 6.7~10 mL / min, and the total mass of the sodium isooctanoate acetone solution is 600g.

5. The synthesis method according to claim 1, characterized in that: The decolorizing agent mentioned in step (1) is activated carbon, and the amount of activated carbon used is 8% to 12% of the mass of 7-ACA.

6. The synthesis method according to claim 1, characterized in that: The acetone washing in step (3) is a two-time washing process, with 50g of acetone used for each washing and the washing temperature ≤10℃.

7. The synthesis method according to claim 1, characterized in that: The amount of triethylamine used in step (1) is 1.0 to 1.1 times the molar amount of 7-ACA.

8. The synthesis method according to any one of claims 1 to 7, characterized in that: The cefotaxime sodium product has a weight yield of 1.5 to 1.7 times that of 7-ACA, an HPLC purity of ≥99.5%, a total impurity content of ≤0.5%, and residual solvents that meet ICH Q3C standards (dichloromethane ≤600 ppm, methanol ≤3000 ppm, acetone ≤5000 ppm).

9. A cefotaxime sodium, wherein the cefotaxime sodium is prepared by the synthetic method according to any one of claims 1 to 8, wherein the cefotaxime sodium is needle-shaped crystal, has an HPLC purity ≥99.5%, a total impurity content ≤0.5%, a residual solvent conforming to ICH Q3C standard, and a weight yield of 1.5 to 1.7 times for 7-ACA.

10. A reaction system for synthesizing cefotaxime sodium, characterized in that, The reaction system includes: Mixed solvent: dichloromethane and methanol, mass ratio (8~12):1; Catalyst: Triethylamine, with a molar amount 1.0 to 1.1 times that of 7-ACA; Salt-forming agent: acetone solution of sodium isooctanoate, concentration 3%~5% w / w; Decolorizing agent: activated carbon, the amount of which is 8%~12% of the mass of 7-ACA.

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