Synthesis process of removing 7-position protected cefditoren mother nucleus by enzyme

Abstract

The present application relates to the technical field of cefditoren mother nucleus synthesis, in particular to a kind of enzyme method removes 7-position protection cefditoren mother nucleus synthesis process, steps include: 7-position protection cefditoren mother nucleus precursor is dispersed in phosphate buffer, and substrate suspension is obtained;Substrate suspension temperature is controlled, and immobilized acylase is added, and water phase mixture is prepared;Emulsifying agent and extractant are added to organic solvent, stirred and mixed, and oil phase system is obtained;Oil phase system is added to water phase mixture, mixed and emulsified, and oil-in-water emulsion system is formed, temperature is controlled, and enzymatic deprotection reaction is carried out;After enzymatic reaction is finished, immobilized acylase is separated and recovered, and filtrate is demulsified, and after standing and layering, it is separated into water phase and organic phase;Cefditoren mother nucleus is separated from the obtained water phase.The present application uses enzyme catalysis deprotection, avoids the destruction of strong acid and strong base environment to cefditoren mother nucleus β-lactam ring by chemical method, byproduct generation amount is significantly reduced, and reaction condition is mild.

Description

Technical Field

[0001] This invention relates to the field of cefotaxime nucleus synthesis technology, specifically to an enzymatic process for the synthesis of cefotaxime nucleus by removing the 7-position protection. Background Technology

[0002] Ceftolenpispirate, also known as cefotaxime, is a third-generation oral cephalosporin with broad-spectrum antibacterial activity against Gram-positive and Gram-negative bacteria. It exhibits particularly strong antibacterial activity against Gram-positive bacteria such as Staphylococcus spp., including Streptococcus pneumoniae, as well as Gram-negative bacteria such as Escherichia coli, Moraxella catarrhalis, and Klebsiella pneumoniae, and anaerobic bacteria such as Streptococcus nitrifyingus and Propionibacterium acnes.

[0003] The cefotaxime core (7-ATCA) is a key intermediate in the synthesis of cefotaxime, and its quality directly determines the efficacy, purity, and safety of the final antibiotic product. The protection and deprotection of the 7-amino group is a crucial step in the synthesis of the cefotaxime core. To avoid unnecessary oxidation, acylation, and other side reactions of the 7-amino group in earlier synthetic reactions, a protecting group is usually introduced at this site. After other reactions are completed, the activity of the 7-amino group is restored through a deprotection reaction.

[0004] In existing technologies, the deprotection process for 7-position protected cefotaxime nuclei mostly employs chemical methods, such as using a system of phosphorus pentachloride and pyridine for the deprotection reaction. Phosphorus pentachloride is hygroscopic during use, producing white fumes and a pungent, irritating odor that strongly irritates the eyes, making operation very inconvenient. The resulting acid mist is not only highly harmful to humans but also highly corrosive to equipment. Furthermore, the treatment of phosphorus- and pyridine-containing wastewater is quite challenging. Therefore, it is necessary to consider other, milder, and more environmentally friendly methods for the 7-position deprotection reaction. Summary of the Invention

[0005] To address the problems existing in the prior art, this invention proposes an enzymatic process for the synthesis of cefotaxime nucleus by removing the 7-position protection. The 7-position protection is removed through an enzymatic hydrolysis reaction, achieving a highly efficient, mild, and environmentally friendly deprotection reaction.

[0006] To solve the above-mentioned technical problems, the preparation method of the present invention includes the following steps: S1. Disperse the 7-position protected cefotaxime precursor in phosphate buffer to obtain a substrate suspension; S2. Control the temperature of the substrate suspension from 0℃ to 15℃, add the immobilized acylase, and stir to prepare an aqueous mixture. S3. Add emulsifier and extractant to organic solvent, stir and mix to obtain oil phase system; S4. Add the oil phase system to the aqueous phase mixture, mix and emulsify to form an oil-in-water emulsion system, control the temperature, and carry out the enzymatic decomposition protection reaction. S5. After the enzymatic hydrolysis reaction is completed, the immobilized acylate is separated and recovered. The filtrate is demulsified, allowed to stand and separate into layers, and then separated to obtain an aqueous phase and an organic phase. S6. The cefotaxime nucleus was isolated from the obtained aqueous phase.

[0007] Preferably, the 7-position protecting group of the 7-position protecting cefotaxime precursor is phenylacetyl or phenoxyacetyl.

[0008] Preferably, the immobilized acylase is a penicillin G acylase or a penicillin V acylase with an enzyme activity ≥500 U / g.

[0009] Preferably, the amount of the immobilized acylase added is 5% to 15% of the mass of the 7-position protected cefotaxime nucleus precursor.

[0010] Preferably, the mass-to-volume ratio of the 7-position protected cefotaxime precursor to the phosphate buffer is 1:3 to 6, and the molar concentration of the phosphate buffer is 0.05 to 0.2 mol / L.

[0011] Preferably, the organic solvent is ethyl acetate, butyl acetate, or dichloromethane.

[0012] Preferably, the volume ratio of the organic solvent to the aqueous mixture is 1:1 to 2.

[0013] Preferably, the amount of emulsifier added is 0.5% to 1.5% of the mass of the organic solvent, and the emulsifier is selected from one or more of the Span series and Tween series.

[0014] Preferably, the amount of the extractant added is 3% to 10% of the mass of the organic solvent, and the extractant is trioctylamine, methyltrioctylammonium chloride or trialkylphosphine oxide.

[0015] Preferably, in step S6, the step of separating the cefotaxime nucleus is as follows: The separated aqueous phase was placed in a reaction vessel and, under stirring, the pH was slowly adjusted to 2.5–3.5 with hydrochloric acid solution, and the temperature was adjusted to 0–5℃. The mixture was allowed to stand for crystallization for 4–6 hours. The crystallized product was collected, washed, and dried to obtain the ceftriaxone nucleus.

[0016] After adopting the above technical solution, the beneficial effects of the present invention are: This invention employs enzyme-catalyzed deprotection, avoiding the damage to the β-lactam ring of the cefotaxime core caused by the strong acid and alkali environments of chemical methods. This significantly reduces the amount of byproducts generated and results in milder reaction conditions. The process of this invention does not require the use of harmful chemical reagents such as strong acids, strong alkalis, or heavy metal catalysts. The reaction waste liquid has low pollutant content, making it environmentally friendly and safe, and meeting the requirements of green chemistry. Attached Figure Description

[0017] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the accompanying drawings used in the description of the embodiments or the prior art will be briefly introduced below.

[0018] Figure 1 The chromatogram of the cefotaxime nucleus from Example 1 is shown below. Figure 2 The chromatogram of the cefotaxime nucleus from Example 2 is shown below. Figure 3 The chromatogram of the cefotaxime nucleus in Example 3 is shown. Detailed Implementation

[0019] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to specific embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and not intended to limit it. Those skilled in the art will recognize that the invention can be practiced without some of these specific details. The following description of the embodiments is merely intended to provide a better understanding of the invention by illustrating examples of it.

[0020] This invention provides an enzymatic process for the synthesis of cefotaxime nucleus with 7-position protection removed. The process removes the 7-position protecting group of the 7-position protected cefotaxime nucleus precursor through enzymatic hydrolysis, achieving a highly efficient, mild, and environmentally friendly deprotection reaction.

[0021] Step 1: Preparation of substrate suspension The 7-protected cefotaxime precursor with a 7-position protecting group of phenylacetyl or phenoxyacetyl was dispersed in phosphate buffer at a mass-to-volume ratio (g / mL) of 1:3 to 6, and stirred until homogeneous to obtain a substrate suspension for later use.

[0022] The molar concentration of phosphate buffer is 0.05–0.2 mol / L, and the pH is 7.5–8.5.

[0023] Step 2: Preparation of the aqueous phase mixture The prepared substrate suspension was placed in a reaction vessel, the low-temperature circulation system was turned on, and the system temperature was stabilized at 0℃~10℃. Immobilized acylated enzyme was added and stirred evenly to prepare an aqueous phase mixture.

[0024] Low-temperature control can inhibit premature enzymatic hydrolysis of precursors, ensuring that precursors participate in the reaction in a concentrated manner during the formal reaction stage, thereby improving the utilization rate of raw materials.

[0025] The amount of immobilized acylase added is 5% to 15% of the mass of the 7-position protected cefotaxime precursor. Penicillin G acylase (with a phenylacetyl group at the 7-position) or penicillin V acylase (with a phenoxyacetyl group at the 7-position) with an enzyme activity ≥600 U / g is selected. The carrier is an amphiphilic carrier phospholipid, glycolipid, or polyethylene glycol-chitosan polymer.

[0026] Step 3: Preparation of the oil phase system Add the emulsifier and extractant to the organic solvent, and start stirring to obtain a homogeneous oil phase system. The organic solvent is selected from ethyl acetate, butyl acetate, and dichloromethane, with a volume ratio of 1:1 to 2 with the aqueous phase mixture. The emulsifier is selected from one or more of the Span series (e.g., Span-80, Span-85) and Tween series (e.g., Tween-65, Tween-80), and the amount added is 0.5% to 1.5% of the organic solvent mass. The extractant is selected from trioctylamine, methyltrioctylammonium chloride, or trialkylphosphine oxide, and the amount added is 3% to 10% of the organic solvent mass.

[0027] Step 4: Enzymatic Deprotection Reaction The oil phase system is added to the aqueous phase mixture, mixed and emulsified to form an oil-in-water emulsion system, and then heated to 32-37°C to carry out an enzymatic desorption protection reaction.

[0028] In oil-in-water emulsion systems, immobilized acylases using amphiphilic substances as carriers can be anchored at the oil-water interface, improving the mass transfer efficiency of subsequent byproducts.

[0029] Immobilized acylase catalyzes substrate deprotection in the aqueous phase, generating cefotaxime nucleus (7-ATCA) and phenylacetic acid / phenoxyacetic acid. 7-ATCA dissolves in the aqueous phase, while phenylacetic acid / phenoxyacetic acid dissociates into anions in the aqueous phase. These anions form ion pairs with the extractant in the oil phase and are simultaneously extracted to the oil phase. This process enables timely transfer of byproducts from the aqueous phase to the oil phase, preventing byproduct accumulation in the aqueous phase, inhibiting enzyme activity, and improving the purity of the target product.

[0030] Step 5: Recovery of immobilized acylase, demulsification and stratification After the enzymatic hydrolysis reaction is completed, add a polyether demulsifier (such as L61) to the reaction substrate at a rate of 0.2% to 0.5% of the total volume of the reaction substrate. Stir to demulsify and promote the coalescence of oil droplets.

[0031] The mixture was allowed to stand and separate into aqueous and oil phases, which were then collected and labeled. The lower aqueous phase was filtered to retain the immobilized acylated enzyme particles.

[0032] Step Six: Isolation of the Cefotaxime nucleus The separated aqueous phase was placed in a reaction vessel and, under stirring, the pH was adjusted to 2.5–3.5 with 2 mol / L hydrochloric acid solution. The temperature was maintained at 0–5 °C throughout the process, and after stirring for 1 hour, the mixture was allowed to stand for crystallization for 4 hours. The crystallized product was collected, washed, and dried to obtain the ceftriaxone nucleus.

[0033] Step 7: Recovery of organic solvents, extractants, and byproducts The separated oil phase is placed in a vacuum distillation vessel for vacuum distillation, and the fraction is collected to obtain the recovered organic solvent, which is then reused in step three.

[0034] After distillation, the distillate is transferred to a separatory vessel, and a 1 mol / L sodium hydroxide solution is added. The mixture is stirred, and the pH is adjusted to 10–11. The product formed by the extractant (e.g., trioctylamine) and byproducts (e.g., phenylacetic acid / phenoxyacetic acid) dissociates, trioctylamine returns to its free state, and the byproducts are converted into sodium phenylacetate / sodium phenoxyacetate. The mixture is allowed to stand and separate into layers; the upper layer is the free extractant, and the lower layer is an aqueous phase containing byproduct salts. The upper extractant layer is separated, dried, and reused in step three.

[0035] The lower aqueous phase containing byproduct salts is slowly adjusted to pH 2.0–2.5 with a 1 mol / L hydrochloric acid solution, and the temperature is adjusted to 0–5°C, allowing for crystallization. After crystallization, the crystals are collected by filtration, washed, and dried to obtain the byproduct phenylacetic acid / phenoxyacetic acid, which can be recycled as a chemical raw material.

[0036] Example 1 This embodiment provides an enzymatic process for the synthesis of cefotaxime nucleus by removing the 7-position protection, including the following steps: S1. Disperse 1000g of 7-phenylacetamido-3-(4-methylthiazolyl-5-yl)vinyl-3-cephalosporin-4-carboxylic acid in 5000mL of phosphate buffer solution with pH 8.0 and concentration of 0.05mol / L at a mass-to-volume ratio (g / mL) of 1:5, stir well to obtain a substrate suspension for later use. S2. Place the prepared substrate suspension in a reaction vessel, turn on the low-temperature circulation system, stabilize the system temperature at 5°C, add 5% of the mass of penicillin G acylase of the 7-position protected cefotaxime precursor, the carrier is polyethylene glycol-chitosan polymer, stir evenly to prepare an aqueous mixture for later use. S3. Measure an equal volume of ethyl acetate to the aqueous phase mixture, add 0.5% by weight of Span-80 organic solvent and 3% by weight of methyltrioctylammonium chloride organic solvent, start stirring to obtain a homogeneous oil phase system, and set aside. S4. Add the oil phase system to the aqueous phase mixture, mix and emulsify to form an oil-in-water emulsion system, heat to 32℃, and carry out an enzyme desorption protection reaction for 2 hours. S5. After the enzymatic hydrolysis reaction is completed, add L61 to the reaction base liquid. The amount added is 0.2% of the total volume of the reaction base liquid. Stir to break the emulsion, let stand and separate the layers, collect the aqueous phase and oil phase respectively, filter the lower aqueous phase and retain the immobilized acylated enzyme particles. S6. Place the separated aqueous phase in a reaction vessel and adjust the pH to 2.5 with 2 mol / L hydrochloric acid solution while stirring. Maintain the temperature at 3.5℃ throughout the process. After stirring for 1 hour, allow the mixture to stand and crystallize. Collect the crystallized product, wash and dry it to obtain cefotaxime nucleus with a purity of 99.02%. S7. Place the separated oil phase in a vacuum distillation kettle for vacuum distillation, collect the fraction, and obtain the recovered organic solvent, which can be reused in step S3. S8. After distillation, the distillation residue is transferred to a separatory vessel, a 1 mol / L sodium hydroxide solution is added, the mixture is stirred, the pH of the system is adjusted to 10, the layers are allowed to stand and separate, the upper layer of extractant is separated, the extractant is dried and reused in step S3. S9. The pH of the lower aqueous phase containing byproduct salts was slowly adjusted to 2.0 with a 1 mol / L hydrochloric acid solution, and the temperature was adjusted to 0℃. The mixture was allowed to stand and crystallize. The crystals were collected by filtration, washed, and dried to obtain the byproduct phenylacetic acid.

[0037] Example 2 This embodiment provides an enzymatic process for the synthesis of cefotaxime nucleus by removing the 7-position protection, including the following steps: S1. Disperse 1000g of 7-phenylacetamido-3-(4-methylthiazolyl-5-yl)vinyl-3-cephalosporin-4-carboxylic acid in phosphate buffer solution with pH 7.5 and concentration of 0.1mol / L at a mass-to-volume ratio (g / mL) of 1:3, stir well to obtain a substrate suspension for later use. S2. Place the prepared substrate suspension in a reaction vessel, turn on the low-temperature circulation system, stabilize the system temperature at 5°C, add 10% of the mass of penicillin G acylase of the 7-position protected cefotaxime precursor, with polyethylene glycol-chitosan polymer as the carrier, stir evenly to prepare an aqueous mixture for later use. S3. Measure 1.5 times the volume of the aqueous phase mixture of butyl acetate, add 1% by weight of emulsifier and 5% by weight of trioctylamine by weight of organic solvent. The emulsifier is a mixture of Span-80 and Tween-80 in a ratio of 3:7. Turn on the stirrer to obtain a uniform oil phase system for later use. S4. Add the oil phase system to the aqueous phase mixture, mix and emulsify to form an oil-in-water emulsion system, heat to 35℃, and carry out an enzyme desorption protection reaction for 2 hours. S5. After the enzymatic hydrolysis reaction is completed, add L61 to the reaction base liquid. The amount added is 0.35% of the total volume of the reaction base liquid. Stir to break the emulsion, let stand to separate the layers, collect the aqueous phase and oil phase respectively, filter the lower aqueous phase, and retain the immobilized acylated enzyme particles. S6. Place the separated aqueous phase in a reaction vessel and adjust the pH to 3.0 with 2 mol / L hydrochloric acid solution while stirring. Maintain the temperature at 0℃ throughout the process. After stirring for 1 hour, allow the mixture to stand and crystallize. Collect the crystallized product, wash and dry it to obtain cefotaxime nucleus with a purity of 99.51%. S7. Place the separated oil phase in a vacuum distillation kettle for vacuum distillation, collect the fraction, and obtain the recovered organic solvent, which can be reused in step S3. S8. After distillation, the distillation residue is transferred to a separatory vessel, a 1 mol / L sodium hydroxide solution is added, the mixture is stirred, the pH of the system is adjusted to 10.5, the layers are allowed to stand and separate, the upper layer of extractant is separated, the extractant is dried and reused in step S3. S9. The pH of the lower aqueous phase containing byproduct salts was slowly adjusted to 2.5 with a 1 mol / L hydrochloric acid solution, and the temperature was adjusted to 3°C. The mixture was allowed to stand and crystallize. The crystals were collected by filtration, washed, and dried to obtain the byproduct phenylacetic acid.

[0038] Example 3 This embodiment provides an enzymatic process for the synthesis of cefotaxime nucleus by removing the 7-position protection, including the following steps: S1. Disperse 1000g of 7-phenylacetamido-3-(4-methylthiazolyl-5-yl)vinyl-3-cephalosporin-4-carboxylic acid in phosphate buffer solution with pH 8.5 and concentration of 0.2mol / L at a mass-to-volume ratio (g / mL) of 1:6, stir well to obtain a substrate suspension for later use. S2. Place the prepared substrate suspension in a reaction vessel, turn on the low-temperature circulation system, stabilize the system temperature at 10℃, add 15% of the mass of penicillin G acylase of the 7-position protected cefotaxime precursor, the carrier is polyethylene glycol-chitosan polymer, stir evenly to prepare an aqueous phase mixture for later use. S3. Measure two times the volume of the aqueous phase mixture of dichloromethane, add 1.5% by weight of Tween-80 organic solvent and 10% by weight of trioctylamine organic solvent, start stirring to obtain a homogeneous oil phase system, and set aside. S4. Add the oil phase system to the aqueous phase mixture, mix and emulsify to form an oil-in-water emulsion system, heat to 37°C, and carry out an enzyme desorption protection reaction for 2 hours. S5. After the enzymatic hydrolysis reaction is completed, add L61 to the reaction base liquid. The amount added is 0.5% of the total volume of the reaction base liquid. Stir to break the emulsion, let stand to separate the layers, collect the aqueous phase and oil phase respectively, filter the lower aqueous phase, and retain the immobilized acylated enzyme particles. S6. Place the separated aqueous phase in a reaction vessel and adjust the pH to 3.5 with 2 mol / L hydrochloric acid solution while stirring. Maintain the temperature at 5℃ throughout the process. After stirring for 1 hour, allow the mixture to stand and crystallize. Collect the crystallized product, wash and dry it to obtain cefotaxime nucleus with a purity of 99.23%. S7. Place the separated oil phase in a vacuum distillation kettle for vacuum distillation, collect the fraction, and obtain the recovered organic solvent, which can be reused in step S3. S8. After distillation, the distillation residue is transferred to a separatory vessel, a 1 mol / L sodium hydroxide solution is added, the mixture is stirred, the pH of the system is adjusted to 11, the layers are allowed to stand and separate, the upper layer of extractant is separated, the extractant is dried and reused in step S3. S9. The pH of the lower aqueous phase containing byproduct salts was slowly adjusted to 2.5 with a 1 mol / L hydrochloric acid solution, and the temperature was adjusted to 5°C. The mixture was allowed to stand and crystallize. The crystals were collected by filtration, washed, and dried to obtain the byproduct phenylacetic acid.

[0039] Samples of the ceftriaxone nuclei prepared in Examples 1-3 were taken, and the purity and related substances of the samples were detected by high performance liquid chromatography (HPLC) at a wavelength of 254 nm.

[0040] The liquid chromatogram of Example 1 is attached. Figure 1 The liquid chromatogram of Example 2 is shown in the appendix. Figure 2 The liquid chromatogram of Example 3 is shown in the appendix. Figure 3 The test results of the cefotaxime nucleus in each embodiment are detailed in Table 1.

[0041] Table 1 Peak Tables for Each Embodiment

[0042] As shown in Table 1, the purity of the main component of cefotaxime prepared by the enzymatic hydrolysis method of this invention is ≥99.0%, and the content of the key impurity E-isomer is ≤0.6%. 3 - The residual 7-ADCA of the isomer and the 7-protected cefotaxime precursor are both controlled below 0.2%. Compared with traditional chemical synthesis methods, this process achieves precise control of isomer impurities from the source, and the main peak chromatographic peak shape is symmetrical (tailing factor close to 1.0), providing a high-quality intermediate guarantee for the subsequent industrial production of high-purity cefotaxime.

[0043] The embodiments described above are not exhaustive and do not limit the invention to specific implementations. Clearly, many modifications and variations can be made based on the above description. These embodiments are selected and specifically described in this specification to better explain the principles and practical applications of the invention, thereby enabling those skilled in the art to effectively utilize the invention and its modifications. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the invention should be included within the scope of protection of the invention.

Claims

1. A process for the enzymatic removal of the 7-position protected cefotaxime nucleus in the synthesis of cefotaxime, characterized in that, Includes the following steps: S1. Disperse the 7-position protected cefotaxime precursor in phosphate buffer to obtain a substrate suspension; S2. Control the temperature of the substrate suspension from 0℃ to 15℃, add the immobilized acylase, and stir to prepare an aqueous mixture. S3. Add emulsifier and extractant to organic solvent, stir and mix to obtain oil phase system; S4. Add the oil phase system to the aqueous phase mixture, mix and emulsify to form an oil-in-water emulsion system, control the temperature, and carry out the enzymatic decomposition protection reaction. S5. After the enzymatic hydrolysis reaction is completed, the immobilized acylate is separated and recovered. The filtrate is demulsified, allowed to stand and separate into layers, and then separated to obtain an aqueous phase and an organic phase. S6. The cefotaxime nucleus was isolated from the obtained aqueous phase.

2. The enzymatic process for removing the 7-position protected cefotaxime nucleus from the cefotaxime nucleus according to claim 1, characterized in that: The 7-position protecting group of the 7-position protected cefotaxime precursor is phenylacetyl or phenoxyacetyl.

3. The enzymatic process for removing the 7-position protected cefotaxime nucleus from the cefotaxime nucleus according to claim 2, characterized in that: The immobilized acylase is a penicillin G acylase or penicillin V acylase with an enzyme activity ≥500 U / g.

4. The enzymatic process for removing the 7-position protected cefotaxime nucleus from the cefotaxime nucleus according to claim 1, characterized in that: The amount of the immobilized acylase added is 5% to 15% of the mass of the 7-position protected cefotaxime nucleus precursor.

5. The enzymatic process for removing the 7-position protected cefotaxime nucleus from the cefotaxime nucleus according to claim 1, characterized in that: The mass-to-volume ratio of the 7-position protected cefotaxime precursor to the phosphate buffer is 1:3 to 6, and the molar concentration of the phosphate buffer is 0.05 to 0.2 mol / L.

6. The enzymatic process for removing the 7-position protected cefotaxime nucleus from the cefotaxime nucleus according to claim 1, characterized in that: The organic solvent is ethyl acetate, butyl acetate, or dichloromethane.

7. The enzymatic process for removing the 7-position protected cefotaxime nucleus from the cefotaxime nucleus according to claim 1, characterized in that: The volume ratio of the organic solvent to the aqueous phase mixture is 1:1 to 2.

8. The enzymatic process for removing the 7-position protected cefotaxime nucleus from the cefotaxime nucleus according to claim 1, characterized in that: The amount of emulsifier added is 0.5% to 1.5% of the mass of the organic solvent, and the emulsifier is selected from one or more of the Span series and Tween series.

9. The enzymatic process for removing the 7-position protected cefotaxime nucleus from the cefotaxime nucleus according to claim 1, characterized in that: The amount of the extractant added is 3% to 10% of the mass of the organic solvent, and the extractant is trioctylamine, methyltrioctylammonium chloride or trialkylphosphine oxide.

10. The enzymatic process for removing the 7-position protected cefotaxime nucleus from the cefotaxime nucleus according to claim 1, characterized in that, In step S6, the steps for isolating the cefotaxime nucleus are as follows: The separated aqueous phase was placed in a reaction vessel and, under stirring, the pH was slowly adjusted to 2.5–3.5 with hydrochloric acid solution, and the temperature was adjusted to 0–5℃. The mixture was allowed to stand for crystallization for 4–6 hours. The crystallized product was collected, washed, and dried to obtain the ceftriaxone nucleus.

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