A synthetic process of cefquinome sulfate
By using a composite adsorbent and catalyst of pyrazolate-based C@MOF and 4-vinylpyridine-styrene copolymer, the problems of slow reaction process and low product purity in the synthesis of cefquinome sulfate were solved, and the production of intermediates and final products with high efficiency was achieved.
Patent Information
- Application Number
- CN202511516320.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2025-10-23
- Publication Date
- 2026-01-06
- Estimated Expiration
- 2045-10-23
AI Technical Summary
The existing process for synthesizing cefquinoxime sulfate is slow, with low product purity and yield, and there is a problem of iodide ions participating in side reactions.
Pyrazolate-based C@MOF and 4-vinylpyridine-styrene copolymer were used as a composite adsorbent and a solid base catalyst, respectively, to adsorb and catalyze the synthesis of cefquinoxime sulfate. The pyrazolate-based C@MOF adsorbed iodide ions and neutralized byproducts, while the 4-vinylpyridine-styrene copolymer maintained the weak alkalinity of the reaction system and promoted the reaction.
It significantly improved the yield of 7-aminocefoquinoxime intermediates and the purity and yield of the final product, cefoquinoxime sulfate, simplified the purification steps, and reduced the formation of byproducts.
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Figure CN120987973B_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of heterocyclic compound technology, and specifically to a synthetic process for cefquinome sulfate. Background Technology
[0002] Cefquinoxime sulfate is an veterinary-specific drug, belonging to the fourth generation of cephalosporins. It is a CVMP-approved drug for treating various serious infectious diseases in animals, including respiratory and lower respiratory tract infections. Its sulfate form is stable, allowing for formulation, easy storage, and convenient transportation, making it ideal for clinical applications. Cefquinoxime sulfate exhibits excellent antibacterial activity, high toxicity, and superior pharmacokinetic characteristics. It is rapidly absorbed by the body, reaching high concentrations in many tissues with low residues. Furthermore, it has low affinity for β-lactamases, high stability, and can rapidly cross the periplasmic space, exhibiting enzyme resistance. It is also effective against a variety of bacteria, particularly at low concentrations, strongly inhibiting Staphylococcus aureus, Pasteurella multocida, Streptococcus, and various enteric bacteria. It even shows high inhibitory activity against some bacteria antagonistic to penicillin.
[0003] Currently, there are three commonly used synthetic steps for cefoquinoxime sulfate. The first method uses cefotaxime acid as a starting material to synthesize cefoquinoxime sulfate. An article published in the *Chinese Journal of Pharmaceutical Industry*, titled "Synthesis of Cefoquinoxime Sulfate," describes a process using hexamethyldisilazane as a silanizing agent and trimethyliodosilane as a catalyst to protect the amino and carboxyl groups of cefotaxime acid. Then, trimethyliodosilane is used to substitute the acetoxy group at the 3-position of the side chain to obtain the iodinated product. Next, 5,6,7,8-tetrahydroquinoline is added to obtain 7-A00 hydroiodate, which is then acidified with sulfuric acid via anion exchange resin to yield the target product. The advantage of this synthetic process is that it uses only one solvent; however, the removal of iodide ions using anion exchange resin is time-consuming, and the yield needs improvement.
[0004] The second method involves synthesizing cefoquinoxime sulfate using 7-ACA as a starting material. An article titled "Synthesis of Cefoquinoxime Sulfate," published in the journal *Applied Chemicals*, describes the synthesis. Using dichloromethane as the reaction solvent, 7-ACA reacts with 5,6,7,8-tetrahydroquinoline in the presence of trimethyliodosilane to yield the intermediate 7-aminocefoquinoxime hydroiodate. This intermediate is then reacted directly with the active AE ester without further treatment, followed by acidification with sulfuric acid to obtain the target product. This reaction route uses relatively small amounts of trimethyliodosilane and 5,6,7,8-tetrahydroquinoline. However, dichloromethane as the reaction solvent has a certain degree of toxicity. Furthermore, the intermediate 7-ACQ exists as hydroiodate and directly proceeds to the next acylation reaction. This means that iodide ions will always be present in the reaction system. These iodide ions may participate in side reactions, increasing the variety and quantity of byproducts and leading to a decrease in the purity of the final product.
[0005] The third method involves synthesizing cefquinome sulfate using GCLE as a raw material. However, this process is complex and requires alkaline hydrolysis of the amide bond, which causes some of the β-lactam rings to cleave, resulting in numerous byproducts and a low yield of the target product.
[0006] Therefore, there is an urgent need to develop a method that can both accelerate the reaction process and improve the purity and yield of the target product in order to solve the problems existing in the above-mentioned technologies. Summary of the Invention
[0007] In view of this, the present invention provides a synthesis process for cefquinoxime sulfate, which can accelerate the reaction process and improve the purity and yield of the target product.
[0008] To achieve the above objectives, the present invention provides a process for synthesizing cefquinome sulfate, comprising the following steps:
[0009] S1. Tris(4-(1H-pyrazol-4-yl)phenyl)amine, N,N-dimethylformamide, and zinc nitrate hexahydrate aqueous solution were mixed, benzoic acid and activated carbon powder were added, ultrasonic treatment was performed, the reaction was heated, cooled to room temperature, the precipitate was collected by centrifugation, and the precipitate was immersed in N,N-dimethylformamide and anhydrous ethanol, respectively. The precipitate was collected by centrifugation and dried to obtain pyrazolate group C@MOF;
[0010] S2. 7-Aminocephalosporanic acid, hexamethyldisilazane, and trimethyliodosilane are mixed and reacted. Pyrazolate group C@MOF, trimethyliodosilane, 5,6,7,8-tetrahydroquinoline, and methanol are added sequentially. The mixture is filtered, hydrochloric acid solution is added, and the mixture is allowed to stand for phase separation. Crystallization occurs, followed by filtration, washing, and drying to obtain 7-aminocephalosporanic acid oxime.
[0011] S3. Mix 7-aminocefoquinoxime, AE-active ester, 2-methyltetrahydrofuran, and 4-vinylpyridine-styrene copolymer, filter, wash, collect the filtrate, concentrate and crystallize, filter, wash, dissolve in water, cool, add sulfuric acid to react, filter, wash, and dry to obtain cefquinoxime sulfate.
[0012] This invention prepares pyrazolate-based C@MOFs for adsorbing iodide ions generated during the production of 7-aminocefoquinoxime (an intermediate) to improve the yield of the intermediate. Activated carbon possesses abundant pores, while the zinc-based metal-organic framework (Zn-MOF-2) in the pyrazolate-based C@MOF contains excellent active sites. Together with the pyrazolate-based ligand, they form a composite adsorbent. The zinc ions in Zn-MOF-2 act as electron pair acceptors and electron pair donors to the reaction byproduct iodide ions, thereby adsorbing iodide ions through coordination. - Tightly bonded to Zn 2+This achieves efficient chemisorption; furthermore, the nitrogen atom on the pyrazole ligand has a certain basicity, which can neutralize the hydroiodic acid byproduct generated during the nucleophilic substitution reaction with 5,6,7,8-tetrahydroquinoline, ultimately neutralizing to form pyrazoleonium salt and iodide ions, generating I... - It can also be used by Zn 2+ Site capture; at the same time, Zn-MOF-2 and activated carbon together construct a larger external surface area and a faster external diffusion rate, which can capture I2 and HI through physical adsorption while improving the adsorption rate of iodide ions. This avoids the problem that highly active HI is not removed in time and further protonates the nitrogen atom of the β-lactam ring, leading to its ring-opening decomposition and the generation of by-products, which reduces the purity and yield of the final product.
[0013] In addition, as the pyrazolate-based C@MOF continuously adsorbs and fixes iodide ions and HI onto its pores and metal sites, it breaks the reaction equilibrium and drives the reaction to proceed to the right, thus playing a certain catalytic role in the reaction. Furthermore, the zinc ions in the MOF, as Lewis acids, can activate the reaction sites and promote the nucleophilic substitution reaction with 5,6,7,8-tetrahydroquinoline, further improving the conversion rate and final yield of the reaction.
[0014] This invention uses a 4-vinylpyridine-styrene copolymer as an insoluble solid base catalyst to catalyze the acylation reaction using 7-aminocefoquinoxime and AE-active ester as raw materials. The pyridine group in the copolymer acts as a weak base, and its nitrogen atom can accept a proton. In the reaction system, it consumes the acid (HX) generated by the acylation reaction through an acid-base neutralization reaction, maintaining the pH of the reaction solution in the weakly alkaline environment required for the deprotonation of the amino group of 7-aminocefoquinoxime, thereby catalyzing the reaction. Furthermore, its solid particle form makes it insoluble in the reaction solvent, and it can be separated from the reaction system by simple filtration after the reaction. Therefore, using the 4-vinylpyridine-styrene copolymer as an insoluble solid base catalyst to catalyze the acylation reaction can both improve the yield and purity of the final product and simplify the final purification steps.
[0015] Optionally, the aqueous solution of zinc nitrate hexahydrate is obtained by mixing and stirring Zn(NO3)2-6H2O and deionized water for 10 min.
[0016] Optionally, in step S1, tris(4-(1H-pyrazole-4-yl)phenyl)amine and N,N-dimethylformamide are mixed and stirred for 10 min, then an aqueous solution of zinc nitrate hexahydrate is added and stirred for 10-15 min, benzoic acid is added and ultrasonically treated for 5-10 min, activated carbon powder is added and ultrasonically treated for 30 min, the mixture is transferred to a reaction vessel, stirred and reacted at 100°C for 48 h, cooled to room temperature, the precipitate is collected by centrifugation, soaked in N,N-dimethylformamide for 16-24 h, then soaked in anhydrous ethanol for 24-48 h, the precipitate is collected by centrifugation, and dried at 80-100°C for 8-12 h to obtain pyrazole acid salt C@MOF.
[0017] This invention uses tris(4-(1H-pyrazol-4-yl)phenyl)amine as a ligand to react with metal ions to form a pyrazolate-based metal-organic framework. The metal-organic framework and activated carbon are tightly bound together through physical interactions such as van der Waals forces and electrostatic interactions to increase the number of active sites in the composite adsorbent. It combines the advantages of chemical adsorption and physical adsorption and can effectively adsorb iodide ions.
[0018] Optionally, the activated carbon powder is biological activated carbon powder, which is prepared by mixing biomass material, KOH and deionized water and stirring for 10-20 min, drying at 90℃ for 8-12 h, placing it in a nitrogen atmosphere with a nitrogen flow rate of 100 mL / min, pyrolyzing at a high temperature of 600-700℃ at 5℃ / min for 1-2 h, cooling to room temperature, washing 2-5 times with a 1 mol / L hydrochloric acid solution, and drying at 90-105℃ for 16-18 h.
[0019] This invention uses natural biomass materials as raw materials, mixes them with potassium hydroxide (KOH) and deionized water, and then pyrolyzes them to obtain bio-activated carbon powder. The KOH activation process enhances the pore structure of the carbon material. During high-temperature pyrolysis in a nitrogen atmosphere, a more regular and uniform pore structure is formed on the surface of the bio-activated carbon powder.
[0020] Preferably, the biomass material can be one of straw, corn cob, or fruit peel.
[0021] Optionally, the 4-vinylpyridine-styrene copolymer is obtained by mixing styrene, 4-vinylpyridine and benzoyl peroxide, sealing the mixture, and heating and stirring it at 80~100℃ for 5~6 hours.
[0022] In this invention, the 4-vinylpyridine-styrene copolymer is a solid base catalyst synthesized through free radical copolymerization. Styrene provides the supporting framework, and 4-vinylpyridine provides the basic active sites. Compared to typical homogeneous base catalysts (such as triethylamine), which possess a certain degree of nucleophilicity and may attack active esters during the reaction, generating byproducts such as N-acylamines, the 4-vinylpyridine-styrene copolymer in this invention is a solid heterogeneous catalyst. Its active sites (pyridine nitrogen) are fixed on the polymer framework, significantly increasing steric hindrance and reducing nucleophilicity, thereby effectively avoiding side reactions initiated by the base catalyst itself. In a homogeneous system, the base is continuously consumed, and the pH gradually decreases, potentially deviating from the optimal reaction range. However, throughout the reaction process, the surface of the 4-vinylpyridine-styrene copolymer can be considered a localized stable pH microenvironment, enabling a more continuous and stable maintenance of the weakly basic conditions required for the reaction, ensuring that the reaction always proceeds under optimal conditions.
[0023] Optionally, in step S2, 7-aminocephalosporanic acid, 2-methyltetrahydrofuran, hexamethyldisilazane, and trimethyliodosilane are added to a reaction flask and mixed. The mixture is then evacuated, heated to reflux, cooled to below 0°C, and pyrazolate-based C@MOF is added. Trimethyliodosilane is then added to react, the temperature is lowered to below 0°C, and 5,6,7,8-tetrahydroquinoline is added to continue the reaction. The temperature is lowered to below 5°C, methanol is added dropwise, the reaction is stirred, and the mixture is filtered using a Buchner funnel. Hydrochloric acid solution is added, and the mixture is allowed to stand for phase separation. The organic phase is washed with hydrochloric acid solution, the aqueous phases are combined, activated carbon is added, and the mixture is stirred to decolorize. The mixture is filtered, acetone is added to the filtrate, and triethylamine is added dropwise to adjust the pH to 3.0-3.5. Crystallization is carried out by slow stirring, and the crystals are filtered. The filter cake is washed 2-4 times with acetone and dried under reduced pressure to obtain 7-aminocephalosporanic acid oxime.
[0024] This invention involves protecting the amino and carboxyl groups of 7-aminocephalosporanic acid and hexamethyldisilazane, performing an iodine substitution reaction at the 3-position using trimethyliodosilane, and finally undergoing a nucleophilic substitution reaction with 5,6,7,8-tetrahydroquinoline to yield 7-aminocephaloquinoxime. The structural formula is shown in the appendix. Figure 1 In formula (I), this process uses 2-methyltetrahydrofuran (2-MeTHF) as a solvent to replace toxic dichloromethane. Compared to dichloromethane, 2-MeTHF has a lower viscosity, flows more easily during the reaction, and better promotes the mixing of reactants, thus increasing the reaction rate. Using C@MOF, all iodine byproducts are immobilized in a solid material. After the reaction is complete, a simple filtration step is all that is needed to completely separate the byproducts from the reaction system. This greatly simplifies the operation. The C@MOF after adsorption saturation can also be collected and processed centrally to recover high-value iodine, achieving resource utilization of waste.
[0025] Optionally, the heating reflux temperature is 40°C for 15-17 hours, the reaction time after adding trimethyliodosilane is 4-5 hours, the reaction time after adding 5,6,7,8-tetrahydroquinoline is 2-3 hours, the stirring reaction time is 30 minutes, the stirring decolorization temperature is 50-60°C for 20-30 minutes, the crystal growth is carried out at 0-10°C for 2-4 hours, and the vacuum drying is carried out at 40°C for 4 hours.
[0026] The present invention incorporates stirring and heating during the decolorization process to improve decolorization efficiency.
[0027] Optionally, the concentration of the hydrochloric acid solution is 6 mol / L; the 7-aminocephalosporanic acid comprises the following raw materials in parts by weight: 25 parts of 7-aminocephalosporanic acid, 17.05 parts of hexamethyldisilazane, 25.67 parts of trimethyliodosilane, 14.4 parts of 5,6,7,8-tetrahydroquinoline, and 0.5-3 parts of pyrazolium salt C@MOF.
[0028] Optionally, in step S3, 7-aminocefoquinoxime, AE-active ester, and 2-methyltetrahydrofuran are mixed, cooled to 0-3°C, stirred for 20-30 min, and 4-vinylpyridine-styrene copolymer is added and reacted for 6-8 h. After filtration, the filter cake is washed with 2-methyltetrahydrofuran, the filtrate is collected, concentrated under reduced pressure, ethyl acetate is added, and crystals are slowly stirred and cultured at 0-5°C for 3 h. After filtration, the filter cake is washed 2-4 times with ethyl acetate, dissolved in deionized water, activated carbon is added, and the mixture is stirred and decolorized at 60-70°C for 20-30 min. After cooling to 10°C, 6 mol / L sulfuric acid is added to adjust the pH to 1.5-2.0, and after cooling to 2-5°C, the mixture is stirred for 1-2 h and cultured for 2 h. After filtration, the mixture is washed with ice water, filtered, and dried under reduced pressure at room temperature for 4 h to obtain cefquinoxime sulfate.
[0029] The cefquinoxime sulfate of this invention is obtained by acylation condensation of 7-aminocefquinoxime (intermediate) and AE-active ester, followed by salt formation with sulfuric acid. A structural diagram of cefquinoxime sulfate is attached. Figure 1 Chinese formula (II). After the acylation condensation reaction is completed, the solid base is filtered off, and the filtrate is directly concentrated and crystallized by adding an antisolvent, which greatly simplifies the purification steps. Using ethyl acetate as an antisolvent reduces the solubility of the product in the solution, forcing the product to precipitate from the solution in the form of crystals, thereby achieving separation and purification. In addition, ethyl acetate can also be used as a washing solvent. After obtaining the crystals by filtration, the filter cake is washed with cold ethyl acetate, which can effectively wash away soluble organic impurities and mother liquor adhering to the surface of the crystals, thereby further improving the purity of the final product.
[0030] Optionally, the cefquinoxime sulfate comprises the following raw materials in parts by weight: 4.2 parts of 7-aminocefquinoxime, 5.3 parts of AE-active ester, 0.1 to 0.3 parts of 4-vinylpyridine-styrene copolymer, 0.5 parts of activated carbon, and 0.59 to 1.18 parts of sulfuric acid.
[0031] The present invention uses the above ratio, which allows the materials to react fully, and the addition of 4-vinylpyridine-styrene copolymer accelerates the overall reaction process.
[0032] The above-described technical solution of the present invention has at least the following beneficial effects:
[0033] 1. Pyrazolate-based C@MOFs significantly improved the yield of 7-aminocephaloquinoxime intermediates through synergistic effects. Zn in the MOFs... 2+ Highly efficient chemisorption of iodide ions is achieved through coordination with iodide ions. The nitrogen atom of the pyrazole ligand neutralizes hydroiodic acid, generating pyrazoleonium salt and iodide ions, thus avoiding the formation of byproducts. The composite material of activated carbon and MOF enhances the adsorption rate, avoids protonation of highly active HI, and reduces side reactions. Continuous adsorption of iodide ions disrupts the reaction equilibrium, driving the reaction in a favorable direction and further improving the conversion rate and yield.
[0034] 2,4-Vinylpyridine-styrene copolymer, as an insoluble solid base catalyst, neutralizes the acid generated during the acylation reaction through the weak basicity of its pyridine group, maintaining the weak basicity of the reaction system and promoting the deprotonation reaction of 7-aminocefoquinoxime. Its solid particulate form allows for simple filtration separation after the reaction, improving catalytic efficiency and facilitating post-processing. Attached Figure Description
[0035] Figure 1 This invention provides the structural formulas for intermediates and products.
[0036] Figure 2 This is a liquid chromatogram of the intermediate synthesized in Example 2 of the present invention;
[0037] Figure 3 The liquid chromatogram of the product synthesized in Example 2 of this invention;
[0038] Figure 4 This is the infrared spectrum of the product synthesized in Example 2 of the present invention. Detailed Implementation
[0039] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. The described embodiments are some embodiments of the present invention, and all other embodiments obtained by those skilled in the art based on the described embodiments of the present invention are within the scope of protection of the present invention.
[0040] Example 1
[0041] 5g of dried corn cob, 5g of KOH and 25mL of deionized water were mixed and stirred for 10min. After drying at 90℃ for 8h, the mixture was placed in a nitrogen atmosphere with a flow rate of 100mL / min and pyrolyzed at 600℃ at 5℃ / min for 1h. After cooling to room temperature, the mixture was washed twice with a 1mol / L hydrochloric acid solution and dried at 90℃ for 16h to obtain bio-activated carbon powder.
[0042] 0.3 g Zn(NO3)2-6H2O and 6 mL deionized water were mixed and stirred for 10 min to obtain an aqueous solution of zinc nitrate hexahydrate. 0.2 g tris(4-(1H-pyrazole-4-yl)phenyl)amine and 30 mL N,N-dimethylformamide were mixed and stirred for 10 min, then the aqueous solution of zinc nitrate hexahydrate was added and stirred for 10 min. 0.25 g benzoic acid was added and sonicated for 5 min. 0.5 g bio-activated carbon powder was added and sonicated for 30 min. The mixture was then transferred to a reaction vessel and stirred at 100 °C for 48 h. After cooling to room temperature, the precipitate was collected by centrifugation, soaked in N,N-dimethylformamide for 16 h, and then soaked in anhydrous ethanol for 24 h. The precipitate was collected by centrifugation and dried at 80 °C for 8 h to obtain pyrazole acid salt C@MOF.
[0043] 0.8 g styrene, 0.2 g 4-vinylpyridine and 10 mg benzoyl peroxide were mixed, sealed, and heated and stirred at 80 °C for 5 h to obtain a 4-vinylpyridine-styrene copolymer.
[0044] 25 g of 7-aminocephalosporanic acid, 120 mL of 2-methyltetrahydrofuran, 22 mL (17.2 g) of hexamethyldisilazane, and 0.25 mL (0.37 g) of trimethyliodosilane were added to a 500 mL reaction flask and mixed thoroughly. The mixture was then refluxed at 40 °C for 15 h under vacuum. After cooling to below 0 °C, 0.5 g of pyrazolate-based C@MOF was added, followed by 18 mL (25.3 g) of trimethyliodosilane. The reaction was continued for 4 h, then cooled to below 0 °C, and 10 mL (10.8 g) of 5,6,7,8-tetrahydroquinoline was added. The reaction was continued for 2 h, then cooled to below 5 °C, and 30 mL of methanol was added dropwise. After stirring for 30 min, the mixture was filtered using a Buchner funnel, and 50 mL of 6 mol / L hydrochloric acid solution was added. The mixture was allowed to stand and separate into two phases. The organic phase was washed with 10 mL of 6 mol / L hydrochloric acid solution. The aqueous phases were combined, and 3 g of activated carbon was added. The mixture was stirred at 50 °C for 20 min to decolorize. After filtration, 300 mL of acetone was added to the filtrate, and triethylamine was added dropwise to adjust the pH to 3.0. The mixture was stirred slowly to induce crystallization, and the crystals were cultured at 0 °C for 2 h. After filtration, the filter cake was washed twice with acetone and dried under reduced pressure at 40 °C for 4 h to obtain a light yellowish-brown powder, 7-aminocefoquinoxime.
[0045] Mix 4g of 7-aminocefoquinoxime, 5g of AE-active ester, and 50mL of 2-methyltetrahydrofuran. Stir mechanically at 0°C for 20 minutes, then maintain the temperature at 0°C and add 0.1g of... 4-Vinylpyridine-styrene copolymer was reacted with continuous stirring for 6 hours. The reaction mixture was then filtered, and the filter cake was washed with 10 mL of cold 2-methyltetrahydrofuran. The filtrate was collected, concentrated under reduced pressure, and ethyl acetate was added. Crystallization was carried out by slow stirring at 0°C for 3 hours. After filtration, the filter cake was washed twice with ethyl acetate. The crude product was dissolved in warm deionized water, and 0.5 g of activated carbon was added. The mixture was stirred at 60°C for 20 min to decolorize. After cooling to 10°C, 1 mL of 6 mol / L sulfuric acid (containing 0.59 g of sulfuric acid) was added to adjust the pH to 1.5. The mixture was then slowly cooled to 2°C at a rate of 0.5°C / min and stirred for 1 hour. After stopping stirring, the mixture was allowed to crystallize for 2 hours. After filtration, the filter cake was washed with ice water, filtered again, and dried under reduced pressure at room temperature for 4 hours to obtain cefquinome sulfate.
[0046] Example 2
[0047] 5g of dried fruit peel, 20g of KOH and 75mL of deionized water were mixed and stirred for 20min. After drying at 90℃ for 12h, the mixture was placed in a nitrogen atmosphere with a flow rate of 100mL / min and pyrolyzed at 700℃ at 5℃ / min for 2h. After cooling to room temperature, the mixture was washed 5 times with a 1mol / L hydrochloric acid solution and dried at 105℃ for 18h to obtain biological activated carbon powder.
[0048] 0.3 g Zn(NO3)2-6H2O and 6 mL deionized water were mixed and stirred for 10 min to obtain an aqueous solution of zinc nitrate hexahydrate. 0.8 g tris(4-(1H-pyrazole-4-yl)phenyl)amine and 30 mL N,N-dimethylformamide were mixed and stirred for 10 min, then the aqueous solution of zinc nitrate hexahydrate was added and stirred for 15 min. 0.25 g benzoic acid was added and ultrasonicated for 10 min. 0.8 g bio-activated carbon powder was added and ultrasonicated for 30 min. The mixture was then transferred to a reaction vessel and stirred at 100 °C for 48 h. After cooling to room temperature, the precipitate was collected by centrifugation, soaked in N,N-dimethylformamide for 24 h, and then soaked in anhydrous ethanol for 48 h. The precipitate was collected by centrifugation and dried at 100 °C for 12 h to obtain pyrazole acid salt C@MOF.
[0049] 0.8 g styrene, 0.4 g 4-vinylpyridine and 10 mg benzoyl peroxide were mixed, sealed, and heated and stirred at 100 °C for 6 h to obtain a 4-vinylpyridine-styrene copolymer.
[0050] 30 g of 7-aminocephalosporanic acid, 120 mL of 2-methyltetrahydrofuran, 25 mL (19.5 g) of hexamethyldisilazane, and 0.3 mL (0.4 g) of trimethyliodosilane were added to a 500 mL reaction flask and mixed thoroughly. The mixture was then refluxed at 40 °C for 17 h under vacuum. After cooling to below 0 °C, 2 g of pyrazolate-based C@MOF was added, followed by 18 mL (25.3 g) of trimethyliodosilane. The reaction was continued for 5 h, then cooled to below 0 °C. 15 mL (16.2 g) of 5,6,7,8-tetrahydroquinoline was added, and the reaction was continued for 3 h. After cooling to below 5 °C, 30 mL of methanol was added dropwise, and the mixture was stirred. After stirring for 30 min, the mixture was filtered using a Buchner funnel, and 50 mL of 6 mol / L hydrochloric acid solution was added. The mixture was allowed to stand and separate into two phases. The organic phase was washed with 10 mL of 6 mol / L hydrochloric acid solution, and the aqueous phases were combined. 5 g of activated carbon was added, and the mixture was stirred at 60 °C for 30 min to decolorize. The mixture was then filtered, and 300 mL of acetone was added to the filtrate. Triethylamine was added dropwise to adjust the pH to 3.5. The mixture was stirred slowly to induce crystallization, and the crystals were cultured at 10 °C for 4 h. The mixture was then filtered, and the filter cake was washed three times with acetone and dried under reduced pressure at 40 °C for 4 h to obtain a light yellowish-brown powder, 7-aminocefoquinoxime.
[0051] Mix 4.5g of 7-aminocefoquinoxime, 5.5g of AE-active ester, and 50mL of 2-methyltetrahydrofuran. Stir mechanically at 3°C for 30 minutes, then maintain the temperature at 3°C and add 0.3g of... 4-Vinylpyridine-styrene copolymer was reacted with continuous stirring for 8 hours. The reaction mixture was then filtered, and the filter cake was washed with 10 mL of cold 2-methyltetrahydrofuran. The filtrate was collected, concentrated under reduced pressure, and ethyl acetate was added. Crystallization was carried out by slow stirring at 5°C for 3 hours. After filtration, the filter cake was washed four times with ethyl acetate. The crude product was dissolved in warm deionized water, and 0.7 g of activated carbon was added. The mixture was stirred at 70°C for 30 min to decolorize. After cooling to 10°C, 1 mL of 6 mol / L sulfuric acid (containing 0.59 g of sulfuric acid) was added to adjust the pH to 1.5. The mixture was then slowly cooled to 5°C at a rate of 0.5°C / min and stirred for 2 hours. After stopping stirring, the mixture was allowed to crystallize for 2 hours. After filtration, the filter cake was washed with ice water, filtered again, and dried under reduced pressure at room temperature for 4 hours to obtain cefquinome sulfate.
[0052] Example 3
[0053] 5g of dried straw, 15g of KOH and 45mL of deionized water were mixed and stirred for 20min. After drying at 90℃ for 10h, the mixture was placed in a nitrogen atmosphere with a flow rate of 100mL / min and pyrolyzed at 650℃ at a rate of 5℃ / min for 1.5h. After cooling to room temperature, the mixture was washed 5 times with a 1mol / L hydrochloric acid solution and dried at 100℃ for 17h to obtain bio-activated carbon powder.
[0054] 0.3 g Zn(NO3)2-6H2O and 6 mL deionized water were mixed and stirred for 10 min to obtain an aqueous solution of zinc nitrate hexahydrate. 0.4 g tris(4-(1H-pyrazole-4-yl)phenyl)amine and 30 mL N,N-dimethylformamide were mixed and stirred for 10 min, then the aqueous solution of zinc nitrate hexahydrate was added and stirred for 15 min. 0.25 g benzoic acid was added and sonicated for 10 min. 0.7 g bio-activated carbon powder was added and sonicated for 30 min. The mixture was then transferred to a reaction vessel and stirred at 100 °C for 48 h. After cooling to room temperature, the precipitate was collected by centrifugation, soaked in N,N-dimethylformamide for 20 h, and then soaked in anhydrous ethanol for 38 h. The precipitate was collected by centrifugation and dried at 90 °C for 12 h to obtain pyrazole acid salt C@MOF.
[0055] 0.8 g styrene, 0.5 g 4-vinylpyridine and 10 mg benzoyl peroxide were mixed, sealed and heated and stirred at 80 °C for 6 h to obtain 4-vinylpyridine-styrene copolymer.
[0056] 28 g of 7-aminocephalosporanic acid, 120 mL of 2-methyltetrahydrofuran, 23.5 mL (18.2 g) of hexamethyldisilazane, and 0.275 mL (0.39 g) of trimethyliodosilane were added to a 500 mL reaction flask and mixed thoroughly. The mixture was then refluxed at 40 °C for 17 h under vacuum. After cooling to below 0 °C, 3 g of pyrazolate-based C@MOF was added, followed by 18 mL (25.3 g) of trimethyliodosilane. The reaction was continued for 5 h, then cooled to below 0 °C. 12.5 mL (13.5 g) of 5,6,7,8-tetrahydroquinoline was added, and the reaction was continued for 3 h. After cooling to below 5 °C, 30 mL of methyl methacrylate was added dropwise. After stirring the alcohol for 30 min, the mixture was filtered using a Buchner funnel, and 50 mL of 6 mol / L hydrochloric acid solution was added. The mixture was allowed to stand and separate into two phases. The organic phase was washed with 10 mL of 6 mol / L hydrochloric acid solution, and the aqueous phases were combined. 3 g of activated carbon was added, and the mixture was stirred and decolorized at 50 °C for 30 min. The mixture was filtered, and 300 mL of acetone was added to the filtrate. Triethylamine was added dropwise to adjust the pH to 3.5. The mixture was stirred slowly to induce crystallization, and the crystals were cultured at 3 °C for 3.5 h. The mixture was then filtered, and the filter cake was washed four times with acetone and dried under reduced pressure at 40 °C for 4 h to obtain a light yellowish-brown powder, 7-aminocefoquinoxime.
[0057] Mix 4.5g of 7-aminocefoquinoxime, 5.5g of AE-active ester, and 50mL of 2-methyltetrahydrofuran. Stir mechanically at 1°C for 30min, then maintain the temperature at 2°C and add 0.3g of... 4-Vinylpyridine-styrene copolymer was reacted with continuous stirring for 8 hours. The reaction mixture was then filtered, and the filter cake was washed with 10 mL of cold 2-methyltetrahydrofuran. The filtrate was collected, concentrated under reduced pressure, and ethyl acetate was added. Crystallization was carried out by slow stirring at 2°C for 3 hours. After filtration, the filter cake was washed four times with ethyl acetate. The crude product was dissolved in warm deionized water, and 0.5 g of activated carbon was added. The mixture was stirred at 60°C for 30 min to decolorize. After cooling to 10°C, 2 mL of 6 mol / L sulfuric acid (containing 1.18 g of sulfuric acid) was added to adjust the pH to 1.5. The mixture was then slowly cooled to 2°C at a rate of 0.5°C / min and stirred for 2 hours. After stopping stirring, the mixture was allowed to crystallize for 2 hours. After filtration, the filter cake was washed with ice water, filtered again, and dried under reduced pressure at room temperature for 4 hours to obtain cefquinome sulfate.
[0058] Example 4
[0059] 5g of dried fruit peel, 15g of KOH and 55mL of deionized water were mixed and stirred for 15min. After drying at 90℃ for 8h, the mixture was placed in a nitrogen atmosphere with a flow rate of 100mL / min and pyrolyzed at 660℃ at a rate of 5℃ / min for 1.5h. After cooling to room temperature, the mixture was washed three times with a 1mol / L hydrochloric acid solution and dried at 95℃ for 17h to obtain bio-activated carbon powder.
[0060] 0.3 g Zn(NO3)2-6H2O and 6 mL deionized water were mixed and stirred for 10 min to obtain an aqueous solution of zinc nitrate hexahydrate. 0.6 g tris(4-(1H-pyrazole-4-yl)phenyl)amine and 30 mL N,N-dimethylformamide were mixed and stirred for 10 min, then the aqueous solution of zinc nitrate hexahydrate was added and stirred for 12 min. 0.25 g benzoic acid was added and sonicated for 7 min. 0.6 g bio-activated carbon powder was added and sonicated for 30 min. The mixture was then transferred to a reaction vessel and stirred at 100 °C for 48 h. After cooling to room temperature, the precipitate was collected by centrifugation, soaked in N,N-dimethylformamide for 18 h, and then soaked in anhydrous ethanol for 36 h. The precipitate was collected by centrifugation and dried at 85 °C for 10 h to obtain pyrazole acid salt C@MOF.
[0061] 0.8 g styrene, 0.3 g 4-vinylpyridine and 10 mg benzoyl peroxide were mixed, sealed, and heated and stirred at 90 °C for 5 h to obtain a 4-vinylpyridine-styrene copolymer.
[0062] 26 g of 7-aminocephalosporanic acid, 120 mL of 2-methyltetrahydrofuran, 22 mL (17.2 g) of hexamethyldisilazane, and 0.25 mL (0.37 g) of trimethyliodosilane were added to a 500 mL reaction flask and mixed thoroughly. The mixture was then refluxed at 40 °C for 16 h under vacuum. After cooling to below 0 °C, 1.5 g of pyrazolate-based C@MOF was added, followed by 18 mL (25.3 g) of trimethyliodosilane. The reaction was continued for 4.5 h, then cooled to below 0 °C. 10 mL (10.8 g) of 5,6,7,8-tetrahydroquinoline was added, and the reaction was continued for 2 h. After cooling to below 5 °C, 30 mL of methanol was added dropwise. After stirring for 30 min, the mixture was filtered using a Buchner funnel, and 50 mL of 6 mol / L hydrochloric acid solution was added. The mixture was allowed to stand and separate into two phases. The organic phase was washed with 10 mL of 6 mol / L hydrochloric acid solution, and the aqueous phases were combined. 3 g of activated carbon was added, and the mixture was stirred at 50 °C for 25 min to decolorize. The mixture was then filtered, and 300 mL of acetone was added to the filtrate. Triethylamine was added dropwise to adjust the pH to 3.2. The mixture was stirred slowly to induce crystallization, and the crystals were cultured at 7 °C for 2.5 h. The mixture was then filtered, and the filter cake was washed three times with acetone and dried under reduced pressure at 40 °C for 4 h to obtain a light yellowish-brown powder, 7-aminocefoquinoxime.
[0063] Mix 4.2g of 7-aminocefoquinoxime, 5.4g of AE-active ester, and 50mL of 2-methyltetrahydrofuran. Stir mechanically at 1°C for 25min, then maintain the temperature at 1°C and add 0.2g of... 4-Vinylpyridine-styrene copolymer was reacted with continuous stirring for 7.5 h. The reaction mixture was then filtered, and the filter cake was washed with 10 mL of cold 2-methyltetrahydrofuran. The filtrate was collected, concentrated under reduced pressure, and ethyl acetate was added. Crystallization was carried out by slow stirring at 2 °C for 3 h. After filtration, the filter cake was washed twice with ethyl acetate. The crude product was dissolved in warm deionized water, and 0.6 g of activated carbon was added. The mixture was stirred at 70 °C for 20 min to decolorize. After cooling to 10 °C, 1 mL of 6 mol / L sulfuric acid (containing 0.59 g of sulfuric acid) was added to adjust the pH to 1.5. The mixture was then slowly cooled to 3 °C at a rate of 0.5 °C / min and stirred for 1.5 h. After stopping stirring, the mixture was allowed to crystallize for 2 h. After filtration, the filter cake was washed with ice water, filtered again, and dried under reduced pressure at room temperature for 4 h to obtain cefquinome sulfate.
[0064] Example 5
[0065] 5g of dried fruit peel, 18g of KOH and 65mL of deionized water were mixed and stirred for 10min. After drying at 90℃ for 10h, the mixture was placed in a nitrogen atmosphere with a flow rate of 100mL / min and pyrolyzed at 680℃ at a rate of 5℃ / min for 1h. After cooling to room temperature, the mixture was washed twice with a 1mol / L hydrochloric acid solution and dried at 105℃ for 18h to obtain bio-activated carbon powder.
[0066] 0.3 g Zn(NO3)2-6H2O and 6 mL deionized water were mixed and stirred for 10 min to obtain an aqueous solution of zinc nitrate hexahydrate. 0.4 g tris(4-(1H-pyrazole-4-yl)phenyl)amine and 30 mL N,N-dimethylformamide were mixed and stirred for 10 min, then the aqueous solution of zinc nitrate hexahydrate was added and stirred for 12 min. 0.25 g benzoic acid was added and ultrasonicated for 8 min. 0.7 g bio-activated carbon powder was added and ultrasonicated for 30 min. The mixture was then transferred to a reaction vessel and stirred at 100 °C for 48 h. After cooling to room temperature, the precipitate was collected by centrifugation, soaked in N,N-dimethylformamide for 22 h, and then soaked in anhydrous ethanol for 40 h. The precipitate was collected by centrifugation and dried at 90 °C for 8 h to obtain pyrazole acid salt C@MOF.
[0067] 0.8 g styrene, 0.5 g 4-vinylpyridine and 10 mg benzoyl peroxide were mixed, sealed, and heated and stirred at 90 °C for 5.5 h to obtain a 4-vinylpyridine-styrene copolymer.
[0068] 28 g of 7-aminocephalosporanic acid, 120 mL of 2-methyltetrahydrofuran, 25 mL (19.5 g) of hexamethyldisilazane, and 0.25 mL (0.37 g) of trimethyliodosilane were added to a 500 mL reaction flask and mixed thoroughly. The mixture was then evacuated and refluxed at 40 °C for 16 h. After cooling to below 0 °C, 1.5 g of pyrazolate-based C@MOF was added, followed by 18 mL (25.3 g) of trimethyliodosilane. The reaction was continued for 4.5 h, then cooled to below 0 °C. 15 mL (16.2 g) of 5,6,7,8-tetrahydroquinoline was added, and the reaction was continued for another 2.5 h. After cooling to below 5 °C, 30 mL of [amount missing] was added dropwise. Methanol was stirred and reacted for 30 min. After filtration using a Buchner funnel, 50 mL of 6 mol / L hydrochloric acid solution was added. The mixture was allowed to stand and separate the phases. The organic phase was washed with 10 mL of 6 mol / L hydrochloric acid solution. The aqueous phases were combined, and 4 g of activated carbon was added. The mixture was stirred and decolorized at 55 °C for 26 min. After filtration, 300 mL of acetone was added to the filtrate, and triethylamine was added dropwise to adjust the pH to 3.4. The mixture was stirred slowly to induce crystallization. The crystals were cultured at 10 °C for 2 h. After filtration, the filter cake was washed twice with acetone and dried under reduced pressure at 40 °C for 4 h to obtain a light yellowish-brown powder, 7-aminocefoquinoxime.
[0069] Mix 4.3g of 7-aminocefoquinoxime, 5.2g of AE-active ester, and 50mL of 2-methyltetrahydrofuran. Stir mechanically at 1°C for 25min, then maintain the temperature at 2°C and add 0.3g of... 4-Vinylpyridine-styrene copolymer was reacted with stirring for 6 hours. The reaction mixture was then filtered, and the filter cake was washed with 10 mL of cold 2-methyltetrahydrofuran. The filtrate was collected, concentrated under reduced pressure, and ethyl acetate was added. Crystallization was carried out by slow stirring at 2°C for 3 hours. After filtration, the filter cake was washed twice with ethyl acetate. The crude product was dissolved in warm deionized water, and 0.5 g of activated carbon was added. The mixture was stirred at 65°C for 25 min to decolorize. After cooling to 10°C, 1.5 mL of 6 mol / L sulfuric acid (containing 0.88 g of sulfuric acid) was added to adjust the pH to 1.8. The mixture was then slowly cooled to 3°C at a rate of 0.5°C / min and stirred for 1.5 hours. After stopping stirring, the mixture was allowed to crystallize for 2 hours. After filtration, the filter cake was washed with ice water, filtered again, and dried under reduced pressure at room temperature for 4 hours to obtain cefquinome sulfate.
[0070] The present invention also includes comparative examples and related experiments.
[0071] Comparative Example 1
[0072] Compared with Example 1, the only difference is that N,N-dimethylformamide was used instead of pyrazolate group C@MOF in the preparation of 7-aminocefoquinoxime. The other preparation steps and components were completely the same, and cefoquinoxime sulfate was finally obtained.
[0073] Comparative Example 2
[0074] Compared with Example 1, the only difference is that activated carbon was not added in the preparation of pyrazolate-based C@MOF. The other preparation steps and components are completely the same, and cefquinoxime sulfate is finally obtained.
[0075] Comparative Example 3
[0076] Compared with Example 1, the only difference is that in the preparation of cefquinoxime sulfate, triethylamine is used instead of 4-vinylpyridine-styrene copolymer. All other preparation steps and components are completely the same, and cefquinoxime sulfate is finally obtained.
[0077] Performance testing
[0078] In the experiments of Examples 1-5 and Comparative Examples 1-3 above, the obtained 7-aminocefoquinoxime was referred to as an intermediate, and its structural diagram is shown in the appendix. Figure 1 The structural diagram of the final prepared cefquinome sulfate (Formula I) is attached. Figure 1 Formula (II) was used to determine the yield and purity of the intermediate and cefquinome sulfate. The detection methods and related results are as follows:
[0079] I. Purity Testing Methods:
[0080] Instrument: Agilent 1260 high performance liquid chromatograph;
[0081] Preparation of phosphate buffer: Mix 1L water, 60mg KH2PO4, and 1.2g Na2HPO4, then add H3PO4 to adjust the pH of the solution to 4.7;
[0082] Mobile phase: phosphate buffer: methanol = 85:15;
[0083] Flow rate: 1.0 mL / min;
[0084] Column: Capcell PAK C18;
[0085] Column temperature: 40℃;
[0086] Wavelength: 270nm;
[0087] Injection volume: 20 μL.
[0088] Solution preparation:
[0089] 1) Accurately weigh 5.00 mg of the intermediate standard, place it in a 10 mL volumetric flask, dissolve it completely in methanol, dilute it to the mark with methanol, and shake well to obtain the standard solution;
[0090] 2) Accurately weigh 5.00 mg of cefquinoxime sulfate sample, place it in a 10 mL volumetric flask, dissolve it completely in methanol, dilute it to the mark with methanol, and shake well to obtain the crude sample solution.
[0091] Yield = ;
[0092] M R : Relative molecular mass of raw materials, m R : Quality of raw material input;
[0093] m P Actual output quality of the product, M P : Relative molecular mass of the product;
[0094] II. Purity Calculation Method: HPLC area normalization method, the specific calculation formula is as follows:
[0095] Sample purity = ;
[0096] C: Target peak area, C0: Sum of the total areas of all chromatographic peaks.
[0097] After high-performance liquid chromatography (HPLC) analysis of the intermediates in Examples 1-5 and Comparative Examples 1-3, as well as cefquinoxime sulfate, the data were compiled, and the purity and yield of the intermediates and cefquinoxime sulfate were recorded in Table 1.
[0098] Table 1
[0099]
[0100] As shown in Table 1, the yields and purities of the intermediates and cefquinome sulfate synthesized in Examples 1-5 were all greater than 88%, and the test results were significantly better than those of the intermediates and cefquinome sulfate synthesized in Comparative Examples 1-3. The intermediate and cefquinome sulfate synthesized in Example 2 had the highest yields and purities. The liquid chromatogram of the synthesized intermediate is shown in the attached table. Figure 2 The liquid chromatogram of the synthesized cefquinoxime sulfate is shown in the appendix. Figure 3 It can also be clearly seen that the intermediate synthesized in Example 2 and cefquinome sulfate have no obvious impurity peaks, indicating high purity. Furthermore, the structure of cefquinome sulfate synthesized in Example 2 was characterized using Fourier transform infrared spectroscopy, and the obtained infrared spectrum is shown in the appendix. Figure 4 In Comparative Example 1, the direct replacement of pyrazolium salt-based C@MOF with N,N-dimethylformamide resulted in a significant decrease in the yield of the intermediate and a certain impact on its purity. In Comparative Example 2, the lack of activated carbon in the pyrazolium salt-based C@MOF led to a certain decrease in the yield and purity of the intermediate. In Comparative Example 3, the use of triethylamine instead of 4-vinylpyridine-styrene copolymer as a base catalyst resulted in a significant decrease in catalytic efficiency, which in turn affected the yield and purity of the final synthesized cefquinome sulfate.
[0101] The above are preferred embodiments of the present invention. Those skilled in the art can make several improvements and modifications without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.
Claims
1. A process for the synthesis of cefquinome sulfate characterized in that, Comprise the following steps: S1, after mixing and stirring tris(4-(1H-pyrazol-4-yl)phenyl)amine and N,N-dimethylformamide for 10 min, add zinc nitrate hexahydrate aqueous solution and mix and stir for 10-15 min, add benzoic acid and ultrasonic treat for 5-10 min, add activated carbon powder and ultrasonic treat for 30 min, then transfer the mixture to a reaction kettle, stir and react at 100℃ for 48 h, cool to room temperature, centrifuge to collect the precipitate, soak in N,N-dimethylformamide for 16-24 h, then soak in anhydrous ethanol for 24-48 h, centrifuge to collect the precipitate, and dry at 80-100℃ for 8-12 h to obtain pyrazole acid salt-based C@MOF; S2, mix 7-aminocephalosporanic acid, 2-methyltetrahydrofuran, hexamethyldisilazane and trimethylsilyl iodide, vacuumize, heat and reflux, cool to below 0℃, add pyrazole acid salt-based C@MOF, then add trimethylsilyl iodide and react, cool to below 0℃, add 5,6,7,8-tetrahydroquinoline and continue to react, cool to below 5℃, add methanol and stir and react, use a Buchner funnel to filter, then add hydrochloric acid solution, stand to separate phases, wash the organic phase with hydrochloric acid solution, combine the aqueous phases, add activated carbon and stir to decolorize, filter, add acetone to the filtrate, and dropwise add triethylamine to adjust the pH to 3.0-3.5, slowly stir and crystallize, crystallize, filter, wash the filter cake with acetone 2-4 times, and dry under reduced pressure to obtain 7-aminocephalosporin quinolone; S3, mix 7-aminocephalosporin quinolone, AE-active ester and 2-methyltetrahydrofuran, cool to 0-3℃, stir for 20-30 min, add 4-vinylpyridine-styrene copolymer and react for 6-8 h, filter, wash the filter cake with 2-methyltetrahydrofuran, collect the filtrate, concentrate under reduced pressure, add ethyl acetate, slowly stir and crystallize, crystallize at 0-5℃ for 3 h, filter, wash the filter cake with ethyl acetate 2-4 times, dissolve in deionized water, add activated carbon, stir and decolorize at 60-70℃ for 20-30 min, cool to 10℃, add 6 mol / L sulfuric acid to adjust the pH to 1.5-2.0, cool to 2-5℃ and stir for 1-2 h, crystallize for 2 h, filter, wash with ice water, filter under suction, and dry under reduced pressure at room temperature for 4 h to obtain cefquinome sulfate; The 4-vinylpyridine-styrene copolymer is obtained by mixing styrene, 4-vinylpyridine and dibenzoyl peroxide, sealing, and heating and stirring at 80-100℃ for 5-6 h.
2. A process for the synthesis of Cefquinome sulfate as claimed in claim 1, wherein, The zinc nitrate hexahydrate aqueous solution is obtained by mixing Zn(NO3)2·6H2O and deionized water and stirring for 10 min.
3. The process for synthesis of Cefquinome sulfate as claimed in claim 1 wherein, The activated carbon powder is a bio-activated carbon powder, which is prepared by mixing biomass material, KOH and deionized water and stirring for 10-20 min, drying at 90℃ for 8-12 h, placing in an atmosphere with a nitrogen flow of 100 mL / min, increasing the temperature to 600-700℃ at 5℃ / min, pyrolyzing for 1-2 h, cooling to room temperature, washing with 1 mol / L hydrochloric acid solution 2-5 times, and drying at 90-105℃ for 16-18 h. The 4-vinylpyridine-styrene copolymer is obtained by mixing styrene, 4-vinylpyridine and dibenzoyl peroxide, sealing, and heating and stirring at 80-100℃ for 5-6 h.
4. The process for synthesis of Cefquinome sulfate as claimed in claim 1 wherein, The heating reflux temperature is 40℃, the time is 15-17h, the time of adding trimethylsilyl iodide is 4-5h, the time of adding 5,6,7,8-tetrahydroquinoline for continuous reaction is 2-3h, the stirring reaction time is 30min, the stirring decoloring temperature is 50-60℃, the time is 20-30min, the crystallization is carried out at 0-10℃ for 2-4h, and the drying under reduced pressure is carried out at 40℃ for 4h.
5. The process for synthesis of Cefquinome sulfate as claimed in claim 1 wherein, The concentration of the hydrochloric acid solution is 6mol / L; the preparation of 7-aminocefquinome in step S2 contains the following raw materials: 7-aminocephalosporanic acid 25 parts, hexamethyldisilazane 17.2g-19.5 parts, trimethylsilyl iodide 25.67 parts, 5,6,7,8-tetrahydroquinoline 10.8-16.2 parts, and pyrazole acid salt base C@MOF 0.5-3 parts.
6. The process for synthesis of Cefquinome sulfate as claimed in claim 1 wherein, The preparation of cefquinome sulfate in step S3 contains the following raw materials: 7-aminocefquinome 4-4.5 parts, AE-active ester 5-5.5 parts, 4-vinylpyridine-styrene copolymer 0.1-0.3 parts, and sulfuric acid 0.59-1.18 parts.
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