Synthesis process of cefquinome sulfate

Abstract

The invention provides a synthesis process of cefquinome sulfate, and belongs to the technical field of heterocyclic compounds, and the synthesis process comprises the following steps: uniformly mixing 7-aminocephalosporanic acid, 2-methyltetrahydrofuran, hexamethyldisilazane and trimethyl iodosilane for reaction, sequentially adding pyrazolate C (at) MOF, trimethyl iodosilane, 5, 6, 7, 8-tetrahydroquinoline and methanol for reaction, carrying out suction filtration, and carrying out reduced pressure distillation to obtain the cefquinome sulfate. Adding a hydrochloric acid solution, standing for phase splitting, crystallizing and drying to obtain 7-aminocefquinome; the preparation method comprises the following steps: uniformly mixing 7-aminocefquinome, AE-active ester, 2-methyltetrahydrofuran and a 4-vinylpyridine-styrene copolymer for reaction, carrying out suction filtration, washing, collecting filtrate, concentrating, dissolving in water, adding sulfuric acid for reaction, filtering and drying to obtain cefquinome sulfate. According to the invention, the reaction process can be accelerated, and the purity and yield of the target product can be improved.

Description

TECHNICAL FIELD

[0001] The application relates to the technical field of heterocyclic compounds, in particular to a synthesis process of cefquinome sulfate. BACKGROUND

[0002] Cefquinome sulfate is an animal-specific drug, belongs to the fourth generation of cephalosporins, and is a drug for animal respiratory tract, lower respiratory tract infection and other various serious infectious diseases determined by CVMP. The sulfate salt is stable in nature, can be prepared into a preparation, is convenient to store and transport, and is very suitable for clinical application. Cefquinome sulfate has good antibacterial activity, low toxicity and excellent pharmacokinetic characteristics, can be rapidly absorbed by the body, can reach a high concentration in many tissues, has low residue, has low affinity to beta-lactamase, high stability, can quickly pass through the periplasmic space, has enzyme resistance, and is effective on various bacteria, in particular, can strongly inhibit Staphylococcus aureus, Pasteurella, Streptococcus and various intestinal bacteria, and even has high inhibition on some penicillin-resistant bacteria.

[0003] At present, there are three kinds of synthesis steps of commonly used cefquinome sulfate. The first kind is to synthesize cefquinome sulfate from cefotaxime acid as raw material, which is published in the article entitled Synthesis of Cefquinome Sulfate in Chinese Pharmaceutical Industry Journal. Hexamethyldisilazane is used as a silanization reagent, trimethylsilyl iodide is used as a catalyst to protect the amino group and the carboxyl group of cefotaxime acid, then trimethylsilyl iodide is used to substitute the acetoxy group on the side chain of 3 to obtain an iodide, 5,6,7,8-tetrahydroquinoline is added to obtain 7-A00 hydroiodic acid salt, anion exchange resin is used, and the target product is obtained by acidification with sulfuric acid. The synthesis process has the advantages that only one solvent is used, but the time consumed by the anion exchange resin for removing iodine ions is too long, and the yield needs to be improved.

[0004] The second kind is to synthesize cefquinome sulfate from 7-ACA as raw material, which is published in the article entitled Synthesis of Cefquinome Sulfate in Applied Chemical Industry Journal. Dichloromethane is used as a reaction solvent, 7-ACA and 5,6,7,8-tetrahydroquinoline are reacted under the action of trimethylsilyl iodide to obtain an intermediate 7-aminocefquinome hydroiodic acid salt, which is directly reacted with an AE active ester without treatment, and the target product is obtained by acidification with sulfuric acid. In the reaction route, the use amount of trimethylsilyl iodide and 5,6,7,8-tetrahydroquinoline is less, but dichloromethane as a reaction solvent has certain toxicity, and in addition, the intermediate 7-ACQ exists in the form of hydroiodic acid salt, which directly performs the next acylation reaction, which means that iodine ions will exist in the reaction system all the time, and these iodine ions may participate in side reactions, thereby increasing the types and quantities of by-products, and reducing the purity of the final product.

[0005] The third is to synthesize cefquinome sulfate by using GCLE as raw material, but the process is complex, and the amide bond needs to be hydrolyzed by alkali, which causes the cleavage of part of the beta-lactam ring, and the target product has a low yield.

[0006] Therefore, it is urgent to develop a method which can accelerate the reaction process and improve the purity and yield of the target product to solve the problems existing in the prior art. SUMMARY

[0007] Therefore, the application provides a synthesis process of cefquinome sulfate, which can accelerate the reaction process and improve the purity and yield of the target product.

[0008] To achieve the above-mentioned object, the application provides a synthesis process of cefquinome sulfate, which comprises the following steps: S1, mixing tris(4-(1H-pyrazole-4-yl)phenyl)amine, N,N-dimethylformamide and an aqueous solution of zinc nitrate hexahydrate, adding benzoic acid and activated carbon powder for ultrasonic treatment, heating and reacting, cooling to room temperature, centrifuging to collect the precipitate, respectively immersing in N,N-dimethylformamide and anhydrous ethanol, centrifuging to collect the precipitate, and drying to obtain pyrazole acid salt-based C@MOF; S2, mixing 7-aminocephalosporanic acid, hexamethyldisilazane and trimethylsilyl iodide, adding pyrazole acid salt-based C@MOF and trimethylsilyl iodide, 5,6,7,8-tetrahydroquinoline and methanol in sequence, filtering, adding hydrochloric acid solution, standing to separate phases, crystallizing, filtering, washing and drying to obtain 7-aminocefquinome; S3, mixing 7-aminocefquinome, AE-active ester, 2-methyltetrahydrofuran and 4-vinylpyridine-styrene copolymer, filtering, washing, collecting the filtrate, concentrating and crystallizing, filtering, washing, dissolving in water, cooling, adding sulfuric acid, filtering, washing and drying to obtain cefquinome sulfate.

[0009] The prepared pyrazole acid salt-based C@MOF is used for adsorbing iodine ions generated in the production of 7-aminocefquinome (intermediate) to improve the yield of the intermediate. The activated carbon has a rich pore structure, the zinc-based metal organic framework structure (Zn-MOF-2) in the pyrazole acid salt-based C@MOF has excellent active sites, and the two form a composite adsorbent in cooperation with the pyrazole acid salt-based ligand. The zinc ions in the Zn-MOF-2 can act as electron pair acceptors and react with the iodine ions (electron pair donors) as by-products to form I - The Zn 2+ The nitrogen atoms on the pyrazole ligand have a certain alkalinity, which can neutralize the by-product hydroiodic acid generated in the nucleophilic substitution reaction with 5,6,7,8-tetrahydroquinoline, and finally generate pyrazolium salt and iodine ions. The generated I- Zn 2+ Site capture; at the same time, Zn-MOF-2 and activated carbon jointly build larger external surface area and faster external diffusion rate, can capture I2 and HI through physical adsorption while improving the adsorption rate of iodine ions, avoiding the problem that high-activity HI is not taken out in time to further protonate the nitrogen atom of the beta-lactam ring, leading to ring-opening decomposition of the beta-lactam ring to generate byproducts, reducing the purity and yield of the final product.

[0010] In addition, with the continuous adsorption of pyrazole acid salt-based C@MOF on iodine ions and HI and the fixation on the pores and metal sites thereof, the reaction equilibrium is broken, the reaction is continuously driven to the right, a certain catalysis is played on the reaction, and the metal zinc ions in the MOF can activate the reaction site as Lewis acid, promote the nucleophilic substitution reaction with 5,6,7,8-tetrahydroquinoline, and further improve the conversion rate and final yield of the reaction.

[0011] The present application uses 4-vinylpyridine-styrene copolymer as an insoluble solid base catalyst to catalyze the acylation reaction with 7-aminocefquinome and AE-activated ester as materials. The pyridine group in the copolymer acts as a weak base, and its nitrogen atom can accept protons. In the reaction system, it consumes the acid (HX) generated by the acylation reaction through acid-base neutralization reaction, so that the pH of the reaction solution is maintained in a weakly basic environment required for the deprotonation of the amino group of 7-aminocefquinome, thereby catalyzing the reaction; and its solid particle form makes it insoluble in the reaction solvent, which can be separated from the reaction system by simple filtration after the reaction is completed, that is, 4-vinylpyridine-styrene copolymer as an insoluble solid base catalyst catalyzing the acylation reaction can not only catalyze the reaction to improve the yield and purity of the final product, but also simplify the final purification step.

[0012] Optionally, the zinc nitrate hexahydrate aqueous solution is obtained by mixing and stirring Zn(NO3)2-6H2O and deionized water for 10 min.

[0013] Optionally, in step S1, after mixing and stirring tris(4-(1H-pyrazol-4-yl)phenyl)amine and N,N-dimethylformamide for 10 min, zinc nitrate hexahydrate aqueous solution is added and mixed 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, then the mixture is transferred to a reaction kettle, stirred at 100℃ for 48 h, cooled to room temperature, centrifuged to collect the precipitate, soaked in N,N-dimethylformamide for 16-24 h, then soaked in anhydrous ethanol for 24-48 h, centrifuged to collect the precipitate, and dried at 80-100℃ for 8-12 h to obtain pyrazole acid salt-based C@MOF.

[0014] The present application uses tris(4-(1H-pyrazol-4-yl)phenyl)amine as a ligand to react with metal ions to form a pyrazolate metal organic framework, and the metal organic framework and activated carbon are tightly combined through physical interactions such as van der Waals forces and electrostatic interactions to increase the number of active sites of the composite adsorbent, combine the advantages of chemical adsorption and physical adsorption, and effectively adsorb iodine ions.

[0015] Optionally, the activated carbon powder is a bio-activated carbon powder, which is prepared by mixing biomass material, KOH and deionized water for 10-20 min, drying at 90 DEG C for 8-12 h, placing in a nitrogen atmosphere with a nitrogen flow of 100 mL / min, increasing to a high temperature of 600-700 DEG C at a rate of 5 DEG C / min, pyrolyzing for 1-2 h, cooling to room temperature, washing 2-5 times with a hydrochloric acid solution with a molar concentration of 1 mol / L, and drying at 90-105 DEG C for 16-18 h.

[0016] The present application uses natural biomass material as a raw material, mixes with potassium hydroxide (KOH) and deionized water, and pyrolyzes to obtain bio-activated carbon powder, and the KOH activation process enhances the pore structure of the carbon material, and when pyrolyzing at a high temperature in a nitrogen atmosphere, the surface of the bio-activated carbon powder forms more regular and uniform pore structures.

[0017] Preferably, the biomass material can be one of straw, corn cob, and fruit peel.

[0018] Optionally, the 4-vinylpyridine-styrene copolymer is obtained by mixing styrene, 4-vinylpyridine and dibenzoyl peroxide, sealing, and heating and stirring at 80-100 DEG C for 5-6 h.

[0019] The 4-vinylpyridine-styrene copolymer in the present application is a solid base catalyst synthesized by free radical copolymerization. Among them, styrene provides a support skeleton, and 4-vinylpyridine provides basic active sites. Compared with general homogeneous base catalysts (such as triethylamine), which have a certain nucleophilicity and may attack active esters in the reaction to generate N-acyl amine and other by-products; the 4-vinylpyridine-styrene copolymer in the present application is a solid heterogeneous catalyst, and its active sites (pyridine nitrogen) are fixed on the polymer skeleton, the steric hindrance is greatly increased, and the nucleophilicity is reduced, thereby effectively avoiding the side reactions caused by the base catalyst itself; in a homogeneous system, the base is continuously consumed, and the pH gradually decreases, which may deviate from the optimal reaction interval, while the 4-vinylpyridine-styrene copolymer can maintain a weak alkaline condition required for the reaction as a local stable pH microenvironment on its surface throughout the reaction process, so that the reaction can be carried out in an optimal state at all times.

[0020] Optionally, in the step S2, 7-aminocephalosporanic acid, 2-methyltetrahydrofuran, hexamethyldisilazane and trimethylsilyl iodide are added into a reaction bottle and mixed, vacuumized, heated to reflux, cooled to below 0 DEG C, after adding pyrazole acid salt base C@MOF, trimethylsilyl iodide is added for reaction, cooled to below 0 DEG C, 5,6,7,8-tetrahydroquinoline is added for continuous reaction, cooled to below 5 DEG C, methanol is added dropwise, stirred for reaction, after using a Buchner funnel for filtration, hydrochloric acid solution is added, phase separation is carried out after standing, the organic phase is washed with hydrochloric acid solution, the water phases are combined, activated carbon is added for stirring and decolorization, filtered, acetone is added into the filtrate, and triethylamine is added dropwise to adjust the pH to 3.0-3.5, slow stirring crystallization is carried out, crystal growth is carried out, filtered, the filter cake is washed with acetone for 2-4 times, and dried under reduced pressure to obtain 7-aminocephalosporin quinolone.

[0021] The present application protects amino and carboxyl by 7-aminocephalosporanic acid and hexamethyldisilazane, carries out 3-position iodine substitution reaction by using trimethylsilyl iodide, and finally carries out nucleophilic substitution reaction with 5,6,7,8-tetrahydroquinoline to obtain 7-aminocephalosporin quinolone, the structural formula is shown in the following formula (I). Figure 1 The present application uses 2-methyltetrahydrofuran (2-MeTHF) as a solvent to replace toxic dichloromethane, and compared with dichloromethane, 2-MeTHF has lower viscosity and is easier to flow in the reaction, so that the mixing of reactants is better promoted, and the reaction rate is improved.

[0022] Optionally, the heating reflux temperature is 40 DEG C, the heating reflux time is 15-17 h, the trimethylsilyl iodide reaction time is 4-5 h, the 5,6,7,8-tetrahydroquinoline reaction time is 2-3 h, the stirring reaction time is 30 min, the stirring and decolorization temperature is 50-60 DEG C, the stirring and decolorization time is 20-30 min, the crystal growth is carried out at 0-10 DEG C for 2-4 h, and the drying under reduced pressure is carried out at 40 DEG C for 4 h.

[0023] In the decolorization process, the present application carries out stirring and heating to improve the decolorization efficiency.

[0024] Optionally, the hydrochloric acid solution has a concentration of 6 mol / L; and the 7-aminocephalosporin quinolone comprises the following raw materials in mass parts: 7-aminocephalosporanic acid 25 parts, hexamethyldisilazane 17.05 parts, trimethylsilyl iodide 25.67 parts, 5,6,7,8-tetrahydroquinoline 14.4 parts, and pyrazole acid salt base C@MOF 0.5-3 parts.

[0025] Optionally, in the step S3, 7-aminocefquinome, AE-active ester and 2-methyltetrahydrofuran are mixed, cooled to 0-3℃, stirred for 20-30 min, 4-vinylpyridine-styrene copolymer is added and reacted for 6-8 h, then filtered, the filter cake is washed with 2-methyltetrahydrofuran, the filtrate is collected, concentrated under reduced pressure, ethyl acetate is added, the crystal is slowly separated out, the crystal is aged at 0-5℃ for 3 h, filtered, the filter cake is washed with ethyl acetate for 2-4 times, dissolved in deionized water, activated carbon is added, stirred and decolorized at 60-70℃ for 20-30 min, cooled to 10℃, 6 mol / L sulfuric acid is added to adjust the pH value to 1.5-2.0, stirred at 2-5℃ for 1-2 h, aged for 2 h, filtered, washed with ice water, filtered under reduced pressure, dried at room temperature for 4 h, and then cefquinome sulfate is obtained.

[0026] The cefquinome sulfate is obtained by acylation and condensation of 7-aminocefquinome (intermediate) and AE-active ester, and finally salted with sulfuric acid. Figure 1 After the acylation and condensation reaction, the solid base is filtered off, the filtrate is directly concentrated and crystallized with an anti-solvent, which greatly simplifies the purification step; ethyl acetate is used as the anti-solvent to reduce the solubility of the product in the solution, so that the product is forced to separate out from the solution in the form of crystals, thereby realizing separation and purification; in addition, ethyl acetate can also be used as a washing solvent, after the crystals are obtained by filtration, the filter cake is washed with cold ethyl acetate, which can effectively wash away the soluble organic impurities and mother liquor attached to the surface of the crystals, thereby further improving the purity of the final product.

[0027] Optionally, the cefquinome sulfate contains the following mass parts of raw materials: 7-aminocefquinome 4.2 parts, AE-active ester 5.3 parts, 4-vinylpyridine-styrene copolymer 0.1-0.3 parts, activated carbon 0.5 parts, and sulfuric acid 0.59-1.18 parts.

[0028] The above-mentioned ratio is adopted in the application, so that the material is fully reacted, and the addition of 4-vinylpyridine-styrene copolymer speeds up the overall reaction process.

[0029] The above-mentioned technical solution of the application at least has the following beneficial effects: 1. The pyrazole acid salt group C@MOF significantly improves the yield of the 7-aminocefquinome intermediate through synergistic effect. 2+ The Zn ions and iodine ions in the MOF realize high-efficiency chemical adsorption through coordination effect, the nitrogen atoms of the pyrazole ligand neutralize hydriodic acid to generate pyrazolium salt and iodine ions, thereby avoiding the generation of by-products. The composite material of activated carbon and MOF improves the adsorption rate, avoids the protonation of high-activity HI, and reduces side reactions. Continuous adsorption of iodine ions breaks the reaction balance, promotes the reaction to proceed in a favorable direction, and further improves the conversion rate and yield.

[0030] 2,4-vinylpyridine-styrene copolymer as insoluble solid base catalyst, through the weak basicity of its pyridine group, neutralizes the acid generated in the acylation reaction, maintains the weak basicity of the reaction system, and promotes the progress of the amino deprotonation reaction of 7-aminocephalosporin quinolone. Its solid particle form makes it easy to separate after the reaction by simple filtration, improves the catalytic efficiency and facilitates the post-treatment. BRIEF DESCRIPTION OF DRAWINGS

[0031] Figure 1 is the structure formula of the intermediate and product in the application; Figure 2 is the liquid chromatogram of the intermediate synthesized in Example 2 of the application; Figure 3 is the liquid chromatogram of the product synthesized in Example 2 of the application; Figure 4 is the infrared spectrum of the product synthesized in Example 2 of the application. DETAILED DESCRIPTION

[0032] In order to make the purpose, technical scheme and advantages of the embodiments of the application clearer, the technical scheme of the embodiments of the application will be described below in combination with the embodiments of the application. The described embodiments are part of the embodiments of the application, and all other embodiments obtained by those skilled in the art based on the described embodiments of the application belong to the scope of protection of the application.

[0033] Example 1 After 5 g of dried corncob, 5 g of KOH and 25 mL of deionized water were mixed and stirred for 10 min, they were dried at 90℃ for 8 h, then placed in a nitrogen atmosphere with a nitrogen flow of 100 mL / min, heated to 600℃ at a rate of 5℃ / min, pyrolyzed for 1 h, cooled to room temperature, washed twice with a hydrochloric acid solution with a molar concentration of 1 mol / L, and dried at 90℃ for 16 h to obtain a bioactive carbon powder.

[0034] 0.3 g of Zn(NO3)2-6H2O and 6 mL of deionized water were mixed and stirred for 10 min to obtain a zinc nitrate hexahydrate aqueous solution; 0.2 g of tris(4-(1H-pyrazol-4-yl)phenyl)amine and 30 mL of N,N-dimethylformamide were mixed and stirred for 10 min, then the zinc nitrate hexahydrate aqueous solution was added and mixed and stirred for 10 min, 0.25 g of benzoic acid was added and ultrasonically treated for 5 min, 0.5 g of bioactive carbon powder was added and ultrasonically treated for 30 min, then the mixture was transferred to a reaction kettle, stirred and reacted at 100℃ for 48 h, cooled to room temperature, centrifuged to collect the precipitate, soaked in N,N-dimethylformamide for 16 h, then soaked in anhydrous ethanol for 24 h, centrifuged to collect the precipitate, and dried at 80℃ for 8 h to obtain a pyrazole acid salt-based C@MOF.

[0035] After mixing 0.8 g of styrene, 0.2 g of 4-vinylpyridine and 10 mg of dibenzoyl peroxide, sealing, heating and stirring at 80°C for 5 h, a 4-vinylpyridine-styrene copolymer was obtained.

[0036] After mixing 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 trimethylsilyl iodide in a 500 mL reaction flask, uniformly mixing, vacuumizing, heating and refluxing at 40°C for 15 h, cooling to below 0°C, adding 0.5 g of pyrazole acid salt-based C@MOF, adding 18 mL (25.3 g) of trimethylsilyl iodide, reacting for 4 h, cooling to below 0°C, adding 10 mL (10.8 g) of 5,6,7,8-tetrahydroquinoline, continuing to react for 2 h, cooling to below 5°C, dropwise adding 30 mL of methanol, stirring and reacting for 30 min, after vacuum filtration using a Buchner funnel, adding 50 mL of a hydrochloric acid solution with a concentration of 6 mol / L, standing and separating the phases, washing the organic phase with 10 mL of a hydrochloric acid solution with a concentration of 6 mol / L, combining the aqueous phases, adding 3 g of activated carbon, stirring and decolorizing at 50°C for 20 min, filtering, adding 300 mL of acetone to the filtrate, dropwise adding triethylamine to adjust the pH to 3.0, slowly stirring and crystallizing, crystallizing at 0°C for 2 h, filtering, washing the filter cake with acetone twice, and drying at 40°C under reduced pressure for 4 h to obtain 7-aminocephalosporin quinolone as a light brownish yellow powder.

[0037] After mixing 4 g of 7-aminocephalosporin quinolone, 5 g of AE-active ester and 50 mL of 2-methyltetrahydrofuran, mechanically stirring at 0°C for 20 min, maintaining the temperature at 0°C, adding 0.1 g of 4-vinylpyridine-styrene copolymer, continuously stirring and reacting for 6 h, vacuum filtering the reaction mixture, washing the filter cake with 10 mL of cold 2-methyltetrahydrofuran, collecting the filtrate, concentrating under reduced pressure, adding ethyl acetate, slowly stirring and crystallizing, crystallizing at 0°C for 3 h, filtering, washing the filter cake with ethyl acetate twice, dissolving the crude product in warm deionized water, adding 0.5 g of activated carbon, stirring and decolorizing at 60°C for 20 min, cooling to 10°C, adding 1 mL of sulfuric acid with a concentration of 6 mol / L (of which the sulfuric acid content is 0.59 g) to adjust the pH to 1.5, slowly cooling to 2°C at a rate of 0.5°C / min, stirring for 1 h, stopping the stirring, crystallizing for 2 h, filtering, washing the filter cake with ice water, vacuum filtering, and drying under reduced pressure at room temperature for 4 h to obtain cefquinome sulfate.

[0038] Example 2 After 5 g of dried peel, 20 g of KOH and 75 mL of deionized water were mixed and stirred for 20 min, dried at 90 ℃ for 12 h, and then placed in a nitrogen atmosphere with a nitrogen flow of 100 mL / min, the temperature was raised to 700 ℃ at a rate of 5 ℃ / min, and pyrolysis was performed for 2 h. After cooling to room temperature, the product was washed 5 times with a 1 mol / L hydrochloric acid solution, and then dried at 105 ℃ for 18 h to obtain a bioactive carbon powder.

[0039] After 0.3 g of Zn(NO3)2-6H2O and 6 mL of deionized water were mixed and stirred for 10 min to obtain a zinc nitrate hexahydrate aqueous solution, 0.8 g of tris(4-(1H-pyrazol-4-yl)phenyl)amine and 30 mL of N,N-dimethylformamide were mixed and stirred for 10 min, and then the zinc nitrate hexahydrate aqueous solution was added and stirred for 15 min. Then, 0.25 g of benzoic acid was added and ultrasonically treated for 10 min, and then 0.8 g of bioactive carbon powder was added and ultrasonically treated for 30 min. The mixture was then transferred to a reaction kettle and stirred at 100 ℃ 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 ℃ for 12 h to obtain a pyrazolate-based C@MOF.

[0040] After 0.8 g of styrene, 0.4 g of 4-vinylpyridine and 10 mg of dibenzoyl peroxide were mixed and sealed, and then heated and stirred at 100 ℃ for 6 h, a 4-vinylpyridine-styrene copolymer was obtained.

[0041] After 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 trimethylsilyl iodide were added to a 500 mL reaction bottle and mixed uniformly, vacuum was applied, and heating reflux was performed at 40 ℃ for 17 h. After cooling to below 0 ℃, 2 g of pyrazolate-based C@MOF was added, followed by the addition of 18 mL (25.3 g) of trimethylsilyl iodide, and reaction was performed for 5 h. The temperature was then lowered to below 0 ℃, 15 mL (16.2 g) of 5,6,7,8-tetrahydroquinoline was added, and reaction was continued for 3 h. The temperature was then lowered to below 5 ℃, 30 mL of methanol was added dropwise, and stirring reaction was performed for 30 min. After suction filtration using a Buchner funnel, 50 mL of a 6 mol / L hydrochloric acid solution was added, phase separation was performed by standing, the organic phase was washed with 10 mL of a 6 mol / L hydrochloric acid solution, the aqueous phases were combined, 5 g of activated carbon was added, and decolorization was performed by stirring at 60 ℃ for 30 min. Filtration was performed, 300 mL of acetone was added to the filtrate, and triethylamine was added dropwise to adjust the pH to 3.5. Slow stirring crystallization was performed, and the crystals were aged at 10 ℃ for 4 h. Filtration was performed, the filter cake was washed with acetone 3 times, and then drying was performed at 40 ℃ under reduced pressure for 4 h to obtain a light brown powder of 7-aminocephalosporin.

[0042] After 4.5 g of 7-aminocefquinome, 5.5 g of AE-active ester and 50 mL of 2-methyltetrahydrofuran were mixed, mechanical stirring was carried out at 3°C for 30 min, then 0.3 g of 4-vinylpyridine-styrene copolymer was added while keeping the temperature at 3°C, and after continuous stirring for 8 h, the reaction mixture was subjected to suction filtration, the filter cake was washed with 10 mL of cold 2-methyltetrahydrofuran, the filtrate was collected and concentrated under reduced pressure, ethyl acetate was added, and the crystals were slowly stirred and separated, and after crystallization at 5°C for 3 h, filtration was carried out, the filter cake was washed with ethyl acetate 4 times, the crude product was dissolved in warm deionized water, 0.7 g of activated carbon was added, and decolorization was carried out at 70°C for 30 min, after cooling to 10°C, 1 mL of sulfuric acid with a concentration of 6 mol / L (wherein the sulfuric acid content is 0.59 g) was added, the pH value was adjusted to 1.5, and after slowly cooling to 5°C at a rate of 0.5°C / min and stirring for 2 h, the stirring was stopped and the crystals were allowed to stand for 2 h, filtration was carried out, the filter cake was washed with ice water, suction filtration was carried out, and drying under reduced pressure at room temperature for 4 h yielded cefquinome sulfate.

[0043] Example 3 After 5 g of dried straw, 15 g of KOH and 45 mL of deionized water were mixed and stirred for 20 min, drying was carried out at 90°C for 10 h, pyrolysis was carried out at a high temperature of 650°C at a nitrogen flow rate of 100 mL / min for 1.5 h, and the temperature was cooled to room temperature, 5 times of washing were carried out with a hydrochloric acid solution with a concentration of 1 mol / L, and drying was carried out at 100°C for 17 h to obtain bioactive carbon powder.

[0044] After 0.3 g of Zn(NO3)2-6H2O and 6 mL of deionized water were mixed and stirred for 10 min, a zinc nitrate hexahydrate aqueous solution was obtained; after 0.4 g of tris(4-(1H-pyrazol-4-yl)phenyl)amine and 30 mL of N,N-dimethylformamide were mixed and stirred for 10 min, the zinc nitrate hexahydrate aqueous solution was added and mixed and stirred for 15 min, 0.25 g of benzoic acid was added and ultrasonically treated for 10 min, and 0.7 g of bioactive carbon powder was added and ultrasonically treated for 30 min, the mixture was transferred to a reaction kettle, and stirring reaction was carried out at 100°C for 48 h, after cooling to room temperature, the precipitate was collected by centrifugation, was soaked in N,N-dimethylformamide for 20 h, and was then soaked in anhydrous ethanol for 38 h, the precipitate was collected by centrifugation, and drying was carried out at 90°C for 12 h to obtain a pyrazole acid salt-based C@MOF.

[0045] After 0.8 g of styrene, 0.5 g of 4-vinylpyridine and 10 mg of dibenzoyl peroxide were mixed, sealing was carried out, and heating and stirring were carried out at 80°C for 6 h to obtain a 4-vinylpyridine-styrene copolymer.

[0046] Into a 500 mL reaction flask, 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 trimethylsilyl iodide were mixed and stirred uniformly, vacuumized, heated to reflux at 40°C for 17 h, cooled to below 0°C, after adding 3 g of pyrazole acid salt-based C@MOF, 18 mL (25.3 g) of trimethylsilyl iodide was added, reacted for 5 h, cooled to below 0°C, 12.5 mL (13.5 g) of 5,6,7,8-tetrahydroquinoline was added, and reacted for another 3 h, cooled to below 5°C, 30 mL of methanol was added dropwise, stirred for 30 min, filtered using a Buchner funnel, 50 mL of 6 mol / L hydrochloric acid solution was added, phase-separated, the organic phase was washed with 10 mL of 6 mol / L hydrochloric acid solution, the water phases were combined, 3 g of activated carbon was added, stirred to decolorize at 50°C for 30 min, filtered, 300 mL of acetone was added to the filtrate, and triethylamine was added dropwise to adjust the pH to 3.5, slowly stirred to crystallize, and crystallized at 3°C for 3.5 h, filtered, the filter cake was washed with acetone 4 times, and dried at 40°C under reduced pressure for 4 h to obtain 7-aminocephalosporin quinolone as a light brownish yellow powder.

[0047] Into a 500 mL reaction flask, 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 trimethylsilyl iodide were mixed and stirred uniformly, vacuumized, heated to reflux at 40°C for 17 h, cooled to below 0°C, after adding 3 g of pyrazole acid salt-based C@MOF, 18 mL (25.3 g) of trimethylsilyl iodide was added, reacted for 5 h, cooled to below 0°C, 12.5 mL (13.5 g) of 5,6,7,8-tetrahydroquinoline was added, and reacted for another 3 h, cooled to below 5°C, 30 mL of methanol was added dropwise, stirred for 30 min, filtered using a Buchner funnel, 50 mL of 6 mol / L hydrochloric acid solution was added, phase-separated, the organic phase was washed with 10 mL of 6 mol / L hydrochloric acid solution, the water phases were combined, 3 g of activated carbon was added, stirred to decolorize at 50°C for 30 min, filtered, 300 mL of acetone was added to the filtrate, and triethylamine was added dropwise to adjust the pH to 3.5, slowly stirred to crystallize, and crystallized at 3°C for 3.5 h, filtered, the filter cake was washed with acetone 4 times, and dried at 40°C under reduced pressure for 4 h to obtain 7-aminocephalosporin quinolone as a light brownish yellow powder.

[0048] Example 4 Into a 500 mL reaction flask, 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 trimethylsilyl iodide were mixed and stirred uniformly, vacuumized, heated to reflux at 40°C for 17 h, cooled to below 0°C, after adding 3 g of pyrazole acid salt-based C@MOF, 18 mL (25.3 g) of trimethylsilyl iodide was added, reacted for 5 h, cooled to below 0°C, 12.5 mL (13.5 g) of 5,6,7,8-tetrahydroquinoline was added, and reacted for another 3 h, cooled to below 5°C, 30 mL of methanol was added dropwise, stirred for 30 min, filtered using a Buchner funnel, 50 mL of 6 mol / L hydrochloric acid solution was added, phase-separated, the organic phase was washed with 10 mL of 6 mol / L hydrochloric acid solution, the water phases were combined, 3 g of activated carbon was added, stirred to decolorize at 50°C for 30 min, filtered, 300 mL of acetone was added to the filtrate, and triethylamine was added dropwise to adjust the pH to 3.5, slowly stirred to crystallize, and crystallized at 3°C for 3.5 h, filtered, the filter cake was washed with acetone 4 times, and dried at 40°C under reduced pressure for 4 h to obtain 7-aminocephalosporin quinolone as a light brownish yellow powder.

[0049] Mix 0.3 g Zn(NO3)2-6H2O and 6 mL deionized water for 10 min to obtain a zinc nitrate hexahydrate aqueous solution; mix 0.6 g of tris(4-(1H-pyrazol-4-yl)phenyl)amine and 30 mL N,N-dimethylformamide for 10 min, then add the zinc nitrate hexahydrate aqueous solution and mix for 12 min, add 0.25 g of benzoic acid and ultrasonic treat for 7 min, add 0.6 g of bio-activated carbon powder and ultrasonic treat for 30 min, then transfer the mixture to a reaction kettle and stir-react at 100℃ for 48 h, cool to room temperature, centrifugally collect the precipitate, immerse in N,N-dimethylformamide for 18 h, then immerse in anhydrous ethanol for 36 h, centrifugally collect the precipitate, and dry at 85℃ for 10 h to obtain pyrazole acid salt-based C@MOF.

[0050] Mix 0.8 g of styrene, 0.3 g of 4-vinylpyridine, and 10 mg of dibenzoyl peroxide, seal, and heat-stir at 90℃ for 5 h to obtain a 4-vinylpyridine-styrene copolymer.

[0051] Mix 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 trimethylsilyl iodide in a 500 mL reaction bottle, mix well, vacuumize, heat-reflux at 40℃ for 16 h, cool to below 0℃, add 1.5 g of pyrazole acid salt-based C@MOF, add 18 mL (25.3 g) of trimethylsilyl iodide, react for 4.5 h, cool to below 0℃, add 10 mL (10.8 g) of 5,6,7,8-tetrahydroquinoline, continue to react for 2 h, cool to below 5℃, dropwise add 30 mL of methanol, stir-react for 30 min, then use a Buchner funnel to suction filter, add 50 mL of a 6 mol / L hydrochloric acid solution, stand to separate phases, wash the organic phase with 10 mL of a 6 mol / L hydrochloric acid solution, combine the aqueous phases, add 3 g of activated carbon, stir-decolor at 50℃ for 25 min, filter, add 300 mL of acetone to the filtrate, and dropwise add triethylamine to adjust the pH to 3.2, slow-stir to crystallize, crystallize at 7℃ for 2.5 h, filter, wash the filter cake with acetone 3 times, and dry at 40℃ under reduced pressure for 4 h to obtain a light brownish yellow powder of 7-aminocephalosporin.

[0052] After 4.2 g of 7-aminocefquinome, 5.4 g of AE-active ester and 50 mL of 2-methyltetrahydrofuran were mixed, mechanical stirring was carried out at 1 ℃ for 25 min, then 0.2 g of 4-vinylpyridine-styrene copolymer was added while keeping the temperature at 1 ℃, and after continuous stirring for 7.5 h, the reaction mixture was subjected to suction filtration, the filter cake was washed with 10 mL of cold 2-methyltetrahydrofuran, the filtrate was collected and concentrated under reduced pressure, ethyl acetate was added, and the crystals were slowly stirred and separated, and after crystallization at 2 ℃ for 3 h, filtration was carried out, the filter cake was washed twice with ethyl acetate, the crude product was dissolved in warm deionized water, 0.6 g of activated carbon was added, and decolorization was carried out at 70 ℃ for 20 min, then after cooling to 10 ℃, 1 mL of sulfuric acid with a concentration of 6 mol / L (containing 0.59 g of sulfuric acid) was added, the pH value was adjusted to 1.5, and after slowly cooling to 3 ℃ at a rate of 0.5 ℃ / min, stirring was carried out for 1.5 h, stirring was stopped, and crystallization was carried out for 2 h, filtration was carried out, the filter cake was washed with ice water, suction filtration was carried out, and drying under reduced pressure at room temperature for 4 h gave cefquinome sulfate.

[0053] Example 5 After 5 g of dried fruit peel, 18 g of KOH and 65 mL of deionized water were mixed and stirred for 10 min, drying was carried out at 90 ℃ for 10 h, then the temperature was raised to 680 ℃ at a rate of 5 ℃ / min under a nitrogen atmosphere with a flow rate of 100 mL / min, pyrolysis was carried out for 1 h, cooling was carried out to room temperature, washing was carried out twice with a hydrochloric acid solution with a concentration of 1 mol / L, and drying was carried out at 105 ℃ for 18 h to give bioactive carbon powder.

[0054] After 0.3 g of Zn(NO3)2-6H2O and 6 mL of deionized water were mixed and stirred for 10 min, a zinc nitrate hexahydrate aqueous solution was obtained; after 0.4 g of tris(4-(1H-pyrazol-4-yl)phenyl)amine and 30 mL of N,N-dimethylformamide were mixed and stirred for 10 min, the zinc nitrate hexahydrate aqueous solution was added and mixed and stirred for 12 min, 0.25 g of benzoic acid was added and ultrasonic treatment was carried out for 8 min, 0.7 g of bioactive carbon powder was added and ultrasonic treatment was carried out for 30 min, then the mixture was transferred to a reaction kettle, stirring was carried out at 100 ℃ for 48 h, cooling was carried out to room temperature, the precipitate was collected by centrifugation, then the precipitate was soaked in N,N-dimethylformamide for 22 h, and then the precipitate was soaked in anhydrous ethanol for 40 h, the precipitate was collected by centrifugation, and drying was carried out at 90 ℃ for 8 h to give a pyrazole acid salt-based C@MOF.

[0055] After 0.8 g of styrene, 0.5 g of 4-vinylpyridine and 10 mg of dibenzoyl peroxide were mixed, sealing was carried out, and heating and stirring were carried out at 90 ℃ for 5.5 h to give 4-vinylpyridine-styrene copolymer.

[0056] Into a 500 mL reaction flask, 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 trimethylsilyl iodide were mixed, vacuumized, heated to reflux at 40℃ for 16 h, cooled to below 0℃, 1.5 g of pyrazole acid salt-based C@MOF was added, then 18 mL (25.3 g) of trimethylsilyl iodide was added, reacted for 4.5 h, cooled to below 0℃, 15 mL (16.2 g) of 5,6,7,8-tetrahydroquinoline was added, and reacted for another 2.5 h, cooled to below 5℃, 30 mL of methanol was added dropwise, stirred for 30 min, then filtered by a Buchner funnel, 50 mL of 6 mol / L hydrochloric acid solution was added, phase separation was performed, the organic phase was washed with 10 mL of 6 mol / L hydrochloric acid solution, the water phases were combined, 4 g of activated carbon was added, stirred to decolorize at 55℃ for 26 min, filtered, 300 mL of acetone was added to the filtrate, and triethylamine was added dropwise to adjust the pH to 3.4, slowly stirred to crystallize, crystallized at 10℃ for 2 h, filtered, the filter cake was washed with acetone twice, and dried at 40℃ under reduced pressure for 4 h to obtain 7-aminocephalosporin quinolone as a light brownish yellow powder.

[0057] Into a 500 mL reaction flask, 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 trimethylsilyl iodide were mixed, vacuumized, heated to reflux at 40℃ for 16 h, cooled to below 0℃, 1.5 g of pyrazole acid salt-based C@MOF was added, then 18 mL (25.3 g) of trimethylsilyl iodide was added, reacted for 4.5 h, cooled to below 0℃, 15 mL (16.2 g) of 5,6,7,8-tetrahydroquinoline was added, and reacted for another 2.5 h, cooled to below 5℃, 30 mL of methanol was added dropwise, stirred for 30 min, then filtered by a Buchner funnel, 50 mL of 6 mol / L hydrochloric acid solution was added, phase separation was performed, the organic phase was washed with 10 mL of 6 mol / L hydrochloric acid solution, the water phases were combined, 4 g of activated carbon was added, stirred to decolorize at 55℃ for 26 min, filtered, 300 mL of acetone was added to the filtrate, and triethylamine was added dropwise to adjust the pH to 3.4, slowly stirred to crystallize, crystallized at 10℃ for 2 h, filtered, the filter cake was washed with acetone twice, and dried at 40℃ under reduced pressure for 4 h to obtain 7-aminocephalosporin quinolone as a light brownish yellow powder.

[0058] The present application also carries out comparative examples and related tests.

[0059] Comparative Example 1 Compared with Example 1, the only difference is that N,N-dimethylformamide is used instead of pyrazole acid salt-based C@MOF in the preparation of 7-aminocephalosporin quinolone, and other preparation steps and components are completely consistent, and finally cefquinome sulfate is prepared.

[0060] Comparative Example 2 The difference compared with Example 1 is only that no activated carbon is added in the preparation of pyrazole acid salt base C@MOF, and other preparation steps and components are completely consistent, and finally cefquinome sulfate is prepared.

[0061] Comparative Example 3 The difference compared with Example 1 is only that triethylamine is used instead of 4-vinylpyridine-styrene copolymer in the preparation of cefquinome sulfate, and other preparation steps and components are completely consistent, and finally cefquinome sulfate is prepared.

[0062] Performance detection test In the test process of the above Examples 1-5 and Comparative Examples 1-3, the obtained 7-aminocefquinome is recorded as an intermediate, and the structural diagram is shown in FIG. Figure 1 The structural diagram of cefquinome sulfate finally prepared is shown in FIG. Figure 1 The yield and purity of the intermediate and cefquinome sulfate are detected, and the detection method and related results are as follows: I. Purity detection method: Instrument: Agilent 1260 high performance liquid chromatograph; Preparation of phosphate buffer: 1L of water, 60mg of KH2PO4, 1.2g of Na2HPO4, and H3PO4 are mixed to adjust the solution pH to 4.7; Mobile phase: phosphate buffer:methanol=85:15; Flow rate: 1.0mL / min; Chromatographic column: Capcell PAK C18; Column temperature: 40℃; Wavelength: 270nm; Injection volume: 20μL.

[0063] Solution preparation: 1) Accurately weigh 5.00mg of intermediate standard sample into a 10mL volumetric flask, add methanol to dissolve completely, then dilute to the mark with methanol, shake well to obtain the standard sample solution; 2) Accurately weigh 5.00mg of cefquinome sulfate sample into a 10mL volumetric flask, add methanol to dissolve completely, then dilute to the mark with methanol, shake well to obtain the crude sample solution.

[0064] Yield= ; M R : Relative molecular mass of raw material, m R : Mass of raw material input; m P : Actual output mass of product, M P : Relative molecular mass of product; II. Purity calculation method: HPLC area normalization method, the specific calculation formula is as follows: Sample purity = C: target peak area, C0: sum of total area of all chromatographic peaks.

[0065] After detecting the intermediates in examples 1-5 and comparative examples 1-3 and cefquinome sulfate by high performance liquid chromatography, the data was sorted, and the purity and yield of the intermediates and cefquinome sulfate were recorded in table 1.

[0066] Table 1

[0067] As can be seen from table 1, the yield of the intermediates and cefquinome sulfate synthesized in examples 1-5 is greater than 88%, and the purity is greater than 98%, and the test results are obviously better than the intermediates and cefquinome sulfate synthesized in comparative examples 1-3; the yield and purity of the intermediates and cefquinome sulfate synthesized in example 2 are the highest, the liquid chromatogram of the synthesized intermediate is shown in the attached Figure 2 , the liquid chromatogram of the synthesized cefquinome sulfate is shown in the attached Figure 3 , it can also be seen that the intermediate and cefquinome sulfate synthesized in example 2 have no obvious impurity peaks and have high purity; in addition, the structure of the cefquinome sulfate synthesized in example 2 was characterized by Fourier infrared spectroscopy, and the obtained infrared spectrum is shown in the attached Figure 4 ; comparative example 1 directly uses N,N-dimethylformamide instead of pyrazole acid salt base C@MOF, which significantly reduces the yield of the intermediate and also affects the purity; comparative example 2 has a certain decrease in the yield and purity of the intermediate due to the absence of activated carbon in the pyrazole acid salt base C@MOF; comparative example 3 uses triethylamine instead of 4-vinylpyridine-styrene copolymer as the base catalyst, which significantly reduces the catalytic efficiency, and the yield and purity of the finally synthesized cefquinome sulfate are affected.

[0068] The above is the preferred embodiment of the present application, and those skilled in the art can make several improvements and refinements without departing from the principles of the present application, and these improvements and refinements should also be considered within the protection scope of the present application.​

Claims

1. A process for the synthesis of cefquinome sulfate characterized in that, Comprising the following steps: S1, mix tri(4-(1H-pyrazol-4-yl)phenyl)amine and N,N-dimethylformamide, zinc nitrate hexahydrate aqueous solution, add benzoic acid, activated carbon powder ultrasonic treatment, heat reaction, cool to room temperature, centrifugal collection of precipitate, respectively immersed in N,N-dimethylformamide, absolute ethanol, centrifugal collection of precipitate, drying to get pyrazole acid base C@MOF; S2, mix 7-aminocephalosporanic acid, hexamethyldisilazane, trimethylsilyl iodide, add pyrazole acid base C@MOF and trimethylsilyl iodide, 5,6,7,8-tetrahydroquinoline, methanol reaction, suction filtration, add hydrochloric acid solution, static phase separation, crystallization, filtration, washing, drying to get 7-aminocephalosporin quinolone; S3, mix 7-aminocephalosporin quinolone, AE-active ester, 2-methyltetrahydrofuran, 4-vinylpyridine-styrene copolymer, reaction, suction filtration, washing, collect filtrate, concentration crystallization, filtration, washing, dissolve in water, cooling, add sulfuric acid reaction, filtration, washing, drying to get cefquinome sulfate.

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, In step S1, after mixing tri(4-(1H-pyrazol-4-yl)phenyl)amine and N,N-dimethylformamide and stirring for 10 min, add zinc nitrate hexahydrate aqueous solution and mix and stir for 10-15 min, add benzoic acid and ultrasonic treatment for 5-10 min, add activated carbon powder and ultrasonic treatment for 30 min, then transfer the mixture to a reaction kettle, stir at 100℃ for 48 h, cool to room temperature, centrifugal collection of precipitate, put into N,N-dimethylformamide for 16-24 h, then put into absolute ethanol for 24-48 h, centrifugal collection of precipitate, and dry at 80-100℃ for 8-12 h to get pyrazole acid base C@MOF.

4. 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, then putting into an atmosphere with nitrogen flow of 100 mL / min, heating to 600-700℃ at 5℃ / min, pyrolyzing for 1-2 h, cooling to room temperature, washing with 1 mol / L hydrochloric acid solution for 2-5 times, and drying at 90-105℃ for 16-18 h.

5. The process for synthesis of Cefquinome sulfate as claimed in claim 1 wherein, 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.

6. The process for synthesis of Cefquinome sulfate as claimed in claim 1 wherein, In the step S2, 7-aminocephalosporanic acid, 2-methyltetrahydrofuran, hexamethyldisilazane and trimethylsilyl iodide are mixed, vacuumized, heated to reflux, cooled to below 0 DEG C, and then pyrazole acid salt-based C@MOF is added, followed by trimethylsilyl iodide reaction, cooling to below 0 DEG C, addition of 5,6,7,8-tetrahydroquinoline for further reaction, cooling to below 5 DEG C, dropwise addition of methanol for stirring reaction, suction filtration through a Buchner funnel, addition of hydrochloric acid solution, phase separation by standing, washing of the organic phase with hydrochloric acid solution, combination of the aqueous phases, stirring decolorization by adding activated carbon, filtration, addition of acetone to the filtrate, dropwise addition of triethylamine to adjust the pH to 3.0-3.5, slow crystallization, crystal aging, filtration, washing of the filter cake with acetone for 2-4 times, and vacuum drying to obtain 7-aminocephalosporin.

7. A process for the synthesis of Cefquinome sulfate as claimed in claim 6 wherein, The heating to reflux is performed at a temperature of 40 DEG C for 15-17 h, the trimethylsilyl iodide reaction is performed for 4-5 h, the addition of 5,6,7,8-tetrahydroquinoline for further reaction is performed for 2-3 h, the stirring reaction is performed for 30 min, the stirring decolorization is performed at a temperature of 50-60 DEG C for 20-30 min, the crystal aging is performed at 0-10 DEG C for 2-4 h, and the vacuum drying is performed at 40 DEG C for 4 h.

8. A process for the synthesis of Cefquinome sulfate as claimed in claim 6 wherein, The hydrochloric acid solution has a concentration of 6 mol / L; and the 7-aminocephalosporin contains the following raw materials in mass parts: 7-aminocephalosporanic acid 25 parts, hexamethyldisilazane 17.2 g-19.5 parts, trimethylsilyl iodide 25.67 parts, 5,6,7,8-tetrahydroquinoline 10.8-16.2 parts, and pyrazole acid salt-based C@MOF 0.5-3 parts.

9. The process for synthesis of Cefquinome sulfate as claimed in claim 1, wherein, In the step S3, 7-aminocephalosporin, AE-active ester and 2-methyltetrahydrofuran are mixed, cooled to 0-3 DEG C, stirred for 20-30 min, added with 4-vinylpyridine-styrene copolymer for reaction for 6-8 h, suction filtered, washed the filter cake with 2-methyltetrahydrofuran, collected the filtrate, vacuum concentrated, added with ethyl acetate, slowly crystallized, aged the crystals at 0-5 DEG C for 3 h, filtered, washed the filter cake with ethyl acetate for 2-4 times, dissolved in deionized water, added with activated carbon, stirred and decolorized at 60-70 DEG C for 20-30 min, cooled to 10 DEG C, added with 6 mol / L sulfuric acid to adjust the pH to 1.5-2.0, cooled to 2-5 DEG C, stirred for 1-2 h, aged the crystals for 2 h, filtered, washed with ice water, suction filtered, and vacuum dried at room temperature for 4 h to obtain cephalosporin sulfate.

10. The process for synthesis of Cefquinome sulfate as claimed in claim 1 wherein, The cephalosporin sulfate contains the following raw materials in mass parts: 7-aminocephalosporin 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.

Images