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CN118561869B - Synthesis method of ceftiofur sodium - Google Patents

Synthesis method of ceftiofur sodium Download PDF

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Publication number
CN118561869B
CN118561869B CN202411061299.1A CN202411061299A CN118561869B CN 118561869 B CN118561869 B CN 118561869B CN 202411061299 A CN202411061299 A CN 202411061299A CN 118561869 B CN118561869 B CN 118561869B
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triethylamine
mofs
ceftiofur sodium
boron trifluoride
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CN118561869A (en
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张斌
王成成
马学善
周圣翔
罗俊峰
任建海
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QILU SYNVA PHARMACEUTICAL CO Ltd
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QILU SYNVA PHARMACEUTICAL CO Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/02—Preparation
    • C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
    • C07D501/06—Acylation of 7-aminocephalosporanic acid
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/1616—Coordination complexes, e.g. organometallic complexes, immobilised on an inorganic support, e.g. ship-in-a-bottle type catalysts
    • B01J31/1625—Coordination complexes, e.g. organometallic complexes, immobilised on an inorganic support, e.g. ship-in-a-bottle type catalysts immobilised by covalent linkages, i.e. pendant complexes with optional linking groups
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/1691—Coordination polymers, e.g. metal-organic frameworks [MOF]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/02—Preparation
    • C07D501/12—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
    • C07D501/36—Methylene radicals, substituted by sulfur atoms
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
    • B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
    • B01J2231/4277—C-X Cross-coupling, e.g. nucleophilic aromatic amination, alkoxylation or analogues

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  • Organic Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Catalysts (AREA)

Abstract

The invention provides a method for synthesizing ceftiofur sodium, which belongs to the technical field of drug synthesis and comprises the following steps: s1, synthesizing an intermediate aminothioxime acyl chloride hydrochloride: suspending the raw material of the aminothioxime hydrochloride in an organic solvent, adding an acyl chloride reagent, and reacting to obtain the aminothioxime acyl chloride hydrochloride; s2, synthesizing ceftiofur sodium: adding the obtained aminothioxime acid chloride hydrochloride into a reaction kettle, adding an organic solvent, 7-ACF and triethylamine for reaction, and obtaining a reaction product after the reaction is finished; s3, purifying a product: and (3) extracting, crystallizing and filtering the reaction product obtained in the step (S2) to obtain the product ceftiofur sodium. The synthesis method of ceftiofur sodium can avoid introducing 2-MBT and other genotoxic impurities, has high reaction conversion rate, and is low in byproducts and easy to remove, thereby being suitable for industrial production.

Description

Synthesis method of ceftiofur sodium
Technical Field
The invention relates to the technical field of medicine synthesis, in particular to a method for synthesizing ceftiofur sodium.
Background
Ceftiofur acts on the transpeptidase to block the synthesis of the mucin, which is an important component of the bacterial cell wall, so that the bacterial cell wall is lost to death, and the effect of rapid sterilization is achieved. The ceftiofur has wide antibacterial spectrum and strong antibacterial activity, and has strong antibacterial activity on gram-positive bacteria, gram-negative bacteria and anaerobic bacteria.
For the synthesis of ceftiofur, the main synthetic route in the industry is to use 7-ACA to react with (2-amino-thiazol-4-yl) -2-methoxyimino-2-acetic acid protected by triphenyl to obtain 7-acylated cephalosporanic acid in the presence of dicyclohexyldiimine and 1-hydroxybenzotriazole. Then reacts with sulfhydryl acid of furan, and finally uses trifluoroacetic acid to remove the triphenyl protection to obtain the ceftiofur acid. The method uses expensive and highly toxic Dicyclohexylcarbodiimide (DCC) in the amidation process, uses corrosive trifluoroacetic acid for protecting groups, has long reaction time and complicated refining method, generates dicyclohexylurea and other byproducts which are not easy to remove, is not suitable for commercialization, and has serious potential safety hazard.
The other method is that ceftiofur is obtained by the reaction of ceftioxime and mercapto acid of furan, the reaction is that ceftiofur is prepared from ceftioxime, nucleophilic displacement reaction is carried out by acetyl group on 3-position of a previous compound and mercapto group on furan ring in the presence of acid or alkali, substitution is unstable, substitution reaction is carried out to prepare ceftiofur, and then the mercapto compound and the derivative of bivalent sulfur are fully released, so that the reaction is difficult to succeed, the conversion rate is low, and the method is not suitable for industrial application.
At present, 7-ACF and MAEM (AE-active ester) are generally used as raw materials for synthesizing ceftiofur sodium, and the MAEM is a product of combining aminothioxime acid and 2-MBT (2-mercaptobenzothiazole), so that the MAEM has large molecular weight and low atom utilization rate in the reaction process, and the removed 2-MBT is remained in the product as a genotoxic impurity, is not easy to remove, and is unfavorable for the green production concept.
Therefore, there is a need to provide a synthetic method which is relatively economical and environment-friendly in raw materials, high in reaction conversion rate, high in atom utilization rate, less in byproducts and easy to remove, and avoids introducing 2-MBT and other genotoxic impurities, and is used for industrial production.
Disclosure of Invention
In view of the above, the invention provides a method for synthesizing ceftiofur sodium, which can avoid introducing 2-MBT and other genotoxic impurities, has high reaction conversion rate, and is low in byproducts and easy to remove, and is suitable for industrial production.
The invention provides a method for synthesizing ceftiofur sodium, which comprises the following steps:
s1, synthesizing an intermediate aminothioxime acyl chloride hydrochloride: suspending the raw material of the aminothioxime hydrochloride in an organic solvent, adding an acyl chloride reagent, and reacting to obtain the aminothioxime acyl chloride hydrochloride;
s2, synthesizing ceftiofur sodium: adding the obtained aminothioxime acid chloride hydrochloride into a reaction kettle, adding an organic solvent, 7-ACF and triethylamine for reaction, and obtaining a reaction product after the reaction is finished;
s3, purifying a product: and (3) extracting, crystallizing and filtering the reaction product obtained in the step (S2) to obtain the product ceftiofur sodium.
According to the invention, the cefotaxime hydrochloride is adopted as a raw material, and is subjected to chlorination reaction to obtain the cefotaxime acyl chloride hydrochloride, and then the cefotaxime hydrochloride is subjected to amidation condensation with 7-ACF, so that the ceftiofur sodium product is obtained, the conversion rate is high, the generation of genotoxic impurity 2-MBT can be avoided, and the byproducts are few; simultaneously, the triethylamine can play a role in catalysis, the triethylamine can also be used as an acid binding agent, and the reaction byproduct hydrogen chloride can be easily removed through salifying the acid binding agent. The whole reaction route is short, raw materials are simplified, the cost is low, the reaction conversion rate can be improved, the introduction of the genotoxic impurity 2-MBT is avoided, the atomic utilization rate is high, and the method accords with the green chemical engineering concept.
The specific synthetic route reaction equation is shown in FIG. 1. The raw material of the aminothioxime hydrochloride can be purchased and can be purchased from Shandong Jincheng pharmaceutical chemical industry Co., ltd, and the product batch number 2312003.
Preferably, in the step S1, the organic solvent used for suspension is acetonitrile, and the acyl chloride reagent is thionyl chloride.
Preferably, the aminothioxime hydrochloride is suspended in an organic solvent acetonitrile, thionyl chloride is added for low-temperature reaction, reduced pressure distillation is carried out after the reaction is finished, and the residual acyl chloride reagent and the organic solvent are removed.
The method adopts acetonitrile as an organic solvent, thionyl chloride as an acyl chloride reagent, and can easily remove the acyl chloride by reduced pressure distillation after the reaction to obtain high-purity aminothioxime acyl chloride hydrochloride.
Preferably, the organic solvent added in the step S2 is dichloromethane.
Preferably, in the step S2, the synthesis reaction of ceftiofur sodium is performed under the protection of nitrogen, so as to facilitate efficient synthesis of the product ceftiofur sodium.
Preferably, in the step S3, an acetone solution of sodium iso-octoate is added for crystallization, and an acetone solution of a salifying agent sodium iso-octoate is added for promoting rapid crystallization and precipitation, and removing impurities, thereby obtaining the high-purity final product ceftiofur sodium.
Preferably, in the step S3, water is added to the reaction product to extract the reaction product to a water phase, acetone is added to the water phase to adjust the pH to 3.0-3.5, sodium chloride is added to carry out layering, acetone is then added, an acetone solution of sodium iso-octoate is added dropwise to carry out crystallization, acetone is used for leaching after filtration, and ventilation and air drying are carried out to obtain the final product ceftiofur sodium.
Preferably, the triethylamine is immobilized on MOFs to form a triethylamine-immobilized catalyst.
Because triethylamine has stronger volatility, the volatilization of the triethylamine can cause certain loss to influence the catalytic effect, and the triethylamine is used as the supplement of acid binding agent salifying, the adding amount is required to be increased, and the amount is large and the triethylamine is easy to remain. According to the invention, by adopting MOFs (metal organic frameworks), namely, the triethylamine is immobilized on the MOFs to form the triethylamine immobilized catalyst, the problem of volatility is solved, the catalytic performance is improved, the catalyst is not influenced to react with hydrogen chloride as an acid binding agent, the hydrogen chloride is absorbed and removed, the residual catalyst is easier to separate and recover from a reaction mixture, no residue exists, and the catalyst can be reused later.
Preferably, the supported catalyst further comprises boron trifluoride, the MOFs adopted are amino-functionalized MOFs, and the triethylamine and the boron trifluoride are grafted to the surface of the MOFs through amino functional groups to form the triethylamine-boron trifluoride supported catalyst.
Because triethylamine and boron trifluoride have the problem of strong volatility, an amine group on the MOFs functionalized by amino forms a hydrogen bond with the triethylamine, and forms a coordination bond with the boron trifluoride to stabilize the positions of the triethylamine and the boron trifluoride in the MOFs structure, the defect of strong volatility of the two catalysts is effectively improved by fixing the two catalysts on the MOFs, the catalysts are easier to separate from a reaction mixture and recycle, and the economy and the sustainability of the process are improved.
Meanwhile, the activation capability of the substrate can be obviously enhanced by combining triethylamine and boron trifluoride through the immobilized catalyst, and particularly in the reaction involving an electrophile, the boron fluoride can form an effective acid-base catalysis pair when being matched with the triethylamine as a weaker base, so that the reaction rate and the selectivity are improved, and the acid-base pair can activate different parts in the reaction simultaneously, so that the synthesis reaction can be promoted, the catalyst consumption can be reduced, and the catalytic efficiency is improved.
Preferably, the preparation method of the triethylamine-boron trifluoride immobilized catalyst comprises the following steps: after alkali treatment is carried out on the amino-functionalized MOFs, adding an ethanol solution of triethylamine into the amino-functionalized MOFs, adsorbing for a period of time, removing unbound triethylamine, adding the ethanol solution of boron trifluoride into the MOFs loaded with the triethylamine by the same method, adsorbing for a period of time, and removing unbound boron trifluoride to obtain the triethylamine-boron trifluoride immobilized catalyst.
The method comprises the steps of slightly alkaline treating amino-functionalized MOFs to ensure the activity of amino groups, adding an ethanol solution of triethylamine into the amino-functionalized MOFs through a solution impregnation method, adsorbing the ethanol solution of triethylamine at a certain temperature for a period of time, vacuumizing or heat treating to remove unbound triethylamine, immobilizing boron trifluoride in the same way, and finally thoroughly washing and drying the MOFs immobilized with the triethylamine and the boron trifluoride to ensure the stability and the purity of the catalyst, thereby obtaining the triethylamine-boron trifluoride immobilized catalyst.
The high porous structure of MOFs provides a great surface area, the opportunity of contacting with HCl molecules is increased, the reaction efficiency and the adsorption capacity are improved, compared with the traditional liquid triethylamine, the triethylamine-boron trifluoride immobilized catalyst composite material is used as the supplement of an acid binding agent, byproducts are converted into salts, the byproduct hydrogen chloride is effectively managed, the reuse of the catalyst can be realized by supplementing the immobilized triethylamine on the MOFs, the economy and the sustainability of the process are greatly enhanced, the residual catalyst is easier to separate from a reaction system, the recycling is realized, the catalytic performance of the catalyst is improved while the volatilization defect of the triethylamine is effectively solved, the production process is more efficient, the recycling and impurity removal are easy, and the method is environment-friendly and environment-friendly.
Preferably, the amino-functionalized MOFs are prepared by dissolving an organic ligand of 2-amino terephthalic acid and zirconium tetrachloride coordination metal salt in DMF and HCl solution, stirring and radiating, cooling to room temperature, filtering and separating a solid product, washing with DMF, washing with deionized water, washing with absolute ethyl alcohol, and drying.
The amino-functionalized metal organic frame material MOFs can be prepared by adopting an organic ligand to react with a coordination metal salt, filtering and separating a solid product, washing with a small amount of DMF, washing with deionized water for several times to remove unreacted salt and other impurities, washing with absolute ethyl alcohol to remove residual moisture, and drying to obtain the amino-functionalized MOFs in a dry state.
The technical scheme of the invention has at least one of the following beneficial effects:
1. According to the invention, the thioxomate hydrochloride is adopted as a raw material, the chlorination reaction is the thioxomate hydrochloride, and amidation condensation is carried out with 7-ACF to obtain the ceftiofur sodium, so that the generation of genotoxic impurity 2-MBT can be avoided, the byproducts are few, the whole reaction route is short, the raw material is simplified, the cost is low, the introduction of the genotoxic impurity 2-MBT can be avoided, the atomic utilization rate is high, the reaction conversion rate is improved, the green chemical engineering concept is met, and meanwhile, the triethylamine can play a catalytic role, promote the efficiency of catalytic reaction, react with the reaction byproduct hydrogen chloride to form salt, and the removal is convenient.
2. According to the invention, triethylamine is immobilized on MOFs, so that the problem of volatility of the triethylamine is solved, meanwhile, in the process of synthesizing the aminothioxime acid chloride, the residual hydrogen chloride which is not removed as a reaction byproduct can be converted into salt by being supplemented as an acid binding agent, the byproduct is further removed, and the convenience in recycling and reutilization of the catalyst can be realized by supplementing the immobilized triethylamine on the MOFs, so that the economy and the sustainability of the process are greatly enhanced.
3. According to the invention, the activation capability of the boron trifluoride on a substrate can be obviously enhanced by combining the triethylamine and the boron trifluoride through the immobilized catalyst, and particularly, in the reaction involving an electrophile, the boron trifluoride can form an effective acid-base catalysis pair when being used together with the triethylamine as a weaker base, so that the reaction rate and the selectivity are improved, and the acid-base pair can activate different parts in the reaction simultaneously, so that the synthesis reaction can be promoted, the catalyst consumption can be reduced, and the catalysis efficiency is improved.
Drawings
FIG. 1 is a schematic diagram of the synthetic route reaction equation of ceftiofur sodium in example 1 of the present invention;
FIG. 2 is a schematic diagram showing the synthetic route reaction equation of ceftiofur sodium in example 2 of the present invention;
FIG. 3 is a mass spectrum of ceftiofur sodium related products prepared by the reaction of example 1 of the present invention;
FIG. 4 is a mass spectrum of ceftiofur sodium related product prepared by the reaction of example 2 of the present invention.
FIG. 5 is a mass spectrum of the ceftiofur sodium related product prepared by the reaction of comparative example 1 of the present invention.
FIG. 6 is a mass spectrum of the ceftiofur sodium related product prepared by the reaction of comparative example 2 of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more clear, 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. It will be apparent that the described embodiments are some, but not all, embodiments of the invention. All other embodiments, which are obtained by a person skilled in the art based on the described embodiments of the invention, fall within the scope of protection of the invention.
Example 1
In a reaction kettle, 300mL of acetonitrile solvent is added, 10.0g of aminothioxime hydrochloride is weighed, and the mixture is added into the reaction kettle and stirred to be uniformly suspended. And slowly dropwise adding 6.0g of thionyl chloride into a reaction kettle, stirring, reacting at a low temperature until the concentration of the thioxomate hydrochloride is 1g/L, and performing reduced pressure distillation after the reaction is finished to remove the residual acyl chloride reagent and the organic solvent, thereby obtaining the intermediate thioxomate hydrochloride.
Adding the obtained intermediate aminothiazolyl oxime chloride hydrochloride into another reaction kettle, adding 200ml of dichloromethane, adding 12.1g of 7-ACF and dropwise adding 5g of triethylamine to perform reaction, adding 50ml of water to extract to a water phase after the reaction is finished, adding 100ml of acetone to adjust the pH value to be 3.1-3.2, adding 7.5g of sodium chloride to layer, adding 800ml of acetone, and dropwise adding 7.0g of sodium iso-octoate acetone solution to crystallize; after filtration, the crystals were rinsed with 150ml of acetone and the rinsed crystals were left to air dry in a ventilated place to obtain the final product ceftiofur sodium. The process reaction equation is shown in FIG. 1.
Example 2
In a reaction kettle, 300mL of acetonitrile solvent is added, 10.2g of aminothioxime hydrochloride is weighed, and the mixture is added into the reaction kettle and stirred to be uniformly suspended. And slowly dropwise adding 6.0g of thionyl chloride into a reaction kettle, stirring, reacting at a low temperature until the concentration of the thioxomate hydrochloride is 1g/L, and performing reduced pressure distillation after the reaction is finished to remove the residual acyl chloride reagent and the organic solvent, thereby obtaining the intermediate thioxomate hydrochloride.
3.6G of triethylamine supported catalyst was placed in a desiccator for pretreatment, water was removed and the catalyst was activated. Adding the obtained intermediate aminothiazolyl oxime chloride hydrochloride into another reaction kettle, adding 200ml of dichloromethane, adding 12.0g of 7-ACF and pretreated triethylamine supported catalyst, stirring, cooling to 5 ℃ under the protection of nitrogen for reaction, separating the supported catalyst, adding 50ml of water for extraction to obtain a water phase, adding 100ml of acetone into the water phase for regulating the pH value to be 3.2-3.3, adding 7.5g of sodium chloride for layering, adding 800ml of acetone, and dropwise adding 5.0g of sodium iso-octoate acetone solution for crystallization; after filtration, the crystals were rinsed with 150ml of acetone and the rinsed crystals were left to air dry in a ventilated place to obtain the final product ceftiofur sodium. The process reaction equation is shown in FIG. 2.
Example 3
In a reaction kettle, 300mL of acetonitrile solvent is added, 10.0g of aminothioxime hydrochloride is weighed, and the mixture is added into the reaction kettle and stirred to be uniformly suspended. And slowly dropwise adding 6.1g of thionyl chloride into a reaction kettle, stirring, reacting at a low temperature until the concentration of the thioxomate hydrochloride is 1g/L, and performing reduced pressure distillation after the reaction is finished to remove the residual acyl chloride reagent and the organic solvent, thereby obtaining the intermediate thioxomate hydrochloride.
2.2G of triethylamine-boron trifluoride supported catalyst was placed in a desiccator for pretreatment, water was removed and the catalyst was activated. Adding the obtained intermediate aminothiazolyl oxime chloride hydrochloride into another reaction kettle, adding 200ml of dichloromethane, adding 12.0g of 7-ACF and pretreated triethylamine-boron trifluoride supported catalyst, stirring, cooling to 5 ℃ under the protection of nitrogen for reaction, separating the supported catalyst, adding 50ml of water for extraction to obtain a water phase, adding 100ml of acetone into the water phase for regulating the pH to be 3.3-3.4, adding 7.6g of sodium chloride for layering, adding 800ml of acetone, and dropwise adding 5.1g of sodium isooctanoate acetone solution for crystallization; after filtration, the crystals were rinsed with 150ml of acetone and the rinsed crystals were left to air dry in a ventilated place to obtain the final product ceftiofur sodium. The process reaction equation is shown in FIG. 2.
Example 4
In a reaction kettle, 300mL of acetonitrile solvent is added, 10.0g of aminothioxime hydrochloride is weighed, and the mixture is added into the reaction kettle and stirred to be uniformly suspended. And slowly dropwise adding 6.2g of thionyl chloride into a reaction kettle, stirring, reacting at a low temperature until the concentration of the thioxomate hydrochloride is 1g/L, and performing reduced pressure distillation after the reaction is finished to remove the residual acyl chloride reagent and the organic solvent, thereby obtaining the intermediate thioxomate hydrochloride.
2.3G of triethylamine-boron trifluoride supported catalyst was placed in a desiccator for pretreatment, water was removed and the catalyst was activated. Adding the obtained intermediate aminothiazolyl oxime chloride hydrochloride into another reaction kettle, adding 200ml of dichloromethane, adding 12.1g of 7-ACF and pretreated triethylamine-boron trifluoride supported catalyst, stirring, cooling to 4 ℃ under the protection of nitrogen for reaction, separating the supported catalyst, adding 50ml of water for extraction to obtain a water phase, adding 100ml of acetone into the water phase for regulating the pH to be 3.1-3.2, adding 7.5g of sodium chloride for layering, adding 800ml of acetone, and dropwise adding 5.0g of sodium isooctanoate acetone solution for crystallization; after filtration, the crystals were rinsed with 150ml of acetone and the rinsed crystals were left to air dry in a ventilated place to obtain the final product ceftiofur sodium.
Example 5
Preparing an amino-functionalized metal organic frame material MOFs, weighing 1.282g of 2-amino terephthalic acid organic ligand and 0.816g of zirconium tetrachloride coordination metal salt in 30ml of DMF and 0.8ml (37 wt%) of concentrated HCl solution in a reaction bottle filled with inert gas, carrying out ultrasonic treatment for 20 minutes, fully stirring and radiating, transferring to a homogeneous reaction kettle, then carrying out reaction for 24 hours at 120 ℃ in an incubator, and naturally cooling to room temperature. The solid product was isolated by filtration, washed with a small amount of DMF, then with deionized water 3 times, finally with absolute ethanol to remove residual moisture, and dried at 90 ℃ for 2h to obtain the amino-functionalized MOFs in dry form.
And (3) immobilizing triethylamine on the amino-functionalized MOFs, slightly alkaline treating the amino-functionalized MOFs, adding an ethanol solution of the triethylamine into the amino-functionalized MOFs through a solution impregnation method, preserving heat, adsorbing for a period of time, vacuumizing to remove unbound triethylamine, washing with absolute ethyl alcohol, and drying to obtain the triethylamine immobilized catalyst.
Example 6
Preparing an amino-functionalized metal organic frame material MOFs, weighing 1.284g of 2-amino terephthalic acid organic ligand and 0.815g of zirconium tetrachloride coordination metal salt, dissolving in 30ml of DMF and 0.8ml (37 wt%) of concentrated HCl solution, carrying out ultrasonic treatment for 20 minutes, fully stirring and radiating, transferring to a homogeneous reaction kettle, reacting for 24 hours at 120 ℃ in an incubator, and naturally cooling to room temperature. The solid product was isolated by filtration, washed with a small amount of DMF, then with deionized water 3 times, finally with absolute ethanol to remove residual moisture, and dried at 90 ℃ for 2h to obtain the amino-functionalized MOFs in dry form.
And (3) immobilizing triethylamine on the amino-functionalized MOFs, slightly alkaline treating the amino-functionalized MOFs, adding an ethanol solution of triethylamine into the amino-functionalized MOFs through a solution impregnation method, preserving heat, adsorbing for a period of time, removing unbound triethylamine through heat treatment, adding an ethanol solution of boron trifluoride into the MOFs loaded with triethylamine through the same method, adsorbing for a period of time, removing unbound boron trifluoride, washing with absolute ethyl alcohol, and drying to obtain the triethylamine-boron trifluoride immobilized catalyst.
The following comparative example tests were also performed.
Comparative example 1
The method for synthesizing the ceftiofur sodium by using 7-ACF and MAEM (AE-active ester) as raw materials in a current common method comprises the following specific steps:
50mL of dichloromethane and a small amount of EDTA-2Na are added into a dry reaction bottle, the mixture is mixed, the temperature is reduced to 0-3 ℃, 3g of 7-ACF and 4g of AE-active ester are added, 3g of triethylamine is slowly added dropwise, and the reaction is carried out for 4 hours under heat preservation. Then adding 20mL of aqueous solution of sodium isooctanoate, stirring and layering, separating out water phase, washing the organic phase with 10mL of distilled water for 3 times, merging the water phase, adding active carbon for decolorization, filtering to obtain filtrate, and dripping 120mL of tetrahydrofuran until crystal precipitation is not increased, and growing the crystal for 1.5h. Vacuum filtration is carried out, the filter cake is washed 3 times by 10mL tetrahydrofuran, and the ceftiofur sodium is obtained after drying.
Comparative example 2
In comparison with example 4, the only difference is that triethylamine is used instead of triethylamine-boron trifluoride supported catalyst, namely: 2.3g of triethylamine-boron trifluoride immobilized catalyst is placed in a dryer for pretreatment, moisture is removed, the catalyst is activated, and instead, 2.3g of triethylamine liquid is directly dripped into a reaction kettle, other components, steps, conditions and the like are kept unchanged, so that ceftiofur sodium is prepared.
(One) performing yield and purity detection of the intermediate: the intermediate obtained in examples 1 to 4 and comparative example 2 was subjected to yield and content detection using a high performance liquid chromatograph, and the results of calculation and summarization are shown in table 1 below.
As can be seen from the results in Table 1, examples 1 to 4 and comparative example 2 of the present invention all show that the raw materials are completely reacted, the yield of the intermediate aminothioxime acid chloride hydrochloride is high, other byproducts are not produced during the reaction, and the purity of the finally obtained aminothioxime acid chloride hydrochloride is relatively high.
(II) detecting the yield and purity of the final product: the final products obtained in examples 1-4 and comparative examples 1-2 were tested for their yields and content using a high performance liquid chromatograph, and the statistical data calculations are summarized in Table 2 below, and the final product detection chromatograms of some examples and comparative examples are shown in FIGS. 3-6.
As can be seen from the results of the above tables 2 and FIGS. 3 to 6, the final products ceftiofur sodium were successfully obtained in examples 1 to 4 and comparative examples 1 to 2, the retention time was about 30min, and there was a distinct chromatographic peak of ceftiofur sodium, wherein no genotoxic impurity 2-MBT was detected in the final products obtained in examples 1 to 4, as in FIGS. 1 and 2, no 2-MBT impurity peak was detected, and the total impurity content was low, both below 0.8%, and the total impurity content of examples 2 to 4 was below 0.4%. In contrast, in comparative example 1, the production of 2-MBT impurity was unavoidable because the 2-MBT impurity peak occurred at about 33min for the retention time, as shown in fig. 5, and even though the subsequent purification was difficult to remove, 2.2% of toxic impurities were still contained, and the total impurity content was high.
As can be seen by combining table 2, fig. 3, fig. 4 and fig. 6, in examples 2-4, the triethylamine-boron trifluoride supported catalyst is adopted, the yield of the product obtained by adopting the common triethylamine liquid is improved, the total impurity content is reduced, and the dosage of the catalyst is reduced, so that the acid-base catalytic system triethylamine-boron trifluoride supported catalyst can improve the catalytic performance, can efficiently perform catalytic reaction, is easy to recycle, does not cause burden to the environment, and reduces the impurity of the product; in particular, as is apparent from comparison of example 4 with comparative example 2, the product obtained in comparative example 2 also does not contain 2-MBT, which is a toxic impurity, and does not have 2-MBT impurity peaks, but the yield is reduced, the content of other impurities is increased, and more other impurity peaks appear in the figure, which indicates that the conventional triethylamine liquid is easy to volatilize, and the use amount is too small, which affects the catalytic performance and the effect of removing byproducts.
The foregoing is a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention and are intended to be comprehended within the scope of the present invention.

Claims (5)

1. The synthesis method of ceftiofur sodium is characterized by comprising the following steps:
s1, synthesizing an intermediate aminothioxime acyl chloride hydrochloride: suspending the raw material of the aminothioxime hydrochloride in an organic solvent, adding an acyl chloride reagent, and reacting to obtain the aminothioxime acyl chloride hydrochloride;
S2, synthesizing ceftiofur sodium: adding the obtained aminothioxime acid chloride hydrochloride into a reaction kettle, adding an organic solvent, 7-ACF and triethylamine for reaction, and obtaining a reaction product after the reaction is finished; immobilizing the triethylamine on MOFs to form a triethylamine immobilized catalyst; the immobilized catalyst also comprises boron trifluoride, the MOFs adopted are amino-functionalized MOFs, and triethylamine and boron trifluoride are grafted to the surface of the MOFs through amino functional groups to form the triethylamine-boron trifluoride immobilized catalyst; the preparation method of the triethylamine-boron trifluoride immobilized catalyst comprises the following steps: after alkali treatment is carried out on amino-functionalized MOFs, adding an ethanol solution of triethylamine into the amino-functionalized MOFs, adsorbing for a period of time, removing unbound triethylamine, adding the ethanol solution of boron trifluoride into the MOFs loaded with the triethylamine by the same method, adsorbing for a period of time, and removing unbound boron trifluoride to obtain a triethylamine-boron trifluoride immobilized catalyst;
Dissolving the amino-functionalized MOFs in DMF and HCl solution through a 2-amino terephthalic acid organic ligand and zirconium tetrachloride coordination metal salt, stirring and radiating, cooling to room temperature, filtering and separating a solid product, washing with DMF, washing with deionized water, washing with absolute ethyl alcohol, and drying to obtain the amino-functionalized MOFs;
S3, purifying a product: extracting, crystallizing and filtering the reaction product obtained in the step S2 to obtain a product ceftiofur sodium; wherein, sodium isooctanoate acetone solution is added for crystallization.
2. The method for synthesizing ceftiofur sodium according to claim 1, wherein in the step S1, the organic solvent used for suspension is acetonitrile, and the acyl chloride reagent is thionyl chloride.
3. The method for synthesizing ceftiofur sodium according to claim 2, wherein the amitioxime hydrochloride is suspended in acetonitrile as an organic solvent, thionyl chloride is added for low-temperature reaction, and reduced pressure distillation is performed after the reaction is finished to remove residual acyl chloride reagent and organic solvent.
4. The method for synthesizing ceftiofur sodium according to claim 1, wherein the organic solvent added in the step S2 is dichloromethane, and the synthesis reaction of ceftiofur sodium is performed under the protection of nitrogen.
5. The method for synthesizing ceftiofur sodium according to claim 1, wherein in the step S3, water is added to the reaction product to extract the reaction product into a water phase, acetone is added to the water phase to adjust the pH to 3.0-3.5, sodium chloride is added to carry out layering, acetone is then added, an acetone solution of sodium iso-octoate is added dropwise to carry out crystallization, acetone is used for leaching after filtration, and ventilation and air drying are carried out, so that the final product ceftiofur sodium is obtained.
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CN105061470A (en) * 2015-08-18 2015-11-18 齐鲁安替（临邑）制药有限公司 One-pot synthesis method of cefotaxime acid
CN116535421A (en) * 2023-07-04 2023-08-04 齐鲁晟华制药有限公司 Synthesis method of ceftiofur sodium

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US6476220B2 (en) * 2000-11-27 2002-11-05 Aurobindo Pharma Limited Process for the preparation of furaca
US20030135041A1 (en) * 2002-01-04 2003-07-17 Orchid Chemicals & Pharmaceuticals Limited, India Synthesis of ceftiofur intermediate
CN107056816B (en) * 2017-04-26 2019-11-15 齐鲁动物保健品有限公司 A kind of method for crystallising of ceftiofur sodium

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105061470A (en) * 2015-08-18 2015-11-18 齐鲁安替（临邑）制药有限公司 One-pot synthesis method of cefotaxime acid
CN116535421A (en) * 2023-07-04 2023-08-04 齐鲁晟华制药有限公司 Synthesis method of ceftiofur sodium

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