Synthesis method of cefminox

Abstract

The invention discloses a synthesis method of cefminox, and belongs to the technical field of pharmaceutical chemical synthesis. Comprising the following steps: dispersing 7 [beta]-amino-7 [alpha]-methoxy-3-[(1-methyl-1H-5-tetrazolyl)-mercaptomethyl]-3-cephem-4-carboxylic acid diphenyl methyl ester in deionized water, and then adding hydrochloric acid for hydrolysis to obtain a compound I; mixing and activating halogenated acid and a carboxyl activator to obtain a pre-activated solution; mixing and stirring the compound I and a pre-activation solution to react to obtain a compound II; d-cysteine hydrochloride and a compound II are mixed and dispersed in purified water to form a mixed solution, and the mixed solution is catalyzed by alkali liquor and then subjected to acid treatment to obtain the cefminox. The preparation method comprises the following steps: taking 7beta-amino-7alpha-methoxy-3-[(1-methyl-1H-5-tetrazolyl)-mercaptomethyl]-3-cephem-4-carboxylic acid diphenyl methyl ester and halogenated acid as initial raw materials for synthesis, carrying out amidation reaction and nucleophilic substitution reaction, and finally, carrying out acid regulation to obtain the cefminox.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and particularly relates to a method for synthesizing cefuroxime. Background Art

[0002] Cefminox, Chinese name is (6R,7S)-7-{(S)-2-[(2-amino-2-carboxyethylthio]-acetylamino}-7-methoxy-3-{(1-methyl-1H-tetrazolyl-5-yl)-thiol}-methyl-8-oxo-5-sulfur-1-azabicyclo[4.2.0]octane-2-carboxylic acid, English name is Cefminx, molecular formula is C 16 H 21 N7O7S3 is a broad-spectrum antibiotic agent with the advantages of multiple antibacterial species and strong sterilization ability. The drug is mainly used in the treatment of respiratory tract infections, urinary tract infections, biliary tract infections and sepsis, and has achieved good results. Cefuroxime is a prodrug of cefuroxime sodium (i.e., the carboxyl group on the cefuroxime nucleus is adjusted to pH by adding alkali to form sodium salt to obtain cefuroxime sodium). Cefuroxime sodium is mainly used clinically because it has good water solubility, bioavailability, stability and fewer side effects. Cefuroxime can inhibit the synthesis of bacterial cell walls and bind to peptidoglycans, inhibiting the binding of peptidoglycans to lipoproteins and promoting the dissolution of bacteria. It shows strong bactericidal activity in a short time and has strong activity against Gram-positive and Gram-negative bacteria, with strong and rapid bactericidal power. It has strong activity against Escherichia coli, Klebsiella pneumoniae, Haemophilus influenzae, Serratia, Salmonella enteritidis, Proteus and Bacteroides fragilis, which is stronger than other similar drugs and is stable to β-lactamases produced by various bacteria.

[0003] The existing synthesis methods of cefuroxime mainly include: (1) using 7β-amino-7α-methoxy-3-[(1-methyl-1H-5-tetrazolyl)-mercaptomethyl]-3-cephem-4-carboxylic acid diphenylmethyl ester (referred to as 7-MAC) as the starting material, introducing bromoacetyl bromide into 7-MAC through acylation reaction between the amino group on 7-MAC and the acyl bromide on bromoacetyl bromide, then removing the carboxyl protecting group on 7-MAC, and then using the remaining bromine atom to react with the thiol group on D-cysteine ​​hydrochloride to undergo nucleophilic substitution reaction to obtain cefuroxime; (2) using the parent nucleus 3-acetoxymethyl-5-sulfur-7-amino-8-oxo-1-azabicyclooct-2-ene-2-carboxylic acid (referred to as 7-ACA) as the starting material, through hydrolysis condensation, then acylation with bromoacetyl bromide, and finally reacting with the thiol group on D-cysteine ​​hydrochloride to undergo nucleophilic substitution reaction to obtain cefuroxime.

[0004] Patent CN101696214A discloses a new route for preparing a cefuroxime sodium compound. The invention uses 7-MAC as a raw material, condenses it with bromoacetyl bromide, and hydrolyzes it to prepare 7β-bromoacetylamino-7α-methoxy-3-(1-methyl-1H-tetrazolyl-5-mercaptomethyl)-3-cephem-4-carboxylic acid, which is then substituted and condensed with D-cysteine ​​hydrochloride, and the pH value is adjusted to obtain cefuroxime sodium.

[0005] Patent CN104031070A discloses a method for synthesizing cefuroxime sodium. The invention uses cefuroxime mother nucleus 7-AMCA as a starting material, acylates it with bromoacetyl bromide, and then undergoes a decarboxylation protection reaction, followed by substitution and condensation with D-cysteine ​​hydrochloride, and finally obtains cefuroxime sodium by adjusting the pH.

[0006] Patent CN108623618A discloses a method for synthesizing cefuroxime sodium. The invention firstly reacts 7β-amino-7α-methoxy-3-[(1-methyl-1H-5-tetrazolyl)-mercaptomethyl]-3-cephem-4-carboxylic acid diphenylmethyl ester, dichloromethane and bromoacetyl bromide under certain conditions to obtain 7β-bromoacetylamino-7α-methoxy-3-[(1-methyl-1H-5-tetrazolyl)-mercaptomethyl]-3-cephem-4-carboxylic acid diphenylmethyl ester, and then removes the carboxylic acid protecting group to obtain 7β-bromoacetylamino-7α-methoxy-3-[(1-methyl-1H-5-tetrazolyl)-mercaptomethyl]-3-cephem-4-carboxylic acid, which is then reacted with D-cysteine ​​hydrochloride to obtain cefuroxime sodium.

[0007] The most critical core step of the above-mentioned synthesis method is that bromoacetyl bromide is acylated with the amino group on 7-MAC or cefminox parent nucleus 7-AMCA by the bromine atom on the acyl halide structure and then bromoacetyl bromide is introduced into the parent nucleus structure, and then the remaining bromine atom is condensed with the sulfhydryl group on D-cysteine ​​hydrochloride, and cefminox sodium is obtained by post-treatment. However, the bromine atom far away from the acyl halide bond on bromoacetyl bromide is easy to react with the tetrazole ring on the parent nucleus structure or replace the amino group on 7-MAC or cefminox parent nucleus 7-AMCA to cause side reactions, and the price of 7-MAC or cefminox parent nucleus 7-AMCA itself is relatively expensive, and too many side reactions not only affect the yield of the product, but also have a greater impact on production cost, so the acid binding agent and reaction temperature required for the reaction need to be more strictly controlled to reduce the occurrence of side reactions, and this control means often requires the coordination of various conditions such as precise production equipment, which is relatively complicated and is not conducive to actual production.

[0008] Therefore, developing a new synthesis method of cefuroxime is of great significance for expanding the synthesis means of cefuroxime and reducing production costs. Summary of the invention

[0009] In view of the deficiencies of the prior art, the present invention uses 7β-amino-7α-methoxy-3-[(1-methyl-1H-5-tetrazolyl)-mercaptomethyl]-3-cephem-4-carboxylic acid diphenylmethyl ester and halogenated acid as synthetic starting materials, and obtains cefminox through amidation reaction and nucleophilic substitution reaction, and finally acid adjustment, thereby solving the technical problems raised in the background technology. Specifically, the technical solution of the present invention includes the following contents: A method for synthesizing cefuroxime, comprising the following steps: 7β-amino-7α-methoxy-3-[(1-methyl-1H-5-tetrazolyl)-mercaptomethyl]-3-cephem-4-carboxylic acid diphenylmethyl ester is dispersed in deionized water, and then hydrochloric acid is added to hydrolyze to obtain compound I; The halogenated acid and the carboxyl activator are mixed and activated for 20 min to 30 min to obtain a pre-activated solution; The compound I and the pre-activated liquid are mixed and stirred to react to obtain compound II; D-cysteine ​​hydrochloride and the compound II are mixed and dispersed in purified water to form a mixed solution, and the mixed solution is catalyzed by alkaline solution and then treated with acid to obtain the cefuroxime.

[0010] Furthermore, the mass concentration of the hydrochloric acid is 10% to 20%.

[0011] Furthermore, the mass ratio of 7β-amino-7α-methoxy-3-[(1-methyl-1H-5-tetrazolyl)-mercaptomethyl]-3-cephem-4-carboxylic acid diphenylmethyl ester: hydrochloric acid: deionized water is 1:2~3:10~15.

[0012] Furthermore, the conditions for the hydrochloric acid hydrolysis include a temperature of 40°C to 50°C and a reaction time of 50min to 70min.

[0013] Furthermore, the halogenated acid includes bromoacetic acid or chloroacetic acid.

[0014] Furthermore, the carboxyl activator is composed of equal amounts of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and N-hydroxysuccinimide.

[0015] Furthermore, the mass ratio of the halogenated acid: carboxyl activator: compound I is 1:3~4:3~4.

[0016] Furthermore, the conditions for the mixed stirring reaction of the compound I and the pre-activation solution include a reaction temperature of 20° C. to 25° C., a reaction time of 15 h to 20 h, and a reaction pH of 5.0 to 5.5.

[0017] Furthermore, the mass ratio of the D-cysteine ​​hydrochloride to the compound II is 3-4:2.5-3.

[0018] Furthermore, the alkali solution includes sodium hydroxide solution or potassium hydroxide solution.

[0019] Furthermore, the conditions for the alkali solution catalysis of the mixed solution include pH 8.0-8.5, reaction temperature 30° C.-40° C. and reaction time 2h-3h.

[0020] Furthermore, the acid reagent for the acid treatment includes a hydrochloric acid solution.

[0021] Furthermore, the pH of the acid treatment is 4.5-5.0.

[0022] Furthermore, the circuit diagram of the synthesis method is as follows:

[0023] Compared with the prior art, the present invention has the following beneficial effects: The invention uses 7β-amino-7α-methoxy-3-[(1-methyl-1H-5-tetrazolyl)-mercaptomethyl]-3-cephem-4-carboxylic acid diphenylmethyl ester and halogenated acid as synthesis starting materials, and innovatively designs a novel synthesis method of cefminox. In the method of the invention, a carboxyl protective agent of 7β-amino-7α-methoxy-3-[(1-methyl-1H-5-tetrazolyl)-mercaptomethyl]-3-cephem-4-carboxylic acid diphenylmethyl ester is removed in advance to obtain compound I. The purpose of pre-hydrolyzing and removing the carboxyl protective agent is that the acidic environment of acid hydrolysis is strong and the treatment time is long. If the decarboxylation treatment is carried out at the end, the amide bond generated by the amidation reaction is easily hydrolyzed. The carboxyl group of the halogenated acid is activated in advance by 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and N-hydroxysuccinimide, and then the amidation condensation reaction of the amino group and the carboxyl group is carried out with compound I to obtain compound II, and compound II is then subjected to nucleophilic substitution with D-cysteine ​​hydrochloride by base catalysis, and then acid is adjusted and de-alkalized to obtain cefminox. Compared with the prior art in which bromoacetyl bromide is introduced into the mother core structure by acylation of the bromine atom on the acyl halide structure with the amino group on 7-MAC or the cefminox mother core 7-AMCA, the bromine atom on the acyl halide structure can be avoided from being substituted with the nitrogen-containing structure such as the tetrazole ring on 7-MAC or the cefminox mother core 7-AMCA to produce side reactions, the amidation reaction conditions of the present invention are mild and easy to create, and the halogenated acid (bromoacetic acid or chloroacetic acid) used in the present invention has a lower price advantage in production cost compared with bromoacetyl bromide. DETAILED DESCRIPTION

[0024] The technical solution of the present invention will be clearly and completely described below through the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative work are within the scope of protection of the present invention.

[0025] Unless otherwise specified, the raw materials and reagents used in the present invention are commercially available or can be prepared by known methods.

[0026] Embodiment 1: A method for synthesizing cefuroxime, specifically comprising the following steps: Weigh 10g of 7β-amino-7α-methoxy-3-[(1-methyl-1H-5-tetrazolyl)-mercaptomethyl]-3-cephem-4-carboxylic acid diphenylmethyl ester and add it to 100g of deionized water, and then disperse it for 60s under 100W ultrasonic power to form a mixed solution. Add 20g of 10% hydrochloric acid solution to the mixed solution and mix and stir evenly, then place it in a water bath at 40°C and heat to hydrolyze for 50min. After the hydrolysis treatment is completed, add sodium hydroxide solution to the hydrolyzate and stir to adjust the pH to 8.0~8.5, then add ethyl acetate to mix, extract, separate and collect the aqueous phase. Add salt solution to the aqueous phase and stir to adjust the pH to 3~3.5, then let it stand for 10min, and then extract with ethyl acetate to obtain an organic phase, rinse the organic phase with deionized water until the rinse wastewater is neutral, then evaporate under reduced pressure to remove ethyl acetate and dry to obtain compound I; Weigh 1g of bromoacetic acid, 1.5g of 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride and 1.5g of N-hydroxysuccinimide and add them to anhydrous dimethyl sulfoxide, then place them in a temperature environment of 25°C and stir for activation for 20 minutes to obtain a pre-activated solution. After the activation treatment is completed, take 3g of compound I and add it to the pre-activated solution and mix and stir, then add phosphate buffer to adjust the pH to 5.0~5.5, and then place it in a water bath environment of 20°C~25°C for a timed reaction of 15h. After the reaction is completed, place the reaction solution in a dialysis bag with a molecular weight cutoff of 300Da for dialysis treatment to collect the dialysate, and then dry the dialysate to obtain compound II; 3 g of D-cysteine ​​hydrochloride and 2.5 g of compound II were weighed and added to 30 g of purified water, and dispersed for 60 seconds under 100 W ultrasonic power to form a mixed solution. Sodium hydroxide solution was added to the mixed solution to adjust the pH to 8.0-8.5, and then heated to 30° C. for 2 hours. After the reaction was completed, it was cooled to room temperature, and then hydrochloric acid was added to adjust the pH to 4.5-5.0, and ethyl acetate was added for mixed extraction to obtain an organic phase. The organic phase was rinsed with deionized water until the pH of the rinse wastewater was neutral, and then the organic phase was dried with a desiccant to remove moisture, and then ethyl acetate was removed by reduced pressure distillation, and then freeze-dried to obtain cefuroxime, which was weighed by an electronic balance to be 2.37 g, and the yield was calculated to be 87.45% based on 2.5 g of compound II as a standard.

[0027] Embodiment 2: A method for synthesizing cefuroxime, specifically comprising the following steps: Weigh 10g of 7β-amino-7α-methoxy-3-[(1-methyl-1H-5-tetrazolyl)-mercaptomethyl]-3-cephem-4-carboxylic acid diphenylmethyl ester and add it to 110g of deionized water, and then disperse it under 100W ultrasonic power for 70s to form a mixed solution. Add 22g of 10% hydrochloric acid solution to the mixed solution and mix and stir evenly, then place it in a water bath at 40°C and heat to hydrolyze for 50min. After the hydrolysis treatment is completed, add sodium hydroxide solution to the hydrolyzate and stir to adjust the pH to 8.0~8.5, then add ethyl acetate to mix, extract, separate and collect the aqueous phase. Add salt solution to the aqueous phase and stir to adjust the pH to 3~3.5, then let it stand for 10min, and then extract with ethyl acetate to obtain an organic phase, rinse the organic phase with deionized water until the rinse wastewater is neutral, then evaporate under reduced pressure to remove ethyl acetate and dry to obtain compound I; Weigh 1g of bromoacetic acid, 1.5g of 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride and 1.5g of N-hydroxysuccinimide and add them to anhydrous dimethyl sulfoxide, then place in a temperature environment of 25°C and stir for activation for 20 minutes to obtain a pre-activated solution. After the activation treatment is completed, take 3.2g of compound I and add it to the pre-activated solution and mix and stir, then add phosphate buffer to adjust the pH to 5.0~5.5, and then place it in a water bath environment of 20°C~25°C for a timed reaction of 16h. After the reaction is completed, place the reaction solution in a dialysis bag with a molecular weight cutoff of 300Da for dialysis treatment to collect the dialysate, and then dry the dialysate to obtain compound II; 3.2 g of D-cysteine ​​hydrochloride and 2.6 g of compound II were weighed and added to 30 g of purified water, and dispersed for 70 seconds under 100 W ultrasonic power to form a mixed solution. Sodium hydroxide solution was added to the mixed solution to adjust the pH to 8.0-8.5, and then heated to 30 ° C for 2 hours. After the reaction was completed, it was cooled to room temperature, and then hydrochloric acid was added to adjust the pH to 4.5-5.0, and ethyl acetate was added for mixed extraction to obtain an organic phase. The organic phase was rinsed with deionized water until the pH of the rinse wastewater was neutral, and then the organic phase was dried with a desiccant to remove moisture, and then ethyl acetate was removed by reduced pressure distillation, and then freeze-dried to obtain cefuroxime, which was weighed by an electronic balance to be 2.53 g, and the yield was calculated to be 89.77% based on 2.6 g of compound II as a standard.

[0028] Embodiment 3: A method for synthesizing cefuroxime, specifically comprising the following steps: Weigh 10g of 7β-amino-7α-methoxy-3-[(1-methyl-1H-5-tetrazolyl)-mercaptomethyl]-3-cephem-4-carboxylic acid diphenylmethyl ester and add it to 120g of deionized water, and then disperse it for 80s under 100W ultrasonic power to form a mixed solution. Add 24g of 10% hydrochloric acid solution to the mixed solution and mix and stir evenly, then place it in a water bath at 45°C and heat to hydrolyze for 60min. After the hydrolysis treatment is completed, add sodium hydroxide solution to the hydrolyzate and stir to adjust the pH to 8.0~8.5, then add ethyl acetate to mix, extract, separate and collect the aqueous phase. Add salt solution to the aqueous phase and stir to adjust the pH to 3~3.5, then let it stand for 10min, and then extract with ethyl acetate to obtain an organic phase, rinse the organic phase with deionized water until the rinse wastewater is neutral, then evaporate under reduced pressure to remove ethyl acetate and dry to obtain compound I; Weigh 1g of bromoacetic acid, 1.75g ​​of 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride and 1.75g ​​of N-hydroxysuccinimide and add them to anhydrous dimethyl sulfoxide, then place in a temperature environment of 25°C and stir for activation for 25 minutes to obtain a pre-activated solution. After the activation treatment is completed, take 3.4g of compound I and add it to the pre-activated solution and mix and stir, then add phosphate buffer to adjust the pH to 5.0~5.5, and then place it in a water bath environment of 20°C~25°C for a timed reaction of 17h. After the reaction is completed, place the reaction solution in a dialysis bag with a molecular weight cutoff of 300Da for dialysis treatment to collect the dialysate, and then dry the dialysate to obtain compound II; 3.4 g of D-cysteine ​​hydrochloride and 2.7 g of compound II were weighed and added to 35 g of purified water, and dispersed for 80 seconds under 100 W ultrasonic power to form a mixed solution. Sodium hydroxide solution was added to the mixed solution to adjust the pH to 8.0-8.5, and then heated to 35 ° C for 2.5 hours. After the reaction was completed, it was cooled to room temperature, and then hydrochloric acid was added to adjust the pH to 4.5-5.0, and ethyl acetate was added for mixed extraction to obtain an organic phase. The organic phase was rinsed with deionized water until the pH of the rinse wastewater was neutral, and then the organic phase was dried with a desiccant to remove moisture, and then ethyl acetate was removed by reduced pressure distillation, and then freeze-dried to obtain cefuroxime, which was weighed by an electronic balance to be 2.66 g, and the yield was calculated to be 90.78% based on 2.7 g of compound II as a standard.

[0029] Embodiment 4: A method for synthesizing cefuroxime, specifically comprising the following steps: Weigh 10g of 7β-amino-7α-methoxy-3-[(1-methyl-1H-5-tetrazolyl)-mercaptomethyl]-3-cephem-4-carboxylic acid diphenylmethyl ester and add it to 130g of deionized water, and then disperse it under 150W ultrasonic power for 90s to form a mixed solution. Add 26g of 20% hydrochloric acid solution to the mixed solution and mix and stir evenly, then place it in a water bath at 45°C and heat to hydrolyze for 60min. After the hydrolysis treatment is completed, add sodium hydroxide solution to the hydrolyzate and stir to adjust the pH to 8.0~8.5, then add ethyl acetate to mix, extract, separate and collect the aqueous phase. Add salt solution to the aqueous phase and stir to adjust the pH to 3~3.5, then let it stand for 20min, and then extract with ethyl acetate to obtain an organic phase, rinse the organic phase with deionized water until the rinse wastewater is neutral, then evaporate under reduced pressure to remove ethyl acetate and dry to obtain compound I; Weigh 1g of chloroacetic acid, 1.75g ​​of 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride and 1.75g ​​of N-hydroxysuccinimide and add them to anhydrous dimethyl sulfoxide, then place in a temperature environment of 25°C and stir for activation for 25 minutes to obtain a pre-activated solution. After the activation treatment is completed, take 3.6g of compound I and add it to the pre-activated solution and mix and stir, then add phosphate buffer to adjust the pH to 5.0~5.5, and then place it in a water bath environment of 20°C~25°C for a timed reaction of 18h. After the reaction is completed, place the reaction solution in a dialysis bag with a molecular weight cutoff of 300Da for dialysis treatment to collect the dialysate, and then dry the dialysate to obtain compound II; 3.6 g of D-cysteine ​​hydrochloride and 2.8 g of compound II were weighed and added to 35 g of purified water, and dispersed for 90 seconds by ultrasonic power treatment of 150 W to form a mixed solution, and potassium hydroxide solution was added to the mixed solution to adjust the pH to 8.0-8.5, and then heated to 35 ° C for 2.5 hours. After the reaction was completed, it was cooled to room temperature, and then hydrochloric acid was added to adjust the pH to 4.5-5.0, and ethyl acetate was added for mixed extraction to obtain an organic phase, and the organic phase was rinsed with deionized water until the pH of the rinse wastewater was neutral, and then the organic phase was dried with a desiccant to remove moisture, and then ethyl acetate was removed by vacuum distillation, and then freeze-dried to obtain cefuroxime, which was weighed by an electronic balance to be 3.05 g, and the yield was calculated to be 91.04% based on 2.8 g of compound II as a standard.

[0030] Embodiment 5: A method for synthesizing cefuroxime, specifically comprising the following steps: Weigh 10g of 7β-amino-7α-methoxy-3-[(1-methyl-1H-5-tetrazolyl)-mercaptomethyl]-3-cephem-4-carboxylic acid diphenylmethyl ester and add it to 140g of deionized water, and then disperse it for 100s under 150W ultrasonic power to form a mixed solution. Add 28g of 20% hydrochloric acid solution to the mixed solution and mix and stir evenly, then place it in a 50℃ water bath and heat to hydrolyze for 70min. After the hydrolysis treatment is completed, add sodium hydroxide solution to the hydrolyzate and stir to adjust the pH to 8.0~8.5, then add ethyl acetate to mix, extract, separate and collect the aqueous phase. Add salt solution to the aqueous phase and stir to adjust the pH to 3~3.5, then let it stand for 20min, and then extract with ethyl acetate to obtain an organic phase, rinse the organic phase with deionized water until the rinse wastewater is neutral, then evaporate under reduced pressure to remove ethyl acetate and dry to obtain compound I; Weigh 1g of chloroacetic acid, 2g of 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride and 2g of N-hydroxysuccinimide and add them to anhydrous dimethyl sulfoxide, then place in a temperature environment of 25°C and stir for activation for 30min to obtain a pre-activated solution. After the activation treatment is completed, take 3.8g of compound I and add it to the pre-activated solution and mix and stir, then add phosphate buffer to adjust the pH to 5.0~5.5, and then place it in a water bath environment of 20°C~25°C for a timed reaction of 19h. After the reaction is completed, place the reaction solution in a dialysis bag with a molecular weight cutoff of 300Da for dialysis treatment to collect the dialysate, and then dry the dialysate to obtain compound II; 3.8 g of D-cysteine ​​hydrochloride and 2.9 g of compound II were weighed and added to 40 g of purified water, and dispersed for 100 s by ultrasonic power treatment of 150 W to form a mixed solution, potassium hydroxide solution was added to the mixed solution to adjust the pH to 8.0-8.5, and then heated to 40 ° C for 3 h. After the reaction was completed, it was cooled to room temperature, and then hydrochloric acid was added to adjust the pH to 4.5-5.0, and ethyl acetate was added for mixed extraction to obtain an organic phase, and the organic phase was rinsed with deionized water until the pH of the rinse wastewater was neutral, and then the organic phase was dried with a desiccant to remove moisture, and then ethyl acetate was removed by vacuum distillation, and then freeze-dried to obtain cefuroxime, which was weighed by an electronic balance to be 3.17 g, and the yield was calculated to be 91.35% based on 2.9 g of compound II as a standard.

[0031] Embodiment 6: A method for synthesizing cefuroxime, specifically comprising the following steps: Weigh 10g of 7β-amino-7α-methoxy-3-[(1-methyl-1H-5-tetrazolyl)-mercaptomethyl]-3-cephem-4-carboxylic acid diphenylmethyl ester and add it to 150g of deionized water, and then disperse it for 110s under 150W ultrasonic power to form a mixed solution. Add 30g of 20% hydrochloric acid solution to the mixed solution and mix and stir evenly, then place it in a 50℃ water bath and heat to hydrolyze for 70min. After the hydrolysis treatment is completed, add sodium hydroxide solution to the hydrolyzate and stir to adjust the pH to 8.0~8.5, then add ethyl acetate to mix, extract, separate and collect the aqueous phase. Add salt solution to the aqueous phase and stir to adjust the pH to 3~3.5, then let it stand for 20min, and then extract with ethyl acetate to obtain an organic phase, rinse the organic phase with deionized water until the rinse wastewater is neutral, then evaporate under reduced pressure to remove ethyl acetate and dry to obtain compound I; Weigh 1g of chloroacetic acid, 2g of 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride and 2g of N-hydroxysuccinimide and add them to anhydrous dimethyl sulfoxide, then place in a temperature environment of 25°C and stir for activation for 30 minutes to obtain a pre-activated solution. After the activation treatment is completed, take 4g of compound I and add it to the pre-activated solution and mix and stir, then add phosphate buffer to adjust the pH to 5.0~5.5, and then place it in a water bath environment of 20°C~25°C for a timed reaction of 20h. After the reaction is completed, place the reaction solution in a dialysis bag with a molecular weight cutoff of 300Da for dialysis treatment to collect the dialysate, and then dry the dialysate to obtain compound II; 4 g of D-cysteine ​​hydrochloride and 3 g of compound II were weighed and added to 40 g of purified water, and dispersed for 110 seconds under an ultrasonic power of 150 W to form a mixed solution. Potassium hydroxide solution was added to the mixed solution to adjust the pH to 8.0-8.5, and then heated to 40° C. for reaction for 3 hours. After the reaction was completed, it was cooled to room temperature, and then hydrochloric acid was added to adjust the pH to 4.5-5.0, and ethyl acetate was added for mixed extraction to obtain an organic phase. The organic phase was rinsed with deionized water until the pH of the rinse wastewater was neutral, and then the organic phase was dried with a desiccant to remove moisture, and then ethyl acetate was removed by vacuum distillation, and then lyophilized to obtain cefuroxime, which was weighed by an electronic balance to be 3.29 g, and the yield was calculated to be 91.64% based on 3 g of compound II as a standard.

[0032] The above-described embodiments provide a detailed description of the technical solutions and beneficial effects of the present invention. It should be understood that the above description is only a specific embodiment of the present invention and is not intended to limit the present invention. Without departing from the spirit and scope of the present invention, the present invention may have various changes and improvements, which fall within the scope of the present invention to be protected.

Claims

1. A method for synthesizing cefuroxime, characterized in that: The synthesis method comprises the following steps: 7β-amino-7α-methoxy-3-[(1-methyl-1H-5-tetrazolyl)-mercaptomethyl]-3-cephem-4-carboxylic acid diphenylmethyl ester is dispersed in deionized water, and then hydrochloric acid is added to hydrolyze to obtain compound I; The halogenated acid and the carboxyl activator are mixed and activated for 20 min to 30 min to obtain a pre-activated solution; The compound I and the pre-activated liquid are mixed and stirred to react to obtain compound II; D-cysteine ​​hydrochloride and the compound II are mixed and dispersed in purified water to form a mixed solution, and the mixed solution is catalyzed by alkaline solution and then treated with acid to obtain the cefuroxime.

2. A method for synthesizing cefuroxime according to claim 1, characterized in that, The mass concentration of the hydrochloric acid is 10% to 20%.

3. A method for synthesizing cefuroxime according to claim 1, characterized in that, The mass ratio of the diphenylmethyl 7β-amino-7α-methoxy-3-[(1-methyl-1H-5-tetrazolyl)-mercaptomethyl]-3-cephem-4-carboxylate: hydrochloric acid: deionized water is 1:2-3:10-15.

4. A method for synthesizing cefuroxime according to claim 1, characterized in that, The conditions of the hydrochloric acid hydrolysis include a temperature of 40° C. to 50° C. and a reaction time of 50 min to 70 min.

5. A method for synthesizing cefuroxime according to claim 1, characterized in that, The halogenated acid includes bromoacetic acid or chloroacetic acid.

6. A method for synthesizing cefuroxime according to claim 1, characterized in that, The mass ratio of the halogenated acid: carboxyl activator: compound I is 1:3-4:3-4.

7. A method for synthesizing cefuroxime according to claim 1, characterized in that: The conditions for the mixed stirring reaction of the compound I and the pre-activation solution include a reaction temperature of 20° C. to 25° C., a reaction time of 15 h to 20 h, and a reaction pH of 5.0 to 5.

5.

8. A method for synthesizing cefuroxime according to claim 1, characterized in that, The mass ratio of D-cysteine ​​hydrochloride to compound II is 3-4:2.5-3.

9. A method for synthesizing cefuroxime according to claim 1, characterized in that: The conditions for the mixed solution alkali catalysis include pH 8.0-8.5, reaction temperature 30° C.-40° C. and reaction time 2 h-3 h.

10. A method for synthesizing cefuroxime according to claim 1, characterized in that: The pH of the acid treatment is 4.5-5.0.

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