Preparation method of ceftaroline fosamil

Abstract

The invention belongs to the technical field of organic synthesis, and provides a preparation method of ceftaroline fosamil. In the preparation process of the 7 beta-phenylacetamido-3-methylsulfonyloxy-3-cephem-4-carboxylic acid diphenyl methyl ester, glacial acetic acid, cyclohexane and water are adopted to replace traditional ethyl acetate crystals, so that the weight yield of the product can be increased; in the preparation process of the 7beta-amino-3-[4-(1-methyl-4-pyridyl)-1, 3-thiazole-2-yl] sulfydryl-3-cephem-4-carboxylic acid hydrochloride, ethyl acetate in a traditional process is replaced with acetone, so that the conversion rate of chloride can be increased, and the weight yield of the product is increased from about 69.4% to 80% or above. Data of the embodiment shows that in the preparation method provided by the invention, the total weight yield of the ceftaroline fosamil is 61% and is higher than 38.5% reported in the literature.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a method for preparing cefuroxime fosamil. Background Art

[0002] Ceftaroline fosamil (PPI-0903, TAK-599, trade name Teflaro®) is the first cephalosporin antibiotic approved by the US FDA for use against MRSA infection. It is also the first cephalosporin antibiotic approved in Europe for use against MRSA infection. It is also a derivative of the fourth-generation cephalosporin cefazolin. As a water-soluble N-phosphonamido prodrug of ceftaroline (PPI-0903M, T-91825), the drug is rapidly hydrolyzed into a biologically active compound, ceftaroline, by phosphatases in the blood after entering the body. It has been reported that ceftaroline fosamil is classified as a "fifth-generation" cephalosporin, which has a good therapeutic effect on resistant Gram-positive and Gram-negative bacteria, providing a new option for the clinical treatment of multidrug-resistant bacterial infections.

[0003] In the prior art, the method for preparing cefuroxime fosamil has the problem of low weight yield, which is only 38.5%. Summary of the invention

[0004] In view of this, an object of the present invention is to provide a method for preparing cefuroxime fosamil, and the preparation method provided by the present invention has a high weight yield.

[0005] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions: The present invention provides a method for preparing cefuroxime fosamil, comprising the following steps: Mixing 3-hydroxycephalosporin, methanesulfonyl chloride, ethyl acetate and N,N-diisopropylethylamine, and sequentially performing a first reaction and a first crystallization to obtain 7β-phenylacetylamino-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester, wherein the reagents for the first crystallization include glacial acetic acid, cyclohexane and water, and the volume ratio of the glacial acetic acid, cyclohexane and water is 7.5:100:100; Mixing 2-mercapto-4-(4-pyridyl)thiazole, sodium methoxide and acetone, and performing a second reaction to obtain a sodium 4-(4-pyridyl)thiazole-2-thiolate solution; The sodium 4-(4-pyridyl)thiazole-2-thiolate solution and the acetone solution of 7β-phenylacetylamino-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester are mixed, and a third reaction and a second crystallization are sequentially performed to obtain 7β-phenylacetylamino-3-[4-(4-pyridyl)-1,3-thiazol-2-yl]sulfhydryl-3-cephem-4-carboxylic acid diphenylmethyl ester, wherein the reagent of the second crystallization comprises glacial acetic acid and water, and the amount ratio of the glacial acetic acid to water is 10 g:100 mL; The 7β-phenylacetylamino-3-[4-(4-pyridyl)-1,3-thiazol-2-yl]thiol-3-cephem-4-carboxylic acid diphenylmethyl ester, iodomethane and ethyl acetate are mixed, and a fourth reaction and a third crystallization are sequentially performed to obtain 7β-phenylacetylamino-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]thiol-3-cephem-4-carboxylic acid diphenylmethyl ester iodide, wherein the reagent for the third crystallization is water; The 7β-phenylacetamido-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl] mercapto-3-cephem-4-carboxylic acid diphenylmethyl ester iodide, phosphorus pentachloride, pyridine and dichloromethane are mixed, and a fifth reaction and a fourth crystallization are performed in sequence to obtain 7β-amino-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl] mercapto-3-cephem-4-carboxylic acid diphenylmethyl ester chloride, wherein the reagent for the fourth crystallization is isopropanol; The 7β-amino-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]mercapto-3-cephem-4-carboxylic acid diphenylmethyl ester chloride, concentrated hydrochloric acid and acetonitrile are mixed, and a sixth reaction and a fifth crystallization are performed in sequence to obtain 7β-amino-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]mercapto-3-cephem-4-carboxylic acid hydrochloride, wherein the reagent for the fifth crystallization is acetone; The 7β-amino-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]thiol-3-cephem-4-carboxylic acid hydrochloride, (Z)-2-(5-dichlorophosphoramido-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetyl chloride, water and triethylamine are mixed, and the seventh reaction and the sixth crystallization are carried out in sequence to obtain 3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]thiol-7β-[2-(5-phosphoramido-1,2,4-thiadiazol-3-yl)-2-(Z)-ethoxyiminoacetamido]-3-cephem-4-carboxylic acid disodium salt, the pH of the sixth crystallization is 5, and the reagent of the sixth crystallization is ethanol; The 3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]thiol-7β-[2-(5-phosphoamido-1,2,4-thiadiazol-3-yl)-2-(Z)-ethoxyiminoacetamido]-3-cephem-4-carboxylic acid disodium salt is sequentially hydrolyzed and subjected to a seventh crystallization to obtain the ceftaroline fosamil, wherein the pH value of the seventh crystallization is 1, and the reagent for the seventh crystallization is an acetic acid aqueous solution, and the volume concentration of the acetic acid aqueous solution is 50%.

[0006] Preferably, during the first reaction, the molar ratio of 3-hydroxycephalosporin to methanesulfonyl chloride is 1:1.4~1.5, the molar ratio of 3-hydroxycephalosporin to N,N-diisopropylethylamine is 1:1.7~2, and the dosage ratio of 3-hydroxycephalosporin to ethyl acetate is 200mmol:50~150mL; the temperature of the first reaction is 0~5°C, and the time is 1~2h.

[0007] Preferably, during the second reaction, the molar ratio of 2-mercapto-4-(4-pyridyl)thiazole and sodium methoxide is 1:0.8~1.25, and the dosage ratio of 2-mercapto-4-(4-pyridyl)thiazole and acetone is 396.3mmol:50~150mL; the temperature of the second reaction is 0~5°C, and the time is 1~2h.

[0008] Preferably, during the third reaction, the molar ratio of 7β-phenylacetylamino-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester to 2-mercapto-4-(4-pyridyl)thiazole is 1:2-2.5, the temperature of the third reaction is 0-5°C, and the time is 4-6h.

[0009] Preferably, during the fourth reaction, the molar ratio of the 7β-phenylacetylamino-3-[4-(4-pyridyl)-1,3-thiazol-2-yl]thiol-3-cephem-4-carboxylic acid diphenylmethyl ester and iodomethane is 1:1~1.2, and the amount ratio of the 7β-phenylacetylamino-3-[4-(4-pyridyl)-1,3-thiazol-2-yl]thiol-3-cephem-4-carboxylic acid diphenylmethyl ester and ethyl acetate is 148mmol:100~200mL; the temperature of the fourth reaction is 20~25°C, and the time is 3~5h.

[0010] Preferably, during the fifth reaction, the molar ratio of the 7β-phenylacetamido-3-[4-(1-methyl-4-pyridinyl)-1,3-thiazol-2-yl]thiol-3-cephem-4-carboxylic acid diphenylmethyl ester iodide, phosphorus pentachloride and pyridine is 1:5~5.5:6.5~7, the temperature of the fifth reaction is 0~5°C, and the time is 2~4h.

[0011] Preferably, during the sixth reaction, the mass fraction of the concentrated hydrochloric acid is 30-36%, the dosage ratio of the 7β-amino-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]mercapto-3-cephem-4-carboxylic acid diphenylmethyl ester chloride and concentrated hydrochloric acid is 122mmom:45-55mL, the temperature of the sixth reaction is 35-40°C, and the time is 4-6h.

[0012] Preferably, during the seventh reaction, the molar ratio of the 7β-amino-3-[4-(1-methyl-4-pyridinyl)-1,3-thiazol-2-yl]thio-3-cephem-4-carboxylic acid hydrochloride and (Z)-2-(5-dichlorophosphoramido-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetyl chloride is 1:1-1.1, the molar ratio of the β-amino-3-[4-(1-methyl-4-pyridinyl)-1,3-thiazol-2-yl]thio-3-cephem-4-carboxylic acid hydrochloride and triethylamine is 1:1-1.1, the temperature of the seventh reaction is 0-5°C, and the time is 2-3h.

[0013] Preferably, the hydrolysis reagents are water and acetic acid, and the volume ratio of water to acetic acid is 1.5:1.

[0014] Preferably, the hydrolysis temperature is 25-35° C. and the time is 0.5-1 h.

[0015] The invention provides a method for preparing cefuroxime fosamil.

[0016] The present invention adopts glacial acetic acid, cyclohexane and water to replace traditional ethyl acetate for crystallization in the preparation process of 7β-phenylacetylamino-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester, which can improve the weight yield of the product; at the same time, ethyl acetate is used to replace tetrahydrofuran as a reaction solvent in the preparation process of 7β-phenylacetylamino-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]thio-3-cephem-4-carboxylic acid diphenylmethyl ester iodide, which is easy to recover the solvent of the mother liquor and also reduces the use of toxic chemical raw materials. In the preparation process of 7β-amino-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]thio-3-cephem-4-carboxylic acid hydrochloride, acetone is used to replace ethyl acetate in the traditional process, which can improve the chloride conversion rate, and the weight yield of the product is increased from about 69.4% to more than 80%. The data in the examples show that in the preparation method provided by the present invention, the total weight yield of cefuroxime is 61%, which is higher than 38.5% reported in the literature.

[0017] Furthermore, the ceftaroline fosamil product obtained by the present invention has high purity (purity ≥ 98.5% or more) and few impurities (related substances < 1.5%). BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 The NMR spectrum of cefuroxime fosamil acetic acid hydrate obtained in Example 1 is shown in FIG. DETAILED DESCRIPTION

[0019] The present invention provides a method for preparing cefuroxime fosamil, comprising the following steps: Mixing 3-hydroxycephalosporin, methanesulfonyl chloride, ethyl acetate and N,N-diisopropylethylamine, and sequentially performing a first reaction and a first crystallization to obtain 7β-phenylacetylamino-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester, wherein the reagents for the first crystallization include glacial acetic acid, cyclohexane and water, and the volume ratio of the glacial acetic acid, cyclohexane and water is 7.5:100:100; Mixing 2-mercapto-4-(4-pyridyl)thiazole, sodium methoxide and acetone, and performing a second reaction to obtain a sodium 4-(4-pyridyl)thiazole-2-thiolate solution; The sodium 4-(4-pyridyl)thiazole-2-thiolate solution and the acetone solution of 7β-phenylacetylamino-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester are mixed, and a third reaction and a second crystallization are sequentially performed to obtain 7β-phenylacetylamino-3-[4-(4-pyridyl)-1,3-thiazol-2-yl]sulfhydryl-3-cephem-4-carboxylic acid diphenylmethyl ester, wherein the reagent of the second crystallization comprises glacial acetic acid and water, and the amount ratio of the glacial acetic acid to water is 10 g:100 mL; The 7β-phenylacetylamino-3-[4-(4-pyridyl)-1,3-thiazol-2-yl]thiol-3-cephem-4-carboxylic acid diphenylmethyl ester, iodomethane and ethyl acetate are mixed, and a fourth reaction and a third crystallization are sequentially performed to obtain 7β-phenylacetylamino-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]thiol-3-cephem-4-carboxylic acid diphenylmethyl ester iodide, wherein the reagent for the third crystallization is water; The 7β-phenylacetamido-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl] mercapto-3-cephem-4-carboxylic acid diphenylmethyl ester iodide, phosphorus pentachloride, pyridine and dichloromethane are mixed, and a fifth reaction and a fourth crystallization are performed in sequence to obtain 7β-amino-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl] mercapto-3-cephem-4-carboxylic acid diphenylmethyl ester chloride, wherein the reagent for the fourth crystallization is isopropanol; The 7β-amino-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]mercapto-3-cephem-4-carboxylic acid diphenylmethyl ester chloride, concentrated hydrochloric acid and acetonitrile are mixed, and a sixth reaction and a fifth crystallization are performed in sequence to obtain 7β-amino-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]mercapto-3-cephem-4-carboxylic acid hydrochloride, wherein the reagent for the fifth crystallization is acetone; The 7β-amino-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]thiol-3-cephem-4-carboxylic acid hydrochloride, (Z)-2-(5-dichlorophosphoramido-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetyl chloride, water and triethylamine are mixed, and the seventh reaction and the sixth crystallization are carried out in sequence to obtain 3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]thiol-7β-[2-(5-phosphoramido-1,2,4-thiadiazol-3-yl)-2-(Z)-ethoxyiminoacetamido]-3-cephem-4-carboxylic acid disodium salt, the pH of the sixth crystallization is 5, and the reagent of the sixth crystallization is ethanol; The 3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]thiol-7β-[2-(5-phosphoamido-1,2,4-thiadiazol-3-yl)-2-(Z)-ethoxyiminoacetamido]-3-cephem-4-carboxylic acid disodium salt is sequentially hydrolyzed and subjected to a seventh crystallization to obtain the ceftaroline fosamil, wherein the pH value of the seventh crystallization is 1, and the reagent for the seventh crystallization is an acetic acid aqueous solution, and the volume concentration of the acetic acid aqueous solution is 50%.

[0020] Unless otherwise specified, the raw materials used in the present invention are preferably commercially available products.

[0021] The invention mixes 3-hydroxycephalosporin, methanesulfonyl chloride, ethyl acetate and N,N-diisopropylethylamine, and sequentially performs a first reaction and a first crystallization to obtain 7β-phenylacetylamino-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester.

[0022] In the present invention, during the first reaction, the molar ratio of the 3-hydroxycephalosporin to methanesulfonyl chloride is preferably 1:1.4-1.5, and is particularly preferably 1:1.4, 1:1.415, 1:1.44 or 1:1.5. In the present invention, the molar ratio of the 3-hydroxycephalosporin to N,N-diisopropylethylamine is preferably 1:1.7-2, and is particularly preferably 1:1.7, 1:1.74, 1:1.8, 1:1.9 or 1:2. In the present invention, the amount ratio of the 3-hydroxycephalosporin to ethyl acetate is preferably 200mmol:50-150mL, and is particularly preferably 200mmol:100mL.

[0023] In the present invention, the temperature of the first reaction is preferably 0-5° C., the time is preferably 1-2 h, and the first reaction is preferably carried out under stirring.

[0024] In a specific embodiment of the present invention, 3-hydroxycephalosporin, methanesulfonyl chloride, ethyl acetate and N,N-diisopropylethylamine are mixed, and the first reaction is preferably carried out in sequence, which preferably includes the following steps: 3-hydroxycephalosporin, ethyl acetate and N,N-diisopropylethylamine are mixed to obtain a first mixed system; the first mixed system is cooled to 0°C and methanesulfonyl chloride is added dropwise; the time of the first reaction is preferably started after the addition of methanesulfonyl chloride is completed.

[0025] In the present invention, the first crystallization reagent includes glacial acetic acid, cyclohexane and water; the volume ratio of the glacial acetic acid, cyclohexane and water is 7.5:100:100. In the present invention, the volume ratio of ethyl acetate to glacial acetic acid is preferably 100:5-10, more preferably 100:7.5.

[0026] In the present invention, the time of the first crystallization is preferably 30 minutes, and the first crystallization is preferably carried out under stirring conditions.

[0027] After the first crystallization, the present invention preferably further comprises: filtering the obtained first crystallization liquid to collect crystals; washing the crystals with water and ethyl acetate in sequence, filtering, and vacuum drying the obtained solid to obtain the 7β-phenylacetylamino-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester. In the present invention, the water for the water washing is preferably purified water; and the temperature for the vacuum drying is preferably 40°C.

[0028] The invention mixes 2-mercapto-4-(4-pyridyl)thiazole, sodium methoxide and acetone, and performs a second reaction to obtain a sodium 4-(4-pyridyl)thiazole-2-thiolate solution.

[0029] In the present invention, during the second reaction, the molar ratio of 2-mercapto-4-(4-pyridyl)thiazole to sodium methoxide is preferably 1:0.8-1.25, and specifically preferably 1:0.8, 1:0.9, 1:0.93, 1:1, 1:1.07, 1:1.1, 1:1.15, 1:1.2 or 1:1.25. In the present invention, the amount ratio of 2-mercapto-4-(4-pyridyl)thiazole to acetone is preferably 396.3mmol:50-150mL, and more preferably 396.3mmol:100mL.

[0030] In the present invention, the temperature of the second reaction is preferably 0-5° C., and the time is preferably 1-2 h; the second reaction is preferably carried out under stirring.

[0031] After the second reaction is completed, the present invention preferably does not undergo any post-treatment to directly obtain the sodium 4-(4-pyridyl)thiazole-2-thiolate solution for use.

[0032] After obtaining the sodium 4-(4-pyridyl)thiazole-2-thiolate solution and 7β-phenylacetylamino-3-methanesulfonyloxy-3-cephem-4-carboxylate benzyl ester, the present invention mixes the sodium 4-(4-pyridyl)thiazole-2-thiolate solution and the acetone solution of 7β-phenylacetylamino-3-methanesulfonyloxy-3-cephem-4-carboxylate, and sequentially performs a third reaction and a second crystallization to obtain 7β-phenylacetylamino-3-[4-(4-pyridyl)-1,3-thiazol-2-yl]thiol-3-cephem-4-carboxylate benzyl ester.

[0033] In the present invention, the amount ratio of 7β-phenylacetylamino-3-methylsulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester to acetone in the acetone solution of 7β-phenylacetylamino-3-methylsulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester is preferably 173mmol:100~200mL, and more preferably 173mmol:150mL.

[0034] In the present invention, during the third reaction, the molar ratio of 7β-phenylacetylamino-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester and 2-mercapto-4-(4-pyridyl)thiazole is preferably 1:2-2.5, specifically preferably 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4 or 1:2.5.

[0035] In a specific embodiment of the present invention, the mixing of the sodium 4-(4-pyridyl)thiazole-2-thiolate solution and the acetone solution of 7β-phenylacetylamino-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester preferably comprises the following steps: adding the acetone solution of 7β-phenylacetylamino-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester dropwise to the sodium 4-(4-pyridyl)thiazole-2-thiolate solution.

[0036] In the present invention, the temperature of the third reaction is preferably 0-5° C., and the time is preferably 4-6 h; the third reaction is preferably carried out under stirring.

[0037] In the present invention, the reagent for the second crystallization comprises glacial acetic acid and water, and the usage ratio of the glacial acetic acid to water is preferably 10 g: 100 mL. In the present invention, the usage ratio of the glacial acetic acid in the reagent for the second crystallization to the acetone in the acetone solution of 7β-phenylacetylamino-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester is preferably 10 g: 150 mL.

[0038] In the present invention, the second crystallization time is preferably 1 hour, and the second crystallization is preferably performed under stirring conditions.

[0039] After the second crystallization, the present invention preferably further comprises: filtering the obtained second crystallization liquid to collect crystals; washing the crystals with water and vacuum drying them in sequence to obtain the 7β-phenylacetylamino-3-[4-(4-pyridyl)-1,3-thiazol-2-yl]thiol-3-cephem-4-carboxylic acid diphenylmethyl ester. In the present invention, the water for the water washing is preferably purified water, the temperature for the vacuum drying is preferably 40°C, and the present invention does not specifically limit the time for the vacuum drying, as long as the vacuum drying can be performed to a moisture content of less than or equal to 1.0%.

[0040] After obtaining 7β-phenylacetylamino-3-[4-(4-pyridyl)-1,3-thiazol-2-yl]thio-3-cephem-4-carboxylic acid benzyl ester, the present invention mixes the 7β-phenylacetylamino-3-[4-(4-pyridyl)-1,3-thiazol-2-yl]thio-3-cephem-4-carboxylic acid benzyl ester, iodomethane and ethyl acetate, and sequentially performs a fourth reaction and a third crystallization to obtain 7β-phenylacetylamino-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]thio-3-cephem-4-carboxylic acid benzyl ester iodide.

[0041] In the present invention, during the fourth reaction, the molar ratio of the 7β-phenylacetylamino-3-[4-(4-pyridyl)-1,3-thiazol-2-yl]mercapto-3-cephem-4-carboxylic acid diphenylmethyl ester and iodomethane is preferably 1:1~1.2, specifically preferably 1:1, 1:1.1 or 1:1.2; the amount ratio of the 7β-phenylacetylamino-3-[4-(4-pyridyl)-1,3-thiazol-2-yl]mercapto-3-cephem-4-carboxylic acid diphenylmethyl ester and ethyl acetate is preferably 148mmol:100~200mL, and more preferably 148mmol:150mL.

[0042] In the present invention, the temperature of the fourth reaction is preferably 20-25° C., the time is preferably 3-5 h, and the fourth reaction is preferably carried out under stirring.

[0043] In the present invention, the reagent of the third crystallization is water, and the water is preferably purified water. In the present invention, the volume ratio of the reagent of the third crystallization to the ethyl acetate in the fourth reaction is preferably 0.8:1.5. In the present invention, the time of the third crystallization is preferably 1h, and the third crystallization is preferably carried out under stirring.

[0044] After the third crystallization, the present invention preferably further comprises: filtering the obtained third crystallization liquid to collect crystals; washing the crystals with water and vacuum drying them in sequence to obtain the 7β-phenylacetamido-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]thiol-3-cephem-4-carboxylic acid diphenylmethyl ester iodide. In the present invention, the water for the water washing is preferably purified water, the temperature of the vacuum drying is preferably 40°C, and the present invention does not specifically limit the time of the vacuum drying, as long as the water content of the vacuum drying is less than or equal to 1.0%.

[0045] After obtaining 7β-phenylacetamido-3-[4-(1-methyl-4-pyridinyl)-1,3-thiazol-2-yl]mercapto-3-cephem-4-carboxylic acid diphenylmethyl ester iodide, the present invention mixes the 7β-phenylacetamido-3-[4-(1-methyl-4-pyridinyl)-1,3-thiazol-2-yl]mercapto-3-cephem-4-carboxylic acid diphenylmethyl ester iodide, phosphorus pentachloride, pyridine and dichloromethane, and sequentially performs a fifth reaction and a fourth crystallization to obtain 7β-amino-3-[4-(1-methyl-4-pyridinyl)-1,3-thiazol-2-yl]mercapto-3-cephem-4-carboxylic acid diphenylmethyl ester chloride.

[0046] In the present invention, during the fifth reaction, the molar ratio of the 7β-phenylacetamido-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]mercapto-3-cephem-4-carboxylic acid diphenylmethyl ester iodide, phosphorus pentachloride and pyridine is preferably 1:5~5.5:6.5~7, specifically preferably 1:5.5:6.7 or 1:5.2:6.7; the amount ratio of the phosphorus pentachloride and dichloromethane is preferably 712mmol:150mL.

[0047] In the present invention, the temperature of the fifth reaction is preferably 0-5° C., the time is preferably 2-4 h, and the fifth reaction is preferably carried out under stirring.

[0048] In a specific embodiment of the present invention, the 7β-phenylacetamido-3-[4-(1-methyl-4-pyridinyl)-1,3-thiazol-2-yl] mercapto-3-cephem-4-carboxylic acid diphenylmethyl ester iodide, phosphorus pentachloride, pyridine and dichloromethane are mixed, and the fifth reaction preferably includes the following steps: mixing phosphorus pentachloride and dichloromethane to obtain a phosphorus pentachloride system; adding pyridine and 7β-phenylacetamido-3-[4-(1-methyl-4-pyridinyl)-1,3-thiazol-2-yl] mercapto-3-cephem-4-carboxylic acid diphenylmethyl ester iodide to the phosphorus pentachloride system in sequence; the pyridine is preferably added dropwise; after the pyridine is added, the present invention preferably further includes stirring at 0~5°C for 1h. In the present invention, the time of the fifth reaction is preferably started from the time when the addition of the 7β-phenylacetamido-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]thiol-3-cephem-4-carboxylic acid diphenylmethyl ester iodide is completed.

[0049] In the present invention, the reagent for the fourth crystallization is isopropanol; the volume ratio of the reagent for the fourth crystallization to the dichloromethane in the fifth reaction is preferably 1:1.5. In the present invention, the time for the fourth crystallization is preferably 1 hour, and the fourth crystallization is preferably carried out under stirring.

[0050] After the fourth crystallization, the present invention preferably further comprises: filtering the obtained fourth crystallization liquid to collect crystals; washing and vacuum drying the crystals in sequence to obtain the 7β-amino-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]thiol-3-cephem-4-carboxylic acid diphenylmethyl ester chloride. In the present invention, the washing reagent is preferably isopropanol, and the vacuum drying temperature is preferably 40°C; the present invention does not specifically limit the vacuum drying time, and vacuum drying is sufficient until the moisture content is less than or equal to 1.0%.

[0051] After obtaining 7β-amino-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]mercapto-3-cephem-4-carboxylic acid diphenylmethyl ester chloride, the present invention mixes the 7β-amino-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]mercapto-3-cephem-4-carboxylic acid diphenylmethyl ester chloride, concentrated hydrochloric acid and acetonitrile, and sequentially performs a sixth reaction and a fifth crystallization to obtain 7β-amino-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]mercapto-3-cephem-4-carboxylic acid hydrochloride.

[0052] In the present invention, during the sixth reaction, the mass fraction of the concentrated hydrochloric acid is preferably 30-36%, specifically preferably 30%, 31%, 32%, 33%, 34%, 35% or 36%; the amount ratio of the 7β-amino-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]mercapto-3-cephem-4-carboxylic acid diphenylmethyl ester chloride and concentrated hydrochloric acid is preferably 122mmol:45-55mL, and more preferably 122mmol:50mL; the amount ratio of the 7β-amino-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]mercapto-3-cephem-4-carboxylic acid diphenylmethyl ester chloride and acetonitrile is preferably 122mmol:50-150mL, and more preferably 122mmol:100mL.

[0053] In the present invention, the temperature of the sixth reaction is preferably 35-40° C., the time is preferably 4-6 hours, and the sixth reaction is preferably carried out under stirring.

[0054] In a specific embodiment of the present invention, the 7β-amino-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]mercapto-3-cephem-4-carboxylic acid diphenylmethyl ester chloride, concentrated hydrochloric acid and acetonitrile are mixed, and the sixth reaction preferably includes the following steps: mixing 7β-amino-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]mercapto-3-cephem-4-carboxylic acid diphenylmethyl ester chloride and acetonitrile, heating to the temperature of the sixth reaction, adding concentrated hydrochloric acid dropwise, and performing the sixth reaction; the time of the sixth reaction is preferably started after the addition of the concentrated hydrochloric acid is completed.

[0055] In the present invention, the reagent for the fifth crystallization is acetone, and the volume ratio of the reagent for the fifth crystallization to acetonitrile in the sixth reaction is preferably 1:1; the time for the fifth crystallization is preferably 2h, and the fifth crystallization is preferably carried out under stirring.

[0056] After the fifth crystallization, the present invention preferably further comprises: filtering the obtained fifth crystallization liquid to collect crystals; washing and vacuum drying the crystals in sequence to obtain the 7β-amino-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]thiol-3-cephem-4-carboxylic acid hydrochloride. In the present invention, the washing reagent is preferably acetone; the vacuum drying temperature is preferably 40°C; the present invention does not specifically limit the vacuum drying time, and the vacuum drying only requires that the moisture content is less than or equal to 1.0%.

[0057] After obtaining 7β-amino-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]thio-3-cephem-4-carboxylic acid hydrochloride, the present invention further comprises the following steps: The method comprises the following steps: mixing 3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]thiol-7β-[2-(5-phosphonamido-1,2,4-thiadiazol-3-yl)-2-(Z)-ethoxyiminoacetyl chloride, water and triethylamine, and sequentially performing the seventh reaction and the sixth crystallization to obtain 3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]thiol-7β-[2-(5-phosphonamido-1,2,4-thiadiazol-3-yl)-2-(Z)-ethoxyiminoacetamido]-3-cephem-4-carboxylic acid disodium salt.

[0058] In the present invention, during the seventh reaction, the molar ratio of the 7β-amino-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]mercapto-3-cephem-4-carboxylic acid hydrochloride and (Z)-2-(5-dichlorophosphoramido-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetyl chloride is preferably 1:1~1.1, specifically preferably 1:1, 1:1.05 or 1:1.1; the molar ratio of the β-amino-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]mercapto-3-cephem-4-carboxylic acid hydrochloride and triethylamine is preferably 1:1~1.1, specifically preferably 1:1, 1:1.04, 1:1.05 or 1:1.1; the amount ratio of water to triethylamine is preferably 150mL:108~115mmol.

[0059] In the present invention, the temperature of the seventh reaction is preferably 0-5° C., the time is preferably 2-3 h, and the seventh reaction is preferably carried out under stirring.

[0060] In the present invention, the seventh reaction of mixing 7β-amino-3-[4-(1-methyl-4-pyridinyl)-1,3-thiazol-2-yl]thio-3-cephem-4-carboxylic acid hydrochloride, (Z)-2-(5-dichlorophosphoramido-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetyl chloride, water and triethylamine preferably comprises the following steps: stirring and dissolving 7β-amino-3-[4-(1-methyl-4-pyridinyl)-1,3-thiazol-2-yl]thio-3-cephem-4-carboxylic acid hydrochloride and water uniformly, cooling to 0°C, and sequentially adding (Z)-2-(5-dichlorophosphoramido-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetyl chloride and triethylamine; the triethylamine is preferably added dropwise; and the time of the seventh reaction is preferably started after the addition of the triethylamine is completed.

[0061] In the present invention, the pH of the sixth crystallization is preferably 5, the reagent for adjusting the pH value of the sixth crystallization is preferably a sodium hydroxide solution, and the concentration of the sodium hydroxide solution is preferably 8 mol / L.

[0062] In the present invention, the reagent for the sixth crystallization is ethanol; the volume ratio of the reagent for the sixth crystallization to the water in the seventh reaction is preferably 1:1.5. In the present invention, the time for the sixth crystallization is preferably 1 hour, and the sixth crystallization is preferably carried out under stirring.

[0063] After the sixth crystallization, the present invention preferably further comprises: filtering the obtained sixth crystallization liquid to collect crystals; washing and vacuum drying the crystals in sequence to obtain the 3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]thiol-7β-[2-(5-phosphoamido-1,2,4-thiadiazole-3-yl)-2-(Z)-ethoxyiminoacetamido]-3-cephem-4-carboxylic acid disodium salt. In the present invention, the washing reagent is preferably ethanol, the vacuum drying temperature is preferably 40°C, and the present invention does not specifically limit the vacuum drying time, as long as the vacuum drying is performed until the moisture content is less than or equal to 1.0%.

[0064] After obtaining the disodium salt of 3-[4-(1-methyl-4-pyridinyl)-1,3-thiazol-2-yl]mercapto-7β-[2-(5-phosphonamido-1,2,4-thiadiazol-3-yl)-2-(Z)-ethoxyiminoacetamido]-3-cephem-4-carboxylic acid, the present invention sequentially hydrolyzes and crystallizes the disodium salt of 3-[4-(1-methyl-4-pyridinyl)-1,3-thiazol-2-yl]mercapto-7β-[2-(5-phosphonamido-1,2,4-thiadiazol-3-yl)-2-(Z)-ethoxyiminoacetamido]-3-cephem-4-carboxylic acid to obtain the cefuroxime fosamil.

[0065] In the present invention, the reagent for hydrolysis is preferably water and acetic acid, and the volume ratio of water to acetic acid is preferably 1.5 to 1.8: 1. In the present invention, the amount ratio of the 3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]thiol-7-,3-1-phosphonamido-1,2,4-thiadiazol-3-yl)-2-(Z)-ethoxyiminoacetamido]-3-cephem-4-carboxylic acid disodium salt to water in the reagent for hydrolysis is preferably 96 mmol: 150 to 180 mL.

[0066] In the present invention, the hydrolysis temperature is preferably 25-35° C., the time is preferably 0.5-1 h, and the hydrolysis is preferably carried out under stirring.

[0067] In the present invention, the pH value of the seventh crystallization is preferably 1, and the pH value of the seventh crystallization is preferably adjusted by sulfuric acid, and the concentration of the sulfuric acid is preferably 1 mol / L.

[0068] In the present invention, the reagent for the seventh crystallization is preferably an acetic acid aqueous solution, and the volume concentration of the acetic acid aqueous solution is preferably 50%; the volume ratio of water in the reagent for the seventh crystallization and the reagent for the hydrolysis is preferably 1: 1. In the present invention, the time for the seventh crystallization is preferably 3 hours, and the seventh crystallization is preferably carried out under stirring.

[0069] After the seventh crystallization, the present invention preferably further comprises: filtering the obtained seventh crystallization liquid to collect crystals; washing and vacuum drying the crystals in sequence to obtain the ceftaroline fosamil. In the present invention, the washing reagent is preferably water, and more preferably purified water. In the present invention, the temperature of the vacuum drying is preferably 30°C; the present invention does not specifically limit the time of the vacuum drying, as long as the vacuum drying is performed until the moisture content is less than or equal to air drying.

[0070] The preparation method of cefuroxime provided by the present invention is described in detail below in conjunction with the examples, but they should not be construed as limiting the scope of protection of the present invention.

[0071] Example 1 (1) Preparation of 7β-phenylacetylamino-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester In a dry glass reaction bottle, add 100g (200mmol) 3-hydroxycephalosporin, 100mL ethyl acetate, 45g (348mmol) N,N-diisopropylethylamine, stir evenly, cool to 0℃, add 32.5g (283mmol) methanesulfonyl chloride dropwise, maintain the solution temperature at 0~5℃, stir and react for 1h, and after the reaction is complete, add 7.5mL glacial acetic acid, 100mL cyclohexane, and 100mL purified water, continue stirring and crystallizing for 30min, filter, wash the material with 100mL purified water, then wash the material with 100mL ethyl acetate, filter, and vacuum dry the material at 40℃ to a moisture content of ≤1.0%, to obtain 108g of light yellow powder material, with a weight yield of 108%.

[0072] (2) Preparation of 7β-phenylacetylamino-3-[4-(4-pyridyl)-1,3-thiazol-2-yl]thiol-3-cephem-4-carboxylic acid diphenylmethyl ester In a dry glass reaction bottle, add 77g (396.3mmol) 2-mercapto-4-(4-pyridyl)thiazole, 100mL acetone, and 20g (370.4mmol) sodium methoxide, stir and cool to 5°C, continue stirring for 1h to obtain a sodium 4-(4-pyridyl)thiazole-2-thiolate solution, and cool to 0°C for use.

[0073] In another dry glass reaction bottle, add 100g (173mmol) 7β-phenylacetylamino-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester and 150mL acetone, stir and dissolve for 0.5h, and complete to obtain an acetone solution of 7β-phenylacetylamino-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester; slowly add the acetone solution of 7β-phenylacetylamino-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester dropwise to the sodium 4-(4-pyridyl)thiazole-2-thiolate solution, and complete the dropwise addition. Control the temperature of the reaction solution to 0~5°C and continue to stir and react for 4h; after the reaction is completed, add 10g glacial acetic acid and 100mL purified water, stir and crystallize for 1h, filter, wash the material with 100mL purified water, and dry the material in vacuo at 40°C to a moisture content of ≤1.0% to obtain 105g of white powder material with a weight yield of 105%.

[0074] (3) Preparation of 7β-phenylacetamido-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]thiol-3-cephem-4-carboxylic acid diphenylmethyl ester iodide In a dry glass reaction bottle, add 100g (148mmol) 7β-phenylacetylamino-3-[4-(4-pyridyl)-1,3-thiazol-2-yl] mercapto-3-cephem-4-carboxylic acid diphenylmethyl ester and 150mL ethyl acetate, stir to dissolve, add 10mL (162mmol) iodomethane, maintain the solution temperature at 20-25℃ and stir to react for 3h. After the reaction is completed, add 80mL purified water, stir and crystallize for 1h, filter, wash the material with 100mL purified water, and dry the material in vacuum at 40℃ until the moisture is ≤1.0%. 95g of white powder material is obtained with a weight yield of 95%.

[0075] (4) Preparation of 7β-amino-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]thio-3-cephem-4-carboxylic acid diphenylmethyl ester chloride In a dry glass reaction bottle, add 150g (712mmol) of phosphorus pentachloride and 150mL of dichloromethane, stir evenly, cool to 0℃, slowly add 70mL (870mmol) of pyridine, maintain the temperature at 0~5℃ and stir for 1h, add 90g (130mmol) of 7β-phenylacetamido-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]thiol-3-cephem-4-carboxylic acid diphenylmethyl ester iodide, maintain the temperature at 0~5℃ and stir for 2h, after the reaction is complete, add 100mL of isopropanol, stir and crystallize for 1h, filter, wash the material with 100mL of isopropanol, and dry the material in vacuum at 40℃ until the moisture is ≤1.0%, to obtain 73g of light yellow powder material with a weight yield of 81%.

[0076] (5) Preparation of 7β-amino-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]thiol-3-cephem-4-carboxylic acid hydrochloride In a clean glass reaction bottle, add 70g (122mmol) 7β-amino-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl] mercapto-3-cephem-4-carboxylic acid diphenylmethyl ester chloride and 100mL acetonitrile. After stirring and heating to 40°C, add 50mL concentrated hydrochloric acid (mass fraction is 35%) dropwise. After the dropwise addition, maintain the solution temperature at 35-40°C and continue stirring and reacting for 4h. After the reaction is completed, add 100mL acetone, stir and crystallize for 2h, filter, wash the material with 100mL acetone, and dry the material in vacuum at 40°C until the moisture is ≤1.0%. 56g of white powder material is obtained with a weight yield of 80%.

[0077] (6) Preparation of 3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]mercapto-7β-[2-(5-phosphonamido-1,2,4-thiadiazol-3-yl)-2-(Z)-ethoxyiminoacetamido]-3-cephem-4-carboxylic acid disodium salt In a clean glass reaction bottle, add 7β-amino-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]thio-3-cephem-4-carboxylic acid hydrochloride 50g (104mmol) and 150mL purified water, stir and dissolve evenly, cool to 0°C, add 40g (114mmol) of ceftaroline side chain (Z)-2-(5-dichlorophosphoramido-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetyl chloride, and dropwise add 15mL (108mmol) of triethylamine, maintain 0~5°C stirring and react for 2h. After the reaction is completed, add dropwise 8mol / L sodium hydroxide solution to adjust the solution pH to 5.0, add 100mL of ethanol, stir well to crystallize for 1h, filter, wash the material with 100mL of ethanol, and dry the material in vacuum at 40°C until the moisture is ≤1.0%, to obtain 73g of white powder material, with a weight yield of 146%.

[0078] (7) Preparation of cefuroxime fosamil In a clean glass reaction bottle, add 3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]thiol-7-,3-1-phosphonamido-1,2,4-thiadiazol-3-yl)-2-(Z)-ethoxyiminoacetamido]-3-cephem-4-carboxylic acid disodium salt 70g (96mmol), water 150mL, acetic acid 100mL, stir and heat to 30℃, hydrolyze for 30min, then adjust the pH value of the solution to 1.0 with 1mol / L sulfuric acid, add 150mL 50% acetic acid aqueous solution, cool to 0~5℃, continue stirring and crystallizing for 3h, filter, wash the material with 100mL purified water, filter, and vacuum dry the material at 30℃ until the moisture content is ≤ air dry to obtain the product ceftaroline fosamil acetic acid hydrate, about 42g, with a weight yield of 60%.

[0079] Figure 1 is the NMR spectrum of cefuroxime acetic acid hydrate obtained in Example 1, from Figure 1 It can be seen that the target product was successfully obtained in this embodiment.

[0080] The obtained ceftaroline fosamil acetic acid hydrate was subjected to liquid chromatography analysis, and the results showed that the peak time of the target product was 20.030 min, and the purity was 98.99%.

[0081] Example 2 (1) Preparation of 7β-phenylacetylamino-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester In a dry glass reaction bottle, add 100g (200mmol) 3-hydroxycephalosporin, 100mL ethyl acetate, 45g (348mmol) N,N-diisopropylethylamine, stir evenly, cool to 0℃, add 33.0g (288mmol) methanesulfonyl chloride dropwise, maintain the solution temperature at 0~5℃, stir and react for 1.5h, and after the reaction is complete, add 7.5mL glacial acetic acid, 100mL cyclohexane, and 100mL purified water, continue stirring and crystallizing for 30min, filter, wash the material with 100mL purified water, then wash the material with 100mL ethyl acetate, filter, and vacuum dry the material at 40℃ to a moisture content of ≤1.0%, to obtain 107g of light yellow powder material with a weight yield of 107%.

[0082] (2) Preparation of 7β-phenylacetylamino-3-[4-(4-pyridyl)-1,3-thiazol-2-yl]thiol-3-cephem-4-carboxylic acid diphenylmethyl ester In a dry glass reaction bottle, add 77g (396.3mmol) 2-mercapto-4-(4-pyridyl)thiazole, 100mL acetone, and 23g (426mmol) sodium methoxide, stir and cool to 5°C, continue stirring for 1h to obtain a sodium 4-(4-pyridyl)thiazole-2-thiolate solution, and cool to 0°C for use.

[0083] In another dry glass reaction bottle, add 100g (173mmol) 7β-phenylacetylamino-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester and 150mL acetone, stir and dissolve for 0.5h, and complete to obtain an acetone solution of 7β-phenylacetylamino-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester; slowly add the acetone solution of 7β-phenylacetylamino-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester dropwise to the sodium 4-(4-pyridyl)thiazole-2-thiolate solution, and complete the dropwise addition. Control the temperature of the reaction solution to 0~5°C, and continue to stir and react for 4.5h; after the reaction is completed, add 10g glacial acetic acid and 100mL purified water, stir and crystallize for 1h, filter, wash the material with 100mL purified water, and dry the material in vacuo at 40°C to a moisture content of ≤1.0% to obtain 104g of white powder material with a weight yield of 104%.

[0084] (3) Preparation of 7β-phenylacetamido-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]thiol-3-cephem-4-carboxylic acid diphenylmethyl ester iodide In a dry glass reaction bottle, add 100g (148mmol) 7β-phenylacetylamino-3-[4-(4-pyridyl)-1,3-thiazol-2-yl] mercapto-3-cephem-4-carboxylic acid diphenylmethyl ester and 150mL ethyl acetate, stir to dissolve, add 11mL (178mmol) iodomethane, maintain the solution temperature at 20-25℃ and stir to react for 4h. After the reaction is completed, add 80mL purified water, stir and crystallize for 1h, filter, wash the material with 100mL purified water, and dry the material in vacuum at 40℃ until the moisture is ≤1.0%. 96g of white powder material is obtained with a weight yield of 96%.

[0085] (4) Preparation of 7β-amino-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]thio-3-cephem-4-carboxylic acid diphenylmethyl ester chloride In a dry glass reaction bottle, add 140g (673mmol) of phosphorus pentachloride and 150mL of dichloromethane, stir evenly, cool to 0℃, slowly add 70mL (870mmol) of pyridine, maintain the temperature at 0~5℃ and stir for 1h, add 90g (130mmol) of 7β-phenylacetamido-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]thiol-3-cephem-4-carboxylic acid diphenylmethyl ester iodide, maintain the temperature at 0~5℃ and stir for 2h, after the reaction is complete, add 100mL of isopropanol, stir and crystallize for 1h, filter, wash the material with 100mL of isopropanol, and dry the material in vacuum at 40℃ until the moisture content is ≤1.0%, to obtain 72.5g of light yellow powder material with a weight yield of 80.6%.

[0086] (5) Preparation of 7β-amino-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]thiol-3-cephem-4-carboxylic acid hydrochloride In a clean glass reaction bottle, add 70g (122mmol) 7β-amino-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl] mercapto-3-cephem-4-carboxylic acid diphenylmethyl ester chloride and 100mL acetonitrile. After stirring and heating to 40°C, add 50mL concentrated hydrochloric acid (mass fraction is 35%) dropwise. After the dropwise addition, maintain the solution temperature at 35-40°C and continue stirring and reacting for 4h. After the reaction is completed, add 100mL acetone, stir and crystallize for 2h, filter, wash the material with 100mL acetone, and dry the material in vacuum at 40°C until the moisture is ≤1.0%. 56g of white powder material is obtained with a weight yield of 80%.

[0087] (6) Preparation of 3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]mercapto-7β-[2-(5-phosphonamido-1,2,4-thiadiazol-3-yl)-2-(Z)-ethoxyiminoacetamido]-3-cephem-4-carboxylic acid disodium salt In a clean glass reaction bottle, add 7β-amino-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]thio-3-cephem-4-carboxylic acid hydrochloride 50g (104mmol) and 150mL purified water, stir and dissolve evenly, cool to 0°C, add 40g (114mmol) of ceftaroline side chain (Z)-2-(5-dichlorophosphoramido-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetyl chloride, and dropwise add 16mL (115mmol) of triethylamine, maintain 0~5°C stirring and react for 2h. After the reaction is completed, add dropwise 8mol / L sodium hydroxide solution to adjust the solution pH to 5.0, add 100mL of ethanol, stir and crystallize for 1h, filter, wash the material with 100mL of ethanol, and dry the material in vacuum at 40°C until the moisture is ≤1.0%, to obtain 74g of white powder material, with a weight yield of 148%.

[0088] (7) Preparation of cefuroxime fosamil In a clean glass reaction bottle, add 3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]thiol-7-,3-1-phosphonamido-1,2,4-thiadiazol-3-yl)-2-(Z)-ethoxyiminoacetamido]-3-cephem-4-carboxylic acid disodium salt 70g (96mmol), water 180mL, acetic acid 100mL, stirring and heating to 30°C, hydrolysis reaction for 30min, then adjust the pH value of the solution to 1.0 with 1mol / L sulfuric acid, add 150mL 50% acetic acid aqueous solution, and cool to 0~5°C, continue stirring and crystallizing for 3h, filter, wash the material with 100mL purified water, filter, and vacuum dry the material at 30°C until the moisture content is ≤ air-dried to obtain the product ceftaroline fosamil acetic acid hydrate, about 41g, and the weight yield is 58.6%.

[0089] The obtained cefuroxime fosamil acetic acid hydrate was subjected to liquid chromatography analysis, and the results showed that the peak time of the target product was 20.030 min, and the purity was 98.85%.

[0090] Comparative Example 1 (1) Preparation of 7β-phenylacetylamino-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester In a dry glass reaction bottle, add 100g (200mmol) 3-hydroxycephalosporin, 100mL ethyl acetate, 45g (348mmol) N,N-diisopropylethylamine, stir evenly, cool to 0℃, add 32.5g (283mmol) methanesulfonyl chloride dropwise, maintain the solution temperature at 0~5℃, stir and react for 1h, after the reaction is complete, add 7.5mL glacial acetic acid, 100mL ethyl acetate, 100mL purified water, continue stirring and crystallizing for 30min, filter, wash the material with 100mL purified water, then wash the material with 100mL ethyl acetate, filter, and vacuum dry the material at 40℃ to a moisture content of ≤1.0%, to obtain 101g of light yellow powder material, with a weight yield of 101%.

[0091] (2) Preparation of 7β-phenylacetylamino-3-[4-(4-pyridyl)-1,3-thiazol-2-yl]thiol-3-cephem-4-carboxylic acid diphenylmethyl ester In a dry glass reaction bottle, add 77g (396.3mmol) 2-mercapto-4-(4-pyridyl)thiazole, 100mL acetone, and 20g (370.4mmol) sodium methoxide, stir and cool to 5°C, continue stirring for 1h to obtain a sodium 4-(4-pyridyl)thiazole-2-thiolate solution, and cool to 0°C for use.

[0092] In another dry glass reaction bottle, add 100g (173mmol) 7β-phenylacetylamino-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester and 150mL acetone, stir and dissolve for 0.5h, and complete to obtain an acetone solution of 7β-phenylacetylamino-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester; slowly add the acetone solution of 7β-phenylacetylamino-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester dropwise to the sodium 4-(4-pyridyl)thiazole-2-thiolate solution, and complete the dropwise addition. Control the temperature of the reaction solution to 0~5°C and continue to stir and react for 4h; after the reaction is completed, add 10g glacial acetic acid and 100mL purified water, stir and crystallize for 1h, filter, wash the material with 100mL purified water, and dry the material in vacuo at 40°C to a moisture content of ≤1.0% to obtain 105g of white powder material with a weight yield of 105%.

[0093] (3) Preparation of 7β-phenylacetamido-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]thiol-3-cephem-4-carboxylic acid diphenylmethyl ester iodide In a dry glass reaction bottle, add 100g (148mmol) 7β-phenylacetylamino-3-[4-(4-pyridyl)-1,3-thiazol-2-yl] mercapto-3-cephem-4-carboxylic acid diphenylmethyl ester and 150mL ethyl acetate, stir to dissolve, add 10mL (162mmol) iodomethane, maintain the solution temperature at 20-25℃ and stir to react for 3h. After the reaction is completed, add 80mL purified water, stir and crystallize for 1h, filter, wash the material with 100mL purified water, and dry the material in vacuum at 40℃ until the moisture is ≤1.0%. 95g of white powder material is obtained with a weight yield of 95%.

[0094] (4) Preparation of 7β-amino-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]thio-3-cephem-4-carboxylic acid diphenylmethyl ester chloride In a dry glass reaction bottle, add 150g (712mmol) of phosphorus pentachloride and 150mL of dichloromethane, stir evenly, cool to 0℃, slowly add 70mL (870mmol) of pyridine, maintain the temperature at 0~5℃ and stir for 1h, add 90g (130mmol) of 7β-phenylacetamido-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]thiol-3-cephem-4-carboxylic acid diphenylmethyl ester iodide, maintain the temperature at 0~5℃ and stir for 2h, after the reaction is complete, add 100mL of isopropanol, stir and crystallize for 1h, filter, wash the material with 100mL of isopropanol, and dry the material in vacuum at 40℃ until the moisture is ≤1.0%, to obtain 73g of light yellow powder material with a weight yield of 81%.

[0095] (5) Preparation of 7β-amino-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]thiol-3-cephem-4-carboxylic acid hydrochloride In a clean glass reaction bottle, add 70g (122mmol) 7β-amino-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl] mercapto-3-cephem-4-carboxylic acid diphenylmethyl ester chloride and 100mL acetonitrile. After stirring and heating to 40°C, add 50mL concentrated hydrochloric acid (mass fraction is 35%) dropwise. After the dropwise addition, maintain the solution temperature at 35-40°C and continue stirring and reacting for 4h. After the reaction is completed, add 100mL acetone, stir and crystallize for 2h, filter, wash the material with 100mL acetone, and dry the material in vacuum at 40°C until the moisture is ≤1.0%. 56g of white powder material is obtained with a weight yield of 80%.

[0096] (6) Preparation of 3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]mercapto-7β-[2-(5-phosphonamido-1,2,4-thiadiazol-3-yl)-2-(Z)-ethoxyiminoacetamido]-3-cephem-4-carboxylic acid disodium salt In a clean glass reaction bottle, add 7β-amino-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]thio-3-cephem-4-carboxylic acid hydrochloride 50g (104mmol) and 150mL purified water, stir and dissolve evenly, cool to 0°C, add 40g (114mmol) of ceftaroline side chain (Z)-2-(5-dichlorophosphoramido-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetyl chloride, and dropwise add 15mL (108mmol) of triethylamine, maintain 0~5°C stirring and react for 2h. After the reaction is completed, add dropwise 8mol / L sodium hydroxide solution to adjust the solution pH to 5.0, add 100mL of ethanol, stir well to crystallize for 1h, filter, wash the material with 100mL of ethanol, and dry the material in vacuum at 40°C until the moisture is ≤1.0%, to obtain 73g of white powder material, with a weight yield of 146%.

[0097] (7) Preparation of cefuroxime fosamil In a clean glass reaction bottle, add 3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]thiol-7-,3-1-phosphonamido-1,2,4-thiadiazol-3-yl)-2-(Z)-ethoxyiminoacetamido]-3-cephem-4-carboxylic acid disodium salt 70g (96mmol), water 150mL, acetic acid 100mL, stir and heat to 30℃, hydrolyze for 30min, then adjust the pH value of the solution to 1.0 with 1mol / L sulfuric acid, add 150mL 50% acetic acid aqueous solution, cool to 0~5℃, continue stirring and crystallizing for 3h, filter, wash the material with 100mL purified water, filter, and vacuum dry the material at 30℃ until the moisture content is ≤ air dry to obtain the product ceftaroline fosamil acetic acid hydrate, about 42g, with a weight yield of 60%.

[0098] Comparative Example 2 (1) Preparation of 7β-phenylacetylamino-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester In a dry glass reaction bottle, add 100g (200mmol) 3-hydroxycephalosporin, 100mL ethyl acetate, 45g (348mmol) N,N-diisopropylethylamine, stir evenly, cool to 0℃, add 32.5g (283mmol) methanesulfonyl chloride dropwise, maintain the solution temperature at 0~5℃, stir and react for 1h, and after the reaction is complete, add 7.5mL glacial acetic acid, 100mL cyclohexane, and 100mL purified water, continue stirring and crystallizing for 30min, filter, wash the material with 100mL purified water, then wash the material with 100mL ethyl acetate, filter, and vacuum dry the material at 40℃ to a moisture content of ≤1.0%, to obtain 108g of light yellow powder material, with a weight yield of 108%.

[0099] (2) Preparation of 7β-phenylacetylamino-3-[4-(4-pyridyl)-1,3-thiazol-2-yl]thiol-3-cephem-4-carboxylic acid diphenylmethyl ester In a dry glass reaction bottle, add 77g (396.3mmol) 2-mercapto-4-(4-pyridyl)thiazole, 100mL acetone, and 20g (370.4mmol) sodium methoxide, stir and cool to 5°C, continue stirring for 1h to obtain a sodium 4-(4-pyridyl)thiazole-2-thiolate solution, and cool to 0°C for use.

[0100] In another dry glass reaction bottle, add 100g (173mmol) 7β-phenylacetylamino-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester and 150mL acetone, stir and dissolve for 0.5h, and complete to obtain an acetone solution of 7β-phenylacetylamino-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester; slowly add the acetone solution of 7β-phenylacetylamino-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester dropwise to the sodium 4-(4-pyridyl)thiazole-2-thiolate solution, and complete the dropwise addition. Control the temperature of the reaction solution to 0~5°C and continue to stir and react for 4h; after the reaction is completed, add 10g glacial acetic acid and 100mL purified water, stir and crystallize for 1h, filter, wash the material with 100mL purified water, and dry the material in vacuo at 40°C to a moisture content of ≤1.0% to obtain 105g of white powder material with a weight yield of 105%.

[0101] (3) Preparation of 7β-phenylacetamido-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]thiol-3-cephem-4-carboxylic acid diphenylmethyl ester iodide In a dry glass reaction bottle, add 100g (148mmol) 7β-phenylacetylamino-3-[4-(4-pyridyl)-1,3-thiazol-2-yl] mercapto-3-cephem-4-carboxylic acid diphenylmethyl ester and 150mL ethyl acetate, stir to dissolve, add 10mL (162mmol) iodomethane, maintain the solution temperature at 20-25℃ and stir to react for 3h. After the reaction is completed, add 80mL purified water, stir and crystallize for 1h, filter, wash the material with 100mL purified water, and dry the material in vacuum at 40℃ until the moisture is ≤1.0%. 95g of white powder material is obtained with a weight yield of 95%.

[0102] (4) Preparation of 7β-amino-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]thio-3-cephem-4-carboxylic acid diphenylmethyl ester chloride In a dry glass reaction bottle, add 150g (712mmol) of phosphorus pentachloride and 150mL of dichloromethane, stir evenly, cool to 0℃, slowly add 70mL (870mmol) of pyridine, maintain the temperature at 0~5℃ and stir for 1h, add 90g (130mmol) of 7β-phenylacetamido-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]thiol-3-cephem-4-carboxylic acid diphenylmethyl ester iodide, maintain the temperature at 0~5℃ and stir for 2h, after the reaction is complete, add 100mL of isopropanol, stir and crystallize for 1h, filter, wash the material with 100mL of isopropanol, and dry the material in vacuum at 40℃ until the moisture is ≤1.0%, to obtain 73g of light yellow powder material with a weight yield of 81%.

[0103] (5) Preparation of 7β-amino-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]thiol-3-cephem-4-carboxylic acid hydrochloride In a clean glass reaction bottle, add 70g (122mmol) 7β-amino-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl] mercapto-3-cephem-4-carboxylic acid diphenylmethyl ester chloride and 100mL acetonitrile. After stirring and heating to 40°C, add 50mL concentrated hydrochloric acid (mass fraction is 35%) dropwise. After the dropwise addition, maintain the solution temperature at 35-40°C and continue stirring and reacting for 4h. After the reaction is completed, add 100mL ethyl acetate, stir and crystallize for 2h, filter, wash the material with 100mL acetone, and dry the material in vacuum at 40°C until the moisture is ≤1.0%. 52g of white powder material is obtained with a weight yield of 74.3%.

[0104] (6) Preparation of 3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]mercapto-7β-[2-(5-phosphonamido-1,2,4-thiadiazol-3-yl)-2-(Z)-ethoxyiminoacetamido]-3-cephem-4-carboxylic acid disodium salt In a clean glass reaction bottle, add 7β-amino-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]thio-3-cephem-4-carboxylic acid hydrochloride 50g (104mmol) and 150mL purified water, stir and dissolve evenly, cool to 0°C, add 40g (114mmol) of ceftaroline side chain (Z)-2-(5-dichlorophosphoramido-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetyl chloride, and dropwise add 15mL (108mmol) of triethylamine, maintain 0~5°C stirring and react for 2h. After the reaction is completed, add dropwise 8mol / L sodium hydroxide solution to adjust the solution pH to 5.0, add 100mL of ethanol, stir well to crystallize for 1h, filter, wash the material with 100mL of ethanol, and dry the material in vacuum at 40°C until the moisture is ≤1.0%, to obtain 73g of white powder material, with a weight yield of 146%.

[0105] (7) Preparation of cefuroxime fosamil In a clean glass reaction bottle, add 3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]thiol-7-,3-1-phosphonamido-1,2,4-thiadiazol-3-yl)-2-(Z)-ethoxyiminoacetamido]-3-cephem-4-carboxylic acid disodium salt 70g (96mmol), water 150mL, acetic acid 100mL, stir and heat to 30℃, hydrolyze for 30min, then adjust the pH value of the solution to 1.0 with 1mol / L sulfuric acid, add 150mL 50% acetic acid aqueous solution, cool to 0~5℃, continue stirring and crystallizing for 3h, filter, wash the material with 100mL purified water, filter, and vacuum dry the material at 30℃ until the moisture content is ≤ air dry to obtain the product ceftaroline fosamil acetic acid hydrate, about 42g, with a weight yield of 60%.

[0106] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for preparing cefuroxime fosamil, characterized in that: The following steps are involved: Mixing 3-hydroxycephalosporin, methanesulfonyl chloride, ethyl acetate and N,N-diisopropylethylamine, and sequentially performing a first reaction and a first crystallization to obtain 7β-phenylacetylamino-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester, wherein the reagents for the first crystallization include glacial acetic acid, cyclohexane and water, and the volume ratio of the glacial acetic acid, cyclohexane and water is 7.5:100:100; Mixing 2-mercapto-4-(4-pyridyl)thiazole, sodium methoxide and acetone, and performing a second reaction to obtain a sodium 4-(4-pyridyl)thiazole-2-thiolate solution; The sodium 4-(4-pyridyl)thiazole-2-thiolate solution and the acetone solution of 7β-phenylacetylamino-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester are mixed, and a third reaction and a second crystallization are sequentially performed to obtain 7β-phenylacetylamino-3-[4-(4-pyridyl)-1,3-thiazol-2-yl]sulfhydryl-3-cephem-4-carboxylic acid diphenylmethyl ester, wherein the reagent of the second crystallization comprises glacial acetic acid and water, and the amount ratio of the glacial acetic acid to water is 10 g:100 mL; The 7β-phenylacetylamino-3-[4-(4-pyridyl)-1,3-thiazol-2-yl]thiol-3-cephem-4-carboxylic acid diphenylmethyl ester, iodomethane and ethyl acetate are mixed, and a fourth reaction and a third crystallization are sequentially performed to obtain 7β-phenylacetylamino-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]thiol-3-cephem-4-carboxylic acid diphenylmethyl ester iodide, wherein the reagent for the third crystallization is water; The 7β-phenylacetamido-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl] mercapto-3-cephem-4-carboxylic acid diphenylmethyl ester iodide, phosphorus pentachloride, pyridine and dichloromethane are mixed, and a fifth reaction and a fourth crystallization are performed in sequence to obtain 7β-amino-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl] mercapto-3-cephem-4-carboxylic acid diphenylmethyl ester chloride, wherein the reagent for the fourth crystallization is isopropanol; The 7β-amino-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]mercapto-3-cephem-4-carboxylic acid diphenylmethyl ester chloride, concentrated hydrochloric acid and acetonitrile are mixed, and a sixth reaction and a fifth crystallization are performed in sequence to obtain 7β-amino-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]mercapto-3-cephem-4-carboxylic acid hydrochloride, wherein the reagent for the fifth crystallization is acetone; The 7β-amino-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]thiol-3-cephem-4-carboxylic acid hydrochloride, (Z)-2-(5-dichlorophosphoramido-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetyl chloride, water and triethylamine are mixed, and the seventh reaction and the sixth crystallization are carried out in sequence to obtain 3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]thiol-7β-[2-(5-phosphoramido-1,2,4-thiadiazol-3-yl)-2-(Z)-ethoxyiminoacetamido]-3-cephem-4-carboxylic acid disodium salt, the pH of the sixth crystallization is 5, and the reagent of the sixth crystallization is ethanol; The 3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]thiol-7β-[2-(5-phosphoamido-1,2,4-thiadiazol-3-yl)-2-(Z)-ethoxyiminoacetamido]-3-cephem-4-carboxylic acid disodium salt is sequentially hydrolyzed and subjected to a seventh crystallization to obtain the ceftaroline fosamil, wherein the pH value of the seventh crystallization is 1, and the reagent for the seventh crystallization is an acetic acid aqueous solution, and the volume concentration of the acetic acid aqueous solution is 50%.

2. The preparation method according to claim 1, characterized in that: During the first reaction, the molar ratio of 3-hydroxycephalosporin to methanesulfonyl chloride is 1:1.4~1.5, the molar ratio of 3-hydroxycephalosporin to N,N-diisopropylethylamine is 1:1.7~2, and the dosage ratio of 3-hydroxycephalosporin to ethyl acetate is 200mmol:50~150mL; the temperature of the first reaction is 0~5°C, and the time is 1~2h.

3. The preparation method according to claim 1, characterized in that: During the second reaction, the molar ratio of 2-mercapto-4-(4-pyridyl)thiazole and sodium methoxide is 1:0.8~1.25, and the dosage ratio of 2-mercapto-4-(4-pyridyl)thiazole and acetone is 396.3mmol:50~150mL; the temperature of the second reaction is 0~5°C, and the time is 1~2h.

4. The preparation method according to claim 1, characterized in that: During the third reaction, the molar ratio of 7β-phenylacetylamino-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester and 2-mercapto-4-(4-pyridyl)thiazole is 1:2-2.5, the temperature of the third reaction is 0-5°C, and the time is 4-6h.

5. The preparation method according to claim 1, characterized in that: During the fourth reaction, the molar ratio of the 7β-phenylacetylamino-3-[4-(4-pyridyl)-1,3-thiazol-2-yl]thiol-3-cephem-4-carboxylic acid diphenylmethyl ester and iodomethane is 1:1~1.2, and the amount ratio of the 7β-phenylacetylamino-3-[4-(4-pyridyl)-1,3-thiazol-2-yl]thiol-3-cephem-4-carboxylic acid diphenylmethyl ester and ethyl acetate is 148mmol:100~200mL; the temperature of the fourth reaction is 20~25°C, and the time is 3~5h.

6. The preparation method according to claim 1, characterized in that: During the fifth reaction, the molar ratio of the 7β-phenylacetamido-3-[4-(1-methyl-4-pyridinyl)-1,3-thiazol-2-yl]thiol-3-cephem-4-carboxylic acid diphenylmethyl ester iodide, phosphorus pentachloride and pyridine is 1:5~5.5:6.5~7, the temperature of the fifth reaction is 0~5°C, and the time is 2~4h.

7. The preparation method according to claim 1, characterized in that: During the sixth reaction, the mass fraction of the concentrated hydrochloric acid is 30-36%, the dosage ratio of the 7β-amino-3-[4-(1-methyl-4-pyridyl)-1,3-thiazol-2-yl]mercapto-3-cephem-4-carboxylic acid diphenylmethyl ester chloride and concentrated hydrochloric acid is 122mmom:45-55mL, the temperature of the sixth reaction is 35-40°C, and the time is 4-6h.

8. The preparation method according to claim 1, characterized in that: During the seventh reaction, the molar ratio of the 7β-amino-3-[4-(1-methyl-4-pyridinyl)-1,3-thiazol-2-yl]thio-3-cephem-4-carboxylic acid hydrochloride and (Z)-2-(5-dichlorophosphoramido-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetyl chloride is 1:1~1.1, the molar ratio of the β-amino-3-[4-(1-methyl-4-pyridinyl)-1,3-thiazol-2-yl]thio-3-cephem-4-carboxylic acid hydrochloride and triethylamine is 1:1~1.1, the temperature of the seventh reaction is 0~5°C, and the time is 2~3h.

9. The preparation method according to claim 1, characterized in that: The reagents for the hydrolysis are water and acetic acid, and the volume ratio of the water to the acetic acid is 1.5-1.8:

1.

10. The preparation method according to claim 1 or 9, characterized in that: The hydrolysis temperature is 25-35° C. and the time is 0.5-1 h.

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