Preparation method of cefpodoxime proxetil

Abstract

The invention relates to a preparation method of cefpodoxime proxetil. The preparation method comprises the following steps: (1) reacting cefpodoxime with 1-iodoethyl isopropyl carbonate in the presence of dichloromethane and triethylamine; (2) mixing the reaction system in the step (1) with hydrochloric acid, standing for layering, and reserving an organic phase layer; (3) mixing the organic phase layer obtained in the step (2) with an acetic acid solution, standing for layering, and retaining a water phase layer; (4) mixing the water phase layer in the step (3) with an organic solvent, standing for layering, and retaining the water phase layer; and (5) carrying out reduced pressure distillation on the water phase layer in the step (4), then adjusting the pH value to be neutral, filtering, and washing and drying a wet product to obtain the cefpodoxime proxetil. The raw materials used in the preparation method are easy to obtain, the cost is low, the prepared product is high in yield and purity, other detection indexes meet the CHP2020 edition Chinese pharmacopoeia, the solubility in trichloromethane meets the KPX edition Korean pharmacopoeia standard, the steps are simple, and the preparation method is suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and particularly relates to a preparation method of cefpodoxime proxetil. Background Art

[0002] The chemical name of cefpodoxime proxetil: (6R,7R)-7-[2-(2-aminothiazol-4-yl)-2-(Z)-(methoxyimino)-acetamido]-3-methoxymethyl-8-oxo-5-thia-1-azabicyclo-[4,2,0]oct-2-ene-2-carboxylic acid isopropoxycarbonyloxyethyl ester. The structural formula of cefpodoxime proxetil is as follows:

[0003]

[0004] Cefpodoxime Proxetil (CPDX-PR) is a third-generation oral cephalosporin. Its structural characteristics are that there is a methoxymethyl group at the 3-position of the cephalosporin skeleton and an ethyl isopropyl carbonate group on the 4-position carboxylic acid. The presence of these two substituents makes it have good oral absorption. The 7-position is connected with a methoxyimino thiazolyl group, which is closely related to its anti-Gram-negative bacterial activity and resistance to β-lactamase. There is an asymmetric carbon atom in the ethyl isopropyl carbonate group, which makes cefpodoxime proxetil form two diastereoisomers, both of which are active ingredients, and are respectively named cefpodoxime proxetil A isomer and cefpodoxime proxetil B isomer. The synthesis of cefpodoxime proxetil mainly uses 7-ACA as a raw material, introduces a side chain at the 7-position amino group, esterifies the 4-position carboxyl group, hydrolyzes the 3-position ester and then carries out methyl etherification.

[0005] In the prior art, cefpodoxime proxetil is mostly synthesized by esterifying cefpodoxime acid (cefpodoxime) with 1-iodoethyl isopropyl carbonate, specifically as follows.

[0006] WO01 / 34611A1 discloses a preparation method of high-purity cefpodoxime proxetil. Cefpodoxime acid is first salted out in a mixed solvent, and then a crown ether is used as a catalyst for the esterification reaction, with a yield of 81.3%. This method has complex processes, high cost of using crown ether, uses isopropyl ether for crystallization, and has a high risk of residual solvents.

[0007] WO02 / 068429A1 discloses a preparation method of cefpodoxime proxetil. Cefpodoxime acid and 1-iodoethyl isopropyl carbonate are used as a catalyst for the esterification reaction with DBU. After the post-treatment solvent ethyl acetate is concentrated under reduced pressure to a certain volume, it is added to cyclohexane to obtain the crude product of cefpodoxime proxetil. The crude product is dissolved in methanol and added to water to obtain cefpodoxime proxetil, with a yield of 69.0% and an HPLC purity of 98.0%. In the process of refining the crude product of this method, it is easy to produce oil, and there are high risks of residual solvents and solubility.

[0008] WO2004048387A1 discloses an improved method for preparing cefpodoxime proxetil. Cefpodoxime acid and 1-iodoethyl isopropyl carbonate are subjected to an esterification reaction under the catalysis of tetramethylguanidine or N,N-diisopropylethylamine base. The post-treatment solvent ethyl acetate is concentrated under reduced pressure to a viscous substance, then dissolved in methanol and concentrated under reduced pressure to a viscous residue. Then, methanol and dilute hydrochloric acid solvent are added and then added to water, and the pH is adjusted to 3.5 - 4.0 with dilute ammonia water until crystallization is complete. The yield is 80.4 - 91.9%, and the HPLC purity is 99.1 - 99.2%. This method requires concentrating ethyl acetate and methanol to a viscous residue under reduced pressure, there is a risk of product decomposition, and it is not suitable for industrial production.

[0009] WO2004056834A1 discloses a method for preparing cefpodoxime proxetil. Cefpodoxime acid and 1-iodoethyl isopropyl carbonate are subjected to an esterification reaction under the catalysis of DBU base to obtain crude cefpodoxime proxetil. The crude cefpodoxime proxetil is prepared into hydrochloride in 4-methyl-2-pentanone, and the cefpodoxime proxetil hydrochloride is neutralized with sodium bicarbonate in methanol to obtain cefpodoxime proxetil. The yield is 77.7%, and the HPLC purity is ≥95%. This method first prepares the crude product, then forms the hydrochloride, and then neutralizes to prepare the finished product. The process is complex, and the yield and purity are low, and it is not suitable for industrial production.

[0010] WO2004060896A1 discloses a method for preparing cefpodoxime proxetil. Cefpodoxime acid and 1-iodoethyl isopropyl carbonate are subjected to an esterification reaction under the catalysis of DBU base. The post-treatment solvent ethyl acetate is concentrated under reduced pressure to a certain volume, and an aqueous solution of methanesulfonic acid is added. After the product is transferred to the aqueous layer, it is washed twice with ethyl acetate and cyclohexane, and then the pH is adjusted to 7 with a sodium bicarbonate solution to obtain cefpodoxime proxetil. The yield is 52.1%. This method has a risk of genotoxic impurities and a low yield.

[0011] CN1305876C discloses a method for preparing high-purity cefpodoxime proxetil in one step. Using cefpodoxime acid as a raw material, after reacting with an organic weak basic salt such as sodium acetate or sodium 2-ethylhexanoate, a side chain is added for an esterification reaction to directly obtain cefpodoxime proxetil. The yield is 73%. This method has a relatively low yield and uses isopropyl ether for crystallization, with a high risk of residual solvents.

[0012] WO2010097675A1 discloses an improved method for preparing cefpodoxime proxetil. Cefpodoxime acid and 1-iodoethyl isopropyl carbonate are subjected to an esterification reaction under the catalysis of DBU and sodium acetate bases. The post-treatment solvent ethyl acetate is concentrated under reduced pressure to a certain volume, and an aqueous solution of methanesulfonic acid is added. After the product is transferred to the aqueous layer, it is washed twice with ethyl acetate and cyclohexane, and then the pH is adjusted to 4.5 with dilute ammonia water to obtain cefpodoxime proxetil. The yield is 93.5%, and the HPLC purity is 99.5%. This method has a risk of genotoxic impurities and requires concentrating ethyl acetate under reduced pressure, there is a risk of product decomposition, and it is not suitable for industrial production.

[0013] EP2520578A1 discloses a purification method of cephalosporins. Cefpodoxime acid and 1-iodoethyl isopropyl carbonate are subjected to an esterification reaction under the catalysis of DBU base. The post-treatment solvent ethyl acetate is concentrated under reduced pressure to a certain volume, and cyclohexane and oxalic acid dihydrate are added to prepare cefpodoxime ester oxalate. The oxalate is dissolved in water and neutralized with sodium bicarbonate solution to pH 5.0 - 5.8 to obtain cefpodoxime ester. This method has complex procedures, uses cyclohexane for crystallization, and has a high risk of residual solvents.

[0014] CN106046024A discloses a preparation method of cefpodoxime ester. Using D-7-ACA as the starting material, there is no need to separate in the middle, and cefpodoxime ester crude product is synthesized in one step, and then the cefpodoxime ester crude product is purified by a simple and feasible recrystallization method to obtain cefpodoxime ester with an HPLC purity of 96%. This method has extremely high safety risks when using ether for ultrasonic washing, the product purity is relatively low, and it uses methanol and N,N-dimethylformamide for crystallization, with a high risk of residual solvents.

[0015] CN109232609A discloses a method for preparing high-purity cefpodoxime ester. Under the action of carbonate and basic ionic liquid, cefpodoxime acid reacts with iodoester in an organic solvent, and after post-treatment, the cefpodoxime ester is obtained. The raw material 1-butyl-3-methylimidazolium hydroxide used in this method is not easily available, there is no separation process in the post-treatment, and the risks of residual solvents and solubility are high.

[0016] CN115093431A discloses a method for synthesizing cefpodoxime ester. Cefpodoxime acid and 1-iodoethyl isopropyl carbonate are subjected to an esterification reaction under the catalysis of tetramethylguanidine base by adding an auxiliary agent sodium cyanoborohydride or sodium triacetoxyborohydride, and the yield is 72.6 - 74.1%. The yield of this method is relatively low.

[0017] In summary, the above methods all have some problems, such as the raw materials are not easily available, the procedures are complex, the operation is not smooth, there are environmental risks, the yield or purity is low, the residual solvents and solubility do not meet the pharmacopoeia standards, etc. Therefore, developing a synthetic process with easily available raw materials, simple procedures, smooth operation, environmental friendliness, economic feasibility, high purity, and residual solvents and solubility meeting the pharmacopoeia standards has become a major technical problem. Summary of the Invention

[0018] The purpose of the present invention is to provide a preparation method of cefpodoxime ester. The raw materials in this preparation method are easily available, low in cost, the steps are simple, environmentally friendly, and the prepared cefpodoxime ester not only meets the pharmacopoeia standards but also has high yield and high purity.

[0019] To achieve the above purpose, the technical solution adopted by the present invention is:

[0020] The present invention provides a method for preparing cefpodoxime proxetil, comprising the following steps:

[0021] (1) React cefpodoxime with 1-iodoethyl isopropyl carbonate in the presence of dichloromethane and triethylamine;

[0022] (2) Mix the reaction system of step (1) with hydrochloric acid, let it stand for layering, and retain the organic phase layer;

[0023] (3) Mix the organic phase layer of step (2) with an acetic acid solution, let it stand for layering, and retain the aqueous phase layer;

[0024] (4) Mix the aqueous phase layer of step (3) with an organic solvent, let it stand for layering, and retain the aqueous phase layer;

[0025] (5) Carry out vacuum distillation on the aqueous phase layer in step (4), then adjust the pH to neutral, filter, and after washing and drying the wet product, the cefpodoxime proxetil is obtained.

[0026] The present invention uses dichloromethane as the reaction solvent and triethylamine as the acid-binding agent to carry out an esterification reaction between cefpodoxime acid and 1-iodoethyl isopropyl carbonate (iodoester). After the reaction is completed, the reaction solution is washed with hydrochloric acid and then an acetic acid solution is added to convert cefpodoxime proxetil into cefpodoxime proxetil acetate and transfer it to the aqueous phase. Then, the cefpodoxime proxetil acetate is washed with an organic solvent to effectively remove impurities in the product. Finally, the cefpodoxime proxetil acetate aqueous solution is subjected to vacuum distillation to remove the dissolved residual organic solvent, and then the pH is adjusted to 7, filtered, washed, and dried to obtain cefpodoxime proxetil with high purity and high yield. The preparation method of the present invention is simple, the raw materials are easy to obtain, the cost is low, the product yield is high and the purity is high, and other detection indicators all meet the requirements of the Chinese Pharmacopoeia 2020 Edition. The solubility in chloroform meets the standards of the Korean Pharmacopoeia KPX Edition, and it is suitable for industrial production.

[0027] Preferably, the preparation method further includes adding 4-dimethylaminopyridine to the reaction system of step (1). Using 4-dimethylaminopyridine as a catalyst can further improve the product yield and purity. [[ID=2३]]

[0028] More preferably, the molar ratio of the cefpodoxime to the 4-dimethylaminopyridine in the feed is 1:(0.01 - 0.1).

[0029] Preferably, the temperature of the reaction in step (1) is controlled at 20°C - 30°C.

[0030] Preferably, the molar ratio of the cefpodoxime to the 1-iodoethyl isopropyl carbonate in the feed is 1:(0.5 - 1.5), more preferably 1:(0.9 - 1.1), such as 1:0.9, 1:1, 1:1.1 or a value between the above two values.

[0031] Preferably, the molar ratio of cefpodoxime to triethylamine in the feeding is 1:(1-1.5), such as 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5 or a value between the above two values.

[0032] Preferably, the feeding ratio of cefpodoxime to dichloromethane is 1 g:(5-15) mL, more preferably 1 g:(8-12) mL, such as 1 g:8 mL, 1 g:9 mL, 1 g:10 mL, 1 g:11 mL, 1 g:12 mL or a value between the above two values.

[0033] Preferably, the molar ratio of hydrogen chloride in hydrochloric acid to cefpodoxime in the feeding is (0.5-1.5):1, more preferably (0.8-1.2):1, such as 0.8:1, 0.9:1, 1:1, 1.1:1, 1.2:1 or a value between the above two values.

[0034] Preferably, the molar ratio of acetic acid to cefpodoxime in the feeding is (1.0-1.5):1, such as 1:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1 or a value between the above two values.

[0035] Preferably, the organic solvent is dichloromethane.

[0036] More preferably, the feeding ratio of the organic solvent to cefpodoxime is (3-10) mL:1 g.

[0037] Even more preferably, the organic solvent is fed in one time or in batches. When the organic solvent is fed in batches, after each feeding, stir, let it stand for stratification, and retain the aqueous layer.

[0038] In some embodiments, the organic solvent is fed in 2-3 times, and the ratio of the feeding amount of each time to the feeding amount of cefpodoxime is (2-4) mL:1 g.

[0039] Preferably, the temperature of reduced pressure distillation is controlled at 20°C-30°C.

[0040] Preferably, ammonia water is used to adjust the pH to neutral.

[0041] Preferably, step (2) further includes washing the organic phase layer with purified water.

[0042] More preferably, the number of washings is one or more times, and the ratio of the purified water used for each washing to the feeding amount of cefpodoxime is (1-5) mL:1 g, even more preferably (2-4) mL:1 g.

[0043] Due to the application of the above technical solution, the present invention has the following advantages compared with the prior art:

[0044] The raw materials used in the preparation method of the present invention are easily available, the cost is low, the yield and purity of the obtained product are high, and other detection indexes all meet the requirements of the Chinese Pharmacopoeia 2020 Edition. The solubility in chloroform meets the standards of the Korean Pharmacopoeia KPX Edition. The steps are simple and suitable for industrial production. Description of the Drawings

[0045] Figure 1 It is the HPLC chromatogram of cefpodoxime proxetil in Example 1;

[0046] Figure 2 It is the HPLC chromatogram of cefpodoxime proxetil in Example 2;

[0047] Figure 3 It is the HPLC chromatogram of cefpodoxime proxetil in Example 3;

[0048] Figure 4 It is the HPLC chromatogram of cefpodoxime proxetil in Comparative Example 1. Detailed Embodiments

[0049] The present invention will be further described below in conjunction with the embodiments. However, the present invention is not limited to the following embodiments. The implementation conditions adopted in the embodiments can be further adjusted according to different requirements of specific use. The implementation conditions not specified are the conventional conditions in the industry. The technical features involved in each implementation manner of the present invention can be combined with each other as long as they do not conflict with each other.

[0050] In the following examples and comparative examples, the raw materials used are obtained commercially or can be prepared according to the existing preparation processes.

[0051] Example 1

[0052] Add 100 mL of dichloromethane to the reaction flask, start stirring, and add 10.0 g (23.4 mmol) of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-(Z)-2-(methoxyimino)acetamido]-3-methoxymethyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (cefpodoxime, CAS No.: 80210-62-4), 2.6 g (25.6 mmol, 1.1 eq) of triethylamine at 20 - 30 °C. Then add 6.0 g (23.4 mmol, 1.0 eq) of 1-iodoethyl isopropyl carbonate (iodoester) and 0.1 g (0.8 mmol, 0.03 eq) of 4-dimethylaminopyridine. Control the temperature at 20 - 30 °C and stir the reaction for 4 h. Add a solution prepared by mixing 2.6 g (25.6 mmol, 1.1 eq) of hydrochloric acid with a mass concentration of 36% and 30 mL of purified water to the reaction flask, stir for 15 min, let it stand for 30 min, separate the layers, and retain the dichloromethane layer. Wash the dichloromethane layer with 30 mL of purified water, stir for 15 min, let it stand for 30 min, separate the layers, and retain the dichloromethane layer. Add 100 mL of purified water and 1.7 g of acetic acid (28.3 mmol, 1.2 eq), stir for 15 min, let it stand for 30 min, separate the layers, and retain the aqueous layer; add 30 mL of dichloromethane to the aqueous layer, stir for 15 min, let it stand for 30 min, separate the layers, and retain the aqueous layer; add 30 mL of dichloromethane to the aqueous layer, stir for 15 min, let it stand for 30 min, separate the layers, and retain the aqueous layer. Distill the aqueous layer under reduced pressure at 20 - 30 °C for 1 h, slowly add 3.3 g of ammonia water with a mass concentration of 25% (23.5 mmol, 1.0 eq) and 30 mL of purified water while stirring, adjust the pH to 7, filter, wash the wet product 3 times with 30 mL of purified water, drain, and dry the wet product in vacuo at 40 °C to constant weight to obtain 12.5 g of cefpodoxime ester, with an HPLC purity of 99.1%, a molar yield of 94.9%, and other detection indicators all meeting the standards of the Chinese Pharmacopoeia 2020 Edition, and the solubility in chloroform meeting the standards of the Korean Pharmacopoeia KPX Edition.

[0053] In this example, HPLC detection was carried out according to the high performance liquid chromatography method (General Chapter 0512, Volume IV of the Chinese Pharmacopoeia 2020 Edition). The chromatographic column was YMC-Pack ODS-AM 4.6 mm × 150 mm, 5 μm. The mobile phase A was water - methanol - formic acid (700:300:1), and the mobile phase B was water - methanol - formic acid (40:960:1). Gradient elution was carried out according to Table 1 below; the flow rate was 1.0 mL / min; the detection wavelength was 254 nm; the column temperature was 30 °C.

[0054] Table 1

[0055] Time (min) Mobile phase A (%) Mobile phase B (%) 0 95 5 26 95 5 58 15 85 62 15 85 63.2 95 5 68 95 5

[0056] Example 2

[0057] Add 100 mL of dichloromethane to the reaction flask, start stirring, and add 10.0 g (23.4 mmol) of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-(Z)-2-(methoxyimino)acetamido]-3-methoxymethyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid at 20 - 30 °C, then add 2.6 g (25.6 mmol, 1.1 eq) of triethylamine, and then add 6.0 g (23.4 mmol, 1.0 eq) of 1-iodoethyl isopropyl carbonate. Control the temperature at 20 - 30 °C and stir the reaction for 4 h. Add a solution prepared by mixing 2.6 g (25.6 mmol, 1.1 eq) of hydrochloric acid with a mass concentration of 36% and 30 mL of purified water to the reaction flask, stir for 15 min, let stand for 30 min, separate the layers, and retain the dichloromethane layer. Wash the dichloromethane layer with 30 mL of purified water, stir for 15 min, let stand for 30 min, separate the layers, and retain the dichloromethane layer. Add 100 mL of purified water and 1.7 g of acetic acid (28.3 mmol, 1.2 eq), stir for 15 min, let stand for 30 min, separate the layers, and retain the aqueous layer; add 30 mL of dichloromethane to the aqueous layer, stir for 15 min, let stand for 30 min, separate the layers, and retain the aqueous layer; add 30 mL of dichloromethane to the aqueous layer, stir for 15 min, let stand for 30 min, separate the layers, and retain the aqueous layer. Distill the aqueous layer under reduced pressure at 20 - 30 °C for 1 h, slowly add 3.3 g of ammonia water with a mass concentration of 25% (23.5 mmol, 1.0 eq) and 30 mL of purified water while stirring, adjust the pH to 7, filter, wash the wet product with 30 mL of purified water 3 times, drain, and dry the wet product in vacuo at 40 °C to constant weight to obtain 11.1 g of cefpodoxime proxetil, with an HPLC purity of 98.6%, a molar yield of 83.9%, and other detection indicators all meeting the standards of the Chinese Pharmacopoeia 2020 edition, and the solubility in chloroform meeting the standards of the Korean Pharmacopoeia KPX edition.

[0058] The HPLC detection of Example 2 is the same as that of Example 1.

[0059] In Example 2, 4-dimethylaminopyridine as a catalyst was not used, and the yield and purity were slightly lower than those of Example 1 where 4-dimethylaminopyridine was used as a catalyst.

[0060] Example 3

[0061] This example is basically the same as Example 1, with the main difference being: the reaction temperature is different, specifically -8 to -5 °C.

[0062] 9.5 g of cefpodoxime proxetil was obtained, with an HPLC purity of 98.3% and a molar yield of 71.6%.

[0063] Example 3 was reacted at a relatively low temperature, resulting in low purity and yield, and its solubility in chloroform did not meet the Korean Pharmacopoeia (KPX) standard.

[0064] Comparative Example 1 (Refer to WO02 / 068429A1)

[0065] 10 g (23.4 mmol) of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-(Z)-2-(methoxyimino)acetamido]-3-methoxymethyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid was added to 60 mL of N,N-dimethylacetamide. The reaction mixture was cooled to -8°C and then, while maintaining the temperature at -8 to -5°C, 3.33 g (21.9 mmol, 0.93 eq) of 1,8-diazobisspiro[5.4.0]undec-7-ene (DBU) was added. 5.85 g (22.7 mmol, 0.97 eq) of 1-iodoethyl isopropyl carbonate was then added. The reaction mixture was stirred and reacted for 45 minutes while maintaining the temperature at -8 to -5°C. The reaction mixture was then poured into 300 mL of ethyl acetate while maintaining the temperature at 20 to 22°C, followed by the addition of 300 mL of water. The reaction mixture was stirred for 10 minutes, and the organic layer was separated. The organic layer was then washed successively with hydrochloric acid solution, sodium thiosulfate solution, and sodium chloride solution. The ethyl acetate layer obtained above was concentrated to approximately 40 mL at 30-35°C and slowly added to 300 mL of cyclohexane over approximately 30 minutes at 25°C. The precipitated solid was filtered and washed with cyclohexane. The wet product was added to 40 mL of methanol at room temperature to obtain a solution, which was concentrated to approximately 30 mL at 30-35°C. The concentrate was added to 180 mL of water at 20-25°C for approximately 15 minutes, resulting in the precipitation of a small amount of oil. With continued stirring, the oil solidified, was filtered, and washed with 20 mL of a cold methanol / water mixture (1:6 v / v). The wet product was dried to yield 9 g of pure cefpodoxime proxetil with an HPLC purity of 97.8% and a molar yield of 67.5%. The solubility in acetonitrile and chloroform did not meet the standards of the Korean Pharmacopoeia (KPX).

[0066] The HPLC detection of Comparative Example 1 is the same as that of Example 1.

[0067] In Comparative Example 1, DBU was used as the base catalyst, and impurity C+B-II was difficult to control; the cyclohexane residue easily exceeded the standard; the methanol solution easily produced oil when added to water; and the solubility in acetonitrile and chloroform was unsatisfactory.

[0068] The above detailed description of the present invention is intended to enable persons familiar with the art to understand the contents of the present invention and implement them. It does not limit the scope of protection of the present invention. Any equivalent changes or modifications made based on the spirit of the present invention should be included in the scope of protection of the present invention.

Claims

1. A preparation method of cefpodoxime proxetil, characterized in that: The preparation method comprises the following steps: (1) React cefpodoxime with 1-iodoethyl isopropyl carbonate in the presence of dichloromethane and triethylamine; (2) Mix the reaction system of step (1) with hydrochloric acid, let it stand for layering, and retain the organic phase layer; (3) Mix the organic phase layer of step (2) with acetic acid solution, let it stand for layering, and retain the aqueous phase layer; (4) Mix the aqueous phase layer of step (3) with an organic solvent, let it stand for layering, and retain the aqueous phase layer; (5) Perform vacuum distillation on the aqueous phase layer in step (4), then adjust the pH to neutral, filter, and after washing and drying the wet product, obtain the cefpodoxime ester; 2. The preparation method of cefpodoxime proxetil according to claim 1, characterized in that: The preparation method further comprises adding 4-dimethylaminopyridine to the reaction system of step (1).

3. The preparation method of cefpodoxime proxetil according to claim 2, characterized in that: The molar ratio of the charged cefpodoxime to the 4-dimethylaminopyridine is 1:(0.01 - 0.1).

4. The preparation method of cefpodoxime proxetil according to claim 1, wherein: Control the reaction temperature in step (1) to be 20°C - 30°C.

5. The preparation method of cefpodoxime proxetil according to claim 1, characterized in that: The molar ratio of the charged cefpodoxime to the 1-iodoethyl isopropyl carbonate is 1:(0.5 - 1.5); and / or, The molar ratio of the charged cefpodoxime to the triethylamine is 1:(1 - 1.5); and / or, The feeding ratio of the cefpodoxime to the dichloromethane is 1 g:(5 - 15) mL.

6. The preparation method of cefpodoxime proxetil according to claim 1, characterized in that: The molar ratio of hydrogen chloride in the hydrochloric acid to the charged cefpodoxime is (0.5 - 1.5):1; and / or, The molar ratio of the acetic acid to the charged cefpodoxime is (1.0 - 1.5):1; and / or, The organic solvent is dichloromethane, the feeding ratio of the organic solvent to the cefpodoxime is (3 - 10) mL:1 g, the organic solvent is fed in one batch or in batches. When the organic solvent is fed in batches, after each feeding, stir, let it stand for layering, and retain the aqueous phase layer.

7. The preparation method of cefpodoxime proxetil according to claim 1, wherein: Control the vacuum distillation temperature to be 20°C - 30°C.

8. The preparation method of cefpodoxime proxetil according to claim 1, wherein: Use ammonia water to adjust the pH to neutral.

9. The preparation method of cefpodoxime proxetil according to claim 1, characterized in that: Step (2) further comprises washing the organic phase layer with purified water.

10. The preparation method of cefpodoxime proxetil according to claim 9, characterized in that: The number of times of the washing is one or more times, and the feeding ratio of the purified water used for each washing to the cefpodoxime is (1 - 5) mL:1 g.

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