Preparation method of cefpodoxime proxetil

Abstract

The invention discloses a preparation method of cefpodoxime proxetil and cefpodoxime acid sodium serving as an intermediate of the cefpodoxime proxetil, and relates to the technical field of medicine synthesis. Comprising the following steps: completely reacting 7-AMCA and AE active ester in the presence of a reaction solvent and triethylamine at controlled temperature, and extracting and separating reaction liquid to obtain a water phase; adding an alkali reagent into the water phase to completely react, so that the cefpodoxime acid sodium salt is separated out; the method comprises the following steps: completely reacting cefpodoxime acid sodium salt with 1-iodoethyl isopropyl carbonate in the presence of an organic solvent and a catalyst, adding a reaction solution into a buffer water system to separate out a wet cefpodoxime proxetil product, and washing and drying to obtain a target product. The cefpodoxime proxetil is prepared by preparing the high-quality cefpodoxime acid sodium salt, the high-quality cefpodoxime proxetil can be obtained through a simple finished product preparation technology, and the quality of the cefpodoxime proxetil can be further improved on the basis that the production cost is controlled.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical synthesis, and particularly relates to a method for preparing cefpodoxime proxetil. Background Art

[0002] Cefpodoxime proxetil is an oral third-generation cephalosporin with a broad antibacterial spectrum, a relatively long half-life, and good tolerance. It has no antibacterial activity itself. After oral administration, it is absorbed through the intestine and hydrolyzed by non-specific esterase in the intestinal wall to cefpodoxime to exert its antibacterial effect. It has a broad antibacterial spectrum against Gram-positive bacteria and Gram-negative bacteria, is stable to β-lactamase, and has a strong affinity with the bacterial action target penicillin-binding proteins (PBPs). It is widely used in the treatment of respiratory tract, urinary tract, gynecological and obstetric infectious diseases, suppurative otitis media, etc. Compared with drugs such as amoxicillin, cefuroxime axetil, cefaclor, and cefixime, it has the advantages of a small treatment dose, fewer administration times, good tolerance, and few side effects, and is one of the best-selling cephalosporin antibiotics on the market.

[0003] Cefpodoxime proxetil, chemically named (6R,7R)-3-methoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-[(Z)-methoxyimino]acetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid-(RS)-1-(isopropoxycarbonyloxy)ethyl ester, and its structural formula is shown as follows. The cephalosporin skeleton has a methoxymethyl group at the 3-position and an ethyl isopropyl carbonate group on the 4-carboxylic acid. The presence of these two substituents gives it good oral absorbability. The 7-position is connected with a methoxyimino thiazolyl group, which is closely related to its activity against Gram-negative bacteria 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. 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.

[0004] Cefpodoxime acid, chemically named (6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido]-3-(methoxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, and its structural formula is shown as follows. It is an important intermediate in the preparation process of cefpodoxime proxetil. In the preparation process of cefpodoxime proxetil, its quality and cost are the main factors affecting the product quality and cost of cefpodoxime proxetil.

[0005]

[0006] The reported methods for producing cefpodoxime proxetil mainly use 7-aminocephalosporanic acid (7-ACA) or 7-amino-3-methoxymethyl-cephalosporanic acid (7-AMCA) as starting materials. The side chain is introduced at the 7-position amino group through the active ester or acyl halide of the side chain to obtain cefpodoxime acid. After esterification with 1-iodoethyl isopropyl carbonate, it is extracted, washed, dried, concentrated, and then crystallized to obtain cefpodoxime proxetil.

[0007] Patent W02013041999A discloses a method using 7-ACA as the starting material, first reacting with methanesulfonic acid to obtain 7-AMCA, and then carrying out an acylation reaction with AE active ester under the catalysis of triethylamine to obtain cefpodoxime acid. The intermediate 7-AMCA obtained by this method is difficult to filter during the post-treatment process, the material properties are poor, and it cannot be mass-produced. At the same time, the relatively expensive methanesulfonic acid reagent is used, resulting in a high production cost. Moreover, the yield and product purity of this method are relatively low.

[0008]

[0009] Patent CN101768171 discloses a method for preparing cefpodoxime proxetil using 7-AMCA and (Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid (cefotaxime acid) as starting materials. Cefotaxime acid is first esterified with p-nitrophenol under the action of triethylamine, then 7-AMCA is added and stirred to react, and the pH value is adjusted with hydrochloric acid to obtain cefpodoxime acid. Then, using PEG6000 as a catalyst, cefpodoxime acid reacts with 1-iodoethyl isopropyl carbonate. After the reaction is completed, isopropyl acetate is added for extraction. The organic phase is washed, dried, decolorized, and then ether is added for crystallization, and dried to obtain cefpodoxime proxetil. This method uses p-nitrophenol as an activator, which is flammable and toxic and is not suitable for use. At the same time, a large amount of ether is used as an anti-solvent during the post-treatment process of cefpodoxime proxetil, with a relatively high safety risk and is not conducive to scale-up production.

[0010]

[0011] Patent CN106046024 discloses a method for preparing cefpodoxime proxetil using deacetyl-7-aminocephalosporanic acid (D-7-ACA) and AE active ester as starting materials. D-7-ACA reacts with trimethyl orthoformate under the catalysis of boron trifluoride etherate to obtain 7-AMCA. Then, it undergoes an acylation reaction with AE active ester under the action of triethylamine to obtain cefpodoxime acid. Subsequently, cefpodoxime acid is dissolved in DMF and reacts with 1-iodoethyl isopropyl carbonate in the presence of sodium acetate and water. After the reaction, chloroform or isopropyl acetate is added for extraction. The organic phase is washed, dried, concentrated, and then ether is added for crystallization. After drying, cefpodoxime proxetil is obtained. The boron trifluoride etherate used in the preparation of 7-AMCA in this method is flammable, toxic, highly irritating, and highly corrosive, posing a significant safety hazard in production. At the same time, the post-treatment process of cefpodoxime proxetil is complex. High-temperature concentration easily degrades the product, and a large amount of ether is used as an anti-solvent during the crystallization process, resulting in a relatively high safety risk and being not conducive to scale-up production.

[0012]

[0013] Patent CN1763046 discloses a method for preparing cefpodoxime proxetil using deacetyl-7-aminocephalosporanic acid (D-7-ACA) and AE active ester as starting materials without going through 7-AMCA. D-7-ACA first reacts with AE active ester under the condition of sodium carbonate to prepare the sodium salt of demethyl cefpodoxime acid, which is dissolved in DMF and reacts with 1-iodoethyl isopropyl carbonate under the condition of DBU. Finally, it forms a methyl ether with methanol. After concentrating to remove methanol, it is extracted with ethyl acetate, and the product is directly obtained after washing, drying, and concentration. This method has a relatively long synthesis route, complex post-treatment, and the final product is obtained by direct concentration, which is not suitable for scale-up production.

[0014]

[0015] In addition, Chinese patents CN101768171B, CN100361996, US patent US2004092734A1, and patent WO2004011471A1, etc., all precipitate the product in an anti-solvent (such as ether, cyclohexane, isopropyl ether, etc.) after extraction and concentration of the organic phase (such as ethyl acetate, propyl acetate, chloroform, etc.) after the reaction. This process is complex, the post-treatment time is long, and at the same time, the organic phase of the product is concentrated by heating, increasing the risk of related substances and affecting the product quality.

[0016] Patent WO2004056834A1 discloses a preparation method of cefpodoxime proxetil. In this method, after the reaction of cefpodoxime acid with 1-iodoethyl isopropyl carbonate is completed, the extraction organic phase is concentrated, then MIBK or acetone is added to dissolve it clearly, concentrated hydrochloric acid is added to form a salt, and crystallization is carried out by stirring to obtain cefpodoxime proxetil hydrochloride. Finally, cefpodoxime proxetil hydrochloride is dissolved in methanol, acetonitrile or THF, and then an aqueous sodium bicarbonate solution is added to decompose the salt and crystallize. This method adds a refining process of decomposing the salt and crystallizing after forming the hydrochloride salt on the basis of the concentration process. Although the product quality is improved, the process flow becomes more complex and the production cost is higher.

[0017] In summary, among the current methods for preparing cefpodoxime proxetil, there are disadvantages such as high raw material prices, high toxicity, flammability and explosiveness, and high equipment requirements. More importantly, the quality of cefpodoxime acid is poor, the post-treatment process for preparing cefpodoxime proxetil is complex, the risk of related substances in the product after concentration is large, the yield is low, and the production cost is high. Therefore, it is necessary to find a more efficient, environmentally friendly and simple method for synthesizing cefpodoxime proxetil with industrial production value, and at the same time improve the product quality of cefpodoxime proxetil. Summary of the Invention

[0018] The purpose of the present invention is to provide a preparation method of cefpodoxime proxetil. The sodium salt of cefpodoxime prepared by a one-pot method reacts with 1-iodoethyl isopropyl carbonate to carry out an esterification reaction. After the reaction is complete, the reaction solution is directly transferred into a buffer water system to precipitate cefpodoxime proxetil, shortening the post-treatment operation process, avoiding the use of a large amount of organic solvents, simplifying the production process, avoiding long-term heating and concentration, facilitating the control of product quality, increasing the yield, and saving costs at the same time.

[0019] In order to solve the above technical problems, the technical solution adopted by the present invention is as follows:

[0020] A preparation method of cefpodoxime proxetil, including the following steps:

[0021] React the sodium salt of cefpodoxime with Compound III in the presence of an organic solvent and a catalyst. After the reaction is completed, pour the reaction solution into a buffer water system to precipitate the wet product of the target product, and obtain the target product after washing and drying;

[0022] The reaction general formula is as follows:

[0023]

[0024] The present invention synthesizes cefpodoxime proxetil using sodium cefpodoxime and 1-iodoethyl isopropyl carbonate (Compound III), avoiding the reintroduction of alkali into the system. The reaction system is more stable, the risk of degradation of related substances is smaller, the quality of the cefpodoxime proxetil finished product is significantly improved, and the process is simple and easy to operate, significantly shortening the post-treatment time. It can not only improve the quality of the cefpodoxime proxetil finished product and control the ratio of isomer A and B peaks, but also further reduce the production cost because the crystallization process uses a buffer water system as an anti-solvent, avoiding the use of a large amount of organic solvents.

[0025] Further, the buffer water system is an aqueous solution of sodium acetate and glacial acetic acid. The mass-volume ratio of sodium acetate in the buffer water system is 2-4%, and the pH value of the buffer water system is 4.3-6.2.

[0026] Further, the mass-volume ratio of sodium cefpodoxime to the buffer water system is 1:40-55;

[0027] Further, the mass-volume ratio is 1:50.

[0028] Further, the molar ratio of sodium cefpodoxime to Compound III is 1:0.80-1:2.00;

[0029] Further, the molar ratio of sodium cefpodoxime to Compound III is 1:1.10-1.20.

[0030] Further, the catalyst is a quaternary ammonium salt, a crown ether or PEG6000, or any two catalysts, or all three catalysts are added, or the catalyst can also be not added.

[0031] A preparation method of sodium cefpodoxime for preparing cefpodoxime proxetil, the preparation method of the sodium cefpodoxime includes the following contents:

[0032] (1) Compound I and Compound II are subjected to a temperature-controlled reaction completely in the presence of a reaction solvent and triethylamine, and the reaction solution is separated by extraction to obtain an aqueous phase;

[0033] (2) An alkali reagent is added to the aqueous phase to react completely, so that sodium cefpodoxime precipitates;

[0034] The reaction general formula is as follows:

[0035]

[0036] The present invention prepares cefpodoxime sodium salt by a one-pot method, with simple post-treatment. The removal effect of related substances in the obtained cefpodoxime sodium salt is significantly better than that of directly precipitating cefpodoxime acid, significantly improving the quality of cefpodoxime acid and facilitating the quality control of the next-step production process of cefpodoxime ester. More importantly, it solves the complex processes of extraction, concentration and then recrystallization commonly used in the post-treatment of the cefpodoxime ester preparation process, simplifies the post-treatment operation, and effectively improves and controls the quality of the finished product.

[0037] Further, in step (2), the method for precipitating cefpodoxime sodium salt is: adding an inorganic salt to the reaction solution; the mass ratio of the inorganic salt to Compound I is 7-9:1.

[0038] Further, the inorganic salt is one or more of sodium carbonate, sodium chloride or sodium acetate.

[0039] Further, the inorganic salt is sodium chloride.

[0040] Further, in step (2), the method for precipitating cefpodoxime sodium salt is: adding n-butanol to the reaction solution, and precipitating cefpodoxime sodium salt after azeotropic water-carrying, repeating twice; wherein, the mass-volume ratio of Compound I to n-butanol for each time is 1:25-30.

[0041] Further, in step (2), the method for precipitating cefpodoxime sodium salt is: adding acetone to the reaction solution, and the mass-volume ratio of Compound I to acetone is 1:30-40.

[0042] Further, in step (1), the molar ratio of Compound I to Compound II is 1:0.80-2.00; the molar ratio of Compound I to triethylamine is 1:0.90-1:2.00.

[0043] Further, the molar ratio of Compound I to Compound II is 1:1.05-1.20; the molar ratio of Compound I to triethylamine is 1:1.00-1.10.

[0044] Further, in step (1), the reaction solvent is a mixed solution of methanol, dichloromethane and water; the temperature range for temperature control is 0°C-20°C.

[0045] Further, the volume ratio of methanol, dichloromethane and water is 4-6:16-18:1.

[0046] Further, in step (1), the extraction solvent is dichloromethane.

[0047] Further, the method for extraction and liquid separation is: adding dichloromethane and water to the reaction solution for extraction, adsorbing the extracted aqueous phase with activated carbon, and then extracting impurities from the adsorbed aqueous phase with dichloromethane, and separating to obtain the aqueous phase.

[0048] Further, in step (2), the alkali reagent is sodium 2-ethylhexanoate, sodium acetate or sodium carbonate; the molar ratio of the alkali reagent to Compound I is 1.05 - 1.20:1.

[0049] Further, the alkali reagent is sodium acetate.

[0050] The beneficial effects of the present invention are as follows:

[0051] 1) The present invention prepares cefpodoxime proxetil from cefpodoxime sodium salt with high quality, and can obtain cefpodoxime proxetil with high quality under a relatively simple finished product preparation process. On the basis of controlling production costs, the quality of cefpodoxime proxetil can be further improved: the sodium salt is prepared by a one-pot method, and the post-treatment is simple. The cefpodoxime sodium salt has a significantly better scavenging effect on related substances than directly precipitating cefpodoxime acid. At the same time, the stability of the sodium salt is better than that of the free acid, which is convenient for controlling impurities in the next esterification reaction; using cefpodoxime sodium salt and 1-iodoethyl isopropyl carbonate to synthesize cefpodoxime proxetil can avoid introducing alkali into the system again, the reaction system is more stable, and the risk of degradation of related substances is smaller, resulting in a significant improvement in the quality of the cefpodoxime proxetil finished product.

[0052] 2) After the esterification reaction of the method of the present invention is completed, the reaction solution is directly transferred to a buffer water system for crystallization to obtain cefpodoxime proxetil, avoiding the complex process operations of first extracting with an organic solvent after the reaction in the reported existing process, then washing, drying, concentrating to obtain an oil, and then crystallizing in an anti-solvent. Considering that the main structure of cefpodoxime proxetil is a β-lactam ring and is sensitive to temperature. The method of the present invention shortens the post-treatment operation process, simplifies the production process, avoids long-term heating and concentration, is convenient for controlling product quality, improves the yield, and saves costs at the same time.

[0053] 3) The cefpodoxime proxetil finished product of the method of the present invention crystallizes in a buffer water system, avoiding the use of a large amount of flammable and explosive organic solvents (ether), significantly reducing the production material cost, and at the same time increasing the safety and operability of the production process. The use of the buffer water system significantly improves the quality and yield of the finished product. Description of the Drawings

[0054] Figure 1 HPLC chromatogram of cefpodoxime acid prepared in Example 3 of the present invention;

[0055] Figure 2 HPLC chromatogram of cefpodoxime proxetil prepared in Example 3 of the present invention. Detailed Embodiments

[0056] The technical solution of the present invention will be described clearly and completely below. Obviously, the embodiments described herein are only a part of the present invention, rather than all embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts fall within the protection scope of the present invention.

[0057] The substances or meanings represented by the impurity codes in Tables 3 - 6 of the present invention are the same as those in the "Pharmacopoeia".

[0058] The high - performance liquid chromatography conditions for cefpodoxime acid used in the present invention are as follows:

[0059] Using octadecylsilane - bonded silica gel as the filler (Waters Xselect HS373, 4.6 mm × 250 mm, 3.5 μm or a chromatographic column with equivalent efficiency); using 0.01 mol / L potassium dihydrogen phosphate solution (weigh 1.36 g of anhydrous potassium hydrogen phosphate and dissolve it in 1000 ml of water) as mobile phase A, and acetonitrile as mobile phase B, and performing linear gradient elution according to Table 1; the flow rate is 1.0 ml per minute; the column temperature is 30 °C; the detection wavelength is 240 nm; the injection volume is 20 μl.

[0060] The high - performance liquid chromatography (HPLC) diagram of the obtained cefpodoxime acid is as Figure 1 shown.

[0061] Table 1 Gradient elution program of cefpodoxime acid

[0062]

[0063]

[0064] The high - performance liquid chromatography conditions for cefpodoxime proxetil used in the present invention are as follows:

[0065] Using octadecylsilane - bonded silica gel as the filler (Agela venusil MP C18 4.6 mm × 150 mm, 5 μm or a chromatographic column with equivalent efficiency), using water - methanol - formic acid (600:400:1) as mobile phase A, and water - methanol - formic acid (50:950:1) as mobile phase B, and performing linear gradient elution according to Table 2; the flow rate is 0.6 ml per minute; the detection wavelength is 254 nm; the injection volume is 20 μl.

[0066] Table 2 Gradient elution program of cefpodoxime acid

[0067]

[0068] Example 1

[0069] Preparation method of Preparation Example No. 1:

[0070] 1) 115 ml of methanol, 350 ml of dichloromethane, 40 g of 7-AMCA, 63.2 g of AE-activator ester and 20 g of water were successively added to the reaction flask. After addition, the temperature was lowered to 0 - 5 °C, and 23.5 g of triethylamine was added dropwise. After the addition, the temperature was maintained at 5 - 10 °C for reaction for 3.0 - 5.0 h. After the reaction ended, 200 ml of dichloromethane and 400 g of water were added, and extraction was carried out at 5 - 10 °C while controlling the temperature. After phase separation, the organic phase was successively extracted with 240 g of water and 300 g of water. The aqueous phases were combined, the temperature was controlled at 10 - 15 °C, the pH was adjusted to 5.5 - 6.0, 2 g of activated carbon was added for adsorption. After adsorption, the aqueous phase was extracted with 200 ml of dichloromethane to remove impurities, and the aqueous phase was reserved for use;

[0071] 2) The temperature of the aqueous phase was controlled at 10 - 15 °C, 13.4 g of sodium acetate was added, and the reaction was stirred for 30 min. The reaction solution was added to 1.2 L of acetone, a solid was precipitated, filtered by suction, washed with 100 × 2 ml of acetone, and dried in vacuo at 40 °C to obtain sodium cefpodoxime;

[0072] 3) 325 ml of DMAc was added to the reaction flask, 50 g of sodium cefpodoxime was added, the temperature was controlled at 0 - 5 °C, and 24.5 g of 1-iodoethyl isopropyl carbonate was added rapidly, and the reaction was carried out for 120 min;

[0073] 4) 2500 ml of purified water and 50 g of sodium acetate were added to another reaction flask. After dissolution and clarification, the pH was adjusted to 4.8 - 5.0 with glacial acetic acid, and the temperature was controlled at 13 - 15 °C for standby. The reaction solution of step (3) was added to the reaction flask, stirred for 25 - 30 min, filtered, washed with 100 × 2 ml of water, and dried to obtain cefpodoxime ester of Preparation Example 1.

[0074] Screening of buffer water systems:

[0075] In Preparation Examples 2 - 5, the sodium acetate / glacial acetic acid in No. 1 was replaced with other substances to form different buffer water systems or without a buffer system. The effects of different buffer water systems on the related substances in the preparation method of the present invention are shown in Table 3.

[0076] Table 3 Comparison of related substances in different buffer systems

[0077]

[0078] Conclusion: It can be seen from Table 3 that when there is no buffer system in Preparation Example 2, the product purity is low and the impurity content is high. In Preparation Examples 3 - 5, the impurities in the products prepared by the buffer systems used are significantly higher than those in the purified water + sodium acetate + glacial acetic acid buffer water system, and the yields are all lower than that of Preparation Example 1. The sodium acetate / glacial acetic acid buffer water system in Preparation Example 1 can significantly improve the quality and yield of cefpodoxime ester finished products.

[0079] Example 2

[0080] Influence of different pH values on the crystallization process:

[0081] Preparation methods for Preparation Examples 6 - 8:

[0082] The preparation methods are the same as those of Preparation Example 1, where the pH values of the buffer water systems are 4.30 - 4.50, 4.80 - 5.00, and 6.00 - 6.20 respectively.

[0083] Table 4 Comparison of related substances at different pH values

[0084]

[0085]

[0086] Conclusion: As can be seen from Table 4, with the increase of the pH value during refined crystallization, impurities C + B2 gradually decrease, impurities D1 + D2 increase to a certain extent, the purity of the main peak decreases, and the yield gradually increases. The inventor also found that the physical properties of the materials obtained by crystallization at different pH values vary greatly. Among them, when the pH value is 4.30 - 4.50, the crystallization material adheres significantly to the wall, the system is viscous, and suction filtration is difficult. When the pH value is 4.80 and above, the physical properties of the material are normal and separation is smooth. At the same time, when the pH value is 6.00 and above, the purity of the main peak decreases.

[0087] Example 3

[0088] 1) Add 115 ml of methanol, 350 ml of dichloromethane, 40 g of 7 - AMCA, 63.2 g of AE - active ester, and 20 g of water to the reaction flask in sequence. After adding, cool down to 0 - 5 °C, and dropwise add 23.5 g of triethylamine. After dropping, keep the temperature at 5 - 10 °C and react for 3.0 - 5.0 h. After the reaction ends, add 200 ml of dichloromethane and 400 g of water, control the temperature at 5 - 10 °C for extraction. After phase separation, the organic phase is extracted with 240 g of water and 300 g of water in sequence. Combine the aqueous phases, control the temperature at 10 - 15 °C, adjust the pH to 5.5 - 6.0, add 2 g of activated carbon for adsorption. After adsorption, extract impurities from the aqueous phase with 200 ml of dichloromethane to obtain the aqueous phase for standby;

[0089] 2) Control the temperature of the aqueous phase at 10 - 15 °C, add 13.4 g of sodium acetate, stir and react for 30 min. Add the reaction solution to 1.2 L of acetone to precipitate solids, filter by suction, wash with 100 × 2 ml of acetone, and dry in vacuum at 40 °C to obtain sodium cefpodoxime;

[0090] 3) Add 325 ml of DMAc to the reaction flask, add 50 g of sodium cefpodoxime, control the temperature at 0 - 5 °C, and quickly add 24.5 g of 1 - iodoethyl isopropyl carbonate, and react for 120 min;

[0091] 4) Add 2500 ml of purified water and 50 g of sodium acetate to another reaction flask. After dissolving completely, adjust the pH to 4.8 - 5.0 with glacial acetic acid, and keep the temperature at 13 - 15 °C for standby. Add the reaction solution from step 3) to the reaction flask, stir for 25 - 30 min, filter, wash with 100 × 2 ml of water, and dry to obtain cefpodoxime proxetil, yield: 84.3% in total.

[0092] Example 4

[0093] 1) Add 115 ml of methanol, 350 ml of dichloromethane, 40 g of 7-AMCA, 63.2 g of AE-activator ester, and 20 g of water to the reaction flask in sequence. After adding, cool down to 0 - 5 °C, and dropwise add 23.5 g of triethylamine. After dropping, keep the temperature at 5 - 10 °C and react for 3.0 - 5.0 h; After the reaction is completed, add 200 ml of dichloromethane and 400 g of water, control the temperature at 5 - 10 °C for extraction. After phase separation, the organic phase is extracted with 240 g of water and 300 g of water in sequence. Combine the aqueous phases, control the temperature at 10 - 15 °C, adjust the pH to 5.0 - 6.0, add 2 g of activated carbon for adsorption. After adsorption, extract impurities from the aqueous phase with 200 ml of dichloromethane to obtain the aqueous phase for standby.

[0094] 2) Keep the temperature of the aqueous phase at 10 - 15 °C, add 13.4 g of sodium acetate, stir and react for 30 min. Add 1000 × 2 ml of n-butanol to the reaction solution, reflux to separate water, precipitate solids, filter by suction, wash with 100 × 2 ml of acetone, and dry at 40 °C under vacuum to obtain sodium cefpodoxime.

[0095] 3) Add 325 ml of DMAc to the reaction flask, add 50 g of sodium cefpodoxime, control the temperature at 0 - 5 °C, and quickly add 24.5 g of 1-iodoethyl isopropyl carbonate, react for 120 min;

[0096] 4) Add 2500 ml of purified water and 50 g of sodium acetate to another reaction flask. After dissolving completely, adjust the pH to 4.8 - 5.0 with glacial acetic acid, and keep the temperature at 13 - 15 °C for standby. Add the reaction solution from step (3) to the reaction flask, stir for 25 - 30 min, filter, wash with 100 × 2 ml of water, and dry to obtain cefpodoxime proxetil, yield: 85.7% in total.

[0097] Example 5

[0098] 1) Add 115 ml of methanol, 350 ml of dichloromethane, 40 g of 7-AMCA, 63.2 g of AE-activator ester and 20 g of water into the reaction flask in sequence. After adding, cool down the temperature to 0 - 5 °C, dropwise add 23.5 g of triethylamine. After dropping, keep the temperature at 5 - 10 °C and react for 3.0 - 5.0 h. After the reaction is completed, add 200 ml of dichloromethane and 400 g of water, control the temperature at 5 - 10 °C for extraction. After phase separation, the organic phase is extracted with 240 g of water and 300 g of water in sequence. Combine the aqueous phases, control the temperature at 10 - 15 °C, adjust the pH to 5.5 - 6.0, add 2 g of activated carbon for adsorption. After adsorption, extract the impurities in the aqueous phase with 200 ml of dichloromethane to obtain the aqueous phase for standby.

[0099] 2) Control the temperature of the aqueous phase at 10 - 15 °C, add 13.4 g of sodium acetate, stir and react for 30 min. Add 310 g of sodium chloride into the reaction solution to precipitate solids. Filter by suction, wash with 100×2 ml of acetone, and dry in vacuum at 40 °C to obtain sodium cefpodoxime.

[0100] 3) Add 325 ml of DMAc into the reaction flask, add 50 g of sodium cefpodoxime, control the temperature at 0 - 5 °C, and quickly add 24.5 g of 1-iodoethyl isopropyl carbonate, react for 120 min.

[0101] 4) Add 2500 ml of purified water and 50 g of sodium acetate into another reaction flask. After dissolving clearly, adjust the pH to 4.8 - 5.0 with glacial acetic acid, and control the temperature at 13 - 15 °C for standby. Add the reaction solution of step (3) into the reaction flask, stir for 25 - 30 min, filter, wash with 100×2 ml of water, and dry to obtain cefpodoxime ester, yield: 84.9% in total.

[0102] Example 6

[0103] 1) Add 115 ml of methanol, 350 ml of dichloromethane, 40 g of 7-AMCA, 63.2 g of AE-activator ester and 20 g of water into the reaction flask in sequence. After adding, cool down the temperature to 0 - 5 °C, dropwise add 23.5 g of triethylamine. After dropping, keep the temperature at 5 - 10 °C and react for 3.0 - 5.0 h. After the reaction is completed, add 200 ml of dichloromethane and 400 g of water, control the temperature at 5 - 10 °C for extraction. After phase separation, the organic phase is extracted with 240 g of water and 300 g of water in sequence. Combine the aqueous phases, control the temperature at 10 - 15 °C, adjust the pH to 5.5 - 6.0, add 2 g of activated carbon for adsorption. After adsorption, extract the impurities in the aqueous phase with 200 ml of dichloromethane to obtain the aqueous phase for standby.

[0104] 2) Control the temperature of the aqueous phase at 10 - 15 °C, add 13.4 g of sodium acetate, stir and react for 30 min. Add the reaction solution into 1.2 L of acetone to precipitate solids. Filter by suction, wash with 100×2 ml of acetone, and dry in vacuum at 40 °C to obtain sodium cefpodoxime.

[0105] 3) Add 325 ml of DMAc to the reaction flask, add 50 g of cefpodoxime sodium salt, add 0.25 g of 18-crown-6, control the temperature at 0 - 5 °C, quickly add 24.5 g of 1-iodoethyl isopropyl carbonate, and react for 60 min;

[0106] 4) Add 2500 ml of purified water and 50 g of sodium acetate to another reaction flask. After dissolving and clarifying, adjust the pH to 4.8 - 5.0 with glacial acetic acid, and control the temperature at 13 - 15 °C for standby. Add the reaction solution from step (3) to the reaction flask, stir for 25 - 30 min, filter, wash with 100 × 2 ml of water, and dry to obtain the yield of cefpodoxime ester: 85.4% in total.

[0107] Comparative Example 1

[0108] Prepare cefpodoxime acid according to the method of patent W02013041999:

[0109] 1) Add 155 ml of methanol and 500 ml of methanesulfonic acid to the reaction flask, control the temperature at 5 - 10 °C, add 100 g of 7-ACA, control the temperature at 10 - 12 °C and stir for 1 - 2 hours. After the reaction is completed, add the reaction solution to 1000 ml of pre-cooled ice water, control the temperature at 0 - 10 °C, and adjust the pH value of the system to 3.3 - 3.5 with 20% ammonia water in about 1 hour, filter, and wash with 100 ml of water to obtain 7-AMCA;

[0110] 2) Add the aforementioned 7-AMCA, 500 ml of methanol, and 50 ml of water to the reaction flask, control the temperature at 15 - 20 °C, add 40.89 g of triethylamine, add 141.58 g of AE-active ester, stir and react for 5 - 6 hours, add 1500 ml of water, adjust the pH to 5.5 - 6.0 with 10% dilute sulfuric acid, filter, continue to adjust the pH of the filtrate to 2.6 - 2.8 with dilute sulfuric acid, perform suction filtration, wash the filter cake with 200 ml of water, and dry at 40 °C under vacuum to obtain cefpodoxime acid.

[0111] Comparative Example 2

[0112] Prepare cefpodoxime acid and cefpodoxime ester according to the method of patent CN101768171:

[0113] 1) Add 250 ml of dichloromethane, 100 g of (Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid (cefotaxime acid), and 55 ml of triethylamine to the reaction flask. Control the temperature at 10°C, add 83.5 g of p-nitrophenol, and react for 1 hour. Then add a solution formed by 122 g of 7-AMCA, 100 ml of triethylamine, and 250 ml of dichloromethane, and react for 3 hours. Add 1500 ml of water, adjust the pH to 5 with 10% hydrochloric acid, separate the layers. Wash the aqueous phase with 250 ml of dichloromethane again, adjust the pH of the aqueous phase to 2.5 with 10% hydrochloric acid, precipitate the solid, filter, wash with 50 ml of acetone, and dry in vacuo at 40°C to obtain cefpodoxime acid;

[0114] 2) Add 1000 ml of DMF to the reaction flask, add the above-mentioned cefpodoxime acid, stir until dissolved and clear, add 45.65 g of sodium acetate and 5 g of water, stir for 30 minutes, control the temperature at 5°C, add 17.5 g of PEG6000, stir for 10 minutes, add 143.8 g of iodoester, control the temperature at 10°C and react for 2 hours. Add 750 ml of propyl acetate and 1000 ml of water, separate the phases. Extract the aqueous phase with 750 ml of propyl acetate, combine the organic phases, wash with 750 ml of brine, dry over anhydrous sodium sulfate, decolorize with 75 g of activated carbon for 1 hour, filter by suction, add 500 ml of ether, stir vigorously, filter, and dry in vacuo at room temperature to obtain cefpodoxime ester.

[0115] Comparative Example 3

[0116] Prepare cefpodoxime acid and cefpodoxime ester according to the method of Patent CN106046024:

[0117] 1) Add 220 mL of trimethyl orthoformate to the reaction flask, control the temperature at -30°C, dropwise add a mixture of 500 mL of boron trifluoride etherate and acetonitrile (1:1) over 45 minutes, stir for 50 minutes, add 240 g of D-7-ACA, stir for 15 minutes, control the temperature at 25°C, and react for 5 - 6 hours. Remove acetonitrile, wash ultrasonically twice with anhydrous ether. After pouring out the ether, add 2500 ml of dichloromethane, stir at 25°C, then add 100 ml of triethylamine at 0°C to adjust the pH to 8 - 9, and then add 378 g of AE-activator ester in three portions while adjusting the pH to 8 - 9 with triethylamine, and react at 0°C for 6 - 7 hours. After the reaction is completed, add 3000 ml of water, separate the layers, collect the aqueous layer, adjust the pH of the aqueous phase to 3 with 6.7 mo1 / L hydrochloric acid, precipitate the solid, filter, wash with 250 ml of acetone, and dry in vacuo at 40°C to obtain cefpodoxime acid;

[0118] 2) Add 1000 ml of DMF and the aforementioned solid into a reaction flask, stir to dissolve, add 88 g of sodium acetate and 50 mL of water, stir at 25 °C for 30 min, cool down to 3 °C, add 270 g of iodoester, react for 2 hours, add 850×2 ml of chloroform for extraction, combine the organic phases, wash twice with 300 ml of sodium bisulfite solution and purified water, dry with anhydrous magnesium sulfate, evaporate the solvent, add 1000 mL of ethyl acetate, filter after vigorous stirring, and dry in vacuum at 25 °C to obtain the crude cefpodoxime proxetil. Dissolve it in 300 mL of methanol and 500 mL of DMF, then place the solution in an ice-water bath, stir for 50 - 60 minutes, filter and dry to obtain cefpodoxime proxetil.

[0119] Comparative Example 4

[0120] Prepare cefpodoxime proxetil according to the method of Patent CN1763046:

[0121] 1) Add 180 ml of acetone, 20 ml of water, and 3.0 g of sodium carbonate into a reaction flask, control the temperature at 5 - 10 °C, add 11.5 g of D-7-ACA, add 19.3 g of AE-activator ester, stir for 30 minutes, naturally warm up to room temperature, react for 5 hours, filter to remove the solid. After the filtrate is concentrated to remove water, add acetone, stir and disperse to obtain a solid, and dry in vacuum at 40 °C;

[0122] 2) Add 80 ml of DMF and 10.6 g of the above solid into a reaction flask, stir to dissolve clearly, control the temperature at -10 °C, add 2.0 g of DBU, under nitrogen protection, slowly add a DMF (20 ml) solution of 10.2 g of iodoester, add it dropwise within 15 minutes, stir and react for 10 minutes, add 1500 ml of ethyl acetate, a large amount of solid precipitates, filter, and the filtrate is washed successively with 500 ml of water, 500×2 ml of 5% sodium bicarbonate, and 500×2 ml of saturated brine. The organic phase is dried with anhydrous magnesium sulfate, concentrated under reduced pressure to remove ethyl acetate, add 1000 ml of isopropyl ether and stir, filter, and dry in vacuum at 40 °C;

[0123] 3) Add 50 ml of dichloromethane into a reaction flask, add 5.4 g of the above solid, control the temperature at -10 °C, add 20 ml of thionyl chloride, react for 3 hours, concentrate under reduced pressure, then add 30 ml of dichloromethane and concentrate. Cool the residue to -10 °C, add triethylamine (2.0 ml) and methanol (50 ml), react for 1 hour, naturally warm up to room temperature, react for 1 hour, concentrate under reduced pressure to remove methanol, dissolve with 150 ml of ethyl acetate, wash successively with 50 ml of 5% sodium bicarbonate solution, water, and saturated brine, dry with anhydrous magnesium sulfate, filter, and concentrate to obtain cefpodoxime proxetil.

[0124] Example 7

[0125] Comparative analysis of related substances:

[0126] The related substances of cefpodoxime acid / sodium salt prepared in Examples 3-5 were compared with those in Comparative Examples 1-3, as shown in Table 5.

[0127] Table 5 Comparison of related substances of cefpodoxime acid / sodium salt

[0128]

[0129] As can be seen from Table 5, the sodium salt was prepared by the one-pot method in the present invention, and the post-treatment was simple. The obtained cefpodoxime sodium salt had a significantly better effect on removing related substances than directly precipitating cefpodoxime acid in Comparative Examples 1-3.

[0130] The related substances of cefpodoxime ester prepared in Examples 3-6 were compared with those in Comparative Examples 2-4, as shown in Table 6.

[0131] Table 6 Comparison of related substances of cefpodoxime ester

[0132]

[0133] As can be seen from Table 6, in the method of the present invention, cefpodoxime sodium salt and 1-iodoethyl isopropyl carbonate were used to synthesize cefpodoxime ester, avoiding the re-introduction of alkali into the system, making the reaction system more stable and reducing the risk of degradation of related substances. At the same time, in the method of the present invention, the cefpodoxime ester finished product crystallized in a buffered water system, avoiding the use of a large amount of flammable and explosive organic solvents (ether), significantly reducing the production material cost, and increasing the safety and operability of the production process, resulting in a significant improvement in the quality of the cefpodoxime ester finished product.

Claims

1. A preparation method of cefpodoxime proxetil, characterized in that, It includes the following contents: React cefpodoxime sodium salt with Compound III in the presence of an organic solvent and a catalyst. After the reaction is completed, pour the reaction solution into a buffer water system to precipitate the wet target product, and obtain the target product after washing and drying. The reaction general formula is as follows:

2. The preparation method according to claim 1, characterized in that, The buffer water system is an aqueous solution of sodium acetate and glacial acetic acid. The mass-volume ratio of sodium acetate in the buffer water system is 2-4%, and the pH value of the buffer water system is 4.3-6.

2.

3. The preparation method according to claim 1, wherein The mass-volume ratio of cefpodoxime sodium salt to the buffer water system is 1:40-55; Further, the mass-volume ratio is 1:

50.

4. The preparation method according to claim 1, characterized in that, The molar ratio of cefpodoxime sodium salt to Compound III is 1:0.80-1:2.00; Further, the molar ratio of cefpodoxime sodium salt to Compound III is 1:1.10-1.

20.

5. The preparation method according to claim 1, characterized in that, The catalyst is a quaternary ammonium salt, a crown ether or PEG6000, or any two catalysts, or all three catalysts are added, or the catalyst can also not be added.

6. A method for preparing sodium cefpodoxime, which is used for preparing cefpodoxime proxetil according to any one of claims 1-5, characterized in that, The preparation method of the cefpodoxime sodium salt includes the following contents: (1) React Compound I and Compound II under temperature control in the presence of a reaction solvent and triethylamine until the reaction is complete, and extract and separate the reaction solution to obtain an aqueous phase; (2) Add an alkali reagent to the aqueous phase until the reaction is complete to precipitate cefpodoxime sodium salt; The reaction general formula is as follows:

7. The preparation method according to claim 6, characterized in that, In step (2), the method for precipitating cefpodoxime sodium salt is: add an inorganic salt to the reaction solution; the mass ratio of the inorganic salt to Compound I is 7-9:1; Further, the inorganic salt is one or more of sodium carbonate, sodium chloride or sodium acetate; Further, the inorganic salt is sodium chloride.

8. The preparation method according to claim 6, characterized in that In step (2), the method for precipitating cefpodoxime sodium salt is: add n-butanol to the reaction solution, and precipitate cefpodoxime sodium salt after azeotropic water removal, and repeat twice; wherein, the mass-volume ratio of Compound I to n-butanol each time is 1:25-30.

9. The preparation method according to claim 6, characterized in that, In step (2), the method for precipitating cefpodoxime sodium salt is: add acetone to the reaction solution, and the mass-volume ratio of Compound I to acetone is 1:30-40.

10. The preparation method according to claim 6, characterized in that, In step (1), the molar ratio of Compound I to Compound II is 1:0.80-2.00; the molar ratio of Compound I to triethylamine is 1:0.90-1:2.00; Further, the molar ratio of Compound I to Compound II is 1:1.05-1.20; the molar ratio of Compound I to triethylamine is 1:1.00-1.

10.

11. The preparation method according to claim 6, characterized in that, In step (1), the reaction solvent is a mixed solution of methanol, dichloromethane and water; the temperature range for temperature control is 0°C-20°C; Further, the volume ratio of methanol, dichloromethane and water is 4-6:16-18:

1.

12. The preparation method according to claim 6, wherein In step (1), the extraction solvent is dichloromethane; Further, the extraction and liquid separation method is: add dichloromethane and water to the reaction solution for extraction, adsorb the extracted aqueous phase with activated carbon, and then extract and remove impurities from the adsorbed aqueous phase with dichloromethane, and separate to obtain an aqueous phase.

13. The preparation method according to claim 6, characterized in that, In step (2), the alkali reagent is sodium isooctanoate, sodium acetate or sodium carbonate; the molar ratio of the alkali reagent to Compound I is 1.05-1.20:1; Further, the alkali reagent is sodium acetate.

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