Preparation method of cefpodoxime proxetil intermediate

Abstract

The invention relates to a preparation method of a cefpodoxime proxetil intermediate, which comprises the following steps: by taking sulfolane as a solvent, reacting 7-ACA with trimethylsilylimidazole to protect carboxyl; then adding a boron trifluoride dimethyl carbonate complex and methanol to carry out a methoxylation reaction; and after the reaction is finished, carrying out post-treatment to obtain 7-AMCA. The method provided by the invention can effectively solve the problems of high raw material price, high-risk catalyst and methoxylation reagent use, low product purity and the like in the prior art, and the product obtained by the method is high in purity, high in yield, simple and convenient to operate and suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical intermediates, and particularly relates to a method for preparing a cefpodoxime axetil intermediate. Background Art

[0002] Cefpodoxime Proxetil (CPDX-PR) is a third-generation oral cephalosporin. Its structural characteristics are a methoxymethyl group attached to 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 gives it good oral absorption. The methoxyiminothiazolyl group is attached to the 7-position, which is closely related to its anti-Gram-negative bacterial activity and resistance to β-lactamase.

[0003] The chemical name of Cefpodoxime Proxetil is (6R,7R)-7-[2-(2-aminothiazol-4-yl)-2-(Z)-(methoxyimino)-acetamido]-3-methoxymethyl-8-oxo-5-thio-1-azabicyclo-[4,2,0]oct-2-ene-2-carboxylic acid isopropyloxycarbonyloxyethyl ester. The structural formula of Cefpodoxime Proxetil is as follows:

[0004]

[0005] 7-AMCA is a key intermediate in the synthesis of cefpodoxime proxetil. Its chemical name is 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid. The structural formula of 7-AMCA is as follows:

[0006]

[0007] One synthetic route for 7-AMCA uses D-7ACA as a raw material, as disclosed in CN106046024, CN117659046A, CN119350367A, CN109956958A, and WO2017153824A. However, this route suffers from the significantly higher price of D-7ACA compared to 7-ACA and a relatively low yield of 7-AMCA (below 88%). Therefore, using D-7ACA as a raw material to prepare 7-AMCA is not competitive in the market.

[0008] Another route for synthesizing 7-AMCA is to use the less expensive 7-ACA (7-aminocephalosporanic acid) as a raw material to prepare 7-AMCA. The related patents and existing problems are as follows:

[0009] EP0485204 discloses a method for preparing alkoxymethylcephalosporins. 11.9 g of a methanol solution of methoxysulfonic acid and 2.10 g of trimethyl borate are added to 15 ml of sulfolane. The mixture is cooled to 15°C, 2.74 g of 7-ACA is added, and the mixture is stirred at 15°C for 1 hour to produce 7-AMCA with a maximum yield of 88%. This method requires the use of expensive trimethyl borate, making it economically unsuitable and environmentally hazardous.

[0010] CN1054984A discloses a method for preparing 7-amino-3-methoxymethylcephem-3-ene-4-carboxylic acid. 20 ml of methanol is added dropwise to 132.5 ml of methanesulfonic acid (2.0 mol) and 17.6 ml of trifluoromethanesulfonic acid (0.2 mol) at -10°C to +5°C over 10 minutes. Then, 54.4 g of 7-ACS (0.2 mol) and 20 ml of methanol are added to the above mixture in the same manner over 12 minutes, while maintaining the temperature at 4 to 6°C. 7-AMCA is obtained in a yield of 56.6% and a purity of 90%.

[0011] WO02060866A2 discloses a method for preparing pure alkoxymethylcephalosporin, using 7-ACA as a raw material, sulfolane as a solvent, methanesulfonic acid and trimethyl borate as catalysts, and methanol as an alkylating agent to prepare 7-AMCA with a yield of 83% and a purity of 95%.

[0012] CN105669701A discloses a method for synthesizing a cefpodoxime axetil intermediate. The method involves adding 50g of methoxysulfonic acid and 2g of dimethylformamide to a container, cooling the container to 15-20°C, and then dropwise adding 11.4g of a trimethyl borate / methanol mixed solution (mass ratio of 7:3). The container is then cooled to 0-5°C. 20g of 7-ACA is added and allowed to react for 2h. Furthermore, 10.8g of a trimethyl borate / methanol mixed solution is added and allowed to react for 3h to obtain 7-AMCA with a yield of 66.88% and a liquid phase purity of approximately 95-96%. The methoxysulfonic acid used in this method is expensive, and the chlorosulfonic acid used to prepare methoxysulfonic acid is a highly toxic reagent that is difficult to purchase and store.

[0013] CN102746322A discloses a method for preparing a cephem intermediate, 7-amino-3-methoxymethyl-2-cephem-2-carboxylic acid. The method uses 7-ACA as a raw material, dimethyl carbonate as a solvent, 40% BF3-methanol as a catalyst, and a 29.5% methanol solution of sodium methoxide as a methylating agent to prepare 7-AMCA with a yield of 82% and a purity of 97.6%. Because sodium methoxide is a strong base, partial over-alkalinity can result in the formation of a large amount of lactone, which can cause the β-lactam to open, resulting in a low purity product.

[0014] CN1377359A and CN112480144A disclose methods for preparing 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid. Both methods use 7-ACA as the raw material, methanesulfonic acid as the catalyst, and trimethyl borate and methanol as the alkylating agents to produce 7-AMCA. While the yield can reach up to 89.6% and the purity can reach up to 99.2%, methanesulfonic acid is corrosive and highly toxic, and trimethyl borate is a moisture-sensitive liquid that generates smoke in air and is highly flammable, making it unsuitable for industrial production.

[0015] CN106478666A discloses a method for preparing 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid. Under nitrogen protection, 300 ml of dimethyl sulfoxide is added to a reaction bottle, 60 g (0.22 mol) of 7-ACA is added, the temperature is controlled at 30-35 ° C, 0.8 g of imidazole is added, 17.75 g (0.11 mol) of hexamethyldisilazane is added, and the mixture is stirred for 60 minutes after addition, and ammonia generated is removed by vacuum for 30 minutes. The temperature was then lowered to 0-5°C, and 23.5g (0.23mol) of trimethyl borate and 8.3g (0.26mol) of methanol were added. Then, 317.1g (3.3mol) of methanesulfonic acid was added, and a mixture of 23.5g (0.23mol) of trimethyl borate and 8.3g (0.26mol) of methanol was slowly added dropwise over 60 minutes. After the addition was complete, 7-AMCA was produced in a 74.5% yield and 99.1% purity. Methanesulfonic acid is corrosive and highly toxic, and trimethyl borate is a moisture-sensitive liquid that generates smoke in air and is highly flammable, making it unsuitable for industrial production.

[0016] US5580978A and WO2013041999A disclose methods for preparing 7-ACA derivatives. These methods use 7-ACA as a raw material, sulfolane as a solvent, boron trifluoride gas as a catalyst, and methanol as a methoxylation reagent to produce 7-AMCA wet products. This method requires the use of hazardous gaseous boron trifluoride, and results in low yield and purity. Furthermore, the product is viscous and difficult to filter.

[0017] WO2011077217A1 discloses an improved method for preparing cefpodoxime. 50g of 7-aminocephalosporanic acid is reacted with 110mL of methanol in trifluoroborane to produce wet-process 7-AMCA. This method results in low yield and purity, and the product is viscous and difficult to filter.

[0018] In summary, the existing synthetic route for preparing 7-AMCA using 7-ACA as a raw material requires the use of a strongly acidic catalyst, methanesulfonic acid, and a highly dangerous methoxylation reagent, trimethyl borate, or dangerous boron trifluoride gas, making it unsuitable for industrial production. Furthermore, the existing technology suffers from low product yield and purity. Summary of the Invention

[0019] The purpose of the present invention is to provide a method for preparing 7-AMCA which has high product purity, high yield, simple operation and is suitable for industrial production.

[0020] In order to achieve the above object, the technical solution adopted by the present invention is:

[0021] The invention provides a preparation method of a cefpodoxime proxetil intermediate. The method comprises the following steps: using sulfolane as a solvent, reacting 7-ACA with trimethylsilyl imidazole to protect the carboxyl group; then adding a boron trifluoride dimethyl carbonate complex and methanol to carry out a methoxylation reaction; and after the reaction is completed, post-processing to obtain 7-AMCA.

[0022] According to some specific embodiments, the feeding mass ratio of the sulfolane to the 7-ACA is 8.0 to 16.0; for example, the feeding mass ratio of the sulfolane to the 7-ACA is 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 15.5 or 16.0, etc.

[0023] According to some specific embodiments, the molar ratio of the trimethylsilyl imidazole to the 7-ACA is 0.8 to 1.2; for example, the molar ratio of the trimethylsilyl imidazole to the 7-ACA is 0.8, 0.9, 1.0, 1.1 or 1.2, etc.

[0024] According to some specific embodiments, the molar ratio of boron trifluoride in the boron trifluoride dimethyl carbonate complex to the 7-ACA is 1.0 to 5.0; for example, the molar ratio of boron trifluoride in the boron trifluoride dimethyl carbonate complex to the 7-ACA is 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5 or 5.0, etc.

[0025] According to some specific embodiments, the molar ratio of the methanol to the 7-ACA is 1.0 to 5.0; for example, the molar ratio of the methanol to the 7-ACA is 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5 or 5.0, etc.

[0026] According to some specific embodiments, the content of boron trifluoride in the boron trifluoride dimethyl carbonate complex is ≥40%.

[0027] According to some specific embodiments, the reaction time of the 7-ACA and the trimethylsilyl imidazole is 0.5 to 1 h; for example, the reaction time is 0.5 h, 0.6 h, 0.7 h, 0.8 h, 0.9 h or 1 h.

[0028] According to some specific embodiments, the methoxylation reaction is carried out at a temperature of 40 to 50°C (e.g., 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C, 49°C or 50°C, etc.), and the reaction time is 3 to 6 h (e.g., 3 h, 3.5 h, 4 h, 4.5 h, 5 h, 5.5 h or 6 h, etc.).

[0029] According to some specific embodiments, the post-treatment method is to add sodium metabisulfite and methanol to the reaction system to quench the reaction; then adjust the pH to 7.0-8.0 with ammonia water, and filter to remove inorganic salts; adjust the pH of the filtrate to 2.8-3.2 with dilute sulfuric acid, crystallize, filter, wash the crystals, and dry to obtain the 7-AMCA.

[0030] Furthermore, the molar ratio of the sodium metabisulfite to the 7-ACA is 0.01 to 0.10; for example, the molar ratio of the sodium metabisulfite to the 7-ACA is 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, etc.

[0031] Furthermore, the mass ratio of methanol to 7-ACA used in the quenching reaction is 1.0 to 5.0, for example, the mass ratio of methanol to 7-ACA is 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5 or 5.0.

[0032] Furthermore, the concentration of the ammonia water is 22% to 25%; for example, the concentration of the ammonia water is 22%, 23%, 24% or 25%.

[0033] Furthermore, the molar ratio of NH3·H2O in the ammonia water to the 7-ACA is 2.0 to 10.0, for example, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5 or 10.0, etc.

[0034] Furthermore, the filtration to remove inorganic salts is controlled to be carried out at 25-30°C; for example, at 25°C, 26°C, 27°C, 28°C, 29°C, or 30°C.

[0035] Furthermore, the filter cake obtained by filtering out the inorganic salts was washed with methanol.

[0036] Furthermore, the feed mass ratio of methanol used for washing the filter cake to the 7-ACA is controlled to be 0.1 to 1.0, for example, the feed mass ratio of methanol used for washing the filter cake to the 7-ACA is controlled to be 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, etc.

[0037] Furthermore, the filtrate after washing with methanol is combined with the filtrate after filtering out inorganic salts for the next treatment.

[0038] Furthermore, the concentration of the dilute sulfuric acid is 10% to 20%, for example, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20%.

[0039] Furthermore, the molar ratio of sulfuric acid in the dilute sulfuric acid to the 7-ACA is 0.5 to 2.0, for example, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, etc.

[0040] Furthermore, the mass ratio of water in the dilute sulfuric acid to the 7-ACA is 1.0 to 3.0, for example, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, etc.

[0041] Furthermore, the crystallization temperature is controlled to be 25-30°C (for example, 25°C, 26°C, 27°C, 28°C, 29°C or 30°C), and the crystallization time is 8-24h (for example, 8h, 9h, 10h, 11h, 12h, 13h, 14h, 15h, 16h, 17h, 18h, 19h, 20h, 21h, 22h, 23h or 24h, etc.).

[0042] Furthermore, the drying temperature is 40-50°C (for example, 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C, 49°C or 50°C, etc.), and the drying method is vacuum drying.

[0043] According to some more specific and preferred embodiments, the preparation method comprises the following steps:

[0044] (1) Add 7-ACA and sulfolane to a reactor, stir to dissolve, then add trimethylsilyl imidazole and stir to react;

[0045] (2) adding boron trifluoride dimethyl carbonate complex at 20°C to 30°C, and then adding methanol at 20°C to 40°C. After the addition is complete, heating to 40°C to 50°C to carry out the reaction;

[0046] (3) After the reaction is completed, the temperature is lowered to 0°C to 5°C, and sodium metabisulfite and methanol are added to quench the reaction;

[0047] (4) Control the temperature to 0°C to 5°C, adjust the pH to 7.0 to 8.0 with aqueous ammonia, and after the addition is complete, raise the temperature to 25°C to 30°C and filter to remove inorganic salts;

[0048] (5) The filtrate is adjusted to pH 2.8-3.2 with dilute sulfuric acid, the temperature is controlled at 25°C-30°C, the crystals are stirred, filtered, and washed;

[0049] (6) The wet product is vacuum dried to obtain 7-AMCA.

[0050] Due to the application of the above technical solution, the present invention has the following advantages compared with the prior art:

[0051] The method of the present invention can effectively solve the problems of expensive raw materials, the use of dangerous catalysts and methoxylation reagents, and low product purity in the prior art. The product obtained by the method has high purity and high yield, is simple to operate, and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0052] Figure 1 is the HPLC spectrum of the cefpodoxime proxetil intermediate 7-AMCA of Example 1;

[0053] Figure 2 is the HPLC spectrum of the cefpodoxime proxetil intermediate 7-AMCA of Example 2;

[0054] Figure 3 This is the HPLC spectrum of the cefpodoxime proxetil intermediate 7-AMCA of Comparative Example 1;

[0055] Figure 4 It is the HPLC spectrum of the cefpodoxime axetil intermediate 7-AMCA in Comparative Example 2. DETAILED DESCRIPTION

[0056] The prior art has problems of expensive raw material, high-risk catalyst and methoxylation reagent, and low product purity. The present inventors have developed a preparation method through a large number of research and experimental verification. The method uses inexpensive 7-ACA as a raw material, uses a good selective sulfolane as a solvent, uses the strongest silane reagent trimethylsilane imidazole as a carboxyl protecting agent to reduce the production of by-product lactone, uses a convenient solid boron trifluoride dimethyl carbonate as a catalyst, and uses methanol as a methoxylation reagent to perform methoxylation reaction. The reaction system is adjusted to neutral to remove inorganic salts, which is conducive to product separation. The pH of the filtrate is adjusted to 2.8-3.2 to prepare 7-AMCA. The method has high product purity (99.4%) and high yield (91.3%), and is simple to operate and suitable for industrial production.

[0057] Further, the present application has the following advantages:

[0058] (1) Trimethylsilane imidazole is used to protect the carboxyl group of 7-ACA to reduce the production of by-product lactone; (2) sulfolane with good selectivity is used as a solvent, and solid boron trifluoride dimethyl carbonate is used as a catalyst, and the sulfolane and boron trifluoride dimethyl carbonate system has mild reaction and less by-products; (3) sodium metabisulfite and methanol are used to quench the reaction, which is conducive to post-treatment; (4) the reaction system is first adjusted to neutral with ammonia water to remove inorganic salts, which is conducive to product separation; (5) the present application has high 7-AMCA purity (99.4%) and high yield (91.3%), and is simple to operate and suitable for industrial production.

[0059] The present application will be further described below in conjunction with examples. However, the present application is not limited to the following examples. The implementation conditions used in the examples can be further adjusted according to different specific requirements. The implementation conditions not specified are conventional conditions in the industry. The technical features involved in each embodiment of the present application can be combined with each other as long as there is no conflict.

[0060] In the following examples and comparative examples, the raw materials used are obtained by market purchase.

[0061] In the following examples and comparative examples, unless otherwise specified, "%" means mass percent.

[0062] Example 1

[0063] To a 2000 ml reaction flask, add 630.0 g of sulfolane (12.6 w / w), start stirring, add 50.0 g of 7-ACA (0.18 mol; 98.8%, Sinopharm Weiqida Pharmaceutical Co., Ltd.), and stir for 0.5 h; add 25.8 g of trimethylsilyl imidazole (0.18 mol, 1 eq), and stir for 0.5 h; add 91.5 g of 40% boron trifluoride dimethyl carbonate complex (0.54 mol, 3 eq; Shandong Heyi Gas Co., Ltd.) at 20-30 ° C; add 17.3 g of methanol (0.54 mol, 3 eq) at a temperature of 20-40 ° C for about 0.5 h; raise the temperature to 40-50 ° C and stir for 0.5 h; control the temperature at 40-50 ° C and stir for 4 h. Cool to 0-5°C, add 1.00g of sodium metabisulfite (0.005mol, 0.03eq) and 160.0g of methanol; control the temperature at 0-5°C, add about 158g of 25% ammonia water (1.13mol, 6.3eq) to adjust the pH to 7.0-8.0, and take about 1h; heat to 25-30°C, filter, wash with 8.0g of methanol, and drain; transfer the filtrate to a 2000ml reaction flask, control the temperature at 25-30°C, add 20.0g of sulfuric acid (0.20mol, 1.1eq) and 100g of purified water to the filtrate, adjust the pH to 2.8-3.2, and take about 1h; control the temperature at 25-30°C and continue stirring for 12h, filter, wash the filter cake with 50.0g of methanol, drain, and dry the wet product at 40-50°C in vacuo to constant weight to obtain 40.7g 7-AMCA, purity 99.4%, HPLC spectrum is attached Figure 1 , yield 91.3%.

[0064] In this embodiment, HPLC detection is carried out in accordance with high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0512), wherein the chromatographic column is octadecylsilane bonded silica gel as a filler (4.6 mm × 150 mm, 5 μm); tetrabutylammonium bromide buffered saline solution (take 3.0 g of tetrabutylammonium bromide, 1.9 g of sodium acetate, 3.2 g of ammonium sulfate, add 950 ml of water to dissolve and mix)-acetonitrile (95:5) is used as mobile phase A, and water-acetonitrile (30:70) is used as mobile phase B, and gradient elution is performed according to Table 1 below; the flow rate is 1.0 ml per minute; the column temperature is 25°C; the injection plate temperature is 5°C; the detection wavelength is 254 nm; and the injection volume is 5 μl.

[0065] Table 1

[0066]

[0067] Example 2

[0068] To a 2000 ml reaction flask, add 630.0 g of sulfolane (12.6 w / w), start stirring, add 50.0 g of 7-ACA (0.18 mol; 98.8%, Sinopharm Weiqida Pharmaceutical Co., Ltd.), and stir for 0.5 h; add 25.8 g of trimethylsilyl imidazole (0.18 mol, 1 eq), and stir for 0.5 h; add 63.0 g of 40% boron trifluoride dimethyl carbonate complex (0.36 mol, 2 eq; Shandong Heyi Gas Co., Ltd.) at 20-30 ° C; add 17.3 g of methanol (0.54 mol, 3 eq) at a temperature of 20-40 ° C for about 0.5 h; raise the temperature to 40-50 ° C and stir for 0.5 h; control the temperature at 40-50 ° C and stir for 4 h. Cool to 0-5°C, add 1.00g of sodium metabisulfite (0.005mol, 0.03eq) and 160.0g of methanol; control the temperature at 0-5°C, add about 105g of 25% ammonia water (0.75mol, 4.2eq) to adjust the pH to 7.0-8.0, and take about 1h; heat to 25-30°C, filter, wash with 8.0g of methanol, and drain; transfer the filtrate to a 2000ml reaction flask, control the temperature at 25-30°C, add 20.0g of sulfuric acid (0.20mol, 1.1eq) and 100g of purified water to the filtrate, adjust the pH to 2.8-3.2, and take about 1h; control the temperature at 25-30°C and continue stirring for 12h, filter, wash the filter cake with 50.0g of methanol, drain, and dry the wet product at 40-50°C in vacuo to constant weight to obtain 40.4g 7-AMCA, purity 99.3%, HPLC spectrum is attached Figure 2 , yield 90.5%.

[0069] Comparative Example 1 does not add trimethylsilyl imidazole, and other parameters are the same as Example 1

[0070] To a 2000 ml reaction flask, add 630.0 g of sulfolane (12.6 w / w) and start stirring. Add 50.0 g of 7-ACA (0.18 mol; 98.8%, Sinopharm Weiqida Pharmaceutical Co., Ltd.) and stir to dissolve. Add 91.5 g of 40% boron trifluoride carbonate dimethyl complex (0.54 mol, 3 eq; Shandong Heyi Gas Co., Ltd.) at 20-30°C. Add 17.3 g of methanol (0.54 mol, 3 eq) at a temperature of 20-40°C for about 0.5 h. Heat to 40-50°C and stir for 0.5 h. Then, control the temperature at 40-50°C and stir for 4 h. Cool to 0-5°C, add 1.00g of sodium metabisulfite (0.005mol, 0.03eq) and 160.0g of methanol; control the temperature at 0-5°C, add about 158g of 25% ammonia water (1.13mol, 6.3eq) to adjust the pH to 7.0-8.0, and take about 1h; heat to 25-30°C, filter, wash with 8.0g of methanol, and drain; transfer the filtrate to a 2000ml reaction flask, control the temperature at 25-30°C, add 20.0g of sulfuric acid (0.20mol, 1.1eq) and 100g of purified water to the filtrate, adjust the pH to 2.8-3.2, and take about 1h; control the temperature at 25-30°C and continue stirring for 12h, filter, wash the filter cake with 50.0g of methanol, drain, and dry the wet product at 40-50°C in vacuo to constant weight to obtain 38.1g 7-AMCA, purity 97.1%, HPLC spectrum is attached Figure 3 , yield 83.8%.

[0071] Comparative Example 2 The reaction solvent is dimethyl carbonate, and the other parameters are the same as those in Example 1

[0072] To a 2000 ml reaction flask, add 630.0 g of dimethyl carbonate (12.6 w / w) and start stirring. Add 50.0 g of 7-ACA (0.18 mol; 98.8%, Sinopharm Weiqida Pharmaceutical Co., Ltd.) and stir to dissolve; add 25.8 g of trimethylsilyl imidazole (0.18 mol, 1 eq) and stir for 0.5 h; add 91.5 g of 40% boron trifluoride dimethyl carbonate complex (0.54 mol, 3 eq; Shandong Heyi Gas Co., Ltd.) at 20-30° C.; add 17.3 g of methanol (0.54 mol, 3 eq) at a temperature of 20-40° C. for about 0.5 h; raise the temperature to 40-50° C. and stir for 0.5 h; then control the temperature at 40-50° C. and stir for 4 h. Cool to 0-5°C, add 1.00g of sodium metabisulfite (0.005mol, 0.03eq) and 160.0g of methanol; control the temperature at 0-5°C, add about 158g of 25% ammonia water (1.13mol, 6.3eq) to adjust the pH to 7.0-8.0, and take about 1h; heat to 25-30°C, filter, wash with 8.0g of methanol, and drain; transfer the filtrate to a 2000ml reaction flask, control the temperature at 25-30°C, add 20.0g of sulfuric acid (0.20mol, 1.1eq) and 100g of purified water to the filtrate, adjust the pH to 2.8-3.2, and take about 1h; control the temperature at 25-30°C and continue stirring for 12h, filter, wash the filter cake with 50.0g of methanol, drain, and dry the wet product at 40-50°C in vacuo to constant weight to obtain 35.4g 7-AMCA, purity 95.2%, HPLC spectrum is attached Figure 4 , yield 76.0%.

[0073] 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 according to the present invention should be included in the scope of protection of the present invention.

Claims

1. A method for preparing a cefpodoxime proxetil intermediate, characterized in that: Using sulfolane as solvent, 7-ACA is reacted with trimethylsilyl imidazole to protect the carboxyl group; then, boron trifluoride dimethyl carbonate complex and methanol are added to carry out methoxylation reaction; after the reaction is completed, 7-AMCA is obtained through post-treatment.

2. The method for preparing a cefpodoxime proxetil intermediate according to claim 1, wherein: The feed mass ratio of the sulfolane to the 7-ACA is 8.0 to 16.0; and / or, The molar ratio of the trimethylsilyl imidazole to the 7-ACA is 0.8 to 1.2; and / or, The molar ratio of boron trifluoride in the boron trifluoride dimethyl carbonate complex to the 7-ACA is 1.0 to 5.0; and / or, The feeding molar ratio of the methanol to the 7-ACA is 1.0 to 5.

0.

3. The method for preparing a cefpodoxime proxetil intermediate according to claim 1, wherein: The content of boron trifluoride in the boron trifluoride dimethyl carbonate complex is ≥40%.

4. The method for preparing a cefpodoxime proxetil intermediate according to claim 1, wherein: The reaction time of 7-ACA and trimethylsilyl imidazole is 0.5 to 1 hour; and / or, The temperature for the methoxylation reaction is 40-50° C., and the reaction time is 3-6 hours.

5. The method for preparing a cefpodoxime proxetil intermediate according to claim 1, wherein: The post-treatment method comprises the following steps: adding sodium metabisulfite and methanol to the reaction system to quench the reaction; adjusting the pH to 7.0-8.0 with aqueous ammonia, filtering to remove inorganic salts; adjusting the pH of the filtrate to 2.8-3.2 with dilute sulfuric acid, crystallizing, filtering, washing the crystals, and drying to obtain the 7-AMCA.

6. The method for preparing a cefpodoxime proxetil intermediate according to claim 5, wherein: The molar ratio of the sodium metabisulfite to the 7-ACA is 0.01 to 0.10; and / or, The feed mass ratio of the methanol to the 7-ACA is 1.0 to 5.

0.

7. The method for preparing a cefpodoxime proxetil intermediate according to claim 5, wherein: The concentration of the ammonia solution is 22% to 25%; and / or, Controlling the filtration and removal of inorganic salts to be carried out at 25-30°C; and / or, The filter cake obtained by filtering out the inorganic salt is washed with methanol, and the feed mass ratio of the methanol to the 7-ACA is controlled to be 0.1 to 1.

0.

8. The method for preparing a cefpodoxime proxetil intermediate according to claim 5, wherein: The concentration of the dilute sulfuric acid is 10% to 20%.

9. The method for preparing a cefpodoxime proxetil intermediate according to claim 5, wherein: The crystallization temperature is controlled to be 25-30°C, and the crystallization time is 8-24 hours.

10. The method for preparing a cefpodoxime proxetil intermediate according to claim 5, wherein: The drying temperature is 40-50° C., and the drying method is vacuum drying.

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