Method for preparing cefixime compound

A technology of cefixime and cefixime methyl ester, which is applied in the field of preparation of cefixime compounds, can solve the problems of harsh reaction conditions, expensive solvents, unfavorable continuity, etc., and achieve increased product yield, increased yield and Purity, the effect of shortening the production cycle

Inactive Publication Date: 2013-12-25

TIANJIN UNIVERSITY OF TECHNOLOGY

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Problems solved by technology

[0010] It can be seen from the above preparation method that THF is used in this process, and the solvent is expensive and difficult to recover, and the mother liquor after crystallization and centrifugation of cefixime methyl ester (MFCEF) will take away part of the material, affecting the yield; Synthesis of cefixime methyl ester (MFFCEF) will generate a by-product 2-mercapto...

Abstract

The invention provides a method for preparing a cefixime compound. According to the method for preparing the cefixime compound, 7-AVCA is used as a raw material, cefixime methyl ester is obtained through action of the 7-AVCA and MICA active ester by means of an acylation reaction on 7-amno of the 7-AVCA, the cefixime methyl ester is not separated, inorganic base hydrolysis and a refining reaction are directly conducted on the cefixime methy ester, and therefore cefixime is obtained. The method for preparing the cefixime compound has the advantages that original expensive reagents such as tetrahydrofuran difficult to recycle are replaced by an organic solvent, the organic solvent and water are immiscible, the reaction solvent is easy to recycle and reuse, the pollution to the environment is reduced, and the production cost is reduced; acylation and hydrolysis are integrated, operation is simplified, the production period is shortened, the yield and the purity are improved, and large-scale industrial production is facilitated.

Application Domain

Organic chemistry

Technology Topic

Carbonyl groupAminoethylene +10

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Examples

Experimental program(4)

Example Embodiment

[0031] Example 1:

[0032] A preparation method of cefixime compound, the steps are as follows:

[0033] 1) Add 300mL of dichloromethane, 45mL of ethanol, 15mL of purified water to a 1000mL four-neck flask, stir and cool to 0-2℃, add 50g of 7-AVCA, 100g of MICA active ester, and slowly add triethyl dropwise at 5℃ It takes about 0.5 hours for 25g of amine. After the addition, the temperature is raised to 5-10°C, and the reaction is carried out for 5 hours under these conditions. The pH is controlled at 7.5-8.0. The 7-AVCA in the reaction solution is detected by HPLC. When <0.5wt%, the reaction is stopped, and a solution of cefixime methyl ester is prepared.

[0034] 2) Add 150 mL of purified water to the above-mentioned cefixime methyl ester solution, stir for 10 minutes, stand still to separate the water phase, and then extract the organic phase twice with 150 mL of purified water, combine the water phases, add 1g sodium silicate and 1g ethylenediamine Tetraacetic acid and 5 g activated carbon were decolorized at room temperature for 30 minutes, filtered, and the filter cake was washed with 15 mL of purified water, and the filtrate and washing liquid were combined to obtain an aqueous solution of cefixime methyl ester.

[0035] 3) Add 25 mL of acetone to the above aqueous solution of cefixime methyl ester and cool to below 0°C. Add 45g of 30wt% sodium hydroxide solution at one time, stir quickly below 0°C for 5 minutes, and detect the cefix in the reaction solution by HPLC Oxime methyl ester Stop the reaction when <0.5 wt%; add 25mL of 6mol/L hydrochloric acid at once to adjust the pH to 5.0-5.5; add 5g activated carbon and 1g ethylenediaminetetraacetic acid and stir for 30 minutes, filter, and then wash the filter cake with 50mL purified water. Combine the filtrate and washing liquid, heat up to 33-35℃, adjust to pH3.0 with 3mol/L hydrochloric acid, the solution will precipitate crystals, stir and cool to 5℃, cultivate the crystals for 2 hours; filter by centrifugation, wash twice with 100mL50wt% acetone aqueous solution , Vacuum-dried at 40-42°C to 10-12wt% of moisture, the white crystals are cefixime compound, the product is 102g, the yield is 90.2%.

[0036] The structural characteristics of the cefixime: 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.568(d,1H, J=8Hz, A),7.255(s,2H,B),6.916(q,1H,J1=11.2Hz,J2=17.2Hz,C),6.816(s,1H,D), 5.788(q,1H,J1=4.8Hz,J2=8.4Hz,E),5.595(d,1H,J=17.6Hz,F),5.323(d,1H,J=11.6Hz,G),5.209(d ,1H,J=4.8Hz,J), 4.602(s,2H,K), 3.837(d,1H,J=17.6Hz,L), 3.578(d,1H,J=17.6Hz,M).

[0037] figure 1 , figure 2 , image 3 These are the hydrogen nuclear magnetic spectrum, carbon nuclear magnetic spectrum and mass spectrum of cefixime prepared in this example. The figures are all on the surface: the prepared cefixime compound completely corresponds to the cefixime standard spectrum, which can confirm the target compound Structure.

Example Embodiment

[0038] Example 2:

[0039] The steps of the preparation method of a cefixime compound are as follows:

[0040] 1) In a 1000mL four-neck flask, add 350mL of chloroform, 60mL of methanol, 25mL of purified water, stir and cool to 0-5℃, add 50g of 7-AVCA, 120g of MICA active ester, and slowly drop 28g of triethylamine at 5℃ About 1 hour, after the addition, the temperature is raised to 8-12°C, and the reaction is conducted for 5.5 hours under this condition, the pH is controlled at 7.5-8.0, and the 7-AVCA in the reaction solution is detected by HPLC <0.5% stop the reaction and prepare a solution of cefixime methyl ester.

[0041] 2) Add 200 mL of purified water to the above cefixime methyl ester solution, stir for 10 minutes, and stand still to separate the water phase. The organic phase was extracted twice with 100 mL of purified water. The aqueous phases were combined, 0.5 g of sodium hydroxide and 0.5 g of ethylenediamine tetraacetic acid, 2.5 g of activated carbon were decolorized at room temperature for 30 minutes, filtered, the filter cake was washed with 10 mL of purified water, and the filtrate and Washing liquid to obtain cefixime methyl ester aqueous solution.

[0042] 3) Add 50 mL of methanol to the above aqueous solution of cefixime methyl ester and lower the temperature to below 0°C, add 60 g of 25 wt% sodium hydroxide solution in one go, stir quickly below 0°C for 10 minutes, and detect the cephalosporin in the reaction solution by HPLC Oxime methyl ester Stop the reaction when <0.5 wt %. Add 30 mL of 6mol/L hydrochloric acid at once to adjust the pH to 4.5-5.0. Add 2.5g activated carbon and 0.5g ethylenediaminetetraacetic acid. Stir for 30 minutes, filter, and then wash the filter cake with 50mL purified water, combine the filtrate and washing liquid, heat up to 33-35°C, adjust to pH 2.5 with 3mol/L hydrochloric acid, crystallize the solution, stir and cool to 5°C, Crystal 3 hours. Centrifugal filtration, washing twice with 50 mL of 50% methanol aqueous solution, vacuum drying at 50-52°C to a moisture content of 10-12 wt%, the off-white crystals are cefixime compound, the product is 98.2g, the yield is 87.6%.

[0043] The hydrogen nuclear magnetic spectrum, carbon nuclear magnetic spectrum and mass spectrum of cefixime prepared in this example are basically the same as those in Example 1.

Example Embodiment

[0044] Example 3:

[0045] A preparation method of cefixime compound, the steps are as follows:

[0046] 1) Add 300 mL of ethyl acetate, 50 mL of methanol, and 30 mL of purified water to a 1000 mL four-neck flask, stir and cool to 5-8°C, add 50 g of 7-AVCA, 125 g of MICA active ester, and slowly add 25 g of cyclohexylamine at 5°C. Approximately 0.5 hours, after the addition, the temperature was raised to 10-15°C, and reacted for 6 hours under these conditions, the pH was controlled at 8.0-8.5, and the 7-AVCA in the reaction solution was detected by HPLC <0.5% stop the reaction and prepare a solution of cefixime methyl ester.

[0047] 2) After the reaction, add 150 mL of purified water, stir for 10 minutes, and stand still to separate the water phase. The organic phase was extracted twice with 150 mL of purified water. The aqueous phases were combined, 1.5 g of sodium hydroxide and 1.5 g of ethylene diamine tetraacetic acid, 5 g of activated carbon were decolorized at room temperature for 30 minutes, filtered, and the filter cake was washed with 10 mL of purified water. The combined filtrate and washing Solution to obtain an aqueous solution of cefixime methyl ester.

[0048] 3) Add 30 mL of ethanol to the above-mentioned cefixime methyl ester aqueous solution and lower the temperature to below -10°C, add 50 g of 30 wt% potassium hydroxide solution at one time, stir quickly below -10°C for 5 minutes, and detect the reaction solution by HPLC Cefixime methyl ester Stop the reaction when <0.5 wt %. Add 25mL of 6mol/L hydrochloric acid at one time to adjust the pH to 5.5-6.0. Add 5g activated carbon and 1.5g ethylenediaminetetraacetic acid and stir for 30 minutes, filter, and then wash the filter cake with 50mL purified water, combine the filtrate and washing liquid, heat up to 33-35℃, adjust to pH3.0 with 3mol/L hydrochloric acid, The solution precipitated crystals, stirred and cooled to 10°C, and cultivated the crystals for 2 hours. Centrifugal filtration, washing with 50 mL of 50% ethanol aqueous solution twice, vacuum drying at 45-50°C to a moisture content of 10-12 wt%, to obtain off-white crystals, namely cefixime compound, 99.7g product, yield 88.9%.

[0049] The hydrogen nuclear magnetic spectrum, carbon nuclear magnetic spectrum and mass spectrum of cefixime prepared in this example are basically the same as those in Example 1.

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Classification and recommendation of technical efficacy words

reduce pollution
Easy to recycle

Method for preparing cefixime compound

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