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The preparation method of cefditoren pivoxil ring-opened product

A technology of cefditoren pivoxil and basic substances, which is applied in the field of impurity analysis in drug synthesis, can solve problems affecting accuracy, cumbersome steps, and difficult to completely separate impurities, and achieve low cost, simple steps, and clinical safety The effect of guarantee

Active Publication Date: 2020-12-25
CHONGQING MEDICAL & PHARMA COLLEGE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] Cefditoren pivoxil open ring is an important impurity that needs to be studied in the quality control of cefditoren pivoxil. At present, the impurity reference substance is mainly obtained by separating and extracting the crude product of cefditoren pivoxil, but the method steps are cumbersome and produce The rate is low, the purity is low, and some impurities with similar structures are difficult to separate completely, thus affecting the accuracy of detection

Method used

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  • The preparation method of cefditoren pivoxil ring-opened product
  • The preparation method of cefditoren pivoxil ring-opened product
  • The preparation method of cefditoren pivoxil ring-opened product

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Add 6.2g of cefditoren pivoxil and 50ml of dimethyl sulfoxide into the reaction bottle, stir and cool down to -20°C, slowly add 0.01mol of sodium hydroxide, heat up to 10°C-20°C to react, after HPLC checks that the reaction is complete, Add 50ml of water and 50ml of ethyl acetate, adjust the pH value to 3-4 with 5% hydrochloric acid under stirring, let stand to separate the layers, extract the water layer with 20ml of ethyl acetate, combine the ethyl acetate layers, wash with saturated brine, anhydrous sulfuric acid Dried over magnesium, filtered, concentrated to dryness under reduced pressure, purified by silica gel column chromatography, eluted with ethyl acetate-petroleum ether (2:1), concentrated to obtain 4.5 g of light yellow solid. The purity of the product detected by HPLC was 97.8%, RRT0.56, which was consistent with the relative retention time of the ring-opened cefditoren pivoxil reference substance.

[0025] The product was analyzed by MS mass spectrometry ...

Embodiment 2

[0036] Add 6.2g of cefditoren pivoxil and 50ml of N,N-dimethylformamide into the reaction bottle, stir and cool down to -15°C, slowly add 0.012mol of potassium hydroxide, heat up to 10°C-20°C for reaction, and check by HPLC After the reaction is complete, add 50ml of water and 50ml of ethyl acetate, adjust the pH value to 3-4 with 10% hydrochloric acid under stirring, let the layers stand, extract the water layer with 20ml of ethyl acetate, combine the ethyl acetate layers, and wash with saturated brine , dried over anhydrous magnesium sulfate, filtered, concentrated to dryness under reduced pressure, separated by silica gel column chromatography, eluted with ethyl acetate-petroleum ether (2:1), and concentrated to obtain 4.5 g of a light yellow solid. The purity of the product detected by HPLC was 95.2%, and the RRT was 0.56, which was consistent with the relative retention time of the ring-opened cefditoren pivoxil reference substance. The product has passed MS, 1 H-NMR and...

Embodiment 3

[0038] Add 6.2g cefditoren pivoxil and 55ml N,N-dimethylacetamide into the reaction bottle, stir and cool down to -5°C, slowly add lithium hydroxide 0.011mol, heat up to 10°C-20°C to react, HPLC After checking that the reaction is complete, add 50ml of water and 50ml of ethyl acetate, adjust the pH value to 3-4 with 1% hydrochloric acid under stirring, let the layers stand, extract the water layer with 20ml of ethyl acetate, combine the ethyl acetate layers, and wash with saturated brine Washed, dried over anhydrous magnesium sulfate, filtered, concentrated to dryness under reduced pressure, purified by silica gel column chromatography, eluted with ethyl acetate-petroleum ether (2:1), concentrated to obtain 4.0 g of light yellow solid. The purity of the product detected by HPLC was 96.2%, and the RRT was 0.56, which was consistent with the relative retention time of the ring-opened cefditoren pivoxil reference substance. The product has passed MS, 1 H-NMR and 13 C NMR struct...

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Abstract

The invention discloses a preparation method of ring-opened cefditoren pivoxil. The method comprises the following steps: cefditoren pivoxil and an organic solvent are added into a reaction container,and are dissolved and cooled to -20 to -5 DEG C under a stirring condition, an alkaline substance is slowly added, the obtained solution is heated to 10-20 DEG C after the completion of the additionof the alkaline substance, and is reacted, ethyl acetate and water are added after the completion of the reaction, the obtained solution undergoes stirring extraction, the pH value of the obtained solution is adjusted to 3-4 by using an acid, the obtained solution stands for layering, and the obtained organic layer is washed with saturated brine, is dried and filtered, is concentrated under a reduced pressure to dryness, and is purified by silica gel column chromatography to obtain the product. The ring-opened cefditoren pivoxil prepared by the preparation method has a content of 95.0% or above and a yield of 70%, provides a theoretic basis for the safety use of medicines, provides an effective data support for the quality standard of the cefditoren pivoxil, and provides an effective guarantee for the clinic safe use of the medicines.

Description

technical field [0001] The invention relates to a preparation method of cefditoren pivoxil ring-opened product, which belongs to the field of impurity analysis in drug synthesis. Background technique [0002] Cefditoren Pivoxil (Cefditoren Pivoxil), the chemical name is (6R,7R)-2,2-dimethylpropionyloxymethyl-7-[(Z)-2-(2-amino-4-thiazolyl) )-2-methoxyiminoacetamido]-3-[(Z)-2-(4-methyl-1,3-thiazol-5-yl)ethenyl]-8-oxo-5- Thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate. [0003] Cefditoren pivoxil is an ester-type oral third-generation cephem antibiotic developed by Japan Meiji Seika Co., Ltd. It was first listed in Japan in 1994 and listed in China in April 2001. The trade name is Meiact. Clinically, it is mainly used to treat infections caused by Gram-positive and Gram-negative bacteria. This product has a wide range of antibacterial effects, especially against Gram-positive bacteria such as Staphylococcus, Streptococcus (including Streptococcus pneumoniae), Escherichia col...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D417/14
CPCC07D417/14
Inventor 李艳杨治国邵倩何东贤杨林
Owner CHONGQING MEDICAL & PHARMA COLLEGE
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