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Preparation methods of Cefditoren acid delta 3 isomer and cefditoren pivoxil delta 3 isomer

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

Active Publication Date: 2019-10-25
CHONGQING MEDICAL & PHARMA COLLEGE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] cefditoren delta 3 isomers and cefditoren pivoxil δ 3 The isomer is an important impurity that needs to be studied in the quality control of cefditoren pivoxil. The impurity reference substance is currently obtained by separating and extracting the crude product of cefditoren pivoxil, but this method has cumbersome steps, low yield and low purity. , some impurities with similar structures are difficult to separate completely, thus affecting the accuracy of detection

Method used

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  • Preparation methods of Cefditoren acid delta 3 isomer and cefditoren pivoxil delta 3 isomer
  • Preparation methods of Cefditoren acid delta 3 isomer and cefditoren pivoxil delta 3 isomer
  • Preparation methods of Cefditoren acid delta 3 isomer and cefditoren pivoxil delta 3 isomer

Examples

Experimental program
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Effect test

Embodiment 1

[0038] 7-ATCAδ 3 Preparation of isomers

[0039]Add 0.1mol of 7-ATCA and 350ml of dichloromethane into a 1000ml three-neck flask, add 0.18mol of BSA (N,O-bistrimethylsilylacetamide) under nitrogen protection, stir until all are dissolved and clear, and cool down to 20°C Next, add 0.16 mol of tributylamine, stir for 40 minutes, heat up to 25°C-30°C, stir for reaction, HPLC detects the conversion of isomers, after the reaction is complete, add 350ml of purified water, stir for 10 minutes, let stand, The aqueous layer was separated, and the aqueous layer was washed 3 times with 50 ml of dichloromethane. Cool the water layer to 2-5°C, adjust the pH value to 3.5 with 15% hydrochloric acid, precipitate crystals, stir for 2 hours, filter, wash the filter cake with cold purified water, and filter to dry. Suspend the wet product in 450ml of methanol, heat to dissolve, filter while hot, the filtrate is cooled and crystallized, filtered, the filter cake is washed with acetone, and drie...

Embodiment 2

[0041] 7-ATCAδ 3 Preparation of isomers

[0042] Add 0.1mol of 7-ATCA and 350ml of dichloromethane into a 1000ml three-neck flask, add 0.22mol of BSA (N,O-bistrimethylsilylacetamide) under nitrogen protection, stir until all are dissolved and clear, and cool down to 20°C Next, add 0.2 mol of diethylamine, stir for 30 minutes, heat up to 25°C-30°C, stir for reaction, and detect the conversion of isomers by HPLC. After the reaction is complete, add 350ml of purified water, stir for 10 minutes, and let stand. The aqueous layer was separated, and the aqueous layer was washed 3 times with 50 ml of dichloromethane. Cool the water layer to 2-5°C, adjust the pH value to 4.5 with 10% hydrochloric acid, precipitate crystals, stir for 2 hours, filter, wash the filter cake with cold purified water, and filter to dry. Suspend the wet product in 450ml of methanol, heat to dissolve, filter while it is hot, the filtrate is cooled and crystallized, filtered, the filter cake is washed with ac...

Embodiment 3

[0044] 7-ATCAδ 3 Preparation of isomers

[0045] Add 0.1mol of 7-ATCA and 350ml of dichloromethane into a 1000ml three-necked flask, add 0.2mol of BSA (N,O-bistrimethylsilylacetamide) under nitrogen protection, stir until completely dissolved and clear, and cool down to 20°C Next, then add 0.18mol of triethylamine, stir for 25 minutes, heat up to 25°C-30°C, stir for reaction, HPLC detects the conversion of isomers, after the reaction is complete, add 350ml of purified water, stir for 10 minutes, let stand, The aqueous layer was separated, and the aqueous layer was washed 3 times with 50 ml of dichloromethane. Cool the water layer to 2-5°C, adjust the pH value to 4.0 with 10% hydrochloric acid, precipitate crystals, stir for 2 hours, filter, wash the filter cake with cold purified water, and filter to dry. Suspend the wet product in 450ml of methanol, heat to dissolve, filter while it is hot, the filtrate is cooled and crystallized, filtered, the filter cake is washed with ac...

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Abstract

The invention discloses preparation methods of Cefditoren acid delta 3 isomer and cefditoren pivoxil delta 3 isomer. The cefditoren acid delta 3 isomer is prepared from the following steps that pure water and tetrahydrofuran are added in a reaction vessel, the temperature is lowered to 0-5 DEG C, a 7-ATCA delta 3 isomer and AE active ester (MAEM) are added, after adding is completed, then organicalkali is dropwise added to control pH of 8.0-8.5, the organic alkali is needed to be additionally added to keep the pH of 8.0-8.5, dichloromethane and water are added after reaction is completed, stirring and extraction are conducted, still standing and layering are conducted, a lower organic layer is discarded, the pH of an upper water layer is 3.0-3.5, stirring and filtering are conducted, andwashing and drying are conducted to obtain a product. The content of the cefditoren acid delta 3 isomer and the cefditoren pivoxil delta 3 isomer which are prepared through the preparation method canreach above 93%.

Description

technical field [0001] The present invention relates to a kind of cefditoren acid delta 3 Isomers and cefditoren pivoxil δ 3 The invention discloses a method for preparing an isomer, 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 Staphyloco...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/60C07D501/06C07D501/04
CPCC07D501/04C07D501/06C07D501/60
Inventor 刘应杰何东贤马杨王梦
Owner CHONGQING MEDICAL & PHARMA COLLEGE
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