Preparation method of cefditoren pivoxil [delta]3 isomer

A technology of cefditoren pivoxil and cefditoren, which is applied in the field of pharmaceutical intermediate synthesis, can solve the problems of low isomerization conversion rate, difficult extraction, difficult selection of mobile phases, etc. Short time, solve the effect of poor selection of mobile phase

Active Publication Date: 2020-06-05
浙江东邦药业有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] And for cefditoren pivoxil there are some impurities also in the process of synthesis, wherein, for cefditoren pivoxil δ 3 Isomer is one of the important impurities in the quality control of cefditoren pivoxil. At present, there are few literatures to report the synthesis method of this impurity. Only some relevant reports are based on cefditoren pivoxil as raw material, under the condition of concentrated ammonia The isomerization reaction is carried out under the following conditions, and finally the product is obtained by column purification
The method needs to be carried out under high-temperature alkaline conditions for a long time, which easily causes cefditoren pivoxil ring-opening and degrades into other impurities, and the isomerization conversion rate is extremely low, and the operation of column purification is also difficult to operate, and the yield Low, and because the raw material cefditoren pivoxil and its δ 3 The polarity of the isomers is very similar, it is difficult to separate, the extraction is also difficult, and the mobile phase is also difficult to choose

Method used

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  • Preparation method of cefditoren pivoxil [delta]3 isomer
  • Preparation method of cefditoren pivoxil [delta]3 isomer
  • Preparation method of cefditoren pivoxil [delta]3 isomer

Examples

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Effect test

Embodiment 1

[0042] In a clean reaction flask, 32.3g (0.1mol, 1eq) of cephalosporin nucleus 7-ATCA shown in formula II was dissolved in 323g of dichloromethane, and then 50.9g (0.25mol, 2.5eq) of BSA (N, O-bistrimethylsilylacetamide), after stirring evenly, add 11.1g (0.11mol, 1.1eq) organic base triethylamine at 25-35°C and control the temperature at 25-30°C for isomerization Reaction, stirring and reacting for 0.5 to 1 hour. After the isomerization reaction, control the temperature of the reaction liquid at 25 to 35°C, add 100 mL of water to the reaction liquid, stir for 5 to 15 minutes, and let it stand for sufficient stratification. Remove the organic layer, collect the water layer feed solution in the reaction bottle, and control the temperature at 25-35°C, add 5% dilute hydrochloric acid solution to the water layer feed solution, adjust the pH value to 2.0-3.0, adjust After it is basically stable, slowly lower the temperature to 5-15°C and carry out stirring and crystallization for 1...

Embodiment 2

[0046]In a clean reaction flask, 32.3 g (0.1 mol, 1 eq) of cephalosporin nucleus 7-ATCA shown in formula II was dissolved in 485 g of dichloromethane, and then 61 g (0.3 mol, 3.0 eq) of BSA (N, O -bistrimethylsilylacetamide), after stirring evenly, add 15.2g (0.15mol, 1.5eq) organic base triethylamine at 25-30°C and control the temperature to carry out isomerization reaction at 25-30°C , stirred and reacted for 1.0 hour. After the isomerization reaction was completed, 150 mL of water was added to the reaction solution at a temperature of 25 to 30 ° C, stirred for 15 minutes, and after standing for sufficient separation, the organic layer was separated and discarded. Collected The water layer feed liquid is in the reaction bottle, and the temperature is controlled at 25-35°C. Add a 10% mass percent dilute hydrochloric acid solution to the collected water layer feed liquid to adjust the pH value to 2.0-2.5, and adjust it to be basically stable. Afterwards, slowly lower the tempe...

Embodiment 3

[0050] In a clean reaction flask, 32.3 g (0.1 mol, 1 eq) of cephalosporin nucleus 7-ATCA shown in formula II was dissolved in 400 g of ethyl acetate, and then 40.7 g (0.2 mol, 2.0 eq) of BSA (N, O-bistrimethylsilylacetamide), after stirring evenly, add 20.2g (0.2mol, 2.0eq) diisopropylamine at 25-30°C and control the temperature at 25-30°C for isomerization Reaction, stirring and reacting for 1.0 hour, after the isomerization reaction, control the temperature of the reaction solution at 25-30°C, add 150mL of water to the reaction solution, stir for 15 minutes, after standing for sufficient separation, separate the liquid and discard the organic layer, Collect the water layer feed liquid in the reaction bottle, and control the temperature at 25-35°C, add 10% dilute hydrochloric acid solution to the collected water layer feed liquid, adjust the pH value to 2.5-3.0, and adjust the basic After stabilization, slowly lower the temperature to 5-10°C and fully stir and crystallize for...

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Abstract

The invention relates to a preparation method of a cefditoren pivoxil [delta]3 isomer, and belongs to the technical field of drug intermediate synthesis. The invention aims to solve the problems of low isomerization and difficulty in separation of existing synthetic products, and provides the method. The method comprises the following steps: adding 7-ATCA, BSA and a first organic alkali into a first non-water-soluble organic solvent to carry out an isomerization reaction; after the reaction is finished, adding water, standing and separating liquid; collecting a water phase, and adding acid into the collected water phase to adjust the pH value to 2.0 to 3.0 to obtain a 7-ATCA[delta]3 isomer shown in the specification; in the presence of a second organic alkali, carrying out a condensation reaction on the 7-ATCA[delta]3 isomer and AE active ester to obtain a corresponding cefditoren [delta]3 isomer shown in the specification, and reacting the cefditoren [delta]3 isomer with iodomethyl pivalate to obtain the cefditoren pivoxil [delta]3 isomer. The method has the advantages that the isomerization rate is high, the yield and purity of the product can be improved, and the separation operation is easy.

Description

technical field [0001] The present invention relates to a kind of cefditoren pivoxil δ 3 The preparation method of the isomer belongs to the technical field of pharmaceutical intermediate synthesis. Background technique [0002] The chemical name of cefditoren pivoxil is 2,2-dimethylpropionyloxymethyl(6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-methyl Oxyiminoacetamido]-3-[(Z)-2-(4-methyl-1,3-thiazol-5-yl)ethenyl]-8-oxo-5-thia-1-nitrogen Heterobicyclo[4.2.0]oct-2-ene-2-carboxylate, its chemical structural formula is as follows: [0003] [0004] Cefditoren pivoxil (Cefditoren pivoxil) is an ester-type oral third-generation cephem antibiotic developed by Japan’s Meiji Seika Co., Ltd. It was first launched in Japan in 1994, and it was launched in China in April 2001. The trade name is Meiai Gram, it is mainly used clinically to treat infections caused by Gram-positive bacteria and Gram-negative bacteria. This product has a wide range of antibacterial effects, especially aga...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/04C07D501/06C07D501/60
CPCC07D501/04C07D501/06C07D501/60
Inventor 周军荣池瀛芮立涛雷维敏高扬叶思思
Owner 浙江东邦药业有限公司
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