Method for preparing cefditoren pivoxil open-cycle dimer

A technology of cefditoren pivoxil and fiditoren pivoxil, applied in the field of impurity analysis in drug synthesis, can solve the problems of affecting accuracy, difficult to completely separate impurities, cumbersome steps, etc., and achieve low cost and safe clinical use Guaranteed, easy-to-step results

Active Publication Date: 2019-09-20
CHONGQING MEDICAL & PHARMA COLLEGE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] Cefditoren pivoxil ring-opening dimer 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 the method steps are cumbersome , the yield 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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  • Method for preparing cefditoren pivoxil open-cycle dimer
  • Method for preparing cefditoren pivoxil open-cycle dimer
  • Method for preparing cefditoren pivoxil open-cycle dimer

Examples

Experimental program
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Effect test

Embodiment 1

[0036] The preparation of the cefditoren pivoxil protected by A, Cbz

[0037] Add 6.2g (0.01mol) of cefditoren pivoxil and 100ml of dichloromethane into the reaction flask, stir and cool down to 0°C, add 0.0101mol of benzyl chloroformate dropwise, and simultaneously add triethylamine dropwise to control the pH of the system to 6.5 After the reaction, add 100ml of water, stir for 15 minutes, let stand to separate layers, wash the organic layer with water, concentrate under reduced pressure to obtain an oil, and proceed to the next step without purification.

[0038] Preparation of the cefditoren pivoxil ring-opened product of B, Cbz protection

[0039] Dissolve the oil from the previous step in 50ml of dimethyl sulfoxide, stir and cool down to -20°C, slowly add 0.01mol sodium hydroxide, heat up to 10°C for reaction, after HPLC checks that the reaction is complete, add 50ml of water and 50ml of ethyl acetate , adjust the pH value to 3.5 with 5% hydrochloric acid under stirring,...

Embodiment 2

[0055] The preparation of the cefditoren pivoxil protected by A, Cbz

[0056] Add 6.2g (0.01mol) of cefditoren pivoxil and 100ml of chloroform into the reaction flask, stir and cool down to 5°C, add 0.012mol of benzyl chloroformate dropwise, and at the same time add diethylamine dropwise to control the pH of the system to 7.5 After the addition, react at about 15°C. After the reaction, add 100ml of water, stir for 15 minutes, let stand to separate layers, wash the organic layer with water, concentrate under reduced pressure to obtain an oil, and directly proceed to the next step without purification.

[0057] Preparation of the cefditoren pivoxil ring-opened product of B, Cbz protection

[0058] Dissolve the oil from the previous step in 50ml of N,N-dimethylformamide, stir and cool down to -15°C, slowly add 0.012mol potassium hydroxide, raise the temperature to 20°C for reaction, after HPLC checks that the reaction is complete, add 50ml of water and 50ml of ethyl acetate, adj...

Embodiment 3

[0065] The preparation of the cefditoren pivoxil protected by A, Cbz

[0066] Add 6.2g (0.01mol) of cefditoren pivoxil and 100ml of dichloromethane into the reaction flask, stir and lower the temperature to 2°C, add 0.0105mol of benzyl chloroformate dropwise, and simultaneously add diisopropylethylamine dropwise to control the system The pH value is 7.0, react at about 10°C after the addition, after the reaction, add 100ml of water, stir for 15 minutes, let stand to separate layers, wash the organic layer with water, concentrate under reduced pressure to obtain an oily substance, and proceed to the next step without purification .

[0067] Preparation of the cefditoren pivoxil ring-opened product of B, Cbz protection

[0068] Dissolve the oil from the previous step in 50ml of N-methylpyrrolidone, stir and cool down to -10°C, slowly add 0.0105mol potassium carbonate, heat up to 15°C for reaction, after HPLC checks that the reaction is complete, add 50ml of water and 50ml of et...

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Abstract

The invention discloses a method for preparing a cefditoren pivoxil open-cycle dimer. The cefditoren pivoxil open-cycle dimer is characterized by being prepared by the following steps of reactions: firstly, protecting amino on cefditoren pivoxil by using Cbz (carbobenzoxyl), carrying out cycle opening so as to obtain a Cbz protected cefditoren pivoxil open-cycle substance, further enabling the Cbz protected cefditoren pivoxil open-cycle substance to react with the cefditoren pivoxil so as to obtain a Cbz protected cefditoren pivoxil open-cycle dimer, and finally removing Cbz protection, so as to obtain a product. The method disclosed by the invention is simple in step, low in cost and applicable to on-scale preparation. The content of the cefditoren pivoxil open-cycle dimer prepared by using the preparation method disclosed by the invention is up to 95.0% or greater, the yield can be up to 58%, theoretic bases are provided for medicine use security, effective data support is provided for quality standards of the cefditoren pivoxil, and effective insurance is provided for clinical use security of medicines.

Description

technical field [0001] The invention relates to a preparation method of cefditoren pivoxil ring-opening dimer, 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 coli...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/24C07D501/04
CPCC07D501/04C07D501/24
Inventor 邵倩杨治国李艳杨林唐倩
Owner CHONGQING MEDICAL & PHARMA COLLEGE
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