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Preparation method of cefditoren pivoxil

A technology of cefditoren pivoxil and cephem, which is applied in the field of antibiotic preparation, can solve the problems of poor configuration selectivity, long time consumption, and poor utilization of solid waste triphenylphosphine, and achieve low cost and high selectivity Effect

Active Publication Date: 2019-02-22
湖北凌晟药业股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In the current synthetic method of cefditoren pivoxil, the ethylenic bond between the cephalosporin nucleus and the thiazole ring is mostly generated by the reaction of phosphorus ylides and aldehydes. Although this method has simple reactions, it needs to use toxic triphenylphosphine, and The yield of wittig reaction is low, it takes a long time, and the configuration selectivity is poor. At the same time, the solid waste triphenylphosphine produced by the reaction is not easy to use, so it can only be treated as solid waste, which increases the cost.

Method used

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  • Preparation method of cefditoren pivoxil

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] A kind of preparation method of cefditoren pivoxil, concrete steps are as follows:

[0024] Dissolve 24.9g of 7-amino-3-chloromethyl-3-cephem-4-carboxylic acid (I) in toluene, add 4g of NaOH, then add 29g of iodomethyl pivalate, reflux for 1.5h, and react After the end, the reaction solution was washed with water, and the solvent was evaporated to obtain 34.8 g of 7-amino-3-chloromethyl-3-cephem-4-carboxylic acid trimethylacetoxymethyl ester (II); Add acetic anhydride to dissolve, add 16.8g urotropine, react at 30°C for 2h, after the reaction, pour the reaction solution into 10% aqueous sodium hydroxide solution, stir for 5min, extract with ethyl acetate, evaporate the organic phase Solvent to obtain 31.7g of compound (Ⅲ); soak 2.7g of magnesium in tetrahydrofuran, then dissolve 14.8g of 4-methyl-5-chloromethylthiazole (Ⅳ) in tetrahydrofuran, drop into the tetrahydrofuran system soaked in magnesium , heating to reflux to initiate the reaction, and reflux for 1 hour aft...

Embodiment 2

[0026] A kind of preparation method of cefditoren pivoxil, concrete steps are as follows:

[0027] Dissolve 24.9g of 7-amino-3-chloromethyl-3-cephem-4-carboxylic acid (I) in toluene, add 6g of NaOH, then add 36g of iodomethyl pivalate, reflux for 1h, and the reaction ends After the reaction liquid was washed with water, the solvent was evaporated to obtain 35.5 g of 7-amino-3-chloromethyl-3-cephem-4-carboxylic acid trimethylacetoxymethyl ester (Ⅱ); Dissolve in acetic anhydride, add 20g urotropine, react at 20°C for 3h, after the reaction, pour the reaction solution into 10% aqueous sodium hydroxide solution, stir for 5min, extract with ethyl acetate, evaporate the organic phase to remove the solvent to obtain Compound (Ⅲ) 32.4g; Soak 2.8g magnesium in tetrahydrofuran, then dissolve 22g 4-methyl-5-chloromethylthiazole (Ⅳ) in tetrahydrofuran, drop into the tetrahydrofuran system soaked in magnesium, heat to reflux Initiate the reaction, reflux the reaction for 1 hour after drop...

Embodiment 3

[0029] A kind of preparation method of cefditoren pivoxil, concrete steps are as follows:

[0030] Dissolve 24.9g of 7-amino-3-chloromethyl-3-cephem-4-carboxylic acid (I) in toluene, add 6g of NaOH, then add 31g of iodomethyl pivalate, reflux for 1h, and the reaction ends After the reaction liquid was washed with water, and the solvent was distilled off, 35.0 g of 7-amino-3-chloromethyl-3-cephem-4-carboxylic acid trimethylacetoxymethyl ester (II) was obtained; (II) was added Dissolve in acetic anhydride, add 18g urotropine, react at 20°C for 3h, after the reaction, pour the reaction solution into 10% aqueous sodium hydroxide solution, stir for 5min, extract with ethyl acetate, evaporate the organic phase to remove the solvent to obtain Compound (Ⅲ) 32.1g; soak 2.8g of magnesium in tetrahydrofuran, dissolve 19g of 4-methyl-5 chloro-methylthiazole (Ⅳ) in tetrahydrofuran, drop into the tetrahydrofuran system soaked in magnesium, and heat to reflux to initiate the reaction. After...

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Abstract

The invention relates to the technical field of preparation of antibiotics, and specifically discloses a preparation method of cefditoren pivoxil. 7-amino-3-chloromethyl-3-cephem-4-carboxylic acid isused as a starting material, iodomethyl pivalate firstly reacts with the carboxyl group in the structure, then trimethyl acetoxymethyl ester of 7-ATCA is obtained by aldehyde reaction of the chloromethyl group, Grignard reaction and dehydration, and the cefditoren pivoxil is obtained by amidation of the trimethyl acetoxymethyl ester and 2-methoxyimino-2-(2-aminothiazo-4-lyl) acetic acid. The method has the advantages of high yield, low cost, short time and more environmental protection.

Description

technical field [0001] The invention relates to the technical field of antibiotic preparation, in particular to a preparation method of cefditoren pivoxil. Background technique [0002] Cefditoren pivoxil is a third-generation cephalosporin antibiotic, developed by Japan’s Meiji Seika Co., Ltd., listed in Japan in 1994, and listed in China in April 2001. The trade name is Meiact. Community-acquired respiratory infections caused by five major pathogenic bacteria, Streptococcus, Haemophilus influenzae, Streptococcus pyogenes, Staphylococcus aureus, and Moraxella catarrhalis, have significant curative effects, especially for penicillin-resistant Streptococcus pneumoniae, aureus Staphylococcus and some enzyme-producing bacteria showed excellent antibacterial activity. The structural formula of cefditoren pivoxil is as follows: [0003] [0004] In the current synthetic method of cefditoren pivoxil, the ethylenic bond between the cephalosporin nucleus and the thiazole ring i...

Claims

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Application Information

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IPC IPC(8): C07D501/04C07D501/24
CPCC07D501/04C07D501/24
Inventor 金联明何健门万辉邹菁
Owner 湖北凌晟药业股份有限公司
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