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Process for preparing 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid

A technology of methoxymethyl and cephem, which is applied in the field of intermediates useful in the preparation of cephalosporin antibiotics, and can solve problems such as poor controllability of the method

Inactive Publication Date: 2002-10-30
HANMI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this method still has to face the difficulty of handling 98% trimethyl borate and suffers from the problem of poor process controllability

Method used

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  • Process for preparing 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] 24.4 ml of methanesulfonic acid were mixed with 6.0 ml of an azeotropic mixture consisting of 70% trimethyl borate and 30% methanol, and the resulting mixture was cooled to 10°C. 10 g of 7-aminocephalosporanic acid was slowly added thereto and allowed to dissolve completely. Then, while the temperature was maintained at 10°C, an additional 6.3 ml of the trimethyl borate-methanol azeotrope was added over 1.5 hours and stirred for a further 1.5 hours. 35 ml of cold water was added dropwise to the resulting mixture, and then 15.6 g of sodium carbonate was carefully added thereto in a small amount, followed by dropwise addition of 100 ml of acetone.

[0026] The resulting mixture was filtered to remove solid sodium methanesulfonate and the filtrate was cooled to 5°C. A solution containing 11.5 g of sodium carbonate dissolved in 40 ml of water was added dropwise to the filtrate over 1 hour to adjust the pH to 3.2. The formed solid was filtered, washed with water and aceton...

Embodiment 2

[0029] 26.8 ml of methanesulfonic acid were mixed with 5.0 ml of an azeotropic mixture consisting of 70% trimethyl borate and 30% methanol, and the resulting mixture was cooled to 10°C. 10 g of 7-aminocephalosporanic acid was slowly added thereto and allowed to dissolve completely. Then, while the temperature was maintained at 10°C, an additional 10.2 ml of the trimethyl borate-methanol azeotrope was added over 1.5 hours, and the mixture was stirred for a further 2 hours. 30 ml of cold water was added dropwise to the resulting mixture, then 15.6 g of sodium carbonate was carefully added thereto in a small amount, and 100 ml of acetone was added dropwise thereto.

[0030] The resulting mixture was filtered to remove solid sodium methanesulfonate and the filtrate was cooled to 5°C. A solution containing 13.9 g of sodium carbonate dissolved in 50 ml of water was added dropwise to the filtrate over 1 hour to adjust the pH to 3.5. The formed solid was filtered, washed with water ...

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PUM

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Abstract

The 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid of the molecular formula (I) can be obtained by azeotroping the 7-aminocephalosporic acid of the molecular formula (II) with trimethyl borate and methanol. The mixture is readily prepared by reaction in the presence of methanesulfonic acid.

Description

technical field [0001] The present invention relates to a high yield process for the preparation of 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid, which is a useful intermediate in the preparation of cephalosporin antibiotics. Background technique [0002] The 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid of molecular formula (I) is the precursor of cefpodoxime propyl axetil, and it has been reported that there are many 7-aminocephalosporins from molecular formula (II) Bacteric acid (7-ACA) begins the process for the preparation of the substance. [0003] For example, 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid has been prepared by protecting the 7-amino group of 7-ACA with phenylacetyl; by methanol-sodium bicarbonate or the action of methanol-calcium chloride to convert 3-acetoxy to methoxy; and to remove the protecting group (see Japanese Patent 82,192,392 and US Patent 4,482,710). However, this method has a problem that the yield is very low (about le...

Claims

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Application Information

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IPC IPC(8): C07D501/04C07B61/00C07D501/00C07D501/22
CPCC07D501/00C07D501/22
Inventor 李宽淳李在宪张永佶朴哲玄朴柯胜金哲庆
Owner HANMI PHARMA
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