7-amino-3-non-3-cephalosporin-4-carbosylic acid preparation method

A cephalosporin and amino technology, which is applied in the field of preparation of 7-amino-3-non-3-cephalosporin-4-carboxylic acid, can solve the problems of high metal ion residues, poor product appearance, harsh use conditions, etc., and achieve reduction The production cost, the process is simple and easy, and the effect of improving product quality

Inactive Publication Date: 2009-02-04
ZHEJIANG APELOA TOSPO PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantage is that tributyltin is expensive, the use conditions are harsh, a large amount of waste containing copper, tin and phosphorus is produced, and the residual metal ions in the product are too hi

Method used

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  • 7-amino-3-non-3-cephalosporin-4-carbosylic acid preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Weigh 46.9 g of 3-hydroxycephalosporin compound 19 (0.1 mol) in a 500 ml three-neck flask (with thermometer and mechanical stirring), and add 200 ml of tetrahydrofuran to dissolve it. The temperature was lowered to -30°C, and 5.4 g of potassium borohydride (0.1 mol) was added. Continue to cool down to -60°C, and slowly add 100ml of ethanol dropwise. After the dropwise addition, the reaction was continued for 1 hour, a sample was taken for HPLC detection, and the content of the reaction raw material 19 was controlled to be ≤0.5%. 400ml of purified water was added, the temperature was slowly raised to room temperature, and a solid was precipitated. The tetrahydrofuran solvent was recovered under reduced pressure at room temperature. After filtration and drying, 42.39 g of white solid product 20 was obtained (90% molar yield, 98% content by HPLC area normalization method).

[0038]Add 42.3 g of the above-mentioned product 20 (0.09 mol) into a 1000 ml three-necked flask,...

Embodiment 2

[0043] Weigh 46.9 g of 3-hydroxycephalosporin compound 19 (0.1 mol) in a 500 ml three-neck flask (with thermometer and mechanical stirring), add 200 ml of dichloromethane to dissolve. The temperature was lowered to -30°C, and 4.18 g of sodium borohydride (0.11 mol) was added. Continue to cool down to -55°C, and slowly add 100ml of methanol dropwise. After the dropwise addition, the reaction was continued for 1 hour, a sample was taken for HPLC detection, and the content of the reaction raw material 19 was controlled to be ≤0.5%. 400ml of purified water was added, the temperature was slowly raised to room temperature, and a solid was precipitated. The dichloromethane and methanol solvents were recovered under reduced pressure at room temperature. After filtration and drying, 41.5 g of white solid product 20 was obtained (88% molar yield, 98.5% content by HPLC area normalization method).

[0044] Add 41.4 g of the above-mentioned product 20 (0.088 mol) into a 1000 ml three-ne...

Embodiment 3

[0046] Weigh 46.9 g of 3-hydroxycephalosporin compound 19 (0.1 mol) in a 500 ml three-neck flask (with thermometer and mechanical stirring), add 100 ml of dichloromethane and 100 ml of tetrahydrofuran to dissolve. The temperature was lowered to -30°C, and 5.4 g of potassium borohydride (0.1 mol) (0.11 mol) was added. Continue to cool down to -60°C, and slowly add 100ml of ethanol dropwise. After the dropwise addition, the reaction was continued for 1 hour, a sample was taken for HPLC detection, and the content of the reaction raw material 19 was controlled to be ≤0.5%. 400ml of purified water was added, the temperature was slowly raised to room temperature, and a solid was precipitated. The dichloromethane and tetrahydrofuran solvents were recovered under reduced pressure at room temperature. After filtration and drying, 43 g of white solid 20 was obtained (91.3% molar yield, 98.7% content by HPLC area normalization method).

[0047] Add 43 g of the above-mentioned product ...

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Abstract

The invention provides a preparation method of 7-amino-3-non-cephem-4-carboxylic acid which is 7-ANCA for short. The preparing procedures are as follows: 7-phenyl acetamide-3-hydroxy-3-cephem-4-carboxylic acid-p-nitrobenzyl ester is taken as raw material; firstly, metal borohydride is used to reduce the double bonds between the 3-parental nucleus and the 4-parental nucleus; sulfuryl etheride is used to esterify the 3-hydroxy, then alkali is used to remove the 3-methanesulfonic acid ester group to restore the double bonds between the 3-parental nucleus and the 4-parental nucleus; finally, a catalytic hydrogenation method is used to remove the protecting group on the 4-carboxyl of the parental nucleus, an enzyme method is used to remove the protecting group on the 7-amino of the parental nucleus, thus obtaining the product 7-ANCA. The invention has the advantages of being simple and feasible technology, improving production quality, reducing production cost and reducing environment pollution.

Description

technical field [0001] The present invention relates to the preparation technology of 7-amino-3-non-3-cephalosporin-4-carboxylic acid (hereinafter referred to as 7-ANCA), which is the common mother nucleus of Ceftizoxime and Ceftibuten. Background technique [0002] Ceftizoxime and ceftibuten belong to the third-generation cephalosporin antibiotics. There are four synthetic methods, and the synthetic routes are as follows: [0003] 1. The reaction formula of synthetic route one is as follows: [0004] [0005] The above synthetic route uses 7-phenylacetamide-3-hydroxyl-3-cephalosporin-4-carboxylic acid-α-phenylbenzyl ester 2 as raw material, and first uses sodium borohydride to reduce the double bond to obtain intermediate 3, then use methylsulfonyl chloride to esterify the 3-position hydroxyl to obtain intermediate 4, use phosphorus pentachloride and pyridine to remove the protecting group on the 7-position amino group to obtain intermediate 5, and then use alkali to re...

Claims

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Application Information

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IPC IPC(8): C07D501/18C07D501/04
CPCY02P20/55
Inventor 李兰杰厉昆李啸风李铭东任红阳
Owner ZHEJIANG APELOA TOSPO PHARMA
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