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Method for preparing 7-amino-3-nor-3-cephalo-4-carboxylic acid

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 residue, harsh use conditions, and poor product appearance, and achieve technological Simple and easy to implement, reduce production costs and improve product quality

Inactive Publication Date: 2011-04-20
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 high
The disadvantage is that the appearance of the product is not good, a large amount of waste containing zinc and phosphorus is produced, and the price of trifluoroacetic acid and zinc metal is relatively high

Method used

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  • Method for preparing 7-amino-3-nor-3-cephalo-4-carboxylic acid
  • Method for preparing 7-amino-3-nor-3-cephalo-4-carboxylic acid
  • Method for preparing 7-amino-3-nor-3-cephalo-4-carboxylic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Weigh 46.9g of 3-hydroxycephalosporin in a 500ml three-neck flask (with thermometer and mechanical stirring) 19 (0.1mol), add 200ml tetrahydrofuran to dissolve. 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, continue to react for 1 hour, take samples for HPLC detection, and control the reaction raw materials 19 Content≤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. Filter and dry to get 42.39g white solid product 20 (The molar yield is 90%, and the HPLC area normalization method content is 98%).

[0051] Add 42.3g of the above product in a 1000ml three-necked bottle 20 (0.09mol), add 300ml tetrahydrofuran to dissolve. Cool down to -15°C, add 13.7 g ...

Embodiment 2

[0058] Weigh 46.9g of 3-hydroxycephalosporin in a 500ml three-neck flask (with thermometer and mechanical stirring) 19 (0.1mol), add 200ml 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, continue to react for 1 hour, take samples for HPLC detection, and control the reaction raw materials 19 Content≤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. Filter and dry to get 41.5g white solid product 20 (The molar yield is 88%, and the HPLC area normalization method content is 98.5%).

[0059] Add 41.4g of the above product in a 1000ml three-necked bottle 20 (0.088mol), add 350ml tetrahydrofuran to dissolve. Cool down ...

Embodiment 3

[0062] Weigh 46.9g of 3-hydroxycephalosporin in a 500ml three-neck flask (with thermometer and mechanical stirring) 19 (0.1mol), add 100ml of dichloromethane and 100ml of tetrahydrofuran to dissolve. The temperature was lowered to -30°C, and 5.4 g of potassium borohydride (0.1 mol) was added (0.11 mol). Continue to cool down to -60°C, and slowly add 100ml of ethanol dropwise. After the dropwise addition, continue to react for 1 hour, take samples for HPLC detection, and control the reaction raw materials 19 Content≤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. Filter and dry to get 43g white solid 20 (The molar yield is 91.3%, and the HPLC area normalization method content is 98.7%).

[0063] Add 43g of the above product in a 1000ml three-necked bottle 20 (0.0913mol), 300ml of 1,...

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Abstract

The invention provides a method for preparing 7-amino-3-nor-3-cephalo-4-carboxylic acid (7-ANCA for short). In the method, 7-phenylacetyl amide-3-hydroxy-3-cephalo-4-carboxylic acid-para-nitrobenzyl ester is taken as a raw material, and the method comprises the following steps of: firstly, reducing a double bond between a 3 position and a 4 position of a parent nucleus by using metal borohydride; secondly, esterifying a 3-position hydroxyl group by using sulfonyl halide; thirdly, removing 3-position methyl sulfonate group by using alkali to restore the double bond between the 3 position and the 4 position; and finally, removing a protective group on a 4-position carboxyl group of the parent nucleus by a catalytic hydrogenation method, and removing a protective group on 7-position amino group of the parent nucleus by an enzymatic method to obtain the 7-ANCA. In the method, the integral process is simple and practicable, the quality of the product is improved, the production cost is reduced, and environmental pollution is reduced.

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. [0002] Background technique [0003] Ceftizoxime and ceftibuten belong to the third generation cephalosporin antibiotics, and its synthetic method is divided into four kinds, and synthetic route is as follows: [0004] 1. The reaction formula of synthetic route 1 is as follows: [0005] [0006] [0007] The above synthetic route uses 7-phenylacetamide-3-hydroxyl-3-cephalosporin-4-carboxylic acid-a-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 inter...

Claims

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Application Information

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IPC IPC(8): C12P17/18
Inventor 厉昆李兰杰李啸风李铭东任红阳
Owner ZHEJIANG APELOA TOSPO PHARMA
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