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Azithromycin related substance and preparation method thereof

A technology related to substances and azithromycin, applied in the preparation of sugar derivatives, chemical instruments and methods, sugar derivatives, etc.

Active Publication Date: 2019-02-01
ZHEJIANG GUOBANG PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In the research on related substances of azithromycin, including the Chinese Pharmacopoeia 2015 edition, the United States Pharmacopoeia USP40 edition, and the European Pharmacopoeia EP9.0 edition, they all introduced the structural formula of each impurity in detail, the relative retention peak time, the content calculation correction factor and the control limit, but The introduction of impurity P all shows that it is an impurity of unknown structure, the relative retention peak time is 0.92 times, and the control limit is 0.2%.

Method used

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  • Azithromycin related substance and preparation method thereof
  • Azithromycin related substance and preparation method thereof
  • Azithromycin related substance and preparation method thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0032] Example 1: Pretreatment of platinum carbon

[0033] Method 1: Take 50 g of platinum carbon (platinum content 5%), add 300 ml of water, stir, and add 0.72 g of ferric chloride, beat for 0.5 hours, and filter to obtain the treated platinum carbon catalyst.

[0034] Method 2: Take 50 g of platinum carbon (platinum content 5%), add 300 ml of water, stir, and add 0.69 g of calcium chloride, beat for 0.5 hour, and filter to obtain the treated platinum carbon catalyst.

[0035] Method 3: Take 50 g of platinum carbon (platinum content 5%), add 300 ml of water, stir, and add 0.53 g of copper chloride, beat for 0.5 hours, and filter to obtain the treated platinum carbon catalyst.

Embodiment 2

[0038] Take 30 g of erythromycin 6,9-imine ether, add 200 ml of methanol, stir to dissolve, and adjust the pH to 4 to 5 with hydrochloric acid. The platinum carbon treated according to method 1 in Example 1 was put into the autoclave, and then the dissolved material was put into the autoclave together to start the hydrogenation operation. The hydrogen pressure is maintained between 1.0-1.2 MPa, the temperature is slowly raised to 55-60°C, and the reaction is carried out for 8-12 hours. After the reaction is over, the hydrogenation feed liquid is taken out, the catalyst is removed by filtration, and the feed liquid is recovered and dried. Add 100ml of acetone to dissolve, add 10g of formic acid, 15g of formaldehyde (37% aqueous solution), adjust the pH to 5-6 with sodium hydroxide (30% aqueous solution), and keep it at 40-50°C for 20-30 hours. After the reaction, the pH value is adjusted to 10-11 with sodium hydroxide (30% aqueous solution). Let stand for layering, take the ac...

Embodiment 3

[0040] Take 30 g of erythromycin 6,9-imine ether, add 200 ml of methanol, stir to dissolve, and adjust the pH to 4 to 5 with hydrochloric acid. Put the platinum carbon treated according to method 2 in Example 1 into the autoclave, and then put the dissolved material into the autoclave together to start the hydrogenation operation. The hydrogen pressure is maintained between 1.0-1.2 MPa, the temperature is slowly raised to 55-60°C, and the reaction is carried out for 8-12 hours. After the reaction is over, the hydrogenation feed liquid is taken out, the catalyst is removed by filtration, and the feed liquid is recovered and dried. Add 100ml of acetone to dissolve, add 10g of formic acid, 15g of formaldehyde (37% aqueous solution), adjust the pH to 5-6 with sodium hydroxide (30% aqueous solution), and keep it at 40-50°C for 20-30 hours. After the reaction, the pH value is adjusted to 10-11 with sodium hydroxide (30% aqueous solution). Let stand for layering, take the acetone or...

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Abstract

The invention relates to an azithromycin related substance and a preparation method thereof, and belongs to the technical field of synthesis of heterocyclic compounds. The preparation method comprisesthe steps: with erythromycin imide ether as a raw material, dissolving, then adjusting the pH to 4-5, adding platinum carbon as a catalyst, introducing hydrogen gas, maintaining the pressure, and carrying out heat preservation reaction, wherein the platinum carbon is pre-treated before being used as the catalyst, wherein the pretreatment comprises the steps of stirring 5% platinum carbon in waterand adding metal ions and beating for half an hour; filtering the catalyst, recovering a material liquid thoroughly and adding acetone, adding formaldehyde formic acid, controlling the pH to 5-6, carrying out heat preservation and carrying out N methylation reaction; after the reaction is finished, extracting and separating to remove a saline water layer, adding water to an organic layer and crystallizing, to obtain a crude product; and purifying, and thus obtaining the finished product. The preparation method is applied in synthesis of azithromycin and the related substance thereof, and theazithromycin not only can be used as a reference substance applied for qualitative and quantitative analysis of azithromycin impurities, but also can be conducive to improvement of the pharmacy safetyof azithromycin.

Description

Technical field [0001] The application relates to an azithromycin related substance, impurity P, and a preparation method thereof, and belongs to the technical field of synthesis of heterocyclic compounds. Background technique [0002] Azithromycin, as the second-generation erythromycin product, is the first semi-synthetic aza 15-membered ring macrolide antibiotic developed by the Croatian Priva Pharmaceutical Company. After oximation of erythromycin A9-keto group, a series of reactions such as Beckman rearrangement, hydrogenation reduction, N-methylation, etc. obtain azithromycin. This structural difference hinders the internal formation of hemiketal acetals, making azithromycin more stable than erythromycin A. Azithromycin and erythromycin have the same antibacterial mechanism. Both bind to the 50S subunit of the ribosome in bacterial cells to hinder bacterial transpeptidation and inhibit the synthesis of RNA-dependent proteins to achieve antibacterial effects. However, due t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H17/08C07H1/00
CPCC07H1/00C07H17/08
Inventor 金勇潘远江李广青谭艳云尤启冬单继雷侯仲轲姚礼高孟仲建
Owner ZHEJIANG GUOBANG PHARMA
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