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Preparation method of azithromycin amine

A technology for dihydrogenoerythromycin and erythromycin, which is applied in the field of medicine, can solve problems such as complicated post-processing, and achieve the effects of reducing production cost, mild reaction conditions and shortening production time.

Active Publication Date: 2014-05-07
ZHEJIANG NEXCHEM PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] The present invention aims to provide a preparation method of dihydrohomoerythromycin, which solves the problem in the prior art that the intermediate erythromycin A6,9 imine ether needs to be extracted and the post-treatment is complicated

Method used

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  • Preparation method of azithromycin amine

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Effect test

Embodiment 1

[0030] Add 85g of erythromycin A9-oxime thiocyanate and 500ml of dichloromethane into a 1000ml reaction bottle, add 20% sodium hydroxide to adjust the pH to 9-11, and separate the layers after all the solids are dissolved, and extract the upper aqueous layer with dichloromethane Once, the dichloromethane layers were combined. Concentrate and distill off dichloromethane, add 250ml of water, cool down to below 10°C, add 25g of methanesulfonyl chloride, and keep warm until the reaction of erythromycin A9-oxime is complete. Use 20% sodium hydroxide to adjust the pH to 3-7, lower the temperature to below 10°C, add 7g of sodium borohydride, keep warm for the reaction to complete, add 1000ml of dichloromethane, adjust the pH to 0.5-2.5 with 10% hydrochloric acid, keep stirring at 0-10°C For 20 minutes, add 20% sodium hydroxide to adjust the pH to 9-11, let stand to separate layers, extract the water layer with 100ml of dichloromethane, combine the dichloromethane layer, add 200ml of ...

Embodiment 2

[0032] Add 85g of erythromycin A9-oxime thiocyanate and 500ml of dichloromethane into a 1000ml reaction bottle, add 80ml of concentrated ammonia water, separate the layers after all the solids are dissolved, extract the upper aqueous layer with dichloromethane again, and combine the dichloromethane layer. Concentrate and distill off dichloromethane, add 250ml of water, cool down to below 10°C, add 25g of methanesulfonyl chloride, and keep warm until the reaction of erythromycin A9-oxime is complete. Use 20% sodium hydroxide to adjust the pH to 3-7, lower the temperature to below 10°C, add 7g of sodium borohydride, keep warm for the reaction to complete, add 1000ml of dichloromethane, adjust the pH to 0.5-2.5 with 10% hydrochloric acid, keep stirring at 0-10°C For 20 minutes, add 20% sodium hydroxide to adjust the pH to 9-11, let stand to separate layers, extract the water layer with 100ml of dichloromethane, combine the dichloromethane layer, add 200ml of water, concentrate un...

Embodiment 3

[0034] Add 85g of erythromycin A9-oxime thiocyanate and 500ml of dichloromethane into a 1000ml reaction bottle, add 20% sodium hydroxide to adjust the pH to 9-11, and separate the layers after all the solids are dissolved, and extract the upper aqueous layer with dichloromethane Once, the dichloromethane layers were combined. Concentrate and distill off dichloromethane, add 250ml of water, cool down to below 10°C, add 25g of methanesulfonyl chloride, and keep warm until the reaction of erythromycin A9-oxime is complete. Use 20% sodium hydroxide to adjust the pH to 3-7, lower the temperature to below 10°C, add 7g of sodium borohydride, keep warm for complete reaction, add 1000ml of chloroform, adjust the pH to 0.5-2.5 with 10% hydrochloric acid, keep stirring at 0-10°C After 20 minutes, add 20% sodium hydroxide to adjust the pH to 9~11, let stand to separate layers, extract the water layer with 100ml of chloroform, combine the chloroform layer, add 200ml of water, concentrate u...

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Abstract

The invention provides a preparation method of azithromycin amine. The preparation method is characterized by adopting a one-pot reaction method. The preparation method comprises the steps of carrying out Beckman rearrangement for erythrocin A9- oxime, water and rearrangement reagent, adjusting the pH value to be 3.0 to 7.0 after the reaction is ended, adding reducing agent to reduce the reactants, and obtaining the azithromycin amine through acid hydrolysis and crystallization. The one-pot reaction of the Beckman rearrangement and reduction is realized by adopting water as the solvent, so that the time for producing erythrocin A9- oxime or erythrocin A9-oxime thiocyanate and the azithromycin amine can be greatly shortened, the procedures can be reduced, the emission of waste gas, waste water and industrial residue can be reduced, the yield is improved by 1 to 3 percent compared with the original process, and the production cost of the azithromycin is further reduced. The midbody erythrocin A6, 9 imino ether is not extracted, and the reaction condition is moderate; the water is used as the reaction solvent, less waste (waste water, waste gas and industrial residue) is produced, and the environmental friendliness can be realized.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a preparation method of dihydrohomoerythromycin. Background technique [0002] Azithromycin (Azithromycin) is a semi-synthetic macrolide antibiotic with broad-spectrum antibacterial effect, and its application in the field of anti-infection in China is very extensive. Azithromycin is usually synthesized from erythromycin thiocyanate through oximation, Beckmann rearrangement, reduction and methylation reactions. In the synthesis process of azithromycin, dihydrohomoerythromycin is an extremely important intermediate and a key step that affects the synthesis yield and production cost of azithromycin. [0003] The chemical structural formula of dihydrohomoerythromycin is as follows: [0004] [0005] Literature Ma Min et al., Improvement of Azithromycin Synthetic Process, Fine Chemical Industry, 2006.8: Synthesis of Compound Ⅳ (dihydrohomoerythromycin) in one pot, erythromycin ...

Claims

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Application Information

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IPC IPC(8): C07H17/00C07H1/00
Inventor 李文辉盛健勇赵满琼童映红
Owner ZHEJIANG NEXCHEM PHARMA
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