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One-pot process for preparing azithromycin

A technology of azithromycin and process method, which is applied in the field of preparation of azithromycin, can solve problems such as low yield, cumbersome operation, and harsh reaction conditions, and achieve the effects of shortening production time, reducing procedures, and reducing the discharge of three wastes

Active Publication Date: 2013-05-08
ZHEJIANG GUOBANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In 2000, William et al. (Heggie, William, De Mouro Vaz Azevedo Mendes. Process for the preparation of azithromycin: US, 6013778 [P]. 2000-01-11.) conducted further research on the above-mentioned one-pot cooking method, but the yield was still Not high, not conducive to industrial applications
[0008]Ma Min et al. ) adopts the "one-pot cooking" synthetic method of Beckmann rearrangement reaction and reduction reaction, uses KBH4 as the reducing agent, reduces the rearrangement product, and hydrolyzes the obtained azoerythromycin borate to obtain monohydrate Azithromycin, recrystallized until azithromycin dihydrate, calculated as erythromycin A oxime, yield 81%, HPLC measured W=98.4%. This process has high yield and good quality, but the reaction conditions are harsh and the operation is cumbersome. Not conducive to industrial production
[0009]The one-pot cooking process can simplify the process and shorten the production time, but the above processes are not conducive to industrial production

Method used

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  • One-pot process for preparing azithromycin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] step one: Same as step 1 of the control example

[0024] Step two: Add 7.5g (0.110mol) sodium formate to the feed liquid, filter to remove the solid, dry the feed liquid under reduced pressure, add acetone 50ml, sodium formate 3.75g (0.0551mol), drop formaldehyde 8ml (0.1207mol), 5 ~ 8ml (0.1109mol ~0.1774mol) formic acid to adjust the pH to 4.5~5.0, keep it warm at 40°C for 24 hours, point the plate to monitor until there is no reductant residue, after the reaction is completed, adjust the pH to 10.2~10.7 with alkali, separate the layers after stirring, extract the water layer with 15ml acetone, Combine the acetone layers, add 300ml of water for crystallization, cool down to 20°C, filter with suction to obtain crude azithromycin, recrystallize from 50ml of acetone to obtain 25.12g (0.0320mol) of azithromycin dihydrate, calculated as erythromycin A6,9-imine ether, yield It was 77.9%, and the HPLC content was 98.07%.

Embodiment 2

[0026] step one: Same as step 1 of the control example

[0027] Step two: Add 3g (0.0441mol) sodium formate to the feed liquid, remove the solid by filtration, recover the feed liquid to dryness under reduced pressure, add acetone 60ml, formaldehyde 8ml (0.1207mol), sodium formate 9.7g (0.143mol), 5 ~ 8ml (0.1109mol ~ 0.1774 mol) formic acid to adjust the pH to 4.5-5.0, keep warm at 40°C for 24 hours, spot plate monitoring until no reducing substance remains, after the reaction is completed, adjust the pH to 10.2-10.7 with alkali, separate layers after stirring, extract the water layer with 15ml acetone, and combine the acetone layer, add 300ml of water for crystallization, lower the temperature to 20°C, and filter with suction to obtain crude azithromycin, recrystallize from 50ml of acetone to obtain 25.75g (0.0328mol) of azithromycin dihydrate, calculated as erythromycin A6,9-imine ether, the yield It was 79.8%, and the HPLC content was 97.79%.

Embodiment 3

[0029] step one: Same as step 1 of the control example

[0030] Step two: Add 9.7g of sodium formate (0.143mol) to the feed liquid, remove the solid by filtration, recover the feed liquid to dryness under reduced pressure, add 50ml of acetone, 8ml of formaldehyde (0.1207mol), 2.46g of sodium formate (0.0362mol), mol) formic acid to adjust the pH to 5.0-5.5, keep it warm at 40°C for 24 hours, point the plate to monitor until there is no reductant residue, after the reaction is completed, adjust the pH to 10.2-10.7 with alkali, separate the layers after stirring, extract the water layer with 15ml acetone, and combine the acetone After adding 300ml of water for crystallization, cool down to 20°C, suction filter to obtain crude azithromycin, recrystallize with 50ml of acetone to obtain azithromycin dihydrate, and dry under reduced pressure to obtain 24.85g (0.0317mol) of azithromycin. Calculated, the yield was 77.1%, and the HPLC content was 98.6%.

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Abstract

The invention mainly discloses a one-pot process for preparing azithromycin. The method which allows azithromycin to be prepared through using erythromycin imino ether without an extraction intermediate comprises the following steps: carrying out catalytic hydrogenation of erythromycin imino ether, filtering out a catalyst, adding formate, fully reacting, filtering, recovering to dryness, adding acetone for dissolving, adding the formate, adding formaldehyde and formic acid in a dropwise manner, carrying out a methylation reaction under an acidic condition to obtain azithromycin, and re-crystallizing to obtain azithromycin dihydrate. The process which realizes one-pot of a reduction reaction and the methylation reaction through the application of the formate has the advantages of substantial shortening of the erythromycin imino ether-to-azithromycin production time, operation reduction, and reduction of the discharge of three wastes, has a yield 1-5% higher than original processes, and allows the product content to be 0.5-1.5% higher than that of the original processes.

Description

Technical field [0001] The present invention involves a method of preparation of Azithromycin, which involves a pot of preparation method for a pot of Achicterin from erythromyfine. Background technique [0002] The synthetic process route of Achithromycin was first developed by Croatia's PLIVA company, including erythromycin [0003] A 贝 a, Beckman's reunion, hydrogenation, and N-methylization four process steps.as follows: [0004] [0005] This process route has been continuously optimized, and more reactions have been studied (Zhao Jiamiao et al.. Azithromycin and its key intermediate synthesis research progress, chemical technology and development, 2009,38, (4): 28-34.)The income and quality are improved than the original process. However, the route of synthetic Azithromycin is relatively long and many processes, which is not conducive to industrial production, and "one pot" can be more suitable for industrial production.There are currently some studies in "one pot". [00...

Claims

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Application Information

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IPC IPC(8): C07H17/00C07H1/00
Inventor 刘康海邱财运金勇侯仲轲王兆刚邱家军
Owner ZHEJIANG GUOBANG PHARMA
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