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Preparation method of azithromycin intermediate

A technology for azithromycin and intermediates, applied in the field of pharmaceutical chemical synthesis, can solve the problems of low yield of azithromycin, easy hydrolysis of boronate intermediates, etc., and achieve the effects of facilitating industrial production, reducing acid degradation products, and reducing preparation costs.

Active Publication Date: 2011-07-20
KAIFENG PHARMA GRP +1
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  • Abstract
  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

[0017] In order to solve the problems such as the low yield of azithromycin in the prior art, the need to use noble metals as catalysts, or the use of reducing agents such as sodium borohydride or potassium borohydride to easily hydrolyze borate intermediates, the purpose of the present invention is to improve the existing technology. Improvement to provide a new azithromycin intermediate - 9-deoxy-9a-aza-9a-erythromycin A preparation method, involving hydrolysis of borate under mild conditions

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Examples

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Embodiment 1

[0029] Embodiment 1 erythromycin A6, the preparation of 9-imine ether

[0030] Add 135g of erythromycin A9-oxime and 60g of alkaline agent sodium bicarbonate into a 1000ml reaction bottle, add 540ml of water, lower the temperature below 5°C, add dropwise acetone solution (50ml) of 30ml of methanesulfonyl chloride, finish dripping in 20min, and keep warm For the reaction, use 20% sodium hydroxide solution to adjust the pH value to 10-11, stir for 1 hour, filter with suction, wash with water to obtain the product, dry it, about 127.8g, the yield is 95%, and the HPLC purity content is 95% after testing .

Embodiment 2

[0031] Embodiment 2 erythromycin A6, the preparation of 9-imine ether

[0032] Add 135g of erythromycin A9-oxime and 60g of alkaline agent sodium bicarbonate into a 1000ml reaction bottle, add 540ml of water, lower the temperature below 5°C, add dropwise acetone solution (50ml) of 50ml of p-toluenesulfonyl chloride, and finish dripping in 20 minutes , heat preservation reaction, adjust the pH value to 10-11 with 20% sodium hydroxide solution, stir for 1h, filter with suction, wash with water, get the product, dry it, about 125.8g, the yield is 94%, and the purity content after testing HPLC is 97%.

Embodiment 3

[0033] Example 3 Preparation of 9-deoxy-9a-aza-9a-erythromycin A

[0034] Add 100ml of water into the three-necked flask, stir, add 20g of rearrangement erythromycin A6,9-imine ether, slowly add 5% sulfuric acid to adjust the pH to 5-6, stir to dissolve, and cool down to -5°C At ~5°C, add potassium borohydride (2.50g) alkaline aqueous solution (pH=10) dropwise, keep the reaction for 3 hours after dropping, add 100ml of chloroform, adjust the pH to 10.5 with alkali, stir at 15°C to 20°C for half an hour, Stand to separate the layers, separate the chloroform, extract the water layer once with 30ml chloroform, combine the chloroform, add 200g water, cool to below 5°C, add 1g gluconic acid, wash with 20% H 2 SO 4 Adjust pH=2.8, stir and keep warm for 30min. Use 20% sodium hydroxide solution to adjust the pH to 10-11, stir for 30 minutes, let stand to separate the layers, separate the chloroform, extract the water layer with 30ml of chloroform once, combine the chloroform, add 10...

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Abstract

The invention discloses a preparation method of azithromycin intermediate, in particular to a preparation method of azithromycin intermediate 9- deoxidation-alpha- heterocyclic nitrogen-9a-erythromycin A, belonging to the field of pharmaceutical chemical synthesis. The preparation method comprises the steps of: in acid aqueous solution, under the action of potassium borohydride or sodium borohydride, carrying out reduction reaction on erythromycin A 6, 9-imine ether, adding organic saccharic acid for hydrolysis reaction, and obtaining the 9-deoxidation-alpha-heterocyclic nitrogen-9a-erythromycin A. By adopting the method, the hydrolysis of boric acid ester is thorough, the products of acid degradation are less, the yield is high, the production cost of azithromycin is remarkably reduced, and the industrialized production can be very smoothly carried out.

Description

technical field [0001] The invention relates to a preparation method of an azithromycin intermediate, in particular to 9-deoxy-9a-aza-9a-erythromycin A [0002] The preparation method of the intermediate belongs to the field of pharmaceutical chemical synthesis. Background technique [0003] Azithromycin is a 15-ring macrolide drug, which is one of the most representative drugs in the new erythromycin. It was developed by Pliva Pharmaceutical Company in Croatia in the late 1970s and was launched in 1981. Pfizer (Pfizer) of the United States obtained its patent right and began to sell it all over the world under the trade name Zithromax (Xishumei). [0004] Azithromycin and erythromycin have commonalities in chemical structure and mechanism of action. They both bind to the ribosomal 50S subunit in bacterial cells, hinder bacterial transpeptide and (or) m-RNA translocation, and inhibit protein synthesis to achieve antibacterial effect. But their biochemical properties are q...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/14
Inventor 朱松林徐海伟张军伟张方杰王新军季明志周振姜平娟陈水库朱成功朱文臣
Owner KAIFENG PHARMA GRP
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