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Method for synthesizing azithromycin rearrangement impurity lactam

A technique for the synthesis of azithromycin, applied in the field of chemistry, can solve the problems of only 55% yield, complex step-by-step operation, only 63%, and achieve the effects of easy distillation and removal, simple post-reaction treatment, and high solubility

Active Publication Date: 2019-04-05
HEC PHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are mainly two methods for synthesizing the impurity after retrieval: 1. Diethyl ether is used as a solvent, and erythromycin oxime is rearranged under the catalysis of pyridine and p-toluenesulfonyl chloride to obtain lactam (Djokic, Slobodan; Kobrehel, Gabrijela; Lazarevski, Gorjana; Lopotar, Nevenka; Tamburasev, Zrinka; et al.; Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry, 1986; p.1881-1890), using the malodorous and irritating pyridine and p-toluenesulfonyl chloride , and the yield is only 63%; 2. Erythromycin A6,9-imine ether reacts step by step under the catalysis of protic solvent nitromethane and acetic acid to generate lactam for about 40 hours, and the step-by-step operation is complicated and the yield is low. Only 55% (Wilkening, Robert R.; Ratcliffe, Ronald W.; Doss, George A.; Mosley, Ralph T.; Ball, Richard G.; Tetrahedron; vol.53; nb.50; 1997; p.16923- 16944)

Method used

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  • Method for synthesizing azithromycin rearrangement impurity lactam
  • Method for synthesizing azithromycin rearrangement impurity lactam
  • Method for synthesizing azithromycin rearrangement impurity lactam

Examples

Experimental program
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Embodiment 1

[0031] Example 1 (2R, 3S, 4R, 5R, 8R, 10R, 11R, 12S, 13S, 14R)-11-[[(3,4,6)-trideoxy-3-(dimethylamino)-β- D-xyl-hexapyranosyl]oxy]-2-ethyl-3,4,10-trihydroxy-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl base-α-L-nucleo-hexapyranosyl)oxy]-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecane-7,15 - Synthesis of diketones

[0032] (3R,4R,5S,6R,9R,10S,11S,12R,13R,15R,Z)-12-[[3,4,6-trideoxy-3-(dimethylamino)-β-D- Wood-hexyranosyl]oxy]-6-ethyl-4,5-dihydroxy-10-[(2,6-dideoxy-3-C-methyl-3-O-methyl-a-L- Nucleo-hexapyranosyl)oxy]-3,5,9,11,13,15-hexamethyl-7,16-dioxo-2-azabicyclo[11.2.1]hexadecane-1- Add 20g of en-8-one (compound II, 26mmol) and 100ml of dichloromethane into a three-necked flask, control the temperature at 20-25°C, add 1.72g (28.6mmol) of glacial acetic acid, and 3.95g (28.6mmol) of potassium carbonate Dissolve in 20ml of water, stir for 2-3 hours, add 20ml of water to wash, separate layers, take the organic layer and distill under reduced pressure to obtain 18.6g of white...

Embodiment 2

[0034] Example 2 (2R, 3S, 4R, 5R, 8R, 10R, 11R, 12S, 13S, 14R)-11-[[(3,4,6)-trideoxy-3-(dimethylamino)-β- D-xyl-hexapyranosyl]oxy]-2-ethyl-3,4,10-trihydroxy-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl base-α-L-nucleo-hexapyranosyl)oxy]-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecane-7,15 - Synthesis of diketones

[0035](3R,4R,5S,6R,9R,10S,11S,12R,13R,15R,Z)-12-[[3,4,6-trideoxy-3-(dimethylamino)-β-D- Wood-hexyranosyl]oxy]-6-ethyl-4,5-dihydroxy-10-[(2,6-dideoxy-3-C-methyl-3-O-methyl-a-L- Nucleo-hexapyranosyl)oxy]-3,5,9,11,13,15-hexamethyl-7,16-dioxo-2-azabicyclo[11.2.1]hexadecane-1- Add 20g of en-8-one (compound II, 26mmol), 50ml of dichloromethane into a three-necked flask, control the temperature at 20-25°C, add 1.72g (28.6mmol) of glacial acetic acid, 3.95g (28.6mmol) of potassium carbonate Dissolve in 20ml of water, stir for 2-3 hours, add 20ml of water to wash, separate layers, take the organic layer and distill under reduced pressure to obtain 17g of white solid, yie...

Embodiment 3

[0037] Example 3 (2R, 3S, 4R, 5R, 8R, 10R, 11R, 12S, 13S, 14R)-11-[[(3,4,6)-trideoxy-3-(dimethylamino)-β- D-xyl-hexapyranosyl]oxy]-2-ethyl-3,4,10-trihydroxy-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl base-α-L-nucleo-hexapyranosyl)oxy]-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecane-7,15 - Synthesis of diketones

[0038] (3R,4R,5S,6R,9R,10S,11S,12R,13R,15R,Z)-12-[[3,4,6-trideoxy-3-(dimethylamino)-β-D- Wood-hexyranosyl]oxy]-6-ethyl-4,5-dihydroxy-10-[(2,6-dideoxy-3-C-methyl-3-O-methyl-a-L- Nucleo-hexapyranosyl)oxy]-3,5,9,11,13,15-hexamethyl-7,16-dioxo-2-azabicyclo[11.2.1]hexadecane-1- Add 20g of en-8-one (compound II, 26mmol) and 100ml of dichloromethane into a three-neck flask, control the temperature at 40-45°C, add 1.72g (28.6mmol) of glacial acetic acid, and 3.95g (28.6mmol) of potassium carbonate Dissolve in 20ml of water, stir for 2-3 hours, add 20ml of water to wash, separate layers, take the organic layer and distill under reduced pressure to obtain 16.2g of white s...

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Abstract

The invention belongs to the technical field of chemistry, and particularly relates to a synthesis method for azithromycin rearrangement impurity lactam. The synthesis method comprises the main step that (3R,4R,5S,6R,9R,10S,11S,12R,13R,15R,Z)-12-[[3,4,6-trideoxy-3-(dimethylamino)-beta-D-xylo-hexopyranosyl]oxy]-6-ethyl-4,5-dihydroxy-10-[(2,6-dideoxy-3-C-methyl-3-O-methyl-a-L-ribo-hexopyranosyl)oxy]-3,5,9,11,13,15-hexamethyl-7,16-dioxa-2-azabicyclo[11.2.1]hexadec-1-en-8-one (a compound II ) is subjected to acidification and alkalization rearrangement and then is refined so as to obtain the rearrangement impurity lactam with the purity of 99.5% or above. The synthesized high-purity azithromycin rearrangement impurity lactam serves as an impurity standard substance for finished product detection, so that positioning and nature determining on impurities is facilitated, and the quality control over azithromycin crude drugs is improved.

Description

technical field [0001] The invention belongs to the technical field of chemistry, and in particular relates to a method for synthesizing azithromycin rearrangement impurity lactam. Background technique [0002] The chemical name of azithromycin is -(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methanol Base-a-L-nucleo-hexapyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-11-[ [3,4,6-trideoxy-3-(dimethylamino)-β-D-xyl-hexapyranosyl]oxy]-1-oxa-6-azacyclopentadecane-15-one, As a second-generation macrolide antibiotic, compared with erythromycin, azithromycin has enhanced chemical stability, reduces the problem of erythromycin losing activity due to acidic degradation, increases blood drug concentration, and greatly prolongs the half-life. Drugs used for infections of the respiratory tract, skin, urinary system, and soft tissues. The drug has been included in the "National List of Essential Drugs" and has broad market prospects. At ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H17/00C07H1/00
CPCC07H1/00C07H17/00
Inventor 杨政唐金龙
Owner HEC PHARM
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