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Synthetic method of azithromycin rearrangement impurity R

A technology of azithromycin and synthetic method, applied in the field of chemistry, to achieve the effect of improving quality, high refining yield and less dosage

Active Publication Date: 2018-09-14
HEC PHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

After searching, there is currently no method to synthesize this impurity, so synthesizing this impurity, determining its structure, and studying its formation mechanism are of great significance to the process optimization and quality improvement of azithromycin

Method used

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  • Synthetic method of azithromycin rearrangement impurity R
  • Synthetic method of azithromycin rearrangement impurity R
  • Synthetic method of azithromycin rearrangement impurity R

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Example 1 (1R, 2R, 3R, 6R, 7S, 8S, 9R, 10R, 12R, 15R)-9[[3,4,6-trideoxy-3-(dimethylamino)-β-D-wood -hexapyranosyl]oxy]-3-ethyl-2,10-dihydroxy-7-[(2,6-dideoxy-3-C-methyl-3-O-methyl-a-L-nucleo -hexapyranosyl)oxy]-2,6,8,10,12,15-hexamethyl-4,16-dioxo-14-azabicyclo[11.2.1]hexadecan-13-ene Synthesis of -5-one

[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 20 g of en-8-one (compound II, 26 mmol), 100 ml of dichloromethane into a three-necked flask, control the temperature at 40 ° C, add 4 g of 5% hydrochloric acid, stir for 5 h, add 20 ml of water to wash, separate layers, and take organic The layers were distilled under reduced pressure to obtain 18 g of white solid, with a yield of 90%.

[0033] (1R,2R,3R,6R,7S,8S,9R,10R,12R,15R)-9[[3,4,6-t...

Embodiment 2

[0035] Example 2 (1R, 2R, 3R, 6R, 7S, 8S, 9R, 10R, 12R, 15R)-9[[3,4,6-trideoxy-3-(dimethylamino)-β-D-wood -hexapyranosyl]oxy]-3-ethyl-2,10-dihydroxy-7-[(2,6-dideoxy-3-C-methyl-3-O-methyl-a-L-nucleo -hexapyranosyl)oxy]-2,6,8,10,12,15-hexamethyl-4,16-dioxo-14-azabicyclo[11.2.1]hexadecan-13-ene Synthesis of -5-one

[0036] (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 20 g of en-8-one (compound II, 26 mmol), 50 ml of dichloromethane into a three-necked flask, control the temperature at 40 ° C, add 4 g of 5% hydrochloric acid, stir for 5 h, add 20 ml of water to wash, separate layers, and take organic The layers were distilled under reduced pressure to obtain 14 g of white solid, with a yield of 70%.

[0037] (1R,2R,3R,6R,7S,8S,9R,10R,12R,15R)-9[[3,4,6-tr...

Embodiment 3

[0039]Example 3 (1R, 2R, 3R, 6R, 7S, 8S, 9R, 10R, 12R, 15R)-9[[3,4,6-trideoxy-3-(dimethylamino)-β-D-wood -hexapyranosyl]oxy]-3-ethyl-2,10-dihydroxy-7-[(2,6-dideoxy-3-C-methyl-3-O-methyl-a-L-nucleo -hexapyranosyl)oxy]-2,6,8,10,12,15-hexamethyl-4,16-dioxo-14-azabicyclo[11.2.1]hexadecan-13-ene Synthesis of -5-one

[0040] (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 20 g of en-8-one (compound II, 26 mmol), 100 ml of dichloromethane into a three-necked flask, control the temperature at 55 ° C, add 4 g of 5% hydrochloric acid, stir for 5 h, add 20 ml of water to wash, separate layers, and take organic The layers were distilled under reduced pressure to obtain 14 g of white solid, with a yield of 70%.

[0041] (1R,2R,3R,6R,7S,8S,9R,10R,12R,15R)-9[[3,4,6-tr...

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Abstract

The invention belongs to the technical field of chemistry, and particularly relates to a synthetic method of an azithromycin rearrangement impurity R. The method mainly comprises the steps that (3R,4R,5S,6R,9R,10S,11S,12R,13R,15R,Z)-12-[[3,4,6-trideoxy-3-(dimethylamino)-beta-D-wood-pyranose group]oxygen]-6-ethyl-4,5-dihydroxyl-10-[(2,6-dideoxy-3-C-methyl-a-L-nuclear-pyranose group)oxygen]-3,5,9,11,13,15-hexamethyl-7,16-dioxy-2-azabicyclo[11.2.1]cetane-1-alkene-8-ketone(compound III) is subjected to acidification rearrangement, and after refining is conducted, the rearrangement impurity R withthe purity being 99.5% or above is obtained. The synthesized high-purity azithromycin rearrangement impurity R serves as an impurity standard substance of finished production detection, locating and qualification on the impurity are enhanced conveniently, and quality control over azithromycin active pharmaceutical ingredient 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 R. 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 prese...

Claims

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Application Information

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IPC IPC(8): C07H1/00C07H1/06C07H17/00
CPCC07H1/00C07H1/06C07H17/00
Inventor 杨政唐金龙
Owner HEC PHARM
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