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Synthetic method of azithromycin impurity F

A technology of azithromycin and synthetic method, applied in the field of chemistry, can solve problems such as low synthetic yield of impurity I, and achieve the effects of stable properties, high reaction efficiency and high yield

Active Publication Date: 2018-11-02
HEC PHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Above-mentioned two routes all will be raw material with impurity I, and the synthesis yield of impurity I is low, 55% (WO2007 / 25098), formylation reagent formyl acetic anhydride is very easy to decompose and needs new preparation

Method used

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  • Synthetic method of azithromycin impurity F
  • Synthetic method of azithromycin impurity F
  • Synthetic method of azithromycin impurity F

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Example 1 (2R, 3S, 4R, 5R, 8R, 10R, 11R, 12S, 13S, 14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl- 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-(N-methylformamido)-β-D-xyl-hexapyranosyl]oxy]-1-oxa-6-azacyclopentadecane-15 Ketone synthesis

[0037] Add 20g (26mmol) of azithromycin, 400ml of methanol-water (4:1) into a three-necked flask, add 6.6g (52mmol) of iodine, 4g (29mmol) of potassium carbonate, 2.4g (32mmol) of ethyl formate, and stir to reflux Reaction for 5 hours; methanol was recovered by distillation under reduced pressure, washed with water, and suction filtered to obtain 18 g of white solid, yield 90%.

[0038] (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-a-L-nucleus -hexapyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-11-[[3,4, Purification of 6-trideoxy-3-(N-methylformamido)-β-D-xyl-hexapyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one

[00...

Embodiment 2

[0040] Example 2 (2R, 3S, 4R, 5R, 8R, 10R, 11R, 12S, 13S, 14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl- 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-(N-methylformamido)-β-D-xyl-hexapyranosyl]oxy]-1-oxa-6-azacyclopentadecane-15 Ketone synthesis

[0041] Add 20g (26mmol) of azithromycin, 200ml of methanol-water (4:1) into a three-necked flask, add 6.6g (52mmol) of iodine, 4g (29mmol) of potassium carbonate, 2.4g (32mmol) of ethyl formate, and stir to reflux Reaction for 5 h; methanol was recovered by distillation under reduced pressure, washed with water, and suction filtered to obtain 15 g of white solid, yield 75%.

[0042] (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-a-L-nucleus -hexapyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-11-[[3,4, Purification of 6-trideoxy-3-(N-methylformamido)-β-D-xyl-hexapyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one

[0043] ...

Embodiment 3

[0044] Example 3 (2R, 3S, 4R, 5R, 8R, 10R, 11R, 12S, 13S, 14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl- 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-(N-methylformamido)-β-D-xyl-hexapyranosyl]oxy]-1-oxa-6-azacyclopentadecane-15 Ketone synthesis

[0045] Add 20g (26mmol) of azithromycin, 400ml of methanol-water (4:1) into a three-necked flask, add 6.0g (47mmol) of iodine, 4g (29mmol) of potassium carbonate, 2.4g (32mmol) of ethyl formate, and stir to reflux Reacted for 5 hours; methanol was recovered by distillation under reduced pressure, washed with water, and suction filtered to obtain 17.8 g of white solid, with a yield of 89%.

[0046] (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-a-L-nucleus -hexapyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-11-[[3,4, Purification of 6-trideoxy-3-(N-methylformamido)-β-D-xyl-hexapyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15...

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Abstract

The invention belongs to the technical field of chemistry, and particularly relates to a synthetic method of azithromycin impurity F. The combination method of the azithromycin impurity F-(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-nucleus-pyranohexyl pyrranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-11-[[3,4,6-trideoxy-3-(N-methylformamido)-beta-D-pyranohexyl]oxy]-1-oxa-6-azacyclopentadecane-15 ketone in (formula I) comprises the main steps as follows: enabling azithromycin (compound II) to be subjected to 3'-N demethylation, performing formylation by using ethyl formate to generate a target product; purifying and then obtaining oxidized impurity with purity greater than 99.5%. The synthesized high-purity azithromycin impurity Fserves as impurity standard substance for finished product detection, is conducive to reinforcing location and nature determination of impurity, and improves quality control on azithromycin bulk drugs.

Description

technical field [0001] The invention belongs to the technical field of chemistry, and in particular relates to a synthesis method of azithromycin impurity F. Background technique [0002] Azithromycin is a second-generation macrolide antibiotic. Compared with erythromycin, azithromycin has enhanced chemical stability, which reduces the problem of erythromycin losing activity due to acidic degradation, increases blood drug concentration, and greatly prolongs the half-life. , is used as a drug for respiratory tract, skin, urinary system and soft tissue infections. The drug has been included in the "National List of Essential Drugs" and has broad market prospects. At present, my country's annual output of azithromycin exceeds 1,000 tons, and it is the main producer of azithromycin in the world. [0003] Impurity F-(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl- a-L-nucleo-hexapyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-1...

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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