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Synthetic method of azithromycin genotoxic impurities

A technology of genotoxicity and synthesis method, applied in the field of chemistry, to achieve the effect of improving quality, high yield and simple operation

Active Publication Date: 2019-01-04
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 genotoxic impurities
  • Synthetic method of azithromycin genotoxic impurities
  • Synthetic method of azithromycin genotoxic impurities

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] The synthesis of embodiment 1 acetone oxime-O-p-methylsulfonate

[0033] Take 20g of hydroxylamine hydrochloride (compound II, 0.29mol), 200ml (2.7mol) of acetone, control the temperature at 10°C, add 80g (0.95mol) of sodium bicarbonate, stir and react for 0.8h, then add 20g (0.10mol) of p-toluenesulfonyl chloride mol), continue to control the temperature at 10°C, react for 4h, add 400ml of water and stir to precipitate a large amount of solid, filter with suction, and dry under reduced pressure at 35°C for 4h to obtain 18.4g (0.08mol) of white solid, yield 92.0%.

[0034] Add 10 g of the crude product of acetone oxime-O-p-methylsulfonate into a single-necked bottle, add 100 ml of 60% acetone aqueous solution, stir at 0-10 ° C for 1 h, filter with suction, and dry to obtain 9.1 g of white solid, with a yield of 91.0%. 99.7% purity.

Embodiment 2

[0035] The synthesis of embodiment 2 acetone oxime-O-p-methylsulfonate

[0036] Take 20g of hydroxylamine hydrochloride (compound II, 0.29mol), 200ml (2.7mol) of acetone, control the temperature at 0°C, add 40g (0.48mol) of sodium bicarbonate, stir and react for 1.5h, then add 15g (0.078mol) of p-toluenesulfonyl chloride mol), continue to control the temperature at 0°C, react for 2h, add 400ml of water and stir to precipitate a large amount of solid, filter with suction, and dry under reduced pressure at 35°C for 4 to obtain 13.7g (0.06mol) of white solid, yield 91.5%.

[0037] Add 10 g of the crude product of acetone oxime-O-p-methylsulfonate into a single-necked bottle, add 80 ml of 60% acetone aqueous solution, stir at 0-10 °C for 1 h, filter with suction, and dry to obtain 9.3 g of white solid, with a yield of 93.0%. 99.5% purity.

Embodiment 3

[0038] Embodiment 3, the synthesis of acetone oxime-O-p-methylsulfonate

[0039] Take 20g of hydroxylamine hydrochloride (compound II, 0.29mol), 200ml (2.7mol) of acetone, control the temperature at 5°C, add 60g (0.71mol) of sodium bicarbonate, stir and react for 1 hour, then add 20g (0.10mol) of p-toluenesulfonyl chloride ), continue to control the temperature at 5°C, react for 3h, add 400ml of water and stir to precipitate a large amount of solid, filter with suction, and dry under reduced pressure at 35°C for 4h to obtain 18.64g (0.08mol) of white solid with a yield of 93.2%.

[0040] Add 10 g of the crude product of acetone oxime-O-p-methylsulfonate into a single-necked bottle, add 100 ml of 60% acetone aqueous solution, stir for 1 h at 0-10 ° C, filter with suction, and dry to obtain 9.3 g of white solid, with a yield of 93.0%. 99.8% pure.

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Abstract

The invention belongs to the field of chemical technology, and in particular relates to a synthetic method of azithromycin genotoxic impurities, wherein the impurity is acetone oxime-O-p-methyl sulfonic acid ester. The preparation method comprises the following main steps: firstly, preparing a compound with acetone and hydroxylamine through oximation, then conducting esterification reaction with the compound and p-toluenesulfonyl chloride, and finally refining the substance to obtain the acetone oxime-methyl sulfonic acid ester impurities with purity of higher than 99.5%. The high purity synthetic acetone oxime-methyl sulfonic acid ester serves as the impurity standard for azithromycin finished products testing, facilitates the enhancement of positioning and qualitative identification of the genotoxic impurities in the testing of the azithromycin finished products, and improves the quality control of the azithromycin crude drugs.

Description

technical field [0001] The invention belongs to the technical field of chemistry, and in particular relates to a method for synthesizing azithromycin genotoxic impurities. Background technique [0002] Genotoxic impurities (or genotoxic impurities, Genotoxic Impurity, GTI) refers to the compound itself directly or indirectly damages cell DNA, produces gene mutation or mutagenesis in vivo, and has the possibility or tendency to cause cancer. Potential Genotoxic Impurities (Potential Genotoxic Impurity, PGI) are similar to genotoxic impurities in structure, and are warning, but compounds such as aflatoxins, nitrosamine compounds, and methylsulfonate that have not been proved by experiments are all It is a common genotoxic impurity. [0003] The characteristic of genotoxic substances is that they can cause damage to the human genetic material at very low concentrations, which in turn can lead to gene mutations and may promote tumorigenesis. Because of its strong toxicity, it ...

Claims

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Application Information

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IPC IPC(8): C07C381/00
CPCC07C381/00
Inventor 覃鹏唐金龙李晓曦
Owner HEC PHARM
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