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A kind of preparation method of macrolide impurity

An impurity, clarithromycin technology, applied in the field of preparation of macrolide impurities, can solve the problems of complicated operation, purification, inability to pass recrystallization and the like

Inactive Publication Date: 2017-01-25
安徽菩提生物医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This preparation method is cumbersome to operate, and cannot be purified by recrystallization due to many by-products. It needs to be purified by column chromatography to obtain higher purity.

Method used

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  • A kind of preparation method of macrolide impurity
  • A kind of preparation method of macrolide impurity
  • A kind of preparation method of macrolide impurity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Embodiment 1 prepares clarithromycin impurity D

[0028] Preparation of N-fluorobisbenzenesulfonamide solution: 5.0 g of N-fluorobisbenzenesulfonamide was dissolved in 15 ml of ethyl acetate to obtain an ethyl acetate solution of N-fluorobisbenzenesulfonamide.

[0029] Add clarithromycin (10g) and ethyl acetate (30ml) into the reaction flask, cool down to -15°C, then slowly add the ethyl acetate solution of N-fluorobisbenzenesulfonamide prepared above dropwise to the system, dropwise After the addition was completed and stirred for 8 hours, 30 g of 3wt% sodium bicarbonate solution was added and stirred for 30 minutes, left to stand and separated to obtain an ethyl acetate layer, and the aqueous layer was extracted with methyl tert-butyl ether (20ml x 2), and the methyl tert-butyl ether was extracted (20ml x 2). The tert-butyl ether layer and ethyl acetate layer were concentrated under reduced pressure to obtain a crude clarithromycin impurity D with a purity of 85.1%. ...

Embodiment 2

[0030] Embodiment 2 prepares clarithromycin impurity D

[0031] Add 10g of clarithromycin to 50mL of dichloromethane, add 4.7g of N-fluorobisbenzenesulfonamide, and react at -10°C for 12h. After the reaction is complete, add 30g of 3% sodium bicarbonate solution and stir for 30 minutes. After placing and separating the liquids, the organic layer was evaporated to dryness to obtain the crude product of clarithromycin impurity D with a purity of 87.2%. Add 60mL of ethanol to the crude product, raise the temperature to 70°C, all the solids dissolve, gradually cool down to 0-5°C (15°C / h), stir for 2h, filter, wash with water, and dry to obtain 8.2g clarithromycin impurity D, HPLC purity ( Peak area) was 99.1%.

Embodiment 3

[0032] Embodiment 3HPLC purity detection condition

[0033] Chromatographic column: Waters BEH X bridge C18 4.6*100mm, 2.5um

[0034] Flow rate: 1.2ml / min

[0035] Column temperature: 60°C

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Abstract

The invention relates to a preparation method of macrolide impurity, in particular to a preparation method of clarithromycin impurity D. The preparation method comprises the following step: in a non-alkaline solvent, allowing clarithromycin to react with N-fluorobenzenesulfonimide under a low temperature. The clarithromycin impurity D can be generated through a single-step reaction under mild conditions, then the clarithromycin impurity D with the purity of higher than 98% can be obtained through recrystallization, and the obtained clarithromycin impurity D can be taken as a reference substance in the quality research of clarithromycin.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a method for preparing macrolide impurities. Background technique [0002] Clarithromycin, whose chemical structure is shown in formula (I), is the antibiotic of second-generation macrolide, has stronger inhibitory action to Gram-positive bacteria such as staphylococcus aureus, streptococcus, pneumococcus etc. , is currently the main species of antibiotics, [0003] [0004] At present, my country's annual output of clarithromycin is more than 1,000 tons, and it is the main producer of clarithromycin API in the world. The production of each batch of clarithromycin API requires the control of impurities in accordance with the regulations of the Pharmacopoeia. Clarithromycin impurity D, also known as nitrogen desmethyl clarithromycin, is a specified impurity in the European and American Pharmacopoeia, and the CAS number is 101666-68- 6. Molecular weight 733.93, white solid, ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H17/08C07H1/00
Inventor 许云鹏陈志军许彩霞
Owner 安徽菩提生物医药科技有限公司