Method for preparing erythrocin A iminoether salt

The technology of erythromycin and imine ether is applied in the field of preparation of erythromycin A imine ether salt, which can solve the problems of low bioavailability and difficult control of dosage, and achieve the effect of saving resources, simple device and reaction system.

Active Publication Date: 2009-12-30
江苏合纵思远生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, erythromycin A is easily decomposed by gastric acid, resulting in low bioavailability and difficulty in controlling the dosage.

Method used

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  • Method for preparing erythrocin A iminoether salt
  • Method for preparing erythrocin A iminoether salt

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Add p-toluenesulfonyl chloride 0.038g (0.2mmol) in a 25ml round bottom flask, add 0.15g (0.2mmol) (9E)-9-deoxy-9-hydroxyimino erythromycin A, p-toluenesulfonyl chloride and (9E)-9-deoxy-9-hydroxyiminoerythromycin A molar ratio is 1:1, then add 11.5g ionic liquid 1-butyl-3-methylimidazolium hexafluorophosphate (40mmol), The molar ratio of room temperature ionic liquid to (9E)-9-deoxy-9-hydroxyiminoerythromycin A is 200:1, put in a magnetic stirrer, stir at 5°C until dissolved, and stop the reaction after 3 hours of reaction . Add 20ml of water three times to extract the ionic liquid phase, layered, add 30ml of dichloromethane to extract the aqueous phase, layered, add an appropriate amount of anhydrous magnesium sulfate to the organic phase to dry, filter, and evaporate the organic phase to dryness with a rotary evaporator. 0.138 g of white powder was obtained with a conversion rate of 92%. The melting point was measured to be 115°C-120°C. HPLC quantitatively measures...

Embodiment 2

[0028] Add p-toluenesulfonyl chloride 0.076g (0.4mmol) in a 25ml round bottom flask, add 0.15g (0.2mmol) (9E)-9-deoxy-9-hydroxyimino erythromycin A, p-toluenesulfonyl chloride and (9E)-9-deoxy-9-hydroxyiminoerythromycin A molar ratio is 2:1, then add 11g ionic liquid 1-butyl-3-methylimidazolium hexafluorophosphate (40mmol), ion The molar ratio of the liquid to (9E)-9-deoxy-9-hydroxyiminoerythromycin A is 200:1, put in a magnetic stirrer, stir at 0°C until dissolved, and stop the reaction after 1.5 hours of reaction. Add 20ml of water three times to extract the ionic liquid phase, layered, add 30ml of dichloromethane to extract the aqueous phase, layered, add an appropriate amount of anhydrous magnesium sulfate to the organic phase to dry, filter, and evaporate the organic phase to dryness with a rotary evaporator. Obtained 0.141g of white powder, the conversion rate was 94%, and the recorded melting point was 117°C-121°C. HPLC quantitatively measured 9-deoxy-6-deoxy-6,9-imino ...

Embodiment 3

[0030]Add 0.066g (0.3mmol) of p-nitrobenzenesulfonyl chloride to a 25ml round bottom flask, add 0.075g (0.1mmol) of (9E)-9-deoxy-9-hydroxyiminoerythromycin A, p-nitro The molar ratio of benzenesulfonyl chloride to (9E)-9-deoxy-9-hydroxyiminoerythromycin A is 3:1, then add 5.1g of ionic liquid 1-butyl-3-methylimidazolium hexafluorophosphate (18mmol), the molar ratio of ionic liquid to (9E)-9-deoxy-9-hydroxyiminoerythromycin A is 180:1, put in a magnetic stirrer, stir at 5°C until dissolved, and react for 2.5 hours After stopping the reaction. Add 20ml of water three times to extract the ionic liquid phase, layered, add 30ml of dichloromethane to extract the aqueous phase, layered, add an appropriate amount of anhydrous magnesium sulfate to the organic phase to dry, filter, and evaporate the organic phase to dryness with a rotary evaporator. Obtained 0.069g of white powder, the conversion rate was 92%, and the recorded melting point was 115°C-120°C. HPLC quantitatively measured...

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Abstract

The invention relates to a clean catalysis synthesizing method for preparing 9-deoxidized-6-deoxidized-6,9-iminoether-(9a-aza-9a)-erythrocin A and 9-deoxidized-11-deoxidized-9,11-iminoether-(9a-aza-9a)-erythrocin A by means of Beckmann rearrangement of (9E)-9-deoxidized-9-hydroxyl imidogen erythrocin A in a single-phase or two-phase room temperature ionic liquid system, or for preparing 9-deoxidized-6-deoxidized-6,9-iminoether-(8a-aza-8a)-erythrocin A and 9-deoxidized-12-deoxidized-9,12-iminoether-(8a-aza-8a)-erythrocin A by means of Beckmann rearrangement of (9Z)-9-deoxidized-9-hydroxyl imidogen erythrocin A in the single-phase or two-phase room temperature ionic liquid system. The catalyst used in the method is a benzene sulfonyl chloride derivative which can generate a corresponding target product in a mild and high-transformation-rate manner. Ionic liquid used for synthesis can be recycled. The method is simple and free of pollution.

Description

technical field [0001] The invention relates to a preparation method of erythromycin A imine ether salt. Background technique [0002] Erythromycin A is the first and most important macrolide antibiotic successfully developed by humans. Erythromycin A has been widely used in anti-infection for half a century. However, erythromycin A is easily decomposed by gastric acid, resulting in problems such as low bioavailability and difficulty in controlling the dose. [0003] The second-generation new erythromycins such as azithromycin developed in the 1980s effectively solved these problems, and also broadened the antibacterial spectrum of erythromycin and improved its pharmacokinetic characteristics. Azithromycin is the first 15-membered ring nitrogen-containing macrolide new drug, which has strong antibacterial activity against Gram-positive bacteria, can inhibit many important Gram-negative bacteria, and has good curative effect on most respiratory tract infections , especiall...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H17/08C07H1/00B01J31/02A61P31/00
Inventor 王建华江志尧
Owner 江苏合纵思远生物科技有限公司
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