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New method for synthesizing tigecycline from demeclocycline

A technology of demethylchlortetracycline and tigecycline, applied in the field of biomedicine, can solve the problems of long reaction steps, easy generation of impurities, and difficult reaction control, etc., and achieve the effect of low cost, high purity and short reaction steps

Active Publication Date: 2019-05-31
HEBEI SHENGXUE DACHENG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] However, this method has defects such as difficult control of the reaction, long reaction steps, and easy generation of impurities, which cannot meet the current development speed of medicine.

Method used

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  • New method for synthesizing tigecycline from demeclocycline
  • New method for synthesizing tigecycline from demeclocycline
  • New method for synthesizing tigecycline from demeclocycline

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Experimental program
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Effect test

Embodiment 1

[0042] During specific implementation: embodiment 1, the synthesis of product I:

[0043] In a stirred three-necked reaction flask, add 10 mL of concentrated sulfuric acid, stir, cool in an ice-salt bath to about -5°C, add 1 g of demethylaureomycin; after adding, control the temperature below 5°C, and then slowly add potassium nitrate 0.5g (or concentrated nitric acid 2mL), keep stirring at about 5°C, react for about 3 hours, and end the reaction; pour the reaction solution into the mixed solution of butyl acetate and n-butanol, crystals are precipitated, filter, yellowish brown crystals are wet Product 2.1g is product I.

Embodiment 2

[0044] Embodiment 2, the synthesis of product II:

[0045] Dissolve 2.1 g of the product I in methanol, add 0.05 g of palladium-carbon Pd / C catalyst, pass hydrogen pressure to above 4.0 MPa, stir at room temperature for 12 h, and the reaction ends. The hydrogen gas was replaced, the reaction kettle was opened, and the product was completely dissolved by adjusting the pH; the catalyst was filtered out, sulfuric acid was added to the filtrate, and crystals began to precipitate, the temperature was lowered and stirred to continue to precipitate crystals, and the yellow crystalline solid intermediate II was obtained by filtration.

Embodiment 3

[0046] Embodiment 3, the synthesis of product III:

[0047] Add intermediate II and purified water into a stirred reaction flask and stir, cool with ice water to 0-15°C, slowly add 0.5g of tert-butylaminoacetyl chloride hydrochloride to maintain the temperature, after the addition is complete, stir at the same temperature until the reaction completely. Adjust the pH of the solution to neutral, extract, concentrate, and crystallize to obtain product III.

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Abstract

The invention provides a new method for synthesizing tigecycline from demeclocycline. The method includes the following steps: preforming a nitration reaction on the demeclocycline, preforming catalytic reduction, reacting with tert-butylamine acetyl chloride hydrochloride, preforming the nitration reaction, preforming catalytic reduction, and preforming methylation reaction to obtain a crude tigecycline product, and the like; and finally, purifying the crude product to obtain tigecycline. The method has the advantages of short reaction steps, high purity, low cost, no toxicity and the like, and is suitable for large-scale production.

Description

technical field [0001] The invention belongs to the field of biomedicine, and in particular relates to a new method for synthesizing tigecycline from desmethylchlortetracycline. Background technique [0002] The synthesis method of tigecycline that has been reported so far generally uses minocycline as a raw material, and tigecycline is obtained through methods such as nitration, reduction, and condensation. [0003] Wyeth, USA, application number 200680026962.8 "Tigecycline and its method for preparing 9-aminominocycline". [0004] [0005] Jiangsu Zhengda Tianqing Pharmaceutical Co., Ltd. CN102617395A "Preparation Method of Glycylcycline Antibiotics" [0006] [0007] The synthetic method of minocycline generally uses demethylchlortetracycline as a raw material, and undergoes dechlorination, dehydroxylation, chlorination, diazotization, and methylation to obtain minocycline hydrochloride. It has the characteristics of many synthetic steps and low yield. [0008] I...

Claims

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Application Information

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IPC IPC(8): C07C237/26C07C231/12C07C231/14
Inventor 王婷曹建全宋志倩郝立波
Owner HEBEI SHENGXUE DACHENG PHARMA