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Method for purifying pleuromulins compound hydrochloride

A technology for pleuromutilin and compounds, which is applied in the field of purifying pleuromutilin compound hydrochloride, can solve the problem of low compound yield, and achieve the effects of high conversion rate, easy purification and high purity

Active Publication Date: 2012-10-03
HUBEI LONGXIANG PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Patent US5545654 reports the method for preparing derivatives of pleuromutilin compounds and purifying pleuromutilin compounds. In the synthesis process of its derivatization, a mixed solvent of alcohol and ketone or a molecular sieve of 0.3nm is used, and the obtained compound The yield is not high

Method used

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  • Method for purifying pleuromulins compound hydrochloride
  • Method for purifying pleuromulins compound hydrochloride
  • Method for purifying pleuromulins compound hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] 1) 14-O-{[1-(2,2-Dimethyl-5(R)-isopropyl-imidazolidin-4-one-3-yl)-2-methylisopropyl]thioacetyl Base} Miaolin

[0038]

[0039] Get 100g 14-O-{1-[(D)-2-amino-3-methylbutyrylamino]-2-methylisopropyl-thioacetyl}miaolin hydrochloride (content 84.7%, mass percentage), dissolved in 1000ml water, then added 1000ml tert-butyl methyl ether, adjusted the pH value to 9-10 with 5N sodium hydroxide solution, separated the organic phase, washed twice with water, each with 100ml of water. Then distill at normal pressure first, then distill under reduced pressure to remove tert-butyl methyl ether, dissolve the residue obtained after distillation in 1000ml of acetone, add 20g of Raney nickel, mix and stir, reflux at 60°C for 30 hours, then filter under reduced pressure, The filtrate was evaporated and concentrated to obtain about 200ml of a clear concentrated solution. Add the seed crystals to the concentrated solution, place it at room temperature for 1 hour, and then place it at 0...

Embodiment 2

[0044] 1) 14-O-{[1-(2,2-Dimethyl-5(S)-isopropyl-imidazolidin-4-one-3-yl)-2-methylisopropyl]thioacetyl Base} Miaolin

[0045]

[0046] Get 10g 14-O-{1-[(L)-2-amino-3-methylbutyrylamino]-2-methylisopropyl-thioacetyl}miaolin hydrochloride (content 83.5%, mass percentage), dissolved in 100ml water, then added 100ml tert-butyl methyl ether, adjusted the pH value to 9-10 with 8N sodium hydroxide, separated the organic phase, and washed twice with water. Then distilled at normal pressure first, then distilled under reduced pressure to remove tert-butyl methyl ether, dissolved the residue after distillation in 200ml acetone, added 3g Raney nickel, mixed and stirred, refluxed at 60°C for 30 hours, then filtered under reduced pressure, the filtrate Evaporate and concentrate to obtain about 20ml of a clear concentrated solution, add the seed crystals to the concentrated solution, place it at room temperature for 1 hour, and then place it at 0-5°C for 2 hours, then filter and dry to o...

Embodiment 3

[0050] 1) l4-O-{[1-(2-methyl-2-ethyl-5(R)-isopropyl-imidazolidin-4-one-3-yl)-2-methylisopropyl] Thioacetyl}myolin

[0051]

[0052] Get 100g 14-O-{1-[(D)-2-amino-3-methylbutyrylamino]-2-methylisopropyl-thioacetyl}miaolin hydrochloride (content 84.7%, mass percentage), dissolved in 1000ml water, then added 1000ml tert-butyl methyl ether, adjusted the pH value to 9-10 with 2N sodium hydroxide solution, separated the organic phase, washed twice with water, each time with 100ml of water. Then distilled at normal pressure first, then distilled under reduced pressure to remove tert-butyl methyl ether, dissolved the residue after distillation in 1000ml 2-butanone, added 6g of Raney nickel, mixed and stirred, refluxed at 80°C for 30 hours, and then pumped under reduced pressure Filtrate, evaporate and concentrate the filtrate to obtain about 200ml of clear concentrated solution, add seed crystals to the concentrated solution, place it at room temperature for 1 hour, then place it ...

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Abstract

The invention relates to a method for purifying hydrochloride of a pleuromutilin compound. The method comprises the following steps: 1) putting the hydrochloride of the pleuromutilin compound into a container to be dissolved by adding water, adjusting the pH value of the solution by a sodium hydroxide solution, and extracting the solution to remove water phase so as to obtain an organic phase; 2)washing the organic phase obtained in the step 1) by water, distilling the organic phase at normal pressure, and distilling the organic phase at the reduced pressure to obtain residue; 3) dissolving the residue obtained in the step 2) in a ketone solvent, adding a catalyst into the mixed solution, mixing and stirring the mixed solution to perform a derivative reaction, filtering the catalyst; vaporizing, concentrating, crystallizing, filtering and drying the obtained filtrate to obtain derivatives of the pleuromutilin compound; and 4) mixing the derivatives with water or ethanol, adding a chlorine hydride solution into the mixed solution to perform a hydrolysis reaction, and drying the hydrolysate by freezing or spraying after the reaction to obtain the hydrochloride of the pleuromutilin compound. The method has high conversion rate when a Raney nickel catalyst is used to perform the derivative reaction; the purity of the hydrochloride is high; and the ketone solvent can be reclaimed and reused.

Description

technical field [0001] The invention relates to a method for purifying pleuromutilin compound hydrochloride, especially for purifying warnemulin hydrochloride to obtain higher purity (above 96%). Background technique [0002] Pleuromutilin compound (1) is a good stable antibacterial agent, and formula (1) is the chemical formula of pleuromutilin compound [0003] [0004] where R 3 and R 4 Is hydrogen, alkyl or alkyl substituents, such compounds were found in European patent EP0153277. However, this compound cannot be obtained in a state of higher purity in any case and therefore not in crystalline form. It is mentioned in European Patent EP0153277 that it can only be purified by chromatography. [0005] Australian Patent No. 392272 discloses a method for extracting and refining compound (3), i.e., warnemulin hydrochloride. Warnemulin belongs to diterpenes, and it belongs to the same class of drugs as tiamulin, which can inhibit Bacterial growth, is animal-specific a...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C323/25C07C319/26
Inventor 赵勇
Owner HUBEI LONGXIANG PHARMA TECH CO LTD