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Method for preparing beta-artemether artemether from artemether mother liquor

A technology of artemether and refining method, which is applied in the field of preparation of β-artemether, can solve the problems of difficult large-scale implementation of chromatography technology, no obvious use value of α-artemether, low conversion and refining efficiency, etc. Achieve the effect of convenient operation, good product purity and waste reduction

Active Publication Date: 2013-10-02
重庆恒芯紫来科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, on the one hand, the chromatography process is difficult to implement on a large scale
In addition, the obtained α-artemether itself has no obvious use value and needs further transformation
[0005] In CN102731523A, α-artemether is chemically converted into β-artemether, then dissolved in methanol, ethanol, ethylene glycol or isopropanol, and then cooled and crystallized to refine β-artemether, but the conversion and purification efficiency is low

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Concentrate the crystallization mother liquor of artemether prepared from dihydroartemisinin until viscous, separate by column chromatography to obtain α-artemether solution, evaporate to remove the organic solvent, and then dry at 50°C until constant weight to obtain crystals.

[0026] In a clean 15L reactor, add 2000ml of toluene, 6000ml of dichloromethane and 1600ml of methanol, plus 800g of the above-mentioned crystals (the content of α-artemether is 90% and the content of β-artemether is 10% as detected by HPLC), Stir to dissolve at 30°C. Add 24g of p-toluenesulfonic acid and stir for 3 hours. Let stand for 0.5 hour, filter, and wash the filtrate with 2800ml of water. After adding 20g of anhydrous magnesium sulfate to dry, shrink the filtrate to dryness to obtain a total of 530g of extract. The concentrate was added to methanol, dissolved at 50°C to form a saturated solution, transferred to an ice-water bath to stir and crystallize for 1 hour, filtered with sucti...

Embodiment 2

[0029] Concentrate the crystallization mother liquor of artemether prepared from dihydroartemisinin until viscous, separate by column chromatography to obtain α-artemether solution, evaporate to remove the organic solvent, and then dry at 50°C until constant weight to obtain crystals.

[0030] In a clean 15L reactor, add 1920ml of toluene, 7680ml of dichloromethane and 1800ml of methanol, plus 800g of the above-mentioned crystals (the content of α-artemether is 90% and the content of β-artemether is 10% as detected by HPLC), Stir to dissolve at 30°C. Add 20g p-toluenesulfonic acid to react for 3 hours. Let stand for 0.5 hour, filter, and wash the filtrate with 3000ml of water. After adding 20g of anhydrous magnesium sulfate and drying, the filtrate was concentrated to an extract. The concentrate was added to methanol, dissolved at 50°C to form a saturated solution, transferred to an ice-water bath, stirred and crystallized for 1 hour, filtered with suction, and dried at 50°C...

Embodiment 3

[0034] Concentrate the artemether mother liquor produced by dihydroartemisinin into artemether and filter and wash it in vacuum at 40°C under reduced pressure, evaporate most of the methanol, and then dry it at 50°C to constant weight to obtain Crystal, take 800g of crystal for later use.

[0035] In a clean 15L reactor, add 2000ml of toluene, 8000ml of dichloromethane and 2500ml of methanol, and then add 800g of crystals (the content of α-artemether is 87% and the content of β-artemether is 13% as detected by HPLC). Stir to dissolve at 32°C. Add 30g p-toluenesulfonic acid to react for 3 hours. Let stand for 0.5 hour, filter, and wash the filtrate with 3000ml of water. After adding 20g of anhydrous magnesium sulfate and drying, the filtrate was concentrated to an extract. The concentrate was added to methanol, dissolved at 50°C to become a saturated solution, transferred to an ice-water bath to stir and crystallize for 1 hour, filtered with suction, and dried at 50°C to con...

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PUM

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Abstract

The invention relates to a preparation method of beta-artemether, in particular relates to a method for preparing beta-artemether artemether from artemether mother liquor. The core steps of a refining method of the beta-artemether raw material are as below: dissolving a beta-artemether raw material in methanol, cooling and crystallizing to obtain a crude product; adding the crude product into an acetone water solution at 50 DEG C; cooling to 5-10 DEG C; mixing and crystallizing for 0.5-2 h; then conducting freeze crystallization at -5-5 DEG C for 3-5 h; conducting suction filtration; washing the filter cake using acetone water solution with weight 0.2-0.5 times that of the filter cake; and drying at 50 DEG C to a constant weight. The invention has the following advantages: the method for conversing alpha-artemether to beta-artemether provided by the invention has high conversion efficiency above 55%; the purity of the beta-artemether in the refined product is more than 99%. Basically, the technology of the invention can be applied to existing artemether mother liquor containing alpha-artemether to improve production efficiency and reduce waste; and the method has simple process, easy operation, and no complicated equipment and technology.

Description

technical field [0001] The invention relates to a method for preparing β-artemether, in particular to a method for preparing β-artemether from artemether mother liquor. Background technique [0002] The chemical name of artemether is (3R,5aS,6R,8aS,9R,10S,12R,12aR)-decahydro-10-methoxy-3,6,9-trimethyl-3,12-oxo- 12H-pyrano[4,3-j]-1,2-benzodisepin (for example: Luo Chun, Huang Jianjun, Yang Liu, etc. "Preparation of β-artemether", China Pharmaceutical Industry Journal, 2012 05 issue). Its epimer, β-artemether, is the preferred antimalarial drug recommended by the World Health Organization. It is a class of new drugs developed by my country and recognized internationally, but its α configuration has no antimalarial effect. [0003] At present, about 20% of α-artemether is produced during the industrial synthesis of artemether. α-artemether mainly exists in the production mother liquor in the form of by-products, and the content in the mother liquor is about 50%. Many arteme...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D493/20
Inventor 王龙军周晓燕宋培森
Owner 重庆恒芯紫来科技有限公司