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One-step green synthesis process of antimalarial raw material benflumetol

A benfluorenol and anti-malarial technology, applied in the field of high-yield and high-purity benfluorenol, can solve the problems of severe condensation reaction conditions, low atom economy, low yield of high-purity fine benfluorenol, etc. Controllable, simple reaction system, green production effect

Inactive Publication Date: 2013-09-25
ZHANG JIA GANG VINSCE BIO PHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In the above method, the reaction yield of fluorene derivative intermediate and p-chlorobenzaldehyde is below 70%, the atom economy is low, and the production cost is too high
In addition, there are too many unreacted raw and auxiliary materials, which makes it difficult to separate and purify the final product benzfluorenol, and finally obtain high-purity refined benzfluorenol with a low yield
At the same time, the literature reports that the condensation reaction conditions are relatively severe, and many other impurities are also generated in the reaction.

Method used

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  • One-step green synthesis process of antimalarial raw material benflumetol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] The synthesis of embodiment 1 benzfluorenol

[0022] Put 500.0kg of α-(di-n-butylamino)-2,7-dichloro-4-fluorenemethanol into a 500L stainless steel reaction kettle, add 3000L of methanol-ethylene glycol (V:V=9:1), stir at room temperature to dissolve scattered. Then 10.0 kg of sodium methoxide was added, and the reaction was stirred at room temperature for 1 h. Then add 180.0 kg of p-chlorobenzaldehyde at one time, then raise the temperature to reflux, and control the reaction at 75°C for about 15 hours. Thin-layer chromatography monitors the raw material α-(di-n-butylamino)-2,7-dichloro-4- The fluorenylmethanol spots disappeared. While stirring, the temperature was lowered to room temperature, and the stirring reaction was continued for 2 h, and benzfluorenol crystals were precipitated, filtered under reduced pressure, and washed with a small amount of methanol or ethanol to obtain crude benzfluorenol.

Embodiment 2

[0023] The synthesis of embodiment 2 benzfluorenol

[0024] 500.0kg of α-(di-n-butylamino)-2,7-dichloro-4-fluorenemethanol was placed in a 500L stainless steel reaction kettle, and 2500L of ethanol-ethylene glycol (V:V=95:5) was added, stirred at room temperature to dissolve scattered. Then 11.0 kg of sodium ethoxide was added, and the reaction was stirred at room temperature for 1 h. Then add 180.0kg of p-chlorobenzaldehyde at one time, then raise the temperature to reflux, and control the reaction at 85°C for about 12h. Thin-layer chromatography monitors the raw material α-(di-n-butylamino)-2,7-dichloro-4- The fluorenylmethanol spots disappeared. While stirring, the temperature was lowered to room temperature, and the stirring reaction was continued for 3 h, and benzfluorenol crystals were precipitated, filtered under reduced pressure, and washed with a small amount of methanol or ethanol to obtain crude benzfluorenol.

Embodiment 3

[0025] The synthesis of embodiment 3 benzfluorenol

[0026] 500.0kg of α-(di-n-butylamino)-2,7-dichloro-4-fluorenemethanol was placed in a 500L stainless steel reaction kettle, and 2500L of toluene-ethylene glycol (V:V=85:15) was added, stirred at room temperature to dissolve scattered. Then 5.0 kg of sodium methoxide and 8.0 kg of potassium acetate were added, and the reaction was stirred at room temperature for 2 h. Then add 185.0 kg of p-chlorobenzaldehyde at one time, then raise the temperature to reflux, and control the reaction at 85 ° C for about 16 hours. Thin-layer chromatography monitors the raw material α-(di-n-butylamino)-2,7-dichloro-4- The fluorenylmethanol spots disappeared. While stirring, the temperature was lowered to room temperature, and the stirring reaction was continued for 3 h, and benzfluorenol crystals were precipitated, filtered under reduced pressure, and washed with a small amount of methanol or ethanol to obtain crude benzfluorenol.

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Abstract

The invention discloses a semisynthesis process for producing benflumetol by taking alpha (di-n-butylamide)-2,7-dichloro-4-fluorenemethanol as a raw material. The process comprises the following steps: dispersing alpha (di-n-butylamide)-2,7-dichloro-4-fluorenemethanol in a mixed solvent, carrying out alkali catalysis and heating reflux on the obtained mixture, and carrying out condensation reaction on the obtained object and p-chlorobenzaldehyde, reducing the temperature to room temperature, and continuing to stir the obtained product so as to separate out coarse benflumetol grains; carrying out recrystallization on the coarse benflumetol grains by using acetone crystallization so as to obtain a fine benflumetol product with a content and a purity of more than 99.0%.

Description

technical field [0001] The present invention relates to the green synthesis of a kind of antimalarial raw material drug benzfluorenol, in particular to the synthesis raw material is the key intermediate-α-(di-n-butylamino)-2,7-dichloro-4-fluorenemethanol, in alkaline High yield and high purity benzfluorenol can be obtained through condensation under conditions and crystallization with a medium polar solvent. Background technique [0002] Benfluorenol is an alkaloid compound containing multiple aromatic rings, which is cis-2-dibutylamino-1-[2,7-dichloro-9-(4-chloro-benzylidene)-9H -Fluoren-4-yl]-ethanol racemic fluorene derivatives. It is successfully researched by the Chinese Academy of Military Medical Sciences and is the first antimalarial drug in my country. Benefantrine has good activity against malaria parasites and parasites, has a very high killing rate against chloroquine-resistant and Plasmodium falciparum, and has a significant killing rate against animal Plasmod...

Claims

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Application Information

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IPC IPC(8): C07C215/38C07C213/08C07C213/10
Inventor 彭学东张梅赵金召阎勇义
Owner ZHANG JIA GANG VINSCE BIO PHARM
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