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Method for preparing alpha-(di-n-butylaminomethyl)-2,7-dichloro-4-fluorenemethanol and the hydrochloride thereof

A technology of di-n-butylaminomethyl and fluorene methanol is applied in chemical instruments and methods, preparation of organic compounds, preparation of aminohydroxy compounds, etc., and can solve the problems of unfavorable industrialized production, cumbersome post-processing methods, and many raw materials consumed. , to achieve the effect of reduced production cost, easy operation and mild reaction conditions

Inactive Publication Date: 2010-06-23
GUILIN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] But when directly synthesizing α-(di-n-butylaminomethyl)-2,7-dichloro-4-fluorenemethanol according to the method shown above, the cycle of preparation is long, the raw materials consumed are more, and the cost is relatively high; When α-(di-n-butylaminomethyl)-2,7-dichloro-4-fluorenemethanol hydrochloride, the post-treatment method used is more loaded down with trivial details, is unfavorable for industrialized production

Method used

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  • Method for preparing alpha-(di-n-butylaminomethyl)-2,7-dichloro-4-fluorenemethanol and the hydrochloride thereof
  • Method for preparing alpha-(di-n-butylaminomethyl)-2,7-dichloro-4-fluorenemethanol and the hydrochloride thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Weigh 20.2g (0.151mol) of anhydrous aluminum trichloride and 12g (0.106mol) of chloroacetyl chloride into 300ml of 1,2-dichloroethane, cool the reactant to 0-5°C, and further Stir the reactant at 5°C for 30 minutes, add 20g (0.085mol) of 2,7-dichlorofluorene, stir the reactant at 0-5°C for 2-3 hours, then allow it to naturally heat up and react for 2-3 hours; After completion, the reactant was cooled to 0-5°C, then 400ml of ice water containing 120ml of concentrated hydrochloric acid was slowly added to the reactant, fully stirred for 30 minutes, and then the organic layer was separated and washed with 50ml of 1,2-dichloroethane The aqueous layer was extracted; the obtained organic layers were combined, washed with water until almost no acidity, and then the solvent was evaporated to dryness, and the residue was 2,7-dichloro-4-chloroacetylfluorene. Add 400ml of absolute ethanol to the residue, control the temperature at 40-45°C, add 8g (0.148mol) of potassium borohydrid...

Embodiment 2

[0030]Weigh 20.2g (0.151mol) of anhydrous aluminum trichloride and 12g (0.106mol) of chloroacetyl chloride into 300ml of dichloromethane, cool the reactant to 0-5°C, and further stir at 0-5°C Add 20g (0.085mol) of 2,7-dichlorofluorene to the reactant for 30 minutes, stir the reactant at 0-5°C for 2-3 hours, then allow it to naturally heat up and react for 2-3 hours; after the reaction is completed, the reaction The mixture was cooled to 0-5°C, and then 400ml of ice water containing 120ml of concentrated hydrochloric acid was slowly added to the reactant, stirred thoroughly for 30 minutes, then the organic layer was separated, and the aqueous layer was extracted with 50ml of dichloromethane; the organic layers obtained were combined, It was washed with water until it was not acidic, and then the solvent was evaporated to dryness, and the residue was 2,7-dichloro-4-chloroacetylfluorene. Add 400ml of absolute ethanol to the residue, control the temperature at 40-45°C, add 8g (0.1...

Embodiment 3

[0032] Add 50.5g (0.379mol) of anhydrous aluminum trichloride and 30g (0.266mol) of chloroacetyl chloride into 900ml of dichloromethane, cool the reactant to 0-5°C, and then stir the reaction at 0-5°C After 30 minutes, add 50 g (0.213 mol) of 2,7-dichlorofluorene, stir the reactant at 0-5°C for 2-3 hours, then allow it to naturally heat up and react for 2-3 hours; after the reaction is completed, the reactant Cool to 0-5°C, then slowly add 1000ml of ice water containing 300ml of concentrated hydrochloric acid to the reactant, stir thoroughly for 30 minutes, then separate the organic layer, extract the aqueous layer with 100ml of dichloromethane; combine the obtained organic layers, and water Wash until no acidity, then evaporate the solvent to dryness, the residue is 2,7-dichloro-4-chloroacetylfluorene. Add 1000ml of absolute ethanol to the residue, control the temperature at 40-45°C, add 20g (0.371mol) of potassium borohydride, maintain the temperature at 40-45°C for 18 hours...

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Abstract

The invention discloses a method for preparing benflumetol intermediate alpha-(di-n-butylaminomethyl)-2, 7- dichloro-4-fluorenemethanol and the hydrochloride thereof. The alpha-(di-n-butylaminomethyl)-2, 7- dichloro-4-fluorenemethanol is obtained by directly reacting 2, 7-Dichlorofluoren as raw material with the chloroacetyl chloride, then reducing the obtained mixture with potassium borohydride or sodium borohydride for 10 to 24 hours, washing the obtained solids with water, then adding the obtained solids into recycled ethanol mother solution concentrate, adding N-Dibutylamine into the mother solution concentrate and the target product is separated from the reaction mixture; the hydrochloride of the alpha-(di-n-butylaminomethyl)-2, 7- dichloro-4-fluorenemethanol is obtained by adding chlorhydric acid into the reaction mixture to salify the reaction mixture and then crystallizing the reaction mixture. The method has cheap raw materials, simple and convenient operations and high yield factor and in particular greatly reduces the production cost by reusing the ethanol mother solution.

Description

(1) Technical field: [0001] The invention relates to a method for preparing a benzfluorenol intermediate, in particular to a method for preparing α-(di-n-butylaminomethyl)-2,7-dichloro-4-fluorenemethanol and its hydrochloride. (two) background technology: [0002] Benzfluorenol (represented by formula I) is a new chemical structure drug synthesized by the Academy of Military Medical Sciences in Beijing, China, and its chemical name is (9Z)-2,7-dichloro-9-[(4-chlorophenyl)methylene base]-α-[(di-n-butylamino)methyl]-9H-fluorene-4-methanol. [0003] [0004] Benefantrine can be used to treat various malaria, and is especially suitable for the treatment of falciparum malaria caused by chloroquine-resistant strains. α-(di-n-butylaminomethyl)-2,7-dichloro-4-fluorenemethanol and its hydrochloride are intermediates for the synthesis of benzfluorenol. The existing method for synthesizing the above-mentioned intermediates is Deng Rongxian et al. α-(Di-n-butylaminomethyl)-2,7-dich...

Claims

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Application Information

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IPC IPC(8): C07C215/28C07C213/02
Inventor 廖文斌郑清四
Owner GUILIN PHARMA
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