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Method of preparing dulouxetine

A duloxetine and isomer technology, applied in the field of compound preparation, can solve the problems of complicated operation, long reaction steps, unsuitable for industrial production, etc.

Inactive Publication Date: 2007-08-08
TIANJIN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The method has long reaction steps and complicated operation, and is not suitable for industrialized production

Method used

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  • Method of preparing dulouxetine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] To a three-necked reaction flask (1000ml) equipped with a reflux condenser, add N,N-dimethylformamide (400mL), and add (S)-3-methylamino-1-(2-thienyl) under stirring -1-propanol (0.3mol, 51.3g), tetrabutylammonium bromide (5g), sodium hydroxide (0.6mol, 24g), 1-fluoronaphthalene (0.6mol, 87.6g) add, be warming up to 80 ℃, reacted for 12 h, cooled the reactant to room temperature, added water (500 mL) and toluene (500 mL), stirred, separated the organic layer, extracted the aqueous layer with ethyl acetate (500 mL×2), combined the organic layers, decolorized, and dried. Filter, concentrate under reduced pressure to about 400mL, add hydrochloric acid ethyl acetate solution to adjust pH3.0, freeze overnight in the refrigerator to precipitate white crystals, filter, wash with cold ethyl acetate to obtain (S)-(+)-N-methyl-3- (1-Naphthyloxy)-3-(2-thienyl)-1-propanamine hydrochloride (66 g, 65.9%).

Embodiment 2

[0030] To a three-necked reaction flask (1000ml) equipped with a reflux condenser, add N,N-dimethylformamide (400mL), and add (R)-3-methylamino-1-(2-thienyl) under stirring -1-propanol (0.3mol, 51.3g), tetrabutylammonium bromide (5g), sodium hydroxide (0.6mol, 24g), 1-fluoronaphthalene (0.6mol, 87.6g) add, be warming up to 80 ℃, reacted for 3h, cooled the reactant to room temperature, added water (500mL) and toluene (500mL), stirred, separated the organic layer, extracted the aqueous layer with ethyl acetate (500mL×2), combined the organic layers, decolorized, dried, Filter, concentrate under reduced pressure to about 400mL, add hydrochloric acid ethyl acetate solution to adjust pH3.0, freeze overnight in the refrigerator to precipitate white crystals, filter, wash with cold ethyl acetate to obtain (R)-N-methyl-3-(1-naphthalene Oxy)-3-(2-thienyl)-1-propanamine hydrochloride (51 g, 50.9%).

Embodiment 3

[0032] In a three-necked reaction flask (1000ml) equipped with a reflux condenser, add N,N-dimethylformamide (400mL), and add 3-methylamino-1-(2-thienyl)-1-propane under stirring Alcohol (0.3mol, 51.3g), tetrabutylammonium bromide (5g), sodium hydroxide (0.3mol, 12g), and 1-fluoronaphthalene (0.6mol, 87.6g) were added, heated to 80°C, and reacted for 1.5 h, the reactant was cooled to room temperature, water (500mL) and toluene (500mL) were added, stirred, the organic layer was separated, the aqueous layer was extracted with ethyl acetate (500mL×2), the organic layers were combined, decolorized, dried, filtered, and Concentrate under pressure to about 400mL, add hydrochloric acid ethyl acetate solution to adjust pH3.0, freeze overnight in the refrigerator to precipitate white crystals, filter, wash with cold ethyl acetate to obtain racemic N-methyl-3-(1-naphthyloxy)-3 -(2-Thienyl)-1-propanamine hydrochloride (58 g, 57.9%).

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Abstract

The invention discloses a making method of donosidine and isomer in the preparing technique of drug composition to treat depression, which comprises the following steps: adding (S)-3-methylamino-1-(2-thiophene)-1-propanol or (R)-3-methylamino-1-(2-thiophene)-1-propanol or racemic 3-methylamino-1-(2-thiophene)-1-propanol in the solvent of N, N-dimethyl formamide or dimethyl sulfoxide; adding sodium hydroxide or potassium hydroxide; adding 1-flutenal or adding benzyl trimethyl amchlor or benzyl triethyl amchlor as phase transfer catalyst in the reacting system; reacting 0.5-24h under 30-150 deg.c; adjusting pH value to 3.0; cooling reacting material; adding water and dichloromethane to do phase separation; evaporating partial organic solvent; adjusting pH value to 3.0; obtaining (S)-(+)-N-methyl-3-(1-naphthoxy)-3-(2-thiophene)-1-propanamine hydrochlorate, (R)-N-methyl-3-(1-naphthoxy)-3-(2-thiophene)-1-propanamine and N-methyl-3-(1-naphthoxy)-3-(2-thiophene)-1-propanamine.

Description

technical field [0001] The invention relates to a preparation method of duloxetine and its isomers, which belongs to the preparation technology of compounds of drugs for treating depression. Background technique [0002] Duloxetine hydrochloride, chemical name (S)-(+)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-1-propanamine hydrochloride Salt, a 5-HT and norepinephrine reuptake inhibitor (SNRI) developed by Eli Lilly Company of the United States, is used for the treatment of major depression in adults, moderate to severe stress urinary incontinence in women and secondary diabetes in adults treatment of peripheral neuralgia. [0003] [0004] The method for the synthesis of duloxetine hydrochloride with (S)-3-dimethylamino-1-(2-thienyl)-1-propanol reported by Eli Lilly and Company is an industrial production method generally adopted at home and abroad. method (US 5362886). In recent years, take (S)-3-methylamino-1-(2-thienyl)-1-propanol as the method report of raw materia...

Claims

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Application Information

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IPC IPC(8): C07D333/20
Inventor 李爱军刘东志周雪琴阴彩霞曹贺
Owner TIANJIN UNIV
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