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Escitalopram oxalate related substances and preparation method thereof

A technology of escitalopram oxalate and related substances, which is applied in the field of escitalopram oxalate related substances and its preparation, and can solve the problems of difficult degradation, separation, limited structural stability of the reaction degree, no compound synthesis reports, etc. question

Active Publication Date: 2018-11-27
连云港恒运药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In the synthesis process of escitalopram oxalate, the cyano group on the benzene ring may react with the Grignard reagent to generate related substances, but due to the limitation of the reaction degree and its own structural stability, it is difficult to obtain it through a large amount of degradation and separation.
And there is no synthetic report of this compound in the literature

Method used

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  • Escitalopram oxalate related substances and preparation method thereof
  • Escitalopram oxalate related substances and preparation method thereof
  • Escitalopram oxalate related substances and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Put compound (II) (50.0g) into a reaction flask, add water (800ml) and NaOH (25.0g), stir and heat, and reflux for 24h. Cool the reaction solution to room temperature, extract with ethyl acetate (800ml×2), adjust the pH of the aqueous layer to about 5 with 2M hydrochloric acid, then concentrate under reduced pressure to remove water, add acetone (800ml) to the residue and stir for 30min, filter, and the filtrate Concentrate and treat once with acetone (800ml). After the filtrate was concentrated, Compound (III) (48.4 g) was obtained as a white solid with a yield of 91.4%.

Embodiment 2

[0032] Put compound (III) (48.4g) into a 1L reaction flask, add thionyl chloride (500ml), stir and heat under reflux for 2 hours. Then concentrated under reduced pressure to remove the solvent, and carried twice with toluene to obtain compound (IV) as a light brown oil, which was directly used in the next step.

Embodiment 3

[0034] Put the compound (IV) obtained in the previous step into THF (600ml), stir and cool down. The temperature was controlled at 0°C, and a mixture of morpholine (16.3g) / triethylamine (38.6g) in THF (200ml) was added dropwise. After dropping, the temperature was raised naturally for 1 hour. The solvent was then concentrated under reduced pressure, and the residue was added to water (600ml) and extracted with chloroform (500ml x 2). The organic layers were combined, washed with water and brine successively, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound (V) (42.9 g) as a brown-yellow oil, with a two-step yield of 73.8%.

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Abstract

The invention relates to an escitalopram oxalate related substance and a preparation method thereof, and particularly, relates to the related substance of an antidepressant drug, the escitalopram oxalate (namely, (S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-formonitrile oxalate), represented as the formula (I) and a preparation method thereof. The escitalopram oxalate, as the target compound, is synthesized through reactions comprising hydrolysis, acylation, condensation, reduction, addition and oxidization to the compound (II) (namely, (S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-formonitrile). According to the method, the compound (I) is chemically synthesized for the first time. By means of the method, the target compound can be obtained through high-efficient and quick separation.

Description

technical field [0001] The present invention relates to 4-dimethylamino-1-{1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-yl }-1-butanone and a preparation method thereof, the compound is a related substance of escitalopram oxalate. Background technique [0002] Escitalopram oxalate (structure below) was first developed by H. Lundbeck A / S of Denmark and Forest Laboratories of the United States. In August 2002, it was approved for marketing by the US FDA. Escitalopram oxalate is the dextro-enantiomer of racemic citalopram, and its mechanism of action is considered to enhance the serotonin (5-HT) energy in the central nervous system and inhibit the reuptake of serotonin. It is a second-generation antidepressant, clinically used for the treatment of depression, and its role in improving "depressed mood" and "work interest" is particularly prominent. [0003] [0004] In the synthesis process of escitalopram oxalate, the cyano group on the benzene...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D307/87
CPCC07D307/87
Inventor 熊龙张庆捷潘必高杨宝海
Owner 连云港恒运药业有限公司
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