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Synthesis method of vortioxetine hydrobromide impurity

A technology of vortioxetine hydrobromide and its synthesis method, which is applied in the field of medicine and chemical industry, can solve the problems of few synthesis reports, etc., and achieve the effects of easy availability of raw materials, improved quality standards, and high purity

Inactive Publication Date: 2019-03-08
合肥创新医药技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] At present, there are few reports on its synthesis at home and abroad.

Method used

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  • Synthesis method of vortioxetine hydrobromide impurity
  • Synthesis method of vortioxetine hydrobromide impurity
  • Synthesis method of vortioxetine hydrobromide impurity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] A kind of synthetic method of vortioxetine hydrobromide impurity proposed by the present invention, the steps are as follows:

[0026] In the 250ml there-necked flask, add 120mg (0.1mmol) tetrakis (triphenylphosphine) palladium, 7.15g triethylamine, 200ml toluene, logical N2 protection, stir at room temperature for 10min; 6.09g (70.7mmol) piperazine, 10g (35.3 mmol) o-bromoiodobenzene was dissolved in 20ml of toluene, added dropwise to a three-necked flask, under the protection of N2, heated and refluxed for 5h, cooled to room temperature, added 100ml of water, stirred for 15min, filtered, the filtrate was separated to remove the water layer, and 15% chlorine was added The sodium chloride solution was washed twice, and the organic layer was dried with anhydrous sodium sulfate and spin-dried.

[0027] Vortioxetine hydrobromide impurity 1,2-bis(piperazin-1-yl)benzene (I) was obtained by column chromatography, and the mobile phase was composed of petroleum ether and ethyl ...

Embodiment 2

[0030] A kind of synthetic method of vortioxetine hydrobromide impurity proposed by the present invention, the steps are as follows:

[0031] Add 120mg (0.1mmol) tetrakis (triphenylphosphine) palladium, 16.9g sodium tert-butoxide, 200ml xylene to a 250ml three-necked flask, pass N2 protection, stir at room temperature for 10min; 12.1g (140.7mmol) piperazine, 10g (35.3mmol) o-bromoiodobenzene was dissolved in 20ml of xylene, added dropwise to a three-necked flask, under the protection of N2, heated and refluxed for 6h, cooled to room temperature, added 100ml of water, stirred for 15min, filtered, the filtrate was separated from the water layer, added Wash twice with 15% sodium chloride solution, dry the organic layer with anhydrous sodium sulfate, and spin dry.

[0032] Vortioxetine hydrobromide impurity 1,2-bis(piperazin-1-yl)benzene (I) was obtained by column chromatography, and the mobile phase was composed of petroleum ether and ethyl acetate at a volume ratio of 100:1.

...

Embodiment 3

[0035] A kind of synthetic method of vortioxetine hydrobromide impurity proposed by the present invention, the steps are as follows:

[0036] Add 120mg (0.1mmol) tetrakis (triphenylphosphine) palladium to 250ml there-necked flask, 15.6g potassium carbonate, 200ml tetrahydrofuran, pass N2 protection, stir at room temperature for 10min; 6.86g (79.6mmol) piperazine, 10g (35.3mmol ) o-bromoiodobenzene was dissolved in 20ml of tetrahydrofuran, added dropwise to a three-necked flask, under the protection of N2, heated and refluxed for 8 hours, cooled to room temperature, added 100ml of water, stirred for 15 minutes, filtered, the filtrate was separated to remove the water layer, and 15% chlorinated The sodium solution was washed twice, and the organic layer was dried with anhydrous sodium sulfate and spin-dried.

[0037] Vortioxetine hydrobromide impurity 1,2-bis(piperazin-1-yl)benzene (I) was obtained by column chromatography, and the mobile phase was composed of petroleum ether an...

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Abstract

The invention discloses a synthesis method of a vortioxetine hydrobromide impurity and relates to the technical field of pharmaceutical chemicals. The method comprises the steps as follows: piperazineand o-phenyldihalide are used as raw materials to be subjected to a condensation reaction under the action of a catalyst tetra(triphenylphosphine)palladium to produce 1,2-bis(piperazine-1-yl)benzene.The raw materials are easy to obtain, the process is simple, a target product has high yield and purity, and the method can be applied to qualitative and quantitative analysis of impurities in vortioxetine hydrobromide production, so that the quality standard of vortioxetine hydrobromide can be improved, and important guiding significance can be provided for safe medication.

Description

technical field [0001] The invention relates to the technical field of medicine and chemical industry, in particular to a method for synthesizing vortioxetine hydrobromide impurities. Background technique [0002] Vortioxetine hydrobromide (Vortioxetine hydrobromide), chemical name: 1-[2-(2,4-dimethyl-phenylmercapto)-phenyl]-piperazine hydrobromide, manufactured by Japan Takeda Pharmaceutical Co., Ltd. Jointly developed by the club and Lundbeck Pharmaceutical Co., Ltd., Denmark, it was launched in Europe in October 2013 for the treatment of severe depression in adults. Its chemical structural formula is as follows: [0003] Vortioxetine hydrobromide is considered to be a new multi-model antidepressant drug. In vitro studies have shown that it can antagonize 5-HT3, 5-HT7 and 5-HT1D receptors, activate 5-HT1A receptors, and partially activate The 5-HT1B receptor and the function of inhibiting the transport of 5-HT are the first antidepressants with multiple pharmacological a...

Claims

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Application Information

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IPC IPC(8): C07D295/023C07D295/02
CPCC07D295/02C07D295/023
Inventor 曹明成年帅黄顺旺曹阳
Owner 合肥创新医药技术有限公司
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