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Preparation method of vortioxetine hydrobromide impurity

A technology of vortioxetine hydrobromide and impurities, applied in directions such as organic chemistry, can solve problems such as few synthetic reports, and achieve the effects of cheap raw materials, mild reaction conditions and high yield

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

AI Technical Summary

Problems solved by technology

[0007] At present, there are few reports on its synthesis at home and abroad.

Method used

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  • Preparation method of vortioxetine hydrobromide impurity
  • Preparation method of vortioxetine hydrobromide impurity
  • Preparation method of vortioxetine hydrobromide impurity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Mix piperazine, o-bromoiodobenzene, sodium tert-butoxide, bis(dibenzylideneacetone) palladium, and toluene evenly, replace the air with nitrogen, reflux for 6.5 hours, cool and filter, wash the filtrate with aqueous sodium chloride, and dry , concentrated to dryness, and then obtained 2-bromophenylpiperazine by column chromatography, wherein the molar ratio of piperazine to o-bromoiodobenzene is 1:1.5, and the molar ratio of piperazine to sodium tert-butoxide is 1:3 , the molar ratio of piperazine and bis(dibenzylideneacetone) palladium is 1:0.005, the weight volume (g / ml) ratio of piperazine and toluene is 1:20, and the column chromatography mobile phase is dichloromethane and methanol Mixed solution, wherein, the volume ratio of dichloromethane and methanol is 20:1;

[0034] The proton nuclear magnetic resonance spectrum, mass spectrogram of gained 2-bromophenylpiperazine see figure 1 , figure 2 .

Embodiment 2

[0036] Mix piperazine, o-bromoiodobenzene, sodium tert-butoxide, bis(dibenzylideneacetone) palladium, and toluene evenly, replace the air with nitrogen, reflux for 6.5 hours, cool and filter, wash the filtrate with aqueous sodium chloride, and dry , concentrated to dryness, and then obtained 1,4-bis(2-bromophenyl)piperazine by column chromatography, wherein the molar ratio of piperazine to o-bromoiodobenzene was 1:2, piperazine, sodium tert-butoxide The molar ratio of piperazine and bis(dibenzylideneacetone) palladium is 1:3, the molar ratio of piperazine and bis(dibenzylideneacetone)palladium is 1:0.005, the weight volume (g / ml) ratio of piperazine and toluene is 1:20, and the column chromatography flow The phase is a mixed solution of petroleum ether and ethyl acetate, wherein the volume ratio of petroleum ether and ethyl acetate is 100:1;

[0037] Gained 1,4-two (2-bromophenyl) piperazine proton nuclear magnetic resonance spectrogram, mass spectrogram see image 3 , Figu...

Embodiment 3

[0039] Mix piperazine, o-bromoiodobenzene, triethylamine, bis(dibenzylideneacetone) palladium, and toluene, replace the air with nitrogen, reflux for 5 hours, cool and filter, wash the filtrate with aqueous sodium chloride, dry, and concentrate to dryness, and then obtain 2-bromophenylpiperazine by column chromatography, wherein the molar ratio of piperazine to o-bromoiodobenzene is 1:1, the molar ratio of piperazine and triethylamine is 1:5, and piperazine , The molar ratio of bis(dibenzylideneacetone) palladium is 1:0.003, the weight volume (g / ml) ratio of piperazine and toluene is 1:15, and the column chromatography mobile phase is a mixed solution of dichloromethane and methanol, Wherein, the volume ratio of dichloromethane and methanol is 30:1.

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Abstract

The invention discloses a preparation method of a vortioxetine hydrobromide impurity. The preparation method comprises the steps as follows: piperazine and o-bromoiodobenzene are subjected to a condensation reaction under the action of an acid binding agent and a catalyst, wherein when the molar ratio of piperazine to o-bromoiodobenzene is 1:(1-1.5), 2-bromophenylpiperazine is obtained through thecondensation reaction; when the molar ratio of piperazine to o-bromoiodobenzene is 1:(2-3), 1,4-bis(2-bromophenyl)piperazine is obtained through the condensation reaction. The synthesis route is short, raw materials are cheap and easy to obtain, the operation is simple, the reaction condition is mild, and a product has high purity and yield.

Description

technical field [0001] The invention relates to the technical field of chemical substance preparation, in particular to a method for preparing vortioxetine hydrobromide impurities. Background technique [0002] Vortioxetine hydrobromide (Vortioxetine hydrobromide), the chemical name is 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] [0004] 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 ph...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/073
CPCC07D295/073
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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