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Novel process for preparation of 1-[2-(2,4-dimethylphenylsulphanyl)phenyl] piperazine

A technology of vortioxetine and a new process, which is applied in the field of medicinal chemistry and can solve problems such as being unsuitable for industrial production

Inactive Publication Date: 2016-04-06
BEIJING VENTUREPHARM BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0012] The reaction is two steps. Although the reaction process is relatively simple and the operation is relatively easy, the palladium precious metal catalyst is used in the reaction process, which is not suitable for industrial production, and the patent has been authorized to enter, and the issue of patent evasion needs to be considered

Method used

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  • Novel process for preparation of 1-[2-(2,4-dimethylphenylsulphanyl)phenyl] piperazine
  • Novel process for preparation of 1-[2-(2,4-dimethylphenylsulphanyl)phenyl] piperazine
  • Novel process for preparation of 1-[2-(2,4-dimethylphenylsulphanyl)phenyl] piperazine

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Experimental program
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Effect test

Embodiment 1

[0024] Dissolve o-bromothiophenol (4.7g, 25mmol) and N-methylpiperazine (2.5g, 25mmol) in 60ml of toluene solvent, heat to 120°C, react overnight, o-bromothiophenol and N-methyl Piperazine undergoes a halogenation reaction. After the reaction is over, stop heating and cool to room temperature. 50ml of water was added, the aqueous phase was separated by filtration, the organic phase was washed with saturated brine and water, and the combined aqueous phase was extracted with toluene. The toluene was removed under reduced pressure to obtain intermediate 1, 4.4 g of the product, and the yield was 85%.

Embodiment 2

[0026] Dissolve Intermediate 1 (4.2g, 20mmol) in 40ml of toluene, add 2,4-dimethyliodobenzene (4.6g, 20mmol), add Pddba 2， rac-BINAP and NaOBu t . Heat to reflux to 100°C and react overnight. After the reaction, stop heating and cool to room temperature. Water was added, the aqueous phase was separated by filtration, the organic phase was washed with brine and water, and the combined aqueous phase was extracted with toluene. Toluene was removed under reduced pressure to obtain intermediate 2. Product 5.4g, yield 87%.

Embodiment 3

[0028] Intermediate 2 (3.1g, 10mmol) and phenyl chloroformate (1.6g, 10mmol) were dissolved in 30mL of tetrahydrofuran, stirred at room temperature for 4h, and the reaction was completed. After cooling to room temperature, the reaction solution was added to 200 mL of water, stirred at room temperature for 2 hours, filtered, washed with water until neutral, and dried to obtain 3.8 g of the product with a yield of 91%.

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Abstract

The present invention discloses a novel process for the preparation of 1-[2-(2,4-dimethylphenylsulphanyl)phenyl] piperazine. The process uses o-halogenated benzenesulfonic acid and m-xylene as raw materials, which are subjected to dehydration condensation with methylsulfonic acid and phosphorus pentoxide as condensing agents to generate halogenated diarylsulfone. Halogenated diarylsulfone and piperazine are subjected to a substitution reaction in an aprotic solvent to produce piperazine ring substituted diarylsulfone; the piperazine ring substituted diarylsulfone is reduced by hexachlorodisilane in an aprotic solvent to obtain a product with high yield. This method has the advantages of cheap and easily available raw materials, avoidance of the usage of a noble metal catalyst and treatment of residual palladium, simple operation, mild reaction conditions, simple post-treatment, and potential application values.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a new process for preparing vortioxetine. Background technique [0002] The chemical name of vortioxetine is 1-[2-(2,4-dimethylphenyl)mercapto]phenyl]-piperazine, which is a serotonin transporter inhibitor and regulates the activity of its receptors. Jointly developed by Lundbeck and Takeda, it was approved by the US FDA in September 2013 under the trade name Brintellix, which is clinically used to treat severe depression and generalized anxiety. [0003] At present, the original research company has disclosed the preparation method of this compound (WO2007144005, CN101472906). There are three synthesis methods for this compound, and the reaction route is as follows: [0004] method 1: [0005] [0006] The reaction process has three steps, and palladium source is used in two steps of reaction, the cost is relatively high, and it is not suitable for industrial production. ...

Claims

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Application Information

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IPC IPC(8): C07D295/096
CPCC07D295/096
Inventor 闫起强赵国磊
Owner BEIJING VENTUREPHARM BIOTECH
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