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Preparation method of Vortioxetine

A vortioxetine, dripping technology, applied in the field of preparation of vortioxetine, can solve the problems of high toxicity of borane, high reaction temperature, unsuitable for large-scale production, etc., to improve production efficiency, high yield, Ease of industrial production

Active Publication Date: 2016-02-17
QILU PHARMA HAINAN +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Borane is very toxic, and the reaction temperature is high during production, which has great potential safety hazards and is not suitable for large-scale production

Method used

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  • Preparation method of Vortioxetine
  • Preparation method of Vortioxetine
  • Preparation method of Vortioxetine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] 100 g of 1-[2-(2,4-dimethyl-phenylthio)-phenyl]-piperazine-2,6-dione (compound 1) was dissolved in 500 ml of ethyl acetate. Add 500ml of ethyl acetate into a 2L reaction flask, cool down to 0-10°C, add 72.7g of titanium tetrachloride and 2.5g of iodine (protected under nitrogen), slowly add 178.1g of triethylsilane dropwise, and complete the dropwise addition in 15 minutes . Then slowly add the prepared Compound 1 solution dropwise, the dropwise addition is completed in 45 minutes, and the temperature is controlled at 0-10°C; after the dropwise addition, the temperature is raised to 25-30°C, and the reaction is stirred for 5h. Slowly drop the reaction system into 200ml of water to quench, and control the temperature at 0-10°C. After the dropwise addition, separate the organic phase, wash the organic phase with saturated sodium chloride solution for 3 times, and then dry over anhydrous sodium sulfate , concentrating under reduced pressure and drying to obtain 87.8 g of ...

Embodiment 2

[0029] 100 g of 1-[2-(2,4-dimethyl-phenylthio)-phenyl]-piperazine-2,6-dione (compound 1) was dissolved in 500 ml of dichloromethane. Add 500ml of dichloromethane into a 2L reaction flask, cool down to 0-10°C, add 75.0g of titanium tetrachloride and 2.8g of iodine (protected under nitrogen); slowly add 180.0g of triethylsilane dropwise, and complete the dropwise addition in 10 minutes . Then slowly add the prepared Compound 1 solution dropwise, and the dropwise addition is completed in 50 minutes. After the dropwise addition, the temperature is raised to 25-30° C., and the reaction is stirred for 4.5 hours. Slowly drop the reaction system into 200ml of water to quench, and control the temperature at 0-10°C. After the dropwise addition, separate the organic phase, wash the organic phase with saturated sodium chloride solution for 3 times, and then dry over anhydrous sodium sulfate , Concentrated under reduced pressure and dried, 88.5 g of white solid was obtained with a yield o...

Embodiment 3

[0031] 100 g of 1-[2-(2,4-dimethyl-phenylthio)-phenyl]-piperazine-2,6-dione (compound 1) was dissolved in 500 ml of dichloromethane. Add 500ml of dichloromethane into a 2L reaction flask, cool down to 0-10°C, add 85.0g of titanium tetrachloride and 3.5g of iodine (protected under nitrogen); slowly add 185.0g of triethylsilane dropwise, and complete the dropwise addition in 15 minutes . Then slowly add the prepared Compound 1 solution dropwise, the dropwise addition is completed in 50 minutes, and the temperature is controlled at 0-10°C; after the dropwise addition, the temperature is raised to 25-30°C, and the reaction is stirred for 5h. Slowly drop the reaction system into 200ml of water to quench, and control the temperature at 0-10°C. After the dropwise addition, separate the organic phase, wash the organic phase with saturated sodium chloride solution for 3 times, and then dry over anhydrous sodium sulfate , concentration under reduced pressure and drying, 88.8 g of white...

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Abstract

The invention discloses a preparation method of Vortioxetine. The method comprises the steps that titanium tetrachloride is dissolved in organic solvent, iodine is added under the protection of nitrogen, triethyl silicane is dropwise added, and then 1-[2-(2,4-dimethyl-thiophenyl)-phenyl]-piperazine-2,6-diketone solution is dropwise added; stirring and reacting are conducted, and after reacting is completed, reaction liquid is dropwise added into water for quenching; washing, drying, concentrating and baking are conducted on an organic phase, and a product is obtained. According to the preparation method of the Vortioxetine, reducing preparation is conducted through the titanium tetrachloride and the triethyl silicane, catalyzing is conducted through the iodine, dangerousness of production operation is reduced, the aftertreatment steps are simple, the product yield is high, and industrial production is easier.

Description

technical field [0001] The invention relates to a preparation method of vortioxetine, which belongs to the technical field of medicine. Background technique [0002] Vortioxetinehydrobromide, chemical name: 1-[2-(2,4-dimethyl-phenylthio)-phenyl]-piperazine hydrobromide, molecular formula: C 18 h 22 N 2 S HBr; molecular weight: 379.36, the structural formula is as follows: [0003] [0004] Vortioxetine hydrobromide is a drug for the treatment of depression launched in the United States by Lundbeck and Takeda. Vortioxetine hydrobromide can inhibit the reuptake of serotonin, and has the functions of 5-HT1A receptor agonist, 5-HT1B receptor partial agonist and 5-HT3, 5-HT1D and 5-HT7 receptor antagonist. The diversity of vortioxetine's action makes it a modulator of neurotransmission in several systems, mainly serotonin, and presumably also norepinephrine, dopamine, histamine, acetylcholine, GABA, and glutamate systems . The relative contribution of each mechanism of a...

Claims

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Application Information

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IPC IPC(8): C07D295/096
CPCC07D295/096
Inventor 高大龙杨庆坤张雷雷李保勇吴柯张兆珍董廷华赵雪宁杨波勇江海平周学文
Owner QILU PHARMA HAINAN
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