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Preparation method of Vortioxetine

A technology of vortioxetine and compound, applied in the field of preparation of vortioxetine, can solve the problem of not fundamentally solving the problem of competitive side reaction of dihalogen, and achieve the problem of solving the problem of competitive side reaction, easy availability of raw materials, and by-products. less effect

Inactive Publication Date: 2014-10-15
冯修武
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0020] This method also does not fundamentally solve the problem of competing side reactions of dihalogens

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

[0039] Under nitrogen protection, 13.8g (0.1mol) compound 2,4-dimethylthiophenol, 28.3g (0.1mol) 2-bromoiodobenzene, 53.0g (0.25mol) were successively put into a 500mL reactor Potassium phosphate and 1.9g (0.01mol) cuprous iodide, 1.15g (0.01mol) L-proline, add 300mL dimethylformamide, stir and heat up to 70-80°C, react for 5h, after the reaction is completed, Add 9.46g (0.11mol) piperazine to the reaction solution, continue the heating reaction for 5-8 hours, steam off part of the solvent after the reaction is completed, add water to the residue, extract three times with dichloromethane, each 300ml, combine the organic layers, Dry, evaporate dichloromethane, recrystallize by adding 200mL acetonitrile to the residue, obtain white solid 28.8g, yield 96.7%, purity 99.2%, maximum simplex 0.05% [HPLC method: chromatographic column Luna Phenyl-Hexyl column (4.6mmx150mm , 3um); mobile phase acetonitrile: 0.05% trifluoroacetic acid solution (60:40); detection wavelength 226Din; colum...

Embodiment 2

[0041]Under nitrogen protection, 13.8g (0.1mol) compound of formula (4) 2,4-dimethylthiophenol, 28.3g (0.1mol) 2-bromoiodobenzene, 63.6g (0.3mol) were successively put into a 500mL reactor Potassium phosphate and 3.8g (0.02mol) cuprous iodide, 2.3g (0.02mol) L-proline, add 300mL dimethylformamide, stir and raise the temperature to 70-80°C, react for 5h, after the reaction is completed, Add 1.03g (0.12mol) piperazine to the reaction solution, continue the heating reaction for 5-8 hours, evaporate part of the solvent after the reaction is completed, add water to the residue, extract three times with dichloromethane, each 300ml, combine the organic layers, After drying, the dichloromethane was distilled off, and the residue was recrystallized by adding 200 mL of acetonitrile to obtain 28.1 g of a white solid, with a yield of 93.7%, a purity of 99.1%, and a maximum of 0.08% impurity.

Embodiment 3

[0043] In the 500mL reactor, drop into 13.8g (0.1mol) formula (4) compound 2,4-dimethylthiophenol, 28.3g (0.1mol) 2-bromoiodobenzene, 53.0g (0.25mol) potassium phosphate and 1.9 g (0.01mol) cuprous iodide, 1.14g (0.01mol) (S,S)-cyclohexanediamine, add 300mL dimethylformamide, heat up to 70-80°C under stirring, react for 5h, after the reaction is completed , add 9.46g (0.11mol) piperazine to the reaction solution, continue to heat the reaction for 5-8 hours, evaporate part of the solvent after the reaction is completed, add water to the residue, extract three times with dichloromethane, 300ml each time, and combine the organic layers , dried, dichloromethane was distilled off, and the residue was recrystallized by adding 200 mL of acetonitrile to obtain 27.9 g of a white solid with a yield of 93.6%, a purity of 98.8%, and a maximum purity of 0.15%.

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Abstract

The invention relates to the preparation method of Vortioxetine. The preparation method is characterized by comprising the steps of: obtaining a compound (formula 2) by carrying out coupling reaction on compound 2,4-dimethylbenzenethiol (formula 4) and compound 2-bromoiodobenzene (formula 3) in the presence of copper iodide, chiral ligand and alkali; obtaining a compound (formula 1) through the reaction of compound in formula 2 and piperazine in the presence of copper iodide, chiral ligand and alkali; or operating the twp steps in one reactor by one-pot method; the preparation method is easy to obtain material, simple in technology, high in product purity, few in by-products and beneficial to industrial production of the bulk drug.

Description

technical field [0001] The invention relates to a preparation method of vortioxetine, which belongs to the field of medicine and chemical industry. Background technique [0002] Vortioxetine is a new type of antidepressant drug developed by Lundbeck of Denmark and Takeda Pharmaceutical of Japan. In September 2013, the drug was approved by the U.S. Food and Drug Administration (FDA). ] piperazine, its structural formula is: [0003] [0004] The drug is thought to work through a combination of 2 mechanisms of action: modulation of receptor activity and inhibition of reuptake. In vitro studies have shown that vortioxetine is a 5-HT3 and 5-HT7 receptor antagonist, a 5-HT1B receptor partial agonist, a 5-HT1A receptor agonist, and a 5-hydroxytryptamine transporter (SERT) inhibitor. Non-clinical studies in vivo have shown that vortioxetine can enhance the levels of neurotransmitters in specific areas of the brain-serotonin, norepinephrine, dopamine, acetylcholine, and histam...

Claims

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Application Information

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IPC IPC(8): C07D295/096
CPCC07D295/096
Inventor 段希福
Owner 冯修武
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