Vortioxetine hydrobromide preparation method

A technology of vortioxetine and o-bromoiodobenzene, which is applied in the field of new antidepressant drugs, can solve the problems of unsuitability for industrial production, poor purity, long route, etc., and solve the problem of competing side reactions, reduce the number of impurities, and improve the yield and the effect of high purity

Inactive Publication Date: 2015-11-18
HEBEI GUOLONG PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] In summary, there are many synthetic methods of vortioxetine hydrobromide at present, but most of them have problems, such as low yield, poor purity, difficult purification, or long routes and many steps, which are not suitable for industrial production

Method used

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  • Vortioxetine hydrobromide preparation method
  • Vortioxetine hydrobromide preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] The first step: the synthesis of 2-(2,4-dimethylphenylsulfanyl) bromobenzene (compound IV)

[0052] Into a 2L single-necked bottle, sequentially add 127.5g (0.45mol) of o-bromoiodobenzene, 68.4g (0.5mol) of 2,4-dimethylthiophenol, 4.3g (22.5mmol) of ketone iodide, and ethylene glycol 56.0g (0.9mol), isopropanol 1.1L, tripotassium phosphate 191.0g (0.9mol), nitrogen gas was introduced under normal pressure and room temperature under stirring, vacuum replaced three times, reacted at 80-90°C for 7-8h, stopped heating, and waited After the reaction solution was cooled to room temperature, the mother liquor was spin-dried at 60-70°C to obtain an oil. Add 1.5 L of dichloromethane to the oil, add 1 L of water, stir at room temperature for 10-20 minutes, filter with diatomaceous earth, and separate the mother liquor. 15% sodium chloride was washed 1 L x 2 times, washed 1 L x 1 time, dried over anhydrous magnesium sulfate for more than 4 hours, and DCM was spin-dried to obtain 1...

Embodiment 2

[0057] The first step: the synthesis of 2-(2,4-dimethylphenylsulfanyl) bromobenzene (compound IV)

[0058] Into a 1L single-necked bottle, sequentially add 28.3g (0.1mol) of o-bromoiodobenzene, 16.6g (0.12mol) of 2,4-dimethylthiophenol, 1.9g (10mmol) of ketone iodide, and 12.4g of ethylene glycol g (0.2mol), 250ml of isopropanol, 42.4g (0.2mol) of tripotassium phosphate, nitrogen gas was introduced under normal pressure and room temperature, and replaced by vacuum three times, reacted at 80-90°C for 7-8h, stopped heating, and the reaction solution was After cooling to room temperature, the mother liquor was spin-dried at 60-70°C to obtain an oil. Add 300ml of dichloromethane to the oil, add 200ml of water, stir at room temperature for 10-20min, filter with diatomaceous earth, separate the mother liquor, and add 15% chlorine Wash with sodium chloride water 200ml x 2 times, water 200nl x 1 time, dry over anhydrous magnesium sulfate for more than 4h, and spin dry DCM to obtain 30...

Embodiment 3

[0062] The first step: the synthesis of 2-(2,4-dimethylphenylsulfanyl) bromobenzene (compound IV)

[0063] Into a 1L single-necked bottle, add 28.3g (0.1mol) of o-bromoiodobenzene, 11.1g (0.08mol) of 2,4-dimethylthiophenol, 0.6g (3mmol) of ketone iodide, and 9.3 g (0.15mol), 250ml of isopropanol, 31.8g (0.15mol) of tripotassium phosphate, nitrogen gas was introduced under normal pressure and room temperature stirring, vacuum replacement was carried out three times, reaction was carried out at 60-70°C for 10h, heating was stopped, and the mother liquor was spin-dried to obtain Oil, add 300ml of dichloromethane to the oil, add 200ml of water, stir at room temperature for 10-20min, filter with diatomaceous earth, separate the mother liquor, wash with 15% sodium chloride 200ml x 2 times, wash 200nl x 1 time , dried over anhydrous magnesium sulfate for more than 4 hours, and spin-dried DCM to obtain 24.5 g of light yellow oil (yield: 100%).

[0064] The second step: the synthesis ...

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Abstract

The invention provides a vortioxetine hydrobromide preparation method. The vortioxetine hydrobromide preparation method comprises the following steps: a reaction is performed between o-bromoiodobenzene and 2,4-dimethylbenzenethiol in a protonic solvent under the action of a cuprous catalyst, glycol and inorganic base to obtain 2-(2,4-dimethylthiophenyl) bromobenzene (a compound IV); the compound IV in an aprotic solvent is coupled with piperazine under the action of a palladium catalyst, a phosphine ligand and organic base; finally, salifying is performed with hydrobromic acid to obtain vortioxetine hydrobromide. Compared with the prior art, the vortioxetine hydrobromide preparation method has the advantages that competition side reactions of dual halogens are avoided, by-products are reduced, the total yield and product purity are high, and the process operation is simple, and suitable for amplification and industrialized production.

Description

technical field [0001] The invention belongs to the field of organic synthesis, in particular to the preparation method of formula (I) compound 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide. Vortioxetine hydrobromide is a new type of antidepressant drug. Background technique [0002] Vortioxetinehydrobromide (Vortioxetinehydrobromide, I) is a new type of antidepressant jointly developed by Lundbeck of Denmark and Takeda Pharmaceutical of Japan, with a trade name of Brintellix. In September 2013, it was approved by the US Food and Drug Administration (FDA) for the treatment of major depressive disorder (MDD) in adults. Its structural formula is as follows: [0003] [0004] Danish Lundbeck Pharmaceutical Company patent No. WO200714405 and No. WO2013102573 reported that o-bromoiodobenzene, 2,4-dimethylthiophenol, piperazine or 2-bromothiophenol, 2,4-dimethyliodide Benzene and piperazine are raw materials in two (dibenzylideneacetone) palladium (Pddba ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/096
CPCC07D295/096
Inventor 曲继广刘翠环印杰樊根遥曹柳姜召红吴楠
Owner HEBEI GUOLONG PHARMA CO LTD
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