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Synthetic method and application of vortioxetine hydrobromide

A technology of vortioxetine hydrobromide and a synthetic method, which is applied in the field of synthesis of vortioxetine hydrobromide, can solve the problems of unsuitability for industrial production, poor purity, long route, etc., and solve the problem of competitive side reactions, Effect of reduced number of impurities, high yield and high purity

Inactive Publication Date: 2017-02-08
合肥美利康医药技术股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] In the prior art, although the synthetic methods of vortioxetine hydrobromide are diverse, most of them have problems, or the yield is low, the purity is poor, the purification is difficult, or the route is long and there are many steps, all of which are not suitable for industrial production

Method used

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  • Synthetic method and application of vortioxetine hydrobromide
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  • Synthetic method and application of vortioxetine hydrobromide

Examples

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Embodiment 1

[0021] The first step: the synthesis of 2-(2,4-dimethylphenylsulfanyl) bromobenzene (compound I)

[0022] 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 13...

Embodiment 2

[0027] The first step: the synthesis of 2-(2,4-dimethylphenylsulfanyl) bromobenzene (compound I)

[0028] 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....

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Abstract

The invention relates to the technical field of medicinal chemical synthesis, and concretely relates to a synthetic method of vortioxetine hydrobromide. The method comprises the following steps: carrying out a reaction on compounds comprising o-bromoiodobenzene and 2,4-dimethylthiophenol in environment containing a catalyst, an inorganic alkali and a protic solvent to obtain 2-(2,4-dimethylthiophenyl)bromobenzene; and coupling 2-(2,4-dimethylthiophenyl)bromobenzene with piperazine in environment containing a catalyst, an organic alkali and an aprotic solvent, and carrying out salt formation on the obtained coupling product and hydrobromic acid to prepare the vortioxetine hydrobromide. Compared with the prior art, the method disclosed in the invention has the advantages of solving of double-halogen competition side reactions, great reduction of generation of byproducts, high total yield, good product purity, simplicity in process operation, and suitableness for amplification and industrial production.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical chemical synthesis, in particular to a method for synthesizing vortioxetine hydrobromide. Background technique [0002] Vortioxetine hydrobromide (I) is a novel 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] In the prior art, although the synthesis methods of vortioxetine hydrobromide are diverse, 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. Contents of the invention [0005] Aiming at the deficiencies of the prior art, the invention provides a method for synthesizing vortioxetine hydrobromide...

Claims

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Application Information

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IPC IPC(8): C07D295/096
CPCC07D295/096
Inventor 孙延标孙明哲方存杰赵冬生方从彬徐奎
Owner 合肥美利康医药技术股份有限公司
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