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Preparation method of vortioxetine

A technology of vortioxetine and dimethylthiophenol, which is applied in the field of organic synthesis route design, can solve the problems of increasing the risk of genotoxic impurities, many impurities in side reactions, and difficult purification, so as to improve atom economy and prepare The effect of simple process and strong operability

Inactive Publication Date: 2019-08-09
YANGTAI PHARMA SHANDONG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

A variety of substitution reactions can occur between 2-bromothiophenol and 2,4-dimethyliodobenzene and piperazine, and the side reactions have many impurities, which are difficult to purify and will inevitably affect the yield
2-halonitrobenzene is used as a raw material, and it takes a long time to condense with 2,4-dimethylthiophenol under alkaline conditions; it is less safe to use hydrogen / metal catalyst for reduction; (2-Halo)ethylamine is a genotoxic impurity, which increases the risk of introducing genotoxic impurities into the finished product
[0013] To sum up, there are many synthetic methods of vortioxetine at present, but most of them have problems, or the route steps are too long and the yield is low, or the purity is poor, the purification is difficult, or the materials are expensive, or the reaction process is dangerous or used. Genotoxic materials, etc., the above methods have their own defects

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

[0053] 2-Bromoiodobenzene (50.0 g, 177.0 mmol) was dissolved in 1000 mL of toluene, 20 mL of tert-butanol, and 2,4-dimethylthiophenol (24.4 g, 177.0 mmol) were added. Nitrogen replacement, N-phenoxycarbonylpiperazine (54.7g, 265.5mmol), tris(dibenzylideneacetone)dipalladium (1.62g, 1.77mmol)), racemic 2,2-bis(diphenyl Phosphino)-1,1-biphenyl (2.21 g, 3.54 mmol) and sodium tert-butoxide (163.4 g, 1.7 mol). Under the protection of nitrogen, react at 110°C for 20h. Cool down to 40°C, add 1000mL of toluene, add diatomaceous earth to filter. The filtrate was washed with 1000 mL of saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the toluene was removed under reduced pressure to obtain 106.1 g of intermediate 1.

[0054] Dissolve 106.1g of intermediate 1 in 1000mL of methanol, add 500mL of 6N hydrochloric acid solution, heat to reflux, and react for 1.5h. After cooling down to room temperature, methanol was removed under reduced pressure to obtain a...

Embodiment 2

[0059] 2-Bromoiodobenzene (50.0 g, 177.0 mmol) was dissolved in 1000 mL of toluene, 50 mL of tert-butanol, and 2,4-dimethylthiophenol (24.4 g, 177.0 mmol) were added. Nitrogen displacement, adding N-phenoxycarbonylpiperazine (91g, 441.5mmol), bis(dibenzylideneacetone)palladium (5.05g, 8.83mmol), racemic 2,2-bis(diphenylphosphino) -1,1-biphenyl (11 g, 17.7 mmol) and sodium tert-butoxide (127 g, 1.3 mol). Under the protection of nitrogen, react at 110°C for 10h. Cool down to 40°C, add 1000mL of toluene, add diatomaceous earth to filter. The filtrate was washed with 1000 mL of saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the toluene was removed under reduced pressure to obtain 98.7 g of intermediate 1.

[0060] Dissolve 98.7g of intermediate 1 in 1000mL of methanol, add 500mL of 6N hydrochloric acid solution, heat to reflux, and react for 1.5h. After cooling down to room temperature, methanol was removed under reduced pressure to obtain a bro...

Embodiment 3

[0064]2-Bromoiodobenzene (50.0 g, 177.0 mmol) was dissolved in 1000 mL of toluene, 51 mL of tert-butanol, and 2,4-dimethylthiophenol (26.9 g, 194.7 mmol) were added. Nitrogen replacement, N-phenoxycarbonylpiperazine (54.7g, 265.5mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (6.48g, 8.85mmol), bis (2-Diphenylphosphophenyl) ether (9.53 g, 17.7 mmol) and sodium tert-butoxide (124.9 g, 1.3 mol). Under the protection of nitrogen, react at 100°C for 10h. Cool down to 40°C, add 1000mL of toluene, add diatomaceous earth to filter. The filtrate was washed with 1000 mL of saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the toluene was removed under reduced pressure to obtain 107.4 g of intermediate 1. Dissolve 107.4g of intermediate 1 in 1000mL of methanol, add 500mL of 6N hydrochloric acid solution, heat to reflux, and react for 1.5h. After cooling down to room temperature, methanol was removed under reduced pressure to obtain a br...

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Abstract

The invention relates to the field of organic synthetic route design, in particular to a preparation method of vortioxetine. The preparation method comprises the steps that 2-bromoiodobenzene (formulaII), 2,4-dimethyl benzenethio (formula III), N-phenoxycarbonyl piperazine (formula IV) and tert butyl alcohol (formula V) are taken as raw materials, in an aprotic solvent and under an alkaline condition, a palladium catalyst and a phosphine ligand are added for catalysis, heating is performed, and an intermediate 1 is formed orientedly; in an acidic condition, N-Boc-vortioxetine (formula VI) inthe intermediate 1 is subjected to Boc protecting group removal, and then a crude vortioxetine product (formula I) is formed through alkaline dissociation. The method has the advantages that the raw materials are simple and easy to obtain, the reaction condition of the process is mild, the product has high yield and high purity, and the method is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of organic synthesis route design, in particular to a preparation method of vortioxetine. Background technique [0002] Vortioxetine is a new drug for the treatment of depression, jointly developed by Lundbeck of Denmark and Takeda of Japan, and approved by the US Food and Drug Administration (FDA) on September 30, 2013 Listed, trade name Brintellix, for the treatment of major depressive disorder (MDD). [0003] Vortioxetine exerts its antidepressant effects primarily by increasing serotonin (5-HT) concentrations in the central nervous system (CNS), and it does not interact with other selective 5-HT reuptake inhibitors (SSRIS) or serotonin-norepinephrine reuptake inhibitors Vortioxetine had little effect on norepinephrine and dopaminergic neurons compared with SNRIS. A number of clinical trials have shown that vortioxetine has good efficacy, safety and tolerability for the treatment of MDD. [0004] According to th...

Claims

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Application Information

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IPC IPC(8): C07D295/096
CPCC07D295/096Y02P20/55
Inventor 郭晓冯永斌赵宗玉
Owner YANGTAI PHARMA SHANDONG
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