Novel preparation method of hydrobromic acid Vortioxetine beta crystalline form

A technology of vortioxetine hydrobromide and vortioxetine, which is applied in the field of drug synthesis, can solve the problems of high purity of vortioxetine hydrobromide, low purity of vortioxetine, high cost, etc. The effect of industrialized production, high product yield and mild process reaction conditions

Active Publication Date: 2015-03-25
郑州大明药物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] The purpose of the present invention is to provide a new method for the preparation of vortioxetine hydrobromide beta crystal form in view of the proble...

Method used

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  • Novel preparation method of hydrobromic acid Vortioxetine beta crystalline form
  • Novel preparation method of hydrobromic acid Vortioxetine beta crystalline form
  • Novel preparation method of hydrobromic acid Vortioxetine beta crystalline form

Examples

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Embodiment 1

[0024] Example 1: This example provides a new method for preparing vortioxetine hydrobromide β crystal form. The specific steps are as follows:

[0025] Step 1: Synthesis of 2-(2,4-dimethylphenylsulfanyl)chlorobenzene

[0026]

[0027] Take a 250ml reaction flask, pour nitrogen into the flask, take 20g (0.14mol) of 2-chlorothiophenol (formula I) and 17.1g (0.14mol) of 2,4-dimethylphenol (formula II) into the reaction Add 153g of ethyl acetate, 0.8g (0.014mol) of nickel nanopowder, 34.4g (0.42mol) of sodium isopropoxide and 10g of anhydrous sodium sulfate into the bottle, stir at room temperature for 20min, warm up to 50℃, and stir for 8h. TLC monitors the progress of the reaction. After the reaction is over, the heating is stopped. After the reaction solution is cooled to room temperature, it is filtered. The filtrate is washed 3 times with 50ml each time. The organic phase is taken and dried with anhydrous sodium sulfate and filtered. The solvent was evaporated under a vacuum of ...

Embodiment 2

[0035] Example 2: This example provides another new method for preparing vortioxetine hydrobromide β crystal form. The specific steps are as follows:

[0036] Step 1: Synthesis of 2-(2,4-dimethylphenylsulfanyl)chlorobenzene

[0037]

[0038] Take a 500ml reaction flask, pour nitrogen into the flask, take 40g (0.28mol) of 2-chlorothiophenol (formula I) and 34.2g (0.28mol) of 2,4-dimethylphenol (formula II) into the reaction Add 306g ethyl acetate, 1.58g (0.027mol) of nickel nanopowder, 71.1g (0.87mol) of sodium isopropoxide and 23.7g of anhydrous sodium sulfate into the bottle, stir at room temperature for 30min, warm up to 60℃, and stir for 9h , TLC monitors the progress of the reaction. After the reaction is over, stop heating, filter the reaction solution after it has cooled to room temperature (20~25℃), wash the filtrate 4 times with 50ml each time, take the organic phase and dry it with anhydrous sodium sulfate overnight , Filter, and use a rotary evaporator to distill off the...

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Abstract

The invention discloses a novel preparation method of a hydrobromic acid Vortioxetine beta crystalline form. The novel preparation method comprises the steps of firstly synthesizing 2-(2,4-dimethyl-phenylsulfanyl)chlorobenzene from 2-chlorobenzenethiol and 2,4-dimethylphenol, adding bi(dibenzylidene acetone)palladium, 1,1'-binaphthyl-2,2'-bisdiphenylphosphino, sodium tert-butoxide and toluene into a reaction bottle, mixing, adding other substances to prepare Vortioxetine, dissolving prepared Vortioxetine by virtue of ethyl acetate with the weight of 14-16 times of that of Vortioxetine to obtain rough hydrobromic acid Vortioxetine, and finally purifying rough hydrobromic acid Vortioxetine to obtain finished hydrobromic acid Vortioxetine. The preparation method has the beneficial effects that the raw materials are easily available, process reaction conditions are mild, a product is high in yield and purity, and industrial production is easily realized; prepared hydrobromic acid Vortioxetine is white crystalline powder, and the purity is more than 99.5%.

Description

Technical field [0001] The invention relates to the field of drug synthesis, in particular to a new method for preparing vortioxetine hydrobromide β crystal form. Background technique [0002] Vortioxetine is a new type of antidepressant drug developed by Danish Lingbei Pharmaceutical Company and Japanese Takeda Pharmaceutical Company. It was approved by the U.S. Food and Drug Administration (FDA) in September 2013 for the treatment of adult major depression. The structural formula of Tioxetine is as follows: [0003] [0004] There are few synthetic methods for vortioxetine in the prior art. At present, the prior art has a long process route, cumbersome operation, long reaction time in some processes, high reaction conditions, and the use of solvents is more toxic, which is not conducive to industrial production; In the "one-pot cooking" method, there are many by-products generated by side reactions in the reaction process, the product purity is low, and the later purification is...

Claims

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Application Information

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IPC IPC(8): C07D295/096
CPCC07D295/096
Inventor 李沁沁王艳侨娄丽丽朱赞梅陈朋卫
Owner 郑州大明药物科技有限公司
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