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A kind of preparation method of vortioxetine hydrobromide crystal

A technology of vortioxetine hydrobromide and vortioxetine, which is applied in the field of medicine and can solve the problems of great harm to the human body and cumbersome operation

Active Publication Date: 2017-03-08
YANGTZE RIVER PHARM GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Chinese patent CN104119298A discloses a crystal form B of vortioxetine hydrobromide. The solvents used in the preparation method of this crystal form are mainly second-class solvents such as toluene and xylene, which are harmful to the human body.
[0007] Chinese patent CN104447622A discloses the preparation method of vortioxetine hydrobromide β crystal form, which needs to be salted under nitrogen condition, and then recrystallized, and the operation is relatively cumbersome

Method used

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  • A kind of preparation method of vortioxetine hydrobromide crystal
  • A kind of preparation method of vortioxetine hydrobromide crystal
  • A kind of preparation method of vortioxetine hydrobromide crystal

Examples

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Embodiment 1

[0039] Embodiment 1 Preparation of vortioxetine hydrobromide crystal

[0040] Dissolve 10 g of vortioxetine free base in 350 ml of ethyl acetate, stir to dissolve at 20°C and then filter, the temperature of the filtrate is controlled at 0°C. Measure 7g of hydrobromic acid (converted to 42.3% actual content), add 50ml of ethyl acetate, and mix well. Add the prepared hydrobromic acid solution dropwise to the free alkali solution at a constant speed, control the temperature at 0°C, and continue stirring at 0°C for 8 hours after the addition. Filter to obtain a filter cake 1, which was rinsed three times with ethyl acetate (10 ml each time), then stirred and washed in 50 ml of ethyl acetate at 0° C. for 2 hours. Filtrate again to obtain filter cake 2, which was rinsed three times with a mixed solution of methyl tert-butyl ether / ethyl acetate (v / v=9 / 1) precooled at 0° C., 10 ml each time. The filter cake was stirred in 200ml of methyl tert-butyl ether at 10°C for 15 hours. Then,...

Embodiment 2

[0041] Embodiment 2 Preparation of vortioxetine hydrobromide crystal

[0042] Dissolve 10 g of vortioxetine free base in 360 ml of ethyl acetate, stir to dissolve at 25°C and filter, and control the temperature of the filtrate at 5°C. Measure 6.4g of hydrogen bromide (converted to 42.3% actual content), add 40ml of ethyl acetate, and mix well. Add the prepared hydrobromic acid solution dropwise to the free alkali solution at a constant speed, control the temperature at 5°C, and continue stirring at 5°C for 4 hours after the addition. Filter to obtain filter cake 1, which was rinsed three times with ethyl acetate (15 ml each time), and then stirred and washed in 60 ml of ethyl acetate at 5°C for 1 hour. Filtrate again to obtain filter cake 2, and filter cake 2 is rinsed 3 times with a mixed solution of methyl tert-butyl ether / ethyl acetate (v / v=10 / 1) that has been pre-cooled at 5°C, each 15ml . The filter cake was stirred in 300 ml of methyl tert-butyl ether at 20° C. for 19...

Embodiment 3

[0043] Embodiment 3 Preparation of vortioxetine hydrobromide crystal

[0044] Dissolve 10 g of vortioxetine free base in 380 ml of ethyl acetate, stir to dissolve at 30°C and then filter, the temperature of the filtrate is controlled at 10°C. Measure 7.7g of hydrobromic acid (converted to 42.3% actual content), add 60ml of ethyl acetate, and mix well. Add the prepared hydrobromic acid solution dropwise to the free alkali solution at a constant speed, control the temperature at 10°C, and continue stirring at 10°C for 2 hours after the addition. Filter to obtain filter cake 1, which was rinsed three times with ethyl acetate (20 ml each time), and then stirred and washed in 45 ml of ethyl acetate at 10° C. for 0.5 hours. Filtrate again to obtain filter cake 2, which was rinsed three times with a mixed solution of methyl tert-butyl ether / ethyl acetate (v / v=12 / 1) precooled at 5° C., 20 ml each time. The filter cake was stirred in 350 ml of methyl tert-butyl ether (MTBE) at 30° C....

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Abstract

The invention discloses a vortioxetine hydrobromide crystal preparation method. The method comprises a, dissolving vortioxetine free alkali in ethyl acetate at a temperature of 20-30 DEG C, b, carrying out filtration, cooling the filtrate to a temperature of 0-10 DEG C, dropwisely adding an ethyl acetate solution of hydrobromic acid into the filtrate along with thermal insulation and then carrying out thermal insulation stirring for 2-8h, c, filtering the mixture subjected to thermal insulation stirring in the step b to obtain filter cake 1, leaching the filter cake 1 by ethyl acetate, and carrying out stirring washing in ethyl acetate at a temperature of 0-10 DEG C for 0.5-5h, d, filtering the mixture subjected to stirring washing in the step c to obtain filter cake 2, leaching the filter cake 2 by methyl tert-butyl ether / ethyl acetate pre-cooled at a temperature of 0-10 DEG C and carrying out stirring washing in methyl tert-butyl ether at a temperature of 10-30 DEG C for 15-24h, and e, filtering the mixture subjected to stirring washing in the step d to obtain filter cake 3, leaching the filter cake 3 by methyl tert-butyl ether and carrying out vacuum drying at a temperature of 40-50 DEG C to obtain the product. The method has the advantages of good repeatability, simple processes, a high yield and high product purity and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a preparation method of vortioxetine hydrobromide crystals. Background technique [0002] Vortioxetine Hydrobromide (Vortioxetine Hydrobromide), the chemical name is 1-[2-[(2,4-dimethylphenyl) mercapto] phenyl] piperazine hydrobromide, and its chemical structure is as follows: [0003] [0004] Vortioxetine hydrobromide is an inhibitor of serotonin transporter and regulates the activity of its receptors. It was jointly developed by Lundbeck and Takeda, and was approved by the US FDA in September 2013. The trade name is Brintellix, which is clinically used to treat major depressive disorder and generalized anxiety disorder. [0005] Chinese patent CN101472906A discloses four crystal forms of vortioxetine hydrobromide α, β, γ, and hemihydrate and their stability, and also discloses their preparation methods. [0006] Chinese patent CN104119298A discloses a crystal...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D295/096
CPCC07B2200/13C07D295/096
Inventor 袁峰泉赵佳陈杨杨陈令武金荣庆尹必喜杨婷婷蔡明君韦洪霞
Owner YANGTZE RIVER PHARM GRP CO LTD
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