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Hydrobromic acid vortioxetine crystal and preparation method therefor

A technology of vortioxetine hydrobromide and crystals, which is applied in the field of medicine and can solve the problems of cumbersome operation and serious human injury

Active Publication Date: 2015-11-04
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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  • Hydrobromic acid vortioxetine crystal and preparation method therefor
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  • Hydrobromic acid vortioxetine crystal and preparation method therefor

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Embodiment 1

[0035] The preparation of embodiment 1 vortioxetine hydrobromide crystal

[0036] Dissolve 10 g of vortioxetine free base in 300 ml of ethyl acetate, stir and dissolve at 15°C, and then filter, and control the temperature of the filtrate at 0°C. Measure 7g of hydrobromic acid (converted based on the actual content of the 42.3% by weight aqueous solution), and add it dropwise to the free alkali solution at a constant speed, and control the temperature at 0°C. After the addition, continue stirring at 0°C for 8 hours. After filtering, the filter cake 1 was rinsed with ethyl acetate and stirred in 50 ml of ethyl acetate for 4 hours at 0°C. Filtration, filter cake 2 was vacuum-dried at 30°C to obtain 11.6 g of off-white solid, with a molar yield of 91%, and a chromatographic purity of 99.91%. The XRPD and IR figures are shown in figure 1 , figure 2 .

Embodiment 2

[0037] The preparation of embodiment 2 vortioxetine hydrobromide crystals

[0038] Dissolve 10 g of vortioxetine free base in 350 ml of ethyl acetate, stir to dissolve at 25°C and then filter, and control the temperature of the filtrate at 5°C. Measure 6.4g of hydrobromic acid (calculated based on the actual content of the 42.3% by weight aqueous solution), and add it dropwise to the free alkali solution at a constant speed, and control the temperature at 5°C. After the addition, continue stirring at 5°C for 6 hours. After filtering, the filter cake 1 was rinsed with an appropriate amount of ethyl acetate and then stirred and washed in 70 ml of ethyl acetate for 5 hours at 5°C. Filtration, filter cake 2 was vacuum-dried at 40° C. to obtain 11.8 g of an off-white solid, with a molar yield of 93%, and a chromatographic purity of 99.90%. figure 1 , figure 2 unanimous.

Embodiment 3

[0039] The preparation of embodiment 3 vortioxetine hydrobromide crystals

[0040] Dissolve 10 g of vortioxetine free base in 400 ml of ethyl acetate, stir and dissolve at 30°C, and then filter, and control the temperature of the filtrate at 15°C. Measure 7.7g of hydrobromic acid (calculated based on the actual content of the 42.3% by weight aqueous solution), and add it dropwise to the free alkali solution at a constant speed, with the temperature controlled at 15°C. After the addition, continue stirring at 15°C for 8 hours. After filtering, the filter cake 1 was rinsed with an appropriate amount of ethyl acetate and stirred in 90 ml of ethyl acetate for 6 hours at 15°C. Filtration, filter cake 2 was vacuum-dried at 50° C. to obtain 12.1 g of an off-white solid, with a molar yield of 95%, and a chromatographic purity of 99.92%. figure 1 , figure 2 unanimous.

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Abstract

The present invention discloses a hydrobromic acid vortioxetine crystal that has diffraction peaks at 8.55+ / -0.2, 13.05+ / -0.2, 13.44+ / -0.2, 14.46+ / -0.2, 15.20+ / -0.2, 16.63+ / -0.2, 16.94+ / -0.2, 17.22+ / -0.2, 17.85+ / -0.2, 19.83+ / -0.2, 20.43+ / -0.2, 21.33+ / -0.2, 23.14+ / -0.2, 23.60+ / -0.2, 24.77+ / -0.2, 26.25+ / -0.2, 26.72+ / -0.2, 26.96+ / -0.2, 29.69+ / -0.2, 30.52+ / -0.2, 33.33+ / -0.2, 33.89+ / -0.2, 34.89+ / -0.2, 35.54+ / -0.2, 37.03+ / -0.2, and 38.33+ / -0.2 in a powder X-ray diffraction diagram represented with 2 theta. In addition, the present invention further discloses a preparation method for the crystal. The hydrobromic acid vortioxetine crystal and the preparation method therefor in the present invention have good repeatability, easy operation, good product stability, and high yield and purity, and are suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a vortioxetine hydrobromide crystal and a preparation method thereof. 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...

Claims

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Application Information

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IPC IPC(8): C07D295/096
CPCC07B2200/13C07D295/096
Inventor 袁峰泉赵佳杨婷婷陈令武金荣庆
Owner YANGTZE RIVER PHARM GRP CO LTD
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