CN105198837B - A kind of Vortioxetine hydrobromic acid salt and preparation method thereof - Google Patents
A kind of Vortioxetine hydrobromic acid salt and preparation method thereof Download PDFInfo
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- CN105198837B CN105198837B CN201410253970.2A CN201410253970A CN105198837B CN 105198837 B CN105198837 B CN 105198837B CN 201410253970 A CN201410253970 A CN 201410253970A CN 105198837 B CN105198837 B CN 105198837B
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Abstract
The invention discloses a kind of Vortioxetine hydrobromic acid salt and preparation method thereof.The Vortioxetine hydrobromic acid salt has characteristic peak in the powder X-ray x ray diffraction collection of illustrative plates for the use of radiation source being Cu K α at 2 θ=4.5 ± 0.2 of the angle of diffraction, 9.1 ± 0.2,11.8 ± 0.2,15.9 ± 0.2,17.1 ± 0.2,18.7 ± 0.2,23.4 ± 0.2,25.4 ± 0.2 degree.The purity of the Vortioxetine hydrobromic acid salt of the present invention is high, preparation method is easy, and favorable reproducibility.
Description
Technical field
The present invention relates to drug field, and in particular to a kind of Vortioxetine hydrobromic acid salt and preparation method thereof.
Background technology
Vortioxetine (Vortioxetine), entitled 1- [2- (2, the 4- dimethylphenylsulfanyl) phenyl] piperazine of chemistry,
Shown in chemical constitution such as following formula (I), trade name
Vortioxetine is a kind of multi-mode antidepressant, is 5-HT reuptaking inhibitors, while be 5-HT3、5-HT7、5-
HT1DAntagonist, the 5-HT of acceptor1BPartial agonist, the 5-HT of acceptor1AReceptor stimulating agent, antidepression is played by adjusting 5-HT
Effect.Internal non-clinical study be proved its can increase neurotransmitters seratonin in brain specific region, norepinephrine,
The level of dopamine, acetylcholine and histamine.
Polymorphism is the critical nature of compound, for most chemicalses, is usually present polymorphism, no
Same crystal-form substances have important influence for the stability of medicine, homogeneity, bioavilability and preparation etc..Mirror
In the pharmacy value of Vortioxetine, it is very heavy to obtain the different crystal forms of purity height, convenient preparation and the compound of favorable reproducibility
Want.
Vortioxetine hydrobromate is the form of hydrobromide of Vortioxetine, shown in its chemical constitution such as following formula (II).
The crystal form situation of Vortioxetine hydrobromate has been reported which reports Vortioxetine in patent CN101472906B
Four kinds of crystal forms of α, β, γ, semihydrate of hydrobromate, wherein beta crystal are most stable.Vortioxetine hydrobromate crystal form situation exists
Also had been reported that in CN101636161A, its protect for beta crystal.
The content of the invention
The technical problems to be solved by the invention are the provision of a kind of Vortioxetine hydrobromic acid salt and its preparation side
Method.The Vortioxetine hydrobromic acid salt of the present invention is δ crystal forms, and the crystal form purity is high, preparation method is easy, and reappearance
It is good.
The present invention is to solve above-mentioned technical problem by the following technical programs：
The present invention provides a kind of Vortioxetine hydrobromic acid salt, the Vortioxetine hydrobromic acid salt is using
Radiation source be Cu-K α powder x-ray diffraction collection of illustrative plates in, 2 θ=4.5 ± 0.2 of the angle of diffraction, 9.1 ± 0.2,11.8 ± 0.2,
There is characteristic peak at 15.9 ± 0.2,17.1 ± 0.2,18.7 ± 0.2,23.4 ± 0.2,25.4 ± 0.2 degree.
Wherein, the relative intensity of the characteristic peak when angle of diffraction is 2 θ is as shown in the table：
Wherein, the secondary peaks and its intensity shown in following table are preferably further included in the X-ray diffracting spectrum：
Present invention also offers the preparation method of Vortioxetine hydrobromic acid salt as described above, it includes following step
Suddenly：Vortioxetine hydrobromate is dissolved in methanol aqueous solution, is concentrated under reduced pressure and is evaporated to obtain solid, by solid vacuum drying, i.e.,
Can.
Wherein, the Vortioxetine hydrobromate can be the disclosed various crystal form Vortioxetine hydrobromic acids in this area
Salt, including four kinds of α, β, γ, semihydrate crystal forms disclosed in patent CN101472906B documents.
Wherein, the percent by volume of the methanol aqueous solution is preferably 10%~50%, is more preferably 33.3%.
Wherein, the volume mass of the methanol aqueous solution and the Vortioxetine hydrobromate than preferably 3~
100ml/g, is more preferably 10ml/g.
Wherein, described be concentrated under reduced pressure can be the condition that is concentrated under reduced pressure commonly used in the art, described to be concentrated under reduced pressure
Temperature is preferably 20~40 DEG C, and the pressure being concentrated under reduced pressure is preferably 0.08~0.1MPa.
Wherein, the temperature of the vacuum drying is preferably 45~55 DEG C, is more preferably 50 DEG C.
On the basis of common knowledge of the art, above-mentioned each optimum condition, can be combined, each preferably real up to the present invention
Example.
The reagents and materials used in the present invention are commercially available.
The positive effect of the present invention is：The purity of the Vortioxetine hydrobromic acid salt of the present invention is high, preparation side
Method is easy, and favorable reproducibility.
Brief description of the drawings
Fig. 1 is the X-ray powder diffraction collection of Vortioxetine hydrobromic acid salt made from embodiment 1.
Fig. 2 is the X-ray powder diffraction collection of Vortioxetine hydrobromate beta crystal.
Embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to the reality
Apply among a scope.The experimental method of actual conditions is not specified in the following example, according to conventional methods and conditions, or according to business
Product specification selects.
Embodiment 1
It is 33.3% first by 1g Vortioxetines hydrobromate (compound as shown in formula (I)) addition 10ml percents by volume
During alcohol is water-soluble, 35 DEG C of decompressions (pressure 0.09MPa) are evaporated to dryness after heating dissolved clarification, and 50 DEG C of vacuum, which are dried, must do 0.95g crystal,
HPLC purity is 99.86%, and single impurity content ＜ 0.1%.
The crystal that the present embodiment is obtained carries out powder x-ray diffraction, and radiation source is Cu-K α, and X-ray diffracting spectrum is such as
Shown in Fig. 1, wherein each characteristic peak and intensity are shown in Table 1.
Table 1
Comparative example 1
It is 33.3% that 10ml percents by volume will be added in 1g Vortioxetines hydrobromate (compound as shown in formula (I))
In methanol aqueous solution, it is heated to stirring after flowing back and is cooled to 25 DEG C.Solid vacuum drying obtains 0.6g beta crystal solids after filtering.Its
X-ray diffracting spectrum is as shown in Figure 2.
Comparative example 2
10ml water will be added in 1g Vortioxetines hydrobromate (compound as shown in formula (I)), stirred after being heated to reflux
Mix and be cooled to 25 DEG C.Solid vacuum drying obtains 0.47g beta crystal solids after filtering.Its X-ray diffracting spectrum is as shown in Figure 2.
Claims (7)
1. a kind of preparation method of Vortioxetine hydrobromic acid salt, it comprises the following steps：Vortioxetine hydrobromate is molten
In methanol aqueous solution, it is concentrated under reduced pressure and is evaporated to obtain solid, by solid vacuum drying, you can；The volume of the methanol aqueous solution
Percentage is 10%~50%；The temperature being concentrated under reduced pressure is 20~40 DEG C, and the pressure being concentrated under reduced pressure is 0.08
~0.1Mpa；The Vortioxetine hydrobromic acid salt using radiation source be Cu-K α powder x-ray diffraction collection of illustrative plates in,
2 θ=4.5 ± 0.2 of the angle of diffraction, 9.1 ± 0.2,11.8 ± 0.2,15.9 ± 0.2,17.1 ± 0.2,18.7 ± 0.2,23.4 ±
0.2nd, there is characteristic peak at 25.4 ± 0.2 degree.
2. the preparation method of Vortioxetine hydrobromic acid salt as claimed in claim 1, it is characterised in that when the angle of diffraction is 2 θ
Characteristic peak relative intensity it is as shown in the table：
3. the preparation method of Vortioxetine hydrobromic acid salt as claimed in claim 1, it is characterised in that the X-ray
The secondary peaks and its intensity shown in following table are further included in diffracting spectrum：
4. such as preparation method according to any one of claims 1 to 3, it is characterised in that the volume of the methanol aqueous solution
Percentage is 33.3%；And/or the volume mass ratio of the methanol aqueous solution and the Vortioxetine hydrobromate is 3
~100ml/g.
5. preparation method as claimed in claim 4, it is characterised in that the methanol aqueous solution and the Vortioxetine hydrogen
The volume mass ratio of bromate is 10ml/g.
6. such as preparation method according to any one of claims 1 to 3, it is characterised in that the temperature of the vacuum drying is
45~55 DEG C.
7. preparation method as claimed in claim 6, it is characterised in that the temperature of the vacuum drying is 50 DEG C.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410253970.2A CN105198837B (en) | 2014-06-09 | 2014-06-09 | A kind of Vortioxetine hydrobromic acid salt and preparation method thereof |
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|---|---|---|---|
| CN201410253970.2A CN105198837B (en) | 2014-06-09 | 2014-06-09 | A kind of Vortioxetine hydrobromic acid salt and preparation method thereof |
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| CN105198837A CN105198837A (en) | 2015-12-30 |
| CN105198837B true CN105198837B (en) | 2018-05-04 |
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Families Citing this family (1)
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| CN105330614A (en) * | 2014-08-04 | 2016-02-17 | 上海诺星医药科技有限公司 | vortioxetine hydrobromide crystal and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101472906A (en) * | 2006-06-16 | 2009-07-01 | H.隆德贝克有限公司 | 1- [2- (2, 4-dimethylphenylsulfanyl) -phenyl] piperazine as a compound with combined serotonin reuptake, 5-HT3 and 5-HT1A activity for the treatment of cognitive impairment |
| CN101636161A (en) * | 2007-03-20 | 2010-01-27 | H.隆德贝克有限公司 | 1- [2-(2,4-dimethylphenylsulfanyl)-phenyl] piperazine as a compound with combined serotonin reuptake, 5-ht3 and 5-ht1a activity for the treatment of pain or residual symptoms in depression relating to |
-
2014
- 2014-06-09 CN CN201410253970.2A patent/CN105198837B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101472906A (en) * | 2006-06-16 | 2009-07-01 | H.隆德贝克有限公司 | 1- [2- (2, 4-dimethylphenylsulfanyl) -phenyl] piperazine as a compound with combined serotonin reuptake, 5-HT3 and 5-HT1A activity for the treatment of cognitive impairment |
| CN101636161A (en) * | 2007-03-20 | 2010-01-27 | H.隆德贝克有限公司 | 1- [2-(2,4-dimethylphenylsulfanyl)-phenyl] piperazine as a compound with combined serotonin reuptake, 5-ht3 and 5-ht1a activity for the treatment of pain or residual symptoms in depression relating to |
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