CN104974110A - New crystal form of 1-[2-(2,4-dimethylphenylsulfenyl)phenyl]piperazine hydrobromide, preparation method and application thereof - Google Patents
New crystal form of 1-[2-(2,4-dimethylphenylsulfenyl)phenyl]piperazine hydrobromide, preparation method and application thereof Download PDFInfo
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- CN104974110A CN104974110A CN201410143889.9A CN201410143889A CN104974110A CN 104974110 A CN104974110 A CN 104974110A CN 201410143889 A CN201410143889 A CN 201410143889A CN 104974110 A CN104974110 A CN 104974110A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
The invention discloses a new crystal form of 1-[2-(2,4-dimethylphenylsulfenyl)phenyl]piperazine hydrobromide, a preparation method and an application thereof. In particularly, the invention relates to the new crystal form, which is represented as the formula (1), of the 1-[2-(2,4-dimethylphenylsulfenyl)phenyl]piperazine hydrobromide and the preparation method thereof. The preparation method includes following steps: (1) heating and dissolving 1-[2-(2,4-dimethylphenylsulfenyl)phenyl]piperazine in any form in an organic solvent; (2) cooling the 1-[2-(2,4-dimethylphenylsulfenyl)phenyl]piperazine solution, adding hydrogen bromide dropwisely to carry out crystallization; and (3) filtering the crystal to obtain the crystal form A. The invention also relates to the application of a drug composition containing the crystal form of the compound in treatment effective dose, and the crystal form and the drug composition in preparation of a medicine for treating cognitive impairment and depression. The new crystal form A is excellent in crystallinity, is simple in preparation method, is stable in physical and chemical properties and is suitable for various preparations.
Description
Technical field
The present invention relates to a kind of new crystal of 1-[2-(2,4-3,5-dimethylphenyl sulfenyl) phenyl] piperazine hydrobromide and preparation method thereof, and the pharmaceutical composition of this compound containing treatment significant quantity.
Background technology
Fertile for Xi Ting (Vortioxetine, Brintellix), chemical name 1-[2-(2,4-3,5-dimethylphenyl sulfenyl) phenyl] piperazine HBr salt (I).Possess following structure:
On September 30th, 2013, FDA (Food and Drug Adminstration) (FDA) ratifies Brintellix (fertile for Xi Ting, Vortioxetine) and is used for the treatment of major depressive disorder adult patient.Brintellix's is granted, is the efficacy and saferry data based on treating major depressive disorder in a comprehensive clinical development project.This project is made up of 7 key researchs, comprise the short-term research that 6 schedule to last 6-8 week, and 1 schedules to last studying for a long period of time of 24-64 week, these results of study show, Brintellix has the remarkable improvement of statistical significance to the overall depressive symptom of major depressive disorder adult patient.Before this, world-leading pharmacy and health care problem are studied and consulting firm---and Decision Resource company (Decision Resources) issues address prediction, by 2022, one-tenth was attached most importance to a pound medicine by Brintellix in the U.S., Japan, the large principal market (France, Germany, Italy, Spain, Britain) of European Union five.According to the data obtained so far, in view of it is on the positive impact of cognition and the side effect attribute that can tolerate, Brintellix estimates to become the most successful new drug in unipolar depression market.The Yuan Yan company of this medicine is Ling Bei (Lundbeck) and military field (Takeda).
Relevant crystal formation patent is that CN101472906B, 2027.6.15 expire, and protects the beta crystal of this compound and this crystal form samples of certain grain size distribution.
Summary of the invention
The object of the present invention is to provide the new crystal of 1-[2-(2,4-3,5-dimethylphenyl sulfenyl) phenyl] piperazine hydrobromide, i.e. crystal form A.
Comprising 2 θ ± 0.2 ° in the XRD figure spectrum of described crystal form A is: 4.18,14.60,17.54,19.14, the diffraction peak of 21.70,22.57.
Preferably, comprising 2 θ ± 0.2 ° in the XRD figure spectrum of described crystal form A is: 4.18,14.60,16.84,17.54,18.67,19.14, the diffraction peak of 21.70,22.57.
Preferred, comprising 2 θ ± 0.2 ° in the XRD figure spectrum of described crystal form A is: 4.18,11.98,12.56,14.02,14.60,14.72,16.55,16.84,17.54,18.66,19.14,20.27,20.70,21.70,22.20,22.57,24.31,25.10,25.62,27.56,28.34,28.74, the diffraction peak of 29.40,31.06.
Particularly preferred, the XRD figure spectrum of described crystal form A as shown in Figure 1.
Another object of the present invention is to provide 1-[2-(2,4-3,5-dimethylphenyl sulfenyl) phenyl] preparation method of piperazine hydrobromide crystal form A, described preparation method comprises: by the 1-[2-(2 of arbitrary form, 4-3,5-dimethylphenyl sulfenyl) phenyl] piperazine heating condition under dissolve in organic solvent, and then instilling hydrogen bromide solution to crystallization, filtration drying obtains crystal form A.
Preferably, described organic solvent refers to ether solvent, includes but not limited to ether, isopropyl ether, methyl tertiary butyl ether and/or tetrahydrofuran (THF), more preferably methyl tertiary butyl ether.
Preferably, described hydrogen bromide solution refers to and is dissolved in certain solvent by bromize hydrogen gas, comprises inorganic solvent, such as water, or organic solvent, such as ether solvent, alcoholic solvent and esters solvent etc.
Preferably, heating for dissolving temperature is generally 30 DEG C to reflux temperature, preferred reflux temperature; The preferred room temperature to 60 DEG C of recrystallization temperature, more preferably 20 DEG C-30 DEG C, most preferably 20 DEG C.
Preferably, the amount of substance of hydrogen bromide should be 0.1 ~ 1.5 times of the amount of substance of 1-shown in formula (I) [2-(2,4-3,5-dimethylphenyl sulfenyl) phenyl] piperazine, preferably 0.5 ~ 1.0 times.
Another object of the present invention is to provide the pharmaceutical composition containing 1-[2-(2,4-3,5-dimethylphenyl sulfenyl) phenyl] piperazine hydrobromide crystal form A.
The present invention also aims to provide crystal form A containing 1-[2-(2,4-3,5-dimethylphenyl sulfenyl) phenyl] piperazine hydrobromide as the pharmaceutical composition of active ingredient and pharmaceutical carrier, thinner or vehicle and other optional treatment component.
Composition of the present invention is suitable for the route of administration such as oral or injection, preferred oral route of administration.Formulation comprises tablet, capsule, dispersion agent and suspensoid.
Another object of the present invention is to provide described 1-[2-(2,4-3,5-dimethylphenyl sulfenyl) phenyl] application of piperazine hydrobromide crystal form A in preparation treatment cognitive disorders or dysthymia disorders.
1-of the present invention [2-(2,4-3,5-dimethylphenyl sulfenyl) phenyl] piperazine hydrobromide crystal form A detects through X-ray diffraction, uses Cu-Ka radiation, confirms that its crystallinity is good.And the fusing point being shown this crystal formation by DSC collection of illustrative plates is about 214 DEG C, the crystal that TGA collection of illustrative plates shows this crystal formation is pure, not containing recrystallisation solvent.The preparation technology of this crystal formation is simple, and crystal formation physicochemical property are stablized, and are applicable to various forms preparation.
Accompanying drawing explanation
Fig. 1 is the XRD figure spectrum of embodiment 1 gained 1-[2-(2,4-3,5-dimethylphenyl sulfenyl) phenyl] piperazine hydrobromide crystal form A;
Fig. 2 is the DSC collection of illustrative plates of embodiment 1 gained 1-[2-(2,4-3,5-dimethylphenyl sulfenyl) phenyl] piperazine hydrobromide crystal form A;
Fig. 3 is the TGA collection of illustrative plates of embodiment 1 gained 1-[2-(2,4-3,5-dimethylphenyl sulfenyl) phenyl] piperazine hydrobromide crystal form A.
Embodiment
Embodiment one:
By 1-[2-(2,4-3,5-dimethylphenyl sulfenyl) phenyl] piperazine 2.0g and methyl tertiary butyl ether 30.0ml is placed in reaction flask, be heated to backflow, solid is dissolved completely, under the condition stirred, naturally cool to 45 DEG C, filtered while hot, slowly drip the hydrogen bromide ethanol 3.4ml solution of 1.58mol/L under room temperature to filtrate, agitation and filtration solid obtains crystal form A, and its XRD figure spectrum as shown in Figure 1, as shown in Figure 2, its TGA collection of illustrative plates as shown in Figure 3 for its DSC collection of illustrative plates.
Embodiment two:
By 1-[2-(2,4-3,5-dimethylphenyl sulfenyl) phenyl] piperazine 2.0g and methyl tertiary butyl ether 30.0ml is placed in reaction flask, be heated to backflow, solid is dissolved completely, under the condition stirred, naturally cool to 45 DEG C, filtered while hot, slowly drip the aqueous solution of hydrogen bromide 0.6ml of 6.5mol/L under room temperature to filtrate, agitation and filtration solid obtains crystal form A, after testing, its XRD figure spectrum is substantially identical with Fig. 1, meets characteristic form A.
Embodiment three:
By 1-[2-(2,4-3,5-dimethylphenyl sulfenyl) phenyl] piperazine 2.0g and methyl tertiary butyl ether 30.0ml is placed in reaction flask, be heated to backflow, solid is dissolved completely, under the condition stirred, naturally cool to 45 DEG C, filtered while hot, slowly drip the hydrogen bromide ethyl acetate solution 0.4ml of 3.5mol/L under room temperature to filtrate, agitation and filtration solid obtains crystal form A, after testing, its XRD figure spectrum is substantially identical with Fig. 1, meets characteristic form A.
Embodiment four:
By 1-[2-(2,4-3,5-dimethylphenyl sulfenyl) phenyl] piperazine 3.0g and methyl tertiary butyl ether 100ml is placed in reaction flask, backflow is put in heating, solid is dissolved completely, naturally cools to 45 DEG C under agitation, filtered while hot, slowly drip the t-butyl methyl ether solution 82ml of 0.12mol/L hydrogen bromide under room temperature to filtrate, stir solids obtains crystal form A, after testing, its XRD figure spectrum is substantially identical with Fig. 1, meets characteristic form A.
Embodiment five:
By 1-[2-(2,4-3,5-dimethylphenyl sulfenyl) phenyl] piperazine 3.0g and ether 85ml is placed in reaction flask, backflow is put in heating, solid is dissolved completely, naturally cools to 25 DEG C under agitation, filter, slowly drip the diethyl ether solution 5.8ml of 1.9mol/L hydrogen bromide under room temperature to filtrate, stir solids obtains crystal form A, after testing, its XRD figure spectrum is substantially identical with Fig. 1, meets characteristic form A.
Embodiment six:
By 1-[2-(2,4-3,5-dimethylphenyl sulfenyl) phenyl] piperazine 3.0g and isopropyl ether 65ml is placed in reaction flask, backflow is put in heating, solid is dissolved completely, naturally cools to 35 DEG C under agitation, filtered while hot, slowly drip the hydrogen bromide isopropyl ether solution 6.7ml of 1.5mol/L under room temperature to filtrate, stir solids obtains crystal form A, after testing, its XRD figure spectrum is substantially identical with Fig. 1, meets characteristic form A.
Embodiment seven:
By 1-[2-(2,4-3,5-dimethylphenyl sulfenyl) phenyl] piperazine 2.0g and tetrahydrofuran (THF) 55ml is placed in reaction flask, backflow is put in heating, solid is dissolved completely, naturally cools to 45 DEG C under agitation, filtered while hot, slowly drip the hydrogen bromide tetrahydrofuran solution 3.0ml of 2.1mol/L under room temperature to filtrate, stir solids obtains crystal form A, after testing, its XRD figure spectrum is substantially identical with Fig. 1, meets characteristic form A.
Experimental example one: stable crystal form Journal of Sex Research
By the 1-[2-(2 of the embodiment of the present invention one gained, 4-3,5-dimethylphenyl sulfenyl) phenyl] crystal form A of piperazine hydrobromide, at high temperature (60 DEG C), under the condition of high humidity (RH92.5%) and illumination, place and within 10 days, do not turn brilliant and degraded, this demonstrate that crystal form A excellent in stability, concrete detection data are as follows:
In addition, through grinding, sieving, water wet heat treatment, ethanol wet heat treatment and tableting processes, crystal form A of the present invention does not change, and shows that crystal form A has excellent preparation processing.
Claims (12)
1. the crystal form A of 1-shown in formula (I) [2-(2,4-3,5-dimethylphenyl sulfenyl) phenyl] piperazine hydrobromide,
It is characterized in that, at least comprising 2 θ ± 0.2 ° in described crystal form X RD collection of illustrative plates is: 4.18,14.60,17.54,19.14, the diffraction peak of 21.70,22.57.
2. 1-[2-(2 shown in formula according to claim 1 (I), 4-3,5-dimethylphenyl sulfenyl) phenyl] crystal form A of piperazine hydrobromide, it is characterized in that, comprising 2 θ ± 0.2 ° in the XRD figure spectrum of described crystal form A is: 4.18,14.60,16.84,17.54,18.67,19.14, the diffraction peak of 21.70,22.57.
3. 1-[2-(2 shown in formula according to claim 1 (I), 4-3,5-dimethylphenyl sulfenyl) phenyl] crystal form A of piperazine hydrobromide, it is characterized in that, comprising 2 θ ± 0.2 ° in the XRD figure spectrum of described crystal form A is: 4.18, 11.98, 12.56, 14.02, 14.60, 14.72, 16.55, 16.84, 17.54, 18.66, 19.14, 20.27, 20.70, 21.70, 22.20, 22.57, 24.31, 25.10, 25.62, 27.56, 28.34, 28.74, 29.40, 31.06 diffraction peak, preferably, the diffraction peak of described crystal form A as shown in Figure 1.
4. the preparation method of the crystal form A of 1-shown in the formula (I) according to claim 1-3 any one [2-(2,4-3,5-dimethylphenyl sulfenyl) phenyl] piperazine bromate, comprises the steps:
1) by the 1-of any form [2-(2,4-3,5-dimethylphenyl sulfenyl) phenyl] piperazine heating for dissolving in organic solvent;
2) by the cooling of the lysate of 1-[2-(2,4-3,5-dimethylphenyl sulfenyl) phenyl] piperazine, hydrogen bromide solution crystallization is dripped;
3) filtering crystals obtains crystal form A.
5. preparation method according to claim 4, is characterized in that, the organic solvent in described step 1) is ether solvent, and preferably, described ether solvent is selected from ether, methyl tertiary butyl ether, isopropyl ether or tetrahydrofuran (THF), more preferably methyl tertiary butyl ether.
6. preparation method according to claim 4, is characterized in that, described step 2) in hydrogen bromide solution be the water of hydrogen bromide, ethanol, ethyl acetate, methyl tertiary butyl ether, isopropyl ether or tetrahydrofuran solution.
7. preparation method according to claim 4, is characterized in that, the amount of substance of hydrogen bromide should be 0.1 ~ 1.5 times of the amount of substance of 1-shown in formula (I) [2-(2,4-3,5-dimethylphenyl sulfenyl) phenyl] piperazine, preferably 0.5 ~ 1.0 times.
8. preparation method according to claim 4, is characterized in that, the temperature of described heating for dissolving is generally 30 DEG C to reflux temperature, preferred reflux temperature; Described step 2) crystallization time temperature preferred room temperature to 60 DEG C, more preferably 20 DEG C-30 DEG C, most preferably 20 DEG C.
9. the crystal form A of 1-shown in the formula (I) comprising described in claim 1-3 any one [2-(2,4-3,5-dimethylphenyl sulfenyl) phenyl] piperazine hydrobromide, and be mixed with the composition of one or more pharmaceutical excipients.
10. composition according to claim 9, is characterized in that, described composition is suitable for oral or drug administration by injection.
11. compositions according to claim 9, is characterized in that, described composition makes tablet, capsule, dispersion agent or suspensoid.
The crystal form A of 1-shown in 12. 1 kinds of formulas (I) according to claim 1-3 any one [2-(2,4-3,5-dimethylphenyl sulfenyl) phenyl] piperazine hydrobromide is for the preparation of the application in treatment cognitive impairment or antidepressant agents.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410143889.9A CN104974110A (en) | 2014-04-10 | 2014-04-10 | New crystal form of 1-[2-(2,4-dimethylphenylsulfenyl)phenyl]piperazine hydrobromide, preparation method and application thereof |
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| CN201410143889.9A CN104974110A (en) | 2014-04-10 | 2014-04-10 | New crystal form of 1-[2-(2,4-dimethylphenylsulfenyl)phenyl]piperazine hydrobromide, preparation method and application thereof |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007144005A1 (en) * | 2006-06-16 | 2007-12-21 | H. Lundbeck A/S | 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 |
| WO2013102573A1 (en) * | 2012-01-03 | 2013-07-11 | H. Lundbeck A/S | Process for the manufacture of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine |
| WO2014044721A1 (en) * | 2012-09-19 | 2014-03-27 | Sandoz Ag | Novel crystalline form of vortioxetine hydrobromide |
-
2014
- 2014-04-10 CN CN201410143889.9A patent/CN104974110A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007144005A1 (en) * | 2006-06-16 | 2007-12-21 | H. Lundbeck A/S | 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 |
| WO2013102573A1 (en) * | 2012-01-03 | 2013-07-11 | H. Lundbeck A/S | Process for the manufacture of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine |
| WO2014044721A1 (en) * | 2012-09-19 | 2014-03-27 | Sandoz Ag | Novel crystalline form of vortioxetine hydrobromide |
Non-Patent Citations (1)
| Title |
|---|
| BENNY BANG-ANDERSEN ET AL: "Discovery of 1-[2-(2,4-Dimethylphenylsulfanyl)phenyl]piperazine (LuAA21004): A Novel Multimodal Compound for the Treatment of Major Depressive Disorder", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
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Address after: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Applicant after: JIANGSU HANSOH PHARMACEUTICAL Co.,Ltd. Applicant after: Lianyungang Hongchuang Pharmaceutical Co.,Ltd. Address before: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Applicant before: JIANGSU HANSOH PHARMACEUTICAL Co.,Ltd. Applicant before: JIANGSU HANSOH PHARMACEUTICAL GROUP LIANYUNGANG HONGCHUANG PHARMACEUTICAL Co.,Ltd. |
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Address after: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Applicant after: JIANGSU HANSOH PHARMACEUTICAL GROUP Co.,Ltd. Applicant after: Lianyungang Hongchuang Pharmaceutical Co.,Ltd. Address before: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Applicant before: Jiangsu best Pharmaceutical Co.,Ltd. Applicant before: Lianyungang Hongchuang Pharmaceutical Co.,Ltd. Address after: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Applicant after: Jiangsu best Pharmaceutical Co.,Ltd. Applicant after: Lianyungang Hongchuang Pharmaceutical Co.,Ltd. Address before: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Applicant before: JIANGSU HANSOH PHARMACEUTICAL Co.,Ltd. Applicant before: Lianyungang Hongchuang Pharmaceutical Co.,Ltd. |
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Effective date of registration: 20160315 Address after: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Applicant after: JIANGSU HANSOH PHARMACEUTICAL GROUP Co.,Ltd. Address before: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Applicant before: JIANGSU HANSOH PHARMACEUTICAL GROUP Co.,Ltd. Applicant before: Lianyungang Hongchuang Pharmaceutical Co.,Ltd. |
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