CN109438391A - A kind of preparation method of hydrobromic acid Vortioxetine impurity - Google Patents
A kind of preparation method of hydrobromic acid Vortioxetine impurity Download PDFInfo
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- CN109438391A CN109438391A CN201811416945.6A CN201811416945A CN109438391A CN 109438391 A CN109438391 A CN 109438391A CN 201811416945 A CN201811416945 A CN 201811416945A CN 109438391 A CN109438391 A CN 109438391A
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- piperazine
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- hydrobromic acid
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- iodobenzene
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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
- C07D295/06—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 halogen atoms or nitro radicals
- C07D295/073—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 halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention discloses a kind of preparation method of hydrobromic acid Vortioxetine impurity, include the following steps: that piperazine and adjacent bromo-iodobenzene carry out condensation reaction under acid binding agent, catalyst action；Wherein, when the molar ratio of piperazine and adjacent bromo-iodobenzene is 1:1-1.5, condensation reaction obtains 2- bromophenyl piperazine；When the molar ratio of piperazine and adjacent bromo-iodobenzene is 1:2-3, condensation reaction obtains Isosorbide-5-Nitrae-two (2- bromophenyl) piperazine.Synthetic route of the present invention is short, and raw material is cheap and easy to get, easy to operate, and reaction condition is mild, product purity height, high income.
Description
Technical field
The present invention relates to chemical substance preparation technical field more particularly to a kind of preparation sides of hydrobromic acid Vortioxetine impurity
Method.
Background technique
Hydrobromic acid Vortioxetine (Vortioxetine hydrobromide), entitled 1- [2- (2, the 4- dimethyl-benzene of chemistry
Sulfydryl)-phenyl]-piperazine hydrobromide, combined by Japanese Takede Chemical Industries Ltd and Lundbeck pharmaceutical Co. Ltd, Denmark
It develops, is listed in October, 2013 in Europe, for treating severe adult's depression.Its chemical structural formula is as follows:
Hydrobromic acid Vortioxetine is considered as a kind of novel multi-model antidepressant, and in vitro study shows that it has can
Antagonism 5-HT3,5-HT7 and 5-HT1D receptor, activates 5-HT1A receptor, and part activates 5-HT1B receptor and inhibits the transhipment of 5-HT
Function, be first antidepressant for having a variety of drug activities.
The key of hydrobromic acid Vortioxetine synthesis is the control of its impurity, therefore the impurity synthesis of hydrobromic acid Vortioxetine
Research is of great significance.2- bromophenyl piperazine (impurity I) and 1,4- bis- (2- bromophenyl) piperazine (impurity II) are that hydrobromic acid is fertile
Two kinds of impurity produced during the preparation process is produced for Xi Ting, structural formula is as follows:
Currently, it is less to synthesize report to it both at home and abroad.Therefore it provides a kind of hydrobromic acid Vortioxetine impurity of simple and effective
Synthetic method, research significance is great, can be used for hydrobromic acid Vortioxetine production in impurity quantification and quantitative analysis, from
And the quality standard of hydrobromic acid Vortioxetine can be improved, important directive significance is provided for people's masses'safety medication.
Summary of the invention
Technical problems based on background technology, the invention proposes a kind of preparation sides of hydrobromic acid Vortioxetine impurity
Method, synthetic route of the present invention is short, and raw material is cheap and easy to get, and easy to operate, reaction condition is mild, product purity height, high income.
A kind of preparation method of hydrobromic acid Vortioxetine impurity proposed by the present invention includes the following steps: piperazine and adjacent bromine
Iodobenzene carries out condensation reaction under acid binding agent, catalyst action；Wherein, when the molar ratio of piperazine and adjacent bromo-iodobenzene is 1:1-1.5,
Condensation reaction obtains 2- bromophenyl piperazine；When the molar ratio of piperazine and adjacent bromo-iodobenzene is 1:2-3, condensation reaction obtains Isosorbide-5-Nitrae-two
(2- bromophenyl) piperazine.
Preferably, condensation reaction carries out in nitrogen atmosphere.
Preferably, acid binding agent is one of triethylamine, sodium tert-butoxide, sodium hydroxide, potassium carbonate；Preferably, acid binding agent
For sodium tert-butoxide.
Preferably, catalyst is double (bis- Ya Benzyl benzylacetones) palladium.
Preferably, piperazine and adjacent bromo-iodobenzene are under acid binding agent, catalyst action, and reflux be condensed anti-in reaction dissolvent
It answers.
Preferably, after condensation reaction, through column chromatographic purifying.
Preferably, reaction dissolvent is at least one of toluene, dimethylbenzene, tetrahydrofuran, methylene chloride.
Preferably, reaction dissolvent is toluene.
Preferably, the column chromatographic flow of 2- bromophenyl piperazine is mutually methylene chloride and methanol mixed solution, wherein dichloromethane
The volume ratio of alkane and methanol is 20-30:1.
Preferably, the column chromatographic flow of Isosorbide-5-Nitrae-two (2- bromophenyl) piperazine is mutually petroleum ether and ethyl acetate mixture,
Wherein, the volume ratio of petroleum ether and ethyl acetate is 100-120:1.
Preferably, the time of condensation reaction is 5-8h.
Preferably, the molar ratio of piperazine and acid binding agent is 1:2-5.
Preferably, the molar ratio of piperazine and acid binding agent is 1:3-4.
Preferably, the molar ratio of piperazine and catalyst is 1:0.003-0.01.
Preferably, the bulking value (g/ml) of piperazine and reaction dissolvent is than being 1:15-25.
The concrete operation step of condensation reaction are as follows: piperazine, adjacent bromo-iodobenzene, acid binding agent, catalyst, reaction dissolvent are mixed,
It is passed through nitrogen, is flowed back, filtrate is washed in cooling filtering, and dry, concentration, column chromatographs to obtain hydrobromic acid Vortioxetine impurity.
Above-mentioned column chromatography is technological means commonly used in the art, the dosage of column chromatographic flow phase is not provided, according to concrete operations
Determine its dosage.
Synthetic route of the invention is short, and raw material is cheap and easy to get, and cost advantage is obvious；Operation of the present invention is simple, reaction condition
Mildly, it is suitble to industrialized production；And synthetic route of the present invention is short, the impurity of product is few, purity is high, and high income；It can be hydrogen
The research of the impurity of bromic acid Vortioxetine bulk pharmaceutical chemicals and preparation provides the reference substance of high-purity.
Detailed description of the invention
Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of 2- bromophenyl piperazine.
Fig. 2 is the mass spectrogram of 2- bromophenyl piperazine.
Fig. 3 is the hydrogen nuclear magnetic resonance spectrogram of 1,4- bis- (2- bromophenyl) piperazine.
Fig. 4 is the mass spectrogram of 1,4- bis- (2- bromophenyl) piperazine.
Specific embodiment
In the following, technical solution of the present invention is described in detail by specific embodiment.
Embodiment 1
By piperazine, adjacent bromo-iodobenzene, sodium tert-butoxide, double (bis- Ya Benzyl benzylacetones) palladium, toluene mixing, it is empty to be passed through nitrogen displacement
Gas, flow back 6.5h, and cooling filtering washs filtrate with sodium-chloride water solution, dry, is concentrated to dryness, then chromatograph to obtain 2- bromine through column
Phenylpiperazine, wherein the molar ratio of piperazine and adjacent bromo-iodobenzene is 1:1.5, piperazine, sodium tert-butoxide molar ratio be 1:3, piperazine,
Double (bis- Ya Benzyl benzylacetones) palladium molar ratio be 1:0.005, piperazine, toluene bulking value (g/ml) than be 1:20, column chromatography
Mobile phase is methylene chloride and methanol mixed solution, wherein the volume ratio of methylene chloride and methanol is 20:1；
The hydrogen nuclear magnetic resonance spectrogram of gained 2- bromophenyl piperazine, mass spectrogram are referring to Fig. 1, Fig. 2.
Embodiment 2
By piperazine, adjacent bromo-iodobenzene, sodium tert-butoxide, double (bis- Ya Benzyl benzylacetones) palladium, toluene mixing, it is empty to be passed through nitrogen displacement
Gas, flow back 6.5h, and cooling filtering washs filtrate with sodium-chloride water solution, dry, is concentrated to dryness, then chromatograph to obtain Isosorbide-5-Nitrae-through column
Two (2- bromophenyl) piperazines, wherein the molar ratio of piperazine and adjacent bromo-iodobenzene is 1:2, piperazine, sodium tert-butoxide molar ratio be 1:3,
Piperazine, double (bis- Ya Benzyl benzylacetones) palladium molar ratio be 1:0.005, piperazine, toluene bulking value (g/ml) than be 1:20, column
Chromatographic flow is mutually petroleum ether and ethyl acetate mixture, wherein the volume ratio of petroleum ether and ethyl acetate is 100:1；
The hydrogen nuclear magnetic resonance spectrogram of gained 1,4- bis- (2- bromophenyl) piperazine, mass spectrogram are referring to Fig. 3, Fig. 4.
Embodiment 3
By piperazine, adjacent bromo-iodobenzene, triethylamine, double (bis- Ya Benzyl benzylacetones) palladium, toluene mixing, it is passed through nitrogen displaced air,
Flow back 5h, and cooling filtering washs filtrate with sodium-chloride water solution, dry, is concentrated to dryness, then chromatograph to obtain 2- bromophenyl piperazine through column
Piperazine, wherein the molar ratio of piperazine and adjacent bromo-iodobenzene is 1:1, piperazine, triethylamine molar ratio be 1:5, piperazine, double (bis- Ya Benzyl bases
Acetone) palladium molar ratio be 1:0.003, piperazine, toluene bulking value (g/ml) than be 1:15, column chromatographic flow is mutually dichloro
Methane and methanol mixed solution, wherein the volume ratio of methylene chloride and methanol is 30:1.
Embodiment 4
By piperazine, adjacent bromo-iodobenzene, sodium hydroxide, double (bis- Ya Benzyl benzylacetones) palladium, methylene chloride mixing, it is passed through nitrogen displacement
Air, flow back 8h, and cooling filtering washs filtrate with sodium-chloride water solution, dry, is concentrated to dryness, then chromatograph to obtain 2- bromine through column
Phenylpiperazine, wherein the molar ratio of piperazine and adjacent bromo-iodobenzene is 1:1.3, piperazine, sodium hydroxide molar ratio be 1:2, piperazine,
Double (bis- Ya Benzyl benzylacetones) palladium molar ratio be 1:0.01, piperazine, methylene chloride bulking value (g/ml) than be 1:25, column layer
Analysing mobile phase is methylene chloride and methanol mixed solution, wherein the volume ratio of methylene chloride and methanol is 25:1.
Embodiment 5
By piperazine, adjacent bromo-iodobenzene, potassium carbonate, double (bis- Ya Benzyl benzylacetones) palladium, tetrahydrofuran mixing, it is empty to be passed through nitrogen displacement
Gas, flow back 7h, and cooling filtering washs filtrate with sodium-chloride water solution, dry, is concentrated to dryness, then chromatograph to obtain Isosorbide-5-Nitrae-two through column
(2- bromophenyl) piperazine, wherein the molar ratio of piperazine and adjacent bromo-iodobenzene is 1:3, piperazine, potassium carbonate molar ratio be 1:4, piperazine
Piperazine, double (bis- Ya Benzyl benzylacetones) palladium molar ratio be 1:0.009, piperazine, tetrahydrofuran bulking value (g/ml) than be 1:18,
Column chromatographic flow is mutually petroleum ether and ethyl acetate mixture, wherein the volume ratio of petroleum ether and ethyl acetate is 120:1.
Embodiment 6
By piperazine, adjacent bromo-iodobenzene, sodium tert-butoxide, double (bis- Ya Benzyl benzylacetones) palladium, dimethylbenzene mixing, it is empty to be passed through nitrogen displacement
Gas, flow back 6h, and cooling filtering washs filtrate with sodium-chloride water solution, dry, is concentrated to dryness, then chromatograph to obtain Isosorbide-5-Nitrae-two through column
(2- bromophenyl) piperazine, wherein the molar ratio of piperazine and adjacent bromo-iodobenzene is 1:2.5, piperazine, sodium tert-butoxide molar ratio be 1:
3.5, piperazine, double (bis- Ya Benzyl benzylacetones) molar ratio of palladium is 1:0.007, piperazine, dimethylbenzene bulking value (g/ml) ratio be
1:22, column chromatographic flow are mutually petroleum ether and ethyl acetate mixture, wherein the volume ratio of petroleum ether and ethyl acetate is
110:1.
The yield of Statistics Implementation example 1-6, and the purity of 2- bromophenyl piperazine, Isosorbide-5-Nitrae-two (2- bromophenyl) piperazine is detected, it ties
Fruit is as follows:
As can be seen from the above table, the purity of high income of the present invention, the hydrobromic acid Vortioxetine impurity being prepared is good.
The foregoing is only a preferred embodiment of the present invention, but scope of protection of the present invention is not limited thereto,
Anyone skilled in the art in the technical scope disclosed by the present invention, according to the technique and scheme of the present invention and its
Inventive concept is subject to equivalent substitution or change, should be covered by the protection scope of the present invention.
Claims (10)
1. a kind of preparation method of hydrobromic acid Vortioxetine impurity, which comprises the steps of: piperazine and adjacent bromo-iodobenzene
Condensation reaction is carried out under acid binding agent, catalyst action；Wherein, when the molar ratio of piperazine and adjacent bromo-iodobenzene is 1:1-1.5, condensation
Reaction obtains 2- bromophenyl piperazine；When the molar ratio of piperazine and adjacent bromo-iodobenzene is 1:2-3, condensation reaction obtains (the 2- bromine of Isosorbide-5-Nitrae-two
Phenyl) piperazine.
2. the preparation method of hydrobromic acid Vortioxetine impurity according to claim 1, which is characterized in that condensation reaction is in nitrogen
It is carried out in atmosphere.
3. the preparation method of hydrobromic acid Vortioxetine impurity according to claim 1 or claim 2, which is characterized in that acid binding agent three
One of ethamine, sodium tert-butoxide, sodium hydroxide, potassium carbonate；Preferably, acid binding agent is sodium tert-butoxide.
4. the preparation method of any one of -3 hydrobromic acid Vortioxetine impurity according to claim 1, which is characterized in that catalyst
For double (bis- Ya Benzyl benzylacetones) palladium.
5. the preparation method of any one of -4 hydrobromic acid Vortioxetine impurity according to claim 1, which is characterized in that piperazine with
Adjacent bromo-iodobenzene is under acid binding agent, catalyst action, and reflux carries out condensation reaction in reaction dissolvent.
6. the preparation method of any one of -5 hydrobromic acid Vortioxetine impurity according to claim 1, which is characterized in that condensation is anti-
Ying Hou, through column chromatographic purifying.
7. the preparation method of hydrobromic acid Vortioxetine impurity according to claim 5, which is characterized in that reaction dissolvent is first
At least one of benzene, dimethylbenzene, tetrahydrofuran, methylene chloride；Preferably, reaction dissolvent is toluene.
8. the preparation method of hydrobromic acid Vortioxetine impurity according to claim 6, which is characterized in that 2- bromophenyl piperazine
Column chromatographic flow is mutually methylene chloride and methanol mixed solution, wherein the volume ratio of methylene chloride and methanol is 20-30:1；It is excellent
The column chromatographic flow of selection of land, Isosorbide-5-Nitrae-two (2- bromophenyl) piperazine is mutually petroleum ether and ethyl acetate mixture, wherein petroleum ether
Volume ratio with ethyl acetate is 100-120:1.
9. the preparation method of any one of -8 hydrobromic acid Vortioxetine impurity according to claim 1, which is characterized in that condensation is anti-
The time answered is 5-8h.
10. the preparation method of any one of -9 hydrobromic acid Vortioxetine impurity according to claim 1, which is characterized in that piperazine
Molar ratio with acid binding agent is 1:2-5；Preferably, the molar ratio of piperazine and acid binding agent is 1:3-4；Preferably, piperazine and catalysis
The molar ratio of agent is 1:0.003-0.01；Preferably, the bulking value (g/ml) of piperazine and reaction dissolvent is than being 1:15-25.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201811416945.6A CN109438391A (en) | 2018-11-26 | 2018-11-26 | A kind of preparation method of hydrobromic acid Vortioxetine impurity |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114075153A (en) * | 2020-08-11 | 2022-02-22 | 成都倍特药业股份有限公司 | Preparation method of vortioxetine impurity |
| CN114965720A (en) * | 2021-02-20 | 2022-08-30 | 成都康弘药业集团股份有限公司 | Method for determining related substances of vortioxetine hydrobromide |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105985301A (en) * | 2015-02-05 | 2016-10-05 | 山东康美乐医药科技有限公司 | Preparation method of vortioxetine hydrobromide |
| CN106083762A (en) * | 2016-07-29 | 2016-11-09 | 北京万全德众医药生物技术有限公司 | Fertile a kind of preparation method for western spit of fland intermediate |
| CN108314661A (en) * | 2017-12-20 | 2018-07-24 | 安徽源久源科技有限公司 | A kind of bis- (2- bromophenyls of 1,4-）The preparation method of piperazine |
-
2018
- 2018-11-26 CN CN201811416945.6A patent/CN109438391A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105985301A (en) * | 2015-02-05 | 2016-10-05 | 山东康美乐医药科技有限公司 | Preparation method of vortioxetine hydrobromide |
| CN106083762A (en) * | 2016-07-29 | 2016-11-09 | 北京万全德众医药生物技术有限公司 | Fertile a kind of preparation method for western spit of fland intermediate |
| CN108314661A (en) * | 2017-12-20 | 2018-07-24 | 安徽源久源科技有限公司 | A kind of bis- (2- bromophenyls of 1,4-）The preparation method of piperazine |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114075153A (en) * | 2020-08-11 | 2022-02-22 | 成都倍特药业股份有限公司 | Preparation method of vortioxetine impurity |
| CN114075153B (en) * | 2020-08-11 | 2023-12-08 | 成都倍特药业股份有限公司 | Preparation method of voathixetine impurity |
| CN114965720A (en) * | 2021-02-20 | 2022-08-30 | 成都康弘药业集团股份有限公司 | Method for determining related substances of vortioxetine hydrobromide |
| CN114965720B (en) * | 2021-02-20 | 2024-02-23 | 成都康弘药业集团股份有限公司 | Method for determining related substances of hydrobromic acid voltammetric acid |
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Application publication date: 20190308 |