CN107915694A - 1 [2 (2,4 3,5-dimethylphenyl sulfydryl) phenyl] piperazine hydrochloride and preparation method thereof - Google Patents
1 [2 (2,4 3,5-dimethylphenyl sulfydryl) phenyl] piperazine hydrochloride and preparation method thereof Download PDFInfo
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- CN107915694A CN107915694A CN201610881616.3A CN201610881616A CN107915694A CN 107915694 A CN107915694 A CN 107915694A CN 201610881616 A CN201610881616 A CN 201610881616A CN 107915694 A CN107915694 A CN 107915694A
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- vortioxetine
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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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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
1 [2 (2,4 3,5-dimethylphenyl sulfydryl) phenyl] piperazine hydrochloride and preparation method thereof, the present invention is by specific preparation method, and obtained hydrochloric acid Vortioxetine HPLC purity is more than 99.5%, and single contaminant is respectively less than 0.1%；It is a kind of in high yield, inexpensive present invention aims at offer, suitable for the compound Vortioxetine of large-scale industrial production and its synthesis technique of hydrochloride.
Description
Technical field
The present invention relates to Vortioxetine salt and its prepare and purify method, belong to pharmaceutical technology field.
Background technology
Patent CN1319958C discloses compound Vortioxetine (Vortioxetine), its structure is shown below, and changes
Scientific name claims to be 1- [2- (2,4- 3,5-dimethylphenyl sulfydryl) phenyl] piperazine, is by Lundbeck (Lindbeck) and military field (Takeda) connection
The serotonin transporter inhibitor of research and development is closed, its hydrobromate is ratified to list in September, 2013 through FDA, trade name
Brintellix, is clinically used for treatment major depressive and generalized anxiety disorder.
Patent CN101472906B discloses Vortioxetine hydrobromate, hydrochloride, mesylate, maleate shape first
Formula, and its synthetic method.Method 1：With the bromo- iodobenzenes of 2-, 2,4- thiophenol dimethyl benzenes, Boc- piperazines in toluene solvant,
Under palladium chtalyst, Vortioxetine is synthesized through one kettle way or two step coupling reactions, then with corresponding acid into salt；Method 2：With the bromo- iodine of 2-
For benzene, 2,4- thiophenol dimethyl benzenes, piperazine in toluene solvant, under palladium chtalyst, synthesized through one kettle way or two step coupling reactions
Vortioxetine.No matter which kind of method, metal palladium complex catalyst is employed, it is expensive, and accessory substance is more, it is not easily-controllable
System, synthetic method is unfavorable for cost control and amplification produces.
Patent CN104011034B is disclosed with piperazine, 1- iodos -2,4- dimethyl benzene and 2- bromothiophenols as raw material,
Equally it is coupled instead through one kettle way under double (dibenzylideneacetone) palladiums and the catalysis of 2,2 '-bis- (diphenylphosphinos) -1,1 '-dinaphthalenes
Vortioxetine should be prepared, then is changed into hydrobromate.Likewise, this method also uses the palladium complex catalyst of costliness.
The content of the invention
It is an object of the invention to provide it is a kind of in high yield, low cost, irrigated suitable for the compound of large-scale industrial production
For Xi Ting and its synthesis technique of hydrochloride.
To achieve the above object, the preparation method of hydrochloric acid Vortioxetine provided by the invention, reaction are as follows：
Step is
1) reaction temperature is 60~100 DEG C, 2, the 4- dimethyl benzene sulphur with the o-fluoronitrobenzene shown in Formulas I and shown in Formula II
Phenol is raw material, and n,N-Dimethylformamide, dimethyl sulfoxide (DMSO), acetonitrile are solvent, and potassium carbonate, sodium carbonate are acid binding agent, reaction life
Into 2- (2,4- dimethyl benzenes sulfenyl) nitrobenzene shown in formula III；
Wherein, the molar ratio of o-fluoronitrobenzene (I) and 2,4- thiophenol dimethyl benzenes (II) is 1~1.5:1；
2) reaction temperature is 20~80 DEG C, and with the 2- (2,4- dimethyl benzene sulfenyl) shown in formula III, nitrobenzene is raw material, second
Alcohol, methanol are solvent, and iron powder is reducing agent, 2- (2,4- dimethyl benzene sulfenyl) aniline shown in reaction production IV；
3) reaction temperature is 80~120 DEG C, and with the 2- (2,4- dimethyl benzene sulfenyl) shown in formula IV, aniline is raw material, first
Benzene, dimethylbenzene are solvent, with the Vortioxetine hydrochloride shown in two (2- chloroethyls) amine hydrochlorates reaction production V；
The molar ratio of wherein 2- (2,4- dimethyl benzenes sulfenyl) aniline (IV) and two (2- chloroethyls) amine is 1:0.95~
1.1；
4) Vortioxetine hydrochloride is refined in ethyl acetate/methyl tertiary butyl ether(MTBE) in the mixed solvent, obtains the salt of high-purity
Sour Vortioxetine hydrochloride；
Wherein the volume ratio of ethyl acetate and methyl tertiary butyl ether(MTBE) is 1:0.5~3.
The present invention's focuses on, and the Vortioxetine of high-purity is prepared using novel method, is avoided expensive
Palladium complex catalyst use, synthesis technique is easy, of low cost, suitable for big production.
The emphasis of the present invention also resides in, and gained hydrochloric acid Vortioxetine purity is more than 99.5%, and maximum list is miscellaneous to be less than 0.1%.
Specific embodiment
Embodiment 1：
By 66.3g o-fluoronitrobenzenes, 65 2,4- thiophenol dimethyl benzenes are added into 400mL n,N-Dimethylformamide,
Lower addition powdered potassium carbonate 30g is stirred at room temperature, when 80 DEG C of stirrings 5 of temperature control are small, a small amount of water is added after cooling, is concentrated under reduced pressure；It is surplus
Excess obtains dark yellow solid 105g with ethyl acetate/petroleum ether mixed solvent crystallization；
Embodiment 2：
2- (2,4- dimethyl benzene sulfenyl) nitrobenzene 100g of the gained of Example 1, adds into 2L water, adds catalytic amount
Ammonium chloride, and iron powder 50g, be warming up to 80 DEG C of reactions 3 it is small when, cooling, filters iron powder, filtrate is transferred to 30% wet chemical
In, after stirring, ethyl acetate extraction is added, organic phase concentration, obtains 73g 2- (2,4- dimethyl benzene sulfenyl) aniline；
Embodiment 3：
70g 2- (2,4- dimethyl benzenes sulfenyl) aniline and 55g bis- (2- chloroethyls) amine hydrochlorate are added to 500mL first
In benzene, when heating reflux reaction 36 is small, cooling, adds 800mL water and 500mL ethyl acetate, liquid separation, organic phase saturation chlorination
Sodium solution washs, anhydrous sodium sulfate drying, filtering, dilute hydrochloric acid tune pH to 2 is added dropwise in filtrate, stirring, separates out solid.Filtering, filter
Cake is washed with ethyl acetate, and drying, obtains hydrochloric acid 43g.
Embodiment 4：
The hydrochloric acid Vortioxetine crude product 40g of gained is added into 80mL ethyl acetate, activated carbon is added, is heated to reflux,
After heat filtering, it is cooled to room temperature, adds t-butyl methyl ether, stirring separates out crystallization, and filtering, drying, obtain hydrochloric acid Vortioxetine
Highly finished product 32g.HPLC purity：99.87%, it is maximum single miscellaneous：0.04%.
Claims (2)
1. a kind of preparation method of high-purity Vortioxetine hydrochloride, reaction process are as follows：
Step is：
1) reaction temperature is 60~100 DEG C, is with the o-fluoronitrobenzene shown in Formulas I and 2, the 4- thiophenol dimethyl benzenes shown in Formula II
Raw material, n,N-Dimethylformamide, dimethyl sulfoxide (DMSO), acetonitrile are solvent, and potassium carbonate, sodium carbonate are acid binding agent, react production
2- (2,4- dimethyl benzenes sulfenyl) nitrobenzene shown in III；Wherein, o-fluoronitrobenzene (I) and 2,4- thiophenol dimethyl benzenes (II)
Molar ratio be 1~1.5:1；
2) reaction temperature is 20~80 DEG C, with 2- (2,4- dimethyl benzene sulfenyl) nitrobenzene shown in formula III for raw material, ethanol,
Methanol is solvent, and iron powder is reducing agent, 2- (2,4- dimethyl benzene sulfenyl) aniline shown in reaction production IV；
3) reaction temperature is 80~120 DEG C, and with the 2- (2,4- dimethyl benzene sulfenyl) shown in formula IV, aniline is raw material, toluene, two
Toluene is solvent, with the Vortioxetine hydrochloride shown in two (2- chloroethyls) amine hydrochlorates reaction production V；Wherein 2- (2,4-
Dimethyl benzene sulfenyl) molar ratio of aniline (IV) and two (2- chloroethyls) amine is 1:0.95~1.1；
4) Vortioxetine hydrochloride is refined in ethyl acetate/methyl tertiary butyl ether(MTBE) in the mixed solvent, and the hydrochloric acid for obtaining high-purity is irrigated
For western spit of fland hydrochloride；Wherein the volume ratio of ethyl acetate and methyl tertiary butyl ether(MTBE) is 1:0.5~3.
2. preparation method according to claim 1, obtained hydrochloric acid Vortioxetine HPLC purity is single miscellaneous more than 99.5%
Matter is respectively less than 0.1%.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610881616.3A CN107915694A (en) | 2016-10-09 | 2016-10-09 | 1 [2 (2,4 3,5-dimethylphenyl sulfydryl) phenyl] piperazine hydrochloride and preparation method thereof |
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| CN201610881616.3A CN107915694A (en) | 2016-10-09 | 2016-10-09 | 1 [2 (2,4 3,5-dimethylphenyl sulfydryl) phenyl] piperazine hydrochloride and preparation method thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111320592A (en) * | 2018-12-17 | 2020-06-23 | 天津理工大学 | Preparation method of 1- [2- (2, 4-dimethylphenylsulfanyl) -phenyl ] piperazine |
| CN115181077A (en) * | 2022-07-27 | 2022-10-14 | 安徽峆一药业股份有限公司 | Synthetic method of vortioxetine with low impurity content |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103936694A (en) * | 2014-04-23 | 2014-07-23 | 中国药科大学 | Preparation method of antidepressant vortioxetine |
| WO2016004908A1 (en) * | 2014-07-08 | 2016-01-14 | Zentiva, K.S. | Method of preparing vortioxetine |
| WO2016079751A2 (en) * | 2014-11-17 | 2016-05-26 | Megafine Pharma (P) Ltd. | A process for preparation of vortioxetine and polymorphs thereof |
| WO2016125191A2 (en) * | 2015-02-04 | 2016-08-11 | Mylan Laboratories Limited | Processes for the preparation of vortioxetine hydrobromide |
-
2016
- 2016-10-09 CN CN201610881616.3A patent/CN107915694A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103936694A (en) * | 2014-04-23 | 2014-07-23 | 中国药科大学 | Preparation method of antidepressant vortioxetine |
| WO2016004908A1 (en) * | 2014-07-08 | 2016-01-14 | Zentiva, K.S. | Method of preparing vortioxetine |
| WO2016079751A2 (en) * | 2014-11-17 | 2016-05-26 | Megafine Pharma (P) Ltd. | A process for preparation of vortioxetine and polymorphs thereof |
| WO2016125191A2 (en) * | 2015-02-04 | 2016-08-11 | Mylan Laboratories Limited | Processes for the preparation of vortioxetine hydrobromide |
Non-Patent Citations (1)
| Title |
|---|
| NEVENKA LAPANJA 等: "A Generic Industry Approach To Demonstrate Efficient Purification of Potential Mutagenic Impurities in the Synthesis of Drug Substances", 《ORG. PROCESS RES. DEV.》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111320592A (en) * | 2018-12-17 | 2020-06-23 | 天津理工大学 | Preparation method of 1- [2- (2, 4-dimethylphenylsulfanyl) -phenyl ] piperazine |
| CN115181077A (en) * | 2022-07-27 | 2022-10-14 | 安徽峆一药业股份有限公司 | Synthetic method of vortioxetine with low impurity content |
| CN115181077B (en) * | 2022-07-27 | 2024-03-29 | 安徽峆一药业股份有限公司 | Synthesis method of vortioxetine with low impurity content |
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