CN104292183A - Preparation method of antidepressant drug Vortioxetine - Google Patents

Preparation method of antidepressant drug Vortioxetine Download PDF

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CN104292183A
CN104292183A CN201410509436.3A CN201410509436A CN104292183A CN 104292183 A CN104292183 A CN 104292183A CN 201410509436 A CN201410509436 A CN 201410509436A CN 104292183 A CN104292183 A CN 104292183A
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compound
formula
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刘学键
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Nantong Fayink High Tech Material Technology Co ltd
Qidong Binhua Water Supply Co ltd
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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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to a preparation method of an antidepressant drug Vortioxetine, which belongs to the technical field of pharmaceutical chemicals. According to the method, by taking water as a solvent, a compound 2,4-dimethylbenzenethiol shown in a formula (4), a compound 2-bromoiodobenzene shown in a formula (3) and a compound piperazine shown in a formula (2) react with copper iodide, a phase transfer reagent and alkali in an aqueous solution so as to obtain a compound shown in a formula (1). The method disclosed by the invention is easily-obtained in raw materials and simple in process; and one-pot reaction operation can be performed, and water is taken as a solvent, so that the method is green and environmental-friendly, and facilitates the industrialized production of the bulk drug.

Description

A kind of antidepressant drug irrigates the preparation method for Xi Ting
Technical field
The present invention relates to a kind of fertile preparation method for Xi Ting, belong to pharmaceutical chemistry technical field.
Background technology
Fertile is a kind of newly-developed antidepressant researched and developed by military field drug company (Takeda Pharmaceutical) of Ling Bei drugmaker of Denmark (Lundbeck) and Japan for Xi Ting (Vortioxetine).In September, 2013, this medicine obtained the listing approval of FDA (Food and Drug Adminstration) (FDA), and commodity are called Brintellix, and chemistry is by name: 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl] piperazine, and its structural formula is:
This medicine is considered to be played a role by combining of 2 kinds of mechanism of action: receptor active regulates and re-uptake suppresses.In vitro study shows, fertile is 5-HT3 and 5-HT7 receptor antagonist, 5-HT1B acceptor portion agonist, 5-HT1A receptor stimulant, serotonin transporter (SERT) inhibitor for Xi Ting.In body, non-clinical study shows, irrigates and can strengthen brain specific region neurotransmitter for western spit of fland---the level of thrombotonin, norepinephrine, Dopamine HCL, vagusstoff, histamine, is used for the treatment of adult's major depressive disorder.
According to the fertile molecular structure for Xi Ting, and adopt reverse reaction analytical method, show that the synthesis of this compound mainly comprises the formation of sulfanyl and the introducing of piperazinyl, and the impact of the generation method of each functional group and the introducing time whole technique of ordered pair is most important.
The fertile principal synthetic routes for Xi Ting, comprises following several:
1.WO2003029232 the synthetic route announced; with N-bromo phenyl-N-protecting group (Pg) piperazine (A) for raw material; be obtained by reacting with 2,4-dimethyl sulfydryl benzene and replace Xi Ting with the fertile of protecting group, then obtain target compound by deprotection.
2. another synthetic route of WO2003029232 announcement, with bromobenzene thioether (B) for raw material, reacts with the piperazine of monosubstituted protection, obtains replacing Xi Ting with the fertile of protecting group, then obtains target compound by deprotection.
Above-mentioned two kinds of methods will realize its preparation by the protection of piperazinyl and deprotection, complex operation, need with dangerous toxic reagents such as ferrocene, and solvent used need through sewage disposal, and total recovery is low, is not suitable for suitability for industrialized production.
3.WO2007144005 also discloses a kind of fertile preparation method for Xi Ting of improvement, namely directly by three functional compounds, under certain catalyst action, is prepared fertile for Xi Ting by the method for the treatment of different things alike.
4.WO2013102573 also discloses a kind of fertile preparation method for Xi Ting of improvement, also by three functional compounds, under certain catalyst action, is prepared fertile for Xi Ting by the method for the treatment of different things alike.
Above-mentioned two kinds of methods, although enormously simplify reactions steps, need use expensive palladium catalyst and Phosphine ligands, organic solvent is also more difficult to be removed, and cost is higher.If so use the method, need equally to solve follow-up issues of purification, the industrialization difficulty of the method is increased.
5. Cen Jun such as to reach at (the Chinese Journal of Pharmaceuticals 2014,45 (4), 301-30303) report another synthetic method, take o-fluoronitrobenzene as raw material and 2, there is nucleophilic substitution, catalytic hydrogen reduction in 4 one thiophenol dimethyl benzenes (3), then two (2 one chloroethyl) amine hydrochlorate cyclization generates fertile for Xi Ting.
Although the method is simple to operate, cost also has certain advantage, and step is longer, and yield also only has 48.7%.
Summary of the invention
The invention provides a kind of antidepressant drug and irrigate preparation method for Xi Ting, the method take water as solvent, and environmental protection, raw material is easy to get, concise in technology.
In order to realize foregoing invention object, present invention employs following technical scheme: a kind of fertile preparation method for Xi Ting, comprise the steps: formula (4) compound 2,4-thiophenol dimethyl benzene, formula (3) compound 2-bromo-iodobenzene and formula (2) compound piperazine cuprous iodide, phase transfer reagent and containing alkali the aqueous solution in carry out the formula that is obtained by reacting (1) compound, reaction scheme is as follows:
Contriver finds, three components raw material described above only, under phase transfer reagent exists, could react in water, and the fertile preparation method for Xi Ting carried out in water never reports.
Wherein, alkali described above is one or more in salt of wormwood, cesium carbonate, sodium carbonate, potassiumphosphate, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, and preferably, the alkali described in step one is potassium hydroxide.
Phase transfer reagent of the present invention is: the polyethers such as chain polyoxyethylene glycol: H (OCH2CH2) nOH, chain dialkylethers: R (OCH2CH2) nOR; The cyclic crown ether classes such as 18 hat 6,15 hats 5, cyclodextrin; The quaternary ammonium salts such as tri-methyl benzyl ammonium bromide, trimethyl benzyl ammonia chloride, benzyltriethylammoinium chloride (TEBA), Tetrabutyl amonium bromide, tetrabutylammonium chloride, 4-butyl ammonium hydrogen sulfate (TBAB), tri-n-octyl methyl ammonium chloride, Dodecyl trimethyl ammonium chloride, tetradecyl trimethyl ammonium chloride, cetyl trimethylammonium bromide; The tertiary amines such as pyridine, Tributylamine; One or more in the quaternary ammonium bases such as trimethyl benzyl ammonium hydroxide and season phosphonium salt class.
Preferably, phase transfer reagent described above is quaternary ammonium salt; More preferably, phase transfer reagent described above is one or more in tri-methyl benzyl ammonium bromide, trimethyl benzyl ammonia chloride, benzyltriethylammoinium chloride (TEBA), Tetrabutyl amonium bromide, tetrabutylammonium chloride, 4-butyl ammonium hydrogen sulfate (TBAB), tri-n-octyl methyl ammonium chloride, Dodecyl trimethyl ammonium chloride, tetradecyl trimethyl ammonium chloride, cetyl trimethylammonium bromide; Most preferably, phase transfer reagent described above is Tetrabutyl amonium bromide.
The temperature of reaction of reaction process described above is 50-100 DEG C, and react 5-24 hour at this temperature, preferably, the temperature of reaction of reaction process described above is 70-80 DEG C, reacts 8-12 hour at this temperature.
Reactant formula (4) compound 2,4-thiophenol dimethyl benzene described above: formula (3) compound 2-bromo-iodobenzene: formula (2) compound piperidine: cuprous iodide: phase transfer reagent: the molar ratio of alkali is 1:1.0-1.5: 1.0-1.5:0.001-0.2:1.1-1.5:2.0-4.5; Preferably, reactant formula (4) compound 2,4-thiophenol dimethyl benzene described above: formula (3) compound 2-bromo-iodobenzene: formula (2) compound piperidine: cuprous iodide: phase transfer reagent: the molar ratio of alkali is 1:1.0-1.2:1.1-1.5:0.01-0.1:1.1-1.5:2.5-3.5.
Beneficial effect of the present invention:
(1) raw material is easy to get, concise in technology, can carries out one pot reaction operation;
(2) water is solvent, environmental protection;
(3) the present invention is simple to operate, is beneficial to the suitability for industrialized production of this bulk drug.
Embodiment
Below in conjunction with several preferred embodiment, technical solution of the present invention is further non-limitingly described in detail.
embodiment 1formula (4) compound 2,4-thiophenol dimethyl benzene, formula (3) compound 2-bromo-iodobenzene and formula (2) compound piperazine are at cuprous iodide
13.8 g (0.1mo1) formula (4) compound 2 is dropped into successively in 500 mL reactors, 4-thiophenol dimethyl benzene, 28.3 g (0.1 mo1) 2-bromo-iodobenzene, 10.3 g (0.12 mo1) piperazine, 16.8 g (0.3 mo1) potassium hydroxide and 1.0g (0.005mol) cuprous iodide, 38.7g(0.12mol) Tetrabutyl amonium bromide, add 300mL water, 70-80 DEG C is warming up under stirring, reaction 10h, after completion of the reaction, with dichloromethane extraction three times, each 300ml, merge organic layer, with saturated aqueous common salt, pure water organic layer, collected organic layer, dry, steam methylene dichloride, residuum adds 200 mL recrystallized from acetonitrile, obtain white solid 27.3g, yield 91.7%, purity 98.9%, [HPLC method: chromatographic column Luna Phenyl-Hexyl post (4.6mmx150mm, 3 um), moving phase acetonitrile: 0.05% trifluoroacetic acid solution (60:40), determined wavelength 226 Din, column temperature 40 DEG C, flow velocity 1 ml/min].
embodiment 2
13.8 g (0.1mo1) formula (4) compound 2 is dropped into successively in 500 mL reactors, 4-thiophenol dimethyl benzene, 28.3 g (0.1 mo1) 2-bromo-iodobenzene, 10.3 g (0.12 mo1) piperazine, 16.8 g (0.3 mo1) potassium hydroxide and 1.9g (0.01mol) cuprous iodide, 33.4g(0.12mol) tetrabutylammonium chloride, add 300mL water, 85-90 DEG C is warming up under stirring, reaction 11h, after completion of the reaction, with dichloromethane extraction three times, each 300ml, merge organic layer, with saturated aqueous common salt, pure water organic layer, collected organic layer, dry, steam methylene dichloride, residuum adds 150 mL acetone recrystallizations, obtain white solid 26.6g, yield 89.3%, purity 97.2%.
embodiment 3
13.8 g (0.1mo1) formula (4) compound 2 is dropped into successively in 500 mL reactors, 4-thiophenol dimethyl benzene, 28.3 g (0.1 mo1) 2-bromo-iodobenzene, 10.3 g (0.12 mo1) piperazine, 12.0 g (0.3 mo1) sodium hydroxide and 1.9g (0.01mol) cuprous iodide, 48.3g(0.15mol) Tetrabutyl amonium bromide, add 300mL water, 85-90 DEG C is warming up under stirring, reaction 11h, after completion of the reaction, with dichloromethane extraction three times, each 300ml, merge organic layer, with saturated aqueous common salt, pure water organic layer, collected organic layer, dry, steam methylene dichloride, residuum adds 150 mL acetone recrystallizations, obtain white solid 26.8g, yield 89.3%, purity 96.5%.
embodiment 4
13.8 g (0.1mo1) formula (4) compound 2 is dropped into successively in 500 mL reactors, 4-thiophenol dimethyl benzene, 28.3 g (0.1 mo1) 2-bromo-iodobenzene, 10.3 g (0.12 mo1) piperazine, 12.0 g (0.3 mo1) sodium hydroxide and 1.9g (0.01mol) cuprous iodide, 29.1g(0.11mol) hexaoxacyclooctadecane-6-6, add 300mL water, 85-90 DEG C is warming up under stirring, reaction 10h, after completion of the reaction, with dichloromethane extraction three times, each 300ml, merge organic layer, with saturated aqueous common salt, pure water organic layer, collected organic layer, dry, steam methylene dichloride, residuum adds 150 mL acetone recrystallizations, obtain white solid 22.4g, yield 75.2%, purity 96.8%.
embodiment 5
13.8 g (0.1mo1) formula (4) compound 2 is dropped into successively in 500 mL reactors, 4-thiophenol dimethyl benzene, 28.3 g (0.1 mo1) 2-bromo-iodobenzene, 10.3 g (0.12 mo1) piperazine, 10.0 g (0.25 mo1) sodium hydroxide and 1.9g (0.01mol) cuprous iodide, the 260g 10% TBAH aqueous solution (0.11mol), add 100mL water, 85-90 DEG C is warming up under stirring, reaction 10h, after completion of the reaction, with dichloromethane extraction three times, each 300ml, merge organic layer, with saturated aqueous common salt, pure water organic layer, collected organic layer, dry, steam methylene dichloride, residuum adds 150 mL acetone recrystallizations, obtain white solid 25.8g, yield 86.6%.
embodiment 6
138 g (1mo1) formula (4) compound 2 is dropped into successively in 5L reactor, 4-thiophenol dimethyl benzene, 283 g (1 mo1) 2-bromo-iodobenzene, 103 g (1.2 mo1) piperazine, 168 g (3 mo1) potassium hydroxide and 10g (0.05mol) cuprous iodide, 387g(1.2mol) Tetrabutyl amonium bromide, add 2.5L water, 70-80 DEG C is warming up under stirring, reaction 10h, after completion of the reaction, with dichloromethane extraction three times, each 2.0L, merge organic layer, with saturated aqueous common salt, pure water organic layer, collected organic layer, dry, steam methylene dichloride, residuum adds 1.5L recrystallized from acetonitrile, obtain white solid 276g, yield 92.6%, purity 98.8%.

Claims (9)

1. an antidepressant drug irrigates the preparation method for Xi Ting, it is characterized in that comprising the steps: formula (4) compound 2,4-thiophenol dimethyl benzene, formula (3) compound 2-bromo-iodobenzene and formula (2) compound piperazine cuprous iodide, phase transfer reagent and containing alkali the aqueous solution in carry out the formula that is obtained by reacting (1) compound, reaction scheme is as follows:
。
2. antidepressant drug as claimed in claim 1 irrigates the preparation method for Xi Ting, it is characterized in that: described phase transfer reagent is one or more in polyethers, cyclic crown ether, quaternary ammonium salt, tertiary amine, quaternary ammonium hydroxide, season phosphonium salt.
3. antidepressant drug as claimed in claim 2 irrigates the preparation method for Xi Ting, it is characterized in that: described phase transfer reagent is quaternary ammonium salt.
4. antidepressant drug as claimed in claim 3 irrigates the preparation method for Xi Ting, it is characterized in that: described phase transfer reagent is one or more in tri-methyl benzyl ammonium bromide, trimethyl benzyl ammonia chloride, benzyltriethylammoinium chloride, Tetrabutyl amonium bromide, tetrabutylammonium chloride, 4-butyl ammonium hydrogen sulfate, tri-n-octyl methyl ammonium chloride, Dodecyl trimethyl ammonium chloride, tetradecyl trimethyl ammonium chloride, cetyl trimethylammonium bromide.
5. antidepressant drug as claimed in claim 4 irrigates the preparation method for Xi Ting, it is characterized in that: described phase transfer reagent is Tetrabutyl amonium bromide.
6. the antidepressant drug as described in as arbitrary in claim 1-5 irrigates the preparation method for Xi Ting, it is characterized in that: the temperature of reaction of reaction process is 50-100 DEG C, and the reaction times is 5-24 hour.
7. antidepressant drug as claimed in claim 6 irrigates the preparation method for Xi Ting, it is characterized in that: the temperature of reaction of reaction process is 70-80 DEG C, and the reaction times is 8-12 hour.
8. the antidepressant drug as described in as arbitrary in claim 1-5 irrigates the preparation method for Xi Ting, it is characterized in that: reactant formula (4) compound 2,4-thiophenol dimethyl benzene: formula (3) compound 2-bromo-iodobenzene: formula (2) compound piperidine: cuprous iodide: phase transfer reagent: the molar ratio of alkali is 1:1.0-1.5: 1.0-1.5:0.001-0.2:1.1-1.5:2.0-4.5.
9. antidepressant drug as claimed in claim 8 irrigates the preparation method for Xi Ting, it is characterized in that: reactant formula (4) compound 2,4-thiophenol dimethyl benzene: formula (3) compound 2-bromo-iodobenzene: formula (2) compound piperidine: cuprous iodide: phase transfer reagent: the molar ratio of alkali is 1:1.0-1.2:1.1-1.5:0.01-0.1:1.1-1.5:2.5-3.5.
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Cited By (5)

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Publication number Priority date Publication date Assignee Title
CN105061364A (en) * 2015-08-17 2015-11-18 河北国龙制药有限公司 Vortioxetine hydrobromide preparation method
CN105315184A (en) * 2015-06-26 2016-02-10 上海医药工业研究院 Preparation method and intermediate of vortioxetine
CN107266390A (en) * 2017-08-07 2017-10-20 山东鲁宁药业有限公司 A kind of new technique for synthesizing of hydrobromic acid Vortioxetine
CN109369517A (en) * 2018-10-24 2019-02-22 郑传花 A kind of preparation method for treating breast cancer medicines intermediate
WO2022052391A1 (en) * 2020-09-10 2022-03-17 苏州富德兆丰生化科技有限公司 Method for synthesizing vortioxetine

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105315184A (en) * 2015-06-26 2016-02-10 上海医药工业研究院 Preparation method and intermediate of vortioxetine
CN105061364A (en) * 2015-08-17 2015-11-18 河北国龙制药有限公司 Vortioxetine hydrobromide preparation method
CN107266390A (en) * 2017-08-07 2017-10-20 山东鲁宁药业有限公司 A kind of new technique for synthesizing of hydrobromic acid Vortioxetine
CN109369517A (en) * 2018-10-24 2019-02-22 郑传花 A kind of preparation method for treating breast cancer medicines intermediate
WO2022052391A1 (en) * 2020-09-10 2022-03-17 苏州富德兆丰生化科技有限公司 Method for synthesizing vortioxetine

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Patentee before: Nantong Fayink High-tech Material Technology Co.,Ltd.

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