CN103936694A - Preparation method of antidepressant vortioxetine - Google Patents
Preparation method of antidepressant vortioxetine Download PDFInfo
- Publication number
- CN103936694A CN103936694A CN201410166305.XA CN201410166305A CN103936694A CN 103936694 A CN103936694 A CN 103936694A CN 201410166305 A CN201410166305 A CN 201410166305A CN 103936694 A CN103936694 A CN 103936694A
- Authority
- CN
- China
- Prior art keywords
- reaction
- preparing
- compound
- solvent
- vii
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the field of medicine synthesis, and particularly relates to a preparation method of antidepressant vortioxetine (I) shown in the specification. The preparation method comprises the following steps: reacting 2-(2,4-diphenylmethylthio)aniline (V) with bis(2-chloroethyl)amine hydrochloride (VI) to obtain vortioxetine hydrochloride (VII), and neutralizing VII through a base, to obtain vortioxetine (I). The total yield of vortioxetine hydrochloride (VII) prepared by the method is 59.8%, the raw materials are low-cost and easily available, and the treatment after reaction is convenient.
Description
Technical field
The present invention relates to the synthetic field of medicine.Be specifically related to for the fertile preparation method for Xi Ting (I) of antidepressant medicine.
Background technology
Fertile for Xi Ting (Vortioxetine), chemistry 1-[2-(2 by name, 4-aminomethyl phenyl sulfenyl) phenyl] piperazine, in September, 2013, the treatment for the major depression of being grown up by FDA (Food and Drug Adminstration) (FDA) approval, is now produced by Lundbeck company of the U.S..The fertile structural formula for Xi Ting is as follows:
Dysthymia disorders is the psychosis that a kind of emotion morbid state changes, and patient or depressed, has strong sadness and disappointed, speaking scarcely,taciturn, or the mad uneasiness of making an uproar, and in high spirits, activity increases extremely.At present, along with the quickening of social high speed development and people's rhythm of life, the patient who suffers from dysthymia disorders increases increasingly, and sickness rate at least exceedes 5% throughout one's life.According to the estimation of the global disease burden project of the World Health Organization, at coming 10 years, major depressive disorder will become the disabled major cause in second, the whole world.
The fertile Xi Ting that replaces is for having selectivity serotonin reuptake inhibitor, 5-HT
3Aacceptor inhibitor, 5-HT
7acceptor inhibitor and part 5-HT
1Bthe newly-developed antidepressant of receptor stimulant multiple action, compared with existing thymoleptic, has onset time faster, less toxic side effect and better antidepressant activity.
At present, the relevant fertile synthetic method for Xi Ting is less both at home and abroad, mainly contains several as follows:
Lundbeck company discloses the fertile preparation method for western spit of fland hydrochloride in patent CN1561336:
The 5 steps reactions such as this route, is substituted for starting raw material with 2-fluoronitrobenzene and 2,4-dimethyl thiophenol, nitroreduction, Cheng Huan, reduction of amide, de-Boc protection make fertile for western spit of fland hydrochloride (8).Wherein preparing compound 6 by compound 4 and 5 need to reflux 60 hours in tetrahydrofuran (THF) (THF); Prepare compound 7 by 6 through reduction and need to use borine tetrahydrofuran solution, not only toxicity is large, price, and also operational requirement is high, is unfavorable for suitability for industrialized production, and yield is lower (47%) also.
Other two kinds of methods are disclosed in document [J.Med.Chem.2011,54,3206 – 3221]:
Method one:
Method two:
Although above two reaction scheme steps are shorter, but all used expensive palladium catalyst, this may cause the heavy metal content of product to exceed standard, and affect the quality of product, the price of the adjacent bromo-iodobenzene of reaction raw materials is also more expensive in addition, causes the high expensive of product.
In patent WO2013/102573, announce the method for a kind of " treating different things alike ":
In patent CN102617513, announce another method of " treating different things alike ":
In two kinds of " treating different things alike " methods, all need to use expensive palladium catalyst above, and expensive raw material 2,4-dimethyl iodobenzene or adjacent bromo-iodobenzene, and complex operation.
Summary of the invention
Technical problem to be solved by this invention is to overcome above-mentioned weak point, and a kind of raw material of research and design is easy to get, and easy and simple to handle, cost is low, and reaction yield is high, the fertile preparation method for Xi Ting (I) that selectivity is good.
Preparation method of the present invention is as follows:
The invention also discloses the fertile method for Xi Ting (I) of preparation taking Compound I I as starting raw material:
2,4-thiophenol dimethyl benzene (II) reacts and obtains 2-(2 with 2-halogenated nitrobenzene (III) under alkaline condition, 4-3,5-dimethylphenyl sulfenyl) oil of mirbane (IV), compound IV obtains 2-(2 through reduction, 4-3,5-dimethylphenyl sulfenyl) aniline (V), compound V reacts with two (2-chloroethyl) amine hydrochlorates (VI) and obtains the fertile western spit of fland hydrochloride (VII) that replaces, and VII obtains fertile for Xi Ting (I) with alkali neutralization.
While preparing IV by II, 2-halogenated nitrobenzene (III) is 2-chloronitrobenzene, 2-bromo nitrobenzene or 2-fluoronitrobenzene preferably; One or any both mixture in the preferred acetonitrile of reaction solvent, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO) or DMF; Preferably under alkaline condition, react the preferred potassium hydroxide of described alkali, sodium hydroxide, sodium methylate, sodium ethylate or sodium hydride.Compound I I: compound III: preferred 1:1～2:1～2 of mol ratio of alkali.2-halogenated nitrobenzene is 2-chloronitrobenzene more preferably.Reaction solvent is DMF more preferably.Alkali is sodium methylate more preferably.
While preparing V by IV, reaction solvent preferably water, methyl alcohol, the mixed solvent of ethanol, Virahol or water and above-mentioned certain solvent.The preferred hydrazine hydrate of reductive agent, iron powder, zinc powder or tin protochloride.Preferably reaction under catalyzer exists, the preferred iron trichloride of described catalyzer and gac, ammonium chloride, hydrochloric acid or sulfuric acid.Reaction solvent particular methanol; The preferred hydrazine hydrate of reductive agent; Catalyzer is iron trichloride and gac more preferably.
While preparing VII by V, a kind of in the preferred propyl carbinol of reaction solvent, ethylene glycol monomethyl ether, diethylene glycol monomethyl ether, diethylene glycol dimethyl ether, chlorobenzene, dimethyl sulfoxide (DMSO), DMF or N,N-dimethylacetamide or both mixtures.Preferably 120 DEG C～180 DEG C of temperature of reaction. preferred 1:1～2 of mol ratio of compound V and two (2-chloroethyl) amine hydrochlorates (VI).Reaction solvent is diethylene glycol dimethyl ether more preferably.More preferably 150 DEG C～160 DEG C of temperature of reaction.More preferably 1:1.1～1.5 of mol ratio of compound V and two (2-chloroethyl) amine hydrochlorates (VI).
While preparing I by VII, the aqueous solution of the preferred sodium hydroxide of described alkali, potassium hydroxide, sodium carbonate, salt of wormwood or sodium bicarbonate; Preferred 1:1～10 of mol ratio of compound VI I and alkali; More preferably 1:1.5～3.
Prepared by aforesaid method is fertile for preparing salify by this area common method in western spit of fland, as hydrobromate, vitriol, tartrate, mesylate etc.Fertile is the hydrobromate with it for Xi Ting clinically, and therefore, the fertile Xi Ting of replacing that aforesaid method can be prepared reacts in solvent with Hydrogen bromide, obtains Hydrogen bromide fertile for Xi Ting.Described solvent is preferably from Virahol, ethanol, methyl alcohol, ethyl acetate, acetone or methylene dichloride.
The fertile total recovery for western spit of fland hydrochloride (VII) of the inventive method preparation is 59.8%, obviously improves than the total recovery of patented method (CN1561336) (40.1%).In addition the yield of, preparing compound IV by Compound I I has also brought up to 90% by 50% in document (J.CHEM.SOC.PERKIN TRANS.II1987 (5), 623-631.).The inventive method reaction raw materials used is cheap and easy to get, and post-reaction treatment is convenient; Also avoided the use of expensive palladium catalyst, be more suitable for the requirement of suitability for industrialized production simultaneously.
Embodiment
Embodiment 1
Synthesizing of 2-(2,4-3,5-dimethylphenyl sulfenyl) oil of mirbane (IV)
In 500ml eggplant-shape bottle, by 2, 4-thiophenol dimethyl benzene (47g, 0.341mol) mix with methyl alcohol 150ml, under ice bath, add sodium methylate (22g, 0.409mol), react 0.5 hour, stopped reaction, revolve desolventizing, add wherein N, dinethylformamide (200ml) and o-chloronitrobenzene (59g, 0.375mol), nitrogen protection, at 10 DEG C, react after 24 hours, stopped reaction, pour in 600ml water, cooling, suction filtration obtains tawny solid, dehydrated alcohol recrystallization obtains faint yellow needle-like crystal 79.3g, productive rate 90.0%, m.p.94 DEG C～96 DEG C..
1H-NMR(300MHz，DMSO-d6)，δ(ppm)：8.23(1H，d，J＝8.1Hz)，7.55～7.32(4H，m，-ArH)，7.29(1H，s)，7.16(1H，d，J＝7.8Hz)，6.64(1H，d，J＝7.8Hz)，2.33(3H，s)，2.21(3H，s).
Synthesizing of 2-(2,4-3,5-dimethylphenyl sulfenyl) aniline (V)
In 1L three-necked bottle, add compound IV (79g, 0.305mol) with methyl alcohol 200ml, add gac (1g, 0.062mol) and Iron(III) chloride hexahydrate (8g, 0.030mol), be heated to reflux, in solution, drip hydrazine hydrate (250ml), dropwise rear continuation reaction 3 hours, stopped reaction, be cooled to room temperature, suction filtration, revolve methyl alcohol, extract by ethyl acetate (200ml × 3), merge organic layer, saturated common salt water washing, anhydrous sodium sulfate drying spends the night, suction filtration, be spin-dried for solvent and obtain faint yellow oily matter 68.4g, productive rate: 97%.
1H-NMR(300MHz，DMSO-d6)，δ(ppm)：7.16～7.09(2H，m，-ArH),7.01(1H，s)，6.85(1H，d，J＝7.8Hz)，6.77(1H，dd，J＝8.1Hz，1.2Hz)，6.59(1H，d，J＝7.8Hz)，6.54(1H，dd，J＝7.5Hz，1.2Hz)，5.23(2H，brs，-NH
2)，2.28(3H，s)，2.18(3H，s).
1-[2-(2,4-aminomethyl phenyl sulfenyl) phenyl] piperazine hydrochloride (VII) synthetic
In 250ml three-necked bottle; add compound V (68g; 0.297mol), two (2-chloroethyl) amine hydrochlorate (58g; 0.325mol) and diethylene glycol dimethyl ether (70ml); under nitrogen protection; be heated to reflux, react 6～8 hours (TLC endpoint detection: sherwood oil: ethyl acetate=10:1), stop heating; be cooled to room temperature; add ethyl acetate 700ml, be cooled to 0 DEG C, separate out a large amount of khaki color solids; suction filtration; after oven dry, obtain khaki color solid 71.7g, productive rate: 72%, m.p.234 DEG C～236 DEG C.(Ref.m.p.～234℃.WO2008113359).
1H-NMR(300MHz，CDCl
3)，δ(ppm)：9.91(2H，s)，7.32(1H，d，J＝7.8Hz)，7.15(1H，s)，7.05～6.52(4H，m，-ArH)，6.54(1H，d，J＝7.8Hz)，3.42(8H，broad?s)，2.36(3H，s)，2.30(3H，s).
1-[2-(2,4-aminomethyl phenyl sulfenyl) phenyl] piperazine (fertile for Xi Ting, I) synthetic
Compound VI I (71g, 0,212mol) is added to the NaOH solution (200ml) of 2mol/L, stir 20 minutes, with ethyl acetate (100ml × 3) extraction, merge organic layer, saturated common salt water washing, anhydrous sodium sulfate drying spends the night, suction filtration, revolves solution and obtains khaki color solid, and dehydrated alcohol recrystallization obtains white crystal 57.1g, productive rate: 90.1%, m.p.116～118 DEG C.(Ref.m.p.～117℃.WO2008113359).
MS(ESI(+)70eV,m/z)：299[M+H]
+.1H-NMR(300MHz，CDCl
3)，δ(ppm)：7.38(1H，d，J＝7.8Hz)，7.15(1H，s)，7.06～6.85(4H，m，-ArH)，6.48(1H，d，J＝7.8Hz)，3.06(8H，broad?s)，2.35(3H，s)，2.31(3H，s)，1.8(1H，s).
Embodiment 2
Synthesizing of 2-(2,4-3,5-dimethylphenyl sulfenyl) oil of mirbane (IV)
In 500ml eggplant-shape bottle, add 2, 4-thiophenol dimethyl benzene (47g, 0.341mol) and potassium hydroxide (22.9g, 0.409mol), add acetonitrile (200ml) and o-fluoronitrobenzene (43g, 0.375mol), nitrogen protection, after back flow reaction 12 hours, stopped reaction, revolve acetonitrile, extract by ethyl acetate (200ml × 3), merge organic layer, saturated common salt water washing, anhydrous sodium sulfate drying spends the night, suction filtration, be spin-dried for solvent and obtain tawny solid, dehydrated alcohol recrystallization obtains faint yellow needle-like crystal 63.3g, productive rate 72.6%, m.p.94 DEG C～96 DEG C..
1H-NMR(300MHz，DMSO-d6)，δ(ppm)：8.23(1H，d，J＝8.1Hz)，7.55～7.32(4H，m，-ArH)，7.29(1H，s)，7.16(1H，d，J＝7.8Hz)，6.64(1H，d，J＝7.8Hz)，2.33(3H，s)，2.21(3H，s).
Synthesizing of 2-(2,4-3,5-dimethylphenyl sulfenyl) aniline (V)
In 1L three-necked bottle, add compound IV (63g, 0.243mol) and methyl alcohol 400ml, add reduced iron powder (27.2g, 0.486mol), be heated to reflux, slowly add concentrated hydrochloric acid 21ml, continue reaction 3 hours, stopped reaction, filtered while hot, the appropriate methanol wash of filter cake, merging filtrate, revolve methyl alcohol, add 200ml water, with ethyl acetate (200ml × 3) extraction, merge organic layer, saturated common salt water washing, anhydrous sodium sulfate drying spends the night, suction filtration, be spin-dried for solvent and obtain faint yellow oily matter 50.1g, productive rate: 90%.
1H-NMR(300MHz，DMSO-d6)，δ(ppm)：7.16～7.09(2H，m，-ArH),7.01(1H，s)，6.85(1H，d，J＝7.8Hz)，6.77(1H，dd，J＝8.1Hz，1.2Hz)，6.59(1H，d，J＝7.8Hz)，6.54(1H，dd，J＝7.5Hz，1.2Hz)，5.23(2H，brs，-NH
2)，2.28(3H，s)，2.18(3H，s).
1-[2-(2,4-aminomethyl phenyl sulfenyl) phenyl] piperazine hydrochloride (VII) synthetic
In 250ml three-necked bottle; add compound V (50g; 0.218mol), two (2-chloroethyl) amine hydrochlorate (46.7g; 0.262mol) with diethylene glycol monomethyl ether 50ml; under nitrogen protection; be heated to 160 DEG C, react 6～12 hours (TLC endpoint detection: sherwood oil: ethyl acetate=10:1), stop heating; be cooled to room temperature; add ethyl acetate 50ml, cooling, separate out gray solid; suction filtration; after oven dry, obtain gray solid 44.6g, productive rate 61%, m.p.234 DEG C～236 DEG C.(Ref.m.p.～234℃.WO2008113359).
1H-NMR(300MHz，CDCl
3)，δ(ppm)：9.91(2H，s)，7.32(1H，d，J＝7.8Hz)，7.15(1H，s)，7.05～6.52(4H，m，-ArH)，6.54(1H，d，J＝7.8Hz)，3.42(8H，broad?s)，2.36(3H，s)，2.30(3H，s).
1-[2-(2,4-aminomethyl phenyl sulfenyl) phenyl] piperazine (fertile for Xi Ting, I) synthetic
Compound VI I (44g, 0.131mol) is added to saturated Na
2cO
3solution (200ml), stir 20 minutes, with ethyl acetate (100ml × 3) extraction, merge organic layer, saturated common salt water washing, anhydrous sodium sulfate drying spends the night, suction filtration, revolves solution and obtains khaki color solid, and Virahol recrystallization obtains light yellow crystal 33.3g, productive rate: 85.2%, m.p.116～118 DEG C.(Ref.m.p.～117℃.WO2008113359).
MS(ESI(+)70eV,m/z)：299[M+H]
+.1H-NMR(300MHz，CDCl
3)，δ(ppm)：7.38(1H，d，J＝7.8Hz)，7.15(1H，s)，7.06～6.85(4H，m，-ArH)，6.48(1H，d，J＝7.8Hz)，3.06(8H，broad?s)，2.35(3H，s)，2.31(3H，s)，1.8(1H，s).
Embodiment 3
Synthesizing of 2-(2,4-3,5-dimethylphenyl sulfenyl) oil of mirbane (IV)
In 500ml eggplant-shape bottle, add 2, 4-thiophenol dimethyl benzene (47g, 0.341mol) and potassium hydroxide (22.9g, 0.409mol), add dimethyl sulfoxide (DMSO) (200ml) and o-fluoronitrobenzene (43g, 0.375mol), nitrogen protection, after back flow reaction 12 hours, stopped reaction, pour in 600ml water, extract by ethyl acetate (200ml × 3), merge organic layer, saturated common salt water washing, anhydrous sodium sulfate drying spends the night, suction filtration, be spin-dried for solvent and obtain tawny solid, dehydrated alcohol recrystallization obtains faint yellow needle-like crystal 65.6g, productive rate 75.6%, m.p.94 DEG C～96 DEG C..
1H-NMR(300MHz，DMSO-d6)，δ(ppm)：8.23(1H，d，J＝8.1Hz)，7.55～7.32(4H，m，-ArH)，7.29(1H，s)，7.16(1H，d，J＝7.8Hz)，6.64(1H，d，J＝7.8Hz)，2.33(3H，s)，2.21(3H，s).
Synthesizing of 2-(2,4-3,5-dimethylphenyl sulfenyl) aniline (V)
In 1L three-necked bottle, add compound IV (65g, 0.251mol) and methyl alcohol 400ml, add reduced iron powder (28g, 0.502mol), ammonium chloride (26.8g, 0.610mol), continue reaction 3 hours, stopped reaction, filtered while hot, the appropriate methanol wash of filter cake, merging filtrate, revolve methyl alcohol, add 200ml water, with ethyl acetate (200ml × 3) extraction, merge organic layer, saturated common salt water washing, anhydrous sodium sulfate drying spends the night, suction filtration, be spin-dried for solvent and obtain faint yellow oily matter 52.8g, productive rate: 92%.
1H-NMR(300MHz，DMSO-d6)，δ(ppm)：7.16～7.09(2H，m，-ArH),7.01(1H，s)，6.85(1H，d，J＝7.8Hz)，6.77(1H，dd，J＝8.1Hz，1.2Hz)，6.59(1H，d，J＝7.8Hz)，6.54(1H，dd，J＝7.5Hz，1.2Hz)，5.23(2H，brs，-NH
2)，2.28(3H，s)，2.18(3H，s).
1-[2-(2,4-aminomethyl phenyl sulfenyl) phenyl] piperazine hydrochloride (VII) synthetic
In 250ml three-necked bottle; add compound V (52g; 0.231mol), two (2-chloroethyl) amine hydrochlorate (49.5g; 0.277mol) with ethylene glycol monomethyl ether 200ml; under nitrogen protection, be heated to 160 DEG C, react 6～12 hours (TLC endpoint detection: sherwood oil: ethyl acetate=10:1); stop heating; be cooled to room temperature, revolve desolventizing, add ethyl acetate 500ml; cooling; separate out khaki color solid, suction filtration, obtains khaki color solid 33.9g after oven dry; productive rate 45%, m.p.234 DEG C～236 DEG C.(Ref.m.p.～234℃.WO2008113359).
1H-NMR(300MHz，CDCl
3)，δ(ppm)：9.91(2H，s)，7.32(1H，d，J＝7.8Hz)，7.15(1H，s)，7.05～6.52(4H，m，-ArH)，6.54(1H，d，J＝7.8Hz)，3.42(8H，broad?s)，2.36(3H，s)，2.30(3H，s).
1-[2-(2,4-aminomethyl phenyl sulfenyl) phenyl] piperazine (fertile for Xi Ting, I) synthetic
Compound VI I (33g, 0.098mol) is added to saturated Na
2cO
3solution (200ml), stir 20 minutes, with ethyl acetate (100ml × 3) extraction, merge organic layer, saturated common salt water washing, anhydrous sodium sulfate drying spends the night, suction filtration, revolves solution and obtains khaki color solid, and dehydrated alcohol recrystallization obtains light yellow crystal 26.5g, productive rate: 90%, m.p.116～118 DEG C.(Ref.m.p.～117℃.WO2008113359).
MS(ESI(+)70eV,m/z)：299[M+H]
+.1H-NMR(300MHz，CDCl
3)，δ(ppm)：7.38(1H，d，J＝7.8Hz)，7.15(1H，s)，7.06～6.85(4H，m，-ArH)，6.48(1H，d，J＝7.8Hz)，3.06(8H，broad?s)，2.35(3H，s)，2.31(3H，s)，1.8(1H，s).
Claims (10)
1. prepare a fertile method for Xi Ting (I), comprise following preparation process:
2. prepare a fertile method for Xi Ting (I), comprise following preparation process:
Wherein X represents halogen.
3. the method for claim 1 or 2, while wherein preparing VII by V, reaction solvent is selected from propyl carbinol, ethylene glycol monomethyl ether, diethylene glycol monomethyl ether, diethylene glycol dimethyl ether, chlorobenzene, dimethyl sulfoxide (DMSO), N, a kind of in dinethylformamide or N,N-dimethylacetamide or both mixtures; Temperature of reaction is 120 DEG C～180 DEG C.
4. the method for claim 3, reaction solvent is diethylene glycol dimethyl ether; Temperature of reaction is 150 DEG C～160 DEG C.
5. the method for claim 1 or 2, wherein compound V is 1:1～2 with the mol ratio of two (2-chloroethyl) amine hydrochlorates.
6. the method for claim 5, compound V is 1:1.1～1.5 with the mol ratio of two (2-chloroethyl) amine hydrochlorates (VI).
7. the method for claim 1 or 2, while wherein preparing I by VII, alkali is the aqueous solution of sodium hydroxide, potassium hydroxide, sodium carbonate or salt of wormwood.
8. the method for claim 2, while wherein preparing IV by II, 2-halogenated nitrobenzene is selected from 2-chloronitrobenzene, 2-bromo nitrobenzene or 2-fluoronitrobenzene; Reaction solvent is selected from one or any both mixture in acetonitrile, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO) or DMF; Under alkaline condition, react, described alkali is potassium hydroxide, sodium hydroxide, sodium methylate, sodium ethylate or sodium hydride.
9. the method for claim 2, while wherein preparing IV by II, Compound I I:III: the mol ratio of alkali is 1:1～2:1～2.
10. the method for claim 2, while wherein preparing V by IV, reaction solvent is selected from water, methyl alcohol, the mixed solvent of ethanol, Virahol or water and above-mentioned arbitrary solvent; Reductive agent is selected from hydrazine hydrate, iron powder, zinc powder or tin protochloride; Catalyzer is selected from iron trichloride, ammonium chloride, hydrochloric acid or sulfuric acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410166305.XA CN103936694A (en) | 2014-04-23 | 2014-04-23 | Preparation method of antidepressant vortioxetine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410166305.XA CN103936694A (en) | 2014-04-23 | 2014-04-23 | Preparation method of antidepressant vortioxetine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103936694A true CN103936694A (en) | 2014-07-23 |
Family
ID=51184607
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410166305.XA Pending CN103936694A (en) | 2014-04-23 | 2014-04-23 | Preparation method of antidepressant vortioxetine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103936694A (en) |
Cited By (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104230852A (en) * | 2014-08-29 | 2014-12-24 | 成都倍特药业有限公司 | Synthetic method of vortioxetine |
| CN104356092A (en) * | 2014-11-27 | 2015-02-18 | 合肥创新医药技术有限公司 | Preparation method for vortioxetine |
| CN104447622A (en) * | 2014-11-28 | 2015-03-25 | 郑州大明药物科技有限公司 | Novel preparation method of hydrobromic acid Vortioxetine beta crystalline form |
| WO2015114395A1 (en) | 2014-01-31 | 2015-08-06 | Egis Gyógyszergyár Zrt. | Process for the preparation of vortioxetine salts |
| CN105153066A (en) * | 2015-09-07 | 2015-12-16 | 浙江大学 | Vortioxetine hydrochloride crystal substance and preparation method thereof |
| CN105541759A (en) * | 2016-01-07 | 2016-05-04 | 美吉斯制药（厦门）有限公司 | Novel method for preparing vortioxetine |
| CN105669594A (en) * | 2014-11-19 | 2016-06-15 | 康普药业股份有限公司 | Preparation method of anti-depression drug 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (VI) |
| WO2016079751A3 (en) * | 2014-11-17 | 2016-07-14 | Megafine Pharma (P) Ltd. | A process for preparation of vortioxetine and polymorphs thereof |
| CN105777667A (en) * | 2014-12-18 | 2016-07-20 | 康普药业股份有限公司 | Preparation method of anti-depression drug 1-[2-(2,4-dimethylphenylthio)phenyl]piperazine |
| CN105837528A (en) * | 2016-05-30 | 2016-08-10 | 大连理工大学 | Preparation method of 2-(methyl sulphonyl)-10H-phenothiazine |
| CN107011289A (en) * | 2017-03-10 | 2017-08-04 | 万全万特制药（厦门）有限公司 | The preparation method of Vortioxetine beta crystal |
| 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 |
| CN107915694A (en) * | 2016-10-09 | 2018-04-17 | 北京阜康仁生物制药科技有限公司 | 1 [2 (2,4 3,5-dimethylphenyl sulfydryl) phenyl] piperazine hydrochloride and preparation method thereof |
| US10428033B2 (en) | 2017-02-15 | 2019-10-01 | Piramal Enterprises Limited | Process for the preparation of vortioxetine and salts thereof |
| CN110452188A (en) * | 2019-09-12 | 2019-11-15 | 蚌埠学院 | A kind of preparation method lying prostrate sulphur Xi Ting |
| 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 |
| CN115368318A (en) * | 2022-06-22 | 2022-11-22 | 山东辰龙药业有限公司 | Synthetic method and application of vortioxetine |
-
2014
- 2014-04-23 CN CN201410166305.XA patent/CN103936694A/en active Pending
Non-Patent Citations (2)
| Title |
|---|
| BENNY BANG-ANDERSEN ET AL.: "Discovery of 1-[2-(2,4-Dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): A Novel Multimodal Compound for the Treatment of Major Depressive Disorder", 《J. MED. CHEM.》 * |
| 王芳 等.: "氢溴酸沃替西汀的合成", 《中国医药工业杂志》 * |
Cited By (22)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015114395A1 (en) | 2014-01-31 | 2015-08-06 | Egis Gyógyszergyár Zrt. | Process for the preparation of vortioxetine salts |
| CN104230852A (en) * | 2014-08-29 | 2014-12-24 | 成都倍特药业有限公司 | Synthetic method of vortioxetine |
| CN104230852B (en) * | 2014-08-29 | 2017-03-29 | 桑迪亚医药技术（上海）有限责任公司 | The fertile synthetic method for Xi Ting |
| WO2016079751A3 (en) * | 2014-11-17 | 2016-07-14 | Megafine Pharma (P) Ltd. | A process for preparation of vortioxetine and polymorphs thereof |
| CN105669594A (en) * | 2014-11-19 | 2016-06-15 | 康普药业股份有限公司 | Preparation method of anti-depression drug 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (VI) |
| CN104356092B (en) * | 2014-11-27 | 2017-03-22 | 合肥创新医药技术有限公司 | Preparation method for vortioxetine |
| CN104356092A (en) * | 2014-11-27 | 2015-02-18 | 合肥创新医药技术有限公司 | Preparation method for vortioxetine |
| CN104447622A (en) * | 2014-11-28 | 2015-03-25 | 郑州大明药物科技有限公司 | Novel preparation method of hydrobromic acid Vortioxetine beta crystalline form |
| CN105777667A (en) * | 2014-12-18 | 2016-07-20 | 康普药业股份有限公司 | Preparation method of anti-depression drug 1-[2-(2,4-dimethylphenylthio)phenyl]piperazine |
| CN105153066A (en) * | 2015-09-07 | 2015-12-16 | 浙江大学 | Vortioxetine hydrochloride crystal substance and preparation method thereof |
| CN105541759A (en) * | 2016-01-07 | 2016-05-04 | 美吉斯制药（厦门）有限公司 | Novel method for preparing vortioxetine |
| CN105837528A (en) * | 2016-05-30 | 2016-08-10 | 大连理工大学 | Preparation method of 2-(methyl sulphonyl)-10H-phenothiazine |
| CN107915694A (en) * | 2016-10-09 | 2018-04-17 | 北京阜康仁生物制药科技有限公司 | 1 [2 (2,4 3,5-dimethylphenyl sulfydryl) phenyl] piperazine hydrochloride and preparation method thereof |
| US10428033B2 (en) | 2017-02-15 | 2019-10-01 | Piramal Enterprises Limited | Process for the preparation of vortioxetine and salts thereof |
| CN107011289A (en) * | 2017-03-10 | 2017-08-04 | 万全万特制药（厦门）有限公司 | The preparation method of Vortioxetine beta crystal |
| 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 |
| CN111320592A (en) * | 2018-12-17 | 2020-06-23 | 天津理工大学 | Preparation method of 1- [2- (2, 4-dimethylphenylsulfanyl) -phenyl ] piperazine |
| CN110452188A (en) * | 2019-09-12 | 2019-11-15 | 蚌埠学院 | A kind of preparation method lying prostrate sulphur Xi Ting |
| CN115368318A (en) * | 2022-06-22 | 2022-11-22 | 山东辰龙药业有限公司 | Synthetic method and application of vortioxetine |
| CN115368318B (en) * | 2022-06-22 | 2023-11-03 | 山东辰龙药业有限公司 | Synthesis method and application of voathixetine |
| 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 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103936694A (en) | Preparation method of antidepressant vortioxetine | |
| NO340420B1 (en) | Process for the preparation of 1- (3- (2- (1-benzothiophen-5-yl) -ethoxy) propyl) azetidin-3-ol or salts thereof | |
| KR102230628B1 (en) | Vortioxetine manufacturing process | |
| JP2015145375A (en) | Method of producing 2-methoxymethyl-1,4-benzenediamine | |
| CN100451015C (en) | Preparing method of imatinib | |
| JP7038263B2 (en) | Method for Producing Morpholine Quinazoline Compound and its Intermediate | |
| CN104230852A (en) | Synthetic method of vortioxetine | |
| WO2016202125A1 (en) | Azd9291 intermediate and preparation method therefor | |
| KR101165996B1 (en) | Phthalazinone derivatives, preparation method thereof and pharmaceutical composition comprising same | |
| JPH1180142A (en) | Production of diphenylalkyl compound | |
| CN104356092A (en) | Preparation method for vortioxetine | |
| CN105198821A (en) | Preparation method of Rociletinib | |
| CN105037236B (en) | Rui Boxini intermediates and preparation method thereof | |
| WO2010122794A1 (en) | Process for production of pyrazinecarboxylic acid derivative, and intermediate for the production | |
| CN102105433B (en) | 6-nitro acetophenone compounds, preparation methods and uses thereof | |
| CN109988108A (en) | A kind of rich preparation method for Buddhist nun of card | |
| US20080058523A1 (en) | Processes for synthesizing piperazine-piperidine compounds | |
| EP3848361A1 (en) | Method of producing tetracyclic compound | |
| CN106916148B (en) | Method for synthesizing brexpiprazole | |
| CN111320592A (en) | Preparation method of 1- [2- (2, 4-dimethylphenylsulfanyl) -phenyl ] piperazine | |
| WO2020171073A1 (en) | Method for producing benzazepine derivative and intermediate of same | |
| CN101538252B (en) | Novel preparation method and intermediate for aripiprazole | |
| JPWO2015012271A1 (en) | Method for producing heterocyclic compound | |
| BRPI0613693A2 (en) | 8-alkoxy-4-methyl-3,4-dihydro-quinazolin-2-yl amines and their uses as 5-ht5a receptor binders | |
| JPH04169583A (en) | Phenothiazine derivative and its production |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20140723 |