WO2014191548A1 - Nouveau procédé pour la synthèse de 1-(2-((2,4-diméthylphényl)thio)phényl)pipérazine - Google Patents

Nouveau procédé pour la synthèse de 1-(2-((2,4-diméthylphényl)thio)phényl)pipérazine Download PDF

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Publication number
WO2014191548A1
WO2014191548A1 PCT/EP2014/061242 EP2014061242W WO2014191548A1 WO 2014191548 A1 WO2014191548 A1 WO 2014191548A1 EP 2014061242 W EP2014061242 W EP 2014061242W WO 2014191548 A1 WO2014191548 A1 WO 2014191548A1
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Prior art keywords
salt
compound
dimethylphenyl
formula
piperazine
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PCT/EP2014/061242
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English (en)
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Borut ZUPANCIC
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Lek Pharmaceuticals D.D.
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Priority to CN201480036897.1A priority Critical patent/CN105339361A/zh
Publication of WO2014191548A1 publication Critical patent/WO2014191548A1/fr

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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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • This invention relates to a new and advantageous process for the synthesis of 1 -(2-((2,4- dimethylphenyl)thio)phenyl)piperazine (vortioxetine) an experimental drug under
  • Vortioxetine is disclosed as Example 1 e in WO 2003/029232 A1 and is described as being prepared analogously to Example 1.
  • the process used to prepare Example 1 involves the preparation of 1 -(2-((2-(trifluoromethyl)phenyl)thio)phenyl)piperazine on a solid polystyrene support, followed by decomplexation using visible light irradiation, and purification by preparative LC-MS and ion-exchange chromatography.
  • the overall yield for the preparation of vortioxetine is described as 17%.
  • vortioxetine is also described by Bang-Andersen et al. in J. Med. Chem. (201 1 ), Vol. 54, 3206-3221.
  • ie/f-butyl 4-(2-bromophenyl)piperazine-1 - carboxylate intermediate is prepared from Boc-piperazine and 2-bromoiodobenzene in a palladium catalyzed coupling reaction.
  • Vortioxetine is deprotected using hydrochloric acid to give vortioxetine hydrochloride.
  • the present invention provides new intermediate compounds, and salts thereof, and their use in a new synthetic process for the production of vortioxetine.
  • the new process provides vortioxetine in a high yield without the use of palladium catalyst and phosphine ligand, nor expensive starting materials.
  • the new intermediate compounds are provided in crystalline form allowing for improved processability, manufacture, and purity of vortioxetine end product.
  • Embodiment 1 A process for the manufacture of a compound of formula (VIII), or salt thereof,
  • Q represents SO or S0 2 and Z represents hydrogen or a protecting group, which comprises the reaction of a compound of formula (VII), or salt thereof,
  • LG represents a leaving group
  • Embodiment 2 A process according to Embodiment 1 wherein LG represents F, CI or Br.
  • Embodiment 3 A process according to Embodiments 1 or 2 wherein Z represents hydrogen, trityl, methanesulfonyl, p-toluenesulfonyl or ie f-butyloxycarbonyl.
  • Embodiment 4 A process according to any one of Embodiments 1 to 3 wherein Z represents hydrogen.
  • Embodiment 5 A process according to any one of Embodiments 1 to 3 wherein Z represents ie f-butyloxycarbonyl.
  • Embodiment 6 A process according to any one of Embodiments 1 to 5 carried out in the presence of a suitable base and a suitable solvent.
  • Embodiment 7 A process according to Embodiment 6 wherein the base is selected from K 2 C0 3 or Cs 2 C0 3 .
  • Embodiment 8 A process according to Embodiments 6 or 7 wherein the solvent is a polar solvent.
  • Embodiment 9 A process according to any one of Embodiments 6 to 8 wherein the solvent is an aprotic solvent.
  • Embodiment 10 A process according to Embodiment 9 wherein the solvent is selected from DMSO and DMF.
  • Embodiment 11 A process according to any one of Embodiments 6 to 10 carried out at a reaction temperature of 50 to 150°C.
  • Embodiment 12 A process according to any one of Embodiments 6 to 10 wherein carried out at a reaction temperature of 90 to 1 10°C.
  • Embodiment 13 A process according to any one of Embodiments 1 to 12 which comprises the additional step of reducing the compound of formula (VIII), or salt thereof, to obtain a compound of formula (IX), or salt thereof,
  • Embodiment 14 A process according Embodiment 13 wherein Q represents SO and the reducing agent is Lawesson's reagent or Mg.
  • Embodiment 15 A process according Embodiment 14 wherein the reducing agent is Lawesson's reagent in THF and the reaction is carried out at a temperature of 20 to 30°C.
  • Embodiment 16 A process according Embodiment 14 wherein the reducing agent is Mg in MeOH and the reaction is carried out at a temperature of 20 to 30°C.
  • Embodiment 17 A process according Embodiment 13 wherein Q represents S0 2 and the reducing agent is DIBAL-H.
  • Embodiment 18 A process according Embodiment 17 wherein the reducing agent is DIBAL-H in toluene and the reaction is carried out at a temperature of 20 to 30°C.
  • Embodiment 19 A process according to any one of Embodiments 13 to 18, wherein Z represents a protecting group in the compound of formula (IX), which comprises the additional steps of deprotecting the compound of formula (IX) and converting the compound of formula (IX), or salt thereof, to its hydrobromide salt.
  • Embodiment 20 A process according to any one of Embodiments 13 to 18, wherein Z represents hydrogen in the compound of formula (IX), which comprises the additional step of converting the compound of formula (IX), or salt thereof, to its hydrobromide salt.
  • Embodiment 21 A process for the manufacture of a compound of formula (IX), or a salt thereof,
  • Z represents hydrogen or a protecting group, which comprises the following steps: (i) the reaction of a compound of formula (VII), or salt thereof,
  • Embodiment 22 A process according to Embodiment 21 wherein:
  • LG represents F, CI or Br
  • step (i) is carried out in the presence of a suitable base and a suitable solvent
  • step (ii) represents SO and in step (ii) the reducing agent is selected from Lawesson's reagent or Mg, or
  • step (ii) represents S0 2 and in step (ii) the reducing agent is DIBAL-H.
  • Embodiment 23 A process according to Embodiment 22 wherein:
  • the base is selected from K 2 C0 3 or Cs 2 C0 3
  • the solvent is an aprotic solvent selected from DMSO and DMF, and the reaction is carried out at a temperature of 50 to 150°C;
  • step (ii) represents SO and in step (ii) the reducing agent is Lawesson's reagent in THF and the reduction is carried out at a temperature of 20 to 30°C,
  • step (ii) represents SO and in step (ii) the reducing agent is Mg in MeOH and the reaction is carried out at a temperature of 20 to 30°C, or
  • step (ii) represents S0 2 and in step (ii) the reducing agent is DIBAL-H in toluene and the reaction is carried out at a temperature of 20 to 30°C.
  • Embodiment 24 A process for the manufacture of vortioxetine, or salt thereof, which comprises the reaction of (2,4-dimethylphenyl)(2-fluorophenyl)sulfane, or salt thereof, with piperazine, or salt thereof.
  • Embodiment 25 A process according to Embodiment 24 carried out in the presence of a suitable base and a suitable solvent.
  • Embodiment 26 A process according to Embodiment 25 wherein the base is selected from K 2 C0 3 , Cs 2 C0 3 , K 3 P0 4 , NaH, 1 ,8-diazabicycloundec-7-ene or 1 ,1 ,3,3-tetramethylguanidine.
  • Embodiment 27 A process according to Embodiments 25 or 26 wherein the solvent is a polar solvent.
  • Embodiment 28 A process according to any one of Embodiments 25 to 27 wherein the solvent is an aprotic solvent.
  • Embodiment 29 A process according to Embodiment 28 wherein the solvent is selected from DMSO and DMF.
  • Embodiment 30 A process according to any one of Embodiments 25 to 29 carried out at a reaction temperature of 100 to 160°C.
  • Embodiment 31 A process according to any one of Embodiments 25 to 29 wherein carried out at a reaction temperature of 130 to 150°C.
  • Embodiment 32 A process according to any one of Embodiments 24 to 31 which comprises the additional step of converting vortioxetine, or salt thereof, to its hydrobromide salt.
  • Embodiment 33 A compound of formula (VII), or salt thereof,
  • Q represents S, SO or S0 2 ;
  • LG represents a leaving group
  • Embodiment 34 A compound according to Embodiment 33 wherein Q represents SO so 2 .
  • Embodiment 35 A compound according to Embodiments 33 or 34 wherein LG represents F, CI or Br.
  • Embodiment 36 A compound according to Embodiment 33 selected from:
  • Embodiment 37 A compound of formula (VIII), or salt thereof,
  • Q represents SO and Z represents a protecting group
  • Q represents S0 2 and Z represents hydrogen or a protecting group.
  • Embodiment 38 A compound according to Embodiment 37 wherein Z represents trityl, methanesulfonyl, p-toluenesulfonyl or ie f-butyloxycarbonyl.
  • Embodiment 39 A compound according to Embodiment 37 wherein Z represents ie f- butyloxycarbonyl.
  • Embodiment 40 A compound according to Embodiment 37 selected from:
  • Embodiment 41 Use of 1 -(2-((2,4-dimethylphenyl)sulfinyl)phenyl)piperazine, or a salt thereof, or a compound according to any one of Embodiments 33 to 40, or a salt thereof, in the manufacture of vortioxetine, or salt thereof.
  • Embodiment 42 Use of 1 -(2-((2,4-dimethylphenyl)sulfinyl)phenyl)piperazine, or a salt thereof, or a compound according to any one of Embodiments 33 to 40, or a salt thereof, in the manufacture of vortioxetine hydrobromide.
  • aprotic solvent represents any solvent which contains no hydrogen atom that is capable of hydrogen bonding.
  • aprotic solvents include, but are not limited to, DMSO and DMF.
  • base represents a molecular entity or chemical species capable of accepting a proton.
  • the term "leaving group” represents an atom or group (charged or uncharged) that becomes detached from an atom in what is considered to be the residual or main part of the substrate in a specified reaction. More particularly, as used herein the "leaving group” represents an atom or group which can be substituted in a reaction of nucleophilic aromatic substitution. Examples of leaving groups as used herein include, but are not limited to, F, CI, Br, p-toluenesulfonyloxy and trifluoromethanesulfonyloxy.
  • protecting group represents any amino protecting group, preferably a hydrolytically cleavable amino protecting group, selected from unsubstituted or substituted ie f-carbyl, alkanoyl, arenecarbonyl, alkanesulfonyl, alkyloxycarbonyl,
  • the "protecting group” represents a generally accepted protecting group, such as trityl (Tr), methanesulfonyl (Ms), p-toluenesulfonyl (Ts) or tert- butyloxycarbonyl (Boc).
  • Tr trityl
  • Ms methanesulfonyl
  • Ts p-toluenesulfonyl
  • Boc tert- butyloxycarbonyl
  • the term “reduction” represents the complete transfer of one or more electrons to a molecular entity.
  • reducing agent represents the molecular entity or chemical species that donates one or more electrons to a molecular entity in a reduction reaction.
  • DIBAL-H diisobutylaluminium hydride
  • mCPBA meia-chloroperoxybenzoic acid
  • the base can be any organic or inorganic base, preferably K 2 C0 3 or Cs 2 C0 3
  • the solvent used can be any polar solvent, preferably DMSO or DMF
  • the preferred temperature for the reaction between la and III is about 90°C.
  • the preferred temperature for the reaction between lb or Ic with III is about 120°C.
  • intermediate III' is oxidized to compound VII with commonly used oxidizing reagents, preferably using mCPBA or H 2 0 2 .
  • oxidizing reagents preferably using mCPBA or H 2 0 2 .
  • one equivalent of oxidant is used compounds Vila and Vllb are prepared, when two or more equivalents of oxidant used compounds Vile and Vlld are prepared.
  • a preferred solvent is EtOAc, and a preferred reaction temperature is about 0°C.
  • vortioxetine (IX) is prepared starting from sulfoxides Vila or Vllb as shown in Scheme 6 above.
  • the F (Vila) or CI (Vllb) substituent was replaced with piperazine to afford intermediate Villa. This reaction is carried out in
  • Vortioxetine (IX) was then isolated after reduction of the sulfoxide moiety to a sulfide moiety using Lawesson reagent in THF at about 25°C or Mg in MeOH at about 25°C.
  • the sulfoxide group can also be reduced using other known literature procedures.
  • vortioxetine (IX) can also be prepared starting from sulfones Vile or Vlld (Scheme 7).
  • the F (Vile) or CI (Vlld) substituent is replaced with piperazine to afford intermediate Vlllb.
  • This reaction is made in DMSO or DMF at a temperature of 50 to 150°C, preferably at 100°C, using Na 2 C0 3 or K 2 C0 3 as a base.
  • Vortioxetine (IX) is then isolated following reduction of the sulfone moiety using DIBAL-H in toluene. The sulfone group can also be reduced using other procedures known in the literature.
  • Vortioxetine (IX) may be transformed into vortioxetine hydrobromide salt (X) by addition of 48% HBr to an iPrOAc solution of IX at 25°C.
  • vortioxetine (IX) is prepared from compound VII and protected piperazine to afford intermediate Villa', when Q is a sulfoxide moiety, and intermediate Vlllb', when Q is a sulfone moiety, (Scheme 8).
  • Intermediate VIII' can then be transformed into vortioxetine (IX) in one reaction step (for example by reduction using an appropriate reagent, such as Lawesson reagent when Q is SO, followed by acidification using HCI or another strong acid, without isolation of intermediate compound IX'), however it is also possible to convert VIII' to vortioxetine (IX) via intermediate VIII (deprotection followed by reduction) or via protected vortioxetine (IX') (reduction followed by deprotection).
  • an appropriate reagent such as Lawesson reagent when Q is SO, followed by acidification using HCI or another strong acid
  • vortioxetine (IX) is prepared directly by reacting (2,4- dimethylphenyl)(2-fluorophenyl)sulfane (Ilia') with piperazine (Scheme 9).
  • an inorganic base such as K 2 C0 3 , Cs 2 C0 3 , K 3 P0 4 or NaH, or an organic base such as 1 ,8-diazabicycloundec-7-ene (DBU) or 1 ,1 ,3,3-tetramethylguanidine, is preferred.
  • the reaction is usually performed at 140°C in a polar solvent, preferably DMF or DMSO.
  • the reaction time is longer than 14 days.
  • Lawesson's reagent (0.65 g, 1.62 mmol) was added to a solution of 1 -(2-((2,4- dimethylphenyl)sulfinyl)phenyl)piperazine Villa (0.50 g, 1 .59 mmol) in THF (10 mL).
  • the reaction mixture so obtained was stirred at r.t. for 18 h and then EtOAc (10 mL) added.
  • the reaction mixture was washed with 1 M NaOH (2 x 15 mL), saturated NaHC0 3 aqueous solution (2 x 15 mL) and brine (2 x 15 mL).

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un nouveau procédé de synthèse pour la production de 1-(2-((2,4-diméthylphényl)thio)phényl)pipérazine (vortioxétine), un médicament expérimental en cours de développement pour le traitement de la dépression et de l'anxiété, lequel procédé comprend la réaction d'un composé de formule (VII) ou d'un sel de celui-ci, (VII) dans laquelle Q représente S, SO ou SO2 et LG représente un groupe partant, avec un composé de formule (XI) ou un sel de celui-ci, (XI) dans laquelle Z représente un atome d'hydrogène ou un groupe de protection. L'invention concerne également de nouveaux composés intermédiaires.
PCT/EP2014/061242 2013-05-31 2014-05-30 Nouveau procédé pour la synthèse de 1-(2-((2,4-diméthylphényl)thio)phényl)pipérazine WO2014191548A1 (fr)

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CN104829557A (zh) * 2015-04-23 2015-08-12 济南百诺医药科技开发有限公司 一种新化合物1-[2-(2,4-二甲基苯基硫基)苯基]-2-氧哌嗪及其制备方法和在沃替西汀合成中的应用
CN105541759A (zh) * 2016-01-07 2016-05-04 美吉斯制药（厦门）有限公司 一种制备沃替西汀的新方法
WO2016125191A2 (fr) 2015-02-04 2016-08-11 Mylan Laboratories Limited Procédés de préparation de bromhydrate de vortioxétine
WO2016135636A1 (fr) 2015-02-25 2016-09-01 Lupin Limited Procédé de préparation de vortioxétine
WO2016151328A1 (fr) 2015-03-26 2016-09-29 Cipla Limited Procédé de fabrication d'inhibiteurs de la recapture de la sérotonine
CN106316985A (zh) * 2015-06-18 2017-01-11 北京深蓝海生物医药科技有限公司 一种β型高效氢溴酸沃替西汀转晶方法
US9550743B2 (en) 2014-11-21 2017-01-24 Dipharma Francis S.R.L. Process for the preparation of an antidepressant and the intermediates thereof
WO2017137048A1 (fr) 2016-02-08 2017-08-17 H. Lundbeck A/S Synthèse de 1-[2-(2,4-diméthyl-phénylsulfanyl)-phényl]pipérazine
WO2017162536A1 (fr) * 2016-03-21 2017-09-28 H. Lundbeck A/S Promédicaments de vortioxétine
WO2018065348A1 (fr) 2016-10-05 2018-04-12 Hexal Ag Nouveau comprimé à enrobage entérique comprenant de la vortioxétine
CN108191792A (zh) * 2017-12-28 2018-06-22 上海博志研新药物技术有限公司 一种氢溴酸沃替西汀及其中间体的制备方法
CN109912538A (zh) * 2019-01-22 2019-06-21 安徽赛乐普制药有限公司 一种抗抑郁药沃替西汀的制备方法
US10519121B2 (en) 2016-12-30 2019-12-31 Apicore Us Llc Process and novel polymorphic form of vortioxetine and its pharmaceutically acceptable salts
JP2021107432A (ja) * 2016-06-16 2021-07-29 サンシャイン・レイク・ファーマ・カンパニー・リミテッドＳｕｎｓｈｉｎｅ Ｌａｋｅ Ｐｈａｒｍａ Ｃｏ．，Ｌｔｄ． ジアリールチオエーテルピペラジン化合物、その調製方法及び使用
WO2022254248A1 (fr) * 2021-05-31 2022-12-08 R L Fine Chem Private Limited Procédé de préparation de 1-(2-((2,4-diméthylphényl)thio)phényl)pipérazine et de ses sels
US11707461B2 (en) 2017-09-20 2023-07-25 Zhejiang Huahai Pharmaceutical Co., Ltd N-formyl vortioxetine and preparation method thereof and solid preparation of vortioxetine

Families Citing this family (4)

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CN107954947A (zh) * 2016-10-14 2018-04-24 北京莱瑞森医药科技有限公司 沃替西汀氢溴酸盐晶型c及其制备方法
CN108047162B (zh) * 2017-12-11 2018-11-27 中山万远新药研发有限公司 一种二芳基亚砜及砜衍生物及其制备方法和应用
CN113943265A (zh) * 2020-07-15 2022-01-18 北京万全阳光医学技术有限公司 一种制备沃替西汀的方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007144005A1 (fr) * 2006-06-16 2007-12-21 H. Lundbeck A/S 1-[2-(2, 4-diméthylphénylsulfanyl)-phényl]pipérazine comme composé présentant une activité sur la sérotonine, 5-ht3 et 5-ht1a pour le traitement du déficit cognitif

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW200932233A (en) * 2007-11-13 2009-08-01 Lundbeck & Co As H Therapeutic uses of compounds having combined SERT, 5-HT3 and 5-HT1a activity

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007144005A1 (fr) * 2006-06-16 2007-12-21 H. Lundbeck A/S 1-[2-(2, 4-diméthylphénylsulfanyl)-phényl]pipérazine comme composé présentant une activité sur la sérotonine, 5-ht3 et 5-ht1a pour le traitement du déficit cognitif

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
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", JOURNAL OF MEDICINAL CHEMISTRY, vol. 54, no. 9, 12 May 2011 (2011-05-12), pages 3206 - 3221, XP055058222, ISSN: 0022-2623, DOI: 10.1021/jm101459g *
DONALD SIKAZWE ET AL: "Binding of Sulfonyl-Containing Arylalkylamines at Human 5-HT6 Serotonin Receptors", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, vol. 49, no. 17, 24 August 2006 (2006-08-24), pages 5217 - 5225, XP008145411, ISSN: 0022-2623, [retrieved on 20060725], DOI: 10.1021/JM060469Q *

Cited By (26)

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Publication number Priority date Publication date Assignee Title
US9550743B2 (en) 2014-11-21 2017-01-24 Dipharma Francis S.R.L. Process for the preparation of an antidepressant and the intermediates thereof
WO2016125191A2 (fr) 2015-02-04 2016-08-11 Mylan Laboratories Limited Procédés de préparation de bromhydrate de vortioxétine
WO2016135636A1 (fr) 2015-02-25 2016-09-01 Lupin Limited Procédé de préparation de vortioxétine
US10227317B2 (en) 2015-02-25 2019-03-12 Lupin Limited Process for the preparation of vortioxetine
WO2016151328A1 (fr) 2015-03-26 2016-09-29 Cipla Limited Procédé de fabrication d'inhibiteurs de la recapture de la sérotonine
CN104829557A (zh) * 2015-04-23 2015-08-12 济南百诺医药科技开发有限公司 一种新化合物1-[2-(2,4-二甲基苯基硫基)苯基]-2-氧哌嗪及其制备方法和在沃替西汀合成中的应用
CN104829557B (zh) * 2015-04-23 2017-06-27 山东百诺医药股份有限公司 一种新化合物1‑[2‑（2,4‑二甲基苯基硫基）苯基]‑2‑氧哌嗪及其制备方法和在沃替西汀合成中的应用
CN106316985A (zh) * 2015-06-18 2017-01-11 北京深蓝海生物医药科技有限公司 一种β型高效氢溴酸沃替西汀转晶方法
CN106316985B (zh) * 2015-06-18 2021-11-09 郑州深蓝海生物医药科技有限公司 一种β型高效氢溴酸沃替西汀转晶方法
CN105541759A (zh) * 2016-01-07 2016-05-04 美吉斯制药（厦门）有限公司 一种制备沃替西汀的新方法
CN108473451A (zh) * 2016-02-08 2018-08-31 H.隆德贝克有限公司 1-[2-(2,4-二甲基-苯基硫烷基)-苯基]哌嗪的合成
US10562872B2 (en) 2016-02-08 2020-02-18 H. Lundbeck A/S Synthesis of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]piperazine
CN108473451B (zh) * 2016-02-08 2022-07-15 H.隆德贝克有限公司 1-[2-(2,4-二甲基-苯基硫烷基)-苯基]哌嗪的合成
CN109071374A (zh) * 2016-02-08 2018-12-21 Aaa化学公司 脂肪胺的芳基化
JP2019506411A (ja) * 2016-02-08 2019-03-07 ハー・ルンドベック・アクチエゼルスカベット １−［２−（２，４−ジメチル−フェニルスルファニル）−フェニル］ピペラジンの合成
WO2017137048A1 (fr) 2016-02-08 2017-08-17 H. Lundbeck A/S Synthèse de 1-[2-(2,4-diméthyl-phénylsulfanyl)-phényl]pipérazine
WO2017162536A1 (fr) * 2016-03-21 2017-09-28 H. Lundbeck A/S Promédicaments de vortioxétine
JP2021107432A (ja) * 2016-06-16 2021-07-29 サンシャイン・レイク・ファーマ・カンパニー・リミテッドＳｕｎｓｈｉｎｅ Ｌａｋｅ Ｐｈａｒｍａ Ｃｏ．，Ｌｔｄ． ジアリールチオエーテルピペラジン化合物、その調製方法及び使用
JP7123211B2 (ja) 2016-06-16 2022-08-22 サンシャイン・レイク・ファーマ・カンパニー・リミテッド ジアリールチオエーテルピペラジン化合物、その調製方法及び使用
WO2018065348A1 (fr) 2016-10-05 2018-04-12 Hexal Ag Nouveau comprimé à enrobage entérique comprenant de la vortioxétine
US10519121B2 (en) 2016-12-30 2019-12-31 Apicore Us Llc Process and novel polymorphic form of vortioxetine and its pharmaceutically acceptable salts
US11707461B2 (en) 2017-09-20 2023-07-25 Zhejiang Huahai Pharmaceutical Co., Ltd N-formyl vortioxetine and preparation method thereof and solid preparation of vortioxetine
CN108191792A (zh) * 2017-12-28 2018-06-22 上海博志研新药物技术有限公司 一种氢溴酸沃替西汀及其中间体的制备方法
CN109912538B (zh) * 2019-01-22 2021-03-12 安徽赛乐普制药有限公司 一种抗抑郁药沃替西汀的制备方法
CN109912538A (zh) * 2019-01-22 2019-06-21 安徽赛乐普制药有限公司 一种抗抑郁药沃替西汀的制备方法
WO2022254248A1 (fr) * 2021-05-31 2022-12-08 R L Fine Chem Private Limited Procédé de préparation de 1-(2-((2,4-diméthylphényl)thio)phényl)pipérazine et de ses sels

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