- Heterogeneous Iron-Catalyzed Hydrogenation of Nitroarenes under Water-Gas Shift Reaction Conditions
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Reduction of various nitroarenes in the presence of heterogeneous iron oxide-based catalyst Fe 2 O 3 /NGr@C under water-gas shift reaction (WGSR) conditions has been demonstrated. The catalytic material is prepared in a straightforward manner via deposition/pyrolysis of iron-phenanthroline complex on carbon support. It shows high chemoselectivity towards the reduction of nitroarenes in the presence of other reducible and/or poisoning-capable functional groups. Hydrogenation is achieved using CO/H 2 O as a hydrogen source. Furthermore, it is demonstrated that the presence of triethylamine additive has a significant positive effect on the rate of reduction.
- Ryabchuk, Pavel,Junge, Kathrin,Beller, Matthias
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Read Online
- Environmentally Benign Large-Scale Synthesis of a Precursor to Vortioxetine
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An eco-friendly, high-yielding, and transition-metal-free synthesis of 2-[(2,4-dimethylphenyl)thio]aniline precursor to vortioxetine is reported. Vortioxetine, a multi-modal acting drug with high affinity for a range of serotonergic targets, is used for the treatment of major depressive disorder (MDD). The synthesis - applicable in multi-gram scale - involves the reaction of bis(2,4-dimethyl)iodonium bromide with commercial 2-aminophenyl disulfide, whereas its reaction with 2-aminothiophenol afforded the same product but in low to moderate yields. This method works equally well in deep eutectic solvents (DESs), based on choline chloride (ChCl).
- Zisopoulou, Stavroula A.,Pafili, Anastasia E.,Gkizis, Petros,Andreou, Thanos,Koftis, Theoharis V.,Lithadioti, Alexandra,Neokosmidis, Efstratios,Gallos, John K.
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Read Online
- Chemoselective Hydrogenation of Nitroarenes Using an Air-Stable Base-Metal Catalyst
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The reduction of nitroarenes to anilines as well as azobenzenes to hydrazobenzenes using a single base-metal catalyst is reported. The hydrogenation reactions are performed with an air-and moisture-stable manganese catalyst and proceed under relatively mild reaction conditions. The transformation tolerates a broad range of functional groups, affording aniline derivatives and hydrazobenzenes in high yields. Mechanistic studies suggest that the reaction proceeds via a bifunctional activation involving metal-ligand cooperative catalysis.
- Zubar, Viktoriia,Dewanji, Abhishek,Rueping, Magnus
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supporting information
p. 2742 - 2747
(2021/05/05)
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- Coupling of thiols and aromatic halides promoted by diboron derived super electron donors
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We have proven that pyridine-boryl complexes can be used as superelectron donors to promote the coupling of thiols and aromatic halides through a SRN1 mechanism. The reaction is efficient for a broad substrate scope, tolerating heterocycles including pyridines, enolizable or reducible functional groups. The method has been applied to intermediates in drug synthesis as well as interesting functionalized polythioethers through a controlled and consecutive intramolecular electron transfer process.
- Franco, Mario,Vargas, Emily L.,Tortosa, Mariola,Cid
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supporting information
p. 11653 - 11656
(2021/11/12)
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- Manufacturing method of vortioxetine hydrobromide
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Is a process for preparing fluoxetine hydrobromide used as an antidepressant. Provided is 1 [(2 dimethylphenyl) sulfanyl] aniline represented by chemical formula 4 - and bis (-chloroethyl) amine hydrochloride and hydrobromic acid represented by the following chemical formula - 2 - are reacted with benzothiazole represented 2,4- by the following general formula 4 or 3 and 2 - 2- [(2,4-dimethylphenyl) sulfanyl] aniline. The method according to claim 6, wherein the thioxanthine hydrobromide is represented by the following formula. Chemical Formula 1. Chemical Formula 2. Chemical Formula 3. Chemical Formula 4. Chemical Formula 6.
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Paragraph 0046; 0070-0071
(2021/11/30)
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- Preparation method of 1-[2-(2, 4-dimethylthiophenyl)-phenyl]piperazine
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The invention relates to a preparation method of 1-[2-(2,4-dimethylthiophenyl)-phenyl]piperazine. The method comprises the steps that 2,4-dimethylthiophenol and 1-halogen-2-nitrobenzene carry out a substitution reaction to prepare 2-(2,4-dimethylthiophenyl) nitrobenzene, 2-(2,4-dimethylthiophenyl) nitrobenzene is reduced to prepare 2-(2,4-dimethylthiophenyl)aniline, and 2-(2,4-dimethylthiophenyl)aniline and bis(2-chloroethyl)amine hydrochloride carry out a cyclization reaction to prepare 1-[2-(2,4-dimethylthiophenyl)-phenyl]piperazine. According to the preparation method, 2,4-dimethylthiophenol and 1-halogen-2-nitrobenzene are used as starting materials, and a substitution reaction, a reduction reaction and a cyclization reaction are carried out to prepare the target compound. The three-step reaction is low in cost, high in yield and easy to purify and industrialize.
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Paragraph 0021; 0027-0031
(2020/07/12)
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- METHOD AND CATALYST FOR PREPARING ANILINE COMPOUNDS AND USE THEREOF
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The present invention provides a method for preparing aniline compounds, and also provides a kind of catalyst and use thereof. This method for synthesizing an aniline compound in the invention includes following steps: use molybdenum oxide and activated carbon as catalyst, hydrazine hydrate as reducing agent, then reduce aromatic nitro compounds to aniline compounds. This method is green and high efficiency, and easy to be applied in industry.
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Paragraph 0054; 0055; 0070; 0071; 0078; 0079; 0080
(2019/04/18)
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- Method for synthesizing aniline compound, catalyst and application thereof
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The invention provides a method for synthesizing an aniline compound, and further provides a catalyst and an application thereof. The method for synthesizing the aniline compound includes the following steps: taking molybdenum-based oxide and activated carbon as catalysts; taking hydrazine hydrate as a reducing agent; and reducing an aromatic nitro compound to the aniline compound. The method forsynthesizing the aniline compound has the characteristics of green and high efficiency, easy industrial application and the like.
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Paragraph 0057; 0058; 0059; 0081; 0082; 0083; 0084-0090
(2019/04/17)
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- A ONE-POT ORGANO-PSEUDOCATALYTIC C-H ACTIVATION APPROACH FOR THE PREPARATION OF VORTIOXETINE AND VORTIOXETINE INTERMEDIATE
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The present invention relates to a novel process for the preparation of Vortioxetine and a key intermediate thereof by employing a novel one-pot organo-pseudocatalytic C-H activation approach via hypervalent iodine chemistry.
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- Preparation method of (by machine translation)
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The benzothiazole derivatives are dissociated into o-aminophenylsulfated phenol under the catalysis of copper (II) or copper salt and react under the catalysis of copper or (III), copper salt to give a protected V-oxiracetaine, 2,4 - and the protected V 2 - (2,4 -cetine compound can) be (V) obtained 2 - (2,4 - under the action of) a (V) compound under (2 - the action) - 4 - of a reaction (VI) rate of Ts (dvcetine) (VII): Ts (dvcetine) (VII) (Mg STR9 (I) # STR9#). The synthesis method is easy to obtain, simple in process, low in cost, high in purity and suitable for industrial production. (by machine translation)
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- Preparation method of antidepressant vortioxetine
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The invention discloses a preparation method of an antidepressant vortioxetine, and relates to the related technical field of bulk drugs. The preparation method comprises the following steps: benzothiazole in the formula is taken as a raw material and coupled with 2,4-dimethylchlorobenzene (III), and 2-(2,4-dimethylphenylsulfanyl)aniline (IV) is produced; iminodiacetic acid (V) is self-condensed,and 2,6-dicarbonylmorpholine (VI) is synthesized; the compound IV 2-(2,4-dimethylphenylsulfanyl)aniline is condensed with the compound (VI) 2,6-dicarbonylmorpholine, 4-[2-(2,4-dimethylphenylthio)phenyl]-3,5-dioxopiperazine (VII) is obtained and further reduced, and vortioxetine is obtained. According to the preparation method of the antidepressant vortioxetine, volatile thiophenol derivatives withmalodorous odor are no longer used, so that the preparation method is environmentally friendly; precious metal and phosphorus ligand are no longer used for catalytic coupling, and the production costis low; operation is simple and safe, and the yield is high; and the prepared vortioxetine has high purity, can meet requirements of bulk drugs, and is suitable for industrial production.
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Paragraph 0032; 0033
(2019/07/04)
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- AN IMPROVED PROCESS FOR PREPARATION AND PURIFICATION OF VORTIOXETINE HYDROBROMIDE
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The present invention is related to an improved process for the preparation and purification of crystalline polymorph of Vortioxetine hydrobromide of Formula-I and Vortioxetine hydrochloride of Formula-Ia. The process according to present invention is operationally simple and suitable for industrial application which will avoid hazardous chemicals and eliminate column chromatography to get ICH quality of pharmaceutically acceptable active pharmaceutical ingredient having snow white appearance.
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Page/Page column 9
(2018/09/19)
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- Synthesis and biological evaluation of some bicyclic [2-(2,4-dimethylphenylthio)phenyl] aniline and its amide derivatives as potential antitubercular agents
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Abstract: In the present investigation, a series of bicyclic [2-(2,4-dimethylphenylthio)phenyl] aniline analogues were synthesized and characterized by IR, NMR (1H and 13C) and mass spectra. All newly synthesized 15 compounds were inspected for their in vitro antitubercular activity against Mycobacterium tuberculosis (MTB) H 37Ra in both active and dormant state using an established XTT Reduction Menadione assay (XRMA). The titled compounds exhibited minimum inhibitory concentration (MIC90) ranging from 0.05 to?>30 (μ g/mL). The potent four compounds were further evaluated in THP-1 infection model where they demonstrated significant antitubercular activity. All the ex vivo active were further evaluated for cytotoxic activity against THP-1, MCK-7 and HeLa cell lines in order to check selectivity index. All compounds were further screened against four different bacteria to assess their selectivity towards MTB. These derivatives could be considered as a precursor structure for further design of antituberculosis agent. Graphical Abstract: SYNOPSIS A series of bicyclic [2-(2,4-dimethylphenylthio)phenyl] aniline analogues were synthesized. All newly synthesized 15 compounds were inspected for their in vitro antitubercular activity against Mycobacterium tuberculosis (MTB) H 37Ra in both active and dormant state using an established XTT Reduction Menadione assay (XRMA).[Figure not available: see fulltext.].
- Patil, Yogesh,Shingare, Ramesh,Chakraborty, Shakti,Borkute, Rachana,Sarkar, Dhiman,Madje, Balaji
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- 1-[2-(2,4-dimethylphenylsulfydryl)phenyl]piperazine hydrochloride and preparation method thereof
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The invention discloses 1-[2-(2,4-dimethylphenylsulfydryl)phenyl]piperazine hydrochloride and a preparation method thereof. By means of the specific preparation method, the HPLC purity of vortioxetinehydrochloride is higher than 99.5%, and the content of
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Paragraph 0021; 0022
(2018/04/28)
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- Clean production method of antidepressant drug intermediate
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The invention belongs to the technical field of medicines and particularly relates to a clean production method of an antidepressant drug intermediate. Aluminum oxide doped silicon dioxide is taken asa carrier, ammonium paratungstate is taken as a modifie
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Paragraph 0028; 0044-0081
(2018/11/27)
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- fertile for the west sandbank synthetic method
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The invention discloses a synthetic method of vortioxetine. The synthetic method comprises the following steps of by adopting a compound as shown in a formula (I) as a raw material, carrying out substitution reaction on the compound and 2,4-dimethyl thiophenol (II) to generate 2-(2,4-dimethyl phenyl alkyl sulfide) nitrobenzene (III); reducing 2-(2,4-dimethyl phenyl alkyl sulfide) nitrobenzene (III) to obtain 2-(2,4-dimethyl phenyl alkyl sulfide) phenylamine (IV); cyclizing 2-(2,4-dimethyl phenyl alkyl sulfide) phenylamine (IV) and N,N-bis(2-chloroethyl)-4-methyl benzsulfamide (VI) to obtain Tos-protecting vortioxetine (V); and preparing vortioxetine (VII) from Tos-protecting vortioxetine (V) under the action of a phenol additive. The synthetic method disclosed by the invention has the advantages of easily available raw material, simple process, low cost and high purity, and is suitable for industrialized production.
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Paragraph 0042; 0043; 0044; 0045
(2017/08/25)
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- NOVEL POLYMORPHIC FORMS OF VORTIOXETINE AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS
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The present invention provides polymorphic forms of Vortioxetine of and its pharmaceutically acceptable salts. Specifically the present invention relates to the novel crystalline forms of Vortioxetine or its pharmaceutically acceptable salts. Moreover, the present invention also provides an amorphous form of Vortioxetine hydrobromide and a stable amorphous co-precipitate of Vortioxetine hydrobromide with pharmaceutically acceptable excipients.
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Paragraph 0181
(2017/08/01)
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- New synthesis process for vortioxetine hydrobromide
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The invention relates to a preparation method of vortioxetine hydrobromide. The method is characterized by: subjecting benzothiazole and dimethyliodobenzen to ring opening reaction under the catalysis of ferric trichloride, then cooperating with dichloroethylamine hydrochloride to generate vortioxetine, and then conducting hydrobromination so as to obtain the target product. The process provided by the invention has the advantages of easily available raw materials, concise technology, high overall yield, few by-product, and simple post-treatment, thus being suitable for industrial production.
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Paragraph 0021; 0022
(2018/01/04)
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- METHOD OF PREPARING VORTIOXETINE
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The new method of preparing 1-(2-(2,4-dimethylphenylsulphanyl)pheny!)piperazine of formula (I) or its salt comprises a reaction of 2-(2,4-dimethylphenylsulphanyl)benzeneamine of formula (XI), wherein Me is methyl, with a suitable precursor of formation of piperazine ring of formula (Xll), wherein LG is a leaving group and R is hydrogen or a protective group, in a suitable organic solvent, wherein the reaction is carried out without presence of a base in a neutral or acidic environment. (Formulae (I), (XI), (XII))
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Page/Page column 7; 12
(2016/01/25)
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- PROCESSES FOR THE PREPARATION OF VORTIOXETINE HYDROBROMIDE
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The present invention relates to a process for the preparation of vortioxetine and its pharmaceutically acceptable salts.
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Page/Page column 30; 31
(2016/09/22)
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- A PROCESS FOR PREPARATION OF VORTIOXETINE AND POLYMORPHS THEREOF
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The present invention relates to an improved process for preparation of vortioxetine or pharmaceutically acceptable salts thereof. The present invention also relates to new process for the preparation of vortioxetine or pharmaceutically acceptable salts thereof. The present invention further relates to novel polymorphs of vortioxetine hydrobromide and process for preparation thereof.
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Page/Page column 25; 26; 32
(2016/06/15)
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- Preparation method of anti-depression drug 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (VI)
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The invention relates to a preparation method of an anti-depression drug 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (VI). The preparation method comprises the following steps: using 2,4-dimethyl thiophenol (I) as the initial raw material; condensing the 2,4-dimethyl thiophenol (I) with 2-halogenated nitrobenzene (II) to obtain 2-(2,4-dimethylphenylsulfanyl)nitrobenzene (III); reducing the 2-(2,4-dimethylphenylsulfanyl)nitrobenzene (III) to obtain 2-(2,4-dimethylphenylsulfanyl)aniline (IV); and performing loop closing on the 2-(2,4-dimethylphenylsulfanyl)aniline (IV) and bis-(2-chloroethyl)amine hydrochloride (V), so that the 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (VI) is prepared. The preparation method disclosed by the invention has the following advantages: the raw materials are low in costs and easy to obtain, the technology is simple, and the preparation method is economical and environmental-friendly as well as suitable for industrial production.
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Paragraph 0059; 0060
(2017/01/12)
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- Preparation method of vortioxetine hydrobromide
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The invention relates to the technical field of preparation of vortioxetine hydrobromide, in particular to a preparation method of vortioxetine hydrobromide. The preparation method comprises the following steps: taking 2,4-dimethyl thiophenol as a raw material to react with o-bromonitrobenzene so as to generate a compound (IV); treating the compound (IV) via a normal pressure catalytic hydrogenation method to obtain a compound (V); treating the compound (V) via a Sandmeyer reaction to obtain a compound (VI); and reacting a compound (VII) with piperazine, and then performing a reaction with hydrobromic acid to generate a salt, thereby obtaining a target compound (I). The method for preparing vortioxetine hydrobromide is relatively short in route, relatively mild in reaction condition, simple, convenient and feasible in after treatment, and more suitable for industrial production requirements.
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Paragraph 0031
(2017/01/19)
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- Synthetic method for vortioxetine hydrobromide
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The invention provides a synthetic method for vortioxetine hydrobromide. Firstly, 2-nitro thiophenol and 2,4-dimethyl iodobenzene are reacted, an intermediate 2-(2,4-dimethyl phenyl sulfenyl) nitrobenzene, the intermediate is subjected to reduction, 2-(2,4-dimethyl phenyl sulfenyl) phenylamine is prepared, then 2-(2,4-dimethyl phenyl sulfenyl) phenylamine and bis(2-chloroethyl)amine hydrochloride are subjected to a cyclization reaction, vortioxetine is prepared, finally, vortioxetine is reacted with hydrobromic acid and is salified, and vortioxetine hydrobromide is prepared. The total yield of vortioxetine hydrobromide can reach 65%, the method has advantages of cheap and easily available initial raw materials and simple synthetic technology, and meets requirements of large-scale industrial production.
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Paragraph 0027
(2016/10/07)
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- A suitable hydrobromidum fertile for method for synthesizing west sandbank industrial production (by machine translation)
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The invention provides a novel method for preparing vortioxetine hydrobromide, and belongs to the technical field of medicine synthesis. The method uses 2-fluoroaniline as a starting material to prepare the clinical medicinal vortioxetine hydrobromide by Boc protection, condensation, deprotection condensation, cyclization and other 4 steps of reaction. The method has the advantages of easy obtained raw material, low price, simple synthesis operation, mild reaction condition, easy control, no high pressure, good reaction selectivity, high yield and suitability for industrial production.
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- SYNTHESIS OF VORTIOXETINE VIA (2,4-DIMETHYLPHENYL)(2-IODOPHENYL)SULFANE INTERMEDIATE
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The present invention provides a new synthetic process for the production of 1 -(2-((2,4-dimethylphenyl)thio)phenyl)piperazine (vortioxetine), a drug for the treatment of depression and anxiety, which is conducted via (2,4-dimethylphenyl)(2-iodophenyl)sulfane intermediate.
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Page/Page column 13; 14
(2015/11/03)
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- PROCESS FOR THE PREPARATION OF VORTIOXETINE SALTS
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The invention relates to an improved process for the preparation of pharmaceutical active ingredients and also to high purity salts and pharmaceutical compositions prepared by said process. More particularly the invention relates to an economical process for the preparation of the compound having the international non-proprietary name (INN) vortioxetine and the chemical nomenclature l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine. Vortioxetine corresponds to the following Formula Still more particularly the invention relates to the preparation of high purity vortioxetine L- (+)-mandelate salt of the Formula IX, the conversion of this salt into other highly pure salts and also to the formulation of said salts.
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Page/Page column 34
(2015/09/23)
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- NEW PROCESS FOR THE SYNTHESIS OF 1-(2-((2,4-DIMETHYLPHENYL)THIO)PHENYL)PIPERAZINE
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The present invention provides new intermediate compounds or formulae (III) and (IVa), and salts thereof, and their use in a new synthetic process for the production of 1-(2-((2,4- dimethylphenyl)thio)phenyl)piperazine (vortioxetine) an experimental drug under development for the treatment of depression and anxiety.
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Page/Page column 16
(2014/10/18)
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- PERMANENTLY POSITIVELY CHARGED ANTIDEPRESSANTS
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The present invention provides compounds comprising a substructure of below formula 3: or a salt or prodrug thereof and the use of such compounds in treatment of e.g. CNS disorders.
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Page/Page column 71; 72
(2013/03/26)
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- Electrochemical Reduction of Some o-Bis(phenylsulphonyl)benzene Derivatives. Effect of the Substrate Structure and of the Addition of Bases on the Product Distribution.
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A study of the electrochemical behaviour of the o-bis(phenylsulphonyl)benzene derivatives (1a-e) in dimethyl sulphoxide containing 0.1M-tetrabutylammonium tetrafluoroborate has been undertaken.The results from cyclic voltammetry, controlled-potential electrolysis, and coulometry strongly argue in support of a mechanism involving initial formation of the radical anion (1)-. which fragments into the ? radical (2) and PhSO2-.Competing pathways for (2) are (a) intramolecular homolytic arylation eventually leading to dibenzothiophene (4) together with dihydrodibenzothiophene (5) derivatives and (b) hydrogen-atom transfer leading to monosulphones (6).The fact that compounds (1a,b) undergo mainly cyclization, whereas the hydrogen-atom transfer predominates in the case of compounds (1c,d), indicates that the structure of the starting substrate is a major governing factor for the above competition.An explanation, based on a concomitance of steric effects of the methyl groups ortho to the phenylsulphonyl substituents, is given.Experiments carried out in the presence of different bases show that the intramolecular arylation leading to the cyclized product can occur also through an unprecedented chain mechanism whose efficiency, which increases as the strength and the concentration of the base is increased, is found in turn to be dependent on the substrate structure.Finally, when arenethiolates are used as bases, a third pathways (the nucleophile-radical coupling step of the SRN1 process) is found to compete for the intermediate ? radical (2) eventually leading to sulphides resulting from the overall substitution of an arylthio for a moiety in (1).When the intramolecular cyclization does not compete efficiently almost quantitative yields of sulphides are obtained via an SRN1 route.
- Novi, Marino,Garbarino, Giacomo,Petrillo, Giovanni,Dell'Erba, Carlo
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p. 623 - 632
(2007/10/02)
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