- Regioselective C-H Thioarylation of Electron-Rich Arenes by Iron(III) Triflimide Catalysis
-
A mild and regioselective method for the preparation of unsymmetrical biaryl sulfides using iron(III) catalysis is described. Activation of N-(arylthio)succinimides using the powerful Lewis acid iron(III) triflimide allowed the efficient thiolation of a range of arenes, including anisoles, phenols, acetanilides, and N-heterocycles. The method was applicable for the late-stage thiolation of tyrosine and tryptophan derivatives and was used as the key step for the synthesis of pharmaceutically relevant biaryl sulfur-containing compounds such as the antibiotic dapsone and the antidepressant vortioxetine. Kinetic studies revealed that while N-(arylthio)succinimides bearing electron-deficient arenes underwent thioarylation catalyzed entirely by iron(III) triflimide, N-(arylthio)succinimides with electron-rich arenes displayed an autocatalytic mechanism promoted by the Lewis basic product.
- Dodds, Amy C.,Sutherland, Andrew
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p. 5922 - 5932
(2021/05/04)
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- Preparation method of novel severe depression treatment drug
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The invention provides a preparation method of novel medicament for treating severe depression, and belongs to the field of drug synthesis. A specific scheme of the invention is as follows: 2,4 - dimethyl thiophenol is used. 2 - Bromoiodobenzene, piperazine is a starting material, cuprous iodide is used as a catalyst, one-pot method is used for preparing the, and an organic base is added in the reaction system. To the preparation process, the reaction can be effectively carried out in a homogeneous phase, so that the reaction speed is obviously increased, and the product yield is greatly improved. The problem that in the prior art, homogeneous phase cannot be formed in a reaction system, the reaction time is over 40 hours, and the cost is not greatly reduced in industrial production is solved. Due to the adoption of triethylamine, N, N - diisopropylethylamine and other organic amines, the reaction can be carried out in a homogeneous phase, so that the secondary reaction is reduced, the yield and the purity are greatly improved. The piperazine does not need to be simultaneously added with the starting materials, the feeding step is optimized, the side reaction is reduced, the processes such as filtering are not increased, the procedures in industrialization are not increased, and the investment of equipment and the like is increased.
- -
-
Paragraph 0033-0036; 0040-0043; 0045-0048; 0050-0053; ...
(2021/10/16)
-
- Preparation method of novel severe depression treatment drug
-
The invention provides a preparation method of novel medicament for treating severe depression, and belongs to the field of drug synthesis. A specific scheme of the invention is as follows: 2,4 - dimethyl thiophenol is used. 2 - Bromoiodobenzene, piperazine is a starting material, cuprous iodide is used as a catalyst, one-pot method is used for preparing the, and an organic base is added in the reaction system. To the preparation process, the reaction can be effectively carried out in a homogeneous phase, so that the reaction speed is obviously increased, and the product yield is greatly improved. The problem that in the prior art, homogeneous phase cannot be formed in a reaction system, the reaction time is over 40 hours, and the cost is not greatly reduced in industrial production is solved. Due to the adoption of triethylamine, N, N - diisopropylethylamine and other organic amines, the reaction can be carried out in a homogeneous phase, so that the secondary reaction is reduced, the yield and the purity are greatly improved. The piperazine does not need to be simultaneously added with the starting materials, the feeding step is optimized, the side reaction is reduced, the processes such as filtering are not increased, the procedures in industrialization are not increased, and the investment of equipment and the like is increased.
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-
Paragraph 0025; 0027; 0029-0031; 0036
(2021/10/30)
-
- Redox-active benzimidazolium sulfonamides as cationic thiolating reagents for reductive cross-coupling of organic halides
-
Redox-active benzimidazolium sulfonamides as thiolating reagents have been developed for reductive C-S bond coupling. The IMDN-SO2R reagent provides a bench-stable cationic precursor to generate a portfolio of highly active N-S intermediates, which can be successfully applied in cross-electrophilic coupling with various organic halides. The employment of an electrophilic sulfur source solved the problem of catalyst deactivation and avoided odorous thiols, featuring practical conditions, broad substrate scope, and excellent tolerance.
- Zhang, Weigang,Huang, Mengjun,Zou, Zhenlei,Wu, Zhengguang,Ni, Shengyang,Kong, Lingyu,Zheng, Youxuan,Wang, Yi,Pan, Yi
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p. 2509 - 2514
(2021/03/01)
-
- Study of the isomeric Maillard degradants, glycosylamine and Amadori rearrangement products, and their differentiation via MS2 fingerprinting from collision-induced decomposition of protonated ions
-
Rationale: The focus of this work was to study glycosylamine and Amadori rearrangement products (ARPs), the two major degradants in the Maillard reactions of pharmaceutical interest, and utilize their MS2 fingerprints by liquid chromatography/high-resolution tandem mass spectrometry (LC/HRMS2) to quickly distinguish the two isomeric degradants. These two types of degradants are frequently encountered in the compatibility and stability studies of drug products containing primary or secondary amine active pharmaceutical ingredients (APIs), which are formulated with excipients consisting of reducing sugar functionalities. Methods: Vortioxetine was employed as the primary model compound to react with lactose to obtain the glycosylamine and ARP degradants of the Maillard reaction, and their MS2 spectra (MS2 fingerprints) were obtained by LC/MS2. Subsequently, the two degradants were isolated via preparative HPLC and their structures were confirmed by one- and two-dimensional (1D and 2D) nuclear magnetic resonance (NMR) determination. Results: The MS2 fingerprints of the two degradants display significantly different profiles, despite the fact that many common fragments are observed. Specifically, protonated glycosylamine shows a prominent characteristic fragment of [Mvort + C2H3O]+ at m/z 341 (Mvort is the vortioxetine core), while protonated ARP shows a prominent characteristic fragment of [Mvort + CH]+ at m/z 311. Further study of the Maillard reactions between several other structurally diverse primary/secondary amines and lactose produced similar patterns. Conclusions: The study suggests that the characteristic MS2 fragment peaks and their ratios may be used to differentiate the glycosylamine and ARP degradants, the two isomeric degradants of the Maillard reaction, which are commonly encountered in finished dosage forms of pharmaceutical products containing primary and secondary amine APIs.
- Wang, Shaolan,Lin, Jinsheng,Li, Dan,Huang, Tianpei,Zhu, Wenquan,Chen, Wenbin,Li, Min,Shen, Weiyang
-
-
- THERAPEUTIC USES OF COMPOUNDS HAVING COMBINED SERT, 5-HT3 AND 5-HT1A ACTIVITY
-
New pharmaceutical uses of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine and pharmaceutically acceptable salts thereof are provided.
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-
-
- Preparation method of 1-[2-(2, 4-dimethylthiophenyl)-phenyl]piperazine
-
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.
- -
-
Paragraph 0032-0037
(2020/07/12)
-
- Vortioxetine impurity 1-[3-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine and use thereof
-
The invention relates to the field of pharmaceutical synthesis, and discloses a vortioxetine impurity 1-[3-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine and a use thereof. During the experiment process of synthesizing vortioxetine, the inventors accidentally find an important impurity I of vortioxetine, namely 1-[3-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine, a preparation method of the impurity I is determined, the structure analysis of the impurity I is performed, and the impurity I is not reported before. The impurity is used as a vortioxetine intermediate, and a reference substance ofthe quality research of the raw medicine and preparations thereof, and a solid foundation for the quality research of vortioxetine is further laid.
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-
Paragraph 0044-0057
(2020/02/27)
-
- Dechalcogenization of Aryl Dichalcogenides to Synthesize Aryl Chalcogenides via Copper Catalysis
-
An application for dechalcogenization of aryl dichalcogenides via copper catalysis to synthesize aryl chalcogenides is disclosed. This approach is highlighted by the practical conditions, broad substrate scope, and good functional group tolerance with several sensitive groups such as aldehyde, ketone, ester, amide, cyanide, alkene, nitro, and methylsulfonyl. Furthermore, the robustness of this methodology is depicted by the late-stage modification of estrone and synthesis of vortioxetine. Remarkably, synthesis of more challenging organic materials with large ring tension under milder conditions and synthesis of some halogen contained diaryl sulfides which could not be synthesized using metal-catalyzed coupling reactions of aryl halogen are successfully accomplished with this protocol.
- Cao, Fei,Chen, Jinhong,Deng, Jiedan,Deng, Xuemei,Hou, Yongsheng,Shao, Xiangfeng,Shi, Tao,Wang, Yongqiang,Wang, Zhen,Wu, Lingxi,Yang, Jinru,Yang, Yuhang
-
p. 2707 - 2712
(2020/03/11)
-
- Preparation method of (by machine translation)
-
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 voltamethine
-
The invention belongs to the technical field of organic synthesis route design and raw material medicine and intermediate preparation thereof, and particularly relates to a preparation method of voltamethine. The preparation method includes: condensing 2, bromoiodobenzene and 2,4-dimethyl phenylthiophenol to generate a first intermediate; condensing the first intermediate as well as N-phenoxycarbonyl piperazin and tert-butylalcohol to generate a second intermediate; removing a Boc protective group from N-Boc-voltamethine in the second intermediate to generate a crude voltamethine via alkalineionization; purifying the crude voltamethine to obtain the voltamethine via salt purificaton and re-alkalization ionization. The preparation method is simple in obtaining of raw materials, high in product yield and purity and is suitable for industrial production.
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-
-
- Preparation method of antidepressant vortioxetine
-
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.
- -
-
Paragraph 0038-0048
(2019/07/04)
-
- Transition-Metal-Free Thioamination of Arynes Using Sulfenamides
-
The insertion of arynes into the S-N σ-bond of sulfenamides allowing the synthesis of o-sulfanylaniline derivatives with reasonable functional group compatibility is presented. The aryne generated from 2-(trimethylsilyl)aryl triflates using CsF in DME was the key for the success of this transition-metal-free thioamination reaction, which involves new C-N and C-S bond formations in a single step under mild conditions. Moreover, the synthetic potential of this method was demonstrated by the synthesis of the antidepressant drug vortioxetine.
- Gaykar, Rahul N.,Bhattacharjee, Subrata,Biju, Akkattu T.
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p. 737 - 740
(2019/01/25)
-
- Preparation method of vortioxetine
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The invention relates to the field of organic synthetic route design, in particular to a preparation method of vortioxetine. The preparation method comprises the steps that 2-bromoiodobenzene (formulaII), 2,4-dimethyl benzenethio (formula III), N-phenoxycarbonyl piperazine (formula IV) and tert butyl alcohol (formula V) are taken as raw materials, in an aprotic solvent and under an alkaline condition, a palladium catalyst and a phosphine ligand are added for catalysis, heating is performed, and an intermediate 1 is formed orientedly; in an acidic condition, N-Boc-vortioxetine (formula VI) inthe intermediate 1 is subjected to Boc protecting group removal, and then a crude vortioxetine product (formula I) is formed through alkaline dissociation. The method has the advantages that the raw materials are simple and easy to obtain, the reaction condition of the process is mild, the product has high yield and high purity, and the method is suitable for industrial production.
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Paragraph 0086
(2019/10/01)
-
- Preparation method of vortioxetine
-
The invention relates to the field of medicines, in particular to a preparation method of vortioxetine. The preparation method comprises the steps that 2-bromoiodobenzene, N-phenoxycarbonyl piperazineand tert butyl alcohol are subjected to condensation to form an intermediate 1, that is a mixture of 4-(2-bromine phenyl) piperazine-1-tertiary butyl carboxylate and 1-(2-bromine phenyl) piperazine;the intermediate 1 and 2,4-dimethyl phenylthiophenol are subjected to condensation to form an intermediate 2, that is a mixture of N-Boc-vortioxetine and vortioxetine; the N-Boc-vortioxetine in the intermediate 2 is subjected to Boc protecting group removal, and then a crude vortioxetine product is formed through alkalization, and the crude vortioxetine product is subjected to salinization, purification and alkaline dissociation to obtain the vortioxetine. The method has the advantages that the raw materials are simple and easy to obtain, the product has high yield and high purity, and the method is suitable for industrial production.
- -
-
Paragraph 0033; 0047-0076; 0078-0080
(2019/10/01)
-
- 1 - [2 - (2, 4 - Dimethyl phenyl sulfanyl) - phenyl] piperazine preparation method
-
The invention relates to a preparation method of 1-[2-(2,4-dimethyl phenylsulfanyl)-phenyl]piperazine. The method includes in the presence of an alkali and a catalyst, a compound II and a compound III are subjected to a reaction in an organic solvent to generate the compound I. The preparation method provided by the invention has no need of use of a palladium catalyst, and has the advantages of low cost, high yield, easy purification, and easy industrialization.
- -
-
Paragraph 0017-0019; 0021; 0023; 0025; 0027
(2018/11/22)
-
- Preparation method of vortioxetine and intermediate thereof
-
The invention discloses a preparation method of vortioxetine and an intermediate thereof. The invention provides a preparation method of a vortioxetine intermediate IV, wherein the preparation methodcomprises the following steps: performing Grignard reaction on a vortioxetine intermediate V and 2,4-dimethyliodobenzene and isopropylmagnesium chloride in an organic solvent to obtain the vortioxetine intermediate IV. The preparation method provided by the invention no longer uses volatile odorous thiophenol derivatives, is environmentally friendly, simple and safe to operate and high in yield; the prepared vortioxetine has high purity, can reach requirements of raw material medicines and is suitable for industrial production.
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-
-
- Diaryl sulfoxide and sulfone derivative as well as preparation method and application thereof
-
The invention discloses diaryl sulfoxide and a sulfone derivative as well as a preparation method and application of diaryl sulfoxide and the sulfone derivative. Free secondary amine groups of 1-[2-(2,4-dimethylphenylthio)phenyl]piperazine are protected by di-tert-butyl dicarbonate, and N-protected sulfoxide and the N-protected sulfone derivative are obtained by controlled oxidation reaction respectively; then, 1-[2-(2,4-dimethylbenzene sulfinyl)phenyl]piperazine hydrobromide (formula-1-1) and 1-[2-(2,4-dimethylbenzenesulfonyl)phenyl]piperazine hydrobromide (formula-1-2) are obtained by a series of deprotection and salt formation steps. The compound is expected to be applied in preparation of medicines for resisting depression, anxiety, epilepsy and schizophrenia.
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-
Paragraph 0048; 0049
(2018/06/28)
-
- The preparation method of the fertile for the west sandbank
-
The invention relates to the field of medicament synthesis, in particular to a novel preparation method for an antidepressant medicament intermediate vortioxetine. The method comprises the following steps of reacting 2,4-dimethylthiophenol with 2-halogen chlorobenzene to obtain an intermediate 2-(2,4-dimethylthiophenyl) chlorobenzene, and reacting the intermediate with piperazine to obtain vortioxetine. According to the method, the total yield can reach 68 to 75 percent, the method has the advantages of starting materials are low in cost and easy to obtain, the process is simple, and the requirements of large-scale production are met.
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Paragraph 0043; 0044; 0045; 0049; 0050; 0051; 0055-0057
(2017/08/25)
-
- High purity hydrobromic fertile forwest sandbank preparation method
-
The invention discloses a preparation method of high-purity vortioxetine hydrobromide. The method comprises the following steps: firstly, synthesizing 2-(2,4-dimethyl phenyl sulfanyl) chlorobenzene from 2-chlorophenol and 2,4-dimethylbenzenethiol; then, adding di(dibenzylideneacetone)palladium, 1,1'-binaphthyl-2,2'-bis(diphenyl phosphine), sodium tert-butoxide, and methylbenzene into a reaction bottle to mix, and adding other materials so as to prepare vortioxetine; and dissolving the prepared vortioxetine by using 14-16 times of ethyl acetate, so that a vortioxetine hydrobromide coarse product is obtained; and finally, purifying the coarse product so as to obtain a vortioxetine hydrobromide fine-product. The method disclosed by the invention is easily-obtained in raw materials, mild in process reaction conditions, high in product yield, high in product purity, and convenient for industrial production. Prepared vortioxetine hydrobromide is white crystalline powder, and the purity is more than 99.5%.
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Paragraph 0024; 0028; 0029; 0030; 0039; 0040; 0041
(2017/08/25)
-
- NOVEL POLYMORPHIC FORMS OF VORTIOXETINE AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS
-
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 0225
(2017/08/01)
-
- PROCESS FOR PREPARATION OF VORTIOXETINE HYDROBROMIDE
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The present invention provides a process for preparation of Vortioxetine hydrobromide (I). The present invention also relates to the novel intermediate and its use in preparation of vortioxetine hydrobromide (I).
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Page/Page column 56
(2017/03/14)
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- A new compound of 1 - [2 - (2, 4 - dimethyl phenyl thio) phenyl] - 2 - oxygen paipai qin and its preparation method and application in the synthesis of fertile for the west sandbank
-
The invention relates to a novel compound 1-[2-(2,4-dimethylphenylthio)phenyl]-2-oxopiperazine and its preparation method and use in vortixetine synthesis. 2-(2,4-dimethylthiophenyl)aniline and chloroacetyl chloride as initial raw materials undergo a synthesis reaction to produce N-2-(2,4-dimethylphenylthio)phenyl-chloroacetamide and the N-2-(2,4-dimethylphenylthio)phenyl-chloroacetamide undergoes a classical Mitsunobu ring closing reaction to produce 1-[2-(2,4-dimethylphenylthio)phenyl]-2-oxopiperazine. The preparation method needs a low reaction temperature and prevents side reactions caused by ring closing high temperature conditions of other routes. The novel compound is used for vortixetine synthesis and has the advantages of simple processes, easy acquisition of raw materials, low cost, mild reaction conditions, safety, environmental friendliness, short reaction time, simple processes and after-treatment, high yield, high product purity and industrial production feasibility.
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-
Paragraph 0094; 0097; 0098
(2017/08/25)
-
- Method for preparing vortioxetine
-
The invention discloses a method for preparing vortioxetine. The preparation method comprises the following steps: enabling 2-bromobenzenamine to react with sodium nitrite so as to obtain a reactive intermediate in the presence of concentrated sulfuric acid; carrying out a reaction with piperazine to obtain an intermediate A, performing alkali regulation on the intermediate A, and synthesizing with 2,4-dimethylthiophenol, thereby obtaining the target product vortioxetine. The method is short in synthetic route, simple in process, high in product yield, and suitable for industrialized production. The structural formula is as shown in the specification.
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-
- INTERMEDIATES AND PROCESSES FOR PREPARATION OF VORTIOXETINE
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The present invention relates to new intermediate compounds useful in the preparation of phenyl-piperazine compounds such as Vortioxetine and process for their preparation. The present invention also relates to process for preparing Vortioxetine or its pharmaceutically acceptable salts using said intermediates.
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Page/Page column 11; 14; 15
(2018/01/20)
-
- 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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-
- fertile for the west sandbank synthetic method
-
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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- fertile for west sandbank salt and its crystal, process for their preparation, pharmaceutical composition and use thereof
-
The present invention relates to the novel vortioxetine salts, solvates and crystalline forms thereof, specifically, vortioxetine hemihydrobromide and a crystalline form thereof, and isopropanol solvate of vortioxetine hydrobromide and a crystalline form thereof. Compared to the known vortioxetine hydrobromide, the vortioxetine salts, solvates and crystalline forms of the present invention have improved features in stability, hygroscopicity and purity. The present invention also relates to preparation methods of the vortioxetine salts, solvates and crystalline forms, pharmaceutical compositions thereof and their uses in the manufacture of antidepressant drugs.
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-
-
- Preparation method for vortioxetine
-
The invention relates to a preparation method for vortioxetine, and belongs to the field of pharmaceutical chemistry. The preparation method for vortioxetine comprises the following steps: 2-bromothiophenol and N-methylpiperazine generate a condensation reaction under an alkaline condition to produce 2-(1-methyl piperazinyl)thiophenol(IV); the 2-(1-methyl piperazinyl)thiophenol(IV) is reacted with 2,4-dimethyliodobenzene(V) under the alkaline condition to produce formula (VI) 1-methyl4-[2-(2,4-methyl phenylthio)]piperazine, the 1-methyl4-[2-(2,4-methyl phenylthio)]piperazine is reacted with chloromethyl phenyl to produce formula (VII), and the formula (VII) is demethylphenylated to obtain vortioxetine(I)..
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-
-
- Novel process for preparation of 1-[2-(2,4-dimethylphenylsulphanyl)phenyl] piperazine
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The present invention discloses a novel process for the preparation of 1-[2-(2,4-dimethylphenylsulphanyl)phenyl] piperazine. The process uses o-halogenated benzenesulfonic acid and m-xylene as raw materials, which are subjected to dehydration condensation with methylsulfonic acid and phosphorus pentoxide as condensing agents to generate halogenated diarylsulfone. Halogenated diarylsulfone and piperazine are subjected to a substitution reaction in an aprotic solvent to produce piperazine ring substituted diarylsulfone; the piperazine ring substituted diarylsulfone is reduced by hexachlorodisilane in an aprotic solvent to obtain a product with high yield. This method has the advantages of cheap and easily available raw materials, avoidance of the usage of a noble metal catalyst and treatment of residual palladium, simple operation, mild reaction conditions, simple post-treatment, and potential application values.
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-
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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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-
- Novel method for preparing vortioxetine
-
The invention relates to a novel method for preparing vortioxetine. Reduction, nucleophilic substitution and coupling are conducted on a 2-nitroiodobenzene compound, and a compound of 1-[2-(2,4-dimethyl phenyl sulfanyl)-phenyl]methyl piperazine; then the obtained compound reacts with phenyl chloroformate to obtain 1-[2-(2,4-dimethyl phenyl sulfanyl)-phenyl]piperazine-1-carboxylic acid phenyl ester which generates vortioxetine after being hydrolyzed under the alkaline condition.
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- Preparation method of Vortioxetine
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The invention discloses a preparation method of Vortioxetine. The method comprises the steps that titanium tetrachloride is dissolved in organic solvent, iodine is added under the protection of nitrogen, triethyl silicane is dropwise added, and then 1-[2-(2,4-dimethyl-thiophenyl)-phenyl]-piperazine-2,6-diketone solution is dropwise added; stirring and reacting are conducted, and after reacting is completed, reaction liquid is dropwise added into water for quenching; washing, drying, concentrating and baking are conducted on an organic phase, and a product is obtained. According to the preparation method of the Vortioxetine, reducing preparation is conducted through the titanium tetrachloride and the triethyl silicane, catalyzing is conducted through the iodine, dangerousness of production operation is reduced, the aftertreatment steps are simple, the product yield is high, and industrial production is easier.
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Paragraph 0013; 0014; 0032; 0033
(2016/10/08)
-
- PROCESS FOR THE PREPARATION OF AN ANTIDEPRESSANT AND THE INTERMEDIATES THEREOF
-
The present invention relates to a process for the preparation of 1-[2-(2,4-dimethylphenylsulphanyl)phenyl]piperazine of formula (I), also known as vortioxetine, salts thereof, and intermediates useful for its synthesis.
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Paragraph 0083
(2016/06/13)
-
- Preparation method of anti-depression drug 1-[2-(2,4-dimethylphenylthio)phenyl]piperazine
-
The invention relates to a preparation method of an anti-depression drug 1-[2-(2,4-dimethylphenylthio)phenyl]piperazine (VI). The method comprises the following steps: condensing an initial raw material 2,4-dimethylthiophenol (I) and t-butyl 2-X halogenated phenyl carbamate (II) to generate t-butyl 2-(2,4-dimethylphenylthioalkyl) phenyl carbamate (III), carrying out Boc group removal on the t-butyl 2-(2,4-dimethylphenylthioalkyl) phenyl carbamate (III) in a proper organic solvent solution of hydrogen chloride to obtain 2-(2,4-dimethylphenylthioalkyl)aniline hydrochloride (IV), and carrying out ring closing on the 2-(2,4-dimethylphenylthioalkyl)aniline hydrochloride (IV) and bis(2-chloroethyl)amine hydrochloride (V) to generate 1-[2-(2,4-dimethylphenylthio)phenyl]piperazine (VI). The preparation method has the advantages of concise technology, economy, environmental protection, and suitableness for industrial production.
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Paragraph 0028; 0029
(2016/10/10)
-
- 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 13
(2016/01/25)
-
- 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 0061; 0062; 0063
(2017/01/12)
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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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- VORTIOXETINE SALT AND CRYSTAL THEREOF, THEIR PREPARATION METHOD, PHARMACEUTICAL COMPOSITIONS AND USAGE
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The present invention relates to the novel vortioxetine salts, solvates and crystalline forms thereof, specifically, vortioxetine hemihydrobromide and a crystalline form thereof, and isopropanol solvate of vortioxetine hydrobromide and a crystalline form thereof. Compared to the known vortioxetine hydrobromide, the vortioxetine salts, solvates and crystalline forms of the present invention have improved features in stability, hygroscopicity and purity. The present invention also relates to preparation methods of the vortioxetine salts, solvates and crystalline forms, pharmaceutical compositions thereof and their uses in the manufacture of antidepressant drugs.
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- Phenyl-Piperazine Derivatives As Serotonin Reuptake Inhibitors
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The invention provides compounds represented by the general formula I wherein the substituents are defined in the application. The compounds are useful in the treatment of an affective disorder, including depression, anxiety disorders including general anxiety disorder and panic disorder and obsessive compulsive disorder.
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Paragraph 0134; 0139
(2016/06/06)
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- A method for preparing fertile for the west sandbank
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The invention relates to the preparation method of Vortioxetine. The preparation method is characterized by comprising the steps of: obtaining a compound (formula 2) by carrying out coupling reaction on compound 2,4-dimethylbenzenethiol (formula 4) and compound 2-bromoiodobenzene (formula 3) in the presence of copper iodide, chiral ligand and alkali; obtaining a compound (formula 1) through the reaction of compound in formula 2 and piperazine in the presence of copper iodide, chiral ligand and alkali; or operating the twp steps in one reactor by one-pot method; the preparation method is easy to obtain material, simple in technology, high in product purity, few in by-products and beneficial to industrial production of the bulk drug.
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Paragraph 0038; 0039
(2017/01/31)
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- Novel preparation method of vortioxetine
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The invention discloses a novel preparation method of vortioxetine. The preparation method comprises that 2, 4-dimethylthiophenol (compound A) and 2-bromoiodobenzene (compound B) undergo a coupling reaction in the presence of cuprous halide, ligand and alkali to produce a compound C, and the compound C and piperazine undergo a reaction in the presence of cuprous halide, ligand and alkali to produce vortioxetine. The preparation method has the advantages of easy acquisition of raw materials, simple processes, high product purity and less by product. The catalysis method can reduce a vortioxetine production cost and is conducive to bulk drug industrial production.
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Paragraph 0009; 0021
(2016/11/17)
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- Antidespressant fertile for method for preparing field of'
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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.
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Paragraph 0022; 0044; 0045
(2016/11/21)
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- Liquid formulations of salts of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine
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Liquid formulations of lactic acid addition salts of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine are provided.
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Page/Page column 14
(2016/11/14)
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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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- 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 35
(2015/09/23)
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- SYNTHESIS OF VORTIOXETINE VIA (2-(PIPERAZINE-1 -YL)PHENYL)ANILINE INTERMEDIATES
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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-(piperazine-1-yl)phenyl)aniline intermediates.
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Page/Page column 20
(2015/08/03)
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- Synthesis of vortioxetine via (2-(piperazine-1-yl)phenyl)aniline intermediates
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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-(piperazine-1-yl)phenyl)aniline intermediates.
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Paragraph 0062; 0063
(2015/07/22)
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- SYNTHESIS OF VORTIOXETINE VIA (2-(PIPERAZINE-1 -YL)PHENVL)LITHIUM INTERMEDIATES
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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-(piperazine-1-yl)phenyl)lithium intermediates.
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- Synthesis of vortioxetine via (2-(piperazine-1-yl)phenyl)lithium intermediates
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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-(piperazine-1-yl)phenyl)lithium intermediates.
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