- 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.
- -
-
-
- Preparation method of high-purity vortioxetine hydrobromide
-
The invention belongs to the field of chemistry, and particularly relates to a preparation method of high-purity vortioxetine hydrobromide. According to the preparation method for preparing the high-purity vortioxetine hydrobromide, the o-fluoronitrobenzene and the piperazine are used as starting raw materials, the vortioxetine hydrobromide is further prepared in the organic solvent, the raw materials used in the method are low in price and cost and easy to operate, and the prepared vortioxetine hydrobromide is high in purity and few in impurity.
- -
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Paragraph 0047; 0069-0070
(2021/05/08)
-
- Manufacturing method of vortioxetine hydrobromide
-
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.
- -
-
Paragraph 0056; 0073-0077
(2021/11/30)
-
- 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.
- -
-
Paragraph 0025-0028; 0031-0036
(2021/10/30)
-
- 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.
- -
-
-
- Preparation method of diaryl sulfide amine compound
-
The invention relates to a preparation method for a diaryl thioether amine compound. Specifically, the invention relates to a preparation method for 1-[2-(2,4-dimethylphenylsulfalkyl)phenyl]piperazine derivative as shown in a formula I which is described in the specification. The preparation method comprises the following steps: subjecting a compound as shown in a formula V and a compound as shown in a formula IV to cyclization, condensation or introduction of an amino protective group; carrying out further condensation; etc. Thus, the target compound is obtained. Compared with other methods, the preparation method provided by the invention has the advantages of good process reproducibility and easy operation and the characteristics of high yield, low cost and high product purity, is more suitable for industrial production and has higher economic benefits.
- -
-
-
- Preparation method of vortioxetine hydrobromide alpha-type crystal
-
The invention relates to the field of medicines, and discloses a preparation method of a vortioxetine hydrobromide alpha-type crystal. The method comprises the following steps: heating and dissolvingfree vortioxetine into isopropyl acetate, dropwise adding the obtained solution into an isopropyl acetate solution of hydrobromic acid, stirring, performing filtration, and drying to obtain the vortioxetine hydrobromide alpha-type crystal. The method has the advantages of good stability, good reproducibility, high yield, high purity, short time consumption, simplicity and convenience in operation,low solvent consumption, high safety, good environmental friendliness and the like, and is particularly suitable for the requirement of large-scale production in the pharmaceutical and chemical industries.
- -
-
Paragraph 0043-0061
(2020/03/06)
-
- PROCESS AND NOVEL POLYMORPHIC FORM OF VORTIOXETINE AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS
-
Processes are disclosed for making vortioxetine and pharmaceutically acceptable salts thereof. A propylene glycol solvate of vortioxetine hydrobromide is disclosed. A novel crystalline form of vortioxetine hydrobromide propylene glycol solvate, designated form AC1, is disclosed along with a method for making same. Form AC1 may be characterized by an x-ray powder diffraction pattern with peaks at about 19.64, 22.85, 25.51, 29.57, 30.18±0.2 degrees 2-theta.
- -
-
-
- AN IMPROVED PROCESS FOR THE PREPARATION OF VORTIOXETINE AND SALTS THEREOF
-
The present invention relates to a novel crystalline polymorphic form of 1-[2-(2,4-dimethyl- phenylsulfanyl)-phenyl]-piperazine hydrochloride; commonly known as vortioxetine hydrochloride (hereafter referred to as the compound (Ia) and process for its preparation comprising of treating the compound (Ia) (as described herein) with a ketone solvent or mixture of ketone solvent with other solvents. The present invention also relates to an improved process for the preparation of vortioxetine hydrobromide (Ia), comprising reacting the compound (I) (as described herein) with hydrogen bromide solution in acetic acid.
- -
-
Page/Page column 13-14
(2019/08/29)
-
- Robust Buchwald-Hartwig amination enabled by ball-milling
-
An operationally simple mechanochemical method for the Pd catalysed Buchwald-Hartwig amination of arylhalides with secondary amines has been developed using a Pd PEPPSI catalyst system. The system is demonstrated on 30 substrates and applied in the context of a target synthesis. Furthermore, the performance of the reaction under aerobic conditions has been probed under traditional solution and mechanochemical conditions, the observations are discussed herein.
- Cao, Qun,Nicholson, William I.,Jones, Andrew C.,Browne, Duncan L.
-
p. 1722 - 1726
(2019/02/20)
-
- Preparation method of alpha crystal form of vortioxetine hydrobromide
-
The invention discloses a preparation method of an alpha crystal form of vortioxetine hydrobromide. The preparation method comprises the following steps that (1) a hydrobromic acid solution and a vortioxetine free base solution are mixed at 25-50 DEG C, and insulated and stirred for 10-240 min; a solvent of the vortioxetine free base solution is ester of C5-C6 and/or ether of C5-C6; and (2) the temperature is lowered to 10-15 DEG C, and the alpha crystal form of vortioxetine hydrobromide is obtained after filtering, washing and drying. According to the preparation method, a method of direct salt formation of a free base is adopted to prepare the alpha crystal form of vortioxetine hydrobromide, the advantages of high yield (90.0%-94.0%), short time consumption (a crystallization process iscompleted within 6h), low energy consumption, simple operation and good reproducibility are achieved, solvents used are all third-class solvents and low in toxicity, the prepared alpha crystal form ofvortioxetine hydrobromide is high in chromatographic purity and stable in crystal form and meets medicinal requirements, and the preparation method is suitable for large-scale industrial production.
- -
-
Paragraph 0050-0057; 0061-0086
(2019/11/12)
-
- Vortioxetine hydrobromide microcrystals and preparation method thereof
-
The invention relates to vortioxetine hydrobromide microcrystals and a preparation method thereof. According to the invention, the vortioxetine hydrobromide microcrystals are obtained by is recrystallizing from vortioxetine hydrobromide by isopropanol, and the obtained vortioxetine hydrobromide microcrystals are short needle-shaped and have a length of not more than 500 mu m, have good stability and processing performance, and are suitable for long-term storage and industrial production.
- -
-
Paragraph 0058-0061; 0082; 0083
(2019/09/16)
-
- Crystalline compound of vortioxetine hydrobromide, and preparation method thereof
-
The present invention relates to a crystalline compound of vortioxetine hydrobromide, and a preparation method thereof. The obtained crystalline compound of vortioxetine hydrobromide has the advantages of high purity, good solubility, low hygroscopicity, good stability under high-temperature and high-humidity conditions, simple preparation method, and suitableness for long-term storage and industrial production.
- -
-
Paragraph 0031-0034
(2019/07/05)
-
- Preparation method of vortioxetine
-
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.
- -
-
Paragraph 0085
(2019/10/01)
-
- 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.
- -
-
-
- PROCESS FOR THE PREPARATION OF VORTIOXETINE AND SALTS THEREOF
-
The present invention provides an improved process for preparation of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine; commonly known as vortioxetine (referred to as the compound (I)) and pharmaceutically acceptable salts thereof; wherein the process comprises reaction of 2-((2,4-dimethylphenyl)thio)aniline (II) with bis(2-alkyl)amine (IIIa) or its salt in the presence of a cyclic amide solvent.
- -
-
Paragraph 0068
(2018/08/30)
-
- AN IMPROVED PROCESS FOR PREPARATION AND PURIFICATION OF VORTIOXETINE HYDROBROMIDE
-
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 10
(2018/09/19)
-
- COCRYSTALS OF VORTIOXETINE HYDROBROMIDE AND RESORCINOL
-
Cocrystals of vortioxetinehydrobromide and resorcinol, their preparation processes, as well as pharmaceutical compositions comprising them. The cocrystals are useful as active pharmaceutical ingredients of medicaments for the treatment of major depressive disorder.
- -
-
Page/Page column 13; 14
(2019/01/06)
-
- New synthesis process for vortioxetine hydrobromide
-
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.
- -
-
-
- 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%.
- -
-
-
- PROCESS FOR PREPARATION OF VORTIOXETINE HYDROBROMIDE
-
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).
- -
-
-
- Synthetic method and application of vortioxetine hydrobromide
-
The invention relates to the technical field of medicinal chemical synthesis, and concretely relates to a synthetic method of vortioxetine hydrobromide. The method comprises the following steps: carrying out a reaction on compounds comprising o-bromoiodobenzene and 2,4-dimethylthiophenol in environment containing a catalyst, an inorganic alkali and a protic solvent to obtain 2-(2,4-dimethylthiophenyl)bromobenzene; and coupling 2-(2,4-dimethylthiophenyl)bromobenzene with piperazine in environment containing a catalyst, an organic alkali and an aprotic solvent, and carrying out salt formation on the obtained coupling product and hydrobromic acid to prepare the vortioxetine hydrobromide. Compared with the prior art, the method disclosed in the invention has the advantages of solving of double-halogen competition side reactions, great reduction of generation of byproducts, high total yield, good product purity, simplicity in process operation, and suitableness for amplification and industrial production.
- -
-
Paragraph 0023; 0024; 0025; 0029; 0030
(2017/06/30)
-
- INTERMEDIATES AND PROCESSES FOR PREPARATION OF VORTIOXETINE
-
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.
- -
-
-
- NOVEL CRYSTALLINE POLYMORPHS OF 1-[2-(2,4-DIMETHYL-PHENYLSULFANYL)-PHENYL]-PIPERAZINE HYDROBROMIDE AND PROCESS FOR PREPARATION THEREOF
-
The present invention relates to novel crystalline polymorphs of 1 -[2-(2,4-dimethyl- phenylsulfanyl)-phenyl] -piperazine hydrobromide represented by the following structural formula- la and process for preparation thereof.
- -
-
Page/Page column 16
(2017/09/27)
-
- 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.
- -
-
Paragraph 0186; 0187; 0188; 0220; 0221; 0222; 0223
(2017/08/01)
-
- Beta type efficient vortioxetine hydrobromide crystal transformation method
-
The invention provides an efficient and concise method for refining and crystal transformation of vortioxetine hydrobromide, and belongs to the technical field of chemical drug synthesis. A vortioxetine synthesis precursor tert-butyl-4-(2-(2,4-dimethyl thiophenol)phenyl)piperazine-1-carbonate has an N-Boc protection group removed by adopting an isopropanol-hydrobromic acid mixed solution, a reaction system is cooled and crystallized, a vortioxetine hydrobromide isopropanol solvate is obtained and is subjected to water azeotropic distillation for one time, and the beta type vortioxetine hydrobromide can be safely and efficiently obtained. The method reduces multi-step tedious refining operation, and also can effectively solve the problems that toluene solvent residues, inorganic salt residues and metal palladium residues in the prior art; and the obtained beta type vortioxetine hydrobromide meets medical needed chemical purity and crystal form purity, and is suitable for industrial production.
- -
-
Paragraph 0022-0031
(2017/02/17)
-
- A hydrobromic fertile for the west sandbank crystal and its preparation method
-
The present invention discloses a hydrobromic acid vortioxetine crystal that has diffraction peaks at 8.55+/-0.2, 13.05+/-0.2, 13.44+/-0.2, 14.46+/-0.2, 15.20+/-0.2, 16.63+/-0.2, 16.94+/-0.2, 17.22+/-0.2, 17.85+/-0.2, 19.83+/-0.2, 20.43+/-0.2, 21.33+/-0.2, 23.14+/-0.2, 23.60+/-0.2, 24.77+/-0.2, 26.25+/-0.2, 26.72+/-0.2, 26.96+/-0.2, 29.69+/-0.2, 30.52+/-0.2, 33.33+/-0.2, 33.89+/-0.2, 34.89+/-0.2, 35.54+/-0.2, 37.03+/-0.2, and 38.33+/-0.2 in a powder X-ray diffraction diagram represented with 2 theta. In addition, the present invention further discloses a preparation method for the crystal. The hydrobromic acid vortioxetine crystal and the preparation method therefor in the present invention have good repeatability, easy operation, good product stability, and high yield and purity, and are suitable for industrial production.
- -
-
Paragraph 0035; 0036; 0037; 0038; 0039; 0040
(2017/09/01)
-
- A hydrobromic fertile for the west sandbank crystal preparation method
-
The invention discloses a vortioxetine hydrobromide crystal preparation method. The method comprises a, dissolving vortioxetine free alkali in ethyl acetate at a temperature of 20-30 DEG C, b, carrying out filtration, cooling the filtrate to a temperature of 0-10 DEG C, dropwisely adding an ethyl acetate solution of hydrobromic acid into the filtrate along with thermal insulation and then carrying out thermal insulation stirring for 2-8h, c, filtering the mixture subjected to thermal insulation stirring in the step b to obtain filter cake 1, leaching the filter cake 1 by ethyl acetate, and carrying out stirring washing in ethyl acetate at a temperature of 0-10 DEG C for 0.5-5h, d, filtering the mixture subjected to stirring washing in the step c to obtain filter cake 2, leaching the filter cake 2 by methyl tert-butyl ether/ethyl acetate pre-cooled at a temperature of 0-10 DEG C and carrying out stirring washing in methyl tert-butyl ether at a temperature of 10-30 DEG C for 15-24h, and e, filtering the mixture subjected to stirring washing in the step d to obtain filter cake 3, leaching the filter cake 3 by methyl tert-butyl ether and carrying out vacuum drying at a temperature of 40-50 DEG C to obtain the product. The method has the advantages of good repeatability, simple processes, a high yield and high product purity and is suitable for industrial production.
- -
-
Paragraph 0039; 0040; 0041; 0042; 0043; 0044
(2017/08/25)
-
- Method for preparing 1-[2-(2,4-dimethyl phenyl thioalkyl)phenyl]piperazine hydrobromide alpha-type crystal
-
The invention provides a method for preparing a 1-[2-(2,4-dimethyl phenyl thioalkyl)phenyl]piperazine hydrobromide alpha-type crystal. The method comprises the steps: dissolving 1-[2-(2,4-dimethyl phenyl thioalkyl)phenyl]piperazine in a reaction solvent, stirring to dissolve completely, dropping hydrobromic acid at the temperature of 40-65 DEG C, after dropping is completed, stirring evenly, carrying out a reaction at the temperature of 40-65 DEG C for 3-65 minutes, and drying a filter cake to obtain the product. The method is simple, good in stability, and high in synthesis yield and purity.
- -
-
Paragraph 0066; 0067; 0068; 0069; 0070; 0071; 0072-0092
(2017/02/09)
-
- Preparation method of vortioxetine hydrobromide
-
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.
- -
-
-
- A suitable hydrobromidum fertile for method for synthesizing west sandbank industrial production (by machine translation)
-
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.
- -
-
-
- PROCESSES FOR THE PREPARATION OF VORTIOXETINE HYDROBROMIDE
-
The present invention relates to a process for the preparation of vortioxetine and its pharmaceutically acceptable salts.
- -
-
-
- Synthetic method for vortioxetine hydrobromide
-
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.
- -
-
-
- 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.
- -
-
-
- VORTIOXETINE SALT AND CRYSTAL THEREOF, THEIR PREPARATION METHOD, PHARMACEUTICAL COMPOSITIONS AND USAGE
-
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.
- -
-
Paragraph 0170; 0171; 0172; 0173
(2017/01/02)
-
- 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.
- -
-
Paragraph 0179-0180
(2017/03/25)
-
- A PROCESS FOR PREPARATION OF VORTIOXETINE AND POLYMORPHS THEREOF
-
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.
- -
-
Page/Page column 27
(2016/06/15)
-
- PROCESS FOR THE PREPARATION OF VORTIOXETINE
-
Disclosed herein a process for the isolation of intermediate of Vortioxetine in a solid state form and an improved, commercially viable and industrially advantageous process for the preparation of vortioxetine or a pharmaceutically acceptable salt thereof, in high yield and purity.
- -
-
-
- Hydrobromidum fertile match sandbank or hydrobromidum fertile forwest sandbank
-
The invention relates to vortioxetine hydrobromide and in particular relates to a crystal of 1-[2-(2,4-dimethylphenylthioxo)phenyl] piperazine hydrobromide. The crystal uses Cu-K alpha radiation. In a powder X-ray diffraction pattern shown by a 2theta angle, diffraction peaks exist at about 6.89 degrees, 9.73 degrees, 13.78 degrees and 14.62 degrees. The invention also relates to a preparation method of the crystal and a drug composition containing the compound. The compound shows the serotonin reabsorption inhibitory activity, has activities towards a serotonin receptor 1A (5-HT1A) and a serotonin receptor 3 (5-HT3), can be used for treating CNS (central nervous system)-related diseases, in particular can be used for treating depressive disorder, especially major depressive disorder of adults, and can be also used for treating other CNS-related diseases.
- -
-
Paragraph 0240; 0241
(2017/12/01)
-
- vortioxetine hydrobromide crystal and preparation method thereof
-
The invention discloses a vortioxetine hydrobromide crystal and a preparation method thereof. A powder X-ray diffraction pattern of the crystal shows characteristic peaks at the diffraction angle 2theta of 5.8+/-0.2, 6.9+/-0.2, 13.2+/-0.2, 14.1+/-0.2, 14.6+/-0.2, 16.2+/-0.2, 17+/-0.2, 18.2+/-0.2, 18.6+/-0.2, 19+/-0.2, 19.5+/-0.2, 20.7+/-0.2, 21.1+/-0.2, 21.6+/-0.2, 21.9+/-0.2, 22.3+/-0.2, 22.7+/-0.2, 23+/-0.2, 23.7+/-0.2, 24.4+/-0.2, 24.8+/-0.2, 25.4+/-0.2, 28.1+/-0.2, 28.5+/-0 2, and 30+/-0.2. The vortioxetine hydrobromide crystal provided by the invention has the advantages of high purity, simple preparation method, and low hygroscopicity. The crystal is not influenced by the change of environmental humidity in raw material preparation, weighing and storage, and maintains uniform and stable quality of the final product.
- -
-
Paragraph 0025; 0026; 0027
(2016/10/07)
-
- fertile match sandbank or fertile for field of ' hydrobromide (by machine translation)
-
The invention relates to a hydrobromide of vortioxetine and in particular relates to a crystal of a compound shown in a formula I in the specification. The crystal uses Cu-K alpha radiation. In a powder X-ray diffraction pattern shown by a 2theta angle, diffraction peaks exist at about 6.89 degrees, 9.73 degrees, 13.78 degrees and 14.62 degrees. The invention also relates to a preparation method of the crystal and a drug composition containing the compound. The compound shows the serotonin reabsorption inhibitory activity, has activities towards a serotonin receptor 1A (5-HT1A) and a serotonin receptor 3 (5-HT3), can be used for treating the CNS (central nervous system)-related diseases, and in particular can be used for treating depressive disorder, especially major depressive disorder of adults.
- -
-
Paragraph 0239; 0240; 0241; 0242
(2017/09/02)
-
- SYNTHESIS OF VORTIOXETINE VIA (2-(PIPERAZINE-1 -YL)PHENYL)ANILINE INTERMEDIATES
-
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.
- -
-
-
- 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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- NEW PROCESS FOR THE SYNTHESIS OF 1-(2-((2,4-DIMETHYLPHENYL)THIO)PHENYL)PIPERAZINE
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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), an experimental drug under development for the treatment of depression and anxiety, which comprises the reaction of a compound of formula (VII), or salt thereof, (VII) wherein Q represents S, SO or SO2 and LG represents a leaving group, with a compound of formula (XI), or salt thereof, (XI) wherein Z represents hydrogen or a protecting group. New intermediate compounds are also provided.
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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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- VORTIOXETINE MANUFACTURING PROCESS
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A process for the manufacture of vortioxetine is provided in which a compound of formula I, formula I is reacted with optionally substituted piperazine and 2,4-dimethylthiophenol(ate) followed by de-complexation.
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Page/Page column 12; 13
(2014/09/03)
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- PROCESS FOR THE MANUFACTURE OF 1-[2-(2,4-DIMETHYL-PHENYLSULFANYL)-PHENYL]-PIPERAZINE
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A process for the manufacture of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine and pharmaceutically acceptable salts is disclosed that involves reacting compounds of formula II, III, IV under Pd catalysis and in presence of phoshine ligands to give Compound I.
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Page/Page column 14; 15
(2013/07/19)
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- Biosynthesis and identification of an N-oxide/N-glucuronide metabolite and first synthesis of an N-O-glucuronide metabolite of Lu AA21004
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This article describes the biosynthesis and identification of a new class of metabolites, a piperazine N-oxide/N-glucuronide metabolite 4-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-1-β-D-glucuronic acid-piperazine 1-oxide (4). The metabolite was found in urine and plasma from humans and animals dosed with 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]-piperazine hydrobromide (Lu AA21004, 1), as a novel multimodal antidepressant under development for treatment of depression. Human liver microsomes in combination with uridine 5′-diphosphoglucuronic acid were used as an in vitro system to generate enough material of 4 to perform one- and two-dimensional 1H and 13C NMR experiments for structure elucidation. Based on rotating frame Overhauser enhancement spectroscopy NMR experiments, the distance correlation between a piperazine proton and the anomeric proton of the glucuronic acid moiety is of a magnitude similar to that of the H-3′ and H-5′ protons and can only be explained by proximity in space and the postulated structure (4). The structural analog, the N-O-glucuronic acid conjugate 6-{4-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazin-1-yloxy}-1- β-D-glucuronic acid (3) was also observed in biological samples from humans and animals and the first organic synthesis and structural identification of this metabolite is also reported. Treatment of the glucuronide metabolites 3 and 4 with β-glucuronidase gave mainly the expected hydrolysis product, the hydroxyl amine 4-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazin-1-ol (2). Copyright
- Uldam, Henriette Kold,Juhl, Martin,Pedersen, Henrik,Dalgaard, Lars
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p. 2264 - 2274
(2012/04/04)
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- PURIFICATION OF 1-[2-(2,4-DIMETHYLPHENYLSULFANYL)PHENYL]PIPERAZINE
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The present invention concerns a process for the manufacture of 1-[2-(2,4- dimethylphenylsulfanyl)phenyl]piperazine.
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Page/Page column 13
(2010/09/17)
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