- Preparation method of vilazodone
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The invention relates to a preparation method of vilazodone. The preparation method comprises the steps of by using a compound 1 and a compound 2 as raw materials, carrying out one-step reaction underthe condition that trifluoroacetic acid is used as a solvent to obtain a compound I, namely the vilazodone. Compared with the prior art, the method has the advantages of short reaction route, easy post-treatment, high yield, cheap and easily available reagents used in the reaction, convenient operation, simple post-treatment, low cost, small environmental pollution, and suitableness for industrial production of vilazodone.
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Paragraph 0033-0052
(2021/02/06)
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- An investigation of the synthesis of vilazodone
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A novel synthetic route toward vilazodone is described by using 4-cyanoaniline and 5-bromo-2-hydroxybenzaldehyde as starting materials, with an overall yield of 24% and 99% purity. First, the intermediate (3-(4-chlorobutyl)-1H-indole-5-carbonitrile) is synthesized via diazotization of 4-cyanoaniline, followed by Fischer indole cyclization with 6-chlorohexanal. Subsequently, another intermediate, 5-(piperazin-1-yl)benzofuran-2-carboxamide, is generated via aromatic nucleophilic substitution of 5-bromobenzofuran-2-carboxamide with piperazine. Finally, vilazodone is obtained via nucleophilic substitution of the above two key intermediates by treatment with Et3N/K2CO3. In comparison to the original process, this route avoids the use of expensive and toxic reagents and resolves issues such as safety, environmental concerns, and high costs.
- Hu, Fan,Su, Weike
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p. 243 - 247
(2020/01/08)
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- Preparation method of vilazodone hydrochloride
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The invention discloses a preparation method of vilazodone hydrochloride. The preparation method comprises the following steps: (1) in the presence of ammonium hydroxide or ammonium hydroxide and N-methylpyrrolidone, enabling 5-(1-piperazinyl)-benzofuran-2-ethyl formate hydrochloride to be subjected to ammonolysis reaction to obtain 5-(1-piperazinyl)-benzofuran-2-formamide; (2) in the presence ofalkali, enabling the 5-(1-piperazinyl)-benzofuran-2-formamide and 3-(4-chlorobutyl) indole-5-formonitrile to be subjected to nucleophilic substitution reaction to obtain a crude product of vilazodone,wherein the alkali is mixed alkali of sodium iodide, N,N-diisopropylethylamine and triethylamine or 1,8-diazabicycloundec-7-ene; (3) refining the crude product of vilazodone to obtain a refined product of vilazodone; and (4) enabling the refined product of vilazodone to be subjected to salt-forming reaction to obtain the vilazodone hydrochloride. By virtue of the ammonolysis reaction and the nucleophilic substitution reaction, the yield is higher, and the purity is higher; and the yield of the vilazodone hydrochloride is increased.
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Paragraph 0063; 0073; 0078; 0084
(2019/02/04)
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- Preparation method of vilazodone or hydrochloride thereof
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The invention relates to a preparation method of an antidepressant drug vilazodone or a hydrochloride thereof, wherein high-purity and high-yield vilazodone is obtain through the crystallization of aN-methylpyrrolidone/water system. According to the present invention, the method overcomes the defects and the disadvantages of the existing vilazodone preparation method, is suitable for the industrial preparation of vilazodone hydrochloride, and has great positive progress effect and practical application value.
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Paragraph 0044; 0045
(2018/09/14)
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- [...] and its salt synthesis method (by machine translation)
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The invention relates to a synthesis method of vilazodone and a salt thereof, belonging to the technical field of drug synthesis. The synthesis method comprises the following steps of: with 5-fluorin-2-hydroxybenzaldehyde as a raw material, subjecting the 5-fluorin-2-hydroxybenzaldehyde and acetobromamide to reaction under the action of an acid binding agent to obtain a compound as shown in the formula (I); subjecting piperazine and the compound (I) as shown in the formula (I) to reaction at the temperature of 100-140 DEG C under the action of alkaline to obtain a compound as shown in the formula (II); and subjecting 3-(4-chlorobutyl)-5-cyanoindole and the compound as shown in the formula (II) to reflux reaction for 14-18h under the actions of a catalyst and alkaline, and then, adding the product into an aqueous alkaline solution until a solid is separated out to obtain a compound as shown in the formula (III), namely the vilazodone, wherein the compounds as shown in the formulas (I), (II) and (III) respectively have the structural formulas in the specification. The synthesis method is low in production cost, environment-friendly, high in conversion ratio, few in byproducts, high in product yield and purity, good in quality and suitable for large-scale industrial production.
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- A PROCESS FOR PREPARATION OF 2-BENZOFURANCARBOXAMIDE, 5-[4-[4-(5CYANO-1H-INDOL-3-YL)BUTYL]-1-PIPERAZINYL] FREE BASE AND ITS HYDROCHLORIDE SALT
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The present invention describes an advantageous, economically viable process for preparing 5-[4-[4-(5-Cyanoindole-3-yl)butyl]Piperazine-1-yl]benzofuran-2-carboxamide free base (Formula-I) and its hydrochloride salt. The instant invention also describes process for preparing 2-benzofurancarboxamide, 5-[4-[4-(5cyano-1H-indol-3-yl)butyl]-1- piperazinyl]intermediates.
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Page/Page column 24
(2016/09/22)
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- For the preparation of the compounds and intermediates thereof the vera assists the alkone and application
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The invention belongs to the field of medicinal chemistry and relates to a compound for preparing vilazodone as well as an intermediate and an application thereof. The compound for preparing vilazodone is shown as a formula I, and the intermediate for synthesizing the compound of the formula I is shown as a formula II. The compound of the formula I can be applied to preparation of vilazodone and pharmaceutically acceptable salts thereof. The compound of the formula I serving as a novel intermediate is applied in preparation of the vilazodone, the defects in the conventional literature report are overcome, metal catalysts with high toxicity and organic phosphorus ligands thereof are avoided, the preparation cost is greatly reduced, the operation is simplified, and the compound is stable and controllable in quality and suitable for large-scale industrial preparation.
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Paragraph 0212; 0222-0224
(2017/03/24)
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- PROCESS FOR PREPARATION OF VILAZODONE, NOVEL INTERMEDIATES THEREOF AND NOVEL CRYSTALLINE FORM THEREOF
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The invention relates to process for preparation of Vilazodone and novel intermediates for synthesis of Vilazodone. The invention also relates to novel crystalline form of Vilazodone hydrochloride and process for preparation thereof.
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- PROCESS FOR PREPARATION OF VILAZODONE AND ITS NOVEL INTERMEDIATES
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The invention relates to process for preparation of Vilazodone and novel intermediates for synthesis of Vilazodone.
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- Vilazodone intermediate preparation method
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The present invention provides a vilazodone intermediate preparation method. According to the method, a caproaldehyde compound is adopted as a starting material, and reacts with a phenylhydrazine or aniline compound, and the obtained compound is subjected to ring closure under catalysis of an acid to obtain 3-(4-chlorobutyl)-5-cyano indole. According to the present invention, the application of the acylation reaction catalyzed through the Lewis acid in the literature is avoided, and the step of the methylene obtaining through carbonyl reduction with red aluminum in the literature is avoided and is not easily achieved in the workshop; and the compound is the key vilazodone synthesis intermediate, and the method has characteristics of easily available raw materials, mild reaction condition, simple operation, easy process control, low cost, and easy industrial production.
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- A process for the preparation of intermediates [...] and the intermediate
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The invention discloses a preparation method of a vilazodone intermediate and an intermediate. The preparation method of the vilazodone intermediate (5-piperazinylbenzofuran-2-formylimine salts) comprises a step of soaking a compound represented by the formula 7 in a water solution of an inorganic strong acid to carry out hydrolysis deprotection salt-forming reactions, which are represented in the description; wherein the X represents an inorganic strong acid, and the inorganic strong acid can be hydrochloric acid, sulfuric acid, or hydrobromic acid. The invention also discloses a preparation method of a compound represented by the formula 7 and a compound represented by the formula 6. The provided preparation method has the advantages of high yield, easy purification, high purity, and low cost, and is suitable for industrial massive production.
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- PROCESS FOR THE PREPARATION OF VILAZODONE HYDROCHLORIDE AND ITS AMORPHOUS FORM
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The present invention relates to an improved process for the preparation of vilazodone Hydrochloride and a process for preparation of novel pure amorphous form of vilazodone hydrochloride.
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Paragraph 0130
(2015/03/31)
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- PREPARATION OF VILAZODONE HYDROCHLORIDE CRYSTALLINE FORM IV
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Provided herein are improved, commercially viable and consistently reproducible processes for the preparation of highly pure crystalline Form IV of Vilazodone hydrochloride, which is free from other polymorphs and undesired solvated forms. Provided also herein is a highly pure and stable Vilazodone hydrochloride crystalline Form IV essentially free of other solid state forms. The highly pure Vilazodone hydrochloride crystalline Form IV essentially free of other solid state forms, made by the processes disclosed herein for use in the pharmaceutical compositions, has a D(90) particle size of less than or equal to about 100 microns.
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Page/Page column 18; 19
(2015/03/28)
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- 4-(2-(6-SUBSTITUTED-HEXYLIDENE) HYDRAZINYL)BENZONITRILE AND PREPARATION THEREOF
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The present teachings provide a compound of Formula (I-B): wherein R1-R10 are as described herein; a pharmaceutically acceptable salt of the compound, a geometric isomer of the compound, or a pharmaceutically acceptable salt of the geometric isomer. Also described are methods of preparing the same, as well as methods for preparing vilazodone using the same.
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- SUBSTANTIALLY PURE VILAZODONE HYDROCHLORIDE AND A PROCESS THEREOF
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The present invention relates to a process for preparation of substantially pure Vilazodone Hydrochloride and also relates to an isolated impurity of Vilazodone. The said process for producing Vilazodone, 1-[4-(5-cyanoindol-3-yl) butyl]-4-(2-carbonyl benzofuran-5-yl) piperazine represented by formula (1) or a pharmaceutically acceptable salt thereof comprises condensing the compound of formula (2) With a compound of formula (3) in an alcoholic solvent to obtain a white to yellow solid; isolating the solid obtained therefrom; slurry washing the solid obtained with water miscible solvent; dissolving the solid obtained therefrom in an amide solvent to obtain a solution; adding an aqueous solution of sodium metabisulphite and an inorganic base to the solution obtained to obtain the compound of formula (1) and optionally converting the solid obtained in step (v) to its pharmaceutically acceptable salt.
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Page/Page column 17
(2015/01/09)
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- POLYMORPHIC FORM OF 5-(4-[4-(5-CYANO-1H-INDOL-3-YL) BUTYL] PIPERAZIN-1-YL) BENZOFURAN-2-CARBOXAMIDE AND PROCESS FOR PREPARING THEREOF
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The present invention provides a solid state Form-Z of 5-(4-[4-(5-cyano-1H-indol-3-yl)butyl]piperazin-1-yl)benzofuran-2-carboxamide. The present invention also provides a process for preparing Form-Z of 5-(4-[4-(5-cyano-1H-indol-3-yl)butyl]piperazin-1-yl)benzofuran-2-carboxamide comprising the steps of i) reacting solid state form of 5-(1-piperazinyl)benzofuran-2-carboxamide or its salts with 3-(4-chlorobutyl)-1H-indole-5-carbonitrile an organic solvent in presence of a base to obtain crude vilazodone free base; ii) purifying the crude vilazodone free base of step (i) in an organic solvent; iii) treating the purified vilazodone free base of step (ii) with an organic solvent to obtain solid state form-Z of vilazodone. The present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of an amorphous form of vilazodone hydrochloride and use of solid state Form-Z of vilazodone for the treatment of major depressive disorders.
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- PROCESS FOR THE PREPARATION OF VILAZODONE OR PHARMACEUTICALLY ACCEPTABLE SALT THEREOF
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The present invention provides a novel intermediate of vilazodone and its process of preparation. The present invention further provides a process for preparing vilazodone or a pharmaceutically acceptable salt thereof using said novel intermediate.
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Page/Page column 17; 18
(2014/05/07)
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- PROCESS FOR THE PREPARATION OF VILAZODONE OR PHARMACEUTICALLY ACCEPTABLE SALT THEREOF
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The present invention provides a novel intermediate of vilazodone and its process of preparation. The present invention further provides a process for preparing vilazodone or a pharmaceutically acceptable salt thereof using the novel intermediate.
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Page/Page column 17
(2014/05/07)
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- IMPROVED PROCESS FOR PREPARING BENZOFURAN-2-CARBOXAMIDE DERIVATIVES
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Provided herein are novel, commercially viable and industrially advantageous processes for the preparation of benzofuran-2-carboxamide derivatives and their intermediates, or a pharmaceutically acceptable salt thereof, in high yield and purity. Provided particularly herein are novel, commercially viable and industrially advantageous processes for the preparation of vilazodone or a pharmaceutically acceptable salt thereof in high yield and purity. Provided also herein is an improved and commercially viable process for the preparation of 3-(4-hydroxybutyl)-1H-indole-5-carbonitrile, in high yield and purity, using novel intermediate compound 3-(4-hydroxybutyryl)-1H-indole-5-carbonitrile.
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- PROCESS FOR THE PREPARATION OF VILAZODONE OR ITS PHARMACEUTICALLY ACCEPTABLE SALTS
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The present invention relates to a process for the preparation of vilazodone or its pharmaceutically acceptable salts. The present invention further provides a crystalline form of vilazodone free base.
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Paragraph 0025
(2014/12/09)
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- SOLID STATE FORMS OF VILAZODONE AND VILAZODONE HYDROCHLORIDE
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The present invention provides solid state forms of Vilazodone and Vilazodone hydrochloride, processes for preparing these solid state forms, and pharmaceutical compositions comprising one or more of these solid state forms
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Paragraph 00287
(2013/06/06)
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- PROCESS FOR THE PREPARATION OF VILAZODONE HYDROCHLORIDE AND ITS AMORPHOUS FORM
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The present invention relates to an improved process for the preparation of vilazodone Hydrochloride and a process for preparation of novel pure amorphous form of vilazodone hydrochloride.
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Page/Page column 25-26
(2013/11/05)
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- CRYSTALLINE FORMS OF VILAZODONE HYDROCHLORIDE AND VILAZODONE FREE BASE
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Provided are crystalline and amorphous vilazodone hydrochloride. Further provided are amorphous solid dispersions of vilazodone hydrochloride with pharmaceutically acceptable carries. Also provided is a process for the preparation of form I of vilazodone free base.
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Page/Page column 81
(2013/12/03)
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- POLYMORPHIC FORM OF 5-(4-[4-(5-CYANO-1H-INDOL-3- YL)BUTYL]PIPERAZIN-1-YL) BENZOFURAN-2-CARBOXAMIDE
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The present invention relates to a process for the preparation of 5-(4-[4-(5- cyano- 1 H-indol-3 -yl)butyl] piperazin- 1 -yl)benzofuran-2-carboxamide of Formula (1) or its pharmaceutically acceptable salt, solvates or hydrates thereof. In particular, the present invention provides a novel intermediate compound, 5-(4-substitutedpiperazin- 1-yl)benzofuran-2-carboxamide of Formula (X). The present invention further provides solid state form of 5-(4-[4-(5-cyano-1H-indol-3- yl) butyl]piperazin-1-yl)benzofuran-2-carboxamide of Formula (1) and process for its preparation.
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- Process for preparing vilazodone hydrochloride
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The present invention relates, in a first aspect, to a process preparing vilazodone hydrochloride that comprises the reaction of 3-(4-chloro-1-hydroxy-butyl)-1H-indol-5-carbonitrile with 5-piperazin-1-yl-benzofuran-2-carboxylate methyl hydrochloride with the formation of a 1,4 -piperazine, with subsequent dehydration, hydrogenation and treatment with ammonia, to obtain vilazodone in free base form that is then converted into the hydrochloride thereof.
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- PROCESS FOR THE PREPARATION OF VILAZODONE OR ITS PHARMACEUTICALLY ACCEPTABLE SALTS
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The present invention relates to a process for the preparation of vilazodone or its pharmaceutically acceptable salts. The present invention further provides a crystalline form of vilazodone free base.
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Page/Page column 4-5
(2013/08/15)
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- Scale-up synthesis of antidepressant drug vilazodone
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A scale-up synthesis of antidepressant drug vilazodone was accomplished in five steps. Friedel-Crafts acylation of 1-tosyl-1H-indole-5-carbonitrile with 4-chlorobutyryl chloride, selective deoxygenation in NaBH4/CF 3COOH system coupled with ethyl 5-(piperazin-1-yl)-benzofuran-2- carboxylate hydrochloride, one-step deprotection and esterolysis, and the final ammonolysis led to the target molecule vilazodone in 52.4% overall yield and 99.7% purity. This convenient and economical procedure is remarkably applicable for scale-up production.
- Hu, Bin,Song, Qiao,Xu, Yungen
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p. 1552 - 1557
(2013/02/25)
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- METHOD FOR THE PRODUCTION OF 5-(4-[4-(5-CYANO-3-INDOLYL)-BUTYL]-1-PIPERAZINYL)-BENZOFURAN-2-CARBOXAMIDE
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The invention relates to a method for the production of 5-(4-[4-(5-cyano-3-indolyl)-butyl]-1-piperazinyl)-benzofuran-2-carboxamide and/or a physiologically-acceptable salt thereof, characterised in that a compound of formula (I), where L = Cl, Br, I, SO2F, SO2CF3, or SO2C2F5 is reacted with 3-(4-piperazin-1-yl-buyl)-indol-5-carbonitrile by transition metal catalyzed coupling using Pd complexes and/or the formed 5-(4[4-(5-cyano-3-indolyl)-butyl]-1-piperazinyl)-benzofuran-2-carboxamide is converted to an acid addition salt thereof by treatment with an acid and a second method characterised in that a compound of formula (Il) as the base or HX salt (where X= CI, or Br) is reacted with 3-(4-oxo-butyl)-1 H-indol-5-carbonitrile by reductive amination and/or 5-(4-[4-(5-cyano- 3-indolyl)-butyl]-1-piperazinyl)-benzofuran-2-carboxamide is converted to an acid addition salt thereof by treatment with an acid.
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Page/Page column 5-6
(2008/06/13)
-
- Synthesis and structure-activity relationship in a class of indolebutylpiperazines as dual 5-HT1A receptor agonists and serotonin reuptake inhibitors
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Systematic structural modifications of indolealkylphenylpiperazines led to improved selectivity and affinity within this class of 5-HT1A receptor agonists. Introduction of electron-withdrawing groups in position 5 on the indole raises serotonin transporter affinity, and the cyano group proved to be the best substituent here. 5-Fluoro and 5-cyano substituted indoles show comparable results in in vitro and in vivo tests, and bioisosterism between these substituents was supported by calculation of the molecular electrostatic potentials and dipole moments. Compounds showing promising in vitro data were further examined in ex vivo (p-chloroamphetamine assay) and in vivo (ultrasonic vocalization) tests. Optimization of the arylpiperazine moiety indicated that the 5-benzofuranyl-2-carboxamide was best suited to increase 5-HT transporter and 5-HT1A receptor affinity and to suppress D2 receptor binding. 5-{4-[4-(5-Cyano-3-indolyl)butyl]-1-piperazinyl}benzofuran-2- carboxamide 29 (vilazodone, EMD 68843) was identified as a highly selective 5-HT1A receptor agonist [GTPγS, ED50 = 1.1 nM] with subnanomolar 5-HT1A affinity [IC50 = 0.2 nM] and as a subnanomolar 5-HT reuptake inhibitor [RUI = 0.5 nM] showing a great selectivity to other GPCRs (e.g., D2, IC50 = 666 nM).
- Heinrich, Timo,B?ttcher, Henning,Gericke, Rolf,Bartoszyk, Gerd D.,Anzali, Soheila,Seyfried, Christoph A.,Greiner, Hartmut E.,Van Amsterdam, Christoph
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p. 4684 - 4692
(2007/10/03)
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- PIPERIDINES AND PIPERAZINES
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Piperidine and piperazine derivatives of the formula I STR1 wherein Ind is an indol-3-yl radical which is unsubstituted or mono-or polysubstituted by OH, OA, CN, Hal, COR 2 or CH 2 R 2, R 1 is benzofuran-5-yl or 2,3-dihydrobenzofuran-5-yl, chroman-6-yl, chroman-4-on-6-yl, 3-chromen-6-yl or chromen-4-on-6-yl, which is unsubstituted or monosubstituted by CN, CH 2 OH, CH 2 OA or COR 2,Q is C m H 2m,N or CR 3,A is alkyl having 1-6 C atoms,Hal is F, C1, Br or I,R 2 is OH, OA, NH 2, NHA or NA 2,R 3 is H, OH or OA and m is 2, 3 or 4,and their physiologically acceptable salts, are active on the central nervous system.
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