- Amidation and N-boc deprotection process improvement for the preparation of 5-(1-Piperazinyl)benzofuran-2-carboxamide, a key intermediate of vilazodone
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An improved process for the preparation of 5-(1-piperazinyl)benzofuran-2- carboxamide, a key intermediate used in the synthesis of antidepressant drug vilazodone is reported.
- Das, Prasenjit,Srivastava, Bindu,Joseph, Sony,Nizar, Hashim,Prasad, Mohan
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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 0063-0068; 0090-0092; 0093-0097
(2019/02/04)
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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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- Preparation method of substituted benzobfuran-2-formamide
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The invention belongs to the technical field of medicine, and discloses a preparation method of substituted benzobfuran-2-formamide (please see the formula in the specification). A compound shown in the formula (2) is obtained by removing the protecting group of a compound (3), and then 5-(1-piperazinyl)-benzofuran-2-formamide (1) is obtained through ammonolysis. The method overcomes the defects of an existing preparation method, operation is easy, use of expensive catalysts is avoided, intermediates can be conveniently separated, and cost is low.
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Paragraph 0047; 0048; 0049
(2016/10/08)
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- Intermediates for preparing [...] 5-piperazinyl-2-acyl substituted benzofuranacetic method (by machine translation)
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The invention discloses a method for preparing a vilazodone intermediate 5-piperazinyl-2-acyl substituted benzofuran. By the method, a corresponding vilazodone intermediate 5-piperazinyl-2-acyl substituted benzofuran is obtained by performing a coupling reaction on 5-halogen-substituted-2-acyl substituted benzofuran and piperazine under the actions of copper serving as a catalyst and a suitable solvent. The invention provides a new method for preparing the vilazodone intermediate 5-piperazinyl-2-acyl substituted benzofuran, has the advantages of short course, conveniences in synthesis, high yield, low cost and the like, and is suitable for industrial production.
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Paragraph 0047
(2016/10/07)
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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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- 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 15
(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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Page/Page column 38
(2014/01/18)
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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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- Method for producing 5-(1-piperazinyl) -benzofuran-2-carboxamide by transition metal-catalyzed amination
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1. Process for the preparation of 5-(1-piperazinyl)benzofuran-2-carboxamide in which, as intermediate step, 5-bromosalicylaldehyde or one of its derivatives is reacted in a transition metal-catalysed amination with R2-piperazine, in which R2 is as defined in claim 1.
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- BENZOFURANS
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Benzofurans of the formula I STR1 and their salts in which R 1, R 2 and X have the meanings indicated in claim 1, are suitable as intermediates in the synthesis of medicaments and show effects on the central nervous system.
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