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Process for preparing vilazodone hydrochloride

a technology of vilazodone and hydrochloride, which is applied in the field of preparing pharmacologically active substances, can solve the problems of difficult management of production systems, and inability to meet the needs of industrial production, etc., and achieves the effect of reducing the cost of vitride and reducing the cost of vilazodon

Inactive Publication Date: 2014-06-12
ERREGIERRE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent describes a new way to make a drug called vilazodone hydrochloride. This process uses new chemicals that are made through a reduction reaction using a specific type of reagent. This new method results in much higher yields of the final drug product. The starting material for this process can be easily obtained using a simple chemical reaction.

Problems solved by technology

However, the use of a reducing agent such as vitride in the synthesis process makes it difficult to manage the production system and requires a series of precautions which make the process of the prior art hardly feasible and cost-effective from an industrial point of view.
Furthermore, vitride is a particularly expensive reducing agent.

Method used

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  • Process for preparing vilazodone hydrochloride
  • Process for preparing vilazodone hydrochloride
  • Process for preparing vilazodone hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

example 1

Process for preparing 5-Piperazin-1-yl-benzofuran-2-carboxylate methyl hydrochloride

Synthesis of 5-aminobenzofuran-2-carboxylic acid methyl ester

[0071]

Load into a flask:5-aminobenzofuran-2-carboxylic acid40 gMethanol200 g HCl gas10 gHeat the ground under reflux for 20 hours.Dry distil and add to the residueToluene40 gDistilled water200 g Ammonia 30%20 gStir under reflux until complete dissolutionCool at 5° C. until crystallization.Filter and wash with:Distilled water15 gDryThere are obtained 32.3 gYield 74.8%

Synthesis of 5-piperazin-1-yl-benzofuran-2-carboxylate methyl hydrochloride

[0072]

Load into a flask:5-Aminobenzofuran-2-carboxylic acid32 gmethyl esterBis-(2-chloroethyl)amine hydrochloride31.4 g  Distilled water128 g Heat under reflux, then addSodium acetate43.2 g  Stir then reflux for 1 hour then add at 30° C.Methylene chloride96 gAmmonia38.4 g  Stir at 30° C., separate the organic phase,which is dry distilled under vacuum, then addto the residue:N,N-dimethylformamide80 gBubble...

example 2

Process for preparing the intermediate 3-(4-Chloro-1-hydroxybutyl)-1H-indol-5-carbonitrile

Synthesis of 3-(4-Chlorobutyryl)-1H-indol-5-carbonitrile

[0073]

Load into a flask:Aluminium trichloride 93 gMethylene chloride320 gHeat under reflux, then add:4-chlorobutyryle chloride100 gWhile maintaining the reflux add aseparately prepared solution of:5-Cyano-indole 40 gMethylene chloride160 gStir at reflux for 30 minutes then pourthe reaction in a flask containingDistilled water400 gHydrochloric acid 32% 32 gOn completion of casting distil up to80° C. Add:Ethyl acetate200 gCool at 5° C., filter and wash with:Ethyl acetate 60 gDistilled water120 gDryThere are obtained 58 gYield: 83.6%

Synthesis of the intermediate compound 3-(4-Chloro-1-hydroxybutyl)-1H-indol-5-carbonitrile

[0074]

Load into a flask:3-(4-Chlorobutyryl)-1H-indol-5-carbonitrile58gTetrahydrofuran116gDistilled water11.6gHeat at 30-35° C., then add a separatelyprepared solution of:Distilled water.29g30% NaOH0.3gSodium borohydride7gStir...

example 3

Process for Preparing Vilazodone (Free Base / Hydrochloride

Synthesis of the intermediate 5-{4-[4-(5-Cyano-1H-indol-3-yl)-4-hydroxybutyl]-piperazin-1-yl}benzofuran-2-carboxylate methyl

[0075]

Load into a flask:5-Piperazin-1-yl-benzofuran-2-carboxylate11.9 g  methyl hydrochlorideSodium bicarbonate6.7 g N,N-dimethylacetamide30 gPotassium iodide1.3 g 3-(4-Chloro-1-hydroxybutyl)-1H-indol-5-carbonitrile12 gHeat at 75° C. for 28 h then add:Distilled water50 gEthyl acetate50 gCool to 5° C., filter and wash with:Distilled water10 gDryThere are obtained 11 gYield 58%

Synthesis of the intermediate 5-{4-[4-(5-Cyano-1H-indol-3-yl)-but-3-enyl]-piperazin-1-yl}-benzofuran-2-carboxylate methyl

[0076]

Load into a flask:5-{4-[4-(5-Cyano-1H-indol-3-yl)-4-hydroxybutyl]- 3 gpiperazin-1-yl}-benzofuran-2-carboxylatemethylDMA15 gAmmonium chloride0.32 g  Heat the mixture at 100° C. for 7 hoursCool to 20° C. then addEthyl acetate25 gAqueous solution of sodium bicarbonate 10%10 gStir and separate the organic phase, t...

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Abstract

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.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority of Italian Patent Application MI2012A000531 filed on Apr. 2, 2012.FIELD OF THE INVENTION[0002]The present invention relates to a process for producing vilazodone, typically in base or hydrochloride form.[0003]The present invention originates in the sector of processes for preparing pharmacologically active substances, in particular piperazine-based substances.BACKGROUND OF THE INVENTION[0004]Vilazodone is the 5-5-{4-[(4-(5-Cyano-1H-indol-3-yl)butyl]piperazin-1-yl}-benzofuran-2-carboxylate methyl molecule provided with molecular weight equal to 477.99.[0005]From a pharmacological point of view, vilazodone is a selective serotonin reuptake inhibitor (SSRI) and a partial agonist of 5-HT1A receptors.[0006]On account of this action thereof, vilazodone falls within the class of antidepressant drugs and finds application in the treatment of psychiatric diseases and in the treatment of major depressive syndrome (M...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D405/12
CPCC07D209/12C07D405/12
Inventor FERRARI, MASSIMODE ZANI, DANIELEBONALDI, MATTEO
Owner ERREGIERRE
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