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Synthesis method of vilazodone intermediate and salt thereof

A synthesis method and step method technology are applied in the field of synthesis of pharmaceutical intermediates, which can solve the problems of operator health hazards, unfavorable industrialized production, long reaction time and the like, and achieve less environmental pollution, simple and easy post-reaction treatment, and reaction steps. less effect

Active Publication Date: 2013-10-23
SUZHOU UUGENE BIOPHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Although the prior art has synthesized vilazodone intermediate 5-(4-[4-(5-cyano-3-indolyl)-butyl]-1-piperazinyl)benzofuran through a one-step method- 2-Carboxylic acid ethyl ester, but in this synthesis method not only use poisonous acetonitrile and easily poisonous acetone solvent, cause great harm to operator's health, be unfavorable for large-scale industrial production; And the reaction time of this synthesis method Long, the post-reaction treatment needs to go through three steps of extraction, column chromatography and recrystallization to obtain the product. The steps are cumbersome, resulting in high raw material costs and post-treatment costs, and the product yield is only about 32%.
In addition, a large amount of three wastes are easily produced during the reaction process, causing serious environmental pollution.

Method used

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  • Synthesis method of vilazodone intermediate and salt thereof
  • Synthesis method of vilazodone intermediate and salt thereof
  • Synthesis method of vilazodone intermediate and salt thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] At room temperature, under nitrogen protection, 2.4g of 1.1-dimethoxy-6-chlorohexane was dissolved in a mixed solution of 24mL of ethanol and 12mL of water, and the temperature was raised to 68°C to completely dissolve. At room temperature, a mixed solvent of 1.9g of 4-cyanophenylhydrazine hydrochloride, 19mL of ethanol and 9.5mL of pure water was slowly added dropwise to the 1.9g of 1.1-dimethoxy-6-chlorohexane reaction solution. Keep warm at 70°C for 0.8 hours, wait for the reaction solution to cool down to room temperature, a large amount of solid precipitates, filter with suction, and recrystallize the filter cake with 50% ethanol aqueous solution to obtain 0.7g of 3-(4-chlorobutyl)-5-cyanoindol Indole.

[0041] At room temperature, add 15mL of anhydrous acetonitrile to the reaction flask under the protection of nitrogen, then add 3.26g of 4-piperazin-1-yl-phenol, 2.35g of MgCl 2 and 6.0mL triethylamine, 1.9g paraformaldehyde, heat up and reflux for 5 hours, wait f...

Embodiment 2

[0045] At room temperature, under nitrogen protection, 5.2 g of 1.1-dimethoxy-6-chlorohexane was dissolved in a mixed solution of 52 mL of methanol and 26 mL of water, and the temperature was raised to 72° C. to completely dissolve. At room temperature, a mixed solvent of 4.8g 4-cyanophenylhydrazine hydrochloride, 48mL methanol and 24mL pure water was slowly added dropwise to the 4.6g1.1-dimethoxy-6-chlorohexane reaction solution, at 72 Keep warm at ℃ for 1.0 hour, wait for the reaction liquid to drop to room temperature, a large amount of solid precipitates, filter with suction, and recrystallize the filter cake with 53% ethanol aqueous solution to obtain 9.5g of 3-(4-chlorobutyl)-5-cyanindole .

[0046] At room temperature, add 50mL tetrahydrofuran to the reaction flask under the protection of nitrogen, then add 3.5g 4-piperazin-1-yl-phenol, 2.4gMgCl 2 and 2.0mL triethylamine, 3.6g paraformaldehyde, heat up and reflux for 4 hours, wait for the reaction solution to cool to r...

Embodiment 3

[0050] At room temperature, under nitrogen protection, 3.6g of 1.1-dimethoxy-6-chlorohexane was dissolved in a mixed solution of 36mL of ethanol and 18mL of water, and the temperature was raised to 72°C to completely dissolve. At room temperature, a mixed solvent of 2.4g 4-cyanophenylhydrazine hydrochloride, 24mL methanol and 12mL pure water was slowly added dropwise to the 4.0g1.1-dimethoxy-6-chlorohexane reaction solution, at 72 Keep warm at ℃ for 1.1 hours, wait until the reaction solution drops to room temperature, a large amount of solid precipitates, filter with suction, and recrystallize the filter cake with 55% ethanol aqueous solution to obtain 4.5g of 3-(4-chlorobutyl)-5-cyanindole .

[0051] At room temperature, add 50mL of toluene to the reaction bottle under the protection of nitrogen, then add 6.0g of 4-piperazin-1-yl-phenol, 3.2g of MgCl 2 And 2.1mL diisopropylethylamine, 3.6g paraformaldehyde, heat up and reflux for 7 hours, wait for the reaction solution to c...

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Abstract

The invention relates to a synthesis method of a vilazodone intermediate 5-(4-[4-(5-cyano-3-indyl)-butyl]-1-piperazinyl)benzofuran-2-carboxylic acid ethyl ester and a salt thereof, belonging to the technical field of drug synthesis. The synthesis method comprises the following steps of: dissolving 3-(4-chlorobutyl)-5-cyanoindole and a catalyst into an inorganic water solution under the protection of nitrogen gas, carrying out heating reflux, stirring, then, adding 5-(piperazinyl-1-yl)benzofuran-2-carboxylic acid ethyl ester and alkaline, reacting at the temperature of 80-110 DEG C for 4-6h, slowly pouring an aqueous alkaline solution while stirring at room temperature until a solid is separated out, and then, carrying out after-treatment to obtain the 5-(4-[4-(5-cyano-3-indyl)-butyl]-1-piperazinyl)benzofuran-2-carboxylic acid ethyl ester. The synthesis method is low in production cost, environment-friendly, high in operation safety, high in product yield and purity, good in quality and suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to a method for synthesizing a pharmaceutical intermediate, in particular to a vilazodone intermediate 5-(4-[4-(5-cyano-3-indolyl)-butyl]-1-piperazinyl ) The synthetic method of ethyl benzofuran-2-carboxylate and its salt belongs to the technical field of pharmaceutical synthesis. Background technique [0002] Vilazodone is a new antidepressant drug developed by Clinical Data for the treatment of depression in adults. The clinical trial data show that compared with the existing clinical antidepressants, vilazodone has the characteristics of rapid onset of action, good tolerance, no sexual dysfunction for patients, and small adverse reactions. Its chemical name is 5-(4-(4-(5-cyano-3-indolyl)butyl)-1-piperazinyl)benzofuran-2-carboxamide hydrochloride, and its chemical formula is: [0003] [0004] And 5-(4-[4-(5-cyano-3-indolyl)-butyl]-1-piperazinyl)benzofuran-2-carboxylic acid ethyl ester and its salts are synthetic virazole ...

Claims

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Application Information

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IPC IPC(8): C07D405/12C07C53/18C07C51/41
Inventor 胡凡王伸勇邵长坤李胜王晓俊胡隽恺
Owner SUZHOU UUGENE BIOPHARMA
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