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Synthesis method of vilazodone and salt thereof

A synthetic method, the technology of vilazodone, which is applied in the field of drug synthesis, can solve the problems of being unsuitable for large-scale industrial production of vilazodone hydrochloride, reducing the utilization rate of production resources, increasing the cost of equipment use, etc., and achieving simple post-reaction treatment Ease of operation, low price, and the effect of increasing product yield

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

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Problems solved by technology

However, this route uses highly toxic and expensive sodium cyanoborohydride as a selective reducing agent, and the intermediate 3-(4-chlorobutyl)-5-cyanindole is synthesized by oxidation, which requires column chromatography Purification, long reaction time, reducing the utilization rate of production resources, and increasing the use cost of equipment, so this synthetic method is only suitable for small-scale experiments, and is not suitable for large-scale industrial production of vilazodone hydrochloride

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] At room temperature, under nitrogen protection, 2.4 g of 1.1-dimethoxy-6-chlorohexane was dissolved in a mixed solution of 24 mL of ethanol and 12 mL of water, and the temperature was raised to 68° C. to dissolve all. At room temperature, a mixed solvent of 1.9 g of 4-cyanophenylhydrazine hydrochloride, 19 mL of ethanol and 9.5 mL of pure water was slowly added dropwise to 2.3 g of the 1.1-dimethoxy-6-chlorohexane reaction solution. The temperature was kept at 70°C for 0.8 hours, and after the reaction solution was lowered to room temperature, a large amount of solid was precipitated, suction filtered, and the filter cake was recrystallized with 50% ethanol aqueous solution to obtain 1.98g of 3-(4-chlorobutyl)-5-cyanoindole indoles.

[0050] Under nitrogen protection, 4.0 g of 5-fluoro-2-hydroxybenzaldehyde was dissolved in 15 mL of acetonitrile to form a reaction solution. Under stirring, 3.26 g of cesium carbonate was added to the reaction solution. After stirring for...

Embodiment 2

[0055] At room temperature, under nitrogen protection, 6.5 g of 1.1-dimethoxy-6-chlorohexane was dissolved in a mixed solution of 65 mL of methanol and 35 mL of water, and the temperature was raised to 70° C. to dissolve all. At room temperature, a mixed solvent of 6.0 g of 4-cyanophenylhydrazine hydrochloride, 60 mL of methanol and 30 mL of pure water was slowly added dropwise to 5.9 g of the 1.1-dimethoxy-6-chlorohexane reaction solution. Incubate for 1.0 hours under the condition of ℃, when the reaction solution is lowered to room temperature, a large amount of solid is precipitated, suction filtration, and the filter cake is recrystallized with 53% ethanol aqueous solution to obtain 8.0g of 3-(4-chlorobutyl)-5-cyanoindole .

[0056]Under the protection of nitrogen, dissolve 7.0g of 5-fluoro-2-hydroxybenzaldehyde in 70mL of N,N-dimethylformamide to form a reaction solution, add 3.0g of triethylamine to the reaction solution under stirring, and stir for 9 Minutes later, 4.1...

Embodiment 3

[0061] At room temperature, 4.5g of 1.1-dimethoxy-6-chlorohexane was dissolved in a mixed solution of 45mL of ethanol and 25mL of water under the protection of nitrogen, and the temperature was raised to 72°C to completely dissolve. At room temperature, a mixed solvent of 3.9g of 4-cyanophenylhydrazine hydrochloride, 39mL of ethanol and 10mL of pure water was slowly added dropwise to the reaction solution of 3.9g of 1.1-dimethoxy-6-chlorohexane, at 72 Keep warm at ℃ for 1.1 hours, wait for the reaction liquid to drop to room temperature, a large amount of solids precipitate out, filter with suction, and recrystallize the filter cake with 55% ethanol aqueous solution to obtain 6.0 g of 3-(4-chlorobutyl)-5-cyanindole .

[0062] Under the protection of nitrogen, dissolve 4.5g of 5-fluoro-2-hydroxybenzaldehyde in 45mL of tetrahydrofuran to form a reaction solution, add 3.9g of N-methylmorpholine to the reaction solution under stirring, stir for 11 minutes under the protection of n...

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Abstract

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.

Description

technical field [0001] The invention relates to a method for synthesizing vilazodone and a salt thereof, and belongs to the technical field of drug synthesis. Background technique [0002] The chemical name of vilazodone is 5-(4-(4-(5-cyano-3-indolyl)butyl)-1-piperazinyl)benzofuran-2-carboxamide, and the English name is 5 -(4-(4-(5-Cyanoindol-3-yl)butyl)-1-piperazinyl)-2-benzofurancarb oxamide, the chemical structure is: [0003] [0004] The chemical structural formula of vilazodone salt is: [0005] Wherein, HX is taken from hydrochloric acid, sulfuric acid, hydrobromic acid, acetic acid, tartaric acid, maleic acid, fumaric acid, oxalic acid, citric acid, phosphoric acid, trifluoroacetic acid, formic acid, succinic acid, mandelic acid, methanesulfonic acid, p-toluene One of sulfonic acid, benzoic acid, p-nitrobenzoic acid and p-hydroxybenzoic acid. [0006] Vilazodone and its salts are new antidepressant drugs developed by Clinical Data for the treatment of depress...

Claims

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Application Information

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IPC IPC(8): C07D405/12
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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