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Method for preparing vilazodone intermediate 3-(4-chlorobutyl)-1H-indol-5-cyano

A technology of vilazodone and intermediate, which is applied in the field of preparing vilazodone intermediate 3-(4-chlorobutyl)-1H-indole-5-cyano group, can solve the problem of high market price of sodium aluminate , not suitable for industrial amplification, not suitable for industrial amplification, etc.

Active Publication Date: 2013-12-25
陕西步长高新制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] In this reaction, there are three problems and defects: one is that the crude product obtained needs to be processed by recrystallization and column chromatography, which is not suitable for industrial scale-up; the other is that the yield of the product obtained is too low, only 26%, The cost is too high, the yield is too low, and it is also not suitable for industrial scale-up; the third is that the market price of dihydrobis(2-methoxyethoxy)sodium aluminate is relatively high, which makes the production cost relatively high
[0016] Patent WO2000035872 (CN1330635A / CN1155568C) reported the use of lithium aluminum hydride, sodium borohydride and boron trifluoride ether to reduce 3-(4-chlorobutyryl)-1H-indole-5-cyano, but the literature shows , did not generate the target product
[0017] In industrial production, sodium borohydride and Lewis acid are often used for reduction, but sodium borohydride is easy to decompose in humid air, not stable enough, and the yield is not satisfactory. Therefore, the above preparation method and the reagent used Neither is the best choice, and further research is needed to optimize

Method used

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  • Method for preparing vilazodone intermediate 3-(4-chlorobutyl)-1H-indol-5-cyano
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  • Method for preparing vilazodone intermediate 3-(4-chlorobutyl)-1H-indol-5-cyano

Examples

Experimental program
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Effect test

Embodiment 1

[0028] Example 1 Add 3-(4-chlorobutyryl)-1H-indole-5-cyano (4.92g, 0.02mol) to a 100ml three-necked flask, and then add 60ml of tetrahydrofuran, stir to make the reaction raw materials fully dissolved in tetrahydrofuran , Then slowly add aluminum trichloride (5.32g, 0.04mol), use an ice bath to control the reaction temperature to 0-10 ℃, after all aluminum trichloride is added, slowly add potassium borohydride (2.16g, 0.04mol), always control the reaction temperature to 0-10°C, monitor the reaction with thin-layer chromatography, after the reaction is completed, slowly add water to the reaction flask to quench the reaction, control the temperature to 0-10°C, and use Extracted with dichloromethane, separated with a camera, washed the organic phase with water and saturated brine, concentrated in vacuo, evaporated to dryness, and recrystallized with acetone to obtain 4.42 g of the product with a yield of 95.05%.

[0029] MS(ESI + , M / e): 246.12[M+H] +

[0030] 1 H-NMR (400MHz, CDCl 3...

Embodiment 2

[0031] Example 2 Add 3-(4-chlorobutyryl)-1H-indole-5-cyano (4.92g, 0.02mol) to a 100ml three-necked flask, and then add 60ml of tetrahydrofuran, stir to make the reaction raw materials fully dissolved in tetrahydrofuran , Then slowly add ferric chloride (6.48g, 0.04mol, use an ice bath to control the reaction temperature to 0-10 ℃, after all ferric chloride is added, slowly add potassium borohydride (2.16g, 0.04mol) , Always control the reaction temperature to 0-10°C, monitor the reaction with thin layer chromatography, after the reaction is completed, slowly add water to the reaction flask to quench the reaction, control the temperature to 0-10°C, use dichloromethane after quenching After extraction and separation with a camera, the organic phase was washed with water and saturated brine, concentrated in vacuo and evaporated to dryness, and recrystallized with acetone to obtain 4.28 g of product with a yield of 92.04%.

Embodiment 3

[0032] Example 3 Add 3-(4-chlorobutyryl)-1H-indole-5-cyano (4.92g, 0.02mol) to a 100ml three-necked flask, and then add 60ml of tetrahydrofuran, stir to make the reaction raw materials fully dissolved in tetrahydrofuran , And then slowly add zinc chloride (5.44g, 0.04mol, use an ice bath to control the reaction temperature to 0-10 ℃, after all the zinc chloride is added, slowly add potassium borohydride (2.16g, 0.04mol) , Always control the reaction temperature to 0-10°C, monitor the reaction with thin layer chromatography, after the reaction is completed, slowly add water to the reaction flask to quench the reaction, control the temperature to 0-10°C, use dichloromethane after quenching After extraction and separation with a camera, the organic phase was washed with water and saturated brine, concentrated in vacuo and evaporated to dryness, and recrystallized with acetone to obtain 4.33 g of the product with a yield of 93.12%.

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Abstract

The invention discloses a method for preparing a vilazodone intermediate 3-(4-chlorobutyl)-1H-indol-5-cyano. By the method, 3-(4-chlorobutyryl)-1H-indol-5-cyano is reduced into the 3-(4-chlorobutyl)-1H-indol-5-cyano by potassium borohydride serving as a reducing agent under the catalysis of lewis acid at the reaction temperature of 0 to 10 DEG C. The method has the advantages of short course, conveniences in synthesis, high yield, low cost and the like, and is suitable for industrial production.

Description

Technical field [0001] The present invention relates to a preparation method of vilazodone intermediate 3-(4-chlorobutyl)-1H-indole-5-cyano. Background technique [0002] Vilazodone hydrochloride, the chemical name is 5-(4-(4-(5-cyano-3-indolyl)butyl)-1-piperazinyl)benzofuran-2-methyl Amide hydrochloride is a new antidepressant drug developed by Clinical Data. In January 2011, it was approved by the U.S. Food and Drug Administration (FDA) for the treatment of depression in adults. Its chemical structure is as follows: [0003] [0004] Verazolone hydrochloride has 5-HT 1A A new type of antidepressant with dual effects of partial receptor activation and 5-HT reuptake inhibition, compared with existing clinical antidepressants, has the characteristics of fast onset and no side effects of sexual dysfunction on patients. [0005] In the process of preparing verazolone, 3-(4-chlorobutyl)-1H-indole-5-cyano is a key intermediate. Patent CN1155568C discloses the preparation method of the...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/10
Inventor 赵步长赵超
Owner 陕西步长高新制药有限公司
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