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A method for preparing vilazodone intermediate 3-(4-chlorobutyl)-1h-indole-5-cyano

A technology for vilazodone and intermediates, which is applied in the field of preparation of vilazodone intermediate 3--1H-indole-5-cyano, can solve the problem of low product yield, unsatisfactory yield, High market price of sodium aluminate and other issues

Active Publication Date: 2016-02-10
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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  • A method for preparing vilazodone intermediate 3-(4-chlorobutyl)-1h-indole-5-cyano
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  • A method for preparing vilazodone intermediate 3-(4-chlorobutyl)-1h-indole-5-cyano

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Example 1 In a 100ml there-necked flask, add 3-(4-chlorobutyryl)-1H-indole-5-cyano (4.92g, 0.02mol), then add 60ml of tetrahydrofuran, stir to fully dissolve the reaction raw materials in tetrahydrofuran , then slowly add aluminum trichloride (5.32g, 0.04mol), use an ice bath to control the reaction temperature to 0-10 ° C, after all aluminum trichloride is added, slowly add potassium borohydride (2.16g, 0.04mol), always control the reaction temperature to 0-10 ℃, 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 ℃, use after quenching Dichloromethane was extracted, the organic phase was separated, the organic phase was washed with water and saturated brine respectively, concentrated in vacuo and 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+...

Embodiment 2

[0031] Example 2 In a 100ml there-necked flask, add 3-(4-chlorobutyryl)-1H-indole-5-cyano (4.92g, 0.02mol), then add 60ml of tetrahydrofuran, stir to fully dissolve the reaction raw materials in tetrahydrofuran , then slowly add ferric chloride (6.48g, 0.04mol, use ice bath to control the reaction temperature to 0-10 ℃, after all the ferric chloride is added, slowly add potassium borohydride (2.16g, 0.04mol) in batches , always control the reaction temperature to 0-10 ℃, 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 ℃, use dichloromethane after quenching Extract, separate the organic phase, wash the organic phase with water and saturated brine respectively, concentrate in vacuo and evaporate to dryness, and recrystallize with acetone to obtain 4.28 g of the product with a yield of 92.04%.

Embodiment 3

[0032] Example 3 In a 100ml there-necked flask, add 3-(4-chlorobutyryl)-1H-indole-5-cyano (4.92g, 0.02mol), then add 60ml of tetrahydrofuran, stir to fully dissolve the reaction raw materials 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 zinc chloride is added, slowly add potassium borohydride (2.16g, 0.04mol) in batches , always control the reaction temperature to 0-10 ℃, 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 ℃, use dichloromethane after quenching Extract, separate the organic phase, wash the organic phase with water and saturated brine respectively, concentrate in vacuo and evaporate to dryness, and recrystallize 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 invention relates to a preparation method of vilazodone intermediate 3-(4-chlorobutyl)-1H-indole-5-cyano. Background technique [0002] Vilazodone hydrochloride, chemical name is 5-(4-(4-(5-cyano-3-indolyl)butyl)-1-piperazinyl)benzofuran-2-carboxamide Hydrochloride is a new antidepressant drug developed by ClinicalData. In January 2011, it was approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult depression. Its chemical structure is as follows: [0003] [0004] Vilazodone hydrochloride has 5-HT 1A Compared with the existing clinical antidepressants, the novel antidepressant with dual effects of partial receptor agonism and 5-HT reuptake inhibition has the characteristics of fast onset of action and no side effects of sexual dysfunction for patients. [0005] In the process of preparing vilazodone, 3-(4-chlorobutyl)-1H-indole-5-cyano is a key intermediate. Patent CN1155568C discloses the preparation method of k...

Claims

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Application Information

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Patent Type & Authority Patents(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