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Preparation method and application of 3-(4-chlorobutyl)-5-cyano-1H-indole

A technology of chlorobutyl and chlorobutyryl, which is applied in the field of preparation of 3--1H-indole-5-cyano group, can solve problems such as being unsuitable for industrial scale-up, unsuitable for industrial scale-up, not generating target products, and the like, Achieve significant creativity and practical application value, low cost, and simplified operation

Active Publication Date: 2012-09-12
HANGZHOU HEZE PHARMA TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0013] In this reaction, there are two 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
[0022] 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

Method used

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  • Preparation method and application of 3-(4-chlorobutyl)-5-cyano-1H-indole

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Embodiment 1

[0048] 3-(4-chlorobutyl)-1H-indole-5-cyano group preparation method one

[0049] The compound represented by formula (I) 3-(4-chlorobutyryl)-1H-indole-5-cyano (21g, 85.4mmol, see Example 8 for the operation method, self-made) was used 200ml of tetrahydrofuran (Hangzhou Gaojing) Dissolve, stir and lower the temperature to 0°C, add trifluoroacetic acid (80ml, 123.2g, Jinan Wanxingda Chemical Industry) dropwise to the reaction solution, control the temperature below 5°C, after the dropping is completed, add in batches (or one-time slow Add) sodium borohydride (10.4g, 273mmol, Tianjin Damao Chemical Preparation Factory), after the addition, stir at room temperature for 12 hours, HPLC monitors the completion of the reaction, add purified water (50ml) to quench the reaction, use ethyl acetate (Hangzhou High Extract with 500ml of crystal), wash the organic phase with water (100ml), saturated brine (100ml), concentrate and spin dry, recrystallize with ethanol (Hangzhou Gaojing) to obtain...

Embodiment 2

[0054] Preparation method two of 3-(4-chlorobutyl)-1H-indole-5-cyano

[0055] The compound represented by formula (I) 3-(4-chlorobutyryl)-1H-indole-5-cyano (21g, 85.4mmol, see Example 8 for the operation method, self-made) was used 200ml of tetrahydrofuran (Hangzhou Gaojing) Dissolve, stir and lower the temperature to 0°C, add trifluoroacetic acid (22ml, 32.1g, Jinan Wanxingda Chemical Industry) dropwise to the reaction solution, control the temperature below 5°C, after the dropwise addition is completed, add sodium borohydride (3.9 g, 102.5mmol, Tianjin Damao Chemical Preparation Factory), after the addition, stir at room temperature for 0.5 hours, HPLC monitors the reaction to complete, add purified water (50ml) to quench the reaction, extract with 500ml ethyl acetate (Hangzhou Gaojing), organic The phase was washed with water (100ml), saturated brine (100ml), concentrated and spin-dried, and column chromatography gave 12.3g of the product with a yield of 62.0% and a melting po...

Embodiment 3

[0058] 3-(4-chlorobutyl)-1H-indole-5-cyano group preparation method three

[0059] The compound represented by formula (I) 3-(4-chlorobutyryl)-1H-indole-5-cyano (21g, 85.4mmol, see Example 8 for the operation method, self-made) was used 200ml of tetrahydrofuran (Hangzhou Gaojing) Dissolve, stir and lower the temperature to 0°C, add trifluoroacetic acid (215ml, 321.0g, Jinan Wanxingda Chemical) into the reaction solution dropwise, control the temperature below 5°C, after the dropwise addition is complete, add sodium borohydride (29.8 g, 0.79mol, Tianjin Damao Chemical Preparation Factory), after the addition, stir at room temperature for 48 hours, HPLC monitoring the reaction is completed, add purified water (50ml) to quench the reaction, extract with 500ml ethyl acetate (Hangzhou Gaojing), organic The phase was washed with water (100ml), saturated brine (100ml), concentrated and spin-dried, and column chromatography gave 14.5g of the product with a yield of 73.0% and a melting po...

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Abstract

The invention relates to a preparation method and application of 3-(4-chlorobutyl)-5-cyano-1H-indole. The preparation method comprises the following steps: after dissolving 3-(4-chlorobutyryl)-5-cyano-1H-indole in a solvent, adding trifluoroacetic acid, adding sodium borohydride in batches, and treating the reaction liquid to obtain the 3-(4-chlorobutyl)-5-cyano-1H-indole. The method overcomes the defects in the existing preparation method of an important intermediate 3-(4-chlorobutyl)-5-cyano-1H-indole of an antidepressant vilazodone hydrochloride, and has obvious creativity and practical application value. The reaction formula is disclosed in the specification.

Description

technical field [0001] The invention relates to a preparation method and application of 3-(4-chlorobutyl)-1H-indole-5-cyano (CAS Registry Number: 143612-79-7). Background technique [0002] The chemical name of Vilazodone Hydrochloride is 5-(4-(4-(5-cyano-3-indolyl)butyl)-1-piperazinyl)benzofuran-2-carboxamide Hydrochloride. is an antidepressant drug developed by Clinical Date. On January 21, 2011, it was approved by the U.S. Food and Drug Administration (FDA) for the treatment of moderate to severe depression in adults. Its chemical structural formula is as follows (Vilazodone Hydrochloride): [0003] [0004] Vilazodone hydrochloride is a 5-HT 1A , a new type of antidepressant with dual effects of partial receptor agonism and 5-HT reuptake inhibition. Compared with the existing clinical antidepressants, it has the characteristics of rapid onset of action and no side effects of sexual dysfunction. In the process of preparing vilazodone and its pharmaceutically accept...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/10
Inventor 陈鸿翔蔡烈峰周俊林洪梅林刘艳
Owner HANGZHOU HEZE PHARMA TECH
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