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Preparation method of 3-(4-chlorobutyl)indole-5-formonitrile

A technology of chlorobutyl and chlorobutyryl, which is applied in the field of preparation of 3-indole-5-carbonitrile, can solve the problems of difficult industrial production, expensive reagents, cumbersome operation, etc., and achieve low production cost and large implementation Value and socio-economic benefits, effects on increased yield and product purity

Inactive Publication Date: 2013-04-24
SHANDONG ZOUPING DAZHAN NEW MATERIALS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The method uses 5-cyanoindole as a raw material, under the catalysis of isobutyl aluminum dichloride and 4-chlorobutyryl chloride to carry out acrylation reaction to obtain 3-(4-chlorobutyryl)indole-5 -Formonitrile is then reduced by bis(2-methoxyethoxy)sodium aluminum hydride to obtain 3-(4-chlorobutyl)indole-5-carbonitrile, the total yield is only 19%, and column chromatography is required Purification, cumbersome operation, the reagents used are expensive and difficult to purchase, and it is difficult to realize industrial production

Method used

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  • Preparation method of 3-(4-chlorobutyl)indole-5-formonitrile

Examples

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Embodiment 1

[0029] Add 50g of 5-cyanindole, 500ml of dichloromethane, and 49.6g of 4-chlorobutyryl chloride into a 1L reaction bottle, cool down to -5°C in an ice bath, add 46.9g of aluminum trichloride in four times, and keep the temperature at -5°C. Stir and react at -0°C for 5 hours, and treat the reaction liquid by conventional methods to obtain 78.1 g of 3-(4-chlorobutyryl)indole-5-carbonitrile; add 800 ml of dichloromethane to the obtained intermediate, and cool down to -5°C in an ice bath , add 24g of sodium borohydride in four times, add 72.2g of trifluoroacetic acid dropwise after addition, keep the temperature below 0°C for 5h, after the reaction is completed, follow the conventional method to obtain 3-(4-chlorobutyl)indole-5 -Formonitrile 61.4g, total yield 75%, HPLC purity 99.5%.

Embodiment 2

[0031] Add 50g of 5-cyanindole, 400ml of dichloromethane, 100ml of nitromethane, 99.2g of 4-chlorobutyryl chloride into a 1L reaction bottle, cool to -5°C in an ice bath, add 93.8g of aluminum trichloride in four times, Keep the temperature at -5-0°C, stir and react for 5 hours, and treat the reaction solution by conventional methods to obtain 75g of 3-(4-chlorobutyryl)indole-5-carbonitrile; add 346.6g of trifluoroacetic acid to the obtained intermediate, and keep the temperature Add 57.6g of sodium borohydride four times below 0°C, keep warm at -5-0°C and stir for 5 hours after the addition, after the reaction is completed, follow the conventional method to obtain 3-(4-chlorobutyl)indole-5-carbonitrile 63g, total yield 77%, HPLC purity 99.3%.

Embodiment 3

[0033] Add 50g of 5-cyanindole, 500ml of petroleum ether, and 74.4g of 4-chlorobutyryl chloride into a 1L reaction bottle, cool down to -5°C in an ice bath, add 70.4g of aluminum trichloride in four times, and keep the temperature at -5- 0°C, stirring and reacting for 5 hours, the reaction solution was treated according to conventional methods to obtain 76.8g of 3-(4-chlorobutyryl)indole-5-carbonitrile; the obtained intermediate was added with 800ml of diethyl ether, cooled to -5°C in an ice bath, and divided into four Add 30 g of sodium borohydride each time, add 150 g of trifluoroacetic acid dropwise after the addition, keep warm at -5-0°C and stir for 5 hours after the addition, after the reaction is completed, post-process according to the conventional method to obtain 3-(4-chlorobutyl)indole-5- Amethonitrile was 60.6g, the total yield was 74%, and the HPLC purity was 99.2%.

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Abstract

The invention relates to a preparation method of 3-(4-chlorobutyl)indole-5-formonitrile. 3-(4-chlorobutyl)indole-5-formonitrile is an important intermediate for synthesis of vilazodone hydrochloride. 5-cyanoindole and 4-chlorobutyryl chloride as raw materials undergo a Friedel-Crafts acylation reaction and then the product is reduced by sodium borohydride / trifluoroacetic acid into 3-(4-chlorobutyl)indole-5-formonitrile. The preparation method utilizes the cheap and easily acquired reagents, has a high yield and high product purity, is simple and reliable, and has a low production cost, a large implement value and social and economic benefits.

Description

technical field [0001] The invention relates to a preparation method of 3-(4-chlorobutyl)indole-5-carbonitrile, which is an important intermediate for synthesizing vilazodone hydrochloride. Background technique [0002] Vilazodone hydrochloride was approved by the US Food and Drug Administration in January 2011 for the treatment of moderate to severe depression in adults. Clinical trial data show that its curative effect is significantly better than that of placebo, with good tolerance and less adverse reactions. [0003] 3-(4-chlorobutyl) indole-5-carbonitrile is a key intermediate for the synthesis of vilazodone hydrochloride, as reported in the Journal of Medicinal Chemistry, 2004, Vol.47, No.19, 4684-4692 A kind of preparation method of compound, synthetic route is as follows: [0004] [0005] The method uses 5-cyanoindole as a raw material, under the catalysis of isobutyl aluminum dichloride and 4-chlorobutyryl chloride to carry out acrylation reaction to obtain 3...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/10
Inventor 李岩任世言林泉生尚积金
Owner SHANDONG ZOUPING DAZHAN NEW MATERIALS
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