Method for preparing 3-(4-chlorobutyryl)-1H-indole-5-methylcyanogen

A technology of chlorobutyryl and indole is applied in the field of preparation of 3--1H-indole-5-methyl cyanide, and can solve the problems of insolubility, difficulty in stirring, difficulty in mass preparation and the like

Inactive Publication Date: 2011-11-23
上海开义医药化工有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0015] According to the above conditions, we found that there are mainly two defects: in aluminum trichloride (AlCl 3 ) catalyzed to produce an insoluble and difficult to stir solid; a considerable amount of by-products
[0016] In addition, according to the method in the above-mentioned document Med.Chem.Lett.2010, 1, 199-203, the obtained target product 3-(4-chlorobutyryl)-1H-indole-5-cyanide needs to pass through the silica gel column layer analysis, separation and purification, so the method is difficult to prepare in large quantities, and is not suitable for preparing intermediate 3-(4-chlorobutyryl)-1H-indole-5-cyanide and target drug vilazodone hydrochloride as an industrial process

Method used

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  • Method for preparing 3-(4-chlorobutyryl)-1H-indole-5-methylcyanogen

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Experimental program
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Embodiment 1

[0035] 3-(4-chlorobutyryl)-1H-indole-5-cyanide (II) preparation method one

[0036] 1H-indole-5-carbonitrile (1.00mol, 142g) was dissolved in 1300ml (1716g) of dichloromethane, stirred until dissolved, under ice bath, the temperature of the system was lowered to 0°C, and tin tetrachloride ( 1.05mol, 274g), the temperature control system is 0-5°C, after dropping, stir for 0.5 hours, add nitromethane 900ml (1017g), add tetrachlorobutyryl chloride (1.00mol, 141g) dropwise after 10min, and react for 1 hour . The reaction solution was poured into 3000ml of ice-water mixture and stirred for 0.5 hours. Add 5000ml of ethyl acetate, extract, adjust the pH of the organic phase to neutral with saturated aqueous sodium carbonate solution, separate the liquids, wash the organic phase with saturated brine, concentrate and wash with 500ml of ethyl acetate to obtain 180.6g of white crystals, with a yield of 73 %. Melting point: 186-189°C.

[0037] ESI-MS[M+H]+: 247.06

[0038] 1 H-NMR (...

Embodiment 2

[0040] 3-(4-chlorobutyryl)-1H-indole-5-cyanide (II) preparation method two

[0041] 1H-indole-5-carbonitrile (1.00mol, 142g) was dissolved in a mixed solvent of 2000ml (2640g) of dichloromethane and 1000ml (1132g) of nitromethane, and the temperature of the system was lowered to 0°C under an ice bath, Tin tetrachloride (1.05mol, 274g) was added dropwise, and the temperature of the system was controlled at 0-5°C. Continue stirring for 0.5 hours after dropping, add tin tetrachloride (1.00mol, 141g) dropwise, react for 0.8 hours, pour the reaction solution into 3000ml ice-water mixture, and stir for 0.5 hours. Add 5000ml of ethyl acetate, extract, adjust the pH of the organic phase to neutral with a saturated sodium carbonate aqueous solution, and separate the layers. The organic phase is washed with saturated brine, concentrated and washed with ethyl acetate to obtain 172.7 g of white crystals, with a yield of 70%.

[0042] ESI-MS[M+H]+: 247.06

Embodiment 3

[0044] 3-(4-chlorobutyryl)-1H-indole-5-cyanide (II) preparation method three

[0045] Dissolve 1H-indole-5-carbonitrile (1.00mol, 142g) in 2000ml (2640g) of dichloromethane, stir until completely dissolved, lower the temperature of the system to -20°C under cooling pump circulation, add tetrachloride dropwise Tin (110mol, 286g), the temperature control system is -10℃~-5℃. Continue to stir for 0.5 hours after dropping, add 1200ml (1260g) of nitroethane, dropwise add tetrachlorobutyryl chloride (1mol, 141g) after 10min, react for 1.5 hours, pour the reaction solution into 3000ml of ice-water mixture, and stir for 0.5 hours . Add 5000ml of ethyl acetate, extract, adjust the pH of the organic phase to neutral with a saturated sodium carbonate aqueous solution, separate the liquids, wash the organic phase with saturated brine, concentrate and wash with 500ml of ethyl acetate to obtain 200.2g of white crystals, with a yield of 81 %.

[0046] ESI-MS[M+H]+: 247.06

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Abstract

The invention provides a method for preparing 3-(4-chlorobutyryl)-1H-indole-5-methylcyanogen. The method provided by the invention comprises the following steps of: dissolving a compound 1H-indole-5-methylcyanogen shown as a formula (I) into a solvent and a cosolvent to react with tetrachlorobutyryl chloride in the presence of a catalyst tin tetrachloride; then collecting the compound 3-(4-chlorobutyryl)-1H-indole-5-methylcyanogen shown as a formula (II) from the reaction product. The method provided by the invention is beneficial to overcoming of defects of the traditional method for preparing antidepressant vilazodone hydrochloride intermediate, namely 3-(4-chlorobutyryl)-1H-indole-5-methylcyanogen, is more suitable for the industrial production in a large scale, and has obvious creativeness and a practical application value. The reaction formula is shown as in the specification.

Description

technical field [0001] The invention relates to a preparation method of 3-(4-chlorobutyryl)-1H-indole-5-cyanide. Background technique [0002] Vilazodone hydrochloride (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 US Food and Drug Administration (FDA) for the treatment of depression in adults. Its chemical structure is as shown in formula (A): [0003] [0004] Vilazodone hydrochloride is a 5-HT 1A Compared with the existing antidepressants in clinical practice, the novel antidepressant has the dual effects of partial receptor agonism and 5-HT reuptake inhibition, and has the characteristics of rapid onset of action and no side effects of sexual dysfunction. [0005] Patents CN1155568C and CN1181067C disclose the preparation method of the key intermediate 3-(4-chlorobutyl)indole-5-cy...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/12
Inventor 许卫张荣箭朱犇
Owner 上海开义医药化工有限公司
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