4-(5-cyano-1h-indol-3-yl) butyl substituted sulfonate compounds and their applications

A compound and sulfonate technology, applied in the field of 4-butyl substituted sulfonate compounds, can solve the problems of low yield and unsuitability for large-scale industrial production, and achieve high purity, great practical application value and excellent reaction conditions mild effect

Inactive Publication Date: 2011-12-07
SHANGHAI INST OF PHARMA IND CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the reduction reaction step of this route, adopt bis(methoxyethoxy) aluminum dihydride as selective reducing agent, the yield of preparing 3-(4-chlorobutyl) indole-5-formonitrile is low, It is only 27%, and it needs to be purified by column chromatography, and it is not suitable for the large-scale industrial preparation of vilazodone hydrochloride

Method used

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  • 4-(5-cyano-1h-indol-3-yl) butyl substituted sulfonate compounds and their applications
  • 4-(5-cyano-1h-indol-3-yl) butyl substituted sulfonate compounds and their applications
  • 4-(5-cyano-1h-indol-3-yl) butyl substituted sulfonate compounds and their applications

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] Preparation of 3-(4-hydroxybutyl)-1H-indole-5-methylcyanide(II)

[0062] At room temperature, 3-(4-chlorobutyryl)-1H-indole-5-methylcyanide (0.02mol, 4.95g) was dissolved in 100ml of isopropanol, stirred for 5min, and sodium borohydride (0.06mol, 2.3 g), the temperature is raised to reflux for 6 hours. The reaction solution was slowly poured into 1N 50ml dilute hydrochloric acid, stirred for 10min, and the organic phase was evaporated under reduced pressure. The remaining solid and aqueous phase were dissolved in 100ml ethyl acetate and separated, the aqueous phase was extracted with 50ml ethyl acetate, and the organic phases were combined. The phase was washed with 30 ml of saturated brine, the organic phase was dried over anhydrous sodium sulfate, the solvent was evaporated, and 3.17 g of white powder was obtained by column chromatography with a yield of 74%.

[0063] ESI-MS[M+H] + : 215.12

[0064] 1 H-NMR(CDCl 3 ): δ1.63-1.70(m, 2H), 1.74-1.83(m, 2H), 2.77(t, 2H, J=7.6Hz...

Embodiment 2

[0066] Preparation of 4-(5-cyano-1H-indol-3-yl)butyl p-toluenesulfonate (I-1)

[0067] Under the protection of nitrogen, 3-(4-hydroxybutyl)-1H-indole-5-methylcyanide (5mmol, 1.07g) was dissolved in 20ml of dichloromethane. Control the temperature in an ice-water bath to 0-5°C, stir for 5min, add triethylamine (15mmol, 2ml), add 4-tolylsulfonyl chloride (5.25mmol, 1g) in 10ml dichloromethane solution dropwise to the above reaction solution, 0.5 After the hour drop, the temperature is raised to 15-20°C and reacted for 5 hours. The reaction solution was poured into 50 ml of water, stirred for 0.5 hours, and separated, the aqueous phase was extracted with 30 ml of dichloromethane, the organic phases were combined, washed with 30 ml of saturated brine, and the organic phase was evaporated to dryness to obtain 1.54 g of solid powder with a yield of 84%.

[0068] ESI-MS[M+Na] + : 391.09

[0069] 1 H-NMR (DMSO-d6): δ 1.60-1.64 (m, 4H), 2.40 (s, 3H), 2.66 (t, 2H, J = 7.8 Hz), 4.08 (t, 2H, J...

Embodiment 3

[0071] Preparation of 4-(5-cyano-1H-indol-3-yl)butylbenzenesulfonate (I-2)

[0072] Under the protection of nitrogen, 3-(4-hydroxybutyl)-1H-indole-5-methylcyanide (5mmol, 1.07g) was dissolved in 20ml of dichloromethane. Control the temperature in an ice-water bath to 0-5°C, add triethylamine (15mmol, 2ml) and stir for 5min. A 10-ml dichloromethane solution of 4-phenylsulfonyl chloride (5.25 mmol, 0.93 g) was added dropwise to the above reaction solution, and after the dropping, the temperature was raised to 15-20° C. and reacted for 12 hours. The reaction solution was poured into 50 ml of water, stirred for 0.5 hours, and separated. The aqueous phase was extracted with 30 ml of dichloromethane, the organic phases were combined, washed with 30 ml of saturated brine, and the organic phase was evaporated to dryness to obtain a solid 1.43 g, with a yield of 79.1%.

[0073] ESI-MS[M+H] + : 355.10

[0074] 1 H-NMR (DMSO): δ 1.60-1.64 (m, 4H), 2.66 (t, 2H, J = 7.8 Hz), 4.08 (t, 2H, J = 5....

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Abstract

The invention discloses a 4-(5-cyano-1H-indol-3-yl) butyl substituted sulfonate compound and its application. The 4-( 5-cyano-1H-indol-3-yl) butyl substituted sulfonate compounds, as new intermediates, in the preparation of vilazodone and its pharmaceutically acceptable salts, overcome the existing The defects and deficiencies in the preparation method reported in the literature are more suitable for the large-scale industrial preparation of vilazodone hydrochloride, which has obvious creativity, great positive progress effect and practical application value. The general structural formula of the compound shown in formula (I) is as follows:

Description

Technical field [0001] The present invention relates to a kind of key intermediates used in the synthesis of vilazodone hydrochloride: 4-(5-cyano-1H-indol-3-yl) butyl substituted sulfonate compounds. technical background [0002] Vilazodone hydrochloride, 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] At present, domestic and foreign documents have disclosed the following methods to prepare vilazodone ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/12C07D405/12
Inventor 李建其王冠王超王佳静
Owner SHANGHAI INST OF PHARMA IND CO LTD
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