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Compound for preparing vilazodone as well as intermediate and application thereof

A technology for compound and indole, applied in the field of compounds for preparing vilazodone, can solve problems such as being unsuitable for mass preparation of vilazodone hydrochloride, and achieve the effects of stable and controllable quality, suitability for industrial production, and easy operation

Active Publication Date: 2014-02-12
NHWA PHARMA CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] This route uses highly toxic sodium cyanoborohydride as a reducing agent, and the preparation of the intermediate 3-(4-oxobutyl)indole-5-carbonitrile requires column chromatography purification, so this method is not suitable for hydrochloric acid Large-scale preparation of vilazodone

Method used

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  • Compound for preparing vilazodone as well as intermediate and application thereof
  • Compound for preparing vilazodone as well as intermediate and application thereof
  • Compound for preparing vilazodone as well as intermediate and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] Preparation of 3-(4-chlorobutyryl)indole-5-carbonitrile

[0066]

[0067] At 0°C, add 1,2-dichloroethane (400 mL) and anhydrous aluminum trichloride (40.0 g, 0.3 moL) into a 2 L three-necked flask equipped with mechanical stirring. At the same temperature, 4-chlorobutyryl chloride (42.2 g, 0.33 moL) was added dropwise, and the dropwise addition was completed in about half an hour, and the stirring was continued for 30 min. Then a solution of 5-cyanindole (36.4 g, 0.25 moL) in 1,2-dichloroethane (400 mL) was added, keeping the temperature at 0-5°C. The dropwise addition was completed within 30 minutes. Remove the ice bath, return to room temperature and continue to stir for 2h.

[0068] Next, 220 g of ice and 220 mL of concentrated hydrochloric acid were added to the reaction mixture. The reaction was stirred overnight at room temperature. After filtration and vacuum drying, 53.8 g of brown solid 3-(4-chlorobutyryl)indole-5-carbonitrile was obtained, with a yield ...

Embodiment 2

[0071] Preparation of 3-(4-bromobutyryl)indole-5-carbonitrile

[0072]

[0073] At 0°C, add 1,2-dichloroethane (200 mL) and anhydrous aluminum trichloride (15.4 g, 0.12 moL) into a 1 L three-necked flask equipped with mechanical stirring. At the same temperature, 4-bromobutyryl chloride (25.0 g, 0.13 moL) was added dropwise, and the addition was completed in about 20 minutes, and the stirring was continued for 30 minutes. Then a solution of 5-cyanindole (14.0 g, 0.096 moL) in 1,2-dichloroethane (200 mL) was added, keeping the temperature at 0-5°C. The dropwise addition was completed within 30 minutes. Remove the ice bath, return to room temperature and continue to stir for 2h.

[0074] Next, 100 g of ice and 100 mL of concentrated hydrochloric acid were added to the reaction mixture. The reaction was stirred overnight at room temperature. After filtration and vacuum drying, 21.8 g of brown solid 3-(4-bromobutyryl)indole-5-carbonitrile was obtained, with a yield of 78%. ...

Embodiment 3

[0077] Preparation of 3-(4-chlorobutyryl)-1-(naphthalene-1-ylsulfonyl)-1H-indole-5-carbonitrile

[0078]

[0079] Suspend NaH (3.0 g, 157.5 mmol) in dry DMF (150 mL), then cool to 0 °C, add 3-(4-chlorobutyryl)indole-5-carbonitrile (15.5 g, 63 mmol) in DMF (150 mL) solution. The mixture was stirred at room temperature for 30 min, then cooled to 0°C again, and 1-naphthalenesulfonyl chloride (15.7 g, 69 mmol) was added dropwise. The mixture was stirred overnight at room temperature.

[0080] Add saturated NH to the reaction mixture 4 Cl aqueous solution 100mL, then extracted with diethyl ether (150mL×3), the organic phase was washed with saturated brine, and dried over anhydrous magnesium sulfate. Filter, evaporate the solvent to dryness, and then recrystallize in acetone to obtain 20.8 g of white solid 3-(4-chlorobutyryl)-1-(naphthalene-1-ylsulfonyl)-1H-indole-5-carbonitrile , the yield was 76%.

[0081] ES Ⅰ-MS[m+1] + :437.

[0082] 1 H NMR (CDCl 3 , 500MHz, TMS) δ2...

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PUM

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Abstract

The invention belongs to the field of medicinal chemistry and relates to a compound for preparing vilazodone as well as an intermediate and an application thereof. The compound for preparing vilazodone is shown as a formula I, and the intermediate for synthesizing the compound of the formula I is shown as a formula II. The compound of the formula I can be applied to preparation of vilazodone and pharmaceutically acceptable salts thereof. The compound of the formula I serving as a novel intermediate is applied in preparation of the vilazodone, the defects in the conventional literature report are overcome, metal catalysts with high toxicity and organic phosphorus ligands thereof are avoided, the preparation cost is greatly reduced, the operation is simplified, and the compound is stable and controllable in quality and suitable for large-scale industrial preparation.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to compounds used for preparing vilazodone, intermediates and applications thereof. technical background [0002] Vilazodone hydrochloride (vilazodone hydrochloride), the chemical name is 5-[4-[4-5[5-cyano-1H-indol-3-yl]butyl]piperazin-1-yl]benzofuran -2 formamide hydrochloride, its trade name is Viibryd. The drug is an antidepressant drug developed by Trovis Pharma LLC pharmaceutical company. It was approved by the FDA in January 2011 and is mainly used for the treatment of severe depression in adults. Its chemical structure is as follows: [0003] [0004] Depression is a common mental illness. Its main symptoms are depression, loss of appetite, sleep disturbance, and even suicide attempts. It is clinically chronic and recurrent. [0005] Vilazodone, as a new generation antidepressant drug, is a combination of 5-HT reuptake inhibitor (SSRI) and 5-HT 1A A novel...

Claims

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Application Information

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IPC IPC(8): C07D405/12C07D209/10
CPCC07D209/10C07D405/12
Inventor 张波马彦琴张桂森杨相平
Owner NHWA PHARMA CORPORATION
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