Preparation method for 3-(4- chlorobutyl)-1H-5-cyanoindole as a vilazodone intermediate

A technology of -1H-5- and vilazodone, which is applied in the field of preparation of key pharmaceutical intermediates, can solve the problems of unfavorable large-scale industrial production, difficulty in separation and purification, and low synthesis efficiency, and achieve high synthesis efficiency, cheap and easy raw materials The effect of easy operation

Inactive Publication Date: 2012-09-26
HUAIHAI INST OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0014] The technical problem to be solved by the present invention is to overcome the high cost, low synthesis efficiency, difficult separation and purification, and no The defect that is beneficial to industrialized large-scale production provides a kind of method of new preparation formula (I) compound 3-(4-chlorobutyl)-1H-5-cyanindole, and this method raw material is cheap and easy to get, and reaction condition is relatively Mild, easy to operate, high synthesis efficiency, conducive to industrial production

Method used

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  • Preparation method for 3-(4- chlorobutyl)-1H-5-cyanoindole as a vilazodone intermediate
  • Preparation method for 3-(4- chlorobutyl)-1H-5-cyanoindole as a vilazodone intermediate
  • Preparation method for 3-(4- chlorobutyl)-1H-5-cyanoindole as a vilazodone intermediate

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Effect test

Embodiment 1

[0033] Embodiment 1 The preparation of formula (IV) compound 3-(4-chlorobutyryl)-1H-5-cyanindole

[0034] Add 16g (0.12mol) of anhydrous aluminum trichloride and 200mL of dichloromethane into the reaction flask, and cool the reaction flask to 0°C, slowly drop 28.2g (0.2mol) of compound 4-chlorobutyryl chloride into , control the reaction temperature not to exceed 5°C, and then stir at 0°C for 0.5h after dropping. Then, 14.2 g (0.1 mol) of the compound of formula (II) 5-cyanindole dissolved in 100 mL of dichloromethane was added dropwise, and the reaction was stirred at room temperature for 1.5 h after the drop was completed. 100g of ice and 100mL of concentrated hydrochloric acid were added, and the reaction was stirred at room temperature for 3h. After filtering, the filter cake was washed with dichloromethane and cold water and dried under vacuum at 50°C to obtain 19.6g of solid, melting point: 168-170°C, yield 80%.

Embodiment 2

[0035] Embodiment 2 The preparation of formula (I) compound 3-(4-chlorobutyl)-1H-5-cyanindole

[0036] Under the protection of nitrogen, 24.6g (0.1mol) of the compound of formula (IV) and 200mL of dichloromethane were added to the reaction flask, and the reaction flask was cooled to -5~-10°C, and 11.4g (0.3mol) of sodium borohydride was added, After stirring and reacting for 15 minutes, slowly add 40 g (0.3 mol) of anhydrous aluminum trichloride, control the reaction temperature not to exceed -5°C, react at -5~-10°C for 0.5h, and then stir at room temperature for 2h. Then the reaction flask was cooled to -5~-10°C, 300 mL of ice water was slowly added dropwise, and stirred at room temperature for 0.5 h after the drop was completed. The solvent was evaporated under reduced pressure, 500 mL of ethyl acetate was added to the residue, the organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a crude solid. ...

Embodiment 3

[0037] Embodiment 3 The preparation of formula (IV) compound 3-(4-chlorobutyryl)-1H-5-cyanindole

[0038]Add 16g (0.12mol) of anhydrous aluminum trichloride and 150mL of dichloromethane into the reaction flask, and cool the reaction flask to -5°C, slowly drop 21.2g (0.15mol) of compound 4-chlorobutyryl chloride Add, control the reaction temperature not to exceed 5°C, and stir at 0°C for 0.5h after dropping. Then, 14.2 g (0.1 mol) of the compound of formula (II) 5-cyanindole dissolved in 100 mL of dichloromethane was added dropwise, and the reaction was stirred at room temperature for 1.5 h after the drop was completed. 100g of ice and 100mL of concentrated hydrochloric acid were added, and the reaction was stirred at room temperature for 2h. After filtering, the filter cake was washed with dichloromethane and cold water and then dried in vacuum at 50°C to obtain 17.9g of solid, melting point: 168-170°C, yield 73%.

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Abstract

The invention discloses a new method for preparing 3-(4- chlorobutyl)-1H-5-cyanoindole as a vilazodone intermediate, comprising the following steps: step (1), a compound of formula II is reacted with a compound of formula III in the presence of an acylation catalyst in an organic solvent to form a compound of formula IV, step (2), the compound of formula IV formed in step (1) is subjected to carbonyl reduction reaction in the presence of a reducing catalyst in the organic solvent. The preparation method for 3-(4- chlorobutyl)-1H-5-cyanoindole as the vilazodone intermediate has cheap and easily-available raw materials, mild reaction condition, simple operation, high synthesis efficiency and is suitable for industrial production, thereby providing a new way for preparing vilazodone.

Description

technical field [0001] The invention belongs to the technical field of preparation of key intermediates of medicines, and in particular relates to a preparation method of an antidepressant drug vilazodone intermediate 3-(4-chlorobutyl)-1H-5-cyanindole. Background technique [0002] According to the statistics of the World Health Organization (WHO) in 2002, there are about 150 million people in the world suffering from different degrees of depression, and the incidence of major depressive disorder (MDD) is also very high among adults. Currently, depression has become the fourth leading disease in the world. With the impact of work pressure, environment and other factors, the number of patients with depression will continue to increase. [0003] Vilazodone (formula A), chemical name 5-[4-[4-(5-cyano-1H-indol-3-yl)butyl]-1-piperazinyl]-2-benzo Furamide is a dual-action selective serotonin reuptake inhibitor and 5-HT developed by Trovis Pharmaceuticals LLC of the United States...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/10
Inventor 王启发程青芳陈娜郑国闯帅美
Owner HUAIHAI INST OF TECH
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