Preparation method of vilazodone hydrochloride intermediate 3-(4-chlorobutyl)-1H-5-cyanindole

A technology of -1H-5- and vilazodone, applied in the direction of organic chemistry and the like, can solve the problems of difficult industrialized large-scale production, low synthesis yield and high technical cost, and achieves high synthesis efficiency, simple post-processing operation, The effect of mild reaction conditions

Active Publication Date: 2015-05-06
BEIJING SINICA TECH
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  • Application Information

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Problems solved by technology

[0016] The purpose of the invention is to provide a new method for preparing vilazodone hydrochloride intermediate 3-(4-chlorobutyl)-1H-5-cyanindole, which overcomes the high technical cost of the existing method and the high synthetic yield. Low, difficult to purify, difficult to produce technical defects in large-scale industrialization

Method used

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  • Preparation method of vilazodone hydrochloride intermediate 3-(4-chlorobutyl)-1H-5-cyanindole
  • Preparation method of vilazodone hydrochloride intermediate 3-(4-chlorobutyl)-1H-5-cyanindole
  • Preparation method of vilazodone hydrochloride intermediate 3-(4-chlorobutyl)-1H-5-cyanindole

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Embodiment 1

[0033] Example 1: Preparation method one of 3-(4-chlorobutyl)-1H-5-cyanindole:

[0034] Disperse 18 grams of sodium borohydride in 200 mL of dichloromethane, slowly add 200 mL of dichloromethane solution dissolved with trichloroacetic acid (80 grams), and add 3-(4-chlorobutyryl)-1H-5- Cyanoindole (20 g), stirred at 30°C for 6 hours. The reaction solution was poured into water, and the water layer was separated. 1N aqueous sodium hydroxide solution was added to the organic phase to adjust the pH value to 7-9, the organic phase was washed with saturated aqueous sodium chloride solution, and the organic solvent was removed under reduced pressure. The crude product was recrystallized from methanol to obtain 15.5 g of off-white product. Yield is 82%, HPLC shows purity: 99.06%.

Embodiment 2

[0035] Embodiment 2: Preparation method two of 3-(4-chlorobutyl)-1H-5-cyanindole:

[0036] Disperse 18 grams of sodium borohydride in 600 mL of dichloromethane, slowly add 600 mL of dichloromethane solution dissolved with trichloroacetic acid (80 grams), and add 3-(4-chlorobutyryl)-1H-5- Cyanoindole (20 g), stirred at 30°C for 6 hours. The reaction solution was poured into water, and the water layer was separated. 1N aqueous sodium hydroxide solution was added to the organic phase to adjust the pH value to 7-9, the organic phase was washed with saturated aqueous sodium chloride solution, and the organic solvent was removed under reduced pressure. The crude product was recrystallized from methanol to obtain 16.8 g of off-white product with a yield of 88.9%.

Embodiment 3

[0037] Example 3: Preparation method three of 3-(4-chlorobutyl)-1H-5-cyanindole:

[0038] Disperse 18 grams of sodium borohydride in 400 mL of dichloromethane, slowly add 300 mL of dichloromethane solution dissolved with trichloroacetic acid (50 grams), and add 3-(4-chlorobutyryl)-1H-5- Cyanoindole (20 g), stirred at 30°C for 6 hours. The reaction solution was poured into water, and the water layer was separated. The organic phase was adjusted to pH 7-9 with 1N aqueous sodium hydroxide solution, washed with saturated aqueous sodium chloride solution, and the organic solvent was removed under reduced pressure. The crude product was recrystallized from methanol to obtain 16.1 g of off-white product. The yield was 85.2%, and the HPLC showed a purity of 98.1%.

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Abstract

The invention relates to a preparation method of 3-(4-chlorobutyl)-1H-5-cyanindole. The above compound is an important intermediate for preparing an antidepressant vilazodone hydrochloride. The method comprises the following steps: dispersing sodium borohydride in a solvent, adding a trichloroacetic acid organic solution, and adding 3-(4-chlorobutylacyl)-1H-5-cyanindole in batches. The preparation method of the vilazodone hydrochloride intermediate 3-(4-chlorobutyl)-1H-5-cyanindole has the advantages of simple operation, low device requirements, high yield, good purity, suitableness for industrial production, and obvious creativity and practical application values. The reaction equation of the method is shown in the specification.

Description

Field of invention: [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method of vilazodone hydrochloride key intermediate 3-(4-chlorobutyl)-1H-5-cyanindole Background technique: [0002] Approved by the US Food and Drug Administration (FDA) on January 21, the trade name Viibryd belongs to 5-HT 1A Partial agonists and selective serotonin reuptake inhibitors are also the first new class of indoalkylamine antidepressants. Its chemical formula structure is: [0003] [0004] Wherein 3-(4-chlorobutyl)-1H-5-cyanindole is the key intermediate for preparing vilazodone hydrochloride, and the following several preparation methods have been announced at home and abroad at present: [0005] 1) In the literature Journal of Medicinal Chemistry, 2004, 47(19): 4684-4692, red aluminum was used as a reducing agent to obtain 3-(4-chlorobutyl)-1H-5-cyanindole, and its reaction equation as follows: [0006] [0007] The reducing agent use...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/10
CPCC07D209/10
Inventor 李小培张翔陈赫岩任明光黄少林赵鸿莲许晓椿
Owner BEIJING SINICA TECH
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