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Preparation method of antidepressant drug-vilazodone

A preparation process and catalyst technology, applied in the direction of organic chemistry, etc., can solve the problems of low yield, difficult industrial scale-up production, unfavorable product purification, etc., and achieve the effect of easy availability of reaction raw materials and convenient post-processing

Inactive Publication Date: 2013-09-18
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] This route not only uses the rare Lewis acid isobutyl aluminum dichloride (i-BuAlCl 2 ) is a catalyst, and there is a by-product of indole 1-position acylation, which is not conducive to the further purification of the product
In the second step reduction reaction of this route, bis(methoxyethoxy)aluminum dihydride reducing agent is used, and the yield is extremely low, only 26%, and the product needs to be purified by column chromatography, which is difficult for industrial scale-up production

Method used

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  • Preparation method of antidepressant drug-vilazodone
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  • Preparation method of antidepressant drug-vilazodone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Synthesis of 1-p-toluenesulfonyl-5-cyanindole (III)

[0029] In a 1L three-necked flask, 5-cyanoindole (10.0g, 0.07mol), toluene (300ml), 30% NaOH (300ml) solution and tetrabutylammonium bromide (2.3g, 7mmol) were mixed at room temperature p-Toluenesulfonyl chloride (14.8 g, 0.074 mol) was added under conditions. Stir for 1 hour to stop the reaction. Extract with dichloromethane (3×125ml), combine the organic layers, wash with saturated brine, and dry over anhydrous sodium sulfate overnight. Suction filtration, the filtrate was spin-dried to obtain 20.4g of white solid, yield 98.01%, m.p.116~118℃.(Ref.m.p.116~118℃.Bioorg.Med.Chem.Lett.2010,20(12),3534-3536 )

Embodiment 2

[0031] Synthesis of 1-p-toluenesulfonyl-3-(4-chlorobutyryl)-5-cyano-1H-indole (IV)

[0032] In a 1L three-necked flask, mix aluminum trichloride (18.7g, 0.14mol), dichloromethane (600ml), 4-chlorobutyryl chloride (12.5g, 0.088mol), add 1-p-toluenesulfonyl-5 - Cyanoindole (20 g). After continuing to stir and react for 8 h, the reaction solution was poured into ice water (600 ml), extracted with ethyl acetate (3×500 ml), the organic layers were combined, washed with saturated brine, and dried overnight over anhydrous sodium sulfate. After suction filtration, the filtrate was spin-dried to obtain 24.3 g of white solid, with a yield of 89.80%, m.p.154-156°C.

[0033] 1H-NMR (300MHz, CDCl 3), δ (ppm): 8.71 (1H, d, J = 1.4Hz, 4-ArH), 8.36 (1H, s, 2-ArH), 8.03 (1H, d, J = 8.7Hz, 7-ArH), 7.86 (2H, d, J = 8.3Hz, 1'-ArH), 7.62 (1H, dd, J = 8.7Hz, J = 1.4Hz, 6-ArH), 7.34 (2H, d, J = 8.3Hz, 2 '-ArH), 3.69 (2H, t, J=6.3Hz, -CH2Cl), 3.13 (2H, t, J=6.3Hz, -COCH2-), 2.26 (2H, qt, J=6.3Hz,...

Embodiment 3

[0035] Synthesis of 1-p-toluenesulfonyl-3-(4-chlorobutyl)-5-cyano-1H-indole (V)

[0036] In a 1L three-necked flask, mix sodium borohydride (34.0g, 0.9mol), dichloromethane (400ml), trifluoroacetic acid (400ml), stir for 0.5 hours and add 1-p-toluenesulfonyl-3-(4 -Chlorobutyryl)-5-cyano-1H-indole (20.0g, 50mmol), the reaction was continued for 8h and stopped. The reaction solution was extracted with ethyl acetate (3×750ml), and the organic layers were combined, washed with saturated sodium carbonate and brine, and dried over anhydrous sodium sulfate overnight. Suction filtration, the filtrate was spin-dried to obtain 18.4g white solid, yield 95.33%, m.p.110~112℃.

[0037] 1H-NMR (300MHz, CDCl 3 ), δ (ppm): 8.06 (1H, d, J = 8.6Hz, 7-ArH), 7.81 (1H, s, 4-ArH), 7.75 (2H, d, J = 8.3Hz, 1'-ArH) , 7.56 (1H, d, J = 8.6Hz, 6-ArH), 7.46 (1H, s, 2-ArH), 7.25 (2H, d, J = 8.3Hz, 2'-ArH), 3.57 (2H, m , -CH2Cl), 2.70 (2H, t, m, Ar-CH 2 ), 2.36 (3H, s, -CH 3 ), 1.84 (4H, m, -CH 2 CH ...

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Abstract

The invention relates to the field of drug synthesis, and in particular relates to a preparation method of an antidepressant drug-vilazodone. The preparation method is characterized by comprising the following steps of: protecting a 1-location nitrogen atom of 5-cyano benzopyrrole used as an initial raw material through utilizing toluenesulfonyl, carrying out 3-location Friedel-Carfts acylation, and selectively reducing carbonyl into methylidyne so as to obtain 1-tosyl-3-(4-chlorobutyl)-5-cyano benzopyrrole; reacting the 1-tosyl-3-(4-chlorobutyl)-5-cyano benzopyrrole with 5-(piperazine-1-radical) benzofuran-2-nonanoic acid-ethyl ester hydrochloride, hydrolyzing through one step, and removing tosyl and ethyl at the same time so as to obtain 5-(4-(4-(5-cyan-1H-benzopyrrole-3-radical) butyl) piperazine-1-radical) benzofuran-2-carboxylic acid; finally, amidating so as to obtain vilazodone, and salifying vilazodone with hydrogen chloride so as to obtain hydrochloric acid vilazodone. The method can be used for overcoming a plurality of defects of a conventional synthetic method, and has the advantages of easiness in raw material acquisition, high yield, good selectivity, convenience in operation, suitability for industrial production and high application value.

Description

technical field [0001] The invention relates to the field of drug synthesis. Specifically related to selective serotonin reuptake inhibitors and partial 5-HT for antidepressants 1A The preparation method of receptor agonist vilazodone (I). Background technique [0002] Vilazodone Hydrochloride, the chemical name is 5-(4-(5-cyano)-3-indolyl)butyl)-1-piperazinyl)benzofuran-2-carboxamide salt salt. It was approved by the US Food and Drug Administration (FDA) for the treatment of major depression in adults in January 2011, and is now produced by Trovis Pharmaceuticals LLC in the United States. The structural formula of vilazodone hydrochloride is as follows: [0003] [0004] Depression is a mental illness with morbid emotional changes. The patient may be depressed, have strong sadness and disappointment, refrain from speaking, or be noisy and restless, with high emotions and abnormally increased activities. At present, with the rapid development of society and the accel...

Claims

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Application Information

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IPC IPC(8): C07D405/12
Inventor 徐云根胡斌聂凤
Owner CHINA PHARM UNIV
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