163521-12-8

Basic information

• Product Name: VILAZODONE
• Synonyms: 5-(4-(4-(5-Cyano-1H-indol-3-yl)butyl)piperazin-1-yl)benzofuran-2-carboxamide;2-BenzofurancarboxaMide,5-[4-[4-(5-cyano-1H-indol-3-yl)butyl]-1-piperazinyl]-;Vilazodonei;Vilazodone 5-[4-[4-(5-Cyanoindol-3-yl)butyl]piperazin-1-yl]benzofuran-2-carboxamide;5-[4-[4-(5-cyano-1H-indol-3-yl)butyl]piperazin-1-yl]-1-benzofuran-2-carboxamide;Vilazodone, >=98%;Vilozodone;VILAZODONE
• CAS NO: 163521-12-8
• Molecular Formula: C₂₆H₂₇N₅O₂
• Molecular Weight: 477.993
• EINECS: 1308068-626-2
• Product Categories: Other APIs;Amines;Aromatics;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 163521-12-8.mol
• Article Data: 30

Chemical Properties

• Melting Point: 203-205°C
• Boiling Point: 745.076 °C at 760 mmHg
• Flash Point: 404.408 °C
• Appearance: Light yellow solid
• Density: 1.343 g/cm³
• Storage Temp.: Refrigerator
• Solubility: DMSO (Slightly)), Methanol (Slightly)
• PKA: 15.98±0.30(Predicted)
• Stability: Very Hygroscopic
• CAS DataBase Reference: VILAZODONE(CAS DataBase Reference)
• NIST Chemistry Reference: VILAZODONE(163521-12-8)
• EPA Substance Registry System: VILAZODONE(163521-12-8)

Safety Data

• Hazardous Substances Data: 163521-12-8(Hazardous Substances Data)

Usage

Description

Vilazodone, developed by Merck KGaA Company, is a serotonergic antidepressant with high affinity and selectivity for the 5-hydroxytrptamine (5-HT) transporter and 5-HT (1A) receptors. It is indicated for the treatment of major depressive disorder (MDD) and can be used as an alternative for patients who cannot tolerate other antidepressant classes. Vilazodone functions as a selective serotonin reuptake inhibitor, preventing serotonin from re-entering cell bodies and prolonging its presence in the synapse. Additionally, it acts as a partial agonist for the serotonin-1A receptor, stimulating serotonin production and increasing its levels in the synaptic cleft, which contributes to its antidepressant effect in vivo. Vilazodone is a light yellow solid and is marketed under the brand name Viibryd.

Uses

Used in Pharmaceutical Industry:
VILAZODONE is used as an antidepressant for the treatment of major depressive disorder (MDD). It is a combined serotonin specific reuptake inhibitor (SSRI) and 5-HT1A receptor partial agonist, providing an alternative for patients who cannot tolerate other antidepressant classes.
Used in Clinical Evaluation:
VILAZODONE is used as a labeled analogue for clinical evaluation in the treatment of major depression, offering a novel compound with potent serotonin reuptake inhibition and high affinity for 5-HT1A receptors.
Used in Antidepressant Research:
VILAZODONE is used as an inhibitor of serotonin reuptake and activator of 5-HT1A receptors in preclinical models of depression in rats and mice, demonstrating efficacy and good selectivity over other monoamine receptors.
Approved by U.S. FDA:
In January 2011, the U.S. FDA approved VILAZODONE for the treatment of major depressive disorder (MDD), recognizing its potential as a novel antidepressant agent with unique properties and benefits for patients.

References

https://www.drugbank.ca/drugs/DB06684 https://en.wikipedia.org/wiki/Vilazodone http://www.rxlist.com/viibryd-drug/indications-dosage.htm

Originator

Merck KGaA (Germany)

Synthetic route

methyl 5-{4-[4-(5-cyano-1H-indol-3-yl)-butyl]-piperazin-1-yl}-benzofuran-2-carboxylate (1236722-93-2) → vilazodone (163521-12-8)

Conditions	Yield
With ammonia In methanol at 25 - 30℃; Concentration; Pressure; Time;	98.5%
With ammonia In methanol at 20℃; for 20h;	Ca. 3 g
With ammonia In methanol at 25 - 30℃;	11g

3-(4-chlorobutyl)-5-cyanoindole (143612-79-7) + 5-(1-piperazinyl)benzofuran-2-carboxamide (183288-46-2) → vilazodone (163521-12-8)

Conditions	Yield
Stage #1: 3-(4-chlorobutyl)-5-cyanoindole With sodium iodide In N,N-dimethyl-formamide at 25 - 30℃; for 0.25h; Stage #2: 5-(1-piperazinyl)benzofuran-2-carboxamide With tetrabutylammomium bromide; sodium hydrogencarbonate In N,N-dimethyl-formamide at 110 - 115℃; for 1.25h; Reagent/catalyst; Temperature; Time; Solvent;	95.7%
With sodium carbonate In water at 90 - 100℃;	94%
Stage #1: 5-(1-piperazinyl)benzofuran-2-carboxamide With hydrogenchloride In water at 20 - 35℃; pH=6.5 - 7; Stage #2: 3-(4-chlorobutyl)-5-cyanoindole With sodium carbonate In water; isopropyl alcohol at 75 - 85℃; for 12h; Reagent/catalyst; pH-value;	94%

5-[4-[4-(5-cyano-1H-indol-3-yl)butyl]-1-piperazinyl]-2-benzofurancarboxylic acid ethyl ester hydrochloride (1422956-25-9) → vilazodone (163521-12-8)

Conditions	Yield
With ammonium hydroxide In methanol at 50℃; for 22h; Reagent/catalyst; Time; Temperature; Autoclave;	93%
Stage #1: 5-[4-[4-(5-cyano-1H-indol-3-yl)butyl]-1-piperazinyl]-2-benzofurancarboxylic acid ethyl ester hydrochloride With potassium carbonate In dichloromethane Stage #2: With sodium methylate; formamide In tetrahydrofuran at 20 - 30℃;	90%
With ammonia In dimethyl sulfoxide at 20 - 35℃;	81.6%
With ammonium hydroxide In 1-methyl-pyrrolidin-2-one	40.5 g

3-(4-hydroxybutyl)-1H-indole-5-carbonitrile (914927-40-5) + 5-(1-piperazinyl)benzofuran-2-carboxamide (183288-46-2) → vilazodone (163521-12-8)

Conditions	Yield
With trifluoroacetic acid at 60℃; for 12h; Temperature;	91.2%

ClH*C33H38N4O5 → vilazodone (163521-12-8)

Conditions	Yield
Stage #1: ClH*C33H38N4O5 With potassium carbonate In dichloromethane Stage #2: With sodium methylate; formamide In tetrahydrofuran at 20 - 30℃; for 8h;	90%

ClH*C34H40N4O5 → vilazodone (163521-12-8)

Conditions	Yield
Stage #1: ClH*C34H40N4O5 With potassium carbonate In dichloromethane Stage #2: With sodium methylate; formamide In tetrahydrofuran at 20 - 30℃;	90%

n-butyl 5-(4-[4-(5-cyano-1H-indol-3-yl)butyl]piperazin-1-yl)benzofuran-2-carboxylate hydrochloride → vilazodone (163521-12-8)

Conditions	Yield
Stage #1: n-butyl 5-(4-[4-(5-cyano-1H-indol-3-yl)butyl]piperazin-1-yl)benzofuran-2-carboxylate hydrochloride With potassium carbonate In dichloromethane Stage #2: With sodium methylate; formamide In tetrahydrofuran at 20 - 30℃; Reagent/catalyst; Solvent; Temperature;	85%

5-[4-[4-[5-cyano-1-(p-toluenesulfonyl)-1H-indol-3-yl]butyl]piperazin-1-yl]benzofuran-2-carboxamide (1415760-77-8) → vilazodone (163521-12-8)

Conditions	Yield
With sodium hydroxide In methanol at 20 - 65℃; for 2h;	84.1%
With sodium hydroxide In methanol at 60 - 65℃; for 2h;	81%
With potassium carbonate In methanol; water for 2h; Inert atmosphere; Reflux;

5-piperazin-1-ylbenzofuran-2-carboxamide hydrochloride + 3-(4-chlorobutyl)-5-cyanoindole (143612-79-7) → vilazodone (163521-12-8)

Conditions	Yield
With potassium hydrogencarbonate; sodium iodide In N,N-dimethyl-formamide at 95 - 105℃; for 20h;	83%

vilazodone N-oxide → vilazodone (163521-12-8)

Conditions	Yield
With sodium tetrahydroborate; trifluoroacetic acid In dichloromethane at 10 - 45℃; for 16h;	82.5%

ethyl 5-(4-(4-(5-cyano-1H-indol-3-yl)butyl)piperazin-1-yl)benzofuran-2-carboxylate hydrochloride → vilazodone (163521-12-8)

Conditions	Yield
With ammonia In dimethyl sulfoxide at 20 - 35℃; under 3750.38 - 4500.45 Torr;	81.6%

5-(4-(3-(5-cyano-1H-indol-3-yl)butyl)piperazin-1-yl)-benzofuran-2-carboxylic acid → vilazodone (163521-12-8)

Conditions	Yield
Stage #1: 5-(4-(3-(5-cyano-1H-indol-3-yl)butyl)piperazin-1-yl)-benzofuran-2-carboxylic acid With 1,1'-carbonyldiimidazole In methanol at 20℃; for 1h; Reflux; Large scale; Stage #2: With ammonia In N,N-dimethyl-formamide for 0.5h; Reagent/catalyst; Large scale;	81%

3-(4-oxobutyl)-1H-indole-5-carbonitrile (913730-89-9) + 5-(1-piperazinyl)benzofuran-2-carboxamide (183288-46-2) → vilazodone (163521-12-8)

Conditions	Yield
Stage #1: 5-(1-piperazinyl)benzofuran-2-carboxamide With sodium cyanoborohydride In methanol at 20℃; Stage #2: 3-(4-oxobutyl)-1H-indole-5-carbonitrile In methanol at 20℃; for 18h;	75.21%

5-(4-(4-(5-cyano-1H-indol-3-yl)butyl)piperazin-1-yl)benzofuran-2-carboxylic acid (163521-19-5) → vilazodone (163521-12-8)

Conditions	Yield
With N,N-diethyl-N-isopropylamine; 2-chloro-1-methyl-pyridinium iodide; ammonia In 1-methyl-pyrrolidin-2-one	72%

5-(4-[4-(5-cyano-3-indolyl)butyl]-1-piperazinyl)benzofuran-2-carboxylic acid ethyl ester (163521-11-7) → vilazodone (163521-12-8)

Conditions	Yield
With potassium hydroxide In methanol	72%
Multi-step reaction with 2 steps 1: KOH / methanol / 3 h / Heating 2: 72 percent / 1-methyl-2-chloropyridinium iodide; Et2NiPr; NH3(g) / 1-methyl-pyrrolidin-2-one View Scheme
With ammonium hydroxide In water; acetonitrile at 0 - 20℃; for 98h; Time; Reagent/catalyst; Temperature;

n-propyl 5-(piperazin-1-yl)benzofuran-2-carboxylate + 3-(4-chlorobutyl)-5-cyanoindole (143612-79-7) → vilazodone (163521-12-8)

Conditions	Yield
Stage #1: n-propyl 5-(piperazin-1-yl)benzofuran-2-carboxylate; 3-(4-chlorobutyl)-5-cyanoindole With tetrabutylammomium bromide; potassium carbonate; potassium iodide In acetonitrile Reflux; Stage #2: With ammonium hydroxide In acetonitrile at 25 - 30℃; for 72h;	72%

isopropyl 5-(piperazin-1-yl)benzofuran-2-carboxylate + 3-(4-chlorobutyl)-5-cyanoindole (143612-79-7) → vilazodone (163521-12-8)

Conditions	Yield
Stage #1: isopropyl 5-(piperazin-1-yl)benzofuran-2-carboxylate; 3-(4-chlorobutyl)-5-cyanoindole With tetrabutylammomium bromide; potassium carbonate; potassium iodide In acetonitrile Reflux; Stage #2: With ammonium hydroxide In acetonitrile at 25 - 30℃; for 72h;	70%

n-butyl 5-(piperazin-1-yl)benzofuran-2-carboxylate + 3-(4-chlorobutyl)-5-cyanoindole (143612-79-7) → vilazodone (163521-12-8)

Conditions	Yield
Stage #1: n-butyl 5-(piperazin-1-yl)benzofuran-2-carboxylate; 3-(4-chlorobutyl)-5-cyanoindole With tetrabutylammomium bromide; potassium carbonate; potassium iodide In acetonitrile Reflux; Stage #2: With ammonium hydroxide In acetonitrile at 25 - 30℃; for 72h;	70%

methyl 5-(1-piperazinyl)-benzofuran-2-carboxylate + 3-(4-chlorobutyl)-5-cyanoindole (143612-79-7) → vilazodone (163521-12-8)

Conditions	Yield
Stage #1: methyl 5-(1-piperazinyl)-benzofuran-2-carboxylate; 3-(4-chlorobutyl)-5-cyanoindole With tetrabutylammomium bromide; potassium carbonate; potassium iodide In acetonitrile Reflux; Stage #2: With ammonium hydroxide In acetonitrile at 25 - 30℃; for 72h;	65%

1H-indole-5-carbonitrile (15861-24-2) → vilazodone (163521-12-8)

Conditions	Yield
Multi-step reaction with 5 steps 1: 73 percent / isobutyl-AlCl2 / CH2Cl2 / 15 - 30 °C 2: 26 percent / sodium bis(2-methoxyethoxy)aluminum hydride / tetrahydrofuran; toluene / 2 h 3: K2CO3; Et3N / acetonitrile / 12 h / Heating 4: KOH / methanol / 3 h / Heating 5: 72 percent / 1-methyl-2-chloropyridinium iodide; Et2NiPr; NH3(g) / 1-methyl-pyrrolidin-2-one View Scheme
Multi-step reaction with 4 steps 1: isobutylaluminum dichloride / dichloromethane 2: sodium bis(2-methoxyethoxy)aluminium dihydride / tetrahydrofuran 3: potassium carbonate / acetonitrile 4: potassium hydroxide / methanol View Scheme
Multi-step reaction with 5 steps 1.1: isobutylaluminum dichloride / dichloromethane 2.1: sodium bis(2-methoxyethoxy)aluminium dihydride / tetrahydrofuran 3.1: potassium carbonate / acetonitrile 4.1: potassium hydroxide / methanol 5.1: 1,1'-carbonyldiimidazole / methanol / 1 h / 20 °C / Reflux; Large scale 5.2: 0.5 h / Large scale View Scheme

ethyl 5-nitrobenzo[d]furan-2-carboxylate (69604-00-8) → vilazodone (163521-12-8)

Conditions	Yield
Multi-step reaction with 5 steps 1: 93 percent / H2 / Raney Ni / methanol / 27 h / 28 °C 2: 27 percent / K2CO3 / butan-1-ol / 48 h / Heating 3: K2CO3; Et3N / acetonitrile / 12 h / Heating 4: KOH / methanol / 3 h / Heating 5: 72 percent / 1-methyl-2-chloropyridinium iodide; Et2NiPr; NH3(g) / 1-methyl-pyrrolidin-2-one View Scheme
Multi-step reaction with 4 steps 1.1: hydrogen; palladium 10% on activated carbon / ethyl acetate / 33 - 38 °C / 3000.3 - 3750.38 Torr 2.1: tetrabutylammomium bromide; potassium carbonate / o-xylene / 32 h / 135 - 140 °C 3.1: tetrabutylammomium bromide; triethylamine / 10 h / 85 - 90 °C 3.2: 50 - 55 °C / pH 2 / Reflux 4.1: ammonia / dimethyl sulfoxide / 20 - 35 °C View Scheme
Multi-step reaction with 4 steps 1.1: hydrogen; palladium 10% on activated carbon / ethyl acetate / 33 - 38 °C / 3000.3 - 3750.38 Torr 2.1: tetrabutylammomium bromide; potassium carbonate / o-xylene / 32 h / 135 - 140 °C 3.1: tetrabutylammomium bromide; triethylamine / 10 h / 85 - 90 °C 3.2: 50 - 55 °C / pH 2 / Reflux 4.1: ammonia / dimethyl sulfoxide / 20 - 35 °C View Scheme

vilazodone (163521-12-8) → 5-(4-[4-(5-cyano-1H-indol-3-yl)butyl]piperazin-1-yl)benzofuran-2-carboxamide hydrochloride

Conditions	Yield
With hydrogenchloride In tetrahydrofuran; water; acetone at 55℃; for 0.5h; pH=1;	99%
With hydrogenchloride In isopropyl alcohol at 80℃; Temperature;	98.7%
Stage #1: vilazodone With pyrographite In isopropyl alcohol at 25 - 30℃; for 0.0833333h; Stage #2: With isopropanolic hydrochloride In isopropyl alcohol at 20 - 45℃; for 2h; Temperature; Time; Solvent;	92%

vilazodone (163521-12-8) → vilazodone hydrochloride

Conditions	Yield
Stage #1: vilazodone In isopropyl alcohol for 0.75h; Reflux; Stage #2: With hydrogenchloride In isopropyl alcohol at 60 - 70℃;	98%
Stage #1: vilazodone With pyrographite In tetrahydrofuran Stage #2: With hydrogenchloride In tetrahydrofuran	98.7%
With hydrogenchloride In tetrahydrofuran; water at 35 - 50℃; for 1h;	95%

trifluoroacetic acid (76-05-1) + vilazodone (163521-12-8) → 5-(4-(4-(5-cyanoindol-3-yl)butyl)-1-piperazinyl)-2-benzofurancarboxamide trifluoroacetate

Conditions	Yield
In ethyl acetate at 85℃; Solvent; Temperature;	93.1%

vilazodone (163521-12-8) → 5-(4-(4-(5-cyanoindol-3-yl)butyl)-1-piperazinyl)-2-benzofurancarboxamide sulfate

Conditions	Yield
With sulfuric acid In n-heptane at 95℃; Reagent/catalyst; Solvent;	92.3%

2(13)CN(1-)*Zn(2+) + vilazodone (163521-12-8) → [13CN]-vilazodone

Conditions	Yield
With dmap; bis(1,5-cyclooctadiene)nickel(0); trimethylphosphane In toluene at 130℃; for 12h; Glovebox; Sealed tube;	91%

Upstream product

• 163521-19-5 5-{4-[4-(5-cyano-1H-indol-3-yl)butyl]piperazin-1-yl}benzofuran-2-carboxylic acid 
• 15861-24-2 1H-indole-5-carbonitrile 
• 69604-00-8 ethyl 5-nitrobenzo[d]furan-2-carboxylate 
• 174775-48-5 ethyl 5-amino-1-benzofuran-2-carboxylate 
• 143612-79-7 3-(4-chlorobutyl)-5-cyanoindole 
• 276863-95-7 3-(4-chlorobutanoyl)-1H-indole-5-carbonitrile 
• 765935-67-9 5-(1-piperazinyl)benzofuran-2-carboxylic acid ethyl ester hydrochloride 
• 163521-11-7 5-(4-[4-(5-cyano-3-indolyl)butyl]-1-piperazinyl)benzofuran-2-carboxylic acid ethyl ester 
• 35351-21-4 5-bromo-2-carboxamidobenzo[b]furan 
• 692756-91-5 3-(4-piperazin-1-yl-butyl)-1H-indole-5-carbonitrile 
• 32685-23-7 5-Cyano-1-(p-toluenesulfonyl)indole 
• 1398358-62-7 3-(4-chlorobutanoyl)-1-tosyl-1H-indole-5-carbonitrile 
• 1398358-69-4 1-p-toluenesulfonyl-3-(4-chlorobutyl)-5-cyanoindole 
• 1422956-25-9 5-[4-[4-(5-cyano-1H-indol-3-yl)butyl]-1-piperazinyl]-2-benzofurancarboxylic acid ethyl ester hydrochloride 

Downstream Products

• 1622425-52-8 1-(2-carbamoylbenzofuran-5-yl)-4-(4-(5-cyano-1H-indol-3-yl)butyl)piperazine 4-oxide 

Relevant articles and documents

Preparation method of vilazodone

The invention relates to a preparation method of vilazodone. The preparation method comprises the steps of by using a compound 1 and a compound 2 as raw materials, carrying out one-step reaction underthe condition that trifluoroacetic acid is used as a solvent to obtain a compound I, namely the vilazodone. Compared with the prior art, the method has the advantages of short reaction route, easy post-treatment, high yield, cheap and easily available reagents used in the reaction, convenient operation, simple post-treatment, low cost, small environmental pollution, and suitableness for industrial production of vilazodone.

Preparation method of vilazodone hydrochloride

The invention discloses a preparation method of vilazodone hydrochloride. The preparation method comprises the following steps: (1) in the presence of ammonium hydroxide or ammonium hydroxide and N-methylpyrrolidone, enabling 5-(1-piperazinyl)-benzofuran-2-ethyl formate hydrochloride to be subjected to ammonolysis reaction to obtain 5-(1-piperazinyl)-benzofuran-2-formamide; (2) in the presence ofalkali, enabling the 5-(1-piperazinyl)-benzofuran-2-formamide and 3-(4-chlorobutyl) indole-5-formonitrile to be subjected to nucleophilic substitution reaction to obtain a crude product of vilazodone,wherein the alkali is mixed alkali of sodium iodide, N,N-diisopropylethylamine and triethylamine or 1,8-diazabicycloundec-7-ene; (3) refining the crude product of vilazodone to obtain a refined product of vilazodone; and (4) enabling the refined product of vilazodone to be subjected to salt-forming reaction to obtain the vilazodone hydrochloride. By virtue of the ammonolysis reaction and the nucleophilic substitution reaction, the yield is higher, and the purity is higher; and the yield of the vilazodone hydrochloride is increased.

For the preparation of the compounds and intermediates thereof the vera assists the alkone and application

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.