163521-11-7

Basic information

• Product Name: 2-Benzofurancarboxylic acid, 5-[4-[4-(5-cyano-1H-indol-3-yl)butyl]-1-piperazinyl]-, ethyl ester
• Synonyms: 2-Benzofurancarboxylic acid, 5-[4-[4-(5-cyano-1H-indol-3-yl)butyl]-1-piperazinyl]-, ethyl ester;5-[4-[4-(5-Cyano-1H-indol-3-yl)butyl]-1-piperazinyl]-2-benzofurancarboxylic acid ethyl ester;ethyl 5-(4-(4-(5-cyano-1H-indol-3-yl)butyl)piperazin-1-yl)benzofuran-2-carboxylate;ethyl 5-(4-(4-(5-cyano-1H-indol-3-yl)butyl)piperazin-1-yl)benzofuran-2-carboxylate Molecular;Vilazodone Ethyl Ester Dihydrochloride;methyl 5-(4-(4-(5-cyano-1H-indol-3-yl)butyl)piperazin-1-yl)benzofuran-2-carboxylate
• CAS NO: 163521-11-7
• Molecular Formula: C₂₈H₃₀N₄O₃
• Molecular Weight: 471
• Mol File: 163521-11-7.mol
• Article Data: 5

Chemical Properties

• Boiling Point: 687.8±55.0 °C(Predicted)
• Appearance: /
• Density: 1.29
• Storage Temp.: 2-8°C
• PKA: 15.98±0.30(Predicted)
• CAS DataBase Reference: 2-Benzofurancarboxylic acid, 5-[4-[4-(5-cyano-1H-indol-3-yl)butyl]-1-piperazinyl]-, ethyl ester(CAS DataBase Reference)
• NIST Chemistry Reference: 2-Benzofurancarboxylic acid, 5-[4-[4-(5-cyano-1H-indol-3-yl)butyl]-1-piperazinyl]-, ethyl ester(163521-11-7)
• EPA Substance Registry System: 2-Benzofurancarboxylic acid, 5-[4-[4-(5-cyano-1H-indol-3-yl)butyl]-1-piperazinyl]-, ethyl ester(163521-11-7)

Safety Data

• Hazardous Substances Data: 163521-11-7(Hazardous Substances Data)

Usage

Uses

Vilazodone ethyl ester dihydrochloride is a precursor to Vilazodone (V265000), a selective serotonin reuptake inhibitor and serotonin 1A receptor agonist that is used to treat patients with major depressive disorder.

Synthetic route

3-(4-chlorobutyl)-5-cyanoindole (143612-79-7) + 5-(1-piperazinyl)benzofuran-2-carboxylic acid ethyl ester hydrochloride → 5-(4-[4-(5-cyano-3-indolyl)butyl]-1-piperazinyl)benzofuran-2-carboxylic acid ethyl ester (163521-11-7)

Conditions	Yield
With potassium carbonate In acetonitrile	32%
With potassium carbonate; triethylamine In acetonitrile for 12h; Heating;

1H-indole-5-carbonitrile (15861-24-2) → 5-(4-[4-(5-cyano-3-indolyl)butyl]-1-piperazinyl)benzofuran-2-carboxylic acid ethyl ester (163521-11-7)

Conditions	Yield
Multi-step reaction with 3 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 View Scheme
Multi-step reaction with 3 steps 1: isobutylaluminum dichloride / dichloromethane 2: sodium bis(2-methoxyethoxy)aluminium dihydride / tetrahydrofuran 3: potassium carbonate / acetonitrile View Scheme

ethyl 5-nitrobenzo[d]furan-2-carboxylate (69604-00-8) → 5-(4-[4-(5-cyano-3-indolyl)butyl]-1-piperazinyl)benzofuran-2-carboxylic acid ethyl ester (163521-11-7)

Conditions	Yield
Multi-step reaction with 3 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 View Scheme

ethyl 5-amino-1-benzofuran-2-carboxylate (174775-48-5) → 5-(4-[4-(5-cyano-3-indolyl)butyl]-1-piperazinyl)benzofuran-2-carboxylic acid ethyl ester (163521-11-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: 27 percent / K2CO3 / butan-1-ol / 48 h / Heating 2: K2CO3; Et3N / acetonitrile / 12 h / Heating View Scheme

3-(4-chlorobutanoyl)-1H-indole-5-carbonitrile (276863-95-7) → 5-(4-[4-(5-cyano-3-indolyl)butyl]-1-piperazinyl)benzofuran-2-carboxylic acid ethyl ester (163521-11-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: 26 percent / sodium bis(2-methoxyethoxy)aluminum hydride / tetrahydrofuran; toluene / 2 h 2: K2CO3; Et3N / acetonitrile / 12 h / Heating View Scheme
Multi-step reaction with 2 steps 1: sodium bis(2-methoxyethoxy)aluminium dihydride / tetrahydrofuran 2: potassium carbonate / acetonitrile View Scheme

3-(4-chlorobutyl)-5-cyanoindole (143612-79-7) + 5-(piperazin-1-yl)benzofuran-2-carboxylic acid ethyl ester → 5-(4-[4-(5-cyano-3-indolyl)butyl]-1-piperazinyl)benzofuran-2-carboxylic acid ethyl ester (163521-11-7)

Conditions	Yield
With tetra-(n-butyl)ammonium iodide; potassium carbonate; potassium iodide In acetonitrile at 20 - 82℃; for 24h; Reagent/catalyst;
Stage #1: 3-(4-chlorobutyl)-5-cyanoindole With copper(l) iodide In diethyl ether for 3.5h; Inert atmosphere; Reflux; Stage #2: 5-(piperazin-1-yl)benzofuran-2-carboxylic acid ethyl ester With sodium methylate In diethyl ether at 90℃; for 5.5h; Concentration; Reagent/catalyst; Solvent; Temperature; Inert atmosphere;	8.9 g

1,1-dimethoxy-6-chlorohexane (92886-57-2) → 5-(4-[4-(5-cyano-3-indolyl)butyl]-1-piperazinyl)benzofuran-2-carboxylic acid ethyl ester (163521-11-7)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: methanol; water / 1 h / 72 °C / Inert atmosphere 2.1: copper(l) iodide / diethyl ether / 3.5 h / Inert atmosphere; Reflux 2.2: 5.5 h / 90 °C / Inert atmosphere View Scheme

1-(4-hydroxyphenyl)piperazine (56621-48-8) → 5-(4-[4-(5-cyano-3-indolyl)butyl]-1-piperazinyl)benzofuran-2-carboxylic acid ethyl ester (163521-11-7)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine; magnesium chloride / toluene / 7 h / Inert atmosphere; Reflux 2.1: sodium iodide; potassium carbonate / N,N-dimethyl-formamide / 5 h / Reflux 3.1: copper(l) iodide / diethyl ether / 3.5 h / Inert atmosphere; Reflux 3.2: 5.5 h / 90 °C / Inert atmosphere View Scheme

5-(4-[4-(5-cyano-3-indolyl)butyl]-1-piperazinyl)benzofuran-2-carboxylic acid ethyl ester (163521-11-7) → 5-(4-(3-(5-cyano-1H-indol-3-yl)butyl)piperazin-1-yl)-benzofuran-2-carboxylic acid

Conditions	Yield
With potassium hydroxide In methanol	80%

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;

5-(4-[4-(5-cyano-3-indolyl)butyl]-1-piperazinyl)benzofuran-2-carboxylic acid ethyl ester (163521-11-7) → 5-(4-(4-(5-cyano-1H-indol-3-yl)butyl)piperazin-1-yl)benzofuran-2-carboxylic acid (163521-19-5)

Conditions	Yield
With potassium hydroxide In methanol for 3h; Heating;

Upstream product

• 56621-48-8 1-(4-hydroxyphenyl)piperazine 
• 92886-57-2 1,1-dimethoxy-6-chlorohexane 
• 143612-79-7 3-(4-chlorobutyl)-5-cyanoindole 
• 163521-20-8 5-(piperazin-1-yl)benzofuran-2-carboxylic acid ethyl ester 
• 276863-95-7 3-(4-chlorobutanoyl)-1H-indole-5-carbonitrile 
• 174775-48-5 ethyl 5-amino-1-benzofuran-2-carboxylate 
• 69604-00-8 ethyl 5-nitrobenzo[d]furan-2-carboxylate 
• 15861-24-2 1H-indole-5-carbonitrile 
• 765935-67-9 5-(1-piperazinyl)benzofuran-2-carboxylic acid ethyl ester hydrochloride 

Downstream Products

• 163521-12-8 vilazodone 
• 163521-19-5 5-{4-[4-(5-cyano-1H-indol-3-yl)butyl]piperazin-1-yl}benzofuran-2-carboxylic acid 

Relevant articles and documents

[...] intermediate and its salt synthesis method

The invention relates to a synthesis method of a vilazodone intermediate 5-(4-[4-(5-cyano-3-indyl)-butyl]-1-piperazinyl)benzofuran-2-carboxylic acid ethyl ester and a salt thereof, belonging to the technical field of drug synthesis. The synthesis method comprises the following steps of: dissolving 3-(4-chlorobutyl)-5-cyanoindole and a catalyst into an inorganic water solution under the protection of nitrogen gas, carrying out heating reflux, stirring, then, adding 5-(piperazinyl-1-yl)benzofuran-2-carboxylic acid ethyl ester and alkaline, reacting at the temperature of 80-110 DEG C for 4-6h, slowly pouring an aqueous alkaline solution while stirring at room temperature until a solid is separated out, and then, carrying out after-treatment to obtain the 5-(4-[4-(5-cyano-3-indyl)-butyl]-1-piperazinyl)benzofuran-2-carboxylic acid ethyl ester. The synthesis method is low in production cost, environment-friendly, high in operation safety, high in product yield and purity, good in quality and suitable for large-scale industrial production.

Scale-up synthesis of antidepressant drug vilazodone

A scale-up synthesis of antidepressant drug vilazodone was accomplished in five steps. Friedel-Crafts acylation of 1-tosyl-1H-indole-5-carbonitrile with 4-chlorobutyryl chloride, selective deoxygenation in NaBH4/CF 3COOH system coupled with ethyl 5-(piperazin-1-yl)-benzofuran-2- carboxylate hydrochloride, one-step deprotection and esterolysis, and the final ammonolysis led to the target molecule vilazodone in 52.4% overall yield and 99.7% purity. This convenient and economical procedure is remarkably applicable for scale-up production.

PIPERIDINES AND PIPERAZINES

Piperidine and piperazine derivatives of the formula I STR1 wherein Ind is an indol-3-yl radical which is unsubstituted or mono-or polysubstituted by OH, OA, CN, Hal, COR 2 or CH 2 R 2, R 1 is benzofuran-5-yl or 2,3-dihydrobenzofuran-5-yl, chroman-6-yl, chroman-4-on-6-yl, 3-chromen-6-yl or chromen-4-on-6-yl, which is unsubstituted or monosubstituted by CN, CH 2 OH, CH 2 OA or COR 2,Q is C m H 2m,N or CR 3,A is alkyl having 1-6 C atoms,Hal is F, C1, Br or I,R 2 is OH, OA, NH 2, NHA or NA 2,R 3 is H, OH or OA and m is 2, 3 or 4,and their physiologically acceptable salts, are active on the central nervous system.