183288-46-2|5-(Piperazin-1-yl)benzofuran-2-carboxamide| Ambeed

Structure of 183288-46-2

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Quality Control of [ 183288-46-2 ] Purity: 97% SDS Specification

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Product Details of [ 183288-46-2 ]

CAS No. :	183288-46-2
Formula :	C₁₃H₁₅N₃O₂
M.W :	245.28
SMILES Code :	O=C(C1=CC2=CC(N3CCNCC3)=CC=C2O1)N
MDL No. :	MFCD20486139
Boiling Point :	No data available
InChI Key :	LLRGOAFFRRUFBM-UHFFFAOYSA-N
Pubchem ID :	9834719

Safety of [ 183288-46-2 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 183288-46-2 ] Show Less

Physicochemical Properties

Num. heavy atoms	18
Num. arom. heavy atoms	9
Fraction Csp3	0.31
Num. rotatable bonds	2
Num. H-bond acceptors	3.0
Num. H-bond donors	2.0
Molar Refractivity	75.67
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	71.5 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.05
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	1.01
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	0.18
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	0.41
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	1.17
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	0.96

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.24
Solubility	1.43 mg/ml ; 0.00582 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-2.1
Solubility	1.94 mg/ml ; 0.00793 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-3.38
Solubility	0.102 mg/ml ; 0.000417 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	No
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	Yes
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	Yes
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-7.08 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	2.45

Application In Synthesis of [ 183288-46-2 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Downstream synthetic route of [ 183288-46-2 ]

[ 183288-46-2 ] Synthesis Path-Downstream 1~35

1
[ 183288-46-2 ]
[ 714950-87-5 ]
[ 714950-88-6 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 2681 - 2684.

2
[ 816429-22-8 ]
[ 183288-46-2 ]
5-{4-[4-(5-cyano-1-methyl-1H-indol-3-yl)-butyl]-piperazin-1-yl}-benzofuran-2-carboxylic acid amide [ No CAS ]

References: [1]Patent: WO2004/113325,2004,A1 .Location in patent: Page/Page column 21.

3
[ 816438-46-7 ]
[ 183288-46-2 ]
5-{4-[4-(5-cyano-2,3-dihydro-1H-indol-3-yl)-butyl]-piperazin-1-yl}-benzofuran-2-carboxamide hydrochloride [ No CAS ]

References: [1]Patent: WO2004/113326,2004,A1 .Location in patent: Page/Page column 24.

4
[ 110-85-0 ]
t-OBu [ No CAS ]
[ 35351-21-4 ]
1-(N,N-dimethylamino)-1'-(dicyclohexylphosphino)biphenyl [ No CAS ]
[ 7440-44-0 ]
[ 183288-46-2 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride;Pd(dba)2; In water; ethyl acetate; toluene;	EXAMPLE 3 Synthesis of 5-(1-piperazinyl)benzofuran-2-carboxamide from 5-bromobenzofuran-2-carboxamide 0.9 g of 5-bromobenzofuran-2-carboxamide, 0.97 g of piperazine and 2.20 g of Na t-OBu are added to a suspension of 0.06 g of Pd(DBA)2 and 0.07 g of 1-(N,N-dimethylamino)-1'-(dicyclohexylphosphino)biphenyl in 50 ml of toluene, and the mixture is warmed at 120-130 for 16 hours under a protective gas. After cooling, the reaction mixture is added to a mixture of 50 ml of water and 10 ml of 37% hydrochloric acid, 100 ml of ethyl acetate are added, and the mixture is stirred for 20 minutes. A little undissolved product is then removed, and the organic phase is separated off. The aqueous phase is washed again by shaking with 50 ml of ethyl acetate and freed from solvent residues under reduced pressure, clarified using charcoal and filtered. The product is precipitated in crystalline form from the filtrate at 20-22 using 20-25 ml of 32% sodium hydroxide solution.

References: [1]Patent: US2003/125558,2003,A1 .

5
P(t-Bu)3 [ No CAS ]
t-OBu [ No CAS ]
[ 35351-21-4 ]
[ 57260-71-6 ]
[ 183288-44-0 ]
[ 183288-46-2 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride;Pd(dba)2; In diethylene glycol dimethyl ether; water;	1) Synthesis of 5-(4-tert-butoxycarbonyl-1-piperazinyl)benzofuran-2-carboxamide from 5-bromobenzofuran-2-carboxamide 0.9 g of 5-bromobenzofuran-2-carboxamide, 1.1 g of BOC-piperazine and 1.45 g of Na t-OBu are added to a suspension of 0.06 g of Pd(DBA)2 and 0.25 g of P(t-Bu)3 in 40 ml of diethylene glycol dimethyl ether, and the mixture is warmed at 120-130 C. for 16 hours under a protective gas. After cooling, the mixture is added to water, and the organic phase is diluted with 100 ml of MTBE and washed with 3*50 ml of water. The solvent is evaporated, and the product formed as a solid is filtered off and purified by crystallization from ethanol (product weight: 0.7 g/55%/m.p. 210-213). The subsequent removal of the BOC protecting group using hydrochloric acid and formation of 5-(1-piperazinyl)benzofuran-2-carboxamide, which are shown below only as a reaction equation, can be carried out, for example, as described in GREENE T. W. and WUTS P. G. M., PROTECTIVE GROUPS IN ORGANIC SYNTHESIS.

References: [1]Patent: US2003/125558,2003,A1 .

6
[ 183288-44-0 ]
[ 183288-46-2 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol hydrochloride;	Example 6 1 g of 5-(4-tert-butoxycarbonyl-1-piperazinyl)-benzofuran-2-carboxamide is dissolved in 50 ml of methanolic HCl and stirred for I hour. After customary working up, 5-(1-piperazinyl)benzofuran-2-carboxamide, m.p. 252-255, is obtained.

References: [1]Organic Process Research and Development,2014,vol. 18,p. 665 - 667.
[2]Patent: US5723614,1998,A .

7
[ 913730-89-9 ]
[ 183288-46-2 ]
vilazodone hydrochloride [ No CAS ]

References: [1]Patent: WO2006/114202,2006,A1 .Location in patent: Page/Page column 6-7.

8
[ 872-50-4 ]
[ 183288-46-2 ]
5-{4-[4-(5-cyano-2,3-dihydro-1H-indol-3-yl)butyl]piperazin-1-yl}benzofuran-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; In methanol; ice-water; water; ethyl acetate;	2.5 g (11 mmol) of the halide prepared as described in a) are dissolved in 50 ml of NMP, and 2.6 g (11 mmol) of 5-piperazin-1-ylbenzofuran-2-carboxamide are added with stirring. The batch is stirred at 125 C. for 24 h. For work-up, the suspension is stirred into 500 ml of ice-water, adjusted to pH 10 using 4% sodium hydroxide solution and extracted three times with 100 ml of ethyl acetate each time. The combined organic phases are washed twice with 100 ml of water each time, dried over sodium sulfate, filtered and evaporated to dryness, giving 2.3 g of crude substance. The residue is chromatographed over silica gel using ethyl acetate and methanol (ratio=9:1), giving 1.5 g of purified product, which is dissolved in 150 ml of acetone and precipitated as pale-brown hydrochloride using one molar hydrochloric acid (pH 3).

References: [1]Patent: US2007/99933,2007,A1 .

9
[ 113964-33-3 ]
[ 183288-46-2 ]
[ 1187322-52-6 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In acetonitrile; for 72h;Heating;	6.6 g of (6-chloro-hex-1-ynyl)-trimethyl-silane, 11 g 5-piperazin-1-yl- benzofuran-2-carboxylic acid amide (Reitz et al., J. Med. Chem. 2005, 38:4211-22), and 8.3 ml_ triethyl-amine were dissolved in 100 mL acetonitrile and heated for 72 h. After cooling to RT the reaction mixture was poured on 10O mL water and 100 mL ethyl acetate. After the usual extraction and purification procedure 3.9 g colorless crystals 5-[4-(6-trimethylsilanyl-hex-5- ynyl)-piperazin-1-yl]-benzofuran-2-carboxylic acid amide were obtained. HPLC: Chromolite Performance RP18-e 100-4,6 mmGradient: ACN/H2O witht 0,05% formic acid Method: Chromolith/Chromolith (extended) flow: 3mL/minRetention (Rt): 2.96 min [M+H]+: 398

References: [1]Patent: WO2009/112139,2009,A1 .Location in patent: Page/Page column 26.

10
[ 143612-79-7 ]
[ 183288-46-2 ]
[ 163521-12-8 ]

Yield	Reaction Conditions	Operation in experiment
95.7%		To a solution of 3-(4-chlorobutyl)-1 H-indole-5-carbonitrile (2.5 g) in DMF (10 mL), sodium iodide (0.8 g) was added and the reaction mass was stirred at about 25-30 C for 15 minutes. Sodium bicarbonate (3.61 g), 5-(piperazin-1 -yl)benzofuran-2- carboxamide (3 g) and tetrabutylammonium bromide (0.51 g) was added to the reaction mass and heated to 110-115 C for 1 hour and 15 minutes. The reaction mass was then allowed to cool to 60 C and water (37.5 mL) was added to the reaction mass slowly. The resulting precipitate was stirred for 60 minutes at about 30 C. The precipitate was filtered, washed with water (10 mL) and dried for 5-6 hours at 60 C under vacuum to afford the desired compound.Yield: 4.5 g (95.7 %). Purity (by HPLC): 97.39 %
94%	With sodium carbonate; In water; at 90 - 100℃;	To a 4-neck round bottomed flak was added 5-(piperazin-l-yl)-l-benzofuran-2-carboxamide (PBA) (lOOg, 0.4078 mol), 3-(4-chlorobutyl)-lH-indole-carbonitrile (CBCI) (104.39g, 0.4486 mol), sodium carbonate (130g, 1.2235 mol) and 1000 ml water. The reaction mass was stirred for 10-15 min. The reaction mass was heated to 90 to 100 C and maintained for about 10 hrs (PBA content is NMT 2.0%).Then the reaction mass was gradually cooled to room temperature and the deposited solid was filtered, washed with isopropyl alcohol and suck dried. The solid thus obtained was slurried with methanol (500 ml) and stirred for 1 hour. The product was collected by filtration. The solid obtained was washed with methanol (500ml), suck dried and dried under vacuum to yield crude Vilazodone. Yield = 72 to 94% HPLC purity = 90-95%
94%		To a clean round bottomed flask was added PBA (lOOgm, 0.408 mol) and DM water (900ml). To the reaction mass was added dil.HCl at 20-35C till pH is in the range of 6.5-7. The reaction mass was stirred for 30 to 45 min. at room temperature and filtered through celite. The filtrate obtained was charged into a 4-neck round bottomed flask and to this were added 3-(4-chlorobutyl)-lH-indole-carbonitrile (CBCL) (95g, 0.408 mol), sodium carbonate (50g, 1.1 mol) and 200ml isopropyl alcohol. The reaction mass was heated to reflux (75-85 C) and maintained for about 12 hrs (CBCI content is NMT 5.0%).Then the reaction mass was cooled to room temperature and the deposited solid was filtered, washed with DM water and suck dried. The wet solid thus obtained was slurried with acetone (700 ml) and the wet solid was collected by filtration and again washed with 200ml acetone. The wet solid obtained was dissolved in DMF (500ml) and filtered through celite to remove insoluble. To the filtrated was added IPA.HC1 and the reaction mass was stirred for 60-90 min. The precipitated solid was collected by filtration, washed with DMF suck dried well. The wet cake was taken in a RBF and to it was added dimethylformamide. Thereafter liquor ammonia was added till pH 8.0-10.0 is obtained, the reaction mass was stirred for 30-45 min. and filtered through celite. To the filtrate was gradually added an aq. solution of sodium metabisulphite (15gm) and sodium carbonate (15 gm) in 400ml water in 45-60 min. The reaction mass was stirred for 60-90 min. the precipitated solid was collected by filtration and slurried with water, suck dried followed by slurry wash with acetone. The wet solid obtained after filtration was dried under vacuum to yield pure Vilazodone base. Yield = 72 to 94% HPLC purity = >99%

65%	With potassium carbonate; triethylamine; In acetonitrile; for 12h;Reflux;	Compound 3 (233 g, 1.0mol) and 6 (245 g, 1.0 mol) were dissolved in acetonitrile (3 L), and then, triethylamine (101 g, 1.0mol) and K2CO3 (138g,1.0mol) were added to the solution. The mixture was heated at reflux for 12 h. Subsequently, the reaction mixture was poured into cold water (3L). After filtration, the solid was dissolved in EtOAc, and then, HCl-EtOAc saturated solution was added to enable crystallization. Product 7 was obtained as a white solid. Yield 287 g (65%) with 99% HPLC purity after the mixture was filtered. m.p. 276.5-279.2C (Lit1 277-279C). 1H NMR (400MHz, DMSO-d6): delta 11.35 (s, 1H), 8.04 (d, J=18.3Hz, 2H), 7.74-6.88 (m, 8H), 3.69-3.15 (m, 8H), 2.74 (t, J= 7.2Hz, 2H), 2.37 (t, J =7.2Hz, 2H), 1.80-1.61 (m, 2H), 1.54 (d, J=6.8Hz, 2H). 13C NMR (100 MHz, DMSO-d6): delta 159.9, 148.8, 147.9, 138.6, 137.7, 127.8, 126.9, 124.7, 124.0, 123.3, 120.9, 117.8, 115.7, 112.4, 111.6, 109.5, 107.3, 100.0, 57.5, 52.8(2), 49.8(2), 27.7, 26.1, 24.1. HRMS (ESI): m/z [M+H]+ calculated for C26H27N5O2: 442.2238, found: 442.2240.
44 g		Example 1 : Preparation of 5- \|4-[4-r5-Cyano- lH-Indol-3-yf)ButyllPiperazin-l-yl}-l- Benzofuran-2-Carboxamide 3-(4-Chlorobutyl)-lH-indole-5-carbonitrile (34.2 g) was added to acetonitrile (300 mL). Sodium iodide (33.1 g) was added to the reaction mixture. The reaction mixture was heated to 80C to 85C and maintained for 60 minutes. The reaction mixture was cooled to 60C. 5-(Piperazin-l -yl)-l-benzofuran-2-carboxamide (30 g) and triethylamine (18.6 g) were added to the reaction mixture. The reaction mixture was heated to 80C to 83C for 18 hours. The reaction mixture was cooled to 20C to 30C. The reaction mixture was added to water (300 mL), dichloromethane (300 mL), and sodium thiosulphate (7.5 g). Concentrated hydrochloric acid (15 mL) was added to the reaction mixture and stirred for 1.5 hours at 20C to 30C. The solid obtained was filtered and washed with dichloromethane (80 mL) and deionized water (150 mL). The reaction mixture was added to ethyl acetate (600 mL) and water (300 mL). Triethyl amine (20 g) was added to the reaction mixture. The reaction mixture was heated to 70C to 75C. The layers obtained were separated and the organic layer was washed with water (100 mL). The organic layer was recovered under vacuum. 2-Propanol (60 mL) was added to the reaction mixture and stirred at 20C to 30C for 1 hour. The reaction mixture was filtered, washed with 2-propanol (30 mL) and dried under vacuum at 45C to 50C for 12 hours to obtain the title compound having XRPD as depicted in Figure 1. Yield: 44.0 g.
	With triethylamine; In acetonitrile; at 35 - 80℃; for 48h;	Acetonitrile (500 ml), 5-(l-piperazinyl) benzofuran-2-carboxamide of Formula (G) (100 g), 3-(4-chlorobutyl)-lH-indole-5-carbonitrile of Formula (H) and Triethyl amine (200 g) were added to a four-neck two litre round bottom flask at 35C and reaction mass was heated to 80C and maintained for 48 hours. The reaction mass was cooled to 55C to afford vilazodone of Formula (1).
	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one;Heating;	3-(4-chlorobutyl)-1H-indole-5-carbonitrile (1.01 g, 1.0 equiv.), <strong>[183288-46-2]5-(piperazin-1-yl)benzofuran-2-carboxamide</strong> (1.10 g, 1.03 equiv.), diisopropylethyl amine (DIPEA, 0.64 g, 1.16 equiv,), and N-Methyl-2-pyrrolidone (NMP, about 40 mL) are charged to a suitable vessel. It is to be noted that 5-(piperazin-1-yl) benzofuran-2-carboxamide may be produced using methods known in the art (see, e.g., U.S. Patent No. 5,977,112). The mixture is heated and stirred until the reaction is complete. Acetonitrile (about 40 mL) and water (about 40 mL) are charged while maintaining elevated temperature. The mixture is cooled slowly to precipitate vilazodone, filtered, and the wet cake is washed with acetonitrile/water and then with acetonitrile. The wet product is dried to provide crude vilazodone. Purification is carried out via conventional means known in the art, e.g., filtration and precipitation.
7 g	With potassium carbonate; In water; toluene; at 90 - 95℃; for 29h;	Example 3: Preparation of vilazodone free basePotassium carbonate (2.8 g) was added to water (25 mL) and stirred for 10 minutes. 5-Piperazin- 1 -ylbenzofuran-2-caboxamide (5.0 g), 3 -(4-chlorobutyl)- 1 H-indole25 5-carbonitrile (5.7 g), and toluene (25 mL) were added to the reaction mixture and thereaction mixture was heated to 90C to 95C for 29 hours. The reaction mixture was cooled to 3 0C, filtered, and washed with water (25 mL). The solid obtained was dried at 45C to 50C to obtain the title compound.Yield: 7.0 g
2.8 mg		-(Piperazin-l-yl)-l-benzofuran-2-carboxamide (5 g; prepared according toExample 2) and 3-(4-chloro butyl)-lH-indole-5-carbonitrile (5.7 g) were added to N-methyl pyrollidone (25 mL). The temperature of the reaction mixture was increased to 110C to 120C and stirred for 2 hours. Tributyl amine (3.77 g) was added to the reaction mixture and stirred at 110C to 120C for 4 hours. The reaction mixture was cooled to 20C to 35C. Hydrobromic acid (2.5 mL) and 2-propanol (50 mL) were added to the reaction mixture. Vilazodone hydrobromide seed (0.005 g) was added to the reaction mixture and stirred at 0C to 5C for 1 hour. The reaction mixture was filtered, and then washed with cooled 2-propanol (25 mL). The reaction mixture was added to a mixture of N-methyl pyrollidone (25 mL) and hydrobromic acid (0.5 mL). 2-Propanol (50 mL) was added to the reaction mixture and stirred for 2 hours. The reaction mixture was filtered and washed with 2-propanol (10 mL). The reaction mixture was added to 2-propanol (100 mL) and deionized water (50 mL). The temperature of the reaction mixture was increased to 80C to 82C. Activated carbon (1 g) was added to the reaction mixture and stirred for 1 hour. The reaction mixture was filtered and washed with 2-propanol (20 mL) and deionized water (10 mL). The pH of the filtrate was adjusted to 7.2 with 7% sodium bicarbonate solution (9 mL). The reaction mixture was filtered and washed with deionized water (20 mL) and 2-propanol (20 mL). The solid obtained was dried in air at 50C to 55C to obtain the title compound. Yield: 2.8 g
	With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 35 - 80℃; for 30h;	DMSO (1000 ml), <strong>[183288-46-2]5-(1-piperazinyl)benzofuran-2-carboxamide</strong> of Formula (G) (100 g), 3-(4-chlorobutyl)-1H-indole-5-carbonitrile of Formula (H) and diisopropylethylamine (DIPEA) (1500 ml) were added to a four-neck two litre round bottom flask at 35 C. and reaction mass was heated to 80 C. and maintained for 30 hours. The reaction mass was cooled to 55 C. The reaction mass was treated with EDTA (3 g) and charcoal (10 g). The residue was filtered and treated with DMSO (800 ml) at 80-85 C. and stirred for 15 minutes. The reaction mass was treated with acetone at 20-25 C. and stirred for 1 hour. The reaction mass was washed with acetone (2100) and treated with acetic acid (720 ml) and methanol (500 ml) at 25-30 C. and stirred for 10 minutes. The reaction mass is heated to 80-81 C. and treated with activated charcoal (10 g) and stirred for 15-20 min. The reaction mass was cooled to 15-20 C., filtered and washed with methanol (2100 ml). The product was dried in hot air oven at 60-65 C. for 12-14 hours. The product was further dried in oven at 105 C. for 4 hours afforded Form-Z of vilazodone of Formula (1). (HPLC purity >99.70%).
44 g		3-(4-Chlorobutyl)-1H-indole-5-carbonitrile (34.2 g) was added to acetonitrile (300 mL). Sodium iodide (33.1 g) was added to the reaction mixture. The reaction mixture was heated to 80 C. to 85 C. and maintained for 60 minutes. The reaction mixture was cooled to 60 C. 5-(Piperazin-1-yl)-1-benzofuran-2-carboxamide (30 g) and triethylamine (18.6 g) were added to the reaction mixture. The reaction mixture was heated to 80 C. to 83 C. for 18 hours. The reaction mixture was cooled to 20 C. to 30 C. The reaction mixture was added to water (300 mL), dichloromethane (300 mL), and sodium thiosulphate (7.5 g). Concentrated hydrochloric acid (15 mL) was added to the reaction mixture and stirred for 1.5 hours at 20 C. to 30 C. The solid obtained was filtered and washed with dichloromethane (80 mL) and deionized water (150 mL). The reaction mixture was added to ethyl acetate (600 mL) and water (300 mL). Triethyl amine (20 g) was added to the reaction mixture. The reaction mixture was heated to 70 C. to 75 C. The layers obtained were separated and the organic layer was washed with water (100 mL). The organic layer was recovered under vacuum. 2-Propanol (60 mL) was added to the reaction mixture and stirred at 20 C. to 30 C. for 1 hour. The reaction mixture was filtered, washed with 2-propanol (30 mL) and dried under vacuum at 45 C. to 50 C. for 12 hours to obtain the title compound having XRPD as depicted in fig.1. Yield: 44.0 g.
	With sodium acetate; In N,N-dimethyl acetamide; at 90℃; for 18h;	36.10 g (155 mmol) of 3-(4-chlorobutyl)-5-cyanoindole was added to a 1 L single-necked flask, <strong>[183288-46-2]5-(piperazin-1-yl)benzofuran-2-carboxamide</strong> 36.00 g (147 mmol), 25.50 g of sodium acetate (310 mmol), stirring in 500mL DMAC, the reaction was carried out at 90 C (outside temperature) for 18 hours, the reaction solution was cooled to room temperature, 1 L of water was added, extraction with ethyl acetate (3 x 400 mL), the organic layers were combined, the organic layer was washed with water (2 x 300 mL), saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give a yellow solid. Using mixed solvent purification, the solid was first dissolved in THF, acetone was added with stirring, methanol, stirring, precipitating solid, filtering, vacuum drying, weighing, vilazodone.
13.2 g	With triethylamine; sodium bromide; In isopropyl alcohol; for 18h;Reflux; Inert atmosphere;	Under nitrogen, the above prepared 6.1g <strong>[183288-46-2]5-(piperazin-1-yl)benzofuran-2-carboxamide</strong>, 5.8 g of 3-(4-chlorobutyl-5-cyanoindole, 3.5 g of sodium bromide and 2.8 g of triethylamine were successively dissolved in 100 mL of isopropanol to form a reaction solution. The reaction was stirred at reflux for 18 hours until the reaction was complete by TLC. The reaction mixture was added dropwise to 150 mL of a 5% aqueous solution of sodium carbonate until a light yellow solid precipitated. The reaction mixture was stirred for 1 hour and filtered to obtain a cake. The cake was washed with 100 mL of water once to obtain 11.8 g of vilazodone , Purity 99.1%, yield was 93.1%.
7.25 kg	With triethylamine; N-ethyl-N,N-diisopropylamine; sodium iodide; In dimethyl sulfoxide; at 25 - 95℃; for 10h;Large scale;	2. In a 100L enamel kettle,Add 57.75 kg of dimethyl sulfoxide and stir.6.22 Kg of <strong>[183288-46-2]5-(1-piperazinyl)-benzofuran-2-carboxamide</strong> of formula III is added,Add 5.22 kg of 3-(4-chlorobutyl)indole-5-carbonitrile of formula IV,3.51kg anhydrous sodium iodide, 3.57kg N,N-diisopropylethylamine and 4.36kg triethylamine(material volume is about 70L), heat up to 95 C, and keep reacting at 95 C for 10 hours.3-(4-Chlorobutyl)indole-5-carbonitrile was completely reacted to room temperature (25 C).The reaction solution was transferred to a 500 L enamel kettle, 36.75 kg of dichloromethane and 157.5 kg of water were added (material volume: about 280 L), stirred for 2 hours, centrifuged, washed with 5 kg of dichloromethane, and centrifuged at 50 ± 2 C. Drying in the wind for 12 hours,Obtaining 9.25 kg of the crude verazodone shown by formula V,The yield is close to the theoretical value and the purity is 90 to 96%.Reaction monitoring: TLC, dichloromethane: methanol (add 2 to 3 drops of ammonia) = 6:1. 3, refined (1) Recrystallization:The first recrystallization: into a 300L enamel reactor, add 9.25kg of verazodone crude and 23L of DMSO, warmed to 50 C, all solids were dissolved under stirring, and then added 92.5L of acetone to continue to raise the temperature to 60 C, add 462.5 g activated carbon, stirring and decoloring for 1h, suction filtration, cooling, adding 92.5L water under stirring, a large amount of solids are precipitated, centrifuged, rinsed with 15L water, blast at 50 CDry for 15~20h, weighing 8.5kg;Second recrystallization: into a 50L reactor, add 8.5kg of verazolonone and 21.1L of DMSO, raise the temperature to 50 C, dissolve all the solids under stirring, add 85L of acetone and continue to raise the temperature to 60 C, add 422.5g Activated carbon, stirring and decoloring for 1h, suction filtration, cooling, adding 85L of water under stirring, a large amount of solids are precipitated, centrifuged, rinsed with 15L of water, blasted at 50 C, saidThe weight is 7.65kg;The third recrystallization: into a 50L reactor, 7.65g of verazosone and 19.15L of DMSO were added, the temperature was raised to 50 C, the solid was completely dissolved under stirring, and 76.5 L of acetone was added to continue heating to 60 C, and 382.5 was added. g activated carbon, stirring and decoloring for 1h, suction filtration, cooling, adding 76.5L water under stirring, a large amount of solids are precipitated, centrifuged, rinsed with 15L water, blasted at 50 C, weighed 7.25kg;

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[ 267644-49-5 ]
[ 183288-46-2 ]

References: [1]Patent: WO2013/175499,2013,A2 .
[2]Patent: WO2014/61004,2014,A2 .
[3]Patent: US2014/179713,2014,A1 .

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5-amino-1-benzofuran-2-carboxamide [ No CAS ]
[ 183288-46-2 ]