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Chemical Structure| 183288-46-2
Chemical Structure| 183288-46-2
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Product Details of [ 183288-46-2 ]

CAS No. :183288-46-2 MDL No. :MFCD20486139
Formula : C13H15N3O2 Boiling Point : -
Linear Structure Formula :- InChI Key :LLRGOAFFRRUFBM-UHFFFAOYSA-N
M.W : 245.28 Pubchem ID :9834719
Synonyms :

Calculated chemistry of [ 183288-46-2 ]

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 : 71.5 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : Yes
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -7.08 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.05
Log Po/w (XLOGP3) : 1.01
Log Po/w (WLOGP) : 0.18
Log Po/w (MLOGP) : 0.41
Log Po/w (SILICOS-IT) : 1.17
Consensus Log Po/w : 0.96

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -2.24
Solubility : 1.43 mg/ml ; 0.00582 mol/l
Class : Soluble
Log S (Ali) : -2.1
Solubility : 1.94 mg/ml ; 0.00793 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.38
Solubility : 0.102 mg/ml ; 0.000417 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.45

Safety of [ 183288-46-2 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

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   1~57

  • 1
  • [ 183288-46-2 ]
  • [ 714950-87-5 ]
  • [ 714950-88-6 ]
  • 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 ]
  • 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 ]
  • 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 ]
YieldReaction ConditionsOperation 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.
  • 5
  • P(t-Bu)3 [ No CAS ]
  • t-OBu [ No CAS ]
  • [ 35351-21-4 ]
  • [ 57260-71-6 ]
  • [ 183288-44-0 ]
  • [ 183288-46-2 ]
YieldReaction ConditionsOperation 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.
  • 6
  • [ 183288-44-0 ]
  • [ 183288-46-2 ]
YieldReaction ConditionsOperation 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.
  • 7
  • [ 913730-89-9 ]
  • [ 183288-46-2 ]
  • vilazodone hydrochloride [ No CAS ]
  • 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 ]
YieldReaction ConditionsOperation 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).
  • 9
  • [ 113964-33-3 ]
  • [ 183288-46-2 ]
  • [ 1187322-52-6 ]
YieldReaction ConditionsOperation 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
  • 10
  • [ 143612-79-7 ]
  • [ 183288-46-2 ]
  • [ 163521-12-8 ]
YieldReaction ConditionsOperation 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 (2*100) 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 (2*100 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;

  • 12
  • 5-amino-1-benzofuran-2-carboxamide [ No CAS ]
  • [ 183288-46-2 ]
  • 13
  • 5-(4-tosylpiperazin-1-yl)benzofuran-2-carboxamide [ No CAS ]
  • [ 183288-46-2 ]
YieldReaction ConditionsOperation in experiment
With hydrogen bromide; 4-hydroxy-benzoic acid; In acetic acid; at 50℃; To a mixture of 500 ml of Hydrobromic Acid in Acetic Acid was added portion wise 169 g of p-Hydroxy Benzoic Acid and stirred. To this mixture was added portion wise 100 g of 5-(4-tosylpiperazin-l-yl)benzofuran-2-carboxamide (F) and stirred for some time after which the temperature was raised to around 50 C and the mass was stirred for 3 hours. After the completion of reaction was checked by TLC, it was slowly cooled at around 10 C and 1.5 liters of cold water was added to it. The solid obtained was filtered and washed with Ethyl Acetate four times and the aqueous layer was then collected and the pH was adjusted to 10 by using sodium hydroxide solution. The mass was stirred for half an hour and the solid thus obtained was filtered, washed with water and dried to afford 5-(l-piperazinyl) benzofuran-2-carboxamide of Formula (G)
With hydrogen bromide; acetic acid; 4-hydroxy-benzoic acid; at 50℃; for 3h; To a mixture of 500 ml of hydrobromic acid in acetic acid was added portion wise 169 g of p-hydroxy benzoic acid and stirred. To this mixture was added portion wise 100 g of 5-(4-tosylpiperazin-1-yl)benzofuran-2-carboxamide (F) and stirred for some time after which the temperature was raised to around 50 C. and the mass was stirred for 3 hours. After the completion of reaction was checked by TLC, it was slowly cooled at around 10 C. and 1.5 liters of cold water was added to it. The solid obtained was filtered and washed with Ethyl Acetate four times and the aqueous layer was then collected and the pH was adjusted to 10 by using sodium hydroxide solution. The mass was stirred for half an hour and the solid thus obtained was filtered, washed with water and dried to afford us with 5-(1-piperazinyl)benzofuran-2-carboxamide of Formula (G)
  • 14
  • [ 6280-80-4 ]
  • [ 183288-46-2 ]
  • 15
  • [ 90-02-8 ]
  • [ 183288-46-2 ]
  • 16
  • [ 6965-69-1 ]
  • [ 183288-46-2 ]
  • 17
  • [ 10242-12-3 ]
  • [ 183288-46-2 ]
  • 18
  • [ 143612-79-7 ]
  • [ 183288-46-2 ]
  • 5-{4-[4-(5-cyano-1H-indol-3-yl)butyl]piperazin-1-yl} benzofuran-2-carboxamide hydrobromide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Example 13: Preparation of Vilazodone Hydrobromide 5-(piperazin- 1 -yl)- 1 -benzofuran-2-carboxamide (50 g) and 3 -(4-chlorobutyl)- 1 Hindole-5-carbonitrile (52.27 g) were added to N-methylpyrollidone (250 mL) at 26C. Thetemperature of the reaction mixture was increased to 120C and maintained at 110C to120C for 2 hours. Tributylamine (37.75 g) was added to the reaction mixture at 117C to118C and the temperature was maintained at 115C to 118C for 6 hours. The reactionmixture was cooled to 30C. 2-Propanol (500 mL) and concentrated (40% to 48%) hydrobromic acid (27 mL) were added to the reaction mixture at 25C to 30C and the reaction mixture was seeded with vilazodone hydrobromide (0.25 g) at 25C to 30C. The reaction mixture was stirred at 25C to 30C for 16 hours. The reaction mixture was filtered and washed with 2-propanol (50 mL x 4) at 25C to 30C.Yield (Wet): 130 g
89 g Example 5: Preparation of vilazodone hydrobromide5-(Piperazin- 1 -yl)- 1 -benzofuran-2-carboxamide (50 g) and 3 -(4-chlorobutyl)- 1 Hindole-5-carbonitrile (52.3 g) were added to N-methyl pyrollidone (250 mL) at 30C. The temperature of the reaction mixture was increased to 120C and maintained at 115C to 120C for 2 hours. Tributylamine (38 g) was added to the reaction mixture at 115C to117C and maintained at 115C to 120C for 6 hours. The reaction mixture was cooled to30C. A solution of 2-propanol (500 mL) and concentrated (40% to 48%) hydrobromic acid (37 g) was added to the reaction mixture at 25C to 30C and seeded with vilazodone hydrobromide (0.25 g) at 25C to 30C. The reaction mixture was stirred at 25C to 30C for 6 hours. The reaction mixture was filtered and washed with 2-propanol (50 mL x 4) at20C to 30C to obtain the title compound.Yield (Wet): 89 g
  • 19
  • [ 143612-79-7 ]
  • [ 183288-46-2 ]
  • vilazodone hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
6.1 g 5-(Piperazin-l-yl)-l-benzofuran-2-carboxamide (5 g) and 3-(4-chlorobutyl)-5- cyanoindole (5.22 g) were added to N-methylpyrrolidone (25 mL). The reaction mixture was heated to 1 10C to 120C for 2 hours. Tributylamine (3.77 g) was added to the reaction mixture at 1 10C to 120C, and the mixture was stirred for 6 hours. The reaction mixture was cooled to 30C and 2-propanol (50 mL) was added to the reaction mixture. Concentrated hydrochloric acid (3.5 mL) was added to the reaction mixture, and it was stirred at 25C to 30C for 3 hours. The solid obtained was filtered, washed with 2- propanol (10 mL), and dried in a vacuum oven at 50C to 55C for 12 hours to obtain the title compound. Yield: 6.1 g
  • 20
  • [ 913730-89-9 ]
  • [ 183288-46-2 ]
  • [ 163521-12-8 ]
YieldReaction ConditionsOperation in experiment
75.21% To a solution of 5-(1 -piperazinyl)benzofuran-2-carboxamide (1 .3 g) in methanol (152.9 mL), sodium cyanoborohydride (0.84 g) was added at 20C and stirred for 5-10 minutes. A solution of 3-(4-oxobutyl)-1 H-indole-5-carbonitrile (1 .83 g) in methanol (38 mL) was added over a period of 15 minutes. The reaction mass was stirred at 20 C for about 18 hours and then cooled to * 0C for 6 hours. The precipitated solid was filtered, washed with water (10 mL), methanol (10 mL) and dried under vacuum. Yield: 1 .76 g (75.21 %).
  • 21
  • [ 1646-29-3 ]
  • [ 183288-46-2 ]
  • 22
  • methyl 5-[4-(benzenesulfonyl)-1-piperazinyl]benzofuran-2-carboxylate [ No CAS ]
  • [ 183288-46-2 ]
  • 23
  • methyl 5-(1-piperazinyl)-benzofuran-2-carboxylate [ No CAS ]
  • [ 183288-46-2 ]
YieldReaction ConditionsOperation in experiment
73.1% With ammonia; In methanol; at 25 - 30℃; Methyl 5-(l-piperazinyl)benzofuran-2-carboxylate (37 g) was added to saturated methanolic ammonia solution (1850 ml) at 25-30C, the mixture was stirred for 6 to 16 hours at the same temperature. The reaction mass was distilled under vacuum to remove the solvent after completion of the reaction. Water (148 ml) was added to the resulting residue, followed by adjusting the pH to 2-4 with concentrated HC1 and then filtering the aqueous layer. The pH of the resulting aqueous layer was adjusted to 9-10 with ammonium hydroxide solution. The separated solid was filtered, washed with water (100 ml) and then dried to produce 25.5 g of 5-(l-piperazinyl)benzofuran-2-carboxamide (Purity by HPLC: 99%; Yield: 73.1%).
  • 24
  • [ 1602487-82-0 ]
  • [ 183288-46-2 ]
YieldReaction ConditionsOperation in experiment
24 g With hydrogenchloride; In water; at 45 - 50℃; for 1h; Step D: 5-(Piperazin-1-yl)-1-benzofuran-2-carboxamide5-(4-Formylpiperazin-1-yl)-1-benzofuran-2-carboxamide (79 g) prepared in step C was added to concentrated hydrochloric acid (100 mL) and stirred at 45C to 50C for 60 minutes. Deionized water (300 mL) was added to the reaction mixture and the pH was adjusted to 10.5 with 20% sodium hydroxide solution (275 mL) at 10C to 25C. Thereaction mixture was filtered and the solid obtained was washed with deionized water (200 mL). The solid obtained was dried in an air oven for 16 hours at 50C to 55C to obtain the title compound.Yield: 24 g
  • 25
  • [ 183288-46-2 ]
  • [ 163521-12-8 ]
  • 26
  • [ 183288-46-2 ]
  • 5-(4-[4-(5-cyano-1H-indol-3-yl)butyl]piperazin-1-yl)benzofuran-2-carboxamide hydrochloride [ No CAS ]
  • 27
  • [ 143612-79-7 ]
  • [ 183288-46-2 ]
  • 5-(4-[4-(5-cyano-1H-indol-3-yl)butyl]piperazin-1-yl)benzofuran-2-carboxamide hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
3-(4-chlorobutyl)- 1 H-indole-5-carbonitrile (7 Kg) and 5-(piperazin- 1 -yI)benzofuran-2- carboxa mide (8.5 Kg) in dimethyl sulfoxide (75 L) & diisopropylethyl amine (100 L) wereadded in a RBF at 25-30C. The reaction mixture was stirred at 80-85C. Another assembly was arranged in tub using ethyl acetate (105 L): methanol (65 L ml): acetone (65 L) and cone. hydrochloric acid (14 L). First reaction mass was treated with second reaction mass within 60 minutes and stirred for 60 minutes. The reaction mixture was filtered and washed with methanol and treated with water (170 L): DMSO (14 L) at 50-55C. The reaction mass wasstirred for 10 minutes and filtered. To the filtrate methanol (65 L) was added and heated at 50-55C for 30 minutes and cooled to 25-30C. The reaction mass was filtered and washed with methanol (7 L). Vilazodone hydrochloride was obtained by treating the reaction mass with a mixture of acetone: water (2:1) (45 L) at 55-60C for 30 minutes. The reaction mass was cooled to 25-30C, filtered and washed with water (5 L).
  • 28
  • [ 183288-46-2 ]
  • vilazodone hydrochloride [ No CAS ]
  • 29
  • [ 143612-79-7 ]
  • [ 183288-46-2 ]
  • [ 1504584-12-6 ]
YieldReaction ConditionsOperation in experiment
5-(piperazin-l-yl)-l-benzofuran-2-carboxamide (50 g; prepared according to Example 2) and 3-(4-chlorobutyl)-lH-indole-5-carbonitrile (52.3 g) were added to N-methyl pyrollidone (250 mL) at 30C. The temperature of the reaction mixture was increased to 120C and maintained at 115C to 120C for 2 hours. Tributylamine (38 g) was added to the reaction mixture at 115C to 117C and the temperature was maintained at 115C to 120C for 6 hours. The reaction mixture was cooled to 30C. 2-propanol (500 mL) and concentrated (40% to 48%) hydrobromic acid (37 g) were added to the reaction mixture at 25 C to 30C and the mixture was seeded with vilazodone hydrobromide (0.25 g) at 25C to 30C. The reaction mixture was stirred at 25C to 30C for 6 hours. The reaction mixture was filtered and washed with 2-propanol (50 mL x 4) at 20C to 30C to obtain the title compound. Yield (Wet): 89 g
  • 30
  • 5-amino-1-benzofuran-2-carboxamide [ No CAS ]
  • [ 334-22-5 ]
  • [ 183288-46-2 ]
YieldReaction ConditionsOperation in experiment
5.6 g 5-Amino-l-benzofuran-2-carboxamide (10 g; prepared according to Example 1) was added to N-methyl pyrollidone (50 mL). Bis-2-chloroethylamine (12.2 g) was added to the reaction mixture. The temperature of the reaction mixture was raised to 150C to 155C and the mixture stirred for 2 hours. Tributyl amine (10.5 g) was added to the reaction mixture and stirred at 150C to 155C for 6 hours. The reaction mixture was cooled to 25 C to 30C. Deionized water (350 mL) was added to the reaction mixture and the pH was adjusted to 12 with 20% sodium hydroxide solution (35 mL). The reaction mixture was cooled to 0C to 5C and stirred for 2 hours. The reaction mixture was filtered and washed with water (50 mL). Deionized water (50 mL) was added to the reaction mixture and the pH was adjusted to 4.7 with concentrated hydrochloric acid (3.1 mL). Activated carbon (1 g) was added to the reaction mixture and stirred for 45 minutes. The reaction mixture was filtered and washed with deionized water (50 mL). The pH of the filtrate was adjusted to 12.0 with 20% sodium hydroxide solution (4 mL). The reaction mixture was cooled to 0C to 5C and stirred for 1 hour. The reaction mixture was filtered and washed with deionized water (2 x 10 mL). The solid obtained was dried in air at 50C to 55C to obtain the title compound. Yield: 5.6 g
  • 31
  • [ 69604-00-8 ]
  • [ 183288-46-2 ]
  • 32
  • ethyl 5-(4-tert-butoxycarbonyl-1-piperazinyl)benzofuran-2-carboxylate [ No CAS ]
  • [ 183288-46-2 ]
  • 33
  • [ 90036-16-1 ]
  • [ 183288-46-2 ]
  • 34
  • [ 276863-95-7 ]
  • [ 183288-46-2 ]
  • vilazodone N-oxide [ No CAS ]
YieldReaction ConditionsOperation in experiment
85% With triethylamine; potassium iodide; In N,N-dimethyl-formamide; at 20 - 90℃; for 49h;Inert atmosphere; 3-(4-chlorobutyryl)-1H-indole-5-carbonitrile (VIII) (95g, 0.41mol, 1.0eq),5- (piperazin-1-yl) benzofuran-2-carboxamide (II) (100 g, 0.41 mol.KI (6.8 g, 0.041 mol, 0.1 eq),TEA (226 ml, 4.0 eq)And DMF (1 L) were added to a 2 L three-necked flask,Stirring under vacuum degassing 2min, nitrogen replacement,So three times.The reaction solution was stirred at room temperature for 1 hour,The temperature was then raised to an internal temperature of 85 to 90 C,Reaction for 48 hours,HPLC monitoring of starting material VIII) Residual less than 3%Stop heating,Cool to room temperature.To the reaction solution was added dropwise 1.1 L of water until the white solid precipitated completely,With about 5 hours,filter,The filter cake was beaten with 2 L of water for 1 hour,filter,Vacuum drying,168 g of crude product was obtained.168 g of crude product was added to 3 L of absolute ethanol,Heated to reflux dissolved,While hot filter,The filtrate slowly cooled to room temperature crystallization.filter,Filter cake with 350ml anhydrous ethanol beating 30min,filter,160g vacuum drying to give white crystals of intermediate (IX) compound.Yield: 85%, purity 99.9% (HPLC)
7.0% With tributyl-amine; In 1-methyl-pyrrolidin-2-one; at 25 - 130℃; for 24h; 5-(Piperazin-l-yl)-l-benzofuran-2-carboxamide of Formula V (10.0 g) and 3-(4- chlorobutanoyl)-lH-indole-5-carbonitrile of Formula VI (11.1 g) were added to N-methyl pyrrolidone (50 mL), followed by the addition of tributyl amine (7.6 g) at 25C to 30C. The reaction mixture was stirred at 120C to 130C for 24 hours. The reaction mixture was cooled to 25C to 30C. 2-Propanol (100 mL) and 2-propanolic hydrochloric acid solution (15 mL; 20%) were added to the reaction mixture at 25C to 30C. The reaction mixture was stirred for 1 hour, filtered, washed with 2-propanol (20 mL), and then washed with methanol (20 mL) to obtain the crude oxo vilazodone (9.5 g). The crude oxo vilazodone obtained (2 g) was purified by passing it through a YMC-Pack ODS-A, 15 mupiiota, 500 mm x 30 mm column at ambient temperature, using a mixture of 0.5 M KH2PO4 buffer and acetonitrile (60:40% v/v ratio; 5000 mL) as the mobile phase, followed by adjusting the pH of the solution to 7.5 ± 0.05 with 10% aqueous ammonia solution (0.2 mL; prepared by dissolving 1 mL of 25% ammonia solution in 10 mL water) to obtain the oxo vilazodone impurity of Formula III. Yield: 7.0% NMR (400 MHz, CDC13), delta (in ppm): 2.05 (m, 2H), 2.56 (t, 2H), 2.70 (t, 4H), 3.01 (t, 2H), 3.13 (t, 4H), 7.19 (m, 2H), 7.53 (m, 4H), 8.38 (s, 1H), 8.67 (m, 1H). Mass: 456.4 [M + H]+; MS/MS: 211.1, 169.0. IR in KBr, (in cm"1): 3418 (N-H stretching), 2221 (CN stretching), 1669, 1616 (-C=0 stretchings), 808, 887 (aryl C-H bendings).
  • 35
  • [ 143612-79-7 ]
  • [ 183288-46-2 ]
  • 5-{4-[4-(5-cyano-1H-indol-3-yl)butyl]piperazin-1-yl}-1-benzofuran-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
95.7% To a solution of 3-(4-chlorobutyl)-1H-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), <strong>[183288-46-2]5-(piperazin-1-yl)benzofuran-2-carboxamide</strong> (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. [0490] Yield: 4.5 g (95.7%) [0491] Purity (by HPLC): 97.39%
  • 36
  • [ 913730-89-9 ]
  • [ 183288-46-2 ]
  • 5-{4-[4-(5-cyano-1H-indol-3-yl)butyl]piperazin-1-yl}-1-benzofuran-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
75.21% To a solution of <strong>[183288-46-2]5-(1-piperazinyl)benzofuran-2-carboxamide</strong> (1.3 g) in methanol (152.9 mL), sodium cyanoborohydride (0.84 g) was added at 20 C. and stirred for 5-10 minutes. A solution of 3-(4-oxobutyl)-1H-indole-5-carbonitrile (1.83 g) in methanol (38 mL) was added over a period of 15 minutes. The reaction mass was stirred at 20 C. for about 18 hours and then cooled to 10 C. for 6 hours. The precipitated solid was filtered, washed with water (10 mL), methanol (10 mL) and dried under vacuum. [0519] Yield: 1.76 g (75.21%).
  • 37
  • [ 110-85-0 ]
  • [ 35351-20-3 ]
  • [ 183288-46-2 ]
YieldReaction ConditionsOperation in experiment
72% With copper dichloride; In dimethyl sulfoxide; at 150℃; Example 1 In 100ml flask was added 5-chloro-benzofuran-2-carboxamide (3.91g,0.02mol), piperazine (3.44g, 0.04mol), copper chloride (0.27g, 0.002mol),And dimethyl sulfoxide (50ml), was heated with stirring at 150C reaction. The reaction was monitored by thin layer chromatography. After the end of the reaction, the solvent was removed, 10ml of diethyl ether was added to the system, with vigorous stirring, to precipitate a solid.The solid was recrystallized from ethyl acetate to give 5-piperazin-yl-benzofuran-2-carboxamide 3.52 g of the, in 72% yield.
  • 38
  • [ 110-85-0 ]
  • [ 35351-21-4 ]
  • [ 183288-46-2 ]
YieldReaction ConditionsOperation in experiment
70% With copper(II) cyanide; In N,N-dimethyl-formamide; at 150℃; Example 3 100ml flask was added three 5-bromo-benzofuran-2-carboxamide (4.80g,0.02mol), piperazine (5.16g, 0.06mol), copper cyanide (0.23g, 0.002mol),And dimethylformamide (50ml), was heated with stirring at 150 reaction. The reaction was monitored by thin layer chromatography, the end of the reactionAfter the solvent was removed, 10ml of diethyl ether was added to the system, with vigorous stirring, to precipitate a solid.The solid was recrystallized from ethyl acetate to give 5-piperazinylbenzofuran-2-carboxamide 3.43g, 70% yield.
  • 39
  • C22H25ClN4O3 [ No CAS ]
  • [ 183288-46-2 ]
  • C35H39N7O5 [ No CAS ]
YieldReaction ConditionsOperation in experiment
0.09 g With triethylamine; potassium iodide; In ethanol; at 80℃; for 72h; Example 7 Weigh 0.2g Compound 30 and 0.23g of 35 mixed with about 50mL of anhydrous ethanol then dissolved, 0.07g triethylamine and 0.02gKI was added and then heated at 80C with stirring. The reaction is for 72h, TCL monitoring (methylene chloride: methanol: aqueous ammonia = 10: 1: 0.1) to the end of the reaction, was purified by column chromatography to obtain 0.09g of 36.
  • 40
  • 5-(4-acetylpiperazin-1-yl)benzofuran-2-carboxylic acid ethyl ester hydrochloride [ No CAS ]
  • [ 183288-46-2 ]
YieldReaction ConditionsOperation in experiment
97% With ammonium hydroxide; at 20℃; for 10h; 5-(4-acetylpiperazin-1-yl)benzofuran-2-carboxylic acid ethyl ester hydrochloride 10g, was added aqueous ammonia 100ml in a 250ml four-necked flask, stirred for 10 hours at room temperature, filtered and dried to give a white solid 6.8 g, yield 97%.
  • 41
  • 5-(4-acetylpiperazin-1-yl)benzofuran-2-carboxamide [ No CAS ]
  • [ 183288-46-2 ]
YieldReaction ConditionsOperation in experiment
78% 5-(4-acetylpiperazin-1-yl)benzofuran-2-carboxamide 9g, 20% HCl in 200ml ethanol was added into a 500ml four-necked flask, the reaction was refluxed for 8 hours, cooled to room temperature, filtered, the filter cake was put into a 100ml four-necked flask then added with aqueous ammonia 50ml, room temperature and stirring 1h, filtration, drying, recrystallized from ethanol to give a white solid 6g, yield 78%
  • 42
  • [ 110-85-0 ]
  • 5-fluorobenzofuran-2-carboxamide [ No CAS ]
  • [ 183288-46-2 ]
YieldReaction ConditionsOperation in experiment
93.9% With potassium carbonate; In dimethyl sulfoxide; at 120℃; for 6h;Inert atmosphere; Under nitrogen atmosphere, 4.25 g of 5-fluorobenzofuran-2-carboxamide prepared as described above, 1.03 g of piperazine and 2.76 g of potassium carbonate dissolved in 20 ml of DMSO to form a reaction solution, the reaction solution heated to 120 C stirring 6 hours to TLC detection reaction complete. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was dissolved in 100 mL of 1 mol/L hydrochloric acid, and the crude product was dissolved in 100 mL of 1 mol/L hydrochloric acid. The mixture was extracted with 100 mL of methyl tert-butyl ether to obtain an aqueous phase. The aqueous phase was adjusted to pH 8 with sodium bicarbonate solid and stirred for 1 hour. After filtration, the filter cake was washed twice with 100 mL of water and dried at 40 C to give 2.30 g of off-white 5-(piperazine-1-yl)benzofuran-2-carboxamide, purity 98.9%, yield 93.9%.
  • 43
  • [ 183288-46-2 ]
  • 5-(4-(4-(5-cyanoindol-3-yl)butyl)-1-piperazinyl)-2-benzofurancarboxamide sulfate [ No CAS ]
  • 44
  • [ 183288-46-2 ]
  • 5-(4-(4-(5-cyanoindol-3-yl)butyl)-1-piperazinyl)-2-benzofurancarboxamide trifluoroacetate [ No CAS ]
  • 45
  • [ 347-54-6 ]
  • [ 183288-46-2 ]
  • 46
  • 3-(4-chlorobutyl)-1-(naphthalen-1-yl-sulfonyl)-1H-indole-5-carbonitrile [ No CAS ]
  • [ 183288-46-2 ]
  • 5-[4-[4-[5-cyano-1-(naphthalen-1-yl-sulfonyl)-1H-indol-3-yl]butyl]piperazin-1-yl]-2-benzofurancarboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
76% With triethylamine; In 1-methyl-pyrrolidin-2-one; at 120℃; for 5h; 5- (piperazin-1-yl) benzofuran-2-carboxamide (6.13g, 0.025mol), 3- (4- chlorobutyl) -1- (naphthalen-1-sulfonyl) -1H - indole-5-carbonitrile (11.0g, 0.026moL), N- methylpyrrolidone (200 mL) were mixed and then added triethylamine (4.44g, 0.044 moL). Was heated to 120 deg.] C, the reaction 5h, TLC the reaction was complete, the reaction mixture was added to 600mL water and stirred at room temperature for 30min, during which solid precipitated, suction filtered, washed with water. The crude product was recrystallized from acetone to give 5- [4- [4- [5-cyano-1- (naphthalen-1-yl-sulfonyl) lH-indol-3-yl] butyl] piperazine - 1- yl] benzofuran-2-carboxamide 12.0g, yield 76%
  • 47
  • 3-(4-chlorobutyl)-1-(naphthalen-2-yl-sulfonyl)-1H-indole-5-carbonitrile [ No CAS ]
  • [ 183288-46-2 ]
  • 5-[4-[4-[5-cyano-1-(naphthalene-2-yl-sulfonyl)-1H-indol-3-yl]butyl]piperazin-1-yl]-2-benzofurancarboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
72% With triethylamine; In 1-methyl-pyrrolidin-2-one; at 120℃; for 5.5h; 5- (piperazin-1-yl) benzofuran-2-carboxamide (6.13g, 0.025moL), 3- (4- chlorobutyl) -1- (naphthalene-2-sulfonyl) -1H - indole-5-carbonitrile (11.0g, 0.026moL), N- methylpyrrolidone (200 mL) were mixed and then added triethylamine (4.44g, 0.044 moL). Was heated to 120 deg.] C, the reaction 5h 30min, TLC the reaction was complete, the reaction mixture was added to 600mL water and stirred at room temperature for 30min, during which solid precipitated, suction filtered, washed with water. The crude product was recrystallized from acetone to give 5- [4- [4- [5-cyano-1- (naphthalene-2-sulfonyl) lH-indol-3-yl] butyl] piperazine -1 - yl] benzo furan-2-carboxamide 11.4g, 72% yield.
  • 48
  • 3-(4-bromobutyl)-1-(naphthalen-1-yl-sulfonyl)-1H-indole-5-carbonitrile [ No CAS ]
  • [ 183288-46-2 ]
  • 5-[4-[4-[5-cyano-1-(naphthalen-1-yl-sulfonyl)-1H-indol-3-yl]butyl]piperazin-1-yl]-2-benzofurancarboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
79% With triethylamine; In 1-methyl-pyrrolidin-2-one; at 120℃; for 5h; 5- (piperazin-1-yl) benzofuran-2-carboxamide (6.13g, 0.025mol), 3- (4- bromobutyl) -1- (naphthalen-1-sulfonyl) -1H - indole-5-carbonitrile (11.6g, 0.026mol), N- methylpyrrolidone (200 mL) were mixed and then added triethylamine (4.44g, 0.044 mol). Was heated to 120 deg.] C, the reaction 5h, TLC the reaction was complete, the reaction mixture was added to 800mL water and stirred at room temperature for 30min, during which solid precipitated, suction filtered, washed with water. The crude product obtained was recrystallized from 200mL of methanol, to give 5- [4- [4- [5-cyano-1- (naphthalen-1-yl-sulfonyl) lH-indol-3-yl] butyl] piperazine 1-yl] benzo furan-2-carboxamide 12.5g, 79% yield.
  • 49
  • 3-(4-bromobutyl)-1-(naphthalene-2-yl-sulfonyl)-1H-indole-5-carbonitrile [ No CAS ]
  • [ 183288-46-2 ]
  • 5-[4-[4-[5-cyano-1-(naphthalene-2-yl-sulfonyl)-1H-indol-3-yl]butyl]piperazin-1-yl]-2-benzofurancarboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
82% With triethylamine; In 1-methyl-pyrrolidin-2-one; at 120℃; for 5h; 5- (piperazin-1-yl) benzofuran-2-carboxamide (6.13g, 0.025mol), 3- (4- bromobutyl) -1- (naphthalene-sulfonyl) lH-indole - 5-carbonitrile (11.6g, 0.026moL), N- methylpyrrolidone (200 mL) were mixed and then added triethylamine (4.44g, 0.044 moL). Was heated to 120 deg.] C, the reaction 5h, TLC the reaction was complete, the reaction mixture was added to 600mL water and stirred at room temperature for 30min, during which solid precipitated, suction filtered, washed with water. The crude product was recrystallized from acetone to give 5- [4- [4- [5-cyano-1- (p-toluenesulfonyl) lH-indol-3-yl] butyl] piperazin-1-yl ] benzo furan-2-carboxamide 12.9g, 82% yield.
  • 50
  • 3-(4-bromobutyl)-1-(phenylsulfonyl)-1H-indole-5-carbonitrile [ No CAS ]
  • [ 183288-46-2 ]
  • 5-[4-[4-[5-cyano-1-(phenylsulfonyl)-1H-indol-3-yl]butyl]piperazin-1-yl]benzofuran-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
84% With triethylamine; In 1-methyl-pyrrolidin-2-one; at 120℃; for 6h; 5- (piperazin-1-yl) benzofuran-2-carboxamide (5.30g, 0.022moL), 3- (4- bromobutyl) -1- (phenylsulfonyl) lH-indole - 5-carbonitrile (9.17g, 0.022moL), N- methylpyrrolidone (200 mL) were mixed and then added triethylamine (4.44g, 0.044 moL), was heated to 120 deg.] C, the reaction 6h, TLC the reaction was complete, the reaction the mixture was added to 600mL water and stirred at room temperature for 30min, during which solid precipitated, suction filtered, washed with water. The crude product obtained was recrystallized from 150mL of methanol, to give 5- [4- [4- [5-cyano-1- (phenylsulfonyl) lH-indol-3-yl] butyl] piperazin-1-yl ] benzo furan-2-carboxamide 10.8g, a yield of 84%.
  • 51
  • 3-(4-bromobutyl)-1-(p-toluenesulfonyl)-1H-indole-5-carbonitrile [ No CAS ]
  • [ 183288-46-2 ]
  • [ 1415760-77-8 ]
YieldReaction ConditionsOperation in experiment
86% With triethylamine; In 1-methyl-pyrrolidin-2-one; at 120℃; for 5h; 5- (piperazin-1-yl) benzofuran-2-carboxamide (5.30g, 0.022moL), 3- (4- bromobutyl) -1- (p-toluenesulfonyl) lH-indole 5-carbonitrile (9.48g, 0.022moL), N- methylpyrrolidone (200 mL) were mixed and then added triethylamine (4.44g, 0.044 moL). Was heated to 120 deg.] C, the reaction 5h, TLC the reaction was complete, the reaction mixture was added to 600mL water and stirred at room temperature for 30min, during which solid precipitated, suction filtered, washed with water. The crude product was recrystallized from acetone to give 5- [4- [4- [5-cyano-1- (p-toluenesulfonyl) lH-indol-3-yl] butyl] piperazin-1-yl ] benzo furan-2-carboxamide 11.27g, 86% yield.
  • 52
  • 5-(1-piperazinyl)benzofuran-2-carboxylic acid ethyl ester hydrochloride [ No CAS ]
  • [ 183288-46-2 ]
YieldReaction ConditionsOperation in experiment
80% With ammonium hydroxide; In 1-methyl-pyrrolidin-2-one; at 40 - 50℃; for 21h;Large scale; 1. To 100 L in the double-layer glass reactor, adding 30 kg of ammonia water and 15 kg N -methyl pyrrolidone, stirring, heated to 40 - 50 C, adding 10 kg of formula II shown 5-(1-piperazinyl)-benzofuran-2- carboxylic acid ethyl ester hydrochloride (the material volume about 55 L), slow heating, the reaction initial period it will be a large number of bubbles, apt to wash the material, lasts about 1 h, stirring for 20 hours, 17 h begin HPLC monitoring reaction (extract the sample, filtering the samples), the basic reaction is complete after the raw materials, to a room temperature (20 C), centrifugal, for 20 kg water is washed to neutral.In the 50 L in the double-layer glass reactor, adding 20 kg of methanol, stirring, added in the solid. Heating, reflux 1 hour, stop heating, the temperature to room temperature (15 - 20 C), centrifugal, water Washing.Solid for 50 ± 2 C drying by blowing 10 - 12 hours, to obtain 6.22 kg of formula III shown 5 - (1 - piperazinyl) - benzofuran -2 - formamide, yield by about 80%.TLC monitoring reaction: dichloromethane: methanol (add 2 - 3 drops of ammonia water)=6:1.
  • 53
  • [ 1761-61-1 ]
  • [ 183288-46-2 ]
  • 54
  • [ 10242-11-2 ]
  • [ 183288-46-2 ]
  • 55
  • 5-(piperazin-1-yl)benzofuran-2-carboxylic acid [ No CAS ]
  • [ 183288-46-2 ]
  • 56
  • C13H13ClN2O2 [ No CAS ]
  • [ 183288-46-2 ]
YieldReaction ConditionsOperation in experiment
196 g With ammonia; In tetrahydrofuran; at 25℃; under 2250.23 Torr; for 0.5h; Compound 22 (246g, 1.0mol) was dissolved in ClCH2CH2Cl, and SOCl2 (119 g, 1mol) was added slowly to the solution and the resulting mixture was stirred at 60C for 4 h. After filtration, the solid was dissolved in tetrahydrofuran (THF) (1 L), and then, NH3 gas (0.3MPa in highpressure reactor) was poured into the solution. The resulting mixture was stirred at 25C for 30 min. After the reaction was complete, the mixture was concentrated under vacuum to provide the product 6. Yield 196 g (80%) with 97% purity. m.p. 251.3-254.3C. (Lit19 253-255C). 1H NMR(400MHz, DMSO-d6): delta 8.19-7.28 (m, 4H), 7.15 (d,J = 6.6 Hz, 2H), 3.02 (d, J= 4.2Hz, 4H), 2.86 (s, 4H), 2.51(s, 1H). 13C NMR (100 MHz, DMSO-d6): delta 159.9, 149.2,148.6, 127.5, 117.9, 111.4, 109.6, 107.3, 107.2, 51.0(2), 45.71, 45.7. HRMS (ESI): m/z [M+H]+ calculated for C13H15N3O2: 246.1237, found: 246.1245.
  • 57
  • [ 914927-40-5 ]
  • [ 183288-46-2 ]
  • [ 163521-12-8 ]
YieldReaction ConditionsOperation in experiment
91.2% With trifluoroacetic acid at 60℃; for 12h; 1-8 Compound 1 (21.4 g, 0.1 mol) and compound 2 (24.5 g, 0.1 mol) were dispersed in trifluoroacetic acid (100 ml), and the temperature was raised to an internal temperature of 60° C. to react for 12 hours. After the reaction, the trifluoroacetic acid was evaporated to dryness, methanol (150ml) was added into the system, heated to reflux for 2h, cooled to room temperature, filtered and dried in vacuum to obtain 40.3g of white powder (Compound I) with a yield of 91.2% and a purity of 99.5% by HPLC.Compound I:
Same Skeleton Products
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