1477-19-6

Usage

Uses

Used in Anticancer Applications:
Benzarone is used as an anticancer agent for its ability to inhibit the EYA protein, which is overexpressed in ovarian and breast cancers. This inhibition helps in controlling tumor growth and progression, making it a valuable compound in the fight against these specific types of cancer.
Used in Pharmaceutical Industry:
Benzarone is used as a key component in the synthesis of Human Uric Acid Transporter 1 inhibitors. These inhibitors are essential for the development of treatments targeting kidney diseases, where the regulation of uric acid transport is crucial for managing the condition and improving patient outcomes.
Used in Research and Development:
As a multifunctional protein inhibitor, Benzarone is also utilized in research and development for its potential applications in understanding the role of EYA proteins in organogenesis and other biological processes. This knowledge can lead to the discovery of new therapeutic approaches and treatments for various diseases and conditions.

Originator

Fragivix,Labaz

Manufacturing Process

The process of preparation of the 2-ethyl-3-(4'-hydroxybenzoyl)benzofurane includes the next steps: 1. To 1 mol of potassium hydroxide in absolute ethanol is added 1 mole of salicylic aldehyde. The mixture is brought to boiling point in water bath until the potassium salt formed is dissolved. One mole of coloroacetone is gradually added and the solution boiled in a reflux condenser for 2 hours. On cooling the potassium chloride precipitate is separated off by filtration. The residue is distilled to give 2-acetyl-1-benzofurane, BP: 135°C/15 mm Hg. 2. It was reduced by hydrazine hydrate in an alkaline medium (by process of Hyuang-Minlon, J.A.C.S., 1946, 68, 2487) to give 2-ethyl-1-benzofurane BP: 211°-212°C. 3. 2-Ethyl-1-benzofurane is condensed with 2-metoxybenzoyl chloride in the presence of tin tetrachloride (according to the process described by Bisagni, J.C.S., 1955, 3694). Thus 2-ethyl-3-(4-methoxybenzoyl)-1-benzofyrane is obtained. BP: 226°C/15 mm Hg. 4. 1 part of 2-ethyl-3-(4-methoxybenzoyl)-1-benzofyrane is mixed with 2 parts of pyridine hydrochloride and heated at an oil bath at 210°C in N2 current for 1 hour. On cooling 10 parts of 0.5 N HCl are added. A water layer is mixed with 20 parts of 1% NaOH. The alkaline layer is separated, acidified with diluted HCl. The dropped precipitate (2-ethyl-3-(4'-hydroxybenzoyl) benzofurane) is recrystallized from acetic acid. MP: 124.3°C.

Therapeutic Function

Antihemorrhagic

World Health Organization (WHO)

Benzarone is given by mouth and applied topically for treatment of various vascular peripheral disorders.The decision to suspend the marketing authorization results from several reports of toxic hepatitis, including one fatal case from within Germany. The product remains registered in Italy and France.

Safety Profile

Poison by intraperitoneal route. An experimental teratogen. Other experimental reproductive effects. A flammable liquid. When heated to decomposition it emits acrid and irritating smoke and fumes. See also KETONES.

InChI:InChI=1/C17H14O3/c1-2-14-16(13-5-3-4-6-15(13)20-14)17(19)11-7-9-12(18)10-8-11/h3-10,18H,2H2,1H3

Synthetic route

(2-ethylbenzofuran-3-yl)(4-methoxyphenyl)methanone (3343-80-4) → benzarone (1477-19-6)

Conditions	Yield
With aluminum (III) chloride In chloroform at 80℃; for 0.5h; Temperature; Reagent/catalyst; Large scale;	95%
Stage #1: (2-ethylbenzofuran-3-yl)(4-methoxyphenyl)methanone With sodium thioethylate In N,N-dimethyl-formamide at 125 - 130℃; for 1h; Stage #2: With water; ammonium chloride In N,N-dimethyl-formamide	90%
With sodium thioethylate In N,N-dimethyl-formamide at 125 - 130℃; for 1h;	90%

benzbromarone (3562-84-3) → benzarone (1477-19-6)

Conditions	Yield
Stage #1: benzbromarone With dichloro[1,1′-bis[bis(1,1-dimethylethyl)phosphino]ferrocene-P,P′]palladium; triethylamine In water at 20℃; for 0.0333333h; Stage #2: With 1,1,3,3-Tetramethyldisiloxane for 11.9667h;	86%

2-ethylbenzofuran (3131-63-3) + 4-methoxy-benzoyl chloride (100-07-2) → benzarone (1477-19-6)

Conditions	Yield
With lewis acid In chloroform at 10 - 30℃; for 4h; Solvent; Temperature;	68.2%

2-ethylbenzofuran (3131-63-3) + 4-(benzyloxy)benzoic acid chloride (1486-50-6) → 3-benzyl-2-ethylbenzofuran (101596-43-4) + benzarone (1477-19-6)

Conditions	Yield
With tin(IV) chloride; benzene

(4-acetoxy-phenyl)-(2-ethyl-benzofuran-3-yl)-ketone (90908-77-3) → benzarone (1477-19-6)

Conditions	Yield
With sodium hydroxide

2-ethylbenzofuran (3131-63-3) → benzarone (1477-19-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: tin (IV)-chloride; benzene 2: aq.-ethanolic NaOH-solution View Scheme
Multi-step reaction with 2 steps 1: tin (IV)-chloride; carbon disulfide 2: pyridine hydrochloride View Scheme
Multi-step reaction with 2 steps 1: tin(IV) chloride / carbon disulfide / 5 - 20 °C / Inert atmosphere; Cooling with ice 2: sodium thioethylate / N,N-dimethyl-formamide / 1 h / 125 - 130 °C View Scheme

4-acetoxybenzoyl chloride (27914-73-4) → benzarone (1477-19-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: tin (IV)-chloride; benzene 2: aq.-ethanolic NaOH-solution View Scheme

4-methoxy-benzoyl chloride (100-07-2) → benzarone (1477-19-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: tin (IV)-chloride; carbon disulfide 2: pyridine hydrochloride View Scheme
Multi-step reaction with 2 steps 1: tin(IV) chloride / carbon disulfide / 5 - 20 °C / Inert atmosphere; Cooling with ice 2: sodium thioethylate / N,N-dimethyl-formamide / 1 h / 125 - 130 °C View Scheme
Multi-step reaction with 2 steps 1: polystyrene-supported aluminum trichloride / dichloromethane / 1 h / 5 - 20 °C / Large scale 2: aluminum (III) chloride / chloroform / 0.5 h / 80 °C / Large scale View Scheme

1-(benzo[b]furan-2-yl)ethanone (1646-26-0) → benzarone (1477-19-6)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: hydrazine / water; diethylene glycol / 120 - 190 °C 1.2: 6 h / 120 - 130 °C 2.1: tin(IV) chloride / carbon disulfide / 5 - 20 °C / Inert atmosphere; Cooling with ice 3.1: sodium thioethylate / N,N-dimethyl-formamide / 1 h / 125 - 130 °C View Scheme
Multi-step reaction with 3 steps 1.1: hydrazine / water; diethylene glycol / 120 - 190 °C 1.2: 6 h / 120 - 130 °C 2.1: carbon disulfide / 0.5 h / Inert atmosphere; Cooling with ice 2.2: 6 h / 20 °C / Cooling with ice 3.1: sodium thioethylate / N,N-dimethyl-formamide / 1 h / 125 - 130 °C View Scheme

salicylaldehyde (90-02-8) → benzarone (1477-19-6)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: potassium carbonate / acetone / 6 h / Reflux 2.1: hydrazine / water; diethylene glycol / 120 - 190 °C 2.2: 6 h / 120 - 130 °C 3.1: tin(IV) chloride / carbon disulfide / 5 - 20 °C / Inert atmosphere; Cooling with ice 4.1: sodium thioethylate / N,N-dimethyl-formamide / 1 h / 125 - 130 °C View Scheme
Multi-step reaction with 3 steps 1.1: potassium hydroxide / ethanol / 2 h / Reflux 1.2: 2 h / Reflux 1.3: 0.17 h / Reflux 2.1: tin(IV) chloride / chloroform / 20 °C / Cooling with ice 3.1: ethanethiol; sodium hydride / N,N-dimethyl-formamide / 3 h / 110 °C View Scheme

benzaldehyde (100-52-7) → benzarone (1477-19-6)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: potassium carbonate / acetone / 6 h / Reflux 2.1: hydrazine / water; diethylene glycol / 120 - 190 °C 2.2: 6 h / 120 - 130 °C 3.1: carbon disulfide / 0.5 h / Inert atmosphere; Cooling with ice 3.2: 6 h / 20 °C / Cooling with ice 4.1: sodium thioethylate / N,N-dimethyl-formamide / 1 h / 125 - 130 °C View Scheme

1-(4-methoxyphenyl)-1,3-pentanedione (54103-36-5) → benzarone (1477-19-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: N-Bromosuccinimide; aluminum (III) chloride / nitromethane / 6 h / 80 °C 2: boron tribromide / dichloromethane / 10 h View Scheme

1-(4-methoxyphenyl)ethanone (100-06-1) → benzarone (1477-19-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium hydride / mineral oil; tetrahydrofuran / Reflux 2: N-Bromosuccinimide; aluminum (III) chloride / nitromethane / 6 h / 80 °C 3: boron tribromide / dichloromethane / 10 h View Scheme

benzarone (1477-19-6) → benzbromarone (3562-84-3)

Conditions	Yield
With bromine; acetic acid In water at 20℃; for 2h;	98%
With N-Bromosuccinimide In dichloromethane; N,N-dimethyl-formamide at -10 - 20℃; for 17h;	82%
With bromine; acetic acid for 0.25h; Product distribution / selectivity;	35%

benzarone (1477-19-6) + 2-bromoethanol (540-51-2) → 2-ethyl-3-[4-(2-hydroxy-ethoxy)-benzoyl]-benzofuran

Conditions	Yield
With sodium hydroxide; potassium carbonate In N,N-dimethyl-formamide; Petroleum ether	97.4%

benzarone (1477-19-6) → Natriumbenzaronsulfat (82699-09-0)

Conditions	Yield
With aminosulfonic acid; sodium carbonate 1.) pyridine, 90 deg C, 2 h, 2.) H2O;	74%

benzarone (1477-19-6) → benziodarone (68-90-6)

Conditions	Yield
With iodine; silver nitrate In methanol at 20℃; for 3h;	46.2%

benzarone (1477-19-6) → (3,5-dibromo-4-methoxy-phenyl)-(2-ethyl-benzofuran-3-yl)-methanone (51073-13-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: aqueous acetic acid; bromine 2: ethanolic KOH-solution View Scheme
Multi-step reaction with 2 steps 1.1: bromine; acetic acid / 0.25 h 2.1: potassium carbonate / tetrahydrofuran / 0.17 h 2.2: 16 h / 40 °C View Scheme

benzarone (1477-19-6) → benziodarone (68-90-6) + benzbromarone (3562-84-3)

aluminum chloride anhydride powder + benzarone (1477-19-6) + chloroacetonitrile (107-14-2) → 5-[4-(2-ethyl-3-benzofuroyl)phenoxymethyl]tetrazole (91627-69-9)

Conditions	Yield
With hydrogenchloride; NaH In tetrahydrofuran; (2S)-N-methyl-1-phenylpropan-2-amine hydrate; N,N-dimethyl-formamide

benzarone (1477-19-6) + epichlorohydrin (106-89-8) → 2-ethyl-3-[4'-(2-hydroxy-3-isopropylamino)propoxybenzoyl]benzofuran + 2-ethyl-3-[4'-(2,3-epoxy)propoxybenzoyl]benzofuran (61085-19-6)

benzarone (1477-19-6) → 5-(2-ethylbenzofuran-3-carbonyl)-2-hydroxy-3-iodobenzonitrile + 5-(2-ethylbenzofuran-3-carbonyl)-2-hydroxyisophthalonitrile

Conditions	Yield
Multi-step reaction with 2 steps 1: silver nitrate; iodine / methanol / 3 h / 20 °C 2: N,N-dimethyl-formamide / 5 h / 100 °C View Scheme

benzarone (1477-19-6) → 5-(2-ethylbenzofuran-3-carbonyl)-2-hydroxybenzonitrile

Conditions	Yield
Multi-step reaction with 3 steps 1: silver nitrate; iodine / methanol / 3 h / 20 °C 2: N,N-dimethyl-formamide / 5 h / 100 °C 3: 5%-palladium/activated carbon; hydrogen / ethyl acetate / 20 °C / 760.05 Torr View Scheme

benzarone (1477-19-6) → 3-bromo-5-(2-ethylbenzofuran-3-carbonyl)-2-hydroxybenzonitrile

Conditions	Yield
Multi-step reaction with 4 steps 1: silver nitrate; iodine / methanol / 3 h / 20 °C 2: N,N-dimethyl-formamide / 5 h / 100 °C 3: 5%-palladium/activated carbon; hydrogen / ethyl acetate / 20 °C / 760.05 Torr 4: N-Bromosuccinimide / N,N-dimethyl-formamide / 20 °C View Scheme

benzarone (1477-19-6) → acetic acid 4-(2-ethylbenzofuran-3-carbonyl)-2,6-diiodophenyl ester

Conditions	Yield
Multi-step reaction with 2 steps 1: silver nitrate; iodine / methanol / 3 h / 20 °C 2: dmap; pyridine / 2 h / 20 °C View Scheme

benzarone (1477-19-6) → acetic acid 4-(2-ethylbenzofuran-3-carbonyl)-2-iodo-6-(trifluoromethyl)phenyl ester

Conditions	Yield
Multi-step reaction with 3 steps 1: silver nitrate; iodine / methanol / 3 h / 20 °C 2: dmap; pyridine / 2 h / 20 °C 3: copper(l) iodide / N,N-dimethyl-formamide / 1 h / 90 °C / Inert atmosphere View Scheme

benzarone (1477-19-6) → (2-ethylbenzofuran-3-yl)[4-hydroxy-3-iodo-5-(trifluoromethyl)phenyl]methanone

Conditions	Yield
Multi-step reaction with 4 steps 1: silver nitrate; iodine / methanol / 3 h / 20 °C 2: dmap; pyridine / 2 h / 20 °C 3: copper(l) iodide / N,N-dimethyl-formamide / 1 h / 90 °C / Inert atmosphere 4: potassium carbonate / methanol / 2 h / 20 °C View Scheme

benzarone (1477-19-6) → 5-(2-ethylbenzofuran-3-carbonyl)-2-hydroxy-3-(trifluoromethyl)benzonitrile

Conditions	Yield
Multi-step reaction with 5 steps 1: silver nitrate; iodine / methanol / 3 h / 20 °C 2: dmap; pyridine / 2 h / 20 °C 3: copper(l) iodide / N,N-dimethyl-formamide / 1 h / 90 °C / Inert atmosphere 4: potassium carbonate / methanol / 2 h / 20 °C 5: N,N-dimethyl-formamide / 100 °C View Scheme

Upstream product

• 3131-63-3 2-ethylbenzofuran 
• 1486-50-6 4-(benzyloxy)benzoic acid chloride 
• 3343-80-4 (2-ethylbenzofuran-3-yl)(4-methoxyphenyl)methanone 
• 100-07-2 4-methoxy-benzoyl chloride 
• 3562-84-3 benzbromarone 
• 54103-36-5 1-(4-methoxyphenyl)-1,3-pentanedione 
• 100-06-1 1-(4-methoxyphenyl)ethanone 
• 100-52-7 benzaldehyde 
• 90-02-8 salicylaldehyde 
• 1646-26-0 1-(benzo[b]furan-2-yl)ethanone 
• 27914-73-4 4-acetoxybenzoyl chloride 
• 90908-77-3 (4-acetoxy-phenyl)-(2-ethyl-benzofuran-3-yl)-ketone 

Downstream Products

• 61085-19-6 2-ethyl-3-[4'-(2,3-epoxy)propoxybenzoyl]benzofuran 
• 68-90-6 benziodarone 
• 91627-69-9 5-[4-(2-ethyl-3-benzofuroyl)phenoxymethyl]tetrazole 
• 3562-84-3 benzbromarone 
• 51073-13-3 benzbromarone methyl ether 
• 82699-09-0 Natriumbenzaronsulfat 

Relevant academic research and scientific papers

Preparation method of benzbromarone

The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of benzbromarone. According to the method disclosed by the invention, polystyrene-loaded aluminum trichloride is used as a catalyst to carry out Friedel-Crafts acylation reaction, so that the catalytic effect is good, and the catalyst can be recycled, in the demethylation reaction process, aluminum trichloride is adopted to replace common pyridine hydrochloride, so that the reaction temperature can be reduced, and the yield can be increased, in the bromination reaction, sodium sulfide and hydrogen peroxide are adopted to replace bromine, so that the technical problems of strong corrosivity of bromine, great harm to human bodies and environmental pollution are solved, and meanwhile, the yield can be further improved.

Synthesis method of benzbromarone key intermediate

The invention relates to the technical field of biological medicines, in particular to a synthesis method of a benzbromarone key intermediate, which comprises the following steps: carrying out Friedel-Crafts acylation reaction on 2-ethyl benzofuran and p-methoxybenzoyl chloride under the catalysis of aluminum trichloride by taking methylbenzene as a solvent to generate 2-ethyl-3-p-methoxybenzoyl-benzofuran; and carrying out a demethylation reaction on 2-ethyl-3-p-methoxybenzoyl-benzofuran and aluminum trichloride by taking toluene as a solvent to obtain the key intermediate 2-ethyl-3-p-hydroxybenzoyl-benzofuran of benzbromarone. The synthesis method of the benzbromarone key intermediate, provided by the invention, is mild in reaction condition, the obtained product is relatively high in purity and yield, and the synthesis method has a good industrial production prospect.

Lewis Acid-Catalyzed Synthesis of Benzofurans and 4,5,6,7-Tetrahydrobenzofurans from Acrolein Dimer and 1,3-Dicarbonyl Compounds

2,3-Disubstituted benzofurans were synthesized from acrolein dimer and 1,3-dicarbonyl compounds by using N-bromosuccinimide as an oxidizing agent. The method was used to synthesize two commercial drug molecules, benzbromarone and amiodarone. The proposed mechanism of the reaction involves a N-bromosuccinimide (NBS)-assisted autotandem catalysis with Lewis acid catalyst. To proof the proposed mechanism, an intermediate was isolated successfully, which can be converted to 4,5,6,7-tetrahydrobenzofurans.

Preparation method of 2-ethyl-3-(4-hydroxylbenzoyl) benzofuran

The invention discloses a preparation method of 2-ethyl-3-(4-hydroxylbenzoyl) benzofuran. According to the preparation method, at first, 1-(4-methoxyphenyl)-1,3-pentanedione and acrolein dimer are taken as raw materials to carry out reactions in the presence of an acid catalyst and a halogenation reagent to prepare 2-ethyl-3-(4-methoxyphenyl) benzofuran; then 2-ethyl-3-(4-methoxyphenyl) benzofuranis processed in an organic solvent containing an acid catalyst, and after de-methylation reactions, 2-ethyl-3-(4-hydroxylbenzoyl) benzofuran is obtained. The whole process of key preparation technologies and parameters of each reaction step are optimized; and compared with a conventional synthesis method, the provided preparation method has the advantages of good economy, high selectivity, littleenvironmental pollution, and large industrial application value.

Industrial production method of benzarone

The invention relates to an industrial production method of benzarone. The method comprises the following steps: (1) 2-ethylbenzofuran, 4-methoxybenzoyl chloride and an inert solvent are added to a reactor and subjected to a reaction at 15-30 DEG C for 0.5-1 h, Lewis acid is added in batches, a thermal insulated reaction is performed for 3-4 h, then quenching, acidification, water washing, distillation, crystallization and filtering are performed, and a benzarone intermediate is obtained; (2) the benzarone intermediate, Lewis acid and the inert solvent are added to another reactor and subjected to a reaction at 15-30 DEG C for 0.5-1 h, the temperature is increased to 100 DEG C or lower, a thermal insulated reaction is performed for 2-3 h, the same postprocessing is performed, and benzaroneis obtained. Friedel-Crafts acylation is adopted, reaction conditions are relatively mild, high temperature and high energy consumption are avoided, so that the problems of high temperature and low yield in production in the prior art are solved, and the method has good application prospect.

Compound for treatment or prevention of hyperuricemia or gout

The invention discloses a compound for treatment or prevention of hyperuricemia or gout. The compound is the compound shown as formula (I) or formula (II) or pharmaceutical acceptable salts thereof. The compound or its pharmaceutical acceptable salts can be applied to urate excretion promotion so as to treat or prevent hyperuricemia or gout. (formula (1), formula (II)).

Ligand-free, palladium-catalyzed dihydrogen generation from TMDS: Dehalogenation of aryl halides on water

A mild and environmentally attractive dehalogenation of functionalized aryl halides has been developed using nanoparticles formed from PdCl2 in the presence of tetramethyldisiloxane (TMDS) on water. The active catalyst and reaction medium can be recycled. This method can also be applied to cascade reactions in a one-pot sequence.

DEVELOPING POTENT URATE TRANSPORTER INHIBITORS: COMPOUNDS DESIGNED FOR THEIR URICOSURIC ACTION

A compound represented by the general Formula (I): a pharmaceutically acceptable salt or ester thereof, a solvate thereof, a chelate thereof, a non-covalent complex thereof, a pro-drug thereof, a deuterated radio-labeled analog thereof, and mixtures of any of the foregoing, wherein: A - K are individually selected from carbon or nitrogen; X = -O, -NR1,or -S; R1-11 are individually selected from the group consisting of-H, C1-C6 alkyl, C6-C aryl, substituted C6-C14 aryl, C1-C14-alkoxy, halogen, hydroxyl, carboxy, cyano, C1-C6-alkanoyloxy, C1-C6-alkylthio, C1-C6-alkylsulfonyl, trifluoromethyl, hydroxy, C2-C6-alkoxycarbonyl, C2-C6-alkanoylamino, -O-R12, S-R12,-SO2-Ri2, -NHSO2R12 and -NHCO2R12, wherein R12 is phenyl, naphthyl, or phenyl or naphthly substituted with one to three groups selected from C1-C6-alkyl, C6-C10 aryl,C1-C6-alkoxy and halogen, and C4-C20 hydroxyheteroaryl wherein the heteroatoms are selected from the group consisting of sulfur, nitrogen, and oxygen.

Developing potent human uric acid transporter 1 (hURAT1) inhibitors

The kidneys are a vital organ in the human body. They serve several purposes including homeostatic functions such as regulating extracellular fluid volume and maintaining acid-base and electrolyte balance and are essential regarding the excretion of metabolic waste. Furthermore, the kidneys play an important role in uric acid secretion/reabsorption. Abnormalities associated with kidney transporters have been associated with various diseases, such as gout. The current study utilized Xenopus oocytes expressing human uric acid transporter 1 (hURAT1; SLC22A12) as an in vitro method to investigate novel compounds and their ability to inhibit 14C-uric acid uptake via hURAT1. We have prepared and tested a series of 2-ethyl-benzofuran compounds and probed the hURAT1 in vitro inhibitor structure-activity relationship. As compared to dimethoxy analogues, monophenols formed on the C ring showed the best in vitro inhibitory potential. Compounds with submicromolar (i.e., IC 50 1000 nM) inhibitors were prepared by brominating the corresponding phenols to produce compounds with potent uricosuric activity.

Preparation of 2-alkyl-3-(4-hydroxybenzoyl)benzofuran

The invention relates to new molecular complexes of general formula: STR1 in which R represents a straight- or branched-chain alkyl radical having from 1 to 4 carbon atoms and R1 represents one of the radicals: STR2 These molecular complexes are especially useful for the preparation of 2-alkyl-3-(4-hydroxybenzoyl)benzofurans.