141645-16-1

Basic information

• Product Name: (2-Butyl-5-nitrobenzofuran-3-yl)(4-hydroxyphenyl)methanone
• Synonyms: (2-Butyl-5-nitrobenzofuran-3-yl)(4-hydroxyphenyl)methanone;2-Butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran;2-butyl-3-[(4-Methoxyphenyl)carbonyl]-6-nitro-1-benzofuran;22-(n-Butyl)-3-(4-hydroxybenzoyl)-5-nitrobenzofuran;2-N-Butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran;(2-Butyl-5-nitro-1-benzofuran-3-yl)(4-hydroxyphenyl)Methanone;(2-butyl-5-nitro-3-benzofuran-3-yl)(4- hydroxyphenyl) Methanone;Methanone,(2-butyl-5-nitro-3-benzofuranyl)(4-hydroxyphenyl)-
• CAS NO: 141645-16-1
• Molecular Formula: C₁₉H₁₇NO₅
• Molecular Weight: 339.345
• EINECS: 1806241-263-5
• Product Categories: API;Dronedarone intermediate
• Mol File: 141645-16-1.mol
• Article Data: 20

Chemical Properties

• Boiling Point: 559.472 °C at 760 mmHg
• Flash Point: 292.158 °C
• Appearance: /
• Density: 1.302 g/cm³
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.636
• Storage Temp.: Sealed in dry,Room Temperature
• Solubility: Chloroform (Slightly), Methanol (Slightly)
• PKA: 7.40±0.15(Predicted)
• Water Solubility: 220μg/L at 20℃
• CAS DataBase Reference: (2-Butyl-5-nitrobenzofuran-3-yl)(4-hydroxyphenyl)methanone(CAS DataBase Reference)
• NIST Chemistry Reference: (2-Butyl-5-nitrobenzofuran-3-yl)(4-hydroxyphenyl)methanone(141645-16-1)
• EPA Substance Registry System: (2-Butyl-5-nitrobenzofuran-3-yl)(4-hydroxyphenyl)methanone(141645-16-1)

Safety Data

• Hazardous Substances Data: 141645-16-1(Hazardous Substances Data)

Usage

Uses

(2-Butyl-5-nitro-3-benzofuranyl)(4-hydroxyphenyl)methanone (Dronedarone USP Related Compound D) is a related compound of Dronedarone (D679445), a drug used for the treatment of atrial fibrillation and atrial flutter in patients who have suffered cardiac arrhythmias.

Flammability and Explosibility

Nonflammable

InChI:InChI=1/C19H17NO5/c1-2-3-4-17-18(19(22)12-5-8-14(21)9-6-12)15-11-13(20(23)24)7-10-16(15)25-17/h5-11,21H,2-4H2,1H3

Synthetic route

(2-butyl-5-nitrobenzofuran-3-yl)(4-methoxyphenyl)methanone (141627-42-1) → 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (141645-16-1)

Conditions	Yield
Stage #1: (2-butyl-5-nitrobenzofuran-3-yl)(4-methoxyphenyl)methanone With aluminum (III) chloride In chlorobenzene at 85℃; for 4h; Stage #2: With water In chlorobenzene at 35 - 60℃;	92%
Stage #1: (2-butyl-5-nitrobenzofuran-3-yl)(4-methoxyphenyl)methanone With aluminum (III) chloride In chlorobenzene at 75℃; for 2h; Stage #2: With water In chlorobenzene at 5 - 65℃; for 0.5h;	92%
In aluminium chloride; ice-water; 1,1-dichloroethane	90.1%

4-hydroxybenzoyl chloride (28141-24-4) + 2-(n-butyl)-5-nitrobenzofuran (133238-87-6) → 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (141645-16-1)

Conditions	Yield
With tin(IV) chloride In dichloromethane at 0 - 20℃; for 2.5h; Friedel-Crafts Acylation;	88%

1-(4-hydroxy-phenyl)-heptane-1,3-dione 3-[O-(4-nitro-phenyl)-oxime] (1253293-38-7) → 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (141645-16-1)

Conditions	Yield
With formic acid; trifluoroacetic acid at 45℃; for 5h; Product distribution / selectivity; Inert atmosphere;	87%
With formic acid; trifluoroacetic acid at 45℃; for 5h; Product distribution / selectivity; Inert atmosphere;	87%
With formic acid; trifluoroacetic acid at 45℃; for 5h; Product distribution / selectivity; Inert atmosphere;	87%
With acetic acid at 115℃; for 3h; Product distribution / selectivity; Industry scale;	78%

4-hydroxy-benzoic acid (99-96-7) + 2-(n-butyl)-5-nitrobenzofuran (133238-87-6) → 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (141645-16-1)

Conditions	Yield
Stage #1: 4-hydroxy-benzoic acid; 2-(n-butyl)-5-nitrobenzofuran With Methyltrichlorosilane; iron(III) chloride In chlorobenzene at 20 - 40℃; for 3.45 - 5h; Stage #2: With ethanol In chlorobenzene at 0 - 30℃; for 0.45 - 0.5h; Product distribution / selectivity;	81.6%
Stage #1: 4-hydroxy-benzoic acid; 2-(n-butyl)-5-nitrobenzofuran With dimethylsilicon dichloride; iron(II) chloride In chlorobenzene at 23 - 50℃; for 5h; Stage #2: With ethanol In chlorobenzene at 20℃; Product distribution / selectivity;	76%
Stage #1: 4-hydroxy-benzoic acid; 2-(n-butyl)-5-nitrobenzofuran With tetrachlorosilane; iron(III) chloride In chlorobenzene at 23 - 50℃; for 5h; Stage #2: With ethanol In chlorobenzene at 20℃; Product distribution / selectivity;	75%
Stage #1: 4-hydroxy-benzoic acid; 2-(n-butyl)-5-nitrobenzofuran With Methyltrichlorosilane; bismuth(lll) trifluoromethanesulfonate In chlorobenzene at 23 - 60℃; for 15h; Stage #2: With ethanol In chlorobenzene at 20℃; Product distribution / selectivity;	10%
With trichlorophosphate; zinc(II) chloride at 23 - 60℃; for 15h; Product distribution / selectivity;	1%

1-(4-hydroxy-phenyl)-heptane-1,3-dione (1137261-89-2) + p-nitrophenoxyamine (33543-55-4) → 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (141645-16-1)

Conditions	Yield
With acetic acid at 70 - 100℃; for 25h; Product distribution / selectivity;	80%
In acetic acid at 70 - 100℃; for 25h; Product distribution / selectivity;	80%
With acetic acid at 70 - 100℃; for 17h; Product distribution / selectivity;	80%
With hydrogen bromide; acetic acid at 20℃; for 1h;

1-(4-hydroxyphenyl)heptane-1,3-dione-3-[O-(4-nitrophenyl)oxime] (1137261-95-0) → 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (141645-16-1)

Conditions	Yield
With acetic acid at 115℃; for 3h; Product distribution / selectivity;	78%

4-acetoxyiodobenzene (33527-94-5) + carbon monoxide (201230-82-2) + 2-(hex-1-yn-1-yl)-4-nitrophenyl acetate (1636167-45-7) → 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (141645-16-1)

Conditions	Yield
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate at 55℃; for 24h; Sealed tube;	76%

2-(2-pentanoyloxy-5-nitrophenyl)-1-(4-methoxyphenyl)-ethanone (1256921-45-5) → 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (141645-16-1)

Conditions	Yield
Stage #1: 2-(2-pentanoyloxy-5-nitrophenyl)-1-(4-methoxyphenyl)-ethanone With tributyl-amine In xylene for 8h; Molecular sieve; Reflux; Stage #2: With hydrogenchloride; tributyl-amine at 200℃; for 4h; Stage #3: With water In tert-butyl methyl ether at 20℃;	65%

1-(4-benzyloxyphenyl)-heptane-1,3-dione (1137261-88-1) + p-nitrophenoxyamine (33543-55-4) → 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (141645-16-1)

Conditions	Yield
With hydrogen bromide; acetic acid at 20℃; for 6h; Product distribution / selectivity;	59%

(2-butyl-5-nitrobenzofuran-3-yl)(4-methoxyphenyl)methanone (141627-42-1) + 2-n-butyl-5-nitro-3-(2'-methoxy)-acetophenonebenzofuran (856758-04-8) → 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (141645-16-1) + 2-(n-butyl)-3-(2-hydroxybenzoyl)-5-nitrobenzofuran (856758-05-9)

Conditions	Yield
Stage #1: (2-butyl-5-nitrobenzofuran-3-yl)(4-methoxyphenyl)methanone; 2-n-butyl-5-nitro-3-(2'-methoxy)-acetophenonebenzofuran; aluminum (III) chloride In chlorobenzene at 60℃; for 7h; Stage #2: With water In chlorobenzene at 60℃;

1-[4-(1-ethoxy-ethoxy)-phenyl]-ethanone → 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (141645-16-1)

Conditions	Yield
Multi-step reaction with 4 steps 1: potassium tert-butylate / Isobutyronitrile / 2 h / 0 - 95 °C 2: water / hydrogenchloride / Isobutyronitrile / 0.25 h / 0 °C 3: dichloromethane / 16 h / 20 °C 4: trifluoroacetic acid; formic acid / 5 h / 45 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1.1: sodium hydride / 1,4-dioxane; mineral oil / 3 h / 70 °C / Inert atmosphere 1.2: 0.5 h / 60 °C 2.1: dichloromethane / 16 h / 20 °C 3.1: trifluoroacetic acid; formic acid / 5 h / 45 °C / Inert atmosphere View Scheme

4-Hydroxyacetophenone (99-93-4) → 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (141645-16-1)

Conditions	Yield
Multi-step reaction with 5 steps 1: sulfuric acid / tetrahydrofuran / 1.75 h / 0 °C 2: potassium tert-butylate / Isobutyronitrile / 2 h / 0 - 95 °C 3: water / hydrogenchloride / Isobutyronitrile / 0.25 h / 0 °C 4: dichloromethane / 16 h / 20 °C 5: trifluoroacetic acid; formic acid / 5 h / 45 °C / Inert atmosphere View Scheme
Multi-step reaction with 4 steps 1.1: sulfuric acid / tetrahydrofuran / 1.75 h / 0 °C 2.1: sodium hydride / 1,4-dioxane; mineral oil / 3 h / 70 °C / Inert atmosphere 2.2: 0.5 h / 60 °C 3.1: dichloromethane / 16 h / 20 °C 4.1: trifluoroacetic acid; formic acid / 5 h / 45 °C / Inert atmosphere View Scheme

C17H24O4 → 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (141645-16-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: water / hydrogenchloride / Isobutyronitrile / 0.25 h / 0 °C 2: dichloromethane / 16 h / 20 °C 3: trifluoroacetic acid; formic acid / 5 h / 45 °C / Inert atmosphere View Scheme

1-(4-hydroxy-phenyl)-heptane-1,3-dione (1137261-89-2) → 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (141645-16-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: dichloromethane / 16 h / 20 °C 2: trifluoroacetic acid; formic acid / 5 h / 45 °C / Inert atmosphere View Scheme

4-methoxy-benzoyl chloride (100-07-2) → 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (141645-16-1)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: aluminum (III) chloride / dichloromethane / 4 h / 25 °C 2.1: aluminum (III) chloride / chlorobenzene / 4 h / 85 °C 2.2: 35 - 60 °C View Scheme
Multi-step reaction with 2 steps 1.1: aluminum (III) chloride / chlorobenzene / 2 h / 25 °C / Reflux 2.1: aluminum (III) chloride / chlorobenzene / 2 h / 75 °C 2.2: 0.5 h / 5 - 65 °C View Scheme
Multi-step reaction with 2 steps 1: aluminum (III) chloride / dichloromethane 2: aluminum (III) chloride / chlorobenzene View Scheme
Multi-step reaction with 2 steps 1.1: aluminum (III) chloride / dichloromethane / 22 h / 25 - 30 °C / Large scale 2.1: aluminum (III) chloride / 40 h / Reflux; Large scale 2.2: 15 °C / Large scale View Scheme

2-(n-butyl)-5-nitrobenzofuran (133238-87-6) → 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (141645-16-1)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: aluminum (III) chloride / dichloromethane / 4 h / 25 °C 2.1: aluminum (III) chloride / chlorobenzene / 4 h / 85 °C 2.2: 35 - 60 °C View Scheme
Multi-step reaction with 2 steps 1.1: aluminum (III) chloride / chlorobenzene / 2 h / 25 °C / Reflux 2.1: aluminum (III) chloride / chlorobenzene / 2 h / 75 °C 2.2: 0.5 h / 5 - 65 °C View Scheme
Multi-step reaction with 2 steps 1: aluminum (III) chloride / dichloromethane 2: aluminum (III) chloride / chlorobenzene View Scheme
Multi-step reaction with 2 steps 1.1: aluminum (III) chloride / dichloromethane / 22 h / 25 - 30 °C / Large scale 2.1: aluminum (III) chloride / 40 h / Reflux; Large scale 2.2: 15 °C / Large scale View Scheme
Multi-step reaction with 2 steps 1: aluminum (III) chloride / dichloromethane / 24 h / 20 °C / Inert atmosphere 2: aluminum (III) chloride / chlorobenzene / 2 h / 80 °C / Inert atmosphere View Scheme

4-nitro-phenol (100-02-7) → 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (141645-16-1)

Conditions	Yield
Multi-step reaction with 10 steps 1: triethylamine / dichloromethane / 1 h / 0 - 5 °C / Inert atmosphere 2: aluminum (III) chloride / nitrobenzene / 5 h / 140 °C 3: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetone / 2 h / 25 - 30 °C 4: bromine / dichloromethane / 1 h / 25 - 30 °C 5: aluminum (III) chloride / dichloromethane / 15 - 20 °C 6: triethylamine / dichloromethane / 2 h / 25 - 30 °C 7: sodium tetrahydroborate / methanol / 0.5 h / 0 - 5 °C 8: hydrogenchloride / methanol; water / 5 h / 90 - 95 °C 9: aluminum (III) chloride / dichloromethane / 5.08 h / 0 - 30 °C 10: aluminum (III) chloride / chlorobenzene / 5.17 h / 20 - 80 °C View Scheme
Multi-step reaction with 5 steps 1: hydrogenchloride / water / 38 h / 40 - 55 °C / Large scale 2: 1,2-dichloro-ethane / 65 - 75 °C / Large scale 3: sodium hydrogencarbonate / 1,2-dichloro-ethane / 55 - 60 °C / Large scale 4: aluminum (III) chloride / 1,2-dichloro-ethane / 35 - 40 °C / Large scale 5: aluminum (III) chloride / chlorobenzene / 65 - 70 °C / Large scale View Scheme

2-butyl-5-nitrobenzofuran-3(2H)-one → 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (141645-16-1)

Conditions	Yield
Multi-step reaction with 4 steps 1: sodium tetrahydroborate / methanol / 0.5 h / 0 - 5 °C 2: hydrogenchloride / methanol; water / 5 h / 90 - 95 °C 3: aluminum (III) chloride / dichloromethane / 5.08 h / 0 - 30 °C 4: aluminum (III) chloride / chlorobenzene / 5.17 h / 20 - 80 °C View Scheme

2-butyl-5-nitro-2,3-dihydrobenzofuran-3-ol → 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (141645-16-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: hydrogenchloride / methanol; water / 5 h / 90 - 95 °C 2: aluminum (III) chloride / dichloromethane / 5.08 h / 0 - 30 °C 3: aluminum (III) chloride / chlorobenzene / 5.17 h / 20 - 80 °C View Scheme

p-nitrophenyl hexanoate (956-75-2) → 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (141645-16-1)

Conditions

Yield

Multi-step reaction with 9 steps 1: aluminum (III) chloride / nitrobenzene / 5 h / 140 °C 2: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetone / 2 h / 25 - 30 °C 3: bromine / dichloromethane / 1 h / 25 - 30 °C 4: aluminum (III) chloride / dichloromethane / 15 - 20 °C 5: triethylamine / dichloromethane / 2 h / 25 - 30 °C 6: sodium tetrahydroborate / methanol / 0.5 h / 0 - 5 °C 7: hydrogenchloride / methanol; water / 5 h / 90 - 95 °C 8: aluminum (III) chloride / dichloromethane / 5.08 h / 0 - 30 °C 9: aluminum (III) chloride / chlorobenzene / 5.17 h / 20 - 80 °C View Scheme

1-(2-hydroxy-5-nitrophenyl)hexan-1-one (1393093-65-6) → 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (141645-16-1)

Conditions

Yield

Multi-step reaction with 8 steps 1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetone / 2 h / 25 - 30 °C 2: bromine / dichloromethane / 1 h / 25 - 30 °C 3: aluminum (III) chloride / dichloromethane / 15 - 20 °C 4: triethylamine / dichloromethane / 2 h / 25 - 30 °C 5: sodium tetrahydroborate / methanol / 0.5 h / 0 - 5 °C 6: hydrogenchloride / methanol; water / 5 h / 90 - 95 °C 7: aluminum (III) chloride / dichloromethane / 5.08 h / 0 - 30 °C 8: aluminum (III) chloride / chlorobenzene / 5.17 h / 20 - 80 °C View Scheme

1-(2-methoxy-5-nitrophenyl)hexan-1-one (1393093-66-7) → 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (141645-16-1)

Conditions

Yield

Multi-step reaction with 7 steps 1: bromine / dichloromethane / 1 h / 25 - 30 °C 2: aluminum (III) chloride / dichloromethane / 15 - 20 °C 3: triethylamine / dichloromethane / 2 h / 25 - 30 °C 4: sodium tetrahydroborate / methanol / 0.5 h / 0 - 5 °C 5: hydrogenchloride / methanol; water / 5 h / 90 - 95 °C 6: aluminum (III) chloride / dichloromethane / 5.08 h / 0 - 30 °C 7: aluminum (III) chloride / chlorobenzene / 5.17 h / 20 - 80 °C View Scheme

2-bromo-1-(2-methoxy-5-nitrophenyl)hexan-1-one (1393093-67-8) → 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (141645-16-1)

Conditions

Yield

Multi-step reaction with 6 steps 1: aluminum (III) chloride / dichloromethane / 15 - 20 °C 2: triethylamine / dichloromethane / 2 h / 25 - 30 °C 3: sodium tetrahydroborate / methanol / 0.5 h / 0 - 5 °C 4: hydrogenchloride / methanol; water / 5 h / 90 - 95 °C 5: aluminum (III) chloride / dichloromethane / 5.08 h / 0 - 30 °C 6: aluminum (III) chloride / chlorobenzene / 5.17 h / 20 - 80 °C View Scheme

2-bromo-1-(2-hydroxy-5-nitrophenyl)hexan-1-one (1393093-68-9) → 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (141645-16-1)

Conditions	Yield
Multi-step reaction with 5 steps 1: triethylamine / dichloromethane / 2 h / 25 - 30 °C 2: sodium tetrahydroborate / methanol / 0.5 h / 0 - 5 °C 3: hydrogenchloride / methanol; water / 5 h / 90 - 95 °C 4: aluminum (III) chloride / dichloromethane / 5.08 h / 0 - 30 °C 5: aluminum (III) chloride / chlorobenzene / 5.17 h / 20 - 80 °C View Scheme

Hexanoyl chloride (142-61-0) → 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (141645-16-1)

Conditions

Yield

Multi-step reaction with 10 steps 1: triethylamine / dichloromethane / 1 h / 0 - 5 °C / Inert atmosphere 2: aluminum (III) chloride / nitrobenzene / 5 h / 140 °C 3: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetone / 2 h / 25 - 30 °C 4: bromine / dichloromethane / 1 h / 25 - 30 °C 5: aluminum (III) chloride / dichloromethane / 15 - 20 °C 6: triethylamine / dichloromethane / 2 h / 25 - 30 °C 7: sodium tetrahydroborate / methanol / 0.5 h / 0 - 5 °C 8: hydrogenchloride / methanol; water / 5 h / 90 - 95 °C 9: aluminum (III) chloride / dichloromethane / 5.08 h / 0 - 30 °C 10: aluminum (III) chloride / chlorobenzene / 5.17 h / 20 - 80 °C View Scheme

2-iodo-4-nitrophenyl acetate (504421-91-4) → 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (141645-16-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine / tetrahydrofuran / 5.5 h / 20 °C / Inert atmosphere 2: tetrakis(triphenylphosphine) palladium(0); potassium carbonate / 24 h / 55 °C / Sealed tube View Scheme

2-iodo-4-nitrophenol (89487-91-2) → 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (141645-16-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: triethylamine / tetrahydrofuran; dichloromethane / 4 h / 0 - 20 °C 2: copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine / tetrahydrofuran / 5.5 h / 20 °C / Inert atmosphere 3: tetrakis(triphenylphosphine) palladium(0); potassium carbonate / 24 h / 55 °C / Sealed tube View Scheme

4-Iodophenol (540-38-5) → 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (141645-16-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: dmap; triethylamine / dichloromethane / 1.5 h / 20 °C 2: tetrakis(triphenylphosphine) palladium(0); potassium carbonate / 24 h / 55 °C / Sealed tube View Scheme

Koshlands reagent I (772-33-8) → 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (141645-16-1)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: triphenylphosphine / dichloromethane / 1 h / Reflux 1.2: 3 h / Reflux 2.1: tin(IV) chloride / dichloromethane / 2.5 h / 0 - 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: triphenylphosphine / dichloromethane / 1 h / 40 °C / Inert atmosphere 1.2: 3 h / 110 °C / Inert atmosphere 2.1: aluminum (III) chloride / dichloromethane / 24 h / 20 °C / Inert atmosphere 3.1: aluminum (III) chloride / chlorobenzene / 2 h / 80 °C / Inert atmosphere View Scheme

n-valeryl chloride (638-29-9) → 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (141645-16-1)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: triphenylphosphine / dichloromethane / 1 h / Reflux 1.2: 3 h / Reflux 2.1: tin(IV) chloride / dichloromethane / 2.5 h / 0 - 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: triphenylphosphine / dichloromethane / 1 h / 40 °C / Inert atmosphere 1.2: 3 h / 110 °C / Inert atmosphere 2.1: aluminum (III) chloride / dichloromethane / 24 h / 20 °C / Inert atmosphere 3.1: aluminum (III) chloride / chlorobenzene / 2 h / 80 °C / Inert atmosphere View Scheme

2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (141645-16-1) + methanesulfonyl chloride (124-63-0) → 4-[(2-butyl-5-nitro-1-benzofuran-3-yl)carbonyl]phenyl-methanesulfonate (1448297-26-4)

Conditions	Yield
With triethylamine In dichloromethane at 20℃; for 12.5h; Reflux;	100%

2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (141645-16-1) + 1,2-Epoxy-3-bromopropane (3132-64-7) → (2-butyl-5-nitro-1-benzofuran-3-yl)[4-(oxiran-2-yl-methoxy)phenyl]methanone

Conditions	Yield
With sodium hydroxide In isopropyl alcohol for 1.5h; Reflux;	100%
Stage #1: 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran With sodium hydroxide In isopropyl alcohol at 20℃; for 0.166667h; Stage #2: 1,2-Epoxy-3-bromopropane In isopropyl alcohol for 1.5h; Reflux;

2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (141645-16-1) + dibutyl-(3-chloro-propyl)-amine (36421-15-5) → (2-butyl-5-nitrobenzofuran-3-yl)(4-(3-(dibutylamino)propoxy)phenyl)methanone (141645-23-0)

Conditions	Yield
Stage #1: 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran With potassium carbonate In toluene at 25 - 110℃; for 0.5h; Large scale; Stage #2: dibutyl-(3-chloro-propyl)-amine In toluene Temperature; Solvent; Reflux; Large scale;	99.5%
Stage #1: 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran With potassium carbonate In acetonitrile for 0.5h; Stage #2: dibutyl-(3-chloro-propyl)-amine In acetonitrile Reflux;	91%
Stage #1: 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran With potassium carbonate In acetonitrile for 0.5h; Reflux; Stage #2: dibutyl-(3-chloro-propyl)-amine In acetonitrile Reflux;	91%

2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (141645-16-1) + 1,3-chlorobromopropane (109-70-6) → (4-(3-chloropropoxy)phenyl)(2-butyl-5-nitrobenzofuran-3-yl)methanone (1310430-03-5)

Conditions	Yield
With potassium carbonate In butanone at 81 - 82℃; for 4h;	99.1%
With potassium carbonate In N,N-dimethyl-formamide at 25℃; for 20h;	88.8%

2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (141645-16-1) + 3-chloro-1,1-diethoxy-propane (35573-93-4) → (2-butyl-5-nitro-1-benzofuran-3-yl)[4-(3,3-diethoxypropoxy)phenyl]methanone (1420181-01-6)

Conditions	Yield
With potassium carbonate; sodium iodide for 6h; Reflux;	99%

2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (141645-16-1) + acrylonitrile (107-13-1) → (5-nitro-2-butylbenzofuran-3-yl)-[4-(2-cyanoethoxy)phenyl]methanone (1401355-76-7)

Conditions	Yield
With N-benzyl-trimethylammonium hydroxide at 80 - 85℃; for 48h;	94.2%
With N-benzyl-trimethylammonium hydroxide at 80 - 85℃; for 48h;	94.2%
With N-benzyl-trimethylammonium hydroxide at 80 - 85℃; for 48h;	94.2%

2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (141645-16-1) + 1-chloro 3-di-n-butylamino propane (90050-13-8) → 2-n-butyl 3-[4-(3-di-n-butylamino-propoxy)benzoyl] 5-nitro benzofuran (141671-42-3)

Conditions	Yield
With sodium hydroxide; potassium carbonate In diethyl ether; butanone	88.76%

2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (141645-16-1) + trifluoromethylsulfonic anhydride (358-23-6) → 4-[(2-butyl-5-nitro-1-benzofuran-3-yl)carbonyl]phenyltrifluoromethanesulfonate (1448297-17-3)

Conditions	Yield
With pyridine In dichloromethane at 0 - 20℃; for 3.16667h; Inert atmosphere;	87%
With triethylamine In dichloromethane at 20℃; for 5.5h; Reflux;

2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (141645-16-1) → (5-amino-2-butyl-1-benzofuran-3-yl)(4-hydroxyphenyl)methanone (1278585-68-4)

Conditions	Yield
With palladium 10% on activated carbon; hydrogen In ethanol at 50℃; under 3750.38 Torr; for 6h;	78.3%

2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (141645-16-1) + 1-chloro-3-hydroxypropane (627-30-5) → 3-{ 4-[(2-butyl-5-nitro-1-benzofuran-3-yl) carbonyl]phenoxy}propan-1-ol (1310430-11-5)

Conditions	Yield
Stage #1: 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran With tetrabutylammomium bromide; potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 50℃; for 0.5h; Stage #2: 1-chloro-3-hydroxypropane In N,N-dimethyl-formamide at 80 - 85℃;	69%
With tetrabutylammomium bromide; potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 80 - 85℃;	69%

2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (141645-16-1) + 1,3-dibromo-propane (109-64-8) → [4-(3-bromo-propoxy)-phenyl]-(2-butyl-5-nitro-benzofuran-3-yl)-methanone (141645-38-7)

Conditions	Yield
With sodium hydroxide In neat (no solvent) for 5h; Reagent/catalyst; Solvent; Reflux;	64%

2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (141645-16-1) + [2H6]-1,3-dibromopropane (120404-22-0) → [4-(3-bromo-[2H6]-propoxy)-phenyl]-(2-butyl-5-nitrobenzofuran-3-yl)-methanone (1542232-34-7)

Conditions	Yield
With sodium hydroxide In water for 8h; Solvent; Reagent/catalyst; Reflux;	62%

2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (141645-16-1) + ethylene dibromide (106-93-4) → 3-[4-(2-bromoethoxy)benzoyl] 2-n-butyl 5-nitro benzofuran (141645-36-5)

Conditions	Yield
With potassium carbonate In butanone	56%

2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (141645-16-1) + β-Propiolactone (57-57-8) → 3-[4-(2-butyl-5-nitro-benzofuran-3-carbonyl)phenoxy]-propionic acid (1542232-29-0)

Conditions	Yield
With potassium tert-butylate In tetrahydrofuran at 20℃; Inert atmosphere; Reflux;	37%

2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (141645-16-1) → 2-n-butyl-3-(3,5-dibromo-4-hydroxybenzoyl)5-nitrobenzofuran

Conditions	Yield
With bromine

2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (141645-16-1) → dronedarone (141626-36-0)

Conditions	Yield
Multi-step reaction with 4 steps 1: potassium carbonate / butanone / 4 h / 81 - 82 °C 2: hydrogen / palladium 10% on activated carbon / ethanol / 2 h / 50 °C / 3750.38 Torr 3: pyridine / dichloromethane / 15 °C 4: sodium iodide / butanone / 16 h View Scheme
Multi-step reaction with 3 steps 1.1: potassium carbonate / butanone / 0.5 h / 20 °C 1.2: 12 h / 78 - 82 °C 2.1: hydrogen / palladium 10% on activated carbon / ethyl acetate / 25 - 35 °C 3.1: triethylamine / dichloromethane / 0.5 h / 20 °C 3.2: 1.5 h / 20 °C View Scheme
Multi-step reaction with 4 steps 1.1: potassium carbonate / acetonitrile / 0.5 h 1.2: Reflux 2.1: hydrogen / Raney nickel / methanol / 45 - 50 °C / 3677.86 Torr 3.1: tetramethlyammonium chloride / toluene / Reflux 4.1: sodium hydroxide / 1 h / 0 - 5 °C View Scheme

2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (141645-16-1) → dronedarone hydrochloride

Conditions	Yield
Multi-step reaction with 5 steps 1: potassium carbonate / butanone / 4 h / 81 - 82 °C 2: hydrogen / palladium 10% on activated carbon / ethanol / 2 h / 50 °C / 3750.38 Torr 3: pyridine / dichloromethane / 15 °C 4: sodium iodide / butanone / 16 h 5: hydrogenchloride / isopropyl alcohol; water / 5 h / 0 °C View Scheme
Multi-step reaction with 4 steps 1.1: potassium carbonate; potassium iodide; tetrabutylammomium bromide / N,N-dimethyl-formamide / 0.5 h / 50 °C 1.2: 80 - 85 °C 2.1: hydrogen / palladium 10% on activated carbon / water; methanol / 40 °C / 3000.3 Torr / Autoclave 3.1: pyridine / dichloromethane / 24 h / 10 - 20 °C 4.1: acetonitrile / Reflux 4.2: 2 h / 40 °C View Scheme
Multi-step reaction with 4 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 20 h / 25 °C 2.1: palladium 10% on activated carbon; ammonium formate / isopropyl alcohol / 0.5 h / 50 °C 3.1: sodium hydrogencarbonate / dichloromethane / 6 h / 35 °C 4.1: N,N-dimethyl-formamide / 4 h / 125 °C 4.2: 2 h / 25 °C View Scheme

2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (141645-16-1) → (4-(3-chloropropoxy)phenyl)(5-amino-2-butylbenzofuran-3-yl)methanone (1309476-89-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium carbonate / butanone / 4 h / 81 - 82 °C 2: hydrogen / palladium 10% on activated carbon / ethanol / 2 h / 50 °C / 3750.38 Torr View Scheme
Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide / 20 h / 25 °C 2: palladium 10% on activated carbon; ammonium formate / isopropyl alcohol / 0.5 h / 50 °C View Scheme

2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (141645-16-1) → N-(2-butyl-3-(4-(3-chloropropoxy)benzoyl)benzofuran-5-yl)methanesulfonamide (1310430-05-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: potassium carbonate / butanone / 4 h / 81 - 82 °C 2: hydrogen / palladium 10% on activated carbon / ethanol / 2 h / 50 °C / 3750.38 Torr 3: pyridine / dichloromethane / 15 °C View Scheme
Multi-step reaction with 3 steps 1: potassium carbonate / N,N-dimethyl-formamide / 20 h / 25 °C 2: palladium 10% on activated carbon; ammonium formate / isopropyl alcohol / 0.5 h / 50 °C 3: sodium hydrogencarbonate / dichloromethane / 6 h / 35 °C View Scheme

Upstream product

• 1137261-89-2 1-(4-hydroxy-phenyl)-heptane-1,3-dione 
• 70726-17-9 (2-hydroxy-5-nitrobenzyl)triphenylphosphine chloride 
• 2973-19-5 2-hydroxy-5-nitrobenzyl chloride 
• 638-29-9 n-valeryl chloride 
• 772-33-8 Koshlands reagent I 
• 28141-24-4 4-hydroxybenzoyl chloride 
• 133238-87-6 2-(n-butyl)-5-nitrobenzofuran 
• 540-38-5 p-Iodophenol 
• 89487-91-2 2-iodo-4-nitrophenol 
• 33527-94-5 4-acetoxyiodobenzene 
• 201230-82-2 carbon monoxide 
• 1636167-45-7 2-(hex-1-yn-1-yl)-4-nitrophenyl acetate 
• 504421-91-4 2-iodo-4-nitrophenyl acetate 
• 142-61-0 Hexanoyl chloride 

Downstream Products

• 141671-42-3 2-n-butyl 3-[4-(3-di-n-butylamino-propoxy)benzoyl] 5-nitro benzofuran 
• 1278585-69-5 N-(2-butyl-3-(4-(3-(dibutylamino)propoxy)benzoyl)benzofuran-5-yl)acetamide 
• 141645-23-0 (2-butyl-5-nitrobenzofuran-3-yl)(4-(3-(dibutylamino)propoxy)phenyl)methanone 
• 1542232-35-8 {4-[3-(tert-butyl-diphenyl-silanyloxy)-3-[²H₂]-propoxy]-phenyl}-(2-butyl-5-nitro-benzofuran-3-yl)-methanone 
• 141645-38-7 [4-(3-bromo-propoxy)-phenyl]-(2-butyl-5-nitro-benzofuran-3-yl)-methanone 
• 1542232-34-7 [4-(3-bromo-[²H₆]-propoxy)-phenyl]-(2-butyl-5-nitrobenzofuran-3-yl)-methanone 
• 1542232-59-6 [²H₂]-N-{2-butyl-3-[4-(3-dibutylamino-3-[²H₂]-propoxy)-benzoyl]-benzofuran-5-yl}-methanesulfonamide hydrochloride 
• 1542232-58-5 N-{2-butyl-3-[4-(3-di-1-[²H₂]-butylamino-[²H₆]-propoxy)-benzoyl]-benzofuran-5-yl}-methanesulfonamide hydrochloride 

Relevant articles and documents

Discovery of dronedarone and its analogues as NLRP3 inflammasome inhibitors with potent anti-inflammation activity

Inhibiting NLRP3 inflammasome activation is a prospective therapeutic strategy for uncontrolled inflammatory diseases. It is the first time that dronedarone, a multiply ion channel blocker, was identified as a NLRP3-inflammasome inhibitor with an IC50 value of 6.84 μM against IL-1β release. A series of novel 5-amide benzofuran derivatives were designed and synthesized as NLRP3-inflammasome inhibitors. Compound 8c showed slightly increased activity (IC50 = 3.85 μM) against IL-1β release. Notably, treatment with 8c could significantly inhibit NLRP3-mediated IL-1β release and ameliorate peritoneal inflammation in a mouse model of sepsis. Collectively, 8c is a promising lead compound for further chemical development as a NLRP3 inhibitor with anti-inflammation effects.

Preparation method of key intermediate of dronedarone

The invention relates to a preparation method of a key intermediate of drug dronedarone for treating atrial fibrillation, and specifically relates to the 2-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran. According to the method provided by the invention, a series of reactions are performed by using inexpensive p-nitrophenol as a starting material to prepare the 2-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran, the process is smooth, the costs are lower, the yield is higher, the controllability is stronger, and the method is suitable for industrial production.

Microwave-assisted synthesis of (2-butyl-5-nitrobenzo[b]furan-3-yl)-[4-(substituted ethynyl)phenyl]methanones

We report a new method for the efficient and rapid synthesis of (2-butyl-5-nitrobenzo[b]furan-3-yl)[4- (substituted ethynyl)phenyl]methanones using a Pd-Cu catalyzed microwave-assisted Sonogashira coupling reaction. In comparison to the conventional heating procedure, the time of synthesis and effort are significantly reduced in the present method, without side-product formation. Microwave irradiation considerably accelerated the formation of (2-butyl-5-nitrobenzo[b]furan-3-yl)[4-(substituted ethynyl)phenyl]methanone analogues.