196597-78-1

Basic information

• Product Name: 1,2,6,7-Tetrahydro-8H-indeno[5,4-b]furan-8-one
• Synonyms: 1,2,6,7-Tetrahydro-8H-indeno[5,4-b]furan-8-one;1,2,6,7-Tetrahydro-8H-indeno[5,4-β]furan-8-one;1,2,6,7-tetrahydroindeno[5,4-b]furan-8-one;Ramelteon Intermediate 1;RaMelteon I;4-b]furan-8-one;7-tetrahydro-;8H-Indeno[5
• CAS NO: 196597-78-1
• Molecular Formula: C11H10O2
• Molecular Weight: 174.2
• EINECS: 1308068-626-2
• Product Categories: Aromatics Compounds;Aromatics;Heterocycles
• Mol File: 196597-78-1.mol

Chemical Properties

• Melting Point: 149-1510C
• Boiling Point: 334.156 °C at 760 mmHg
• Flash Point: 165.595 °C
• Appearance: White solid
• Density: 1.289 g/cm³
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.624
• Storage Temp.: Sealed in dry,Room Temperature
• Solubility: Chloroform (Slightly), Ethyl Acetate (Slightly)
• CAS DataBase Reference: 1,2,6,7-Tetrahydro-8H-indeno[5,4-b]furan-8-one(CAS DataBase Reference)
• NIST Chemistry Reference: 1,2,6,7-Tetrahydro-8H-indeno[5,4-b]furan-8-one(196597-78-1)
• EPA Substance Registry System: 1,2,6,7-Tetrahydro-8H-indeno[5,4-b]furan-8-one(196597-78-1)

Safety Data

• HazardClass: IRRITANT
• Hazardous Substances Data: 196597-78-1(Hazardous Substances Data)

Usage

Chemical Properties

White Solid

InChI:InChI=1/C11H10O2/c12-9-3-1-7-2-4-10-8(11(7)9)5-6-13-10/h2,4H,1,3,5-6H2

Synthetic route

1-(2,3-dihydrobenzofuran-4-yl)-2-propen-1-one (1205098-83-4) → 1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one (196597-78-1)

Conditions	Yield
With copper(II) bis(trifluoromethanesulfonate) In 1,2-dichloro-ethane at 10 - 20℃; for 16h; Solvent; Reagent/catalyst;	96.3%
With sulfuric acid In pentane at 67℃; Product distribution / selectivity; Inert atmosphere;
With sulfuric acid In water; pentane at 67℃; for 0.5h; Inert atmosphere;

4,5-dibromo-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one (196597-77-0) → 1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one (196597-78-1)

Conditions	Yield
With hydrogen; acetic acid; 10percent Pd/C/H2O at 20℃; for 1h;	89%
With hydrogen; sodium acetate; 5% palladium over charcoal In water; acetic acid at 20℃;	89%
With hydrogen; sodium acetate; palladium 10% on activated carbon In methanol at 40℃; under 2175.22 - 3675.37 Torr; for 8h;	88.6%

4,5-dibromo-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one (196597-77-0) → C11H12O (1092507-06-6) + 2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-ol (1092507-07-7) + 1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one (196597-78-1)

Conditions	Yield
With hydrogen; sodium acetate; acetic acid; palladium 10% on activated carbon under 1471.14 - 2206.72 Torr;	A n/a B n/a C 85%

6,7-dihydro-8H-indeno-[5,4-b]furan-8-one (15480-25-8) → 1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one (196597-78-1)

Conditions	Yield
With hydrogen; 5% Pd(II)/C(eggshell); triethylamine In tetrahydrofuran; ethanol at 35℃; under 4500.45 - 5250.53 Torr; for 24h;	62%

4-tert-butyl-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one (1198465-69-8) → 1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one (196597-78-1)

Conditions	Yield
With hydrogenchloride; aluminum (III) chloride In benzene	20%

2,3-Dihydrobenzofuran (496-16-2) → 1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one (196597-78-1)

Conditions	Yield
Multi-step reaction with 9 steps 1.1: 92 percent / TiCl4 / CH2Cl2 / 1 h 2.1: NaH / tetrahydrofuran / 0.33 h / 20 °C 2.2: 88 percent / tetrahydrofuran / 1 h / 20 °C 3.1: 99 percent / H2 / 10percent Pd/C/H2O / ethanol / 2 h / 20 °C 4.1: 97 percent / NaOAc; AcOH; Br2 / 1 h / 20 °C 5.1: 53 percent / AcOH; Fe; Br2 / 5 h / 50 °C 6.1: 93 percent / aq. KOH / ethanol / 1 h / 90 °C 7.1: SOCl2 / 75 °C 8.1: AlCl3 / 1,2-dichloro-ethane / 20 °C 9.1: 89 percent / AcOH; H2 / 10percent Pd/C/H2O / 1 h / 20 °C View Scheme
Multi-step reaction with 9 steps 1.1: 86 percent / POCl3 / 12 h / 80 - 85 °C 2.1: NaH / tetrahydrofuran / 0.33 h / 20 °C 2.2: 88 percent / tetrahydrofuran / 1 h / 20 °C 3.1: 99 percent / H2 / 10percent Pd/C/H2O / ethanol / 2 h / 20 °C 4.1: 97 percent / NaOAc; AcOH; Br2 / 1 h / 20 °C 5.1: 53 percent / AcOH; Fe; Br2 / 5 h / 50 °C 6.1: 93 percent / aq. KOH / ethanol / 1 h / 90 °C 7.1: SOCl2 / 75 °C 8.1: AlCl3 / 1,2-dichloro-ethane / 20 °C 9.1: 89 percent / AcOH; H2 / 10percent Pd/C/H2O / 1 h / 20 °C View Scheme
Multi-step reaction with 6 steps 1.1: trichlorophosphate / 5.17 h / 30 - 98 °C 2.1: sodium methylate / toluene / 0.25 h / 0 - 30 °C 3.1: hydrogen / nickel / methanol / 4 h / 50 °C 4.1: bromine; sodium acetate; acetic acid / 14 h / 20 - 28 °C 5.1: thionyl chloride / N,N-dimethyl-formamide / 1,2-dichloro-benzene / 2 h / 28 - 60 °C 5.2: 1 h / -5 - 5 °C 6.1: hydrogen; sodium acetate / raney chloride / methanol / 50 °C View Scheme

2,3-dihydro-benzofuran-5-carbaldehyde (55745-70-5) → 1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one (196597-78-1)

Conditions	Yield
Multi-step reaction with 8 steps 1.1: NaH / tetrahydrofuran / 0.33 h / 20 °C 1.2: 88 percent / tetrahydrofuran / 1 h / 20 °C 2.1: 99 percent / H2 / 10percent Pd/C/H2O / ethanol / 2 h / 20 °C 3.1: 97 percent / NaOAc; AcOH; Br2 / 1 h / 20 °C 4.1: 53 percent / AcOH; Fe; Br2 / 5 h / 50 °C 5.1: 93 percent / aq. KOH / ethanol / 1 h / 90 °C 6.1: SOCl2 / 75 °C 7.1: AlCl3 / 1,2-dichloro-ethane / 20 °C 8.1: 89 percent / AcOH; H2 / 10percent Pd/C/H2O / 1 h / 20 °C View Scheme
Multi-step reaction with 5 steps 1.1: sodium methylate / toluene / 0.25 h / 0 - 30 °C 2.1: hydrogen / nickel / methanol / 4 h / 50 °C 3.1: bromine; sodium acetate; acetic acid / 14 h / 20 - 28 °C 4.1: thionyl chloride / N,N-dimethyl-formamide / 1,2-dichloro-benzene / 2 h / 28 - 60 °C 4.2: 1 h / -5 - 5 °C 5.1: hydrogen; sodium acetate / raney chloride / methanol / 50 °C View Scheme
Multi-step reaction with 6 steps 1.1: piperidine; pyridine / 6 h / 120 °C 2.1: thionyl chloride / 0.67 h / 26 - 73 °C / Heating / reflux 3.1: hydrogen / nickel / methanol / 4 h / 50 °C 4.1: bromine; sodium acetate; acetic acid / 14 h / 20 - 28 °C 5.1: thionyl chloride / N,N-dimethyl-formamide / 1,2-dichloro-benzene / 2 h / 28 - 60 °C 5.2: 1 h / -5 - 5 °C 6.1: hydrogen; sodium acetate / raney chloride / methanol / 50 °C View Scheme
Multi-step reaction with 5 steps 1.1: piperidine; pyridine; acetic acid / 4 - 5 h / 100 °C 1.2: 2 - 3 h / 20 °C 2.1: sodium hydroxide; hydrogen; ammonium formate / palladium 10% on activated carbon / water / 5 - 6 h / 20 °C 3.1: bromine; sodium acetate; acetic acid / 2 - 3 h / 0 - 45 °C 4.1: thionyl chloride / N,N-dimethyl-formamide / 1 - 2 h / 20 °C 4.2: 1 - 2 h / 0 - 5 °C 5.1: hydrogen; sodium acetate; acetic acid / palladium 10% on activated carbon / 1471.14 - 2206.72 Torr View Scheme
Multi-step reaction with 6 steps 1: sodium t-butanolate / toluene / 1 h 2: acetic acid; hydrogen; 5%-palladium/activated carbon / 1 h / 50 °C / 1470.15 - 2205.22 Torr 3: acetic acid; sodium acetate; bromine / 6 h / 20 °C / Cooling 4: thionyl chloride / 1,2-dichloro-benzene; N,N-dimethyl-formamide / 42 °C 5: aluminum (III) chloride / 0.5 h / Cooling with ice 6: hydrogen; sodium acetate; palladium 10% on activated carbon / methanol / 2 h / 40 °C / 2205.22 - 3675.37 Torr View Scheme

ethyl (E)-3-(2,3-dihydrobenzofuran-5-yl)-2-propenoate (196597-65-6) → 1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one (196597-78-1)

Conditions	Yield
Multi-step reaction with 7 steps 1: 99 percent / H2 / 10percent Pd/C/H2O / ethanol / 2 h / 20 °C 2: 97 percent / NaOAc; AcOH; Br2 / 1 h / 20 °C 3: 53 percent / AcOH; Fe; Br2 / 5 h / 50 °C 4: 93 percent / aq. KOH / ethanol / 1 h / 90 °C 5: SOCl2 / 75 °C 6: AlCl3 / 1,2-dichloro-ethane / 20 °C 7: 89 percent / AcOH; H2 / 10percent Pd/C/H2O / 1 h / 20 °C View Scheme
Multi-step reaction with 5 steps 1: acetic acid; hydrogen; 5%-palladium/activated carbon / 1 h / 50 °C / 1470.15 - 2205.22 Torr 2: acetic acid; sodium acetate; bromine / 6 h / 20 °C / Cooling 3: thionyl chloride / 1,2-dichloro-benzene; N,N-dimethyl-formamide / 42 °C 4: aluminum (III) chloride / 0.5 h / Cooling with ice 5: hydrogen; sodium acetate; palladium 10% on activated carbon / methanol / 2 h / 40 °C / 2205.22 - 3675.37 Torr View Scheme

ethyl 3-(2,3-dihydro-1-benzofuran-5-yl)propanoate (196597-66-7) → 1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one (196597-78-1)

Conditions	Yield
Multi-step reaction with 6 steps 1: 97 percent / NaOAc; AcOH; Br2 / 1 h / 20 °C 2: 53 percent / AcOH; Fe; Br2 / 5 h / 50 °C 3: 93 percent / aq. KOH / ethanol / 1 h / 90 °C 4: SOCl2 / 75 °C 5: AlCl3 / 1,2-dichloro-ethane / 20 °C 6: 89 percent / AcOH; H2 / 10percent Pd/C/H2O / 1 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: bromine; sodium acetate; acetic acid / 14 h / 20 - 28 °C 2.1: thionyl chloride / N,N-dimethyl-formamide / 1,2-dichloro-benzene / 2 h / 28 - 60 °C 2.2: 1 h / -5 - 5 °C 3.1: hydrogen; sodium acetate / raney chloride / methanol / 50 °C View Scheme
Multi-step reaction with 4 steps 1: acetic acid; sodium acetate; bromine / 6 h / 20 °C / Cooling 2: thionyl chloride / 1,2-dichloro-benzene; N,N-dimethyl-formamide / 42 °C 3: aluminum (III) chloride / 0.5 h / Cooling with ice 4: hydrogen; sodium acetate; palladium 10% on activated carbon / methanol / 2 h / 40 °C / 2205.22 - 3675.37 Torr View Scheme

ethyl 3-(7-bromo-2,3-dihydro-1-benzofuran-5-yl)propanoate (196597-67-8) → 1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one (196597-78-1)

Conditions	Yield
Multi-step reaction with 5 steps 1: 53 percent / AcOH; Fe; Br2 / 5 h / 50 °C 2: 93 percent / aq. KOH / ethanol / 1 h / 90 °C 3: SOCl2 / 75 °C 4: AlCl3 / 1,2-dichloro-ethane / 20 °C 5: 89 percent / AcOH; H2 / 10percent Pd/C/H2O / 1 h / 20 °C View Scheme

3-(6,7-dibromo-2,3-dihydro-benzofuran-5-yl)-propionyl chloride (227179-21-7) → 1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one (196597-78-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: AlCl3 / 1,2-dichloro-ethane / 20 °C 2: 89 percent / AcOH; H2 / 10percent Pd/C/H2O / 1 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1: aluminum (III) chloride / 0.5 h / Cooling with ice 2: hydrogen; sodium acetate; palladium 10% on activated carbon / methanol / 2 h / 40 °C / 2205.22 - 3675.37 Torr View Scheme

ethyl 3-(6,7-dibromo-2,3-dihydrobenzofuran-5-yl) propionic acid (196597-76-9) → 1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one (196597-78-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: SOCl2 / 75 °C 2: AlCl3 / 1,2-dichloro-ethane / 20 °C 3: 89 percent / AcOH; H2 / 10percent Pd/C/H2O / 1 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1.1: thionyl chloride / N,N-dimethyl-formamide / 1,2-dichloro-benzene / 2 h / 28 - 60 °C 1.2: 1 h / -5 - 5 °C 2.1: hydrogen; sodium acetate / raney chloride / methanol / 50 °C View Scheme
Multi-step reaction with 2 steps 1.1: thionyl chloride / N,N-dimethyl-formamide / 1 - 2 h / 20 °C 1.2: 1 - 2 h / 0 - 5 °C 2.1: hydrogen; sodium acetate; acetic acid / palladium 10% on activated carbon / 1471.14 - 2206.72 Torr View Scheme
Multi-step reaction with 3 steps 1: thionyl chloride / 1,2-dichloro-benzene; N,N-dimethyl-formamide / 42 °C 2: aluminum (III) chloride / 0.5 h / Cooling with ice 3: hydrogen; sodium acetate; palladium 10% on activated carbon / methanol / 2 h / 40 °C / 2205.22 - 3675.37 Torr View Scheme

ethyl 3-(6,7-dibromo-2,3-dihydro-1-benzofuran-5-yl)propanoate (196597-75-8) → 1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one (196597-78-1)

Conditions	Yield
Multi-step reaction with 4 steps 1: 93 percent / aq. KOH / ethanol / 1 h / 90 °C 2: SOCl2 / 75 °C 3: AlCl3 / 1,2-dichloro-ethane / 20 °C 4: 89 percent / AcOH; H2 / 10percent Pd/C/H2O / 1 h / 20 °C View Scheme

6-hydroxy-7-(2-mesyloxyethyl)indan-1-one (1198465-72-3) → 1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one (196597-78-1)

Conditions	Yield
With triethylamine In ethyl acetate for 3h; Reflux;	4.47 g

formaldehyd (50-00-0) + 1-(dihydrobenzofuran-4-yl)ethanone (1205098-82-3) → 1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one (196597-78-1)

Conditions	Yield
Stage #1: formaldehyd; 1-(dihydrobenzofuran-4-yl)ethanone With dicyclohexylammonium trifloroacetate In 1,4-dioxane at 100℃; for 4h; Stage #2: With sulfuric acid In pentane at 67℃; Inert atmosphere;

6-hydroxy-1-indanone (62803-47-8) → 1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one (196597-78-1)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: potassium carbonate / acetone / 5 h / Reflux 2.1: N,N-dimethyl-aniline / Inert atmosphere; Reflux 2.2: 25 °C 3.1: ozone / dichloromethane / -78 - 20 °C / Inert atmosphere 3.2: 20 °C 4.1: toluene-4-sulfonic acid / toluene / 0.75 h / Reflux 5.1: hydrogen / triethylamine; 5% Pd(II)/C(eggshell) / ethanol; tetrahydrofuran / 24 h / 35 °C / 4500.45 - 5250.53 Torr View Scheme

6-allyloxy-indan-1-one → 1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one (196597-78-1)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: N,N-dimethyl-aniline / Inert atmosphere; Reflux 1.2: 25 °C 2.1: ozone / dichloromethane / -78 - 20 °C / Inert atmosphere 2.2: 20 °C 3.1: toluene-4-sulfonic acid / toluene / 0.75 h / Reflux 4.1: hydrogen / triethylamine; 5% Pd(II)/C(eggshell) / ethanol; tetrahydrofuran / 24 h / 35 °C / 4500.45 - 5250.53 Torr View Scheme

6-hydroxy-7-allyl-indan-1-one → 1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one (196597-78-1)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: ozone / dichloromethane / -78 - 20 °C / Inert atmosphere 1.2: 20 °C 2.1: toluene-4-sulfonic acid / toluene / 0.75 h / Reflux 3.1: hydrogen / triethylamine; 5% Pd(II)/C(eggshell) / ethanol; tetrahydrofuran / 24 h / 35 °C / 4500.45 - 5250.53 Torr View Scheme

2-methoxy-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one (1290145-09-3) → 1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one (196597-78-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: toluene-4-sulfonic acid / toluene / 0.75 h / Reflux 2: hydrogen / triethylamine; 5% Pd(II)/C(eggshell) / ethanol; tetrahydrofuran / 24 h / 35 °C / 4500.45 - 5250.53 Torr View Scheme

3-(2,3-dihydro-1-benzofuran-5-yl)prop-2-enoic acid (198707-57-2) → 1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one (196597-78-1)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: thionyl chloride / 0.67 h / 26 - 73 °C / Heating / reflux 2.1: hydrogen / nickel / methanol / 4 h / 50 °C 3.1: bromine; sodium acetate; acetic acid / 14 h / 20 - 28 °C 4.1: thionyl chloride / N,N-dimethyl-formamide / 1,2-dichloro-benzene / 2 h / 28 - 60 °C 4.2: 1 h / -5 - 5 °C 5.1: hydrogen; sodium acetate / raney chloride / methanol / 50 °C View Scheme
Multi-step reaction with 4 steps 1.1: sodium hydroxide; hydrogen; ammonium formate / palladium 10% on activated carbon / water / 5 - 6 h / 20 °C 2.1: bromine; sodium acetate; acetic acid / 2 - 3 h / 0 - 45 °C 3.1: thionyl chloride / N,N-dimethyl-formamide / 1 - 2 h / 20 °C 3.2: 1 - 2 h / 0 - 5 °C 4.1: hydrogen; sodium acetate; acetic acid / palladium 10% on activated carbon / 1471.14 - 2206.72 Torr View Scheme

ethyl 3-(2,3-dihydrobenzofuran-5-yl)acrylate (217483-05-1) → 1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one (196597-78-1)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: hydrogen / nickel / methanol / 4 h / 50 °C 2.1: bromine; sodium acetate; acetic acid / 14 h / 20 - 28 °C 3.1: thionyl chloride / N,N-dimethyl-formamide / 1,2-dichloro-benzene / 2 h / 28 - 60 °C 3.2: 1 h / -5 - 5 °C 4.1: hydrogen; sodium acetate / raney chloride / methanol / 50 °C View Scheme

3-(2,3-dihydro-1-benzofuran-5-yl)propanoic acid (215057-28-6) → 1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one (196597-78-1)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: bromine; sodium acetate; acetic acid / 2 - 3 h / 0 - 45 °C 2.1: thionyl chloride / N,N-dimethyl-formamide / 1 - 2 h / 20 °C 2.2: 1 - 2 h / 0 - 5 °C 3.1: hydrogen; sodium acetate; acetic acid / palladium 10% on activated carbon / 1471.14 - 2206.72 Torr View Scheme

2,3-dihydro-1-benzofuran-4-carbaldehyde (209256-42-8) → 1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one (196597-78-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: tetrahydrofuran / 6.5 h / -10 - 20 °C 2: Dess-Martin periodane / dichloromethane / 2 h / 20 °C 3: copper(II) bis(trifluoromethanesulfonate) / 1,2-dichloro-ethane / 16 h / 10 - 20 °C View Scheme

1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one (196597-78-1) → 2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-ol (1092507-07-7)

Conditions	Yield
With sodium tetrahydroborate In tetrahydrofuran; methanol at 0 - 20℃; for 6h;	100%

4-chlorobenzaldehyde (104-88-1) + 1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one (196597-78-1) → (E)-7-(4-chlorobenzylidene)-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one

Conditions	Yield
With sodium hydroxide In water at 20℃; for 0.366667h; Green chemistry;	98%

2-chloro-6-fluorobenzaldehyde (387-45-1) + 1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one (196597-78-1) → (E)-7-(2-chloro-6-fluorobenzylidene)-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one

Conditions	Yield
With sodium hydroxide In water at 20℃; for 0.166667h; Green chemistry;	98%
With sodium hydroxide In water

2-chloro-benzaldehyde (89-98-5) + 1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one (196597-78-1) → (E)-7-(2-chlorobenzylidene)-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one

Conditions	Yield
With sodium hydroxide In water at 20℃; for 0.333333h; Green chemistry;	97%
With sodium hydroxide In water

2,3-dichlorobenzylaldehyde (6334-18-5) + 1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one (196597-78-1) → (E)-7-(2,3-dichlorobenzylidene)-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one

Conditions	Yield
With sodium hydroxide In water at 20℃; for 0.483333h; Green chemistry;	96%

3,4-dichlorobenzaldehyde (6287-38-3) + 1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one (196597-78-1) → (E)-7-(3,4-dichlorobenzylidene)-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one

Conditions	Yield
With sodium hydroxide In water at 20℃; for 0.6h; Green chemistry;	96%

methylbenzenesulfonylmethylisonitrile + 1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one (196597-78-1) → 2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-carbonitrile

Conditions	Yield
With potassium tert-butylate In 1,2-dimethoxyethane; ethanol at 0 - 60℃; for 18h;	95%

1-naphthaldehyde (66-77-3) + 1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one (196597-78-1) → (E)-7-(naphthalen-1-ylmethylene)-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one

Conditions	Yield
With sodium hydroxide In water at 20℃; for 0.516667h; Green chemistry;	95%

2,4-dichlorobenzaldeyhde (874-42-0) + 1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one (196597-78-1) → (E)-7-(2,4-dichlorobenzylidene)-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one

Conditions	Yield
With sodium hydroxide In water at 20℃; for 0.583333h; Green chemistry;	95%

benzaldehyde (100-52-7) + 1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one (196597-78-1) → (E)-7-benzylidene-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one

Conditions	Yield
With sodium hydroxide In water at 20℃; for 0.5h; Reagent/catalyst; Green chemistry;	94%
With sodium hydroxide In water

2,6-dichlorobenzaldehyde (83-38-5) + 1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one (196597-78-1) → (E)-7-(2,6-dichlorobenzylidene)-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one

Conditions	Yield
With sodium hydroxide In water at 20℃; for 0.583333h; Green chemistry;	94%
With sodium hydroxide In water

cyanoacetic acid (372-09-8) + 1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one (196597-78-1) → 2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)acetonitrile (221530-44-5)

Conditions	Yield
With piperidine at 100 - 110℃;	93%

3,4-dimethoxy-benzaldehyde (120-14-9) + 1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one (196597-78-1) → (E)-7-(3,4-dimethoxybenzylidene)-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one

Conditions	Yield
With sodium hydroxide In water at 20℃; for 0.666667h; Green chemistry;	93%

(4-isopropylbenzaldehyde) (122-03-2) + 1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one (196597-78-1) → (E)-7-(4-isopropylbenzylidene)-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one

Conditions	Yield
With sodium hydroxide In water at 20℃; for 0.5h; Green chemistry;	91%

Cyclopropanecarboxaldehyde (1489-69-6) + 1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one (196597-78-1) → (E)-7-(cyclopropylmethylene)-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one

Conditions	Yield
With sodium hydroxide In water at 20℃; for 0.416667h; Green chemistry;	90%

malononitrile (109-77-3) + 1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one (196597-78-1) → C14H10N2O

Conditions	Yield
With ammonium acetate; acetic acid In toluene Reagent/catalyst; Solvent;	89.8%

diethyl 1-cyanomethylphosphonate (2537-48-6) + 1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one (196597-78-1) → 2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)acetonitrile (221530-44-5)

Conditions	Yield
Stage #1: diethyl 1-cyanomethylphosphonate With sodium hydride In tetrahydrofuran; mineral oil at 20℃; for 0.5h; Horner-Wadsworth-Emmons olefination; Stage #2: 1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one In tetrahydrofuran; mineral oil at 40℃; for 1h; Horner-Wadsworth-Emmons olefination;	89%
Stage #1: diethyl 1-cyanomethylphosphonate With sodium methylate In tetrahydrofuran at 20℃; for 1h; Stage #2: 1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one In tetrahydrofuran at 20℃; for 2.25h;	80%
Stage #1: diethyl 1-cyanomethylphosphonate With sodium hydride In tetrahydrofuran at 25℃; for 1h; Large scale; Stage #2: 1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one In tetrahydrofuran; water for 3.5h; Large scale;	5.1 kg
In methanol at 20℃; for 0.25h; Alkaline conditions;
With sodium methylate at 5 - 25℃;

diethyl 1-cyanomethylphosphonate (2537-48-6) + 1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one (196597-78-1) → (E)-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-ylidene)acetonitrile (196597-79-2)

Conditions	Yield
With sodium methylate In methanol; water; toluene	88%
With sodium methylate In methanol; toluene at 20℃; Wittig Reaction;	88%
With sodium methylate In methanol; toluene at 0℃; for 5h;	84.4%

p-trifluoromethoxybenzaldehyde (659-28-9) + 1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one (196597-78-1) → (E)-7-(4-[trifluoromethoxy]benzylidene)-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one

Conditions	Yield
With sodium hydroxide In water at 20℃; for 0.333333h; Green chemistry;	86%

3-Cyanobenzaldehyde (24964-64-5) + 1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one (196597-78-1) → (E)-3-((8-oxo-1,2,6,8-tetrahydro-7H-indeno[5,4-b]furan-7-ylidene)methyl)benzonitrile

Conditions	Yield
With sodium hydroxide In water at 20℃; for 0.666667h; Green chemistry;	85%

4-Trifluoromethylbenzaldehyde (455-19-6) + 1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one (196597-78-1) → (E)-7-(4-[trifluoromethyl]benzylidene)-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one

Conditions	Yield
With sodium hydroxide In water at 20℃; for 0.383333h; Green chemistry;	83%

diethoxyphosphoryl-acetic acid ethyl ester (867-13-0) + 1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one (196597-78-1) → ethyl (2)-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylideneacetate (1093972-05-4)

Conditions	Yield
Stage #1: diethoxyphosphoryl-acetic acid ethyl ester With sodium hydride In toluene at 0 - 5℃; for 2h; Stage #2: 1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one In toluene at 90 - 100℃; for 15 - 18h;	80%
Stage #1: diethoxyphosphoryl-acetic acid ethyl ester With sodium hydride In toluene; mineral oil at 0 - 20℃; Inert atmosphere; Stage #2: 1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one In toluene; mineral oil at 90 - 100℃; Inert atmosphere;

[bromo(difluoro)methyl](trimethyl)silane (115262-01-6) + 1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one (196597-78-1) → 8-fluoro-1,2-dihydronaphtho[2,1-b]furan-9-ol

Conditions	Yield
Stage #1: [bromo(difluoro)methyl]-trimethyl-silane; 1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one With tetrabutylammomium bromide In toluene at 110℃; for 7h; Sealed tube; Stage #2: With tetrabutyl ammonium fluoride In toluene at 20℃; for 2h;	80%

1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one (196597-78-1) + 3-Fluorobenzaldehyde (456-48-4) → (E)-7-(3-fluorobenzylidene)-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one

Conditions	Yield
With sodium hydroxide In water at 20℃; for 0.433333h; Green chemistry;	80%

2-chloro-3-quinoline carboxaldehyde (73568-25-9) + 1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one (196597-78-1) → (E)-7-([2-chloroquinolin-3-yl]methylene)-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one

Conditions	Yield
With sodium hydroxide In water at 20℃; for 0.3h; Green chemistry;	75%

diethoxyphosphoryl-acetic acid ethyl ester (867-13-0) + 1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one (196597-78-1) → ethyl (Z)-2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)acetate

Conditions	Yield
Stage #1: diethoxyphosphoryl-acetic acid ethyl ester With sodium hydride In toluene at 20℃; for 2h; Cooling with ice; Stage #2: 1,2,6,7-tetrahydro-8H-indeno[5,4-b]-furan-8-one In toluene at 90℃; Cooling with ice;	74%

Upstream product

• 196597-65-6 ethyl (E)-3-(2,3-dihydrobenzofuran-5-yl)-2-propenoate 
• 496-16-2 2.3-dihydrobenzofuran 
• 1198465-72-3 6-hydroxy-7-(2-mesyloxyethyl)indan-1-one 
• 1198465-69-8 4-tert-butyl-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one 
• 50-00-0 formaldehyd 
• 1205098-82-3 1-(2,3-dihydrobenzofuran-4-yl)ethan-1-one 
• 211310-11-1 1-(3-(vinyloxy)phenyl)ethan-1-one 
• 121-71-1 3-Hydroxyacetophenone 
• 209256-42-8 2,3-dihydro-1-benzofuran-4-carbaldehyde 
• 215057-28-6 3-(2,3-dihydro-1-benzofuran-5-yl)propanoic acid 
• 217483-05-1 ethyl 3-(2,3-dihydrobenzofuran-5-yl)acrylate 
• 198707-57-2 3-(2,3-dihydro-1-benzofuran-5-yl)prop-2-enoic acid 
• 15480-25-8 6,7-dihydro-8H-indeno-[5,4-b]furan-8-one 
• 1290145-09-3 2-methoxy-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one 

Downstream Products

• 196597-79-2 (E)-2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)acetonitrile 
• 196597-26-9 ramelteon 

Relevant articles and documents

Concise Six-Step Asymmetric Approach to Ramelteon from an Acetophenone Derivative Using Ir, Rh, Cu, and Ni Catalysis

A concise six-step asymmetric synthesis of nearly enantiomerically pure ramelteon was developed from a monocyclic precursor with a 17% overall yield and a 97% ee in the asymmetric step. The synthetically challenging tricyclic 1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan core of ramelteon was assembled by using Ir-catalyzed O-vinylation and Rh-catalyzed vinyl ether annulation through directed C-H bond activation, while the chirality was introduced with enantioselective reduction of an α,β-unsaturated nitrile moiety under hydrosilylation conditions using a CuII/Walphos type catalyst. The presented methodology represents the shortest synthetic approach to ramelteon.

Preparation method 1, 2, 6, 7 - tetrahydro - 8H - indeno [5, 4 - b] furan -8 - ketone

The invention provides a preparation method of 1, 2, 6, 7 - tetrahydro - 8H - indeno [5, 4 - b] furan -8 - ketone, which comprises the following steps of (1) taking compound II as a raw material, adding a halogenating agent and hydrogen peroxide to halogenate to obtain compound III: 3 - X - 4 - hydroxybenzoic acid. (2) The compound III was mixed with 1 - bromo -2 - chloroethane and an alkali metal hydroxide to give compound IV: 3 - X - 4 - (2 - chloroethoxy) phenylpropionic acid. (3) Compound IV was added to nitrobenzene, and an acylation reagent was added to react to give compound V: 3 - X - 4 - (2 - chloroethoxy) phenylpropionyl chloride. (4) To the reaction system, aluminum trichloride was added to react to give compound VI: 4 - X - 1, 2, 6, 7 - tetrahydro - 8H - indeno [5, 4 - b] furan -8 - ketone. (5) Compound VI was added to toluene, and a palladium carbon and sodium acetate aqueous solution were added to catalyze hydrogenation to give compound I: 1, 2, 6, 7 - tetrahydro - 8H - indeno [5, 4 - b] furan -8 - ketone.

A thunder-US for amine preparation method for the synthesis of the key intermediate

The invention discloses a synthetic preparation method for a key intermediate of ramelteon 1,2,6,7-tretrahydro-8H-indeno[5,4-b]furan-8-one. According to the preparation method, by taking 2,3-dihydrobenzofuran-4-formaldehyde as an initial raw material, the key intermediate of ramelteon 1,2,6,7-tretrahydro-8H-indeno[5,4-b]furan-8-one is synthesized through Grignard reaction, oxidizing reaction and Nazarov cyclization reaction. The preparation method has the advantages of being high in reaction selectivity, few in side effects, high in total yield and quality, environmental-friendly, simple and convenient in process operation, high in stability and controllability and the like, and is suitable for industrial large-scaled production.

Pharmaceutical preparation containing copolyvidone

A stabilized preparation which comprises: a unstable drug in a polyethylene glycol-containing preparation; and a coating agent comprising a copolyvidone instead of polyethylene glycol with which the drug is coated.

A method of preparing intermediates lei Meiti amine

The invention relates to a preparation method of a Ramelteon intermediate. The Ramelteon intermediate is prepared by taking 4,5-dibromo-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one as a raw material, and then subjecting the raw material to a series of simple reactions so as to obtain the Ramelteon intermediate. The preparation method of the Ramelteon intermediate has the advantages of high yield, high product purity, simple operation, low cost, and suitability for mass production.

PROCESS FOR PREPARING 1,2,6,7-TETRAHYDRO-8H-INDENO[5,4-B]FURAN-8-ONE

The invention provides a process for preparing 1,2,6,7-tetrahydro-8H-indeno-[5,4-b]furan-8-one (I), said process comprising the steps: (i) subjecting 6-hydroxy-7-allyl-indan-1-one to ozonolysis followed by reduction in the presence of methanol to form 2-methoxy-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one; (ii) subjecting 6-hydroxy-7-allyl-indan-1-one to alcohol elimination to form 6,7-dihydro-8H-indeno-[5,4-b]furan-8-one; and (iii) subjecting 6,7-dihydro-8H-indeno-[5,4-b]furan-8-one to hydrogenation to obtain 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one.

SYNTHESIS OF 1-(2,3-DIHYDROBENZOFURAN-4-YL)ETHANONE AS INTERMEDIATE IN THE PREPARATION OF RAMELTEON

The present invention relates in general to the field of organic chemistry and in particular to the preparation of 1-(2,3-dihydrobenzofuran-4-yl)ethanone, an intermediate in preparation of (S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)ethyl]propionamide, i.e. ramelteon.

SYNTHESIS OF 6,7-DIHYDRO-1H-INDENO[5,4-B]FURAN-8(2H)-ONE AS INTERMEDIATE IN THE PREPARATION OF RAMELTEON

The present invention describes the preparation of 6, 7 -dihydro-1H-indeno[5, 4 -b] furan-8 (2H) -one of formula V, a key intermediate in preparation of ramelteon. The present invention also describes further preceding intermediate compounds useful for the synthesis of 6, 7-dihydro-1H-indeno[5, 4-b] furan-8 (2H) -one.

SYNTHESIS OF (S)-N-[2-(1,6,7,8-TETRAHYDRO-2H-INDENO-[5,4-B]FURAN-8-YL)ETHYL]PROPIONAMIDE

The present invention relates in general to the field of organic chemistry and in particular to the preparation of (S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)ethyl]propionamide, i.e. ramelteon, and analogues thereof.

PROCESS FOR PREPARATION OF (S)-N-[2-(1,6,7,8-TETRAHYDRO-2H-INDENO[5,4-B]FURAN-8-YL)ETHYL] PROPIONAMIDE AND NOVEL INTERMEDIATES THEREOF

Disclosed herein process for preparation of (S)-Ramelteon and intermediates thereof.