127264-14-6

Basic information

• Product Name: 5-(2-Bromoethyl)-2,3-dihydrobenzofuran
• Synonyms: 5-(2-Bromoethyl)-2,3-dihydrobenzo[b]furan;5-(2-BROMOETHYL)-2,3-DIHYDROBENZOFURAM;5-(2-bromoethyl)-2,3-dihydrobenzofuran (Darifenacin);5-(2-BROMOETHYL)-2,3-DIHYDROBENZOFURAN,HPLC 98%;5-(2-BROMOETHYL)-2,3-DIHYDROBENZOFURAN 97.0%;5-(2-Bromoethyl)-2,3-dihydrobenzo[2,3-β]furan;5-(2 Bromoethyl)-2,3-dihyrobenzofuran;Darifenacin IMpurity B
• CAS NO: 127264-14-6
• Molecular Formula: C₁₀H₁₁BrO
• Molecular Weight: 227.1
• EINECS: 1592732-453-0
• Product Categories: Pharmaceutical material and intermeidates;Fluorobenzene;APIs Intermediate;INTERMEDIATESOFDARIFENACIN;Furan&Benzofuran;API intermediates;Aromatics Compounds;Furans;Aromatics;Heterocycles;Benzodiozoles, Benzodioxines & Benzodioxepines;Methyl Halides;Benzofuran
• Mol File: 127264-14-6.mol
• Article Data: 19

Chemical Properties

• Melting Point: 65-67°C
• Boiling Point: 287.7 °C 760 mmHg
• Flash Point: 113.8°C
• Appearance: off-white powder
• Density: 1.459 g/cm³
• Vapor Pressure: 0.00424mmHg at 25°C
• Refractive Index: 1.592
• Storage Temp.: Keep in dark place,Inert atmosphere,Room temperature
• Solubility: Chloroform, Methanol
• CAS DataBase Reference: 5-(2-Bromoethyl)-2,3-dihydrobenzofuran(CAS DataBase Reference)
• NIST Chemistry Reference: 5-(2-Bromoethyl)-2,3-dihydrobenzofuran(127264-14-6)
• EPA Substance Registry System: 5-(2-Bromoethyl)-2,3-dihydrobenzofuran(127264-14-6)

Safety Data

• Hazard Codes: Xi,Xn
• Statements: 22
• Hazardous Substances Data: 127264-14-6(Hazardous Substances Data)

Usage

Chemical Properties

Off-White Powder

InChI:InChI=1/C10H11BrO/c11-5-3-8-1-2-10-9(7-8)4-6-12-10/h1-2,7H,3-6H2

Synthetic route

5-(2-hydroxyethyl)-2,3-dihydrobenzofuran (87776-76-9) → 2,3-dihydro-5-(2-bromoethyl)benzofuran (127264-14-6)

Conditions	Yield
With carbon tetrabromide; triphenylphosphine In dichloromethane at 20℃; for 63h;	84%
With phosphorus tribromide In chloroform Reflux;	75.9%
	73%

2-bromo-1-(2,3-dihydrobenzofuran-5-yl)ethan-1-one (151427-19-9) → 2,3-dihydro-5-(2-bromoethyl)benzofuran (127264-14-6)

Conditions	Yield
Stage #1: 2-bromo-1-(2,3-dihydrobenzofuran-5-yl)ethan-1-one With sodium tetrahydroborate In tetrahydrofuran at 5 - 10℃; for 1h; Inert atmosphere; Stage #2: With aluminum (III) chloride In tetrahydrofuran at 45 - 50℃; for 4h; Inert atmosphere;	74%

2-(2,3-dihydrobenzofuran-5-yl)ethylchloride (943034-50-2) → 2,3-dihydro-5-(2-bromoethyl)benzofuran (127264-14-6)

Conditions	Yield
With sodium bromide In acetone for 48h; Heating / reflux;

1-(2,3-dihydrobenzofuran-5-yl)ethanone (90843-31-5) → 2,3-dihydro-5-(2-bromoethyl)benzofuran (127264-14-6)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: toluene-4-sulfonic acid / methanol / 0.5 h / 0 - 5 °C 1.2: 6 h / 0 - 5 °C 2.1: sodium tetrahydroborate / tetrahydrofuran / 1 h / 5 - 10 °C / Inert atmosphere 2.2: 4 h / 45 - 50 °C / Inert atmosphere View Scheme

2,3-Dihydrobenzofuran (496-16-2) → 2,3-dihydro-5-(2-bromoethyl)benzofuran (127264-14-6)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: aluminum (III) chloride / dichloromethane / 0.5 h / 0 - 5 °C / Inert atmosphere 1.2: 0.5 h / 0 - 5 °C / Inert atmosphere 2.1: toluene-4-sulfonic acid / methanol / 0.5 h / 0 - 5 °C 2.2: 6 h / 0 - 5 °C 3.1: sodium tetrahydroborate / tetrahydrofuran / 1 h / 5 - 10 °C / Inert atmosphere 3.2: 4 h / 45 - 50 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1.1: aluminum (III) chloride / dichloromethane / 1 h / 0 - 10 °C 1.2: 10 - 20 °C 2.1: sodium tetrahydroborate; boron trifluoride diethyl etherate / tetrahydrofuran / 4 h / 0 - 10 °C / Reflux 3.1: phosphorus tribromide / chloroform / Reflux View Scheme
Multi-step reaction with 5 steps 1.1: aluminum (III) chloride / dichloromethane / 1 h / 0 - 10 °C 1.2: 10 - 20 °C 2.1: water; sodium hydroxide / 20 °C 3.1: hydrazine hydrate; sodium hydroxide / 90 - 100 °C 4.1: sodium tetrahydroborate; boron trifluoride diethyl etherate / tetrahydrofuran / 4 h / 0 - 10 °C / Reflux 5.1: phosphorus tribromide / chloroform / Reflux View Scheme

2-chloro-1-(2,3-dihydrobenzofuran-5-yl)ethanone (64089-34-5) → 2,3-dihydro-5-(2-bromoethyl)benzofuran (127264-14-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium tetrahydroborate; sulfuric acid / tetrahydrofuran / 10 h / -5 - 0 °C 2: sodium bromide / acetone / 48 h / Heating / reflux View Scheme

ethyl 2( 2,3-dihydro-1-benzofuran-5-yl)oxoacetate (79002-49-6) → 2,3-dihydro-5-(2-bromoethyl)benzofuran (127264-14-6)

Conditions	Yield
Multi-step reaction with 4 steps 1: water; sodium hydroxide / 20 °C 2: hydrazine hydrate; sodium hydroxide / 90 - 100 °C 3: sodium tetrahydroborate; boron trifluoride diethyl etherate / tetrahydrofuran / 4 h / 0 - 10 °C / Reflux 4: phosphorus tribromide / chloroform / Reflux View Scheme

C10H7O4(1-)*Na(1+) → 2,3-dihydro-5-(2-bromoethyl)benzofuran (127264-14-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: hydrazine hydrate; sodium hydroxide / 90 - 100 °C 2: sodium tetrahydroborate; boron trifluoride diethyl etherate / tetrahydrofuran / 4 h / 0 - 10 °C / Reflux 3: phosphorus tribromide / chloroform / Reflux View Scheme

2,3-dihydrobenzofuran-5-acetic acid (69999-16-2) → 2,3-dihydro-5-(2-bromoethyl)benzofuran (127264-14-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium tetrahydroborate; boron trifluoride diethyl etherate / tetrahydrofuran / 4 h / 0 - 10 °C / Reflux 2: phosphorus tribromide / chloroform / Reflux View Scheme

4-hydroxyphenylacetate (156-38-7) → 2,3-dihydro-5-(2-bromoethyl)benzofuran (127264-14-6)

Conditions	Yield
Multi-step reaction with 7 steps 1: potassium iodide; sodium hydroxide / dimethyl sulfoxide / 50 - 80 °C 2: toluene-4-sulfonic acid / Reflux; Large scale 3: polyphosphoric acid / toluene / 105 - 110 °C 4: sodium hydroxide; water / methanol / 25 - 30 °C 5: sodium hydroxide; hydrogen / methanol; water / 60 - 65 °C / 6080.41 - 7600.51 Torr 6: sodium tetrahydroborate; boron trifluoride diethyl etherate / tetrahydrofuran / 4 h / 10 °C / Reflux 7: phosphorus tribromide / chloroform / Reflux View Scheme
Multi-step reaction with 7 steps 1: potassium iodide; sodium hydroxide / dimethyl sulfoxide / 50 - 80 °C 2: toluene-4-sulfonic acid / Reflux; Large scale 3: polyphosphoric acid / toluene / 105 - 110 °C 4: hydrogen; acetic acid; palladium 10% on activated carbon / methanol / 65 - 70 °C / 3040.2 - 3800.26 Torr 5: sodium hydroxide; water / methanol / 25 - 60 °C 6: sodium tetrahydroborate; boron trifluoride diethyl etherate / tetrahydrofuran / 4 h / 10 °C / Reflux 7: phosphorus tribromide / chloroform / Reflux View Scheme

4-((2,2-dimethoxy)ethoxy)phenylacetic acid → 2,3-dihydro-5-(2-bromoethyl)benzofuran (127264-14-6)

Conditions	Yield
Multi-step reaction with 6 steps 1: toluene-4-sulfonic acid / Reflux; Large scale 2: polyphosphoric acid / toluene / 105 - 110 °C 3: hydrogen; acetic acid; palladium 10% on activated carbon / methanol / 65 - 70 °C / 3040.2 - 3800.26 Torr 4: sodium hydroxide; water / methanol / 25 - 60 °C 5: sodium tetrahydroborate; boron trifluoride diethyl etherate / tetrahydrofuran / 4 h / 10 °C / Reflux 6: phosphorus tribromide / chloroform / Reflux View Scheme
Multi-step reaction with 6 steps 1: toluene-4-sulfonic acid / Reflux; Large scale 2: polyphosphoric acid / toluene / 105 - 110 °C 3: sodium hydroxide; water / methanol / 25 - 30 °C 4: sodium hydroxide; hydrogen / methanol; water / 60 - 65 °C / 6080.41 - 7600.51 Torr 5: sodium tetrahydroborate; boron trifluoride diethyl etherate / tetrahydrofuran / 4 h / 10 °C / Reflux 6: phosphorus tribromide / chloroform / Reflux View Scheme

methyl 4-((2,2-dimethoxy)ethoxy)phenylacetate → 2,3-dihydro-5-(2-bromoethyl)benzofuran (127264-14-6)

Conditions	Yield
Multi-step reaction with 5 steps 1: polyphosphoric acid / toluene / 105 - 110 °C 2: hydrogen; acetic acid; palladium 10% on activated carbon / methanol / 65 - 70 °C / 3040.2 - 3800.26 Torr 3: sodium hydroxide; water / methanol / 25 - 60 °C 4: sodium tetrahydroborate; boron trifluoride diethyl etherate / tetrahydrofuran / 4 h / 10 °C / Reflux 5: phosphorus tribromide / chloroform / Reflux View Scheme
Multi-step reaction with 5 steps 1: polyphosphoric acid / toluene / 105 - 110 °C 2: sodium hydroxide; water / methanol / 25 - 30 °C 3: sodium hydroxide; hydrogen / methanol; water / 60 - 65 °C / 6080.41 - 7600.51 Torr 4: sodium tetrahydroborate; boron trifluoride diethyl etherate / tetrahydrofuran / 4 h / 10 °C / Reflux 5: phosphorus tribromide / chloroform / Reflux View Scheme

methyl 2-(benzofuran-5-yl)acetate (121638-36-6) → 2,3-dihydro-5-(2-bromoethyl)benzofuran (127264-14-6)

Conditions	Yield
Multi-step reaction with 4 steps 1: sodium hydroxide; water / methanol / 25 - 30 °C 2: sodium hydroxide; hydrogen / methanol; water / 60 - 65 °C / 6080.41 - 7600.51 Torr 3: sodium tetrahydroborate; boron trifluoride diethyl etherate / tetrahydrofuran / 4 h / 10 °C / Reflux 4: phosphorus tribromide / chloroform / Reflux View Scheme
Multi-step reaction with 4 steps 1: hydrogen; acetic acid; palladium 10% on activated carbon / methanol / 65 - 70 °C / 3040.2 - 3800.26 Torr 2: sodium hydroxide; water / methanol / 25 - 60 °C 3: sodium tetrahydroborate; boron trifluoride diethyl etherate / tetrahydrofuran / 4 h / 10 °C / Reflux 4: phosphorus tribromide / chloroform / Reflux View Scheme

benzofuran-5-yl-acetic acid (142935-60-2) → 2,3-dihydro-5-(2-bromoethyl)benzofuran (127264-14-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium hydroxide; hydrogen / methanol; water / 60 - 65 °C / 6080.41 - 7600.51 Torr 2: sodium tetrahydroborate; boron trifluoride diethyl etherate / tetrahydrofuran / 4 h / 10 °C / Reflux 3: phosphorus tribromide / chloroform / Reflux View Scheme

methyl 2-(2,3-dihydrobenzofuran-5-yl)acetate (155852-41-8) → 2,3-dihydro-5-(2-bromoethyl)benzofuran (127264-14-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium hydroxide; water / methanol / 25 - 60 °C 2: sodium tetrahydroborate; boron trifluoride diethyl etherate / tetrahydrofuran / 4 h / 10 °C / Reflux 3: phosphorus tribromide / chloroform / Reflux View Scheme

styrene (292638-84-7) + 2,3-dihydro-5-(2-bromoethyl)benzofuran (127264-14-6) + 1-benzyl-4-iodo-5-methylpyridin-2(1H)-one → (E)-1-benzyl-3-(2-(2,3-dihydrobenzofuran-5-yl)ethyl)-5-methyl-4-styrylpyridin-2(1H)-one

Conditions	Yield
With palladium diacetate; potassium carbonate In 1,4-dioxane at 105℃; for 36h; Inert atmosphere;	96%

2,3-dihydro-5-(2-bromoethyl)benzofuran (127264-14-6) + bromobenzene (108-86-1) → 5-(1-phenylethyl)-2,3-dihydrobenzofuran

Conditions	Yield
With nickel(II) iodide; Bathocuproine; tetrabutylammomium bromide; zinc at 20℃; regioselective reaction;	95%
With nickel(II) bromide dimethoxyethane; [Ir(dF(CF3)ppy)2(phen)]PF6; Bathocuproine; diisopropylamine; magnesium bromide In N,N-dimethyl-formamide at 20℃; for 24h; Inert atmosphere; Glovebox; Sealed tube; Irradiation; regioselective reaction;	87%

2,3-dihydro-5-(2-bromoethyl)benzofuran (127264-14-6) + (S)-2,2-diphenyl-2-(pyrrolidin-3-yl)-acetamide L-tartrate → (S)-darifenacin hydrobromide (133099-07-7)

Conditions	Yield
Stage #1: 2,3-dihydro-5-(2-bromoethyl)benzofuran; (S)-2,2-diphenyl-2-(pyrrolidin-3-yl)-acetamide L-tartrate With potassium hydroxide; triethylmethylammonium chloride In water; toluene at 100℃; for 15.25h; Stage #2: With hydrogen bromide In water; toluene Product distribution / selectivity;	93.2%
Stage #1: (S)-2,2-diphenyl-2-(pyrrolidin-3-yl)-acetamide L-tartrate With potassium hydroxide; triethylmethylammonium chloride In 2-methyltetrahydrofuran; water at 60 - 70℃; Stage #2: 2,3-dihydro-5-(2-bromoethyl)benzofuran In 2-methyltetrahydrofuran; water for 16h; Heating / reflux; Stage #3: With hydrogen bromide In 2-methyltetrahydrofuran; water at 0 - 20℃; for 2h; Product distribution / selectivity;	90.67%
Stage #1: 2,3-dihydro-5-(2-bromoethyl)benzofuran; (S)-2,2-diphenyl-2-(pyrrolidin-3-yl)-acetamide L-tartrate With potassium hydroxide; triethylmethylammonium chloride In water; butanone at 75℃; for 6h; Stage #2: With hydrogen bromide In water; butanone at 0 - 5℃; for 2h; Product distribution / selectivity;	84.92%

2,3-dihydro-5-(2-bromoethyl)benzofuran (127264-14-6) + 4-Bromodiphenyl ether (101-55-3) → C22H20O2

Conditions	Yield
With nickel(II) iodide; Bathocuproine; tetrabutylammomium bromide; zinc at 20℃; regioselective reaction;	90%

5-bromo-1H-indole (10075-50-0) + 2,3-dihydro-5-(2-bromoethyl)benzofuran (127264-14-6) → C18H17NO

Conditions	Yield
With nickel(II) iodide; Bathocuproine; tetrabutylammomium bromide; zinc at 20℃; regioselective reaction;	90%

2,3-dihydro-5-(2-bromoethyl)benzofuran (127264-14-6) + 3-(S)-(+)-(1-cyano-1,1-diphenylmethyl)pyrrolidine hydrobromide → (-)-3S-(1-carbonitrile-1,1-diphenylmethyl)-1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]pyrrolidine hydrobromide

Conditions	Yield
Stage #1: 2,3-dihydro-5-(2-bromoethyl)benzofuran; 3-(S)-(+)-(1-cyano-1,1-diphenylmethyl)pyrrolidine hydrobromide With potassium carbonate In water at 75℃; for 4h; Stage #2: With hydrogen bromide In water	89.93%

2,3-dihydro-5-(2-bromoethyl)benzofuran (127264-14-6) + 4,4,5,5-tetramethyl-[1,3,2]-dioxaboralane (25015-63-8) → 2-[2-(2,3-dihydro-1-benzofuran-5-yl)ethyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Conditions	Yield
Stage #1: 4,4,5,5-tetramethyl-[1,3,2]-dioxaboralane With bis(cyclopentadienyl)titanium dichloride; lithium methanolate In tert-butyl methyl ether for 0.5h; Stage #2: 2,3-dihydro-5-(2-bromoethyl)benzofuran In tert-butyl methyl ether at 60℃; under 760.051 Torr; for 24h; Inert atmosphere;	89%
Stage #1: 4,4,5,5-tetramethyl-[1,3,2]-dioxaboralane With bis(cyclopentadienyl)titanium dichloride; lithium methanolate In tert-butyl methyl ether for 0.5h; Inert atmosphere; Glovebox; Stage #2: 2,3-dihydro-5-(2-bromoethyl)benzofuran In tert-butyl methyl ether at 60℃; for 24h; Sealed tube;	89%

2,3-dihydro-5-(2-bromoethyl)benzofuran (127264-14-6) + (2-bromo-2-fluoroethyl)benzene (151588-78-2) → C18H19FO

Conditions	Yield
With nickel(II) bromide dimethoxyethane; tetra-(n-butyl)ammonium iodide; potassium carbonate; 2,6-bis(4,5-dihydro-1H-imidazol-2-yl)pyridine; 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinane In 1-methyl-pyrrolidin-2-one at 60℃; for 24h; Inert atmosphere; Sealed tube; Glovebox;	88%

glutaric anhydride, (108-55-4) + 2,3-dihydro-5-(2-bromoethyl)benzofuran (127264-14-6) → C14H18O3

Conditions	Yield
With [2,2]bipyridinyl; bis(1,5-cyclooctadiene)nickel (0); zinc In N,N-dimethyl acetamide at 80℃; for 12h;	87%

2,3-dihydro-5-(2-bromoethyl)benzofuran (127264-14-6) + 2,2-diphenyl-2-[(3S)-pyrrolidin-3-yl]acetamide (134002-25-8) → (S)-darifenacin hydrobromide (133099-07-7)

Conditions	Yield
Stage #1: 2,3-dihydro-5-(2-bromoethyl)benzofuran; 2,2-diphenyl-2-[(3S)-pyrrolidin-3-yl]acetamide With potassium hydroxide; triethylmethylammonium chloride In water; butanone at 75℃; for 6h; Heating / reflux; Stage #2: With hydrogen bromide In water; butanone	84.92%
Stage #1: 2,3-dihydro-5-(2-bromoethyl)benzofuran; 2,2-diphenyl-2-[(3S)-pyrrolidin-3-yl]acetamide With potassium carbonate In acetonitrile at 70 - 75℃; for 2h; Stage #2: With hydrogen bromide In water; acetone at 0 - 25℃; Product distribution / selectivity;
With potassium carbonate In acetonitrile

succinic acid anhydride (108-30-5) + 2,3-dihydro-5-(2-bromoethyl)benzofuran (127264-14-6) → 5-(2,3-dihydro-benzofuran-5-yl)-valeric acid

Conditions	Yield
With [2,2]bipyridinyl; bis(1,5-cyclooctadiene)nickel (0); zinc In N,N-dimethyl acetamide at 80℃; for 12h;	82%

2,3-dihydro-5-(2-bromoethyl)benzofuran (127264-14-6) + 3-methyl-2,3,4,6-tetrahydro-1H-benzo[c][2,7]naphthyridin-5-one → C23H24N2O2

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 80℃;	75%

2,3-dihydro-5-(2-bromoethyl)benzofuran (127264-14-6) + 1-bromo-3,4,5-trimethoxybenzene (2675-79-8) → C19H22O4 + C19H22O4

Conditions	Yield
With nickel(II) iodide; Bathocuproine; tetrabutylammomium bromide; zinc at 20℃; regioselective reaction;	A 75% B n/a

2,3-dihydro-5-(2-bromoethyl)benzofuran (127264-14-6) + Cyclopentyl bromide (137-43-9) → C15H19BrO

Conditions	Yield
With nickel(II) iodide; C17H20N2O2; lithium bromide; zinc In 1-methyl-pyrrolidin-2-one at 30℃; for 24h; regioselective reaction;	75%

2,3-dihydro-5-(2-bromoethyl)benzofuran (127264-14-6) + N-(4-bromophenyl)benzamide (7702-38-7) → C23H21NO2

Conditions	Yield
With nickel(II) iodide; Bathocuproine; tetrabutylammomium bromide; zinc at 20℃; regioselective reaction;	73%

2,3-dihydro-5-(2-bromoethyl)benzofuran (127264-14-6) + fenofibrate (49562-28-9) → isopropyl2-(4-(4-(1-(2,3-dihydrobenzofuran-5-yl)ethyl)benzoyl)phenoxy)-2-methylpropanoate

Conditions	Yield
With 2.9-dimethyl-1,10-phenanthroline; nickel(II) perchlorate hexahydrate; tetrabutylammomium bromide In N,N-dimethyl acetamide at 20℃; for 10h; Glovebox; Sealed tube; Electrochemical reaction; Inert atmosphere; regioselective reaction;	72%

2,3-dihydro-5-(2-bromoethyl)benzofuran (127264-14-6) + 5-bromo-2-(4-morpholinyl)pyridine (200064-11-5) → C19H22N2O2

Conditions	Yield
With nickel(II) iodide; Bathocuproine; tetrabutylammomium bromide; zinc at 20℃; regioselective reaction;	69%

2,3-dihydro-5-(2-bromoethyl)benzofuran (127264-14-6) + ethyl 4-phenyl-1,2,5,6-tetrahydropyridine-3-carboxylate (1423014-09-8) → ethyl 1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-4-phenyl-1,2,5,6-tetrahydropyridine-3-carboxylate hydrochloride

Conditions	Yield
Stage #1: 2,3-dihydro-5-(2-bromoethyl)benzofuran; ethyl 4-phenyl-1,2,5,6-tetrahydropyridine-3-carboxylate With potassium carbonate; potassium iodide In acetonitrile Reflux; Inert atmosphere; Stage #2: With hydrogenchloride In diethyl ether; water Inert atmosphere;	52%

2,3-dihydro-5-(2-bromoethyl)benzofuran (127264-14-6) + (3S)-pyrrolidin-3-yl-cyclopentyl(hydroxy)phenyl acetate (719278-77-0) → (3S)-1-[[2-(2,3-dihydro-1-benzofuran-5-yl)ethyl]pyrolidin-3-yl]cyclopentyl(hydroxy)phenyl acetate

Conditions	Yield
With potassium carbonate; potassium iodide In acetonitrile for 8h; Heating / reflux;	50%

2,3-dihydro-5-(2-bromoethyl)benzofuran (127264-14-6) + (3S)-pyrrolidin-3-yl-(2R)-cyclopentyl(hydroxy)phenyl acetate → (3S)-1-[[2-(2,3-dihydro-1-benzofuran-5-yl)ethyl]pyrolidin-3-yl](2R)-cyclopentyl(hydroxy)phenyl acetate

Conditions	Yield
With potassium carbonate; potassium iodide In acetonitrile for 8h; Heating / reflux;	46%

2,3-dihydro-5-(2-bromoethyl)benzofuran (127264-14-6) + C19H22N2O (910108-52-0) → 2-{(3R)-1-[2-(2,3-dihydro-1-benzofuran-5-yl)ethyl]piperidin-3-yl}-2,2-diphenylacetamide

Conditions	Yield
With potassium carbonate In acetonitrile Heating / reflux;	45%

2,3-dihydro-5-(2-bromoethyl)benzofuran (127264-14-6) + 5-methoxylindole (1006-94-6) → C19H19NO2

Conditions	Yield
With norborn-2-ene; palladium diacetate; potassium carbonate at 80℃; for 18h; Inert atmosphere;	28%

2,3-dihydro-5-(2-bromoethyl)benzofuran (127264-14-6) + 2,2-diphenyl-2-[(3S)-pyrrolidin-3-yl]acetamide (134002-25-8) → darifenacin (133099-04-4)

Conditions	Yield
With potassium carbonate In acetonitrile for 2h; Heating / reflux;	9%
With potassium phosphate In water; toluene at 20 - 90℃; for 3.5h; Product distribution / selectivity;
With potassium carbonate In water; toluene at 20 - 90℃; for 3.5h; Product distribution / selectivity;
With potassium phosphate In cyclohexane; water at 20 - 90℃; for 3.5h; Product distribution / selectivity;
With potassium hydroxide In acetonitrile at 40 - 50℃; for 18h; Product distribution / selectivity;

2,3-dihydro-5-(2-bromoethyl)benzofuran (127264-14-6) → (S)-darifenacin hydrobromide (133099-07-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium hydroxide / acetonitrile / 18 h / 40 - 50 °C 2: hydrogen bromide / water; acetone / 2.25 - 12 h / 0 - 30 °C View Scheme
Multi-step reaction with 3 steps 1: potassium carbonate / acetonitrile 2: ammonia / methanol / 5 - 7 h / 28 - 45 °C 3: hydrogen bromide / water; acetone / 2.25 - 12 h / 0 - 30 °C View Scheme

2,3-dihydro-5-(2-bromoethyl)benzofuran (127264-14-6) + C21H26N2O → 2-{(3R)-1-[2-(2,3-dihydro-1-benzofuran-5-yl)ethyl]piperidin-3-yl}-N,N-dimethyl-2,2-diphenylacetamide

Conditions	Yield
With potassium carbonate In acetonitrile Heating / reflux;

Upstream product

• 156-38-7 4-hydroxyphenylacetate 
• 121638-36-6 methyl 2-(benzofuran-5-yl)acetate 
• 142935-60-2 benzofuran-5-yl-acetic acid 
• 155852-41-8 methyl 2-(2,3-dihydrobenzofuran-5-yl)acetate 
• 69999-16-2 2,3-dihydrobenzofuran-5-acetic acid 
• 79002-49-6 ethyl 2( 2,3-dihydro-1-benzofuran-5-yl)oxoacetate 
• 64089-34-5 2-chloro-1-(2,3-dihydrobenzofuran-5-yl)ethanone 
• 496-16-2 2.3-dihydrobenzofuran 
• 151427-19-9 2-bromo-1-(2,3-dihydrobenzofuran-5-yl)ethan-1-one 
• 90843-31-5 1-(2,3-dihydrobenzofuran-5-yl)ethanone 
• 943034-50-2 2-(2,3-dihydrobenzofuran-5-yl)ethylchloride 
• 87776-76-9 5-(2-hydroxyethyl)-2,3-dihydrobenzofuran 

Downstream Products

• 133099-04-4 darifenacin 
• 1072227-73-6 2,2-diphenyl-2-{(S)-1-[2-(2,3-dihydro-benzofuran-5-yl)-ethyl]-pyrrolidin-3-yl}-acetic acid methyl ester 
• 133099-07-7 (S)-darifenacin hydrobromide 
• 586346-94-3 darifenacin hydrochloride 
• 133099-05-5 2-{(3R)-1-[2-(2,3-dihydro-1-benzofuran-5-yl)ethyl]pyrrolidin-3-yl}-2,2-diphenylacetamide 
• 1404054-53-0 (R)-3-((bis(3-fluorophenyl)methoxy)carbonyl amino)-1-(2-(2,3-dihydrobenzofuran-5-yl)ethyl)-1-azoniabicyclo[2.2.2]octane bromide 

Relevant articles and documents

Darifenacin intermediate 2, 3 - dihydro - 5 - benzofuran acetic acid preparation new method of (by machine translation)

The invention relates to a darifenacin intermediate - 2, 3 - dihydro - 5 - benzofuran acetic acid. By the P-hydroxy-acetic acid and bromo acetaldehyde acetal as the starting material, the presence of O - alkylation reaction under a condition of the corresponding ether compound; then by esterification reaction to obtain the corresponding ester; in PPA (poly phosphoric acid) under the action of the, cyclization to obtain 2, 3 - benzofuran - 5 - acetate; 2, 3 - benzofuran - 5 - acetic acid layer which hydrolysis, to acidify the corresponding carboxylic acid; obtained by catalytic hydrogenation of 2, 3 - dihydro - 5 - benzofuran acetic acid; or the first 2, 3 - benzofuran - 5 - acetate obtained by catalytic hydrogenation of 2, 3 - dihydro - 5 - benzofuran acetic acid esters; and hydrolyzed, acidified to obtain 2, 3 - dihydro - 5 - benzofuran acetic acid. The method of the invention by simple and safe, each reaction raw materials are cheap and easy to obtain, the reaction yield is high, and is particularly suitable for industrial production of 2, 3 - dihydro - 5 - benzofuran acetic acid. (by machine translation)

A new solvent system (Cyclopentyl methyl ether-water) in process development of darifenacin HBr

Darifenacin is a potent and competitive M3 selective receptor antagonist (M3SRA), and its hydrobromide salt (1) is the active ingredient of pharmaceutical formulations for oral treatment of urinary incontinence. The present work demonstrates an efficient, commercial manufacturing process for darifenacin hydrobromide (1).

SUBSTITUTED PYRROLIDINES

Disclosed herein are substituted pyrrolidine-based muscarinic receptor modulators of Formula I, process of preparation thereof, pharmaceutical compositions thereof, and methods of use thereof.