461432-23-5

Basic information

• Product Name: 5-bromo-2-chloro-4’-ethoxydiphenylmethane
• Synonyms: 5-bromo-2-chloro-4’-ethoxydiphenylmethane;Benzene, 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]-;4-(5-Bromo-2-chlorobenzyl)phenyl ethyl ether;Dapagliflozin Intermediate 1;4-broMo-1-chloro-2-[(4-ethoxyphenyl)Methyl]-;2-(4-Methoxybenzyl)-4-broMo-1-chlorobenzene;1-(5-broMo-2-chlorobenzyl)-4-ethoxybenzene;5-broMo-2-chloro-4&rsquo
• CAS NO: 461432-23-5
• Molecular Formula: C₁₅H₁₄BrClO
• Molecular Weight: 325.62806
• EINECS: 1592732-453-0
• Product Categories: Halides;Phenyls & Phenyl-Het
• Mol File: 461432-23-5.mol
• Article Data: 38

Chemical Properties

• Boiling Point: 392.976 °C at 760 mmHg
• Flash Point: 191.465 °C
• Appearance: /
• Density: 1.371 g/cm³
• Storage Temp.: Sealed in dry,Room Temperature
• CAS DataBase Reference: 5-bromo-2-chloro-4’-ethoxydiphenylmethane(CAS DataBase Reference)
• NIST Chemistry Reference: 5-bromo-2-chloro-4’-ethoxydiphenylmethane(461432-23-5)
• EPA Substance Registry System: 5-bromo-2-chloro-4’-ethoxydiphenylmethane(461432-23-5)

Safety Data

• Hazardous Substances Data: 461432-23-5(Hazardous Substances Data)

Usage

Uses

5-Bromo-2-chloro-4'-ethoxydiphenylmethane is a hydrocarbon derivative and can be used as an intermediate for dapagliflozin.

Synthetic route

(5-bromo-2-chlorophenyl)(4-ethyloxyphenyl)methanone (461432-22-4) → 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5)

Conditions	Yield
With triethylsilane; boron trifluoride diethyl etherate In 1,2-dichloro-ethane; acetonitrile at 0 - 50℃; for 3h;	97%
Stage #1: (5-bromo-2-chlorophenyl)(4-ethyloxyphenyl)methanone With sodium tetrahydroborate In dichloromethane; acetonitrile at 30 - 40℃; for 0.5h; Stage #2: With chloro-trimethyl-silane In dichloromethane; acetonitrile at 30 - 40℃; for 3h; Stage #3: With boron trifluoride diethyl etherate In dichloromethane; acetonitrile at 0 - 35℃; for 8h; Inert atmosphere;	96%
Stage #1: (5-bromo-2-chlorophenyl)(4-ethyloxyphenyl)methanone With sodium tetrahydroborate In tetrahydrofuran at 10 - 15℃; for 0.5h; Inert atmosphere; Industry scale; Stage #2: With aluminum (III) chloride In tetrahydrofuran at -5 - 70℃; for 20h; Inert atmosphere; Stage #3: With water at 0 - 40℃; Inert atmosphere;	94%

4-(5-bromo-2-chlorobenzyl)phenol (864070-18-8) + ethyl iodide (75-03-6) → 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5)

Conditions	Yield
With potassium carbonate; potassium iodide In acetone at 20℃;	96%

4-bromo-1-chloro-2-(chloromethyl)benzene + Phenetole (103-73-1) → 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5)

Conditions	Yield
With aluminum (III) chloride In ethyl acetate at 78℃; for 9h; Cooling with ice; Large scale;	89%

5-bromo-2-amino-4'-ethoxydiphenylmethane → 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5)

Conditions	Yield
Stage #1: 5-bromo-2-amino-4'-ethoxydiphenylmethane With hydrogenchloride; sodium nitrite In water at -5 - 0℃; for 3h; Large scale; Stage #2: With hydrogenchloride; copper(l) chloride In water at 20 - 80℃; for 4h; Large scale;	83%
Stage #1: 5-bromo-2-amino-4'-ethoxydiphenylmethane With hydrogenchloride; sodium nitrite In water at -5℃; for 3h; Industrial scale; Stage #2: With copper(l) chloride In water at 20 - 80℃; for 4h; Industrial scale;	83%
Stage #1: 5-bromo-2-amino-4'-ethoxydiphenylmethane With hydrogenchloride; sodium nitrite In water at -5 - 0℃; for 3h; Large scale; Stage #2: With hydrogenchloride; copper(l) chloride In water at 20 - 80℃; for 3h; Large scale;	79%

Phenetole (103-73-1) + 5-Bromo-2-chlorobenzyl bromide (149965-41-3) → 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5)

Conditions	Yield
With zinc(II) chloride at 75℃; for 6h;	71%

(5-bromo-2-chlorophenyl)(4-ethyloxyphenyl)methanone (461432-22-4) + 1,2-dichloro-ethane (107-06-2) → 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5)

Conditions	Yield
With potassium hydroxide; BF3.Et2O; Et3SiH In water; acetonitrile

5-bromo-2-chlorobenzoic acid (21739-92-4) → 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 20 h / 20 °C 1.2: 3 h / 0 - 24 °C 2.1: triethylsilane; boron trifluoride diethyl etherate / dichloromethane / 1 h / 0 - 24 °C View Scheme
Multi-step reaction with 3 steps 1: oxalyl dichloride / dichloromethane; N,N-dimethyl-formamide / 20 °C 2: aluminum (III) chloride / dichloromethane / 1 h / -5 - 0 °C 3: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / -20 - 20 °C View Scheme
Multi-step reaction with 3 steps 1: thionyl chloride; N,N-dimethyl-formamide / dichloromethane / 2 h / Reflux 2: aluminum (III) chloride / dichloromethane / 1 h / Ca. -12 - Ca.-8 °C / Inert atmosphere 3: triethylsilane / dichloromethane / 0.3 h / 0 - 15 °C View Scheme

Phenetole (103-73-1) → 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 20 h / 20 °C 1.2: 3 h / 0 - 24 °C 2.1: triethylsilane; boron trifluoride diethyl etherate / dichloromethane / 1 h / 0 - 24 °C View Scheme
Multi-step reaction with 2 steps 1.1: N,N-dimethyl-formamide; oxalyl dichloride / dichloromethane / 15 h / 25 - 30 °C 1.2: 2 h / 0 - 10 °C 2.1: aluminum (III) chloride; sodium tetrahydroborate / Dimethyl ether / 30 h / 0 - 65 °C View Scheme
Multi-step reaction with 2 steps 1: aluminum (III) chloride / dichloromethane / -10 - 5 °C / Inert atmosphere 2: 1,1,3,3-Tetramethyldisiloxane / 5 - 20 °C View Scheme
Multi-step reaction with 2 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 3 h 1.2: 1 h / 4 - 5 °C 2.1: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / 5 - 10 °C View Scheme
Multi-step reaction with 2 steps 1: aluminum (III) chloride / dichloromethane / 1 h / -20 - 20 °C 2: triethylsilane; boron trifluoride diethyl etherate / 1,2-dichloro-ethane; acetonitrile / 3 h / 0 - 50 °C View Scheme

5-bromo-2-chloro-benzoyl chloride (21900-52-7) → 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: aluminum (III) chloride / dichloromethane / 1 h / -5 - 0 °C 2: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / -20 - 20 °C View Scheme
Multi-step reaction with 2 steps 1: aluminum (III) chloride / dichloromethane / 1 h / Ca. -12 - Ca.-8 °C / Inert atmosphere 2: triethylsilane / dichloromethane / 0.3 h / 0 - 15 °C View Scheme
Multi-step reaction with 2 steps 1.1: aluminum (III) chloride / dichloromethane / 0.5 h / 0 °C 1.2: 0 °C 2.1: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / -10 - 20 °C View Scheme

5-bromo-2-chlorobenzoic acid (21739-92-4) + Phenetole (103-73-1) → 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5)

Conditions	Yield
Stage #1: 5-bromo-2-chlorobenzoic acid With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 25 - 30℃; for 1h; Inert atmosphere; Stage #2: Phenetole With aluminum (III) chloride In dichloromethane at 0 - 5℃; for 2h; Stage #3: With triethylsilane In dichloromethane at 20 - 25℃; for 36h; Reagent/catalyst; Temperature;	2.5 g

4-Bromo-2-methylaniline (583-75-5) → 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: copper(l) chloride; hydrogenchloride; sodium nitrite / water; 1,4-dioxane / 3.5 h / -5 - 80 °C 2: 2,2'-azobis(isobutyronitrile); N-Bromosuccinimide / chloroform / 5 h / Reflux 3: zinc(II) chloride / 6 h / 75 °C View Scheme

o-toluidine (95-53-4) → 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5)

Conditions	Yield
Multi-step reaction with 4 steps 1: N-Bromosuccinimide / N,N-dimethyl-formamide / 0 °C 2: copper(l) chloride; hydrogenchloride; sodium nitrite / water; 1,4-dioxane / 3.5 h / -5 - 80 °C 3: 2,2'-azobis(isobutyronitrile); N-Bromosuccinimide / chloroform / 5 h / Reflux 4: zinc(II) chloride / 6 h / 75 °C View Scheme

5-bromo-2-chlorobenzoic acid (21739-92-4) + C8H12O → 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: oxalyl dichloride / dichloromethane; N,N-dimethyl-formamide / 10 - 30 °C 1.2: 1 h / Cooling with ice 2.1: boron trifluoride diethyl etherate; triethylsilane / dichloromethane; acetonitrile / 30 °C / Cooling with ice View Scheme

4-hydroxy-benzaldehyde (123-08-0) → 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: potassium carbonate / N,N-dimethyl-formamide; toluene / 2 h / 60 °C / Large scale 2.1: hydroxylamine hydrochloride / ethanol / 4 h / Reflux; Large scale 2.2: 5 h / Reflux; Large scale 3.1: hydrogenchloride; boron trichloride; calcium chloride / chlorobenzene / 20 h / 100 °C / Large scale 4.1: hydrogenchloride; sodium nitrite / water / 3 h / -5 - 0 °C / Large scale 4.2: 3 h / 20 - 80 °C / Large scale 5.1: lithium chloride; sodium tetrahydroborate / ethanol / 5 h / -5 - 70 °C / Large scale View Scheme
Multi-step reaction with 5 steps 1.1: potassium carbonate; tetrabutylammomium bromide / 10 h / 130 °C / Industrial scale 2.1: palladium(II) hydroxide; hydrogen / ethanol / 6 h / Reflux; Industrial scale 3.1: hydrogen fluoride / ethyl acetate / 8.5 h / Cooling with ice; Industrial scale 4.1: hydrogenchloride / water; methanol / 6 h / 80 °C / Industrial scale 5.1: hydrogenchloride; sodium nitrite / water / 3 h / -5 °C / Industrial scale 5.2: 4 h / 20 - 80 °C / Industrial scale View Scheme

5-bromo-2-amino-4'-ethoxybenzophenone → 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: hydrogenchloride; sodium nitrite / water / 3 h / -5 - 0 °C / Large scale 1.2: 3 h / 20 - 80 °C / Large scale 2.1: lithium chloride; sodium tetrahydroborate / ethanol / 5 h / -5 - 70 °C / Large scale View Scheme

4-ethoxybenzonitrile (25117-74-2) → 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: hydrogenchloride; boron trichloride; calcium chloride / chlorobenzene / 20 h / 100 °C / Large scale 2.1: hydrogenchloride; sodium nitrite / water / 3 h / -5 - 0 °C / Large scale 2.2: 3 h / 20 - 80 °C / Large scale 3.1: lithium chloride; sodium tetrahydroborate / ethanol / 5 h / -5 - 70 °C / Large scale View Scheme

4-ethoxybenzaldehyde (10031-82-0) → 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: hydroxylamine hydrochloride / ethanol / 4 h / Reflux; Large scale 1.2: 5 h / Reflux; Large scale 2.1: hydrogenchloride; boron trichloride; calcium chloride / chlorobenzene / 20 h / 100 °C / Large scale 3.1: hydrogenchloride; sodium nitrite / water / 3 h / -5 - 0 °C / Large scale 3.2: 3 h / 20 - 80 °C / Large scale 4.1: lithium chloride; sodium tetrahydroborate / ethanol / 5 h / -5 - 70 °C / Large scale View Scheme
Multi-step reaction with 4 steps 1.1: palladium(II) hydroxide; hydrogen / ethanol / 6 h / Reflux; Industrial scale 2.1: hydrogen fluoride / ethyl acetate / 8.5 h / Cooling with ice; Industrial scale 3.1: hydrogenchloride / water; methanol / 6 h / 80 °C / Industrial scale 4.1: hydrogenchloride; sodium nitrite / water / 3 h / -5 °C / Industrial scale 4.2: 4 h / 20 - 80 °C / Industrial scale View Scheme

4-bromo-aniline (106-40-1) → 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: hydrogenchloride; boron trichloride; calcium chloride / chlorobenzene / 20 h / 100 °C / Large scale 2.1: hydrogenchloride; sodium nitrite / water / 3 h / -5 - 0 °C / Large scale 2.2: 3 h / 20 - 80 °C / Large scale 3.1: lithium chloride; sodium tetrahydroborate / ethanol / 5 h / -5 - 70 °C / Large scale View Scheme
Multi-step reaction with 4 steps 1.1: water; methanol / 5 h / 20 °C / Cooling with ice; Large scale 2.1: aluminum (III) chloride / ethyl acetate / 8 h / Cooling with ice; Reflux; Large scale 3.1: hydrogenchloride / water; methanol / 6 h / 80 °C / Large scale 4.1: hydrogenchloride; sodium nitrite / water / 3 h / -5 - 0 °C / Large scale 4.2: 4 h / 20 - 80 °C / Large scale View Scheme
Multi-step reaction with 4 steps 1.1: water; methanol / 5.5 h / 20 °C / Cooling with ice; Industrial scale 2.1: hydrogen fluoride / ethyl acetate / 8.5 h / Cooling with ice; Industrial scale 3.1: hydrogenchloride / water; methanol / 6 h / 80 °C / Industrial scale 4.1: hydrogenchloride; sodium nitrite / water / 3 h / -5 °C / Industrial scale 4.2: 4 h / 20 - 80 °C / Industrial scale View Scheme

p-cresol (106-44-5) → 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: potassium carbonate / N,N-dimethyl-formamide; toluene / 2.5 h / 60 °C / Large scale 2.1: N-chloro-succinimide; dibenzoyl peroxide / Petroleum ether / 8 h / Reflux; Large scale 3.1: zinc(II) chloride / ethyl acetate / 8 h / Reflux; Large scale 4.1: hydrogenchloride; sodium nitrite / water / 3 h / -5 - 0 °C / Large scale 4.2: 3 h / 20 - 80 °C / Large scale View Scheme
Multi-step reaction with 5 steps 1.1: potassium carbonate; tetrabutylammomium bromide / 10 h / 130 °C / Large scale 2.1: N-Bromosuccinimide; dibenzoyl peroxide / chloroform / 6 h / Reflux; Large scale 3.1: aluminum (III) chloride / ethyl acetate / 8 h / Cooling with ice; Reflux; Large scale 4.1: hydrogenchloride / water; methanol / 6 h / 80 °C / Large scale 5.1: hydrogenchloride; sodium nitrite / water / 3 h / -5 - 0 °C / Large scale 5.2: 4 h / 20 - 80 °C / Large scale View Scheme

1-ethoxy-4-methylbenzene (622-60-6) → 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: N-chloro-succinimide; dibenzoyl peroxide / Petroleum ether / 8 h / Reflux; Large scale 2.1: zinc(II) chloride / ethyl acetate / 8 h / Reflux; Large scale 3.1: hydrogenchloride; sodium nitrite / water / 3 h / -5 - 0 °C / Large scale 3.2: 3 h / 20 - 80 °C / Large scale View Scheme
Multi-step reaction with 4 steps 1.1: N-Bromosuccinimide; dibenzoyl peroxide / chloroform / 6 h / Reflux; Large scale 2.1: aluminum (III) chloride / ethyl acetate / 8 h / Cooling with ice; Reflux; Large scale 3.1: hydrogenchloride / water; methanol / 6 h / 80 °C / Large scale 4.1: hydrogenchloride; sodium nitrite / water / 3 h / -5 - 0 °C / Large scale 4.2: 4 h / 20 - 80 °C / Large scale View Scheme

2-chloro-benzaldehyde (89-98-5) → 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5)

Conditions	Yield
Multi-step reaction with 4 steps 1: N-Bromosuccinimide / dichloromethane / 10.5 h / 5 °C / Large scale 2: sodium tetrahydroborate / ethanol / 4 h / 20 °C / Large scale 3: thionyl chloride / 3 h / 70 °C / Large scale 4: aluminum (III) chloride / ethyl acetate / 9 h / 78 °C / Cooling with ice; Large scale View Scheme

2-chloro-5-bromobenzaldehyde (189628-37-3) → 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium tetrahydroborate / ethanol / 4 h / 20 °C / Large scale 2: thionyl chloride / 3 h / 70 °C / Large scale 3: aluminum (III) chloride / ethyl acetate / 9 h / 78 °C / Cooling with ice; Large scale View Scheme

5-bromo-2-chlorobenzyl alcohol (149965-40-2) → 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: thionyl chloride / 3 h / 70 °C / Large scale 2: aluminum (III) chloride / ethyl acetate / 9 h / 78 °C / Cooling with ice; Large scale View Scheme

4-ethoxybenzyl bromide (2606-57-7) → 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: aluminum (III) chloride / ethyl acetate / 8 h / Cooling with ice; Reflux; Large scale 2.1: hydrogenchloride / water; methanol / 6 h / 80 °C / Large scale 3.1: hydrogenchloride; sodium nitrite / water / 3 h / -5 - 0 °C / Large scale 3.2: 4 h / 20 - 80 °C / Large scale View Scheme

4-bromoacetanilide (103-88-8) → 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: aluminum (III) chloride / ethyl acetate / 8 h / Cooling with ice; Reflux; Large scale 2.1: hydrogenchloride / water; methanol / 6 h / 80 °C / Large scale 3.1: hydrogenchloride; sodium nitrite / water / 3 h / -5 - 0 °C / Large scale 3.2: 4 h / 20 - 80 °C / Large scale View Scheme
Multi-step reaction with 3 steps 1.1: hydrogen fluoride / ethyl acetate / 8.5 h / Cooling with ice; Industrial scale 2.1: hydrogenchloride / water; methanol / 6 h / 80 °C / Industrial scale 3.1: hydrogenchloride; sodium nitrite / water / 3 h / -5 °C / Industrial scale 3.2: 4 h / 20 - 80 °C / Industrial scale View Scheme

2'-(4-ethoxybenzyl)-4'-bromoacetanilide → 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: hydrogenchloride / water; methanol / 6 h / 80 °C / Large scale 2.1: hydrogenchloride; sodium nitrite / water / 3 h / -5 - 0 °C / Large scale 2.2: 4 h / 20 - 80 °C / Large scale View Scheme
Multi-step reaction with 2 steps 1.1: hydrogenchloride / water; methanol / 6 h / 80 °C / Industrial scale 2.1: hydrogenchloride; sodium nitrite / water / 3 h / -5 °C / Industrial scale 2.2: 4 h / 20 - 80 °C / Industrial scale View Scheme

(2-chloro-5-bromophenyl)(4-fluorophenyl)methanone (915095-85-1) → 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hydroxide / N,N-dimethyl-formamide / 50 - 60 °C 2: sodium tetrahydroborate / tetrahydrofuran / 0.5 h / 10 °C / Inert atmosphere View Scheme

fluorobenzene (462-06-6) → 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: thionyl chloride; N,N-dimethyl-formamide / dichloromethane / 39 - 42 °C 1.2: Reflux 2.1: sodium hydroxide / N,N-dimethyl-formamide / 50 - 60 °C 3.1: sodium tetrahydroborate / tetrahydrofuran / 0.5 h / 10 °C / Inert atmosphere View Scheme

4-ethoxybenzyl alcohol (6214-44-4) → 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: hydrogen fluoride / ethyl acetate / 8.5 h / Cooling with ice; Industrial scale 2.1: hydrogenchloride / water; methanol / 6 h / 80 °C / Industrial scale 3.1: hydrogenchloride; sodium nitrite / water / 3 h / -5 °C / Industrial scale 3.2: 4 h / 20 - 80 °C / Industrial scale View Scheme

4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5) → 4-(5-bromo-2-chlorobenzyl)phenol (864070-18-8)

Conditions	Yield
With boron tribromide; sodium hydrogencarbonate In dichloromethane at 20 - 30℃; for 0.5h; Inert atmosphere;	100%
Stage #1: 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene With boron trichloride In dichloromethane at 0℃; for 0.5h; Inert atmosphere; Stage #2: With boron tribromide In dichloromethane at 0℃;	98%
With boron tribromide In dichloromethane for 1h;	95%

4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5) + (3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-one (1461750-25-3) → C42H43ClO6

Conditions	Yield
Stage #1: 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene With n-butyllithium In tetrahydrofuran; hexane at -80 - -75℃; for 3h; Inert atmosphere; Stage #2: (3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-one In tetrahydrofuran; hexane at -80 - -75℃; for 4h;	100%
Stage #1: 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5h; Sealed tube; Stage #2: (3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-one In tetrahydrofuran; hexane at -78℃; for 1h; Sealed tube;

4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5) + (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one (32469-28-6, 55515-28-1, 55515-29-2, 32384-65-9) → (2S,3R,4S,5R,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-3,4,5-tris(trimethylsilyloxy)-6-(trimethylsilyloxymethyl)tetrahydropyran-2-ol

Conditions	Yield
Stage #1: 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.666667h; Inert atmosphere; Stage #2: (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one In tetrahydrofuran; hexane at -78℃; for 5h; Inert atmosphere;	100%
Stage #1: 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene With n-hexyllithium In tetrahydrofuran; hexane; toluene at -84 - -74℃; for 1h; Large scale; Stage #2: (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one In tetrahydrofuran; hexane; toluene at -74 - -15℃; for 2h; Large scale;
Stage #1: 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.666667h; Inert atmosphere; Stage #2: (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one In tetrahydrofuran; hexane at -78℃; for 5h;
Stage #1: 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.666667h; Stage #2: (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one In tetrahydrofuran; hexane at -78℃; for 5h;

4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5) + (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-one → (2S,3R,4S,5R,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-3,4,5-tris(trimethylsilyloxy)-6-(trimethylsilyloxymethyl)tetrahydropyran-2-ol

Conditions	Yield
Stage #1: 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.666667h; Inert atmosphere; Stage #2: (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-one In tetrahydrofuran; hexane at -78℃; for 5h; Inert atmosphere;	100%

4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5) + (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one (32469-28-6, 55515-28-1, 55515-29-2, 32384-65-9) → (3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (461432-24-6)

Conditions	Yield
Stage #1: 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene With n-butyllithium; isopropylmagnesium chloride In tetrahydrofuran; hexane; toluene at -30℃; for 1h; Stage #2: (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one In tetrahydrofuran; hexane; toluene for 1h;	99%
Stage #1: 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene With n-butyllithium In tetrahydrofuran; toluene at -78 - -70℃; for 0.5h; Stage #2: (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one In tetrahydrofuran; toluene at -70℃; for 0.5h; Stage #3: With methanesulfonic acid In methanol at 20℃; for 16h; Further stages.;	85%

4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5) + (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one (32469-28-6, 55515-28-1, 55515-29-2, 32384-65-9) → (3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,3,4,5-tetraol

Conditions	Yield
Stage #1: 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene With n-butyllithium In tetrahydrofuran; toluene at -80 - -70℃; for 0.5h; Inert atmosphere; Stage #2: (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one In tetrahydrofuran; toluene at -80 - -70℃; for 1h; Stage #3: With trifluoroacetic acid In tetrahydrofuran; water; toluene at -20 - 20℃;	98.4%
Stage #1: 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene With n-butyllithium In tetrahydrofuran; hexane; toluene at -80 - -78℃; for 0.5h; Inert atmosphere; Large scale; Stage #2: (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one In tetrahydrofuran; hexane; toluene for 1h; Cooling; Large scale; Stage #3: With trifluoroacetic acid In tetrahydrofuran; hexane; water; toluene at -30 - 15℃; for 2h; Large scale;

4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5) + 2-chloro-N-methoxy-N-methylacetamide (67442-07-3) → 2-chloro-1-(4-chloro-3-(4-ethoxybenzyl)phenyl)ethanone

Conditions	Yield
Stage #1: 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.75h; Stage #2: 2-chloro-N-methoxy-N-methylacetamide In tetrahydrofuran; hexane at -78℃; for 3h;	98%

4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5) → 2-chloro-4'-ethoxydiphenylmethane + 1-benzyl-4-ethoxybenzene (35672-52-7)

Conditions	Yield
With palladium on activated charcoal; hydrogen In ethanol at 20℃; for 3h; Reagent/catalyst;	A n/a B 96%

4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5) → 2-chloro-4'-ethoxydiphenylmethane

Conditions	Yield
With n-butyllithium In tetrahydrofuran; toluene at -78℃; for 0.5h;	93%
Stage #1: 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene With n-butyllithium In tetrahydrofuran at -78℃; for 0.5h; Stage #2: With ammonium chloride In tetrahydrofuran at 20℃; for 0.5h;	93%

4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5) + (3R,4R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5,5-difluorotetrahydro-2H-pyran-2-one (1369405-80-0) → C42H41ClF2O6 (1369406-03-0)

Conditions

Yield

Stage #1: 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene With n-butyllithium In tetrahydrofuran; hexane; toluene at -78℃; for 1h; Inert atmosphere; Stage #2: (3R,4R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5,5-difluorotetrahydro-2H-pyran-2-one In tetrahydrofuran; hexane; toluene at -98℃; for 3h; Stage #3: With water; ammonium chloride In tetrahydrofuran; hexane; toluene at -98 - 20℃; stereoselective reaction;

91%

4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5) → (5-bromo-2-chlorophenyl)(4-ethyloxyphenyl)methanone (461432-22-4)

Conditions	Yield
With tert.-butylhydroperoxide; copper(II) acetate monohydrate In water at 80℃; for 8h;	90%

4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5) + (3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-thiopyran-2-one (131757-92-1) → 2,3,4,6-tetra-O-benzyl-1-C-[4-chloro-3-(4-ethoxybenzyl)phenyl]-5-thio-D-glucopyranose (1221506-04-2)

Conditions	Yield
Stage #1: 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene With magnesium; ethylene dibromide In tetrahydrofuran at 20℃; Reflux; Stage #2: (3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-thiopyran-2-one In tetrahydrofuran at 20℃; for 1h; Grignard reaction; Stage #3: With ammonium chloride In tetrahydrofuran; water Saturated solution;	89%

(3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-one (13096-62-3) + 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5) → C49H49ClO7

Conditions	Yield
Stage #1: 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene With n-butyllithium In tetrahydrofuran; hexane; toluene at -78℃; for 0.5h; Stage #2: (3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-one In tetrahydrofuran; hexane; toluene at -78℃;	88%

4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5) + C19H25NO6 → C30H31ClO6

Conditions	Yield
Stage #1: 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene With isopropylmagnesium chloride In tetrahydrofuran at -5 - 0℃; for 1h; Inert atmosphere; Stage #2: C19H25NO6 In tetrahydrofuran at 25 - 30℃; Inert atmosphere;	88%

4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5) + 2,3,4,5,6-penta-O-benzyl aldehydo D-glucose (78699-85-1) → 2-chloro-(1-methoxy-2,3,4,5,6-penta-benzyl-D-glucose)-2-ethoxydiphenylmethane

Conditions	Yield
Stage #1: 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene With n-butyllithium In tetrahydrofuran; hexane at -70℃; for 1h; Stage #2: 2,3,4,5,6-penta-O-benzyl-aldehydo-D-glucose In tetrahydrofuran; hexane at -70℃; for 2h; Stage #3: With water In tetrahydrofuran; hexane at -70 - 20℃; for 20h;	87.1%

4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5) + 2,3,4,6-Tetra-O-benzyl-D-glucopyranose (4291-69-4, 6386-24-9, 6564-72-3, 59531-24-7, 69257-52-9, 78184-89-1, 78609-16-2, 78609-17-3, 78609-18-4, 96553-53-6, 104111-61-7, 131347-08-5, 4132-28-9) → 2,3,4,6-tetrakis(benzyloxy)-1-(4-chloro-3-(4-ethoxybenzyl)phenyl)hexane-1,5-diol

Conditions	Yield
Stage #1: 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene With iodine; magnesium In tetrahydrofuran at 60℃; for 1h; Stage #2: 2,3,4,6-Tetra-O-benzyl-D-glucopyranose With isopropylmagnesium bromide In tetrahydrofuran at 0 - 60℃; for 2h;	87%

4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5) + ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)(morpholin-4-yl)methanone (1103738-19-7) → (4-chloro-3-(4-ethoxybenzyl)phenyl)((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuran[2,3-d][1,3]dioxolan-5-yl)methanone (1103738-30-2)

Conditions	Yield
Stage #1: 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene With n-butyllithium In tetrahydrofuran at -80 - -70℃; for 1h; Stage #2: ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)(morpholin-4-yl)methanone In tetrahydrofuran at -80 - 0℃;	86.3%

4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5) + (4R,5S,6R)-4,5,6-tris(benzyloxy)-3-((benzyloxy)methyl)-2-cyclohexen-1-one (110391-10-1) → C50H49ClO6 (1413373-21-3)

Conditions	Yield
Stage #1: 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene With magnesium; ethylene dibromide In tetrahydrofuran for 1h; Inert atmosphere; Reflux; Stage #2: (4R,5S,6R)-4,5,6-tris(benzyloxy)-3-((benzyloxy)methyl)-2-cyclohexen-1-one In tetrahydrofuran at 25℃; for 3h; Inert atmosphere; Stage #3: With ammonium chloride In tetrahydrofuran; water	86%

4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5) + 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide (572-09-8) → (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (461432-25-7)

Conditions	Yield
Stage #1: 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene With isopropylmagnesium chloride In tetrahydrofuran at -5 - 0℃; for 2h; Stage #2: 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide With N,N,N,N,-tetramethylethylenediamine; isopropylmagnesium chloride; cobalt(II) chloride In tetrahydrofuran; 2-methyltetrahydrofuran at 0 - 30℃; for 2.5h; Reagent/catalyst; Solvent;	84%
Stage #1: 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene With n-butyllithium In tetrahydrofuran; acetone at -78℃; for 1h; Inert atmosphere; Stage #2: 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide With copper(l) iodide In tetrahydrofuran at -40 - -30℃; for 1h; Reagent/catalyst; Temperature;

4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5) + acetic anhydride (108-24-7) → 1-(4-chloro-3-(4-ethoxybenzyl)phenyl)ethanone

Conditions	Yield
Stage #1: 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene With magnesium; methyl iodide In tetrahydrofuran for 1h; Reflux; Stage #2: acetic anhydride In tetrahydrofuran at -20 - 20℃; for 3h;	84%

4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5) + 3,4,5-tris[(trimethylsilyl)oxy]-6-{[(trimethylsilyl)oxy]methyl}-tetrahydro-2H-pyran-2-one + allyl alcohol (107-18-6) → 2-allyloxy-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyI-tetrahydro-pyran-3,4,5-triol

Conditions	Yield
Stage #1: 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene With n-butyllithium In tetrahydrofuran; hexane; toluene at -80 - -70℃; for 1h; Stage #2: 3,4,5-tris[(trimethylsilyl)oxy]-6-{[(trimethylsilyl)oxy]methyl}-tetrahydro-2H-pyran-2-one In tetrahydrofuran; hexane; toluene at -80 - -70℃; Stage #3: allyl alcohol With methanesulfonic acid In tetrahydrofuran; hexane; toluene at -80 - -20℃;	83%
Stage #1: 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene With n-butyllithium In tetrahydrofuran; hexane; toluene at -80 - -70℃; for 1h; Stage #2: 3,4,5-tris[(trimethylsilyl)oxy]-6-{[(trimethylsilyl)oxy]methyl}-tetrahydro-2H-pyran-2-one In tetrahydrofuran; hexane; toluene at -80 - -70℃; Stage #3: allyl alcohol With methanesulfonic acid In tetrahydrofuran; hexane; toluene at -80 - 20℃;

4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5) + (2R,3S,4S)-2,3,4-tris(benzyloxy)-4-(4-((benzyloxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-1-(4-methylpiperazin-1-yl)butan-1-one (1431329-05-3) → (2R,3S,4S)-2,3,4-tribenzyloxy-4-(4-((benzyloxy)methyl)-2,2-dimethyl-1,3-dioxanepent-4-yl)-1-(4-chloro-3-(4-ethoxybenzyl)phenyl)butan-1-one

Conditions	Yield
Stage #1: 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene With isopropylmagnesium chloride In tetrahydrofuran at -5 - 0℃; for 1h; Inert atmosphere; Stage #2: (2R,3S,4S)-2,3,4-tris(benzyloxy)-4-(4-((benzyloxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-1-(4-methylpiperazin-1-yl)butan-1-one In tetrahydrofuran at 20 - 30℃; Inert atmosphere;	83%

4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5) + C18H42O6Si4 → (2S,3R,4S,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol (714269-57-5)

Conditions	Yield
With n-butyllithium In tetrahydrofuran; hexane; toluene at -78 - -65℃; for 2h; Inert atmosphere;	78.6%

4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5) + (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one (32469-28-6, 55515-28-1, 55515-29-2, 32384-65-9) → (2S,3R,4S,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol (714269-57-5)

Conditions	Yield
Stage #1: 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene With sec.-butyllithium In tetrahydrofuran; cyclohexane at -78 - -68℃; for 1h; Stage #2: (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one In tetrahydrofuran; n-heptane; cyclohexane at -78 - -68℃; for 30h;	78.3%
Stage #1: 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene With n-butyllithium In tetrahydrofuran; hexane; toluene at -78℃; for 1h; Large scale; Stage #2: (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one With n-butyllithium In tetrahydrofuran; hexane; toluene at -78℃; for 3h; Large scale;	78%
Stage #1: 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene With n-butyllithium In tetrahydrofuran; hexane; toluene at -78℃; for 1h; Inert atmosphere; Industrial scale; Stage #2: (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one With methanesulfonic acid In tetrahydrofuran; methanol; hexane; toluene at -78 - 40℃; for 14h; Industrial scale;	78%
Multi-step reaction with 2 steps 1.1: N,N,N',N'',N'''-pentamethyldiethylenetriamine; n-butyllithium / tetrahydrofuran / 1 h / -78 °C / Inert atmosphere 1.2: 2 h / -78 °C / Inert atmosphere 2.1: methanol / 10 h / 20 °C View Scheme

4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5) + methanesulfonic acid (75-75-2) + (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one (32469-28-6, 55515-28-1, 55515-29-2, 32384-65-9) → (2S,3R,4S,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol (714269-57-5)

Conditions

Yield

Stage #1: 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene With n-butyllithium In tetrahydrofuran; hexane; toluene at -78℃; for 1h; Inert atmosphere; Large scale; Stage #2: (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one In tetrahydrofuran; hexane; toluene at -78℃; for 3h; Large scale; Stage #3: methanesulfonic acid In methanol at 0 - 40℃; for 11h; Large scale;

78%

(4R,5S,6R)-4,5-bis(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-one (79999-46-5, 72605-77-7) + 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5) → C42H43ClO6

Conditions	Yield
Stage #1: 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene With n-butyllithium In tetrahydrofuran; hexane; toluene at -78℃; for 0.5h; Stage #2: (4R,5S,6R)-4,5-bis(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-one In tetrahydrofuran; hexane; toluene at -78℃; for 0.5h;	78%

Upstream product

• 461432-22-4 (5-bromo-2-chlorophenyl)(4-ethyloxyphenyl)methanone 
• 915095-85-1 (5-bromo-2-chlorophenyl)(4-fluorophenyl)methanone 
• 462-06-6 fluorobenzene 
• 609-65-4 o-chlorobenzoyl chloride 
• 118-91-2 ortho-chlorobenzoic acid 
• 6214-44-4 4-ethoxybenzyl alcohol 
• 103-88-8 4-bromoacetanilide 
• 2606-57-7 4-ethoxybenzyl bromide 
• 103-73-1 Phenetole 
• 149965-40-2 5-bromo-2-chlorobenzyl alcohol 
• 189628-37-3 2-chloro-5-bromobenzaldehyde 
• 89-98-5 2-chloro-benzaldehyde 
• 622-60-6 1-ethoxy-4-methylbenzene 
• 106-44-5 p-cresol 

Downstream Products

• 461432-24-6 (3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol 
• 1413373-21-3 C₅₀H₄₉ClO₆ 
• 1662702-90-0 2-chloro-4'-ethoxydiphenylmethane 
• 1079083-63-8 (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-hydroxybenzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate 
• 912917-85-2 (2S,3S,4R,5R,6R)-2-(3-(4-acetoxybenzyl)-4-chlorophenyl)-6-(acetoxymethyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate 
• 864070-37-1 (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol 
• 1369405-90-2 (2S,4R,5S,6R)-4,5-bis(benzyloxy)-2-((benzyloxy)methyl)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)-3,3-difluorotetrahydro-2H-pyran 
• 1369406-03-0 C₄₂H₄₁ClF₂O₆ 
• 1118566-51-0 4-bromo-2-(4-(2-(but-2-ynyloxy)ethoxy)benzyl)-1-chlorobenzene 
• 1118566-56-5 2-(4-(2-(allyloxy)ethoxy)benzyl)-4-bromo-1-chlorobenzene 
• 1118566-69-0 2-(4-(5-bromo-2-chlorobenzyl)phenoxy)ethyl 4-methylbenzenesulfonate 
• 1118566-50-9 2-(4-(5-bromo-2-chlorobenzyl)phenoxy)ethanol 

Relevant articles and documents

Synthesis method for preparing 5-bromo-2-chloro-4'-ethoxydiphenylmethane

The present invention relates to a method for preparing 5-bromo-2-chloro-4'-ethoxydiphenylmethane, first of all o-chlorobenzoic acid chlorination made of o-chlorobenzoyl chloride, and then fuucylation to make 2-chloro-4'-iodobenzophenone, further brominated to make 5-bromo-2-chloro-4'-iododibenzophenone, and then reduced to make 5-bromo-2-chloro-4'-iododiphenylmethane, and finally by substitution reaction to make 5-bromo-2-chloro-4'-ethoxydiphenylmethane. The method of the present invention is streamlined, the resulting product purity is high, the raw materials used, excipients are common compounds, the use of low toxicity solvents and can be recycled, will not produce phosphorus-containing wastewater, high safety and environmental friendliness, low cost, low requirements for equipment, suitable for industrial production.

Synthesis method of dapagliflozin intermediate 5-bromo-2-chloro-4 '-ethoxydiphenylmethane

The invention discloses a synthesis method of a dapagliflozin intermediate 5-bromo-2-chloro-4 '-ethoxydiphenylmethane. The method comprises the following steps: using 5-bromo-2-chlorobenzoic acid as araw material to be acylated by thionyl chloride, and then carrying out acylation reaction with 1-nitro-4-(phenoxymethyl) benzene, reducing, acetylating, hydrogenating and ethylating to obtain the dapagliflozin intermediate 5-bromo-2-chloro-4'-ethoxydiphenylmethane. The method can effectively avoid the acylation reaction ortho-position by-product so that the preparation of dapagliflozin is convenient for quality control, the reaction is mild, the yield is high and the method has an industrial application prospect.

Preparation method of sugar-reducing medicine dapagliflozin

The invention discloses a preparation method for hypoglycemic drugdapagliflozin. The method comprises the steps that 4-hydroxybenzaldehyde is adopted as a starting raw material, alkylation, carbonyl reduction, chlorination and alkylation reaction with asepsin, diazotization and chlorination are performed to obtain a dapagliflozinmidbody 5-bromo-2-chloro-4'-ethyoxyl diphenylmethane, then, the midbody and 2,3,4,6-tetra-O-trimethyl silicone-D-glucolactone are subjected to condensation, etherification and methoxyl removal to obtain the hypoglycemic drugdapagliflozin. The raw materials adopted by the technological path are low in price and easy to obtain, the technology can achieve industrialization easily, and the final product is high in purity; the technological path is novel, the syntheticroute is short, no risky or complex technology exists in the reactions, equipment is simple, operation is easy and convenient, and the method is suitable for industrial production.