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

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

Used in Pharmaceutical Industry:
5-bromo-2-chloro-4'-ethoxydiphenylmethane is used as an intermediate for dapagliflozin, a medication used to treat type 2 diabetes. As an intermediate, it plays a crucial role in the synthesis of dapagliflozin, which helps regulate blood sugar levels and improve the management of diabetes in patients.

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

• 21739-92-4 5-bromo-2-chlorobenzoic acid 
• 6214-44-4 4-ethoxybenzyl alcohol 
• 864070-18-8 4-(5-bromo-2-chlorobenzyl)phenol 
• 75-03-6 ethyl iodide 
• 462-06-6 fluorobenzene 
• 915095-85-1 (5-bromo-2-chlorophenyl)(4-fluorophenyl)methanone 
• 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

• 960494-15-9 C₃₃H₅₇ClO₇Si₄ 
• 864070-18-8 4-(5-bromo-2-chlorobenzyl)phenol 
• 461432-24-6 (3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol 
• 714269-57-5 (2S,3R,4S,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol 
• 1018898-78-6 (S)-[(3aS,5S,6R,6aS)-6-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-tetrahydro-furo[2,3-d][1,3]dioxol-5-yl]-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-methanol 
• 1192136-42-7 C₂₉H₄₁ClO₆Si 
• 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 
• 1413373-21-3 C₅₀H₄₉ClO₆ 

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.

PREPARATION OF HIGHLY PURE AMORPHOUS DAPAGLIFLOZIN

A novel and improved process for the preparation of amorphous dapagliflozin is disclosed. The present invention further provides pharmaceutical compositions containing amorphous dapagliflozin, optionally in a combination with one or more other active substances and methods for making the same.

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 5-bromo-2-chloro-4 '-ethoxydiphenylmethane

The invention relates to a preparation method of 5-bromo-2-chloro-4 '-ethoxydiphenylmethane. The preparation method is characterized by comprising the following steps: step S1, preparation of 5-bromo-2-chlorobenzoyl chloride, step S2, preparation of 5-bromo-2-chloro-4'-ethoxybenzophenone, and step S3, preparation of 5-bromo-2-chloro-4 '-ethoxydiphenylmethane. The invention further discloses the 5-bromine-2-chloro-4 '-ethoxydiphenylmethane prepared according to the preparation method of the 5-bromine-2-chloro-4'-ethoxydiphenylmethane. The invention further discloses the 5-bromine-2-chloro-4 '-ethoxydiphenylmethane prepared according to the preparation method of the 5-bromine-2-chloro-4'-ethoxydiphenylmethane. According to the preparation method of the 5-bromo-2-chloro-4 '-ethoxydiphenylmethane, traditional preparation process conditions are optimized and innovated, the method effectively improves the product purity, the reaction conversion rate and the production efficiency, has no special requirements on reaction conditions and equipment, is suitable for industrial production, causes less pollution to the environment and effectively realizes good combination of economic benefits, social benefits and ecological benefits.

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.

A SGLT2 inhibitor intermediates preparation method (by machine translation)

The invention discloses a SGLT2 inhibitor intermediates preparation method, comprises the following steps: (1) 5 - halo - 2 - chlorobenzoic acid and fluorobenzene to Friedel-crafts reaction, to obtain (5 - halo - 2 - chlorophenyl) (4 - fluorophenyl) a ketone; (2) under the action of the inorganic base, (5 - halo - 2 - chlorophenyl) (4 - fluorophenyl) methanone and ethanol undergo the substitution reaction, after the reaction is finished after treatment to obtain (5 - halo - 2 - chlorophenyl) (4 - ethoxy) a ketone; (3) (5 - halo - 2 - chlorophenyl) (4 - ethoxy) methanone in the reducing agent under the effect of the reduction reaction of carbonyl, get said SGLT2 inhibitor intermediates. The preparation method is through adopting the inorganic alkali and ethanol instead of the ethoxide reagent and DMSO (or DMF), not only can effectively reduce the cost, but also more environmentally friendly. (by machine translation)

Synthetic method for dapagliflozin

The invention relates to a synthetic method for dapagliflozin. The synthetic method is characterized in that 4-methylphenol is taken as a starting raw material, alkylation and bromination are performed, an alkylation reaction is performed with antisepsin, diazotization and chlorination are performed, and condensation, etherification and desmethoxy are performed with 2,3,4,6-tetrakis-O-trimethylsilyl-D-gluconolactone to obtain a hypoglycemic drug (dapagliflozin). The synthetic method has the following advantages: 4-methylphenol is taken as the starting raw material, and 4-methylphenol is low inprice and easily accessible than 5-bromo-2-chlorobenzoic acid; by adoption of the process, industrialization can be easily realized; in the synthesis process, raw materials which are highly toxic arenot used, so that dangerous processes are avoided; the synthesis path is short and novel, so that the operation is simple and convenient; and by adoption of the synthesis path, the purity of a finalproduct can be improved, and the purity can be 99% or above.

Dapagliflozin preparation method

The invention relates to a Dapagliflozin preparation method, which comprises the following steps: using 2-chlorobenzaldehyde as a starting material, carrying out bromination, reducing, chlorinating tosynthesize 5-bromo-2-chlorobenzyl chloride, carrying out Friedel-Crafts alkylation reaction between 5-bromo-2-chlorobenzyl chloride and phenetole to synthesize 5-bromo-2-chloro-4'-ethyoxyldiphenylmethane, conducting condensation between 5-bromo-2-chloro-4'-ethyoxyldiphenylmethane and 2,3,4,6-tetra-O-trimethylsilyl-D-glucolactone, carrying out trimethylsilyl deprotection, conducting etherification, and reducing for demethylation to obtain a hypoglycemic drug Dapagliflozin. The invention has the following advantages: according to the Dapagliflozin preparation method, 2-chlorobenzaldehyde, whichis used as a starting material, is cheaper and easily available in comparison with 5-bromo-2-chlorobenzoic acid, and the technology is easy for industrialization; during the synthetic process, no rawmaterials which cause severe toxicity will be used and furthermore there is no dangerous process; the synthetic route is short and novel and the operation is simple; and through the synthetic route,purity of the final product can be raised, and the purity can reach 99% and above.

Design, synthesis and biological evaluation of nitric oxide releasing derivatives of dapagliflozin as potential anti-diabetic and anti-thrombotic agents

The cardiovascular complications were highly prevalent in type 2 diabetes mellitus (T2DM), even at the early stage of T2DM or the state of intensive glycemic control. Therefore, there is an urgent need for the intervention of cardiovascular complications in T2DM. Herein, the new hybrids of NO donor and SGLT2 inhibitor were design to achieve dual effects of anti-hyperglycemic and anti-thrombosis. As expected, the preferred hybrid 2 exhibited moderate SGLT2 inhibitory effects and anti-platelet aggregation activities, and its anti-platelet effect mediated by NO was also confirmed in the presence of NO scavenger. Moreover, compound 2 revealed significantly hypoglycemic effects and excretion of urinary glucose during an oral glucose tolerance test in mice. Potent and multifunctional hybrid, such as compound 2, is expected as a potential candidate for the intervention of cardiovascular complications in T2DM.

6-halogenated glucose C-glycoside as well as preparation method and application thereof

The invention discloses a 6-halogenated glucose C-glycoside as well as a preparation method and application thereof. A structure of 6-halogenated glucose C-glycoside is shown in formula I; an intermediate can be synthesized efficiently with cheap and easily available raw materials; meanwhile, when the raw material is used for synthesizing Jardiance, dapagliflozin and the like, a reaction yield ishigh, and an obtained product has high purity and relatively high industrial application prospect.