915095-94-2

Basic information

• Product Name: (3S)-3-[4-[(2-Chloro-5-iodophenyl)methyl]phenoxy]tetrahydro-furan
• Synonyms: (3S)-3-[4-[(2-Chloro-5-iodophenyl)methyl]phenoxy]tetrahydro-furan;(S)-3-(4-(2-chloro-5-iodobenzyl)phenoxy)-tetrahydrofuran;(S)-3-(4-(2-chloro-5-fluorobenzyl)phenoxy)-tetrahydrofuran;EMpagliflozin iMpurity C;(S)-4-iodo-1-chloro-2-(4-tetrahydrofuran-3-yloxy-benzyl)-benzene;(3S)-3-{4-[(2-chloro-5-iodophenyl)methyl]phenoxy}oxolane;(3S)-3-[4-(2-chloro-5-iodobenzyl)-phenoxy]-tetrahydrofuran;Furan, 3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydro-, (3S)-
• CAS NO: 915095-94-2
• Molecular Formula: C₁₇H₁₆ClIO₂
• Molecular Weight: 306.7591432
• EINECS: 1592732-453-0
• Product Categories: Empagliflozin Intermediate;Empagliflozin
• Mol File: 915095-94-2.mol
• Article Data: 12

Chemical Properties

• Boiling Point: 476.0±45.0 °C(Predicted)
• Appearance: /
• Density: 1.578±0.06 g/cm3 (20 ºC 760 Torr)
• Storage Temp.: 2-8°C(protect from light)
• CAS DataBase Reference: (3S)-3-[4-[(2-Chloro-5-iodophenyl)methyl]phenoxy]tetrahydro-furan(CAS DataBase Reference)
• NIST Chemistry Reference: (3S)-3-[4-[(2-Chloro-5-iodophenyl)methyl]phenoxy]tetrahydro-furan(915095-94-2)
• EPA Substance Registry System: (3S)-3-[4-[(2-Chloro-5-iodophenyl)methyl]phenoxy]tetrahydro-furan(915095-94-2)

Safety Data

• Hazardous Substances Data: 915095-94-2(Hazardous Substances Data)

Usage

Physical Form

Solid

Uses

(3S)-3-[4-[(2-Chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran can be used as reactant/reagent in preparation of C-?aryl D-?glurofuranoside compounds useful as reference compounds in the quality control of gliflozin type medicine.

Synthetic route

(S)-(2-chloro-5-iodophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-87-3) → (3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran (915095-94-2)

Conditions	Yield
With aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane In toluene at 0 - 23℃; for 2.5h;	93%
With aluminum (III) chloride; sodium tetrahydroborate In tetrahydrofuran for 5h; Reflux;	90%
With potassium borohydride; trifluoroacetic acid In tetrahydrofuran at 0 - 20℃; for 0.5h;	85%

4-(2-chloro-5-iodobenzyl)phenol (1459754-32-5) + toluene-4-sulfonic acid (S)-(tetrahydrofuran-3-yl)ester (112052-11-6) → (3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran (915095-94-2)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; potassium iodide In acetonitrile at 50 - 55℃; Large scale;	90.1%

(S)-3-(4-(5-iodo-2-aminobenzyl)phenoxy)tetrahydrofuran → (3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran (915095-94-2)

Conditions	Yield
Stage #1: (S)-3-(4-(5-iodo-2-aminobenzyl)phenoxy)tetrahydrofuran With hydrogenchloride; sodium nitrite In water at -10 - 0℃; for 2.5h; Stage #2: With hydrogenchloride; copper(l) chloride In water at 20 - 80℃; for 3h;	75.2%

fluorobenzene (462-06-6) → (3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran (915095-94-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: oxalyl dichloride / N,N-dimethyl-formamide / 5 h / 25 - 30 °C 2: potassium tert-butylate / tetrahydrofuran / 3 h / 16 - 25 °C 3: 1,1,3,3-Tetramethyldisiloxane / aluminum (III) chloride / toluene / 2.5 h / 18 - 26 °C View Scheme
Multi-step reaction with 3 steps 1.1: oxalyl dichloride / N,N-dimethyl-formamide / 5 h / 25 - 30 °C 1.2: 6 h / 20 - 30 °C 2.1: potassium tert-butylate / tetrahydrofuran / 4 h / 16 - 25 °C 2.2: 1.83 h / 20 - 21 °C 3.1: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / toluene / 2.5 h / 18 - 26 °C View Scheme
Multi-step reaction with 3 steps 1.1: oxalyl dichloride; aluminum (III) chloride / N,N-dimethyl-formamide / 25 - 45 °C / Industry scale 2.1: potassium tert-butylate / tetrahydrofuran / 4 h / 16 - 25 °C / Industry scale 3.1: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / toluene / 2.5 h / 18 - 26 °C / Industry scale 3.2: 20 - 51 °C / Industry scale View Scheme
Multi-step reaction with 3 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 3 h 1.2: 1 h / 0 - 5 °C 2.1: potassium tert-butylate / tetrahydrofuran / 1 h / 16 - 25 °C 3.1: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / 5 - 10 °C View Scheme

2-chloro-5-iodobenzoic acid (19094-56-5) → (3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran (915095-94-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: oxalyl dichloride / N,N-dimethyl-formamide / 5 h / 25 - 30 °C 2: potassium tert-butylate / tetrahydrofuran / 3 h / 16 - 25 °C 3: 1,1,3,3-Tetramethyldisiloxane / aluminum (III) chloride / toluene / 2.5 h / 18 - 26 °C View Scheme
Multi-step reaction with 3 steps 1.1: oxalyl dichloride / N,N-dimethyl-formamide / 5 h / 25 - 30 °C 1.2: 6 h / 20 - 30 °C 2.1: potassium tert-butylate / tetrahydrofuran / 4 h / 16 - 25 °C 2.2: 1.83 h / 20 - 21 °C 3.1: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / toluene / 2.5 h / 18 - 26 °C View Scheme
Multi-step reaction with 3 steps 1.1: oxalyl dichloride; aluminum (III) chloride / N,N-dimethyl-formamide / 25 - 45 °C / Industry scale 2.1: potassium tert-butylate / tetrahydrofuran / 4 h / 16 - 25 °C / Industry scale 3.1: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / toluene / 2.5 h / 18 - 26 °C / Industry scale 3.2: 20 - 51 °C / Industry scale View Scheme

(2-chloro-5-iodophenyl)(4-fluorophenyl)methanone (915095-86-2) → (3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran (915095-94-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium tert-butylate / tetrahydrofuran / 3 h / 16 - 25 °C 2: 1,1,3,3-Tetramethyldisiloxane / aluminum (III) chloride / toluene / 2.5 h / 18 - 26 °C View Scheme
Multi-step reaction with 2 steps 1.1: potassium tert-butylate / tetrahydrofuran / 4 h / 16 - 25 °C 1.2: 1.83 h / 20 - 21 °C 2.1: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / toluene / 2.5 h / 18 - 26 °C View Scheme
Multi-step reaction with 2 steps 1.1: potassium tert-butylate / tetrahydrofuran / 4 h / 16 - 25 °C / Industry scale 2.1: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / toluene / 2.5 h / 18 - 26 °C / Industry scale 2.2: 20 - 51 °C / Industry scale View Scheme
Multi-step reaction with 2 steps 1: potassium tert-butylate / tetrahydrofuran / 0.5 h / 7 - 10 °C 2: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / toluene / 2.5 h / 0 - 23 °C View Scheme
Multi-step reaction with 2 steps 1: potassium tert-butylate / tetrahydrofuran / 20 °C 2: sodium tetrahydroborate; aluminum (III) chloride / tetrahydrofuran / 5 h / Reflux View Scheme

2-chloro-5-iodobenzoylchloride (281652-58-2) → (3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran (915095-94-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: aluminum (III) chloride / 1 h / 0 - 25 °C 2: potassium tert-butylate / tetrahydrofuran / 0.5 h / 7 - 10 °C 3: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / toluene / 2.5 h / 0 - 23 °C View Scheme
Multi-step reaction with 3 steps 1: aluminum (III) chloride / dichloromethane / 6 h / -5 °C 2: potassium tert-butylate / tetrahydrofuran / 20 °C 3: sodium tetrahydroborate; aluminum (III) chloride / tetrahydrofuran / 5 h / Reflux View Scheme

phenol (108-95-2) → (3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran (915095-94-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: polyposphoric acid / 50 - 85 °C 2: potassium iodide; potassium carbonate / acetonitrile / 50 - 55 °C 3: potassium borohydride; trifluoroacetic acid / tetrahydrofuran / 0.5 h / 0 - 20 °C View Scheme

(2-chloro-5-iodophenyl)(4-hydroxyphenyl)methanone (1459754-40-5) → (3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran (915095-94-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium iodide; potassium carbonate / acetonitrile / 50 - 55 °C 2: potassium borohydride; trifluoroacetic acid / tetrahydrofuran / 0.5 h / 0 - 20 °C View Scheme

4-hydroxybenzyl chloride (35421-08-0) → (3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran (915095-94-2)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sulfonyl chloride / dichloromethane / 3 h / -5 - 0 °C 1.2: 4.5 h / Reflux 2.1: zinc(II) chloride / ethyl acetate / 6 h / Reflux 3.1: hydrogenchloride; sodium nitrite / water / 2.5 h / -10 - 0 °C 3.2: 3 h / 20 - 80 °C View Scheme

2-chloro-5-iodobenzoic acid (19094-56-5) + (S)-3-phenoxytetrahydrofuran → (3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran (915095-94-2)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: oxalyl chloride / dichloromethane; N,N-dimethyl-formamide / 4 h / 20 °C 1.2: 3 h / 0 - 20 °C 2.1: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / 0 - 20 °C View Scheme

4-iodo-2-(4-methoxybenzyl)aniline → (3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran (915095-94-2)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: hydrogenchloride; sodium nitrite / water / 2.5 h / -10 - 0 °C / Large scale 1.2: 1.5 h / 70 - 80 °C / Large scale 2.1: boron tribromide / dichloromethane / 1.5 h / -15 °C / Inert atmosphere; Large scale 3.1: N-ethyl-N,N-diisopropylamine; potassium iodide / acetonitrile / 50 - 55 °C / Large scale View Scheme

p-methoxybenzyl chloride (824-94-2) → (3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran (915095-94-2)

Conditions

Yield

Multi-step reaction with 4 steps 1.1: zinc(II) chloride / ethyl acetate / 7 h / Reflux; Large scale 2.1: hydrogenchloride; sodium nitrite / water / 2.5 h / -10 - 0 °C / Large scale 2.2: 1.5 h / 70 - 80 °C / Large scale 3.1: boron tribromide / dichloromethane / 1.5 h / -15 °C / Inert atmosphere; Large scale 4.1: N-ethyl-N,N-diisopropylamine; potassium iodide / acetonitrile / 50 - 55 °C / Large scale View Scheme

p-aminoiodobenzene (540-37-4) → (3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran (915095-94-2)

Conditions

Yield

Multi-step reaction with 4 steps 1.1: zinc(II) chloride / ethyl acetate / 7 h / Reflux; Large scale 2.1: hydrogenchloride; sodium nitrite / water / 2.5 h / -10 - 0 °C / Large scale 2.2: 1.5 h / 70 - 80 °C / Large scale 3.1: boron tribromide / dichloromethane / 1.5 h / -15 °C / Inert atmosphere; Large scale 4.1: N-ethyl-N,N-diisopropylamine; potassium iodide / acetonitrile / 50 - 55 °C / Large scale View Scheme

(3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran (915095-94-2) + (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) → 1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-D-glucopyranoside (1417573-74-0)

Conditions	Yield
Stage #1: (3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran With isopropylmagnesium chloride; lithium chloride In tetrahydrofuran at 20℃; 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 at -25℃; for 1h; Inert atmosphere;	96%

(3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran (915095-94-2) + C8CuF9 (140468-35-5) → C25H16ClF9O2

Conditions	Yield
In N,N-dimethyl-formamide at 70℃; for 33h;	96%

(3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran (915095-94-2) + pentafluoroethylcopper(I) (60007-39-8) → (S)-3-(4-(2-chloro-5-(perfluoroethyl)benzyl)phenoxy)tetrahydrofuran

Conditions	Yield
In N,N-dimethyl-formamide at 80℃; for 36h; Inert atmosphere; Sealed tube; Glovebox;	93%

(3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran (915095-94-2) + 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide (572-09-8) → 1-chloro-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-2-(4-(R)-tetrahydrofuran-3-yloxy-benzyl)-benzene (915095-98-6)

Conditions	Yield
With bis(acetylacetonate)nickel(II); magnesium chloride; 4,4',4-tri-tert-butyl-2,2':6',2-terpyridine; zinc In tetrahydrofuran at 20℃; Schlenk technique; Inert atmosphere; Cooling with ice;	90%

(3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran (915095-94-2) + (1,5-anhydro-2-deoxy-4,6-O-bis(tert-butylsilylidene)-3-O-triisopropylsilyl-D-arabino-hex-1-enitol)boronic acid pinacol ester (842132-50-7) → C40H61ClO6Si2

Conditions	Yield
With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate In 1,2-dimethoxyethane; water for 8h; Reflux; Inert atmosphere; Large scale;	89%

(3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran (915095-94-2) + (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,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,3,4,5-tetraol (1279691-35-8)

Conditions	Yield
Stage #1: (3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran; (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one With TurboGrignard In tetrahydrofuran at -30 - -20℃; for 1h; Inert atmosphere; Stage #2: With citric acid In tetrahydrofuran; water for 0.5h; Inert atmosphere;	82.2%
Stage #1: (3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran With isopropylmagnesium chloride; lithium chloride In acetonitrile at -20 - -15℃; 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 acetonitrile at -10 - 0℃; for 8h; Solvent; Large scale;

(3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran (915095-94-2) + C18H42O6Si4 → C23H27ClO8

Conditions	Yield
Stage #1: (3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran With n-butyllithium In tetrahydrofuran; hexane at -60 - -50℃; for 0.833333h; Inert atmosphere; Stage #2: C18H42O6Si4 In tetrahydrofuran; hexane at -50℃; Inert atmosphere; Stage #3: With hydrogenchloride In isopropyl alcohol at 0 - 20℃;	80%

(3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran (915095-94-2) + trans-4-Octene (14850-23-8) → (S)-3-(4-(2-chloro-5-octylbenzyl)phenoxy)tetrahydrofuran

Conditions	Yield
With nickel(II) bromide dimethoxyethane; potassium fluoride; Triethoxysilane; 2-(6-methylpyridin-2-yl)-4,5-dihydrooxazole In N,N-dimethyl-formamide for 24h; Inert atmosphere; Sealed tube; regioselective reaction;	78%

(3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran (915095-94-2) + C18H42O6Si4 → (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1279691-36-9)

Conditions	Yield
With n-butyllithium In tetrahydrofuran; hexane; toluene at -78 - -65℃; for 2h; Inert atmosphere;	77.6%

(3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran (915095-94-2) + C30H66O6Si4 → C25H31ClO8

Conditions	Yield
With n-butyllithium In tetrahydrofuran; hexane; toluene at -78 - -65℃; for 2h; Inert atmosphere;	76.9%

(3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran (915095-94-2) + (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) → empagliflozin (864070-44-0)

Conditions	Yield
Stage #1: (3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran With isopropylmagnesium chloride; lithium chloride In tetrahydrofuran at -21 - -15℃; for 1.83333h; Stage #2: (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one In dichloromethane; acetonitrile at -25 - -13℃; for 2.91667h;	73%
Stage #1: (3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran With isopropylmagnesium chloride; lithium chloride In tetrahydrofuran at -21 - -15℃; for 1.83333h; Industry scale; Stage #2: (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one In tetrahydrofuran at -25 - -18℃; for 2.91667h; Industry scale; Stage #3: With citric acid In water at -13 - 19℃; Product distribution / selectivity; Industry scale;	73%

(3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran (915095-94-2) + C41H34O12S → C51H43ClO11

Conditions	Yield
Stage #1: (3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran With TurboGrignard In tetrahydrofuran at -10 - 0℃; Cooling with ice; Inert atmosphere; Stage #2: C41H34O12S With 2,6-bis((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)pyridine In tetrahydrofuran at 40 - 50℃; Inert atmosphere;	73%

(3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran (915095-94-2) + 2-(but-3-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane → 2-(1-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)butyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Conditions	Yield
With potassium fluoride; 6,6'-dimethyl-2,2'-bipyridine; nickel(II) bromide 2-methoxyethyl ether complex; Triethoxysilane; potassium iodide In N,N-dimethyl acetamide; acetonitrile at 30℃; for 18h; Sealed tube; regioselective reaction;	67%

methanesulfonic acid (75-75-2) + (3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran (915095-94-2) + (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) → C24H29ClO8

Conditions

Yield

Stage #1: (3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran With n-butyllithium In tetrahydrofuran; hexane; toluene at -72 - -60℃; 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; hexane; toluene at -72℃; for 2h; Inert atmosphere; Stage #3: methanesulfonic acid In tetrahydrofuran; methanol; hexane; toluene at 20℃;

60.1%

(3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran (915095-94-2) + trifluorormethanesulfonic acid (1493-13-6) + 1,3,5-trimethyl-benzene (108-67-8)

Conditions	Yield
With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 0 - 20℃; for 2h; Inert atmosphere;	30%

+ (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one → C35H59ClO7Si4

Conditions

Yield

Stage #1: (3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran With isopropylmagnesium chloride; lithium chloride In tetrahydrofuran at -23 - -22℃; for 0.333333h; Stage #2: (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one In tetrahydrofuran at -20℃; for 2h; Stage #3: With ammonium chloride In tetrahydrofuran; water Product distribution / selectivity;

(3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran (915095-94-2) → C17H16Cl2MgO2

Conditions	Yield
With TurboGrignard In tetrahydrofuran at -15 - 21℃; for 1.83333h; Product distribution / selectivity;

(3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran (915095-94-2) → (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1279691-36-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.5 h / -20 - 10 °C 2: hydrogenchloride / isopropyl alcohol / 5 h / 38 - 42 °C / pH 2 3: hydrogenchloride / isopropyl alcohol; methanol View Scheme
Multi-step reaction with 2 steps 1: lithium chloride; isopropylmagnesium chloride / tetrahydrofuran / -30 - -20 °C / Inert atmosphere; Large scale 2: hydrogenchloride / methanol; water / 4 h / 20 °C / Large scale View Scheme
Multi-step reaction with 2 steps 1.1: TurboGrignard / tetrahydrofuran / 1 h / -30 - -20 °C / Inert atmosphere 1.2: 0.5 h / Inert atmosphere 2.1: hydrogenchloride / water / 1 h / 20 - 30 °C View Scheme

(3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran (915095-94-2) → empagliflozin (864070-44-0)

Conditions	Yield
Multi-step reaction with 4 steps 1: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.5 h / -20 - 10 °C 2: hydrogenchloride / isopropyl alcohol / 5 h / 38 - 42 °C / pH 2 3: hydrogenchloride / isopropyl alcohol; methanol 4: aluminum (III) chloride; triethylsilane / dichloromethane; acetonitrile / 0.5 h / 20 - 25 °C View Scheme
Multi-step reaction with 3 steps 1: lithium chloride; isopropylmagnesium chloride / tetrahydrofuran / -30 - -20 °C / Inert atmosphere; Large scale 2: hydrogenchloride / methanol; water / 4 h / 20 °C / Large scale 3: aluminum (III) chloride; triethylsilane / acetonitrile; dichloromethane View Scheme
Multi-step reaction with 3 steps 1.1: TurboGrignard / tetrahydrofuran / 1 h / -30 - -20 °C / Inert atmosphere 1.2: 0.5 h / Inert atmosphere 2.1: hydrogenchloride / water / 1 h / 20 - 30 °C 3.1: aluminum (III) chloride; triethylsilane / dichloromethane; acetonitrile View Scheme

(3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran (915095-94-2) → (2S,3R,4S,5R,6R)-6-(acetoxymethyl)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triyl triacetate

Conditions	Yield
Multi-step reaction with 4 steps 1: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.5 h / -20 - 10 °C 2: hydrogenchloride / isopropyl alcohol / 5 h / 38 - 42 °C / pH 2 3: hydrogenchloride / isopropyl alcohol; methanol 4: triethylamine; dmap / tetrahydrofuran View Scheme

(3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran (915095-94-2) → (2S,3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-2-methoxytetrahydro-2H-pyran

Conditions	Yield
Multi-step reaction with 4 steps 1: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.5 h / -20 - 10 °C 2: hydrogenchloride / isopropyl alcohol / 5 h / 38 - 42 °C / pH 2 3: hydrogenchloride / isopropyl alcohol; methanol 4: sodium hydride / tetrahydrofuran; N,N-dimethyl-formamide View Scheme

(3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran (915095-94-2) → (2S,3R,4S,5R,6R)-3,4,5-tris(allyloxy)-6-((allyloxy)methyl)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-2-methoxytetrahydro-2H-pyran

Conditions	Yield
Multi-step reaction with 4 steps 1: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.5 h / -20 - 10 °C 2: hydrogenchloride / isopropyl alcohol / 5 h / 38 - 42 °C / pH 2 3: hydrogenchloride / isopropyl alcohol; methanol 4: sodium hydride / tetrahydrofuran; N,N-dimethyl-formamide View Scheme

(3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran (915095-94-2) → (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-trityl triacetate + C31H35ClO11

Conditions	Yield
Multi-step reaction with 5 steps 1.1: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.5 h / -20 - 10 °C 2.1: hydrogenchloride / isopropyl alcohol / 5 h / 38 - 42 °C / pH 2 3.1: hydrogenchloride / isopropyl alcohol; methanol 4.1: sodium hydride / tetrahydrofuran; N,N-dimethyl-formamide 5.1: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / 0.5 h / 15 - 20 °C 5.2: 90 °C View Scheme
Multi-step reaction with 5 steps 1: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.5 h / -20 - 10 °C 2: hydrogenchloride / isopropyl alcohol / 5 h / 38 - 42 °C / pH 2 3: hydrogenchloride / isopropyl alcohol; methanol 4: triethylamine; dmap / tetrahydrofuran 5: aluminum (III) chloride; triethylsilane / dichloromethane; acetonitrile / 0.5 h / 15 - 20 °C View Scheme

(3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran (915095-94-2) → 2,3,4,6-tetra-O-benzyl-1-deoxy-1-((S)-(4-chloro-3-(4-(tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-β-D-glucopyranose + C51H51ClO7

Conditions

Yield

Multi-step reaction with 5 steps 1: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.5 h / -20 - 10 °C 2: hydrogenchloride / isopropyl alcohol / 5 h / 38 - 42 °C / pH 2 3: hydrogenchloride / isopropyl alcohol; methanol 4: sodium hydride / tetrahydrofuran; N,N-dimethyl-formamide 5: aluminum (III) chloride; triethylsilane / dichloromethane; acetonitrile / 0.5 h / 15 - 20 °C View Scheme

Upstream product

• 17696-62-7 Phenyl 4-hydroxybenzoate 
• 25804-49-3 tert-butyl 4-hydroxybenzoate 
• 27522-79-8 p-hydroxybenzoylethylamine 
• 19094-56-5 2-chloro-5-iodobenzoic acid 
• 35421-08-0 4-hydroxybenzyl chloride 
• 1459754-40-5 (2-chloro-5-iodophenyl)(4-hydroxyphenyl)methanone 
• 108-95-2 phenol 
• 281652-58-2 2-chloro-5-iodobenzoylchloride 
• 915095-86-2 (2-chloro-5-iodophenyl)(4-fluorophenyl)methanone 
• 462-06-6 fluorobenzene 
• 915095-87-3 (S)-(2-chloro-5-iodophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone 
• 540-37-4 p-aminoiodobenzene 
• 824-94-2 p-methoxybenzyl chloride 
• 1459754-32-5 4-(2-chloro-5-iodobenzyl)phenol 

Downstream Products

• 1279691-36-9 (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol 
• 864070-44-0 empagliflozin 
• 2069942-68-1 (2S,3R,4S,5R,6R)-6-(acetoxymethyl)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triyl triacetate 
• 915095-99-7 (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-trityl triacetate 
• 915095-99-7 C₃₁H₃₅ClO₁₁ 
• 1620758-33-9 (2R,3R,4R,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol 
• 1620758-34-0 (1R,2S,3R,4R,5S)-1-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)hexane-1,2,3,4,5,6-hexaol 

Relevant articles and documents

Preparation process of empagliflozin intermediate

The invention discloses a preparation process of an empagliflozin intermediate, and relates to the technical field of biological pharmacy, the process comprises the following steps: taking a compound of a formula d structure and s-3-hydroxytetrahydrofuran (namely a compound e) as initial raw materials, dehydrating to obtain a compound of a formula c structure; sequentially adding alkali metal and a chlorination reagent to obtain a compound b; further performing Friedel-Crafts reaction with a compound with a structure as shown in a formula f under the catalytic action of Lewis acid to synthesize a compound with a structure as shown in a formula a; and finally, carrying out reduction reaction to obtain a target compound with a structure shown in a formula g. The preparation method is low in cost, easy to operate, less in wastewater, easy in post-treatment, high in yield, high in product purity and suitable for industrial production.

Design, synthesis and anticancer activities of halogenated Phenstatin analogs as microtubule destabilizing agent

A series of halogenated Phenstatin analogs were designed as microtubule destabilizing agent by docking study. It was synthesized within three steps starting from 2-chloro-5-iodobenzoic acid and substituted benzene. All the products were characterized by 1H NMR and 13C NMR spectral analysis, and the stereochemical structure was also confirmed by a single crystal X-ray diffraction crystallographic analysis. The microtubule destabilizing activities were evaluated in vitro with human liver cancer Huh-7 cell line and human lung cancer A549 cell line. Some of the HPAs were achieved IC50 about 5.0 μM against human liver cancer Huh-7 cells. [Figure not available: see fulltext.].

Dicyclic derivative of glucoside as well as preparation method and application of dicyclic derivative

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