915095-94-2

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

• 35421-08-0 4-hydroxybenzyl chloride 
• 17696-62-7 Phenyl 4-hydroxybenzoate 
• 25804-49-3 tert-butyl 4-hydroxybenzoate 
• 27522-79-8 p-hydroxybenzoylethylamine 
• 540-37-4 p-aminoiodobenzene 
• 824-94-2 p-methoxybenzyl chloride 
• 1459754-32-5 4-(2-chloro-5-iodobenzyl)phenol 
• 112052-11-6 toluene-4-sulfonic acid (S)-(tetrahydrofuran-3-yl)ester 
• 19094-56-5 2-chloro-5-iodobenzoic acid 
• 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 

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 
• 1417573-74-0 1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-D-glucopyranoside 

Relevant academic research and scientific papers

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.

Empagliflozin intermediate preparation method

The invention discloses an empagliflozin intermediate preparation method, which comprises: carrying out substitution by using p-methoxybenzyl chloride and p-iodoaniline as starting raw materials to obtain a compound IV, performing diazotization and a Sandmeyer reaction to obtain a compound III, further performing demethylation under the action of boron tribromide to obtain a compound II, and finally performing condensation with (S)-3-p-toluenesulfonyloxy tetrahydrofuran to obtain the target compound I, wherein the product purity is greater than or equal to 99.0%. According to the invention, the preparation method has advantages of simple and easily available raw materials, low cost, simple operation steps, simple post-treatment and high product yield, and is 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

The invention relates to a dicyclic derivative of glucoside as well as a preparation method and the application of the dicyclic derivative. Specifically, the invention relates to a compound as shown in Formula I, a stereisomer or pharmaceutically acceptable salt or ester of the compound, a pharmaceutical composition of the compound, and application of the compound in preparation of drugs for treating diabetes or relevant diseases.

Synthesis method of Empagliflozin intermediate

The invention discloses a synthesis method of an Empagliflozin intermediate. The synthesis method uses 4-hydroxybenzyl chloride as a starting material to sequentially react with methanesulfonyl chloride and (S)-3-hydroxytetrahydrofuran to obtain compound III, then react with 4-iodoaniline to obtain compound IV, and finally react with cuprous chloride after diazotization to obtain (S)-3-(4-(5-iodine-2-chlorobenzyl)phenoxy) tetrahydrofuran. The raw materials used in the synthesis method are simple and easy to obtain, the operation steps are simple, the post-treatment is simple, the product yieldis high, and the method is suitable for industrial production.

Preparation method of Jardiance

The invention discloses a preparation method of Jardiance. The preparation method comprises the following steps: (1) performing a Grignard exchange reaction on a compound 5, then enabling the compound 5 after the Grignard exchange reaction to react with a glucose lactone derivative 6 so as to obtain a compound 7 (as shown in the description), wherein X is bromine or iodine, LG is chlorine, bromine, mesyloxy or tosyl, and PG is acetyl, tert- butanoyl or benzoyl; (2) under the action of alkali, performing deprotection on the compound 7 so as to obtain a finished product namely an Jardiance type compound 8 (as shown in the description). The preparation route is simple to operate, the reaction steps are reduced, the yield is high, the obtained product is high in purity, and the preparation method is suitable for scaled production.

Empagliflozin intermediate, and preparation method and application thereof

The invention provides an empagliflozin intermediate. The structural formula of the empagliflozin intermediate is shown in the description. The invention also provides a preparation method of the empagliflozin intermediate, and an application of the empagliflozin intermediate in the preparation of empagliflozin. The empagliflozin key intermediate provided by the invention is pivaloyl protected empagliflozin, and empagliflozin can be obtained by removing the above protection group from the intermediate.

Efficient synthesis of empagliflozin, an inhibitor of SGLT-2, utilizing an AlCl3-promoted silane reduction of a β-glycopyranoside

An efficient production synthesis of the SGLT-2 inhibitor Empagliflozin (5) from acid 1 is described. The key tactical stage involves I/Mg exchange of aryl iodide 2 followed by addition to glucono lactone 3 in THF. Subsequent in situ treatment of the resulting lactol with HCl in MeOH produces β-anomeric methyl glycopyranoside 4 which is, without isolation, directly reduced with Et3SiH mediated by AlCl3 as a Lewis acid in CH 2Cl2/MeCN to afford 5 in 50% overall yield. The process was implemented for production on a metric ton scale for commercial launch.

METHOD FOR THE PREPARATION OF A CRYSTALLINE FORM OF 1-CHLORO-4- (BETA-D-GLUCOPYRANOS-1-YL)-2-(4-((S)-TETRAHYDROFURAN-3-YLOXY)BENZYL)BENZENE

The invention relates to a method for the preparation for a crystalline form of 1-chloro-4-(Β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene. In addition the invention relates to a crystalline form obtainable by this method, to a pharmaceutical composition and to the use thereof for preparing medicaments.

PROCESSES FOR PREPARING OF GLUCOPYRANOSYL-SUBSTITUTED BENZYL-BENZENE DERIVATIVES

The present invention relates to processes for preparing a glucopyranosyl-substituted benzyl-benzene derivative of general formula III, wherein R1 is defined according to claim 1.