915095-86-2

Usage

Uses

Used in Pharmaceutical Industry:
(2-Chloro-5-iodophenyl)(4-fluorophenyl)methanone is used as a reagent in the synthesis of Empagliflozin (E521510), a selective inhibitor of the SGLT-2 enzyme. This enzyme plays a crucial role in glucose reabsorption in the kidneys, and its inhibition helps in reducing blood glucose levels, making Empagliflozin a potential treatment for diabetes mellitus. (2-Chloro-5-iodophenyl)(4-fluorophenyl)methanone's role in the synthesis process is vital for the development of new drugs targeting diabetes management.

Synthetic route

fluorobenzene (462-06-6) + 2-chloro-5-iodobenzoic acid (19094-56-5) → (2-chloro-5-iodophenyl)(4-fluorophenyl)methanone (915095-86-2)

Conditions	Yield
With oxalyl dichloride; N,N-dimethyl-formamide at 25 - 30℃; for 5h;	94%
Stage #1: fluorobenzene; 2-chloro-5-iodobenzoic acid With oxalyl dichloride In N,N-dimethyl-formamide at 25 - 30℃; for 5h; Stage #2: With aluminum (III) chloride; water at 20 - 30℃; for 6h;	94%
With aluminum (III) chloride; oxalyl dichloride In N,N-dimethyl-formamide at 25 - 45℃; Industry scale;	94%

2-chloro-5-iodobenzoylchloride (281652-58-2) + fluorobenzene (462-06-6) → (2-chloro-5-iodophenyl)(4-fluorophenyl)methanone (915095-86-2)

Conditions	Yield
With aluminum (III) chloride In dichloromethane at -5℃; for 6h;	93.4%
Stage #1: 2-chloro-5-iodobenzoylchloride; fluorobenzene With aluminum (III) chloride at 0 - 75℃; for 1.5h; Friedel Crafts Acylation; Stage #2: With water at 0 - 25℃;
With aluminum (III) chloride at 0 - 25℃; for 1h; Friedel-Crafts Acylation; regioselective reaction;	121 g
With aluminum (III) chloride at 25℃; Inert atmosphere;	105 g
With aluminum (III) chloride In dichloromethane at 20℃; for 3h; Friedel-Crafts Acylation; Cooling with ice;	42.1 g

(2-chloro-5-aminophenyl)(4-fluorophenyl)methanone → (2-chloro-5-iodophenyl)(4-fluorophenyl)methanone (915095-86-2)

Conditions	Yield
Stage #1: (2-chloro-5-aminophenyl)(4-fluorophenyl)methanone With sulfuric acid; sodium nitrite In water at 0 - 10℃; Large scale; Stage #2: With urea; potassium iodide In water at 0 - 20℃; for 0.5h; Large scale;	91.6%

2-chloro-5-iodobenzoic acid (19094-56-5) → (2-chloro-5-iodophenyl)(4-fluorophenyl)methanone (915095-86-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: oxalyl dichloride; N,N-dimethyl-formamide / fluorobenzene / 2 h / 15 - 25 °C 2: aluminum (III) chloride / 1 h / 0 - 25 °C View Scheme
Multi-step reaction with 2 steps 1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2 h / 20 °C 2: aluminum (III) chloride / dichloromethane / 6 h / -5 °C View Scheme
Multi-step reaction with 2 steps 1: N,N-dimethyl-formamide; oxalyl dichloride / dichloromethane / 2 h / 20 °C 2: aluminum (III) chloride / dichloromethane / 3 h / 20 °C / Cooling with ice View Scheme

ortho-chlorobenzoic acid (118-91-2) → (2-chloro-5-iodophenyl)(4-fluorophenyl)methanone (915095-86-2)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: sulfuric acid; nitric acid / 2 h / -5 - 20 °C / Large scale 2.1: thionyl chloride / dichloromethane; N,N-dimethyl-formamide / 3 h / 20 - 25 °C / Autoclave; Reflux 3.1: aluminum (III) chloride / dichloromethane / 5 h / 0 - 5 °C / Autoclave; Large scale 4.1: iron; ammonium chloride / ethanol; water / 5 h / 78 - 80 °C / Autoclave; Large scale 5.1: sodium nitrite; sulfuric acid / water / 0 - 10 °C / Large scale 5.2: 0.5 h / 0 - 20 °C / Large scale View Scheme

2-chloro-5-nitrobenzoic acid (2516-96-3) → (2-chloro-5-iodophenyl)(4-fluorophenyl)methanone (915095-86-2)

Conditions

Yield

Multi-step reaction with 4 steps 1.1: thionyl chloride / dichloromethane; N,N-dimethyl-formamide / 3 h / 20 - 25 °C / Autoclave; Reflux 2.1: aluminum (III) chloride / dichloromethane / 5 h / 0 - 5 °C / Autoclave; Large scale 3.1: iron; ammonium chloride / ethanol; water / 5 h / 78 - 80 °C / Autoclave; Large scale 4.1: sodium nitrite; sulfuric acid / water / 0 - 10 °C / Large scale 4.2: 0.5 h / 0 - 20 °C / Large scale View Scheme

2-chloro-5-nitrobenzoylchloride (25784-91-2) → (2-chloro-5-iodophenyl)(4-fluorophenyl)methanone (915095-86-2)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: aluminum (III) chloride / dichloromethane / 5 h / 0 - 5 °C / Autoclave; Large scale 2.1: iron; ammonium chloride / ethanol; water / 5 h / 78 - 80 °C / Autoclave; Large scale 3.1: sodium nitrite; sulfuric acid / water / 0 - 10 °C / Large scale 3.2: 0.5 h / 0 - 20 °C / Large scale View Scheme

(2-chloro-5-iodophenyl)(4-fluorophenyl)methanone (915095-86-2) → (2-chloro-5-iodophenyl)(4-hydroxyphenyl)methanone (1459754-40-5)

Conditions	Yield
With acetylhydroxamic acid; potassium carbonate In dimethyl sulfoxide at 80℃; for 6h;	95.4%

(2-chloro-5-iodophenyl)(4-fluorophenyl)methanone (915095-86-2) + ethanol (64-17-5) → (2-chloro-5-iodo-phenyl)-(4-ethoxyphenyl)methanone (1103738-26-6)

Conditions	Yield
With sodium hydroxide at 50 - 65℃; Temperature; Reagent/catalyst;	94.3%

(2-chloro-5-iodophenyl)(4-fluorophenyl)methanone (915095-86-2) + (S)-3-hydroxytetyrahydrofurane (86087-23-2) → (S)-(2-chloro-5-iodophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-87-3)

Conditions	Yield
With potassium tert-butylate In tetrahydrofuran at 16 - 25℃; for 3h;	91.8%
Stage #1: (2-chloro-5-iodophenyl)(4-fluorophenyl)methanone; (S)-3-hydroxytetyrahydrofurane With potassium tert-butylate In tetrahydrofuran at 16 - 25℃; for 4h; Stage #2: With water at 20 - 21℃; for 1.83333h;	91.8%
With potassium tert-butylate In tetrahydrofuran at 16 - 25℃; for 4h; Industry scale;	91.8%

(2-chloro-5-iodophenyl)(4-fluorophenyl)methanone (915095-86-2) + potassium ethoxide (917-58-8) → (2-chloro-5-iodo-phenyl)-(4-ethoxyphenyl)methanone (1103738-26-6)

Conditions	Yield
In N,N-dimethyl-formamide at 40℃; for 1h; Cooling with ice;	87.2%

(2-chloro-5-iodophenyl)(4-fluorophenyl)methanone (915095-86-2) + sodium ethanolate (141-52-6) → (2-chloro-5-iodo-phenyl)-(4-ethoxyphenyl)methanone (1103738-26-6)

Conditions	Yield
In N,N-dimethyl-formamide at 20℃; for 1.5h; Solvent; Temperature; Cooling with ice;	86.5%

(2-chloro-5-iodophenyl)(4-fluorophenyl)methanone (915095-86-2) → 1-chloro-2-(4-fluorobenzyl)-4-iodobenzene

Conditions	Yield
With triethylsilane; boron trifluoride diethyl etherate In dichloromethane; acetonitrile at 0 - 20℃;	83%

(2-chloro-5-iodophenyl)(4-fluorophenyl)methanone (915095-86-2) + lithium ethoxide (2388-07-0) → (2-chloro-5-iodo-phenyl)-(4-ethoxyphenyl)methanone (1103738-26-6)

Conditions	Yield
In dimethyl sulfoxide at 0℃; for 3h;	82.7%

(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-iodophenyl)(4-fluorophenyl)methanone (915095-86-2) → C17H16Cl2MgO2

Conditions	Yield
Multi-step reaction with 3 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 3: TurboGrignard / tetrahydrofuran / 1.83 h / -15 - 21 °C View Scheme

(2-chloro-5-iodophenyl)(4-fluorophenyl)methanone (915095-86-2) → empagliflozin (864070-44-0)

Conditions	Yield
Multi-step reaction with 3 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 3.1: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.83 h / -21 - -15 °C 3.2: 2.92 h / -25 - -13 °C View Scheme
Multi-step reaction with 3 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 3.1: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.83 h / -21 - -15 °C / Industry scale 3.2: 2.92 h / -25 - -18 °C / Industry scale 3.3: -13 - 19 °C / Industry scale View Scheme
Multi-step reaction with 6 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 3: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.5 h / -20 - 10 °C 4: hydrogenchloride / isopropyl alcohol / 5 h / 38 - 42 °C / pH 2 5: hydrogenchloride / isopropyl alcohol; methanol 6: aluminum (III) chloride; triethylsilane / dichloromethane; acetonitrile / 0.5 h / 20 - 25 °C View Scheme
Multi-step reaction with 6 steps 1: potassium tert-butylate / tetrahydrofuran / 2 - 10 °C 2: sodium tetrahydroborate / ethanol / 20 - 25 °C 3: methanesulfonic acid / 20 - 30 °C 4: n-butyllithium / tetrahydrofuran; hexane / -75 - -70 °C / Inert atmosphere 5: methanesulfonic acid / 20 - 25 °C 6: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / -40 - 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 6 steps 1: potassium tert-butylate / tetrahydrofuran / 2 - 10 °C 2: sodium tetrahydroborate / ethanol / 20 - 25 °C 3: triethylamine / dichloromethane / 0 - 35 °C 4: n-butyllithium / tetrahydrofuran; hexane / -75 - -70 °C / Inert atmosphere 5: methanesulfonic acid / 0 - 35 °C 6: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / -40 - 20 °C / Inert atmosphere View Scheme

(2-chloro-5-iodophenyl)(4-fluorophenyl)methanone (915095-86-2) → C35H59ClO8Si4

Conditions	Yield
Multi-step reaction with 3 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 3: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.5 h / -20 - 10 °C View Scheme

(2-chloro-5-iodophenyl)(4-fluorophenyl)methanone (915095-86-2) → C24H29ClO8

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

(2-chloro-5-iodophenyl)(4-fluorophenyl)methanone (915095-86-2) → (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 5 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 3: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.5 h / -20 - 10 °C 4: hydrogenchloride / isopropyl alcohol / 5 h / 38 - 42 °C / pH 2 5: hydrogenchloride / isopropyl alcohol; methanol View Scheme

(2-chloro-5-iodophenyl)(4-fluorophenyl)methanone (915095-86-2) → (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 6 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 3: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.5 h / -20 - 10 °C 4: hydrogenchloride / isopropyl alcohol / 5 h / 38 - 42 °C / pH 2 5: hydrogenchloride / isopropyl alcohol; methanol 6: triethylamine; dmap / tetrahydrofuran View Scheme

(2-chloro-5-iodophenyl)(4-fluorophenyl)methanone (915095-86-2) → (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 6 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 3: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.5 h / -20 - 10 °C 4: hydrogenchloride / isopropyl alcohol / 5 h / 38 - 42 °C / pH 2 5: hydrogenchloride / isopropyl alcohol; methanol 6: sodium hydride / tetrahydrofuran; N,N-dimethyl-formamide View Scheme

(2-chloro-5-iodophenyl)(4-fluorophenyl)methanone (915095-86-2) → (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 6 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 3: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.5 h / -20 - 10 °C 4: hydrogenchloride / isopropyl alcohol / 5 h / 38 - 42 °C / pH 2 5: hydrogenchloride / isopropyl alcohol; methanol 6: sodium hydride / tetrahydrofuran; N,N-dimethyl-formamide View Scheme

(2-chloro-5-iodophenyl)(4-fluorophenyl)methanone (915095-86-2) → (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 7 steps 1.1: potassium tert-butylate / tetrahydrofuran / 0.5 h / 7 - 10 °C 2.1: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / toluene / 2.5 h / 0 - 23 °C 3.1: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.5 h / -20 - 10 °C 4.1: hydrogenchloride / isopropyl alcohol / 5 h / 38 - 42 °C / pH 2 5.1: hydrogenchloride / isopropyl alcohol; methanol 6.1: sodium hydride / tetrahydrofuran; N,N-dimethyl-formamide 7.1: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / 0.5 h / 15 - 20 °C 7.2: 90 °C View Scheme
Multi-step reaction with 7 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 3: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.5 h / -20 - 10 °C 4: hydrogenchloride / isopropyl alcohol / 5 h / 38 - 42 °C / pH 2 5: hydrogenchloride / isopropyl alcohol; methanol 6: triethylamine; dmap / tetrahydrofuran 7: aluminum (III) chloride; triethylsilane / dichloromethane; acetonitrile / 0.5 h / 15 - 20 °C View Scheme

(2-chloro-5-iodophenyl)(4-fluorophenyl)methanone (915095-86-2) → 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 7 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 3: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.5 h / -20 - 10 °C 4: hydrogenchloride / isopropyl alcohol / 5 h / 38 - 42 °C / pH 2 5: hydrogenchloride / isopropyl alcohol; methanol 6: sodium hydride / tetrahydrofuran; N,N-dimethyl-formamide 7: aluminum (III) chloride; triethylsilane / dichloromethane; acetonitrile / 0.5 h / 15 - 20 °C View Scheme

(2-chloro-5-iodophenyl)(4-fluorophenyl)methanone (915095-86-2) → 1-chloro-4-(2,3,4,6-tetra-O-allyl-D-glucopyranos-1-yl)-2-(4-(S)-tetrahydrofuran-3-yloxy-benzyl)-benzene + C35H43ClO7

Conditions

Yield

Multi-step reaction with 7 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 3: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.5 h / -20 - 10 °C 4: hydrogenchloride / isopropyl alcohol / 5 h / 38 - 42 °C / pH 2 5: hydrogenchloride / isopropyl alcohol; methanol 6: sodium hydride / tetrahydrofuran; N,N-dimethyl-formamide 7: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / 0.5 h / 15 - 20 °C View Scheme

(2-chloro-5-iodophenyl)(4-fluorophenyl)methanone (915095-86-2) → C23H27ClO7

Conditions

Yield

Multi-step reaction with 7 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 3: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.5 h / -20 - 10 °C 4: hydrogenchloride / isopropyl alcohol / 5 h / 38 - 42 °C / pH 2 5: hydrogenchloride / isopropyl alcohol; methanol 6: boron trifluoride diethyl etherate / water 7: triethylsilane View Scheme

(2-chloro-5-iodophenyl)(4-fluorophenyl)methanone (915095-86-2) → C23H27ClO8

Conditions

Yield

Multi-step reaction with 6 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 3: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.5 h / -20 - 10 °C 4: hydrogenchloride / isopropyl alcohol / 5 h / 38 - 42 °C / pH 2 5: hydrogenchloride / isopropyl alcohol; methanol 6: boron trifluoride diethyl etherate / water View Scheme

(2-chloro-5-iodophenyl)(4-fluorophenyl)methanone (915095-86-2) → (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

Conditions	Yield
Multi-step reaction with 7 steps 1.1: potassium tert-butylate / tetrahydrofuran / 0.5 h / 7 - 10 °C 2.1: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / toluene / 2.5 h / 0 - 23 °C 3.1: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.5 h / -20 - 10 °C 4.1: hydrogenchloride / isopropyl alcohol / 5 h / 38 - 42 °C / pH 2 5.1: hydrogenchloride / isopropyl alcohol; methanol 6.1: sodium hydride / tetrahydrofuran; N,N-dimethyl-formamide 7.1: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / 0.5 h / 15 - 20 °C 7.2: 90 °C View Scheme
Multi-step reaction with 5 steps 1.1: potassium tert-butylate / tetrahydrofuran / 20 °C 2.1: sodium tetrahydroborate; aluminum (III) chloride / tetrahydrofuran / 5 h / Reflux 3.1: n-butyllithium / toluene / 3 h / -20 °C / Inert atmosphere 3.2: 1 h / 0 °C / Inert atmosphere 4.1: toluene / 6 h / 110 °C / Inert atmosphere 5.1: sodium methylate; methanol / 5 h / Reflux View Scheme

(2-chloro-5-iodophenyl)(4-fluorophenyl)methanone (915095-86-2) → (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

Conditions	Yield
Multi-step reaction with 3 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 3: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.5 h / -20 - 10 °C View Scheme

(2-chloro-5-iodophenyl)(4-fluorophenyl)methanone (915095-86-2) → C17H16ClIO3

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium tert-butylate / tetrahydrofuran / 2 - 10 °C 2: sodium tetrahydroborate / ethanol / 20 - 25 °C View Scheme

(2-chloro-5-iodophenyl)(4-fluorophenyl)methanone (915095-86-2) → C20H24ClIO3Si

Conditions	Yield
Multi-step reaction with 3 steps 1: potassium tert-butylate / tetrahydrofuran / 2 - 10 °C 2: sodium tetrahydroborate / ethanol / 20 - 25 °C 3: triethylamine / dichloromethane / 0 - 35 °C View Scheme

(2-chloro-5-iodophenyl)(4-fluorophenyl)methanone (915095-86-2) → C18H18ClIO3

Conditions	Yield
Multi-step reaction with 3 steps 1: potassium tert-butylate / tetrahydrofuran / 2 - 10 °C 2: sodium tetrahydroborate / ethanol / 20 - 25 °C 3: methanesulfonic acid / 20 - 30 °C View Scheme

Upstream product

• 281652-58-2 2-chloro-5-iodobenzoylchloride 
• 462-06-6 fluorobenzene 
• 2516-96-3 2-chloro-5-nitrobenzoic acid 
• 25784-91-2 2-chloro-5-nitrobenzoylchloride 
• 118-91-2 ortho-chlorobenzoic acid 
• 19094-56-5 2-chloro-5-iodobenzoic acid 

Downstream Products

• 915095-87-3 (S)-(2-chloro-5-iodophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone 
• 915095-94-2 (3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran 
• 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 
• 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 
• 1103738-26-6 (2-chloro-5-iodo-phenyl)-(4-ethoxyphenyl)methanone 
• 864070-37-1 (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol 
• 1204220-63-2 (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol 
• 1103738-29-9 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene 

Relevant academic research and scientific papers

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.

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)

Synthesis method for (2-chloro-5-iodophenyl)(4-fluorophenyl)ketone

The invention discloses a synthesis method for (2-chloro-5-iodophenyl)(4-fluorophenyl)ketone. According to the method, with cheap o-chlorobenzoic acid as a starting material, (2-chloro-5-iodophenyl)(4-fluorophenyl)ketone is obtained by nitration, Friedel-Crafts acylation and reduction and finally by Sandmeyer reaction for iodination. The materials used by the method are cheap and easy to obtain, and the method adopting Sandmeyer reaction for iodination can increase the iodine utilization rate, and has the characteristics of simplicity in operation, high yield, high purity and suitability for industrialized production. (The chemical formula is shown in the specification).

Preparation method of SGLT2 inhibitor intermediate

The invention provides a preparation method of an SGLT2 inhibitor intermediate II. The preparation method includes that a compound V and an ethoxide reagent are subjected to nucleophilic substitution in a proper solution to obtain a compound II, wherein the compounding formula is shown as below, and X in the compound V structure is selected from Br or I. By the compounding route, the problem of purification difficulty caused by plenty of isomers in compounding routes in documentary reports is solved. Reaction operations are simple and convenient, the reagent is low in cost and easy to get, and the obtained product does not contain the isomers. The route is suitable for industrial 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.

PROCESS FOR THE PREPARATION OF EMPAGLIFLOZIN

An improved process for the preparation of empagliflozin is disclosed. Novel intermediates of formulas (13) and (14) for the preparation of empagliflozin are also disclosed, wherein R1 and R2 are independently hydrogen or hydroxyl protecting groups.

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.