915095-87-3

Usage

Uses

Used in Pharmaceutical Industry:
(2-Chloro-5-iodophenyl)[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methanone is used as a chemical intermediate for the production of Empagliflozin, a medication that acts as a selective SGLT-2 inhibitor. This inhibition helps in improving glycemic control in diabetic rats, offering a potential therapeutic approach for managing diabetes and its associated complications.

Synthesis

To a solution of the fluoride VIII.1 (208kg), tetrahydrofuran (407kg) and (S)-3- hydroxytetrahydrofuran (56kg) is added potassium-terf-butanolate solution (20%) in tetrahydrofuran (388kg) within 3 hrs at 16 to 25°C temperature. After completion of the addition, the mixture is stirred for 60min at 20°C temperature. Then the conversion is determined via HPLC analysis. Water (355kg) is added within 20 min at a temperature of 21 °C (aqueous quench). The reaction mixture is stirred for 30 min (temperature: 20°C). The stirrer is switched off and the mixture is left stand for 60 min (temperature: 20°C). The phases are separated and solvent is distilled off from the organic phase at 19 to 45°C temperature under reduced pressure. 2- Propanol (703kg) is added to the residue at 40 to 46°C temperature and solvent is distilled off at 41 to 50°C temperature under reduced pressure. 2-Propanol (162kg) is added to the residue at 47°C temperature and solvent is distilled off at 40 to 47°C temperature under reduced pressure. Then the mixture is cooled to 0°C within 1 hr 55 min. The product is collected on a centrifuge, washed with a mixture of 2- propanol (158kg) and subsequently with terf.-butylmethylether (88kg) and dried at 19 to 43°C under reduced pressure. 227kg (91 ,8%) of product are obtained as colourless solid. The identity of the product is determined via infrared spectrometry.

Synthetic route

(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-hydroxyphenyl)methanone (1459754-40-5) + (R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (219823-47-9) → (S)-(2-chloro-5-iodophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-87-3)

Conditions	Yield
With potassium carbonate; potassium iodide In acetonitrile at 50 - 55℃;	87%

2-chloro-5-iodobenzoic acid (19094-56-5) + (S)-3-phenoxytetrahydrofuran → (S)-(2-chloro-5-iodophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-87-3)

Conditions	Yield
Stage #1: 2-chloro-5-iodobenzoic acid With oxalyl chloride In dichloromethane; N,N-dimethyl-formamide at 20℃; for 4h; Friedel-Crafts Acylation; Stage #2: (S)-3-phenoxytetrahydrofuran With aluminum (III) chloride In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 3h;	81%

fluorobenzene (462-06-6) → (S)-(2-chloro-5-iodophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-87-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: oxalyl dichloride / N,N-dimethyl-formamide / 5 h / 25 - 30 °C 2: potassium tert-butylate / tetrahydrofuran / 3 h / 16 - 25 °C View Scheme
Multi-step reaction with 2 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 View Scheme
Multi-step reaction with 2 steps 1: oxalyl dichloride; aluminum (III) chloride / N,N-dimethyl-formamide / 25 - 45 °C / Industry scale 2: potassium tert-butylate / tetrahydrofuran / 4 h / 16 - 25 °C / Industry scale View Scheme
Multi-step reaction with 2 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 View Scheme

2-chloro-5-iodobenzoic acid (19094-56-5) → (S)-(2-chloro-5-iodophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-87-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: oxalyl dichloride / N,N-dimethyl-formamide / 5 h / 25 - 30 °C 2: potassium tert-butylate / tetrahydrofuran / 3 h / 16 - 25 °C View Scheme
Multi-step reaction with 2 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 View Scheme
Multi-step reaction with 2 steps 1: oxalyl dichloride; aluminum (III) chloride / N,N-dimethyl-formamide / 25 - 45 °C / Industry scale 2: potassium tert-butylate / tetrahydrofuran / 4 h / 16 - 25 °C / Industry scale View Scheme

2-chloro-5-iodobenzoylchloride (281652-58-2) → (S)-(2-chloro-5-iodophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-87-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: aluminum (III) chloride / 1 h / 0 - 25 °C 2: potassium tert-butylate / tetrahydrofuran / 0.5 h / 7 - 10 °C View Scheme
Multi-step reaction with 2 steps 1: aluminum (III) chloride / 25 °C / Inert atmosphere 2: potassium tert-butylate / tetrahydrofuran / 2 - 10 °C View Scheme
Multi-step reaction with 2 steps 1: aluminum (III) chloride / dichloromethane / 6 h / -5 °C 2: potassium tert-butylate / tetrahydrofuran / 20 °C View Scheme

phenol (108-95-2) → (S)-(2-chloro-5-iodophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-87-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: polyposphoric acid / 50 - 85 °C 2: potassium iodide; potassium carbonate / acetonitrile / 50 - 55 °C View Scheme

(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%

(S)-(2-chloro-5-iodophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-87-3) → C17H16Cl2MgO2

Conditions	Yield
Multi-step reaction with 2 steps 1: 1,1,3,3-Tetramethyldisiloxane / aluminum (III) chloride / toluene / 2.5 h / 18 - 26 °C 2: TurboGrignard / tetrahydrofuran / 1.83 h / -15 - 21 °C View Scheme

(S)-(2-chloro-5-iodophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-87-3) → empagliflozin (864070-44-0)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / toluene / 2.5 h / 18 - 26 °C 2.1: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.83 h / -21 - -15 °C 2.2: 2.92 h / -25 - -13 °C View Scheme
Multi-step reaction with 2 steps 1.1: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / toluene / 2.5 h / 18 - 26 °C / Industry scale 1.2: 20 - 51 °C / Industry scale 2.1: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.83 h / -21 - -15 °C / Industry scale 2.2: 2.92 h / -25 - -18 °C / Industry scale 2.3: -13 - 19 °C / Industry scale View Scheme
Multi-step reaction with 5 steps 1: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / toluene / 2.5 h / 0 - 23 °C 2: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.5 h / -20 - 10 °C 3: hydrogenchloride / isopropyl alcohol / 5 h / 38 - 42 °C / pH 2 4: hydrogenchloride / isopropyl alcohol; methanol 5: aluminum (III) chloride; triethylsilane / dichloromethane; acetonitrile / 0.5 h / 20 - 25 °C View Scheme
Multi-step reaction with 5 steps 1: sodium tetrahydroborate / ethanol / 20 - 25 °C 2: methanesulfonic acid / 20 - 30 °C 3: n-butyllithium / tetrahydrofuran; hexane / -75 - -70 °C / Inert atmosphere 4: methanesulfonic acid / 20 - 25 °C 5: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / -40 - 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 5 steps 1: sodium tetrahydroborate / ethanol / 20 - 25 °C 2: triethylamine / dichloromethane / 0 - 35 °C 3: n-butyllithium / tetrahydrofuran; hexane / -75 - -70 °C / Inert atmosphere 4: methanesulfonic acid / 0 - 35 °C 5: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / -40 - 20 °C / Inert atmosphere View Scheme

(S)-(2-chloro-5-iodophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-87-3) → C35H59ClO8Si4

Conditions	Yield
Multi-step reaction with 2 steps 1: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / toluene / 2.5 h / 0 - 23 °C 2: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.5 h / -20 - 10 °C View Scheme

(S)-(2-chloro-5-iodophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-87-3) → C24H29ClO8

Conditions	Yield
Multi-step reaction with 3 steps 1: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / toluene / 2.5 h / 0 - 23 °C 2: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.5 h / -20 - 10 °C 3: hydrogenchloride / isopropyl alcohol / 5 h / 38 - 42 °C / pH 2 View Scheme

(S)-(2-chloro-5-iodophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-87-3) → (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 4 steps 1: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / toluene / 2.5 h / 0 - 23 °C 2: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.5 h / -20 - 10 °C 3: hydrogenchloride / isopropyl alcohol / 5 h / 38 - 42 °C / pH 2 4: hydrogenchloride / isopropyl alcohol; methanol View Scheme

(S)-(2-chloro-5-iodophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-87-3) → (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 5 steps 1: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / toluene / 2.5 h / 0 - 23 °C 2: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.5 h / -20 - 10 °C 3: hydrogenchloride / isopropyl alcohol / 5 h / 38 - 42 °C / pH 2 4: hydrogenchloride / isopropyl alcohol; methanol 5: triethylamine; dmap / tetrahydrofuran View Scheme

(S)-(2-chloro-5-iodophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-87-3) → (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 5 steps 1: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / toluene / 2.5 h / 0 - 23 °C 2: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.5 h / -20 - 10 °C 3: hydrogenchloride / isopropyl alcohol / 5 h / 38 - 42 °C / pH 2 4: hydrogenchloride / isopropyl alcohol; methanol 5: sodium hydride / tetrahydrofuran; N,N-dimethyl-formamide View Scheme

(S)-(2-chloro-5-iodophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-87-3) → (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 5 steps 1: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / toluene / 2.5 h / 0 - 23 °C 2: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.5 h / -20 - 10 °C 3: hydrogenchloride / isopropyl alcohol / 5 h / 38 - 42 °C / pH 2 4: hydrogenchloride / isopropyl alcohol; methanol 5: sodium hydride / tetrahydrofuran; N,N-dimethyl-formamide View Scheme

(S)-(2-chloro-5-iodophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-87-3) → (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 6 steps 1.1: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / toluene / 2.5 h / 0 - 23 °C 2.1: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.5 h / -20 - 10 °C 3.1: hydrogenchloride / isopropyl alcohol / 5 h / 38 - 42 °C / pH 2 4.1: hydrogenchloride / isopropyl alcohol; methanol 5.1: sodium hydride / tetrahydrofuran; N,N-dimethyl-formamide 6.1: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / 0.5 h / 15 - 20 °C 6.2: 90 °C View Scheme
Multi-step reaction with 6 steps 1: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / toluene / 2.5 h / 0 - 23 °C 2: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.5 h / -20 - 10 °C 3: hydrogenchloride / isopropyl alcohol / 5 h / 38 - 42 °C / pH 2 4: hydrogenchloride / isopropyl alcohol; methanol 5: triethylamine; dmap / tetrahydrofuran 6: aluminum (III) chloride; triethylsilane / dichloromethane; acetonitrile / 0.5 h / 15 - 20 °C View Scheme

(S)-(2-chloro-5-iodophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-87-3) → 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 6 steps 1: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / toluene / 2.5 h / 0 - 23 °C 2: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.5 h / -20 - 10 °C 3: hydrogenchloride / isopropyl alcohol / 5 h / 38 - 42 °C / pH 2 4: hydrogenchloride / isopropyl alcohol; methanol 5: sodium hydride / tetrahydrofuran; N,N-dimethyl-formamide 6: aluminum (III) chloride; triethylsilane / dichloromethane; acetonitrile / 0.5 h / 15 - 20 °C View Scheme

(S)-(2-chloro-5-iodophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-87-3) → 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 6 steps 1: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / toluene / 2.5 h / 0 - 23 °C 2: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.5 h / -20 - 10 °C 3: hydrogenchloride / isopropyl alcohol / 5 h / 38 - 42 °C / pH 2 4: hydrogenchloride / isopropyl alcohol; methanol 5: sodium hydride / tetrahydrofuran; N,N-dimethyl-formamide 6: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / 0.5 h / 15 - 20 °C View Scheme

(S)-(2-chloro-5-iodophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-87-3) → C23H27ClO7

Conditions

Yield

Multi-step reaction with 6 steps 1: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / toluene / 2.5 h / 0 - 23 °C 2: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.5 h / -20 - 10 °C 3: hydrogenchloride / isopropyl alcohol / 5 h / 38 - 42 °C / pH 2 4: hydrogenchloride / isopropyl alcohol; methanol 5: boron trifluoride diethyl etherate / water 6: triethylsilane View Scheme

(S)-(2-chloro-5-iodophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-87-3) → C23H27ClO8

Conditions	Yield
Multi-step reaction with 5 steps 1: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / toluene / 2.5 h / 0 - 23 °C 2: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.5 h / -20 - 10 °C 3: hydrogenchloride / isopropyl alcohol / 5 h / 38 - 42 °C / pH 2 4: hydrogenchloride / isopropyl alcohol; methanol 5: boron trifluoride diethyl etherate / water View Scheme

(S)-(2-chloro-5-iodophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-87-3) → (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 6 steps 1.1: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / toluene / 2.5 h / 0 - 23 °C 2.1: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.5 h / -20 - 10 °C 3.1: hydrogenchloride / isopropyl alcohol / 5 h / 38 - 42 °C / pH 2 4.1: hydrogenchloride / isopropyl alcohol; methanol 5.1: sodium hydride / tetrahydrofuran; N,N-dimethyl-formamide 6.1: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / 0.5 h / 15 - 20 °C 6.2: 90 °C View Scheme
Multi-step reaction with 4 steps 1.1: sodium tetrahydroborate; aluminum (III) chloride / tetrahydrofuran / 5 h / Reflux 2.1: n-butyllithium / toluene / 3 h / -20 °C / Inert atmosphere 2.2: 1 h / 0 °C / Inert atmosphere 3.1: toluene / 6 h / 110 °C / Inert atmosphere 4.1: sodium methylate; methanol / 5 h / Reflux View Scheme

(S)-(2-chloro-5-iodophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-87-3) → (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 2 steps 1: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / toluene / 2.5 h / 0 - 23 °C 2: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.5 h / -20 - 10 °C View Scheme

(S)-(2-chloro-5-iodophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-87-3) → C17H16ClIO3

Conditions	Yield
With sodium tetrahydroborate In ethanol at 20 - 25℃;	98 g

(S)-(2-chloro-5-iodophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-87-3) → C20H24ClIO3Si

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

(S)-(2-chloro-5-iodophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-87-3) → C18H18ClIO3

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

(S)-(2-chloro-5-iodophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-87-3) → C38H67ClO9Si5

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium tetrahydroborate / ethanol / 20 - 25 °C 2: triethylamine / dichloromethane / 0 - 35 °C 3: n-butyllithium / tetrahydrofuran; hexane / -75 - -70 °C / Inert atmosphere View Scheme

(S)-(2-chloro-5-iodophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-87-3) → C25H31ClO9

Conditions	Yield
Multi-step reaction with 4 steps 1: sodium tetrahydroborate / ethanol / 20 - 25 °C 2: methanesulfonic acid / 20 - 30 °C 3: n-butyllithium / tetrahydrofuran; hexane / -75 - -70 °C / Inert atmosphere 4: methanesulfonic acid / 20 - 25 °C View Scheme
Multi-step reaction with 4 steps 1: sodium tetrahydroborate / ethanol / 20 - 25 °C 2: triethylamine / dichloromethane / 0 - 35 °C 3: n-butyllithium / tetrahydrofuran; hexane / -75 - -70 °C / Inert atmosphere 4: methanesulfonic acid / 0 - 35 °C View Scheme

(S)-(2-chloro-5-iodophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-87-3) → C36H61ClO9Si4

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium tetrahydroborate / ethanol / 20 - 25 °C 2: methanesulfonic acid / 20 - 30 °C 3: n-butyllithium / tetrahydrofuran; hexane / -75 - -70 °C / Inert atmosphere View Scheme

(S)-(2-chloro-5-iodophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-87-3) → C24H29ClO9

Conditions	Yield
Multi-step reaction with 4 steps 1: sodium tetrahydroborate / ethanol / 20 - 25 °C 2: methanesulfonic acid / 20 - 30 °C 3: n-butyllithium / tetrahydrofuran; hexane / -75 - -70 °C / Inert atmosphere 4: hydrogenchloride; water / methanol / 20 - 25 °C View Scheme

(S)-(2-chloro-5-iodophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-87-3) → C43H59ClO11

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium tetrahydroborate; aluminum (III) chloride / tetrahydrofuran / 5 h / Reflux 2.1: n-butyllithium / toluene / 3 h / -20 °C / Inert atmosphere 2.2: 1 h / 0 °C / Inert atmosphere 3.1: toluene / 6 h / 110 °C / Inert atmosphere View Scheme

Upstream product

• 915095-86-2 (2-chloro-5-iodophenyl)(4-fluorophenyl)methanone 
• 86087-23-2 (S)-3-hydroxytetyrahydrofurane 
• 462-06-6 fluorobenzene 
• 19094-56-5 2-chloro-5-iodobenzoic acid 
• 637-87-6 1-Chloro-4-iodobenzene 
• 27522-79-8 p-hydroxybenzoylethylamine 
• 25804-49-3 tert-butyl 4-hydroxybenzoate 
• 17696-62-7 Phenyl 4-hydroxybenzoate 
• 108-95-2 phenol 
• 1459754-40-5 (2-chloro-5-iodophenyl)(4-hydroxyphenyl)methanone 
• 219823-47-9 (R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate 
• 281652-58-2 2-chloro-5-iodobenzoylchloride 

Downstream Products

• 864070-44-0 empagliflozin 
• 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 
• 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 
• 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 

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.

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.

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.

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.

METHOD FOR THE PREPARATION OF A CRYSTALLINE FORM

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.