866607-35-4

Usage

Uses

Used in Pharmaceutical Industry:
D-Glucitol, 1,5-anhydro-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]Methyl]-4-Methylphenyl]-, tetraacetate, (1S)(9CI) is used as an intermediate in the synthesis of Canagliflozin for the treatment of type 2 diabetes and obesity. Canagliflozin functions as a sodium/glucose cotransporter 2 (SGLT2) inhibitor, which dose-dependently reduces the renal threshold for glucose excretion and increases urinary glucose excretion, thus helping to manage blood sugar levels in patients with type 2 diabetes and obesity.

Flammability and Explosibility

Notclassified

Synthetic route

(2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) (898566-17-1) + 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide (572-09-8) → (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (866607-35-4)

Conditions	Yield
Stage #1: (2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) With isopropylmagnesium chloride In tetrahydrofuran at 0 - 10℃; for 2h; Inert atmosphere; Stage #2: 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide In tetrahydrofuran at -15 - 10℃; for 2h; Reagent/catalyst; Inert atmosphere;	86.2%
With bis(acetylacetonate)nickel(II); magnesium chloride; 4,4',4-tri-tert-butyl-2,2':6',2-terpyridine; zinc In tetrahydrofuran for 20h; Schlenk technique; Inert atmosphere; Cooling with ice;	75%
With magnesium chloride In tetrahydrofuran at 15℃; stereoselective reaction;	60%

methyl 2,3,4,6-tetra-O-acetyl-1-C-(3-{[5-(4-fluoro-phenyl)-2-thienyl]methyl}-4-methylphenyl)-D-glucopyranoside → (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (866607-35-4)

Conditions	Yield
With boron trifluoride diethyl etherate In water; acetonitrile	85%
With triethylsilane; trifluoroborane diethyl ether In acetonitrile at 0 - 5℃; for 4h;	22 g
With triethylsilane; boron trifluoride diethyl etherate In acetonitrile at 0℃; for 4h;	11.12 g
With triethylsilane; boron trifluoride diethyl etherate In water; acetonitrile at 5 - 20℃; Temperature; Large scale;	28.6 kg

canagliflozin (842133-18-0) + acetic anhydride (108-24-7) → (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (866607-35-4)

Conditions	Yield
With dmap; triethylamine In ethyl acetate at 20 - 30℃; for 1h;	80%
With 4-methyl-morpholine; dmap In tetrahydrofuran at -10 - 20℃; for 1.25h;	78%
With 4-methyl-morpholine; dmap In dichloromethane at -5 - 5℃; for 4h; Reagent/catalyst;	69.5%

(2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) (898566-17-1) + acetic anhydride (108-24-7) + (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) → (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (866607-35-4)

Conditions

Yield

Stage #1: (2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) With n-butyllithium In tetrahydrofuran; hexane at -75 - -70℃; for 1h; Inert atmosphere; Large scale; Stage #2: (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one In tetrahydrofuran; hexane at -60 - 20℃; for 1h; Large scale; Stage #3: acetic anhydride Large scale; Further stages;

60%

2-[(5-bromo-2-methyl-phenyl)methyl]-5-(4-fluorophenyl)thiophene (1030825-20-7) + 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl chloride (4451-35-8) → (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (866607-35-4)

Conditions

Yield

With nickel(II) bromide dimethoxyethane; diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate; [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine-N1,N1′]bis{3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-κN]phenyl-κC}iridium(III) hexafluorophosphate; 4,4'-di-tert-butyl-2,2'-bipyridine; N,N,N',N'-tetramethylguanidine In acetonitrile at 25℃; for 24h; Inert atmosphere; Sealed tube; Irradiation; diastereoselective reaction;

48%

((3R,4S,5R,6R)-6-(acetoxymethyl)-2-((5-(4-(fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triyl)triacetate → (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (866607-35-4)

Conditions	Yield
Stage #1: ((3R,4S,5R,6R)-6-(acetoxymethyl)-2-((5-(4-(fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triyl)triacetate With triethylsilane; boron trifluoride diethyl etherate In acetonitrile at 0 - 20℃; Stage #2: With water; potassium carbonate In acetonitrile at 20℃; Cooling with ice;

(3(R),4(S),5(R)-triacetoxy-6-{3-[5-(4-fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxy-tetrahydro-pyran-2(R)-yl)-methanol acetate → (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (866607-35-4)

Conditions	Yield
Stage #1: (3(R),4(S),5(R)-triacetoxy-6-{3-[5-(4-fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxy-tetrahydro-pyran-2(R)-yl)-methanol acetate With triethylsilane; boron trifluoride diethyl etherate In acetonitrile at 2℃; for 1.5h; Stage #2: With water; sodium carbonate In acetonitrile at 45℃; Product distribution / selectivity;

2-[(5-bromo-2-methyl-phenyl)methyl]-5-(4-fluorophenyl)thiophene (1030825-20-7) → (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (866607-35-4)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: n-butyllithium / tetrahydrofuran; toluene; hexane / -75 - -65 °C / Inert atmosphere 1.2: -75 - -70 °C 1.3: 12 h / -75 - 30 °C 2.1: boron trifluoride diethyl etherate; triethylsilane / dichloromethane / 0 - 5 °C 3.1: dmap / acetone / 5 h / 0.25 - 0.5 °C View Scheme
Multi-step reaction with 4 steps 1.1: sodium iodide; copper(l) iodide; N,N`-dimethylethylenediamine / toluene; diethylene glycol dimethyl ether / 36 h / Inert atmosphere; Reflux 2.1: tetrahydrofuran / 1 h / 0 - 5 °C / Inert atmosphere 2.2: 2 h / 0 - 5 °C 2.3: 2 h / Cooling 3.1: 4-methyl-morpholine; dmap / toluene; ethyl acetate / 15 h / 0 - 20 °C 4.1: triethylsilane; boron trifluoride diethyl etherate / acetonitrile / 4 h / 0 °C View Scheme

4-fluoroboronic acid (1765-93-1) → (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (866607-35-4)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: tetrakis(triphenylphosphine) palladium(0); sodium carbonate / 1,2-dimethoxyethane; water / 25 - 75 °C / Inert atmosphere 2.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 0.1 h / 25 - 30 °C / Inert atmosphere 2.2: 0 - 15 °C / Inert atmosphere 3.1: aluminum (III) chloride; sodium tetrahydroborate / 1,2-dimethoxyethane / 0 - 70 °C 4.1: n-butyllithium / tetrahydrofuran; toluene; hexane / -75 - -65 °C / Inert atmosphere 4.2: -75 - -70 °C 4.3: 12 h / -75 - 30 °C 5.1: boron trifluoride diethyl etherate; triethylsilane / dichloromethane / 0 - 5 °C 6.1: dmap / acetone / 5 h / 0.25 - 0.5 °C View Scheme

2-(4-fluorophenyl)thiophene (58861-48-6) → (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (866607-35-4)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 0.1 h / 25 - 30 °C / Inert atmosphere 1.2: 0 - 15 °C / Inert atmosphere 2.1: aluminum (III) chloride; sodium tetrahydroborate / 1,2-dimethoxyethane / 0 - 70 °C 3.1: n-butyllithium / tetrahydrofuran; toluene; hexane / -75 - -65 °C / Inert atmosphere 3.2: -75 - -70 °C 3.3: 12 h / -75 - 30 °C 4.1: boron trifluoride diethyl etherate; triethylsilane / dichloromethane / 0 - 5 °C 5.1: dmap / acetone / 5 h / 0.25 - 0.5 °C View Scheme
Multi-step reaction with 3 steps 1.1: thionyl chloride / dichloromethane; N,N-dimethyl-formamide / 1 h / Reflux 1.2: 1 h / 0 - 30 °C 2.1: s-butylmagnesium chloride; lithium chloride / toluene; tetrahydrofuran / 2 h / -5 - 0 °C 2.2: -45 - -35 °C 3.1: boron trifluoride diethyl etherate; triethylsilane / acetonitrile / 1 h / 30 - 42 °C View Scheme
Multi-step reaction with 5 steps 1.1: thionyl chloride / dichloromethane; N,N-dimethyl-formamide / 1 h / Reflux 1.2: 1 h / 0 - 30 °C 2.1: sodium tetrahydroborate / tetrahydrofuran; water / 4 h / 30 °C 3.1: methanesulfonic acid / methanol / 3 h / 30 °C 4.1: s-butylmagnesium chloride; lithium chloride / toluene; tetrahydrofuran / 2 h / -5 - 0 °C 4.2: -45 - -35 °C 5.1: boron trifluoride diethyl etherate; triethylsilane / acetonitrile / 1 h / 30 - 42 °C View Scheme

(5-bromo-2-methylphenyl)[5-(p-fluorophenyl)thiophene-2-yl]methanone (1132832-75-7) → (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (866607-35-4)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: aluminum (III) chloride; sodium tetrahydroborate / 1,2-dimethoxyethane / 0 - 70 °C 2.1: n-butyllithium / tetrahydrofuran; toluene; hexane / -75 - -65 °C / Inert atmosphere 2.2: -75 - -70 °C 2.3: 12 h / -75 - 30 °C 3.1: boron trifluoride diethyl etherate; triethylsilane / dichloromethane / 0 - 5 °C 4.1: dmap / acetone / 5 h / 0.25 - 0.5 °C View Scheme

5-iodo-2-methylbenzoic acid (54811-38-0) → (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (866607-35-4)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: thionyl chloride / dichloromethane; N,N-dimethyl-formamide / 1 h / Reflux 1.2: 1 h / 0 - 30 °C 2.1: s-butylmagnesium chloride; lithium chloride / toluene; tetrahydrofuran / 2 h / -5 - 0 °C 2.2: -45 - -35 °C 3.1: boron trifluoride diethyl etherate; triethylsilane / acetonitrile / 1 h / 30 - 42 °C View Scheme
Multi-step reaction with 5 steps 1.1: thionyl chloride / dichloromethane; N,N-dimethyl-formamide / 1 h / Reflux 1.2: 1 h / 0 - 30 °C 2.1: sodium tetrahydroborate / tetrahydrofuran; water / 4 h / 30 °C 3.1: methanesulfonic acid / methanol / 3 h / 30 °C 4.1: s-butylmagnesium chloride; lithium chloride / toluene; tetrahydrofuran / 2 h / -5 - 0 °C 4.2: -45 - -35 °C 5.1: boron trifluoride diethyl etherate; triethylsilane / acetonitrile / 1 h / 30 - 42 °C View Scheme

[5-(4-fluorophenyl)thiophen-2-yl](5-iodo-2-methylphenyl)methanol → (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (866607-35-4)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: methanesulfonic acid / methanol / 3 h / 30 °C 2.1: s-butylmagnesium chloride; lithium chloride / toluene; tetrahydrofuran / 2 h / -5 - 0 °C 2.2: -45 - -35 °C 3.1: boron trifluoride diethyl etherate; triethylsilane / acetonitrile / 1 h / 30 - 42 °C View Scheme

C19H16FIOS → (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (866607-35-4)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: s-butylmagnesium chloride; lithium chloride / toluene; tetrahydrofuran / 2 h / -5 - 0 °C 1.2: -45 - -35 °C 2.1: boron trifluoride diethyl etherate; triethylsilane / acetonitrile / 1 h / 30 - 42 °C View Scheme

2,3,4,6-tetra-O-acetyl-D-glucono-1,5-lactone (61259-48-1, 73322-42-6) → (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (866607-35-4)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: s-butylmagnesium chloride; lithium chloride / toluene; tetrahydrofuran / 2 h / -5 - 0 °C 1.2: -45 - -35 °C 2.1: boron trifluoride diethyl etherate; triethylsilane / acetonitrile / 1 h / 30 - 42 °C View Scheme
Multi-step reaction with 2 steps 1.1: s-butylmagnesium chloride; lithium chloride / toluene; tetrahydrofuran / 2 h / -5 - 0 °C 1.2: -45 - -35 °C 2.1: boron trifluoride diethyl etherate; triethylsilane / acetonitrile / 1 h / 30 - 42 °C View Scheme

C33H35FO11S → (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (866607-35-4)

Conditions	Yield
With triethylsilane; boron trifluoride diethyl etherate In acetonitrile at 30 - 42℃; for 1h;	73 g

D-Glucono-1,5-lactone (90-80-2) → (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (866607-35-4)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: trifluoroacetic acid 2.1: s-butylmagnesium chloride; lithium chloride / toluene; tetrahydrofuran / 2 h / -5 - 0 °C 2.2: -45 - -35 °C 3.1: boron trifluoride diethyl etherate; triethylsilane / acetonitrile / 1 h / 30 - 42 °C View Scheme
Multi-step reaction with 3 steps 1.1: trifluoroacetic acid 2.1: s-butylmagnesium chloride; lithium chloride / toluene; tetrahydrofuran / 2 h / -5 - 0 °C 2.2: -45 - -35 °C 3.1: boron trifluoride diethyl etherate; triethylsilane / acetonitrile / 1 h / 30 - 42 °C View Scheme
Multi-step reaction with 4 steps 1.1: tetrahydrofuran; 1-methyl-pyrrolidin-2-one / Inert atmosphere 2.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -75 - -70 °C / Inert atmosphere 2.2: 1 h / -60 °C 3.1: dmap; methylamine / 1-methyl-pyrrolidin-2-one / 1 h / 0 - 30 °C 4.1: triethylsilane; trifluoroborane diethyl ether / acetonitrile / 4 h / 0 - 5 °C View Scheme
Multi-step reaction with 4 steps 1: 4-methyl-morpholine / tetrahydrofuran 2: n-butyllithium / toluene; dibutyl ether 3: dmap; 4-methyl-morpholine / dichloromethane 4: boron trifluoride diethyl etherate / acetonitrile; water View Scheme
Multi-step reaction with 2 steps 1.1: 4-methyl-morpholine / tetrahydrofuran / 20 °C / Inert atmosphere; Large scale 2.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -75 - -70 °C / Inert atmosphere; Large scale 2.2: 1 h / -60 - 20 °C / Large scale 2.3: Large scale View Scheme

(5-(4-fluorophenyl)thiophen-2-yl)(5-iodo-2-methylphenyl)methanone → (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (866607-35-4)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: s-butylmagnesium chloride; lithium chloride / toluene; tetrahydrofuran / 2 h / -5 - 0 °C 1.2: -45 - -35 °C 2.1: boron trifluoride diethyl etherate; triethylsilane / acetonitrile / 1 h / 30 - 42 °C View Scheme
Multi-step reaction with 4 steps 1.1: sodium tetrahydroborate / tetrahydrofuran; water / 4 h / 30 °C 2.1: methanesulfonic acid / methanol / 3 h / 30 °C 3.1: s-butylmagnesium chloride; lithium chloride / toluene; tetrahydrofuran / 2 h / -5 - 0 °C 3.2: -45 - -35 °C 4.1: boron trifluoride diethyl etherate; triethylsilane / acetonitrile / 1 h / 30 - 42 °C View Scheme

C32H31FO11S → (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (866607-35-4)

Conditions	Yield
With triethylsilane; boron trifluoride diethyl etherate In acetonitrile at 30 - 42℃; for 1h;	73 g

(2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) (898566-17-1) → (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (866607-35-4)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: tetrahydrofuran / 1 h / 0 - 5 °C / Inert atmosphere 1.2: 2 h / 0 - 5 °C 1.3: 2 h / Cooling 2.1: 4-methyl-morpholine; dmap / toluene; ethyl acetate / 15 h / 0 - 20 °C 3.1: triethylsilane; boron trifluoride diethyl etherate / acetonitrile / 4 h / 0 °C View Scheme
Multi-step reaction with 3 steps 1.1: TurboGrignard / tetrahydrofuran / 1 h / -18 - -13 °C / Inert atmosphere; Large scale 1.2: 1 h / -15 - -10 °C / Large scale 1.3: 1 h / 20 °C / Large scale 2.1: dmap; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 0 - 10 °C / Large scale 3.1: triethylsilane; boron trifluoride diethyl etherate / acetonitrile; water / 5 - 20 °C / Large scale View Scheme

(3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1030825-21-8) → (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (866607-35-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: dmap; methylamine / 1-methyl-pyrrolidin-2-one / 1 h / 0 - 30 °C 2: triethylsilane; trifluoroborane diethyl ether / acetonitrile / 4 h / 0 - 5 °C View Scheme
Multi-step reaction with 2 steps 1: 4-methyl-morpholine; dmap / toluene; ethyl acetate / 15 h / 0 - 20 °C 2: triethylsilane; boron trifluoride diethyl etherate / acetonitrile / 4 h / 0 °C View Scheme
Multi-step reaction with 2 steps 1: dmap; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 0 - 10 °C / Large scale 2: triethylsilane; boron trifluoride diethyl etherate / acetonitrile; water / 5 - 20 °C / Large scale View Scheme

(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) → (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (866607-35-4)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -75 - -70 °C / Inert atmosphere 1.2: 1 h / -60 °C 2.1: dmap; methylamine / 1-methyl-pyrrolidin-2-one / 1 h / 0 - 30 °C 3.1: triethylsilane; trifluoroborane diethyl ether / acetonitrile / 4 h / 0 - 5 °C View Scheme
Multi-step reaction with 3 steps 1: n-butyllithium / toluene; dibutyl ether 2: dmap; 4-methyl-morpholine / dichloromethane 3: boron trifluoride diethyl etherate / acetonitrile; water View Scheme
Multi-step reaction with 3 steps 1.1: TurboGrignard / tetrahydrofuran / 1 h / -18 - -13 °C / Inert atmosphere; Large scale 1.2: 1 h / -15 - -10 °C / Large scale 1.3: 1 h / 20 °C / Large scale 2.1: dmap; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 0 - 10 °C / Large scale 3.1: triethylsilane; boron trifluoride diethyl etherate / acetonitrile; water / 5 - 20 °C / Large scale View Scheme

C42H44F2N2S2Zn*Br2Cl2Mg2 + 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide (572-09-8) → (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (866607-35-4) + (2R,3R,4R,5S)-2-(acetoxymethyl)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate

Conditions	Yield
With dichloro(1,2-{bis[3,5-bis(trimethylsilyl)pheny]phosphino-κP}benzene)iron(II) In tetrahydrofuran at 0 - 25℃; for 36h; Inert atmosphere; Overall yield = 0.467 g; diastereoselective reaction;	A 0.168 g B 0.236 g

(2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) (898566-17-1) + 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide (572-09-8) → (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (866607-35-4) + (2R,3R,4R,5S)-2-(acetoxymethyl)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate

Conditions	Yield
With nickel(II) perchlorate hexahydrate; 4,4'-di-tert-butyl-2,2'-bipyridine; magnesium chloride; zinc In N,N-dimethyl acetamide Reagent/catalyst; Solvent; Temperature; Schlenk technique; Inert atmosphere; Cooling with ice; Overall yield = 80 %; Optical yield = 20 %de;
With dmap; nickel(II) perchlorate hexahydrate; hydrogen bromide; acetic acid; magnesium chloride; zinc In tetrahydrofuran at 25℃; for 12h; Schlenk technique; Sealed tube; Inert atmosphere; Overall yield = 57.5 mg; stereoselective reaction;	A n/a B n/a

α-D-glucopyranose peracetylate (604-68-2) → (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (866607-35-4)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: hydrogen bromide; acetic acid / dichloromethane / 2 h / 0 - 10 °C 2.1: isopropylmagnesium chloride / tetrahydrofuran / 2 h / 0 - 10 °C / Inert atmosphere 2.2: 2 h / -15 - 10 °C / Inert atmosphere View Scheme

β-D-glucose pentaacetate (604-69-3) → (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (866607-35-4)

Conditions

Yield

Multi-step reaction with 2 steps 1: titanium tetrachloride / chloroform / 3 h / 70 °C 2: [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine-N1,N1′]bis{3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-κN]phenyl-κC}iridium(III) hexafluorophosphate; nickel(II) bromide dimethoxyethane; N,N,N',N'-tetramethylguanidine; diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate; 4,4'-di-tert-butyl-2,2'-bipyridine / acetonitrile / 24 h / 25 °C / Inert atmosphere; Sealed tube; Irradiation View Scheme

(2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (866607-35-4) → canagliflozin (842133-18-0)

Conditions	Yield
With methanol; sodium methylate at 20℃; for 12h; Sealed tube;	99%
With water; sodium hydroxide In tetrahydrofuran; methanol at 20 - 25℃; for 1.16667h;	98%
With di(n-butyl)tin oxide In methanol for 24h; Reflux; Inert atmosphere;	95%

(2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (866607-35-4) → 4-(6-deoxy-β-D-glucopyranosyl)-2-[5-(4-fluorophenyl)thiophen-2-ylmethyl]-1-methylbenzene

Conditions	Yield
With methanol; lithium hydroxide In tetrahydrofuran; water at 0 - 20℃; for 2h;

Upstream product

• 842133-18-0 canagliflozin 
• 108-24-7 acetic anhydride 
• 572-09-8 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide 
• 604-69-3 β-D-glucose pentaacetate 
• 1030825-20-7 3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl bromide 
• 4451-35-8 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl chloride 
• 898566-17-1 (2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) 
• 604-68-2 α-D-glucopyranose peracetylate 
• 32469-28-6 (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one 
• 1222075-02-6 methyl 2,3,4,6-tetra-O-acetyl-1-C-(3-{[5-(4-fluoro-phenyl)-2-thienyl]methyl}-4-methylphenyl)-D-glucopyranoside 
• 1030825-21-8 methyl 1-C-(3-{[5-(4-fluorophenyl)-2-thienyl]methyl}-4-methyl-phenyl)-D-glucopyranoside 
• 90-80-2 D-Glucono-1,5-lactone 
• 61259-48-1 2,3,4,6-tetra-O-acetyl-D-glucono-1,5-lactone 
• 54811-38-0 5-iodo-2-methylbenzoic?acid 

Downstream Products

• 842133-18-0 canagliflozin 

Relevant academic research and scientific papers

Stereoselective Preparation of C-Aryl Glycosides via Visible-Light-Induced Nickel-Catalyzed Reductive Cross-Coupling of Glycosyl Chlorides and Aryl Bromides

A nickel-catalyzed cross-coupling reaction of glycosyl chlorides with aryl bromides has been developed. The reaction proceeds smoothly under visible-light irradiation and features the use of bench-stable glycosyl chlorides, allowing the highly stereoselective synthesis of C-aryl glycosides. (Figure presented.).

Preparation method of canagliflozin

The invention discloses a preparation method of canagliflozin. According to the method, the reaction of each step in a route is improved, so that the conversion rate of raw materials is increased, andintroduction of potential toxic compounds is avoided. In addition, reaction conditions are mild; operation is simple; purity of an obtained product is high; quality of drugs is improved; and the preparation method is suitable for industrial production.

Preparation method of canagliflozin

The invention belongs to the technical field of chemical synthesis of medicines, and concretely relates to a preparation method of canagliflozin. The preparation method comprises the following steps:carrying out an acetylation and bromination reaction on d-glucose used as a starting raw material in order to prepare bromotetraacetylglucose; carrying out a Grignard exchange reaction on 2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene and a Grignard reagent at a low temperature, and reacting the obtained reaction product with the bromotetraacetylglucose to form an acetyl protected intermediate; and reacting the intermediate with an alkaline solution, and purifying the obtained reaction product to obtain the canagliflozin. The preparation method has the advantages of mild conditions, safety in operation and simple post-treatment; and the product has a high purity, a detection result shows that the product contains no alpha-isomer, and the product is safe.

Carbon-aryl glycoside SGLT-2 inhibitor precursor and synthesis method thereof

The invention relates to a plurality of carbon-aryl glycoside SGLT-2 inhibitor precursors and a synthesis method thereof. The method takes glycosyl bromide and aryl iodide (bromide) as substrates, thesubstrates react for 1-2 days through ice water bath and the room temperature mixing condition under the effects of a catalyst, a ligand, a reducing agent and an additive, and a precursor compound ofcarbon-aryl glycoside SGLT-2 inhibitor drug is obtained. The synthesis method has the advantages that the precursor compound is convenient to hydrolyze, the conversion rate is high, the catalyst metal is cheap, the product is easily and massively prepared and not prone to deteriorating, the reaction is moderate, one-pot reaction and one-step reaction are achieved, the steps are simple, the methodis safe to operate, the yield is high, and the stereoscopic selectivity is good.

Nickel-catalyzed reductive coupling of glucosyl halides with aryl/vinyl halides enabling β-selective preparation of C-aryl/vinyl glucosides

This work describes stereoselective preparation of β-C-aryl/vinyl glucosides via mild Ni-catalyzed reductive arylation and vinylation of C1-glucosyl halides with aryl and vinyl halides. A broad range of aryl halides and vinyl halides were employed to yield C-aryl/vinyl glucosides in 42%–93% yields. Good to excellent β-selectivities were obtained for C-glucosides by using tridentate ligand.

Preparation method of canagliflozin

The invention relates to a preparation method of canagliflozin, and the preparation method is characterized in that the preparation method comprises the following steps: 1) reacting 2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl) methyl ] thiophene with an alkaline reagent and 2,3,4, 6-tetra-O-(trimethylsilyl)- D- glucolactone under a low-temperature condition, and carrying out methylation and deprotection reaction with a methanol solution of methanesulfonic acid to generate an intermediate 1; 2) under a low-temperature condition, reacting the intermediate 1 with triethyl silane and boron trifluoride diethyl etherate, and carrying out post-treatment to obtain an intermediate 2; 3) under a low-temperature condition, reacting the intermediate 2 with an organic base, DMAP and acetic anhydride,and purifying to obtain an intermediate 3; and 4) reacting the intermediate 3 with an alkaline water solution, and purifying after the reaction to obtain the canagliflozin. The method is mild in conditions, safe to operate, simple in post-treatment and high in product purity, no alpha-isomer is detected; the product is safer.

C- aryl glycoside compound and synthesis method thereof

The invention relates to a C-aryl glycoside compound and a synthesis method thereof. A structural formula of the compound is shown in the description, wherein R is H, acetyl, methyl formate group, NHBoc or 4-methoxy; basic reaction takes glycosyl bromide and aryl iodine (bromine) as a substrate, and reaction is gently performed for 6-12 hours under icy-water bath or normal temperature under actions of a catalyst, a ligand, a reducer and an additive, so that the C-aryl glycoside compound is obtained. The catalyst metal is relatively cheap, raw materials are simple and easily available, the reaction is moderate, one-step reaction is performed, steps are simple, operations are safe, and the yield is relatively high, so that stereoselectivity is relatively good.

Stereoselective Preparation of α- C-Vinyl/Aryl Glycosides via Nickel-Catalyzed Reductive Coupling of Glycosyl Halides with Vinyl and Aryl Halides

Facile preparation of the α-C-vinyl and -aryl glycosides has been developed via mild Ni-catalyzed reductive vinylation and arylation of C1-glycosyl halides with vinyl/aryl halides. Good to high α-selectivities were achieved for C-glucosides, galactosides, maltoside, and mannosides, which were dictated by the employment of pyridine type ligands. As such, the present work represents unprecedented control for a high level of α-selectivity for C-vinyl-glucosides using cross-coupling approaches and offers hitherto optimal α-selective preparation of C-aryl glucosides via catalyst-controlled coupling strategies.

Preparing method of canagliflozin

The invention relates to a preparing method of canagliflozin. The preparing method comprises the steps of after adding 2-(2-methyl-5-bromobenzyl)-5-(4-fluorobenzene)thiophene into organic solvent A tobe subjected to dissolved clarification, preparing lithium salt at low temperature through an alkaline reagent, then conducting a reaction with gluconolactone protected by silylation, continuing to add methanesulfonic acid to be subjected to an etherification reaction, after the reaction is completed, adding an alkaline solution to adjust the pH value to 7-8, after liquid separation, using organic solvent B to extract the water layer, fusing organic layers and washing and concentrating to obtain an oil substance, an intermediate shown in the formula I; reducing the intermediate through a reductant at minus 50-minus 40 DEG C to obtain a coarse product of canagliflozin; further crystalizing the coarse product of canagliflozin through acetylation to obtain an intermediate of acetyl canagliflozin; finally hydrolyzing and crystalizing the intermediate of acetyl canagliflozin under alkaline conditions to obtain canagliflozin. Canagliflozin prepared according to the method is high in yield and purity.

Canagliflozin drug impurity as well as preparation method and application thereof

The invention discloses a canagliflozin drug impurity as well as a preparation method and application thereof. The invention provides a compound as well as a preparation method and application thereof. The method comprises the following steps: (1) enabling the compound as shown in formula 2 to be in contact with an alkaline lithium hydroxide aqueous solution to obtain a coarse product containing a compound as shown in formula 3, wherein the coarse product contains a compound as shown in formula 1; (2) crystallizing and filtering the coarse product to obtain mother liquor; (3) concentrating the mother liquor to obtain residues; and (4) crystallizing and filtering the residues in an L-proline-containing organic solvent, thus obtaining the compound as shown in formula 1. The method provided by the invention can realize directed preparation of the compound as shown in formula 1, and a reliable impurity contrast is provided for quality research on industrially produced canagliflozin-series diabetes treatment drug products and quantitative control over impurities.