866607-35-4

Basic information

• Product Name: D-Glucitol, 1,5-anhydro-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]Methyl]-4-Methylphenyl]-, tetraacetate, (1S)- (9CI)
• Synonyms: D-Glucitol, 1,5-anhydro-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]Methyl]-4-Methylphenyl]-, tetraacetate, (1S)- (9CI);(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;(1S)-1,5-Anhydro-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol tetraacetate;Canagliflozin Impurity 11;Tetra Acetyl Canagliflozin
• CAS NO: 866607-35-4
• Molecular Formula: C32H33FO9S
• Molecular Weight: 612.6624232
• Mol File: 866607-35-4.mol
• Article Data: 20

Chemical Properties

• Melting Point: 160-170 °C
• Boiling Point: 658.3±55.0 °C(Predicted)
• Appearance: /
• Density: 1.32±0.1 g/cm3(Predicted)
• Vapor Pressure: 0Pa at 20℃
• CAS DataBase Reference: D-Glucitol, 1,5-anhydro-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]Methyl]-4-Methylphenyl]-, tetraacetate, (1S)- (9CI)(CAS DataBase Reference)
• NIST Chemistry Reference: D-Glucitol, 1,5-anhydro-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]Methyl]-4-Methylphenyl]-, tetraacetate, (1S)- (9CI)(866607-35-4)
• EPA Substance Registry System: D-Glucitol, 1,5-anhydro-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]Methyl]-4-Methylphenyl]-, tetraacetate, (1S)- (9CI)(866607-35-4)

Safety Data

• Hazardous Substances Data: 866607-35-4(Hazardous Substances Data)

Usage

Uses

The title compound is an intermediate in the synthesis of Canagliflozin which is a sodium/glucose cotransporter 2 (SGLT2) inhibitor. Canagliflozin has been shown to dose dependently reduce calculated renal threshold for glucose excretion and increase urinary glucose excretion. Canagliflozin is a candidate for the treatment of 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 
• 898566-17-1 (2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) 
• 1030825-21-8 methyl 1-C-(3-{[5-(4-fluorophenyl)-2-thienyl]methyl}-4-methyl-phenyl)-D-glucopyranoside 
• 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 
• 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 
• 572-09-8 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide 
• 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 
• 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 articles and documents

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 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.

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

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