1358581-37-9

Basic information

• Product Name: (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)Methyl)-4-Methylphenyl)-tetrahydro-6-(hydroxyMethyl)-2-Methoxy-2H-pyran-3,4,5-triol
• Synonyms: (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)Methyl)-4-Methylphenyl)-tetrahydro-6-(hydroxyMethyl)-2-Methoxy-2H-pyran-3,4,5-triol;Methyl 1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-alpha-D-glucopyranoside;(2S,3R,4S,5S,6R)-2-[3-[[5-(4-fluorophenyl)-2-thienyl]Methyl]-4-Methyl-phenyl]-6-(hydroxyMethyl)-2-Methoxy-tetrahydropyran-3,4,5-triol;(2S,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;2-Methoxy Canagliflozin
• CAS NO: 1358581-37-9
• Molecular Formula: C₂₅H₂₇FO₆S
• Molecular Weight: 474.5416832
• Mol File: 1358581-37-9.mol
• Article Data: 13

Chemical Properties

• Boiling Point: 644.5±55.0 °C(Predicted)
• Appearance: /
• Density: 1.41±0.1 g/cm3(Predicted)
• PKA: 12.73±0.70(Predicted)
• CAS DataBase Reference: (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)Methyl)-4-Methylphenyl)-tetrahydro-6-(hydroxyMethyl)-2-Methoxy-2H-pyran-3,4,5-triol(CAS DataBase Reference)
• NIST Chemistry Reference: (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)Methyl)-4-Methylphenyl)-tetrahydro-6-(hydroxyMethyl)-2-Methoxy-2H-pyran-3,4,5-triol(1358581-37-9)
• EPA Substance Registry System: (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)Methyl)-4-Methylphenyl)-tetrahydro-6-(hydroxyMethyl)-2-Methoxy-2H-pyran-3,4,5-triol(1358581-37-9)

Safety Data

• Hazardous Substances Data: 1358581-37-9(Hazardous Substances Data)

Usage

Uses

1-Methoxy Canagliflozin is an impurity in the synthesis of the drug Canagliflozin (C175190). Canagliflozin 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.

Synthetic route

methanol (67-56-1) + (2R,3S,4R,5R)-1-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-2,3,4,5,6-pentahydroxyhexan-1-one → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions	Yield
With methanesulfonic acid Large scale;	96.6%
With methanesulfonic acid at 15℃; for 3h; Industrial scale;

methanol (67-56-1) + 2-[(5-bromo-2-methyl-phenyl)methyl]-5-(4-fluorophenyl)thiophene (1030825-20-7) + (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) → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions

Yield

Stage #1: 3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl bromide With n-butyllithium In tetrahydrofuran; hexane; toluene at -78℃; for 1h; Stage #2: (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one In tetrahydrofuran; hexane; toluene at -78℃; for 3h; Stage #3: methanol With methanesulfonic acid In tetrahydrofuran; hexane; toluene at -78 - 40℃; for 10h;

83%

2-[(5-bromo-2-methyl-phenyl)methyl]-5-(4-fluorophenyl)thiophene (1030825-20-7) + C70H82O6Si4 → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions	Yield
With sec.-butyllithium In tetrahydrofuran; hexane; toluene at -78 - -65℃; for 2h; Inert atmosphere;	77.8%

methanesulfonic acid (75-75-2) + C36H56FO6SSi4(1-)*Li(1+) → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions	Yield
In methanol at 20℃; for 10h;	77.6%

methanesulfonic acid (75-75-2) + (2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) (898566-17-1) + (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one (32469-28-6, 55515-28-1, 55515-29-2, 32384-65-9) → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions	Yield
Stage #1: (2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene); (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one With n-butyllithium In tetrahydrofuran; toluene at -85 - -65℃; for 2h; Stage #2: methanesulfonic acid In tetrahydrofuran; methanol; toluene at 20℃; for 16h; Time;	77.5%

methanesulfonic acid (75-75-2) + 2-[(5-bromo-2-methyl-phenyl)methyl]-5-(4-fluorophenyl)thiophene (1030825-20-7) + (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) → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions	Yield
Stage #1: 3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl bromide; (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one With n-butyllithium In tetrahydrofuran; hexane; toluene at -100 - -90℃; for 1h; Inert atmosphere; Stage #2: methanesulfonic acid In tetrahydrofuran; methanol; hexane; toluene at -100 - 20℃;	77%

2-[(5-bromo-2-methyl-phenyl)methyl]-5-(4-fluorophenyl)thiophene (1030825-20-7) + C18H42O6Si4 → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions	Yield
With tert.-butyl lithium In tetrahydrofuran; toluene; pentane at -78 - -65℃; for 2h; Inert atmosphere;	76.7%

(2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) (898566-17-1) + toluene-4-sulfonic acid (104-15-4) + (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one (32469-28-6, 55515-28-1, 55515-29-2, 32384-65-9) → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions	Yield
Stage #1: (2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene); (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one With n-butyllithium In tetrahydrofuran; toluene at -85 - -65℃; for 2h; Stage #2: toluene-4-sulfonic acid In tetrahydrofuran; methanol; toluene at 20℃; for 16h;	72.4%

methanesulfonic acid (75-75-2) + (2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) (898566-17-1) + 2,3,4,6-tetra-O-acetyl-D-glucono-1,5-lactone (61259-48-1, 73322-42-6) → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions	Yield
Stage #1: (2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) With TurboGrignard In tetrahydrofuran; toluene at -10 - -5℃; for 2h; Inert atmosphere; Stage #2: 2,3,4,6-tetra-O-acetyl-D-glucono-1,5-lactone In tetrahydrofuran; toluene at -45 - -40℃; for 2h; Inert atmosphere; Stage #3: methanesulfonic acid In methanol at 40℃; for 4h;	37.5%

methanesulfonic acid (75-75-2) + (5-bromo-2-chloro-phenyl)-[5-(4-fluorophenyl)-2-thienyl]methanone (1358581-35-7) + (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) → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions	Yield
Stage #1: (5-bromo-2-chloro-phenyl)-[5-(4-fluorophenyl)-2-thienyl]methanone With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1h; 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 -78℃; for 2h; Stage #3: methanesulfonic acid In tetrahydrofuran; methanol; hexane at 20℃; for 16h;	36.7%

5-bromo-2-chlorobenzoic acid (21739-92-4) → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: thionyl chloride / toluene; N,N-dimethyl-formamide / 5 h / 0 - 100 °C 2.1: aluminum (III) chloride / dichloromethane / 16.5 h / -10 - 20 °C 3.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C 3.2: 2 h / -78 °C 3.3: 16 h / 20 °C View Scheme

4-fluoroboronic acid (1765-93-1) → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: tetrakis(triphenylphosphine) palladium(0); potassium carbonate / Dimethyl ether; water / 0.5 h / 100 °C / Microwave irradiation 2.1: aluminum (III) chloride / dichloromethane / 16.5 h / -10 - 20 °C 3.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C 3.2: 2 h / -78 °C 3.3: 16 h / 20 °C View Scheme
Multi-step reaction with 5 steps 1.1: tetrabutylammomium bromide; palladium diacetate; potassium carbonate / water / 2 h / 20 °C 2.1: sodium tetrahydroborate; ethanol / 6 h / 20 °C 3.1: thionyl chloride / 3 h / 70 °C 4.1: aluminum (III) chloride / ethyl acetate / 8 h / 80 °C / Cooling with ice 5.1: n-butyllithium / tetrahydrofuran; toluene; hexane / 1 h / -78 °C 5.2: 3 h / -78 °C 5.3: 10 h / -78 - 40 °C View Scheme

2-(4-fluorophenyl)thiophene (58861-48-6) → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: aluminum (III) chloride / dichloromethane / 16.5 h / -10 - 20 °C 2.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C 2.2: 2 h / -78 °C 2.3: 16 h / 20 °C View Scheme

5-bromo-2-chloro-benzoyl chloride (21900-52-7) → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: aluminum (III) chloride / dichloromethane / 16.5 h / -10 - 20 °C 2.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C 2.2: 2 h / -78 °C 2.3: 16 h / 20 °C View Scheme

D-glucono-1,4-lactone (1198-69-2) → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: 4-methyl-morpholine / tetrahydrofuran / 1 h / -10 - 45 °C 2: tert.-butyl lithium / tetrahydrofuran; toluene; pentane / 2 h / -78 - -65 °C / Inert atmosphere View Scheme

methanol (67-56-1) + C36H56FO6SSi4(1-)*Li(1+) → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions	Yield
With hydrogenchloride In 2-methyltetrahydrofuran; hexane; toluene at -10 - -5℃; for 2h; Inert atmosphere;	25 g

(3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one (32469-28-6, 55515-28-1, 55515-29-2, 32384-65-9) → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: n-butyllithium / toluene / -18 - -5 °C 2: methanol / 0 - 20 °C View Scheme

2-[(5-bromo-2-methyl-phenyl)methyl]-5-(4-fluorophenyl)thiophene (1030825-20-7) → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: n-butyllithium / toluene / -18 - -5 °C 2: methanol / 0 - 20 °C View Scheme

methanesulfonic acid (75-75-2) + 1-[1-hydroxy-2,3,4,6-tetra-O-(trimethylsilyl)-β-D-glucopyranosyl]-4-methyl-3-[[5-(4-fluorophenyl)-2-thienyl]methyl]benzene (1132832-76-8) → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions	Yield
In methanol at 0 - 20℃;

5-iodo-2-methylbenzoic acid (54811-38-0) → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: N,N-dimethyl-formamide; thionyl chloride / chlorobenzene / 4 h / 65 - 70 °C / Inert atmosphere; Industrial scale 2.1: aluminum (III) chloride / chlorobenzene / 4 h / 50 - 55 °C / Industrial scale 3.1: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / chlorobenzene / 10 - 50 °C / Industrial scale 4.1: n-butyllithium / tetrahydrofuran; toluene; hexane / -50 °C 4.2: 3 h / 0 °C 5.1: methanesulfonic acid / 3 h / 15 °C / Industrial scale View Scheme
Multi-step reaction with 5 steps 1.1: N,N-dimethyl-formamide; thionyl chloride / chlorobenzene / 4 h / 65 - 70 °C / Inert atmosphere; Industrial scale 2.1: aluminum (III) chloride / chlorobenzene / 4 h / 50 - 55 °C / Industrial scale 3.1: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / chlorobenzene / 10 - 50 °C / Industrial scale 4.1: n-butyllithium / tetrahydrofuran; toluene; hexane / -70 °C / Industrial scale 4.2: 3 h / 0 °C / Industrial scale 5.1: methanesulfonic acid / 3 h / 15 °C / Industrial scale View Scheme

5-iodo-2-methylbenzoyl chloride (108440-70-6) → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: aluminum (III) chloride / chlorobenzene / 4 h / 50 - 55 °C / Industrial scale 2.1: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / chlorobenzene / 10 - 50 °C / Industrial scale 3.1: n-butyllithium / tetrahydrofuran; toluene; hexane / -50 °C 3.2: 3 h / 0 °C 4.1: methanesulfonic acid / 3 h / 15 °C / Industrial scale View Scheme
Multi-step reaction with 4 steps 1.1: aluminum (III) chloride / chlorobenzene / 4 h / 50 - 55 °C / Industrial scale 2.1: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / chlorobenzene / 10 - 50 °C / Industrial scale 3.1: n-butyllithium / tetrahydrofuran; toluene; hexane / -70 °C / Industrial scale 3.2: 3 h / 0 °C / Industrial scale 4.1: methanesulfonic acid / 3 h / 15 °C / Industrial scale View Scheme

(5-(4-fluorophenyl)thiophen-2-yl)(5-iodo-2-methylphenyl)methanone → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / chlorobenzene / 10 - 50 °C / Industrial scale 2.1: n-butyllithium / tetrahydrofuran; toluene; hexane / -50 °C 2.2: 3 h / 0 °C 3.1: methanesulfonic acid / 3 h / 15 °C / Industrial scale View Scheme
Multi-step reaction with 3 steps 1.1: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / chlorobenzene / 10 - 50 °C / Industrial scale 2.1: n-butyllithium / tetrahydrofuran; toluene; hexane / -70 °C / Industrial scale 2.2: 3 h / 0 °C / Industrial scale 3.1: methanesulfonic acid / 3 h / 15 °C / Industrial scale View Scheme

(2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) (898566-17-1) → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: n-butyllithium / tetrahydrofuran; toluene; hexane / -70 °C / Industrial scale 1.2: 3 h / 0 °C / Industrial scale 2.1: methanesulfonic acid / 3 h / 15 °C / Industrial scale View Scheme

5-bromo-2-thiophencarboxaldehyde (4701-17-1) → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: tetrabutylammomium bromide; palladium diacetate; potassium carbonate / water / 2 h / 20 °C 2.1: sodium tetrahydroborate; ethanol / 6 h / 20 °C 3.1: thionyl chloride / 3 h / 70 °C 4.1: aluminum (III) chloride / ethyl acetate / 8 h / 80 °C / Cooling with ice 5.1: n-butyllithium / tetrahydrofuran; toluene; hexane / 1 h / -78 °C 5.2: 3 h / -78 °C 5.3: 10 h / -78 - 40 °C View Scheme

5-(4-fluorophenyl)thiophene-2-carboxaldehyde (249504-38-9) → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: sodium tetrahydroborate; ethanol / 6 h / 20 °C 2.1: thionyl chloride / 3 h / 70 °C 3.1: aluminum (III) chloride / ethyl acetate / 8 h / 80 °C / Cooling with ice 4.1: n-butyllithium / tetrahydrofuran; toluene; hexane / 1 h / -78 °C 4.2: 3 h / -78 °C 4.3: 10 h / -78 - 40 °C View Scheme

[5-(4-fluorophenyl)thiophen-2-yl]methanol (1225916-69-7) → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: thionyl chloride / 3 h / 70 °C 2.1: aluminum (III) chloride / ethyl acetate / 8 h / 80 °C / Cooling with ice 3.1: n-butyllithium / tetrahydrofuran; toluene; hexane / 1 h / -78 °C 3.2: 3 h / -78 °C 3.3: 10 h / -78 - 40 °C View Scheme

2-chloromethyl-5-(4-fluorophenyl)thiophene → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: aluminum (III) chloride / ethyl acetate / 8 h / 80 °C / Cooling with ice 2.1: n-butyllithium / tetrahydrofuran; toluene; hexane / 1 h / -78 °C 2.2: 3 h / -78 °C 2.3: 10 h / -78 - 40 °C View Scheme

methanol (67-56-1) + 1-[1-hydroxy-2,3,4,6-tetra-O-(trimethylsilyl)-β-D-glucopyranosyl]-4-methyl-3-[[5-(4-fluorophenyl)-2-thienyl]methyl]benzene (1132832-76-8) → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions	Yield
With methanesulfonic acid at -30 - 20℃; Reagent/catalyst; Temperature;	54.9 g

2-[(5-bromo-2-methyl-phenyl)methyl]-5-(4-fluorophenyl)thiophene (1030825-20-7) + (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) → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: N,N,N',N'',N'''-pentamethyldiethylenetriamine; n-butyllithium / tetrahydrofuran / 1 h / -78 °C / Inert atmosphere 1.2: 2 h / -78 °C / Inert atmosphere 2.1: methanol / 10 h / 20 °C View Scheme

(2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9) → canagliflozin (842133-18-0)

Conditions	Yield
With triethylsilane; boron trifluoride diethyl etherate In dichloromethane at -40 - 0℃; for 3h;	90%
Stage #1: (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol With aluminum (III) chloride In dichloromethane; acetonitrile at -5℃; for 0.5h; Stage #2: With triethylsilane In dichloromethane; acetonitrile at -5 - 10℃; for 2h;	79%
With triethylsilane; acetonitrile boron trifluoride complex In n-heptane at -5 - 5℃; for 5h;	77.5%

(2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9) + tert-butyldimethylsilyl chloride (18162-48-6) → (2S,3R,4S,5S,6R)-6-[(tertbutyl(dimethyl)silyl)oxymethyl]-2-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol (1358581-40-4)

Conditions	Yield
With pyridine; dmap for 16h;	89.7%

Upstream product

• 1030825-20-7 3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl bromide 
• 1198-69-2 D-glucono-1,4-lactone 
• 67-56-1 methanol 
• 32469-28-6 (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one 
• 4701-17-1 5-bromo-2-thiophencarboxaldehyde 
• 249504-38-9 5-(4-fluorophenyl)thiophene-2-carboxaldehyde 
• 1225916-69-7 [5-(4-fluorophenyl)thiophen-2-yl]methanol 
• 75-75-2 methanesulfonic acid 
• 898566-17-1 (2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) 
• 61259-48-1 2,3,4,6-tetra-O-acetyl-D-glucono-1,5-lactone 
• 1132832-76-8 1-[1-hydroxy-2,3,4,6-tetra-O-(trimethylsilyl)-β-D-glucopyranosyl]-4-methyl-3-[[5-(4-fluorophenyl)-2-thienyl]methyl]benzene 
• 108440-70-6 5-iodo-2-methylbenzoyl?chloride 
• 54811-38-0 5-iodo-2-methylbenzoic?acid 
• 104-15-4 toluene-4-sulfonic acid 

Downstream Products

• 1358581-40-4 (2S,3R,4S,5S,6R)-6-[(tertbutyl(dimethyl)silyl)oxymethyl]-2-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol 
• 1358581-42-6 [[(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy]tert-butyl-dimethyl-silane 
• 1358581-43-7 [(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-6-methoxy-tetrahydropyran-2-yl]methanol 
• 1358581-44-8 (2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 
• 1358581-46-0 (2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde 
• 1358581-50-6 [(3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol 
• 842133-18-0 canagliflozin 
• 1589590-87-3 (2R,3R,4R,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol 

Relevant articles and documents

Telescoped lithiation, C-arylation and methoxylation in flow-batch hybrid toward the synthesis of canagliflozin

We report a highly efficient three-step flow-batch hybrid procedure for the synthesis of a key canagliflozin intermediate. The telescoped process provides exquisite control over an exothermic and mixing sensitive lithiation and subsequent C-arylation within a microstructured flow reactor. Methoxylation reagents are then added in flow, before reaching completion in a batch vessel. The flow process afforded the target intermediate in 76% yield, with a throughput of 26.8 g/h.

Method for preparing intermediates of gliflozin hypoglycemic drugs

The invention belongs to the technical field of medicine synthesis, and relates to a novel method for preparing key intermediates of gliflozin hypoglycemic drugs, in particular to a preparation methodof key intermediates (C-1, D-1 and E-1) of canagliflozin, dapagliflozin and empagliflozin. The method comprises the following steps: 1) in the presence of a cosolvent, carrying out halogen metal exchange on a raw material, namely aryl bromide 2 and an organic lithium reagent to obtain an aryl lithium reagent 3, and carrying out a nucleophilic addition reaction on the aryl lithium reagent 3 and TMS-protected glucolactone 4 to obtain a transition product 5; and 2) removing a TMS protecting group from the transition product 5, and converting hemiketal into ketal to obtain the key intermediate 1with a single configuration. According to the method, the key intermediates (C-1, D-1 and E-1) of canagliflozin, dapagliflozin and empagliflozin can be stereoselectively synthesized, reaction yield isrelatively high (more than 75%), and product purity is high (wherein HPLC purity is about 95%); so reduction preparation of a final product in the next step is facilitated.

Preparation method of Canagliflozin intermediate

The invention provides a preparation method of a Canagliflozin intermediate. According to the method, a stable reagent is added to an organic solvent mixing system containing 2-(5-BroMo-2-Methylbenzyl)-5-(4-fluorophenyl)thiophene(compound III) and n-Butyllithium, so that the phenomenon that when the n-Butyllithium is used, reaction products are complex, and more by-products exist, can be improved.The method is stable and high in repetition rate, the purity of the obtained intermediate is as high as 94.7%, the continuous reaction yield can achieve 93.8%, and the preparation method has industrial application prospects.