898566-17-1

Basic information

• Product Name: 2-(4-Fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene
• Synonyms: Thiophene, 2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]-;2-(4-Fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene;2-(4-Fluorophenyl)-5-(5-iodo-2-Methylbenzyl)thiophene;Canagliflozin iMpurity D;2-((5-IODO-2-METHYLPHENYL)METHYL)-5-(4-FLUOROPHENYL)THIOPHENE;Canagliflozin INT5;Canagliflozin Intermediate1;2-(4-Fluorophenyl)
• CAS NO: 898566-17-1
• Molecular Formula: C₁₈H₁₄FIS
• Molecular Weight: 408.27
• EINECS: 1592732-453-0
• Mol File: 898566-17-1.mol

Chemical Properties

• Melting Point: 109-110 °C
• Boiling Point: 450.2 °C at 760 mmHg
• Flash Point: 226.1 °C
• Appearance: /
• Density: 1.533
• Vapor Pressure: 0-0Pa at 20-25℃
• Refractive Index: 1.643
• Storage Temp.: 2-8°C(protect from light)
• Solubility: DMSO (Sparingly), Methanol (Slightly)
• CAS DataBase Reference: 2-(4-Fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene(CAS DataBase Reference)
• NIST Chemistry Reference: 2-(4-Fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene(898566-17-1)
• EPA Substance Registry System: 2-(4-Fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene(898566-17-1)

Safety Data

• Hazardous Substances Data: 898566-17-1(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
2-(4-Fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene is used as an intermediate in the synthesis of Canagliflozin (C175190), a sodium/glucose cotransporter 2 (SGLT2) inhibitor. Canagliflozin is a promising candidate for the treatment of type 2 diabetes and obesity, as it helps regulate blood sugar levels and promotes weight loss.
Used in Antidiabetic Applications:
As an antidiabetic agent, 2-(4-Fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene contributes to the development of medications that can effectively manage and treat type 2 diabetes. Its role in the synthesis of Canagliflozin highlights its potential in providing a therapeutic option for patients suffering from this chronic condition.

InChI:InChI=1/C18H14FIS/c1-12-2-7-16(20)10-14(12)11-17-8-9-18(21-17)13-3-5-15(19)6-4-13/h2-10H,11H2,1H3

Synthetic route

(5-(4-fluorophenyl)thiophen-2-yl)(5-iodo-2-methylphenyl)methanone → (2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) (898566-17-1)

Conditions	Yield
With triethylsilane; boron trifluoride diethyl etherate In dichloromethane; acetonitrile at 0 - 35℃;	85%
With sodium tetrahydroborate; chloro-trimethyl-silane; boron trifluoride diethyl etherate In dichloromethane; acetonitrile at 5 - 35℃; for 0.5h;	81.1%
With triethylsilane; boron trifluoride diethyl etherate In dichloromethane; acetonitrile at 0 - 28℃; Inert atmosphere;	70.3%
With aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane In chlorobenzene at 10 - 50℃; Reagent/catalyst; Solvent; Concentration; Temperature; Industrial scale;	65.2 kg
With aluminum (III) chloride In chlorobenzene at 10 - 50℃; for 4h;	11.48 g

2-(4-fluorophenyl)thiophene (58861-48-6) + 5-iodo-2-methylbenzoyl chloride (108440-70-6) → (2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) (898566-17-1)

Conditions	Yield
With aluminum (III) chloride Solvent; Temperature; Friedel-Crafts Acylation;	80%
Stage #1: 5-iodo-2-methylbenzoyl chloride With aluminum (III) chloride In dichloromethane at 2℃; for 0.25h; Stage #2: 2-(4-fluorophenyl)thiophene In dichloromethane at 2 - 20℃; for 2.41667h; Product distribution / selectivity;

2-[(5-bromo-2-methyl-phenyl)methyl]-5-(4-fluorophenyl)thiophene (1030825-20-7) → (2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) (898566-17-1)

Conditions	Yield
With sodium iodide; N,N`-dimethylethylenediamine; copper(l) iodide In diethylene glycol dimethyl ether; toluene at 110℃;
With copper(l) iodide; sodium iodide; N,N`-dimethylethylenediamine In diethylene glycol dimethyl ether; toluene at 20℃; Inert atmosphere; Reflux;
With copper(l) iodide; sodium iodide; N,N`-dimethylethylenediamine In diethylene glycol dimethyl ether; toluene for 36h; Inert atmosphere; Reflux;	94.9 g

ortho-methylbenzoic acid (118-90-1) → (2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) (898566-17-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: iodic acid / 20 °C / Molecular sieve 2: thionyl chloride 3: aluminum (III) chloride View Scheme

5-iodo-2-methylbenzoic acid (54811-38-0) → (2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) (898566-17-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: thionyl chloride 2: aluminum (III) chloride View Scheme
Multi-step reaction with 3 steps 1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 20 °C / Inert atmosphere 2: aluminum (III) chloride / dichloromethane / 7.5 h / 0 - 20 °C / Inert atmosphere 3: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / 0 - 28 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1: N,N-dimethyl-formamide; thionyl chloride / chlorobenzene / 4 h / 65 - 70 °C / Inert atmosphere; Industrial scale 2: aluminum (III) chloride / chlorobenzene / 4 h / 50 - 55 °C / Industrial scale 3: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / chlorobenzene / 10 - 50 °C / Industrial scale View Scheme
Multi-step reaction with 3 steps 1: thionyl chloride; N,N-dimethyl-formamide / chlorobenzene / 4 h / 65 - 70 °C / Inert atmosphere 2: aluminum (III) chloride / chlorobenzene / 4 h / 10 - 55 °C 3: aluminum (III) chloride / chlorobenzene / 4 h / 10 - 50 °C View Scheme

5-iodo-2-methylbenzoyl chloride (108440-70-6) → (2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) (898566-17-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: aluminum (III) chloride / dichloromethane / 7.5 h / 0 - 20 °C / Inert atmosphere 2: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / 0 - 28 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1: aluminum (III) chloride / chlorobenzene / 4 h / 50 - 55 °C / Industrial scale 2: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / chlorobenzene / 10 - 50 °C / Industrial scale View Scheme

(2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) (898566-17-1) + (3-bromo-4, 4, 4-trifluorobutyl)benzene → (S)-2-(4-fluorophenyl)-5-(2-methyl-5-(1,1,1-trifluoro-4-phenylbutan-2-yl)benzyl)thiophene

Conditions	Yield
With nickel(II) bromide dimethoxyethane; manganese; (4R,4'R)-4,4'-di(heptan-4-yl)-4,4',5,5'-tetrahydro-2,2'-bioxazole; tetra-(n-butyl)ammonium iodide In tetrahydrofuran at -10℃; for 22h; Sealed tube; Inert atmosphere; enantioselective reaction;	95%

methanol (67-56-1) + (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) → (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)

Conditions	Yield
Stage #1: (2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) With magnesium In tetrahydrofuran at 0 - 25℃; Inert atmosphere; Stage #2: (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one In tetrahydrofuran at 0℃; Inert atmosphere; Stage #3: methanol With methanesulfonic acid In tetrahydrofuran at 20℃; Inert atmosphere;	93.3%
Stage #1: (2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) With s-butylmagnesium chloride; lithium chloride In tetrahydrofuran at -25 - -20℃; for 1h; Inert atmosphere; Stage #2: (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one In tetrahydrofuran at -25 - -20℃; for 2h; Stage #3: methanol With methanesulfonic acid for 18h; Reagent/catalyst;	93.7%
Stage #1: (2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) With n-butyllithium In dibutyl ether; toluene Stage #2: (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one In toluene Stage #3: methanol With methanesulfonic acid In toluene
Stage #1: (2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) With TurboGrignard In tetrahydrofuran at -18 - -13℃; 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 at -15 - -10℃; for 1h; Large scale; Stage #3: methanol With hydrogenchloride at 20℃; for 1h; Large scale;	23.5 kg

tetraacetyl thioglucose (19879-84-6) + (2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) (898566-17-1) → C32H33FO9S2

Conditions	Yield
With palladium; triethylamine In tetrahydrofuran at 20℃; for 1h; Inert atmosphere;	90%

(2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) (898566-17-1) + N,N-dimethyl-formamide (68-12-2, 33513-42-7) → 3-{[5-(4-fluorophenyl)thiophen-2-yl]methyl}-4-methylbenzonitrile

Conditions	Yield
With tert.-butylhydroperoxide; copper(II) nitrate trihydrate; water; acetic acid at 130℃; for 48h;	87%

(2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) (898566-17-1) + 4-(p-methoxyphenyl)but-1-ene (20574-98-5) → 2-(4-fluorophenyl)-5-(5-(1-(4-methoxyphenyl)butyl)-2-methylbenzyl)thiophene

Conditions	Yield
With dimethylsulfide borane complex; (6,6’-dimethyl-2,2'-bipyridine)nickel(II) dibromide; lithium methanolate In N,N-dimethyl acetamide at -19℃; for 12h; Inert atmosphere; Sealed tube; Glovebox; regioselective reaction;	87%

(2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) (898566-17-1) + 2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosyl bromide (81058-27-7) → (2S,3S,4R,5R,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(pivaloyloxymethyl)tetrahydro-2H-pyran-3,4,5-thiyl tris(2,2-dimethylpropanoate) (1283129-18-9)

Conditions	Yield
Stage #1: (2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) With n-butyllithium; zinc dibromide In n-heptane; dibutyl ether; toluene at -10 - 25℃; for 2.5h; Inert atmosphere; Stage #2: 2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosyl bromide In n-heptane; dibutyl ether; toluene at 95℃; for 6.5h; Product distribution / selectivity;	86.6%
Stage #1: (2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) With TurboGrignard In tetrahydrofuran at 0 - 10℃; for 1h; Large scale; Stage #2: 2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosyl bromide In tetrahydrofuran at 0 - 10℃; for 3h; Large scale;	85%

(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) → (3R,4R,5S)-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%

(2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) (898566-17-1) + carbon dioxide (124-38-9) → C19H15FO2S

Conditions	Yield
With n-butyllithium In tetrahydrofuran; hexane at -78 - 20℃; for 10h; Temperature; Solvent; Inert atmosphere;	86.1%

1-propenylbenzene (873-66-5) + (2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) (898566-17-1) → (R)-2-(4-fluorophenyl)-5-(2-methyl-5-(1-phenylpropyl)benzyl)thiophene

Conditions	Yield
With potassium fluoride; dimethoxymethylsilane; (1,2-dimethoxyethane)dichloronickel(II); (4R,4'R)-1,1'-bis(3-(tert-butyl)phenyl)-4,4'-di(heptan-4-yl)-4,4',5,5'-tetrahydro-1H,1'H-2,2'-biimidazole at 22 - 26℃; for 24h; Sealed tube; enantioselective reaction;	85%

(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) → (2R,3S,4R,5R)-1-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-2,3,4,5,6-pentahydroxyhexan-1-one

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; hexane; toluene at -70℃; Industrial scale; Stage #2: With trifluoroacetic acid In tetrahydrofuran; hexane; water; toluene at 0℃; for 3h; Solvent; Reagent/catalyst; Temperature; Industrial scale;

84.23%

(2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) (898566-17-1) + C26H35BrCl8O9 → C44H49Cl8FO9S

Conditions	Yield
With n-hexyllithium; lithium bromide; zinc dibromide In hexane; dibutyl ether; toluene at 10 - 80℃; for 12h;	79.1%

(2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) (898566-17-1) + 2,3,4,6-O-tetrachloropivaloyl-α-D-bromoglucopyranose → C44H53Cl4FO9S

Conditions	Yield
With n-butyllithium; isopropylmagnesium chloride; lithium chloride In tetrahydrofuran; hexane at -10℃; for 3h; Reagent/catalyst; Solvent; Temperature; Inert atmosphere;	78.2%

(2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) (898566-17-1) + bis(pinacol)diborane (73183-34-3) → 2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Conditions	Yield
With 10H-phenothiazine; caesium carbonate In acetonitrile for 48h; Irradiation; Sealed tube; Inert atmosphere;	78%

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%

(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) → (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)

Conditions	Yield
With n-butyllithium In tetrahydrofuran; toluene at -85 - -65℃; for 2h; Solvent;	77.5%
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; Stage #2: (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one at -60℃; for 1h;
Stage #1: (2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) In tetrahydrofuran at 0 - 5℃; for 1h; Inert atmosphere; Stage #2: (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one In tetrahydrofuran at 0 - 5℃; for 2h; Stage #3: With methanesulfonic acid In methanol for 2h; Cooling;

(2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) (898566-17-1) + 2,3,4,6-O-tetrakis(3-chloro-2,2-dichloromethylpropionyl)-α-D-bromoglucopyranose → C44H45Cl12FO9S

Conditions	Yield
With n-hexyllithium; lithium bromide; zinc dibromide In hexane; dibutyl ether; toluene at 10 - 80℃; for 12h;	76.1%

(2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) (898566-17-1) + (4R,5S,6R)-4,5,6-tris(benzyloxy)-3-((benzyloxy)methyl)-2-cyclohexen-1-one (110391-10-1) → (1R,4R,5S,6R)-4,5,6-tris(benzyloxy)-3-(benzyloxymethyl)-1-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)cyclohex-2-enol (1413373-77-9)

Conditions	Yield
Stage #1: (2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) With TurboGrignard In tetrahydrofuran at -10℃; for 1h; Inert atmosphere; Stage #2: (4R,5S,6R)-4,5,6-tris(benzyloxy)-3-((benzyloxy)methyl)-2-cyclohexen-1-one In tetrahydrofuran at -10 - 0℃; for 4h; Inert atmosphere;	75.6%

(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%

(2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) (898566-17-1) + 2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosyl bromide (81058-27-7) → C44H57FO9S

Conditions	Yield
With lithium bromide; zinc dibromide In diethyl ether at -76℃; Temperature; Reagent/catalyst; Solvent;	71%

2,3,4,6-Tetra-O-benzyl-D-glucopyranose (4291-69-4, 6386-24-9, 6564-72-3, 59531-24-7, 69257-52-9, 78184-89-1, 78609-16-2, 78609-17-3, 78609-18-4, 96553-53-6, 104111-61-7, 131347-08-5, 4132-28-9) + (2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) (898566-17-1) → (3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-2-ol

Conditions

Yield

Stage #1: 2,3,4,6-Tetra-O-benzyl-D-glucopyranose With sodium hydrogencarbonate; acetic acid; potassium bromide In dichloromethane; water at 20℃; for 0.25h; Stage #2: With sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical In water at 20 - 35℃; Stage #3: (2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) With n-butyllithium In tetrahydrofuran; hexane at -70 - -30℃; Concentration; Solvent; Temperature; Inert atmosphere;

70.2%

(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) → (3R,4R,5S)-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%

allylbenzene (300-57-2) + (2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) (898566-17-1) + bis(pinacol)diborane (73183-34-3) → 2-(3-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-3-phenylpropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Conditions	Yield
With [nickel(II)dichloride(dimethoxyethane)]; quinoline; lithium methanolate In 1,4-dioxane at 30℃; Inert atmosphere; Sealed tube; regioselective reaction;	42%

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%

(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) → 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)

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 trimethylsilylmethyllithium In tetrahydrofuran; hexane at -40℃; Stage #2: With water; sodium hydrogencarbonate In tetrahydrofuran; hexane at -40℃;

(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) → methyl 1-C-(3-{[5-(4-fluorophenyl)-2-thienyl]methyl}-4-methylphenyl)-D-glucopyranoside

Conditions	Yield
Stage #1: (2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) With TurboGrignard In tetrahydrofuran at 0 - 5℃; Inert atmosphere; Stage #2: (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one In tetrahydrofuran at 0 - 5℃; Product distribution / selectivity; Inert atmosphere;

(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) → (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

Conditions

Yield

Stage #1: (2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) With sec-butylmagnesium chloride lithium chloride In toluene at -10 - 0℃; for 1.75h; Inert atmosphere; Stage #2: 2,3,4,6-tetra-O-acetyl-D-glucono-1,5-lactone In tetrahydrofuran; toluene at -35℃; for 1.25h; Inert atmosphere; Stage #3: With acetic acid In tetrahydrofuran; water; toluene at -35 - 25℃; Product distribution / selectivity;

(2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) (898566-17-1) → canagliflozin (842133-18-0)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: trimethylsilylmethyllithium / toluene; diethyl ether; pentane / 0.75 h / -50 °C / Inert atmosphere 1.2: 1 h / 25 °C 2.1: ethyl acetate; toluene / 21 h / 75 °C / Inert atmosphere 3.1: methanol / 16 h / 20 - 60 °C 4.1: water / 1 h / 0 °C View Scheme
Multi-step reaction with 4 steps 1.1: n-hexyllithium / toluene; hexane; cyclopentyl methyl ether / 1.17 h / -45 - -25 °C / Inert atmosphere 2.1: zinc dibromide; lithium bromide / cyclopropyl methyl ether / -25 - 0 °C 2.2: 48.5 h / 20 - 65 °C 3.1: methanol / 16 h / 20 - 60 °C 4.1: water / 1 h / 0 °C View Scheme
Multi-step reaction with 3 steps 1.1: acetic acid; potassium bromide; sodium hydrogencarbonate / water; dichloromethane / 0.25 h / 20 °C 1.2: 20 - 35 °C 1.3: -70 - -30 °C / Inert atmosphere 2.1: triethylsilane; boron trifluoride diethyl etherate / dichloromethane / 0.5 h / -40 - -20 °C / Inert atmosphere 3.1: trimethylsilyl iodide / dichloromethane / 0 - 30 °C View Scheme

Upstream product

• 1030825-20-7 3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl bromide 
• 58861-48-6 2-(4-fluorophenyl)thiophene 
• 108440-70-6 5-iodo-2-methylbenzoyl?chloride 
• 118-90-1 ortho-methylbenzoic acid 
• 54811-38-0 5-iodo-2-methylbenzoic?acid 
• 460-00-4 1-Bromo-4-fluorobenzene 
• 462-06-6 fluorobenzene 
• 366-77-8 4-(4-fluorophenyl)-4-oxopropionic acid 

Downstream Products

• 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 
• 842133-18-0 canagliflozin 
• 1283129-18-9 (2S,3S,4R,5R,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(pivaloyloxymethyl)tetrahydro-2H-pyran-3,4,5-triyl tris(2,2-dimethylpropanoate) 
• 1283129-24-7 C₃₆H₂₈F₂S₂Zn 
• 1373555-12-4 C₂₆H₂₅FO₅S 
• 1373555-05-5 (2S,3R,4R,5S,6R)-2-[3-((5-(4-fluorophenyl)thienyl)-2-methylene)-4-chloro-phenyl]-6-methylsulfonyltetrahydropyran-3,4,5-triol 
• 1373555-14-6 C₃₀H₃₁FO₇S₂ 
• 1373554-86-9 (2S,3R,4R,5S,6R)-2-[3-((5-(4-fluorophenyl)thienyl)-2-methylene)-4-methylphenyl]-6-methylthiotetrahydropyran-3,4,5-triol 
• 1373555-86-2 C₃₀H₃₁FO₉S₂ 
• 1373555-13-5 C₃₁H₃₁FO₉S 

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