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
• Article Data: 11

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

2-(4-Fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene is an antidiabetic agent and a Canagliflozin (C175190) intermediate. Canagliflozin is a sodium/glucose cotransporter 2 (SGLT2) inhibitor and a candidate for the treatment of type 2 diabetes and obesity.

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

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

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 
• 1413373-77-9 (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 
• 1672658-93-3 C₂₄H₂₅FO₆S 
• 1358581-37-9 (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 

Relevant articles and documents

Preparation method of carbagliflozin intermediate and application of intermediate in preparation of glipizide

The invention provides a preparation method of a carbagliflozin intermediate and an application thereof in preparation of glipizide. To the preparation method, 5 - iodine -2 - methylbenzoic acid and a chlorination reagent are subjected to a Fourier acylation reaction, 5 - iodine -2 - methylbenzoyl chloride is obtained. The 5 -iod -2 -methylbenzoyl chloride and 2 - (4 - fluorophenyl) thiophene were subjected to a Fries alkylation reaction to give (5 -iod -2 -methylphenyl) (5 - (4 - fluorophenyl) thiophene -2 -yl) methyl ketone. (5 -iod -2 -methylphenyl) (5 - (4 - fluorophenyl) thiophene -2 -yl) methyl ketone was subjected to a carbonyl reduction reaction to give a crude product of. The intermediate crude product is subjected to purification treatment to obtain the glipizide intermediate. The preparation method has the advantages of mild reaction conditions, simple operation, environmental protection, safety, suitability for industrial mass production, and high product yield and purity.

SYNTHESIS, CRYSTAL STRUCTURE, ANTI-LUNG CANCER ACTIVITY OF 2-(4-FLUOROPHENYL)-5- (5-IODO-2-METHYLBENZYL)THIOPHENE

Abstract: New heterocycle compound 2-(4-fluorophenyl)-5-(5-iodo-2-methylbenzyl)thiophene (1), designed using5-iodo-2-methylbenzoic acid (2) as the starting material is successfully obtained via the multiple synthesis route and finally characterized by IR, 1H NMR, and single crystal X-ray crystallography. In addition, the in vitro anticancer activity of compound 1 on three human lung cancer cells (H20, H2227, and H69) is further determined, which suggests that compound 1 may be a potential anticancer agent.

Synthesis and Optimization of Canagliflozin by Employing Quality by Design (QbD) Principles

Efforts toward a synthesis and process optimization of canagliflozin 1 are described. Canagliflozin synthesis was accomplished via purified open ring intermediate 12. The process was optimized by employing quality by design (QbD) methodologies, and a telescopic strategy was executed for the first three and last two steps in a total six-step sequence. Optimization of the Friedel-Craft acylation reaction followed by Lewis acid mediated reductive elimination, n-BuLi mediated C-arylation, and reductive demethoxylation was performed to develop a robust process. These steps were found to be critical; therefore, critical process parameters (CPPs) were identified by employing design of experiment (DoE) methodology. In addition, control strategies for dealing with impurities are described.