1103738-29-9

Basic information

• Product Name: 4-Iodo-1-chloro-2-(4-ethoxybenzyl)benzene
• Synonyms: 4-Iodo-1-chloro-2-(4-ethoxybenzyl)benzene;1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene;1-Chloro-2-[(4-ethoxyphenyl)Methyl]-4-iodobenzene;Benzene, 1-chloro-2-[(4-ethoxyphenyl)Methyl]-4-iodo-;EOS-61384;Ipragliflozin intermediate 2
• CAS NO: 1103738-29-9
• Molecular Formula: C₁₅H₁₄ClIO
• Molecular Weight: 372.62853
• Mol File: 1103738-29-9.mol
• Article Data: 15

Chemical Properties

• Boiling Point: 411.2±40.0 °C(Predicted)
• Appearance: off-white solid
• Density: 1.531±0.06 g/cm3(Predicted)
• Storage Temp.: 2-8°C(protect from light)
• Solubility: DMSO (Slightly), Methanol (Slightly)
• CAS DataBase Reference: 4-Iodo-1-chloro-2-(4-ethoxybenzyl)benzene(CAS DataBase Reference)
• NIST Chemistry Reference: 4-Iodo-1-chloro-2-(4-ethoxybenzyl)benzene(1103738-29-9)
• EPA Substance Registry System: 4-Iodo-1-chloro-2-(4-ethoxybenzyl)benzene(1103738-29-9)

Safety Data

• Hazardous Substances Data: 1103738-29-9(Hazardous Substances Data)

Usage

Description

4-Iodo-1-chloro-2-(4-ethoxybenzyl)benzene is an organic compound with a molecular structure that features an iodine atom at the 4-position, a chlorine atom at the 1-position, and a 4-ethoxybenzyl group attached to the 2-position of a benzene ring. 4-Iodo-1-chloro-2-(4-ethoxybenzyl)benzene is characterized by its potential reactivity and structural diversity, making it a valuable intermediate in the synthesis of various pharmaceutical compounds.

Uses

Used in Pharmaceutical Synthesis:
4-Iodo-1-chloro-2-(4-ethoxybenzyl)benzene is used as a key intermediate in the synthesis of Dapagliflozin (D185370), a sodium-glucose transporter 2 (SGLT2) inhibitor. Dapagliflozin is a medication used to treat type 2 diabetes by reducing the reabsorption of glucose in the kidneys, leading to increased excretion of glucose in the urine and improved glycemic control.
In the pharmaceutical industry, 4-Iodo-1-chloro-2-(4-ethoxybenzyl)benzene serves as a crucial building block for the development of new drugs targeting diabetes and other related metabolic disorders. Its unique structure allows for further functionalization and modification to optimize the pharmacological properties of the resulting compounds.

InChI:InChI=1S/C15H14ClIO/c1-2-18-14-6-3-11(4-7-14)9-12-10-13(17)5-8-15(12)16/h3-8,10H,2,9H2,1H3

Synthetic route

(2-chloro-5-iodo-phenyl)-(4-ethoxyphenyl)methanone (1103738-26-6) → 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene (1103738-29-9)

Conditions	Yield
With triethylsilane; boron trifluoride diethyl etherate In acetonitrile at 5 - 20℃; for 17.5h;	97.4%
With triethylsilane; boron trifluoride diethyl etherate In acetonitrile at 5 - 20℃; for 17.508h; Inert atmosphere;	97.4%
Stage #1: (2-chloro-5-iodo-phenyl)-(4-ethoxyphenyl)methanone With sodium tetrahydroborate In tetrahydrofuran for 0.5h; Inert atmosphere; Stage #2: With aluminum (III) chloride at 10℃; for 0.5h; Reflux;	91.2%

2-bromomethyl-1-chloro-4-iodo-benzene (793695-85-9) + 4-bromoethoxybenzene (588-96-5) → 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene (1103738-29-9)

Conditions	Yield
Stage #1: 4-bromoethoxybenzene With iodine; magnesium; methoxybenzene at 47℃; for 3.2h; Stage #2: 2-bromomethyl-1-chloro-4-iodo-benzene With copper(l) iodide at -18 - 20℃; for 16.2h; Temperature;	95.9%

2-chloro-5-iodobenzoylchloride (281652-58-2) + Phenetole (103-73-1) → 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene (1103738-29-9)

Conditions	Yield
Stage #1: 2-chloro-5-iodobenzoylchloride; Phenetole With aluminum (III) chloride In dichloromethane at -5 - 15℃; Stage #2: at 25 - 30℃; for 26h;	67%
Stage #1: Phenetole With aluminum (III) chloride In dichloromethane at -3 - 5℃; for 0.5h; Stage #2: 2-chloro-5-iodobenzoylchloride In dichloromethane at 0 - 25℃; for 12h; Stage #3: In dichloromethane at 30℃; for 16h;	67%
Stage #1: 2-chloro-5-iodobenzoylchloride; Phenetole With aluminum (III) chloride In dichloromethane at 0 - 5℃; for 2h; Stage #2: In dichloromethane at 25 - 30℃; for 26h;	67%

aq sodium bicarbonate + boron trifluoride-diethyletherate + (2-chloro-5-iodo-phenyl)-(4-ethoxyphenyl)methanone (1103738-26-6) → 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene (1103738-29-9)

Conditions	Yield
With triethylsilane In acetonitrile

2-chloro-5-iodobenzoylchloride (281652-58-2) → 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene (1103738-29-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: aluminum (III) chloride / dichloromethane / 2.33 h / -7 - 9 °C / Inert atmosphere 2: boron trifluoride diethyl etherate; triethylsilane / acetonitrile / 17.5 h / 5 - 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1.1: aluminum (III) chloride / dichloromethane / 0.12 h / -7 - 9 °C / Inert atmosphere 1.2: 2.22 h / 3 - 5 °C 2.1: boron trifluoride diethyl etherate; triethylsilane / acetonitrile / 17.5 h / 5 - 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1: aluminum (III) chloride / dichloromethane / 2 h / 5 - 15 °C / Industrial scale 2: triethylsilane; boron trifluoride diethyl etherate / acetonitrile / 2.5 h / 20 - 30 °C / Industrial scale View Scheme
Multi-step reaction with 2 steps 1: aluminum (III) chloride; water / dichloromethane / 2 h / 5 - 15 °C / Industrial scale 2: triethylsilane; boron trifluoride diethyl etherate / acetonitrile / 2.5 h / 20 - 30 °C / Industrial scale View Scheme

2-chloro-5-iodobenzoic acid (19094-56-5) → 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene (1103738-29-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: oxalyl dichloride / N,N-dimethyl-formamide / dichloromethane / 20.93 h 2: aluminum (III) chloride / dichloromethane / 2.33 h / -7 - 9 °C / Inert atmosphere 3: boron trifluoride diethyl etherate; triethylsilane / acetonitrile / 17.5 h / 5 - 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 16 h / 10 - 25 °C 2.1: aluminum (III) chloride / dichloromethane / -5 - 15 °C 2.2: polymethylhydrosiloxane (PMHS) / 26 h / 25 - 30 °C View Scheme
Multi-step reaction with 2 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 16.17 h / 10 - 25 °C 2.1: aluminum (III) chloride / dichloromethane / 0.5 h / -3 - 5 °C 2.2: 12 h / 0 - 25 °C 2.3: polymethylhydrosiloxane (PMHS) / 16 h / 30 °C View Scheme

Phenetole (103-73-1) → 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene (1103738-29-9)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: oxalyl chloride / dichloromethane; N,N-dimethyl-formamide / 4 h / 20 °C 1.2: 3 h / 0 - 20 °C 2.1: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / 0 - 20 °C View Scheme

fluorobenzene (462-06-6) → 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene (1103738-29-9)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: thionyl chloride; N,N-dimethyl-formamide / dichloromethane / 39 - 42 °C 1.2: Reflux 2.1: sodium hydroxide / 50 - 65 °C 3.1: sodium tetrahydroborate / tetrahydrofuran / 0.5 h / Inert atmosphere 3.2: 0.5 h / 10 °C / Reflux View Scheme

(2-chloro-5-iodophenyl)(4-fluorophenyl)methanone (915095-86-2) → 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene (1103738-29-9)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium hydroxide / 50 - 65 °C 2.1: sodium tetrahydroborate / tetrahydrofuran / 0.5 h / Inert atmosphere 2.2: 0.5 h / 10 °C / Reflux View Scheme

1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene (1103738-29-9) + C30H33NO6 → C41H39ClO6

Conditions	Yield
Stage #1: 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene With TurboGrignard In tetrahydrofuran at -5 - 0℃; for 1h; Stage #2: C30H33NO6 In tetrahydrofuran; toluene at -5 - 0℃;	91%

1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene (1103738-29-9) + C20H27NO7 → C31H33ClO7

Conditions	Yield
Stage #1: 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene With isopropylmagnesium chloride In tetrahydrofuran at -5 - 0℃; for 1h; Inert atmosphere; Stage #2: C20H27NO7 In tetrahydrofuran at 25 - 30℃; Inert atmosphere;	91%

2-methylmercapto-ethanol (5271-38-5) + 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene (1103738-29-9) → C16H17ClOS

Conditions	Yield
With potassium tert-butylate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; palladium dichloride In 5,5-dimethyl-1,3-cyclohexadiene at 120℃; for 12h;	91%

1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene (1103738-29-9) + (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-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (461432-24-6)

Conditions	Yield
Stage #1: 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene With TurboGrignard In tetrahydrofuran at -5 - 0℃; for 2h; 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; n-heptane at -5 - 0℃; for 2h; Stage #3: With hydrogenchloride In tetrahydrofuran; methanol; n-heptane at 0 - 20℃; for 16h;	90%

1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene (1103738-29-9) + C26H25ClO5 → C41H39ClO6

Conditions	Yield
Stage #1: 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene With TurboGrignard In tetrahydrofuran at -5 - 0℃; Stage #2: C26H25ClO5 In tetrahydrofuran; toluene at 0 - 5℃;	90%

1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene (1103738-29-9) + ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)(morpholin-4-yl)methanone (1103738-19-7) + isopropylmagnesium chloride (1068-55-9) → (4-chloro-3-(4-ethoxybenzyl)phenyl)((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuran[2,3-d][1,3]dioxolan-5-yl)methanone (1103738-30-2) + C11H18O5 + (4-chloro-3-(4-ethoxybenzyl)phenyl)((3aS,5S,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)methanone

Conditions

Yield

Stage #1: 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene; isopropylmagnesium chloride In tetrahydrofuran at 0℃; for 6h; Industrial scale; Stage #2: ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)(morpholin-4-yl)methanone With tert-butylmagnesium chloride In tetrahydrofuran at -10 - -5℃; for 6.5h; Industrial scale; Stage #3: With citric acid In tetrahydrofuran; water at 0 - 5℃; for 1h; Industrial scale; stereoselective reaction;

A 87% B n/a C n/a

1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene (1103738-29-9) + (2R,3S,4S)-2,3,4-tris(benzyloxy)-4-(4-((benzyloxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-1-(4-methylpiperazin-1-yl)butan-1-one (1431329-05-3) → (2R,3S,4S)-2,3,4-tribenzyloxy-4-(4-((benzyloxy)methyl)-2,2-dimethyl-1,3-dioxanepent-4-yl)-1-(4-chloro-3-(4-ethoxybenzyl)phenyl)butan-1-one

Conditions	Yield
Stage #1: 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene With butyl magnesium bromide In tetrahydrofuran at -5 - 0℃; for 1h; Inert atmosphere; Stage #2: (2R,3S,4S)-2,3,4-tris(benzyloxy)-4-(4-((benzyloxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-1-(4-methylpiperazin-1-yl)butan-1-one In tetrahydrofuran at 20 - 30℃; Inert atmosphere;	86%

ethylthioacetic acid methyl ester (2432-51-1) + 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene (1103738-29-9) + carbon monoxide (201230-82-2) → C17H17ClO2S

Conditions	Yield
With potassium tert-butylate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; palladium dichloride In 5,5-dimethyl-1,3-cyclohexadiene at 130℃; under 15001.5 Torr; for 16h;	86%

1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene (1103738-29-9) + 2-N-(quinolin-8-yl)carbamoyl-3,4,6-tri-O-benzyl-D-glucal → 2-N-(quinolin-8-yl)carbamoyl1-(4-chloro-3-(4-ethoxybenzyl)-benzene)-3,4,6-tri-O-benzyl-D-glucal

Conditions	Yield
With dichloro(1,5-cyclooctadiene)palladium(II); silver(I) acetate; potassium carbonate; citric acid In toluene at 130℃; for 3h; Schlenk technique; Inert atmosphere;	85%

1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene (1103738-29-9) + (2,3,4,6-tetra-O-benzyl-2-β-D-glucopyranosyl)tri-n-butylstannane → (2R,3R,4R,5S,6S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)tetrahydro-2H-pyran

Conditions	Yield
With potassium fluoride; tris-(dibenzylideneacetone)dipalladium(0); C51H73O2P; copper(l) chloride In 1,4-dioxane at 110℃; for 72h; Inert atmosphere;	83%
With potassium fluoride; tris-(dibenzylideneacetone)dipalladium(0); bis(3,5-bis(trifluoromethyl)phenyl)(2’,4’,6’-triisopropyl-3,6-dimethoxy-[1,1’-biphenyl]-2-yl)phosphine; copper(l) chloride In 1,4-dioxane at 110℃; for 72h; Inert atmosphere;	83%

1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene (1103738-29-9) + tri-n-butyl-(β-D-glucopyranosyl)stannane → dapagliflozin (461432-26-8)

Conditions	Yield
With potassium fluoride; tris-(dibenzylideneacetone)dipalladium(0); bis(3,5-bis(trifluoromethyl)phenyl)(2’,4’,6’-triisopropyl-3,6-dimethoxy-[1,1’-biphenyl]-2-yl)phosphine; copper(l) chloride In 1,4-dioxane at 110℃; for 72h; Inert atmosphere;	82%

1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene (1103738-29-9) + (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-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol (714269-57-5)

Conditions	Yield
Stage #1: 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene; (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one With TurboGrignard In tetrahydrofuran at -30 - -20℃; for 1h; Inert atmosphere; Stage #2: With methanesulfonic acid In tetrahydrofuran; methanol at -10 - 30℃; for 2h; Inert atmosphere;	81.8%

1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene (1103738-29-9) + ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)(morpholin-4-yl)methanone (1103738-19-7) → (4-chloro-3-(4-ethoxybenzyl)phenyl)((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuran[2,3-d][1,3]dioxolan-5-yl)methanone (1103738-30-2)

Conditions	Yield
Stage #1: 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene With isopropylmagnesium chloride In tetrahydrofuran at -5℃; for 3h; Industry scale; Stage #2: ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)(morpholin-4-yl)methanone With tert-butylmagnesium chloride In tetrahydrofuran at -25 - -20℃; for 3.68333h; Product distribution / selectivity; Industry scale;	81%
Stage #1: 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene With isopropylmagnesium chloride In tetrahydrofuran at -5℃; for 3h; Industry scale; Stage #2: ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)(morpholin-4-yl)methanone With tert-butylmagnesium chloride In tetrahydrofuran at -25 - -20℃; Product distribution / selectivity; Industry scale;	81%
With n-butyllithium In tetrahydrofuran at 0 - 20℃; for 4.5h;	76%
Stage #1: 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene With isopropylmagnesium chloride In tetrahydrofuran at 0 - 5℃; for 1.5h; Stage #2: ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)(morpholin-4-yl)methanone In tetrahydrofuran at 0 - 20℃; Product distribution / selectivity;	76%
Stage #1: 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene With isopropylmagnesium chloride In tetrahydrofuran at 0 - 5℃; for 1.5h; Stage #2: ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)(morpholin-4-yl)methanone In tetrahydrofuran at 0 - 20℃; for 3h; Reagent/catalyst; Temperature;	178 mg

1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene (1103738-29-9) + 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide (572-09-8) → (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (461432-25-7)

Conditions	Yield
Stage #1: 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene With isopropylmagnesium chloride In 2-methyltetrahydrofuran at -5 - 0℃; for 2h; Stage #2: 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide With N,N,N,N,-tetramethylethylenediamine; isopropylmagnesium chloride; cobalt(III) acetylacetonate In 2-methyltetrahydrofuran at 0 - 30℃; for 2.5h;	78%
Stage #1: 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene With isopropylmagnesium chloride In tetrahydrofuran at -10 - -5℃; for 2h; Inert atmosphere; Stage #2: 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide With copper dichloride In tetrahydrofuran at 5 - 10℃; for 13h; Reagent/catalyst;	75%

aq NH4Cl + 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene (1103738-29-9) + ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)(morpholin-4-yl)methanone (1103738-19-7) → (4-chloro-3-(4-ethoxybenzyl)phenyl)((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuran[2,3-d][1,3]dioxolan-5-yl)methanone (1103738-30-2)

Conditions	Yield
With i-PrMgCl In tetrahydrofuran	76%

4-methylsulfanyl-2-butanone (34047-39-7) + 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene (1103738-29-9) + carbon monoxide (201230-82-2) → C17H17ClO2S

Conditions	Yield
With potassium tert-butylate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; palladium dichloride In 5,5-dimethyl-1,3-cyclohexadiene at 130℃; under 15001.5 Torr; for 16h;	75%

1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene (1103738-29-9) + formamide (77287-34-4, 77287-35-5, 60100-09-6) → 4-chloro-3-(4-ethoxybenzyl)benzonitrile

Conditions	Yield
With zinc diacetate; nixantphos In 1-methyl-pyrrolidin-2-one at 140℃; for 24h; Inert atmosphere;	73%

1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene (1103738-29-9) + 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide (572-09-8) → (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (461432-25-7) + C29H33ClO10

Conditions	Yield
With bis(acetylacetonate)nickel(II); magnesium chloride; 4,4',4-tri-tert-butyl-2,2':6',2-terpyridine; zinc In tetrahydrofuran at 20℃; Schlenk technique; Inert atmosphere; Cooling with ice;	A 65% B n/a

1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene (1103738-29-9) + (3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one (147556-23-8) → (3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)tetrahydro-2H-pyran-2-ol

Conditions	Yield
Stage #1: 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene With isopropylmagnesium chloride In tetrahydrofuran at 20℃; for 2h; Inert atmosphere; Stage #2: (3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one With copper(l) iodide In tetrahydrofuran at 20℃; for 3h; Inert atmosphere;	58.8%

1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene (1103738-29-9) → 4-chloro-3-(4-ethoxybenzyl)benzenesulfonic acid

Conditions	Yield
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; Aminoiminomethanesulfinic acid In dimethyl sulfoxide at 100℃; for 14h; Green chemistry;	52%

1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene (1103738-29-9) + N-Methyl-N-phenethylamine (589-08-2) → 4-chloro-3-(4-ethoxybenzyl)-N-methyl-N-phenethylbenzenesulfonamide

Conditions	Yield
With dmap; 1-ethenyl-4-methylbenzene; palladium(II) acetylacetonate; 2,3,4,5-tetrabromothiophene 1,1-dioxide In dimethyl sulfoxide at 95℃; for 24h; Sealed tube; Inert atmosphere;	45%

1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene (1103738-29-9) → (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(methylsulfanyl)tetrahydro-2-H-pyran-3,4,5-triol (1018899-04-1)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: isopropylmagnesium chloride / tetrahydrofuran / 3 h / -5 °C / Industry scale 1.2: -25 - -20 °C / Industry scale 2.1: sodium tetrahydroborate; methanol; cerium(III) chloride heptahydrate / -78 - 0 °C 3.1: acetic acid / water / 15 h / 100 °C 3.2: 0 - 20 °C 4.1: thiourea; trimethylsilyl trifluoromethanesulfonate / 1,4-dioxane / 3.5 h / 80 °C 4.2: 3 h / 20 °C 5.1: sodium methylate / methanol / 2.25 h / 20 °C / Industry scale; Inert atmosphere 5.2: 1.5 h / 0 - 20 °C / Industry scale View Scheme
Multi-step reaction with 5 steps 1.1: isopropylmagnesium chloride / tetrahydrofuran / 1.5 h / 0 - 5 °C 1.2: 3 h / 0 - 20 °C 2.1: sodium tetrahydroborate; cerium(III) chloride heptahydrate; methanol / -78 - -70 °C 3.1: acetic acid / water / 15 h / 100 °C 3.2: 2 h / 0 - 20 °C 4.1: thiourea; trimethylsilyl trifluoromethanesulfonate / 1,4-dioxane / 3.5 h / 80 °C 4.2: 3 h / 20 °C 5.1: sodium methylate / methanol / 2.25 h / 20 °C / Inert atmosphere; Large scale View Scheme

1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene (1103738-29-9) → [(2S,3S,4R,5S,6R)-4,5-diacetoxy-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-methylthiotetrahydropyran-3-yl]acetate (1018899-03-0)

Conditions

Yield

Multi-step reaction with 4 steps 1.1: isopropylmagnesium chloride / tetrahydrofuran / 3 h / -5 °C / Industry scale 1.2: -25 - -20 °C / Industry scale 2.1: sodium tetrahydroborate; methanol; cerium(III) chloride heptahydrate / -78 - 0 °C 3.1: acetic acid / water / 15 h / 100 °C 3.2: 0 - 20 °C 4.1: thiourea; trimethylsilyl trifluoromethanesulfonate / 1,4-dioxane / 3.5 h / 80 °C 4.2: 3 h / 20 °C View Scheme

1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene (1103738-29-9) → acetic acid (3S,4R,5S,6S)-2,4,5-triacetoxy-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-tetrahydropyran-3-yl ester (1018898-84-4)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: isopropylmagnesium chloride / tetrahydrofuran / 3 h / -5 °C / Industry scale 1.2: -25 - -20 °C / Industry scale 2.1: sodium tetrahydroborate; methanol; cerium(III) chloride heptahydrate / -78 - 0 °C 3.1: acetic acid / water / 15 h / 100 °C 3.2: 0 - 20 °C View Scheme

Upstream product

• 1103738-26-6 (2-chloro-5-iodo-phenyl)-(4-ethoxyphenyl)methanone 
• 281652-58-2 2-chloro-5-iodobenzoylchloride 
• 19094-56-5 2-chloro-5-iodobenzoic acid 
• 103-73-1 Phenetole 
• 462-06-6 fluorobenzene 
• 915095-86-2 (2-chloro-5-iodophenyl)(4-fluorophenyl)methanone 
• 793695-85-9 2-bromomethyl-1-chloro-4-iodo-benzene 
• 588-96-5 4-bromoethoxybenzene 
• 25784-91-2 2-chloro-5-nitrobenzoylchloride 
• 2516-96-3 2-chloro-5-nitrobenzoic acid 

Downstream Products

• 1103738-30-2 (4-chloro-3-(4-ethoxybenzyl)phenyl)((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuran[2,3-d][1,3]dioxolan-5-yl)methanone 
• 1018899-04-1 (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(methylsulfanyl)tetrahydro-2-H-pyran-3,4,5-triol 
• 1018899-03-0 [(2S,3S,4R,5S,6R)-4,5-diacetoxy-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-methylthiotetrahydropyran-3-yl]acetate 
• 1018898-84-4 acetic acid (3S,4R,5S,6S)-2,4,5-triacetoxy-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-tetrahydropyran-3-yl ester 
• 461432-24-6 (3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol 
• 960404-86-8 (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,3,4,5-tetraol 
• 461432-26-8 dapagliflozin 
• 714269-57-5 (2S,3R,4S,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol 
• 461432-25-7 (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate 
• 1408077-50-8 C₁₅H₁₅ClO₂ 

Relevant articles and documents

Palladium-Catalyzed Reaction of Aryl Iodides and Glycal Enones: Application in the Preparation of Dapagliflozin Analogues

An efficient approach for the preparation of C-1 aryl enones from aryl iodides and glycal enones by palladium-catalyzed cross-coupling reactions under ligand-free conditions was developed. A wide range of aryl iodides bearing electron-donating and withdrawing groups underwent oxidative C-1 arylation with galactal, glucal and rhamnal enones in the presence of Pd(OAc)2 and AgNO3 under mild conditions. The protecting groups, including benzyl, acetyl, pivaloyl, and benzoyl groups, were found to be compatible under standard reaction conditions. The developed methodology was applied for the preparation of dapagliflozin analogues (SGLT-2 inhibitors). Regioselective nitration of C-1 aryl enones provides C-2 nitro aryl enones in good yields.

Process development of sotagliflozin, a dual inhibitor of sodium- Glucose cotransporter-1/2 for the treatment of diabetes

The development of an efficient manufacturing process for sotagliflozin (LX4211), a dual inhibitor of sodium- glucose cotransporter-1/2 (SGLT-1/2) for the treatment of diabetes, is described. Sotagliflozin features five contiguous chiral centers on the carbohydrate core flanked by a thioether group and a biaryl moiety. Three chiral centers are obtained from the starting material L-xylose, while the other two were established (or modified) via three highly stereoselective transformations: Luche reduction (dr: 97/3), dynamic kinetic resolution of anomeric hemiacetal (dr: 95/5), and Lewis acid-promoted thiolation (dr: 1000/ 1). Global deprotection of the resulting penultimate intermediate with catalytic sodium methoxide followed by recrystallization furnishes sotagliflozin. The longest linear sequence consists of 10 steps from L-xylose with an overall yield of 40%. This process has been performed on multi-hundred kilogram batches to satisfy the drug substance development demands.

Synthetic method of 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene

The invention belongs to the field of pharmaceutical synthesis and discloses a synthetic method of 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene. The synthetic method comprises the following steps: (S1) dissolving 4-bromobenzene ether into a solvent, adding magnesium, and reacting under the catalysis of iodine, so as to obtain a Grignard reagent; and (S2) dissolving 2-(bromomethyl)-4-iodochlorobenzeneinto the solvent, adding the Grignard reagent prepared in the step S1, and reacting under the catalysis of cuprous iodide, so as to obtain 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene. The method is short in synthetic route, the final product purity reaches up to 99.5%, and the yield reaches up to 95.9%, so that the method is beneficial to the industrialization production.