714269-57-5

Basic information

• Product Name: (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxyMethyl)-2-Methoxytetrahydro-2H-pyran-3,4,5-triol
• Synonyms: (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxyMethyl)-2-Methoxytetrahydro-2H-pyran-3,4,5-triol;Methyl 1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-alpha-D-glucopyranoside;a-D-Glucopyranoside, Methyl 1-C-[4-chloro-3-[(4-ethoxyphenyl)Methyl]phenyl]-;Methyl 1-C-[4-chloro-3-(4-ethoxybenzyl)phenyl]-α-D-Glucopyranoside;DAPAGLIFLOZIN intermediate;Dapagliflozin Intermediate 3;(2S,3R,4S,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol;Dapagliflozin Impurity 16
• CAS NO: 714269-57-5
• Molecular Formula: C₂₂H₂₇ClO₇
• Molecular Weight: 438.89858
• EINECS: 1312995-182-4
• Mol File: 714269-57-5.mol
• Article Data: 22

Chemical Properties

• Boiling Point: 609.6±55.0 °C(Predicted)
• Appearance: /
• Density: 1.39±0.1 g/cm3 (20 ºC 760 Torr)
• Storage Temp.: 2-8°C
• Solubility: Acetonitrile (Slightly), DMSO (Slightly), Methanol (Slightly), Water (Slightly)
• PKA: 12.59±0.70(Predicted)
• Stability: Hygroscopic
• CAS DataBase Reference: (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxyMethyl)-2-Methoxytetrahydro-2H-pyran-3,4,5-triol(CAS DataBase Reference)
• NIST Chemistry Reference: (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxyMethyl)-2-Methoxytetrahydro-2H-pyran-3,4,5-triol(714269-57-5)
• EPA Substance Registry System: (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxyMethyl)-2-Methoxytetrahydro-2H-pyran-3,4,5-triol(714269-57-5)

Safety Data

• Hazardous Substances Data: 714269-57-5(Hazardous Substances Data)

Usage

Appearance

Solid

Uses

1α-Methyl Dapagliflozin is an antidiabetic agent and intermediate of Dapagliflozin (D226255]), a sodium-glucose transporter 2 inhibitor.

Synthetic route

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%

methanesulfonic acid (75-75-2) + C33H56ClO7Si4(1-)*Li(1+) → (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
In methanol at 20℃; for 10h;	81.4%

4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5) + C18H42O6Si4 → (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
With n-butyllithium In tetrahydrofuran; hexane; toluene at -78 - -65℃; for 2h; Inert atmosphere;	78.6%

4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5) + (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: 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene With sec.-butyllithium In tetrahydrofuran; cyclohexane at -78 - -68℃; 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; n-heptane; cyclohexane at -78 - -68℃; for 30h;	78.3%
Stage #1: 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene With n-butyllithium In tetrahydrofuran; hexane; toluene at -78℃; for 1h; Large scale; Stage #2: (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 -78℃; for 3h; Large scale;	78%
Stage #1: 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene With n-butyllithium In tetrahydrofuran; hexane; toluene at -78℃; for 1h; Inert atmosphere; Industrial scale; Stage #2: (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one With methanesulfonic acid In tetrahydrofuran; methanol; hexane; toluene at -78 - 40℃; for 14h; Industrial scale;	78%
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

4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5) + methanesulfonic acid (75-75-2) + (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: 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene With n-butyllithium In tetrahydrofuran; hexane; toluene at -78℃; 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; toluene at -78℃; for 3h; Large scale; Stage #3: methanesulfonic acid In methanol at 0 - 40℃; for 11h; Large scale;

78%

4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5) + 2,3,5,6-tetra-O-(tert-butyldimethylsilyl)-D-glucono-1,4-lactone (318967-97-4) → (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
With n-butyllithium In tetrahydrofuran; hexane; toluene at -78 - -65℃; for 2h; Inert atmosphere;	77.3%

methanol (67-56-1) + (2S,3R,4S,5R,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-3,4,5-tris(trimethylsilyloxy)-6-(trimethylsilyloxymethyl)tetrahydropyran-2-ol → (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
With toluene-4-sulfonic acid at 20℃; for 12h; Inert atmosphere;	71.6%
With n-butyllithium; toluene-4-sulfonic acid at 20℃; for 12h;	141.5 g

(2S,3R,4S,5R,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-3,4,5-tris(trimethylsilyloxy)-6-(trimethylsilyloxymethyl)tetrahydropyran-2-ol → (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
With toluene-4-sulfonic acid In methanol at 20 - 30℃; for 12h; Inert atmosphere;	71.6%

methanol (67-56-1) → (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: 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene With n-butyllithium In tetrahydrofuran; hexane; toluene at -30℃; 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 -30 - -24℃; Stage #3: methanol In tetrahydrofuran; hexane; toluene at -10 - 35℃; for 23h; Acidic conditions;

(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
Multi-step reaction with 2 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 0.67 h / -78 °C / Inert atmosphere 1.2: 5 h / -78 °C / Inert atmosphere 2.1: toluene-4-sulfonic acid / 12 h / 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 0.67 h / -78 °C 1.2: 5 h / -78 °C 2.1: n-butyllithium; toluene-4-sulfonic acid / 12 h / 20 °C View Scheme

methanol (67-56-1) + 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5) + (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: 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene With n-butyllithium In tetrahydrofuran; hexane; toluene at -65℃; 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 -65℃; for 2h; Stage #3: methanol With hydrogenchloride; water In tetrahydrofuran; hexane; toluene at 20℃;
Stage #1: 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene; (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one With n-butyllithium In tetrahydrofuran at -85 - -70℃; for 2h; Inert atmosphere; Stage #2: methanol With methanesulfonic acid In tetrahydrofuran at -75 - 15℃; for 18h; Inert atmosphere;
With n-butyllithium; methanesulfonic acid In tetrahydrofuran; toluene at -15 - 5℃; for 0.0113889h;

2-chloro-5-iodobenzoylchloride (281652-58-2) → (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
Multi-step reaction with 2 steps 1.1: aluminum (III) chloride / dichloromethane / 0.5 h / -3 - 5 °C 1.2: 12 h / 0 - 25 °C 1.3: polymethylhydrosiloxane (PMHS) / 16 h / 30 °C 2.1: TurboGrignard / tetrahydrofuran / 1.5 h / -5 - 0 °C / Inert atmosphere 2.2: 1 h / -5 - 0 °C 2.3: 16 h / -10 - 20 °C View Scheme
Multi-step reaction with 2 steps 1.1: aluminum (III) chloride / dichloromethane / 2 h / 0 - 5 °C 1.2: polymethylhydrosiloxane / 26 h / 25 - 30 °C 2.1: TurboGrignard / tetrahydrofuran / 0.67 h / -60 - -50 °C / Inert atmosphere 2.2: 5.67 h / -60 - -50 °C / Inert atmosphere 2.3: 18 h / -10 - 15 °C View Scheme

Phenetole (103-73-1) → (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
Multi-step reaction with 3 steps 1.1: N,N-dimethyl-formamide; oxalyl dichloride / dichloromethane / 15 h / 25 - 30 °C 1.2: 2 h / 0 - 10 °C 2.1: aluminum (III) chloride; sodium tetrahydroborate / Dimethyl ether / 30 h / 0 - 65 °C 3.1: n-butyllithium / tetrahydrofuran; toluene / 1 h / -75 - -60 °C 3.2: 3 h / -75 - -60 °C 3.3: 18 h / -75 - 25 °C View Scheme

D-Glucono-1,5-lactone (90-80-2) → (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
Multi-step reaction with 2 steps 1.1: 4-methyl-morpholine / tetrahydrofuran / 17 h / 5 - 25 °C / Inert atmosphere; Large scale 2.1: TurboGrignard / tetrahydrofuran / 0.67 h / -60 - -50 °C / Inert atmosphere 2.2: 5.67 h / -60 - -50 °C / Inert atmosphere 2.3: 18 h / -10 - 15 °C View Scheme
Multi-step reaction with 3 steps 1.1: 4-methyl-morpholine / tetrahydrofuran / 10 h / 20 °C / Inert atmosphere 2.1: n-butyllithium / tetrahydrofuran; hexane / 0.67 h / -78 °C / Inert atmosphere 2.2: 5 h / -78 °C / Inert atmosphere 3.1: toluene-4-sulfonic acid / 12 h / 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1.1: 4-methyl-morpholine / tetrahydrofuran / 8 h / 20 - 30 °C / Inert atmosphere 2.1: n-butyllithium / tetrahydrofuran; hexane / 0.67 h / -78 °C / Inert atmosphere 2.2: 5 h / -78 °C / Inert atmosphere 3.1: toluene-4-sulfonic acid / methanol / 12 h / 20 - 30 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1.1: 4-methyl-morpholine / tetrahydrofuran / 10 h / 20 °C 2.1: n-butyllithium / tetrahydrofuran; hexane / 0.67 h / -78 °C 2.2: 5 h / -78 °C 3.1: n-butyllithium; toluene-4-sulfonic acid / 12 h / 20 °C View Scheme

2-chloro-5-iodobenzoic acid (19094-56-5) → (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
Multi-step reaction with 3 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 3.1: TurboGrignard / tetrahydrofuran / 1.5 h / -5 - 0 °C / Inert atmosphere 3.2: 1 h / -5 - 0 °C 3.3: 16 h / -10 - 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 16 h / 10 - 25 °C 2.1: aluminum (III) chloride / dichloromethane / 2 h / 0 - 5 °C 2.2: polymethylhydrosiloxane / 26 h / 25 - 30 °C 3.1: TurboGrignard / tetrahydrofuran / 0.67 h / -60 - -50 °C / Inert atmosphere 3.2: 5.67 h / -60 - -50 °C / Inert atmosphere 3.3: 18 h / -10 - 15 °C View Scheme

methanol (67-56-1) + (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,3,4,5-tetraol (960404-86-8) → (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
With hydrogenchloride In tetrahydrofuran at -10 - 15℃; for 18h; Temperature;
With methanesulfonic acid In neat (no solvent) at 20℃; for 6h; Inert atmosphere;

methanol (67-56-1) + 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 With TurboGrignard In tetrahydrofuran at -5 - 0℃; for 1.5h; Inert atmosphere; Stage #2: (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one With TurboGrignard In tetrahydrofuran; n-heptane at -5 - 0℃; for 1h; Stage #3: methanol With hydrogenchloride In tetrahydrofuran; n-heptane; water at -10 - 20℃; for 16h; Concentration; Temperature;
Stage #1: 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene With TurboGrignard In tetrahydrofuran at -60 - -50℃; for 0.666667h; 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 -60 - -50℃; for 5.66667h; Inert atmosphere; Stage #3: methanol With hydrogenchloride; water In tetrahydrofuran at -10 - 15℃; for 18h; Temperature; Time;

C34H59ClO7Si4 (1528636-28-3) → (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
With water; sodium hydroxide In tetrahydrofuran; hexane; toluene for 1h;	7.69 kg

(3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-one → (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
Multi-step reaction with 2 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 0.67 h / -78 °C / Inert atmosphere 1.2: 5 h / -78 °C / Inert atmosphere 2.1: toluene-4-sulfonic acid / methanol / 12 h / 20 - 30 °C / Inert atmosphere View Scheme

D-glucono-1,4-lactone (1198-69-2) → (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
Multi-step reaction with 2 steps 1: 4-methyl-morpholine / tetrahydrofuran / 1 h / -10 - 45 °C 2: n-butyllithium / tetrahydrofuran; toluene; hexane / 2 h / -78 - -65 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1: triethylamine / tetrahydrofuran / 1 h / -10 - 45 °C 2: n-butyllithium / tetrahydrofuran; toluene; hexane / 2 h / -78 - -65 °C / Inert atmosphere View Scheme

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) + C21H27ClO7

Conditions	Yield
Stage #1: 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene With TurboGrignard In tetrahydrofuran at -5 - 0℃; 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 5℃; for 3h; Inert atmosphere; Stage #3: With hydrogenchloride; methanol In tetrahydrofuran Inert atmosphere;

5-bromo-2-chlorobenzoic acid (21739-92-4) → (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
Multi-step reaction with 3 steps 1.1: N,N-dimethyl-formamide; oxalyl dichloride / dichloromethane / 15 h / 25 - 30 °C 1.2: 2 h / 0 - 10 °C 2.1: aluminum (III) chloride; sodium tetrahydroborate / Dimethyl ether / 30 h / 0 - 65 °C 3.1: n-butyllithium / tetrahydrofuran; toluene / 1 h / -75 - -60 °C 3.2: 3 h / -75 - -60 °C 3.3: 18 h / -75 - 25 °C View Scheme

(5-bromo-2-chlorophenyl)(4-ethyloxyphenyl)methanone (461432-22-4) → (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
Multi-step reaction with 2 steps 1.1: aluminum (III) chloride; sodium tetrahydroborate / Dimethyl ether / 30 h / 0 - 65 °C 2.1: n-butyllithium / tetrahydrofuran; toluene / 1 h / -75 - -60 °C 2.2: 3 h / -75 - -60 °C 2.3: 18 h / -75 - 25 °C View Scheme

3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-one → (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
Multi-step reaction with 2 steps 1.1: 4-methyl-morpholine / tetrahydrofuran / 15 h / 0 - 40 °C 2.1: n-butyllithium / tetrahydrofuran; toluene / 1 h / -75 - -60 °C 2.2: 3 h / -75 - -60 °C 2.3: 18 h / -75 - 25 °C View Scheme

4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5) + 3,4,5-tris[(trimethylsilyl)oxy]-6-{[(trimethylsilyl)oxy]methyl}-tetrahydro-2H-pyran-2-one → (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: 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene With n-butyllithium In tetrahydrofuran; toluene at -75 - -60℃; for 1h; Stage #2: 3,4,5-tris[(trimethylsilyl)oxy]-6-{[(trimethylsilyl)oxy]methyl}-tetrahydro-2H-pyran-2-one In tetrahydrofuran; toluene at -75 - -60℃; for 3h; Stage #3: With methanesulfonic acid In tetrahydrofuran; methanol; toluene at -75 - 25℃; for 18h;	82 g

2-chloro-benzaldehyde (89-98-5) → (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

Multi-step reaction with 5 steps 1.1: N-Bromosuccinimide / dichloromethane / 10.5 h / 5 °C / Large scale 2.1: sodium tetrahydroborate / ethanol / 4 h / 20 °C / Large scale 3.1: thionyl chloride / 3 h / 70 °C / Large scale 4.1: aluminum (III) chloride / ethyl acetate / 9 h / 78 °C / Cooling with ice; Large scale 5.1: n-butyllithium / tetrahydrofuran; toluene; hexane / 1 h / -78 °C / Large scale 5.2: 3 h / -78 °C / Large scale View Scheme

2-chloro-5-bromobenzaldehyde (189628-37-3) → (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
Multi-step reaction with 4 steps 1.1: sodium tetrahydroborate / ethanol / 4 h / 20 °C / Large scale 2.1: thionyl chloride / 3 h / 70 °C / Large scale 3.1: aluminum (III) chloride / ethyl acetate / 9 h / 78 °C / Cooling with ice; Large scale 4.1: n-butyllithium / tetrahydrofuran; toluene; hexane / 1 h / -78 °C / Large scale 4.2: 3 h / -78 °C / Large scale View Scheme

5-bromo-2-chlorobenzyl alcohol (149965-40-2) → (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
Multi-step reaction with 3 steps 1.1: thionyl chloride / 3 h / 70 °C / Large scale 2.1: aluminum (III) chloride / ethyl acetate / 9 h / 78 °C / Cooling with ice; Large scale 3.1: n-butyllithium / tetrahydrofuran; toluene; hexane / 1 h / -78 °C / Large scale 3.2: 3 h / -78 °C / Large scale View Scheme

4-bromo-1-chloro-2-(chloromethyl)benzene → (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
Multi-step reaction with 2 steps 1.1: aluminum (III) chloride / ethyl acetate / 9 h / 78 °C / Cooling with ice; Large scale 2.1: n-butyllithium / tetrahydrofuran; toluene; hexane / 1 h / -78 °C / Large scale 2.2: 3 h / -78 °C / Large scale View Scheme

4-bromo-aniline (106-40-1) → (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
Multi-step reaction with 5 steps 1.1: water; methanol / 5 h / 20 °C / Cooling with ice; Large scale 2.1: aluminum (III) chloride / ethyl acetate / 8 h / Cooling with ice; Reflux; Large scale 3.1: hydrogenchloride / water; methanol / 6 h / 80 °C / Large scale 4.1: hydrogenchloride; sodium nitrite / water / 3 h / -5 - 0 °C / Large scale 4.2: 4 h / 20 - 80 °C / Large scale 5.1: n-butyllithium / tetrahydrofuran; toluene; hexane / 1 h / -78 °C / Inert atmosphere; Large scale 5.2: 3 h / -78 °C / Large scale 5.3: 11 h / 0 - 40 °C / Large scale View Scheme
Multi-step reaction with 5 steps 1.1: water; methanol / 5.5 h / 20 °C / Cooling with ice; Industrial scale 2.1: hydrogen fluoride / ethyl acetate / 8.5 h / Cooling with ice; Industrial scale 3.1: hydrogenchloride / water; methanol / 6 h / 80 °C / Industrial scale 4.1: hydrogenchloride; sodium nitrite / water / 3 h / -5 °C / Industrial scale 4.2: 4 h / 20 - 80 °C / Industrial scale 5.1: n-butyllithium / tetrahydrofuran; toluene; hexane / 1 h / -78 °C / Inert atmosphere; Industrial scale 5.2: 14 h / -78 - 40 °C / Industrial scale View Scheme

Upstream product

• 461432-23-5 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene 
• 32469-28-6 (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one 
• 67-56-1 methanol 
• 75-75-2 methanesulfonic acid 
• 1103738-29-9 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene 
• 6214-44-4 4-ethoxybenzyl alcohol 
• 10031-82-0 4-ethoxybenzaldehyde 
• 123-08-0 4-hydroxy-benzaldehyde 
• 106-44-5 p-cresol 
• 103-88-8 4-bromoacetanilide 
• 2606-57-7 4-ethoxybenzyl bromide 
• 622-60-6 1-ethoxy-4-methylbenzene 
• 106-40-1 4-bromo-aniline 
• 149965-40-2 5-bromo-2-chlorobenzyl alcohol 

Downstream Products

• 461432-26-8 dapagliflozin 
• 960404-59-5 C₄H₆O₂*C₂₂H₂₇ClO₇ 
• 1528636-29-4 ((2R,3R,4S,5R,6S)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-methoxy-3,4,5-tris-(trimethylsilyloxy)tetrahydro-2H-pyran-2-yl)methanol 
• 1528636-33-0 (2S,3R,4S,5R,6S)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-methoxy-3,4,5-tris-(trimethylsilyloxy)tetrahydro-2H-pyran-2-carbaldehyde 
• 1528636-39-6 (2S,3R,4S,5S)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6,6-bis(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol 
• 1210344-57-2 Ertugliflozin 
• 1528636-28-3 C₃₄H₅₉ClO₇Si₄ 

Relevant articles and documents

AN EFFICIENT PROCESS FOR THE PREPARATION OF ERTUGLIFLOZIN L-PYROGLUTAMIC ACID AND INTERMEDIATES THEREOF

The present invention relates to an efficient process for the preparation of Ertugliflozin L-pyroglutamic acid of formula (I) and intermediate thereof, in environment friendly conditions. The present invention further relates to a process for the preparation of substantially pure intermediate of formula (IV).

Refining method of SGLT-2 inhibitor intermediate

The invention discloses a refining method of an SGLT-2 inhibitor intermediate; the SGLT-2 inhibitor intermediate is represented by the formula (I), wherein the definition of substituent groups in theformula (I) is detailed in the specification. The refining method includes the following steps: the SGLT-2 inhibitor intermediate is dissolved in a polar organic solvent and cooled to ultra-low temperature, the non-polar organic solvent is added, and the solid SGLT-2 inhibitor intermediate is obtained. The refining method is different from a conventional recrystallization technology, and can refine materials that are not easy to solidify at room temperature. A new choice is provided for refining the materials with low melting point and high viscosity. The refining method is suitable for industrialized scale-up production.

Synthetic method of dapagliflozin

Disclosed is a synthesis method of dapagliflozin. The method includes providing a microreactor having at least 4 reaction units in series, delivering a 5-bromo-2-chloro-4'-ethoxydiphenylmethane solution and an alkyllithium solution into a first reaction unit and controlling the reaction temperature in the first reaction unit to be -5 to -40 DEG C; after the reaction is completed, making a reactionsolution flow into a second reaction unit, and delivering trimethylsilyl protected gluconolactone or a solution thereof to the second reaction unit; after the reaction is completed, making a reactionsolution flow into a third reaction unit and delivering a mixed solution of methanol and methane sulfonic acid to the third reaction unit; making a reaction solution flow into a fourth reaction unitafter the reaction is completed and delivering a mixed solution of boron trifluoride diethyl etherate and Triethylsilane into the fourth reaction unit.