1279691-36-9

Basic information

• Product Name: (2S,3R,4S,5S,6R)-2-(3-(4-((S)-tetrahydrofuran-3-yloxy)benzyl)-4-chlorophenyl)-tetrahydro-6-(hydroxyMethyl)-2-Methoxy-2H-pyran-3,4,5-triol
• Synonyms: (2S,3R,4S,5S,6R)-2-(3-(4-((S)-tetrahydrofuran-3-yloxy)benzyl)-4-chlorophenyl)-tetrahydro-6-(hydroxyMethyl)-2-Methoxy-2H-pyran-3,4,5-triol;Methyl 1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]Methyl]phenyl]-alpha-D-glucopyranoside;(2S,3R,4S,5S,6R)-2-(4-Chloro-3-(4-((S)-tetrahydrofuran-3-yloxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol;Empagliflozin Intermediate3;Empagliflozin Intermediates;(3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol;Methyl 1-C-(4-chloro-3-{4-[(3S)-tetrahydro-3-furanyloxy]benzyl}phenyl)-α-D-glucopyranoside
• CAS NO: 1279691-36-9
• Molecular Formula: C₂₄H₂₉ClO₈
• Molecular Weight: 480.93526
• EINECS: 1592732-453-0
• Mol File: 1279691-36-9.mol
• Article Data: 14

Chemical Properties

• Boiling Point: 663.4±55.0 °C(Predicted)
• Appearance: /
• Density: 1.43±0.1 g/cm3(Predicted)
• PKA: 12.59±0.70(Predicted)
• CAS DataBase Reference: (2S,3R,4S,5S,6R)-2-(3-(4-((S)-tetrahydrofuran-3-yloxy)benzyl)-4-chlorophenyl)-tetrahydro-6-(hydroxyMethyl)-2-Methoxy-2H-pyran-3,4,5-triol(CAS DataBase Reference)
• NIST Chemistry Reference: (2S,3R,4S,5S,6R)-2-(3-(4-((S)-tetrahydrofuran-3-yloxy)benzyl)-4-chlorophenyl)-tetrahydro-6-(hydroxyMethyl)-2-Methoxy-2H-pyran-3,4,5-triol(1279691-36-9)
• EPA Substance Registry System: (2S,3R,4S,5S,6R)-2-(3-(4-((S)-tetrahydrofuran-3-yloxy)benzyl)-4-chlorophenyl)-tetrahydro-6-(hydroxyMethyl)-2-Methoxy-2H-pyran-3,4,5-triol(1279691-36-9)

Safety Data

• Hazardous Substances Data: 1279691-36-9(Hazardous Substances Data)

Usage

Uses

1-Methoxy Empagliflozin is an impurity in the synthesis of Empagliflozin drug (E521510), which is potent and selective inhibitor of sodium glucose co-transporter-2 (SGLT-2).

Synthetic route

methanol (67-56-1) + (2S,3R,4S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,3,4,5-tetraol (1279691-35-8) → (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1279691-36-9)

Conditions	Yield
With hydrogenchloride In water at 20 - 30℃; for 1h;	90.5%
With hydrogenchloride In water at 20℃; pH=0; Product distribution / selectivity;
With trifluoroacetic acid at 20℃; for 5h; Reagent/catalyst; Large scale;	10 kg

methanol (67-56-1) + (S)-4-bromo-1-chloro-2-(4-tetrahydrofuran-3-yloxy-benzyl)benzene (915095-89-5) + (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-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1279691-36-9)

Conditions	Yield
Stage #1: (S)-4-bromo-1-chloro-2-(4-tetrahydrofuran-3-yloxy-benzyl)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: methanol With methanesulfonic acid In tetrahydrofuran; hexane; toluene at 0 - 40℃; for 10h; Large scale;	87%
Stage #1: (S)-4-bromo-1-chloro-2-(4-tetrahydrofuran-3-yloxy-benzyl)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; hexane; toluene at -78℃; for 3h; Inert atmosphere; Large scale; Stage #2: methanol With methanesulfonic acid In tetrahydrofuran; hexane; toluene at 0 - 40℃; for 10h; Inert atmosphere; Large scale;	84%

(S)-4-bromo-1-chloro-2-(4-tetrahydrofuran-3-yloxy-benzyl)benzene (915095-89-5) + (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-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1279691-36-9)

Conditions

Yield

Stage #1: (S)-4-bromo-1-chloro-2-(4-tetrahydrofuran-3-yloxy-benzyl)benzene With n-butyllithium In tetrahydrofuran; 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 In tetrahydrofuran; toluene at -78℃; for 3h; Large scale; Stage #3: With methanesulfonic acid In tetrahydrofuran; methanol; toluene at 0 - 40℃; for 10h; Large scale;

84%

(3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran (915095-94-2) + C18H42O6Si4 → (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1279691-36-9)

Conditions	Yield
With n-butyllithium In tetrahydrofuran; hexane; toluene at -78 - -65℃; for 2h; Inert atmosphere;	77.6%

methanesulfonic acid (75-75-2) + C35H58ClO8Si4(1-)*Li(1+) → (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1279691-36-9)

Conditions	Yield
In methanol at 20℃; for 10h;	76.3%

(S)-(2-chloro-5-iodophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-87-3) → (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1279691-36-9)

Conditions	Yield
Multi-step reaction with 4 steps 1: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / toluene / 2.5 h / 0 - 23 °C 2: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.5 h / -20 - 10 °C 3: hydrogenchloride / isopropyl alcohol / 5 h / 38 - 42 °C / pH 2 4: hydrogenchloride / isopropyl alcohol; methanol View Scheme

(3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran (915095-94-2) → (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1279691-36-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.5 h / -20 - 10 °C 2: hydrogenchloride / isopropyl alcohol / 5 h / 38 - 42 °C / pH 2 3: hydrogenchloride / isopropyl alcohol; methanol View Scheme
Multi-step reaction with 2 steps 1: lithium chloride; isopropylmagnesium chloride / tetrahydrofuran / -30 - -20 °C / Inert atmosphere; Large scale 2: hydrogenchloride / methanol; water / 4 h / 20 °C / Large scale View Scheme
Multi-step reaction with 2 steps 1.1: TurboGrignard / tetrahydrofuran / 1 h / -30 - -20 °C / Inert atmosphere 1.2: 0.5 h / Inert atmosphere 2.1: hydrogenchloride / water / 1 h / 20 - 30 °C View Scheme

C35H59ClO8Si4 → (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1279691-36-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrogenchloride / isopropyl alcohol / 5 h / 38 - 42 °C / pH 2 2: hydrogenchloride / isopropyl alcohol; methanol View Scheme

C24H29ClO8 → (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1279691-36-9)

Conditions	Yield
With hydrogenchloride In methanol; isopropyl alcohol	204 g

2-chloro-5-iodobenzoic acid (19094-56-5) → (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1279691-36-9)

Conditions

Yield

Multi-step reaction with 7 steps 1: oxalyl dichloride; N,N-dimethyl-formamide / fluorobenzene / 2 h / 15 - 25 °C 2: aluminum (III) chloride / 1 h / 0 - 25 °C 3: potassium tert-butylate / tetrahydrofuran / 0.5 h / 7 - 10 °C 4: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / toluene / 2.5 h / 0 - 23 °C 5: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.5 h / -20 - 10 °C 6: hydrogenchloride / isopropyl alcohol / 5 h / 38 - 42 °C / pH 2 7: hydrogenchloride / isopropyl alcohol; methanol View Scheme

2-chloro-5-iodobenzoylchloride (281652-58-2) → (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1279691-36-9)

Conditions

Yield

Multi-step reaction with 6 steps 1: aluminum (III) chloride / 1 h / 0 - 25 °C 2: potassium tert-butylate / tetrahydrofuran / 0.5 h / 7 - 10 °C 3: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / toluene / 2.5 h / 0 - 23 °C 4: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.5 h / -20 - 10 °C 5: hydrogenchloride / isopropyl alcohol / 5 h / 38 - 42 °C / pH 2 6: hydrogenchloride / isopropyl alcohol; methanol View Scheme

(2-chloro-5-iodophenyl)(4-fluorophenyl)methanone (915095-86-2) → (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1279691-36-9)

Conditions

Yield

Multi-step reaction with 5 steps 1: potassium tert-butylate / tetrahydrofuran / 0.5 h / 7 - 10 °C 2: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / toluene / 2.5 h / 0 - 23 °C 3: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.5 h / -20 - 10 °C 4: hydrogenchloride / isopropyl alcohol / 5 h / 38 - 42 °C / pH 2 5: hydrogenchloride / isopropyl alcohol; methanol View Scheme

D-glucono-1,4-lactone (1198-69-2) → (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1279691-36-9)

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

methanol (67-56-1) + (2S,3R,4S,5R,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-ol → (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1279691-36-9)

Conditions	Yield
With methanesulfonic acid at 40 - 43℃; for 3h; Large scale;	4.18 kg

C18H42O6Si4 → (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1279691-36-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: lithium chloride; isopropylmagnesium chloride / tetrahydrofuran / -30 - -20 °C / Inert atmosphere; Large scale 2: hydrogenchloride / methanol; water / 4 h / 20 °C / Large scale View Scheme

(2S,3R,4S,5R,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-ol → (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1279691-36-9)

Conditions	Yield
With hydrogenchloride In methanol; water at 20℃; for 4h; Large scale;

4-bromo-aniline (106-40-1) → (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1279691-36-9)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: water; methanol / 3.5 h / 20 °C / Cooling with ice; Large scale 2.1: ethyl acetate / 0.5 h / Cooling with ice; Large scale 2.2: 6.5 h / 20 - 75 °C / Cooling with ice; Large scale 3.1: hydrogenchloride / water; ethanol / 8 h / Reflux; Large scale 4.1: hydrogenchloride; sodium nitrite / water / 2 h / -5 - 0 °C / Large scale 4.2: 3 h / 60 °C / Large scale 5.1: potassium tert-butylate / tetrahydrofuran / 1 h / 0 - 10 °C / Inert atmosphere; Large scale 6.1: n-butyllithium / tetrahydrofuran; toluene; hexane / 1 h / -78 °C / Inert atmosphere; Large scale 6.2: 3 h / -78 °C / Large scale 6.3: 10 h / 0 - 40 °C / Large scale View Scheme

4-bromoacetanilide (103-88-8) → (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1279691-36-9)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: ethyl acetate / 0.5 h / Cooling with ice; Large scale 1.2: 6.5 h / 20 - 75 °C / Cooling with ice; Large scale 2.1: hydrogenchloride / water; ethanol / 8 h / Reflux; Large scale 3.1: hydrogenchloride; sodium nitrite / water / 2 h / -5 - 0 °C / Large scale 3.2: 3 h / 60 °C / Large scale 4.1: potassium tert-butylate / tetrahydrofuran / 1 h / 0 - 10 °C / Inert atmosphere; 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: 10 h / 0 - 40 °C / Large scale View Scheme

p-fluorotoluene (352-32-9) → (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1279691-36-9)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: N-Bromosuccinimide; dibenzoyl peroxide / chloroform / 6 h / 70 °C / Large scale 2.1: ethyl acetate / 0.5 h / Cooling with ice; Large scale 2.2: 6.5 h / 20 - 75 °C / Cooling with ice; Large scale 3.1: hydrogenchloride / water; ethanol / 8 h / Reflux; Large scale 4.1: hydrogenchloride; sodium nitrite / water / 2 h / -5 - 0 °C / Large scale 4.2: 3 h / 60 °C / Large scale 5.1: potassium tert-butylate / tetrahydrofuran / 1 h / 0 - 10 °C / Inert atmosphere; Large scale 6.1: n-butyllithium / tetrahydrofuran; toluene; hexane / 1 h / -78 °C / Inert atmosphere; Large scale 6.2: 3 h / -78 °C / Large scale 6.3: 10 h / 0 - 40 °C / Large scale View Scheme

4-Fluorobenzyl bromide (459-46-1) → (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1279691-36-9)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: ethyl acetate / 0.5 h / Cooling with ice; Large scale 1.2: 6.5 h / 20 - 75 °C / Cooling with ice; Large scale 2.1: hydrogenchloride / water; ethanol / 8 h / Reflux; Large scale 3.1: hydrogenchloride; sodium nitrite / water / 2 h / -5 - 0 °C / Large scale 3.2: 3 h / 60 °C / Large scale 4.1: potassium tert-butylate / tetrahydrofuran / 1 h / 0 - 10 °C / Inert atmosphere; 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: 10 h / 0 - 40 °C / Large scale View Scheme

N-[4-bromo-2-(4-fluorobenzyl)]acetanilide → (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1279691-36-9)

Conditions

Yield

Multi-step reaction with 4 steps 1.1: hydrogenchloride / water; ethanol / 8 h / Reflux; Large scale 2.1: hydrogenchloride; sodium nitrite / water / 2 h / -5 - 0 °C / Large scale 2.2: 3 h / 60 °C / Large scale 3.1: potassium tert-butylate / tetrahydrofuran / 1 h / 0 - 10 °C / Inert atmosphere; Large scale 4.1: n-butyllithium / tetrahydrofuran; toluene; hexane / 1 h / -78 °C / Inert atmosphere; Large scale 4.2: 3 h / -78 °C / Large scale 4.3: 10 h / 0 - 40 °C / Large scale View Scheme

4-bromo-2-(4-fluorobenzyl)aniline → (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1279691-36-9)

Conditions

Yield

Multi-step reaction with 3 steps 1.1: hydrogenchloride; sodium nitrite / water / 2 h / -5 - 0 °C / Large scale 1.2: 3 h / 60 °C / Large scale 2.1: potassium tert-butylate / tetrahydrofuran / 1 h / 0 - 10 °C / Inert atmosphere; Large scale 3.1: n-butyllithium / tetrahydrofuran; toluene; hexane / 1 h / -78 °C / Inert atmosphere; Large scale 3.2: 3 h / -78 °C / Large scale 3.3: 10 h / 0 - 40 °C / Large scale View Scheme

4-bromo-2-(4-fluorobenzyl)chlorobenzene → (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1279691-36-9)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: potassium tert-butylate / tetrahydrofuran / 1 h / 0 - 10 °C / Inert atmosphere; Large scale 2.1: n-butyllithium / tetrahydrofuran; toluene; hexane / 1 h / -78 °C / Inert atmosphere; Large scale 2.2: 3 h / -78 °C / Large scale 2.3: 10 h / 0 - 40 °C / Large scale View Scheme

o-toluidine (95-53-4) → (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1279691-36-9)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: N-Bromosuccinimide / dichloromethane / 10 h / 5 °C / Cooling with ice; Large scale 2.1: hydrogenchloride; sodium nitrite / water / 3 h / -5 - 0 °C / Large scale 2.2: 3 h / 60 °C / Large scale 3.1: N-Bromosuccinimide; dibenzoyl peroxide / chloroform / 4 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 / 3 h / -78 °C / Inert atmosphere; Large scale 5.2: 10 h / 0 - 40 °C / Inert atmosphere; Large scale View Scheme

(S)-3-phenoxytetrahydrofuran → (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1279691-36-9)

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 / 3 h / -78 °C / Inert atmosphere; Large scale 2.2: 10 h / 0 - 40 °C / Inert atmosphere; Large scale View Scheme
Multi-step reaction with 2 steps 1.1: ethyl acetate / 0.5 h / Cooling with ice; Large scale 1.2: 8.5 h / 78 °C / Cooling with ice; Large scale 2.1: n-butyllithium / tetrahydrofuran; toluene / 1 h / -78 °C / Large scale 2.2: 3 h / -78 °C / Large scale 2.3: 10 h / 0 - 40 °C / Large scale View Scheme

4-Bromo-2-methylaniline (583-75-5) → (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1279691-36-9)

Conditions

Yield

Multi-step reaction with 4 steps 1.1: hydrogenchloride; sodium nitrite / water / 3 h / -5 - 0 °C / Large scale 1.2: 3 h / 60 °C / Large scale 2.1: N-Bromosuccinimide; dibenzoyl peroxide / chloroform / 4 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 / 3 h / -78 °C / Inert atmosphere; Large scale 4.2: 10 h / 0 - 40 °C / Inert atmosphere; Large scale View Scheme

2-chloro-5-bromotoluene (54932-72-8) → (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1279691-36-9)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: N-Bromosuccinimide; dibenzoyl peroxide / chloroform / 4 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 / 3 h / -78 °C / Inert atmosphere; Large scale 3.2: 10 h / 0 - 40 °C / Inert atmosphere; Large scale View Scheme

5-Bromo-2-chlorobenzyl bromide (149965-41-3) → (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1279691-36-9)

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 / 3 h / -78 °C / Inert atmosphere; Large scale 2.2: 10 h / 0 - 40 °C / Inert atmosphere; Large scale View Scheme

fluorobenzene (462-06-6) → (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1279691-36-9)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: potassium tert-butylate / tetrahydrofuran; tert-butyl alcohol / 1.5 h / 0 - 10 °C / Inert atmosphere; 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 / 3 h / -78 °C / Inert atmosphere; Large scale 3.2: 10 h / 0 - 40 °C / Inert atmosphere; Large scale View Scheme
Multi-step reaction with 3 steps 1.1: potassium tert-butylate / tetrahydrofuran / 1 h / 0 - 10 °C / Inert atmosphere; Large scale 2.1: ethyl acetate / 0.5 h / Cooling with ice; Large scale 2.2: 8.5 h / 78 °C / Cooling with ice; Large scale 3.1: n-butyllithium / tetrahydrofuran; toluene / 1 h / -78 °C / Large scale 3.2: 3 h / -78 °C / Large scale 3.3: 10 h / 0 - 40 °C / Large scale View Scheme

4-bromo-1-chloro-2-(chloromethyl)benzene → (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1279691-36-9)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: ethyl acetate / 0.5 h / Cooling with ice; Large scale 1.2: 8.5 h / 78 °C / Cooling with ice; Large scale 2.1: n-butyllithium / tetrahydrofuran; toluene / 1 h / -78 °C / Large scale 2.2: 3 h / -78 °C / Large scale 2.3: 10 h / 0 - 40 °C / Large scale View Scheme

(2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1279691-36-9) → 1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-D-glucopyranoside (1417573-74-0)

Conditions	Yield
With triethylsilane; aluminum (III) chloride In dichloromethane; acetonitrile at 13 - 20℃; for 5h; Inert atmosphere; Cooling with ice;	96.25%

(2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1279691-36-9) + acetic anhydride (108-24-7) → (2S,3R,4S,5R,6R)-6-(acetoxymethyl)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triyl triacetate

Conditions	Yield
With dmap; triethylamine In tetrahydrofuran	94%

(2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1279691-36-9) + benzyl bromide (100-39-0) → (2S,3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-2-methoxytetrahydro-2H-pyran

Conditions	Yield
With sodium hydride In tetrahydrofuran; N,N-dimethyl-formamide	87%

(2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1279691-36-9) → empagliflozin (864070-44-0)

Conditions	Yield
With triethylsilane; aluminum (III) chloride In dichloromethane; acetonitrile	82.5%
With triethylsilane; aluminum (III) chloride In dichloromethane; acetonitrile at -5 - 10℃; for 2h; Large scale;	78%
Stage #1: (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol With aluminum (III) chloride In dichloromethane; acetonitrile at 5℃; for 0.5h; Large scale; Stage #2: With triethylsilane In dichloromethane; acetonitrile at 10℃; for 2h; Large scale;	78%

(2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1279691-36-9) + allyl bromide (106-95-6) → (2S,3R,4S,5R,6R)-3,4,5-tris(allyloxy)-6-((allyloxy)methyl)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-2-methoxytetrahydro-2H-pyran

Conditions	Yield
With sodium hydride In tetrahydrofuran; N,N-dimethyl-formamide	82%

(2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1279691-36-9) → (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-trityl triacetate + C31H35ClO11

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium hydride / tetrahydrofuran; N,N-dimethyl-formamide 2.1: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / 0.5 h / 15 - 20 °C 2.2: 90 °C View Scheme
Multi-step reaction with 2 steps 1: triethylamine; dmap / tetrahydrofuran 2: aluminum (III) chloride; triethylsilane / dichloromethane; acetonitrile / 0.5 h / 15 - 20 °C View Scheme

(2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1279691-36-9) → 2,3,4,6-tetra-O-benzyl-1-deoxy-1-((S)-(4-chloro-3-(4-(tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-β-D-glucopyranose + C51H51ClO7

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hydride / tetrahydrofuran; N,N-dimethyl-formamide 2: aluminum (III) chloride; triethylsilane / dichloromethane; acetonitrile / 0.5 h / 15 - 20 °C View Scheme

(2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1279691-36-9) → 1-chloro-4-(2,3,4,6-tetra-O-allyl-D-glucopyranos-1-yl)-2-(4-(S)-tetrahydrofuran-3-yloxy-benzyl)-benzene + C35H43ClO7

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hydride / tetrahydrofuran; N,N-dimethyl-formamide 2: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / 0.5 h / 15 - 20 °C View Scheme

(2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1279691-36-9) → C23H27ClO7

Conditions	Yield
Multi-step reaction with 2 steps 1: boron trifluoride diethyl etherate / water 2: triethylsilane View Scheme

(2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1279691-36-9) → C23H27ClO8

Conditions	Yield
With boron trifluoride diethyl etherate In water

(2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1279691-36-9) → (2R,3R,4R,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium hydride / tetrahydrofuran; N,N-dimethyl-formamide 2.1: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / 0.5 h / 15 - 20 °C 2.2: 90 °C View Scheme

Upstream product

• 67-56-1 methanol 
• 1279691-35-8 (2S,3R,4S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,3,4,5-tetraol 
• 1198-69-2 D-glucono-1,4-lactone 
• 915095-94-2 (3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran 
• 915095-86-2 (2-chloro-5-iodophenyl)(4-fluorophenyl)methanone 
• 281652-58-2 2-chloro-5-iodobenzoylchloride 
• 19094-56-5 2-chloro-5-iodobenzoic acid 
• 915095-87-3 (S)-(2-chloro-5-iodophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone 
• 915095-89-5 (S)-4-bromo-1-chloro-2-(4-tetrahydrofuran-3-yloxy-benzyl)benzene 
• 32469-28-6 (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one 
• 75-75-2 methanesulfonic acid 
• 90-80-2 D-Glucono-1,5-lactone 
• 149965-40-2 5-bromo-2-chlorobenzyl alcohol 
• 89-98-5 2-chloro-benzaldehyde 

Downstream Products

• 864070-44-0 empagliflozin 
• 915095-99-7 (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-trityl triacetate 
• 915095-99-7 C₃₁H₃₅ClO₁₁ 
• 1620758-33-9 (2R,3R,4R,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol 
• 2069942-68-1 (2S,3R,4S,5R,6R)-6-(acetoxymethyl)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triyl triacetate 
• 1417573-74-0 1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-D-glucopyranoside 

Relevant articles and documents

Synthesis, Isolation, Characterization and Suppression of Impurities during Optimization of Empagliflozin (Jardiance)

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Method for preparing intermediates of gliflozin hypoglycemic drugs

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

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.