1210344-57-2

Basic information

• Product Name: PF-04971729
• Synonyms: PF-04971729/PF04971729;1,6-Anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-5-C-(hydroxymethyl)-beta-L-idopyranose;PF 04971729-00;PF-04971729/Ertugliflozin;1,6-Anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-5-C-(hydroxymethyl)-beta-L-idopyranose PF-04971729(Ertugliflozin);Ertugliflozin, >=98%;Ertugliflozin : PF 04971729-00;Leuco methylthioninium
• CAS NO: 1210344-57-2
• Molecular Formula: C₂₂H₂₅ClO₇
• Molecular Weight: 436.88
• Product Categories: API
• Mol File: 1210344-57-2.mol

Chemical Properties

• Boiling Point: 630.5±55.0 °C(Predicted)
• Appearance: /
• Density: 1.455
• Storage Temp.: Sealed in dry,Store in freezer, under -20°C
• Solubility: DMSO (Slightly), Methanol (Slightly)
• PKA: 12.95±0.70(Predicted)
• CAS DataBase Reference: PF-04971729(CAS DataBase Reference)
• NIST Chemistry Reference: PF-04971729(1210344-57-2)
• EPA Substance Registry System: PF-04971729(1210344-57-2)

Safety Data

• Hazardous Substances Data: 1210344-57-2(Hazardous Substances Data)

Synthetic route

C28H35ClO8 → Ertugliflozin (1210344-57-2)

Conditions	Yield
With water; trifluoroacetic acid at 20℃; for 1h;	92%

[(3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-phenyl)methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol → Ertugliflozin (1210344-57-2)

Conditions	Yield
With hydrogenchloride; palladium 10% on activated carbon; hydrogen In tetrahydrofuran; methanol; water at 30℃; for 8h;	91.4%

[(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octane-1-yl]methanol → Ertugliflozin (1210344-57-2)

Conditions	Yield
With hydrogenchloride; palladium 10% on activated carbon; hydrogen In tetrahydrofuran; methanol; water at 20℃; for 3h;	89%
With palladium on activated charcoal; hydrogen In ethanol; ethyl acetate at 20℃; for 6h;	80%
With palladium on activated charcoal; hydrogen In tetrahydrofuran; methanol; 1,2-dichloro-benzene at 25 - 30℃; under 1500.15 - 2625.26 Torr; for 6h;	13.5 g

C50H59ClO8Si → Ertugliflozin (1210344-57-2)

Conditions	Yield
With trifluoroacetic acid In water at 20℃; for 1h;	85%

{(2S,3S)-3,4,5-tris-benzyloxy-5-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6,8-dioxa-bicyclo[3.2.1]oct-1-yl}-methanol (1210763-25-9) → Ertugliflozin (1210344-57-2) + (1S,2S,3S,4S,5S)-5-[4-chloro-3-(4-ethoxybenzyl)phenyl]-1-hydroxymethyl-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol (1210344-58-3)

Conditions	Yield
With formic acid; palladium In tetrahydrofuran; ethanol at 20℃; for 2h;	A 29% B 15%

C28H37ClO7S2 (1233482-00-2) → Ertugliflozin (1210344-57-2)

Conditions	Yield
With trifluoroacetic acid at 23℃; for 96h; stereoselective reaction;	491 mg

(2R,3S,4S)-2,3,4-tris(benzyloxy)-1-(3-((benzyloxy)(4-ethoxyphenyl)methyl)-4-chlorophenyl)-4-(4-((benzyloxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-butan-1-one → Ertugliflozin (1210344-57-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: trifluoroacetic acid; triethylsilane / toluene / 20 °C 2: 5%-palladium/activated carbon; hydrogenchloride; hydrogen / toluene; methanol; water / 18 h / 25 °C / 2585.81 Torr / Inert atmosphere View Scheme

(2S,3S,4R)-2,3,4-tris(benzyloxy)-1-((benzyloxy)-methyl)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6,8-dioxabicyclo[3.2.1]octane (1629222-50-9) → Ertugliflozin (1210344-57-2)

Conditions	Yield
With hydrogenchloride; 5%-palladium/activated carbon; hydrogen In methanol; water; toluene at 25℃; under 2585.81 Torr; for 18h; Inert atmosphere;
With hydrogenchloride; 5%-palladium/activated carbon; hydrogen In methanol; water; toluene at 25℃; under 2585.81 Torr; for 18h;

(1R,2S,3S,4R,5S)-1-(acetoxymethyl)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triyl triacetate (1298086-18-6) → Ertugliflozin (1210344-57-2)

Conditions	Yield
With sodium methylate In methanol at 20℃; for 0.25h;
With sodium methylate In methanol at 20℃; for 3.25h; Inert atmosphere;

(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 oxalate (1431329-06-4) → Ertugliflozin (1210344-57-2)

Conditions

Yield

Multi-step reaction with 4 steps 1.1: sodium hydrogencarbonate / toluene; water / 0.17 h / 20 °C 2.1: n-butyllithium / toluene; 2-methyltetrahydrofuran; hexane / -15 - 20 °C / Inert atmosphere 2.2: 0.17 h / -15 °C / Inert atmosphere 3.1: trifluoroacetic acid; triethylsilane / toluene / 20 °C 4.1: 5%-palladium/activated carbon; hydrogenchloride; hydrogen / toluene; methanol; water / 18 h / 25 °C / 2585.81 Torr / Inert atmosphere View Scheme

(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) → Ertugliflozin (1210344-57-2)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: n-butyllithium / toluene; 2-methyltetrahydrofuran; hexane / -15 - 20 °C / Inert atmosphere 1.2: 0.17 h / -15 °C / Inert atmosphere 2.1: trifluoroacetic acid; triethylsilane / toluene / 20 °C 3.1: 5%-palladium/activated carbon; hydrogenchloride; hydrogen / toluene; methanol; water / 18 h / 25 °C / 2585.81 Torr / Inert atmosphere View Scheme

(2S,3R,4S,5R,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-3,4,5-tris(trimethylsilyloxy)-6-(trimethylsilyloxymethyl)tetrahydropyran-2-ol → Ertugliflozin (1210344-57-2)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: methanesulfonic acid / toluene; tetrahydrofuran; hexane / 25.83 h / -71 - 20 °C / Large scale 2.1: pyridinium p-toluenesulfonate / dichloromethane; water / 8 h / 20 °C / Large scale 3.1: dimethyl sulfoxide; triethylamine; sulfur trioxide pyridine complex / dichloromethane / 3.75 h / 10 - 12 °C / Large scale 4.1: sodium ethanolate; ethanol / 4.08 h / 55 °C / Large scale 4.2: 0.83 h / 55 °C / Large scale 5.1: SiliaBond tosic acid / dichloromethane / 18 h / 20 °C / Large scale View Scheme

C34H59ClO7Si4 (1528636-28-3) → Ertugliflozin (1210344-57-2)

Conditions

Yield

Multi-step reaction with 4 steps 1.1: pyridinium p-toluenesulfonate / dichloromethane; water / 8 h / 20 °C / Large scale 2.1: dimethyl sulfoxide; triethylamine; sulfur trioxide pyridine complex / dichloromethane / 3.75 h / 10 - 12 °C / Large scale 3.1: sodium ethanolate; ethanol / 4.08 h / 55 °C / Large scale 3.2: 0.83 h / 55 °C / Large scale 4.1: SiliaBond tosic acid / dichloromethane / 18 h / 20 °C / Large scale View Scheme

(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) → Ertugliflozin (1210344-57-2)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: 1H-imidazole / dichloromethane / 1 h / 5 - 20 °C / Large scale 2.1: pyridinium p-toluenesulfonate / dichloromethane; water / 8 h / 20 °C / Large scale 3.1: dimethyl sulfoxide; triethylamine; sulfur trioxide pyridine complex / dichloromethane / 3.75 h / 10 - 12 °C / Large scale 4.1: sodium ethanolate; ethanol / 4.08 h / 55 °C / Large scale 4.2: 0.83 h / 55 °C / Large scale 5.1: SiliaBond tosic acid / dichloromethane / 18 h / 20 °C / Large scale View Scheme
Multi-step reaction with 7 steps 1.1: triethylamine / dichloromethane / 10 - 30 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 - 5 °C 2.2: 2 h / 0 - 30 °C 3.1: acetyl chloride; methanol / dichloromethane / 0.5 h / 25 - 30 °C 4.1: oxalyl dichloride; dimethyl sulfoxide / dichloromethane / 2.5 h / -80 - -65 °C 4.2: 2 h / -80 - 30 °C 5.1: potassium hydroxide / N,N-dimethyl-formamide; water / 5 h / 10 - 30 °C 6.1: trifluoroacetic acid / dichloromethane / 5 h / -10 - 30 °C 7.1: palladium on activated charcoal; hydrogen / tetrahydrofuran; methanol; 1,2-dichloro-benzene / 6 h / 25 - 30 °C / 1500.15 - 2625.26 Torr View Scheme
Multi-step reaction with 8 steps 1.1: triethylamine / dichloromethane / 10 - 30 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 - 5 °C 2.2: 2 h / 0 - 30 °C 3.1: acetyl chloride; methanol / dichloromethane / 0.5 h / 25 - 30 °C 4.1: oxalyl dichloride; dimethyl sulfoxide / dichloromethane / 2.5 h / -80 - -65 °C 4.2: 2 h / -80 - 30 °C 5.1: potassium hydroxide / N,N-dimethyl-formamide; water / 8 h / 10 - 30 °C 6.1: sodium tetrahydroborate; methanol / 1 h / 20 - 25 °C 7.1: trifluoroacetic acid / dichloromethane / 5 h / -10 - 30 °C 8.1: palladium on activated charcoal; hydrogen / tetrahydrofuran; methanol; 1,2-dichloro-benzene / 6 h / 25 - 30 °C / 1500.15 - 2625.26 Torr View Scheme

((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 (1528636-29-4) → Ertugliflozin (1210344-57-2)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: dimethyl sulfoxide; triethylamine; sulfur trioxide pyridine complex / dichloromethane / 3.75 h / 10 - 12 °C / Large scale 2.1: sodium ethanolate; ethanol / 4.08 h / 55 °C / Large scale 2.2: 0.83 h / 55 °C / Large scale 3.1: SiliaBond tosic acid / dichloromethane / 18 h / 20 °C / Large scale View Scheme

(2S,3R,4S,5S)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6,6-bis(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1528636-39-6) → Ertugliflozin (1210344-57-2)

Conditions	Yield
With SiliaBond tosic acid In dichloromethane at 20℃; for 18h; Large scale;

(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) → Ertugliflozin (1210344-57-2)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: n-hexyllithium / toluene; tetrahydrofuran; hexane / 1 h / -84 - -74 °C / Large scale 1.2: 2 h / -74 - -15 °C / Large scale 2.1: methanesulfonic acid / toluene; tetrahydrofuran; hexane / 25.83 h / -71 - 20 °C / Large scale 3.1: pyridinium p-toluenesulfonate / dichloromethane; water / 8 h / 20 °C / Large scale 4.1: dimethyl sulfoxide; triethylamine; sulfur trioxide pyridine complex / dichloromethane / 3.75 h / 10 - 12 °C / Large scale 5.1: sodium ethanolate; ethanol / 4.08 h / 55 °C / Large scale 5.2: 0.83 h / 55 °C / Large scale 6.1: SiliaBond tosic acid / dichloromethane / 18 h / 20 °C / Large scale View Scheme
Multi-step reaction with 6 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -75 - -65 °C 1.2: 6 h / -25 - 20 °C 2.1: 1H-imidazole / dichloromethane / 0 - 35 °C 3.1: toluene-4-sulfonic acid; pyridine / water / 0 - 35 °C 4.1: triethylamine; sulfur trioxide pyridine complex; dimethyl sulfoxide / dichloromethane / 0 - 10 °C 5.1: sodium ethanolate / ethanol / 50 - 55 °C 6.1: methanesulfonic acid / dichloromethane / 5 h / 25 - 35 °C View Scheme

4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene (461432-23-5) → Ertugliflozin (1210344-57-2)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: n-hexyllithium / toluene; tetrahydrofuran; hexane / 1 h / -84 - -74 °C / Large scale 1.2: 2 h / -74 - -15 °C / Large scale 2.1: methanesulfonic acid / toluene; tetrahydrofuran; hexane / 25.83 h / -71 - 20 °C / Large scale 3.1: pyridinium p-toluenesulfonate / dichloromethane; water / 8 h / 20 °C / Large scale 4.1: dimethyl sulfoxide; triethylamine; sulfur trioxide pyridine complex / dichloromethane / 3.75 h / 10 - 12 °C / Large scale 5.1: sodium ethanolate; ethanol / 4.08 h / 55 °C / Large scale 5.2: 0.83 h / 55 °C / Large scale 6.1: SiliaBond tosic acid / dichloromethane / 18 h / 20 °C / Large scale View Scheme
Multi-step reaction with 8 steps 1.1: n-butyllithium / tetrahydrofuran; toluene / 1 h / -75 - -60 °C 1.2: 3 h / -75 - -60 °C 1.3: 18 h / -75 - 25 °C 2.1: triethylamine / dichloromethane / 10 - 30 °C 3.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 - 5 °C 3.2: 2 h / 0 - 30 °C 4.1: acetyl chloride; methanol / dichloromethane / 0.5 h / 25 - 30 °C 5.1: oxalyl dichloride; dimethyl sulfoxide / dichloromethane / 2.5 h / -80 - -65 °C 5.2: 2 h / -80 - 30 °C 6.1: potassium hydroxide / N,N-dimethyl-formamide; water / 5 h / 10 - 30 °C 7.1: trifluoroacetic acid / dichloromethane / 5 h / -10 - 30 °C 8.1: palladium on activated charcoal; hydrogen / tetrahydrofuran; methanol; 1,2-dichloro-benzene / 6 h / 25 - 30 °C / 1500.15 - 2625.26 Torr View Scheme
Multi-step reaction with 9 steps 1.1: n-butyllithium / tetrahydrofuran; toluene / 1 h / -75 - -60 °C 1.2: 3 h / -75 - -60 °C 1.3: 18 h / -75 - 25 °C 2.1: triethylamine / dichloromethane / 10 - 30 °C 3.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 - 5 °C 3.2: 2 h / 0 - 30 °C 4.1: acetyl chloride; methanol / dichloromethane / 0.5 h / 25 - 30 °C 5.1: oxalyl dichloride; dimethyl sulfoxide / dichloromethane / 2.5 h / -80 - -65 °C 5.2: 2 h / -80 - 30 °C 6.1: potassium hydroxide / N,N-dimethyl-formamide; water / 8 h / 10 - 30 °C 7.1: sodium tetrahydroborate; methanol / 1 h / 20 - 25 °C 8.1: trifluoroacetic acid / dichloromethane / 5 h / -10 - 30 °C 9.1: palladium on activated charcoal; hydrogen / tetrahydrofuran; methanol; 1,2-dichloro-benzene / 6 h / 25 - 30 °C / 1500.15 - 2625.26 Torr View Scheme

3,4,5-tris[(trimethylsilyl)oxy]-6-{[(trimethylsilyl)oxy]methyl}-tetrahydro-2H-pyran-2-one → Ertugliflozin (1210344-57-2)

Conditions	Yield
Multi-step reaction with 8 steps 1.1: n-butyllithium / tetrahydrofuran; toluene / 1 h / -75 - -60 °C 1.2: 3 h / -75 - -60 °C 1.3: 18 h / -75 - 25 °C 2.1: triethylamine / dichloromethane / 10 - 30 °C 3.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 - 5 °C 3.2: 2 h / 0 - 30 °C 4.1: acetyl chloride; methanol / dichloromethane / 0.5 h / 25 - 30 °C 5.1: oxalyl dichloride; dimethyl sulfoxide / dichloromethane / 2.5 h / -80 - -65 °C 5.2: 2 h / -80 - 30 °C 6.1: potassium hydroxide / N,N-dimethyl-formamide; water / 5 h / 10 - 30 °C 7.1: trifluoroacetic acid / dichloromethane / 5 h / -10 - 30 °C 8.1: palladium on activated charcoal; hydrogen / tetrahydrofuran; methanol; 1,2-dichloro-benzene / 6 h / 25 - 30 °C / 1500.15 - 2625.26 Torr View Scheme
Multi-step reaction with 9 steps 1.1: n-butyllithium / tetrahydrofuran; toluene / 1 h / -75 - -60 °C 1.2: 3 h / -75 - -60 °C 1.3: 18 h / -75 - 25 °C 2.1: triethylamine / dichloromethane / 10 - 30 °C 3.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 - 5 °C 3.2: 2 h / 0 - 30 °C 4.1: acetyl chloride; methanol / dichloromethane / 0.5 h / 25 - 30 °C 5.1: oxalyl dichloride; dimethyl sulfoxide / dichloromethane / 2.5 h / -80 - -65 °C 5.2: 2 h / -80 - 30 °C 6.1: potassium hydroxide / N,N-dimethyl-formamide; water / 8 h / 10 - 30 °C 7.1: sodium tetrahydroborate; methanol / 1 h / 20 - 25 °C 8.1: trifluoroacetic acid / dichloromethane / 5 h / -10 - 30 °C 9.1: palladium on activated charcoal; hydrogen / tetrahydrofuran; methanol; 1,2-dichloro-benzene / 6 h / 25 - 30 °C / 1500.15 - 2625.26 Torr View Scheme

5-bromo-2-chlorobenzoic acid (21739-92-4) → Ertugliflozin (1210344-57-2)

Conditions	Yield
Multi-step reaction with 10 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 4.1: triethylamine / dichloromethane / 10 - 30 °C 5.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 - 5 °C 5.2: 2 h / 0 - 30 °C 6.1: acetyl chloride; methanol / dichloromethane / 0.5 h / 25 - 30 °C 7.1: oxalyl dichloride; dimethyl sulfoxide / dichloromethane / 2.5 h / -80 - -65 °C 7.2: 2 h / -80 - 30 °C 8.1: potassium hydroxide / N,N-dimethyl-formamide; water / 5 h / 10 - 30 °C 9.1: trifluoroacetic acid / dichloromethane / 5 h / -10 - 30 °C 10.1: palladium on activated charcoal; hydrogen / tetrahydrofuran; methanol; 1,2-dichloro-benzene / 6 h / 25 - 30 °C / 1500.15 - 2625.26 Torr View Scheme
Multi-step reaction with 11 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 4.1: triethylamine / dichloromethane / 10 - 30 °C 5.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 - 5 °C 5.2: 2 h / 0 - 30 °C 6.1: acetyl chloride; methanol / dichloromethane / 0.5 h / 25 - 30 °C 7.1: oxalyl dichloride; dimethyl sulfoxide / dichloromethane / 2.5 h / -80 - -65 °C 7.2: 2 h / -80 - 30 °C 8.1: potassium hydroxide / N,N-dimethyl-formamide; water / 8 h / 10 - 30 °C 9.1: sodium tetrahydroborate; methanol / 1 h / 20 - 25 °C 10.1: trifluoroacetic acid / dichloromethane / 5 h / -10 - 30 °C 11.1: palladium on activated charcoal; hydrogen / tetrahydrofuran; methanol; 1,2-dichloro-benzene / 6 h / 25 - 30 °C / 1500.15 - 2625.26 Torr View Scheme
Multi-step reaction with 6 steps 1.1: N,N-dimethyl-formamide / N,N-dimethyl-formamide / 12 h / 20 °C 2.1: aluminum (III) chloride / dichloromethane / 1 h / -20 - 20 °C 3.1: triethylsilane; boron trifluoride diethyl etherate / 1,2-dichloro-ethane; acetonitrile / 3 h / 0 - 50 °C 4.1: n-butyllithium / tetrahydrofuran; hexane / 0.75 h / -78 °C 4.2: 48 h / -78 - 20 °C 5.1: osmium(VIII) oxide; 4-methylmorpholine N-oxide; citric acid / water; acetone / 12 h / 20 °C 6.1: trifluoroacetic acid / water / 1 h / 20 °C View Scheme
Multi-step reaction with 7 steps 1.1: N,N-dimethyl-formamide / N,N-dimethyl-formamide / 12 h / 20 °C 2.1: aluminum (III) chloride / dichloromethane / 1 h / -20 - 20 °C 3.1: triethylsilane; boron trifluoride diethyl etherate / 1,2-dichloro-ethane; acetonitrile / 3 h / 0 - 50 °C 4.1: magnesium; methyl iodide / tetrahydrofuran / 1 h / Reflux 4.2: 3 h / -20 - 20 °C 5.1: lithium diisopropyl amide / tetrahydrofuran; hexane / 0.25 h / -78 °C 5.2: 13.25 h / -78 - 20 °C 6.1: osmium(VIII) oxide; 4-methylmorpholine N-oxide; citric acid / water; acetone / 12 h / 20 °C 7.1: trifluoroacetic acid / water / 1 h / 20 °C View Scheme
Multi-step reaction with 8 steps 1.1: N,N-dimethyl-formamide / N,N-dimethyl-formamide / 12 h / 20 °C 2.1: aluminum (III) chloride / dichloromethane / 1 h / -20 - 20 °C 3.1: triethylsilane; boron trifluoride diethyl etherate / 1,2-dichloro-ethane; acetonitrile / 3 h / 0 - 50 °C 4.1: n-butyllithium / tetrahydrofuran; hexane / 0.75 h / -78 °C 4.2: 3 h / -78 °C 5.1: acetonitrile / 12 h / Reflux 5.2: 3 h / 20 °C 6.1: toluene / 12 h / Reflux 7.1: osmium(VIII) oxide; 4-methylmorpholine N-oxide; citric acid / water; acetone / 12 h / 20 °C 8.1: trifluoroacetic acid / water / 1 h / 20 °C View Scheme

Phenetole (103-73-1) → Ertugliflozin (1210344-57-2)

Conditions	Yield
Multi-step reaction with 10 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 4.1: triethylamine / dichloromethane / 10 - 30 °C 5.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 - 5 °C 5.2: 2 h / 0 - 30 °C 6.1: acetyl chloride; methanol / dichloromethane / 0.5 h / 25 - 30 °C 7.1: oxalyl dichloride; dimethyl sulfoxide / dichloromethane / 2.5 h / -80 - -65 °C 7.2: 2 h / -80 - 30 °C 8.1: potassium hydroxide / N,N-dimethyl-formamide; water / 5 h / 10 - 30 °C 9.1: trifluoroacetic acid / dichloromethane / 5 h / -10 - 30 °C 10.1: palladium on activated charcoal; hydrogen / tetrahydrofuran; methanol; 1,2-dichloro-benzene / 6 h / 25 - 30 °C / 1500.15 - 2625.26 Torr View Scheme
Multi-step reaction with 11 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 4.1: triethylamine / dichloromethane / 10 - 30 °C 5.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 - 5 °C 5.2: 2 h / 0 - 30 °C 6.1: acetyl chloride; methanol / dichloromethane / 0.5 h / 25 - 30 °C 7.1: oxalyl dichloride; dimethyl sulfoxide / dichloromethane / 2.5 h / -80 - -65 °C 7.2: 2 h / -80 - 30 °C 8.1: potassium hydroxide / N,N-dimethyl-formamide; water / 8 h / 10 - 30 °C 9.1: sodium tetrahydroborate; methanol / 1 h / 20 - 25 °C 10.1: trifluoroacetic acid / dichloromethane / 5 h / -10 - 30 °C 11.1: palladium on activated charcoal; hydrogen / tetrahydrofuran; methanol; 1,2-dichloro-benzene / 6 h / 25 - 30 °C / 1500.15 - 2625.26 Torr View Scheme
Multi-step reaction with 5 steps 1.1: aluminum (III) chloride / dichloromethane / 1 h / -20 - 20 °C 2.1: triethylsilane; boron trifluoride diethyl etherate / 1,2-dichloro-ethane; acetonitrile / 3 h / 0 - 50 °C 3.1: n-butyllithium / tetrahydrofuran; hexane / 0.75 h / -78 °C 3.2: 48 h / -78 - 20 °C 4.1: osmium(VIII) oxide; 4-methylmorpholine N-oxide; citric acid / water; acetone / 12 h / 20 °C 5.1: trifluoroacetic acid / water / 1 h / 20 °C View Scheme
Multi-step reaction with 6 steps 1.1: aluminum (III) chloride / dichloromethane / 1 h / -20 - 20 °C 2.1: triethylsilane; boron trifluoride diethyl etherate / 1,2-dichloro-ethane; acetonitrile / 3 h / 0 - 50 °C 3.1: magnesium; methyl iodide / tetrahydrofuran / 1 h / Reflux 3.2: 3 h / -20 - 20 °C 4.1: lithium diisopropyl amide / tetrahydrofuran; hexane / 0.25 h / -78 °C 4.2: 13.25 h / -78 - 20 °C 5.1: osmium(VIII) oxide; 4-methylmorpholine N-oxide; citric acid / water; acetone / 12 h / 20 °C 6.1: trifluoroacetic acid / water / 1 h / 20 °C View Scheme
Multi-step reaction with 7 steps 1.1: aluminum (III) chloride / dichloromethane / 1 h / -20 - 20 °C 2.1: triethylsilane; boron trifluoride diethyl etherate / 1,2-dichloro-ethane; acetonitrile / 3 h / 0 - 50 °C 3.1: n-butyllithium / tetrahydrofuran; hexane / 0.75 h / -78 °C 3.2: 3 h / -78 °C 4.1: acetonitrile / 12 h / Reflux 4.2: 3 h / 20 °C 5.1: toluene / 12 h / Reflux 6.1: osmium(VIII) oxide; 4-methylmorpholine N-oxide; citric acid / water; acetone / 12 h / 20 °C 7.1: trifluoroacetic acid / water / 1 h / 20 °C View Scheme

(5-bromo-2-chlorophenyl)(4-ethyloxyphenyl)methanone (461432-22-4) → Ertugliflozin (1210344-57-2)

Conditions	Yield
Multi-step reaction with 10 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 3.1: triethylamine / dichloromethane / 10 - 30 °C 4.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 - 5 °C 4.2: 2 h / 0 - 30 °C 5.1: acetyl chloride; methanol / dichloromethane / 0.5 h / 25 - 30 °C 6.1: oxalyl dichloride; dimethyl sulfoxide / dichloromethane / 2.5 h / -80 - -65 °C 6.2: 2 h / -80 - 30 °C 7.1: potassium hydroxide / N,N-dimethyl-formamide; water / 8 h / 10 - 30 °C 8.1: sodium tetrahydroborate; methanol / 1 h / 20 - 25 °C 9.1: trifluoroacetic acid / dichloromethane / 5 h / -10 - 30 °C 10.1: palladium on activated charcoal; hydrogen / tetrahydrofuran; methanol; 1,2-dichloro-benzene / 6 h / 25 - 30 °C / 1500.15 - 2625.26 Torr View Scheme
Multi-step reaction with 9 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 3.1: triethylamine / dichloromethane / 10 - 30 °C 4.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 - 5 °C 4.2: 2 h / 0 - 30 °C 5.1: acetyl chloride; methanol / dichloromethane / 0.5 h / 25 - 30 °C 6.1: oxalyl dichloride; dimethyl sulfoxide / dichloromethane / 2.5 h / -80 - -65 °C 6.2: 2 h / -80 - 30 °C 7.1: potassium hydroxide / N,N-dimethyl-formamide; water / 5 h / 10 - 30 °C 8.1: trifluoroacetic acid / dichloromethane / 5 h / -10 - 30 °C 9.1: palladium on activated charcoal; hydrogen / tetrahydrofuran; methanol; 1,2-dichloro-benzene / 6 h / 25 - 30 °C / 1500.15 - 2625.26 Torr View Scheme
Multi-step reaction with 4 steps 1.1: triethylsilane; boron trifluoride diethyl etherate / 1,2-dichloro-ethane; acetonitrile / 3 h / 0 - 50 °C 2.1: n-butyllithium / tetrahydrofuran; hexane / 0.75 h / -78 °C 2.2: 48 h / -78 - 20 °C 3.1: osmium(VIII) oxide; 4-methylmorpholine N-oxide; citric acid / water; acetone / 12 h / 20 °C 4.1: trifluoroacetic acid / water / 1 h / 20 °C View Scheme
Multi-step reaction with 5 steps 1.1: triethylsilane; boron trifluoride diethyl etherate / 1,2-dichloro-ethane; acetonitrile / 3 h / 0 - 50 °C 2.1: magnesium; methyl iodide / tetrahydrofuran / 1 h / Reflux 2.2: 3 h / -20 - 20 °C 3.1: lithium diisopropyl amide / tetrahydrofuran; hexane / 0.25 h / -78 °C 3.2: 13.25 h / -78 - 20 °C 4.1: osmium(VIII) oxide; 4-methylmorpholine N-oxide; citric acid / water; acetone / 12 h / 20 °C 5.1: trifluoroacetic acid / water / 1 h / 20 °C View Scheme
Multi-step reaction with 6 steps 1.1: triethylsilane; boron trifluoride diethyl etherate / 1,2-dichloro-ethane; acetonitrile / 3 h / 0 - 50 °C 2.1: n-butyllithium / tetrahydrofuran; hexane / 0.75 h / -78 °C 2.2: 3 h / -78 °C 3.1: acetonitrile / 12 h / Reflux 3.2: 3 h / 20 °C 4.1: toluene / 12 h / Reflux 5.1: osmium(VIII) oxide; 4-methylmorpholine N-oxide; citric acid / water; acetone / 12 h / 20 °C 6.1: trifluoroacetic acid / water / 1 h / 20 °C View Scheme

(2S,3R,4S,5S,6R)-6-[(tert-butyl(dimethyl)silyl)oxymethyl]-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol → Ertugliflozin (1210344-57-2)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 - 5 °C 1.2: 2 h / 0 - 30 °C 2.1: acetyl chloride; methanol / dichloromethane / 0.5 h / 25 - 30 °C 3.1: oxalyl dichloride; dimethyl sulfoxide / dichloromethane / 2.5 h / -80 - -65 °C 3.2: 2 h / -80 - 30 °C 4.1: potassium hydroxide / N,N-dimethyl-formamide; water / 5 h / 10 - 30 °C 5.1: trifluoroacetic acid / dichloromethane / 5 h / -10 - 30 °C 6.1: palladium on activated charcoal; hydrogen / tetrahydrofuran; methanol; 1,2-dichloro-benzene / 6 h / 25 - 30 °C / 1500.15 - 2625.26 Torr View Scheme
Multi-step reaction with 7 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 - 5 °C 1.2: 2 h / 0 - 30 °C 2.1: acetyl chloride; methanol / dichloromethane / 0.5 h / 25 - 30 °C 3.1: oxalyl dichloride; dimethyl sulfoxide / dichloromethane / 2.5 h / -80 - -65 °C 3.2: 2 h / -80 - 30 °C 4.1: potassium hydroxide / N,N-dimethyl-formamide; water / 8 h / 10 - 30 °C 5.1: sodium tetrahydroborate; methanol / 1 h / 20 - 25 °C 6.1: trifluoroacetic acid / dichloromethane / 5 h / -10 - 30 °C 7.1: palladium on activated charcoal; hydrogen / tetrahydrofuran; methanol; 1,2-dichloro-benzene / 6 h / 25 - 30 °C / 1500.15 - 2625.26 Torr View Scheme

tert-butyl-dimethyl-[[(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxyl]silane → Ertugliflozin (1210344-57-2)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: acetyl chloride; methanol / dichloromethane / 0.5 h / 25 - 30 °C 2.1: oxalyl dichloride; dimethyl sulfoxide / dichloromethane / 2.5 h / -80 - -65 °C 2.2: 2 h / -80 - 30 °C 3.1: potassium hydroxide / N,N-dimethyl-formamide; water / 5 h / 10 - 30 °C 4.1: trifluoroacetic acid / dichloromethane / 5 h / -10 - 30 °C 5.1: palladium on activated charcoal; hydrogen / tetrahydrofuran; methanol; 1,2-dichloro-benzene / 6 h / 25 - 30 °C / 1500.15 - 2625.26 Torr View Scheme
Multi-step reaction with 6 steps 1.1: acetyl chloride; methanol / dichloromethane / 0.5 h / 25 - 30 °C 2.1: oxalyl dichloride; dimethyl sulfoxide / dichloromethane / 2.5 h / -80 - -65 °C 2.2: 2 h / -80 - 30 °C 3.1: potassium hydroxide / N,N-dimethyl-formamide; water / 8 h / 10 - 30 °C 4.1: sodium tetrahydroborate; methanol / 1 h / 20 - 25 °C 5.1: trifluoroacetic acid / dichloromethane / 5 h / -10 - 30 °C 6.1: palladium on activated charcoal; hydrogen / tetrahydrofuran; methanol; 1,2-dichloro-benzene / 6 h / 25 - 30 °C / 1500.15 - 2625.26 Torr View Scheme

[(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methanol → Ertugliflozin (1210344-57-2)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: oxalyl dichloride; dimethyl sulfoxide / dichloromethane / 2.5 h / -80 - -65 °C 1.2: 2 h / -80 - 30 °C 2.1: potassium hydroxide / N,N-dimethyl-formamide; water / 5 h / 10 - 30 °C 3.1: trifluoroacetic acid / dichloromethane / 5 h / -10 - 30 °C 4.1: palladium on activated charcoal; hydrogen / tetrahydrofuran; methanol; 1,2-dichloro-benzene / 6 h / 25 - 30 °C / 1500.15 - 2625.26 Torr View Scheme
Multi-step reaction with 5 steps 1.1: oxalyl dichloride; dimethyl sulfoxide / dichloromethane / 2.5 h / -80 - -65 °C 1.2: 2 h / -80 - 30 °C 2.1: potassium hydroxide / N,N-dimethyl-formamide; water / 8 h / 10 - 30 °C 3.1: sodium tetrahydroborate; methanol / 1 h / 20 - 25 °C 4.1: trifluoroacetic acid / dichloromethane / 5 h / -10 - 30 °C 5.1: palladium on activated charcoal; hydrogen / tetrahydrofuran; methanol; 1,2-dichloro-benzene / 6 h / 25 - 30 °C / 1500.15 - 2625.26 Torr View Scheme

3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-one → Ertugliflozin (1210344-57-2)

Conditions	Yield
Multi-step reaction with 10 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 3.1: triethylamine / dichloromethane / 10 - 30 °C 4.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 - 5 °C 4.2: 2 h / 0 - 30 °C 5.1: acetyl chloride; methanol / dichloromethane / 0.5 h / 25 - 30 °C 6.1: oxalyl dichloride; dimethyl sulfoxide / dichloromethane / 2.5 h / -80 - -65 °C 6.2: 2 h / -80 - 30 °C 7.1: potassium hydroxide / N,N-dimethyl-formamide; water / 8 h / 10 - 30 °C 8.1: sodium tetrahydroborate; methanol / 1 h / 20 - 25 °C 9.1: trifluoroacetic acid / dichloromethane / 5 h / -10 - 30 °C 10.1: palladium on activated charcoal; hydrogen / tetrahydrofuran; methanol; 1,2-dichloro-benzene / 6 h / 25 - 30 °C / 1500.15 - 2625.26 Torr View Scheme
Multi-step reaction with 9 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 3.1: triethylamine / dichloromethane / 10 - 30 °C 4.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 - 5 °C 4.2: 2 h / 0 - 30 °C 5.1: acetyl chloride; methanol / dichloromethane / 0.5 h / 25 - 30 °C 6.1: oxalyl dichloride; dimethyl sulfoxide / dichloromethane / 2.5 h / -80 - -65 °C 6.2: 2 h / -80 - 30 °C 7.1: potassium hydroxide / N,N-dimethyl-formamide; water / 5 h / 10 - 30 °C 8.1: trifluoroacetic acid / dichloromethane / 5 h / -10 - 30 °C 9.1: palladium on activated charcoal; hydrogen / tetrahydrofuran; methanol; 1,2-dichloro-benzene / 6 h / 25 - 30 °C / 1500.15 - 2625.26 Torr View Scheme

(2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde → Ertugliflozin (1210344-57-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: potassium hydroxide / N,N-dimethyl-formamide; water / 5 h / 10 - 30 °C 2: trifluoroacetic acid / dichloromethane / 5 h / -10 - 30 °C 3: palladium on activated charcoal; hydrogen / tetrahydrofuran; methanol; 1,2-dichloro-benzene / 6 h / 25 - 30 °C / 1500.15 - 2625.26 Torr View Scheme
Multi-step reaction with 4 steps 1: potassium hydroxide / N,N-dimethyl-formamide; water / 8 h / 10 - 30 °C 2: sodium tetrahydroborate; methanol / 1 h / 20 - 25 °C 3: trifluoroacetic acid / dichloromethane / 5 h / -10 - 30 °C 4: palladium on activated charcoal; hydrogen / tetrahydrofuran; methanol; 1,2-dichloro-benzene / 6 h / 25 - 30 °C / 1500.15 - 2625.26 Torr View Scheme

methyl 2,3,4-tri-O-benzyl-1-C-[4-chloro-3-(4-ethoxybenzyl)phenyl]-5-(hydroxymethyl)-α-D-gluco-hexodialdo-1,5-pyranoside → Ertugliflozin (1210344-57-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium tetrahydroborate; methanol / 1 h / 20 - 25 °C 2: trifluoroacetic acid / dichloromethane / 5 h / -10 - 30 °C 3: palladium on activated charcoal; hydrogen / tetrahydrofuran; methanol; 1,2-dichloro-benzene / 6 h / 25 - 30 °C / 1500.15 - 2625.26 Torr View Scheme

(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 → Ertugliflozin (1210344-57-2)

Conditions	Yield
With 5%-palladium/activated carbon; hydrogen; acetic acid In methanol at 40 - 50℃; under 1500.15 Torr;

C42H57ClO11 → Ertugliflozin (1210344-57-2)

Conditions	Yield
With sodium ethanolate In ethanol at 30 - 35℃;

Ertugliflozin (1210344-57-2) + benzaldehyde dimethyl acetal (1125-88-8) → (4aS,7S,8R,9R,9aS)-7-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2-phenylhexahydro-4a,7-epoxy[1,3]dioxino[5,4-c]oxepine-8,9-diol

Conditions	Yield
With toluene-4-sulfonic acid In acetonitrile at 20 - 30℃; for 0.5h; Inert atmosphere;	100%

Ertugliflozin (1210344-57-2) + acetic anhydride (108-24-7) → (1R,2S,3S,4R,5S)-1-(acetoxymethyl)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triyl triacetate (1298086-18-6)

Conditions	Yield
With pyridine In toluene at 5 - 20℃; for 24.25h; Inert atmosphere;	89%
With pyridine In toluene at 5 - 20℃; for 24.25h;	5.4%

Ertugliflozin (1210344-57-2) + L-Pyroglutamic acid (98-79-3) → (1S,2S,3S,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol (1:1) compound with (S)-5-oxopyrrolidine-2-carboxylic acid (1210344-83-4)

Conditions	Yield
Stage #1: Ertugliflozin In methanol; water; isopropyl alcohol at 40 - 60℃; under 30 Torr; Stage #2: L-Pyroglutamic acid In methanol; water; isopropyl alcohol at 40 - 80℃;	85.3%
In water; isopropyl alcohol at 40 - 80℃; for 10h; Inert atmosphere;	85%
In ethanol; water at 75 - 80℃;	78%
In water at 25 - 30℃; for 2.5h; Solvent;	0.472 g
In acetonitrile at 25 - 30℃; for 0.25h;	1.1 g

Ertugliflozin (1210344-57-2) + benzaldehyde dimethyl acetal (1125-88-8) → (2R,4aS,7S,8R,9R,9aS)-7-[4-chloro-3-(4-ethoxybenzyl)phenyl]-2-phenyltetrahydro-4a,7-epoxy[1,3]dioxino[5,4-c]oxepine-8,9(4H,5H)-diol

Conditions	Yield
With toluene-4-sulfonic acid In N,N-dimethyl-formamide at 80℃; for 16h;	84%

Ertugliflozin (1210344-57-2) + acetic anhydride (108-24-7) → [(1R,2S,3S,4R,5S)-2,3,4-triacetoxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octane-1-yl]acetic acid methyl ester

Conditions	Yield
With pyridine; dmap In dichloromethane at 20℃; for 3h;	82%

Ertugliflozin (1210344-57-2) + acetic anhydride (108-24-7) → ((1R,2S,3S,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl)-phenyl)-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2.1]octan-1-yl)methyl acetate (1298086-20-0)

Conditions	Yield
With pyridine In toluene at -10 - 20℃; for 8.28333h;	79.7%
With pyridine In toluene at -10 - 20℃; for 19.1h; Inert atmosphere;	19.2 g

Ertugliflozin (1210344-57-2) + 4-nitro-benzoyl chloride (122-04-3) → C50H37ClN4O19 (1292821-53-4)

Conditions	Yield
With dmap; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0 - 60℃;	73%

Ertugliflozin (1210344-57-2) → methyl (2S,3S,4S,5R,6R)-3,4,5-tris(acetyloxy)-6-{[(1S,2S,3S,4R,5S)-4-(acetyloxy)-5-[4-chloro-3-(4-ethoxybenzyl)phenyl]-2-hydroxy-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]oct-3-yl]oxy}tetrahydro-2H-pyran-2-carboxylate

Conditions	Yield
Multi-step reaction with 3 steps 1.1: toluene-4-sulfonic acid / N,N-dimethyl-formamide / 16 h / 80 °C 2.1: trimethylsilyl trifluoromethanesulfonate / dichloromethane / 2 h / -20 - -10 °C / Molecular sieve 2.2: 72 h / 23 °C 3.1: trifluoroacetic acid / dichloromethane; water / 19 h / 23 °C View Scheme

Ertugliflozin (1210344-57-2) → C28H32ClO13(1-)*Na(1+)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: toluene-4-sulfonic acid / N,N-dimethyl-formamide / 16 h / 80 °C 2.1: trimethylsilyl trifluoromethanesulfonate / dichloromethane / 2 h / -20 - -10 °C / Molecular sieve 2.2: 72 h / 23 °C 3.1: trifluoroacetic acid / dichloromethane; water / 19 h / 23 °C 4.1: sodium hydroxide / water; methanol / 16 h / 23 °C View Scheme

Ertugliflozin (1210344-57-2) + benzaldehyde dimethyl acetal (1125-88-8) → (2R,4aS,7S,8R,9S,9aS)-8-(acetyloxy)-7-[4-chloro-3-(4-ethoxybenzyl)phenyl]-2-phenyltetrahydro-4a,7-epoxy[1,3]dioxino[5,4-c]oxepin-9(4H,5H)-yl methyl 2,3,4-tri-O-acetyl-beta-D-glucopyranosiduronate

Conditions	Yield
Multi-step reaction with 2 steps 1.1: toluene-4-sulfonic acid / N,N-dimethyl-formamide / 16 h / 80 °C 2.1: trimethylsilyl trifluoromethanesulfonate / dichloromethane / 2 h / -20 - -10 °C / Molecular sieve 2.2: 72 h / 23 °C View Scheme

Ertugliflozin (1210344-57-2) + L-Pyroglutamic acid (98-79-3) → (1R,2S,3S,4R,5R)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol L-pyroglutamic acid

Conditions	Yield
With water In isopropyl alcohol at 20 - 55℃; for 3h; Large scale;	9.59 kg

Ertugliflozin (1210344-57-2) → (1S,2S,3S,4R,5S)-3,4-dibenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octan-2-ol

Conditions	Yield
Multi-step reaction with 3 steps 1.1: toluene-4-sulfonic acid / acetonitrile / 0.5 h / 20 - 30 °C / Inert atmosphere 2.1: sodium hydride / tetrahydrofuran; mineral oil / 1.5 h / 0 - 30 °C / Inert atmosphere 2.2: 12 h / 0 - 30 °C / Inert atmosphere 3.1: toluene-4-sulfonic acid / acetonitrile / 12 h / 20 - 30 °C / Inert atmosphere View Scheme

Upstream product

• 1210763-25-9 {(2S,3S)-3,4,5-tris-benzyloxy-5-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6,8-dioxa-bicyclo[3.2.1]oct-1-yl}-methanol 
• 1233482-00-2 C₂₈H₃₇ClO₇S₂ 
• 1629222-50-9 (2S,3S,4R)-2,3,4-tris(benzyloxy)-1-((benzyloxy)-methyl)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6,8-dioxabicyclo[3.2.1]octane 
• 1298086-18-6 (1R,2S,3S,4R,5S)-1-(acetoxymethyl)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triyl triacetate 
• 1431329-06-4 (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 oxalate 
• 1431329-05-3 (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 
• 1528636-28-3 C₃₄H₅₉ClO₇Si₄ 
• 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 
• 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 
• 21739-92-4 5-bromo-2-chlorobenzoic acid 
• 103-73-1 Phenetole 
• 461432-22-4 (5-bromo-2-chlorophenyl)(4-ethyloxyphenyl)methanone 
• 1335-57-5 3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-one 

Downstream Products

• 1292821-53-4 C₅₀H₃₇ClN₄O₁₉ 
• 1298086-20-0 ((1R,2S,3S,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl)-phenyl)-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2.1]octan-1-yl)methyl acetate 
• 1298086-18-6 (1R,2S,3S,4R,5S)-1-(acetoxymethyl)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triyl triacetate 
• 1210344-83-4 (1S,2S,3S,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol (1:1) compound with (S)-5-oxopyrrolidine-2-carboxylic acid 

Relevant articles and documents

AN IMPROVED PURIFICATION PROCESS FOR THE PREPARATION OF ERTUGLIFLOZIN AND ERTUGLIFLOZIN L-PYROGLUTAMIC ACID CO-CRYSTAL

The present invention relates to an improved purification process for the preparation of Ertugliflozin (I) and its further conversion to Ertugliflozin L-pyroglutamic acid (L-PGA) co-crystal (II).

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).

AMORPHOUS ERTUGLIFLOZIN AND PROCESS FOR ITS PREPARATION

An amorphous form of ertugliflozin and process for its preparation is described. A solid form of ertugliflozin and process for preparation thereof is also described.

A NOVEL PROCESS FOR THE PREPARATION OF SGLT-2 INHIBITORS

The present invention relates to a novel process for the preparation of SGLT-2 inhibitors via addition of a hydroxymethylene group in an open chain intermediate, readily accessible from D-glucose.

Glucopyranosyl derivative and its use in medicine (by machine translation)

The invention relates to a as sodium-dependent glucose transporter (SGLTs) inhibitors of the glucopyranosyl derivative, containing the pharmaceutical composition and its use in medicine, in particular of formula (I) indicated by the glucopyranosyl derivative or its pharmaceutically acceptable salt or all of its stereoisomers, or containing the pharmaceutical composition and said derivative and pharmaceutical composition for the preparation of a medicine for treating diabetes and diabetes related diseases of the use. (by machine translation)

NOVEL POLYMORPHIC FORMS OF ((1S,2S,3S,4R,5S))-2,3,4-(TRIS-BENZYLOXY)-5-(4-CHLORO-3-(4-ETHOXY-BENZYL)PHENYL)-6,8-DIOXA-BICYCLO[3.2.1]OCT-1-YL-METHANOL

The present invention relates to novel polymorph of (( 1 S.2S.3S,4R,5S))-2,3,4-(tris- benzyloxy)-5-(4-chloro-3-(4-ethoxy-benzyl)phenyl)-6,8-dioxa-bicyclo[3.2.1]oct-1 -yl- methanol of formula (I) wherein Bn refers to benzyl. Characterized by X-ray powder diffraction pattern peaks selected form 5.7, 14.0, 15.6, 15.9, 17.3, 18.8, 19.7, 19.8, 23.0 ±0.2° 2θ. and DSC isothermal peak ranging between 99- 103°C. The invention also relates to process for the preparation of said novel crystalline Form designated as Form-G of ((1S,2S,3S,4R,5S))-2,3,4-(tris-benzyloxy)-5-(4-chloro-3-(4-ethoxy- benzyl)phenyl)-6,8-dioxa-bicyclo[3.2.1]oct-1-yl-methanol of formula (I). This compound of Formula (I) is useful as an intermediate in the preparation of Ertugliflozin, which is used in the treatment of type 2 diabetes mellitus.

Studies towards the synthesis of ertugliflozin from L-Arabinose

A new method for the diastereoselective synthesis of enantiomerically pure ertugliflozin was developed. The crucial step involves an aldol condensation between 1-(4-chloro-3-(4-ethoxybenzyl)phenyl)ethanone and (4R,5R)-5-(((tert-butyldimethylsilyl)oxy)methyl)-2,2-dimethyl-5-((trityloxy)methyl)-1,3-dioxolane-4-carbaldehyde, which was prepared from known 2-C-trityloxymethyl-2,3-O-isopropylidene-L-erythrose (easily accessible in three steps from L-arabinose) by standard reduction/oxidation and protection/deprotection manipulations. Dihydroxylation of the aldol condensation product and further global deprotection led to the formation of the target molecule.

Preparation method of sodium-glucose cotransporter 2 inhibitor

The invention discloses a preparation method of a sodium-glucose cotransporter 2 inhibitor. The preparation method specifically relates to a reaction step for converting a compound of a formula III into a compound of a formula II by a 'one-pot method' in a palladium carbon/acid or 1,2-dichlorobenzene catalytic system, wherein the definition of each substituent in the formula II and the formula IIIare the same as that in the description. The method has simple operation and low cost, and is suitable for large-scale production.

PROCESSES FOR THE PREPARATION OF ERTUGLIFLOZIN

The present invention relates to processes for the preparation of ertugliflozni. The present invention also provides compounds of Formula (III), Formula (IV), and Formula (VII), processes for their preparation, and their use for the preparation of ertugliflozin. The processes of the present invention involve protecting the ertugliflozin intermediate compound with a suitable protecting group which provides ertugliflozin having high purity and yield.

Preparation method of ertugliflozin and intermediate of ertugliflozin

The invention provides a synthesis method of ertugliflozin. The route relates to a new intermediate compound 3 and a compound 5, an SGLT-2 inhibitor ertugliflozin is prepared by virtue of the new intermediate compound 3 and the compound 5, and the preparation method is simple in process route, low in cost and applicable to industrial production. (The compound 3 and the compound 5 are described in the specification.).