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
• Article Data: 15

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)

Usage

Uses

Ertugliflozin is a sodium/glucose cotransporter 2 (SGLT2) inhibitor used to treat type 2 diabetes.

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

• 461432-24-6 (3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol 
• 60405-34-7 6-O-benzoyl-2,3:4,5-di-O-isopropylidene-D-glucose diethyl dithioacetal 
• 127138-50-5 Benzoic acid (4R,5R,4'S,5'R)-5'-formyl-2,2,2',2'-tetramethyl-[4,4']bi[[1,3]dioxolanyl]-5-ylmethyl ester 
• 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 
• 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 
• 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 
• 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 
• 1528636-28-3 C₃₄H₅₉ClO₇Si₄ 

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).

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.

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.