761423-87-4

Usage

Uses

Used in Pharmaceutical Industry:
Ipragliflozin is used as a potent and selective inhibitor of sodium-glucose cotransporter-2 (SGLT2) for the treatment of type 1 and type 2 diabetes. It works by blocking the reabsorption of glucose in the kidneys, leading to increased glucose excretion and reduced plasma glucose levels. This mechanism of action helps improve glycemic control and insulin sensitivity in diabetic patients.
Additionally, Ipragliflozin has been shown to decrease plasma levels of insulin and glucose in an oral glucose tolerance test in a mouse model of diabetes induced by high-fat diet, streptozotocin, and nicotinamide. Furthermore, it has been demonstrated to reduce plasma and hepatic levels of inflammatory markers such as IL-6, TNF-α, CCL2, and CRP, suggesting potential anti-inflammatory effects that may contribute to its therapeutic benefits in diabetes management.

History

Ipragliflozin L-proline was approved in Japan in January 2014 for the treatment of type 2 diabetes. The drug was discovered by Astellas Pharma and co-developed and marketed with Kotobuki Pharmaceutical and Merck Sharp Dohme as Suglat?. Similar to empagliflozin (XIII), ipragliflozin L-proline is a sodium-glucose 1956 A. C. Flick et al. / Bioorg. Med. Chem. 24 (2016) 1937–1980 co-transporter-2 inhibitor which prevents glucose reabsorption by excreting excess glucose in the urine. Ipragliflozin exhibits remarkable selectivity over SLGT-1 (>250x).

Trade name

Suglat

Synthesis

Commercial 5-bromo-2-fluorobenzaldehyde (123) was subjected to nucleophilic attack upon subjection to lithiated benzo[b]thiophene (124) to afford the dibenzylic alcohol 125 in 85% yield. This alcohol was then halogenated by means of thionyl chloride in acetonitrile to give 126, which was followed by treatment with sodium borohydride to give rise to 2-(5-bromo-2-fluorophenyl)- 1-benzothiophene (127), which was isolated by crystallization from 2-propanol and methanol in 81% yield across the two steps. Bromide 127 then underwent lithium–halogen exchange prior to exposure to 2,3,4,6-tetrakis-O-(trimethylsilyl)- D-glucono-1,5-lactone (128) in toluene. Without workup, the resulting mixture was treated with a solution of methanol and HCl at 0 C to give a globally desilylated a-glucopyranoside intermediate. Subjection to acetic anhydride and 4-dimethylaminopyridine furnished tetra-O-acetyl ipragliflozin (129) in 75% yield for the 3 steps. Polyacetate 129 was then saponified using aqueous sodium hydroxide and the product was crystallized from methanol and water and subsequently treated with D-proline in ethanol to furnish the desired product ipragliflozin D-proline (XVI) in 68% yield.

Mode of action

Ipragliflozin is a selective SGLT2 (sodium-glucose co-transporter 2) inhibitor discovered through research collaboration with Kotobuki Pharmaceutical Co., Ltd. SGLTs are membrane proteins that exist on the cell surface and transfer glucose into cells. SGLT2 is a subtype of the sodium-glucose co-transporters and plays a key role in the reuptake of glucose in the proximal tubule of the kidneys. Ipragliflozin reduces blood glucose levels by inhibiting the reuptake of glucose.

Synthetic route

(1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-[3-[(1-benzothiophen-2-yl)methyl]-4-fluorophenyl]-D-sorbitol (1034305-21-9) → (2S,3R,4R,5S,6R)-2-(3-(benzo[b]thiophen-2-ylmethyl)-4-fluorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (761423-87-4) + (1R)-1,5-anhydro-1-{3-[(1-benzothiophen-2-yl)methyl]-4-fluorophenyl}-D-glucitol

Conditions	Yield
With lithium hydroxide monohydrate; water In tetrahydrofuran; methanol at 15℃; for 4h; Temperature; Reagent/catalyst; Concentration; Industrial scale;	A 99.5% B 99%

(1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-[3-[(1-benzothiophen-2-yl)methyl]-4-fluorophenyl]-D-sorbitol (1034305-21-9) → (2S,3R,4R,5S,6R)-2-(3-(benzo[b]thiophen-2-ylmethyl)-4-fluorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (761423-87-4)

Conditions	Yield
Stage #1: (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-[3-[(1-benzothiophen-2-yl)methyl]-4-fluorophenyl]-D-sorbitol With methanol; water; sodium hydroxide at 25 - 49.1℃; Stage #2: With hydrogenchloride In methanol; water at 20.2 - 60℃;	97%
With water; potassium carbonate In toluene at 10℃;	80.1%

(1S)-1,5-anhydro-1-{3-[(1-benzothiophen-2-yl)methyl]-4-fluorophenyl}-2,3,4,6-tetra-O-pivaloyl-D-glucitol → (2S,3R,4R,5S,6R)-2-(3-(benzo[b]thiophen-2-ylmethyl)-4-fluorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (761423-87-4)

Conditions	Yield
With methanol; sodium methylate at 65℃; for 3h;	95.3%

(1S)-1,5-anhydro-1-[3-(1-benzothiophen-2-ylmethyl)-4-fluorophenyl]-2,3,4,6-tetra-O-benzyl - D-glucitol (761423-01-2) → (2S,3R,4R,5S,6R)-2-(3-(benzo[b]thiophen-2-ylmethyl)-4-fluorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (761423-87-4)

Conditions	Yield
Stage #1: (1S)-1,5-anhydro-1-[3-(1-benzothiophen-2-ylmethyl)-4-fluorophenyl]-2,3,4,6-tetra-O-benzyl - D-glucitol With boron trichloride In n-heptane; dichloromethane; pentamethylbenzene, at -78℃; for 3h; Inert atmosphere; Stage #2: With methanol In n-heptane; dichloromethane; pentamethylbenzene, at -78℃;	87.8%
With pentamethylbenzene,; boron trichloride In dichloromethane at -78℃; for 4h; Solvent;	75%
Stage #1: (1S)-1,5-anhydro-1-[3-(1-benzothiophen-2-ylmethyl)-4-fluorophenyl]-2,3,4,6-tetra-O-benzyl - D-glucitol With pentamethylbenzene,; boron trichloride In n-heptane; dichloromethane at -78℃; for 4h; Stage #2: With methanol In n-heptane; dichloromethane at -78 - 20℃;	64%
With pentamethylbenzene,; boron trichloride In n-heptane; dichloromethane at -78℃; for 2h;

C25H29FO5S → (2S,3R,4R,5S,6R)-2-(3-(benzo[b]thiophen-2-ylmethyl)-4-fluorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (761423-87-4)

Conditions	Yield
With triethylsilane; boron trichloride acetic acid In dichloromethane at -20 - 0℃;	71.4%

C24H27FO5S → (2S,3R,4R,5S,6R)-2-(3-(benzo[b]thiophen-2-ylmethyl)-4-fluorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (761423-87-4)

Conditions	Yield
With triethylsilane; boron trichloride acetic acid In dichloromethane; acetonitrile at -20 - 0℃;	70.2%

1-(3-(benzo[b]thiophen-2-ylmethyl)-4-fluorophenyl)-3,4,6-tri-O-tert-butyldimethylsilyl-D-glucal → (2S,3R,4R,5S,6R)-2-(3-(benzo[b]thiophen-2-ylmethyl)-4-fluorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (761423-87-4)

Conditions	Yield
Stage #1: 1-(3-(benzo[b]thiophen-2-ylmethyl)-4-fluorophenyl)-3,4,6-tri-O-tert-butyldimethylsilyl-D-glucal With borane-THF In tetrahydrofuran at 0℃; for 12h; Stage #2: With dihydrogen peroxide; sodium hydroxide at 20℃; for 24h;	49%
Stage #1: 1-(3-(benzo[b]thiophen-2-ylmethyl)-4-fluorophenyl)-3,4,6-tri-O-tert-butyldimethylsilyl-D-glucal With borane-THF In tetrahydrofuran at 0℃; for 12h; Stage #2: With dihydrogen peroxide; sodium hydroxide In tetrahydrofuran; water at 20℃; for 24h;	49%
Multi-step reaction with 2 steps 1.1: borane-THF / tetrahydrofuran / 12 h / 0 °C 1.2: 24 h / 0 - 20 °C 2.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 2 h / 20 °C View Scheme

1-(3-(benzo[b]thiophen-2-methyl)-4-fluorophenyl)-3-O-triisopropylsilyl-4,6-O-di-tert-butylsilylene-D-glucal → (2S,3R,4R,5S,6R)-2-(3-(benzo[b]thiophen-2-ylmethyl)-4-fluorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (761423-87-4)

Conditions	Yield
Stage #1: 1-(3-(benzo[b]thiophen-2-methyl)-4-fluorophenyl)-3-O-triisopropylsilyl-4,6-O-di-tert-butylsilylene-D-glucal With borane-THF In tetrahydrofuran at 0℃; for 12h; Stage #2: With dihydrogen peroxide; sodium hydroxide at 20℃; for 24h;	45%
Stage #1: 1-(3-(benzo[b]thiophen-2-methyl)-4-fluorophenyl)-3-O-triisopropylsilyl-4,6-O-di-tert-butylsilylene-D-glucal With borane-THF In tetrahydrofuran at 0℃; for 12h; Stage #2: With tetrabutyl ammonium fluoride; dihydrogen peroxide; sodium hydroxide In water at 20℃; for 24h;	45%

(1-benzothiophen-2-yl)(5-bromo-2-fluorophenyl)methanol (1034305-11-7) → (2S,3R,4R,5S,6R)-2-(3-(benzo[b]thiophen-2-ylmethyl)-4-fluorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (761423-87-4)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: triethylsilane; boron trifluoride diethyl etherate / dichloromethane / 0.5 h / -20 °C 2.1: n-butyllithium / tetrahydrofuran; hexane; toluene / 0.17 h / -78 °C 2.2: 2 h / -78 °C 3.1: pentamethylbenzene,; boron trichloride / n-heptane; dichloromethane / 4 h / -78 °C 3.2: -78 - 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: triethylsilane; boron trifluoride diethyl etherate / dichloromethane / 0.5 h / -20 °C 2.1: n-butyllithium / dibutyl ether; toluene; n-heptane / 2 h / -40 °C / Inert atmosphere 2.2: 2 h / 20 - 90 °C 3.1: pentamethylbenzene,; boron trichloride / dichloromethane / 4 h / -78 °C View Scheme

2-[(5-bromo-2-fluorophenyl)methyl]-1-benzothiophene (1034305-17-3) → (2S,3R,4R,5S,6R)-2-(3-(benzo[b]thiophen-2-ylmethyl)-4-fluorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (761423-87-4)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: n-butyllithium / tetrahydrofuran; hexane; toluene / 0.17 h / -78 °C 1.2: 2 h / -78 °C 2.1: pentamethylbenzene,; boron trichloride / n-heptane; dichloromethane / 4 h / -78 °C 2.2: -78 - 20 °C View Scheme
Multi-step reaction with 2 steps 1.1: n-butyllithium / toluene; dibutyl ether / 3 h / -20 °C 1.2: 1 h / 0 °C 1.3: 3 h / 100 °C 2.1: sodium methylate; methanol / 3 h / 65 °C View Scheme
Multi-step reaction with 2 steps 1.1: n-butyllithium / dibutyl ether; toluene; n-heptane / 2 h / -40 °C / Inert atmosphere 1.2: 2 h / 20 - 90 °C 2.1: pentamethylbenzene,; boron trichloride / dichloromethane / 4 h / -78 °C View Scheme
Multi-step reaction with 4 steps 1.1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate / 1,4-dioxane / 10 h / 80 °C / Schlenk technique 2.1: bis(1,5-cyclooctadiene)nickel (0); tricyclohexylphosphine tetrafluoroborate; potassium hydroxide / tetrahydrofuran / 12 h / 80 °C / Sealed tube 3.1: borane-THF / tetrahydrofuran / 12 h / 0 °C 3.2: 24 h / 0 - 20 °C 4.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 2 h / 20 °C View Scheme

5-bromo-2-fluorobenzaldehyde (93777-26-5) → (2S,3R,4R,5S,6R)-2-(3-(benzo[b]thiophen-2-ylmethyl)-4-fluorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (761423-87-4)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 1.5 h / -78 °C 1.2: 2 h / -78 °C 2.1: triethylsilane; boron trifluoride diethyl etherate / dichloromethane / 0.5 h / -20 °C 3.1: n-butyllithium / tetrahydrofuran; hexane; toluene / 0.17 h / -78 °C 3.2: 2 h / -78 °C 4.1: pentamethylbenzene,; boron trichloride / n-heptane; dichloromethane / 4 h / -78 °C 4.2: -78 - 20 °C View Scheme
Multi-step reaction with 4 steps 1.1: n-butyllithium / tetrahydrofuran / 1.5 h / -78 °C 1.2: 2 h / -78 °C 2.1: triethylsilane; boron trifluoride diethyl etherate / dichloromethane / 0.5 h / -20 °C 3.1: n-butyllithium / dibutyl ether; toluene; n-heptane / 2 h / -40 °C / Inert atmosphere 3.2: 2 h / 20 - 90 °C 4.1: pentamethylbenzene,; boron trichloride / dichloromethane / 4 h / -78 °C View Scheme

Benzo[b]thiophene (95-15-8) → (2S,3R,4R,5S,6R)-2-(3-(benzo[b]thiophen-2-ylmethyl)-4-fluorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (761423-87-4)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 1.5 h / -78 °C 1.2: 2 h / -78 °C 2.1: triethylsilane; boron trifluoride diethyl etherate / dichloromethane / 0.5 h / -20 °C 3.1: n-butyllithium / tetrahydrofuran; hexane; toluene / 0.17 h / -78 °C 3.2: 2 h / -78 °C 4.1: pentamethylbenzene,; boron trichloride / n-heptane; dichloromethane / 4 h / -78 °C 4.2: -78 - 20 °C View Scheme
Multi-step reaction with 4 steps 1.1: n-butyllithium / tetrahydrofuran / 1.5 h / -78 °C 1.2: 2 h / -78 °C 2.1: triethylsilane; boron trifluoride diethyl etherate / dichloromethane / 0.5 h / -20 °C 3.1: n-butyllithium / dibutyl ether; toluene; n-heptane / 2 h / -40 °C / Inert atmosphere 3.2: 2 h / 20 - 90 °C 4.1: pentamethylbenzene,; boron trichloride / dichloromethane / 4 h / -78 °C View Scheme

2,3,5,6-tetra-O-(tert-butyldimethylsilyl)-D-glucono-1,4-lactone (318967-97-4) → (2S,3R,4R,5S,6R)-2-(3-(benzo[b]thiophen-2-ylmethyl)-4-fluorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (761423-87-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: sec.-butyllithium / tetrahydrofuran; toluene; hexane / 2 h / -78 - -65 °C / Inert atmosphere 2: boron trichloride acetic acid; triethylsilane / dichloromethane / -20 - 0 °C View Scheme

D-glucono-1,4-lactone (1198-69-2) → (2S,3R,4R,5S,6R)-2-(3-(benzo[b]thiophen-2-ylmethyl)-4-fluorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (761423-87-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: 4-methyl-morpholine / tetrahydrofuran / 1 h / -10 - 45 °C 2: n-butyllithium / tetrahydrofuran; toluene; hexane / 2 h / -78 - -65 °C / Inert atmosphere 3: boron trichloride acetic acid; triethylsilane / dichloromethane; acetonitrile / -20 - 0 °C View Scheme
Multi-step reaction with 3 steps 1: triethylamine / tetrahydrofuran / 1 h / -10 - 45 °C 2: sec.-butyllithium / tetrahydrofuran; toluene; hexane / 2 h / -78 - -65 °C / Inert atmosphere 3: boron trichloride acetic acid; triethylsilane / dichloromethane / -20 - 0 °C View Scheme

C18H42O6Si4 → (2S,3R,4R,5S,6R)-2-(3-(benzo[b]thiophen-2-ylmethyl)-4-fluorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (761423-87-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: n-butyllithium / tetrahydrofuran; toluene; hexane / 2 h / -78 - -65 °C / Inert atmosphere 2: boron trichloride acetic acid; triethylsilane / dichloromethane; acetonitrile / -20 - 0 °C View Scheme

2-[(5-bromo-2-fluorophenyl)methyl]-1-benzothiophene (1034305-17-3) → (2S,3R,4R,5S,6R)-2-(3-(benzo[b]thiophen-2-ylmethyl)-4-fluorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (761423-87-4) + (1R)-1,5-anhydro-1-{3-[(1-benzothiophen-2-yl)methyl]-4-fluorophenyl}-D-glucitol

Conditions

Yield

Multi-step reaction with 3 steps 1.1: s-butylmagnesium chloride; n-butyllithium; lithium chloride / tetrahydrofuran; hexane / 3.17 h / -10 °C / Inert atmosphere; Industrial scale 1.2: 3 h / -10 °C / Industrial scale 2.1: pyridine; dmap / dichloromethane / 2 h / 25 °C / Industrial scale 3.1: lithium hydroxide monohydrate; water / tetrahydrofuran; methanol / 4 h / 15 °C / Industrial scale View Scheme

(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,4R,5S,6R)-2-(3-(benzo[b]thiophen-2-ylmethyl)-4-fluorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (761423-87-4) + (1R)-1,5-anhydro-1-{3-[(1-benzothiophen-2-yl)methyl]-4-fluorophenyl}-D-glucitol

Conditions

Yield

Multi-step reaction with 3 steps 1.1: s-butylmagnesium chloride; n-butyllithium; lithium chloride / tetrahydrofuran; hexane / 3.17 h / -10 °C / Inert atmosphere; Industrial scale 1.2: 3 h / -10 °C / Industrial scale 2.1: pyridine; dmap / dichloromethane / 2 h / 25 °C / Industrial scale 3.1: lithium hydroxide monohydrate; water / tetrahydrofuran; methanol / 4 h / 15 °C / Industrial scale View Scheme

2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosyl bromide (81058-27-7) → (2S,3R,4R,5S,6R)-2-(3-(benzo[b]thiophen-2-ylmethyl)-4-fluorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (761423-87-4)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: n-butyllithium / toluene; dibutyl ether / 3 h / -20 °C 1.2: 1 h / 0 °C 1.3: 3 h / 100 °C 2.1: sodium methylate; methanol / 3 h / 65 °C View Scheme
Multi-step reaction with 2 steps 1.1: n-butyllithium / toluene; hexane; dibutyl ether / 3.33 h / -20 °C / Inert atmosphere 1.2: 1.33 h / 0 °C / Inert atmosphere 1.3: 3 h / 100 °C / Inert atmosphere 2.1: sodium methylate; methanol / 3 h / 65 °C View Scheme

(2R,3R,4S,5R,6R)-2-chloro-6-(pivaloyloxymethyl)tetrahydro-2H-pyran-3,4,5-triyl tris(2,2-dimethylpropanoate) → (2S,3R,4R,5S,6R)-2-(3-(benzo[b]thiophen-2-ylmethyl)-4-fluorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (761423-87-4)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: n-butyllithium / toluene; dibutyl ether / 3 h / -20 °C 1.2: 1 h / 0 °C 1.3: 3 h / 100 °C 2.1: sodium methylate; methanol / 3 h / 65 °C View Scheme

2-[(5-iodo-2-fluorophenyl)methyl]-1-benzothiophene → (2S,3R,4R,5S,6R)-2-(3-(benzo[b]thiophen-2-ylmethyl)-4-fluorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (761423-87-4)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: n-butyllithium / toluene; dibutyl ether / 3 h / -20 °C 1.2: 1 h / 0 °C 1.3: 3 h / 100 °C 2.1: sodium methylate; methanol / 3 h / 65 °C View Scheme
Multi-step reaction with 2 steps 1.1: n-butyllithium / toluene; hexane; dibutyl ether / 3.33 h / -20 °C / Inert atmosphere 1.2: 1.33 h / 0 °C / Inert atmosphere 1.3: 3 h / 100 °C / Inert atmosphere 2.1: sodium methylate; methanol / 3 h / 65 °C View Scheme

α-D-glucopyranose peracetylate (604-68-2) → (2S,3R,4R,5S,6R)-2-(3-(benzo[b]thiophen-2-ylmethyl)-4-fluorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (761423-87-4)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: hydrogen bromide; acetic acid / dichloromethane / 0.67 h / 0 °C 2.1: Acidic conditions 3.1: iron(II) sulfate / methanol / 12 h 4.1: n-butyllithium / dibutyl ether; toluene; n-heptane / 2 h / -40 °C / Inert atmosphere 4.2: 2 h / 20 - 90 °C 5.1: pentamethylbenzene,; boron trichloride / dichloromethane / 4 h / -78 °C View Scheme

2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide (572-09-8) → (2S,3R,4R,5S,6R)-2-(3-(benzo[b]thiophen-2-ylmethyl)-4-fluorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (761423-87-4)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: Acidic conditions 2.1: iron(II) sulfate / methanol / 12 h 3.1: n-butyllithium / dibutyl ether; toluene; n-heptane / 2 h / -40 °C / Inert atmosphere 3.2: 2 h / 20 - 90 °C 4.1: pentamethylbenzene,; boron trichloride / dichloromethane / 4 h / -78 °C View Scheme

1-bromo-α-D-glucopyranose (61403-85-8) → (2S,3R,4R,5S,6R)-2-(3-(benzo[b]thiophen-2-ylmethyl)-4-fluorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (761423-87-4)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: iron(II) sulfate / methanol / 12 h 2.1: n-butyllithium / dibutyl ether; toluene; n-heptane / 2 h / -40 °C / Inert atmosphere 2.2: 2 h / 20 - 90 °C 3.1: pentamethylbenzene,; boron trichloride / dichloromethane / 4 h / -78 °C View Scheme

2,3,4,6-tetra-O-benzyl-α-D-glucopyranosyl bromide (4196-35-4) → (2S,3R,4R,5S,6R)-2-(3-(benzo[b]thiophen-2-ylmethyl)-4-fluorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (761423-87-4)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: n-butyllithium / dibutyl ether; toluene; n-heptane / 2 h / -40 °C / Inert atmosphere 1.2: 2 h / 20 - 90 °C 2.1: pentamethylbenzene,; boron trichloride / dichloromethane / 4 h / -78 °C View Scheme

alpha-D-glucopyranose (492-62-6) → (2S,3R,4R,5S,6R)-2-(3-(benzo[b]thiophen-2-ylmethyl)-4-fluorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (761423-87-4)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: sodium acetate / 0.17 h / 140 °C 2.1: hydrogen bromide; acetic acid / dichloromethane / 0.67 h / 0 °C 3.1: Acidic conditions 4.1: iron(II) sulfate / methanol / 12 h 5.1: n-butyllithium / dibutyl ether; toluene; n-heptane / 2 h / -40 °C / Inert atmosphere 5.2: 2 h / 20 - 90 °C 6.1: pentamethylbenzene,; boron trichloride / dichloromethane / 4 h / -78 °C View Scheme

1-phenylsulfonyl-3,4,6-tri-O-tert-butyldimethylsilyl-D-glucal → (2S,3R,4R,5S,6R)-2-(3-(benzo[b]thiophen-2-ylmethyl)-4-fluorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (761423-87-4)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: bis(1,5-cyclooctadiene)nickel (0); tricyclohexylphosphine tetrafluoroborate; potassium hydroxide / tetrahydrofuran / 12 h / 80 °C / Sealed tube 2.1: borane-THF / tetrahydrofuran / 12 h / 0 °C 2.2: 24 h / 0 - 20 °C 3.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 2 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1.1: tricyclohexylphosphine tetrafluoroborate; potassium hydroxide; bis(1,5-cyclooctadiene)nickel (0) / tetrahydrofuran / 12 h / 60 °C 2.1: borane-THF / tetrahydrofuran / 12 h / 0 °C 2.2: 24 h / 20 °C View Scheme
Multi-step reaction with 4 steps 1.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 2 h / 20 °C 1.2: 6 h / -35 °C / Inert atmosphere 2.1: 1H-imidazole / N,N-dimethyl-formamide / 6 h / -35 °C / Inert atmosphere 3.1: tricyclohexylphosphine tetrafluoroborate; potassium hydroxide; bis(1,5-cyclooctadiene)nickel (0) / tetrahydrofuran / 12 h / 60 °C 4.1: borane-THF / tetrahydrofuran / 12 h / 0 °C 4.2: 24 h / 20 °C View Scheme
Multi-step reaction with 4 steps 1.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 2 h / 20 °C 1.2: 6 h / -35 °C / Inert atmosphere 2.1: triisopropylsilyl chloride / N,N-dimethyl-formamide / 6 h / -35 °C / Inert atmosphere 3.1: tricyclohexylphosphine tetrafluoroborate; potassium hydroxide; bis(1,5-cyclooctadiene)nickel (0) / tetrahydrofuran / 60 - 80 °C 4.1: borane-THF / tetrahydrofuran / 12 h / 0 °C 4.2: 24 h / 20 °C View Scheme

C36H72O7SSi4 → (2S,3R,4R,5S,6R)-2-(3-(benzo[b]thiophen-2-ylmethyl)-4-fluorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (761423-87-4)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: tetrahydrofuran / -78 °C / Inert atmosphere 2.1: bis(1,5-cyclooctadiene)nickel (0); tricyclohexylphosphine tetrafluoroborate; potassium hydroxide / tetrahydrofuran / 12 h / 80 °C / Sealed tube 3.1: borane-THF / tetrahydrofuran / 12 h / 0 °C 3.2: 24 h / 0 - 20 °C 4.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 2 h / 20 °C View Scheme

C36H72O5SSi4 → (2S,3R,4R,5S,6R)-2-(3-(benzo[b]thiophen-2-ylmethyl)-4-fluorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (761423-87-4)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 2 h / 0 - 20 °C 2.1: tetrahydrofuran / -78 °C / Inert atmosphere 3.1: bis(1,5-cyclooctadiene)nickel (0); tricyclohexylphosphine tetrafluoroborate; potassium hydroxide / tetrahydrofuran / 12 h / 80 °C / Sealed tube 4.1: borane-THF / tetrahydrofuran / 12 h / 0 °C 4.2: 24 h / 0 - 20 °C 5.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 2 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 2 h / 0 - 20 °C 1.2: -78 °C / Inert atmosphere 2.1: tricyclohexylphosphine tetrafluoroborate; potassium hydroxide; bis(1,5-cyclooctadiene)nickel (0) / tetrahydrofuran / 12 h / 60 °C 3.1: borane-THF / tetrahydrofuran / 12 h / 0 °C 3.2: 24 h / 20 °C View Scheme
Multi-step reaction with 5 steps 1.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 2 h / 0 - 20 °C 1.2: -78 °C / Inert atmosphere 2.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 2 h / 20 °C 2.2: 6 h / -35 °C / Inert atmosphere 3.1: 1H-imidazole / N,N-dimethyl-formamide / 6 h / -35 °C / Inert atmosphere 4.1: tricyclohexylphosphine tetrafluoroborate; potassium hydroxide; bis(1,5-cyclooctadiene)nickel (0) / tetrahydrofuran / 12 h / 60 °C 5.1: borane-THF / tetrahydrofuran / 12 h / 0 °C 5.2: 24 h / 20 °C View Scheme
Multi-step reaction with 5 steps 1.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 2 h / 0 - 20 °C 1.2: -78 °C / Inert atmosphere 2.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 2 h / 20 °C 2.2: 6 h / -35 °C / Inert atmosphere 3.1: triisopropylsilyl chloride / N,N-dimethyl-formamide / 6 h / -35 °C / Inert atmosphere 4.1: tricyclohexylphosphine tetrafluoroborate; potassium hydroxide; bis(1,5-cyclooctadiene)nickel (0) / tetrahydrofuran / 60 - 80 °C 5.1: borane-THF / tetrahydrofuran / 12 h / 0 °C 5.2: 24 h / 20 °C View Scheme

3-(benzo[b]thiophen-2-ylmethyl)-4-fluorophenylboronic acid pinacol ester → (2S,3R,4R,5S,6R)-2-(3-(benzo[b]thiophen-2-ylmethyl)-4-fluorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (761423-87-4)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: bis(1,5-cyclooctadiene)nickel (0); tricyclohexylphosphine tetrafluoroborate; potassium hydroxide / tetrahydrofuran / 12 h / 80 °C / Sealed tube 2.1: borane-THF / tetrahydrofuran / 12 h / 0 °C 2.2: 24 h / 0 - 20 °C 3.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 2 h / 20 °C View Scheme

(2S,3R,4R,5S,6R)-2-(3-(benzo[b]thiophen-2-ylmethyl)-4-fluorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (761423-87-4) + L-proline (147-85-3) → Ipragliflozin L-proline (951382-34-6)

Conditions	Yield
In dichloromethane at 35℃; for 3h;	99%
In ethanol; water at 100℃; for 0.5h;	83.7%
In ethanol at 100℃; for 0.5h;

(2S,3R,4R,5S,6R)-2-(3-(benzo[b]thiophen-2-ylmethyl)-4-fluorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (761423-87-4) + p-toluenesulfonyl chloride (98-59-9) → ((2R,3S,4R,5R,6S)-6-(3-(benzo[b]thiophen-2-ylmethyl)-4-fluorophenyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)methyl 4-methylbenzenesulfonate

Conditions	Yield
With pyridine at 0℃; for 3h;	72%

(2S,3R,4R,5S,6R)-2-(3-(benzo[b]thiophen-2-ylmethyl)-4-fluorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (761423-87-4) → (2S,3S,5R,6R)-2-(3-(benzo[b]thiophen-2-ylmethyl)-4-fluorophenyl)-3,5-dihydroxy-6-(hydroxymethyl)dihydro-2H-pyran-4(3H)-one

Conditions	Yield
Stage #1: (2S,3R,4R,5S,6R)-2-(3-(benzo[b]thiophen-2-ylmethyl)-4-fluorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol With bis(tri-n-butyltin)oxide In chloroform for 2h; Inert atmosphere; Molecular sieve; Reflux; Stage #2: With bromine In dichloromethane; chloroform at 0℃; for 0.666667h;	17%

(2S,3R,4R,5S,6R)-2-(3-(benzo[b]thiophen-2-ylmethyl)-4-fluorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (761423-87-4) → (2S,3R,4S,5S,6R)-2-(3-(benzo[b]thiophen-2-ylmethyl)-4-fluorophenyl)-6-methyltetrahydro-2H-pyran-3,4,5-triol

Conditions	Yield
Multi-step reaction with 2 steps 1: pyridine / 3 h / 0 °C 2: lithium aluminium tetrahydride / tetrahydrofuran / 4 h / 0 - 65 °C View Scheme

Upstream product

• 761423-01-2 (1S)-1,5-anhydro-1-[3-(1-benzothiophen-2-ylmethyl)-4-fluorophenyl]-2,3,4,6-tetra-O-benzyl - D-glucitol 
• 1034305-21-9 (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-[3-[(1-benzothiophen-2-yl)methyl]-4-fluorophenyl]-D-sorbitol 
• 1034305-11-7 (1-benzothiophen-2-yl)(5-bromo-2-fluorophenyl)methanol 
• 1034305-17-3 2-[(5-bromo-2-fluorophenyl)methyl]-1-benzothiophene 
• 93777-26-5 5-bromo-2-fluorobenzaldehyde 
• 95-15-8 Benzo[b]thiophene 
• 318967-97-4 2,3,5,6-tetra-O-(tert-butyldimethylsilyl)-D-glucono-1,4-lactone 
• 1198-69-2 D-glucono-1,4-lactone 
• 32469-28-6 (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one 
• 81058-27-7 2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosyl bromide 
• 604-68-2 α-D-glucopyranose peracetylate 
• 572-09-8 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide 
• 61403-85-8 1-bromo-α-D-glucopyranose 
• 4196-35-4 2,3,4,6-tetra-O-benzyl-α-D-glucopyranosyl bromide 

Downstream Products

• 951382-34-6 Ipragliflozin L-proline 

Relevant academic research and scientific papers

A concise and practical stereoselective synthesis of ipragliflozin L-proline

A concise and practical stereoselective synthesis of ipragliflozin L-proline was presented starting from 2-[(5-iodo-2-fluorophenyl)methyl]-1-benzothiophene and 2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosyl bromide without catalyst via iodine–lithium–zinc exchange. The overall yield was 52% in three steps and the product purity was excellent. Two key diastereomers were prepared with efficient and direct access to the α-C-arylglucoside.

Preparation method of diabetes-treating medicine, namely ipragliflozin or derivative thereof

The invention provides a preparation method of a diabetes-treating medicine, namely ipragliflozin or a derivative thereof. According to the preparation method, alpha-O-alkenyl sulfone is used as an electrophilic reagent for the Suzuki-Miyaura coupling reaction; the reaction raw material alpha-O-alkenyl sulfone is simple to prepare and stable in structure, and can overcome the defects of instability, preparation difficulty and the like when organic halide and sulfonic acid are used as electrophilic reagents for the Suzuki-Miyaura coupling reaction. Meanwhile, the reaction are mild in reaction conditions, compatible with a wide range of heterocyclic rings and various functional groups, high in yield and capable of realizing large-scale process production. Since alpha-O-alkenyl sulfone is used as the electrophilic reagent for the Suzuki-Miyaura coupling reaction, high-yield generation of aryl glucoside and open-chain alkenyl ether can be realized, medicines for treating type 2 diabetes mellitus, namely ipragliflozin and 2-deoxyipragliflozin can also be prepared, and the application scope of the preparation method is wide.

Suzuki-Miyaura coupling reaction using alpha-O-alkenyl sulfone as electrophilic reagent and application thereof

The invention provides a Suzuki-Miyaura coupling reaction using alpha-O-alkenyl sulfone as an electrophilic reagent. The reaction comprises the following steps: weighing alpha-O-alkenyl sulfone, an organic boron reagent, a ligand, an alkali and a catalyst, and carrying out reacting in a solvent. The invention also provides application of the coupling reaction. According to the invention, alpha-O-alkenyl sulfone is used as the electrophilic reagent for the Suzuki-Miyaura coupling reaction, and the reaction raw material alpha-O-alkenyl sulfone is simple to prepare and stable in structure, and can overcome the defects of instability, preparation difficulty and the like when organic halide and sulfonic acid are used as electrophilic reagents for the Suzuki-Miyaura coupling reaction. Meanwhile,the reaction are mild in reaction conditions, compatible with a wide range of heterocyclic rings and various functional groups, high in yield and capable of realizing large-scale process production.Since the alpha-O-alkenyl sulfone is used as the electrophilic reagent for the Suzuki-Miyaura coupling reaction, high-yield generation of aryl glucoside and open-chain alkenyl ether can be realized, medicines for treating type 2 diabetes mellitus, namely ipragliflozin and 2-deoxyipragliflozin can also be prepared, and the application scope of the reaction is wide.

Ni-Catalyzed Suzuki-Miyaura Cross-Coupling of α-Oxo-vinylsulfones to Prepare C-Aryl Glycals and Acyclic Vinyl Ethers

We demonstrate that readily available and bench-stable α-oxo-vinylsulfones are competent electrophiles in Ni-catalyzed Suzuki-Miyaura cross-coupling reactions. The C-sulfone bond in the α-oxo-vinylsulfone motif is cleaved chemoselectively in these reactions, furnishing C-aryl glycals or acyclic vinyl ethers in high yields. These reactions proceed under mild conditions and tolerate a remarkable scope of heterocycles and functional groups. Preliminary mechanistic studies revealed the importance of an α-heteroatom in facilitating these transformations.

Ni-Catalyzed Suzuki-Miyaura Cross-Coupling of α-Oxo-vinylsulfones to Prepare C-Aryl Glycals and Acyclic Vinyl Ethers

We demonstrate that readily available and bench-stable α-oxo-vinylsulfones are competent electrophiles in Ni-catalyzed Suzuki-Miyaura cross-coupling reactions. The C-sulfone bond in the α-oxo-vinylsulfone motif is cleaved chemoselectively in these reactions, furnishing C-aryl glycals or acyclic vinyl ethers in high yields. These reactions proceed under mild conditions and tolerate a remarkable scope of heterocycles and functional groups. Preliminary mechanistic studies revealed the importance of an α-heteroatom in facilitating these transformations.

Halopivalylglucopyranose and preparation method for SGLT2 inhibitor

The invention belongs to the technical field of drug synthesis. The invention relates to a novel method for preparing a compound (including Canagliflozin, Dapagliflozin, Empagliflozin and Ipragliflozin) with inhibitory activity on sodium-dependent glucose transporters (SGLT) existing in the intestines or the kidneys. The invention discloses a 1,2,3,4,6-penta-O-halopivalylglucopyranose, the generalstructural formula of which is formula I. The invention further discloses a 2,3,4,6-tetra-O-halopivalyl-Alpha-D-haloglucopyranose (haloglucose for short), the general structural formula of which is formula III. The invention further discloses a preparation method for an SGLT2 inhibitor. The SGLT2 inhibitor which is prepared by adopting the method disclosed by the invention has the technical advantages of high purity, high yield, easiness in operation, suitability for industrial production and the like.

Method for synthesizing ipragliflozin

The invention discloses a method for synthesizing ipragliflozin. The method comprises the following steps: (1) generating alkylation reaction by formula-4 compound and formula-5 compound to generate aformula-6 compound; (2) carrying out deprotection on the formula-6 compound to generate a formula-7 compound, i.e., ipragliflozin. Compared with the prior art, the preparation method disclosed by theinvention is characterized in that adopted starting raw materials are cheap and can be easily obtained, a synthesis route is short, operation is convenient, cost is lower and general yield is high. The method conforms to the concept of green chemistry and is suitable for industrial production. (The formulas are shown in the description.).

Pipeline synthesis process for liflozin drugs

The invention relates to a pipeline synthesis process for liflozin drugs. The synthesis process is based on a pipeline reactor, and the pipeline reactor comprises a first pipeline section used for preheating and a second pipeline section used for reacting. The synthesis process comprises the following steps: respectively dissolving raw materials in an organic solvent, respectively pumping the materials into the pipeline reactor, and enabling the materials to enter the first pipeline section to be preheated; preheating for multiple time, enabling the materials to respectively enter the second pipeline section, pumping an aqueous solution of inorganic base through a joint of the second pipeline section, remaining for multiple time and discharging, performing after-treatment, thereby obtaining the raw liflozin drugs. Compared with the prior art, the pipeline synthesis process disclosed by the invention has the beneficial effects that the equipment miniaturization and continuous production of production of the raw liflozin drugs can be realized by utilizing the pipeline reaction process, the mass transfer and heat transfer of the materials are stable, and the pipeline reaction has high synthesis efficiency compared with a batch reaction.

Synthetic method of Ipragliflozin

The invention provides a synthetic method of Ipragliflozin. The synthetic method comprises the following steps: exchanging a prepared compound organic metallic reagent and 2-(5-bromo-2-benzyl) benzothiophene halogen to obtain an arene metal compound intermediate; enabling coupling reaction between the arene metal compound intermediate and glucolactone; conducting dehydroxylation protection to obtain 1-C-[3-(benzo[B]thien-2-ylmethyl)-4-fluorophenyl]-ALPHA-D-pyran glucitol; reducing 1-C-[3-(benzo[B]thien-2-ylmethyl)-4-fluorophenyl]-ALPHA-D-pyran glucitol to obtain crude Ipragliflozin; conducting acylation, recrystallization and deacylation reaction on crude Ipragliflozin to obtain pure Ipragliflozin. As the compound organic metallic reagent is adopted, the reaction temperature is improved, the cost is lowered, and the synthetic method is suitable for industrial production; as water solution dehydroxylation protection of acid is adopted, the crude product is a solid but not an oily substance; the disposal is convenient and the reaction time is shortened.

Preparation method of SGLT-2 inhibitor compound

The invention relates to a preparation method of SGLT-2 inhibitor compound. The preparation method comprises the following steps: performing hydroxyl protection, coupling reaction, hydroxyl de-protection, ketalation and the like to the compound A so as to obtain an intermediate I; and then preparing the SGLT-2 inhibitor compound by the obtained intermediate I.