864070-44-0

Basic information

• Product Name: Empagliflozin
• Synonyms: EMpagliflozin;BI-10773;(1S)-1,5-Anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-D-glucitol;EMpagliflozin/ BI-10773;EMPAGLIFLBZIN;(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((S)-tetrahydrofuran-3-yloxy)benzyl)phenyl)-6-(hydroxyMethyl)-tetrahydro-2H-pyran-3,4,5-triol;D-Glucitol, 1,5-anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]M ethyl]phenyl]-, (1S)-;(1S)-1,5-Anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-D-glucitol Empagliflozin BI 10773
• CAS NO: 864070-44-0
• Molecular Formula: C₂₃H₂₇ClO₇
• Molecular Weight: 450.90928
• EINECS: 1592732-453-0
• Product Categories: API;Inhibitors;Empagliflozin
• Mol File: 864070-44-0.mol

Chemical Properties

• Boiling Point: 665℃
• Flash Point: 356℃
• Appearance: /
• Density: 1.398
• Storage Temp.: 2-8°C
• Solubility: insoluble in H2O; ≥20.75 mg/mL in DMSO; ≥7.06 mg/mL in EtOH with ultrasonic
• PKA: 13.23±0.70(Predicted)
• CAS DataBase Reference: Empagliflozin(CAS DataBase Reference)
• NIST Chemistry Reference: Empagliflozin(864070-44-0)
• EPA Substance Registry System: Empagliflozin(864070-44-0)

Safety Data

• Hazardous Substances Data: 864070-44-0(Hazardous Substances Data)

Usage

Clinical research

FDA approval of empagliflozin(Jardiance) was based on the results of seven clinical trials conducted in nearly 4,500 patients with type 2 diabetes mellitus. Compared to the placebo group, all patients taking empagliflozin(Jardiance) had a significantly lower HbA1c level. The most common adverse reactions are urinary tract infections and female reproductive system infections. On March 21, 2014, European Medicines Agency (EMA) Commission on Human Medicines recommended the approval of the sodium glucose co-transporter-2 (SGLT2) inhibitor (empagliflozin) for the treatment of adult type 2 diabetes mellitus. On May 23, 2014, European Medicines Agency (EMA) approved for empagliflozin’s listing in Europe. On June 16, 2014, the Boehringer-Erya Diabetes Federation released the latest data of empagliflozin Phase II clinical trials at the 74th American Diabetes Association Science Conference (ADA2014). In a two-year study, empagliflozin or glimepiride was used in the treatment of adult patients with type 2 diabetes based on metformin. The results showed that empagliflozin(Jardiance) reduced HbA1c more significantly compared with glimepiride, while the effect of weight and blood pressure treatment are equivalent with glimepiride. Another 52-week study was conducted in patients with type 2 diabetes who were still unable to adequately control blood glucose levels with high doses of insulin (with or without metformin). The results showed that compared with placebo, Jardiance significantly reduced blood glucose levels and weight, and reduced the dose of insulin, with Jardiance or placebo on a daily basis with multiple injections of insulin. In both studies, the safety of empagliflozin was consistent with previous studies. FDA-related reports write that the drug should not be used in the following types of patients: type 1 diabetes, elevated blood or urine ketones (diabetic ketoacidosis), severe kidney damage, end-stage renal disease or dialysis patients. The most common side effects are urinary tract infections and female genital infections. Empagliflozin can cause dehydration and lead to decreased blood pressure, resulting in patients with dizziness or fainting and decreased renal function. The risk of older patients, especially those with impaired renal function and diuretics, appears to be greater. FDA requires Boehring and Eli Lilly to conduct four post-marketing studies: complete ongoing cardiovascular outcome trials, pediatric pharmacokinetics and pharmacodynamics trials, pediatric safety and efficacy trials, toxicity test for the drug (especially effect for renal function, bone and growth and development)

Precautions

Do NOT use empagliflozin if: you are allergic to any ingredient in empagliflozin you have type 1 diabetes you have high blood or urine ketone levels (diabetic ketoacidosis) you have severe kidney problems or are on dialysis

References

https://en.wikipedia.org/wiki/Empagliflozin https://www.drugs.com/cdi/empagliflozin.html

Uses

Empagliflozin is a novel, potent and selective SGLT-2 inhibitor, improves glycaemic control and features of metabolic syndrome in diabetic rats.

Definition

ChEBI: A C-glycosyl compound consisting of a beta-glucosyl residue having a (4-chloro-3-{4-[(3S)-tetrahydrofuran-3-yloxy]benzyl}phenyl group at the anomeric centre. A sodium-glucose co-transporter 2 inhibitor u ed as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Side effects

Empagliflozin had a low incidence of adverse reactions. Compared with the placebo group, the incidence of common adverse reactions was 2%, including urinary tract infection, female reproductive system fungal infection, upper respiratory tract infection, polyuria, dyslipidemia (dose-related low-density lipoprotein increased), arthralgia, fungal infection of male reproductive system, hypoglycemia (the incidence of hypoglycemia increased when empagliflozin was combined with insulin or sulfonylurea hypoglycemic drugs), nausea. Other adverse reactions less than 2% were common in thirst (polydipsia, polydipsia), hypovolemia, and renal dysfunction.

Synthesis

Commercial 5-iodo-2-chlorobenzoic acid (97) was first converted to the corresponding acid chloride, prior to subjection to commercially available fluorobenzene (98) under Friedel–Crafts conditions to generate the desired fluorobenzophenone 99 in 94% yield after isolation by recrystallization from aqueous isopropanol. The fluorobenzophenone (99) was then reacted with commercially available (S)-3-hydroxytetrahydrofuran (100) and potassium tertbutoxide in THF to afford ethereal benzophenone 101. Next, removal of the ketone functionality within 101 was achieved through the use of 1,1,3,3-tetramethyldisiloxane (TMDS) in the presence of aluminum chloride in toluene to deliver diaryl iodide 102. This iodide was subsequently converted to the corresponding Grignard reagent and subjected to gluconolactone 103, giving rise to an intermediate lactol which was then sequentially treated with aqueous citric acid, methanolic HCl, and triethylsilyl hydride and aluminum trichloride to ultimately furnish empagliflozin (XIII) in 73% yield across the four-step protocol.

Drug interactions

Potentially hazardous interactions with other drugs None known

Metabolism

In vitro studies suggested that the main route of metabolism is glucuronidation by the uridine 5'-diphospho-glucuronosyltransferases UGT2B7, UGT1A3, UGT1A8, and UGT1A9Following administration of oral [14C]-empagliflozin solution to healthy volunteers, approximately 96% of the drug-related radioactivity was eliminated in faeces (41%) or urine (54%). The majority of drug-related radioactivity recovered in faeces was unchanged parent drug and approximately half of drug-related radioactivity excreted in urine was unchanged parent drug

Synthetic route

C29H32BrClO9 → empagliflozin (864070-44-0)

Conditions	Yield
With water; potassium hydroxide In acetonitrile at 50 - 60℃; Reagent/catalyst;	93.8%

(2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-trityl triacetate → empagliflozin (864070-44-0)

Conditions	Yield
With potassium carbonate In tetrahydrofuran at 40 - 45℃;	93%
With sodium hydroxide In methanol at 20℃; for 1h;	91.7%
With lithium hydroxide In methanol; water at 0 - 5℃; Reagent/catalyst;	89.2%

C51H43ClO11 → empagliflozin (864070-44-0)

Conditions	Yield
With sodium methylate In tetrahydrofuran at 40 - 45℃;	90%

C43H59ClO11 → empagliflozin (864070-44-0)

Conditions	Yield
With lithium hydroxide In ethanol; water at 40 - 45℃;	87%

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

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

C40H63ClO7Si2 → empagliflozin (864070-44-0)

Conditions	Yield
Stage #1: C40H63ClO7Si2 With tetrabutyl ammonium fluoride In tetrahydrofuran at 60℃; for 6h; Large scale; Stage #2: With ethanol In toluene at 0 - 75℃; for 2.5h; Large scale;	81%

2,3,4,6-tetra-O-benzyl-1-deoxy-1-((S)-(4-chloro-3-(4-(tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-β-D-glucopyranose → empagliflozin (864070-44-0)

Conditions	Yield
With palladium 10% on activated carbon; hydrogen In methanol at 20℃; for 18h; Reagent/catalyst;	80%

(3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran (915095-94-2) + (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one (32469-28-6, 55515-28-1, 55515-29-2, 32384-65-9) → empagliflozin (864070-44-0)

Conditions	Yield
Stage #1: (3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran With isopropylmagnesium chloride; lithium chloride In tetrahydrofuran at -21 - -15℃; for 1.83333h; Stage #2: (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one In dichloromethane; acetonitrile at -25 - -13℃; for 2.91667h;	73%
Stage #1: (3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran With isopropylmagnesium chloride; lithium chloride In tetrahydrofuran at -21 - -15℃; for 1.83333h; Industry scale; Stage #2: (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one In tetrahydrofuran at -25 - -18℃; for 2.91667h; Industry scale; Stage #3: With citric acid In water at -13 - 19℃; Product distribution / selectivity; Industry scale;	73%

C25H31ClO8 → empagliflozin (864070-44-0)

Conditions	Yield
With triethylsilane; boron trifluoride diethyl etherate In dichloromethane; acetonitrile at -20 - 0℃;	71.7%

C23H27ClO8 → empagliflozin (864070-44-0)

Conditions	Yield
With triethylsilane; boron trifluoride diethyl etherate In acetonitrile at 0 - 25℃; Inert atmosphere; Large scale;	60%

(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (864070-37-1) + (R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (219823-47-9) → empagliflozin (864070-44-0)

Conditions	Yield
With caesium carbonate In N,N-dimethyl-formamide at 75℃; for 21h;	57%
With caesium carbonate In N,N-dimethyl-formamide at 75℃; for 18h;	49%
With caesium carbonate In N,N-dimethyl-formamide at 75℃; for 18h;	49%
With caesium carbonate at 25 - 40℃;
With caesium carbonate In N,N-dimethyl-formamide at 30 - 45℃; for 24h;	0.55 kg

1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-D-glucopyranoside (1417573-74-0) → empagliflozin (864070-44-0)

Conditions	Yield
With triethylsilane; aluminum (III) chloride In dichloromethane; acetonitrile at 20 - 25℃;	57%

methyl-1-C-(4-chloro-3-{4-[(3S)-tetrahydrofuran-3-yloxy]benzyl}phenyl)-D-glucopyranoside (915095-96-4) → empagliflozin (864070-44-0)

Conditions	Yield
With triethylsilane; boron trifluoride diethyl etherate In dichloromethane; acetonitrile at -20 - 10℃; for 2h; Product distribution / selectivity;
Multi-step reaction with 3 steps 1: trimethylsilan; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / -40 - -30 °C 2: isopropyl alcohol; dichloromethane / 40 - 50 °C 3: ethyl acetate; water / 25 - 50 °C View Scheme
Multi-step reaction with 3 steps 1: dmap / dichloromethane; pyridine / -5 - 30 °C / Large scale 2: boron trifluoride diethyl etherate; triethylsilane / acetonitrile; water / 0 - 10 °C / Large scale 3: lithium hydroxide / tetrahydrofuran; methanol / 10 - 40 °C View Scheme

fluorobenzene (462-06-6) → empagliflozin (864070-44-0)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: oxalyl dichloride / N,N-dimethyl-formamide / 5 h / 25 - 30 °C 1.2: 6 h / 20 - 30 °C 2.1: potassium tert-butylate / tetrahydrofuran / 4 h / 16 - 25 °C 2.2: 1.83 h / 20 - 21 °C 3.1: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / toluene / 2.5 h / 18 - 26 °C 4.1: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.83 h / -21 - -15 °C 4.2: 2.92 h / -25 - -13 °C View Scheme
Multi-step reaction with 4 steps 1.1: oxalyl dichloride; aluminum (III) chloride / N,N-dimethyl-formamide / 25 - 45 °C / Industry scale 2.1: potassium tert-butylate / tetrahydrofuran / 4 h / 16 - 25 °C / Industry scale 3.1: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / toluene / 2.5 h / 18 - 26 °C / Industry scale 3.2: 20 - 51 °C / Industry scale 4.1: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.83 h / -21 - -15 °C / Industry scale 4.2: 2.92 h / -25 - -18 °C / Industry scale 4.3: -13 - 19 °C / Industry scale View Scheme
Multi-step reaction with 4 steps 1.1: potassium tert-butylate / tetrahydrofuran; tert-butyl alcohol / 1.5 h / 0 - 10 °C / Inert atmosphere; Large scale 2.1: aluminum (III) chloride / ethyl acetate / 9 h / 78 °C / Cooling with ice; Large scale 3.1: n-butyllithium / tetrahydrofuran; toluene; hexane / 3 h / -78 °C / Inert atmosphere; Large scale 3.2: 10 h / 0 - 40 °C / Inert atmosphere; Large scale 4.1: aluminum (III) chloride; triethylsilane / dichloromethane; acetonitrile / 2 h / -5 - 10 °C / Large scale View Scheme
Multi-step reaction with 4 steps 1.1: potassium tert-butylate / tetrahydrofuran / 1 h / 0 - 10 °C / Inert atmosphere; Large scale 2.1: ethyl acetate / 0.5 h / Cooling with ice; Large scale 2.2: 8.5 h / 78 °C / Cooling with ice; Large scale 3.1: n-butyllithium / tetrahydrofuran; toluene / 1 h / -78 °C / Large scale 3.2: 3 h / -78 °C / Large scale 3.3: 10 h / 0 - 40 °C / Large scale 4.1: aluminum (III) chloride / dichloromethane; acetonitrile / 0.5 h / 5 °C / Large scale 4.2: 2 h / 10 °C / Large scale View Scheme

2-chloro-5-iodobenzoic acid (19094-56-5) → empagliflozin (864070-44-0)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: oxalyl dichloride / N,N-dimethyl-formamide / 5 h / 25 - 30 °C 1.2: 6 h / 20 - 30 °C 2.1: potassium tert-butylate / tetrahydrofuran / 4 h / 16 - 25 °C 2.2: 1.83 h / 20 - 21 °C 3.1: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / toluene / 2.5 h / 18 - 26 °C 4.1: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.83 h / -21 - -15 °C 4.2: 2.92 h / -25 - -13 °C View Scheme
Multi-step reaction with 4 steps 1.1: oxalyl dichloride; aluminum (III) chloride / N,N-dimethyl-formamide / 25 - 45 °C / Industry scale 2.1: potassium tert-butylate / tetrahydrofuran / 4 h / 16 - 25 °C / Industry scale 3.1: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / toluene / 2.5 h / 18 - 26 °C / Industry scale 3.2: 20 - 51 °C / Industry scale 4.1: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.83 h / -21 - -15 °C / Industry scale 4.2: 2.92 h / -25 - -18 °C / Industry scale 4.3: -13 - 19 °C / Industry scale View Scheme
Multi-step reaction with 8 steps 1: oxalyl dichloride; N,N-dimethyl-formamide / fluorobenzene / 2 h / 15 - 25 °C 2: aluminum (III) chloride / 1 h / 0 - 25 °C 3: potassium tert-butylate / tetrahydrofuran / 0.5 h / 7 - 10 °C 4: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / toluene / 2.5 h / 0 - 23 °C 5: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.5 h / -20 - 10 °C 6: hydrogenchloride / isopropyl alcohol / 5 h / 38 - 42 °C / pH 2 7: hydrogenchloride / isopropyl alcohol; methanol 8: aluminum (III) chloride; triethylsilane / dichloromethane; acetonitrile / 0.5 h / 20 - 25 °C View Scheme

(2-chloro-5-iodophenyl)(4-fluorophenyl)methanone (915095-86-2) → empagliflozin (864070-44-0)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: potassium tert-butylate / tetrahydrofuran / 4 h / 16 - 25 °C 1.2: 1.83 h / 20 - 21 °C 2.1: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / toluene / 2.5 h / 18 - 26 °C 3.1: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.83 h / -21 - -15 °C 3.2: 2.92 h / -25 - -13 °C View Scheme
Multi-step reaction with 3 steps 1.1: potassium tert-butylate / tetrahydrofuran / 4 h / 16 - 25 °C / Industry scale 2.1: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / toluene / 2.5 h / 18 - 26 °C / Industry scale 2.2: 20 - 51 °C / Industry scale 3.1: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.83 h / -21 - -15 °C / Industry scale 3.2: 2.92 h / -25 - -18 °C / Industry scale 3.3: -13 - 19 °C / Industry scale View Scheme
Multi-step reaction with 6 steps 1: potassium tert-butylate / tetrahydrofuran / 0.5 h / 7 - 10 °C 2: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / toluene / 2.5 h / 0 - 23 °C 3: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.5 h / -20 - 10 °C 4: hydrogenchloride / isopropyl alcohol / 5 h / 38 - 42 °C / pH 2 5: hydrogenchloride / isopropyl alcohol; methanol 6: aluminum (III) chloride; triethylsilane / dichloromethane; acetonitrile / 0.5 h / 20 - 25 °C View Scheme
Multi-step reaction with 6 steps 1: potassium tert-butylate / tetrahydrofuran / 2 - 10 °C 2: sodium tetrahydroborate / ethanol / 20 - 25 °C 3: methanesulfonic acid / 20 - 30 °C 4: n-butyllithium / tetrahydrofuran; hexane / -75 - -70 °C / Inert atmosphere 5: methanesulfonic acid / 20 - 25 °C 6: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / -40 - 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 6 steps 1: potassium tert-butylate / tetrahydrofuran / 2 - 10 °C 2: sodium tetrahydroborate / ethanol / 20 - 25 °C 3: triethylamine / dichloromethane / 0 - 35 °C 4: n-butyllithium / tetrahydrofuran; hexane / -75 - -70 °C / Inert atmosphere 5: methanesulfonic acid / 0 - 35 °C 6: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / -40 - 20 °C / Inert atmosphere View Scheme

(S)-(2-chloro-5-iodophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-87-3) → empagliflozin (864070-44-0)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / toluene / 2.5 h / 18 - 26 °C 2.1: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.83 h / -21 - -15 °C 2.2: 2.92 h / -25 - -13 °C View Scheme
Multi-step reaction with 2 steps 1.1: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / toluene / 2.5 h / 18 - 26 °C / Industry scale 1.2: 20 - 51 °C / Industry scale 2.1: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.83 h / -21 - -15 °C / Industry scale 2.2: 2.92 h / -25 - -18 °C / Industry scale 2.3: -13 - 19 °C / Industry scale View Scheme
Multi-step reaction with 5 steps 1: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / toluene / 2.5 h / 0 - 23 °C 2: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.5 h / -20 - 10 °C 3: hydrogenchloride / isopropyl alcohol / 5 h / 38 - 42 °C / pH 2 4: hydrogenchloride / isopropyl alcohol; methanol 5: aluminum (III) chloride; triethylsilane / dichloromethane; acetonitrile / 0.5 h / 20 - 25 °C View Scheme
Multi-step reaction with 5 steps 1: sodium tetrahydroborate / ethanol / 20 - 25 °C 2: methanesulfonic acid / 20 - 30 °C 3: n-butyllithium / tetrahydrofuran; hexane / -75 - -70 °C / Inert atmosphere 4: methanesulfonic acid / 20 - 25 °C 5: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / -40 - 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 5 steps 1: sodium tetrahydroborate / ethanol / 20 - 25 °C 2: triethylamine / dichloromethane / 0 - 35 °C 3: n-butyllithium / tetrahydrofuran; hexane / -75 - -70 °C / Inert atmosphere 4: methanesulfonic acid / 0 - 35 °C 5: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / -40 - 20 °C / Inert atmosphere View Scheme

(3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran (915095-94-2) → empagliflozin (864070-44-0)

Conditions	Yield
Multi-step reaction with 4 steps 1: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.5 h / -20 - 10 °C 2: hydrogenchloride / isopropyl alcohol / 5 h / 38 - 42 °C / pH 2 3: hydrogenchloride / isopropyl alcohol; methanol 4: aluminum (III) chloride; triethylsilane / dichloromethane; acetonitrile / 0.5 h / 20 - 25 °C View Scheme
Multi-step reaction with 3 steps 1: lithium chloride; isopropylmagnesium chloride / tetrahydrofuran / -30 - -20 °C / Inert atmosphere; Large scale 2: hydrogenchloride / methanol; water / 4 h / 20 °C / Large scale 3: aluminum (III) chloride; triethylsilane / acetonitrile; dichloromethane View Scheme
Multi-step reaction with 3 steps 1.1: TurboGrignard / tetrahydrofuran / 1 h / -30 - -20 °C / Inert atmosphere 1.2: 0.5 h / Inert atmosphere 2.1: hydrogenchloride / water / 1 h / 20 - 30 °C 3.1: aluminum (III) chloride; triethylsilane / dichloromethane; acetonitrile View Scheme

C35H59ClO8Si4 → empagliflozin (864070-44-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: hydrogenchloride / isopropyl alcohol / 5 h / 38 - 42 °C / pH 2 2: hydrogenchloride / isopropyl alcohol; methanol 3: aluminum (III) chloride; triethylsilane / dichloromethane; acetonitrile / 0.5 h / 20 - 25 °C View Scheme

C24H29ClO8 → empagliflozin (864070-44-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrogenchloride / isopropyl alcohol; methanol 2: aluminum (III) chloride; triethylsilane / dichloromethane; acetonitrile / 0.5 h / 20 - 25 °C View Scheme

2-chloro-5-iodobenzoylchloride (281652-58-2) → empagliflozin (864070-44-0)

Conditions	Yield
Multi-step reaction with 7 steps 1: aluminum (III) chloride / 1 h / 0 - 25 °C 2: potassium tert-butylate / tetrahydrofuran / 0.5 h / 7 - 10 °C 3: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / toluene / 2.5 h / 0 - 23 °C 4: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.5 h / -20 - 10 °C 5: hydrogenchloride / isopropyl alcohol / 5 h / 38 - 42 °C / pH 2 6: hydrogenchloride / isopropyl alcohol; methanol 7: aluminum (III) chloride; triethylsilane / dichloromethane; acetonitrile / 0.5 h / 20 - 25 °C View Scheme
Multi-step reaction with 7 steps 1: aluminum (III) chloride / 25 °C / Inert atmosphere 2: potassium tert-butylate / tetrahydrofuran / 2 - 10 °C 3: sodium tetrahydroborate / ethanol / 20 - 25 °C 4: methanesulfonic acid / 20 - 30 °C 5: n-butyllithium / tetrahydrofuran; hexane / -75 - -70 °C / Inert atmosphere 6: methanesulfonic acid / 20 - 25 °C 7: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / -40 - 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 7 steps 1: aluminum (III) chloride / 25 °C / Inert atmosphere 2: potassium tert-butylate / tetrahydrofuran / 2 - 10 °C 3: sodium tetrahydroborate / ethanol / 20 - 25 °C 4: triethylamine / dichloromethane / 0 - 35 °C 5: n-butyllithium / tetrahydrofuran; hexane / -75 - -70 °C / Inert atmosphere 6: methanesulfonic acid / 0 - 35 °C 7: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / -40 - 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 8 steps 1: aluminum (III) chloride / chlorobenzene / 1.5 h / 5 °C / Inert atmosphere 2: aluminum (III) chloride / chlorobenzene / 5 - 60 °C / Inert atmosphere 3: 1,1,3,3-tetramethyldisilazane / chlorobenzene / 5.5 h / 5 - 25 °C 4: dmap; triethylamine / dichloromethane / 3 h / 5 - 28 °C 5: n-butyllithium / tetrahydrofuran; toluene; hexane / 4 h / -80 °C / Inert atmosphere; Large scale 6: methanesulfonic acid / tetrahydrofuran; toluene; hexane / 12.5 h / -70 - 30 °C / Inert atmosphere 7: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / 9 h / -30 - -5 °C 8: caesium carbonate / N,N-dimethyl-formamide / 24 h / 30 - 45 °C View Scheme

(2-chloro-5-bromophenyl)(4-fluorophenyl)methanone (915095-85-1) → empagliflozin (864070-44-0)

Conditions	Yield
Multi-step reaction with 6 steps 1: potassium tert-butylate / tetrahydrofuran / 2 - 10 °C 2: sodium tetrahydroborate / ethanol / 20 - 25 °C 3: triethylamine / dichloromethane / 0 - 35 °C 4: n-butyllithium / tetrahydrofuran; hexane / -75 - -70 °C / Inert atmosphere 5: methanesulfonic acid / 0 - 35 °C 6: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / -40 - 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 7 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 100 - 110 °C 2.1: aluminum (III) chloride; sodium tetrahydroborate / tetrahydrofuran / 24.5 h / 0 - 60 °C 3.1: n-butyllithium / tetrahydrofuran / 1 h / -80 - -70 °C 3.2: -80 - 0 °C 4.1: sodium tetrahydroborate; cerium(III) chloride heptahydrate / methanol / 2 h / -80 - 70 °C 5.1: acetic acid / water / 100 °C 5.2: 5 h / 0 - 30 °C 6.1: potassium fluoride; trimethylsilyl trifluoromethanesulfonate / acetonitrile / -80 - -70 °C 7.1: potassium hydroxide; water / acetonitrile / 50 - 60 °C View Scheme
Multi-step reaction with 5 steps 1: potassium tert-butylate / tetrahydrofuran / 2 h / 0 - 10 °C 2: aluminum (III) chloride; potassium borohydride / tetrahydrofuran / 6 h / 20 °C 3: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate / 1,4-dioxane / 8 h / 8 °C / Inert atmosphere 4: tetrakis(triphenylphosphine) palladium(0); potassium dihydrogenphosphate / toluene / 12 h / 105 °C 5: sodium hydroxide / methanol / 1 h / 20 °C View Scheme

(S)-(5-bromo-2-chlorophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-84-0) → empagliflozin (864070-44-0)

Conditions	Yield
Multi-step reaction with 5 steps 1: sodium tetrahydroborate / ethanol / 20 - 25 °C 2: triethylamine / dichloromethane / 0 - 35 °C 3: n-butyllithium / tetrahydrofuran; hexane / -75 - -70 °C / Inert atmosphere 4: methanesulfonic acid / 0 - 35 °C 5: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / -40 - 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1.1: potassium borohydride; aluminium trichloride / tetrahydrofuran / 0.5 h / 0 - 20 °C 2.1: TurboGrignard / tetrahydrofuran / -10 - 0 °C / Cooling with ice; Inert atmosphere 2.3: 40 - 50 °C / Inert atmosphere 3.1: lithium hydroxide / ethanol; water / 40 - 45 °C View Scheme
Multi-step reaction with 3 steps 1.1: potassium borohydride; aluminium trichloride / tetrahydrofuran / 0.5 h / 0 - 20 °C 2.1: TurboGrignard / tetrahydrofuran / 0.5 h / -10 - 0 °C / Cooling with ice; Inert atmosphere 2.2: 40 - 50 °C / Inert atmosphere 3.1: potassium carbonate / tetrahydrofuran / 40 - 45 °C View Scheme

C17H16BrClO3 → empagliflozin (864070-44-0)

Conditions	Yield
Multi-step reaction with 4 steps 1: triethylamine / dichloromethane / 0 - 35 °C 2: n-butyllithium / tetrahydrofuran; hexane / -75 - -70 °C / Inert atmosphere 3: methanesulfonic acid / 0 - 35 °C 4: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / -40 - 20 °C / Inert atmosphere View Scheme

2-chloro-5-bromobenzaldehyde (189628-37-3) → empagliflozin (864070-44-0)

Conditions	Yield
Multi-step reaction with 5 steps 1: n-butyllithium / tetrahydrofuran; hexane / -75 - -70 °C / Inert atmosphere 2: triethylamine / dichloromethane / 0 - 35 °C 3: n-butyllithium / tetrahydrofuran; hexane / -75 - -70 °C / Inert atmosphere 4: methanesulfonic acid / 0 - 35 °C 5: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / -40 - 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 5 steps 1.1: sodium tetrahydroborate / ethanol / 4 h / 20 °C / Large scale 1.2: pH 4-5 / Cooling with ice; Large scale 2.1: thionyl chloride / 3 h / 70 °C / Large scale 3.1: ethyl acetate / 0.5 h / Cooling with ice; Large scale 3.2: 8.5 h / 78 °C / Cooling with ice; Large scale 4.1: n-butyllithium / tetrahydrofuran; toluene / 1 h / -78 °C / Large scale 4.2: 3 h / -78 °C / Large scale 4.3: 10 h / 0 - 40 °C / Large scale 5.1: aluminum (III) chloride / dichloromethane; acetonitrile / 0.5 h / 5 °C / Large scale 5.2: 2 h / 10 °C / Large scale View Scheme

(S)-3-(4-bromophenoxy)tetrahydrofuran (857854-82-1) → empagliflozin (864070-44-0)

Conditions

Yield

Multi-step reaction with 5 steps 1: n-butyllithium / tetrahydrofuran; hexane / -75 - -70 °C / Inert atmosphere 2: triethylamine / dichloromethane / 0 - 35 °C 3: n-butyllithium / tetrahydrofuran; hexane / -75 - -70 °C / Inert atmosphere 4: methanesulfonic acid / 0 - 35 °C 5: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / -40 - 20 °C / Inert atmosphere View Scheme

C20H24BrClO3Si → empagliflozin (864070-44-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: n-butyllithium / tetrahydrofuran; hexane / -75 - -70 °C / Inert atmosphere 2: methanesulfonic acid / 0 - 35 °C 3: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / -40 - 20 °C / Inert atmosphere View Scheme

C17H16ClIO3 → empagliflozin (864070-44-0)

Conditions	Yield
Multi-step reaction with 4 steps 1: triethylamine / dichloromethane / 0 - 35 °C 2: n-butyllithium / tetrahydrofuran; hexane / -75 - -70 °C / Inert atmosphere 3: methanesulfonic acid / 0 - 35 °C 4: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / -40 - 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 4 steps 1: methanesulfonic acid / 20 - 30 °C 2: n-butyllithium / tetrahydrofuran; hexane / -75 - -70 °C / Inert atmosphere 3: methanesulfonic acid / 20 - 25 °C 4: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / -40 - 20 °C / Inert atmosphere View Scheme

C20H24ClIO3Si → empagliflozin (864070-44-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: n-butyllithium / tetrahydrofuran; hexane / -75 - -70 °C / Inert atmosphere 2: methanesulfonic acid / 0 - 35 °C 3: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / -40 - 20 °C / Inert atmosphere View Scheme

empagliflozin (864070-44-0) + acetic anhydride (108-24-7) → (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-trityl triacetate

Conditions	Yield
With pyridine; dmap In dichloromethane at 20℃; for 4h;	91%

empagliflozin (864070-44-0) → C23H28O7

Conditions	Yield
With ethanol for 0.5h; Reflux; Large scale;	90%

empagliflozin (864070-44-0) + (2E)-but-2-enedioic acid (110-17-8) → C23H27ClO7*C4H4O4

Conditions	Yield
In methanol for 1.8h; Reflux;	90%

empagliflozin (864070-44-0) + citric acid (77-92-9) → empagliflozin citrate

Conditions	Yield
In ethanol for 1.5h; Solvent; Reflux;	89%
In methanol for 1.8h; Reflux;	85%

empagliflozin (864070-44-0) + L-Pyroglutamic acid (98-79-3) → C23H27ClO7*C5H7NO3

Conditions	Yield
In methanol for 0.833333h;	83%

empagliflozin (864070-44-0) + acetic anhydride (108-24-7) → (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-(((S)-tetrahydrofuran-2-yl)oxy)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate

Conditions	Yield
With potassium carbonate In 1,4-dioxane at 60℃; for 24h;	61%

Upstream product

• 462-06-6 fluorobenzene 
• 19094-56-5 2-chloro-5-iodobenzoic acid 
• 915095-94-2 (3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran 
• 32469-28-6 (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one 
• 915095-86-2 (2-chloro-5-iodophenyl)(4-fluorophenyl)methanone 
• 915095-87-3 (S)-(2-chloro-5-iodophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone 
• 281652-58-2 2-chloro-5-iodobenzoylchloride 
• 21739-92-4 5-bromo-2-chlorobenzoic acid 
• 21900-52-7 5-bromo-2-chloro-benzoyl chloride 
• 1198-69-2 D-glucono-1,4-lactone 
• 108-95-2 phenol 
• 637-87-6 1-Chloro-4-iodobenzene 

Downstream Products

• 915095-99-7 (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-trityl triacetate 

Relevant articles and documents

Synthetic method of empagliflozin

The invention discloses a synthesis method of empagliflozin. According to the method, (S)-3-(4-(5-bromo-2-chlorobenzyl) phenoxy) tetrahydrofuran is adopted as a starting raw material and is coupled with 2, 3, 4, 6-tetrabenzyl-D-glucopyranosyl-1, 5-lactone under the catalysis of Pd2 (dba) 3 and the combined action of p-toluenesulfonhydrazide, Xphos and lithium tert-butoxide to generate an intermediate I, double bonds of the intermediate I are subjected to hydrogenation reduction through raney nickel, meanwhile, debenzylation is conducted, and the empagliflozin is obtained. The method does not need butyl lithium, Grignard reagent and other dangerous materials, has the advantages of short reaction route, simple reaction and post-treatment, high safety, few side reactions, high product yield and high purity, and is especially suitable for industrial production.

Preparation method of SGLT-2 inhibitor and intermediate

The invention discloses a preparation method of an SGLT-2 inhibitor and an intermediate. The method comprises the following steps: (1) reacting a compound A with chlorosilane under the action of an acid-binding agent to generate a compound B; (2) mixing the compound B and a compound C to obtain a compound D; and (3) reacting the compound D with a reducing agent and a catalyst to obtain the SGLT-2 inhibitor compound.

Synthetic method of empagliflozin

The invention belongs to the technical field of raw material medicine preparation, and relates to a synthetic method of an SGLT-2 inhibitor empagliflozin, which comprises the following steps: 1) taking glucose as an initial raw material, and preparing an active intermediate 3 through full acylation, selective hydrolysis and esterification; 2) reacting the intermediate 3 with chlorobenzene under the catalysis of boron trifluoride/diethyl ether to generate an intermediate 4, and reacting the intermediate 4 with paraformaldehyde and phenoxy tetrahydrofuran to generate an intermediate 5; and 3) removing the protecting group under the action of alkali to obtain the final product empagliflozin. The method is simple to operate, low-temperature reaction in the prior art is avoided, and the purity of the obtained product is higher.

IMPROVED PROCESS FOR THE PREPARATION OF EMPAGLIFLOZIN AND ITS CRYSTALLINE POLYMORPH

The present invention relates to an improved method for the production of Empagliflozin formula (I). The invention further relates to the preparation of a crystalline form of Empagliflozin and its particle size having a coarser particle or a D50 equal to or greater than 60 μm and a D90 equal to or greater than 180 μm. (I)

Preparation method of glucopyranosyl substituted benzyl benzene derivative and intermediate thereof

The invention relates to a preparation method of a glucopyranosyl substituted benzyl benzene derivative and an intermediate thereof, and a method for preparing a compound represented by a formula (I),wherein the group R is defined in claim 1. The method is simple to operate, high in product yield, good in selectivity and suitable for industrial production. The present invention relates to theintermediate obtained in the method.

Synthetic method of empagliflozin

The invention provides a brand-new synthesis process of empagliflozin. According to the process, a boric acid ester is used for halogen removal, and specific reaction conditions are combined, so thatempagliflozin can be prepared with high yield and simplicity and convenience in operation. The synthesis method of empagliflozin has the advantages of mild reaction conditions, high total yield, few side reactions and convenience in operation, thereby being beneficial to industrial production and cost control.

Preparation method suitable for industrial production of empagliflozin

The invention belongs to the technical field of organic synthesis route design and medicine and chemical engineering, particularly relates to a synthesis method of a sodium-glucose cotransporter 2(SGLT2) inhibitor, and more particularly relates to a preparation method of empagliflozin. The empagliflozin is synthesized by taking (3S)-3-[4-[(2-chloro-5-iodophenyl) methyl] phenoxy] tetrahydrofuran and glucono delta-lactone as initial raw materials through a series of substep reactions such as protection, addition, substitution, deprotection and reduction. In the synthesis steps disclosed by the invention, a staged target product does not need to be separated and purified after each step of reaction, and the target product is finally obtained by directly subjecting a high-purity reaction intermediate to subsequent steps. The preparation method is simple in process, simple and convenient to operate and good in industrial prospect.

Synthesizing method suitable for industrial empagliflozin production

The invention discloses a synthesizing method suitable for industrial empagliflozin production. The synthesizing method includes: subjecting a compound as shown in formula (II) to reduction reaction to obtain a compound as shown in formula (I), and removing the protecting groups of the compound as shown in formula (I) to obtain empagliflozin. The synthesizing method has the advantages that the method is simple in process, only needs one-step reduction reaction and can effectively reduce the repeated use of high-toxicity and high-risk chemicals; in addition, the intermediate purified after derivation protection, effective process control is achieved, and product quality is increased; the method is high in practical application value and suitable for industrial production.

Refining method of SGLT-2 inhibitor intermediate

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