842133-18-0

Basic information

• Product Name: Canagliflozin
• Synonyms: TA 7284;Canaglifozion;D-Glucitol, 1,5-anhydro-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]Methyl]-4-Methylphenyl]-, (1S)-;Cango coluMn net;Canagliflozin WS;Canagliflozin(TA-7284);(2S,3R,4R,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)-tetrahydro-2H-pyran-3,4,5-triol;Canaglifozin
• CAS NO: 842133-18-0
• Molecular Formula: C₂₄H₂₅FO₅S
• Molecular Weight: 444.5157032
• EINECS: 1308068-626-2
• Product Categories: Aromatics;Heterocycles;Inhibitors;Intermediates & Fine Chemicals;Pharmaceuticals;Sulfur & Selenium Compounds;Other APIs;Stable Isotopes
• Mol File: 842133-18-0.mol

Chemical Properties

• Boiling Point: 642.9±55.0 °C at 760 mmHg
• Flash Point: 342.6±31.5 °C
• Appearance: /
• Density: 1.364
• Storage Temp.: -20°C
• Solubility: Soluble in DMSO (40 mg/ml)
• PKA: 13.34±0.70(Predicted)
• Stability: Stable for 2 years from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 1 month.
• CAS DataBase Reference: Canagliflozin(CAS DataBase Reference)
• NIST Chemistry Reference: Canagliflozin(842133-18-0)
• EPA Substance Registry System: Canagliflozin(842133-18-0)

Safety Data

• Hazardous Substances Data: 842133-18-0(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Canagliflozin is used as an antidiabetic drug for the treatment of type 2 diabetes in adults. It functions by inhibiting the sodium/glucose cotransporter 2 (SGLT2) in the kidney, which reduces glucose reabsorption and promotes glucose excretion in the urine, leading to a decrease in blood glucose levels.
Used in Obesity Treatment:
Canagliflozin is also a candidate for the treatment of obesity due to its ability to increase urinary glucose excretion, which can lead to weight loss. By reducing the amount of glucose absorbed by the body, Canagliflozin may help to decrease overall calorie intake and promote weight reduction.

Oral diabetes drugs

Canagliflozin is an Inhibitor drug for SGLT2. It can lower blood glucose levels by expelling the glucose from the body through the kidneys after its decomposition. In addition, Canagliflozin has a broad prospect due to its significant antiobesity effects and few hypoglycemic events. According to the results of 2 phase III clinical trials on June 9th, 2012, Canagliflozin, which is an Experimental type 2 diabetes drug of JNJ is better than Januvia of Merck or an older drug called glimepiride. Meanwhile, Canagliflozin has a more significant antiobesity effect. Compared with glimepiride, it causes less hypoglycemic events. On January 11th, 2013, Janssen Pharmaceutical of JNJ announced that its diabetes drug canagliflozin (trade name INVOKANA?）was recommended and approved by the committee of experts of FDA by the vote of 10 to 5 to treat adult patients with type 2 diabetes. On march 29th, 2013, canagliflozin (trade name INVOKANA, Janssen Pharmaceutical China of JNJ）was approved by the US Food and Drug Administration (FDA) to control blood glucose of adult patients with type 2 diabetes. On December 25th, 2013, Janssen Pharmaceutical of JNJ announced that new diabetes drug INVOKANA（canagliflozin）was approved by European Commission（EC）to treat adult patients with type 2 diabetes and improve glucose control. In September, 2014, Canagliflozin Won the positive Suggestions for recommend approval of Committee for Medicinal Products for Human Use （CHMP） of? European Medicines Agency (EMA). In addition, Canagliflozin has been approved by FDA in March this year, and approved by Australia rencently. Canagliflozin is a once daily oral diabetes drug, which works by inhibiting sodium glucose co-transporter 2 (SGLT2）as a new drug. It can lower blood glucose levels by interdicting the blood glucose reabsorption of the kidneys and increasing the excretion of blood glucose in urine. Compared with non-diabetic population, the kidneys of adult patients with type 2 diabetes absorb a large number of glucose into the blood stream, which will push up the blood glucose levels. Canagliflozin is one of the most promising drug candidates of JNJ. The department of Janssen Pharmaceutical of JNJ has the rights to sell this drug in North America, South America, Europe, Middle East, Africa, Australia, New Zealand and some Asian countries.

Clinical study

Canagliflozin is the first FDA approved inhibitor for SGLT2 and used to treat adult patients with type 2 diabetes. As a kind of glucose transporter, SGLT has two subtypes of SGLT1and SGLT2, which are distributed in the intestinal mucosa and renal tubular respectively, and able to transport glucose into the blood. Canagliflozin can inhibit SLCT2 and, interdict the reabsorption of glucose in Renal tubular and increase the excretion of blood glucose in urine. Thus, the blood glucose levels can be lowered. Glucose was passed into the urine through the kidneys, accompanied by renal impairment, symptomatic hypotension, fungal infections and other side effects. 9 clinical trials involving 10285 patients have demonstrated the safety and efficacy of Invokana, either used alone or in combination with other hypoglycemic agents. In a double-blind controlled trial for 26 weeks, 584 adult patients with type 2 diabetes were divided into three groups, namely 100mg Canagliflozin group, 300mg Canagliflozin group and placebo group. Compared with placebo group, the HbA1c of the 100mg Canagliflozin group and 300mg Canagliflozin group was lowed extra 0.91% and 1.16% respectively.

How it works

Invokana is in a class of drugs called sodium-glucose transport protein 2 (or SGLT2) inhibitors, which drugs work by increasing the amount of glucose that gets passed out in the urine. When blood passes through the kidneys, the kidneys filter glucose out of the blood and the SGLT proteins then help reabsorb glucose back into the blood. SGLT2 proteins are responsible for 90% of the glucose that is reabsorbed, so by blocking the action these proteins, less glucose is reabsorbed and so more glucose is excreted via the urine.

Invokana tables

Invokana is supplied as film-coated tablets for oral administration, containing 102 and 306 mg of canagliflozin in each tablet strength, corresponding to 100 mg and 300 mg of canagliflozin (anhydrous), respectively. Inactive ingredients of the core tablet are croscarmellose sodium, hydroxypropyl cellulose, lactose anhydrous, magnesium stearate, and microcrystalline cellulose. The magnesium stearate is vegetable-sourced. The tablets are finished with a commercially available film-coating consisting of the following excipients: polyvinyl alcohol (partially hydrolyzed), titanium dioxide, macrogol/PEG, talc, and iron oxide yellow, E172 (100 mg tablet only).

Taboo

You should not use Invokana if you have severe kidney disease (or if you are on dialysis). Invokana is not for treating type 1 diabetes.

References

https://www.drugs.com/cdi/canagliflozin.html http://www.diabetes.co.uk/diabetes-medication/invokana-canagliflozin.html

References

Nomura et al. (2010), Discovery of canagliflozin, a novel C-glucoside with thiophene ring, as sodium-dependent glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes mellitus; J. Med. Chem., 53 6355 Shaw et al. (2011), Canagliflozin, a novel inhibitor of sodium glucose co-transporter 2, dose dependently reduces calculated renal threshold for glucose excretion and increases urinary glucose excretion in healthy subjects; Diabetes Obes. Metab., 13 669 Mantovani et al. (2020), Sodium-Glucose Cotransporter-2 Inhibitors for Treatment of Nonalcoholic Fatty Liver Disease: A Meta-Analysis of Randomized Controlled Trials; Metabolites, 11 22 Miller et al. (2020), Canagliflozin extends life span in genetically heterogeneous male but not female mice; JCI Insight, 5 e140019 Vilani et al. (2016), The diabetes medication Canagliflozin reduces cancer cell proliferation by inhibiting mitochondrial complex-I supported respiration; Mol. Metab., 5 1048 Xu et al. (2020), Inhibitory effects of canagliflozin on pancreatic cancer are mediated via the downregulation of glucose transporter-1 and lactate dehydrogenase A; Int. J. Oncol. 57 1223

Originator

Mitsubishi Tanabe Pharma (Japan)

Clinical Use

Sodium-glucose co-transporter 2 inhibitor: Treatment of type 2 diabetes

Drug interactions

Potentially hazardous interactions with other drugs Antibacterials: concentration reduced by rifampicin. Lipid-regulating drugs: avoid canagliflozin for 1 hour before or 4-6 hours after bile acid sequestrants.

Metabolism

O-glucuronidation is the major metabolic elimination pathway mainly by UGT1A9 and UGT2B4 to two inactive metabolites. CYP3A4-mediated (oxidative) metabolism of canagliflozin is minimal (approximately 7%) in humans.

Synthetic route

(3R,4R,5S)-2-(acetoxymethyl)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (866607-35-4) → canagliflozin (842133-18-0)

Conditions	Yield
With water; sodium hydroxide In tetrahydrofuran; methanol at 20 - 25℃; for 1.16667h;	98%
With di(n-butyl)tin oxide In methanol for 24h; Reflux; Inert atmosphere;	95%
With methanol; sodium methylate In tetrahydrofuran at 0 - 10℃; for 3h; Reagent/catalyst;	94.9%

(2S,3S,4R,5R,6R)-6-(benzoylmethyl)-3,4,5-tribenzoyl-2-{3-[(5-(4-fluorophenyl)-2-thienyl)methyl]-4-methylphenyl}-2H-glucopyranoside → canagliflozin (842133-18-0)

Conditions	Yield
With sodium methylate In tetrahydrofuran; methanol at 40℃; for 2h;	96%

C44H45Cl12FO9S → canagliflozin (842133-18-0)

Conditions	Yield
With water; lithium hydroxide In methanol at 0 - 5℃; for 16h;	93.3%

C44H49Cl8FO9S → canagliflozin (842133-18-0)

Conditions	Yield
With water; lithium hydroxide In methanol at 0 - 5℃; for 16h;	92.1%

C44H53Cl4FO9S → canagliflozin (842133-18-0)

Conditions	Yield
With water; potassium hydroxide In tetrahydrofuran; methanol at 0 - 5℃; for 16h; Reagent/catalyst; Solvent;	92.1%

(2R,3R,4R,5S,6S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-6-(3-((5-(4-fluorophenyl)-thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran → canagliflozin (842133-18-0)

Conditions	Yield
With trimethylsilyl iodide In dichloromethane at 0 - 20℃; for 8h; Inert atmosphere; Schlenk technique; Glovebox;	92%
With palladium 10% on activated carbon In dichloromethane Inert atmosphere;	90%
With trimethylsilyl iodide In dichloromethane at 0 - 30℃; Concentration; Reagent/catalyst; Temperature; Solvent;	90%

(2S,3S,4R,5R,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(pivaloyloxymethyl)tetrahydro-2H-pyran-3,4,5-thiyl tris(2,2-dimethylpropanoate) (1283129-18-9) → canagliflozin (842133-18-0)

Conditions	Yield
With hydrogenchloride In methanol; water for 2h; Reflux; Large scale;	91%
With methanol; sodium methylate at 60℃; for 16h; Product distribution / selectivity;	90%
Multi-step reaction with 2 steps 1: methanol / 16 h / 20 - 60 °C 2: water / 1 h / 0 °C View Scheme

(2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9) → canagliflozin (842133-18-0)

Conditions	Yield
With triethylsilane; boron trifluoride diethyl etherate In dichloromethane at -40 - 0℃; for 3h;	90%
Stage #1: (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol With aluminum (III) chloride In dichloromethane; acetonitrile at -5℃; for 0.5h; Stage #2: With triethylsilane In dichloromethane; acetonitrile at -5 - 10℃; for 2h;	79%
With triethylsilane; acetonitrile boron trifluoride complex In n-heptane at -5 - 5℃; for 5h;	77.5%

C44H57FO9S → canagliflozin (842133-18-0)

Conditions	Yield
With methanol Temperature;	85%

(3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1030825-21-8) → canagliflozin (842133-18-0)

Conditions	Yield
Stage #1: (3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol With triethylsilane; boron trifluoride diethyl etherate In dichloromethane at -25 - -10℃; for 2h; Stage #2: With sodium hydrogencarbonate In dichloromethane; water at -10℃; Temperature;	81.36%
With triethylsilane; boron trifluoride diethyl etherate In dichloromethane Inert atmosphere; Cooling with acetone-dry ice; Cooling with ice; enantioselective reaction;	56.7%
With triethylsilane; boron trifluoride diethyl etherate In dichloromethane at 0 - 5℃;

(2S,3R,4R,5S,6R)-2-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol piperdine-4-carboxylic acid complex → canagliflozin (842133-18-0)

Conditions	Yield
In tert-butyl methyl ether; water for 1h;	80%

2,4-di-O-tert-butyldiphenylsilyl-1-C-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-β-D-glucopyranoside (1432591-84-8) → canagliflozin (842133-18-0)

Conditions	Yield
With tetrabutyl ammonium fluoride In tetrahydrofuran at 20℃; for 4h;	73%
With tetrabutyl ammonium fluoride In tetrahydrofuran at 20℃; for 4h; Inert atmosphere;	68%

bis(3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl)chloroalane + levoglucosan (498-07-7) → canagliflozin (842133-18-0)

Conditions	Yield
Stage #1: levoglucosan With diisobutylaluminium hydride In toluene at 20℃; for 0.116667h; Inert atmosphere; Schlenk technique; Stage #2: bis(3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl)chloroalane In dibutyl ether; toluene at 140℃; for 20h;	50%

1-[1-hydroxy-2,3,4,6-tetra-O-(trimethylsilyl)-β-D-glucopyranosyl]-4-methyl-3-[[5-(4-fluorophenyl)-2-thienyl]methyl]benzene (1132832-76-8) → canagliflozin (842133-18-0)

Conditions	Yield
With triethylsilane; boron trifluoride diethyl etherate In 1,1-dichloroethane at -30 - 20℃; for 1.5 - 2h; Product distribution / selectivity;

(2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) (898566-17-1) → canagliflozin (842133-18-0)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: trimethylsilylmethyllithium / toluene; diethyl ether; pentane / 0.75 h / -50 °C / Inert atmosphere 1.2: 1 h / 25 °C 2.1: ethyl acetate; toluene / 21 h / 75 °C / Inert atmosphere 3.1: methanol / 16 h / 20 - 60 °C 4.1: water / 1 h / 0 °C View Scheme
Multi-step reaction with 4 steps 1.1: n-hexyllithium / toluene; hexane; cyclopentyl methyl ether / 1.17 h / -45 - -25 °C / Inert atmosphere 2.1: zinc dibromide; lithium bromide / cyclopropyl methyl ether / -25 - 0 °C 2.2: 48.5 h / 20 - 65 °C 3.1: methanol / 16 h / 20 - 60 °C 4.1: water / 1 h / 0 °C View Scheme
Multi-step reaction with 3 steps 1.1: acetic acid; potassium bromide; sodium hydrogencarbonate / water; dichloromethane / 0.25 h / 20 °C 1.2: 20 - 35 °C 1.3: -70 - -30 °C / Inert atmosphere 2.1: triethylsilane; boron trifluoride diethyl etherate / dichloromethane / 0.5 h / -40 - -20 °C / Inert atmosphere 3.1: trimethylsilyl iodide / dichloromethane / 0 - 30 °C View Scheme

C18H14FLiS → canagliflozin (842133-18-0)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: zinc dibromide; lithium bromide / cyclopropyl methyl ether / -25 - 0 °C 1.2: 48.5 h / 20 - 65 °C 2.1: methanol / 16 h / 20 - 60 °C 3.1: water / 1 h / 0 °C View Scheme

(2S,3S,4R,5R,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(pivaloyloxymethyl)tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate) → canagliflozin (842133-18-0)

Conditions	Yield
With water at 0℃; for 1h;

C36H28F2S2Zn (1283129-24-7) → canagliflozin (842133-18-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: ethyl acetate; toluene / 21 h / 75 °C / Inert atmosphere 2: methanol / 16 h / 20 - 60 °C 3: water / 1 h / 0 °C View Scheme

alpha-D-glucopyranose (492-62-6) → canagliflozin (842133-18-0)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: triethylamine / dmap / dichloromethane / 20.5 h / 0 - 20 °C / Inert atmosphere 2.1: trimethylsilyl bromide / zinc dibromide / dichloromethane / 24 h / 20 °C / Inert atmosphere 2.2: 0 °C / pH 7 - 8 3.1: n-butyllithium; zinc dibromide / n-heptane; toluene; dibutyl ether / 2.5 h / -10 - 25 °C / Inert atmosphere 3.2: 6.5 h / 95 °C 4.1: methanol / sodium methylate / 16 h / 60 °C View Scheme
Multi-step reaction with 4 steps 1: pyridine; dmap; thionyl chloride / dichloromethane / 2 h / 48 - 50 °C / Reflux; Large scale 2: zinc dibromide; trimethylsilyl bromide / dichloromethane / 10 - 25 °C / Inert atmosphere 3: zinc dibromide; lithium bromide / diethyl ether / -76 °C 4: methanol View Scheme
Multi-step reaction with 4 steps 1.1: pyridine; dmap / dichloromethane / 20.5 h / 0 - 20 °C / Inert atmosphere 2.1: zinc dibromide / dichloromethane / 0.08 h / 20 °C / Inert atmosphere 2.2: 24 h / 20 °C 3.1: isopropylmagnesium chloride; lithium chloride; n-butyllithium / tetrahydrofuran; hexane / 3 h / -10 °C / Inert atmosphere 4.1: water; potassium hydroxide / tetrahydrofuran; methanol / 16 h / 0 - 5 °C View Scheme

(2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) (898566-17-1) + 2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosyl bromide (81058-27-7) → canagliflozin (842133-18-0)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: n-butyllithium; zinc dibromide / n-heptane; toluene; dibutyl ether / 2.5 h / -10 - 25 °C / Inert atmosphere 1.2: 6.5 h / 95 °C 2.1: methanol / sodium methylate / 16 h / 60 °C View Scheme

1,2,3,4,6-penta-O-pivaloyl-D-glucopyranoside (1213234-53-7) → canagliflozin (842133-18-0)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: trimethylsilyl bromide / zinc dibromide / dichloromethane / 24 h / 20 °C / Inert atmosphere 1.2: 0 °C / pH 7 - 8 2.1: n-butyllithium; zinc dibromide / n-heptane; toluene; dibutyl ether / 2.5 h / -10 - 25 °C / Inert atmosphere 2.2: 6.5 h / 95 °C 3.1: methanol / sodium methylate / 16 h / 60 °C View Scheme
Multi-step reaction with 3 steps 1: zinc dibromide; trimethylsilyl bromide / dichloromethane / 10 - 25 °C / Inert atmosphere 2: zinc dibromide; lithium bromide / diethyl ether / -76 °C 3: methanol View Scheme

1,6-anhydro-2,4-di-O-tert-butyldiphenylsilyl-β-D-glucopyranose (1432591-75-7) → canagliflozin (842133-18-0)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: magnesium / tetrahydrofuran; ethylene dibromide / 2 h / Reflux 1.2: 1 h / 20 °C 1.3: 5 h / 20 - 150 °C 2.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 4 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1.1: magnesium; ethylene dibromide / tetrahydrofuran / Inert atmosphere; Schlenk technique; Reflux 1.2: 1 h / 20 °C / Inert atmosphere; Schlenk technique; Reflux 2.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 4 h / 20 °C / Inert atmosphere View Scheme

levoglucosan (498-07-7) → canagliflozin (842133-18-0)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: 1H-imidazole / tetrahydrofuran / 0 °C 2.1: magnesium / tetrahydrofuran; ethylene dibromide / 2 h / Reflux 2.2: 1 h / 20 °C 2.3: 5 h / 20 - 150 °C 3.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 4 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: 1H-imidazole / tetrahydrofuran / 0 - 20 °C / Inert atmosphere; Schlenk technique 2.1: magnesium; ethylene dibromide / tetrahydrofuran / Inert atmosphere; Schlenk technique; Reflux 2.2: 1 h / 20 °C / Inert atmosphere; Schlenk technique; Reflux 3.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 4 h / 20 °C / Inert atmosphere View Scheme

1,6-anhydro-β-D-glucopyranose 2,4-O-phenylboronate (32741-93-8) → canagliflozin (842133-18-0)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: water / dimethylsulfoxide-d6 / 1 h / 20 °C / Inert atmosphere 2.1: diisobutylaluminium hydride / toluene / 0.12 h / 20 °C / Inert atmosphere; Schlenk technique 2.2: 20 h / 140 °C View Scheme

2-[(5-bromo-2-methyl-phenyl)methyl]-5-(4-fluorophenyl)thiophene (1030825-20-7) → canagliflozin (842133-18-0)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: n-butyllithium / toluene; di-isopropyl ether; hexane / 0 °C / Inert atmosphere; Schlenk technique 1.2: 90 °C / Inert atmosphere; Schlenk technique 2.1: diisobutylaluminium hydride / toluene / 0.12 h / 20 °C / Inert atmosphere; Schlenk technique 2.2: 20 h / 140 °C View Scheme
Multi-step reaction with 2 steps 1.1: n-butyllithium / tetrahydrofuran; toluene; hexane / -75 - -65 °C / Inert atmosphere 1.2: -75 - -70 °C 1.3: 12 h / -75 - 30 °C 2.1: boron trifluoride diethyl etherate; triethylsilane / dichloromethane / 0 - 5 °C View Scheme
Multi-step reaction with 3 steps 1.1: n-butyllithium / tetrahydrofuran / 1 h / -78 °C / Inert atmosphere 1.2: 3 h / 20 °C 2.1: triethylsilane; boron trifluoride diethyl etherate / chloroform / 3 h / -40 - 20 °C / Inert atmosphere 3.1: palladium 10% on activated carbon / dichloromethane / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1: n-butyllithium / toluene / -18 - -5 °C 2: methanol / 0 - 20 °C 3: acetonitrile boron trifluoride complex; triethylsilane / n-heptane / 5 h / -5 - 5 °C View Scheme
Multi-step reaction with 5 steps 1.1: sodium iodide; copper(l) iodide; N,N`-dimethylethylenediamine / toluene; diethylene glycol dimethyl ether / 36 h / Inert atmosphere; Reflux 2.1: tetrahydrofuran / 1 h / 0 - 5 °C / Inert atmosphere 2.2: 2 h / 0 - 5 °C 2.3: 2 h / Cooling 3.1: 4-methyl-morpholine; dmap / toluene; ethyl acetate / 15 h / 0 - 20 °C 4.1: triethylsilane; boron trifluoride diethyl etherate / acetonitrile / 4 h / 0 °C 5.1: lithium hydroxide monohydrate; water / tetrahydrofuran; methanol / 19.5 h / 20 - 24 °C View Scheme

2-[(5-bromo-2-methyl-phenyl)methyl]-5-(4-fluorophenyl)thiophene (1030825-20-7) + 3,4,6-tri-O-benzyl-D-glucal epoxide (74372-90-0) → canagliflozin (842133-18-0)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: tri-n-butyllithium magnesate complex / tetrahydrofuran; hexane; diethyl ether / 0.33 h / 0 °C / Inert atmosphere 1.2: 0 - 20 °C / Inert atmosphere 2.1: sodium iodide; chloro-trimethyl-silane / acetonitrile / 1 h / 0 - 20 °C View Scheme
Multi-step reaction with 2 steps 1.1: tri-n-butyllithium magnesate complex / tetrahydrofuran; hexane; diethyl ether / 0.33 h / 0 °C / Inert atmosphere 1.2: 0.5 h / 0 °C / Inert atmosphere 1.3: 0 - 20 °C / Inert atmosphere 2.1: sodium iodide; chloro-trimethyl-silane / acetonitrile / 1 h / 0 - 20 °C View Scheme

(2S,3S,4R,5R,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-3-ol → canagliflozin (842133-18-0)

Conditions	Yield
With chloro-trimethyl-silane; sodium iodide In acetonitrile at 0 - 20℃; for 1h;	0.31 g

(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) → canagliflozin (842133-18-0)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: n-butyllithium / tetrahydrofuran; toluene; hexane / 2 h / -70 - -60 °C / Inert atmosphere 2.1: methanesulfonic acid / tetrahydrofuran; toluene; hexane / -70 - 30 °C / Inert atmosphere 3.1: triethylsilane / dichloromethane / -75 - -70 °C 3.2: -75 - 0 °C View Scheme
Multi-step reaction with 3 steps 1.1: n-butyllithium / tetrahydrofuran; toluene; hexane / 1.5 h / -80 - -70 °C 1.2: -80 - -70 °C 1.3: -80 - 20 °C 2.1: n-butyllithium / tetrahydrofuran; toluene; hexane / 1.5 h / -80 - -70 °C 2.2: -80 - -70 °C 2.3: -80 - 20 °C 3.1: triethylsilane / dichloromethane; acetonitrile / 1 h / -55 - -40 °C / Inert atmosphere 3.2: 2 h / -55 - -40 °C View Scheme
Multi-step reaction with 3 steps 1: n-butyllithium / toluene / -18 - -5 °C 2: methanol / 0 - 20 °C 3: acetonitrile boron trifluoride complex; triethylsilane / n-heptane / 5 h / -5 - 5 °C View Scheme
Multi-step reaction with 2 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -75 - -70 °C / Inert atmosphere; Large scale 1.2: 1 h / -60 - 20 °C / Large scale 1.3: Large scale 2.1: lithium hydroxide monohydrate / tetrahydrofuran; methanol / 2 h / 0 - 20 °C View Scheme
Multi-step reaction with 4 steps 1.1: TurboGrignard / tetrahydrofuran / 1 h / -18 - -13 °C / Inert atmosphere; Large scale 1.2: 1 h / -15 - -10 °C / Large scale 1.3: 1 h / 20 °C / Large scale 2.1: dmap; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 0 - 10 °C / Large scale 3.1: triethylsilane; boron trifluoride diethyl etherate / acetonitrile; water / 5 - 20 °C / Large scale 4.1: lithium hydroxide; water / tetrahydrofuran; methanol / 2 h / 20 °C / Large scale View Scheme

D-Glucono-1,5-lactone (90-80-2) → canagliflozin (842133-18-0)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: 4-methyl-morpholine / tetrahydrofuran / -10 - 30 °C 2.1: n-butyllithium / tetrahydrofuran; toluene; hexane / 2 h / -70 - -60 °C / Inert atmosphere 3.1: methanesulfonic acid / tetrahydrofuran; toluene; hexane / -70 - 30 °C / Inert atmosphere 4.1: triethylsilane / dichloromethane / -75 - -70 °C 4.2: -75 - 0 °C View Scheme
Multi-step reaction with 4 steps 1.1: trifluoroacetic acid 2.1: s-butylmagnesium chloride; lithium chloride / toluene; tetrahydrofuran / 2 h / -5 - 0 °C 2.2: -45 - -35 °C 3.1: boron trifluoride diethyl etherate; triethylsilane / acetonitrile / 1 h / 30 - 42 °C 4.1: sodium methylate / methanol / 1 h / Reflux View Scheme
Multi-step reaction with 4 steps 1.1: trifluoroacetic acid 2.1: s-butylmagnesium chloride; lithium chloride / toluene; tetrahydrofuran / 2 h / -5 - 0 °C 2.2: -45 - -35 °C 3.1: boron trifluoride diethyl etherate; triethylsilane / acetonitrile / 1 h / 30 - 42 °C 4.1: sodium methylate / methanol / 1 h / Reflux View Scheme
Multi-step reaction with 3 steps 1.1: 4-methyl-morpholine / tetrahydrofuran / 20 °C / Inert atmosphere; Large scale 2.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -75 - -70 °C / Inert atmosphere; Large scale 2.2: 1 h / -60 - 20 °C / Large scale 2.3: Large scale 3.1: lithium hydroxide monohydrate / tetrahydrofuran; methanol / 2 h / 0 - 20 °C View Scheme

canagliflozin (842133-18-0) + L-proline (147-85-3) → L-proline-(2S,3R,4R,5S,6R)-2-{3-[5-(4-fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (1409936-68-0)

Conditions	Yield
In n-heptane; ethyl acetate at 60 - 65℃; for 5h; Solvent; Inert atmosphere;	93%
In acetone for 0.166667h; Product distribution / selectivity;
In ethanol; water	0.3 g

canagliflozin (842133-18-0) + acetic anhydride (108-24-7) → (3R,4R,5S)-2-(acetoxymethyl)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (866607-35-4)

Conditions	Yield
With dmap; triethylamine In ethyl acetate at 20 - 30℃; for 1h;	80%
With 4-methyl-morpholine; dmap In tetrahydrofuran at -10 - 20℃; for 1.25h;	78%
With 4-methyl-morpholine; dmap In dichloromethane at -5 - 5℃; for 4h; Reagent/catalyst;	69.5%

isonipecotic acid (498-94-2) + canagliflozin (842133-18-0) → (2S,3R,4R,5S,6R)-2-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol piperdine-4-carboxylic acid complex

Conditions	Yield
In water; acetone at 40℃; for 6h; Solvent;	80%

canagliflozin (842133-18-0) + (S)-2-methylpyrrolidine-2-carboxylic acid (42856-71-3) → (2S,3R,4R,5S,6R)-2-[3-[[5-(4-fluorophenyl)thiophen-2-yl]methyl]-4-methylphenyl]-6-(hydroxymethyl)oxane-3,4,5-triol alpha-methyl-L-proline

Conditions	Yield
In dichloromethane at 20 - 30℃; Reagent/catalyst;	66%

canagliflozin (842133-18-0) → (2S,3R,4R,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)(hydroperoxy)methyl)-4-methylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

Conditions	Yield
Stage #1: canagliflozin With dihydrogen peroxide In water; acetonitrile at 60℃; for 12h; Stage #2: With dihydrogen peroxide; fluorophosphoric acid In water; acetonitrile at 25℃; for 48h;	35%
Multi-step reaction with 3 steps 1: 2,3-dicyano-5,6-dichloro-p-benzoquinone / ethanol / 24 h / 20 °C 2: sodium tetrahydroborate / tetrahydrofuran / 5 h / 20 °C / Inert atmosphere 3: dihydrogen peroxide; sulfuric acid / tetrahydrofuran / 24 h / 20 °C / Inert atmosphere View Scheme

canagliflozin (842133-18-0) + acetic anhydride (108-24-7) → C31H33FO7S + C28H29FO7S

Conditions	Yield
With 4-methyl-morpholine In dichloromethane at -10 - 20℃; for 1h;	A 19.1% B 21.4%

canagliflozin (842133-18-0) → (1S)-1,5-anhydro-1-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol hemihydrate

Conditions	Yield
With water In acetone at 20℃; for 18h; Product distribution / selectivity;

Upstream product

• 1358581-37-9 (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol 
• 1198-69-2 D-glucono-1,4-lactone 
• 1030825-21-8 methyl 1-C-(3-{[5-(4-fluorophenyl)-2-thienyl]methyl}-4-methyl-phenyl)-D-glucopyranoside 
• 4451-35-8 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl chloride 
• 604-69-3 β-D-glucose pentaacetate 
• 1672658-93-3 C₂₄H₂₅FO₆S 
• 1225916-69-7 [5-(4-fluorophenyl)thiophen-2-yl]methanol 
• 249504-38-9 5-(4-fluorophenyl)thiophene-2-carboxaldehyde 
• 4701-17-1 5-bromo-2-thiophencarboxaldehyde 
• 604-68-2 α-D-glucopyranose peracetylate 
• 572-09-8 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide 

Downstream Products

• 866607-35-4 (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate 
• 1951467-29-0 [2-methyl-5-(β-D-glucopyranosyl)phenyl][5-(4-fluorophenyl)-2-thienyl]methanol 
• 928672-86-0 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene hydrate 
• 1432187-87-5 canagliflozin L-phenylalanine complex 
• 1432187-89-7 canagliflozin D-proline complex 
• 1409936-69-1 (2S,3R,4R,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol citric acid co-crystal 
• 1409936-68-0 L-proline-(2S,3R,4R,5S,6R)-2-{3-[5-(4-fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol 
• 928672-86-0 (1S)-1,5-anhydro-1-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol hemihydrate 

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Preparation method of canagliflozin

The invention discloses a preparation method of canagliflozin. According to the method, the reaction of each step in a route is improved, so that the conversion rate of raw materials is increased, andintroduction of potential toxic compounds is avoided. In addition, reaction conditions are mild; operation is simple; purity of an obtained product is high; quality of drugs is improved; and the preparation method is suitable for industrial production.

Syntheses of SGLT2 inhibitors by Ni- And Pd-catalyzed fukuyama coupling reactions

Nickel- and palladium-catalyzed Fukuyama coupling reactions of a D-gluconolactone-derived thioester with arylzinc reagents at ambient temperature provided the corresponding multifunctional aryl ketones in high yield. Ligand screening for the nickel-catalyzed Fukuyama coupling reactions indicated that 1,2- bis(dicyclohexylphosphino)ethane (dCype) served as a superior supporting ligand to improve the product yield. In addition, Pd/C was a practical alternative that enabled ligand-free Fukuyama coupling reactions and was efficiently applied to the key C-C bond-forming step to prepare canagliflozin and dapagliflozin, which are diabetic SGLT2 inhibitors of current interest.

Preparation method of canagliflozin

The invention relates to a preparation method of canagliflozin, and the preparation method is characterized in that the preparation method comprises the following steps: 1) reacting 2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl) methyl ] thiophene with an alkaline reagent and 2,3,4, 6-tetra-O-(trimethylsilyl)- D- glucolactone under a low-temperature condition, and carrying out methylation and deprotection reaction with a methanol solution of methanesulfonic acid to generate an intermediate 1; 2) under a low-temperature condition, reacting the intermediate 1 with triethyl silane and boron trifluoride diethyl etherate, and carrying out post-treatment to obtain an intermediate 2; 3) under a low-temperature condition, reacting the intermediate 2 with an organic base, DMAP and acetic anhydride,and purifying to obtain an intermediate 3; and 4) reacting the intermediate 3 with an alkaline water solution, and purifying after the reaction to obtain the canagliflozin. The method is mild in conditions, safe to operate, simple in post-treatment and high in product purity, no alpha-isomer is detected; the product is safer.

CANAGLIFLOZIN SUBSTANTIALLY FREE OF HYDROPEROXIDE IMPURITY

The present invention relates to a process for the preparation of Canagliflozin (I), which is substantially free of hydroperoxide impurity (II).

Preparation method of canagliflozin

The invention relates to a synthesis method of canagliflozin. According to the synthesis method, 4-fluorophenylboronic acid is taken as an initial raw material to be coupled with 5-bromo-thiophene-2-formaldehyde to synthesize 5-(4-fluorophenyl)thiophene-2-formaldehyde, the 5-(4-fluorophenyl)thiophene-2-formaldehyde undergoes reduction and chlorination and then undergoes Friedel-Crafts alkylation reaction with 4-bromotoluene to synthesize 2-(2-methyl-5-bromobenzyl)-5-(4-fluorophenyl)thiophene, and the 2-(2-methyl-5-bromobenzyl)-5-(4-fluorophenyl)thiophene undergoes condensation, etherificationand methoxyl removal with 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone to obtain the hypoglycemic drug canagliflozin. The preparation method has the following advantages: compared with the conventional preparation methods, the synthesis process takes the 4-fluorobenzeneboronic acid as an initial raw material, so that the raw material is cheap and easy to get, the process is easy to realize industrialization, the synthesis route is short and the operation is easy; in the synthesis process, bromine is not used or butyl lithium does not need to be used twice, so that the risk of the process can be reduced; in addition, the preparation method is capable of improving the yield of canagliflozin products to 70% or more.

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.

Preparation method of canagliflozin

The invention belongs to the technical field of chemical synthesis of medicines, and concretely relates to a preparation method of canagliflozin. The preparation method comprises the following steps:carrying out an acetylation and bromination reaction on d-glucose used as a starting raw material in order to prepare bromotetraacetylglucose; carrying out a Grignard exchange reaction on 2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene and a Grignard reagent at a low temperature, and reacting the obtained reaction product with the bromotetraacetylglucose to form an acetyl protected intermediate; and reacting the intermediate with an alkaline solution, and purifying the obtained reaction product to obtain the canagliflozin. The preparation method has the advantages of mild conditions, safety in operation and simple post-treatment; and the product has a high purity, a detection result shows that the product contains no alpha-isomer, and the product is safe.