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
• Article Data: 45

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

Abstract

Canagliflozin(Invokana) is an oral diabetes medicine that helps control blood sugar levels. It works by helping the kidneys get rid of glucose from your bloodstream. Invokana is used together with diet and exercise to treat type 2 diabetes. To mention the advantage, this drug helps patients to reduce blood sugars without increasing the likelihood of gaining weight as long as a healthy, balanced diet is followed and regular exercise taken.

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

Different sources of media describe the References of 842133-18-0 differently. You can refer to the following data:
1. https://www.drugs.com/cdi/canagliflozin.html http://www.diabetes.co.uk/diabetes-medication/invokana-canagliflozin.html
2. 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

Description

In March 2013, the US FDA approved canagliflozin (JNJ-28431754; TA-7284) for the treatment of type 2 diabetes in adults. Canagliflozin is the first US-approved sodium-glucose co-transporter (SGLT) inhibitor for the treatment of type 2 diabetes. Inhibition of renal SGLT suppresses glucose reabsorption, which permits glucose excretion into urine and reduction of hyperglycemia. Canagliflozin was discovered through structural modifications of phlorizin, a known inhibitor of renal glucose reabsorption. Early modifications of OH groups on the glucose moiety were insufficient to adequately impair hydrolysis by intestinal β-glucosidase. Introduction of the C-glucoside moiety, as in the clinical candidate dapagliflozin, afforded sufficient resistance to hydrolysis. Finally, incorporation of the thiophene moiety in canagliflozin provided improved potency for hSGLT2 (exclusive to kidney), IC50=2.2 nM, while offering significant selectivity over hSGLT1 (in kidney and heart), IC50=910 nM. Hyperglycemic, high-fat (HF) diet fedmice (KKstrain) that received a single 3 mg/kg oral dose of canagliflozin had a 48% reduction in blood glucose levels after 6 h versus vehicle-treatedmice. Noteworthy in themultistep synthesis of canagliflozin is the stereoselective formation of the β-C-glucoside which is accomplished by coupling of the aryllithiumaglycone with 2,3,4,6-tetra-O-trimethylsilyl-β-Dgluconolactone followed by desilylation and stereoselective reduction with triethylsilane and boron trifluoride etherate.

Chemical Properties

Pale Yellow Solid

Originator

Mitsubishi Tanabe Pharma (Japan)

Uses

Canagliflozin is a sodium/glucose cotransporter 2 (SGLT2) inhibitor. Canagliflozin has been shown to dose dependently reduce calculated renal threshold for glucose excretion and increase urinary glucose excretion. Canagliflozin is a candidate for the treatment of type 2 diabetes and obesity.

Definition

ChEBI: A C-glycosyl compound that is used (in its hemihydrate form) for treatment of type II diabetes via inhibition of sodium-glucose transport protein subtype 2.

Brand name

Invokana

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

• 1030825-21-8 methyl 1-C-(3-{[5-(4-fluorophenyl)-2-thienyl]methyl}-4-methyl-phenyl)-D-glucopyranoside 
• 1432591-84-8 2,4-di-O-tert-butyldiphenylsilyl-1-C-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-β-D-glucopyranoside 
• 498-07-7 levoglucosan 
• 1432591-75-7 1,6-anhydro-2,4-di-O-tert-butyldiphenylsilyl-β-D-glucopyranose 
• 1283129-24-7 C₃₆H₂₈F₂S₂Zn 
• 898566-17-1 (2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) 
• 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 
• 1132832-76-8 1-[1-hydroxy-2,3,4,6-tetra-O-(trimethylsilyl)-β-D-glucopyranosyl]-4-methyl-3-[[5-(4-fluorophenyl)-2-thienyl]methyl]benzene 
• 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 

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 

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