Dapagliflozin

Base Information

• Chemical Name: Dapagliflozin
• CAS No.: 461432-26-8
• Molecular Formula: C21H25ClO6
• Molecular Weight: 408.879
• European Community (EC) Number: 639-683-0
• UNII: 1ULL0QJ8UC
• DSSTox Substance ID: DTXSID20905104
• Nikkaji Number: J2.928.717A
• Wikipedia: Dapagliflozin
• Wikidata: Q409898
• NCI Thesaurus Code: C78126
• RXCUI: 1488564
• Pharos Ligand ID: 2NSHZBU641RM
• Metabolomics Workbench ID: 144441
• ChEMBL ID: CHEMBL429910
• Mol file: 461432-26-8.mol

Synonyms:(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol;BMS 512148;BMS-512148;BMS512148;dapagliflozin;Farxiga;forxiga

Chemical Property of Dapagliflozin

Chemical Property:

• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.614
• Boiling Point: 609.045 °C at 760 mmHg
• PKA: 13.23±0.70(Predicted)
• Flash Point: 322.139 °C
• PSA: 99.38000
• Density: 1.349 g/cm³
• LogP: 1.84440
• Storage Temp.: 2-8°C
• Solubility.: DMSO (Slightly), Methanol (Slightly)
• XLogP3: 2.3
• Hydrogen Bond Donor Count: 4
• Hydrogen Bond Acceptor Count: 6
• Rotatable Bond Count: 6
• Exact Mass: 408.1339662
• Heavy Atom Count: 28
• Complexity: 472

Purity/Quality:

99%, ^*data from raw suppliers

Dapagliflozin ^*data from reagent suppliers

Safty Information:

• Pictogram(s):  
• Hazard Codes: 

MSDS Files:

SDS file from LookChem

Useful:

• Canonical SMILES: CCOC1=CC=C(C=C1)CC2=C(C=CC(=C2)C3C(C(C(C(O3)CO)O)O)O)Cl
• Isomeric SMILES: CCOC1=CC=C(C=C1)CC2=C(C=CC(=C2)[C@H]3[C@@H]([C@H]([C@@H]([C@H](O3)CO)O)O)O)Cl
• Recent ClinicalTrials: Use of Dapagliflozin to Reduce Burden of Atrial Fibrillation in Patients Undergoing Catheter Ablation of Symptomatic Atrial Fibrillation
• Recent EU Clinical Trials: SGLT2 inhibition in addition to lifestyle intervention and risk for complications in subtypes of patients with prediabetes - a randomized, placebo controlled, multi-center trial
• Recent NIPH Clinical Trials: Effect of Long-Acting vs. Short-Acting Loop Diuretics and Neurohormonal Agents on Patients' Quality-of-Life Among Patients with Heart Failure
• Drug interactions: This product is mainly metabolized in the liver by UGT1A9 metabolism, being the P-glycoprotein substrate. Study confirmed that the pharmacokinetics of daglitazone was not affected by metformin, pioglitazone, sitagliptin, glimepiride, voglibose, and simvastatin, valsartan, warfarin, and digoxin. The serum concentrations of the above-mentioned drugs are also not clinically significantly affected by daglitazone. Rifampicin can reduce the exposure amount of daglitazone by 22% while mefenamic acid can increase the body exposure amount by 51%, but have no clinically significant effect on 24 h urine glucose excretion.
• Description: The Australian Therapeutic Goods Administration (TGA) and the European Commission approved dapagliflozin in October and November 2012, respectively, as an adjunct to diet and exercise for the treatment of type 2 diabetes. Dapagliflozin is a potentially attractive therapy due to its glucosesensitive and insulin-independent mechanism of action. It is a first-in-class selective SGLT2 inhibitor (IC50=1.1 nM; selectivity vs. SGLT1 >1000) that lowers the renal threshold for reabsorption of glucose, allowing excess glucose to be eliminated via the kidneys. In normal rats, administration of dapagliflozin promotes dose-dependent excretion of up to 1900 mg of glucose over a 24 h period, with amaximal effect at 3 mg/kg. In a ratmodel of diabetes, pretreatment with the pancreatic toxin streptozotocin results in hyperglycemia that is reduced 55% by administration of a single 0.1 mg/kg dose of dapagliflozin compared with vehicle. Aryl O-glucoside SGLT2 inhibitors were early entrants into the clinic, but the aryl C-glucoside linkage found in dapagliflozin confers resistance to glucosidase-mediated metabolism leading to improved clinical utility relative to aryl O-glucosides. The modified carbohydrate–aglycone linkage required concomitant adjustment from an ortho- to a meta-substituted arylglucoside to achieve potent SGLT2 inhibition. Dapagliflozin was synthesized in several steps via reaction of an aryllithium with per-silylated gluconolactone to form the key C-glucoside linkage. An alpha-selective reduction of the resultant anomeric glycoside gave the desired beta-Carylglucoside. The main circulating (inactive) metabolite is the result of 3-O-glucuronidation of the glucosylmoiety. Of the minority metabolites, the main oxidative species result from O-dealkylation of the ethoxy-group and hydroxylation of the biarylmethane moiety. Inhibiting renal glucose reabsorbtion through the sodium-glucose cotransporter (SGLT) offers an insulin-independent alternative to controlling blood glucose concentrations in patients with type 2 diabetes. While the majority of glucose is reabsorbed from glomerular filtrate by SGLT2, which is predominantly expressed in the kidney S1 segment of the proximal tubule, SGLT1 reabsorbs glucose in the distal S3 segment of the renal proximal tubule as well as from the small intestine. Dapagliflozin is a first generation, selective SGLT inhibitor that blocks glucose transport with about 100-fold selectivity for SGLT2 (Ki = 6 nM; EC50 = 1.1 nM) over SGLT1 (Ki = 390 nM). After single oral doses ranging from 0.1 to 1.0 mg/kg, dapagliflozin increases urinary glucose excretion in both normal and diabetic rats, improves glucose tolerance in normal rats, and reduces hyperglycemia in Zucker diabetic fatty rats. Within two weeks of treating diabetic rats with 0.1 to 1.0 mg/kg dapagliflozin, fasting and fed glucose levels have been shown to be significantly lowered as a result of increased glucose utilization accompanied by reduced glucose production.
• Uses: A sodium-glucose transporter 2 inhibitor. therapeutic for diabetes I or II, and hyperglycemia
• Clinical Use: Selective and reversible inhibitor of sodium-glucose co-transporter 2:Treatment of type 2 diabetes

Technology Process of Dapagliflozin

There total 101 articles about Dapagliflozin which guide to synthetic route it. The literature collected by LookChem mainly comes from the sharing of users and the free literature resources found by Internet computing technology. We keep the original model of the professional version of literature to make it easier and faster for users to retrieve and use. At the same time, we analyze and calculate the most feasible synthesis route with the highest yield for your reference as below:

synthetic route:

Reference yield: 100.0%

(2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (461432-25-7) → dapagliflozin (461432-26-8,1373321-04-0)

Guidance literature:

With lithium hydroxide; In tetrahydrofuran; ethanol;

DOI:10.1021/jm701272q

Reference yield: 98.83%

2-chloro-5-(2,3,4,6-tetra-O-trimethylsilyl-D-glucopyranose-1-yl)-4'-ethoxydiphenylmethane → dapagliflozin (461432-26-8,1373321-04-0)

Guidance literature:

With lithium hydroxide; In tetrahydrofuran; methanol; water; at 0 - 20 ℃; for 7h; Temperature;

Reference yield: 98.7%

C21H25ClO6*C3H8O2 → dapagliflozin (461432-26-8,1373321-04-0)

Guidance literature:

In n-heptane; tert-butyl methyl ether; at -15 - 50 ℃; Inert atmosphere;

upstream raw materials:

(2S,3R,4S,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol

(2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate

(3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol

2-chloro-5-iodobenzoylchloride

Downstream raw materials:

dapagliflozin (S) propylene glycol hydrate

L-proline (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyI]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol complex

(2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-trityloxymethyl-tetrahydro-pyran-3,4,5-triol

Refernces

• 1、 -. "PREPARATION OF HIGHLY PURE AMORPHOUS DAPAGLIFLOZIN". Page/Page column 26-27. . Retrieved 2021/12/13.
• 2、 -. "Preparation method of dapagliflozin". Paragraph 0019; 0056; 0063-0064; 0071-0072. . Retrieved 2021/10/27.