461432-26-8 Usage
Uses
Used in Pharmaceutical Industry:
Dapagliflozin is used as a therapeutic agent for the treatment of type 1 and type 2 diabetes, as well as hyperglycemia. It is particularly effective due to its insulin-independent mechanism of action, which makes it a valuable alternative for controlling blood glucose concentrations in patients with diabetes.
Used in Diabetes Management:
Dapagliflozin is used as an insulin-independent alternative to improve glycemic control in adults with type 2 diabetes. It works by inhibiting renal glucose reabsorption through the sodium-glucose cotransporter (SGLT), which allows for increased urinary glucose excretion and improved glucose tolerance.
Used in Clinical Trials:
Dapagliflozin has been used in clinical trials to demonstrate its effectiveness in reducing hyperglycemia in diabetic rats and improving glucose utilization and reducing glucose production in diabetic patients. The Australian Therapeutic Goods Administration (TGA) and the European Commission approved dapagliflozin in October and November 2012, respectively, for use in the treatment of type 2 diabetes.
Diabetes drugs
Dapagliflozin (ForxigaTM) is a new antidiabetic drug jointly developed by Bristol-Myers Squibb and AstraZeneca, being approved by the European Medicines Agency (EMA) on November 12, 2012. It is also the first approved SGLT2 inhibitor for the treatment of type II diabetes, being an important option in the treatment of diabetes, and is used to improve glycemic control as an adjunct to dietary and exercise for adults with type II diabetes.
Dapagliflozin is a sodium-glucose co-transporter 2 inhibitor. On January 8, 2014, the US Food and Drug Administration (FDA) have approved it for being used in the treatment of type II diabetes. Meanwhile, FDA requires the producers to conduct post-marketing research on drug-related risks.
The post-marketing trial requested by the FDA includes a cardiovascular outcome trial for assessing the cardiovascular risk for high-risk patients after treatment with dapagliflozin at baseline and a study to assess the risk of bladder cancer in recruited patients. Another study will assess the bladder tumor-promoting effect of this drug on rodent animals. Two studies will assess the pharmacokinetics, efficacy and safety of dapagliflozin in pediatric patients; a set of strengthened pharmacovigilance program will monitor liver abnormalities and pregnancy outcome reports in patients receiving daglitazone. Dapagliflozin will be marketed under the tradename Farxiga by Haoeyou Pharmacy.
The above information is edited by Andy of lookchem.
Pharmacological effects
Dapagliflozin works through inhibiting sodium-glucose transporter 2 (SGLT2), a protein in the kidney that reabsorbs glucose into the bloodstream. This allows extra glucose to be excreted through the urine, improving glycemic control without increasing insulin secretion. The use of this drug requires patients with normal renal function while patients of moderate to severe renal insufficiency should be disabled to use this drug. Single application of this product or combination with metformin, pioglitazone, glimepiride, insulin and other drugs can significantly reduce the HbA1c and fasting blood glucose of patients suffering type II diabetes. The frequency of the adverse reaction was similar to placebo with low risk of hypoglycemia, being able to reduce body weight.
The efficacy of dapagliflozin is comparable with the dipeptidyl peptidase inhibitors, and several new hypoglycemic drugs, and can also mildly lower the blood pressure and body weight. The drug has 5mg and 10mg two tablets to choose from, can be either used alone or together with insulin, including other diabetes drugs.
Pharmacokinetics
In healthy subjects, dapagliflozin was rapidly absorbed after oral administration with a peak time Tmax being 1 to 2 hours, a protein binding rate of 91%, an oral bioavailability of about 78% and a plasma terminal half-life of 12.9 hours. After oral administration, the drug is mainly metabolized by the uridine diphosphate glucuronosyltransferase 1A9 (UGT1A9) into the inactive metabolite in the liver with the smaller part being metabolized by the P450 enzyme and of no inhibitory or inducing effect on the P450 enzyme. Drug prototypes and related metabolites were excreted through urine (75%) and faeces (21%). Compare simultaneous administration of this product with high-fat food and with the fasting administration, Tmax can be extended by 1-fold, but the absorption did not affect the degree, so can be administrated together with the food.
The pharmacokinetics of daglitazone was significantly affected by renal function. Diabetic patients with mild, moderate or severe renal insufficiency are merged to be subject to oral administration of 20 mg ? d-1 daglitazone for 7 days. The mean systemic exposure amount, compared with patients with normal renal function, is respectively 32%, 60% and 87% higher. For patients with normal renal function, mild insufficiency, moderate insufficiency and severe insufficiency, the urinary glucose excretion amount in 24 hours of steady state was 85, 52, 18 and 11g, successively.
Kasichayanula et al have studied the pharmacokinetic effects of liver dysfunction on daglitazone. The patients with mild, moderate and severe hepatic insufficiency having a single oral dose of 10 mg of daglitazone, the Cmax of each group was 12% lower, 12% higher and 40% higher than that with normal liver function, respectively. The AUC of each group was significantly higher than that of normal liver function by 3%, 36% and 67%.
Therefore, it is not recommended to apply daglitazone to patients of moderate and severe renal dysfunction. Severe liver dysfunction patients need to reduce the use of dose.
Synthesis method
5-bromo-2-chlorobenzoic acid is subject to acylating chlorination, and has Friedel-Crafts reaction with phenylethyl ether for reduction of its carbonyl group, generating 5-bromo-2-chloro-4'-ethoxydiphenyl methane, further subjecting to condensation with 2, 3, 4, 6-tetra-O-trimethylsilyl-D-glucopyranosanoic acid-1,5-lactone. The anomeric carbon hydroxyl group is subject to etherification and deprotection to give 2-chloro-5-(1-methoxy-D-glucopyranose-I-yl)-4'-ethoxydiphenylmethane, and then use Et3SiH/BF3 ? OEt2 for reduction to remove methoxy, followed by acetic anhydride esterification and hydrolysis to give hypoglycemic agents daglitazone with the overall yield of about 40%.
Fig.1 shows the chemical reaction route of synthesizing dapagliflozin.
Safety
Daglitazone has excellent tolerance and safety with the incidence of adverse events associated with 10 mg ? d-1 daglitazone being similar to that of placebo. Common adverse events included hypoglycemia, polyuria, back pain, genital infections, urinary tract infections, dyslipidemia and hematocrit (HCT) increase. The overall risk of hypoglycemia is low, and the incidence of hypoglycemia is associated with other basic hypoglycemic agents. The incidence of hypoglycemia was higher in patients subjecting to joint treatment between daglitazone and sulfonylureas or insulin compared with placebo. Therefore, when this product is used in combination with insulin or insulin secretagogue, you may need to adjust the dose of the latter one.
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.
Originator
Bristol-Myers Squibb (United States)
Clinical Use
Selective and reversible inhibitor of sodium-glucose
co-transporter 2:Treatment of type 2 diabetes
in vitro
ec50 values of 1.1 nm for hsglt2 and 1.4 μm for hsglt1 determined for dapagliflozin corresponded to 1200-fold selectivity for sglt2 as compared with phlorizin’s 10-fold selectivity. dapagliflozin inhibitory potencies against rat sglt (rsglt)2 and hsglt2 were comparable, but the selectivity of dapagliflozin for rsglt2 versus rsglt1 decreased to 200-fold [1].
in vivo
in vivo, dapagliflozin acutely induced renal glucose excretion in diabetic and normal rats, improved glucose tolerance in normal rats, as well as reduced hyperglycemia in zucker diabetic fatty rats after single oral doses ranging between 0.1 and 1.0 mg/kg [2].
Metabolism
Dapagliflozin is extensively metabolised, primarily
to dapagliflozin 3-O-glucuronide, which is an
inactive metabolite. The formation of dapagliflozin
3-O-glucuronide is mediated by UGT1A9, an enzyme
present in the liver and kidney, and CYP-mediated
metabolism was a minor clearance pathway in humans.
About 75% of the dose is excreted in the urine and 21%
in the faeces.
references
[1] meng w, ellsworth ba, nirschl aa, mccann pj, patel m, girotra rn, wu g, sher pm, morrison ep, biller sa, zahler r, deshpande pp, pullockaran a, hagan dl, morgan n, taylor jr, obermeier mt, humphreys wg, khanna a, discenza l, robertson jg, wang a, han s, wetterau jr, janovitz eb, flint op, whaley jm, washburn wn. discovery of dapagliflozin: a potent, selective renal sodium-dependent glucose cotransporter 2 (sglt2) inhibitor for the treatment of type 2 diabetes. j med chem. 2008 mar 13;51(5):1145-9. [2] han s, hagan dl, taylor jr, xin l, meng w, biller sa, wetterau jr, washburn wn, whaley jm. dapagliflozin, a selective sglt2 inhibitor, improves glucose homeostasis in normal and diabetic rats. diabetes. 2008 jun;57(6):1723-9.[3] bailey cj, iqbal n, t'joen c, list jf. dapagliflozin monotherapy in drug-na?ve patients with diabetes: a randomized-controlled trial of low-dose range. diabetes obes metab. 2012 oct;14(10):951-9.
Check Digit Verification of cas no
The CAS Registry Mumber 461432-26-8 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 4,6,1,4,3 and 2 respectively; the second part has 2 digits, 2 and 6 respectively.
Calculate Digit Verification of CAS Registry Number 461432-26:
(8*4)+(7*6)+(6*1)+(5*4)+(4*3)+(3*2)+(2*2)+(1*6)=128
128 % 10 = 8
So 461432-26-8 is a valid CAS Registry Number.
InChI:InChI=1/C21H25ClO6/c1-2-27-15-6-3-12(4-7-15)9-14-10-13(5-8-16(14)22)21-20(26)19(25)18(24)17(11-23)28-21/h3-8,10,17-21,23-26H,2,9,11H2,1H3/t17-,18-,19+,20-,21+/m1/s1
461432-26-8Relevant articles and documents
Preparation method of dapagliflozin
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Paragraph 0057; 0066-0071; 0080-0084; 0093-0097; 0106;..., (2022/01/12)
The invention relates to a preparation method of dapagliflozin. The preparation method comprises the following steps: reacting a compound 1 serving as a raw material with butyl lithium in an organic solvent at a low temperature, adding a compound 2, carrying out a series of reactions to prepare a compound 3 with higher purity, reacting the compound 3 with silane and boron trifluoride acetic acid or boron trifluoride diethyl etherate to prepare a compound 4. A tedious reaction process is avoided, and the utilization rate of raw materials and the purity of products are improved. The method for preparing dapagliflozin has the advantages of simple operation, high product conversion rate (up to 99%), few impurities, and high product purity, and is suitable for industrial production.
Facile Approach to C-Glucosides by Using a Protecting-Group-Free Hiyama Cross-Coupling Reaction: High-Yielding Dapagliflozin Synthesis
Vaňková, Karolína,Rahm, Michal,Choutka, Jan,Pohl, Radek,Parkan, Kamil
, p. 10583 - 10588 (2021/06/25)
Access to unprotected (hetero)aryl pseudo-C-glucosides via a mild Pd-catalysed Hiyama cross-coupling reaction of protecting-group-free 1-diisopropylsilyl-d-glucal with various (hetero)aryl halides has been developed. In addition, selected unprotected pseudo-C-glucosides were stereoselectively converted into the corresponding α- and β-C-glucosides, as well as 2-deoxy-β-C-glucosides. This methodology was applied to the efficient and high-yielding synthesis of dapagliflozin, a medicament used to treat type 2 diabetes mellitus. Finally, the versatility of our methodology was proved by the synthesis of other analogues of dapagliflozin.
PREPARATION OF HIGHLY PURE AMORPHOUS DAPAGLIFLOZIN
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Page/Page column 25-26, (2021/12/13)
A novel and improved process for the preparation of amorphous dapagliflozin is disclosed. The present invention further provides pharmaceutical compositions containing amorphous dapagliflozin, optionally in a combination with one or more other active substances and methods for making the same.
Method for synthesizing diabetes medicine by D - gluconic acid - δ δ-lactone
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, (2021/11/10)
The invention discloses a method for synthesizing a diabetes drug by D - gluconic acid - δ δ-lactone. To the technical field of drug synthesis, D - glucose acid - δ δ-lactone is used as a raw material, and then subjected to catalytic hydrogenation and bromination reaction through three-silyl protecting reaction, then condensed with 5 - bromo -2 - chloro -4’ - ethoxy diphenyl methane, and finally, trimethyl silicon-based protection is removed. To the method for synthesizing the diabetes medicine by D - gluconic acid - δ δ-lactone, D - gluconic acid - δ δ-lactone is adopted as the starting raw material, the reaction process is simple, the intermediate is easy to purify, and the raw materials used in the reaction are easily obtained. The reaction process is more mild than the prior art. The yield of the final product can reach 95.89% or above, and the purity can reach 99.5% or more.
Preparation method of dapagliflozin
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Paragraph 0019; 0056; 0063-0064; 0071-0072, (2021/10/27)
The invention discloses a preparation method of dapagliflozin. The preparation method comprises the following steps: (1) reacting a compound solution as shown in a formula II and an n-butyllithium solution in a first microreactor in a microchannel reaction device; (2) reacting effluent of the first microreactor with a compound as shown in a formula III in a second microreactor in the microchannel reaction device to obtain a compound as shown in a formula IV; (3) carrying out reduction reaction on the compound shown in the formula IV in a third microreactor in the microchannel reaction device to obtain a compound shown in a formula V; and (4) deprotecting the compound as shown in the formula V to obtain dapagliflozin as shown in the formula I. According to the method disclosed by the invention, benzyl-protected glucolactone is adopted as a starting raw material, so that generation and multiple derivatization of isomer impurities and ring-opening impurities are avoided, the stereoselectivity is relatively high, and post-treatment steps and waste generation are reduced; and meanwhile, the yield is high, the purity is high, the synthesis steps are few, the operation is simple and convenient, and the safety is high.
Pivaloyl-protected glucosyl iodide as a glucosyl donor for the preparation of β-C-glucosides
Triantakonstanti, Virginia V.,Toskas, Alexandros,Iordanidis, Nicolaos S.,Andreou, Thanos,Koftis, Theoharis V.,Gallos, John K.
, (2020/07/13)
A method for the selective synthesis of β-C-glucosides using α-D-tetra-O-pivaloylglucosyl iodide as a glucosyl donor is reported. Its diastereoselectivity differs from that of the respective acetyl-protected glucosyl bromide, as it reported in the literature under similar reaction conditions. The concentration of the catalyst, the solvent and the type of additive used are crucial factors that determine the reaction selectivity. This method has been applied in a short synthesis of dapagliflozin. The stability of α-D-tetra-O-pivaloylglucosyl iodide in CDCl3 and THF at reflux was also studied. All side products in the coupling and decomposition reactions were isolated and characterized, and possible pathways for their formation are proposed.
Preparation method of dapagliflozin
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, (2020/05/05)
The invention relates to a preparation method of dapagliflozin. The preparation method comprises the following steps: by using 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene as an initial raw material, reacting with magnesium by using iodine granules as an initiator to prepare a Grignard reagent of iodo-benzene; carrying out bromination reaction on peracetylated sugar and hydrogen bromide in an aceticacid solution to prepare 2,3,4,6-tetraacetylglucosamine bromide; adding the prepared Grignard reagent of iodo-benzene into a methylbenzene/tetrahydrofuran solution, dropwise adding a rare earth catalyst and 2,3,4,6-tetraacetylglucosamine bromide into the methylbenzene/tetrahydrofuran solution, reacting to obtain an intermediate compound of dapagliflozin; and adding the prepared intermediate compound of dapagliflozin into a tetrahydrofuran/ethanol/water solution of sodium hydroxide, removing acetyl after alkaline hydrolysis, and re-crystallizing to obtain dapagliflozin. The reaction raw materials are easy to obtain, the preparation method is simple, the conditions are mild, the preparation method is safer and more environmentally friendly, the yield is high, the purity can reach 99%, and the method is suitable for large-scale production.
Syntheses of SGLT2 inhibitors by Ni- And Pd-catalyzed fukuyama coupling reactions
Kato, Daiki,Mashima, Kazushi,Nagae, Haruki,Seki, Masahiko,Talode, Jalindar,Tsurugi, Hayato
, p. 12382 - 12392 (2020/11/09)
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.
A Concise and Efficient Synthesis of Dapagliflozin
Yu, Jun,Cao, Ying,Yu, Haizhou,Wang, Jinjia
, p. 1458 - 1461 (2019/08/12)
A concise and efficient synthesis of the SGLT-2 inhibitor dapagliflozin (1) has been developed. This route involves ethyl C-aryl glycoside 9 as the key intermediate, which is easily crystallized and purified as the crystalline n-propanol solvate with high purity (>98.5%). The tetra-O-unprotected compound 9 could be directly reduced to crude dapagliflozin with high diastereoselectivity. The final pure API product 1 was isolated and purified with high purity (>99.7%). The process has been implemented on a multikilogram scale.
Facile and green synthesis of dapagliflozin
Hu, Lin,Zou, Ping,Wei, Wanguo,Yuan, Xi-Meng,Qiu, Xiao-Long,Gou, Shao-Hua
, p. 3373 - 3379 (2019/11/11)
A facile and green synthetic route was developed for the preparation of dapagliflozin (1), a selective sodium-dependent glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes. Key reaction steps include a direct Friedel–Crafts acylation and a synthesis of diaryl ketal moiety in one-pot manner without waste water generation. Furthermore, the reduction of the diaryl ketone and C-phenylglucoside were achieved in one-pot manner to generate dapagliflozin (1) more efficiently. The synthetic route featured the usage of commercial available and easily handling reagents with shorter reaction steps and less waste disposal.
