Edoxaban

Base Information

• Chemical Name: Edoxaban
• CAS No.: 480449-70-5
• Deprecated CAS: 876652-15-2
• Molecular Formula: C₂₄H₃₀ClN₇O₄S
• Molecular Weight: 548.066
• Hs Code.: 2934999090
• European Community (EC) Number: 859-181-7
• UNII: NDU3J18APO
• DSSTox Substance ID: DTXSID50197398
• Nikkaji Number: J2.812.474K
• Wikipedia: Edoxaban
• Wikidata: Q21011234
• NCI Thesaurus Code: C96539
• RXCUI: 1599538
• Pharos Ligand ID: H4H6UMZTCDHY
• Metabolomics Workbench ID: 152130
• ChEMBL ID: CHEMBL1269025
• Mol file: 480449-70-5.mol

Synonyms:DU-176;DU-176b;edoxaban;edoxaban tosylate;N-(5-chloropyridin-2-yl)-N'-((1S,2R,4S)-4-(N,N-dimethylcarbamoyl)-2-(5-methyl-4,5,6,7- tetrahydro(1,3)thiazolo(5,4-c)pyridine-2-carboxamido)cyclohexyl)oxamide;N-(5-chloropyridin-2-yl)-N'-((1S,2R,4S)-4-(N,N-dimethylcarbamoyl)-2-(5-methyl-4,5,6,7-tetrahydrothiazolo(5,4-c)pyridine-2-carboxamido)cyclohexyl)ethanediamide p-toluenesulfonate monohydrate;Savaysa

Chemical Property of Edoxaban

Chemical Property:

• PKA: 9.46±0.70(Predicted)
• PSA: 164.87000
• Density: 1.43g/cm³
• LogP: 2.08230
• Storage Temp.: Hygroscopic, Refrigerator, under inert atmosphere
• Solubility.: Chloroform (Slightly), DMSO (Slightly, Heated), Methanol (Slightly, Heated)
• XLogP3: 1.4
• Hydrogen Bond Donor Count: 3
• Hydrogen Bond Acceptor Count: 8
• Rotatable Bond Count: 5
• Exact Mass: 547.1768513
• Heavy Atom Count: 37
• Complexity: 880

Purity/Quality:

98% ^*data from raw suppliers

Edoxaban ^*data from reagent suppliers

Safty Information:

• Pictogram(s):  
• Hazard Codes: 

MSDS Files:

SDS file from LookChem

Useful:

• Drug Classes: Anticoagulants
• Canonical SMILES: CN1CCC2=C(C1)SC(=N2)C(=O)NC3CC(CCC3NC(=O)C(=O)NC4=NC=C(C=C4)Cl)C(=O)N(C)C
• Isomeric SMILES: CN1CCC2=C(C1)SC(=N2)C(=O)N[C@@H]3C[C@H](CC[C@@H]3NC(=O)C(=O)NC4=NC=C(C=C4)Cl)C(=O)N(C)C
• Recent ClinicalTrials: PREvention of STroke in Intracerebral haemorrhaGE Survivors With Atrial Fibrillation
• Recent EU Clinical Trials: What is the optimal antithrombotic strategy in patients with atrial fibrillation having acute coronary syndrome or undergoing percutaneous coronary intervention?
• Recent NIPH Clinical Trials: Phase III Investigator-Initiated Trial to Investigate Safety and Efficacy of Edoxaban in Patients with Chronic Thromboembolic Pulmonary Hypertension
• Uses: oral factor Xa inhibitor
• Indications: Edoxaban is a direct oral anticoagulant (DOAC). It exerts its effects by inhibiting factor Xa (FXa). Edoxaban was FDA approved in early 2015 to treat deep venous thrombosis, pulmonary embolism and decrease the risk of hypercoagulability related illness; stroke, and systemic embolism (SE) in subjects with nonvalvular atrial fibrillation (NVAF).When compared to the popularly used anticoagulant warfarin, edoxaban entails more limited monitoring and possesses a reduced risk for significant bleeding and fewer interactions with other agents.Edoxaban is the most current direct oral anticoagulant (DOAC) and does not associate with the CYP-450 system.Various clinical trials and studies (ENGAGE AF-TIMI and Hokusai-VTE) expressed edoxaban's effectiveness compared to the conventional vitamin K antagonist warfarin. It was demonstrated to be non-inferior in preventing blood clots when compared to warfarin. Edoxaban is the second FDA-approved anticoagulant agent with once-daily administration.Contrary to the other direct oral anticoagulants, apixaban and rivaroxaban, edoxaban has not yet received approval for secondary and postoperative prophylaxis for venous thromboembolism (VTE).FDA-Approved Indications:Deep venous thrombosisPulmonary embolismNonvalvular atrial fibrillation (NVAF)https://www.ncbi.nlm.nih.gov/
• Drug interactions: The majority of edoxaban pharmacokinetic drug interactions result from inhibition or induction of the P-gp efflux transporter,which is responsible for intestinal transport.Edoxaban taken with quinidine demonstrates an increase in edoxaban Cmax of 85% and AUS of 77%.Coadministration with dronedarone resulted in a Cmax and AUC increase of 46% and 85%，respectively.This drug interaction also increased the 24-h edoxaban concentration by 158%.Additionally, verapamil increased the edoxaban Cmax by 53%, the AUC by 53%, and the 24-h edoxaban concentration by 29%.146 As per the phase 3 clinical trial, patients receiving quinidine, dronedarone,or verapamil should receive the reduced dose of 30 mg daily instead of 60 mg daily.It should be noted that patients receiving azole antifungal agents, such as ketoconazole, or protease inhibitors were excluded from the phase 3 trial because of concerns about increased edoxaban exposure.Conversely, the use of rifampin, a P-gp inducer, resulted in a significant 34% reduction in the edoxaban AUC.Therefore, the combination of rifampin and edoxaban should be avoided.

Technology Process of Edoxaban

There total 87 articles about Edoxaban 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: 99.69%

5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloric acid salt (720720-96-7) + carbamic acid, N-[(1R,2S,5S)-2-[[2-[(5-chloro-2-pyridinyl)amino]-2-oxoacetyl]amino]-5-[(dimethylamino)carbonyl]cyclohexyl]-1,1-dimethylethyl ester (480452-36-6) → edoxaban (480449-70-5)

Guidance literature:

carbamic acid, N-[(1R,2S,5S)-2-[[2-[(5-chloro-2-pyridinyl)amino]-2-oxoacetyl]amino]-5-[(dimethylamino)carbonyl]cyclohexyl]-1,1-dimethylethyl ester; With 1-butyl-3-methylimidazolium hydroxide; methanesulfonic acid; In acetonitrile; for 10h;

5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloric acid salt; With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In acetonitrile; at 10 ℃; for 20h; Reagent/catalyst;

Reference yield: 95.0%

N1-[(1S,2R,4S)-2-amino-4-[(dimethylamino)carbonyl]cyclohexyl]-N2-(5-chloro-2-pyridyl)ethanediamide (480452-37-7) + 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid (758685-72-2) → edoxaban (480449-70-5)

Guidance literature:

5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid; With pyridine; 1,1'-carbonyldiimidazole; In dichloromethane; at 20 - 25 ℃; for 1h;

N¹-[(1S,2R,4S)-2-amino-4-[(dimethylamino)carbonyl]cyclohexyl]-N²-(5-chloro-2-pyridyl)ethanediamide; With pyridine; In dichloromethane; at 20 ℃; for 2h;

Reference yield: 92.9%

N-(5-chloropyridin-2-yl)-N'-[(1S,2R,4S)-2-amino-4-(N,N-dimethylcarbamoyl)cyclohexyl]ethanediamide methanesulfonate + 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid 2,4,6-trichlorophenyl ester → edoxaban (480449-70-5)

Guidance literature:

With potassium phosphate; In N,N-dimethyl-formamide; at 20 ℃; for 3h;

upstream raw materials:

N¹-[(1S,2R,4S)-2-amino-4-[(dimethylamino)carbonyl]cyclohexyl]-N²-(5-chloro-2-pyridyl)ethanediamide

5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloric acid salt

carbamic acid, N-[(1R,2S,5S)-2-[[2-[(5-chloro-2-pyridinyl)amino]-2-oxoacetyl]amino]-5-[(dimethylamino)carbonyl]cyclohexyl]-1,1-dimethylethyl ester

tert-butyl N-[(1R,2S,5S)-2-azido-5-[(dimethylamino)carbonyl]cyclohexyl]carbamate

Downstream raw materials:

[14C]-Edoxaban tosylate

Refernces

• 1、 -. "Method for preparing edoxaban from trichloroacetophenone onium salt derivatives". Paragraph 0091-0096. . Retrieved 2020/07/21.
• 2、 -. "Intermediate for preparing edoxaban free alkali, and preparation method and application of intermediate". . . Retrieved 2020/10/21.