141626-36-0

Basic information

• Product Name: Dronedarone
• Synonyms: Dronedarone;2-Butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl]-5-(methylsulfonamido)benzofuran;N-(2-Butyl-3-(4-(3-(dibutylamino)propoxy)benzoyl)-5-benzofuranyl)methanesulfonamide;N-(2-butyl-3-(4-(3-(dibutylaMino)propoxy)benzoyl)benzofuran-5-yl)MethanesulfonaMide;MethanesulfonaMide,N-[2-butyl-3-[4-[3-(dibutylaMino)propoxy]benzoyl]-5-benzofuranyl]-;N-[2-butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl]-1-benzofuran-5-yl]methanesulfonamide
• CAS NO: 141626-36-0
• Molecular Formula: C₃₁H₄₄N₂O₅S
• Molecular Weight: 556.764
• Product Categories: Cardiovascular APIs
• Mol File: 141626-36-0.mol

Chemical Properties

• Melting Point: 65.3°
• Boiling Point: 683.9 °C at 760 mmHg
• Flash Point: 367.4 °C
• Appearance: /
• Density: 1.143 g/cm³
• Vapor Pressure: 1.47E-18mmHg at 25°C
• Refractive Index: 1.563
• Storage Temp.: 2-8°C
• Solubility: ≥27.84 mg/mL in DMSO; insoluble in H2O; ≥49.8 mg/mL in EtOH
• PKA: 7.40±0.30(Predicted)
• CAS DataBase Reference: Dronedarone(CAS DataBase Reference)
• NIST Chemistry Reference: Dronedarone(141626-36-0)
• EPA Substance Registry System: Dronedarone(141626-36-0)

Safety Data

• Hazardous Substances Data: 141626-36-0(Hazardous Substances Data)

Usage

Uses

Used in Cardiology:
Dronedarone is used as an antiarrhythmic agent for the treatment of atrial fibrillation (AF) and atrial flutter (AFL). It is specifically indicated to reduce the risk of cardiovascular hospitalization in patients with paroxysmal or persistent AF or AFL, with a recent episode of AF/AFL and associated cardiovascular risk factors, who are in sinus rhythm or who will be cardioverted. Dronedarone is a potent blocker of multiple ion currents and exhibits antiadrenergic effects, making it effective in maintaining normal sinus rhythm in patients with AF.
Overall, dronedarone is well tolerated, with the most common side effects being gastrointestinal in nature, such as nausea, vomiting, and diarrhea.

Originator

Sanofi-Aventis (US)

Clinical Use

Anti-arrhythmic:Maintenance of sinus rhythm after successful cardioversion in adult clinically stable patients with paroxysmal or persistent atrial fibrillation

Drug interactions

Potentially hazardous interactions with other drugsAnti-arrhythmics: increased risk of myocardial depression with other anti-arrhythmics; increased risk of ventricular arrhythmias with amiodarone or disopyramide - avoid. Antibacterials: increased risk of ventricular arrhythmias with clarithromycin, telithromycin and erythromycin; concentration reduced by rifampicin - avoidAnticoagulants: increased anti-coagulant effect with coumarins and phenindione; increased dabigatran concentration - avoid; avoid with rivaroxaban; concentration of edoxaban increased - reduce dose of edoxaban.Antidepressants: concentration possibly reduced by St John’s wort - avoid; increased risk of ventricular arrhythmias with tricyclic antidepressants, citalopram and escitalopram - avoid.Antiepileptics: concentration possibly reduced by fosphenytoin, phenytoin, carbamazepine, phenobarbital and primidone - avoid.Antifungals: concentration increased by ketoconazole - avoid; avoid with itraconazole, posaconazole and voriconazole.Antipsychotics: increased risk of ventricular arrhythmias with antipsychotics that prolong the QT interval; increased risk of ventricular arrhythmias with phenothiazines - avoid.Antivirals: avoid with ritonavir; increased risk of ventricular arrhythmias with saquinavir - avoid.Beta-blockers: increased risk of myocardial depression; concentration of metoprolol and propranolol possibly increased; increased risk of ventricular arrhythmias with sotalol - avoid.Calcium channel blockers: concentration increased by nifedipine; increased risk of bradycardia and myocardial depression with diltiazem and verapamil.Cytotoxics: possibly increases bosutinib concentration - avoid or consider reducing bosutinib dose; possibly increases ibrutinib concentration - reduce ibrutinib doseDigoxin: increased concentration (halve digoxin maintenance dose).Fingolimod: possibly increased risk of bradycardia.Grapefruit juice: concentration of dronedarone increased - avoid.Lipid-lowering drugs: concentration of atorvastatin and rosuvastatin possibly increased; increased risk of myopathy with simvastatin; concentration of lomitapide possibly increased - avoid.Tacrolimus: manufacturer advises use with caution.

Metabolism

Dronedarone is extensively metabolised in the liver, mainly by the cytochrome P450 isoenzyme CYP3A4 to a less active N-debutyl metabolite, and several inactive metabolitesAbout 6% of an oral dose is excreted in the urine (entirely metabolites) and 84% in the faeces (metabolites and unchanged drug).

InChI:InChI=1/C31H44N2O5S/c1-5-8-12-29-30(27-23-25(32-39(4,35)36)15-18-28(27)38-29)31(34)24-13-16-26(17-14-24)37-22-11-21-33(19-9-6-2)20-10-7-3/h13-18,23,32H,5-12,19-22H2,1-4H3

Upstream product

• 141625-93-6 dronedarone hydrochloride 
• 141644-91-9 (5-amino-2-butyl-benzofuran-3-yl)-[4-(3-dibutylamino-propoxy)-phenyl]-methanone 
• 124-63-0 methanesulfonyl chloride 
• 141626-26-8 5-amino 3-[4-(3-di-n-butylamino-propoxy)benzoyl] 2-n-butyl benzofuran 
• 1310430-05-7 N-(2-butyl-3-(4-(3-chloropropoxy)benzoyl)benzofuran-5-yl)methanesulfonamide 
• 111-92-2 dibutylamine 
• 1310430-06-8 C₂₃H₂₆BrNO₅S 
• 1310430-09-1 3-{4-[(2-butyl-5-methanesulfonamide-1-benzofuran-3-yl)carbonyl]phenoxy}propyl methanesulfonate 
• 1312300-15-4 C₃₀H₃₃NO₈S₂ 
• 1310430-08-0 C₂₃H₂₇NO₆S 
• 141645-16-1 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran 
• 65136-48-3 4-(3-chloropropoxy)benzoic acid chloride 
• 401840-61-7 4-(3-bromopropoxy)benzoyl chloride 
• 437652-07-8 N-(2-butyl-2,3-dihydro-5-benzofuranyl)methanesulfonamide 

Downstream Products

• 141625-93-6 dronedarone hydrochloride 
• 1337978-10-5 dronedarone fumarate 
• 1337955-85-7 2-butyl-3-(4-[3-(dibutylamino)propoxy]benzoyl)-5-methansulfonylamino-benzofuran mesylate 

Relevant articles and documents

Convergent synthesis of dronedarone, an antiarrhythmic agent

We have developed a convergent synthesis of dronedarone, an antiarrhythmic agent. The key steps of the process are the construction of a benzofuran skeleton by iodocyclization and the carbonylative Suzuki-Miyaura cross-coupling for biaryl ketone formation. This synthetic route required only eight steps from 2-amino-4-nitrophenol in 23% overall yield.

Concise total synthesis of antiarrhythmic drug dronedarone via a conjugate addition followed intramolecular heck cyclization

A concise, scalable, and an efficient total synthesis for dronedarone (2) was described using conjugate addition followed by intramolecular Heck cyclization. The other key reaction includes selective reduction of nitro functionality and addition of lithiated terminal alkyne to the aldehyde. The overall yield of this approach is 44% in six steps.

Visible-Light-Induced Radical Carbo-Cyclization/ gem-Diborylation through Triplet Energy Transfer between a Gold Catalyst and Aryl Iodides

Geminal diboronates have attracted significant attention because of their unique structures and reactivity. However, benzofuran-, indole-, and benzothiophene-based benzylic gem-diboronates, building blocks for biologically relevant compounds, are unknown. A promising protocol using visible light and aryl iodides for constructing valuable building blocks, including benzofuran-, indole-, and benzothiophene-based benzylic gem-diboronates, via radical carbo-cyclization/gem-diborylation of alkynes with a high functional group tolerance is presented. The utility of these gem-diboronates has been demonstrated by a 10 g scale conversion, by versatile transformations, by including the synthesis of approved drug scaffolds and two approved drugs, and even by polymer synthesis. The mechanistic investigation indicates that the merging of the dinuclear gold catalyst (photoexcitation by 315-400 nm UVA light) with Na2CO3 is directly responsible for photosensitization of aryl iodides (photoexcitation by 254 nm UV light) with blue LED light (410-490 nm, λmax = 465 nm) through an energy transfer (EnT) process, followed by homolytic cleavage of the C-I bond in the aryl iodide substrates.

Efficient Syntheses of Diverse, Medicinally Relevant Targets Planned by Computer and Executed in the Laboratory

The Chematica program was used to autonomously design synthetic pathways to eight structurally diverse targets, including seven commercially valuable bioactive substances and one natural product. All of these computer-planned routes were successfully executed in the laboratory and offer significant yield improvements and cost savings over previous approaches, provide alternatives to patented routes, or produce targets that were not synthesized previously. Although computers have demonstrated the ability to challenge humans in various games of strategy, their use in the automated planning of organic syntheses remains unprecedented. As a result of the impact that such a tool could have on the synthetic community, the past half century has seen numerous attempts to create in silico chemical intelligence. However, there has not been a successful demonstration of a synthetic route designed by machine and then executed in the laboratory. Here, we describe an experiment where the software program Chematica designed syntheses leading to eight commercially valuable and/or medicinally relevant targets; in each case tested, Chematica significantly improved on previous approaches or identified efficient routes to targets for which previous synthetic attempts had failed. These results indicate that now and in the future, chemists can finally benefit from having an “in silico colleague” that constantly learns, never forgets, and will never retire. Multistep synthetic routes to eight structurally diverse and medicinally relevant targets were planned autonomously by the Chematica computer program, which combines expert chemical knowledge with network-search and artificial-intelligence algorithms. All of the proposed syntheses were successfully executed in the laboratory and offer substantial yield improvements and cost savings over previous approaches or provide the first documented route to a given target. These results provide the long-awaited validation of a computer program in practically relevant synthetic design.

A short synthesis of Dronedarone

A modification of the Nenitzescu reaction was used to obtain Dronedarone from quinonimine 20 and 1,3-diketone 14 (R = CH2CH2CH2NBu2) in a two-stage process in almost 55% overall yield. Our results represent significant improvement over other state-of-the-art methods as no extra steps for the decoration of the benzofuran core are required.

PROCESS FOR PREPARATION OF DRONEDARONE BY REMOVAL OF HYDROXYL GROUP

The invention relates to a process for preparation of dronedarone of formula (I) and pharmaceutically acceptable salts thereof characterized in that from the compound of formula (II). the hydroxyl group is removed, and the obtained product is isolated and, if desired, converted into a pharmaceutically acceptable salt thereof.

PROCESS FOR THE PREPARATION OF DRONEDARONE BY OXIDATION OF A SULPHENYL GROUP

The invention relates to a novel process for the preparation of dronedarone (I) and pharmaceutically acceptable salts thereof which comprises oxidizing a compound of formula (IV) or a salt thereof with an oxidizing agent in an organic or inorganic solvent or solvent mixture, and isolating the obtained product and, if desired, converting it into a pharmaceutically acceptable salt thereof. Further aspects of the invention include the novel intermediary compound of formula (IV), and a process for the preparation thereof.

Identification and characterization of potential impurities of dronedarone hydrochloride

Six potential process related impurities were detected during the impurity profile study of an antiarrhythmic drug substance, Dronedarone (1). Simple high performance liquid chromatography and liquid chromatography-mass spectrometry methods were used for the detection of these process impurities. Based on the synthesis and spectral data (MS, IR, 1H NMR, 13C NMR, and DEPT), the structures of these impurities were characterized a s 5-amino-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-2-n-butylbenzofuran (impurity I); N-(2-butyl-3-(4-(3-(dibutylamino)propoxy)-benzoyl)benzofuran-5-yl)-N- (methylsulfonyl)-methanesulfonamide (impurity II); N-(2-butyl-3-(4-(3- (dibutylamino)propoxy)benzoyl)benzofuran-5-yl)-1-chloromethanesulfonamide (impurity III); N-{2-propyl-3-[4-(3-dibutylaminopropoxy)benzoyl]benzofuran-5-yl} - methanesulfonamide (impurity IV); N-(2-butyl-3-(4-(3-(dibutylamino)propoxy) benzoyl)benzofuran-5-yl)-formamide (impurity V); and (2-butyl-5-((3- (dibutylamino)propyl)amino)benzofuran-3-yl)(4-(3- (dibutylamino)propoxy)phenyl) methanone (impurity VI). The synthesis and characterization of these impurities are discussed in detail.

PROCESS FOR SYNTHESIZING KETO-BENZOFURAN DERIVATIVES

The invention relates to a process for synthesizing benzofuran derivatives, in particular dronedarone of formula (D), comprising a step of Friedel-Crafts acylation starting from a sulfonamido-benzofuran ester intermediate.

REDUCTIVE AMINATION PROCESS FOR PREPARATION OF DRONEDARONE USING AMINE INTERMEDIARY COMPOUND

The invention relates to a novel process for preparation of drohedarone of formula (I) and pharmaceutically acceptable salts thereof characterized in that a compound of formula (II) is reacted in the presence of a reductive agent with butyraldehyde and/or butanoic acid, and isolating the obtained product and, if desired, converting it into a pharmaceutically acceptable salt thereof. The invention also relates to some hovel intermediary compounds and the preparation thereof.