141625-93-6

Basic information

• Product Name: DRONEDARONE HYDROCHLORIDE
• Synonyms: Multaq;N-(2-butyl-3-{4-[3-(dibutylaMino)propoxy]benzoyl}-1-benzofuran-5-yl)MethanesulfonaMide hydrochloride (1:1);N-(2-Butyl-3-(4-(3-(dibutylamino)propoxy)benzoyl)-benzofuran-5-yl)methanesulfonamide hydrochlorid;Dronedarone Hydrocholoride;N-[2-butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl]-5-benzofuranyl]-methanesulfonamide,hydrochloride (1:1);SR33589;N-[2-butyl-3-[4-(3-dibutyl-aminopropoxy) benzoyl] methanesulfonamide hydrochloride;SR-33589B
• CAS NO: 141625-93-6
• Molecular Formula: C31H44N2O5S.ClH
• Molecular Weight: 593.224
• EINECS: 1308068-626-2
• Product Categories: Amines;Aromatics;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 141625-93-6.mol

Chemical Properties

• Melting Point: NA (low-melting)
• Boiling Point: 683.9 °C at 760 mmHg
• Flash Point: 367.4 °C
• Appearance: white to off-white/
• Vapor Pressure: 1.47E-18mmHg at 25°C
• Storage Temp.: Refrigerator
• Solubility: DMSO: soluble15mg/mL, clear
• Stability: Hygroscopic
• Merck: 14,3449
• CAS DataBase Reference: DRONEDARONE HYDROCHLORIDE(CAS DataBase Reference)
• NIST Chemistry Reference: DRONEDARONE HYDROCHLORIDE(141625-93-6)
• EPA Substance Registry System: DRONEDARONE HYDROCHLORIDE(141625-93-6)

Safety Data

• RIDADR: UN 3077 9 / PGIII
• WGK Germany: 3
• Hazardous Substances Data: 141625-93-6(Hazardous Substances Data)

Usage

Uses

Used in Cardiovascular Drugs:
Dronedarone Hydrochloride is used as a therapeutic agent for the treatment of atrial fibrillation and atrial flutter in patients who have experienced cardiac arrhythmias. Its application in this industry is due to its ability to help regulate heart rhythm and reduce the risk of complications associated with these conditions.

Biological Activity

dronedarone hcl is an amiodarone analogue which has been shown an effective and promising treatment for atrial fibrillation (af) [1].

Biochem/physiol Actions

Dronedarone is a Class III antiarrhythmic and a multi-channel blocker for atrial fibrillation. It blocks potassium, sodium, and calcium channels and also exhibits antiadrenergic properties.

Clinical Use

Dronedarone hydrochloride (also known as SR33589 and marketed as Multaq) is a drug developed by Sanofi-Aventis for cardiac arrhythmias (irregular heartbeat) that was approved by the FDA in July 2009. Dronedarone is used for the treatment of atrial fibrillation and atrial flutter in patients whose hearts have either returned to normal rhythm or who undergo drug therapy or electroshock treatment to maintain normal cardio rhythm. Dronedarone is less lipophilic than amiodarone, exhibits a much smaller volume of distribution and a half-life of 24 h, this stands in contrast to competitor amiodarone’s half-life of several weeks. As a result of these pharmacokinetic characteristics, dronedarone dosing may be less complicated than amiodarone.

Synthesis

The synthesis of dronedarone relies on the preparation of the benzofuran core 34, of which three main routes have been reported, but two possess obvious overlap and are considered more process-amenable. Starting from methyl 2-(2-formylphenoxy)hexanoate (32), this aldehyde can either be nitrated, then saponified or saponified and then nitrated to procure nitroacid 33 (the Scheme). The benzofuran ring is then secured through the use of acetic anhydride and base in the presence of DMF at elevated temperature. The key benzofuran 34 can be produced by either route in 62% yield on gramscale by this method. Friedel–Crafts acylation involving anisoyl chloride and tin tetrachloride constructed the diaryl ketone 35. Cleavage of the methyl ether through the use of aluminum trichloride in refluxing DCE provided phenol 36. Alkylation of phenol 36 with aminoalkyl chloride 37 gave ether 38. Subsequent reduction of the nitro group via catalytic hydrogenation and sulfonylation of the resulting amine provided dronedarone (VII) which was isolated as its HCl salt.

in vitro

dronedarone has been demonstrated to inhibit muscarinic acetylcholine receptor-operated k+ current ik(ach) induced by carbachol or gtp-gamma-s with ic50 values of 10nm and <100nm, respectively, in cells isolated from guinea pig atria. notably, dronedarone was 100-fold potent and selective over amiodarone in inhibiting ik(ach) [1].

in vivo

dronedarone has shown to block arterial thrombus formation, decrease platelet aggregation and reduce plasminogen activator inhibitor-1 (pai1) expression in c57bl/6 mice [2].

references

[1] guillemare e1, marion a, nisato d, gautier p. inhibitory effects of dronedarone on muscarinic k+ current in guinea pig atrial cells. j cardiovasc pharmacol. 2000 dec;36(6):802-5.[2] breitenstein a1, sluka sh, akhmedov a, stivala s, steffel j, camici gg, riem hh, beer hj, studt jd, duru f, luscher tf, tanner fc. dronedarone reduces arterial thrombus formation. basic res cardiol. 2012 nov;107(6):302.

InChI:InChI=1/C31H44N2O5S.ClH/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;1H

Upstream product

• 1310430-09-1 3-{4-[(2-butyl-5-methanesulfonamide-1-benzofuran-3-yl)carbonyl]phenoxy}propyl methanesulfonate 
• 111-92-2 dibutylamine 
• 1312300-15-4 C₃₀H₃₃NO₈S₂ 
• 616-05-7 2-bromohexanoic acid 
• 42768-46-7 2-bromohexanoyl chloride 
• 104-94-9 4-methoxy-aniline 
• 51-66-1 4-methoxyacetanilide 
• 1333493-68-7 1-{4-[3-(di-n-butylamino)propoxy]phenyl}-1,3-heptanedione 
• 73021-84-8 N-(4-oxocyclohexa-2,5-dien-1-ylidene)methanesulphonamide 
• 141644-91-9 (5-amino-2-butyl-benzofuran-3-yl)-[4-(3-dibutylamino-propoxy)-phenyl]-methanone 
• 124-63-0 methanesulfonyl chloride 
• 637-88-7 1,4-Cyclohexanedione 
• 500791-70-8 5-amino-2-n-butyl-3-[4-(3-di-n-butylamino propoxy)benzoyl]benzofuran bisoxalate 
• 1333493-64-3 C₂₈H₄₈N₂O₂ 

Downstream Products

• 1354567-97-7 N-[2-butyl-3-[4-(3-(di-n-butylamino)propoxy)benzoyl]-5-benzofuranyl]methanesulfonamide hydrobromide 

Relevant articles and documents

An improved scalable route to pure dronedarone hydrochloride

An efficient scalable synthesis for dronedarone hydrochloride (2) via Friedel-Craft acylation of 2-(-2-butyl-1-benzofuran-5-yl)-1H-isoindole-1,3(2H) dione (12) with 4-(3-chloropropoxy) benzoic acid (13) in good yield and high purity has been developed by using Eaton's reagent instead of hazardous and toxic metal halide catalyst like AlCl3 or SnCl4.

An improved and efficient process for the production of dronedarone hydrochloride, an antiarrhythmia drug

An improved, high-yielding, and efficient process for the production of dronedarone hydrochloride (1), a class III antiarrhythmia drug for the prevention of cardiac arrhythmias such as atrial fibrillation (AF) is described. The developed process avoids isolation of unstable intermediates at several stages by telescoping the steps upon individual optimization, thereby minimizing the turnaround time of the batch cycle and increasing the throughput. Potential impurities (byproducts) arise during the reaction at various stages, and carry-over impurities from starting materials were controlled selectively by designing reaction conditions and suitable workup procedures, resulting in an increased overall yield from 33% (as per processes reported in the literature) to 66%.

Preparation method for dronedarone hydrochloride

The invention relates to a preparation method for dronedarone hydrochloride. The preparation method includes utilizing 1,4-cyclohexanedione as a raw material to generate dihalogenated-1,4-cyclohexanedione through halogenation reaction with chlorine or bro

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.

Method for synthesizing [...] reach silom

The invention discloses a dronedarone synthesis method. According to the method, 4-[3-(dibutylamino)propoxy]methyl benzoate, 4-[3-(dibutylamino)propoxy]benzoic acid hydrochloride, 4-[3-(dibutylamino)propoxy]benzoyl chloride, 2-bromohexanoyl chloride, p-methoxyacetanilide, 3-(2-bromohexanoyl chloride)-4-hydroxyacetanilide, N-2-butyl-5-benzofuranamine hydrochloride, N-[(2-butyl-2,3-2H-5-benzofuran)methanesulfonamide], N-2-butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl]-5-benzofuran]-methanesulfonamide and dronedarone are obtained through step-reactions. The dronedarone synthesis method is simple in process, convenient to operate and high in rate of production.

METHOD FOR PREPARING 5-AMINO-BENZOFURAN DERIVATIVES

The invention relates to a method for preparing 5-amino-benzoyl-benzofuran derivatives having the general formula in which R1 is hydrogen or an alkyl or aryl group and R2 is hydrogen, an alkyl, alkoxy or dialkylaminoalkoxy group. Acc

PROCESS FOR PREPARING DRONEDARONE AND SALTS THEREOF

The present disclosure relates to processes for preparing dronedarone or pharmaceutically acceptable salts thereof.

A facile and efficient synthesis of dronedarone hydrochloride

A facile and efficient synthesis of dronedarone hydrochloride starting from commercially available 4- nitrophenol is described. This approach features a tandem-type synthesis of 3-carbonylated benzofuran involving cyclization of 2-ethynylphenol followed by CO2 fixation at the 3-position of the benzofuran ring mediated by potassium carbonate without the addition of any transition metal catalyst.

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.

KETOBENZOFURAN DERIVATIVES, METHOD FOR SYNTHESIZING SAME, AND INTERMEDIATES

The present disclosure relates to ketobenzofuran derivatives of the general formula (I): as well as to a method of synthesizing the same by coupling a quinonimine and an enaminone by a Nenitzescu reaction and to the intermediates of the synthesis thereof.