DRONEDARONE

DRONEDARONE



Dronedarone (development codename SR33589 and marketed as Multaq) is a drug by Sanofi-Aventis, mainly for the indication ofcardiac arrhythmias. It was approved by the FDA on July 2, 2009

• Dronedarone (SR33589) is a benzofuran derivative that is a new potent drug in the treatment of arrhythmia. Chemically, dronedarone is similar to amiodarone, but it has no iodine, so it is less lipophilic than amiodarone. Dronedarone not only retains the curative effects of amiodarone, but also has no extracardiac adverse response of amiodarone. It is expected to become a drug that is more safe, tolerated better by patients, and one alternative of amiodarone for the treatment of arrhythmia.
• [0003]
  Along with the faster moving social modernization process and the higher social pressure people bear, the number of patients with cardiovascular disease in our country is increasing. Cardiovascular disease is listed as one of the top ten causes of death. Therefore, the development of dronedarone will bring great economic benefit and social benefit. Dronedarone is represented as formula [I]:
  

  
• [0004]
  US5223510A disclosed a process for preparing dronedarone as shown in scheme 1. In this patent, dronedarone is prepared by converting 2-butyl-5-nitrobenzofuran to 5-amino-2- butyl-3-(4-[3-(dibutylamino)propoxy]benzoyl)benzofuran (compound A) via acylation, hydrolysis, O-alkylation and reduction; then reacting the compound A with methanesulfonyl chloride in the presence of triethylamine as a catalyst to obtain acyl compound; and then purifying the acyl compound by column chromatography. Finally, dronedarone hydrochloride is obtained by treating dronedarone with hydrogen chloride-ether in ethyl acetate.
  

  

  
• [0005]
  In this process, the compound A is reacted with methanesulfonyl chloride to easily obtain the undesired double methanesulfonyl compound (a compound of formula Ia), which requires a further purification of dronedarone by column chromatography. It is not very economic for industrial production. In addition, an additional salifying step of dronedarone hydrochloride is needed which costs more reaction equipment and reduces overall yield, and increases production costs at the same time.
  

  
• [0006]
  Many processes for the acylation of amines have been reported.US 5,223,510A also disclosed that double methanesulfonyl compound IIa, not monomethyl sulfonyl compound (II), is obtained by reacting 5-amino-2-butyl-benzofuran in carbon tetrachloride with methanesulfonyl chloride in the presence of triethylamine as a catalyst. Compound IIa can be converted to compound II via deacylation with an additional deacylation step, which also increases the production cost, and is unfavorable for industrialized production. It is shown in scheme 2:
  

  

  
• [0007]
  WO 03/048144A2 reported a process for preparing compound II by adjusting the proportion of compound II and compound IIa under different catalysts to an optimized condition (5<Pka<10) by using 2-butylbenzofuran-5-amine.
• [0008]
  Subsequently, US2005049302 described a process for preparing compound II, not compound IIa, from 5-amino-2-butyl-benzofuran. In this process, compound II is reacted with compound III in the presence of tin tetrachloride (scheme 3) to obtain dronedarone with low yield and complicated operations, such as column chromatography etc., which is not suitable for industrial production.
  

  

http://www.google.com/patents/EP2581369A1?cl=en

 The process comprises reacting 5-amino-2-butyl-3-(4-[3-(dibutylamino)propoxy]benzoyl)benzofuran (compound A) with methanesulfonyl chloride to provide dronedarone hydrochloride; and then converting the dronedarone hydrochloride to highly pure dronedarone via treatment with an alkaline solution, or based on the need, converting to other pharmaceutically acceptable salts of dronedarone. It is shown in scheme 4:

Example 1Step 1) Preparation of crude dronedarone hydrochloride
• [0036]
  In a 5L flask, 480 g compound A (1mol) and 1.7 L acetonitrile were added and heated to reflux to obtain a mixture. Then, 100 mL methanesulfonyl chloride (1.29mol)/800mL acetonitrile were added dropwise to the mixture within 25∼30min. The reaction was maintained at reflux for 8 h. Then, the reaction was naturally cooled to obtain a solid. The next day, the solid obtained was filtered and dried to obtain 530 g crude dronedarone hydrochloride. Yield: 89.2%, Purity of HPLC: 99.5%.
Step 2) Preparation of dronedarone hydrochloride
• [0037]
  In a 5L flask, 530 g crude dronedarone hydrochloride, 3 L acetone and 100 mL water were added and heated to reflux for dissolving completely. The reaction mass was cooled for crystallization in an ice water bath under automatic stirring. About 30 minutes later, lots of solid was precipitated. The solid obtained was filtered and washed with acetone and dried to obtain 440 g targeted compound. Yield: 83%, mp:141.5∼143°C, Purity of HPLC: 99.8%, MS:[M+H]⁺m/e 557.50.
  

  

  Table 1. dronedarone hydrochloride ¹H-NMR data and assignments

  Chemical shift (ppm)	multiplicity	The number of protons	Proton assignment	The chemical shifts of the relevant hydrogen (ppm)
  0.799-0.829	t	3	27	1.226-1.270
  0.908-0.937	t	6	22, 22'	1.323-1.368
  1.226-1.270	m	2	26	0.799-0.829, 1.647-1.738
  1.323-1.368	m	4	21, 21'	0.908-0.937, 1.647-1.738
  1.647-1.738	m	6	20, 20', 25	1.226-1.270, 1.323-1.368, 2.801-2.831, 3.036-3.079
  2.230-2.262	m	2	17	3.209-3.250, 4.207-4.231
  2.801-2.831	t	2	24	1.647-1.738
  2.902	s	3	23
  3.036-3.079	m	4	19, 19'	1.647-1.738, 11.0
  3.209-3.250	m	2	18	2.230-2.262, 11.0
  4.207-4.231	t	2	16	2.230-2.262
  7.100-7.117	d	2	12, 14	7.793-7.811
  7.240-7.262	d	1	6	7.613-7.631
  7.307-7.311	s	1	2
  7.613-7.631	d	1	5	7.240-7.262
  7.793-7.811	d	2	11, 15	7.100-7.117
  9.660	s	1	NH	Disappeared after exchange with D2O
  11.0	br	1	HCl	3.036-3.079, 3.209-3.250, Disappeared after exchange with D2O

Org. Process Res. Dev., 2014, 18 (1), pp 157–162

DOI: 10.1021/op400190b

http://pubs.acs.org/doi/abs/10.1021/op400190b

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 as 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.

Dronedarone

Systematic (IUPAC) name
N-(2-Butyl-3-(p-(3-(dibutylamino)propoxy)benzoyl)- 5-benzofuranyl)methanesulfonamide
Clinical data
Trade names	Multaq
AHFS/Drugs.com	monograph
MedlinePlus	a609034
Licence data	US FDA:link
Pregnancy category	US: X (Contraindicated)
Legal status	US: ℞-only
Routes of administration	Oral
Pharmacokinetic data
Bioavailability	15% (with a high-fat meal)[1]
Protein binding	>98%
Metabolism	Extensive hepatic (mainly by CYP3A)
Half-life	13–19 hours
Excretion	Feces (84%), urine (~6%)
Identifiers
CAS Registry Number	141626-36-0
ATC code	C01BD07
PubChem	CID 208898
ChemSpider	180996
UNII	JQZ1L091Y2
KEGG	D02537
ChEBI	CHEBI:50659
ChEMBL	CHEMBL184412
Chemical data
Formula	C31H44N2O5S
Molecular mass	556.758 g/mol

US5223510 †

Jul 26, 1991

Jun 29, 1993

Sanofi

Alkylaminoalkyl derivatives of benzofuran, benzothiophene, indole and indolizine, process for their preparation and compositions containing them

AHMED KAMAL ET AL: 'BASE-FREE MONOSULFONYLATION OF AMINES USING TOSYL OR MESYL CHLORIDE IN WATER' TETRAHEDRON LETTERS vol. 49, no. 2, 13 November 2007, pages 348 - 353, XP022386883
2	†	AKITO YASUHARA ET AL: 'SELECTIVE MONODESULFONYLATION OF N,N-DISULFONYLARYLAMINES WITH TETRABUTYLAMMONIUM FLUORIDE' CHEM. PHARM. BULL vol. 47, no. 6, June 1999, pages 809 - 812, XP003033477
3	*	KAMAL ET AL: "Base-free monosulfonylation of amines using tosyl or mesyl chloride in water", TETRAHEDRON LETTERS, PERGAMON, GB, vol. 49, no. 2, 13 November 2007 (2007-11-13), pages 348-353, XP022386883, ISSN: 0040-4039, DOI: 10.1016/J.TETLET.2007.11.044
4	*	No further relevant documents disclosed
5	†	See also references of WO2011153923A1

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