WO2013014479A1

WO2013014479A1 - Reductive animation process for preparation of dronedarone using aldehyde intermediary compound

Info

Publication number: WO2013014479A1
Application number: PCT/HU2012/000064
Authority: WO
Inventors: Antal Friesz; Zsolt DOMBRÁDY
Original assignee: Sanofi
Priority date: 2011-07-26
Filing date: 2012-07-23
Publication date: 2013-01-31

Abstract

The invention relates to a novel process for preparation of dronedarone of formula (I) and pharmaceutically acceptable salts thereof, characterized in that the compound of formula (II) is reacted with dibutylamine of formula (III), under reducing circumstances, and the obtained product is isolated and, if desired, converted into a pharmaceutically acceptable salt thereof, The invention also relates to some novel intermediary compounds and the preparation thereof.

Description

Reductive amination process lor preparation of dronedarone using aldehyde

intermediary compound

FIELD OF THE INVENTION

This invention relates to a novel process for the preparation of dronedarone and pharmaceutically acceptable salts thereof, to novel intermediary compounds used in this process and their preparation.

TECHNICAL BACKGROUND

Dronedarone is a known drug for the treatment of arrhythmia and has the chemical name of N-[2-n-butyl-3 -[4-[3-(di-n-butylamino)propoxy]benzoyl]benzofuran-5- yl]methanesulfon-amide [see also formula (I) below] . There are some known processes for the preparation of dronedarone as follows:

In EP 0471609 the following scheme is disclosed for the preparation of dronedarone [^"Process A]

sulfonylation

The above mentioned patent description discloses some new intermediary compounds, too.

In WO 02/48078 the following scheme is disclosed for the preparation of dronedarone [Process B] :

The novelty of the process is based on the adaptation of the Friedel-Crafts reaction in the first step. The process and the intermediary compounds used for the preparation of the benzoylchloride compound of the first step are also disclosed in this document. The further steps of the process are identical with the final steps of the synthetic route disclosed in EP 0471609 [Process A] , but in the claims the whole synthetic route is claimed, up to dronedarone.

In WO 02/48132 (Sanofi) the following reaction route is disclosed [Process C] , This method is the so called superconvergent route. In the first step of it 5-amino-2-butyl- benzofuran

is mesylated and the obtained 2-butyl-5-methanesulfonamido-benzofuran (in HC1 salt form) is further reacted in the next step as follows:

In this process the order of reaction steps are altered, the reduction and the

methansulfonylation steps are performed at the beginning of the procedure. Besides the reaction route for preparation of dronedarone, the starting material 2-butyl-5- methansulfonamido-benzofuran and its preparation is also claimed.

From among the mentioned procedures the first one [Process A] is the so called linear synthesis. In this way of procedure the different parts of the dronedarone are stepwise built up on the starting compound. This method is the least economical because the step by step building of the chemical groups is performed where more and more complicated and expensive molecules are applied which rises the costs of preparation. Furthermore, it comprises complicated and dangerous reaction step because aluminium chloride is used in the cleaving reaction of the methoxy group which makes the industrial feasibility more complicated.

In WO 02/48078 (Process B) a shorter synthetic route is disclosed which makes this process more economical, but its last reaction step remained the methansulfonylation reaction of the amino group, This reaction step (see the method described in example 6 of of WO 02/48078) is complicated and give a low yield, only 61 .6%. Pure product can be obtained after purification using chromatographic column purification, which method is necessary because of the separation difficulties of the bis-methanesulfonylated product.

The process disclosed in WO 02/48 132 (process C) is simpler and more economical taken into consideration the number of the reaction steps, Unfortunately, in the last reaction step rather impure dronedarone, HC1 (hydrochloride salt) is formed which is the obvious consequence of the presence of dibutylamino group in the Friedel-Crafts reaction. According to Examples 3 and 4. the crude dronedarone hydrochloride salt is prepared with a yield of 90% which was further purified and finally the crude dronedarone base was produced with a yield of 86%, This base is reacted with hydrogen chloride gas dissolved in isopropanol which results in pure dronedarone hydrochloride salt, No yield was given for this reaction step. According to example 5 crude dronedarone hydrochloride salt was prepared with a yield of 90%. which was washed with water and reacted with hydrogen chloride gas dissolved in isopropanol, resulting dronedarone hydrochloride salt again. The quality of this product is not known. However, neither the components used in the Friedel-Crafts reaction nor the resulted products and by-products are soluble in water, the washing step with water cannot result any purification apart from the removal of inorganic salts.

It is an object of present invention to provide a novel process for the preparation of dronedarone of formula (1). Starting with known and commercially available materials, using, simple and environmentally compatible reagents and solvents to afford high overall yields and good purity of the product.

SUMMARY OF THE INVENTION

The main aspect of the invention is a process for preparation of dronedarone (I) and pharmaceutically acceptable salts thereof l

O nButyl

(I)

wherein a compound of formula (II) O

CPL SCvNH 0— (CH — C

(Π)

is reacted with dibutylamine of formula (III)

(III)

under reducing circumstances,

and the obtained product is isolated and. if desired, converted into a pharmaceutically acceptable salt thereof.

Present invention avoids the drawbacks of the procedures mentioned before, because formation of dronedarone in the final step is completed with reductive amination process between the new aldehyde of formula (II) and dibutylamine. Intermediary compounds of the procedure (II). (IV). (V). (VI) are new, so further aspects of the invention are the novel intermediary compounds and the methods for the preparation thereof (see below" in the "Detailed description of the invention" part). Compound of formula (VII) is know n from Patent EP WO 0471609 (Sanofi) and compounds of formula (VIII) and the other reagents are available from commercial sources (e.g. Aldrich).

DETAILED DESCRIPTION OF THE INVENTION

Therefore the present invention relates to a process for the preparation of dronedarone and pharmaceutically acceptable salts thereof. The whole process - starting from compounds available commercial sources - reads as follows:

A For the preparation of compounds of formula (VI)

nButy

(VI)

where R is alkyl in each occurrence, independently from each other,

the compound of formula (VII) ^"0 nButyl

(VII)

is reacted with a compound of formula (VIII)

— R

Hlg— (CH₂)₂— CH

O—

(VIII)

where R is alkyl in each occurrence, independently from each other, and Hlg stands for halogen.

Typically the reaction is carried out in a solvent or solvent mixture, typically in presence of an alkali halogenide, e.g. sodium or potassium iodide. In some embodiments the reaction is carried out in the presence of a base, which can be an alkali carbonate, .e.g. sodium or potassium carbonate.

The solvent can be an alcohol or keton type solvent or mixture thereof, e.g. it can be methanol, ethanol, acetone, methyl ethyl keton.

B For the preparation of compounds of formula (V)

(V)

where R is alkyl in each occurrence, independently from each other,

an above compound of formula (VI) is hydrogenated.

Typically the hydrogenation is carried out in the presence of catalyst, e.g. palladium catalyst. The hydrogenation process is carried out in a solvent typically, e.g. the solvent is selected from the group of C alcohols, ethyl acetate and cyclohexane, e.g. the solvent is methanol or ethanol.

C) For the preparation of compounds of formula (IV)

nButyl

(IV)

where R is alkyl in each occurrence, independently from each other.

an above compound of formula (V) is mesylated.

, Typically the reaction is carried out in an indifferent solvent, typically in the presence of an acid binding agent. In another embodiment the solvent is selected from the group of dichloromethane. dichloroethane and chlorobenzene. Typically the acid binding agent is a tertiary nitrogen base, for example pyridine or triethylamine. '

In the process a mesvlating reagent should be applied. It can be any reagent which can be used for inserting a CH3 S O2- group into the free amino group of compound of general formula (V). It is practical to use methanesulfonic anhydride or methanesulfonvl halogenide, e.g. methanesulfonvl chloride.

D For the reparation of compound of formula (II)

(Π)

an above compound of formula (IV) is hydrolysed.

Typically the hydrolysis is carried out in the presence of acid. The acid can be a strong inorganic acid, e .g sulphuric acid or p-toluene sulfonic acid. Typically the hydrolysis is carried out in a solvent, which can be selected from the group of of ethanol, THF or chlorinated solvents e.g. dichloromethane.

The reaction temperature is typically between 20-80°C .

E) Finally, for the preparation of dronedarone (I) and pharmaceutically acceptable salts thereof l

0 nButyl

(I)

compound of formula (II) is reacted with compound of formula (III)

(III)

among reductive conditions.

Typically the reaction is canned out in presence of catalyst, e.g. Raney- i, under hydrogen pressure which can be up to 20 bar. e.g. 5 to 1 0 bar. The reaction also can be carried out in the presence of a borohydride type compound (instead of the above catalyst and hydrogen atmosphere), which can be e.g. tnacetoxyborohydride or sodium borohydride.

The reaction can be^' carried out in indifferent solvent or solvent mixture. Typically the^' solvent is selected from the group of alcohols (e.g. methanol or ethanol), halogenated alkanes (e.g. dichloromethane or 1 ,2-dichloroethane), ethers (e.g. tetrahydrofurane (THF)) or nitriles (e.g. acetonitrile).

The reaction is performed at temperature between 0 to 80 °C, e.g. between 10 to 60°C. Typically reaction is carried out between 50 to 55 °C.

The applicable acid for the preparation of pharmaceutically acceptable salts can be any- inorganic or organic acid which forms an acid addition salt with the compound of general formula (I). Exemplary acids which can form an acid addition salt are as follows: acetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzoic acid, benzenesulfonic acid, methansulfonic acid, ethansulfonic acid, boric acid, butyric acid, citric acid, ethanesulfonic acid, fumaric acid, hydrogen chloride, hydrogen bromide^", hydrogen iodide, 2- hydroxyethanesulfonic acid, maleic acid, oxalic acid, methanesulfonic acid, nitric acid, salicylic acid, tartaric acid, sulfuric acid (forming sulfate or bisulfate anion), sulfonic acid (such as those mentioned herein), succinic acid, toluenesulfonic acid and the like. The hydrogen halogenide salts are typical, especially the hydrogen chloride salt.

Here it is mentioned that on the mesylate group of compound of general formula (I) (see the ^"left side" of the molecules) a salt formation can be carried out (on the amide part of it) by a strong base. e.g. an alkaline hydroxide, typically by sodium hydroxide. However, these salts have less practical importance, but they are within the scope of salts which can be prepared by the claimed process. It means that the phrase "salts" embraces both the acid addition salts and the salts formed by bases (basic salts) in case of compounds of general formula (I).

The further starting materials are commercially available or can be prepared b applying known synthetic ways.

Other objects of the invention are the novel intermediary compounds applied in the processes, namely the following compounds:

- Compound of formula (II) and salts thereof

0 nButyl (Π)

Com ounds of formula (IV) and salts thereof

nButyl

(IV)

where R, independently in each. occurrence, is alkyl.

- Compounds of formula (V) and salts thereof

O nButy

(V

where R is alkyl in each occurrence, independently from each other.

- Compounds of formula (VI)

(VI)

Other objects of the invention are the processes for the preparation of the novel intermediary compounds, namely the following ones:

- Process for preparation of compound of formula (II) and salts thereof

(Π)

wherein a compound of formula (IV)

nButy

(IV)

where R is alkyl in each occurrence, independently from each other,

is hydrolysed.

The typical reaction conditions are disclosed above in point D).

- Process for preparation of compounds of formula (IV) and salts thereof wherein a compound of formula (V)

(V)

where R is alkyl in each occurrence, independently from each other, is mesylated, and the obtained product is isolated and, if desired, converted into a pharmaceutically acceptable salt thereof. The typical reaction conditions are disclosed above in point C).

- Process for preparation of compounds of formula (V) and salts thereof wherein a compound of formula (VI)

(VI)

where R is alkyl in each occurrence, independently from each other, is hydrogenated, and the obtained product is isolated and, if desired, converted into a pharmaceutically acceptable salt thereof.

The typical reaction conditions are disclosed above in point B).

- Process for preparation of compounds of formula (VI) wherein the compound of formula VII)

is reacted with a com ound of formula (VIII)

(VIII)

The typical reaction conditions are disclosed above in point A).

In the processes for the preparation of the intermediary compounds the product is isolated as a base typically (if the compound has a free amino or an alkylated amino group). If desired, the isolated base can be converted into a salt (acid adition salt) thereof, which is typically a pharmaceutically acceptable salt [the possible acids are mentioned in point F)] . Theoretically the acid addition salt can be prepared directly if the relating acid is in the final reaction mixture from which the solid product is made (however, this way is not applied in case of these compounds where the base type form has practical importance).

Here it is mentioned that some of the above intermediary compounds have a mesylate group (see the "left side" of the molecules) where a salt formation can be carried out (on the amide part of it) by a strong base, e.g. an alkaline hydroxide, typically by sodium hydroxide. However, these salts have less practical importance, but they are within the scope of salts which can be prepared by the claimed process, i.e. the phrase "salts" embraces the salts formed by bases (basic salts) in such cases (where the molecule has a mesylate group).

In the above reactions the temperature is chosen according to the general practice of a person skilled in organic chemistry. Typically the temperature is between 10 °C and the boiling point of the applied solvent (which can be the mixture of the mentioned solvents in a specific embodiment). Applicable temperature values can be found in the examples.

All the above reactions are carried out under atmospheric pressure with the exception of the hydrogenation steps where higher pressure also can be applied, typically up to 20 bar. e.g. 5 to 10 bar.

Examples

Example 1

X-[2-butyl-3- {4-[(3-dibut)'lamino)propoxy]benzoyl } - l -benzofuran-5-yl]- methanesulfonamide (I)

1 g of N- {2-butyl-3-[4-(3 -oxopropoxy)benzoyl]- l -benzofuran-5-yl } - methanesulfonamide and 0.30 g of dibutylamine were dissolved in 15 ml methanol, 0.25 g of Raney Xi was added and the mixture was stirred under hydrogen pressure of 10 bar at 50°C for 4 hours. When no hydrogen consumption was observed the mixture was worked up as follows: the reaction mixture was cooled down to ambient temperature, the hydrogen pressure was led out and the reactor was flushed with nitrogen, After this the catalyst was filtered out and the solvent was evaporated. The residue was dissolved in isopropyl acetate and washed with 1 5 ml of water with 10 ml of 5% \aHC0₃ solution and with 10 ml of water.- The solvent was evaporated.

Yield: 1 .24 g ( 101 %)

The product was purified by its oxalate salt as follows: to the residue 4 ml of methylethyl ketone is added and the mixture heated to70 °C . To this solution 0.24 g of oxalic acid dissolved in l .5 ml of methylethyl ketone is added at 70° C. After cooling to 20 °C in 6 hours the mixture is stirred at 10 °C for 1 hour and filtered. To the obtained oxalate salt 2,5 ml of water and 4 ml of dichloromethane and 0.63 g of potassium carbonate are added. After stirring for 30 minutes the separated potassium oxalate is filtered and washed with 2 ml of dichloromethane and the solvent is evaporated.

Yield of purified product: 1.14 g (91%).

Purity of product: 99.8% (HPLC)

lH R(D SO): 0.8-0.9ppm (m, 9H); 1.2-1.5ppm (m, 10H); 1.67ppm (5 \ 2H); 1 ,87ppm (5\ 2H); 2.38ppm (ΐ. J=7.2Hz_; 4H); 2.57ppm (m, 2H); 2.88ppm (t, J=7.5Hz, 2H); 2.91ppm (s, 3H); 9.51ppm (t, J=6.2Hz, 2H); 7.09ppm (d, J=8.8Hz, 2H); 7.24ppm (dd, J=8.9, 2.2Hz.1H); 7.38ppm (d, J=2.1Hz, 1H); 7.65ppm (d, J=8.8Hz, 1H); 7.81ppm (d, J=8.8Hz, 2^'H)

Example 2

N-[2-butyl-3-{4-[(3-dibutylamino)propoxy]benzoyl}-l-benzofuran-5- yl]methanesulfonamide (I)

1,1 g N-{2-butyl-3-[4-(3-oxopropoxy)benzoyl]-l-benzofuran-5-yl}- methanesulfonamide and 0.29 g of dibutylamine were dissolvent in 25 -ml of dichloromethane. 0.19 g triacetoxyborohvdride was added and the reaction mixture was stirred at 25°C for 12 hours . The reaction mixture was evaporated and the residue was dissolved in 20 ml of isopropyl acetate. The solution was washed with 20 ml of water, 10 ml of 5% NaHCO . solution and with 10 ml of water. The solvent was evaporated.

Yield: 1.25 g (100%)

The product was purified by chromatography (90%) on silicagel using ethyl acetate/ hexane (1 :3) mixture as eluent.

Purity of product: 99.9% (HPLC)

The product was identical with the compound prepared in example 1. Example 3

-[2-but\ -3-{4-[(3-dibutylamino)propoxy]benzoyl}-l-benzofuran-5-yl]- methanesulfonamide (I)

The process was performed according to example 1 with the difference that instead of methanol ethanol was used.

Yield of purified product: 90% Purity: 99.8% (HPLC)

Example 4 ^■

N-[2-butyl-3- {4-[(3 -dibutylamino)propoxy]benzoyl } - l -benzofuran-5-yl]- methanesulfonamide (I)

The process was performed according to example 2 with the difference that instead of triacetoxy borohydride 0.25 g of sodium borohydride was used at 55°C for 8 hours.

Yield of purified product: 85%

Purity: 99.7% (HPLC)

The product was identical with compound prepared in example 2. Example 5 -

\- {2-butyl-3 -[4-(3-oxopropoxy)benzoyl]- l -benzofuran-5-yl }methanesulfonamide (II)

1 g of N- {2-butyl-3-[4-(3.3-diethoxypi poxy)benzoyl]- l -benzofuran-5-yl } - methanesulfon-amide (IV) was dissolved in 10 ml of THF and 2.5 ml of aqueous sulfuric acid was added (prepared: 0.5 ml of sulfuric acid was diluted with 14 ml of water) and the mixture was warmed at 50°C for 2 hours. The mixture was stirred for additional 2 hours and the mixture was cooled. THF was distilled out in reduced pressure under 40°C. To the . residue 1 0 ml of dichloromethane was added. The phases were separated and the dichloromethane was evaporated.

Yield: 0.86 g (99%)

Purity: 97.4% (HPLC)

l H MR(DMSO):

Example 6

N^T- {2-butyl-3 , [4-(3 -oxopiOpoxy)benzoyl]- l -benzofuran-5-yl} methanesulfonamide (II) The process was performed according to example 5 with the difference that instead of sulphuric acid p-toluenesulfonic acid was used and the solvent was dichloromethane.

Yield: 0.84 g (98%)

Purity: 97.7% (HPLC)

The product was identical with compound prepared in example 5 ,

Example 7 N-{2-butyl-3-[4-(3,3-diethoxypropoxy)benzoyl]-l-benzofuran-5- yl } methanesulfonamide (IV)

0.9 g of (5-aniino-2-butyl-l-benzofuran-3-yl)[4-(3,3-diethoxypropoxy)phenyl]- methanone (V) was dissolved in 10 ml of dichloromethane. The mixture was warmed to 30- 35°C and at this temperature 0.18 g of pyridine was added. .26 g bf methanesulfonyl chloride was added in 30 min at this temperature and the mixture was stirred at 30-35°C for 2 hours, The mixture was washed with 2 x 15 ml of water, 2 x 15 ml of 5% NaHCC>3 and with 1 x 15 ml of water. The dichloromethane was evaporated.

Yield: 80%

Purity: 87% (HPLC)

lHN R(DMSO): 0.8ppm (t, J=7.44Hz, 3H); 1.12ppm (t, J=7.10Hz, 6H); 1.24ppm (sxt, J=7.37Hz, 2H); 1.65ppm (quin, J=7.44Hz_; 2H); 2.02ppm (q, J=6.10Hz, 2H); 2.80ppm (t, J=7.44Hz, 2H); 2.88ppm (s, 3H); 3.47ppm (dq, ^' J=9.58Hz, 7.03Hz, 2H); 3.62ppm (dq, J=9.50, 7.06Hz, 2H); 4,12ppm (t. J=6.29Hz, 2H); 4.72ppm (t, J=5.61Hz, IH); 7.08ppm (d, J=8.93Hz, 2H); 7.21ppm (dd, J=8.81, 2.17Hz, IH); 7.29ppm (d, J=2.29Hz, IH); 7.62ppm (d, J=8.70 Hz, IH); 7.78ppm(d, J=8.93Hz, 2H)

Example 8

(5-amino-2-butyl -benzofuran-3-yl)[4^'-(3,3-diethoxypropoxy)phenyl]methanone (V) 1.13 g of (2-butyl-5-nitro-l-benzofuran3-yl)[4-(3,3-diethoxypropoxy)phenyl]- methanone (VI) was dissolved in 25 ml of methanol and 0.5 g of 10 w/w% Pd/C of was added. The mixture was stirred at 50°C under hydrogen pressure of 10 bar for 4 hours. The catalyst was filtered out and the solvent was evaporated.

Yield: 1.02 g (98%)

Purity: 94% (HPLC)

lHXMR(DMSO): 0.8ppm (t, J=7.32Hz, 3H); 1.12ppm (t, J=7.10Hz, 6H); 1.22ppm (sxt, J=7.30Hz_: 2H); 1.62ppm (quin, J=7.44Hz_; 2H); 2.02ppm (q, J=6.18Hz, 2H); 2.72ppm (t, J=7.55Hz, 2H); 3.47ppm (dq, J=9.61, 7.10Hz, 2H); 3.62ppm (dq, J=9.61, 7.10Hz, 2H);

4.1 lppm (t, J-6.29Hz, 2H); 4.72ppm (t, J=5.61Hz, IH); 5.63ppm (d, J=2.06Hz, IH); 6.58ppm (dd, J=8.58, 2,17Hz, IH); 7.08ppm (d, J=8.70Hz, 2H); 7.27ppm (d, J=8.70Hz, IH); 7.75ppm (d, J=8.70Hz, 2H)

Example 9 (2-butyl-5-nitro-l-benzofuran3-yl)[4-(3,3-diethoxypropoxy)phenyl]methanone (VI)

10 g of (2-butyl-5-nitro-l-benzofur-3-yl)[4-hydroxyphenyl]methanone (VII) was dissolved in 75 ml of methylethylketone.12.2 g of potassium carbonate, 4.4 g of sodium iodide and 9.95 g of 3-chloropropionaldehyde diethyl acetale (VIII) were added and the mixture was stirred at boiling point for 6 hours. The salt was filtered and the solvent evaporated.

Yield: 13.7 g (99%)

Purity: 96.8% (HPLC)

1H N R(DMSO): 8.21-8.27ppm (m.2H); 7.91ppm (d, J=9.61Hz, 1H); 7.81ppm (d, J=8.93Hz_; 2H); 7.1 lppm (d, J=8.70Hz, 2H); 4.72ppm (t, J=5.72HZ, 1H); 4.13ppm (t, J=6.41Hz, 2H); 3.62ppm (dq, J=9.61, 7.10Hz, 2H); 3.47ppm (dq, J=9.56.6.96Hz, 2H); 2.83ppm (t, J=7.55Hz, 2H); 2.02ppm (q, J=6.10Hz, 2H); 1.68ppm (quin, J=7.44Hz, 2H); 1.24ppm (sxt, J=7.60Hz, 2H); l.llppm (t, J=6.98Hz, 6H); 0.80ppm (t, J=7.32Hz, 3H)

Claims

Claims RECORD COPY

1 . Process for preparation ol dronedarone (I) and pharmaceutically acceptable salts thereof

(I)

characterized in that a compound of formula (II)

Ό nButyl (Π)

is reacted with dibutylamine of formula (III)

(III)

under reducing circumstances.

2. Process according to claim 1 characterized in that the reaction is carried out in the presence of a catalyst, under hydrogen pressure, or in the presence of a borohydride type compound.

3. The compound of formula (II) and salts thereof

(Π)

4. Process for preparation of compound of formula (II) and salts thereof

nButyl (Π)

characterized in that a compound of formula (IV)

CH,

(IV)

where R is alkyl in each occurrence, independently from each other,

is hydrolysed.

and the obtained product is isolated and, if desired, converted into a pharniaceuticall acceptable salt thereof.

5. A compounds of formula (IV) and salts thereof

0— R

Ό nButyl (IV)

where R, independently in each occurrence, is alkyl.

6. Process for preparation of compounds of formula (IV) and salts thereof

CH SO--NH

characterized is that a com ound of formula (V)

(V)

where R is alkyl in each occurrence, independently from each other, is mesylated, and the obtained product is isolated and, if desired, converted into a pharmaceutically acceptable salt thereof.

7 , The compounds of formula (V) and salts thereof

(V)

where R is alkyl in each occurrence, independently from each other.

8. Process for preparation of compounds of formula (V) and salts thereof,

(V)

characterized in that a compound of formula (VI)

(VI)

9. The compounds of formula (VI)

(VI)

10. Process for preparation of compounds of formula (VI)

(VI)

characterized in that the com ound of formula (VII)

(VII)

is reacted with a compound of formula (VIII)

(VIII)

where R is alkyl in each occurrence, independently from each other, and Hlg standssen.

1 1. Process for the preparation of dronedarone (I)

and pharmaceutically acceptable salts thereof , characterized in that the compound of formula (VII) is reacted according to claim 10 with a compound of formula (VIII)

— R

Hlg— (CH₂)₂— CH

^ O— R

(VIII)

where R is alkyl in each occurrence, independently from each other, and Hlg stands for halogen,

the obtained compound of formula (VI) - where R is alkyl in each occurrence, independently from each other - is hydrogenated according to claim 8.

the obtained compound of formula (V) - where R is alkyl in each occurrence, independently from each other - is mesylated according to claim 6.

the obtained compound of formula (IV) - where R is alkyl in each occurrence, independently from each other - is hydrolysed according to claim 4.

the obtained compound of formula (II) is is reacted with dibutylamine of formula (III) ._/•nButyl

nButyl (III)

under reducing circumstances according to claims 1 and 2

and the obtained dronedarone of the formula (I) is isolated and, if desired, converted into a pharmaceutically acceptable salt thereof,