WO2011070380A1

WO2011070380A1 - New process for the preparation of dronedarone

Info

Publication number: WO2011070380A1
Application number: PCT/HU2010/000128
Authority: WO
Inventors: Antal Friesz; Zsolt DOMBRÁDY; Marianna CSATÁRINĖ NAGY
Original assignee: Sanofi-Aventis
Priority date: 2009-12-08
Filing date: 2010-11-23
Publication date: 2011-06-16
Also published as: UY33094A; AR079269A1; HU0900759D0; AU2010329655A1; RU2012128568A; CN102741238A; BR112012013753A2; JP2013512944A; AU2010329655B2; SG181562A1; US20130261321A1; US20120289717A1; HUP0900759A2; US8889734B2; IL220170A0; MX2012006654A; EP2509971A1; TW201144291A; CA2781647A1; US8501971B2

Abstract

The subject of the present invention is a novel process for the preparation of N- [2-n-butyl-3-{4-[(3-dibutylamino)propoxy]benzoyl}-1-benzofuran-5- yl] methanesulfonamide of formula (I) and the new intermediates of the preparation process.

Description

New process for the preparation of dronedarone

The present invention relates to novel process for the preparation of the N- [2-«-butyl-3-{4-[(3-dibutylamin0)-propoxy]benzoyl}-l-benzofuran-5-yl]methane- sulfonamide (dronedarone) of formula I and its pharmaceutically acceptable salts, and to the new intermediates of the reparation process.

Dronedarone of formula I is used in the treatment of certain pathological changes of the cardiovascular system, especially in the treatment of angina pectoris, high blood pressure, arrhythmia and insufficient cerebral blood circulation (EP 0471609 B l).

There are several known methods for the preparation of dronedarone of formula I. One prior art process (EP 0471609 B l) reacts 2-hydroxy-5-nitro- benzylbromide (VII)

with triphenylphosphine, and the thus obtained 2-hydroxy-5-nitro-benzyl-triphenyl- phosphonium bromide (VIII)

is reacted with pentanoyl chloride to give 2-«-butyl-5-nitro-benzoruran (IX)

IX

Treatment of IX with anisoyl chloride under Friedel-Crafts conditions gives 2-n- butyl-3-(4-methoxy-benzoyl)-5-nitro-benzofuran (X)

which is heated in the presence of aluminum chloride to obtain 2-n-butyl-3-(4- hydroxy-benzoyl)-5-nit -benzofuran (XI)

XI Industrial application of this last reaction step involves difficulties, because 2-n- butyl-3-(4-methoxybenzoyl)-5-nitro-benzofuran (X) is mutagenic, and aluminum chloride is harmful for the health. The resulting 2-«-butyl-3-(4-hydroxybenzoyl)-5- nitro-benzofuran (XI) on reaction with dibutylamino-propylchloride furnishes 2-n- butyl-3-[4 (3 I)

XII which is reduced in the presence of platinum oxide catalyst to the 5-amino-2-«-

XIV and the thus obtained 2-«-butyl-3-[4-(3-dibutylamino-propoxy)benzoyl]-5-nitro- benzofuran (XII) is reduced in the presence of platinum oxide catalyst to the 5- amino-2-«-butyl-3-[4-(3-dibutylamino-propoxy)benzoyl]benzofuran (XIII).

Mesylation of the latter gives dronedarone (I). In the course of the last, mesylation step, however, a double mesylated derivative is also formed, the yield is low and the purification of dronedarone by column chromatography is complicated. The industrial application of the method is therefore not economical.

The third known method for the preparation of dronedarone (I) is disclosed in patent application of publication number WO 02/48132. This superrconvergent method contains the following steps:

5-amino-2-n-butyl-benzofuran (XV)

XV is mesylated and the resulting 2-«-butyl-5-mesylamino-benzofuran (III)

Me

nBu is reacted with 4-[3-(dibutylamino)propoxy]benzoyl chloride hydrochloride salt (XlVa)

XlVa under Friedel-Crafts conditions, to obtain the hydrochloride salt of dronedarone (la).

la

In this method the order of the reaction steps is changed, the reduction step and the mesylation are at the beginning of the synthesis.

This method is very simple and economical regarding the number of the reaction steps. Its drawback is, however, that in the last step the hydrochloride salt of dronedarone is obtained in a substantially contaminated form. This can be explained by the presence of the dibutylamino-propyl group in the Friedel-Crafts reaction. In the published examples the yield is 90%, during the purification steps first the raw dronedarone hydrochloride, then, following treatment with hydrogen chloride solution in isopropanol, the purified dronedarone hydrochloride is obtained (90%). . .

Another drawback of the method is that the reactants used in the Friedel- Crafts reaction and the obtained by-products are insoluble in water, thus they cannot be removed from the system by aqueous washing. Our aim was to work out a novel method for the preparation of dronedarone and its pharmaceutically acceptable salts, which method avoids the above mentioned disadvantages, and is economical and industrially applicable.

We have

-wherein

activated hydroxyl group- is reacted with dibutylamine, and optionally transformed into its salts, then this method avoids the disadvantages of the processes mentioned before, it is economical and also suitable for industrial application.

One reactant is dibutylamine, which is volatile and thus can be removed from the system and reused after workup, the other is a compound of the general formula (II) -where the meaning of X is as defined above- which can be treated well under the applied reaction conditions. By choosing suitable reaction conditions, dronedarone of formula (I) is obtained in appropriate purity and yield, no byproduct is formed, only a few percent of the unreacted starting material may remain in the reaction mixture, and this can be reused.

According to our invention the reaction of the compound of the general formula (II) -wherein X stands for chloro-, bromo- or iodo atom, hydroxyl- or activated hydroxyl group- with dibutylamine is carried out using equivalent amount or excess of dibutylamine. The reaction is performed in an organic solvent or in a mixture of organic solvents. For organic solvent, ketones (acetone, methyl ethyl ketone), for mixture of organic solvents, mixtures of ketones and aromatic hydrocarbons (xylene, toluene) are used. Optionally other organic solvents and their mixtures can also be used. .

According to our invention the compound of the general formula (II) -where the meaning of X is as defined above- is reacted with dibutylamine, optionally in the presence of a catalyst. If in the general formula (II) the meaning of X is chloro- or bromo atom, then iodides (as for example sodium iodide or potassium iodide) are used as catalyst. If in the general formula (II) the meaning of X is hydroxyl group, then [Ru( -cymene)Cl₂]₂ and 1,1 '-bis-(diphenylphosphino) ferrocene or [Ru( - cymene)Cl₂]₂ and bis-(2-diphenylphosphinophenyl)ester compounds are used. If in the general formula (II) the meaning of X is iodo atom or activated hydroxyl group, then no catalyst is used.

. The reaction of the compound of the general formula (II) -wherein X stands for chloro-, bromo- or iodo atom, hydroxyl- or activated hydroxyl group- with dibutylamine is carried out at the boiling point of the applied solvents or between 60-120°C.

In the compounds of the general formula (II) the hydroxyl group may be activated with methylsulfonyl or substituted benzenesulfonyl group. The substituent of the benzenesulfonyl group may be C₁.₄-alkyl group, halogen atom or nitro group.

According to one embodiment of our invention the 2-«-butyl-5-mesylamino- benzofuran (III)

is reacted with an acid halide of the general formula (IV)

IV

where

Y stands for chloro- or bromo atom, X represents halogen atom or protected hydroxy 1 group, and the thus obtained compound of formula (II) -where the meanings of X are defined above- is reacted with dibutylamine in a manner as described above, to obtain dronedarone of formula (I).

According to our invention the reaction of the benzofuran derivative of formula (III) with the acid halide of the general formula (IV) - where the meanings of X and Y are as defined above- is carried out in the presence of Friedel-Crafts catalyst in a halogenated organic solvent or in nitrobenzene.

The reaction of the compounds (III) and (IV) is carried out in a temperature range of 10-80 °C.

According to another embodiment of the invention, a compound of the general formula t (VI),

VI

wherein X represents chloro-, bromo- or iodo atom, hydroxy^ or activated hydroxyl group, is subjected to hydrogenation reaction and the thus obtained compound of the general formula (V)

wherein X represents chloro-, bromo- or iodo atom, hydroxyl- or activated hydroxyl group, is mesylated and the resulting compound of formula (II) is reacted, in the above described manner with dibutylamine, to give dronedarone of formula (I). ^■ , .··

The hydrogenation reaction of the compound of formula (VI) is carried out in the presence of a catalyst. In one version of the method palladium catalyst is used. In another version of the method platinum catalyst is applied. The hydrogenation reaction of the compound of formula (VI) is performed in an organic solvent, in a temperature range of 10-80 °C.

The mesylation of the compound of formula (V) is carried out with methanesulfonyl chloride or with methanesulfonic anhydride. The mesylation of the compound of formula (V) is performed in an inert solvent. According to one preferred embodiment of the reaction, ether or a halogenated solvent is used. The mesylation of the compound of formula (V) is carried out in a temperature range of 5-80 °C. The mesylation of the compound of formula (V) is carried out in the presence of a base. According to one preferred embodiment of the reaction an amine (pyridine, triethylamine) is used as base. ·

The benzofuran derivatives of the general formula (II) (CH₂ ) -X

where X stands for chloro-, bromo- or iodo atom, hydroxyl- or activated hydroxyl group;

the benzofuran derivatives of the eneral formula (V),

wherein X stands for chloro-, bromo- or iodo atom, hydroxyl- or activated hydroxyl group; .

and

the benzofuran derivatives of the general formula (VI),

wherein X stands for chloro-, bromo- or iodo atom, hydroxyl- or activated hydroxyl group are new compounds, not known from the literature.

In one embodiment of the present invention the compounds of the general formula (II), where the meanings of X are defined above, are prepared by reacting the compounds of formula (III) with the compounds of the general formula (IV) - wherein Y stands for chloro- or bromp atom, and X represents a halogen atom or a protected hydroxyl group. The compound of formula (III) is known, its preparation by mesylation of 5-amino-2-«-butyl-benzofuran is described in patent application WO 02/048132. The compounds of the general formula (IV) wherein the meanings of X and Y are defined above, are also known from the literature, their preparation is disclosed in patent EP 0471609 Bl.

<· In another embodiment of the present invention the compounds of the general formula (II) - where the meaning of X is defined above - are prepared by mesylation of a compound of the general formula (V) - wherein X means chloro-, bromo- or iodo atom, hydroxyl- or activated hydroxyl group. The compound of the general formula (V) - where the meaning of X is defined above - is prepared by catalytic hydrogenation of the benzofuran derivative of the general formula (VI) - where the meaning of X is defined above. The compound of the general formula (VI), wherein X represents bromo atom, is known from the literature. The compound itself, and its preparations are disclosed by the Applicant in patent EP 0471609 Bl. The preparation of the compounds of the general formula (VI) - wherein X means chloro-, bromo- or iodo atom, hydroxyl- or activated hydroxyl group - from the benzofuran derivative (XI), is carried out by analogy of the method described in EP 0471609 Bl.

Further details of the invention are demonstrated by the following examples, without limiting the claims to examples.

. ^'

Example 1.

(2-fl-butyl-5-nitro- 1 -benzofuran-3-yl)-r4-(3-chloropropoxy)phenyl] methanone, compound of the general formula (VI) wherein X is chloro atom

40 g (2-n-butyl-3-(4-hydroxybenzoyl)-5-nitro-benzofuran (XI) was dissolved in 320 ml methyl ethyl ketone and to the solution 48.9 g potassium carbonate was added. During stirring 37.2 g l-bromo-3-chloropropane was added and the mixture was heated to reflux (81-82°C) and stirred at that temperature for 4 hours. After cooling, the solid salt was filtered off and washed with 3 x, 20 ml methyl ethvl ketone. The filtrate was evaporated. The removed methyl ethyl ketone which ^r contains the excess of l-bromo-3-chloropropane is used in the next reaction.

Mass of the product: 44.93 g. (99.1%)

Purity (HPLC): 98.9%

Molecular weight: (calculated): 416.1265 Da .

(measured): 416.1274 Da

1H NMR (DMSO): 0.84ppm (t, J=7.4Hz, 3H); 1.27ppm (6\ 2H); 1.72ppm (5\ 2H); 2.26ppm (5', J=6.5Hz, 2H); 2.88ppm (t, J=6.5HZ, 2H); 3.86ppm (t,J=6.5Hz, 2H); 4.26ppm (t, J=6.0Hz; 2H); 7.17ppm (d, J=8,8Hz, 2H); 7.86ppm (d, J=8.7Hz, 2H); 7.96ppm (m, 1H); 8.29ppm (m, 1+lH) ^' . -

Example 2.

(5-Amino-2-w-butyl-benzofuran-3-yl)-r4-(3-chloropropoxy)phenvn methanone, compound of the general formula (V) wherein X is chloro atom

Into a 500 ml hydrogenation reactor equipped with turbo stirrer were added 93.8 g (2-«-butyl-5-nitro-l-benzofuran-3-yl)-[4-(3-chloro-propoxy)phenyl]- methanone -the compound of the general formula (VI), where X is chloro atom- and 470 ml abs. ethanol, and then 4.9 g 10% palladium on carbon catalyst. The reaction mixture was heated to 50°C under stirring at a speed of 800 rotation/minute. Under cooling, hydrogen under 5 bar pressure was set to the reactor and the mixture was stirred at that pressure and temperature for 2 hours. After cooling the catalyst was filtered off and the solvent was removed.

Mass of product: 85.46 g (98%).

Purity (HPLC): 93.8%

Molecular weight: (calculated): 386.1523 Da

(measured): 386.1524 Da

Ή NMR (DMSO): 0.82ppm (t, J=7.4Hz, 3H); 1.24ppm (6\ 2H); 1.64ppm (5',2H); 2.22ppm (5\ 2H); 2.75ppm (t, J=7.6Hz, 2H); 3.78ppm (t, J=6.4Hz, 2H); 4.9ppm (t, J=5.9Hz, 2H); 6.62ppm (d, J=2.3Hz, IH); 6.65ppm (dd, J=8.7; 2.3Hz, - IH); 7.05ppm (d, J=8.6Hz, 2H); 7.22ppm (d, J=8.7Hz, IH); 7.77ppm (d, J=8.7Hz, 2H)

Example 3.

(5-Amino-2- -butyl-benzofuran-3-yl)- 4-(3-bromo-propoxy)phenyll methanone, compound of the general formula (V) wherein X is bromo atom

The process as described in Example 2. was followed, starting from (2-«-but l-5-nitro-l-benzofuran-3-yl)-[4-(3-bromopropoxy)phenyl]methanone -the compound of the general formula (VI) where X is bromo atom.

Yield of the product: 97.6%

Purity (HPLC): 92.4%

Molecular weight: (calculated): 430.1018 Da

(measured): 430.1032 Da

^!H NMR (DMSO): 0.83ppm (t, J=6.8Hz, 3H); 1.26ppm (t, J=6.8Hz, 2H); 1.69ppm (m, 2H); 2.25ppm (m, IH); 2.33ppm (m, IH); 2.84ppm (m, 2H); 3.72ppm (m, IH); 3.86ppm (m, IH); 4.25ppm (m, 2H); 7.15ppm (d, J=8.1Hz, 2H); 7.39ppm (d, 8:1Hz, IH); 7.51ppm (S, IH); 7.82ppm (d, J=8.1Hz, 3H) ^'

Example 4. ,

N-(2-»-butyl-3- 4-(3-chloropropoxy)benzoyll benzofuran-5-yl) methane

sulfonamide, compound of the general formula (II) wherein X is chloro atom

8.7 g (5-amino-2-«-butyl-benzofuran-3-yl)-[4-(3-chloropropoxy)phenyl] methanone—the compound of the general formula (V) wherein X is chloro atom - was stirred in 90 ml dichloromethane until complete dissolution. The solution was cooled to 15°C and keeping this temperature 1.8 g pyridine, then dropwise, at 15°C, in 15 minutes 2.6 g methanesulfonyl chloride were added. After checking the reaction mixture by HPLC, further 0.19 g pyridine and 0.26 g methanesulfonvl chloride were added and stirring was continued for 30 minutes. The reaction mixture was washed with 2 x 20 ml water, 2 x 20 ml 5% hydrochloric acid, and 2 x

20 ml 5% NaHCO₃ solution, and then it was evaporated.

Mass of the product: 10.1 g (96.6%)

Purity: 87.5%

Following crystallisation from abs. ethanol (yield 72%), the purity (by HPLC) of the product: 100%

Melting point: 109.7-1 10.3°C

Ή NMR (DMSO-D6): 9.61ppm (1H), 7.82ppm (J=8.7Hz, 2H), 7.65ppm (d, IH), 7.31 ppm (dd, J=2.1Hz, 1H), 7.24 ppm (dd, J=8.8Hz, 1H), 7.14 ppm (2H), 4.25ppm (t, J=6.0Hz, 2H), 3.85 ppm (t, J-6.4Hz, 2H), 2.92 ppm (S, 2H), 2.84ppm (t, J=7.5Hz, 2H), 2.25pprri (m, 2H), 1.69 ppm (m, 2H), 1.28ppm (m, 2H), 0.84ppm (t, J=7.3Hz, 3H) Example 5.

N-(2-ft-biity 1-3 - 4-(3 -bromopropoxy)-benzoy llbenzofuran-5 -y 1)

methanesulfonamide, compound of the general formula (II where X is bromo atom The process as described in Example 4. was followed, starting from

(5-amino-2-n-butyl-benzofuran-3-yl)-[4-(3-bromopropoxy)phenyl]methanone -the compound of the general formula (V) where X is bromo atom.

Yield of the product: 95.8% - . Purity: 86.8% (HPLC)

Molecular weight: (calculated): 508.0793 Da

(measured): 508.0780 Da

1H NMR (DMSO): 0.84ppm (t, J=7.3Hz, 3H); 1.26ppm (6', 2H); 1.69ppm (5', 2H); 2.33ppm (5', 2H); 2.84ppm (t, J=6.5Hz, 2H); 2.92ppm (s, 3H); 3.73ppm (t, J=6.5Hz, 2H); 4.23ppm (t, J=6.0Hz, 2H); 7.14ppm (d, J=8.8Hz, 2H); 7.23ppm (dd, J=8.9; 2.3Hz, 1H; 7.25ppm (d, J=2.1Hz, TH; 7.66ppm (d, J=8.8Hz, 1H; 7.82ppm (d, J=8.8Hz, 2H) , Example 6.

N-(2-/¾-butyl-3-[4-(3-chloropropoxy)ben^

compound of the general formula (ID, where X is chloro atom

' .^■ _,

5.2 g 2-«-butyl-5-mesylamino-benzofuran (III) was mixed with 30 ml dichloromethane and to the resulting suspension 5.55 g 4-(3-chloropropoxy)benzoic acid chloride -the compound of the general formula (IV), where X and Y are chloro atom- was slowly added. The reaction mixture was cooled to 5°C and in 15 minutes, in four portions 3.89 g iron(III) chloride was added, keeping the temperature between 5-10°C. The mixture was stirred at 20°C for 1 hour, then heated to 40- 45°C and in 30 minutes 54 ml water was added. The mixture was stirred at that temperature for 30 minutes. The phases were, still warm, separated. The dichloromethane phase was washed by stirring with 2 x 16 ml 5% NaHCO₃ solution, then with 2 x 16 ml water. The solvent was removed by evaporation.

Mass of the product: 9.13 g (98.4%)

Purity (HPLC) 89.6%.

After crystallisation (88%) from abs. ethanol, the purity of the product (by HPLC): 100%

Melting point: 109.8-1 10.2°C

The product is identical with the product prepared in Example 4.

Example 7. N-(2-ft-buty 1-3 -[4-(3 -chloropropoxy benzoy 1] benzofuran-5 -y Dmethanesulfonamide, compound of the general formula (II), where X is chloro atom

The reaction was performed as described in Example 6., but chlorobenzene was used as solvent, instead of dichloromethane.

Mass of the product: 97.6%

Purity (HPLC): 88.6% Example 8.

N-(2-½-butyl-3-r4-(3-chloropropoxy)be^

compound of the general formula (II), where X is chloro atom

The reaction was performed as described in Example J., but aluminum chloride was used instead of iron(III) chloride.

Yield of the product: 96.8%

- Purity (HPLC): 86.5%

- .

Example 9.

N-(2- 7-butyl-3-r4-(3-bromopropoxy)benzoyl1benzofuran-5-yl)methanesulfonamide, the compound of the general formula (II), where X is bromo atom

To the suspension of 5 g 2-n-butyr-5-mesylamino-benzofuran (III) in 35 ml dichloromethane was slowly added 5.19 g 4-(3-bromopropoxy)benzoyl chloride - the compound of the general formula (IV), where X is bromo atom and Y is chloro atom. The reaction mixture was cooled to 5°C and in 20 minutes, in five portions 9 g iron(III) chloride was added, maintaining the temperature between 5-10°C\ The mixture was stirred at 20°C for 1 hour, then heated to 40-45°C, and in 30 minutes 55 ml water was added. The mixture was stirred at that temperature for 40 minutes. The phases were, still warm, separated. The dichloromethane phase was washed by stirring with 2 x 16 ml 5% NaHCO₃ solution, then with 2 x 16 ml water. The solvent was removed by evaporation.

Mass of the product: 8.1 g (93.4%)

Purity (HPLC) 88.2%.

The product is identical with the product prepared in Example 5. Example 10.

N-(2- -butyl-3- 4_"(3-bromopropoxy)benzoyllbenzomran-5-yl)methanesulfonami the compound of the general formula (II), where X is bromo atom

■ .. ^'

The reaction was performed as described in Example 9., but chlorobenzene was used as solvent, instead of dichloromethane.

Mass of the product: Ί.9 g

Purity (HPLC): 86.7%

Example 11.

N-(2-«-bu l-3- 4-(3-brom0propoxy)benzoyllbenzofuran-5-yl)methanesulfonamide, the compound of the general formula (II), where X is bromo atom

The reaction was performed as described in Example 9., but aluminum chloride catalyst was used, instead of iron(III) chloride

Mass of the product: 8.0 g

Purity (HPLC): 85.6%

' _, .

Example 12.

N- [2- -buty 1-3 - { 4- [(3 -dibuty lamino)propoxy ]benzoy 11-1 -benzofuran-5 -y Π- methanesulfonamide, the compound of the general formula (I)

5 g N-(2-«-butyl-3-[4-(3-chloropropoxy)benzoyl]benzofuran-5-yl)- methanesulfonamide -the compound of the general formula (II), where X is chloro atom- was dissolved in 90 ml methyl ethyl ketone, then 16.7 g dibutylamine and 6.46 g sodium iodide were added and the mixture was stirred for 16 hours. The reaction mixture was evaporated, 100 ml dichloromethane and 100 ml water were added. The phases were separated. The organic phase was washed by stirring with 50 ml 5% hydrochloric acid, then with 50 ml water. The solvent was distilled off. The dibutylamine recovered from the solvent was used in a next reaction.

Mass of the product: 5.9 g (100.0%)

Purity (HPLC): 98.7%

The product is purified through its oxalate salt (90%).

Purity of the oxalate salt (HPLC): 100%

1H NMR (DMSO): 0.8-0.9ppm (m, 9H); 1.2-1.5ppm (m, lOH); 1.67ppm (5\ 2H); 1.87ppm (5', 2H); 2.38ppm (t, J=7.2Hz, 4H); 2.57ppm (m, 2H); 2.81ppm (t, J=7.5Hz, 2H); 2.91ppm (s, 3.H); 9.51ppm (t, J=6.2Hz, 2H); 7.09ppm (d, J=8.8Hz, 2H); 7.24ppm (dd, J=8.9; 2.2Hz, IH); 7.38ppm (d, J=2.1Hz, IH); 7.65ppm (d, J=8.8Hz, lH); 7.81ppm (d, J=8.8Hz, 2H)

Example 13. N- 2-^-buty 1-3 - { 4- [(3 -dibutylamino)propoxy1 benzoyl } - 1 -benzofuran- 5 - yl] - methanesulfonamide, the compound of the general formula (I)

The reaction was performed as described in Example 12., but potassium iodide was used, instead of sodium iodide.

Mass of the product: 100.0%

Purity (HPLC): 97.8% ^

Example 14. N- 2-«-butyl-3-(4-[(3-dibutylamino)propoxylbenzoy -l-benzofuran-5-yl]- methanesulfonamide, the compound of the general formula (I)

The reaction was performed as described in Example 12., but acetone was used, instead of methyl ethyl ketone.

Mass of the product: 98.7%

Purity (HPLC): 97.1% Example 15.

N-[2-^-butyl-3-(4-f(3-dibutylamino)propoxy benzovU-l-benzofuran-5-yn- methanesulfonamide, the compound of the general formula (I)

The reaction was performed as described in Example 12., but for solvent, a 9:1 mixture of methyl ethyl ketone and toluene was used.

Yield of the product: 98.8% , /- . - . ^' ·

Purity (HPLC): 98.7%

Example 16.

N-[2-^-butyl-3-(4-r(3-dibutylamino)propoxy1benzoy -l-benzofuran-5-yll- methanesulfonamide, the compound of the general formula (I)

The reaction was performed as described in Example 12., using N-(2-«- butyl-3-[4-(3-bromopropoxy)benzoyl]benzofuran-5-yl)methanesulfonamide -the compound of the general formula (II), where X is bromo atom- for starting material.

Yield of the product: 98.7%

Purity (HPLC): 97.7%

The product is identical with the product prepared in Example 12. -

Example 17.

N- [2-w-buty 1-3 - { 4- [(3 -dibuty lamino)propoxyl benzoyl } - 1 -benzofuran-5 - yll- methanesulfonamide, the compound of the general formula (I)

The reaction was performed as described in Example 12., with the difference that the starting material was N-(2-n-butyl-3-[4-(3-methanesulfonyloxy- propoxy)benzoyl]benzofuran-5-yl)methanesulfonamide -the compound of the general formula (II), where X is methanesulfonyloxy group- and sodium iodide was not used. ,

Yield of the product: 89.1% Purity (HPLC): 98.1% Example 18. N-[2-w-butyl-3- (4-f (3-dibutylamino)propoxyJbenzoyl }- 1 -benzofuran-5-νΠ- methanesulfonamide, the compound of the general formula (I)

The reaction was performed as described in Example 12., with the difference that the starting material was N-(2-«-butyl-3-[4-(3-tosyloxy- propoxy)benzoyl]benzofuran-5-yl)-methanesUlforiamide -the compound of the general formula (II), where X is tosyloxy group- and sodium iodide was not used.

Yield of the product: 97.81%

Purity (HPLC): 97.6% Example 19.

N-[2-«-butyl-3-(4- (3-dibutylamino)propoxylbenzoyl -l-benzofuran-5-yl1- methanesulfonamide, the compound of the general formula (I) - . , · 0.5 g N-(2-«-butyl-3-[4-(3-hydroxy-propoxy)-benzoyl]-benzofuran-5-yl)- methanesulfonamide -the compound of the general formula (II), where X is hydroxyl group- was dissolved in, 8 ml toluene. To the solution 1.5 g dibutylamine and 1.2 mol% [Ru(/?-cymene)Cl2]2 and 2.5 mol% l, l '-bis-(diphenylphosphino)- ferrocene catalysts were added and the reaction mixture was kept under reflux for 24 hours. The solvent was removed by evaporation, the residue was taken up in 10 ml dichloromethane and washed by stirring with 5 ml 1% hydrochloric acid, then with 10 ml water. The solvent was removed by evaporation.

Mass of the product: 0,51 g (82.5%)

Purity (HPLC): 92.4%

The product is identical with the product prepared according to Example 12. Example 20.

N-r2-¾-butyl-3-{4-f(3-dibutylamino)propoxylberi2oyl)-l-benzoruran-5-yl]- methanesulfonamide hydrogen chloride salt,

the compound of the general formula (la)

5 g dronedarone base was dissolved in 24 ml isopropanol and 0.98 g 37% hydrochloric acid was added to it. The mixture was cooled to 0°C and kept at that temperature for 5 hours. The precipitated white crystals were collected, washed with 3.5 ml isopropanol. The product was dried at 50°C under vacuum.

Mass of the product: 5.2 g (97.6%)

Purity (HPLC): 100%

Claims

1. Process for the preparation of N-[2-«-butyl-3-{4-[(3- dibutylamino)propoxy]benzoyl}-l-benzofuran-5-yl]methanesulfonamide of formula I

and its

at a benzofuran derivative of the general formula II

II

-wherein X represents chloro-, br mo- or iodo atom, hydroxyl- or activated hydroxy 1 group- is reacted with dibutylamine and, if desired, the salt of the product is formed.

2. The process according to claim 1., c h a r a c t a r i z e d in t h a t the reaction is carried out with excess of dibutylamine.

3. The process according to any of claims 1-21, cha rac ta rized in that the reaction is carried out in an organic solvent or in the mixture of organic solvents.

4. The process according to claim 3., charactarized in that the organic solvent is selected from ketones.

5. The process according to claim 4., c h a r a c t a r i z e d i n th t the ketone is acetone or methyl ethyl ketone.

6. The process according to claim 3., char ctarized in that as for mixture of organic solvents, the mixture of ketone and aromatic hydrocarbon is used. 7. The process according to claim 6., c h a r a c t a r i z e d in that as for aromatic hydrocarbon, toluene or xylene is used.

8. The process according to any of claims 1-7., c h a ra c ta riz e d i n that in the case where in the general formula II the meaning of X is chloro- or bromo atom or hydroxyl group, the reaction is carried out in the presence of a catalyst.

9. The process according to8., charactarized in that in the case where in the general formula II the meaning of X is chloro- or bromo atom, the catalyst is sodium- or potassium iodide.

10. The process according to claim 8., c h a racta rized in th at in the case where in the general formula II the meaning of X is hydroxyl group, the catalysts are [Ru(p-cymene)Cl₂]₂ and l, -bis-(diphenylphosphino)ferrocene or [Ru( -cymene)Cl₂]₂ and bis-(2-diphenylphosphinophenyl)-ester compounds. „

11. The process according to any of claims 1-10., cha r ctarized in t h a t the reaction is carried out at the boiling point of the solvents or at a temperature between 60-120°C.

12. The process according to any of claims 1-11., charactarized in t h a t in the case where in the general formula II the meaning of X is activated hydroxyl group, the activating group is mesyloxy- or substituted benzenesulfonyloxy group.

13. The process according to 12., c h a r cta rize d i n th a t the substituents of the substituted benzenesulfonyloxy group are selected from methyl group, nitro group or halogen atom.

14. The process according to any of claims 1-13., characta rized in that the benzofuran derivative of formula III

IV where

Y represents chloro- or bromo atom, X represents; halogen atom or protected hydroxyl group, and the resulting benzofuran derivative of the general formula II

-where the meaning of X is defined aboye- is reacted with dibutylamine and, if desired, the salt of the product is formed.

15. The process according to claim 14., c h a r a c t a r i z e d i n that the reaction of the compound of formula III with the compounds of the general formula IV is carried out in the presence of Friedel-Crafts catalyst.

16. The process according to claim 15., c h a r a c t a r i z e d i n t h a t aluminum chloride or iron(III) chloride are used as Friedel-Crafts catalysts.

17. The process according to claim 14., c h a r a c t a r i z e d i n that the reaction of the compound of formula III with the compounds of the general formula IV is carried out in halogenated solvents.

18., The process according to claim 17., c h a r a c t e r i z e d i n that dichloromethane, dichloroethane or chlorobenzene are used as halogenated solvents. ^{' ■} .. ^' . ■ ^'

19. The process according to claim 14., c h a r a c t a r i z e d i n that the reaction of the compound of formula III with the compounds of the general formula IV is carried out in nitrobenzene.

20. The process according to claim 14., c h a r a c t a r i z e d i n that the reaction of the compound of formula III with the compounds of the general formula IV is carried out at a temperature between 10-80 °C.

21. The process according to any of claims 1-13., c h a racte rized in that

a.) a compound of the general formula VI

where X represents chloro-, bromo- or iodo atom, hydroxyl- or activated hydroxyl group- . _^

is subjected to hydrogenation reaction,

and then

b.) the resulting compound of the general formula V,

where X represents chloro-, bromo- or iodo atom, hydroxyl- or activated hydroxyl group- is mesylated,

and

c.) the resulting benzofuran derivative of the general formula II

II where X represents chloro-, bromo- or iodo atom, hydroxyl- or activated hydroxyl group- is reacted with dibutylamine and, if desired, the thus obtained compound of the general formula I is transformed into its salt.

22. Reaction step a.) of the process according to claim 21., charactarized i, n that the hydrogenation reaction is carried out in the presence of catalyst.

23. The process according to claim 22., c h a racta rized in th at palladium or platinum are applied as catalysts.

24. Reaction step a.) of the process according to / claim 21., charactarized in that the reaction is carried out in organic solvent at a temperature between 10-80 °C.

25. Reaction step b.) of the process according to claim 21., charactarized in that methanesulfonyl chloride or methanesulfonic anhydride are used as mesylating agents.

26. Reaction step b.) of the process according to claim 21., charactarized in that the reaction is carried out in inert solvents. 27. The process according to claim 26., c ha rac ta rized i n th a t ethers or halogenated hydrocarbons are used as inert solvents.

28. Reaction step b.) of the process according to claim 21., charactarized in that the reaction is carried out at a temperature between 5-80 °C.

29. Reaction step b.) of the process according to claim 21., characterized in that the reaction is carried out in the presence of a base.

30. The process according to claim 29., c h a racte rized in th a t amine compounds are used as base.

31. tha t pyrid

where X is chloro-, bromo- or iodo atom, hydroxyl- or activated hydroxyl group.

where X is chloro-, bromo- or iodo atom, hydroxyl- or activated hydroxyl group.

35. The compounds as defined in claim 34., where X is mesyloxy group or substituted benzenesulfonyloxy group.

The compounds of the general formula VI,

VI where X is chloro or iodo atom, hydroxyl- or activated hydroxyl group.

37. The eompounds. as defined in claim 36., where X is mesyloxy group substituted benzenesulfonyloxy group.