Title of Invention

"METHANESULPHONAMIDO-BENZOFURAN, PREPARATION METHOD AND USE THEREOF AS SYNTHESIS INTERMEDIATE"

Abstract The invention concerns 2-butyl-5-methanesulphonamido-benzofuran, its preparation and its use. Said compound is a synthesis intermediate in particular for preparing dronedarone.
Full Text METHANESULPHONAMIDO-BENZOFURAN, PREPARATION METHOD AND USE THEREOF AS SYNTHESIS INTERMEDIATE
The present invention relates, in a general way, to a (methanesulfonamido)benzofuran derivative, to its method of preparation and to its use as a synthesis intermediate.
More precisely, the subject of the invention is 2-butyl-5-(methanesulfonamido)benzofuran of formula:
(Figure Remove)CHaSOaHh
(1)
This compound has proved particularly useful as an intermediate product for the final preparation of (aminoalkoxybenzoyl)benzofuran derivatives, in particular of 2-butyl-3-(4-[3-(dibutylamino)propoxy]-benzoyl)-5-(methanesulfonamido)benzofuran commonly called dronedarone and its pharmaceutically acceptable salts.
Thi s (methanesulfonamido)benzofuran
derivative and its pharmaceutically acceptable salts have been described in patent EP0471609 as well as its therapeutic applications. In the cardiovascular field, this compound has proved particularly useful especially as an antiarrhvthmic agent.

There has been reported in patent EP0471609, mentioned above, a method for preparing 3-[4-(aminoalkoxy)benzoyl]benzofuran or benzo[b]thiophene derivatives by attaching an aminoalkoxybenzoyl chain to a benzofuran or benzo[b]thiophene derivative, according to which method there is first added to the benzofuran or benzo[b]thiophene derivative in question a benzoyl group containing in the para position an oxygen protected with a methyl group, deprotection is carried out in order to regenerate the hydroxyl functional group and finally the desired aminoalkyl chain is introduced.
More specifically, this method when applied to the preparation of dronedarone comprises the sequence of steps below:
a) reaction of 2-butyl-5-nitrobenzofuran with anisoyl
chloride in the presence of tin tetrachloride based on
the Friedel-Crafts reaction conditions and hydrolysis
to form 2-butyl-3-(4-methoxybenzoyl)-5-nitrobenzofuran,
b) demethylatiori of the compound thus obtained in the
presence of 2.25 molar equivalents of aluminum chloride
and hydrolysis so as to form 2-butyl-3-(4-
hydroxybenzoyl)-5-nitrobenzofuran,
c) condensation of the compound obtained with 1-chloro-
3-(dibutylamino)propane in the presence of potassium

carbonate, to give 2-butyl-3-(4-[3-(dibutylamino)propoxyj benzoyl)-5-nitrobenzofuran,
d) hydrogenation of the compound thus formed, in the
presence of platinum oxide, which gives 5-amino-2-
butyl-3-(4-[3-dibutylamino)propoxy]benzoylbenzofuran,
e) reaction of the 5-aminobenzofuran derivative thus
obtained with methanesulfonyl chloride in the presence
of triethylamine, which gives dronedarone.
However, this method is not without some disadvantages because, in particular, of the use of aluminum chloride. Indeed, the use of this method on an industrial scale causes high discharges of aluminum hydroxide whose treatment, in order to avoid problems of pollution, is found to be expensive. In addition, the use of 2-butyl-3-(4-methoxybenzoyl)-5-nitrobenzofuran should be avoided as far as possible because of its mutagenic properties.
However, the desired compound is produced with a maximum yield of 60% from 2-butyl-5-nitrobenzofuran according to this method comprising a relatively large number of steps since at least five steps are necessary for the final formation of dronedarone.
The search for an industrial method for the preparation of dronedarone or its pharmaceutically acceptable salts using easily accessible and inexpensive synthesis intermediates based on a more

direct method than the earlier method and not using aluminum chloride therefore remains of unquestionable interest.
There has been reported in J. Med. Chem. 1984, 21_, 1057-1066 a more convergent method for attaching an aminoalkoxybenzoyl chain to a benzo[b]thiophene derivative without an intermediate step of protecting/deprotecting the hydroxyl functional group. However, this method still proposes on page 1064 the use of aluminum chloride in particularly large quantities since it is of the order of 9 molar equivalents.
According to this method, the
benzo[b]thiophene derivative in question is condensed, in an organic phase consisting of dichloroethane, with the hydrochloride of the chloride of the aminoalkoxybenzoyl derivative, this being in the presence of aluminum chloride.
After hydrolysis, the hydrochloride of the desired 3-[4-(aminoalkoxy)benzoyljbenzo[b]thiophene is recovered partly from the organic phase and partly from the aqueous phase by three extractions with chloroform and then treated with sodium hydroxide.
In the context of the preparation of the present invention, this method is applied starting with 2-butyl-5-nitrobenzofuran in order to directly prepare

2-butyl-3-(4-[3-(dibutylamino)propoxy]benzoyl)-5-nitrobenzofuran, this being using the following steps:
• treatment of 2-butyl-5-nitrobenzofuran by means of
4-[3-(dibutylamino)propoxy]benzoyl chloride
hydrochloride in the presence of 9 molar equivalents
of aluminum chloride, this being in an organic phase,
• hydrolysis, recovery of 2-butyl-3-(4-[3-
(dibutylamino)propoxy]benzoyl)-5-ni trobenzo furan hydrochloride and treatment with sodium hydroxide so as to form the desired 2-butyl-3—(4-[3-(dibutylamino)propoxy]benzoyl)-5-nitrobenzofuran.
However, this method has proved unsuitable at the industrial level because, on the one hand, of the enormous quantity of aluminum hydroxide thus produced and, on the other hand, of the large amount of impurities recovered and, consequently, of the low yield of 2-butyl-3- (4- [3- (dibutylamino)propoxy] -5-nitrobenzofuran (20 to 30%).
However, it has been found, surprisingly, that it is possible, starting with 2-butyl-5-(methanesulfonamido)benzofuran and using appropriate quantities of a Lewis acid in a Friedel-Crafts reaction, to directly obtain dronedarone hydrochloride with excellent yields since they are at least 85%, it being possible for this hydrochloride to be recovered in a remarkably advantageous manner since it is practically entirely found not in the aqueous phase as

might have been predicted but in the organic phase used, which avoids the need to carry out several extractions of this same aqueous phase as in the earlier method.
In addition, the 2-butyl-5-
(methanesulfonamido)benzofuran may itself be obtained with great ease and high yields, since they are above 75%, from 5~amino~2-butylbenzofuran and even from the precursor of the latter, namely 2-butyl-5-riitrobenzofuran.
2-Butyl-5-(methanesulfonamido)benzofuran is a novel product which can be easily obtained in crystalline form, unlike 2-butyl-5-nitrobenzofuran whose crystalline state may be difficult to obtain. This methanesulfonamido derivative therefore has an undeniable advantage over the nitro derivative in question.
Consequently, the invention relates to 2-butyl-5-(methanesulfonamido)benzofuran as a novel industrial product useful in particular as synthesis intermediate, for example for the preparation of dronedarone or its pharmaceutically acceptable salts.
Thus, according to the invention, 2-butyl-5-(methanesulfonamido)benzofuran is prepared by reacting 5-amino-2-butylbenzofuran with methanesulfonyl chloride or methanesulfonic anhydride, the reaction taking place

in the presence of an acid acceptor such as triethylarnine or ammonia, giving the desired compound. Generally, the reaction takes place at room temperature and in one or more apolar solvents preferably chosen from halogenated hydrocarbons and ethers such as, for example, methyl tert-butyl ether, tetrahydrofuran, dichloromethane or dichloroethane.
5~Amino-2-butylbenzofuran, for its part, may be prepared by hydrogenating 2-butyl-5-nitrobenzofuran in the presence of an appropriate catalyst, giving the desired compound.
As catalyst, a platinum derivative such as platinum oxide or an ammonium formate/palladized charcoal system is normally used, the hydrogenation taking place at room temperature and optionally under pressure, for example at a pressure of the order of 20 to 30 bar.
This hydrogenation, which is carried out with excellent yields of up 100%, has unquestionable advantages compared with the hydrogenation of 2-butyl-3 -(4-[3-(dibutylamino)propoxy]benzoyl)-5-nitrobenzofuran of the earlier method. Indeed, 2-butyl-5-nitrobenzofuran, apart from the nitro group, contains no other functional group which can be modified by this reaction, unlike the 2-butyl-3-(4-[3-(dibutylamino)propoxy]benzoyl)-5-nitrobenzofuran

derivative whose hydrogenation can prove difficult because of the by-products formed.
As indicated above, 2-butyl-5-
(methanesulfonamido)benzofuran can be used for the preparation of dronedarone.
Thus, according to the invention, dronedarone is prepared by first forming its hydrochloride, that is to say by reacting, in an organic phase, 2-butyl-5-(methanesulfonamido)benzofuran with 4-[3-(dibutylamino)propoxyjbenzoyl chloride hydrochloride, this being in the presence of a Lewis acid as catalyst and by hydrolyzing in order to form dronedarone hydrochloride which is recovered from the organi c pha s e.
The reaction, which is performed under
Friedel-Crafts reaction conditions, is normally carried out at room temperature and in an organic phase consisting of one or more solvents chosen from halogenated or nonhalogenated hydrocarbons, preferably of the aliphatic, alicyclic or aromatic type. Generally, halogenated, preferably chlorinated, hydrocarbons of the aliphatic, alicyclic or aromatic type, such as for example dichloromethane, dichloroethane or chlorobenzene, are used.
In addition, the Lewis acid may be aluminum chloride, zinc chloride, boron trifluoride, stannic chloride, titanium tetrachloride or preferably ferric

chloride. It is also possible to use a mixture of these Lewis acids. This Lewis acid is used at concentrations which do not exceed 5 molar equivalents, in particular in an amount of 2 to 5 molar equivalents. More particularly, this Lewis acid is used at concentrations which do not exceed 4 molar equivalents. Still more particularly, this Lewis acid is used at concentrations which do not exceed 3 molar equivalents, in particular in an amount of 2 to 3 molar equivalents, preferably 2.5 molar equivalents.
Finally, 4-[3-(dibutylamino)propoxy]benzoyl chloride hydrochloride is used at concentrations of the order of 1 to 1.3 molar equivalents.
The dronedarone hydrochloride thus obtained is then converted, after isolation, to dronedarone by treating with a basic agent such as an alkali metal hydroxide, for example sodium hydroxide, an alkali metal carbonate or an alkali metal hydrogen carbonate such as sodium hydrogen carbonate, which gives the desired compound.
According to a preferred embodiment of the invention, dronedarone is prepared without isolating its hydrochloride which is transiently formed, that is to say in the actual medium where this hydrochloride is prepared.
Consequently, according to one variant of the invention, dronedarone is prepared by means of a method

according to which, in an organic phase consisting of one or more solvents chosen from halogenated or nonhalogenated hydrocarbons, 2-butyl-5-(methanesulfonamido)benzofuran is reacted with 4-[3-(dibutylamino)propoxyjbenzoyl chloride hydrochloride, this being in the presence of a maximum of 5 molar equivalents, in particular of a maximum of 4 molar equivalents, and preferably of a maximum of 3 molar equivalents of a Lewis acid as catalyst, hydrolysis is carried out in order to obtain transiently, and without isolation, dronedarone hydrochloride which is recovered in the organic phase and the hydrochloride formed is treated with a basic agent, giving dronedarone.
According to another aspect of the invention, dronedarone may be obtained using a three-stage method starting with 2-butyl-5-nitrobenzofuran.
Consequently, another subject of the invention relates to the preparation of dronedarone starting with 2-butyl-5-nitrobenzofuran according to a method by which:
a) 2-butyl-5-nitrobenzofuran is hydrogenated in the
presence of an appropriate catalyst, to form 5-amino-2-
butylbenzofuran,
b) the compound thus obtained is reacted with
methanesulfonyl chloride or methanesulfonic anhydride,
the reaction taking place in the presence of an acid

acceptor, to form 2-butyl-5-(methanesulfonamido)benzofuran,
c) the methanesulfonamido derivative thus obtained is reacted, in an organic phase consisting of one or more solvents chosen from halogenated or nonhalogenated hydrocarbons, with 4-[3-(dibutylamino)propoxy]benzoyl chloride hydrochloride, this being in the presence of a maximum of 5 molar equivalents, in particular of a maximum of 4 molar equivalents and preferably of a maximum of 3 molar equivalents of a Lewis acid as catalyst, hydrolysis is carried out in order to obtain transiently, and without isolation, dronedarone hydrochloride which is recovered in the organic phase and the hydrochloride formed is treated with a basic agent, giving dronedarone.
Subsequently, the dronedarone obtained
according to either method or variant of the invention may be treated, if necessary, with an organic or inorganic acid to form a pharmaceutically acceptable salt, of this compound.
4-[3-(Dibutylamino)propoxy]benzoyl chloride hydrochloride, for its part, may be prepared according to the succession of steps below:
a) l-dibutylamino-3-chloropropane is reacted with a Ci-C4 alkyl p-hydroxybenzoate, for example methyl p-hydroxybenzoate, this being in the presence of a basic agent such as an alkali metal carbonate, for

example potassium carbonate, to give a methyl 4-[3-(dibutylamino)propoxyjbenozate,
b) the ester thus obtained is saponified in the
presence of an alkali metal hydroxide, for example
sodium hydroxide, and then the salt thus formed is
treated with hydrochloric acid to give
4-[3-(dibutylamino) propoxyjberlzoic acid hydrochloride,
c) the hydrochloride thus formed is treated with a
chlorinating agent, for example thionyl chloride, to
give the desired compound.
This use of the method of the invention for the preparation of dronedarone has proved superior to the method of patent EP0471609 in particular because of a smaller number of steps, namely three instead of five starting with 2~butyl-5-nitrobenzofuran and a higher overall yield since it is greater than 65%, or even 70%.
Moreover, this method of the invention involves, in each step, benzofuran intermediates of relatively simple structure, and consequently inexpensive, unlike the earlier method which uses in each of its steps benzofuran derivatives of a fairly elaborate sti~ucture.
The following nonlimiting examples illustrate the invention.

PREPARATIONS
A. l-Dibutylamirio-3-chloropropane Into all reactor, there are introduced 288.4 g (3.392 mol) of 20% aqueous ammonia, and then there are added, over 10 minutes and at room temperature (22 ± 2°C), 618 g (1.696 mol) of l-dibutylamino-3-chloropropane? hydrochloride (titer 66.5%) . The medium is stirred for 45 minutes at room temperature and it is allowed to separate by settling for 30 minutes. The bottom aqueous phase (pH =11) is removed, and the organic phase is washed with 300 ml of deionized water at room temperature. The medium is stirred for 30 minutes, separated by settling for 30 minutes and the bottom aqueous phase (pH = 9) is drawn of f .
In this manner, 346.3 g of the desired compound are recovered.
Yield: 99.4%.
B. Methyl 4- [3- (dibutyland.no)propoxy] -
benzoate
200 g (1.3 mol) of methyl p-hydroxybenzoate and 1.6 1 of N,N-dimethylformamide are introduced into a 2 1 round-bottomed flask. The mixture is stirred and 232 g (1.66 mol) of potassium carbonate are added thereto. The medium is heated to 100°C and then the ]-dibutylamino-3-chloropropane prepared in step A. above is introduced over 10 minutes. The reaction

medium is kept for 1 hour at 100 ± 2°C and then cooled to 25°C. The inorganic salts are filtered off and the filtrate is rinsed with twice 50 ml of N,N-dimethylformamide and concentrated in a rotary evaporator until a temperature of 85°C and a pressure of 5 mmHg are obtained.
In this manner, 472.7 g of the desired product are obtained in the form of an orange oil. Purity (HPLC or high-performance liquid chromatography)
Desired compound: 99.7% Methyl p-hydroxybenzoate: 0.1% C. 4-[3-(Dibutylamino)propoxy]benzole acid hy d r o c h 1 o ri d e
436.3 g of methyl 4-[3-(dibutylamino)-
propoxyjbenzoate arid 1.092 1 of methanol are introduced into a 2 1 round-bottomed flask. The mixture is stirred and 360 g (1.8 mol) of 20% sodium hydroxide are introduced over about 5 minutes.
The medium is heated at 65°C for about 30 minutes and kept at. this temperature for 2 hours. The reaction medium is cooled to 30°C and concentrated in a rotary evaporator (temperature of the bath: 30°C, pressure 30 mmHg), which gives 937 g of residue which is diluted by adding 2.8 1 of deionized water. The solution is cooled to 10 ± 2°C and then, without exceeding 20°C,

260 ml (about 3 mol) of a 36% hydrochloric acid are introduced.
It is checked that the pH is less than 1, and then the suspension is cooled to 10 ± 2°C. This temperature is maintained for 30 minutes, the crystals formed are drained and the cake is washed with twice 200 ml of deionized water. It is then dried in a ventilated oven at 50°C to a constant weight (24 hours).
In this manner, 416.2 g of the desired compound are obtained. Yield: 100%. Purity (HPLC)
Desired compound: 99.5%
Methyl 4-[3-(dibutylamino)propoxy]benzoate: 0.1%
D. 4-[3-(Dibutylamino)propoxy]benzoyl chloride hydrochloride
63.3 g (0.184 mol) of
4-[3-(dibutylamino)propoxy]benzole acid hydrochloride, 300 ml of chlorobenzene and 2 drops of N,N-dimethyIformamide are introduced into a round-bottomed flask. 43.8 g (0.368 mol) of thionyl chloride are introduced, over about 45 minutes, while the mixture is kept under an inert atmosphere. The medium is kept for 1 hour at 85 ± 1°C and then about 115 g of a mixtiare of chlorobenzene and thionyl chloride is distilled under a gradual vacuum.

In this manner, the desired compound is obtained in the form of an oil and in crude form.
EXAMPLE 1 5-Amino-2-butylbenzofuran
Method I
182 g of 2-butyl-5-nitrobenzofuran and 730 ml of ethanol are introduced into a hydrogenation apparatus, and then 9.1 g of about 97% platinum oxide are added. A hydrogen stream is bubbled through, with stirring at a pressure of 25 bar (the temperature increases spontaneously to 60°C) and the medium is cooled to 20°C. The medium is filtered, rinsed with 400 ml of ethanol and concentrated at 50°C under
vacuum.
In this manner, 5-amino-2-butylbenzofuran is
obtained.
Weight yield: 99.2%
Method II
1 g of 2-butyl-5-nitrobenzofuran and 4 ml of
ethanol are introduced into a closed reactor and then
1.48 g of ammonium formate and 0.1 g of 5% palladized
charcoal are added. The medium is stirred and heated at
50°C for 5 hours and then cooled to 20°C, and filtered.
The medium is rinsed with 4 ml of ethanol and
concentrated at 50°C, under vacuum.
In this manner, 5-amino-2-butylbenzofuran is
obtained.

EXAMPLE 2 2 -Butyl -5 - (methanesulfonamido) benzofuran
100 g of 5-amino-2-butylbenzofuran, 192 ml of tetrahydrofuran and 96 ml of methyl tert-butyl ether are introduced into a round-bc'ttomed flask. 59.35 g of methanesulfonyl chloride are added, at 20°C, followed by 43.23 g of 20% aqueous ammonia. 44.51 g of methanesulfonyl chloride are then introduced, followed by 86.47 g of 20% aqueous ammonia. 48 ml of water are then added, the medium is separated by settling and the organic phase is washed twice with 211 g of 10% aqueous sodium chloride solution. The medium is separated by settling and concentrated at 40°C under vacuum, to give the desired compound in crude form (weight yield: 100%).
135.6 g of the residue thus obtained are introduced into 1220 ml of methyl tert-butyl ether and 13.56 g of carbon black are added.
The medium is stirred under reflux for 15 minutes, filtered and rinsed with 204 ml of methyl tert-butyl ether. The filtrate is heated under reflux and then cooled to 40°C. The medium is then seeded with 2-butyl-3-(methanesulfonamido)benzofuran, cooled to -5°C and stirred at this temperature for 30 minutes. The medium is filtered and rinsed at -5°C with twice 1 volume of methyl tert-butyl ether.

In this manner, the desired compound is obtained with a weight yield of 78.5%. NMR (nuclear magnetic resonance) spectrum (300 MHz; Solvent: CDC13 Concentration: 40 mg/ml Temperature for analysis: 300 K


12
14
CH,
(Figure Remove)

(Table Remove)
EXAMPLE 3
Dronedarone hydrochloride
A mixture of 8 g of 2-butyl-5-
(methanesulfonamido)benzofuran, 11.9 g of 4-[3-(dibutylamino)propoxyjbenzoyl chloride hydrochloride and 24 ml of dichloromethane is first of all prepared. This mixture is then introduced into a medium consisting of 11.9 g of ferric chloride and 24 ml of dichloromethane. The reaction medium is heated under reflux for 2 hours and cooled to 20°C. 40 ml of water are added and the medium is separated by settling.
In this manner, dronedarone hydrochloride is obtained in crude form. Chemical yield: 90%.
EXAMPLE 4 Dronedarone hydrochloride
A. Dronedarone
The dronedarone hydrochloride obtained in Example 3 above is washed twice, this being with 24 ml of water, and then with 16 ml of a 10% aqueous sodium hydroxide solution and finally with 16 ml of water.
In this manner, dronedarone in crude form is obtained. Chemical yield: 86%.
B- Dronedarone hydrochloride
The dronedarone in crude form obtained in the preceding paragraph A. is concentrated and taken up in

24 ml of isopropanol. 3.24 g of 37% hydrochloric acid are added and then the medium is cooled to 0°C. The medium is filtered and washed with 8 ml of isopropanol.
In this manner, dronedarone hydrochloride is obtained.
EXAMPLE 5
Dronedarone hydrochloride - Preparation on a pilot scale
5.1. Dronedarone hydrochloride
A mixture of 10 kg of 2-butyl-5-(methanesulfonamido)benzofuran, 13 kg of 4-[3-(dibutylamino)propoxy]benzoyl hydrochloride and 70 1 of dichloromethane is first of all prepared. 19.9 kg of aluminum chloride are then introduced into this mixture (4 molar equivalents of Lewis acid are thus used; 2.5 molar equivalents of ferric chloride were used for the above Example 3). The medium is stirred at 25°C for two hours. This medium is added to 60 1 of water and the medium is separated by settling.
In this manner, dronedarone hydrochloride in crude form is obtained.
Chemical yield = 90%.
«
5.2. Dronedarone and then dronedarone hydrochloride
The dronedarone hydrochloride obtained in the preceding step is washed 5 times with 60 1 of water. The dronedarone is concentrated and taken up in 94 1 of

isopropanol. 1.8 kg of water and 0.38 kg of hydrochloric acid are added. The medium is cooled to -5°C. The medium is filtered, and washed with 22 1 of isopropanol.
In this manner, dronedarone hydrochloride is obtained.
Chemical yield = 90%.

CLAIMS
1. 2-Butyl-5-(methanesulfonamido)benzo
furan .
2. A method for preparing 2-butyl-5-
(methanesulfonamido)benzofuran, characterized in that
5-amino-2-butylbenzofuran is reacted with
methanesulf orryl chloride or methansulfonic anhydride,
the reaction taking place in the presence of an acid
acceptor, giving the desired compound.
3. A method for preparing dronedarone,
characterized in that, in an organic phase consisting
of one or more solvents chosen from halogenated or
nonhalogenated hydrocarbons, 2-butyl~5-
(methanesulfonamido)benzofuran is reacted with 4-[3-
(dibutylamino)propoxy]benzoyl chloride hydrochloride,
this being in the presence of a maximum of 5 molar
equivalents of a Lewis acid as catalyst, and then
hydrolysis is carried out so as to form dronedarone
hydrochloride which is recovered in the organic phase,
which is isolated and which is treated with a basic
agent, to give the desired compound.
4. The method as claimed in claim 3, characterized in that 2-butyl-5-
(methanesulfonamido)benzofuran is reacted with 4-[3-(dibutylamino)propoxy]benzoyl chloride hydrochloride in the presence of a maximum of 4 molar equivalents of the Lewis acid.

5. The method as claimed in claim 3 or 4,
characterized in that 2-butyl-5-
(methanesulf onamido) benzofurari is reacted with 4-[3-
(dibutylamino)propoxy]benzoyl chloride hydrochloride in
the presence of a maximum of 3 molar equivalents of the
Lewis acid.
6. A method for preparing dronedarone,
characterized in that, in an organic phase consisting
of one or more solvents chosen from halogenated or
nonhalogenated hydrocarbons, 2-butyl-5-
(methanesulfonamido)benzofuran is reacted with 4-[3-
(dibutylamino)propoxy]benzoyl chloride hydrochloride, this being in the presence of a maximum of 5 molar equivalents of a Lewis acid as catalyst, and then hydrolysis is carried out in order to obtain transiently, and without isolation, dronedarone hydrochloride which is recovered in the organic phase and which is treated with a basic agent, giving the desired compound.
7. The method as claimed in claim 6,
characterized in that 2-butyl-5-
(methanesulfonamido)benzofuran is reacted with 4-[3-(dibutylamino)propoxy]benzoyl chloride hydrochloride in the presence of a maximum of 4 molar equivalents of the Lewis acid.
8. The method as claimed in claim 6 or 7,
characterized in that 2-butyl-5-

(methanesulfonamido)benzofuran is reacted with 4-[3-
(dibutylamino)propoxy]benzoyl chloride hydrochloride in
the presence of a maximum of 3 molar equivalents of the
Lewis acid.
9. A method for preparing dronedarone,
characterized in that:
a) 2-butyl --5-nitrobenzofuran is hydrogenated in the
presence of an appropriate catalyst, to form 5-amino-2-
butylbenzof urari,
b) the compound thus obtained is reacted with
methanesulfonyl chloride or methanesulfonic anhydride,
the reaction taking place in the presence of an acid
acceptor, to form 2-butyl-5-
(methanesulfonamido)benzofuran,
c) the methanesulfonamido derivative thus obtained is
reacted, in an organic phase consisting of one or more
solvents chosen from halogenated or nonhalogenated
hydrocarbons, with 4-[3-(dibutylamino)propoxy]benzoyl
chloride hydrochloride, this being in the presence of a
maximum of 5 molar equivalents of a Lewis acid as
catalyst, and then hydrolysis is carried out in order
to obtain transiently, and without isolation,
dronedarone hydrochloride which is recovered in the
organic phase and which is treated with a basic agent,
giving the desired compound.
10. The method as claimed in claim 9, characterized in that in step c), the

methanesulfonamido derivative thus obtained is reacted with 4-[3-(dibutylamino)propoxy]benzoyl chloride hydrochloride in the presence of a maximum of 4 molar equivalents of the Lewis acid.
11. The method as claimed in claim 9 or 10,
characterized in that in step c), the
methanesulfonamido derivative thus obtained is reacted with 4-[3 -(dibutylamino)propoxy]benzoyl chloride hydrochloride in the presence of a maximum of 3 molar equivalents of the Lewis acid.
12. The method as claimed in one of claims 3
to 11, characterized in that the organic phase consists
of one or more solvents chosen from halogenated
hydrocarbons of the aliphatic, alicyclic or aromatic
type.
13. The method as claimed in one of claims 3
to 12, characterized in that the Lewis acid is chosen
from the group consisting of aluminum chloride, zinc
chloride, boron trifluoride, stannic chloride, titanium
tetrachloride, ferric chloride; and mixtures thereof.
14. The method as claimed in one of claims 3
to 13, characterized in that the Lewis acid is ferric
chloride.
15. The method as claimed in one of claims
3, 6, 9, 13 and 14, characterized in that the Lewis
acid is used in an amount of 2 to 5 molar equivalents.

16. The method as claimed in one of claims 3
to 11, 13 and 14, characterized in that the Lewis acid
is used in an amount of 2 to 3 molar equivalents.
17. The method as claimed in one of claims 3
to 16, characterized in that the
4-[3-(dibutylamino)propoxy]benzoyl chloride hydrochloride is used at concentrations of the order of .1 to 1.3 molar equivalents.
18. The method as claimed in one of claims 3
to 17, characterized in that the basic agent is sodium
hydroxide or sodium hydrogen carbonate.

Documents:

00812-delnp-2003-abstract.pdf

00812-delnp-2003-claims.pdf

00812-delnp-2003-correspondence-others.pdf

00812-delnp-2003-description (complete).pdf

00812-delnp-2003-form-1.pdf

00812-delnp-2003-form-18.pdf

00812-delnp-2003-form-2.pdf

00812-delnp-2003-form-3.pdf

00812-delnp-2003-form-5.pdf

00812-delnp-2003-gpa.pdf

00812-delnp-2003-pct-409.pdf

812-DELNP-2003-Abstract-(25-02-2008).pdf

812-DELNP-2003-Claims-(25-02-2008).pdf

812-DELNP-2003-Correspondence-Others-(25-02-2008).pdf

812-DELNP-2003-Form-2-(25-02-2008).pdf

812-DELNP-2003-Form-3-(25-02-2008).pdf

812-DELNP-2003-GPA-(25-02-2008).pdf

812-DELNP-2003-PCT-409-(25-02-2008).pdf

812-DELNP-2003-Petition-137-(25-02-2008).pdf


Patent Number 216294
Indian Patent Application Number 00812/DELNP/2003
PG Journal Number 13/2008
Publication Date 28-Mar-2008
Grant Date 12-Mar-2008
Date of Filing 26-May-2003
Name of Patentee SANOFI-SYNTHELABO
Applicant Address 174, AVENUE DE FRANCE, F-75013 PARIS, FRANCE,
Inventors:
# Inventor's Name Inventor's Address
1 NOEL FINO 6, RUE DU BICENTENAIRE, F-04160 CHATEAU-ARNOUS, FRANCE
2 CORINNE LEROY SAINT AVONSS, F-05700 ORPIERRE, FRANCE,
PCT International Classification Number C07D 307/79
PCT International Application Number PCT/FR01/03899
PCT International Filing date 2001-12-10
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 00/16,070 2000-12-11 France