PROCESS FOR PREPARING AMINOBENZOFURAN DERIVATIVES
The present invention relates generally to the preparation of
aminobenzofuran derivatives.
More specifically, the invention relates to a process for preparing 5-
aminobenzofuran derivatives of general formula:

and also to the addition salts thereof, in which R1 represents hydrogen or an
alkyl group and R2 represents an alkyl or dialkylaminoalkyl group.
In formula I above:
• R1 represents, in particular, a linear or branched C1-C8 alkyl group,
especially a linear or branched C1-C4 alkyl group such as methyl, ethyl,
n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl,
• R2 represents, in particular, a linear or branched C1-C8 alkyl group,
especially a linear or branched C1-C4 alkyl group such as methyl, ethyl,
n-propyi, isopropyl, n-butyl, sec-butyl or tert-butyi or alternatively a
dialkylaminoalkyl group in which each linear or branched alkyl group is of
C1-C8 and especially in which each linear or branched alkyl group is of
C1-C4, such as methyl, ethyl, n-propy!, isopropyl, n-butyl, sec-butyl or
tert-butyl.
In particular, R1 represents n-butyl and R2 represents 3-(di-n-
butylamino)propyl.
Among the compounds of formula I above, 2-n-buty!{4-[3-(di-n-
butylamino)propoxy]benzoyl}-5-aminobenzofuran described in patent EP
0 471 609 proves to be particularly useful as an intermediate product for the
final preparation of aminoalkoxybenzoylbenzofuran derivatives, in particular
for the preparation of 2-n-butyl-3-{4-[3-(di-n-butylamino)propoxy]benzoyl}-5-
methanesulfonamidobenzofuran, commonly known as dronedarone, and also

the pharmaceutically acceptable salts thereof. This
methanesulfonamidobenzofuran derivative was described in the patent
mentioned previously, along with its therapeutic applications, especially in the
cardiovascular field where it proved to be particularly advantageous, for
example as an antiarrhythmic agent.
In addition, that same patent EP 0 471 609 disclosed a process for
synthesizing 2-n-butyi-3-{4-[3-(di-n-butylamino)propoxy]benzoyl}-5-
aminobenzofuran using 2-n-butyl-3-{4-[3-(di-n-butylamino)propoxy]benzoyl}-5-
nitrobenzofuran, which is reduced, under pressure, with hydrogen in the
presence of platinum oxide as catalyst, to give the desired compound.
However, this process is not without drawbacks inherent especially to
the type of reaction used, namely hydrogenation under pressure, which entails
an industrial risk.
The search for a process for preparing 2-n-butyl-3-{4-[3-(di-n-
butylamino)propoxy]benzoyl}-5-aminobenzofuran that is capable of
overcoming this drawback and disadvantage thus remains of fundamental
interest.
Patent application US 4 666 931 and the articles Chemistry of
Heterocyclic Compounds (1975), vol. 11, pp. 1361 -1364, Journal of
Organometallic Chemistry (1998), vol. 560, pp. 163-167 and Bulletin of the
Chemical Society of Japan (1967), vol. 40, pp. 1724-1726 describe N-
phenylalkylamide and 5-N-alkylamidobenzofuran derivatives, but do not in any
way suggest their use in the preparation of compounds of formula (I)
according to the invention.
Furthermore, WO 03/040 120 describes a process for preparing
dronedarone, in six steps, using a Friedel-Crafts reaction. However, that
document does not describe the preparation of dronedarone comprising a
simple step of treating a 5-N-alkylamidobenzofuran derivative of formula (lla)
according to the invention with a strong acid.
According to the invention, the 5-aminobenzofuran derivatives of
formula I may be prepared by treating, with a strong acid such as a hydracid,
for example hydrofluoric acid, a 5-N-alkylamidobenzofuran derivative of
general formula:


in which R1 and R2 have the same meaning as previously and R3 represents a
linear or branched C1-C4 alky! group, for example methyl, to form an acid-
addition salt of the compound of formula I, which salt is itself treated, if
necessary, with a basic agent such as an alkali metal hydroxide, to give this
compound of formula I in free base form.
Hereinabove and heretnbelow, unless specifically mentioned:
The term "strong acid" means any chemical compound which has a
very high capacity for introducing protons into the reaction medium and which
is characterized, in aqueous solution, by a pKa of less than or equal to 1. The
term "strong acid" especially means any hydracid such as chosen from
hydrochloric acid, hydrobromic acid and hydrofluoric acid.
The term "basic agent" means any chemical compound which has a
high affinity for protons H+ and which is characterized, in aqueous solution, by
a pKa of greater than 7. The term "basic agent" especially means bases of
any type such as chosen from organic bases, weak bases and strong bases,
chosen especially from tertiary amines, alkali metal carbonates and alkali
metal hydroxides.
The term "strong base" means any chemical compound which has a
very high affinity for protons H+ and which is characterized, in aqueous
solution, by a pKa of greater than 14. The term "strong base" especially
means any alkali metal hydroxide, such as chosen from sodium hydroxide and
potassium hydroxide.
The acid treatment may be undertaken in a polar solvent such as an
alcohol, for example ethanol, using an acid generally in excess, for example
from 1 to 6 equivalents of this acid per equivalent of compound of formula II.
Moreover, the acid-addition salt of the compound of formula I may be
treated with a basic agent, after isolation from the reaction medium in which it
is formed or, on the contrary, in situ, i.e. within this same reaction medium.

The starting compounds of formula II may be prepared according to the
following reaction scheme:



i.e. starting with a compound of formula III, in which R3 has the same meaning
as previously, which compound is heated in the presence of trifluoroacetic
acid in a suitable solvent, usually an amine, for example
hexamethylenetetramine, to form an N-phenylalkylamide derivative of formula
IV in which R3 has the same meaning as previously.
This amide of formula IV is then reacted with an ester of formula V in
which R1 has the same meaning as previously, R4 represents a linear or
branched C1-C4 alkyl group and Hal represents a halogen, for example
bromine, in the presence of a basic agent, generally a weak base such as an
alkali metal carbonate, and by heating in a polar solvent so as to form an ester
of formula VI in which R1, R3 and R4 have the same meaning as previously.
The ester of formula VI is then saponified in the presence of a strong
base, generally an alkali metal hydroxide, the reaction usually taking place at

room temperature and in a suitable solvent, for example an ether, to give a
salt of a carboxylic acid derivative, which is treated with a strong acid, such as
a hydracid, for example hydrofluoric acid, which gives a carboxylic acid
derivative of formula VII in which R1 and R3 have the same meaning as
previously.
The compound of formula VII thus produced is then cyclized to a
benzofuran derivative of formula VIII in which R1 and R3 have the same
meaning as previously, this being done in the presence of an organic base,
generally a tertiary amine, and of a benzenesulfonyl chloride. The reaction is
usually performed by heating in a suitable solvent, in general an aprotic
solvent such as an aromatic hydrocarbon or an ether.
The benzofuran derivative of formula VIII thus obtained is then coupled
with an acyl halogen of formula IX in which R5 represents a linear or branched
C1-C4 alkyl group, for example methyl, and Hal has the same meaning as
previously, for example chlorine, this being done in the presence of a Lewis
acid, for example ferric chloride, and in a non-polar solvent, for example a
halogenated compound. The reaction medium thus obtained is then
hydrolyzed in the presence of a strong acid, for example a hydracid, to
produce a ketone of formula X in which R1, R3 and R5 have the same meaning
as previously.
This ketone of formula X is then dealkylated by heating in the presence
of aluminum chloride and in a non-polar solvent, usually a halogenated
solvent such as chlorobenzene, to form a 4-hydroxyphenyl derivative of
formula XI in which R1 and R3 have the same meaning as previously.
Thereafter, the compound of formula XI is reacted with an alkyl halide
of formula XII in which R2 has the same meaning as previously and Hal has
the same meaning as previously, for example chlorine, the reaction taking
place in the presence of a basic agent such as an alkali metal carbonate and
by heating usually in a polar solvent such as a ketone, to give the desired
compound of formula II.
Another subject of the present invention relates to the N-
phenylalkylamide derivatives of general formula:


in which R3 has the same meaning as previously and Y represents hydrogen
or a group of general formula:

in which R1' and R6 represent, independently of each other, hydrogen
or a linear or branched C1-C4 alkyl group,
to the exclusion of the compounds for which R3 = Me, Et or isopropyl
and Y = H.
Among the N-phenylalkylamide derivatives of general formula XIII,
mention may be made of those in which R3 represents a linear or branched
C1-C4 alkyl group and Y represents a group of general formula XIV:

in which R1' and R6 represent, independently of each other, hydrogen
or a linear or branched C1-C4 alkyl group.
Among the compounds of formula XIII, mention may be made of the
following subgroup in which Y represents hydrogen or the group XIV in which
R1 represents n-butyl, and also of the compounds of formula XIII in which R3
represents methyl.

Moreover, among the compounds of formula XIII, mention may further
be made of the subgroups in which R3 represents methyl, Y represents
hydrogen or the group XIV in which R1 represents n-butyl and R6 represents
hydrogen or methyl.
Consequently, the subgroups of the N-pheny!aIky!amide derivatives of
formula XIII may be those in which:
a) R3 represents methyl and Y represents the group XIV in which R1'
represents n-butyl and R6 represents methyl,
b) R3 represents methyl and Y represents the group XIV in which R1'
represents n-butyl and R6 represents hydrogen.
In addition, another subject of the present invention concerns the 5-N-
alkylamidobenzofuran derivatives of general formula:

in which R1' and R3 have the same meaning as previously and Z represents
hydrogen or a group of general formula:

in which R2' represents hydrogen, a linear or branched C1-C4 alkyl group or a
dialkylaminoalkyl group in which each linear or branched alkyl group is of C1-
C4,
to the exclusion of the compounds for which R3 = Me, Z = H and R1' = H, Me,
Et or n-Bu.
Among the 5-N-alkylamidobenzofuran derivatives of general formula
XV, mention may be made of those in which R1' represents hydrogen or a
linear or branched C1-C4 alkyl group, R3 represents a linear or branched C1-C4
alkyl group and Z represents a group of general formula XVI:


in which R2' represents hydrogen, a linear or branched C1-C4 alkyl group or a
dialkylaminoaikyl group in which each linear or branched alkyl group is of C1-
C4.
Among the compounds of formula XV above, mention may be made of
those in which R1' represents n-butyl, and also of the compounds of formula
XV in which R3 represents methyl.
Moreover, among the compounds of formula XV, mention may be
made of the following subgroups in which Z represents hydrogen or a group
XVI in which R2' represents hydrogen, methyl or 3-(di-n-butylamino)propyl.
Moreover, among the compounds of formula XV, mention may also be
made of those in which R1' represents n-butyl, R3 represents methyl and R2'
represents hydrogen, methyl or 3-(di-n-butylamino)propyl.
Consequently, subgroups of the 5-N-alkylamidobenzofuran derivatives
of formula XV may be those in which:
a) R1' represents n-butyl, R3 represents methyl and Z represents the
group XVI in which R2' represents hydrogen,
b) R1' represents n-butyl, R3 represents methyl and Z represents the
group XVI in which R2' represents methyl,
c) R1' represents n-butyl, R3 represents methyl and Z represents the
group XVI in which R2' represents 3-(di-n-butylamino)propyl.
An additional subject of the present invention concerns the use of
compounds of formula II for the preparation of dronedarone and of
pharmaceutically acceptable salts thereof.
Thus, according to another characteristic of the present invention,
dronedarone of formula:


and pharmaceutically acceptable salts thereof, may be obtained:
a) by treating a 5-N-alkylamidobenzofuran derivative of general formula:

in which R3 has the same meaning as previously, for example methyi, with a
strong acid such as a hydracid, for example hydrofluoric acid, to form an
addition salt (also known as an "acid-addition salt") of 2-n-butyl-3-{4-[3-(di-n-
butylamino)propoxy]benzoyl}-5-aminobenzofuran of formula:

which salt is itself treated with a basic agent such as an alkali metal hydroxide,
to give this compound of formula la in free base form,
b) by coupling this 5-aminobenzofuran derivative of formula la with
methanesulfonyl chloride to form the dronedarone compound in free base
form, which may be reacted, if necessary, with an acid to produce a
pharmaceutically acceptable salt of this compound.
The 5-N-alkylamidobenzofuran derivatives of formula IIa may
themselves be obtained by performing a sequence of steps according to
which:
a) an N-phenylafkylamide derivative of general formula:

in which R3 has the same meaning as previously, is reacted with an
ester of general formula:


in which R4 and Hal have the same meaning as previously, and in
doing so in the presence of a basic agent and by heating in a polar
solvent to form an ester of general formula:

in which R3 and R4 have the same meaning as previously,
b) the ester of formula Vla is saponified in the presence of a strong base,
the reaction proceeding at room temperature and in a suitable solvent,
to give a carboxylic acid derivative, which is treated with a strong acid
to form the carboxylic acid derivative of general formula:

in which R3 has the same meaning as previously,
c) the carboxylic acid derivative of formula Vlla is cyclized by heating in
an aprotic solvent and in the presence of an organic base and a
benzenesulfonyl halide to form a benzofuran derivative of general
formula:


in which R3 has the same meaning as previously,
d) the benzofuran derivative of formula Vllla is coupled with an acyl
halide of general formula:

in which R5 and Hai have the same meaning as previously, this being
done in the presence of a Lewis acid and in a non-polar solvent, the
reaction medium thus formed then being hydrolyzed in the presence of
a strong acid to form a ketone of general formula:

in which R3 and R5 have the same meaning as previously,
e) the ketone of formula Xa is dealkylated in the presence of aluminum
chloride and in a non-polar solvent to form a 4-hydroxyphenyl derivative
of general formula:


in which R3 has the same meaning as previously,
f) the 4-hydroxyphenyl derivative of formula Xla is reacted with an alkyl
halide of general formula:

in which Hai has the same meaning as previously, the reaction taking
place in the presence of a basic agent and by heating in a polar
solvent, to form the desired compound of formula lla.
The nonlimiting example that follows illustrates the invention.
PREPARATIONS
A. N-(3-Formvi-4-hvdroxvphenyl)acetarnide (compound IV: R3= CH3)
25 g of N-(4-hydroxyphenyl)acetamide (0.165 mol; 1 equivalent) and
92.7 g of trifluoroacetic acid (0.661 mol; 4 equivalents) are placed in a 500 ml
reactor. The mixture is stirred, and 92.7 g of hexamethylenetetramine (0.661
mol; 4 equivalents) are then added portionwise. The reaction is exothermic. A
temperature of 70°C is maintained over 18 hours, while monitoring the
reaction progress by thin-layer chromatography (eluent: 8/2
toluene/methanol). The reaction medium is allowed to warm to room
temperature. It becomes thick, and is diluted by addition of 200 ml of water to
facilitate the stirring. 100 ml of ethyl acetate are then added. Stirring is
continued and the phases are allowed to separate by settling. 300 ml of water
and 200 ml of ethyl acetate are added, the mixture is stirred and the phases
are then allowed to separate by settling. The aqueous phase is removed first,
then the organic phase. The organic phase is then washed twice with 150 ml
of water in total to collect, after phase separation, a new organic phase and a
new aqueous phase. This new organic phase is then concentrated on a rotary
evaporator (T = 45°C; 50 mmHg). 14 g of the desired compound are thus
obtained in the form of crystals recovered from an orange-red solution.

B. Methyl 2-(2-formyl-4-N-acetamidophenoxy)hexanoate (compound VI:
R1= n-C4H9; R3= CH3; R4= CH3)
5.1 g of N-(3-formyI-4-hydroxyphenyl)acetamide (compound IV) (0.028
mmoi; 1 equivalent) and 10 ml of N,N-dimethylformamide (2 volumes) are
placed in a conical flask. The reaction mixture is stirred at 50°C, which gives a
first dark orange solution.
Potassium carbonate (0.6 equivalent) and 8 ml of N,N-
dimethylformamide (1.5 volumes) are placed in a 50 mi reactor. The mixture is
stirred at 50°C and the first solution is then added. Stirring is continued at
50°C for 1 hour, which gives a second solution.
6.5 g of methyl 2-bromoheptanoate (compound V) (1.05 equivalents)
are then prepared in 5 ml of N,N-dimethylformamide, and are added to the
second solution, and the whole is then stirred at 75°C for 5 hours. The
reaction mixture is taken up in 15 ml of dichloromethane and 15 ml of water,
stirred, and the two phases are separated by settling. The dichloromethane
phase is washed with water (3 x 10 ml) and this phase is then concentrated
on a rotary evaporator to give 9 g of brown crystals. These crystals are
reslurried in 20 ml of water and then crushed by spatula to recover finely
divided crystals suspended in the water. The mixture is then filtered, which
gives 8.9 g of wet crystals, which are taken up in 25 ml of methyl tert-butyl
ether. 5 ml of methanol are added and the mixture is then refluxed for 1 hour
in the presence of carbon black (0.1 g). The hot reaction mixture is filtered
through Celite and then concentrated to 50%. 4 g of a precipitate with an
organic purity of 98% are thus recovered. The filtrate is again concentrated
and then stirred at room temperature, which brings about the appearance of a
new precipitate, which is filtered off and dried. 1.6 g of the desired compound
are thus recovered.

C. 2-(2-Formyl-4-N-acetamidophenoxy)hexanoic acid
(compound Vll: R1= n-C4H9; R3= CH3)
3.5 g of methyl 2-(2-formyl-4-N-acetamidophenoxy)hexanoate
(compound VI) (0.0114 mol; 1 equivalent) and then about 15 ml of methyl tert-
butyl ether (about 3 volumes) are placed in a round-bottomed flask. The
mixture is stirred at room temperature so as to form a suspension of this ester.
A sodium hydroxide solution (0.57 g/5 ml of water) is then added and the
mixture is stirred for 1 hour. 5 ml of water are then added and stirring is
continued until total dissolution of the ester compound is obtained. Two
phases are thus recovered, one of methyl tert-butyl ether, the other an
aqueous phase containing a carboxylic acid. These two phases are separated
by settling and 5 ml of 36% hydrochloric acid/5 ml of water are then added to
the aqueous phase (pH = 14). The aqueous phase is brought to pH 1, which
brings about the appearance of a yellow precipitate, and is then stirred for 30
minutes at room temperature. The precipitate is filtered off through a sinter,
which gives 3.1 g of an orange-yellow mass with an organic purity of 99.7%.
This mass is taken up in 20 ml of acetone, brought to reflux and then filtered
while hot. 1.7 g of wet white compound are thus obtained, and are dried to

give 1.5 g of the desired compound in the form of white crystals with an
organic purity of 99.7%.



D. 2-n-Butyl-5-N-acetamidobenzofuran (compound VIII: R1= n-C4H9; R3= CH3)
1 g of benzenesulfonyl chloride and 1 ml of toluene are placed in a
round-bottomed flask. The mixture is stirred, 1.3 g of triethylamine (3.6
equivalents) are introduced and stirring is continued at 80°C for 20 minutes,
during which time the reaction medium becomes increasingly dark. A solution
of 1 g of 2-(2-formyl-4-N-acetamidophenoxy)hexanoic acid (compound VII)
(0.00355 mol; 1 equivalent) in 3 ml of toluene and 2 ml of methyi tert-butyl
ether is then introduced. The mixture is heated at 80°C for 2 hours while
monitoring the reaction kinetics by gas chromatography. The reaction mixture
is cooled to about 50°C and hydrolyzed by adding 4 ml of water. The toluene
phase and the aqueous phase are separated by settling. 2 ml of water and 0.2
ml of 36% hydrochloric acid are added to this organic phase. The mixture is
stirred for 5 minutes and the two phases are then separated by settling. The
toluene phase is washed with 2 ml of water, and the two phases are
separated by settling. The organic phase is washed with a solution of 0.9 g of

sodium hydroxide at 23% in 1.5 ml of water. The mixture is stirred, the toluene
phase is separated out by settling and washed with 2 g of 10% sodium
chloride solution. The two phases are separated by settling and the toluene
phase is concentrated on a rotary evaporator to recover 1.1 g of desired
compound in the form of a brown oil.



E. 2-n-Butyl-3-(4-methoxvbenzovl)-5-N-acetamidobenzofuran (compound X:
R1= n-C4H9; R3= CH3; R5=CH3)
10 g of 2-n-butyl-5-N-acetamidobenzofuran (compound VIM) (0.04 mol;
1 equivalent) and then a solution of 29.4 g of 4-methoxybenzoyl chloride
(compound IX) (0.054 mol; 1.25 g equivalents) in dichloroethane are placed in
a 250 ml reactor. The whole is stirred at 40°C until dissolution is complete,
and 8.8 g of ferric chloride (0.054 mol; 1.25 equivalents) are then added
portionwise. The temperature is maintained at 40°C for 1 hour while
monitoring the reaction progress. The reaction medium is hydrolyzed by
adding 100 ml of water, and is heated to 50°C. The two phases are then
separated by settling, and the organic phase is recovered and concentrated
under vacuum on a rotary evaporator. 21 g of an orange oil which forms
crystals are thus obtained. This oil is taken up in 40 ml of ethyl acetate
(2 volumes) and brought to reflux in a round-bottomed flask, which brings
about dissolution of the crystals. The reaction medium is allowed to cool to
room temperature with stirring, which brings about the appearance of a
precipitate, which is kept in contact with an ice bath (5°C) for 10 minutes. The
reaction medium is filtered and pale yellow crystals are recovered. These
crystals are dried in a vacuum oven at 50°C to give 10.1 g of crystals. These
crystals are taken up in ethyl acetate (4 volumes) and the whole is then

refluxed until dissolution is complete. The reaction medium is allowed to cooi
to room temperature, and the crystals formed are then filtered off through a
sinter. The crystals obtained are rinsed with 10 ml of ethyl acetate and dried in
an oven at 50°C to give 8.2 g of desired compound in the form of a first crop of
crystals (organic purity: 99.7%) and 1.3 g of the same compound in the form
of a second crop of crystals (organic purity: 99.1%).



F. 2-n-Butyl-3-(4-hvdroxvbenzoyl)-5-N-acetamidobenzofuran (compound XI:
R1= n-C4H9; R3= CH3)
5 g of 2-n-butyl-3-(4-methoxybenzoyl)-5-N-acetamidobenzofuran
(compound X) (0.0137 moi; 1 equivalent) and 15 ml of chlorobenzene (3
volumes) are placed in a 250 ml reactor. The mixture is stirred at 60°C until
the methoxy derivative is partially dissolved, followed by addition, in a single
portion, of 5.5 g of aluminum chloride (0.0411 mo!; 3 equivalents), which
brings about a change in the reaction medium. The methoxy derivative is
dissolved and a temperature of 60°C is maintained for 4 hours. The mixture is

then hydrolyzed by adding 15 ml of water (3 volumes) while stirring at about
45°C ± 5°C. The reaction medium is then extracted with n-butanol at a
temperature of about 45°C. The two phases are separated by settling while
hot. A butanol phase is thus recovered, in which is observed a precipitate
which appears when the temperature lowers. The organic phase is filtered and
2 g of a white product are thus recovered. The filtrate is concentrated under
vacuum on a rotary evaporator and the 4 g of oil thus obtained and the
precipitate are then taken up in ethyl acetate (2 volumes). The medium is then
heated to reflux to dissolve the particles, and is allowed to cool to room
temperature. The crystals obtained are filtered off and 1.3 g of a slightly yellow
product are thus recovered (organic purity: 97.9%). A further recrystallization
from ethyl acetate is performed using the filtrate obtained, which makes it
possible to recover 0.8 g of desired compound with an organic purity of
96.6%.



G. 2-n-Butyl-3-(4-[3-(di-n-butylamino)propoxy]benzoyl)-5-N-
acetamidobenzofuran (compound II: R1= n-C4Hg; R2= 3-(di-n-
butyiamino)propyl; R3= CH3)

4 g of 2-n-butyl-3-(4-hydroxybenzoyl)-5-N-acetamidobenzofuran
(compound XI) (0.0114 mol; 1 equivalent), 2.1 g of potassium carbonate (1.3
equivalents) and 15 ml of methyl ethyl ketone are placed in a three-necked
round-bottomed flask. The reaction medium is stirred, and 2.8 g of 1-chloro-3-
(di-n-butylamino)propane (compound XII) (0.0137 mol; 1.2 equivalents) are
added at a temperature of 80°C and the whole is heated at the reflux
temperature of the methyl ethyl ketone for at least 8 hours. The white deposit
formed around the flask is recovered and is then stirred again by adding a
further 0.1 equivalent of chloramine. Heating is continued for about 5 hours
and the reaction medium is then concentrated under vacuum on a rotary
evaporator. The oil thus obtained is taken up in 15 ml of water and 15 ml of
methyl tert-butyl ether, and the two phases are separated by settling. The
organic phase is washed with 0.5 equivalent of acetic acid in 15 mi of water.
The mixture is stirred, the phases are separated by settling and the organic
phase is washed with 15 ml of water. This organic phase is concentrated, and
5.2 g of desired compound are thus recovered in the form of a whitish oil.



EXAMPLE
2-n-Butyl-3-(4-r3-(di-n-butylamino)propoxy1benzoyl)-5-aminobenzofuran
hydrochloride (compound I: R1= n-C4Hc9; R2= 3-(di-n-butylamino)propyl)
1 equivalent of 2-n-butyl-3-{4-[3-(di-n-butylamino)propoxy]benzoyl}-5-N-
acetamidobenzofuran (compound II) and 4 volumes of ethanol are placed in a
reactor. 6 equivalents of 36% hydrochloric acid are then added and the
reaction medium is heated to reflux, which brings about formation of the
desired hydrochloride. The reaction medium is then washed, at room
temperature, with aqueous sodium carbonate solution so as to liberate this
hydrochloride, which passes into the aqueous phase, from which it is
extracted.
In this manner, the desired compound is obtained in an organic purity
of 93%.
Degree of conversion of compound II: 100%
The conversion of 2-n-butyl-3-{4-[3-(di-n-butylamino)propoxy]benzoyl}-
5-aminobenzofuran hydrochloride into dronedarone hydrochloride is then
performed as described in patent EP 0 471 609.

CLAIMS
1. Process for preparing 5-aminobenzofuran derivatives of general
formula:

and also the addition salts thereof, in which R1 represents hydrogen or an
alkyl group and R2 represents an alkyl or dialkylaminoalkyl group,
characterized in that a 5-N-alkylamidobenzofuran derivative of general
formula:

in which R1 and R2 have the same meaning as previously and R3 represents a
linear or branched C1-C4 alkyl group, is treated with a strong acid to form an
acid-addition salt of the compound of formula I, which salt is itself treated, if
necessary, with a basic agent to form this compound of formula I in free base
form.
2. Process according to Claim 1, characterized in that:
• R1 represents a linear or branched C1-C8 alkyl group,
• R2 represents a linear or branched C1-C8 alkyl group or a
dialkylaminoalkyl group in which each linear or branched alkyl group is
of C1-C8.
3. Process according to Claim 1 or 2, characterized in that:
• R1 represents a linear or branched C1-C4 alkyl group,
• R2 represents a linear or branched C1-C4 alkyl group or a
dialkylaminoalkyl group in which each linear or branched alkyl group is
of C1-C4.

4. Process according to one of Claims 1 to 3, characterized in that the 5-
N-acetamidobenzofuran derivative of formula II is obtained by reaction
between a 4-hydroxyphenyl derivative of general formula:

in which R1 represents hydrogen or an alkyl group and R3 represents a linear
or branched C1-C4 alkyl group, and an alkyl halide of general formula:
Hal - R2
XII
in which R2 represents an alkyl or dialkylaminoalkyl group and Hal represents
a halogen, the reaction taking place in the presence of a basic agent and by
heating in a polar solvent, to form the desired compound.
5. Process according to Claim 4, characterized in that the 4-
hydroxyphenyl derivative of formula XI is obtained by dealkylation of a ketone
of general formula:

in which R1 represents hydrogen or an alkyl group and R3 and R5 each
represent a linear or branched C1-C4 alkyl group, this being done in the
presence of aluminum chloride and in a non-polar solvent, to form the desired
compound.
6. Process according to Claim 5, characterized in that the ketone of
formula X is obtained by coupling between, on the one hand, a benzofuran
derivative of general formula:


VIII
in which R1 represents hydrogen or an alkyl group and R3 represents a linear
or branched C1-C4 alkyl group, and, on the other hand, an acyl halide of
general formula:

in which R5 represents a linear or branched C1-C4 alkyl group and Hal
represents a halogen, this being done in the presence of a Lewis acid and in a
non-polar solvent, the reaction medium thus formed then being hydrolyzed in
the presence of a strong acid to form the desired compound.
7. Process according to Claim 6, characterized in that the benzofuran
derivative of formula VIII is obtained by cyclization of a carboxylic acid
derivative of general formula:

in which R1 represents hydrogen or an alkyl group and R3 represents a linear
or branched C1-C4 alkyl group, this being done by heating in an aprotic solvent
and in the presence of an organic base and a benzenesulfonyl halide, to form
the desired compound.
8. Process according to Claim 7, characterized in that the carboxylic acid
derivative of formula VII is obtained by saponification of an ester of general
formula:


in which R1 represents hydrogen or an alkyl group and R3 and R4 each
represent a linear or branched C1-C4 alkyl group, this being done in the
presence of a strong base, the reaction taking place at room temperature and
in a suitable solvent, to give a salt of the carboxylic acid derivative, which is
then treated with a strong acid to form the desired compound.
9. Process according to Claim 8, characterized in that the ester of formula
VI is obtained by reacting an N-phenylalkylamide derivative of general
formula:

in which R3 represents a linear or branched C1-C4 aikyl group, with an ester of
general formula:

in which R1 represents hydrogen or an alkyl group, R4 represents a linear or
branched C1-C4 alkyl group and Hal represents a halogen, this being done in
the presence of a basic agent and by heating in a polar solvent, to form the
desired compound.
10. Process for preparing 2-n-butyl-3-{4-[3-(di-n-
butylamino)propoxy]benzoyl}-5-methanesulfonamidobenzofuran or
dronedarone of formula:


and also pharmaceutically acceptable salts thereof, characterized in that:
a) a 5-N-alkylamidobenzofuran derivative of general formula:

in which R3 represents a linear or branched C1-C4 alkyl group, is treated with a
strong acid to form an acid-addition salt of 2-n-butyl-3-{4-[3-(di-n-butylamino)-
propoxy]benzoyl}-5-aminobenzofuran of formula:

which salt is itself treated with a basic agent to produce this compound of
formula la in free base form,
b) the 2-n-butyl-3-{4-[3-(di-n-butylamino)propoxy]benzoyl}-5-aminobenzofuran
thus obtained is treated with methanesulfonyl chloride to form the
dronedarone compound in free base form, which may be reacted, if
necessary, with an acid to produce a pharmaceutically acceptable salt of this
compound.
11. Process according to Claim 10, characterized in that the 5-N-
alkylamidobenzofuran derivative of formula lla is obtained by performing a
sequence of steps according to which:
a) an N-phenylalkylamide derivative of general formula:


in which R3 represents a linear or branched C1-C4 alkyl group, is reacted with
an ester of general formula:

in which R4 represents a linear or branched C1-C4 alkyl group and Hal
represents a halogen, this being done in the presence of a basic agent and by
heating in a polar solvent, to form an ester of general formula:

in which R3 and R4 have the same meaning as previously,
b) the ester of formula Vla is saponified in the presence of a strong
base, the reaction proceeding at room temperature and in a suitable solvent,
to give a salt of the carboxylic acid derivative, which is treated with a strong
acid to form the carboxylic acid derivative of general formula:

in which R3 has the same meaning as previously,
c) the carboxylic acid derivative of formula Vlla is cyclized by
heating in an aprotic solvent and in the presence of an organic base and a
benzenesulfonyl halide to form a benzofuran derivative of general formula:


in which R3 has the same meaning as previously,
d) the benzofuran derivative of formula Vllla is coupled with an acyl
halide of general formula:

in which R5 represents a C1-C4 alkyl group and Hal represents a halogen, this
being done in the presence of a Lewis acid and in a non-polar solvent, the
reaction medium thus formed then being hydrolyzed in the presence of a
strong acid to form a ketone of general formula:

in which R3 and R5 have the same meaning as previously,
e) the ketone of formula Xa is dealkylated in the presence of
aluminum chloride and in a non-polar solvent to form a 4-hydroxyphenyl
derivative of general formula:

in which R3 has the same meaning as previously,

f)the 4-hydroxyphenyl derivative of formula Xla is reacted with an alkyl
halide of general formula:

in which Hal has the same meaning as previously, the reaction taking place in
the presence of a basic agent and by heating in a polar solvent, to form the
desired compound of formula lla.
12. Process according to Claim 10 or 11, characterized in that R3, R4 and
R5 each represent methyl and Hal represents chlorine or bromine.
13. N-Phenylalkylamide derivatives of general formula:

in which R3 represents a linear or branched C1-C4 alkyl group and Y
represents hydrogen or a group of general formula:

in which R1' and R6 each independently represent hydrogen or a linear or
branched C1-C4 alkyl group,
with the exclusion of the compounds for which R3 = Me, Et, and isopropyl, and
Y = H.
14. N-Phenylalkylamide derivatives according to Claim 13, characterized in
that R3 represents methyl and Y represents the group XIV in which R1'
represents n-butyl and R6 represents methyl.
15. N-Phenylalkylamide derivatives according to Claim 13, characterized in
that R3 represents methyl and Y represents the group XIV in which R1'
represents n-butyl and R6 represents hydrogen.
16. 5-N-Alkylamidobenzofuran derivatives of general formula:


in which R1' represents hydrogen or a linear or branched C1-C4 alkyl group, R3
represents a linear or branched C1-C4 alkyl group and Z represents hydrogen
or a group of general formula:

in which R2' represents hydrogen, a linear or branched C1-C4 alkyl group or a
dialkylaminoalkyl group in which each linear or branched alkyl group is of C1-
C4,
with the exclusion of the compounds for which R3 = Me, Z = H, and R'1 = H,
Me, Et and n-Bu.
17. 5-N-Alkylamidobenzofuran derivative according to Claim 16,
characterized in that R1' represents n-butyl, R3 represents methyl and Z
represents the group XVI in which R2' represents hydrogen.
18. 5-N-Alkylamidobenzofuran derivative according to Claim 16,
characterized in that R1' represents n-butyl, R3 represents methyl and Z
represents the group XVI in which R2' represents methyl.
19. 5-N-Alkylamidobenzofuran derivative according to Claim 16,
characterized.in that R1' represents n-butyl, R3 represents methyl and Z.
represents the group XVI in which R2' represents 3-(di-n-butylamino)propyl.