PROCESS FOR PREPARING BENZOFURAN DERIVATIVES
SUBSTITUTED AT POSITION 5
The present invention relates generally to the preparation of
benzofuran derivatives substituted at position 5.
The invention relates to a process for preparing benzofuran derivatives
substituted at position 5 of general formula:

in which R represents a nitro or ester group -COOR' in which R'
represents a hydrogen atom or an alkyl group, R1 represents hydrogen or an
alkyl group and R2 represents hydrogen, a halogen or a hydroxyl, haloalkyl,
alkyl, alkoxy, dialkyiaminoalkoxy ordialkylaminoalkyl group.
More specifically, the invention relates to a process for preparing
compounds of formula (I) in which R represents a nitro group, these
compounds of formula (I) being known as 5-nitrobenzofuran derivatives of
general formula I':

in which R represents a nitro group, R1 represents hydrogen or an alkyl
group and R2 represents hydrogen, a halogen or an alkyl, alkoxy' or
dialkyiaminoalkoxy group.
More specifically, the invention relates to a process for preparing
compounds of formula (I) in which R represents an ester group -COOR',
these compounds of formula (I) being known as benzofuran derivatives
substituted at position 5 of general formula I":

in which R represents an ester group -COOR' in which R' represents a
hydrogen atom or an alkyl group, R1 represents an alkyl group and R2
represents hydrogen or a hydroxyl, haloalkyl, dialkylaminoalkoxy or
dialkylaminoalkyl group.
In formulae I, I' and I" above:
• R1 in particular represents 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, or
alternatively a substituted or unsubstituted phenyl group,
• R2 in particular represents a chlorine, bromine or iodine or 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; a linear or branched C1-C8 alkoxy group,
especially a linear or branched C1-C4 alkoxy group such as
methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy or
tert-butoxy; or a dialkylaminoalkyl group or alternatively a
dialkylaminoalkoxy group in which each linear or branched alkyl
group is of C1-C8 and the linear or branched alkoxy group is of C1--
C8, especially in which each linear or branched alkyl group is of C1--
C4 such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or
tert-butyl and the linear or branched alkoxy group is of C1-C4 such
as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy or
tert-butoxy,
• R' is a linear or branched C1-C4 alkyl group such as isopropyl.
According to one embodiment, R1 represents n-butyl and R2
represents 3-(di-n-butylamino)propoxy.
According to one embodiment, R1 represents n-butyl and R2
represents 3-(di-n-butylamino)propyl.
The compounds of formula I above and more specifically those of
formula I' are, for the majority, compounds described in patent EP 0 471 609
where they are presented as intermediate products for the preparation of
aminoalkoxybenzoylbenzofuran derivatives that are useful for their
therapeutic applications in the cardiovascular field.
Among these aminoalkoxybenzoylbenzofuran derivatives, 2-n-butyl-3-
{4-[3-(di-n-butylamino)propoxy]benzoyl}-5-methanesulfonamidobenzofuran,
commonly known as dronedarone, and also pharmaceuticaily acceptable
salts thereof, has proven to be particularly advantageous especially as an
antiarrhythmic agent.
Patent application WO 2009/044 143 and patent EP 0 471 609
disclose various process steps which, when combined, make it possible,
starting with 4-hydroxyacetophenone, to gain access to 2-n-butyl-3-{4-[3-(di-
n-butyiamino)propoxy]benzoyl}-5-nitrobenzofuran (referred to hereinbelow as
Compound A), which is an intermediate that is particularly advantageous for
preparing dronedarone. According to this process, the reaction sequence
below may be envisioned:
a) coupling 4-hydroxyacetophenone with ethyl valerate in the presence
of an alkali metal alkoxide (yield: 65%),
b) cyclization of the 1-(4-hydroxyphenyl)-1,3-heptanedione thus
obtained with 0-(4-nitrophenyl)hydroxylamine to form 2-n-butyl-3-(4-
hydroxybenzoyl)-5-nitrobenzofuran (yield: 69%). These steps are described in
patent application WO 2009/044 143,
c) etherification of the 5-nitrobenzofuran derivative thus formed with 1-
chloro-3-(di-n-butylamino)propane to form compound A (yield: 88.76%).
This step is described in patent EP 0 471 609.
Consequently, Compound A could not be obtained in an overall yield of
greater than 39% starting with 4-hydroxyacetophenone and according to the
combination of steps reported above:
The search for a preparation process capable of providing Compound
A starting with 4-hydroxyacetophenone and in overall yields that are
significantly higher than those provided in the prior art consequently remains
of unquestionable interest.
It has now been found that Compound A can be synthesized in overall
yields of at least 56% starting with 4-hydroxyacetophenone by means of the
combination of steps using 1-{4-[3-(di-n-butylamino)propoxy]phenyl}-1,3-
heptanedione rather than 1-(4-hydroxyphenyl)-1,3-heptanedione.
The compounds of formula I above and more specifically those of
formula I" are, for the majority, compounds described in patent EP 1 315 709
where they are presented as intermediate products for the final preparation of
aminoalkylbenzoylbenzofuran derivatives that are useful for their therapeutic
applications in the cardiovascular field.
Among these aminoalkylbenzoylbenzofuran derivatives, isopropyl 2-
butyl-3-{4-[3-(dibutylamino)propyl]benzoyl}-1-benzofuran-5-carboxylate,
commonly known as celivarone, and also the pharmaceutically acceptable
salts thereof, has proven to be particularly advantageous especially as an
antiarrhythmic agent.
Contrary to the synthetic route described in patent EP 1 315 709, this
synthetic route is convergent and makes it possible to reduce the number of
steps. This route thus constitutes an economically viable alternative. This
route makes it possible especially to avoid a Sonogashira-type organometallic
coupling step which uses expensive reagents and a Friedel-Crafts step which
generates large amounts of aluminum salts.
According to the invention, the benzofuran derivatives substituted at
position 5 of formula I may be prepared by coupling, in the presence of an
acid, the hydroxylamine of formula II:

in which R represents a nitro or ester group -COOR', R' having the
same meaning as previously, with a diketone of general formula III:

in which R1 and R2 have the same meaning as previously, to form an
oxime of general formula:

in the form of a mixture of E and 2 isomers, in which R1 and R2 have
the same meaning as previously, and this oxime is cyclized by heating to form
the desired compound.
According to one embodiment of the invention, the 5-nitrobenzofuran
derivatives of formula I' may be prepared by coupling, in the presence of an
acid, 0-(4-nitrophenyl)hydroxylamine of formula Il', this compound
corresponding to the compound of formula II in which R represents -NO2:

with a diketohe of general formula EH:

in which R1 and R2 have the same meaning as previously, to form an
oxime of general formula:

in the form of a mixture of E and Z isomers, in which R1 and R2 have
the same meaning as previously, and this oxime is cyclized by heating to form
the desired compound; the compound of formula IV corresponding to the
compound of formula IV in which R represents -NO2.
According to one embodiment of the invention, the benzofuran
derivatives of formula I" may be prepared by coupling, in the presence of an
acid, the compound of formula II", this compound corresponding to the
compound of formula II in which R represents -COOR', R' being as defined
previously:

with a diketone of general formula III:

IN
in which R1 and R2 have the same meaning as previously, to form an
oxime of general formula:

in the form of a mixture of E and Z isomers, in which R1 and R2 have
the same meaning as previously, and this oxime is cyclized by heating to form
the desired compound; the compound of formula IV corresponding to the
compound of formula IV in which R represents -COOR', R" being as defined
previously.
According to one embodiment, the oxime is reacted to form a salt such
as the hydrochloride.
Usually, the coupling is performed in the presence of an acid,
preferably a weak acid, optionally combined with a strong acid, generally an
organic or mineral acid such as a hydracid, for example hydrochloric acid.
This acid or this mixture of acids may be combined, where appropriate, with
an organic or mineral solvent, for example N, N-dimethylformamide, dimethyl
sulfoxide, an ether such as tetrahydrofuran, diethyl ether or dioxane, or
alternatively an alcohol such as methanol or ethanol. However, according to a
preferred embodiment, the coupling proceeds solely in an acidic medium
which serves both as reagent and as solvent.
The weak acid in question is generally chosen from acids whose
boiling point is less than 150°C, for example formic acid or, preferably, acetic
acid. In addition, this weak acid may be used in solution, for example in water
or in an organic or mineral solvent or, preferably, alone. By way of example,
when this weak acid is acetic acid, it preferably corresponds to glacial acetic
acid.
The coupling reaction usually proceeds at room temperature to form
the oxime of formula IV. This oxime is then cyclized by in situ heating, i.e. in
the same medium in which it is formed. In another manner, the cyclization of
this oxime may be performed ex situ, i.e. separately from the medium in
which it is formed, and in a solvent such as, for example, the solvent used
during this formation.
Usually, the process of the invention proceeds at a temperature
ranging from room temperature up to about 150°C. In general, this process is
undertaken at room temperature when the acid corresponds to a mixture of
strong acid and weak acid, but at a higher temperature when the acid
corresponds solely to a weak acid. By way of example, when the weak acid is
acetic acid, the reaction temperature will be about 117°C-118°C.
The starting compound of formula II may be obtained according to the
following reaction scheme:

i.e. starting with a halobenzene of formula V in which R represents a
nitro or -COOR' group and Hal represents a halogen, for example chlorine or
fluorine, which is reacted in the presence of a basic agent such as an alkali
metal hydroxide or an alkali metal alkoxide such as sodium tert-butoxide or
potassium tert-butoxide, in particular potassium tert-butoxide, with an imidate
of formula VI in which R3 represents a linear or branched C1-C4 alkyl group,
for example ethyl, and R4 represents a linear or branched C1-C4 alkyl group,
for instance methyl, the reaction preceding at room temperature and
preferably in a polar solvent such as N,N-dimethylformamide to form an
oxime of formula VII in which R3 and R4 have the same meaning as
previously. This oxime is then treated with a strong acid such as hydrochloric
acid to form the compound of formula II in the form of an acid-addition salt,
which is then optionally subjected to the action of a strong base such as
sodium hydroxide, to obtain the compound of formula II in free base form.
According to one embodiment, the starting compound of formula Il
may be obtained according to the following reaction scheme:

i.e. starting with a halonitrobenzene of formula V in which Hal
represents a halogen, for example chlorine, this compound of formula V
corresponding to a compound of formula V in which R represents -NO2, which
is reacted in the presence of a basic agent such as an alkali metal hydroxide,
with an imidate of formula VI in which R3 represents a linear or branched C1-
C4 alkyl group, for example ethyl, and R4 represents a linear or branched C1-
C4 alky! group, for instance methyl, the reaction proceeding at room
temperature and, preferably, in a polar solvent such as N,N-
dimethylformamide to form an oxime of formula VII' in which R3 and R4 have
the same meaning as previously, this compound of formula VII' corresponding
to a compound of formula VII in which R represents a nitro group. This oxime
is then treated with a strong acid such as hydrochloric acid to form the
compound of formula II' in the form of an acid-addition salt, which is then
subjected to the action of a strong base such as sodium hydroxide, to obtain
the compound of formula II' in free base form.
The starting compound of formula II" may be obtained according to the
following reaction scheme:

i.e. starting with a halobenzene of formula V" in which Hal represents a
halogen, for example chlorine or fluorine, this compound of formula V"
corresponding to a compound of formula V in which R represents a group
-COOR', R' being as defined previously, which is reacted in the presence of a
basic agent such as an alkali metal alkoxide such as sodium tert-butoxide or
potassium tert-butoxide, with an imidate of formula VI in which R3 represents
a linear or branched C1-C4 alkyl group, for example ethyl, and R4 represents a
linear or branched C1-C4 alkyl group, for instance methyl, the reaction
proceeding at room temperature and, preferably, in a polar solvent such as
N,N-dimethylformamide to form an oxime of formula VII" in which R3 and R4
have the same meaning as previously, this compound of formula VII"
corresponding to a compound of formula VII in which R represents a group
-COOR', R' being as defined previously. This oxime is then treated with a
strong acid such as hydrochloric acid to form the compound of formula II in
the form of an acid-addition salt, which is then optionally subjected to the
action of a strong base such as sodium hydroxide, to obtain the compound of
formula II" in free base form.
As regards the starting diketones of formula III, they may be prepared
in various ways according to their chemical structure.
Thus, according to one embodiment, the compounds of formula III' in
which R1 has the same meaning as previously and R2 represents an alkoxy or
dialkylaminoalkoxy group are referred to hereinbelow as compounds of
formula XII. They may be obtained according to the following reaction
scheme:

i.e. by reacting 4-hydroxyacetophenone of formula VIII with a halide of
formula IX in which R2' represents an alkyl or dialkylaminoalkyl group and X
represents a halogen such as chlorine or a sulfonate group, in the presence
of a basic agent, generally a weak base such as an alkali metal carbonate
and usually by heating in a polar solvent such as methyl ethyl ketone to give
the acetophenone derivatives of formula X in which R2' has the same
meaning as previously.
Preferably, R2' represents 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 or alternatively R2' represents
a dialkylaminoalkyi group in which each linear or branched alkyl group is of
C1-C8, especially in which each linear or branched alkyl group is of C1-C4
such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl ortert-butyl.
The compound of formula X is then coupled with an ester of formula XI
in which R1 and R3 have the same meaning as previously, the coupling taking
place in the presence of a strong base such as an alkali metal alkoxide and
usually in a polar solvent, for example N-methyl-2-pyrrolidinone, to form a
diketone of formula XII.
The diketone thus obtained is then isolated directly from the medium in
which it is formed or, preferably, after treatment with a strong acid such as
hydrochloric acid so as to form an acid-addition salt thereof, for example the
hydrochloride. If necessary, this diketone of formula XII in free base form may
be regenerated from the acid-addition salt thus obtained, by treating this salt
with a basic agent, for example a weak base such as an alkali metal
carbonate or hydrogen carbonate.
According to another embodiment, the compounds of formula III" in
which R1 has the same meaning as previously and R2 represents an alkoxy or
dialkylaminoalkoxy group are referred to hereinbelow as compounds of
formula XII'. They may be obtained according to the following reaction
scheme:
i.e. by reacting a compound of formula XIII in which X' represents a
halogen such as chlorine with a halide of formula XIV in which R4 is an alkyl
group, especially a C1-C4 alkyl group such as a methyl group and X"
represents a halogen such as chlorine, in the presence of a Lewis acid such
as aluminum trichloride or iron trichloride at room temperature in an organic
solvent such as dichloromethane to give the compounds of formula XV in
which R4 has the same meaning as previously.
The compound of formula XV is then coupled with an amine of formula
XVI in which R5 is an alkyl group, especially a C1-C4 alkyl group such as n-
butyl, in the presence of an iodide such as potassium iodide or sodium iodide
dissolved in a polar aprotic solvent such as methyl isobutyl ketone (MIBK) to
give a compound of formula XVII in which R'2 represents a dialkylaminoalkyl
group in which the alkyl group represents a C1-C4 alkyl group such as an n-
butyl group.
The compound of formula XVII is then coupled with an ester of formula
XI in which R1 and R3 have the same meaning as previously, the coupling
taking place in the presence of a strong base such as an alkali metal alkoxide
and usually in a polar solvent such as N-methyl-2-pyrrolidinone to form a
ketone of formula XII'.
The diketone thus obtained is then isolated directly from the medium in
which it is formed or, preferably, after treatment with a strong acid such as
hydrochloric acid so as to form an acid-addition salt thereof, for example the
hydrochloride. If necessary, this diketone of formula XII in free base form may
be regenerated from the acid-addition salt thus obtained, by treating this salt
with a basic agent, for example a weak base such as an alkali metal
carbonate or hydrogen carbonate.
Another subject of the invention relates to the derivatives of general
formula:

and also to the acid-addition salts thereof, in which R2' has the same
meaning as previously, L represents a bond or an oxygen atom and Y
represents:
a) a group of general formula:

in which R1' represents a C1-C4 alkyl group, or
b) a group of general formula:

in which R1' has the same meaning as previously and R represents a
nitro or -COOR' group, R' having the same meaning as previously, these
derivatives being, when Y represents the group XX, in the form of the E
isomer, the Z isomer or mixtures of these isomers.
Another subject of the invention relates to compounds of formula XVIII,
referred to hereinbelow as benzoyloxy derivatives of general formula XVIII':

and also to the acid-addition salts thereof, in which R2' has the same
meaning as previously and Y represents:
a) a group of general formula:

in which R1' represents a C1-C4 alkyl group, or
b) a group of general formula:

in which R1' has the same meaning as previously, these benzoyloxy
derivatives being, when Y represents the group XX', in the form of the E
isomer, the Z isomer or mixtures of these isomers, this group of formula XX'
corresponding to a compound of formula XX in which R represents a nitro
group.
Another subject of the invention relates to compounds of formula XVlll,
referred to hereinbelow as derivatives of general formula XVlll":

and also to the acid-addition salts thereof, in which R2' has the same
meaning as previously and Y represents:
a) a group of general formula:

in which R1' represents a C1-C4 alkyl group, or
b) a group of genera! formula:

in which R1' and R' have the same meaning as previously, these
derivatives being, when Y represents the group XX", in the form of the E
isomer, the Z isomer or mixtures of these isomers, this compound
corresponding to a compound of formula XX in which R represents a group
-COOR', R' being as defined previously.
Among the compounds of formula XVIII, those in which Y represents
the group of formula XIX or the group of formula XX in which R1' represents n-
butyl constitute preferred compounds.
Moreover, the compounds of formula XVIII in which R2' represents 3-
(di-n-butylamino)propyl also fortm preferred compounds.
Moreover, the compounds of formula XVIII in which L represents a
bond also form preferred compounds.
Moreover, the compounds of formula XVIII in which L represents an
oxygen atom also form preferred compounds.
Consequently, compounds of the invention that are particularly
preferred are represented by the benzoyloxy derivatives of formula XVIII in
which:
a) R2' represents 3-(di-n-butylamino)propyl, L represents a bond and Y
represents the group of formula XIX in which R1' represents n-butyl,
b) R2' represents 3-(di-n-butylamino)propyl, L represents a bond and Y
represents the group of formula XX in which R1' represents n-butyl,
this compound being in the form of the E isomer, the Z isomer or a
mixture of these isomers.
Consequently, compounds of the invention that are particularly
preferred are represented by the benzoyloxy derivatives of formula XVIII in
which:
a) R2' represents 3-(di-n-butylamino)propyl, L represents an oxygen
atom and Y represents the group of formula XIX in which R1'
represents n-butyl,
b) R21 represents 3-(di-n-butylamino)propyl, L represents an oxygen
atom and Y represents the group of formula XX in which R1'
represents n-butyl, this compound being in the form of the E
isomer, the Z isomer or a mixture of these isomers.
Among the compounds of formula XVIII', those in which Y represents
the group of formula XIX or the group of formula XX' in which R1' represents
n-butyl constitute preferred compounds.
Moreover, the compounds of formula XVIII' in which R2' represents 3-
(di-n-butylamino)propyl also form preferred compounds.
Consequently, compounds of the invention that are particularly
preferred are represented by the benzoyloxy derivatives of formula XVIII' in
which:
a) R2' represents 3-(di-n-butylamino)propyl and Y represents the
group of formula XIX in which R-T represents n-butyl,
b) R2' represents 3-(di-n-butylamino)propyl and Y represents the
group of formula XX' in which R1' represents n-butyl, this compound
being in the form of the E isomer, the Z isomer or a mixture of these
isomers.
Consequently, compounds of the invention that are particularly
preferred are represented by the benzoyloxy derivatives of formula XVIII' in
which:
a) R2' represents 3-(di-n-butylamino)propyl and Y represents the
group of formula XIX in which RV represents n-butyl,
b) R2' represents 3-(di-n-butylamino)propyl and Y represents the
group of formula XX' in which R1' represents n-butyl, this compound
being in the form of the E isomer, the Z isomer or a mixture of these
isomers.
Among the compounds of formula XVIII", those in which Y represents
the group of formula XIX or the group of formula XX" in which R1' represents
n-butyl constitute preferred compounds.
Moreover, the compounds of formula XVIII" in which R2' represents 3-
(di-n-butylamino)propyl also form preferred compounds.
Consequently, compounds of the invention that are particularly
preferred are represented by the derivatives of formula XVIII" in which:
a) R2' represents 3-(di-n-butylamino)propyl and Y represents the
group of formula XIX in which R1' represents n-butyl,
b) R2' represents 3-(di-n-butylamino)propyl and Y represents the
group of formula XX" in which R1' represents n-butyl, this
compound being in the form of the E isomer, the Z isomer or a
mixture of these isomers.
Consequently, compounds of the invention that are particularly
preferred are the benzoyloxy derivatives of formula XVIII" in which:
a) R2' represents 3-(di-n-butylamino)propyl and Y represents the
group of formula XIX in which R1' represents n-butyl,
b) R2' represents 3-(di-n-butylamino)propyl and Y represents the
group of formula XX" in which RV represents n-butyl, this
compound being in the form of the E isomer, the Z isomer or a
mixture of these isomers.
The non-limiting examples that follow illustrate the invention. In these
examples, the abbreviations below have the indicated meanings:
TLC: thin-layer chromatography
HPLC: high-performance liquid chromatography
LC method used for the analysis of the preparations 2:

PREPARATIONS 1
I. O-(4-Nitrophenyl)hydroxylamine (compound II)
. A. Ethyl 4-nitrophenoxvethaneimidoate (compound VII: R3 = C2H5;
R4 = CH3)
To a suspension of 23.8 g (0.42 mo!) of potassium hydroxide in 220 mi
of N,N-dimethylformamide at 10°C are added 40.0 g of ethyl N-
hydroxyethaneimidoate (0.39 mol) (compound VI: R3 = C2H5; R4 = CH3). A
solution of 55.6 g of 4-chloronitrobenzene (0.35 mol) (compound V: Hal = CI)
(55.6 g) in N,N-dimethylformamide is then added slowly, at 10°C. The mixture
is stirred for 24 hours at 20°C and 1L of water is then added. The precipitate
is filtered off and the solid is washed with water and oven-dried at 30°C under
vacuum to constant weight.
Mass obtained: 72 g
Yield: 91 w/w%
B. O-(4-Nitrophenyl)hydroxylamine (compound Il)
To a solution of 71.2 g of ethyl 4-nitrophenoxyethaneimidoate
(0.32 mol) (compound VII) in 925 ml of acetonitrile are added slowly, at 20°C,
35 ml of 37% hydrochloric acid (0.38 mol). The reaction medium is stirred at
20°C for 2 hours and then filtered, and the 0-(4-nitrophenyl)hydroxylamine
hydrochloride thus formed is dried at 30°C in a vacuum oven. With stirring,
this hydrochloride is dissolved in a mixture formed from 800 ml of
dichloromethane and of a sodium hydroxide solution (16.8 g in 500 ml) and
the phases are then allowed to separate by settling. The organic phase is
separated out and washed with 500 ml of water. This organic phase is
evaporated on a rotary evaporator and the solid obtained is then dried in a
vacuum oven.
Mass obtained: 45.5 g
Yield: 93 w/w%

A. 1-Chloro-3-(di-n-butvlamino)propane (compound IX: R2' = 3-(di-
n-butylamino)propyl; X = CI)
70.8 ml of 20% aqueous ammonia solution and then 138.8 ml of a
68.4% solution of 1-chloro-3-(di-n-butylamino)propane hydrochloride (403.9
mmol) are placed in a reactor at room temperature (20-25°C). The mixture is
rinsed with water and then stirred for 15 minutes at 20-25°C, after which the
phases are allowed to separate by settling. The aqueous phase is removed
and the organic phase is washed with water. After stirring for 15 minutes, the
phases are allowed to separate by settling and the aqueous phase is
removed. The organic phase thus obtained contains, in crude form, the
desired compound IX, which is stored at 5°C under nitrogen.
B. 4-[3-(Di-n-butylamino)propoxylacetophenone (compound X: R2'
= 3-(di-n-butyIamino)propyl)
47.9 g of 4-hydroxyacetophenone (compound VIII) (351.8 mmol) are
placed in a reactor and 220 ml of methyl ethyl ketone (4.61 volumes) are
added. The mixture is stirred until dissolution is complete, 53.5 g of potassium
carbonate (387 mmol) are added and the suspension is stirred again. It is
heated to reflux, 1-chloro-3-(di-n-butylamino)propane (compound IX) in free
base form is added slowly and the addition funnel is rinsed with methyl ethyl
ketone. Refluxing is continued overnight. When the reaction is complete, the
mixture is cooled to room temperature and the methyl ethyl ketone is distilled
off. The reaction medium is cooled to 25°C and 200 ml of water are then
added. 200 ml of methyl tert-butyl ether are added, the phases are allowed to
separate by settling and are separated to give a first aqueous phase and a
first organic phase. This aqueous phase and a first organic phase are
extracted. This aqueous phase is then extracted with methyl tert-butyl ether,
to give a second organic phase. The organic phases are combined and
washed with a mixture formed from 200 ml of water, 2.24 ml of 90% acetic
acid and 3.75 g of sodium chloride and then twice with aqueous sodium
chloride solution. The organic phase is then brought to dryness to obtain the
desired compound X.
Mass obtained: 108.4 g
Appearance: very slightly viscous yellow oil
a) eluent: 90/10 dichloromethane/methanol
Rf = 0.48
b) eluent: 95/0.5 dichloromethane/methanol
Rf = 0.34
Yield: 100.8w/w%
C. 1-(4-r3-(Di-n-butyiamino)propoxy]phenyl}-1.3-heptanedione
hydrochloride (hydrochloride of compound XII: Ri = n-C4H9; R2'
= 3-(di-n-butylamino)propyl)
108.4 g of 4-(di-n-butyIaminopropoxy)acetophenone (compound X)
(355 mmoi), 58.1 mi of ethyl pentanoate (39 mmol) and 325 ml of N-methyl-2-
pyrrolidinone are placed in a reactor. The mixture is stirred and cooled to 5°C,
followed by portionwise addition of 57.5 g of sodium methoxide (1.064 mmol;
3 equivalents). The reaction medium is then allowed to warm to room
temperature with continued stirring, which gives compound XII in free base
form.
105 g of 37% hydrochloric acid solution are placed in a 1L Keller flask.
The solution is cooled to 5°C and the preceding reaction mixture is added
slowly to the hydrochloric acid solution while controlling the exothermicity. At
the end of the addition, the reaction medium is transferred into two 1L conical
flasks. It is extracted with water and ethyl acetate, twice more with ethyl
acetate and then again twice with ethyl acetate. The combined organic
phases are washed twice with 150 ml of water. The organic phase is dried,
300 ml of methylcyclohexane are added and the resulting mixture is stirred
until a suspension is obtained. It is filtered and the product is rinsed with
methylcyclohexane and dried under vacuum at 40°C to obtain the
hydrochloride of the desired compound XII.
Mass obtained: 121.8 g
Appearance: cream-colored solid
a) TLC (eluent: 90/10 dichloromethane/methanol)
Rf: 0.52
b) HPLC
Rt: 16.0 minutes
Yield: 80.6 w/w%.
D. 1-{4-[3-(Di-n-butylamino)propoxy1phenyl}-1,3-heptanedione
(compound XII: R1 = n-C4H9; R2' = 3-(di-n-butylamino)propyl)
To 19.6 g of 1-{4-[3-(di-n-butylamino)propoxy]phenyl}-1,3-heptane-
dione hydrochloride, obtained after the extraction described in the preceding
paragraph, are added 40 ml of sodium bicarbonate (10 w/w% and 20 ml of
water). The mixture is extracted with twice 30 ml of dichloromethane and the
organic phases are washed with 60 ml of water. The resulting organic phase
is dried over sodium sulfate and evaporated to dryness under vacuum on a
rotary evaporator to recover 16.7 g of an orange-cofored oil.
EXAMPLE 1
2-n-Butvl-3-{4-[3-(di-n-butvlamino)propoxy]benzoyl}-5-nitrobenzofuran
(compound !: R1 = n-C4H9; R2 = 3-(di-n-butylamino)propoxy)
7.11 g of 1-{4-[3-(di-n-butylamino)propoxy]phenyl}-1,3-heptanedione
(compound XII or III) (optical purity: 95%; 17 mmol), 2.81 g of 0-(4-
nitrophenyl)hydroxylamine (compound II) (18 mmol) and 34 ml of acetic acid
are placed in a 100 ml Keller flask. The mixture is stirred at room temperature
for 12 hours (formation of the oxime of formula IV: R1 = n-C4H9; R2 = 3-(di-n-
butylamino)propoxy) and is then refluxed (117°C) for 6 hours. The reaction
medium is evaporated to dryness on a rotary evaporator and the crude
reaction product is diluted with 60 ml of ethyl acetate. The resulting solution is
then hydrolyzed by addition of 100 ml of basic sodium carbonate solution
(20 w/w%), the phases are separated by settling and the organic phase is
washed with three times 100 ml of water to neutral pH. The organic phase is
dried over sodium sulfate, the suspension is filtered and the solvent is
evaporated off to dryness using a rotary evaporator.
Mass obtained: 9.01 g
Appearance: colored oil
Titer of the crude product by TLC: 67%
Chemical yield: 69%
PREPARATIONS 2
I. 2-Propyl 4-(aminoxy)benzoate

25 g of 4-fluorobenzoic acid are placed in 150 mL of iPA in a reactor,
the suspension is then heated to 75°C and 691 µL of DMF are added.
14.9 mL (24.4 g) of thionyi chloride SOCI2 are added. The reaction mixture is
refluxed overnight and the mixture is then concentrated, followed by addition
of 100 mL of 5% aqueous ammonia solution and 100 mL of DCM. The
organic DCM phase is washed again with water and the pH is adjusted to 7
by addition of dilute hydrochloric acid solution. 31 g of a golden yellow liquid
are obtained.
Mass yield = 95%
LC: Rt= 19.9 minutes
B. 2-Propyl4-({[(1Z)-1-ethoxvethylidene]amino}oxy)benzoate

6.1 g of N-hydroxyethaneimidoate in 50 mL of DMF are placed in a
reactor and are then cooled to 0°C, followed by addition of 6.7 g of t-BuOK.
The mixture is warmed to room temperature and stirred for 30 minutes,
followed by addition of 10 g of the product obtained in the preceding step. The
reaction mixture is stirred for 2 hours at room temperature, followed by
addition of 100 mL of water and 50 mL of DCM. The organic phase is washed
with brine and then concentrated to obtain 22.2 g of a golden yellow liquid.
Yield = 84%
LC: Rt = 24.9 minutes
C. 2-Propyl 4-(aminoxy)benzoate
17 g of the concentrated product obtained in the preceding step (i.e.
about 14 g of estimated pure product), 30 mL of dioxane and 11.7 g of 36%
hydrochloric acid solution are placed in a round-bottomed flask. The reaction
progress is monitored by liquid chromatography. At the end of the reaction,
the reaction mixture is filtered through a Buchner funnel and then washed
with 5 mL of dioxane. The filtrate is concentrated under vacuum on a
rotavapor; the yellow precipitate is taken up in 20 mL of iPA and dissolved
while hot. After cooling to room temperature, isopropyl ether is added and the
crystals formed are then filtered off: 0.4 g of expected product is isolated. A
second crystallization crop from methylcyclohexane (MCH) makes it possible
to recover a further 11.5 g.
Yield = 95%
LC: Rt= 14.8 minutes

84 mL of CH2CI2 and 14.4 g (1.1 eq.) of aluminum trichloride (AICI3) are
placed in a reactor at 20°C with stirring. The reaction medium is cooled to
-7°C and 8.5 g (1.1 eq.) of acetyl chloride are then added. The mixture is
stirred for 30 minutes and 15 g of 1-chloro-3-phenylpropane are then added
at 0°C. At the end of the reaction, the reaction mixture is poured over about
30 minutes with vigorous stirring into 75 mL of 5% hydrochloric acid solution.
The mixture is stirred for 1 hour at 10°C; the phases are then separated by
settling and the aqueous phase is extracted with CH2CI2. The organic phases
are combined and washed successively with 2N HCI solution, 1N sodium
hydroxide solution and water.
The organic phase is dried over Na2SO4 and then filtered. After
evaporating to dryness, 19.9 g of a yellow oil are obtained.
Quantitative yield
LC: Rt= 18 minutes

20.5 g of the product obtained in the preceding step and 100 mL of
MIBK are placed in a reactor. This solution is stripped with about 50 ml of
MIBK under vacuum (60°C/100 mbar). The solution is then adjusted to 130 g
by adding MIBK. To this solution are added 2.7 g of sodium iodide with
vigorous stirring, followed by addition over 10 minutes, at about 20°C, of 31 g
(2.5 eq.) of dibutylamine. The reaction medium is refluxed with vigorous
stirring for 14 hours. The reaction mixture is cooled to 20°C and hydrolyzed
with water. The organic phase is successively washed with water,
hydrochloric acid solution, water, aqueous potassium carbonate solution and
aqueous sodium chloride solution. The aqueous phases are treated with
sodium hydroxide and back-extracted with dichforomethane. The organic
phases are combined to give, after concentrating to dryness, 20.6 g of a
brown oil.
Yield = 74%
LC: Rt= 10.5 minutes
C. 1-{4-f3-(Dibutylamino)propvHphenyl)heptane-1,3-dione
10 g of the product obtained in the preceding step, 5 g of ethyl
pentanoate and 30 mL of NMP are placed in a reactor. 5.6 g of sodium
methoxide are added, at 5°C. The mixture is warmed to room temperature
and the reaction progress is monitored by thin-layer chromatography. At the
end of the reaction, the reaction medium is poured into a mixture of 10.1 g of
37% hydrochloric acid solution, 45 g of water and 45 g of ice. The product is
then extracted with twice 50 mL of heptane and the combined organic phases
are washed with 100 mL of water. The organic phases are washed with
aqueous sodium bicarbonate solution. The organic phase is concentrated to
give 10.6 g of a carmine-red liquid.
Yield = 82%
LC: Rt= 14.3 and 17 minutes
The two main peaks on LC at Rt = 14.3 minutes and Rt = 17 minutes
correspond to the expected product in ketone and enol form.

Structure confirmed by mass spectrometry analysis (M+H = 374 i.e.
MW = 373).
EXAMPLE 2
Synthesis of celivarone

2.16 g of 2-propyi 4-({[(1Z)-1-ethoxyethylidene]amino}oxy)benzoate,
6 ml of formic acid and 2 g of 1-{4-[3-(dibutylamino)propyi]phenyl}heptane-
1,3-dione are placed in a reactor.
890 uL of HCI (37%) are added and the reaction medium is heated at
50°C for 2 hours (the end of reaction is monitored by LC). The medium is
hydrolyzed by adding 20 ml_ of aqueous sodium bicarbonate solution. The
mixture is extracted with 25 ml_ of DCM and the DCM phase is then washed
with 15 ml_ of water. After concentrating under vacuum, 3.1 g of crude
product are isolated in the form of an oil. The product is purified by
chromatography on silica gel, eluting with a DCM/iPA mixture, and 1.1 g of
celivarone base are recovered in oil form in the main fraction.
Yield = 38%
LC: Rt = 20 minutes.
CLAIMS
1. A process for preparing benzofuran derivatives substituted at position 5
of general formula:

in which R represents a nitro or ester group -COOR', in which R' represents a
hydrogen atom or an alkyl group, R1 represents hydrogen or an alkyl group
and R2 represents hydrogen, a halogen or a hydroxyl, haloalkyi, alkyl, alkoxy,
dialkylaminoalkoxy or dialkylaminoalkyl group, characterized in that the
hydroxylamine of formula:

is coupled, in the presence of an acid, with a diketone of general formula:

in which R1 and R2 have the same meaning as previously, to form an oxime of
general formula:

in the form of a mixture of E and Z isomers, in which R1 and R2 have the
same meaning as previously, and this oxime is cyclized by heating to form the
desired compound.
2. The process as claimed in claim 1, characterized in that R represents
an ester -COOR' in which R' represents an alkyl group, R1 represents an alkyl
group and R2 represents hydrogen or a hydroxyl, haloalkyl,
dialkylaminoalkoxy or dialkylaminoalkyl group.
3. The process as claimed in claim 1 or 2, characterized in that the acid is
a weak acid optionally combined with a strong acid.
4. The process as claimed in claim 3, characterized in that the weak acid
is acetic acid.
5. The process as claimed in one of claims 1 to 4, characterized in that
the oxime is cyclized in the medium in which it is formed.
6. The process as claimed in one of claims 1 to 5, characterized in that:
• R1 represents a linear or branched C1-C8 alkyl group,
• R2 represents a linear or branched C1-C8 alkyl group, a linear or
branched C1-C8 alkoxy group or a dialkylaminoalkoxy group in which
each alkyl group is of C1-C8 and the linear or branched alkoxy group is
of C1-C8.
7. The process as claimed in claim 6, characterized in that:
• R1 represents a linear or branched C1-C4 alkyl group,
• R2 represents a linear or branched C1-C4 alkyl group, a linear or
branched C1-C4 alkoxy group or a dialkylaminoalkoxy group in which
each alkyl group is of C1-C4 and the linear or branched alkoxy group is
of C1-C4.
8. The process as claimed in claim 6 or 7, characterized in that R1
represents n-butyl and R2 represents 3-(di-n-butylamino)propoxy.
9. The process as claimed in claim 6 or 7, characterized in that R1
represents n-butyl and R2 represents 3-(di-n-butylamino)propoxy.
10. The process as claimed in one of claims 1 to 9, characterized in that
the compound of formula II is obtained by reacting a halobenzene of general
formula:

in which Hal represents a halogen, with an imidate of general formula:

in which R3 and R4 each represent a linear or branched C1-C4 alkyl group, the
reaction proceeding at room temperature and in a polar solvent, to form an
oxime of general formula:

in which R3 and R4 have the same meaning as previously, this oxime is
treated with a strong acid to form the desired compound of formula II in the
form of the acid-addition salt, and this salt is then subjected to the action of a
strong base to obtain the compound of formula II in free base form.
11. The process as claimed in one of claims 1 to 9, characterized in that
the diketones of formula III in which R1 represents hydrogen or an alkyl group
and R2 represents an alkoxy or diaminoaikoxy group may be obtained:
a) by reacting 4-hydroxyacetophenone of formula:

with a halide of general formula:

in which R2' represents an alkyl or dialkylaminoaikyl group and X represents a
halogen or a sulfonate group, in the presence of a basic agent, and by
heating in a polar solvent to give the acetophenone derivatives of general
formula:

in which R2' has the same meaning as previously,
b) by coupling the compound of formula X with an ester of general formula:

in which R1 has the same meaning as previously and R3 represents a linear
or branched C1-C4 alkyl group, the coupling taking place in the presence of a
strong base and in a polar solvent, to form a diketone of general formula:

in which R2 and R2' have the same meaning as previously, and this diketone
is isolated directly from the medium in which it is formed or after treatment
with a strong acid to form an acid-addition salt thereof.
12. The process as claimed in one of claims 1 to 9, characterized in that
the compound of formula ll", i.e. a compound of formula II in which is
obtained by reacting a halobenzene of general formula:

in which Hal represents a halogen, with an imidate of general formula:

in which R3 and R4 each represent a linear or branched C1-C4 aikyl group, the
reaction proceeding at room temperature and in a polar solvent, to form an
oxime of general formula:

in which R3 and R4 have the same meaning as previously, this oxime is
treated with a strong acid to form the desired compound of formula II' in the
form of an acid-addition salt thereof, and this salt is then subjected to the
action of a strong base to obtain the compound of formula II in free base form.
13. The process as claimed in one of claims 1 to 9, characterized in that
the diketones of formula III" in which R1 represents hydrogen or an aikyl
group and R2 represents an alkoxy or dialkylaminoalkoxy group may be
obtained in the following manner:
a) a compound of formula XIII

is reacted with a compound of formula XIV

to obtain a compound of formula XV

b) said compound of formula XV is reacted with a compound of formula XIV
HN(R5)2 to obtain a compound of formula XVII:

c) said compound of formula XVII is reacted with a compound of formula XI

to obtain the compound of formula III".
14. A benzoyloxy derivative of genera! formula:

and also acid-addition salts thereof in which L represents a bond or an
oxygen atom, 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 and Y represents:
a) a group of general formula:

in which R1' represents a C1-C4 alkyl group, or
b) a group of general formula:

in which R1' has the same meaning as previously, these derivatives being,
when Y represents a group XX, in the form of the E isomer, the Z isomer or a
mixture of these isomers.
15. The benzoyloxy derivative as claimed in claim 12, in which Y
represents the group of formula XIX or the group of formula XX in which R1'
represents n-butyl.
16. The benzoyloxy derivative as claimed in claim 12, in which R2'
represents 3-(di-n-butylamino)propyl.
13. The benzoyloxy derivative as claimed in claim 12, in which R2'
represents 3-(di-n-butylamino)propyl, L represents an oxygen atom and Y
represents the group of formula XIX in which R1' represents n-butyl.
14. The benzoyloxy derivative as claimed in claim 12, in which R2'
represents 3-(di-n-butylamino)propyl, L represents an oxygen atom and Y
represents the group of formula XX in which R1' represents n-butyl, this
compound being in the.form of the E isomer, the Z isomer or a mixture of
these isomers.
15. The benzoyloxy derivative as claimed in claim 12, in which R2'
represents 3-(di-n-butylamino)propyl, L represents a bond and Y represents
the group of formula XIX in which R1' represents n-butyl.
16. The benzoyloxy derivative as claimed in claim 12, in which R2'
represents 3-(di-n-butyiamino)propyl, L represents a bond and Y represents
the group of formula XX in which R1' represents n-butyLthis compound being
in the form of the E isomer, the Z isomer or a mixture of these isomers.