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

in which R represents an alkyl or aryl group and R1 and
R2, which may be identical or different, each represent
hydrogen or an alkyl or aryl group.
In formula I above, R, R1 or 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-propyl, isopropyl, n-butyl or tert-butyl or
alternatively a substituted or unsubstituted phenyl
group.
Among the group R, mention may be made of methyl,, and
among the group Rl, mention may be made of n-butyl.
In addition, in this formula I, among the group R,
mention may be made of methyl, among the group R1, mention
may be made of n-butyl and among the group R2, mention may
be made of hydrogen.
Among the compounds of formula I above, 2-n-butyl-5-
sulfoamidobenzofuran described in patent application WO
02/48132 has proven to be particularly useful as an
intermediate product for the final preparation of amino-

alkoxybenzoylbenzofuran 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 pharmaceutically
acceptable salts thereof. This methanesulfonamidobenzo-
furan derivative was described in patent EP 047 1 609,
along with its therapeutic uses, especially in the
cardiovascular field, where it proved to be particularly
advantageous, for example, as an antiarryhythmic agent.
A process for synthesizing dronedarone was described in
patent application WO 02/48132, mentioned previously,
using 2-n-butyl-5-nitrobenzofuran, which is reduced,
under pressure with hydrogen in the presence of platinum
oxide as catalyst to form 2-n-butyl-5-aminobenzofuran.
This benzofuran derivative is then subjected to the
action of methanesulfonyl chloride, which gives 2-n-
butyl-5-methanesulfonamidobenzofuran, which is treated
with 4-[3-(di-n-butylamino)propoxy]benzoyl chloride to
obtain dronedarone.
However, this process is not free of inherent drawbacks
especially regarding the type of reaction used for the
reagents used, namely hydrogenation under pressure, which
entails an industrial risk, and also a treatment with
methanesulfonyl chloride, a hazardous reagent which may
generate genotoxic impurities (methanesulfonates).
The search for a process for preparing 2-n-butyl-5-
methanesulfonamidobenzofuran that is capable of
overcoming these drawbacks and disadvantages thus remains
of fundamental interest.
It has now been found that it is possible to obtain this
methanesulfonamidobenzofuran derivative, in good yield,
by using reagents and reaction steps that are free of the
drawbacks and disadvantages reported previously since it

does not make use either of a catalytic hydrogenation
reaction under pressure or of methanesulfonyl choride.
According to the invention, the 5-sulfonamidobenzofuran
derivatives of formula I may be prepared by coupling a
benzofuran derivative of general formula:

in which R1 and R2 have the same meaning as previously and
X represents chlorine, bromine or iodine or a sulfonate
group of general formula:
R3-SO2-O- III
in which R3 represents a trifluoromethane (-CF3) or
imidazolyl group, with a sulfonamide derivative of
general formula:
R-SO2-NH2 IV
in which R has the same meaning as previously, in the
presence of a basic agent and of a catalytic system
formed from a complex between a palladium compound and a
ligand, which gives the desired compounds.
The palladium complex used in the process of the
invention is generally in the form of a palladium (0)
compound, for instance:
• tris(dibenzylideneacetone)dipalladium (0), referred
to hereinbelow as Pd2 (dba)3 or, advantageously,
• bis(dibenzylideneacetone)palladium(0) , referred to
hereinbelow as Pd(dba)2
and of a ligand generally chosen from phosphines, usually
diarylphosphines.

These diarylphosphines are generally substituted in
various ways. Thus, the aryl ring, such as phenyl, not
bearing the phosphorus atom, may be mono- or especially"
polysubstituted, for example with an isopropyl group,
while the aryl ring, especially phenyl, bearing the
phosphorus atom, may in addition be mono- or polysub-
stituted. For example, this aryl ring does not comprise
any substituents other than the phosphorus atom.
The phosphorus atom may itself be substituted, for
example mono- or especially disubstituted, for -example
with alkyl or cycloalkyl groups such as tert-butyl or
cyclohexyl.
By way of example, the following compounds may be used as
ligands:
* 2- (di-tert-butylphosphino)-2',4',6'-triisopropyl-1,1'-
biphenyl, referred to hereinbelow as ligand LI,
* 2-(dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-
biphenyl, referred to hereinbelow as ligand L2,
* 2-(dicyclohexylphosphino)-2',6'-dimethoxy-1,1'-
biphenyl, referred to hereinbelow as ligand L3,
* 2-(di-tert-butylphosphino)-3,4,5,6-tetramethyl-
2',4',6'-triisopropyl-1,1'-biphenyl, referred to
hereinbelow as ligand L4.
The ligand LI is particularly advantageous.
The basic agent used in the process according to the
invention may be chosen especially from alkoxides, but
more generally from weaker bases such as phosphates or
carbonates, for example alkali metal phosphates or alkali
metal carbonates such as tripotassium phosphate,
potassium carbonate or cesium carbonate.
In general, the coupling reaction is performed hot, for
example at a temperature of between 60 °C and 120 °C, and

in a suitable solvent. This solvent may correspond to an
alcohol, for instance tert-butanol, to an ether, for
instance tetrahydrofuran or dioxane, or to a hydrocarbon,
preferably an aromatic hydrocarbon, for instance toluene.
However, dioxane is a solvent of choice in the context of
the present invention.
The starting compounds of formula II may be prepared in
various ways according to their chemical structure, as
described hereinbelow.
A.- The compounds of formula II in which X represents
chlorine, bromine or iodine may be obtained according to
the following reaction scheme:

i.e. starting with a 2-hydroxyphenyl derivative of the
formula V in which R2 has the same meaning as previously
and X1 represents chlorine, bromine or iodine, which is
reacted with a halo ester of formula VI in which R1 has
the same meaning as previously, Hal represents a halogen,
preferably bromine, and R4 represents a C1-C4 alkyl group,
for instance ethyl, to form an ester of formula VII in

which R1, R2, R4 and X1 have the same meaning as
previously.
The reaction generally proceeds by heating in a suitable
solvent, in particular a polar solvent such as N, N-
dimethylf ormamide and in the presence of a basic agent
such as an alkali metal carbonate.
The ester of formula VII is then saponified in a solvent,
especially an ether, and in the presence of a suitable
basic agent such as an alkali metal hydroxide, to form
the corresponding salt of a carboxylic acid derivative,
which is then treated with a strong acid, in a solvent
such as an aromatic hydrocarbon, to give the carboxylic
acid derivative of formula VIII in which R1, R2 and X1
have the same meaning as previously.
In a subsequent step, the carboxylic acid derivative of
formula VIII is then cyclized by heating in the presence
of a benzenesulfonyl halide and of an acid acceptor such
as a tertiary amine, the reaction generally proceeding by
heating in a solvent such as an aromatic hydrocarbon, to
give the compounds of formula IX in which X1, R1 and R2
have the same, meaning as previously, i.e. the desired
compounds of formula II.
B.- The compounds of formula II in which X represents a
sulfonate group may be obtained according to the
following reaction scheme:


mainly starting with 1,4-benzoquinone of formula X, which
is treated with a silyl enol ether of formula XI in which
R1 and R2 have the same meaning as previously and Ra
represents a linear or branched C1-C4 alkyl group or a
phenyl group, to form the 5-hydroxybenzofuran derivatives
of formula XII in which R1 and R2 have the same meaning as
previously.
The compound of formula XII is then coupled with a
sulfonyl derivative of formula XIII in which Hal has the
same meaning as previously, preferably chlorine, and R3
has the same meaning as previously, in the presence of an
acid acceptor, which gives the sulfonate derivatives of
formula XIV in which R1r R2 and R3 have the same meaning
as previously, i.e. the desired compounds of formula II.
The benzofuran derivatives of general formula:


in which R'3 represents a trifluoromethane or imidazolyl
group, represent another subject of the present
invention.
The non-limiting examples that follow illustrate the
invention. In these examples, the abbreviations below are
used:
TLC: thin-layer chromatography
HPLC; high-performance liquid chromatography
HPTLC: high-performance thin-layer chromatography
NMR: nuclear magnetic resonance
K3PO4: tripotassium phosphate
CS2CO3: cesium carbonate
THF: tetrahydrofuran
PREPARATIONS
A. Ethyl 2-(4-bromo-2-formylphenoxy)hexanoate (compound
VII: R1 - n-C4H9; R2 =H; R4 = C2H5; X1 = Br)
8.9 g of potassium carbonate (64.3 mmol) and 45 ml of
N,N-dimethylformamide are placed in an equipped reactor
and then heated to 55°C with stirring. A solution of 22 g
of 2-hydroxy-5-bromobenzeneformaldehyde (compound VIII: X1
- Br) (107.2 mmol) in 40 ml of N, N-dimethylf ormamide is
then poured in dropwise onto the mixture at 55 °C, and the
addition funnel is then rinsed with 10 ml of N,N-
dimethylformamide. The medium is stirred at 55°C for 30
minutes and then heated to 80°C. 20.8 ml of ethyl 2-
bromohexanoate (compound IX: R1 = n-C4H9; R4 = C2H5; Hal =
Br) (112.6 mmol) are added, and the addition funnel is
rinsed with 10 ml of N, N-dimethylformamide. The reaction
medium is maintained at 80°C with stirring; the reaction
progress is monitored by TLC (eluent: 7/1
methylcyclohexane/ethyl acetate; Rf of compound VIII:
0.53; Rf of compound X: 0.44).

At the end' of the reaction, the temperature of the
reaction medium is cooled to 20°C, 100 ml of deionized
water are then added slowly, leading to the demixing of
an oil. This oil is decanted and separated from the
aqueous phase, and then washed with 100 ml of water.
After decantation and separation, the oil is diluted with
60 ml of toluene, and this organic phase is then washed
again with 100 ml of deionized water. This last aqueous
phase is back-extracted with 60 ml of ethyl acetate. The
organic phases are combined and then concentrated on a
rotary evaporator to give 34.9 g of the desired compound
X in the form of an orange-yellow oil.
Yield: 95%
1H NMR (400 MHz, CDC13) : 5 0.93 (t, J=7 . 4 Hz, 3H, -CH2-CH2-
CH3); 1.23 (t, J = 7 Hz, 3H, -O-CH2CH3); 1.36-1.43 (m, 2H,
-CH2-CH2-CH3; 1.45-1. 54 (m, 2H, -CH2-CH2-CH2-) ; 1. 99-2 . 05
(m, 2H, -CH2-CH2-CH-) ; 4.20 (q, J=7.2 Hz, 2H, -O-CH2-CH3;
4.71 (t, J - 6Hz, 1H, -CH2-CH-O-); 6.71 (d, J=8.8Hz, 1H,
ArH); 7.56 (dd, J-9 and 2.6 Hz, 1H, ArH); 7.94 (d, J=2.4
Hz, 1H, ArH); 10.49 (s, 1H, CHO)
13C NMR (CDCl3) : δ 188.3 - 170.6 - 159.3 - 138.1 - 131.1 -
126.9 - 115.2 .- 114.5 - 77.4 - 61.6 - 32.3 --27.3- -22.3 -
14.2 - 13.9 ppm
In the same manner, but starting with 10 g or 50 g of
compound V, the desired compound VII was obtained in
yields of 98% and 94%, respectively.
B. 2-{4-Bromo-2-formylphenoxy)hexanoic acid (compound
VIII: R1= n-C4H9; R2=H; X1 = Br)
60 g of ethyl 2-(4-bromo-2-formylphenoxy)hexanoate
(compound X) (0.17 mmol) and 52 ml of methyl tert-butyl
ether are placed in an equipped reactor. 78 ml of

deionized water and a solution of 9.37 g of 23% sodium
hydroxide (0.23 mmol) in 31.4 g of deionized water are
added, at 20°C. The reaction medium is heated to 40°C
with stirring and the saponification of the ester is
monitored by TLC (eluent: 8/2 methylcyclohexane/ethyl
acetate + a few drops of acetic acid; Rf of the compound
X = 0.52; Rf of compound XI = 0.08).
At the end of the reaction, the temperature of the
reaction medium is returned to 20°C and 25.5 g of sodium
chloride (0.43 mol) in 130 ml of deionized water are
added, followed by 27 0 ml of toluene. With stirring, the
reaction medium is acidified by slow addition of 2 0 ml of
37% hydrochloric acid solution, without exceeding 25°C.
The two phases are decanted and separated, and the
organic phase is then washed with 8 0 ml of deionized
water. After separation of the phases, the organic phase
is concentrated under vacuum on a rotary evaporator to
give 54.7 g of a red oil, which crystallizes when cold.
After reslurrying in a diisopropyl ether/heptane mixture,
45.5 g of the desired compound XI are isolated in the
form of a yellow-white solid.
Yield: 82%
1H NMR (400 MHz, CDC13) : δ 0.93 (t, J=7 .2 Hz, 3H, -CH2-CH2-
CH3) ; 1.37-1.44 (m, 2H, -CH2-CH2-CH3) ; 1.49-1. 57 (m, 2H, -
CH2-CH2-CH2-) ; 2.05-2.11 (m, 2H, -CH2-CH2-CH-) ; 4.79 (t,
J=6Hz, 1H, -CH2-CH-CO-) ; 6.78 (d, J = 8. 8 Hz, 1H, ArH) ;
7.61 (dd, J=8.8 and 2.4 Hz, 1H, ArH); 7.94 (d, J=2.4 Hz,
1H, ArH); 10.39 (s, 1H, CHO)
13C NMR (CDCl3) : δ 188.6 - 174.3 - 158.6 - 138.3 - 132.4 -
127.0 - 115.5 - 114.9 - 77.2 - 32.2 - 27.1 - 22.3 -
13.8 ppm
C. 2-n-Butyl-5-bromobenzofuran (compound IX:

R1=n-C4-H9; R2 = H; X1 = Br)
25.8 ml of benzenesulfonyl chloride (0.202 mol; 1.4
equivalents) and 4 0 ml of toluene are placed in an
equipped reactor and the mixture is stirred at 80°C.
65 ml of anhydrous triethylamine (0.47 mol) and then
45.2 g of 2-(4-bromo-2-formylphenoxy)hexanoic acid
(compound XI) (0.144 mol) dissolved in 2 50 ml of toluene
are then added slowly at 80 °C. The reaction progress is
monitored by TLC (eluent: 8 0/20 methylcyclohexane/ethyl
acetate; Rf of compound XI = 0.08; Rf of the desired
compound XII = 0.80).
At the end of the reaction, the temperature of the
reaction medium is returned to 20°C. The excess
benenesulfonyl chloride is destroyed by addition of
250 ml of aqueous 5% sodium hydroxide solution. The
phases are decanted and separated and the organic phase
is then washed with a mixture of 70 ml of deionized water
and 6.8 ml of 37% hydrochloric acid. The phases are
decanted and separated and the organic phase is then
washed with 75 ml of deionized water. The organic phase
is washed with a solution of 7.73 g of sodium hydroxide
dissolved in 67 ml of deionized water. The phases are
decanted and separated and the organic phase is then
washed with a solution of 7.53 g of sodium chloride in
70 ml of deionized water. The pH of the aqueous phase is
adjusted to between 5 and 8 with 7% hydrochloric acid
solution. The phases are decanted and separated and the
organic phase is then concentrated on a rotary evaporator
to give 37.2 g of a brown oil.
This oil is purified by chromatography on silica gel
(eluent: 8 0/20 methylcyclohexane/ethyl acetate) to give
24.3 g of the desired compound XII in the form of a
yellow oil.
Yield: 67%

1H NMR (400 MHz, DMSO-d6): δ 0.91 (t, J=7.2 Hz, 3H, -CH2-
CH2-CH3) ; 1 - 30-1 .40 (m, 2H, -CH2-CH.2-CH3) ; 1 . 61-1 . 69 (m,
2H, -CH2-CH2-CH2-) ; 2.76 (t, J=7.4 Hz, 2H, -CH2-CH2-Cq) ;
6.57 (s, 1H, ArH); 7.33 (dd, J=8.8 and 2Hz, 1H, ArH);
7.46 (d, J= 8.8Hz, 1H, ArH); 7.72 (dd, 2Hz, 1H, ArH)

EXAMPLES 1 to 5
2-n-Butyl-5-methanesulfonamidobenzofuran (compound I:
R= CH3 ; R1= n-C4H9, R2= H)
The following are placed in a 20 ml tube predried in an
oven: 2 equivalents of base and 1.5 equivalents of
methanesulfonamide, 2 mol% of Pd(dba)2 and 5 mol% of 2-
(di-tert-butylphosphino)-2',4',6'-triisopropyl-1, 1'-
biphenyl (ligand L1). The tube is stoppered with a septum
and placed under an inert atmosphere of argon, and 1
equivalent of 2-n-butyl-5-bromobenzofuran (compound IX or
III) dissolved in 10 volumes of solvent is then added by
syringe. The reaction medium is then stirred and heated
to the reflux point of the solvent or at 100°C for 24
hours, while monitoring the reaction progress by TLC
(eluent: 20/80 ethyl acetate/methylcyclohexane) or by
HPLC. At the end of the reaction, the reaction medium is
diluted with ethyl acetate and then filtered while hot.
The filtrate is then concentrated to give, when cold,
crystallization of the desired compound I.
The following results were obtained:


EXAMPLE 6
2-n-Butyl-5-methanesulfonamidobenzofuran
(compound I: R= CH3; R1 = n-C4H9, R2= H)
The following are placed in an equipped reactor under an
argon atmosphere: 13 g of cesium carbonate (39.9 . mmol) ,
3 g of methanesulfonamide (31.5 mmol), 250 mg of Pd(dba)2
(0.4 mmol) and 440 mg of 2-(di-tert-butylphosphino)-
2',4',6'-triisopropyl-1,1'-biphenyl (ligand L1)
(1.04 mmol). 5.5 g of 2-n-butyl-5-bromobenzofuran
(compound IX or III) (21.7 mmol) dissolved in 55 ml of
dioxane are then added by syringe. The reaction medium is
then stirred and heated at 100°C for 24 hours.
The reaction medium is then diluted with 4 0 ml of ethyl
acetate and the first crystallization crop is filtered
off on a Buchner funnel. After isolation of a second
crop, 3.6 g of the desired compound I are isolated in the
form of a snow-white powder.
Yield: 68%
1H NMR (400 MHz, DMSO~d6) : δ 0.91 (t, J=7.4 Hz, 3H, -CH2-
CH2-CH3) ; 1.31-1.40 (m, 2H, -CH2-CH2-CH3) ; 1 .59-1. 66 (m,
2H, -CH2-CH2-CH2-) ; 2.47 (s, 3H, CH3-SO2-) ; 2. 66 (t,
J=7.4 Hz, 2H, -CH2-CH2-Cq-) ; 6.27 (s, 1H, ArH) ; 6. 61 (dd,
J=8.8 and 2Hz, 1H, ArH) ; 6.94 (d, J=2Hz, 1H, ArH) ; 7.02
(dd, J=8.8 Hz, 1H, ArH)
13C NMR (DMSOd6); δ 157.6 - 147.2 - 147.0 - 128.6 - 117.9.
- 109.4 - 108.8 - 101.8 - 38.3 - 29.3 - 27.4 - 21.6 -
13.6 ppm

CLAIMS
1. A process for preparing 5-sulfonamidobenzofuran
derivatives of general formula:

in which R represents an alkyl or aryl group and R1
and R2, which may be identical or different, each
represent hydrogen or an alkyl or aryl group,
characterized in that a benzofuran derivative of
general formula:

in which R1 and R2 have the same meaning as
previously and X represents chlorine, bromine or
iodine or a sulfonate group of general formula:
R3-SO2-O-
III
in which R3 represents a trifluoromethane or
imidazolyl group, is coupled with a sulfonamide
derivative of general formula:

R-SO2-NH2
in which R has the same meaning as previously, in
the presence of a basic agent and of a catalytic
system formed from a complex between a palladium
compound and a ligand, which gives the desired
compounds.
2. The process as claimed in claim 1, characterized in
that R, R1 or R2 represents a linear or branched C1-C8
alkyl group or a substituted or unsubstituted phenyl
group.
3. The process as claimed in claim 1 or 2,
characterized in that R, R1 or R2 represents a linear
or branched C1-C4 alkyl group.
4 . The process as claimed in one of claims 1 to 3,
characterized in that R represents methyl, R1
represents n-butyl and R2 represents hydrogen.
5. The process as claimed in one of claims 1 to 4,
characterized in that the palladium compound is
bis(dibenzylideneacetone)palladium(0),
6. The process as claimed in one of claims 1 to 4,
characterized in that the palladium compound is
tris(dibenzylideneacetone)dipalladium (0).
7. The process as claimed in one of claims 1 to 6,
characterized in that the ligand is 2-(di-tert-
butylphosphino)-2',4',6'-triisopropyl-1,1'-biphenyl.

8. The process as claimed in one of claims 1 to 7,
characterized in that the basic agent is an alkali
metal phosphate or an alkali metal carbonate.
9. The process as claimed in claim 8, characterized in
that the basic agent is tripotassium phosphate,
potassium carbonate or cesium carbonate.
10. The process as claimed in one of claims 1 to 9,
characterized in that the coupling is performed at a
temperature of between 60°C and 120°C.
11. The process as claimed in one of claims 1 to 10,
characterized in that the coupling is performed in a
solvent chosen from an alcohol, an ether and an
aromatic hydrocarbon.
12. The process as claimed in claim 11, characterized in
that the solvent is dioxane.
13. A benzofuran derivative of general formula:

in which R' 3 represents a trifluoromethane or
imidazolyl group.
14. The benzofuran derivative as claimed in claim 13, in
which R'3 represents a trifluoromethane group.
15. The benzofuran derivative as claimed in claim 13,
in which R'3 represents an imidazolyl group.