Novel process for the preparation of dronedarone
This invention relates to a novel process for the preparation of N-[2-n-butyl
[(3-di-n-butylamino)propoxy]benzoyl}-l-benzofuran-5-yl]-methanesulfonamide
(dronedarone) of formula I
and its pharmaceutically acceptable salts, as well as to the new intermediates of the
preparation process.
Dronedarone of the formula I is useful in the treatment of certain pathological
changes of the cardiovascular system, first of all in the treatment of angina pectoris, high
blood pressure, arrhythmia and insufficient cerebral blood flow (EP 0471609 Bl).
Presently several methods for the preparation of Dronedarone of formula I are
known. In one of the prior art methods (EP 0471609 Bl) the 2-n-butyl-5-nitro-benzofuran
of formula VIII
is reacted with anisoyl chloride under Friedel-Crafts conditions, the resulting
IX
2-n-butyl-3-(4-methoxy-benzoyl)-5-nitro-benzofuran of formula IX is then heated
presence of aluminum chloride,
to obtain the 2-n-butyl-3-(4-hydroxy-benzoyl)-5-nitro-benzofuran of formula X.
Utilization of this reaction step in industrial scale, however, involves difficulties,
because the compound of formula IX is mutagenic, and aluminum chloride is harmful to
the health. Reaction of the resulting compound of formula X with di-n-butylamino-propyl
chloride gives the 2-n-butyl-3-[4-(3-di-n-butylamino-propoxy)-benzoyl]-5-nitrobenzofuran
of formula XI,
5-amino-2-n-butyl-3-[4-(3-di-n-butylamino-propoxy)benzoyl]benzofuran of formula XII.
Finally, mesylation of the compound of formula XII leads to dronedarone of formula I .
This is a linear synthesis, where the parts of the desired molecule are built up
stepwise, using more and more complicated molecules in the consecutive steps, which is
economically unfavourable.
In the last step, the selective mesylation of the amino group of the compound of
formula XII does not take place easily, therefore the double mesylated derivative also
appears beside dronedarone of formula I . According to the literature, this process, after
purification by column chromatography, furnishes dronedarone in 61.6% yield, but the
process is complicated, not suitable for industrial application
Another process for the preparation of dronedarone is described in patent
application of publication number WO 02/48132. This super-convergent route [Process C]
consists of the following steps:
The 5-amino-2-n-butyl-benzofuran of formula XIII
XIII
is mesylated and the resulting 2-n-butyl-5-methylsulfonamido-benzofuran of formula V
is reacted under Friedel-Crafts conditions with the hydrochloride salt of the 4-[3-(di-nbutylamino)
propoxy] benzoyl chloride of formula IV
IV
to obtain the hydrochloride salt of dronedarone of formula I.
In this method the sequence of the reaction steps is changed, the reduction and the
mesylation steps are at the beginning of the synthesis.
The process disclosed in WO 02/48132 (process C) is simpler and more economical
taken into consideration the number of the reaction steps. Unfortunately, in the last
reaction step rather impure dronedarone.HC1 is formed which is the obvious consequence
of the presence of dibutylamino group in the Friedel-Crafts reaction. According to
Examples 3 and 4, the crude dronedarone hydrochloric acid is be prepared with a yield of
90% which was further purified and finally the crude dronedarone base was produced with
a yield of 86%. This base is reacted with hydrochloric gas dissolved in isopropanol which
results in pure dronedarone hydrochloric salt. No yield was given for this reaction step.
According to example 5 crude dronedarone hydrochloric salt dissolved in dichlorometane
was prepared with a yield of 90%, which was washed with water and reacted with
hydrochloric acid gas dissolved in isopropanol, resulting dronedarone hydrochloric acid
salt again. The quality of this product is not known.
Another drawback of the method is that the reactants used in the Friedel-Crafts
reaction and the obtained by-products are insoluble in water, thus they cannot be removed
from the system by aqueous washing.
Our aim was to work out a novel method for the preparation of dronedarone and its
pharmaceutically acceptable salts, which method avoids the above mentioned
disadvantages and is economical and industrially applicable.
We have found that if the acyl group of the benzofuran derivative of formula II -
where R represents Ci-4 alkyl-, C -4 alkoxy- or aryl group -,
II
is selectively cleaved, then dronedarone of formula I is obtained in good yield and in
appropriate purity.
According to our invention the cleavage of the acyl group from the compound of
formula II - where the meaning of is as defined above - is performed in an alcoholic
solvent or in the mixture of alcoholic solvents, in the presence of an alkali alcoholate,
alkali hydroxide or an inorganic acid. As for alcoholic solvent methanol, ethanol or their
mixture is applied. As for alkali alcoholate sodium- or potassium methylate, or sodium- or
potassium ethylate is applied. As for alkali hydroxide sodium- or potassium hydroxide is
applied. As for inorganic acid hydrochloric acid or sulfuric acid is applied. The reaction is
carried out at a temperature between 20 °C and the boiling point of the solvent or the
solvent mixture.
When carrying out the process according to our invention,
a/1) the 2-n-butyl-5-methylsulfonamido-benzofuran of formula V
V
is acylated with an acid halide of the general formula VI
R
VI
- where R stands for C alkyl-, C 1-4 alkoxy- or aryl group, X means halogen atom-,
or
a/2) a compound of the general formula VII
VII
- where R stands for C alkyl-, Ci-4 alkoxy- or aryl group - is mes
and
b) the thus obtained compound of the general formula III
III
- where the meaning of R is as defined above - is reacted with the hydrochloride of the 4-
(3-di-n-butylamino-propoxy)benzoyl chloride of formula IV,
nBu
IV
and
c) from the resulting benzofuran derivative of the general formula II
II
- where the meaning of R is as defined above -, the acyl group is selectively cleaved by
the method described above.
The meanings of the above mentioned substituents are :
By C alkyl group we mean a saturated, straight or branched aliphatic group
consisting of 1-4 carbon atoms, such as methyl-, ethyl-, propyl-, isopropyl-, butyl-,
isobutyl-, secondary-butyl-, tertiary-butyl group.
By CM alkoxy group we mean -0-(C M alkyl group) - where the meaning of the
Ci-4 alkyl group is defined above -, such as methoxy-, ethoxy-, propoxy-, isopropoxy-,
butoxy-, isobutoxy-, secondary-butoxy- or tertiary-butoxy group.
By halogen atom we mean chloro, fluoro, iodo or bromo atom.
By aryl group we mean phenyl or naphthyl group, which optionally may be monoor
multi-substituted with CM alkyl-, CM alkoxy- group and with halogen atom.
According to our invention the reaction of 2-n-butyl-5-methylsulfonamidobenzofuran
of formula V
with the compound of the general formula VI
O X
R
VI
- where the meanings of R and X are as defined above- is carried out in an inert organic
solvent or in the mixture of inert organic solvents. As for inert organic solvent, halogenated
organic solvents (dichloromethane, dichloroethane, chlorobenzene) may be applied.
The reaction of the compounds of the general formulae V and VI is carried out in the
presence of an acid binder. As for acid binder, tertiary amines (trialkylamine or pyridine)
can be applied.
The mesylation reaction of the compound of the general formula VII
VII
- where the meaning of R is defined above - is carried out in the presence of an inert
organic solvent or mixture of inert organic solvents. As for inert organic solvent,
halogenated organic solvents (dichloromethane, dichloroethane, chlorobenzene) are
applied.
The mesylation reaction of the compound of the general formula VII - where the meaning
of R is defined above - is carried out in the presence of an acid binder. As for acid binder,
tertiary amines (trialkylamine or pyridine) are applied.
The reaction of a compound of the general formula III
III
- where the meaning of R is defined above - with the hydrochloride of the compound of
formula IV
IV
is performed in an inert organic solvent or in the mixture of inert organic solvents. As for
inert organic solvent, halogenated organic solvents (dichloromethane, dichloroethane,
chlorobenzene) are applied.
The reaction of a compound of the general formula III and the compound of formula IV is
carried out in the presence of a Lewis-acid (iron(III) chloride or aluminum chloride). The
Lewis-acid is applied in an amount of maximum 5 equivalents.
The hydrochloride of the 4-(3-di-n-butylamino-propoxy)benzoyl chloride of formula IV
IV
and its preparation is known from the literature (EP 0471609 Bl).
The 2-n-butyl-5-methylsulfonamido-benzofuran of formula V
and its preparation is known from the literature (WO 02/048132).
The compound of the general formula VII
VII
- where R stands for methyl group - and its preparation is known from the literature
(WO03/040120).
The compounds of the general formula II
II
- where R stands for C .4 alkyl, C alkoxy or aryl group-,
the compounds of the general formula III
III
- where R stands for C | .4 alkyl, C [-4 alkoxy or aryl group-,
and
the compounds of the general formula VII
VII
- where R stands for C2-4 alkyl, C alkoxy or aryl group - are new compounds, not
described in the literature.
Further details of the invention are demonstrated by the following examples, but
the Applicant is not limiting the claims to the examples.
Example 1.
N-[2-n-butyl-3 -[4- [-3 (-di-n-buty lamino)propoxy]benzo yl] -1-benzofuran-5 -y1] -
methanesulfonamide (I)
2 g of N-[2-n-butyl-3-[4-[3(-di-n-butylamino)propoxy]benzoyl]-l-benzofuran-5-yl]-N'-
acetyl-methanesulfonamide (the compound of the general formula II, where R represents
methyl group) is dissolved in 20 ml of methanol. After complete dissolution, 1.05 g of
sodium methylate is added, the reaction mixture is heated to 60 °C and stirred at that
temperature for 2 hours. The mixture is cooled to room temperature and the solvent is
removed by evaporation. The residue is dissolved in 95 ml of dichloromethane and
washed with 2 x 30 ml of water.
After evaporation 1.74 g (94%) raw product is obtained.
Purity (HPLC): 95.7%.
The raw product is purified through its oxalate salt.
Purity of the liberated dronedarone base: 100%.
H NMR (DMSO): 0.8-0.9 (m, 9H); 1.2-1.5 ( , 10H); 1.67 (5 , 2H); 1.87 (5 2H); 2.38 (t,
J = 7.2 Hz, 4H); 2.57 (m, 2H); 2.81 (t, J = 7.5 Hz, 2H); 2.91 (s, 3H); 4.15 (t, J = 6.2 Hz,
2H); 7.09 (d, J = 8.8 Hz, 2H); 7.24 (dd, J = 8.9, 2.2 Hz, 1H); 7.34 (d, J = 2.1 Hz, 1H);
7.65 (d, J = 8.8 Hz, 1H); 7.81 (d, J = 8.8 Hz, 2H).
Example 2.
N-[2-n-butyl-3-[4-[-3(-di-n-butylamino)propoxy]benzoyl]-l-benzofuran-5-yl]-
methanesulfonamide (I)
2 g of N-[2-n-butyl-3-[4-[3(-di-n-butylamino)propoxy]benzoyl]-l-benzofuran-5-yl]- N'-
ethoxycarbonyl-methanesulfonamide (the compound of the general formula II, where R
represents ethoxy group) is dissolved in 20 ml of methanol. After complete dissolution
0.89 g of sodium hydroxide is added, the reaction mixture is heated to 65 °C, stirred at that
temperature for 2 hours, then cooled to room temperature and the solvent is removed by
evaporation. The residue is dissolved in 30 ml of dichloromethane and washed with 2 x 25
ml of water. The solvent is removed by evaporation.
Mass of the raw product: 1.68 g (94.8 %).
Purity (HPLC): 96.7%.
The raw product is purified through its oxalate salt.
Purity of the liberated dronedarone base: 100%.
The product is identical with that obtained in Example 1.
Example 3.
N-[2-n-butyl-3-[4-[-3(-di-n-butylamino)propoxy]benzoyl]-l-benzofuran-5-yl]-
methanesulfonamide (I)
2.5 g of N-[2-n-butyl-3-[4-[3(-di-n-butylamino)propoxy]benzoyl]-l-benzofuran-5-yl]-N'-
benzoyl-methanesulfonamide (the compound of the general formula II where R represents
phenyl group) is dissolved in the mixture of 20 ml of methanol and 1.15 ml of
hydrochloric acid (37%). The reaction mixture is heated to 55-60 °C, stirred at that
temperature for 3 hours, then cooled to room temperature and the solvent is removed by
evaporation. The residue is dissolved in 25 ml of dichloromethane, and then 20 ml of water
is added to it. The pH of the mixture is adjusted to 7 and the phases are separated. The
dichloromethane phase is washed with 2 x 20 ml of 5 % sodium carbonate solution, then
with 2 x 20 ml of water. The solvent is removed by evaporation.
Mass of the raw product: 2.02 g (95.8 %).
The raw product is purified through its oxalate salt.
Purity of the oxalate salt: 100%.
The product is identical with that obtained in Example 1.
Example 4.
N-[2-n-butyl-3-[4-[-3(-di-n-butylamino)propoxy]benzoyl]-l-benzofuran-5-yl]-
methanesulfonamide (I)
The procedure as described in Example 1. is followed, with the difference that potassium
methylate is used, instead of sodium methylate.
Yield: 94.5 %.
Purity (HPLC): 96.4 %.
Example 5.
N-[2-n-butyl-3 -[4- [-3(-di-n-butylamino)propoxy] benzoyl] -1-benzofuran-5 -yl] -
methanesulfonamide (I)
The procedure as described in Example 3. is followed, with the difference that instead of
hydrochloric acid solution, potassium hydroxide in methanol as solvent is used.
Yield: 94.7 %.
Purity (HPLC): 95.9 %.
Example 6.
N-[2-n-buty 1-3 -[4- [-3-(di-n-butylamino)propoxy]benzoyl] -1-benzofuran-5 -yl] -N' -acety 1-
methanesulfonamide (compound of the general formula II, where R represents methyl
group)
2 g of N-acetyl-N'-(2-n-butyl-l-benzofuran-5-yl)-methanesulfonamide (compound of the
general formula III, where R represents methyl group) is dissolved in 12 ml of
dichloromethane and 2.4 g of 4-(di-n-butylamino-propoxy)benzoyl chloride hydrochloride
(IV) is added to the solution. The reaction mixture is cooled to 5°C and in four portions,
during 15 minutes 0.98 g iron(III) chloride is added. The reaction mixture is warmed to
20 °C, stirred at that temperature for 1 hour, then warmed to 35-40 °C and 16 ml of water
is added to it. After 30 minutes of stirring the phases are separated. The dichloromethane
phase is washed at 35-40 °C with 7 ml of water, 2 x 7 ml of 5 % sodium hydrogen
carbonate solution, then again with 2 x 7 ml of water, and then it is evaporated.
Mass of the raw product: 3.78 g (97.6 %).
Purity (HPLC): 92.5 %.
NMR (DMSO): 7,83 (d, J=8.8 Hz, 2H); 7.8 l(d, J=8.7 Hz, 1H); 7.54(d, J=2.2 Hz, 1H);
7.47 (dd, J=2.2, 8.7 Hz, 1H); 7.09 (d, J=8.8 Hz, 2H); 4,15 (t, J=6.0 Hz, 2H); 3.54 (s, 3H);
2.83 (t, J=7.5 Hz, 2H); 2,.4 (m, 2H); 2.37 (t, J=7.1 Hz, 4H); 1.93 (s, 3H); 1.87 (5 J=6.6
Hz, 2H); 1.70 (5 J=7.5 Hz, 2H); 1.37 (m, 4H); 1,.8 (m, 6H); 0.86 (t, J=7.2 Hz, 6H); 0.84
(t, J=7.3 Hz, 3H).
Molar mass [M+H]+ calculated = 599,3 155 Da
[M+H]+ measured = 599,3 157 Da
Example 7.
N-[2-n-butyl-3-[4-[-3-(di-n-butyl·amino)propoxylbenzoyl]-l-benzofuran-5-yl]-N , -
ethoxycarbonyl-methanesulfonamide (compound of the general formula II. where R
represents ethoxy group)
2 g of N-ethoxy-N , -(2-n-butyl-l-benzofuran-5-yl)-methanesulfonamide (compound of the
general formula III, where R represents ethoxy group) is dissolved in 12 ml of
dichloromethane and 2.3 g of the hydrochloride of 4-(di-n-butylamino-propoxy)benzoyl
chloride (IV) is added to the solution. The reaction mixture is cooled to 5°C and in four
portions, in a period of 5 minutes 1.0 g iron(III) chloride is added. The reaction mixture is
warmed to 20 °C, stirred at that temperature for 1 hour, warmed to 35-40 °C and 16 ml of
water is added to it. After 30 minutes of stirring the phases are separated. The
dichloromethane phase is washed at 35-40 °C with 7 ml of water, 2 x 7 ml of 5 % sodium
hydrogen carbonate solution, and again with 2 x 7 ml of water, then evaporated.
Mass of the raw product: 3.7 g (95.1 %).
Purity (HPLC): 93.7 %.
NMR (DMSO): 7.82 (d, J=8.8Hz, 2H); 7.74 (d, J=8.7Hz, 1H); 7.46 (d, J=2.2Hz, 1H);
7.38 (dd, J = 2.3, 8.7 Hz, 1H); 7.09 (d, J=8.8 Hz, 2H); 4.21 (q, J = 7.2 Hz, 2H); 4. 15 (t,
J=6.1 Hz, 2H); 3.59 (s, 3H); 2.81 (t, J = 7.6 Hz, 2H); 2.53 (m, 2H); 2.37 (t, J = 7.2 Hz,
4H); 1.87 (5',J = 6.5 Hz, 2H); 1.70 (5 J = 7.4 Hz, 2H); 1.36 (m, J=6.5 Hz, 4H); 1.27 (m,
6H); 1.18 (t, J=7.0 Hz, 3H); 0.85 (t, J=7.3 Hz, 6H) 0.83 (d, J=7.3Hz, 3H).
Molar mass [M+H calculated = 629,3260 Da
[M+H]+ measured = 629,325 1 Da
Example 8.
N-[2-n-buty 1-3 -[4- [-3 -(di-n-buty lamino)propoxy] benzoyl] -1-benzofuran-5 -yl] -NT -benzoy 1-
methanesulfonamide (compound of the general formula II. where R represents phenyl
group)
2.5 g of N-benzoyl-N'-(2-n-butyl-l-benzofuran-5-yl)-methanesulfonamide (compound of
the general formula III, where R represents phenyl group) is dissolved in 16 ml of
dichloromethane and 2.5 g of the hydrochloride of 4-(di-n-butylamino-propoxy)benzoyl
chloride (IV) is added to the solution. The reaction mixture is cooled to 5°C and in four
portions, in a period of 15 minutes 0.9 g aluminum chloride is added. The reaction mixture
is warmed to 35-40 °C and 20 ml of water is added to it. After 30 minutes of stirring the
phases are separated. The dichloromethane phase is washed at 35-40 °C with 10 ml of
water, 2 x 10 ml of 5 % sodium hydrogen carbonate solution, then again with 2 x 10 ml of
water, then evaporated.
Mass of the raw product: 4.42 g (99 %).
Purity (HPLC): 94.5 %.
Molar mass [M+H]+ calculated = 661 ,33 11 Da
[M+H]+ measured = 661,3310 Da
Example 9.
N-[2-n-buty 1-3 -[4- [-3-(di-n-butylamino)propoxy] benzoyl] -1-benzofuran-5 -yl] -N -
ethoxycarbonyl-methanesulfonamide (compound of the general formula II. where R
represents ethoxy group)
The procedure as described in Example 7. is followed, with the difference that
chlorobenzene is used as solvent, instead of dichloromethane, and aluminum chloride is
used as Lewis acid, instead of iron(III) chloride.
Yield: 93.7 %.
Purity (HPLC): 95.7 %.
Example 10.
N-acetyl-N , -(2-n -butyl- l-benzofuran-5- n - methanesulfonamide (compound of the
general formula HI. where R represents methyl group)
10 g of (2-n-butyl-benzofuran-5-yl)-methanesulfonamide (V) is dissolved in 50 ml
dichloromethane. The reaction mixture is cooled to 10 °C and 5.5 g of pyridine is added.
To the resulting clear solution 5.73 g of acetyl chloride (compound of the general formula
VI, where R represents methyl group, X represents chloro atom) is added at 10 °C, in a
period of 30 minutes, and the mixture is stirred at that temperature for 1 hour. The reaction
mixture is allowed to warm to room temperature and stirred for 4 hours. The
dichloromethane suspension is washed with 2 x 100 ml water, the phases are separated
and the dichloromethane phase is evaporated.
Mass of the raw product: 12.9 g.
Purity (HPLC): 98 %.
H NMR (DMSO-d 6): 7.68 (d, J = 2.1 Hz, 1H); 7.64 (d, J = 8.6 Hz, 1H); 7.32 (dd, J = 8.5
Hz; 2.2 Hz , 1H); 6.7 (s, 1H); 3.57 (s, 3H); 2.84 (t, J = 7.5 Hz, 2H); 1.93 (s, 3H); 1.72 (5
J = 7.5 Hz, 2H); 1.42 (6 J = 7.5 Hz, 2H); 0.96 (t , J = 7.6 Hz, 6H).
Molar mass [M+H]+ calaculated = 3 10,1 113 Da
[M+H]+ measured = 3 10, 096 Da
Example 11.
N-ethoxycarbonyl-N , -(2-n -butyl- l-benzofuran-5-vD- methanesulfonamide (compound of
the general formula III, where R represents ethoxy group)
5 g of (2-n-butyl-benzofuran-5-yl)-methanesulfonamide is dissolved in 38 ml of
dichloromethane. The reaction mixture is cooled to 10 °C and 4.0 g of pyridine is added.
To the resulting clear solution 5.38 g of ethyl chloro formate (compound of the general
formula VI, where R represents ethoxy group, X represents chloro atom) is added at 10 °C,
in a period of 30 minutes. The mixture is stirred at that temperature for 1 hour, then
allowed to warm to room temperature and stirred at room temperature for 2 hours. The
dichloromethane suspension is washed with 2 x 50 ml of water, 1 x 50 ml of 5 % sodium
hydrogen carbonate solution, then again with 1 x 50 ml of water, and evaporated.
Mass of the residue: 6 g.
To this residue 15 ml of isopropanol is added and the mixture is heated to reflux
temperature. From the resulting clear solution white crystalline material precipitates upon
cooling.
Mass of the raw product: 5.3 g (84 %).
Melting point: 97.2 °C.
Purity (HPLC): 100 %.
1H NMR (DMSO-d 6): 7.58 (d, J = 1.9 Hz, 1H); 7.57 (d, J = 9.0 Hz, 1H); 7.22 (dd, J = 8.5
Hz, 2.2 Hz , 1H); 6.67 (d, J = 0.3 Hz, 1H); 4.22 (q, J = 7.1 Hz, 2H); 3.61 (s, 3H); 2.83 (t, J
= 7.4 Hz, 2H); 1.72 (5 J = 7.5 Hz, 2H); 1.41 (6 J = 7.5 Hz, 4H); 1.17 (t, J = 7,1 Hz,
3H); 0.96 (t, J = 7.4 Hz, 3H).
Molar mass [M+H]+ calculated = 340, 12 1 Da
[M+H]+ measured = 340,1216 Da
Example 12.
N-benzoyl-N'-(2-n -butyl- l-benzofuran-5-yl)- methanesulfonamide (compound of the
general formula III, where R represents phenyl group)
2 g of (2-n-butyl-benzofuran-5-yl)-methanesulfonamide (V) is dissolved in 15 ml of
dichloromethane. The reaction mixture is cooled to 10 °C and 1. 1 g of pyridine is added,
then at 10 °C, in a period of 30 minutes 1.96 g of benzoyl chloride (compound of the
general formula VI, where R represents phenyl group, X represents chloro atom) is added
and the mixture is stirred at that temperature for 5.5 hours. The reaction mixture is washed
with 2 x 20 ml of water, 1 x 20 ml of 5 % sodium hydrogen carbonate solution, again with
1 x 20 ml of water and evaporated.
Mass of the raw product: 2.8 g (100 %).
Purity (HPLC): 98 %.
Ή NMR (DMSO-d 6): 7.63 (d, J=1.7 Hz, 1H); 7.57 (d, J=7.3 Hz, 2H); 7.47 (d, J=8.6 Hz,
1H); 7.37 (t,J = 7.1 Hz, 1H); 7.3 (m, 3H); 6.60 (s, 1H); 3.59 (s, 3H); 2.76 (t, J = 7.5 Hz,
2H); 1.66 (5 J = 7.4 Hz, 2H); 1.37 (5 J=7.4 Hz, 2H); 0.92 (t, J=7.4 Hz, 3H).
Molar mass [M+H]+ calculated = 372,1270 Da
[M+H]+ measured = 372,1281 Da
Example 13.
N-acetyl-N , -(2-n -butyl- l-benzofuran-5-yP- methanesulfonamide (compound of the
general formula III, where R represents methyl group)
2 g of (2-n-butyl-benzofuran-5-yl)-acetamide (compound of the general formula VII,
where R represents methyl group) is dissolved in 20 ml of dichloromethane. The reaction
mixture is heated to 30-35 °C and at first during 15 minutes 0.76 mg of pyridine, then
during 30 minutes 1.1 g of methanesulfonyl chloride are added. The reaction mixture is
stirred at 30-35 °C for 5 hours, then washed with 1 x 15 ml of water, 1 x 15 ml of 5 %
hydrochloric acid solution, and again with 1 x 15 ml of water, then evaporated.
Mass of the product: 2.2 g (82.9 %).
Purity (HPLC): 92.1 %.
The product is identical with that obtained according to Example 10.
Example 14.
N-ethoxycarbonyl-N , -(2-n -butyl- l-benzofuran-5-yl)- methanesulfonamide (compound of
the general formula III, where R represents ethoxy group)
2.2 g of (2-n-butyl-benzofuran-5-yl)ethoxycarbonylamide (compound of the general
formula VII, where R represents ethoxy group) is dissolved in 20 ml of dichloromethane.
The reaction mixture is heated to 30-35 °C and at first during 15 minutes 0.83 mg of
pyridine, and then during 30 minutes 1.3 g of methanesulfonyl chloride is added. The
reaction mixture is stirred at that temperature for 4.5 hours, and then it is washed with 1 x
15 ml of water, 1 x 15 ml of 5 % hydrochloric acid solution, again with 1 x 15 ml of water,
and then evaporated.
Mass of the product: 2.4 g (84.2%)
The product is recrystallized from 5 ml of isopropanol.
Yield: 82.7 %.
The product is identical with the compound obtained according to Example 11.
Example 15.
N-benzoyl-N'-(2-n -butyl- l-benzofuran-5-yl)- methanesulfonamide (compound of the
general formula III, where R represents phenyl group)
1.8 g of 2-(2-n-butyl-benzofuran-5-yl)-benzamide (compound of the general formula VII,
where R represents phenyl group) is dissolved in 19 ml of dichloromethane. The reaction
mixture is heated to 30-35 °C and at first during 15 minutes 0.53 mg of pyridine, and then
during 30 minutes 0.78 g of methanesulfonyl chloride is added.
The reaction mixture is stirred at 30-35 °C for 6 hours, then washed with 1 x 15 ml of
water, 1 x 15 ml of 5 % hydrochloric acid solution, and again with 1 x 1 ml of water, then
evaporated.
Mass of the product: 2.1 g (92 %).
Purity (HPLC): 94.7 %.
The product is identical with the compound obtained according to Example 12.
Example 16.
N-benzoyl-N'-(2-n -butyl- l-benzofuran-5-yD- methanesulfonamide (compound of the
general formula III, where R represents phenyl group)
The procedure as described in Example 15. is followed, with the difference that
triethylamine is used, instead of pyridine.
Yield: 92.9 %.
Purity (HPLC): 95.2 %.
The product is identical with the compound obtained according to Example 15.
Example 17.
2-n-butyl-benzofuran-5-yl)ethoxycarbonylamide (compound of the general formula VII,
where R represents ethoxy group)
1 g of 5-amino-2-n-butyl-benzofuran is dissolved in 10 ml of dichloromethane and at first
0.46 g pyridine dissolved in 1 ml of dichloromethane is added dopwise in 5 minutes at
room temperature, then 0.63 g of ethyl chloroformate in 1 ml of dichloromethane in 30
minutes at room temperature. The dichloromethane solution is washed with 1 x 15 ml of
water, 1 x 15 ml of 5% sodium hydrocarbonate solution, 1 x 15 ml of water, 1 x 5 ml of
5% hydrochloric acid solution and 1 x 15 ml of water, and then it was evaporated.
Mass of the product: 1.0 g (73%). It crystallizes while standing.
Purity (HPLC): 98.1%
Melting point: 59.9-60.7 °C
HNM (DMSO) 0.91 (t, J=7.32 Hz, 3H); 1.25 (t, J=7.10 Hz , 3H); 1.35 (sxt, J=7.42 Hz,
2H); 1.65 (quin, J=7.50 Hz, 2H); 2.72 (t, J=7.55 Hz, 2H); 4.12 (q, J=7.10 Hz. 2H); 6.52 (s,
1H); 7.24 (dd, J=8.70 Hz, 1H); 7.37 (d, J=8.70, 1.37 Hz, 1H); 7.67 (br.s.lH).
Example 18.
2-(2-n-butyl-benzofuran-5-yl)benzamide (compound of the general formula VII. where R
represents phenyl group)
1 g of 5-amino-2-n-butyl-benzofuran is dissolved in 10 ml of dichloromethane and at first
0.46 g pyridine dissolved in 1 ml of dichloromethane is added dropwise in 5 minutes at
room temperature, then 0.98 g of benzoyl chloride is added in 1 ml of dichloromethane in
30 minutes at room temperature. The dichloromethane solution is washed with 1 x 15 ml of
water, with 1 x 15 ml of 5% sodium hydrocarbonate solution with 1 x 15 ml of water with
1 x 15 ml of 5% hydrochloric acid solution and with 1 x 15 ml of water, and then it was
evaporated.
Mass of the product: 1.39 g (89.6%)
Purity (HPLC): 97.5%
Melting point: 116.6-1 18.0°C
'HNMR (DMSO) 0.92 (t, J=7.32 Hz, 3H); 1.38 (sxt, J=7.42 Hz , 2H); 1.68 (quin, J=7.50
Hz, 2H); 2.76 (t, J-7.55 Hz, 2H); 6.60 (s, IH); 7.46 (d, J=8.70 Hz, IH); 7.51-7.56 (m, 3H);
7.59 (tt, J=7.32, 2.00 Hz, IH); 7.98 (d, J=7.10 Hz, 2H); 8.02 (d, J=1.83 Hz, IH).
Claims
1. Process for the preparation of N-[2-n-butyl-3-(4-[(3-di-n-butylamino)-
propoxy]benzoyl}benzofuran-5-yl]-methanesulfonamide of formula I
and pharmaceutically acceptable salts thereof c h a r a c t e r i z e d i n t h a t, the acyl
group of the benzofuran derivative of the general formula II
II
where R represents C alkyl-, C 1-4 alkoxy- or aryl group - is selectively cleaved
and if desired, the resulting compound of formula I is transformed into its salt.
2. The process as defined in claim 1. c h a r a c t e r i z e d i n t h a t, the reaction
is carried out in an alcoholic organic solvent or in the mixture of alcoholic organic solvents.
3. The process as defined in any of claims 1-2 c h a r a c t e r i z e d i n t h a t,
the reaction is carried out in the presence of an alkali alcoholate.
4. The process as defined in any of claims 1-2 c h a r a c t e r i z e d i n t h a t,
the reaction is carried out in the presence of an alkali metal- or alkali earth metal hydroxide.
5. The process as defined in any of claims 1-2 c h a r a c t e r i z e d i n t h a t,
the reaction is carried out in the presence of an inorganic acid.
6. The process as defined in any of claims 1-5. c h a r a c t e r i z e d i n t h a t,
the reaction is carried out at a temperature between 20°C and the boiling point of the
applied solvent or solvent mixture.
7. The process as defined in any of claims 1-6. c h a r a c t e r i z e d i n t h a t,
a) the 2-n-butyl-5-methylsulfonamido-benzofuran of formula V
is reacted with an acid halide of the general formula VI
VI
where R represents C alkyl-, C alkoxy- or aryl group, and X represents halogen atom
and
b) the thus obtained compound of the general formula III
III
- where R represents C alkyl-, CM alkoxy- or aryl group - is reacted in the presence of a
Lewis-acid with the hydrochloride of the 4-(3-di-n-butylamino-propoxy)benzoyl chloride
of formula IV,
nBu
IV
and
c) from the resulting benzofuran derivative of the general formula II
- where R represents C alkyl-, CM alkoxy- or aryl group - the acyl group is selectively
cleaved, and if desired, the thus obtained compound of formula I is transformed into its salt.
8. Step a) of the process defined in claim 7. c h a r a c t e r i z e d i n t h a t, the
reaction is carried out in an inert organic solvent or in the mixture of inert organic solvents.
9. Step a) of the process defined in claim 7. c h a r a c t e r i z e d i n t h a t, the
reaction is carried out in the presence of an acid binder.
10. Step b) of the process defined in claim 7. c h a r a c t e r i z e d i n t h a t, the
reaction is carried out in an inert organic solvent or in the mixture of inert organic solvents.
11. The process as defined in any of claims 1-6. c h a r a c t e r i z e d i n t h a ,
a) a compound of the general formula VII
VII
- where R represents C !-4 alkyl-, C alkoxy- or aryl group - is mesylated,
and
b) the resulting compound of the general formula III
III
- where R represents C 1-4 alkyl-, CM alkoxy- or aryl group - is reacted in the presence of a
Lewis-acid with the hydrochloride of the 4-(3-di-n-butylamino-propoxy)benzoyl chloride
of formula IV,
IV
and
c) from the thus obtained benzofuran derivative of the general formula II
II
- where R represents C1-4 alkyl-, Ci-4 alkoxy- or aryl group - the acyl group is selectively
cleaved, and if desired, the resulting compound of formula I is transformed into its salt.
12. Step a) of the process defined in claim 11. c h a r a c t e r i z e d i n t h a t, the
reaction is carried out in an inert organic solvent or in the mixture of inert organic solvents.
13. Step a) of the process defined in claim 11. c h a r a c t e r i z e d i n t h a t, the
reaction is carried out in the presence of an acid binder.
14. Step b) of the process defined in claim 11. c h a r a c t e r i z e d i n t h a t,
the reaction is carried out in an inert organic solvent or in the mixture of inert organic
solvents.
The compounds of the general formula II
II
- where R represents Ci-4 alkyl-, C alkoxy- or aryl
16. The compounds of the general formula III,
III
- where R represents C1-4 alkyl-, C1.4 alkoxy- or aryl group.
17. The compounds of the general formula VII,
VII
- where R represents C alkyl-, C alkoxy- or aryl group.