Process for preparation of dronedarone by N-butylation
FIELD OF THE INVENTION
This invention relates to a novel process for the preparation of dronedarone and
pharmaceutically acceptable salts thereof, to novel intermediary compounds used in this process
and their preparation.
TECHNICAL BACKGROUND
Dronedarone is a known drug for the treatment of arrhythmia and has the chemical name
of N-[2-n-butyl-3-[4-[3-(di-n-butylamino)propoxy]benzoyl]benzofuran-5-yl]methanesulfonamide
[see also formula (I) below]. There are some known processes for the preparation of
dronedarone as follows:
In EP 0471609 the following scheme is disclosed for the preparation of dronedarone
[Process A]

The novelty of the process is based on the adaptation of the Friedel-Crafts reaction in the
first step. The process and the intermediary compounds used for the preparation of the
benzoylchloride compound of the first step are disclosed, too, in this document. The further steps
of the process are identical with the final steps of the synthetic route disclosed in EP 0471609
[Process A], but in the claims the whole synthetic route is claimed, up to dronedarone.
In WO 02/48132 (Sanofi) the following reaction route is disclosed [Process C]. This
method route. In the first step of it 5-amino-2-butyl-benzofuran
is mesylated and the obtained 2-butyl-5-methanesulfonamido-benzofuran (in HC1 salt
form) is further reacted in the next step as follows:
In this process the order of reaction steps are altered, the reduction and the
methansulfonylation steps are performed at the beginning of the procedure. Besides the reaction
route for preparation of dronedarone, the starting material 2-butyl-5-methansulfonamidobenzofuran
and its preparation is also claimed.
From among the mentioned procedures the first one [Process A] is the so called linear
synthesis. In this way of procedure the different parts of the dronedarone are stepwise built up on
the starting compound. This method is the least economical because the step by step building of
the chemical groups is performed where more and more complicated and expensive molecules
are applied which rises the costs of preparation. Furthermore, it comprises complicated and
dangerous reaction step because aluminium chloride is used in the cleaving reaction of the
methoxy group which makes the industrial feasibility more complicated.
In WO 02/48078 (Process B) a shorter synthetic route is disclosed which makes this
process more economical, but its last reaction step remained the methansulfonylation reaction of
the amino group. This reaction step (see the method described in example 6 of of WO 02/48078)
is complicated and give a low yield, only 61.6 %. Pure product can be obtained after purification
using chromatographic column purification, which method is necessary because of the separation
difficulties of the bis-methanesulfonylated product.
The process disclosed in WO 02/48 132 (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.HCl (hydrochloride salt) 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 hydrochloride salt is 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 hydrogen chloride gas dissolved in isopropanol which results in pure dronedarone
hydrochloride salt. No yield was given for this reaction step. According to example 5 crude
dronedarone hydrochloride salt was prepared with a yield of 90%, which was washed with water
and reacted with hydrogen chloride gas dissolved in isopropanol, resulting dronedarone
hydrochloride salt again. The quality of this product is not known. However, neither the
components used in the Friedel-Crafts reaction nor the resulted products and by-products are
soluble in water, the washing step with water cannot result any purification apart from the
removal of inorganic salts.
There is another drawback of this process, namely, a dimesylated side-product is formed
in the mesylation reaction of the 5-amino-2-butyl-benzofuran. The purification is carried out by
crystallization which has a yield of 78.5 %.
It is an object of the present invention to provide a novel process for the preparation of
dronedarone of formula (I), starting with known and commercially available materials, applying
simple and environmentally compatible reagents and solvents to afford high overall yields and
good purity of the product.
SUMMARY OF THE INVENTION
The main aspect of the invention is a process for the preparation of dronedarone (I) and
pharmaceutically acceptable salts thereof
which comprises reacting the compound of formula (II) or salt thereof
and inorganic esters of butanol. We have found surprisingly that compounds of formula (III) can
be connected to the amino group of the compound of formula (II) in a way where connection
takes part only on the free amino group [see the "right" side of formula (II)] and not on the
sulphonamide group [see the "left" side of formula (II)].
Compounds of formula (III) can be purchased or can be prepared by known methods (J.
of Steroid Biochemistry and Molecular Biology 80, (2002), 429-440; Synthesis (1979, 882).
Starting materials of formula (III) are also known from EP 0471609 and compound of formula
(X) from WO 02/48 132.
Further aspects of the invention are the novel intermediary compounds and the methods
for the preparation thereof (see below in the "Detailed description of the invention" part).
DETAILED DESCRIPTION OF THE INVENTION
Therefore the present invention relates to a process for the preparation of dronedarone
and pharmaceutically acceptable salts thereof. The whole process - starting from compounds
available commercial sources - reads as follows:
A) For the preparation of compounds of formula (V)
(V)
the compound of formula (X)
(X)
is reacted with com ound of formula (XI)
(XI)
under Friedel-Crafts reaction conditions, where Pg is amino protecting group, typically an
A-CO- group, where A is alkyl, alkoxy, aryl or aryloxy group, e.g. it is ethoxycarbonyl.
The reaction is carried out halogene a d/or nitro group containing solvents, e.g.
dichloromethane, dichloroethane, chlorobenzene, nitromethane, nitrobenzene. Catalyst also can
be applied, e.g. A1C13, FeCl 3 ,SnCl 4, TiCl .
Compound (II) can be prepared from the above compound (V) by removing Pg (see
below).
Another way for the preparation of compound (II) reads as follows:
(VII)
a compound of formula (VIII)
(VIII)
is reacted with acrylonitrile of formula of CH =CH-CN (IX).
Compound (VIII) is known from EP 0 471 609 (Sanofi).
Typically the reaction is carried out in a solvent (which can be e.g. a alcohol,
typically methanol or ethanol), and typically a strong basic catalyst is applied. This catalyst is
. • 7
selected typically from the group of alkali alkoxydes and quaternary ammonium hydroxides, and
it can be e.g. benzyltrimethylammonium hydroxide.
Typically the reaction is carried out in the excess of acrylonitrile as solvent at the boiling
point of the solvent, e.g. about 70 to 90 °C . Typically strong water free ammonium quaternary
hydroxides or alkali alkoxydes can be applied as catalyst.
C) For the preparation of compound of formula (VI)
an above compound of formula (VII) is hydrogenated.
The reaction is carried out among usual hydrogenation conditions. For example, the
hydrogenation process is carried out in a solvent in the presence of catalyst, e.g. Pd or Pt catalyst,
typically Pd/C. Typically the solvent is selected from the group of Ci-4 alcohols, ethyl acetate
and cyclohexane, e.g. the solvent is methanol or ethanol.
D) For the preparation of compound of formula (IV)
an above compound of formula (VI) is mesylated.
Typically the reaction is carried out in an indifferent solvent, typically in the presence of
an acid binding agent. In a practical embodiment the solvent is selected from the group of
dichloromethane, dichloroethane and chlorobenzene. Typically the. acid binding agent is a
tertiary nitrogen base, for example pyridine or triethylamine.
In the process a mesylating reagent should be applied. It can be any reagent which can be
used for inserting a CH3SO2- group into the free amino group of compound of formula (VI). It is
practical to use methanesulfonic anhydride or methanesulfonyl halogenide, e.g. methanesulfonyl
chloride.
the above compound of formula (IV) is hydrogenated.
The reaction is carried out among usual hydrogenation conditions. For example the
hydrogenation process is carried out in a solvent in the presence of catalyst, e.g. Ni catalyst,
which is typically Raney-Ni. Typically the solvent is selected from the group of C1-4 alcohols,
ethyl acetate and cyclohexane; e.g. the solvent is methanol or ethanol.
E ) Alternatively, compound of formula (II) can be prepared from another starting
alka ne y ro ys s (see e.g. the o ow ng oo : P p J. Koc ens t, rotect ng roups, .
as
a base and, if desired, converted it into a pharmaceutically acceptable salt thereof.
Typical meanings of L are selected from the group of halogen, methanesulfonyloxy,
trifluoromethanesulfonyloxy and benzenesulfonyloxy, optionally substituted with halogen, alkyl,
alkoxy, nitro or protected amino group. '
In another embodiment the reaction step F is carried out in a solvent (or solvent mixture),
optionally in the presence of a base and/or catalyst. In another embodiment the reaction is carried
out in a solvent and both base and catalyst is applied.
The above solvent typically is selected from the group of ketones, alcohols, esters,
amides, ethers, dimethylsulfoxide and aromatic solvents and any mixtures thereof. In a specific
embodiment the solvent is a ketone, e.g. acetone or methylethylketone. In another embodiment
the solvent is an alcohol, e.g. methanol, ethanol, isopropanol or n-butanol.
Typically the reaction is carried out in the presence of a base, which can be selected from
the group of nitrogen-containing bases, e.g. from the group of pyridine, 2-methyl pyridine and
triethylamine.
In another embodiment L is halogen, e.g. chlorine, and the reaction is carried out in the
presence of a catalyst, which can be selected from the group of alkyl iodides, e.g. it is sodium
iodide.
The temperature applied in the reaction is typically between 0 °C and the boiling point of
the solvent (which can be a solvent mixture, as it was mentioned above), e.g. between 60-120°C.
Typically the atmospheric pressure is applied during the reaction.
The applicable acid for the preparation of pharmaceutically acceptable salts can be any
inorganic or organic acid which forms an acid addition salt with the compound of general
formula (I). Exemplary acids which can form an acid addition salt are as follows: acetic acid,
adipic acid, alginic acid, ascorbic acid, aspartic acid, benzoic acid, benzenesulfonic acid,
methansulfonic acid, ethansulfonic acid, boric acid, butyric acid, citric acid, , fumaric acid,
hydrogen chloride, hydrogen bromide, hydrogen iodide, -hydroxyethanesulfonic acid, maleic
acid, oxalic acid, , nitric acid, salicylic acid, tartaric acid, sulfuric acid (forming sulfate or
bisulfate anion), sulfonic acid (such as those mentioned herein), succinic acid, toluenesulfonic
aci and the like. The hydrogen halogenide salts are typical, especially the hydrogen chloride
salt.
Here it is mentioned that on the mesylate group of compound of general formula (I) (see
the "left side" of the molecules) a salt formation can be carried out (on the amide part of it) by a
strong base, e.g. an alkaline hydroxide, typically by sodium hydroxide. However, these salts
have less practical importance, but they are within the scope of salts. It means that the phrase
"salts" embraces both the acid addition salts and the salts formed by bases (basic salts) in case of
compounds of general formula (I).
As it was mentioned above the further starting materials are commercially available or
can be prepared by applying known synthetic ways, e.g. as it is given in the relating examples 10
to 13.
Other objects of the invention are the novel intermediary compounds applied
processes, namely the following compounds:
' - Com ound of formula (II) and salts thereof
( )
(V)
where Pg is an amino protecting group, typically an A-CO- group, where A is alkyl,
alkoxy, aryl or aryloxy group, e.g. it is ethoxycarbonyl.
- Compound of formula (VI) and salts thereof
- Compound of formula (VII)
(VII)
novel
. - (IV)
is hydrogenated or .
b) a compound of formula (V).
(V)
is deprotected, where Pg is an amino protecting group.
The hydrogenation and the deprotection can be carried out as it was disclosed above in
point E) and in point E'), respectively.
- Process for preparation of compound of formula (IV) and salts thereof where the
compound of formula (VI)
nButyl
(VI)
is mesylated.
The mesylation can be carried out is as it was disclosed above in point D).
- Process for preparation of compounds of formula (V) and salts thereof where the
compound of formula (X)
is reacted with a compound of formula (XI)
(XI)
under Friedel-Crafts reaction conditions, where Pg is amino protecting group, typically an
A-CO- group, where A is alkyl, alkoxy, aryl or aryloxy group, e.g. it is ethoxycarbpnyl.
The reaction can be carried out is as it was disclosed above in point A).
- Process for preparation of compound of formula (VI) and salts thereof, where the
compound of formula (VII)
is hydrogenated.
The hydrogenation can be carried out is it was disclosed above in point C).
- Process for preparation of compound of formula (VII), where the compound of formula
(VIII)
(VIII)
is reacted with acrylonitrile of formula CH2=CH-CN (IX).
The reaction can be carried out is it was disclosed above in point B).
In the processes for the preparation of the intermediary compounds the product is isolated
as a base typically (if the compound has a free amino or an alkylated amino group). If desired,
the isolated base can be converted into a salt (acid adition salt) thereof, which is typically a
pharmaceutically acceptable salt [the possible acids are mentioned in point F)]. Theoretically the
acid addition salt can be prepared directly if the relating acid is in the final reaction mixture from
which the solid product is made (however, this way is not applied in case of these compounds
where the base type form has practical importance).
Here it is mentioned that some of the above intermediary compounds have a mesylate
group (see the "left side" of the molecules) where a salt formation can be carried out (on the
amide part of it) by a strong base, e.g. an alkaline hydroxide, typically by sodium hydroxide.
However, these salts have less practical importance, but they are within the scope of salts which
can be prepared by the claimed process, i.e. the phrase "salts" embraces the salts formed by
bases (basic salts) in such cases (where the molecule has a mesylate group).
In the above reactions the temperature is chosen according to the general practice of a
person skilled in organic chemistry. Typically the temperature is between 10 °C and the boiling
point of the applied solvent (which can be the mixture of the mentioned solvents in a specific
embodiment). Applicable temperature values can be found in the examples.
All the above reactions are carried out under atmospheric pressure with the exception of
the hydrogenation steps where higher pressure also can be applied, typically up to 20 bar, e.g. 5
to 10 bar.
As used herein, the term alkyl includes straight or branched aliphatic hydrocarbon chains
of 1 to 6 carbon atoms, e.g., methyl, ethyl, isopropyl and t-butyl.
As used herein, the terni "alkoxy" includes alkyl-O- groups. Non-limiting examples of
suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy!
As used herein, the term "aryl" includes aromatic monocyclic or multicyclic ring systems
comprising 6 to about 14 carbon atoms, preferably 6 to about 10 carbon atoms. Non-limiting
examples of suitable aryl groups include phenyl and naphthyl.
As used herein, the term "aryloxy" includes aryl-O- groups.
As used herein, the term „halogen" includes fluoro, chloro, bromo and iodo atoms.
Examples
- Example 1
N-[2-butyl-3- {4-[(3-dibutylamino)propoxy]benzoyl} -1-benzofuran-5-
yl]methanesulfonamide (I)
l g of N-[2-butyl-3-{4-[(3-amino)propoxy]benzoyl}-l-benzofuran-5-yl]-
methansulfonamide (II) is dissolved in 5 ml of methyl ethyl ketone. 0.18 g of pyridine and 0.34 g
of sodium iodide are added and the mixture is heated to boiling point. 0.62 g of 1-bromobutane
(III) dissolved in 1 ml of methyl ethyl ketone is added at this temperature during 1 minutes and
the mixture is boiled for 16 hours. The reaction mixture is evaporated, 20ml of water and 20 ml
of dichloromethane are added. The organic phase is washed with 5 ml of 5 % NaHC0 3 solution,
separated and evaporated. The product is purified by forming its oxalate salt as follows: to the
residue 4 ml of methylethyl ketone is added and the mixture heated to70 °C . To this solution
0.24 g of oxalic acid dissolved inl. 5 ml of methylethyl ketone is added at 70° C. After cooling to
20 °C in 6 hours the mixture is stirred at 10 °C for 1 hour and filtered. To the obtained oxalate
salt 2.5 ml of water and 4 ml of dichloromethane and 0.63g of potassium carbonate are added.
After stirring for 30 minutes the separated potassium oxalate is filtered and washed with 2 ml of
dichloromethane and the solvent is evaporated.
Yield: l.lg'(88 %). Purity of the oxalate salt: 99.8 % (HPLC).
1H NMR(DMSO): 0.8-0.9 ppm (m, 9H); 1.2-1.5 ppm (m, 10H); 1.67 ppm (5', 2H); 1.87
ppm (5', 2H); 2.38 ppm (t, J=7.2 ,Hz, 4H); 2.57 ppm (m, 2H); 2.88 ppm (t, J=7.5Hz, 2H); 2.91
ppm (s, 3H); 9.51 ppm (t, J=6.2Hz, 2H); 7.09 ppm (d, J=8.8Hz, 2H); 7.24 ppm (dd, J=8.9, 2.2Hz,
lH); 7.38 ppm (d, J=2.1Hz, 1H); 7.65 ppm (d, J=8.8Hz, 1H); 7.81 ppm (d, J=8.8Hz, 2H)
Example 2
N-[2-butyl-3-{4-[(3-dibutylamino)propoxy]benzoyl}-l-benzofuran-5- -
yl]methanesulfonamide (I)
0.8 g of N-[2-butyl-3-{4-[(3-amino)propoxy] benzoyl }-1-benzofuran-5-
yl]methanesulfonamide (II) is dissolved in 5 ml of n-butanol. 0.15 g of pyridine is added and the
mixture is heated to 70 °C at this temperature 0.68 g of butyl-methanesulfohate (III) dissolved in
1ml of n-butanol is added during 15 minutes and the mixture is kept at 70 °C for 14 hours. [The
methanesulfonate is prepared according to the procedure described in J . of Steroid Biochemistry
and Molecular Biology 80 (2002) 429-440.] The reaction mixture is evaporated and 20 ml of
dichloromethane and 10 ml of water is added. The phases are separated. The organic phase is
washed with 10ml of NaHC0 3 of 5 %. The organic phase is evaporated. The product is purified
by on silica gel (ethyl acetate/hexane; 1:3 v/v ).
Yield: 0.79 g (79 %). Purity: 100 % (HPLC).
The product is identical with the compound prepared in example 1.
Example 3
N-[2-butyl-3-{4-[(3-dibutylamino)propoxy]benzoyl}-l-benzofuran-5-
yl]methanesulfonamide (I)
The process is performed according to example 2 with the difference that instead of 0.68
g of butyl methanesulfonate 1.0 g of butyl-(4-toluene-sulfonate) (III) is added [prepared
according to the method in Synthesis (1979), 11, 882]. Yield of purified product: 0.81 g (81 % ).
Purity: 100 % (HPLC).
Example 4
N-[2-butyl-3-{4-[(3-dibutylamino)propoxy]benzoyl}-l-benzofuran-5-
yljmethanesulfonamide (I)
The process is performed according to example 1 with the difference that instead of 0.15
g of pyridine 0.22 g of triethylamine is used.
Yield of purified product: 1.04 g (83 % ) . Purity: 100 % (HPLC).
Example 5
N-[2-butyl-3- {4-[(3-amino)propoxy]benzoyl} - -benzofuran-5-yl]methanesulfon-amide
( )
3.0 g of N-[2-butyl-3-{4-[2-cyanoethoxy]benzoyl}-l-benzofuran-5-
yl]methanesulfonamide (IV) is dissolved in 300 ml of methanol and 5 g of Raney-Ni catalyst is
added: The mixture is stirred at 25 °C at 10 bar H2 pressure for 24 hours. The catalyst is filtered
and the solvent is evaporated.
Yield: 2.94 g (98 % %). Purity: 75 % (HPLC).
IH NMR(DMSO): 7.77 ppm ( , J=8,7Hz, 2H); 7.59 ppm (d, J=8.70Hz, IH); 7.23 ppm (d,
J=2.06Hz, IH); 7.18 ppm (dd, J=8.81, 2.17Hz, IH); 7.07 ppm (d, J=8.7Hz, 2H); 4.14 ppm (t,
J=6.41Hz, 2H); 2.85 ppm (s, 3H); 2.80 ppm (t, J=7.10Hz, 2H); 2.71 ppm (t, J=6.75Hz, 2H); 1.82
ppm (quin, J=6.52Hz, 2H); 1.65 ppm (quin, J=7.30Hz, 2H); 1.24 ppm (5xt, J=7.32Hz, 2H); 0.80
Example 6 . .
N-[2-butyl-3-{4-[2-cyanoethoxy]benzoyl}-l-benzofuran-5-yl]methanesulfonamide (IV)
4.0 g of (5-amino-2-butyl-benzofur-3-yl)-[4-(2-cyanoethoxy)phenyl]methanon (VI) is
dissolved in 40 ml of dichloromethane. The mixture is warmed to 30-35 °C and 1.05 g of
pyridine is added at this tempereature in 5 minutes. At this temperature 1.5 g of methanesulfonyl
chloride is added in 5 minutes and the mixture is stirred at 30-35 °C for 3 hours! The mixture is
cooled to 20 °C and washed with 2 x 15 ml of water, 2 x 15 ml of NaHC0 3 of 5 % and l 15 ml
of water. The phases are separated and'the dichloromethane is evaporated.
Yield: 4.81 g (100 %). Purity: 94.8 % (HPLC). Mp.: 120.9-12 1.7°C
H NMR(DMSO): 9.6 ppm (s, IH) 7.79 ppm (d, J-8.93 Hz, 2 H) 7.62 ppm (d, J=8.93 Hz,
IH) 7.27 ppm (d, J=2.06 Hz, 1 H) 7.21 ppm (dd, J=8.70, 2.06 Hz, 1 H) 7.13 ppm (d, J=8.93 Hz,
2 H) 4.3 1 ppm (t, J=5.84 Hz, 2 H) 3.07 ppm (t, J=5.84 Hz, 2 H) 2.88 ppm (s, 3 H) 2.80 ppm (t,
J=7.44 Hz, 2 H) 1.65 ppm (quin, J=7.44 Hz, 2 H) 1.24 ppm (sxt, J=7.37 Hz, 2 H) 0.80 ppm (t,
=7.44 Hz 3 H)
Example 7
(5-amino-2-butyl-benzofur-3-yl)-[4-(2-cyanoethoxy)phenyl]methanon (VI)
1 g' of (5-nitro-2-butyl-benzofur-3-yl)-[4-(2-cyanoethoxy)phenyl]methanon (VII) is
dissolved in 15 ml of methanol and 0,1 g of 10 w/w % wet Pd/C catalyst is added and the
reaction mixture is heated to 50°C with a stirring of 800 round/min. Hydrogen pressure of 5 bar
is set in the reactor and the mixture is stirred at this temperature for 2 hours. After cooling to
room temperature the catalyst is filtered off and the solvent is evaporated.
Yield: 0.92 g (100 %). Purity (HPLC): 97.3 %.
H NMR(DMSO); 7.76 ppm (d, J=8,93Hz, 2H); 7.26 ppm (d, J=8.70Hz, IH); 7.12 ppm
(d, J=8.70Hz, 2H); 6.57 ppm (dd, J-8.70, 2.29Hz, IH); 6.49 ppm (d, J-2.29Hz, IH); 4.30 ppm (t,
J=5.84Hz, 2H); 3.06 ppm (t, J=5.84Hz, 2H); 2.73 ppm (t, J=7.55Hz, 2H); 1.62 ppm (quin,
J=7.50Hz, 2H); 1.23 ppm (sxt, J=7.28Hz, 3H); 0.80 ppm (t, J=7.32Hz, 4H)
[M+H]+
f0und=363.171 1 Da. [M+H]+
calculated=363.1709 Da.
Example 8
(5-nitro-2-butyl-benzofur-3-yl)-[4-(2-cyanoethoxy)phenyl]methanon (VII)
27.8 g of (2-butyl-5-nitrp-l-benzofur-3-yl)-(4-hydroxyphenyl)methanon (VIII), 43.5 g of
acrylonitrile and 3.8 g of Triton B (benzyltrimethylammonium hydroxide) are added and heated
under stirring to 80-85°C and stirred at this temperature for 48 hours. After cooling the reaction
mixture to room temperature it is evaporated and the acrylonitrile is recovered for the next trial.
To the residue 150 ml of dichloromethane is added and washed with 3 x 80 ml of sodium
hydroxide of 5 %. From the sodium hydroxide solution 16.2 g of starting (2-butyl-5-nitro-lbenzofur-
3-yl)-(4-hydroxyphenyl)methanon is recovered.
The dichloromethane solution is evaporated.
Yield: 12.07 g (94.2 % for the consumed starting material). Purity: 97.6 % (HPLC).
Mp.: 108.6-108.9 °C
1H NMR(DMSO): 0.80 ppm (t, J=7.44Hz, 3H); 1.24 ppm (sxt, J=7.37Hz, 2H); 1.68 ppm
(quin, J=7.50Hz, 2H); 2.84 ppm (t, J=7.55Hz, 2H); 3.07 ppm (t, J=5.95Hz, 2H); 4.33 ppm (t,
J=5.95Hz, 2H); 7.15 ppm (d, J=8,70Hz, 2H); 7.84 ppm (d, J=8.70Hz, 2H); 7.92 ppm (d, 9.84Hz,
1H); 8.22-8.28 ppm (m,2H)
Example 9
N-[2-butyl-3-{4-[(3-amino)propoxy]benzoyl}-l-benzofuran-5-yl]methanesulfonamide
( )
4.0 g of N-[2-butyl-3-{4-[(3-ethoxycarbonylamino)propoxy]benzoyl}-l-benzofuran-5-
yl]-methanesulfonamide (V) is added to 30 ml of methanol and 0.62 g of sodium hydroxide is
dissolved in it. The reaction mixture is boiled for 3 hours and the solvent is evaporated. To the
obtained solid material 20 ml of water is added and the pH of the solution is set to pH=6
with 2N HC1 solution. The separated oil is extracted with 20 ml of dichloromethane. The
dichloromethane is evaporated. The residual material is identical with compound prepared in
example 5.
Yield: 2.82 g (82 %). Purity: 79 % (HPLC).
Example 10
N-[2-butyl-3-{4-[(3-ethoxycarbonylamino)propoxy]benzoyl} l-benzofuran-5-yl]methanesulfonamide
(V)
1.6 g of N-(2-butyl-l-benzofuran-5-yl)methanesulfonamide (X) and 15 ml of
dichloromethane is stirred at room temperature for 5 minutes. To this suspension 2.4 g of 4-[(3-
carbethoxyamino)-prppoxy]benzoylchloride (XI) is added at a slow rate. The mixture is cooled
down to 5 °C and 1.21 g of Fe(III)chloride is added in 4 portions in 20 minutes at a temperature
of 5-10 °C. The mixture is stirred for additional 3 hours at 20 °C. The mixture is heated to 40-
45 °C and 27 ml of water is added in 20 minutes. The reaction mixture is stirred at this
temperature for 30 minutes. The phases are separated and the organic phase is washed with 1 x 8
ml of water, 2 x 8 ml of NaHC0 3 of 5 % and with 2 x 8 ml of water. The solvent is evaporated.
The residual material is purified with chromatography.
Yield of purified product: 2.23g (72.1 %). Purity (HPLC): 91.2 % .
p.: 155.7-156.9 C
1H NMR(DMSO): 9.57 ppm (s, 1H); 7.77 ppm (d. J=8.7Hz. 2H); 7.61 ppm (d. J=8.8Hz.
1H); 7.27 ppm (d. J=1.6Hz, lH); 7.20 ppm (dd, J=8.8, 2.1Hz, 1H); 7.17 ppm (t, 5.0Hz, 1H); 7.06
ppm (d, J=8.6Hz, 2H); 4.09 ppm (t, J=6.2Hz, 2H); 3.97 ppm (q, J=7.1Hz, 2H); 3.15 ppm (q,
J=6 2Hz, 2H); 2.88 ppm (s,3H); 2.80 ppm (t, J=7.4Hz, 2H); 1.88 ppm (5 H=6.4Hz, 2H); 1.65
ppm (5', J=7.4Hz, 2H); 1.23 ppm (6 J=7.4Hz,2H); 1,14 ppm (t, J=7.0Hz, 3H); 0.80 ppm (t,
J=7.3Hz, 3H)
Example 11
4-[(3-carbethoxyamino)propoxy]benzoic acid (XII)
0.4 g of sodium hydroxide and 1.06 g of sodium carbonate is dissolved in 8 ml of water.
1.15 g of 4-[3-aminopropoxy]benzoic acid (XIII) is added to this solution under stirring. The
mixture is cooled to 10 °C and stirred at this temperature for 1 hours. 1.09 g of ethoxycarbonyl
chloride is added in 20 minutes and the mixture is stirred at 25 °C for 3 hours. The mixture is
extracted with 25 ml of dichloromethane and the phases are separated. The pH of the aqueous
solution is set to pH=l with diluted hydrochloride acid and the precipitated white material is
stirred in the suspension formed at 10 °C for T hours and filtered, washed with. 3 x 1.0 ml of
water and dried under reduced pressure at 70 °C.
Yield: 1.28 g (81 %). Purity (HPLC): 92.8 %. Mp.: 147.9-149.1 °C.
1H NMR(DMSO): 12.6 ppm (w, 1H); 7.87 ppm (d, 8.8Hz, 2H); 7.16 ppm (t, J=5.6Hz,
1H); 6.99 ppm (d, J=8.8Hz, 2H); 4.05 ppm (t, J=6.2Hz, 2H); 3.96 ppm (q, J=7.1Hz, 2H); 3.13
ppm (q, J=6.1Hz, 2H); 1.86 ppm (5', J=6.5Hz, 2H); 1.14 ppm (t, J=7.0Hz, 3H)
Example 12
4-(3-aminopropoxy)benzoic acid HC1 salt (XIII)
24.5 g of methyl [4-3(aminopropoxy)benzoate] (XIV) is added to a aqueous solution
prepared from 8.4 g of sodium hydroxide and 33.6 ml of water. 56 ml of methanol is added
under stirring and the mixture is boiled for 6 hours. The solvent is evaporated. To the solid
residue 150 ml of water is added and the solution is extracted with 20 ml of dichloromethane.
The pH of the aqueous solution is set to pH=l with diluted hydrochloric acid. The separated
material is washed with 3 x 100 ml of water and dried under reduced pressure at 70 °C.
Yield: 23.2 g (85.8 %). Purity: 87 % (HPLC). Mp.: 270.0-279.8 °C.
Example 13
Methyl[4-(3-aminopropoxy)benzoate] (XIV)
2.1 g of methyl(2-cyanoethoxy)benzoate (XV) (prepared according to the method
disclosed in Japanese Patent Appl. No. 19660803) is dissolved in 30 ml of methanol. 0.5 g of
Raney-Ni is added and the mixture is hydrogenated at 50 °C under 10 bar of hydrogen pressure
for 4 hours. The catalyst is filtered and the solvent evaporated. The product is obtained as an oil.
[Helv. Chim. Acta, Vol. 66., Fasc. 2(1983) No. 42.]
Yield: 2.14 g (100 % ) . Purity: 84 % (HPLC).
Claims
1. Process for the preparation of dronedarone (I) and pharmaceutically acceptable salts
thereof
0 nButyl
(I)
which comprises reacting the compound of formula (II) or salt thereof
nButyl
(II)
with a compound of formula L-(CH2)3-CH3 (III), where L is a leaving group,
and the obtained product is isolated and, if desired, converted into a pharmaceutically
acceptable salt thereof.
2. Process according to claim 1, characterized in that L is selected from the group of
halogen, methanesulfonyloxy, trifluoromethanesulfonyloxy and benzenesulfonyloxy, optionally
substituted with halogen, alkyl, alkoxy, nitro or protected amino group.
3. Process according to claim 1, characterized in that the reaction is carried out in solvent
and in the presence of base and/or catalyst.
4. Process .according to claim 3, characterized in that the solvent is selected from the
group of ketones, alcohols, esters, amides, ethers, dimethylsulfoxide and aromatic solvents and
any mixtures thereof.
5. The compound of formula (II) and salts thereof
6. Process for preparation of compound of formula (II) and salts thereof
()
characterized in that
a) the compound of formula (IV)
(IV)
is hydrogenated or
b) a compound of formula (V)
is deprotected, where Pg is an amino protecting group,
and the obtained product is isolated and, if desired, converted into a pharmaceutically
acceptable salt thereof.
7. The compound of formula (IV) salts thereof
(IV)
8. Process for preparation of compound of formula (IV) and salts thereof
(IV)
characterized in that the compound of formula (VI)
(VI)
is mesylated,
and the obtained product is isolated and, if desired, converted into a pharmaceutically
acceptable salt thereof.
(V)
characterized in that the compound of formula (X)
(X)
is reacted with compound of formula (XI)
(XI)
under Friedel-Crafts reaction conditions, where Pg is amino protecting group,
and the obtained product is isolated and, if desired, converted into a pharmaceutically
acceptable salt thereof.
11. Process according to claim 10 characterized in that the reaction is carried out
indifferent solvent in presence of acid binding agent and the mesylating reagent
meth fonyl chloride.
13. Process for preparation of compound of formula (VI) and salts thereof
(VI)
characterized in that the com ound of formula (VII)
(VII)
is hydrogenated,
and the obtained product is isolated and, if desired, converted into a pharmaceutically
acceptable salt thereof.
14. The compound of formula (VII)
(VII)
characterized in that the compound of formula (VIII)
(VIII)
is reacted with acrylonitrile of formula CH =CH-CN (IX),
and the obtained product is isolated.