Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2003-06-10
2004-12-07
Trinh, Ba K. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S462000, C549S467000, C549S469000
Reexamination Certificate
active
06828448
ABSTRACT:
The present invention relates, in a general way, to a (methanesulfonamido)benzofuran derivative, to its method of preparation and to its use as a synthesis intermediate.
More precisely, the subject of the invention is 2-butyl-5-(methanesulfonamido)benzofuran of formula:
This compound has proved particularly useful as an intermediate product for the final preparation of (aminoalkoxybenzoyl)benzofuran derivatives, in particular of 2-butyl-3-(4-[3-(dibutylamino)propoxy]-benzoyl)-5-(methanesulfonamido)benzofuran commonly called dronedarone and its pharmaceutically acceptable salts.
This (methanesulfonamido)benzofuran derivative and its pharmaceutically acceptable salts have been described in patent EP0471609 as well as its therapeutic applications. In the cardiovascular field, this compound has proved particularly useful especially as an antiarrhythmic agent.
There has been reported in patent EP0471609, mentioned above, a method for preparing 3-[4-(aminoalkoxy)benzoyl]benzofuran or benzo[b]thiophene derivatives by attaching an aminoalkoxybenzoyl chain to a benzofuran or benzo[b]thiophene derivative, according to which method there is first added to the benzofuran or benzo[b]thiophene derivative in question a benzoyl group containing in the para position an oxygen protected with a methyl group, deprotection is carried out in order to regenerate the hydroxyl functional group and finally the desired aminoalkyl chain is introduced.
More specifically, this method when applied to the preparation of dronedarone comprises the sequence of steps below:
a) reaction of 2-butyl-5-nitrobenzofuran with anisoyl chloride in the presence of tin tetrachloride based on the Friedel-Crafts reaction conditions and hydrolysis to form 2-butyl-3-(4-methoxybenzoyl)-5-nitrobenzofuran,
b) demethylation of the compound thus obtained in the presence of 2.25 molar equivalents of aluminum chloride and hydrolysis so as to form 2-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran,
c) condensation of the compound obtained with 1-chloro-3-(dibutylamino)propane in the presence of potassium carbonate, to give 2-butyl-3-(4-[3-(dibutylamino]propoxylbenzoyl)-5-nitrobenzofuran,
d) hydrogenation of the compound thus formed, in the presence of platinum oxide, which gives 5-amino-2-butyl-3-(4-[3-dibutylamino)propoxy]benzoylbenzofuran,
e) reaction of the 5-aminobenzofuran derivative thus obtained with methanesulfonyl chloride in the presence of triethylamine, which gives dronedarone.
However, this method is not without some disadvantages because, in particular, of the use of aluminum chloride. Indeed, the use of this method on an industrial scale causes high discharges of aluminum hydroxide whose treatment, in order to avoid problems of pollution, is found to be expensive. In addition, the use of 2-butyl-3-(4-methoxybenzoyl)-5-nitrobenzofuran should be avoided as far as possible because of its mutagenic properties.
However, the desired compound is produced with a maximum yield of 60% from 2-butyl-5-nitrobenzofuran according to this method comprising a relatively large number of steps since at least five steps are necessary for the final formation of dronedarone.
The search for an industrial method for the preparation of dronedarone or its pharmaceutically acceptable salts using easily accessible and inexpensive synthesis intermediates based on a more direct method than the earlier method and not using aluminum chloride therefore remains of unquestionable interest.
There has been reported in J. Med. Chem. 1984, 27, 1057-1066 a more convergent method for attaching an aminoalkoxybenzoyl chain to a benzo[b]thiophene derivative without an intermediate step of protecting/deprotecting the hydroxyl functional group. However, this method still proposes on page 1064 the use of aluminum chloride in particularly large quantities since it is of the order of 9 molar equivalents.
According to this method, the benzo[b]thiophene derivative in question is condensed, in an organic phase consisting of dichloroethane, with the hydrochloride of the chloride of the aminoalkoxybenzoyl derivative, this being in the presence of aluminum chloride.
After hydrolysis, the hydrochloride of the desired 3-[4-(aminoalkoxy)benzoyl]benzo[b]thiophene is recovered partly from the organic phase and partly from the aqueous phase by three extractions with chloroform and then treated with sodium hydroxide.
In the context of the preparation of the present invention, this method is applied starting with 2-butyl-5-nitrobenzofuran in order to directly prepare 2-butyl-3-(4-[3-(dibutylamino)propoxyl]benzoyl)-5-nitrobenzofuran, this being using the following steps:
treatment of 2-butyl-5-nitrobenzofuran by means of 4-[3-(dibutylamino)propoxy]benzoyl chloride hydrochloride in the presence of 9 molar equivalents of aluminum chloride, this being in an organic phase,
hydrolysis, recovery of 2-butyl-3-(4-[3-(dibutylamino)propoxy]benzoyl)-5-nitrobenzofuran hydrochloride and treatment with sodium hydroxide so as to form the desired 2-butyl-3-(4-[3-(dibutylamino)propoxy]benzoyl)-5-nitrobenzofuran.
However, this method has proved unsuitable at the industrial level because, on the one hand, of the enormous quantity of aluminum hydroxide thus produced and, on the other hand, of the large amount of impurities recovered and, consequently, of the low yield of 2-butyl-3-(4-[3-(dibutylamino)propoxy]-5-nitrobenzofuran (20 to 30%).
However, it has been found, surprisingly, that it is possible, starting with 2-butyl-5-(methanesulfonamido)benzofuran and using appropriate quantities of a Lewis acid in a Friedel-Crafts reaction, to directly obtain dronedarone hydrochloride with excellent yields since they are at least 85%, it being possible for this hydrochloride to be recovered in a remarkably advantageous manner since it is practically entirely found not in the aqueous phase as might have been predicted but in the organic phase used, which avoids the need to carry out several extractions of this same aqueous phase as in the earlier method.
In addition, the 2-butyl-5-(methanesulfonamido)benzofuran may itself be obtained with great ease and high yields, since they are above 75%, from 5-amino-2-butylbenzofuran and even from the precursor of the latter, namely 2-butyl-5-nitrobenzofuran.
2-Butyl-5-(methanesulfonamido)benzofuran is a novel product which can be easily obtained in crystalline form, unlike 2-butyl-5-nitrobenzofuran whose crystalline state may be difficult to obtain. This methanesulfonamido derivative therefore has an undeniable advantage over the nitro derivative in question.
Consequently, the invention relates to 2-butyl-5-(methanesulfonamido)benzofuran as a novel industrial product useful in particular as synthesis intermediate, for example for the preparation of dronedarone or its pharmaceutically acceptable salts.
Thus, according to the invention, 2-butyl-5-(methanesulfonamido)benzofuran is prepared by reacting 5-amino-2-butylbenzofuran with methanesulfonyl chloride or methanesulfonic anhydride, the reaction taking place in the presence of an acid acceptor such as triethylamine or ammonia, giving the desired compound. Generally, the reaction takes place at room temperature and in one or more apolar solvents preferably chosen from halogenated hydrocarbons and ethers such as, for example, methyl tert-butyl ether, tetrahydrofuran, dichloromethane or dichloroethane.
5-Amino-2-butylbenzofuran, for its part, may be prepared by hydrogenating 2-butyl-5-nitrobenzofuran in the presence of an appropriate catalyst, giving the desired compound.
As catalyst, a platinum derivative such as platinum oxide or an ammonium formate/palladized charcoal system is normally used, the hydrogenation taking place at room temperature and optionally under pressure, for example at a pressure of the order of 20 to 30 bar.
This hydrogenation; which is carried out with excellent yields of up 100%, has unquestionable advantages compared with the hydrogenation of 2
Fino Noël
Leroy Corinne
Alexander Michael D.
Dupont Paul E.
Sanofi-Synthelabo
Trinh Ba K.
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