Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-04-11
2003-04-29
Dentz, Bernard (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S043000, C549S049000, C549S051000, C549S057000, C549S058000, C549S459000, C549S469000
Reexamination Certificate
active
06555697
ABSTRACT:
The present invention relates to a novel process for preparing a benzofuran or benzothiophene type compound by cyclising an aromatic compound carrying firstly, a side chain containing at least two carbon atoms, one of the carbon atoms being connected to the benzene ring via an oxygen or sulphur atom, the other carbon atom being in the carboxylic form, and secondly, carrying a formyl group in the ortho position with respect to said chain.
More particularly, the invention relates to the preparation of 2-n-butyl-5-nitrobenzofuran.
Benzofuran or benzothiophene type structures are encountered in many molecules used in the pharmaceutical field. In particular, European patent EP-A-0 471 609 describes a process for preparing n-butyl-2-nitro-5-benzofuran, which consists of reacting 2-hydroxy-5-nitro-benzyltriphenylphosphonium bromide with pentanoyl chloride in the presence of pyridine: 2-hydroxy-5-nitro-benzyltriphenylphosphonium bromide is obtained from 2-hydroxy-5-nitro-benzyl bromide and triphenylphosphine.
The aim of the present invention is to provide another process for liquid phase preparation that can produce a good yield of 5-nitrobenzofuran.
We have now discovered, and this constitutes the subject matter of the present invention, a process for preparing a benzofuran or benzothiophene type compound from an aromatic compound carrying firstly, a side chain comprising at least two carbon atoms, one of the carbon atoms being connected to the aromatic ring via an oxygen or sulphur atom, the other carbon atom being in the carboxylic form, and secondly, carrying a formyl group in the position ortho to said chain, characterized in that it consists of cyclising the latter, in a medium comprising a carboxylic acid anhydride and in the presence of a base selected from metallic or ammonium carbonates and/or bicarbonates.
A preferred variation of the process of the invention consists of preparing a benzofuran or benzothiophene type compound from an aromatic compound carrying firstly, a side chain comprising at least two carbon atoms, one of the carbon atoms being connected to the aromatic ring via an oxygen or sulphur atom, the other carbon atom being in the carboxylic form, and secondly, carrying a formyl group in the position ortho to said chain, by cyclising the latter in the presence of an effective quantity of a base as defined above, in a medium comprising a carboxylic acid anhydride and in the presence of an organic solvent.
We have discovered that using an organic solvent such as dimethylformamide facilitates recovery of the cyclised product while reducing the quantity of carboxylic acid anhydride employed.
The starting reactant in the process of the invention is an aromatic compound, preferably a benzene compound, carrying a side chain and a formyl group in the position ortho to the side chain.
The side chain has 3 features:
an oxygen or sulphur atom connects the side chain to the benzene ring;
2 carbon atoms connected together included in the 5 atom cycle that also includes the 2 carbon atoms of the benzene ring;
a carboxylic or thiocarboxylic group in the position &bgr; with respect to the oxygen or sulphur atom.
The starting reagent can be depicted as follows:
in which formula (I):
R
1
represents a hydrogen atom, a linear or branched alkyl group containing 1 to 12 carbon atoms, a phenyl group optionally substituted by an alkyl group containing 1 to 4 carbon atoms, or a halogenophenyl group;
Z represents an oxygen or sulphur atom;
R represents a hydrogen atom or a substituent;
n is a number equal to 0, 1, 2 or 3, preferably 0;
when n is greater than 1, two groups R and the successive 2 atoms of the benzene ring can together form a saturated, unsaturated or aromatic cycle containing 5 to 7 carbon atoms.
In formula (I), the benzene ring may carry a substituent.
The scope of the invention does not exclude the presence on the benzene ring of any type of substituent, provided that it does not react under the conditions of the invention.
More particular examples of group R that can be mentioned include:
a nitro group;
a hydroxyl group;
a linear or branched alkyl group containing 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl;
an alkoxy group containing 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms;
an ester group containing 1 to 10 carbon atoms, preferably 1 to 4 carbon atoms;
an alkylamide group containing 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms;
a carboxamide group;
a halogen atom;
a trifluoromethyl group.
When n is greater than 1, two groups R and the successive 2 atoms of the benzene ring can together form a saturated, unsaturated or aromatic cycle containing 5 to 7 carbon atoms, preferably 6 carbon atoms. Advantageously, two groups R form a benzene ring.
Group R
1
is advantageously an alkyl group containing 1 to 4 carbon atoms.
The invention does not exclude the fact that R
2
represents a further group such as cycloalkyl, phenyl or arylalkyl, but since group R
2
is eliminated, it is important from an economic viewpoint that it should be as simple as possible, for example a lower alkyl group, i.e., containing 1 to 4 carbon atoms. R
2
can also represent a hydrogen atom, which corresponds to the presence of a carboxylic group.
Preferred substrates for use in the process of the invention have formula (I) in which R represents a hydrogen atom, a nitro group, methyl or ethyl group, or a methoxy or ethoxy group.
In formula (I), Z preferably represents an oxygen atom.
In formula (I), R can represent a nitro group, preferably in the position meta to the formyl group.
In accordance with the process of the invention, the aromatic compound, preferably with formula (I), is cyclised in the presence of a base selected from metallic or ammonium carbonates and/or bicarbonates.
Suitable bases that can be mentioned in particular are alkali or alkaline-earth metal carbonates and bicarbonates. Caesium carbonate can be used, but preferably, sodium carbonate or potassium carbonate is used.
In accordance with the process of the invention, the aromatic compound, preferably with formula (I), is cyclised in a carboxylic acid anhydride.
More particularly, this latter has the following formula:
in which formula (VI):
R
a
and R
b
, which may be identical or different, represent a monovalent hydrocarbon group that may or may not be substituted, which can be a linear or branched, saturated or unsaturated acyclic aliphatic group; or a monocyclic saturated, unsaturated or aromatic carbocyclic group;
R
a
and R
b
can together form a divalent linear or branched, saturated or unsaturated aliphatic group containing at least 2 carbon atoms.
Groups R
a
and R
b
are preferably selected such that the anhydride is liquid under the reaction conditions.
The anhydride used may or may not be cyclic.
More precisely, a cyclic anhydride containing 5 to 10 carbon atoms in the cycle can be used that may or may not contain a double bond, one of the atoms can be replaced by an oxygen atom.
Preferably, the cyclic anhydrides are saturated or contain a double bond and 5 or 6 atoms in the cycle.
The cycle can comprise one or more substituents. More particular examples of substituents that can be cited are linear or branched alkyl groups containing 1 to 12 carbon atoms, preferably 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or halogen atoms or a trihalogenomethyl group.
More particularly, when using a non cyclic anhydride with formula (VI), groups R
a
and R
b
, which may be identical or different, represent:
a linear or branched acyclic aliphatic group preferably containing 1 to 24, more preferably 1 to 12 carbon atoms, which may be saturated or comprise one or more unsaturated bonds in their chain, generally 1 to 3 unsaturated bonds, which may be simple double bonds: the hydrocarbon chain may be interrupted by one of the following groups: —O—; —CO—; and/or carry one or more substituents, in particular: —X; —CX
3
;
a saturated, unsaturated or aromatic carbocyclic g
Dentz Bernard
Rhodia Chimie
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