FR2800064A1 - Preparation of pharmaceutically useful benzofurans or benzothiophene derivatives in high yield, by cyclization of substituted benzaldehyde using carboxylic anhydride in presence of (bi)carbonate salt - Google Patents

Abstract

Preparation of a benzofuran or benzothiophene compound (I) from an aromatic compound (II), involves cyclization of (II) in a medium comprising a carboxylic acid anhydride in presence of at least one base selected from metal or ammonium carbonates and/or bicarbonates. Preparation of a benzofuran or benzothiophene compound (I) from an aromatic compound (II), having (i) a side-chain of at least 2C, one C of which is bonded to the benzene ring via O or S and another of which is in carboxylic form and (ii) a formyl group in the ortho-position to the side-chain (i), involves cyclization of (II) in a medium comprising a carboxylic acid anhydride in presence of at least one base selected from metal or ammonium carbonates and/or bicarbonates.

Description

 PROGEDE <U> DE </ U> PREPARATION <U> OF A </ U> COMPOUND <U> OF </ U> TYPE BENZOFURANE <U> OR </ U> BENZOTHIOPHENE. The subject of the present invention is a novel process for the preparation of a benzofuran or benzothiophene-type compound by cyclization of an aromatic compound carrying, on the one hand, a side chain comprising at least two carbon atoms, one of the carbon atoms being connected to the benzene ring by an oxygen or sulfur atom, the other carbon atom is in carboxylic form and on the other hand a formyl group ortho position with respect to said chain.

The invention relates more particularly to the preparation of 2-n-butyl-5-nitrobenzofuran.

Benzofuran or benzothiophene structures are found in many molecules used in the pharmaceutical field. In particular, a process for the preparation of n-butyl-2-nitro-5-benzofuran is described in EP-A-0 471 609 which comprises reacting the 2-hydroxy-5-nitrobromobenzyl obtained from p- nitrophenol and triphenylphosphine leading to 2-hydroxy-5-nitro-benzyltriphenylphosphonium bromide which by reaction with pentanoyl chloride in the presence of triethylamine provides access to 2-n-butyl-5-nitrobenzofuran.

The objective of the present invention is to provide another liquid phase preparation process for obtaining 5-nitrobenzofuran with a very good reaction yield.

It has now been found and this is the object of the present invention a process for the preparation of a benzofuran or benzothiophene compound from an aromatic compound on the one hand, and a side chain comprising at least two carbon atoms, one of the carbon atoms being connected to the aromatic ring by an oxygen or sulfur atom, the other carbon atom being in carboxylic form and on the other hand a formyl group in ortho position with respect to said chain. characterized in that it consists in effecting the cyclization of the latter, in the presence of an effective amount of a base, in a medium comprising a carboxylic acid anhydride. The starting reagent of the process of the invention is an aromatic compound, preferably benzene, which carries a side chain and a formyl group in the ortho position of the side chain.

dans ladite formule (I) - R représente un atome d'hydrogène ou un substituant, - R, représente un atome d'hydrogène ou un groupe alkyle linéaire ou ramifié ayant de 1 à 12 atomes de carbone, - Z représente un atome d'oxygène ou de soufre, - n est un nombre égal à 0,1, 2, ou 3, de préférence, égal à 0. Dans la formule (I), le cycle benzénique peut porter un substituant. L'invention n'exclut pas la présence sur le cycle benzénique de tout type de substituant dans la mesure où il ne réagisse pas dans les conditions de l'invention. The side chain has 3 characteristics - an oxygen or sulfur atom connects the side chain to the benzene ring, - a number of carbon atoms of 2 chains linearly involved in the 5-atom ring which also involves the 2 atoms of carbon of the benzene ring, - a carboxylic or thiocarboxylic group in position (3 with respect to the carbon atom of the benzene ring to which the chain is connected, Thus, the starting reagent can be symbolized by the following form

in said formula (I) - R represents a hydrogen atom or a substituent, - R, represents a hydrogen atom or a linear or branched alkyl group having 1 to 12 carbon atoms, - Z represents an atom of oxygen or sulfur, n is a number equal to 0.1, 2 or 3, preferably equal to 0. In formula (I), the benzene ring may carry a substituent. The invention does not exclude the presence on the benzene ring of any type of substituent insofar as it does not react under the conditions of the invention.

As more specific examples of R groups, there may be mentioned inter alia - a nitro group, - a hydroxyl group, - a linear or branched alkyl group having 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 having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, - an alkylamide group having from 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, - a carboxamide group, - a halogen atom, - a trifluoromethyl group.

The preferred substrates of the process of the invention correspond to formula (I) in which R represents a hydrogen atom, a nitro group, a methyl or ethyl group, a methoxy or ethoxy group.

In the formula (I), R may represent a nitro group preferably in the meta position relative to the formyl group.

According to the process of the invention, the cyclization of the aromatic compound preferably having the formula (I) is carried out in the presence of a base.

As bases which may be used, mention may be made of sodium carbonate, potassium carbonate, barium hydroxide, calcium hydroxide or an organic base such as an amine, especially triethylamine or pyridine.

According to the process of the invention, the cyclization of the aromatic compound preferably having the formula (I) is carried out in a carboxylic acid anhydride.

dans ladite formule (NI) - Ra et Rb, identiques ou différents, représentent un groupe hydrocarboné monovalent, substitué ou non qui peut être un groupe aliphatique acyclique, saturé ou insaturé, linéaire ou ramifié ; un groupe carbocyclique ou hétérocyclique saturé, insaturé ou aromatique, monocyclique ou polycyclique, - Ra et Rb pouvant former ensemble un groupe divalent aliphatique saturé ou insaturé, linéaire ou ramifié, ayant au moins 2 atomes de carbone. The latter responds more particularly to the following formula

in said formula (NI) - Ra and Rb, identical or different, represent a substituted or unsubstituted monovalent hydrocarbon group which may be an acyclic aliphatic group, saturated or unsaturated, linear or branched; a saturated, unsaturated or aromatic, monocyclic or polycyclic carbocyclic or heterocyclic group, - Ra and Rb may together form a saturated or unsaturated divalent aliphatic group, linear or branched, having at least 2 carbon atoms.

The groups Ra and Rb are preferably chosen such that the acid is liquid under the reaction conditions.

The anhydride used may be cyclic or not.

More specifically, use is made of a cyclic anhydride having 5 to 10 atoms in the ring not comprising or comprising a double bond, one of the atoms may be replaced by an oxygen atom. The cyclic anhydrides used preferentially are saturated or comprise a double bond and have 5 or 6 atoms in the ring.

The cycle may include one or more substituents. As more particular examples of substituents, mention may be made, in particular, of a linear or branched acyclic aliphatic group preferably having from 1 to 24, preferably from 1 to 12 carbon atoms, saturated or comprising one to more unsaturations on the chain, generally , 1 to 3 unsaturations which may be single or conjugated double bonds or triple bonds: the hydrocarbon chain may be interrupted by one of the following groups -O-; -CO-; and / or carrier of one or more substituents, in particular: -OH; -CHO; -COX; -X; -CX3.

Preferred substituents are selected from. an alkyl group, linear or branched, having 1 to 24 carbon atoms, preferably 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,. a linear or branched alkenyl group having from 2 to 12 carbon atoms, preferably from 2 to 4 carbon atoms, such as vinyl, allyl, a linear or branched alkynyl group having from 2 to 12 carbon atoms, preferably -CH2-C-CH, a linear or branched alkoxy group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy,. a halogen atom or a trihalomethyl group.

With regard to the use of a non-cyclic anhydride corresponding to the formula (NI), the groups Ra and Rb, which may be identical or different, more particularly represent a linear or branched acyclic aliphatic group preferably having from 1 to 24, preferably, from 1 to 12 carbon atoms, saturated or comprising one to more unsaturations on the chain, generally 1 to 3 unsaturations which may be single or conjugated double bonds or triple bonds: the hydrocarbon chain may be interrupted by one or more one of the following groups: -O-; -CO-; and / or carrier of one or more substituents, in particular: -OH; -CHO; -COX; -X; -CX3.

a carbocyclic group, saturated, unsaturated or aromatic, having from 3 to 8 carbon atoms, preferably 6 carbon atoms, optionally carrying one or more halogen atoms, preferably chlorine or bromine, or of which one of the carbon atoms is a carbonyl group, - a saturated or unsaturated heterocyclic group, in particular containing 5 or 6 atoms in the ring, of which 1 or 2 heteroatoms preferably an oxygen atom.

Among the groups specified, Ra and Rb preferably represent a linear or branched alkyl or alkenyl group comprising from 1 to 12 carbon atoms, optionally carrying one or more halogen atoms, a cyclohexyl or phenyl group, optionally carrying of one or more halogen atoms, a trihalomethyl group, a furyl group, a tetrahydrofuryl group. By way of examples of anhydrides, mention may be made of acetic anhydride, propanoic anhydride, isobutyric anhydride, trichloroacetic anhydride, trifluoroacetic anhydride and benzoic anhydride.

monochloroacetyl anhydride, dichloroacetyl anhydride, pivalic anhydride.

The invention does not exclude the carboxylic anhydride being generated in the medium from a carboxylic acid.

According to the process of the invention, the cyclization of the starting <B> substrate is conducted in the presence of a base and a carboxylic acid anhydride.

More specifically, the amount of base, expressed as the ratio between the number of moles of base and the number of moles of starting substrate preferably corresponding to formula (I), varies between 0.05 and 1.0 and is preferably between 0.1 and 0.2.

The amount of carboxylic acid anhydride employed is such that the carboxylic acid anhydride mole ratio of the formula (I) preferably varies between 2 and 10.

The cyclization reaction of the starting substrate takes place at a temperature which is advantageously between 50 ° C. and 130 ° C., preferably between 100 ° C. and 103 ° C.

From a practical point of view, the reaction is simple to implement. The order of implementation of the reactants is not critical. Preferably, the substrate, the carboxylic anhydride and then the base are charged and heated to the desired temperature.

dans ladite formule M, R, Rt, Y et n ont la signification donnée précédemment. On récupère le composé de type benzofurane ou benzothiophène selon les techniques classiques utilisées, notamment par distillation ou par extraction dans un solvant approprié tel que notamment le méthylcyclohexane ou l'éther de pétrole. At the end of the reaction, the cyclized product which preferably corresponds to the following formula (V) is obtained

in said formula M, R, Rt, Y and n have the meaning given above. The benzofuran or benzothiophene type compound is recovered according to the standard techniques used, in particular by distillation or by extraction in a suitable solvent such as in particular methylcyclohexane or petroleum ether.

dans laquelle - R représente un atome d'hydrogène ou un substituant tel que défini précédemment, - R, représente un groupe alkyle linéaire ou ramifié ayant de 1 à 12 atomes de carbone, - R2 représente un atome d'hydrogène, un groupe hydrocarboné ayant de 1 à 12 atomes de carbone qui peut être un groupe alkyle linéaire ou ramifié, un groupe cycloalkyle, un groupe phényle ou un groupe phénylalkyle. The method of the invention can be applied both to known substrates described in the literature and to new substrates described below and yes to the following formula (I ')

in which - R represents a hydrogen atom or a substituent as defined above, - R, represents a linear or branched alkyl group having from 1 to 12 carbon atoms, - R2 represents a hydrogen atom, a hydrocarbon group having from 1 to 12 carbon atoms which may be a linear or branched alkyl group, a cycloalkyl group, a phenyl group or a phenylalkyl group.

Z represents an oxygen or sulfur atom; n is a number equal to 0.1, 2 or 3, preferably equal to 0. In formula (I '), the benzene ring may carry a substituent . As more specific examples of R groups, there may be mentioned inter alia - a hydroxyl group, - a linear or branched alkyl group having 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 having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, an alkylamide group having 1 to 6 atoms carbon, preferably 1 to 4 carbon atoms, a carboxamide group, a halogen atom, a trifluoromethyl group.

The preferred compounds of the process of the invention have the formula (I ') wherein R represents a hydrogen atom, a methyl or ethyl group, a methoxy or ethoxy group.

The R group is preferably an alkyl group having 1 to 4 carbon atoms.

The invention does not exclude the fact that R2 represents another group such as cycloalkyl, phenyl or arylalkyl but the R2 group being eliminated, it is interesting from an economic point of view that it is as simple as possible for example, a lower alkyl group.

R2 may also represent a hydrogen atom which corresponds to the presence of a carboxylic group but the acid form is not preferred over the ester form because it follows in the step O- or S -alkylation, an additional consumption of the base.

dans ladite formule (II'), R, Rt, R2, Z et n ont la signification donnée précédemment. Le composé aromatique de formule (II') peut être obtenu selon un procédé qui consiste à faire réagir - un composé de type 2-hydroxy- ou 2-thiobenzaldéhyde de formule (III')

dans ladite formule (III'), R, Z et n ont la signification donnée précédemment, - et un un ester d'un acide a-halogénocarboxylique de formule (IV')

dans ladite formule (IV') - X représente un atome d'halogène, de préférence un atome de brome ou de chlore, - R, , R2ont la signification donnée précédemment. The nitroaromatic compound of formula (I ') can be obtained by a process consisting in performing the selective nitration at the 5-position of an aromatic compound corresponding to formula (II')

in said formula (II '), R, Rt, R2, Z and n have the meaning given above. The aromatic compound of formula (II ') can be obtained by a process which comprises reacting a 2-hydroxy-or 2-thiobenzaldehyde compound of formula (III')

in said formula (III '), R, Z and n have the meaning given above, and an ester of an α-halocarboxylic acid of formula (IV')

in said formula (IV ') - X represents a halogen atom, preferably a bromine or chlorine atom, - R, R 2 have the meaning given above.

According to the process of the invention, starting from a new intermediate of manufacture corresponding to the formula (I ').

It can be obtained according to a nitration reaction selectively at the 5-position of a compound corresponding to the formula (II ') O- or S-alkylated, by reaction of the latter with a source of NO 2 +, preferably in the presence of an organic solvent.

For this purpose, said compound is reacted with a source of NO 2 +.

Thus, nitrogen dioxide NO 2, nitrogenous anhydride N 2 O 3, nitrogen peroxide N 2 O 4, nitrogen oxide NO associated with an oxidizing agent such as, for example, nitric acid, can be used. nitrogen dioxide or oxygen. In the case where the reagent is gaseous under the reaction conditions, it is bubbled in the medium.

It is also possible to use nitrous acid, a nitrosyl or nitrosulfate or a nitrous salt, preferably an alkali metal salt, and even more preferentially, sodium associated with an oxidizing agent, preferably acid nitric.

It is also possible to use alkyl nitrites associated with an oxidizing agent and more particularly those having the formula (VII) RANO (VII) in said formula (VII), Ra represents a linear or branched alkyl group having 1 to 12 carbon atoms, preferably 1 to 4 carbon atoms.

The amount of NO2 + source is at least equal to the stoichiometric amount of the O- or S-alkylated aromatic compound. Thus, the ratio between the number of moles of NO 2 + source and the number of moles of O- or S-alkylated aromatic compound is advantageously between 1.0 and 1.2.

However, it is possible to use a catalytic amount such that the abovementioned ratio is between 0.01 and 0.1 by combining the source of NO 2 + with nitric acid.

A solution of concentrated nitric acid having a preferential concentration of between 70 and 99% is preferentially used.

A variant of the process of the invention consists in using a sulphonitric mixture (mixture of nitric acid and sulfuric acid comprising from 50 to 98% by weight of nitric acid).

The amount of nitric acid expressed by the molar ratio of the aromatic compound O- or S-alkyl-nitric acid generally varies between 0.9 and 1.1, preferably between 0.95 and 1.05.

The amount of sulfuric acid expressed by the aromatic compound O- or S-alkyl-sulfuric acid molar ratio generally varies between 0.9 and 1.1, preferably between 0.95 and 1.05.

The concentration of sulfuric acid is advantageously between 50% and 98%.

For this purpose, use is made of nitric acid or a precursor of nitric acid such as for example nitrogen peroxide.

The nitration reaction may be conducted in an organic solvent which is inert under the reaction conditions. We choose, preferably, aprotic and polar.

As more specific examples of organic solvents, mention may be made of aliphatic halogenated hydrocarbons and more particularly perchlorinated hydrocarbons such as in particular tetrachloromethane and hexachloroethane; partially chlorinated hydrocarbons such as dichloromethane 1,2-dichloroethane.

Dichloromethane is the preferred solvent.

As regards the concentration of the O- and S-alkylated aromatic compound, in the reaction medium, it is preferably between 0.2 and 3 mol / l and preferably between 0.3 and 1.5 mol / l.

This is usually introduced in liquid form. The reaction is advantageously carried out at a temperature of between -5 ° C. and 10 ° C. under an inert gas atmosphere.

The process of the invention is generally carried out under atmospheric pressure but can also be carried out under slightly reduced pressure, for example between 500 and 760 mmHg.

According to a preferred variant of the process of the invention, the step of nitration under a controlled atmosphere of inert gases is carried out. It is possible to establish an atmosphere of rare gases, preferably argon, but it is more economical to use nitrogen.

Several modes of implementation can be envisaged.

A first variant consists in first charging the sulfuric acid solution and then adding in parallel the O- or S-alkylated aromatic compound and the nitric acid.

According to another variant, the sulfuric acid solution and the nitric acid are introduced and then the O- or S-alkylated aromatic compound is added, preferably in portions or continuously by casting.

Another variant lies in the fact of introducing in parallel, on a base of tank, the O- or S-alkylated aromatic compound on one side and the sulfuric acid and the nitric acid on the other.

The reaction advantageously lasts between 3 and 10 hours.

At the end of the reaction, the desired product corresponding to formula (I ') is obtained. The product is recovered according to conventional techniques used in the technical field.

In particular, it is possible to carry out a hydrolysis with water, preferably with ice which is used for example in the range of 100 to 150% by weight of the compound of formula (I ').

A solid is obtained which is separated according to conventional solid / liquid separation techniques, preferably by filtration.

The desired product is thus obtained.

The compound of formula (II ') which is involved in the preparation of the compound of formula (I') can be obtained in particular according to an O- or S-alkylation reaction of a compound of 2-hydroxy- or 2-thiobenzaldehyde type. formula (III ') with an ester of an α-halocarboxylic acid of formula (IV').

One embodiment comprises reacting an aromatic compound of formula (11l ') with an ester of an α-halocarboxylic acid of formula (IV') the reaction being conducted in the presence of a base, preferably in an organic solvent . Among the compounds of formula (III '), salicylic aldehyde is preferred. As regards the ester of an α-halocarboxylic acid of formula (IV '), preference is given to methyl or ethyl 6-bromohexanoate.

The molar ratio between the compound of formula (III ') and the compound of formula (IVI is advantageously chosen between 1 and 1.2.

According to the process of the invention, the 2-hydroxy-or 2-thiobenzaldehyde compound of formula (III ') in salified form is reacted with the ester of the α-halocarboxylic acid of formula (IV'), in an organic solvent as defined.

It is possible to use a salified form of a 2-hydroxy-or 2-thiobenzaldehyde compound prepared extemporaneously but it is also possible to prepare it in situ by reacting the compound of 2-hydroxy- or 2-thiobenzaldehyde type and the base.

Thus, in the process of the invention, there is a base which can be inorganic or organic.

A strong base is preferably chosen, that is to say a base having a pKb greater than 9: the pKb is defined as the cologarithm of the dissociation constant of the measured base, in an aqueous medium, at 25.degree.

Particularly suitable for carrying out the process of the invention are inorganic bases such as alkali metal salts, preferably an alkali metal hydroxide which may be sodium or potassium hydroxide, a carbonate or hydrogencarbonate an alkali metal, preferably sodium carbonate.

It is also possible to use an organic base such as a quaternary ammonium hydroxide or an amine.

As examples of quaternary ammonium hydroxide, preference is given to using tetraalkylammonium or trialkylbenzylammonium hydroxides, the identical or different alkyl groups of which represent a linear or branched alkyl chain having from 1 to 12 carbon atoms, preferably from 1 to 12 carbon atoms. at 6 carbon atoms.

Tetramethylammonium hydroxide, tetraethylammonium hydroxide or tetrabutylammonium hydroxide are preferably chosen.

It is also possible according to the invention to use trialkylbenzylammonium hydroxides and especially trimethylbenzylammonium hydroxide.

As examples of amines, mention may be made, inter alia, of tertiary amines. Among the bases that can be used, mention should be made of tertiary amines and more particularly those corresponding to the general formula (VIII) N - (R 3) 3 (VIII) in which - the groups R 3, which are identical or different, represent hydrocarbon radicals having 1 to 20 carbon atoms, such as alkyl, cycloalkyl, aryl or heterocyclic groups; - 2 groups R3 form together and with the nitrogen atom a heterocycle having 4 to 6 atoms.

More particularly, the symbols R 3 represent an alkyl group having 1 to 10 carbon atoms and preferably 1 to 4 carbon atoms or a cyclopentyl or cyclohexyl group or a pyridinyl group; Two groups R3 together form, with the nitrogen atom, a piperidine or pyrrolidine ring.

Examples of such amines include triethylamine, tri-n-propylamine, tri-tert-butylamine, methyldibutylamine, methyldicyclohexylamine, ethyldiisopropylamine, N, N-diethylcyclohexylamine, dimethylamino-4-pyridine, N-methylpiperidine, N-ethylpiperidine, Nn-butylpiperidine, 1,2-dimethylpiperidine, N-methylpyrrolidine, 1,2-dimethylpyrrolidine.

For economic reasons, one chooses from all the bases, preferentially sodium or potassium carbonate.

Although the form of implementation of the base is in solid form, it is also possible to use a base in solution. The concentration of the basic starting solution is not critical. The alkali metal hydroxide solution used has a concentration generally of between 10 and 50% by weight.

The amount of base introduced into the reaction medium takes into account the amount necessary to salify the hydroxyl or thiol function of the 2-hydroxy- or 2-thiobenzaldehyde compound.

Generally, the amount of base relative to the 2-hydroxy- or 2-thiobenzaldehyde compound varies between 90 and 120% of the stoichiometric amount.

Salification of the hydroxyl or thiol group of the starting substrate of formula (III ') may be carried out optionally in a preliminary step. The compound of formula (III ') can thus be salified either by introducing the base and then reacting it at a temperature advantageously between 0 ° C. and 100 ° C., preferably between 25 ° C. and 50 ° C., or by introducing the base into At the same time as the compound of formula (IV ') According to the invention, the O- or S-alkylation reaction is advantageously carried out in the liquid phase comprising the compound of formula (III') and the compound of formula (IV ') , in the presence of a base.

One of the starting reagents can serve as a reaction solvent but it is also possible to use an organic solvent.

An organic solvent is chosen which is less active than the starting substrate and which preferably solubilizes it.

As examples of suitable solvents for the present invention, there may be mentioned in particular aromatic hydrocarbons, halogenated or not, aliphatic, cycloaliphatic or aromatic ether-oxides.

As examples of aliphatic hydrocarbons, there may be mentioned more aromatic hydrocarbons and more particularly aromatic hydrocarbons such as benzene, toluene, xylenes, cumene, petroleum fractions consisting of a mixture of alkylbenzenes, especially Solvesso type.

As regards the aliphatic or aromatic halogenated hydrocarbons, there may be mentioned more particularly dichloromethane, 1,2-dichloroethane, mono- or dichlorobenzene.

Aliphatic, cycloaliphatic or aromatic ether-oxides and, more particularly, dipropyl ether, diisopropyl ether, dibutyl ether, methyl-tert-butyl ether, dimethyl ether, and the like can also be used as organic solvents. ethylene glycol (or glyme), dimethyl ether diethylene glycol (or diglyme); phenyl ether; dioxane, tetrahydrofuran (THF).

As examples of more polar aprotic organic solvents which can also be used in the process of the invention, mention may be made more particularly of alpha or aromatic nitrites such as acetonitrile, propionitrile and benzonitrile; linear or cyclic carboxamides such as N, N-dimethylacetamide (DMAC), dimethylformamide (DMF), diethylformamide or 1-methyl-2-pyrrolidinone (NMP).

Preferred solvents are DMAC or DMF.

It is also possible to use a mixture of organic solvents.

As regards the concentration of the 2-hydroxy-or 2-thiobenzenoidal type compound in the reaction medium, it is preferably between 2% and 50% by weight. A variant of the process of the invention consists in adding iodide ions in order to accelerate the reaction. Thus, it is possible to use in particular alkali metal iodides, preferably potassium iodide or tetraalkylammonium iodides, preferably tetrabutylammonium iodide.

The amount of iodide involved, expressed as the ratio between the number of moles of iodized salt and the number of moles of compound of formula (III ') can vary between 0.05 and 0.2.

The temperature of the reaction of the aromatic compound of formula (III ') with an ester of an α-halocarboxylic acid of formula (IV') is advantageously between 0 ° C. and 100 ° C., preferably between 25 ° C. and 50 ° C.

The reaction is generally carried out under atmospheric pressure.

According to a preferred variant of the process of the invention, the process of the invention is carried out under a controlled atmosphere of inert gases. It is possible to establish an atmosphere of rare gases, preferably argon, but it is more economical to use nitrogen.

From a practical point of view, the method is simple to implement.

All the reactants, the base, the organic solvent or the iodide ions are loaded.

The medium is brought to the reaction temperature chosen.

As mentioned previously, it is possible to perform the salification in a preliminary step and to introduce the compound of formula (III ') the base and the organic solvent, to bring the medium to the chosen temperature and then to add the compound of formula (IV') and the ions iodide and then heat.

The desired product is obtained which corresponds to formula (II '). The product obtained is recovered in a conventional manner.

For example, the salts formed during the reaction can be removed by adding water and extracting said product in the organic phase in a suitable solvent, for example isopropyl ether.

The organic solvent can be removed in a conventional manner by evaporation.

dans la formule (N'), R, R,, Z et n ont la signification donnée précédemment. Quand le composé de formule (II') comprend à titre de groupe COOR2, une fonction ester au lieu d'une fonction carboxylique, il est nécessaire d'effectuer au préalable une étape de saponification. The cyclization of the compound of formula (I ') is carried out according to the process of the invention to obtain a heterocyclic compound corresponding to the general formula (V')

in the formula (N '), R, R 1, Z and n have the meaning given above. When the compound of formula (II ') comprises as COOR2 group, an ester function instead of a carboxylic function, it is necessary to perform a prior saponification step.

For this purpose, the compound of formula (I ') is thus reacted with a base in a hydro-organic medium.

As a base, preference is given to soda or potash which are used in the form of flakes or concentrated solutions, for example at 40% for sodium hydroxide.

The amount of base used, expressed as the ratio between the number of moles of the compound of formula (I ') and the number of moles of base, is preferably chosen between 1 and 5 and more preferably between 1 and 2.

The base is solubilized in an aqueous or hydro-organic medium. It is preferable to use a polar organic solvent.

As examples of organic solvents suitable for the present invention, there may be mentioned more particularly aliphatic alcohols such as ethanol, propanol, butanol, pentanol, ethylene glycol; cycloaliphatic alcohols, especially cyclohexanol and arylaliphatic alcohols, more particularly benzyl alcohol. Monomethyl, monoethyl, monopropylic and monobutyl ethers of ethylene glycol sold under the trade name Cellosolves may also be used.

The concentration of the compound of formula (I ') in the reaction medium (water + organic solvents) advantageously varies between 5 and 50%, preferably between 5 and 20% by weight.

The volume ratio between the organic solvent and the water may vary, for example, from 0.1 to 0.9, and is preferably from 0.1 to 0.2.

The choice of the organic solvent and the water / organic solvent ratio is determined in such a way that the solution obtained is homogeneous.

The saponification reaction is carried out at a temperature between room temperature and the reflux temperature of the reaction mixture, preferably at a temperature in the region of 50 ° C. By ambient temperature, a temperature of between 15 ° C. and 25 ° C. is generally understood. a practical embodiment of the invention, the compound of formula (I ') is introduced into the aqueous or hydro-organic medium and then the base is added and then the reaction medium is brought to the chosen temperature.

At the end of the reaction, if necessary, the excess base is neutralized with an acidic solution, preferably a solution of mineral acid or a mineral salt, such as, for example, hydrochloric acid or chlorine chloride. ammonium.

The resulting product precipitates and is separated by conventional solid / liquid separation techniques, preferably by filtration.

The cyclization is then carried out in accordance with the process of the invention. There is obtained a benzofuran or benzothiophene derivative nitrated in the 5-position and corresponding to the formula (V ').

The process of the invention is particularly suitable for the preparation of 2-n-butyl-5-nitrobenzofuran.

Examples of embodiments of the invention are given below. These examples are given for illustrative purposes and without limitation.

<U> Example 1 </ U> <U> Preparation of </ U> 5-nutro-2-buly benzofuran.

In a 200 ml reactor containing 80 g of acetic anhydride was charged 23.4 g of 2- (2-formyl-4-nitro-phenoxy) hexanoic acid and 2.3 g of potassium carbonate.

The reaction mixture is heated under a nitrogen atmosphere at reflux, at a temperature in the region of 130 ° C., for 5 hours.

After returning to a temperature in the region of 25 ° C., the medium is extracted with 15 times 50 ml of petroleum ether (40-65 ° C.

The collected organic phases are washed with 300 ml of an aqueous solution of sodium hydrogencarbonate (10%) and dried over magnesium sulphate.

Thus, after evaporation of the solvents under reduced pressure, 11.2 g of 5-nitro-2-butylbenzofuran (RR weight = 62%) are obtained in the form of a yellow oil (NMR purity = 95%). Its NMR spectrum is following 1H NMR (DMSO-d6):? 0.91 (t, 3H, CH3); 1.37 (m, 2H, CJ 2 -CH 3); 1.67 (m, 2H, CB 2 -CH 2 -CH 3); 2.81 (m, 2H, CH 2 -C =); 6.81 (s, 1H, CH =); 7.71 (d, J = 9 Hz, 1H, ArH); 8.12 (dd, J = 9 Hz, J = 2.5 Hz, 1H, ArH); 8.47 (d, J = 2.5 Hz, 1H, ArH). The purity of the product is estimated to be greater than 95 mol%. Exemplp, 2 <U> Preparation of 2- (2-Formyl-Nitro-ohenoxy) -hexanoic acid.

2- (2-formyl-5-nitro-phenoxy) -hexanoic acid can be prepared in the following manner. In a 250 ml tetracol reactor equipped with pale Teflon half moon stirring, a thermometer, a 50 ml addition funnel, a coil condenser and a nitrogen inlet, 29.5 g of methyl 2- (2-formyl-5-nitro-phenoxy) -hexanoate are successively charged, 148 ml of water.

8.4 g of a 50% aqueous solution of sodium hydroxide are added over 20 minutes.

After stirring for 15 minutes at a temperature in the region of 25 ° C., the reaction medium is heated for 2 hours with stirring at around 50 ° C.

The clear medium obtained in red color is partially evaporated (50 ml) to remove methanol formed and then rediluted with 50 ml of water.

The pH of the reaction medium is brought to about 1.8 by slow addition of 10.8 g of concentrated hydrochloric acid while maintaining the temperature in the vicinity of 45 ° C. with stirring.

After stirring for one hour, the temperature of the medium is brought to around 55 ° C. for 20 minutes and then left at ambient temperature for 12 hours.

The solid product is separated by filtration on N 3 sintered glass and washed with twice 50 ml of water and then dried in an oven for 12 hours at a temperature of 55 C.

26.8 g of 2- (2-formyl-5-nitro-phenoxy) -hexanoic acid are thus obtained in the form of a light yellow solid melting at 110-111 ° C. and titrating 97.5% by potentiometric assay.

<U> Example <B> 3 </ U> </ U> Preparation <U> of methyl </ U> 2- (2-formyl-Qhh-n-oxy) -hexanoate <U>. </ U>

Methyl 2- (2-formyl-phenoxy) -hexanoate can be prepared in the following manner: In a 250 ml tetracol flask equipped with pale Teflon half-moon stirring, a thermometer, an ampoule of addition of 50 ml, a coil condenser and a nitrogen inlet, 123 g of concentrated sulfuric acid 96%. The reaction medium is cooled to a temperature in the region of 5 ° C. and 30 g (0.12 mol) of methyl 2- (2-formylphenoxy) hexanoate are then added at this same temperature.

After stirring for 15 minutes, 15.9 g (0.126 mol) of sulfonitrile (50 I 50) are added over 2 hours while maintaining the temperature of the reaction medium at around 5 ° C., then 76.9 g of ice-cream are added over 30 minutes. at a titre of 60% in H2SO4- The reaction mixture is filtered on N3 sintered glass.

The filtrate is washed with twice 50 ml of water and then dried under reduced pressure (20 mm of mercury) at 40 ° C. for 3 hours.

The crude product obtained is dissolved in 100 ml of dichloromethane and washed with twice 50 ml of water.

The decanted organic phase is concentrated on a rotary evaporator of 20 to 70 ° C. under 20 mm of mercury (duration <B>: 2 hours).

32.7 g of beige yellow solid product is thus obtained, ie a yield of methyl 2- (2-formyl-5-nitro-phenoxy) -hexanoate of 92.4%, titrating 96.7% by gas chromatography.

 Exempt <U> Preparation of Methyl 2- (2-formyl) -Nhenoxyl-Hexanoate </ U>.

Methyl 2- (2-formyl-phenoxy) -hexanoate may be prepared in the following manner: In a 1-liter tetracol reactor equipped with half-moon stirring, a thermometer, a coil condenser and of a 500 ml addition funnel, 87.1 g (0.714 mol) of salicylic aldehyde, 158.2 g (0.756 mol) of methyl 2-bromo-hexanoate, 103.5 are successively charged under a controlled atmosphere. g (0.75 mol) of potassium carbonate and 5.9 g (0.0355 mol) of potassium iodide.

400 g of dimethylformamide are added and the mixture is heated with stirring at a temperature in the region of 80 ° C. for 4 h 15 min.

After returning to a temperature in the region of 25 ° C., the reaction mixture is filtered on n-3 sintered glass and washed with 50 g of dimethylformamide.

The filtrate is concentrated by evaporation under reduced pressure (25-40 mbar) and then diluted with 100 ml of water in the concentrated reaction medium and successively extracted with 1 time 100 ml of dichloromethane and 50 ml of dichloromethane.

The combined organic phases are washed with 50 ml of water. The reaction medium is then concentrated to dryness by evaporation under reduced pressure.

There is thus obtained 176.1 g of clear yellow liquid corresponding to a yield of 98.6% of methyl 2- [2- (formyl) phenoxy] hexanoate grading 99.6% purity by gas chromatography.

Claims (15)

<1> A process for the preparation of a benzofuran or benzothiophene-type compound from an aromatic compound carrying, on the one hand, a side chain comprising at least two carbon atoms, one of the carbon atoms being connected to the benzene ring by an oxygen or sulfur atom, the other carbon atom is in carboxylic form and on the other hand a formyl group in the ortho position with respect to said chain. characterized in that it consists in effecting the cyclization of the latter, in the presence of an effective amount of a base, in a medium comprising a carboxylic acid anhydride.   2 - Process according to claim 1 characterized in that the starting aromatic compound corresponds to the following formula

    in said formula (I) - R represents a hydrogen atom or a substituent, - R, represents a hydrogen atom or a linear or branched alkylw group having from 1 to 12 carbon atoms, - Z represents an atom of oxygen or sulfur, n is a number equal to 0.1, 2, or 3, preferably equal to 0. 3 - Process according to claim 2 characterized in that R represents a hydrogen atom or one of the following groups - a nitro group - a hydroxyl group - a linear or branched alkyl group having from 1 to 6 atoms carbon, preferably 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, - an alkoxy group having 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, an alkylamide group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, a carboxamide group, a halogen atom, a trifluoromethyl group. 4 - Process according to claim 2 characterized in that R represents a hydrogen atom, a nitro group, a methyl or ethyl group, a methoxy or ethoxy group. 5 - Process according to claim 2 characterized in that R, represents an alkyl group having 1 to 4 carbon atoms.   6 - Process according to one of claims 1 and 2 characterized in that the base used is sodium carbonate, potassium carbonate, barium hydroxide, calcium hydroxide or an organic base such as a preferably amine, triethylamine or pyridine. 7 - Process according to one of claims 1 and 2 characterized in that the carboxylic acid anhydride corresponds to the following formula

    in said formula (VI) - Ra and Rb, which may be identical or different, represent a substituted or unsubstituted monovalent hydrocarbon group which may be a linear or branched, saturated or unsaturated, acyclic aliphatic group; a saturated, unsaturated or aromatic, monocyclic or polycyclic carbocyclic or heterocyclic group, - Ra and Rb may together form a saturated or unsaturated divalent aliphatic group, linear or branched, having at least 2 carbon atoms. 8 - Process according to claim 7, characterized in that the carboxylic anhydride is a cyclic anhydride having from 5 to 10 atoms in the ring not comprising or comprising a double bond, one of the atoms being able to be replaced by a hydrogen atom. 'oxygen. 9 - Process according to claim 7, characterized in that the carboxylic anhydride is a non-cyclic anhydride corresponding to formula (VI), in which the groups Ra and Rb, which are identical or different, represent a linear or branched acyclic aliphatic group having preferably from 1 to 24, preferably from 1 to 12 carbon atoms, saturated or comprising one to more unsaturations on the chain, generally 1 to 3 unsaturations which may be single or conjugated double bonds or triple bonds: hydrocarbon chain which can be interrupted by one of the following groups: -O-; -CO-; andlor carrying one or more substituents, especially: OH; -CHO; -COX; -X; -CX3. a carbocyclic group, saturated, unsaturated or aromatic, having from 3 to 8 carbon atoms, preferably 6 carbon atoms, optionally carrying one or more halogen atoms, preferably chlorine or bromine, or of which one of the carbon atoms is a carbonyl group, - a saturated or unsaturated heterocyclic group, in particular containing 5 or 6 atoms in the ring, of which 1 or 2 heteroatoms preferably an oxygen atom. 10 - Process according to claim 7 characterized in that the carboxylic anhydride is acetic anhydride. 11 - Process according to one of claims 1 to 10, characterized in that the amount of base expressed by the ratio between the number of moles of base and the number of moles of starting substrate preferentially corresponding to the formula (I) varies between 0.05 and 1.0 and is preferably between 0.1 and 0.2. 12 - Process according to one of claims 1 to 11, characterized in that the amount of carboxylic acid anhydride used is such that the carboxylic acid anhydride molar ratiocomposed of formula (I) varies between 2 and 10 .   13 - Method according to one of claims 1 to 12 characterized in that the cyclization reaction takes place at a temperature which is between 50 C and 130 C, preferably between 100 C and 103 C. 14 - Process according to one of claims 1 to 13, characterized in that the concave product corresponds to the following formula (III)

    in said formula (III), R, R 1, Y and n have the meaning given above in one of claims 2 to 5. 15 - Process according to claim 14 characterized in that the cyclized product is 2-n-butyl-5-nitrobenzofuran.