IE904642A1 - Process for the preparation of mono- or poly-alkoxylated¹aromatic compounds - Google Patents

Abstract

Process for the preparation of mono- or polyalkoxylated aromatic compounds from aromatic compounds carrying at least one halogen atom. The invention relates to a process for the preparation of alkoxylated aromatic compounds which consists in reacting an aromatic compound carrying at least one halogen atom with an alkali metal or alkaline-earth metal alcoholate in the presence of a copper catalyst, and characterised in that the operation is carried out in the presence of a cocatalyst which is an unsaturated compound chosen from organic isocyanides, isocyanates and alkynedioic esters. In an alternative embodiment, the invention is also aimed at the reaction of the product obtained after alkoxylation and carrying a hydroxyl group, with an alkylating agent. The invention is perfectly well suited for the preparation of 3,4,5-trimethoxybenzaldehyde and of 3,4-dimethoxybenzaldehyde.

Description

The present invention relates to a process for the preparation of mono- or poly-alkoxylated aromatic compounds from aromatic compounds containing at least one halogen atom.

The invention relates to a process for the preparation of alkoxylated aromatic compounds which comprises reacting an aromatic compound containing at least one halogen atom with an alkali metal or alkaline earth metal alcoholate, in the presence of a copper catalyst, which is characterised in that the reaction is carried out in the presence of a co-catalyst which is an unsaturated compound selected from the organic isocyanides, the isocyanates, and the esters of alkynedioic acids.

In a variant of the process, the invention relates also to the reaction of the product containing a hydroxy group obtained after alkoxylation, with an alkylation agent.

The invention is particularly suitable for the s preparation of 3,4,5-trimethoxybenzaldehyde and 3,4dimethoxybenzaldehyde.

PATENTS ACT, 1964 COMPLETE SPECIFICATION L..............................PROCESS FOR THE PREPARATION OF MONO- OR POLY-ALKOXYLATED AROMATIC COMPOUNDS RHONE-POULENC CHIMIE, a French Body Corporate of 25 Quai Paul Doumer, 92408 Courbevoie, France. -1IE 904642 - 1 ftPROCESS FOR THE PREPARATION OF MONO- OR POLY-ALKOXYLATED AROMATIC COMPOUNDS The present invention relates to a process for the preparation of mono- or poly-alkoxylated aromatic compounds from aromatic compounds containing at least one halogen atom.

The invention also relates to a process for the preparation of polyalkoxylated aromatic compounds from aromatic compounds containing at least one halogen atom and at least one hydroxy group.

The invention relates more especially to the preparation of 3,4,5-trimethoxybenzaldehyde from 5-bromo4-hydroxy-3-methoxybenzaldehyde, commonly known as 5bromovanillin, and of 3,4-dimethoxybenzaldehyde, known as veratraldehyde, from 3-bromo-4-hydroxybenzaldehyde.

In the following description of the present invention, there is to be understood by aromatic compound the conventional concept of aromaticity as defined in the literature, especially by Jerry MARCH - Advanced Organic Chemistry, 3rd edition, John Wiley and Sons, 1985 p. 37 et. seq..

Polyalkoxylated aromatic compound denotes an aromatic compound containing at least two alkoxy radicals.

The introduction of one or a plurality of alkoxy or aralkoxy substituents onto an aromatic nucleus by the reaction of a mono- or poly-halogenated compound with an alkali metal or alkaline earth metal alcoholate in the presence of a catalyst formed by an ester of formic acid, called a formate, and a cuprous salt is known from patent GB-A-2 089 672. In that process, the formate used is essentially methyl formate. A major difficulty in carrying out such a process lies in the use of methyl formate. In particular that reactant is not easy to handle since it is very volatile at room temperature and consequently poses safety hazards. In addition, it should be noted that in the case of methoxylation, for example, of bromobenzene with sodium methoxide, in the presence of methyl formate and cuprous bromide, the reaction is long and incomplete because 44 % of the bromobenzene remains unreacted.

Furthermore, in the case of methoxylation of halogenated aromatic compounds that also contain an aldehyde function, especially 5-bromo-4-hydroxy-3methoxybenzaldehyde, by reaction with sodium methoxide in the presence of the catalyst and co-catalyst mentioned above, the reaction is similarly very slow and it is necessary in that process to protect the aldehyde function by converting it into acetal form.

One of the objects of the present invention is to provide a process for the alkoxylation of mono- or polyhalogenated aromatic compounds which enables the abovementioned disadvantages to be avoided.

It is another object of the present invention to provide a process which is also suitable for halogenated aromatic compounds that contain an aldehyde function without it being necessary to protect the aldehyde function.

Finally, another object of the invention is that the process of the invention should be such that it permits, without having to change the reactor, alkylation of the aromatic compounds containing both an alkoxy group and a hydroxy group obtained after alkoxylation.

It has now been found that it was possible to carry out under good conditions the alkoxylation of mono- or poly-halogenated aromatic compounds, optionally containing an aldehyde function, in the presence of a copper catalyst if the reaction was carried out in the presence of an effective amount of a co-catalyst selected from the organic isocyanides, the isocyanates, and the esters of alkynedioic acids.

It was also demonstrated that it was possible at the end of the alkoxylation reaction to follow on, in the same reaction medium, with an alkylation reaction, without an additional operation.

The object of the present invention is thus a general process for the preparation of polyalkoxylated aromatic compounds of the general formula (I): (I) in which m and n are integers, n is an integer greater than or equal to 1, m is an integer greater than or equal to 0, the sum of m and n preferably being between 1 and 6, Ro represents a cyclic aromatic radical containing at least 5 atoms in the ring, optionally substituted and representing at least one of the following radicals : an aromatic, monocyclic or polycyclic carbocyclic radical, an aromatic, monocyclic or polycyclic heterocyclic radical containing at least one of the hetero atoms Ο, N and S, R represents a hydrocarbon radical containing from 1 to 12 carbon atoms which may be a linear or branched, saturated or unsaturated, acyclic aliphatic radical; a saturated or unsaturated, monocyclic or polycyclic, cycloaliphatic radical; or a linear or branched, saturated or unsaturated, cycloaliphatic or arylaliphatic radical; Rj is a linear or branched alkyl radical containing from 1 to 6 carbon atoms, which process comprises reacting: - an aromatic compound containing at least one halogen atom and, optionally, a hydroxy group and corresponding to the general formula (II): (HOf^-Ro-fXJn (II) in which: - m and n are integers, . n is an integer greater than or equal to 1, . m is an integer greater than or equal to 0, . the sum of m and n preferably being between and 6, - X represents an iodine, bromine or chlorine atom, Ro represents a cyclic aromatic radical containing at least 5 atoms in the ring, optionally substituted and representing at least one of the following radicals : . an aromatic, monocyclic or polycyclic carbocyclic radical, . an aromatic, monocyclic or polycyclic heterocyclic radical containing at least one of the hetero atoms Ο, N and S, - with an alkali metal or alkaline earth metal alcoholate of the general formula (III) : MW+[O-R]w- (III) in which: - M represents an alkali metal or alkaline earth metal, - w represents the valency of the alkali metal or alkaline earth metal, - R represents a hydrocarbon radical containing from 1 to 12 carbon atoms which may be a linear or branched, saturated or unsaturated, acyclic aliphatic radical; a saturated or unsaturated, monocyclic or polycyclic, cycloaliphatic radical; or a linear or branched, saturated or unsaturated, cycloaliphatic or arylaliphatic radical; in the presence of a copper catalyst, which is copper and/or a copper compound, which process is characterised in that the reaction is carried out in the presence of an effective amount of a co-catalyst which is an unsaturated compound selected from the organic isocyanides, the isocyanates and the esters of alkynedioic acids.

In the present text, in a simplified manner ’’alkoxy radicals denotes radicals of the R-O- type in which R represents a saturated or unsaturated aliphatic radical, a saturated or unsaturated cycloaliphatic radical, or an aliphatic radical carrying a saturated, unsaturated or aromatic carbocycle.

In all cases, the substitution of the halogen atom by the radical R-O- is referred to hereinafter as the alkoxylation reaction, whatever the nature of the radical R.

The term alcoholate is used generically in the present text and also includes the metal aralkoxides.

The invention relates more especially to aromatic compounds of formula (II) which contain at least one halogen atom and optionally a hydroxy group and in which the radical Ro represents: 1° - an aromatic, monocyclic or polycyclic carbocyclic radical.

Polycyclic carbocyclic radical means: . a radical which comprises at least 2 aromatic carbocycles which together form ortho or ortho and pericondensed systems, a radical which comprises at least 2 carbocycles, only one of which is aromatic, which together form ortho or ortho and pericondensed systems. 2° - an aromatic, monocyclic or polycyclic heterocyclic radical; Polycyclic heterocyclic radical denotes: a radical which comprises at least 2 heterocycles containing at least one hetero atom in each ring, at least one of the rings being aromatic and the rings together forming ortho or ortho and pericondensed systems, . a radical which comprises at least one hydrocarbon ring and at least one heterocycle, at least one of the rings being aromatic and the rings together forming ortho or ortho and pericondensed systems, 3° - a divalent radical composed of an arrangement of groups, such as those defined in paragraphs 1 and/or 2, bonded to one another: . by a valency bond, . by an alkylene or alkylidene radical containing from 1 to 4 carbon atoms, preferably a methylene or isopropylidene radical, . by one of the following groups: -O- , -CO- , —S— , —SO— , —SO2- , -N- , -CO-NI I R2 in which formulae R2 represents a hydrogen atom or an alkyl radical containing from l to 4 carbon atoms, a cyclohexyl or phenyl radical.

The following may be mentioned as examples of radicals listed under 1° to 3°: 1° - phenyl, tolyl and xylyl radicals; naphthyl and anthryl radicals, 2° - furyl, pyrrolyl, thienyl, isoxazolyl, furazanyl, isothiazolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl and pyrimidinyl radicals; quinolyl, naphthyridinyl, benzofuranyl and indolyl radicals, 3° - biphenyl, 1,1'-methylenebiphenyl, 1,1'-isopropy1idenebiphenyl, 1,1'-oxybiphenyl and 1,11-iminobiphenyl radicals.

Preferred compounds are those corresponding to formula (II) in which the radical Ro represents a benzene nucleus.

As mentioned hereinbefore, the radical Ro, which is an aromatic radical containing at least one halogen atom, may also contain one or a plurality of other substituents which may be another hydroxy group or another halogen atom or an entity of any other kind provided it does not interfere with the reaction. Generally, a plurality of substituents denotes fewer than four substituents on an aromatic nucleus.

The following groups or functions may be mentioned as examples of substituents, which are given by way of illustration and are not of a limiting nature: - a radical of the formula -R3-OH in which the radical R3 represents a valency bond or a linear or branched, saturated or unsaturated, divalent hydrocarbon radical containing from 1 to 4 carbon atoms, such as, for example, methylene, ethylene, propylene, isopropylene or isopropylidene, - a linear or branched alkyl radical containing from to 6 carbon atoms, preferably from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl or tert.-butyl, - a linear or branched alkenyl radical containing from 2 to 6 carbon atoms, preferably from 2 to 4 carbon atoms, such as vinyl or allyl, - a linear or branched alkoxy radical containing from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, such as a methoxy, ethoxy, propoxy, isopropoxy or butoxy radical, - a group -CHO, - an acyl group containing from 2 to 6 carbon atoms, - a radical of the formula -R3-COOH, R3 having the meaning given hereinbefore, - a radical of the formula -R3-COOR4 in which R3 has the meaning given hereinbefore and R4 represents a linear or branched alkyl radical containing from 1 to 6 carbon atoms, - a radical of the formula -R3-NH2 with an Nprotected NH2 group, R3 having the meaning given hereinbefore, - a radical of the formula -R3-N(R5)2 in which R3 has the meaning given hereinbefore and each of the R5 radicals, which may be the same or different, represents a hydrogen atom or a linear or branched alkyl radical containing from 1 to 6 carbon atoms, - a radical of the formula -R3-CO-N(R5)2, R3 and R5 having the meaning given hereinbefore, - a radical of the formula -R3-Z in which R3 has the meaning given hereinbefore and Z denotes a halogen atom X, such as defined hereinbefore, a fluorine atom or a CF3 group.

If substituents are present on the aromatic nucleus, then it is necessary to ensure that the substitution does not interfere with the desired product.

Similarly, if a primary amine function is present, it may be necessary to N-protect it with a protecting group, for example an acyl or more especially an acetyl group.

If the ring carries a group of the -R3-COOR4 type, the group R4 will be exchanged for the group R originating from the alkali metal or alkaline earth metal alcoholate, if R4 and R are alkyl groups of a different nature.

If the ring carries an acid function of the -R3-COOH type, the group will be salified and thus cause additional consumption of the alcoholate used.

When the aromatic ring carries an aliphatic side chain with a halogen atom X present, the latter may also be substituted by the group R-O- originating from the alkali metal or alkaline earth metal alcoholate and it will then be necessary to take this into account in determining the amounts of reactants to be used.

The following may be mentioned as examples of preferred substituents without implying any limitation: - one or a plurality of alkyl radicals containing from 1 to 4 carbon atoms, - one or a plurality of alkoxy radicals containing from 1 to 4 carbon atoms, - one or a plurality of hydroxy radicals.

There may be mentioned as examples of aromatic compounds containing at least one halogen atom and corresponding to the general formula (II) more especially: - bromobenzene - dibromobenzenes - tribromobenzenes - 1,2,4,5-tetrabromobenzene - hexabromobenzene - 2-bromomesitylene - 5-bromo-l,2,4-trimethylbenzene - l-bromo-4-tert.-butylbenzene - bromostyrenes - 2-bromochlorobenzene - 3-bromochlorobenzene - 10 - 4-bromochlorobenzene - 2-bromo-5-chlorotoluene - bromodichlorobenzenes - 5-bromo-2-fluorotoluene - bromo(trifluoromethyl)benzenes - bromofluorobenzenes - bromodifluorobenzenes - bromotrifluorobenzenes - bromotetrafluorobenzenes - l-bromo-2-nitrobenzene - l-bromo-4-nitrobenzene - 2-bromo-4-nitrotoluene - 2-bromo-5-nitrotoluene - 2-bromo-6-nitrotoluene - 1-bromonaphthalene - 2-bromonaphthalene - 9-bromoanthracene - l-bromo-2-methylnaphthalene - l-bromo-4-methylnaphthalene - 2-bromo-6-methoxynaphthalene - 2-bromoanisole - 3-bromoanisole - 4-bromoanisole - 2,6-dibromo-4-methylanisole - Ι’α,α,α-trifluorobromoanisole - bromofluoroanisoles - 4-bromophenetole - l-bromo-2,4-dimethoxybenzene - l-bromo-2,5-dimethoxybenzene - 2-bromobenzoic acid - 3-bromobenzoic acid - 4-bromobenzoic acid - 3-bromo-4-methylbenzoic acid - the methyl ester of (3,5-dibromo-4-acetamido) benzoic acid - the ethyl ester of (3,5-dibromo-4-acetamido)IE 904642 benzoic acid - the methyl ester of (3,5-dibromo-4-methoxy) benzoic acid - the ethyl ester of (3,5-dibromo-4-methoxy)benzoic acid - the methyl ester of (3,5-dibromo-4-ethoxy)benzoic acid - the ethyl ester of (3,5-dibromo-4-ethoxy)benzoic acid - 2’-bromoacetophenone - 31-bromoacetophenone - 4'-bromoacetophenone - 2-bromoacetanilide - 3-bromoacetanilide - 4-bromoacetanilide - bromomethylacetanilides - bromofluoroacetanilides - 4-bromo-2-(trifluoromethyl)-acetanilide - N,N-dimethyl-bromoacetanilide - 4-bromo-2-chloroacetanilide - bromodifluoroacetanilides - 2-bromobenzonitrile - 3-bromobenzonitrile - 4-bromobenzonitrile - 2-bromobenzamide - 4-bromobenzamide - bromothiophenols - 4-bromodiphenyl ether - 4-bromobenzophenone - mono- or poly-brominated biphenyls - 4-bromo-3-nitrobiphenyl - 4-bromo-3-methylpyrazole - 4-bromo-3,5-dimethylpyrazole - 12 - 3-bromofuran - 5-bromoindole - 2-bromothiophene - 3-bromothiophene - 2-bromopyridine - 3-bromopyridine - 4-bromopyridine - 4-bromoisoquinoline - 4-bromo-l,2-(methylenedioxy)-benzene.

Of the compounds corresponding to the general formula (II) , the invention relates more especially to the following mono- or poly-halogenated aromatic compounds: - bromobenzene - dibromobenzenes - tribromobenzenes - 1,2,4,5-tetrabromobenzene - hexabromobenzene - bromostyrenes - 2-bromochlorobenzene - bromofluorobenzenes - bromodifluorobenzenes - bromotrifluorobenzenes - bromotetrafluorobenzenes - 2-bromoanisole - 3-bromoanisole - 4-bromoanisole - 2,6-dibromo-4-methylanisole - 2-bromobenzoic acid - 3-bromobenzoic acid - 4-bromobenzoic acid - the methyl ester of (3,5-dibromo-4-acetamido)benzoic acid - the ethyl ester of (3,5-dibromo-4-acetamido)benzoic acid - 13 - the methyl ester of (3,5-dibromo-4-methoxy)benzoic acid - the ethyl ester of (3, 5-dibromo-4-methoxy)benzoic acid - the methyl ester of (3,5-dibromo-4-ethoxy)benzoic acid - the ethyl ester of (3,5-dibromo-4-ethoxy)benzoic acid - 4-bromo-2-(trifluoromethyl)-acetanilide - mono- or poly-brominated biphenyls - 2-bromothiophene - 3-bromothiophene - 2-bromopyridine - 3-bromopyridine - 4-bromopyridine A preferred embodiment of the invention comprises a process for the preparation of alkoxylated aromatic compounds containing at least one hydroxy group of the general formula (Ia): (HOtn-Ro-(O-R)n (la) in which - m and n are integers greater than or equal to 1, the sum of m and n preferably being between 2 and 6, - Ro and R have the meaning given hereinbefore, which process comprises reacting an aromatic compound containing at least one halogen atom and at least one hydroxy group and corresponding to the general formula (Ha) : (Ha) in which: - 14 - m and n are integers greater than or equal to 1, the sum of m and n preferably being between 2 and 6, - X represents an iodine, bromine or chlorine atom, - Ro has the meaning given hereinbefore, - with an alkali metal or alkaline earth metal alcoholate of the general formula (III) MW+ [O - R]w- (III) in which - M represents an alkali metal or alkaline earth metal, - w represents the valency of the alkali metal or alkaline earth metal, - R has the meaning given hereinbefore, in the presence of a copper catalyst which is copper and/or a copper compound, which process is characterised in that the reaction is carried out in the presence of an effective amount of a co-catalyst selected from the organic isocyanides, the isocyanates, and the esters of alkynedioic acids.

There may be mentioned as examples of aromatic compounds containing at least one halogen atom and at least one hydroxy group and corresponding to the general formula (Ila) more especially: - 2-bromophenol - 3-bromophenol - 4-bromophenol - l-bromo-2-naphthol - 6-bromo-2-naphtho1 - 2-bromo-4-methylphenol - 4-bromo-2,6-dimethylphenol - 4-bromo-3,5-dimethylphenol - 2,6-dibromo-4-methylphenol - 15 - 2-bromo-p-cresol - 2-bromo-4-chlorophenol - 4-bromo-2-chlorophenol - 4-bromo-6-chloro-o-cresol - bromofluorophenols - 4-bromo-3,5-dihydroxybenzoic acid - 5-bromo-2,4-dihydroxybenzoic acid - bromo-bis-phenols - bromo-4,4'-isopropylidene-bis-phenols The alkali metal or alkaline earth metal alcoholate used in the process of the invention corresponds to formula (III) in which w is 1 or 2 and R represents: 1° - a linear or branched alkyl, alkenyl, alkadienyl or alkynyl radical preferably containing fewer than 6 carbon atoms, 2° - a cycloalkyl or cycloalkenyl radical preferably containing from 5 to 7 carbon atoms; cyclohexyl, in particular, may be mentioned, 3° - a linear or branched, saturated or unsaturated, acyclic aliphatic radical as defined in 1°, containing a cyclic substituent. Ring denotes a saturated, unsaturated or aromatic carbocyclic ring. Benzyl may be mentioned as an example.

Of the alcoholates mentioned hereinbefore, there are preferably used in the process of the invention alkali metal alcoholates and, more especially, the sodium or potassium alcoholates of primary or secondary alkanols containing from 1 to 4 carbon atoms are particularly suitable.

Those most frequently used are sodium methoxide and sodium ethoxide.

A preferred embodiment of the invention is a process for the preparation of an alkoxylated aromatic compound falling within the definition of formula (I) and corIE 904642 responding more especially to the general formula (Ib): (Ib) in which - R' and R6, which may be the same or different, each represents a linear or branched alkyl radical containing from 1 to 4 carbon atoms, - it also being possible for R$ to represent a hydrogen atom, a linear or branched alkoxy radical containing from 1 to 4 carbon atoms or a hydroxy radical.

The process of the invention for the preparation of an alkoxylated aromatic compound corresponding to the general formula (Ib) is a process which comprises reacting: - an aromatic compound containing at least one halogen atom and at least one hydroxy group and falling within the general definition of formula (II), which is a halohydroxybenzaldehyde corresponding to the general formula (lib): (Hb) in which: - 17 - X represents an iodine, bromine or chlorine atom, - R7 represents a hydrogen atom, an iodine, bromine or chlorine atom, an alkyl radical containing from 1 to 4 carbon atoms, an alkoxy radical containing from 1 to 4 carbon atoms or a hydroxy radical, it being possible for the hydroxy radical in the said formula (lib) to be in the ortho. meta or para position of the aldehyde function, - with an alkali metal or alkaline earth metal alcoholate containing from 1 to 4 carbon atoms, in the presence of a copper catalyst which is copper and/or a copper compound, which process is characterised in that the reaction is carried out in the presence of an effective amount of a co-catalyst selected from the organic isocyanides, the isocyanates, and the esters of alkynedioic acids.

There may be mentioned as examples of the substrates preferably used more especially compounds corresponding to the general formula (lib) in which: • Group I : - the OH radical is in the para position in relation to the CHO function, - the halogen atom X is in the ortho position in relation to the OH radical, - the radical R7 is in the ortho position in relation to the OH radical.

. Group II : - the OH radical is in the ortho position in relation to the CHO function, - the halogen atom X is in the para position in relation to the OH radical, - the radical R7 is in the ortho position in relation to the OH radical.

• Group III : - the OH radical is in the ortho position in - 18 relation to the CHO function, - the halogen atom X is in the ortho position in relation to the OH radical, - the radical R7 is in the para position in relation to the OH radical, . Group IV : - the OH radical is in the meta position in relation to the CHO function, - the halogen atom X is in the ortho position in relation to the OH radical, - the radical R7 is in the para position in relation to the OH radical.

. Group V : - the OH radical is in the meta position in relation to the CHO function, - the halogen atom X is in the para position in relation to the OH radical, - the radical R7 is in the ortho position in relation to the OH radical.

The compounds of formula (lib) preferably used correspond more precisely to the following formulae: (Ilbi) OH R7 j CHO (lib2) X in which - X and R7 have the meanings given hereinbefore.

Especially preferably used in the process of the invention is a halohydroxybenzaldehyde corresponding to the general formula (Ilbj) in which X is a bromine atom and R7 denotes a methoxy or ethoxy radical.

There may be mentioned more specifically as examples of halohydroxybenzaldehydes corresponding to formula (lib) used as substrates in the present process: - 3-bromo-4-hydroxybenzaldehyde, - 3-iodo-4-hydroxybenzaldehyde - 3,5-dibromo-4-hydroxybenzaldehyde - 3,5-diiodo-4-hydroxybenzaldehyde - 5-bromo-3-methoxy-4-hydroxybenzaldehyde - 5-iodo-3-methoxy-4-hydroxybenzaldehyde - 5-bromo-3-ethoxy-4-hydroxybenzaldehyde - 5-iodo-3-ethoxy-4-hydroxybenzaldehyde - 3-bromo-4,5-dihydroxybenzaldehyde - 3-iodo-4,5-dihydroxybenzaldehyde - 3-bromo-2,5-dihydroxybenzaldehyde - 3-iodo-2,5-dihydroxybenzaldehyde - 2-bromo-4-hydroxybenzaldehyde - 2-iodo-4-hydroxybenzaldehyde - 4-bromo-3-hydroxybenzaldehyde - 4-iodo-3-hydroxybenzaldehyde - 3-bromo-2-hydroxybenzaldehyde - 20 - 3-iodo-2-hydroxybenzaldehyde - 5-bromo-2-hydroxybenzaldehyde - 5-iodo-2-hydroxybenzaldehyde.

In a preferred embodiment of the process of the invention for the preparation of alkoxylated aromatic compounds of formula (lb), the alkali metal or alkaline earth metal alcoholate of formula (III) is preferably a sodium or potassium alcoholate of a primary or secondary alkanol containing from 1 to 4 carbon atoms, preferably sodium methoxide or ethoxide.

In accordance with the process of the invention, the aromatic compound containing at least one halogen atom and optionally a hydroxy group and corresponding to formula (II) is reacted with an alkali metal or alkaline earth metal alcoholate of the formula (III) in the presence of a copper catalyst and a co-catalyst selected from the organic isocyanides, the isocyanates, and the esters of alkynedioic acids.

The copper compounds used as catalysts are known. Generally they are any inorganic or organic compounds of copper I or copper II.

Copper metal may be used, but its action is slower because it must first of all be partly converted into copper I or copper II.

There may be mentioned as copper compounds, without any limitation being implied, cuprous chloride, cupric chloride, basic copper(II) carbonate, cuprous nitrate, cupric nitrate, cupric sulphate, cupric acetate, cupric trifluoromethylsulphonate, cupric hydroxide, copper(II) picolinate, copper(I) methoxide, copper(II) methoxide, copper(II) chelate of 8-quinoline, and copper compounds of the formulae C1CuOCH3 and Cu2(OCH3)2(acac)2The organic isocyanides used in the invention are - 21 more especially the isocyanides of the general formula (IV) : CN-R8 (IV) in which Rg represents: - a linear or branched alkyl radical containing from to 12 carbon atoms, - a cycloalkyl radical containing from 5 to 12 carbon atoms, a cycloalkyl radical containing 5 or 12 carbon atoms substituted by one or two alkyl radicals containing from 1 to 12 carbon atoms, - an aryl radical containing from 6 to 12 carbon atoms, - an aryl radical that is substituted by 1 or 2 alkyl radicals containing from 1 to 12 carbon atoms, Of the organic isocyanides, there are generally used compounds of formula (IVa) which correspond to compounds of formula (IV) in which Rg represents: - a linear or branched alkyl radical containing from to 8 carbon atoms, such as ethyl, propyl, isopropyl, n-butyl, sec.-butyl, isobutyl, tert.butyl, n-pentyl, n-hexyl, 2-ethylhexyl or n-octyl, - a cyclohexyl radical, - a phenyl radical, - a benzyl or phenethyl radical.

There may be mentioned as non-limiting examples of such organic isocyanides ethyl isocyanide, n-butyl isocyanide, tert.-butyl isocyanide, phenyl isocyanide and cyclohexyl isocyanide.

The isocyanates used in the invention may be aliphatic, aromatic or cycloaliphatic monoisocyanates or polyisocyanates and their carbamates.

There may be mentioned as non-limiting examples of such isocyanates especially butyl isocyanate, 1,6diisocyanato-hexane, 1,5-diisocyanato-2-methylpentane, 1,4-diisocyanato-2-ethylbutane, isophorone diisocyanate, hexyl isocyanate, phenyl isocyanate, cyclohexyl isocyanate and toluene diisocyanates.

The esters of alkynedioic acids used in the invention are more especially the compounds of the general formula (V): Rg-OOC-C = C-COO-R10 (V) in which R9 and R10, which may be the same or different, each represents: - a linear or branched alkyl radical containing from 1 to 12 carbon atoms, - a cycloalkyl radical containing from 5 to 12 carbon atoms, - a cycloalkyl radical containing from 5 to 12 carbon atoms that is substituted by one or two alkyl radicals containing from 1 to 12 carbon atoms, - an aryl radical containing from 6 to 12 carbon atoms, - an aryl radical that is substituted by 1 or 2 alkyl radicals containing from 1 to 12 carbon atoms.

Of the esters of alkynedioic acids there are preferably used compounds of formula (Va) that correspond to compounds of formula (Va) in which R9 and R10 represent: - a linear or branched alkyl radical containing from 1 to 12 carbon atoms, - a cycloalkyl radical containing 5 or 6 carbon atoms, - a phenyl radical, - a phenyl radical of which the alkyl moiety comprises from 1 to 4 carbon atoms.

There may be mentioned as non-limiting examples of such esters of formula (V) especially dimethyl-2-butyne1,4-dioate, diethy1-2-butyne-l,4-dioate, di-n-propyl-2butyne-l,4-dioate, di-n-butyl-2-butyne-l,4-dioate, bis(2ethylhexyl)2-butyne-l,4-dioate, diphenyl-2-butyne-l,4dioate and dicyclohexyl-2-butyne-l,4-dioate.

In accordance with the process of the invention, the aromatic compound containing at least one halogen atom and optionally a hydroxy group and corresponding to formula (II) is reacted with an alkali metal or alkaline earth metal alcoholate of formula (III) in the presence of a copper catalyst and a co-catalyst selected from the organic isocyanides, the isocyanates, and the esters of alkynedioic acids.

The process of the invention is also suitable when the compound of formula (II) has more than one halogen atom. In that case, polyalkoxylation will be carried out, the only condition being simply to adapt the quantity of the alkali metal or alkaline earth metal alcoholate to be used.

According to the process of the invention, the alkoxylation of the aromatic compound containing at least one halogen atom and optionally a hydroxy group and corresponding to formula (II) is carried out in an organic medium most commonly consisting of the alkanol corresponding to the alkali metal or alkaline earth metal alcoholate used.

The solvent used is preferably methanol or ethanol.

When the alkali metal or alkaline earth metal alcoholate has a carbon condensation greater than 4 carbon atoms, it is desirable to use a solvent that is inert with respect to the reaction, preferably a polar aprotic solvent.

There may be mentioned as examples of polar aprotic solvents suitable for carrying out the process of the invention more especially ethers and, more specifically, dimethyl ethers derived from ethylene oxide or propylene oxide, such as ethylene glycol dimethyl ether (or 1,2dimethoxyethane), diethylene glycol dimethyl ether (or 1,5-dimethoxy-3-oxapentane), 1,8-dimethoxy-3,6-dioxaoctane, 1,ll-dimethoxy-3,6,9-trioxaundecane, 1,2-dimethoxy-l-methylethane, 1,5-dimethoxy-l,4-dimethyl-3oxapentane and 1,7-dimethoxy-l,4-dimethyl-3,6-dioxaoctane.

It is also possible to use a plurality of solvents.

Of the solvents mentioned above, ethylene glycol dimethyl ether and diethylene glycol dimethyl ether are preferred.

The concentration of the compound of formula (II) expressed by weight of the said compound (II) relative to the total weight of compound (II) + solvent, is generally from 3 to 40 % and, preferably, from 10 to 30 %.

The quantity of alkali metal or alkaline earth metal alcoholate used is equal to or greater than the stoichiometric amount necessary on the one hand to convert the halogen atom or atoms into alkoxy groups and, on the other hand, if the aromatic nucleus contains one or a plurality of OH groups, to effect salification of the OH group or groups. In the case where the compound of formula (II) is a phenolic compound, it is converted into alkali metal or alkaline earth metal phenolate.

Generally, the alkali metal or alkaline earth metal alcoholate is used in an amount corresponding to the stoichiometric amount necessary to salify the hydroxy groups plus an amount that is from 1 to 5 times, preferably from 1 to 3 times, the stoichiometric amount necessary to convert the halogen atom or atoms into alkoxy groups.

The concentration of the alkali metal or alkaline - 25 earth metal alcoholate is advantageously higher than mol/litre and is preferably between 1 and 5 mols/litre.

It should be noted that the upper limit is not critical.

Conveniently, the alkali metal or alkaline earth metal alcoholate is formed in situ by reacting excess alkanol with the chosen alkali metal or alkaline earth metal.

The amount of copper catalyst used in the process of the invention can vary over a wide range.

Usually, the molar ratio of copper catalyst to compound of formula (II) is from 1 to 50 %, preferably from 2 % to 20 %.

The amount of unsaturated compound, defined hereinbefore as co-catalyst, normally used in the process of the invention is such that the molar ratio of unsaturated compound to copper catalyst is from 1.0 to 20.0 and preferably from 1.0 to 10.0, most preferably from 1.0 to 5.0.

The amount of unsaturated compound may, as regards its upper limit, also be expressed in relation to the compound of formula (II).

There will thus generally be used a maximum of mols of unsaturated compound per mol of compound of formula (II) and preferably 1 mol of unsaturated compound per mol of compound of formula (II)· The temperature of the alkoxylation reaction is generally between 60°C and 220°C, preferably between 100°C and 180°C.

The pressure is not a critical parameter in itself, but to reach the temperatures indicated above without loss of solvent, the process is usually carried out under autogenous pressure.

Generally this autogenous pressure of the reaction mixture is lower than or equal to 5 mPa (50 bars).

The duration of the alkoxylation reaction may vary widely between 1 and 10 hours, preferably between 2 and 5 hours.

As mentioned hereinbefore, another object of the present invention is a process for the preparation of polyalkoxylated aromatic compounds from alkoxylated aromatic compounds obtained according to the alkoxylation process of the invention.

Thus, it was also found that when the product obtained at the end of the alkoxylation reaction also contained a hydroxy group, this could be subjected to an O-alkylation reaction by adding the alkylation agent directly to the reaction medium.

One variant of the invention thus comprises a process for the preparation of polyalkoxylated aromatic compounds of the general formula (I): (Rl-°tm~R0~(o-R)n (I) in which: - m and n are integers greater than or equal to 1, the sum of m and n preferably being between 2 and 6, - Ro and R have the meaning given hereinbefore, - R^ is a linear or branched alkyl radical containing from 1 to 6 carbon atoms, which process is charaterised in that the following steps are carried out in succession: 1° - an aromatic compound containing at least one halogen atom and at least one hydroxy group and corresponding to the general formula (Ila): (Ha) in which: - m and n are integers greater than or equal to 1, the sum of m and n preferably being between 2 and 6, - X represents an iodine, bromine or chlorine atom, - Ro has the meaning given hereinbefore, is reacted with an alkali metal or alkaline earth metal alcoholate of the general formula (III): MW+ [0 - R]w- (III) in which : - M represents an alkali metal or alkaline earth metal, - w represents the valency of the alkali metal or alkaline earth metal, - R has the meaning given hereinbefore, in the presence of a copper catalyst, which is copper and/or a copper compound, and an effective amount of a co-catalyst chosen from the organic isocyanides, the isocyanates, and the esters of alkynedioic acids. 2° - The 0-alkylation of the hydroxy group or groups of the product so obtained after alkoxylation is effected by adding directly to the organic reaction medium an alkylation agent selected from lower alkyl halides, dialkyl sulphates and dialkyl carbonates.

A preferred embodiment of the invention comprises a process for the preparation of a polyalkoxylated aromatic compound falling within the definition of formula (I) and corresponding more especially to the general formula (Ib«) : CHO in which - R', R'i and Rg, which may be the same or different, each represents a linear or branched alkyl radical containing from 1 to 4 carbon atoms, - it also being possible for Rg to represent a hydrogen atom or a linear or branched alkoxy radical containing from 1 to 4 carbon atoms.

The process according to the invention for the preparation of a polyalkoxylated aromatic compound corresponding to the general formula (Ib1) comprises the following steps: 1° - An aromatic compound containing at least one halogen atom and at least one hydroxy group and falling within the general definition of formula (II), which is a halohydroxybenzaldehyde corresponding to the general formula (lib) as defined hereinbefore, is reacted with an alkali metal or alkaline earth metal alcoholate containing from 1 to 4 carbon atoms, in the presence of a copper catalyst, which is copper and/or a copper compound, and an effective amount of a co-catalyst selected from the organic isocyanides, the isocyanates, and the esters of alkynedioic acids. 2° - The O-alkylation of the hydroxy group or groups of the product so obtained after alkoxylation is effected by adding directly to the organic reaction medium an alkylation agent that supplies the alkyl radical R'^ containing from 1 to 4 carbon atoms.

According to one variant of the process of the invention, the aromatic compound containing at least one halogen atom and at least one hydroxy group and corresponding to formula (Ila) and, preferably, formula (lib), is subjected to an alkoxylation reaction by reacting the said compound with the alkali metal or alkaline earth metal alcoholate, in the presence of a copper catalyst and a co-catalyst of the unsaturated type, then the aromatic compound so obtained containing at least one alkoxy group and at least one hydroxy group is subjected to O-alkylation by reaction with an alkylation agent.

Within the scope of the present invention, for example a 3,4-dialkoxy- and a 3,4,5-trialkoxy-benzaldehyde are prepared from a 3-halo-4-hydroxybenzaldehyde and a 5-halo-4-hydroxy-3-alkoxybenzaldehyde of formula (lib), respectively, by subjecting the substrates first to alkoxylation then to O-alkylation.

In the case where the compound of formula (Ila) contains one or more than one halogen atom and one or more than one hydroxy group, a mono- or poly-alkoxylation, as the case may be, will be carried out in the first step, or a mono- or poly-O-alkylation will be carried out in the second step, the only condition being simply to adapt the quantities of the reactants as a function of the number of groups to be substituted.

In an additional step of the process of the invention, the O-alkylation of the aromatic compound obtained beforehand, which contains at least one alkoxy group and at least one hydroxy group, may be carried out.

For this purpose, the compound is placed in contact with an alkylation agent. It is possible to use alkyl sulphates of the formula Rj-O-302-O-Rj or alkyl carbonates of the formula Rj-O-CO-O-Rj, Rj in the said formulae representing a linear or branched alkyl radical containing from 1 to 6 carbon atoms.

Of the alkylation agents mentioned above, dimethyl sulphate or dimethyl carbonate are preferred.

The preferred alkylation agent according to the invention, however, is a lower alkyl halide corresponding to the general formula (VI): Rj-X (VI) - 30 in which formula X represents a bromine, chlorine or iodine atom and Rj represents a linear or branched alkyl radical containing from 1 to 6 carbon atoms.

Of the halides of formula (VI), it is preferable to use those corresponding to formula (Via) in which X is a chlorine atom and R'^ is a linear or branched alkyl radical containing from 1 to 4 carbon atoms.

A methyl or ethyl halide is most often used.

Of the halides, chlorides, bromides and iodides are generally used and, more specifically, methyl chloride, chloroethane, methyl bromide and bromoethane.

Since they cost less, methyl chloride and chloroethane are preferably used.

One variant of the invention comprises adding to the reaction medium, preferably before the addition of the alkylation agent, a salt in the form of an iodide, so as to have enhanced kinetics. There may be mentioned as salts alkali metal iodides, especially sodium, potassium or lithium iodide.

Generally the O-alkylation reaction follows on directly after the alkoxylation reaction, with the alkylation agent being introduced at the required temperature. In certain cases, however, it may be more advantageous to maintain the pH at a value between 6 and 12 for the duration of the reaction.

When operating at a pH lower than 6, a decrease in O-alkylation as well as a slowing down of that reaction is observed.

Preferably, the pH of the medium is maintained between 9 and 11.

The regulation of the pH can, if necessary, be ensured by the continuous addition of a base, preferably an aqueous solution of an alkali metal hydroxide. Any alkali metal hydroxide may be used. For economic reasons, however, sodium hydroxide is preferred.

With regard to the amount of reactants to be used in - 31 this step of the process of the invention, the preferred amounts are defined hereinafter.

The amount of alkylation agent used is a function of the number of hydroxy groups present on the aromatic nucleus of the intermediate product obtained after alkoxylation. It is preferably at least equal to the stoichiometric amount up to a possible excess of 200 %. Preferably, it is equal to the stoichiometric amount.

By way of example, the molar ratio of alkyl halide to alkoxyhydroxybenzaldehyde varies from 1.0 to 3.0 and, preferably, is in the vicinity of 1.0, and the molar ratio of alkyl halide to alkoxydihydroxybenzaldehyde varies from 2.0 to 6.0 and, preferably, is in the vicinity of 2.0.

The amount of base is so determined that the pH is maintained within the range mentioned above.

The amount of salt in the form of iodide used according to another preferred variant of the invention can also vary widely. Usually, the molar ratio of salt in the form of iodide to alkylation agent varies from 0.05 to 0.20 and is preferably approximately 0.10.

As regards the reaction conditions, the temperature of the O-alkylation reaction is not critical; it has an effect on the kinetics of the reaction. Generally, the O-alkylation reaction is carried out at between 80°C and 200°C. Preferably the reaction is at a temperature of between 100°C and 160°C.

The pressure is not critical. It has an effect on the kinetics of the reaction. It usually varies between atmospheric pressure and 50 bars and is preferably between atmospheric pressure and 20 bars.

The pressure is usually created by the reactive solvent and the alkylation agent used for the O-alkylation, if they are gaseous under the reaction conditions .

The duration of the O-alkylation is a function in - 32 particular of the reaction temperature. It varies most often between 1 hour and 8 hours. Generally a duration of from 1 to 4 hours is sufficient.

According to one practical method of carrying out the invention, all the reactants of the first step may be mixed, that is to say the aromatic compound of formula (II), the copper catalyst and the co-catalyst of the unsaturated type, and after the mixture has been heated for the duration necessary for the alkoxylation reaction, the alkylation agent and optionally a base may be added to the reaction medium.

A preferred mode of carrying out the invention comprises first of all preparing a solution of the alkali metal alcoholate in the corresponding alkanol at a concentration of, for example, 20 to 50 % by weight.

The apparatus is charged, under an inert gas atmosphere, preferably a nitrogen atmosphere, with the aromatic compound of formula (II) , the copper catalyst, then the co-catalyst of the unsaturated type, and then the alkali metal alcoholate solution is introduced.

The reaction medium is then heated to a temperature of between 60°C and 220°C, preferably between 100°C and 180°C, for the predetermined duration.

The alkylation agent, preferably the alkyl halide, which may be liquid or gaseous, is then introduced, and the solution of alkali metal hydroxide, if this is required for adjusting the pH in the aforementioned range, is injected or introduced in parallel.

Heating is maintained between 80°C and 200°C, preferably between 100°C and 160°C, for the period necessary for the O-alkylation reaction.

When the reaction is complete, the polyalkoxylated aromatic compound of formula (I) obtained is separated according to conventional separation methods, either by distillation or by extraction with an appropriate - 33 solvent, for example toluene in the case of 3,4,5trimethoxybenzaldehyde.

It is possible to remove the copper catalyst from the reaction medium by conventional treatments, especially by treatment with an acid.

The process of the invention permits alkoxylation, with a very good yield, of any substrate carrying a halogen atom.

Another advantage of the process of the invention is that, in its preferred form, it uses a common solvent that presents few problems and is readily recyclable.

The process of the invention is particularly suitable for the preparation of the following alkoxybenzaldehydes: - 3,4,5-trimethoxybenzaldehyde - 3,4-dimethoxybenzaldehyde - 3,4-diethoxybenzaldehyde - 3-ethoxy-4-methoxybenzaldehyde The 3,4,5-trimethoxybenzaldehyde which can be prepared according to the process of the invention is used especially for the preparation of pharmaceutical products.

One of the particularly interesting advantages of the process of the invention is that it enables the alkoxylation reaction to be carried out without it being necessary to protect the aldehyde function.

Another advantage of the process of the invention is that it permits the alkoxylation and O-alkylation reactions to be carried out in succession in the same reactor.

In the case of the preparation of 3,4,5-trimethoxybenzaldehyde, its preparation from 5-bromo-4-hydroxy-3methoxybenzaldehyde is carried out in a substantially homogeneous organic medium, without separation of the alkoxylated intermediate product, which is very advantageous from a commercial point of view.

The Examples which follow illustrate the invention but do not constitute any limitation.

In the Examples the abbreviations have the following meanings: BHMB : 5-bromo-4-hydroxy-3-methoxybenzaldehyde BHB : 3-bromo-4-hydroxybenzaldehyde syringaldehyde : 4-hydroxy-3,5-dimethoxybenzaldehyde Number of mols of converted compound of formula (II) TT = - % Number of mols of compound of formula (II) introduced Number of mols of compound of formula (I) formed RT = - % Number of mols of compound of formula (II) converted Number of mols of compound of formula (I) formed RR = - % Number of mols of compound of formula (II) introduced EXAMPLE 1 Methoxylation of 5-bromo-4-hvdroxy-3-methoxvbenzaldehvde The following are introduced into a 40 cm3 Teflon-coated reactor equipped with a heating system and stirring means: - 2.22 g (0.0096 mol) of 5-bromo-4-hydroxy-3-methoxybenzaldehyde (BHMB) - 2.16 g (0.040 mol) of sodium methoxide - 25 cm3 of methanol - 0.099 g (0.001 mol) of cuprous chloride - 0.4 cm3 (0.0038 mol) of n-butyl isocyanide.

The whole is heated for 3 hours at 125°C with stirring. The reaction mixture is cooled to room temperature and then diluted with 80 cm3 of distilled water. The pH of the resulting mixture is then adjusted to 4 with sulphuric acid.

The insoluble portion is filtered off and the BHMB that remains and the syringaldehyde (4-hydroxy-3,5-dimethoxybenzaldehyde) that has been formed are determined by high-performance liquid chromatography (HPLC).

The following results are obtained: - conversion (TT) of the BHMB : 100% - yield (RT) of syringaldehyde relative to converted BHMB : 94% EXAMPLE 2 Methoxylation of 5-bromo-4-hydroxy-3-methoxvbenzaldehvde Example 1 is repeated using the same charges and the same operating conditions, but the n-butyl isocyanide is replaced by tert.-butyl isocyanide. : 98% : 99% The following results are obtained: - conversion (TT) of the BHMB - yield (RT) of syringaldehyde EXAMPLE 3 Methoxvlation of 5-bromo-4-hvdroxv-3-methoxvbenzaldehvde Example 1 is repeated using the same charges and the same operating conditions, but the n-butyl isocyanide is replaced by 0.476 g (0.004 mol) of phenyl isocyanate and the cuprous chloride is replaced by 0.110 g (0.0005 mol) of basic copper(II) carbonate of the formula CuCO3,Cu(OH)2.

The following results are obtained: - conversion (TT) of the BHMB : 95% - yield (RT) of syringaldehyde : 99% EXAMPLE 4 Methoxvlation of 3-bromo-4-hvdroxvbenzaldehyde The following are introduced into a 40 cm3 Teflon-coated reactor equipped with a heating system and magnetic stirring means: - 1.02 g (0.005 mol) of 3-bromo-4-hydroxybenzaldehyde (BHB) - 1.08 g (0.020 mol) of sodium methoxide - 10 cm3 of methanol - 0.055 g (0.00025 mol) of basic copper(II) carbonate of the formula CuC03,Cu(OH)2 - 0.2 cm3 (0.0019 mol) of n-butyl isocyanide.

The whole is heated for 4¾ hours at 125°C with stirring.

The reaction mixture is cooled to room temperature and diluted with distilled water. The pH of the reaction mixture is adjusted to 4 with sulphuric acid, and the mixture is determined by HPLC. : 75% : 99% The following results are obtained: - conversion (TT) of the BHB - yield (RT) of vanillin EXAMPLE 5 Methoxvlation of 3-bromo-4-hvdroxybenzaldehvde Example 4 is repeated using the same charges and the same operating conditions, but the n-butyl isocyanide is replaced by tert.-butyl isocyanide.

The following results are obtained: - conversion (TT) of the BHB : 88% - yield (RT) of vanillin : 93% EXAMPLE 6 Methoxvlation of 5-bromo-4-hvdroxv-3-methoxvbenzaldehvde Example 1 is repeated using the same charges and the same operating conditions, but the n-butyl isocyanide is replaced by 0.577 g (0.004 mol) of dimethyl-2-butyne-l,4dioate.

The following results are obtained: - conversion (TT) of the BHMB : 100% - yield (RT) of syringaldehyde : 97% EXAMPLE 7 Methoxylation of bromobenzene The following are introduced into a 40 cm3 Teflon-coated reactor equipped with a heating system and stirring - 38 means: - 1.57 g (0.010 mol) of bromobenzene - 2.71 g (0.015 mol) of a 30% solution of sodium methoxide in methanol - 0.110 g (0.0005 mol) of basic copper(II) carbonate of the formula CuC03,Cu(OH)2 - 0.44 g (0.004 mol) of cyclohexyl isocyanide.

The whole is heated for 5¾ hours at 125°C.

After the reaction medium has been treated as in Example 1, 0.83 g of anisole is determined by gas-phase chromatography, which corresponds to a yield (RR) of 76.4%.

EXAMPLE 8 Methoxvlation of bromobenzene Example 7 is repeated, but the cyclohexyl isocyanide is replaced by 0.57 g (0.004 mol) of dimethyl-2-butyne-l,4dioate. 0.96 g of anisole is obtained, which corresponds to a yield (RR) of 88.8%.

EXAMPLE 9 Methoxvlation of 5-bromo-4-hydroxy-3-methoxybenzaldehyde followed bv methylation The following are introduced under a nitrogen atmosphere into a 3.9 litre stainless steel reactor equipped with a heating system and stirring means: - 170.5 g (0.738 mol) of 5-bromo-4-hydroxy-3-methoxybenzaldehyde (BHMB) - 162 g of sodium methoxide - 1785 cm3 (1428 g) of methanol - 8.3 g (0.0377 mol) of basic copper(II) carbonate of the formula CuC03,Cu(OH)2 - 29.7 g (0.300 mol) of n-butyl isocyanide.

The whole is heated for 4 hours at 125°C with stirring, under autogenous pressure, in order to carry out the methoxylation reaction.

The reaction mixture is cooled to 120°C and then 150 g of methyl chloride are introduced. The reaction mixture is kept at 12 0°C for 3 hours and is then cooled to room temperature. The insoluble portion is separated off by filtration.

The BHMB that has not reacted and the 3,4,5-trimethoxybenzaldehyde obtained are determined by high-performance liquid chromatography.

The results obtained are as follows: - conversion of the BHMB (TTBHMB %) = - yield of TMBA (R,lTMBA = - yield of syringaldehyde (RTsyringaldehyde %) = 100% 82% 16%

Claims (41)

1. Process for the preparation of polyalkoxylated aromatic compounds of the general formula (I): ( R 1 °tm“ R o—t°~ R )n (I) in which m and n are integers, n is an integer greater than or equal to 1, m is an integer greater than or equal to 0, . the sum of m and n preferably being between 1 and 6, R o represents a cyclic aromatic radical containing at least 5 atoms in the ring, optionally substituted and representing at least one of the following radicals : . an aromatic, monocyclic or polycyclic carbocyclic radical, an aromatic, monocyclic or polycyclic heterocyclic radical containing at least one of the hetero atoms Ο, N and S, R represents a hydrocarbon radical containing from 1 to 12 carbon atoms which may be a linear or branched, saturated or unsaturated, acyclic aliphatic radical; a saturated or unsaturated, monocyclic or polycyclic, cycloaliphatic radical; or a linear or branched, saturated or unsaturated, cycloaliphatic or arylaliphatic radical; Rj is a linear or branched alkyl radical containing from 1 to 6 carbon atoms, which process comprises reacting: - an aromatic compound containing at least one halogen atom and, optionally, a hydroxy group and corresponding to the general formula (II): (HOfjjj-R^—(X) n (II) in which: - m and n are integers, . n is an integer greater than or equal to 1, . m is an integer greater than or equal to 0, . the sum of m and n preferably being between 1 and 6, X represents an iodine, bromine or chlorine atom, - R o represents a cyclic aromatic radical containing at least 5 atoms in the ring, optionally substituted and representing at least one of the following radicals : . an aromatic, monocyclic or polycyclic carbocyclic radical, . an aromatic, monocyclic or polycyclic heterocyclic radical containing at least one of the hetero atoms 0, N and S, - with an alkali metal or alkaline earth metal alcoholate of the general formula (III): M w+ [O-R] w - (III) in which: - M represents an alkali metal or alkaline earth metal, - w represents the valency of the alkali metal or alkaline earth metal, - R represents a hydrocarbon radical containing from 1 to 12 carbon atoms which may be a linear or branched, saturated or unsaturated, acyclic aliphatic radical; a saturated or unsaturated, monocyclic or polycyclic, cycloaliphatic radical; or a linear or branched, saturated or unsaturated, cycloaliphatic or arylaliphatic radical; in the presence of a copper catalyst, which is copper - 42 and/or a copper compound, which process is characterised in that the reaction is carried out in the presence of an effective amount of a co-catalyst which is an unsaturated compound selected from the organic isocyanides, the isocyanates, and the esters of alkynedioic acids.

2. Process according to claim 1, characterised in that the aromatic compound of formula (II) is an aromatic compound containing at least one halogen atom and at least one hydroxy group and corresponding to the general formula (Ila): (HOj (Ha) in which: m and n are integers greater than or equal to 1, the sum of m and n preferably being between 2 and 6, X represents an iodine, bromine or chlorine atom, R o has the meaning given hereinbefore.

3. Process according to either claim 1 or claim 2, characterised in that the aromatic compound containing at least one halogen atom and optionally a hydroxy group corresponds to the general formula (II) in which R o represents 1°) an aromatic, monocyclic or polycyclic carbocyclic radical, 2°) an aromatic, monocyclic or polycyclic heterocyclic radical, 3°) a divalent radical composed of an arrangement of groups, such as those defined in paragraphs 1 and/or 2, bonded to one another: . by a valency bond, by an alkylene or alkylidene radical containing from 1 to 4 carbon atoms, preferably a methylene or isopropylidene radical, by one of the following groups: -o- , -CO- , -s- , —SO— , —so 2 — , -N- , -CO—N1 R 2 R 2 in which formulae R 2 represents a hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms, a cyclohexyl or phenyl radical.

4. Process according to one of claims 1 to 3, characterised in that the aromatic compound containing at least one halogen atom and, optionally, a hydroxy group corresponds to the general formula (II) in which R o is substituted by one or a plurality of substituents such as: - a radical of the formula -R 3 -OH in which the radical R 3 represents a valency bond or a linear or branched, saturated or unsaturated, divalent hydrocarbon radical containing from 1 to 4 carbon atoms, such as, for example, methylene, ethylene, propylene, isopropylene or isopropylidene, - a linear or branched alkyl radical containing from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl or tert.-butyl, - a linear or branched alkenyl radical containing from 2 to 6 carbon atoms, preferably from 2 to 4 carbon atoms, such as vinyl or allyl, - a linear or branched alkoxy radical containing from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, such as a methoxy, ethoxy, propoxy, isopropoxy or butoxy radical, - a group -CHO, - an acyl group containing from 2 to 6 carbon atoms, - a radical of the formula -R3-COOH, R 3 having the meaning given hereinbefore, - a radical of the formula -R 3 -COOR 4 in which R 3 has the meaning given hereinbefore and R 4 represents a linear or branched alkyl radical containing from 1 to 6 carbon atoms, - a radical of the formula -R 3 -NH 2 with an Nprotected NH 2 group, R 3 having the meaning given hereinbefore, - a radical of the formula -R 3 -N(R 5 ) 2 in which R 3 has the meaning given hereinbefore and each of the R5 radicals, which may be the same or different, represents a hydrogen atom or a linear or branched alkyl radical containing from 1 to 6 carbon atoms, - a radical of the formula -R 3 -CO-N(R 5 ) 2 , R 3 and R5 having the meaning given hereinbefore, - a radical of the formula -R 3 -Z in which R 3 has the meaning given hereinbefore and Z denotes a halogen atom X, such as defined hereinbefore, a fluorine atom or a CF 3 group.

5. Process according to one of claims 1 to 4, characterised in that the aromatic compound containing at least one halogen atom and optionally a hydroxy group corresponds to the general formula (II) in which R o is a benzene nucleus.

6. Process according to claim 1, characterised in that the aromatic compound containing at least one halogen atom and corresponding to the general formula (II) is selected from: - bromobenzene - dibromobenzenes - tribromobenzenes - 1,2,4,5-tetrabromobenzene - hexabromobenzene - bromostyrenes - 2-bromochlorobenzene - bromofluorobenzenes - bromodifluorobenzenes - bromotrifluorobenzenes - bromotetrafluorobenzenes - 2-bromoanisole - 3-bromoanisole - 4-bromoanisole - 2,6-dibromo-4-methylanisole - 2-bromobenzoic acid - 3-bromobenzoic acid - 4-bromobenzoic acid - the methyl ester of (3,5-dibromo-4-acetamido) benzoic acid - the ethyl ester of (3,5-dibromo-4-acetamido)benzoic acid - the methyl ester of (3,5-dibromo-4-methoxy)benzoic acid - the ethyl ester of (3,5-dibromo-4-methoxy)benzoic acid - the methyl ester of (3,5-dibromo-4-ethoxy)benzoic acid - the ethyl ester of (3,5-dibromo-4-ethoxy)benzoic acid - 4-bromo-2-(trifluoromethyl)-aniline - mono- or poly-brominated biphenyls - 2-bromothiophene - 3-bromothiophene - 2-bromopyridine - 3-bromopyridine - 4-bromopyridine.

7. Process according to claim 2, characterised in that the aromatic compound containing at least one halogen atom and at least one hydroxy group and corresponding to the general formula (Ila) is selected from: - 2-bromophenol - 3-bromophenol - 4-bromophenol - l-bromo-2-naphthol - 6-bromo-2-naphthol - 2-bromo-4-methylphenol - 4-bromo-2,6-dimethylphenol - 4-bromo-3,5-dimethylphenol - 2,6-dibromo-4-methylphenol - 2-bromo-p-cresol - 2-bromo-4-chlorophenol - 4-bromo-2-chlorophenol - 4-bromo-6-chloro-o-cresol - bromofluorophenols - 4-bromo-3,5-dihydroxybenzoic acid - 5-bromo-2,4-dihydroxybenzoic acid - bromo-bis-phenols - bromo-4,4 *-isopropylidene-bis-phenols

8. Process according to either claim 1 or claim 2, characterised in that the aromatic compound containing at least one halogen atom and at least one hydroxy group is a halohydroxybenzaldehyde corresponding to the general formula (lib) : (Hb) - 47 in which: - X represents an iodine, bromine or chlorine atom, - R 7 represents a hydrogen atom, an iodine, bromine or chlorine atom, an alkyl radical containing from 1 to 4 carbon atoms, an alkoxy radical containing from 1 to 4 carbon atoms or a hydroxy radical, it being possible for the hydroxy radical in the said formula (lib) to be in the ortho, meta or para position of the aldehyde function.

9. Process according to claim 8, characterised in that the halohydroxybenzaldehyde corresponds to the general formula (lib) in which: • Group I : - the OH radical is in the para position in relation to the CHO function, - the halogen atom X is in the ortho position in relation to the OH radical, - the radical R 7 is in the ortho position in relation to the OH radical. • Group II : - the OH radical is in the ortho position in relation to the CHO function, - the halogen atom X is in the para position in relation to the OH radical, - the radical R 7 is in the ortho position in relation to the OH radical. . Group III : - the OH radical is in the ortho position in relation to the CHO function, - the halogen atom X is in the ortho position in relation to the OH radical, - the radical R 7 is in the para position in relation to the OH radical, . Group IV : - the OH radical is in the meta position in relation to the CHO function, - the halogen atom X is in the ortho position in relation to the OH radical, - the radical R 7 is in the para position in relation to the OH radical. . Group V : - the OH radical is in the meta position in relation to the CHO function, - the halogen atom X is in the para position in relation to the OH radical, - the radical R 7 is in the ortho position in relation to the OH radical.

10. Process according to one of claims 8 and 9, characterised in that the halohydroxybenzaldehyde corresponds to one of the following formulae (lib!) (IIb 2 ) (IIb 3 ) in which - X and R 7 have the meanings given hereinbefore.

11. Process according to any one of claims 8 to 10 , characterised in that the halohydroxybenzaldehyde is selected from: - 3-bromo-4-hydroxybenzaldehyde, - 3-iodo-4-hydroxybenzaldehyde - 3,5-dibromo-4-hydroxybenzaldehyde - 3,5-diiodo-4-hydroxybenzaldehyde - 5-bromo-3-methoxy-4-hydroxybenzaldehyde - 5-iodo-3-methoxy-4-hydroxybenzaldehyde - 5-bromo-3-ethoxy-4-hydroxybenzaldehyde - 5-iodo-3-ethoxy-4-hydroxybenzaldehyde - 3-bromo-4,5-dihydroxybenzaldehyde - 3-iodo-4,5-dihydroxybenzaldehyde - 3-bromo-2,5-dihydroxybenzaldehyde - 3-iodo-2,5-dihydroxybenzaldehyde - 2-bromo-4-hydroxybenzaldehyde - 2-iodo-4-hydroxybenzaldehyde - 4-bromo-3-hydroxybenzaldehyde - 4-iodo-3-hydroxybenzaldehyde - 3-bromo-2-hydroxybenzaldehyde - 3-iodo-2-hydroxybenzaldehyde - 5-bromo-2-hydroxybenzaldehyde - 5-iodo-2-hydroxybenzaldehyde.

12. Process according to one of claims 1 to 11, characterised in that the alkali metal or alkaline earth metal alcoholate corresponds to the general formula (III) in which R represents a linear or branched alkyl, alkenyl, alkadienyl or alkynyl radical preferably containing fewer than 6 carbon atoms or a cyclohexyl or benzyl radical.

13. Process according to one of claims 1 to 12, characterised in that the alkali metal alcoholate is a sodium or potassium alcoholate of a primary or secondary alkanol containing from 1 to 4 carbon atoms.

14. Process according to one of claims 1 to 13, characterised in that the alkali metal alcoholate is sodium methoxide or sodium ethoxide.

15. Process according to one of claims 1 to 14, characterised in that the catalyst is an organic or inorganic copper(I) or copper(II) compound selected from cuprous chloride, cupric chloride, basic copper(II) carbonate, cuprous nitrate, cupric nitrate, cupric sulphate, cupric acetate, cupric trifluoromethylsulphonate, cupric hydroxide, copper(II) picolinate, copper(I) methoxide, copper(II) methoxide, copper(II) chelate of 8-quinoline, and copper compounds of the formulae CICuOCHg and Cu 2 (OCH3) 2 (acac) 2 .

16. Process according to one of claims 1 to 15, characterised in that the co-catalyst is an isocyanide of the general formula (IV): CN-R 8 (IV) in which R 8 represents: - a linear or branched alkyl radical containing from 1 to 12 carbon atoms, - a cycloalkyl radical containing from 5 to 12 carbon atoms, - a cycloalkyl radical containing 5 or 12 carbon atoms that is substituted by one or two alkyl radicals containing from 1 to 12 carbon atoms, - an aryl radical containing from 6 to 12 carbon - 51 atoms, - an aryl radical that is substituted by 1 or 2 alkyl radicals containing from 1 to 12 carbon atoms.

17. Process according to claim 16, characterised in that the co-catalyst is an isocyanide of the general formula (IVa) CN-R 8 (IVa) in which Rg represents: - a linear or branched alkyl radical containing from 2 to 8 carbon atoms, - a cyclohexyl radical, - a phenyl radical, - a benzyl or phenethyl radical.

18. Process according to either claim 16 or claim 17, characterised in that the co-catalyst is an isocyanide selected from ethyl isocyanide, n-butyl isocyanide, tert.-butyl isocyanide, phenyl isocyanide and cyclohexyl isocyanide.

19. Process according to one of claims 1 to 15, characterised in that the co-catalyst is an aliphatic, aromatic or cycloaliphatic monoisocyanate or polyisocyanates or a carbamate thereof.

20. Process according to claim 19, characterised in that the co-catalyst is an isocyanate selected from butyl isocyanate, 1,6-diisocyanato-hexane, 1,5-diisocyanato-2methylpentane, 1,4-diisocyanato-2-ethylbutane, isophorone diisocyanate, hexyl isocyanate, phenyl isocyanate, cyclohexyl isocyanate and toluene diisocyanates. - 52

21. Process according to one of claims 1 to 15, characterised in that the co-catalyst is an ester of an alkynedioic acid of the general formula (V): R 9 -OOC-C = C-COO-R 10 (V) in which Rg and R 10 , which may be the same or different, each represents: - a linear or branched alkyl radical containing from 1 to 12 carbon atoms, - a cycloalkyl radical containing from 5 to 12 carbon atoms, - a cycloalkyl radical containing from 5 to 12 carbon atoms that is substituted by one or two alkyl radicals containing from 1 to 12 carbon atoms, - an aryl radical containing from 6 to 12 carbon atoms, - an aryl radical that is substituted by 1 or 2 alkyl radicals containing from 1 to 12 carbon atoms.

22. Process according to claim 21, characterised in that the co-catalyst is an ester of an alkynedioic acid of the general formula (Va) Rg-OOC-C = C-COO-R 10 (Va) in which Rg and R 10 , which may be the same or different, each represents: - a linear or branched alkyl radical containing from 1 to 12 carbon atoms, - a cycloalkyl radical containing 5 or 6 carbon atoms, - a phenyl radical, - a phenyl radical of which the alkyl moiety comprises from 1 to 4 carbon atoms.

23. Process according to either claim 21 or claim 22, characterised in that the co-catalyst is an ester of alkynedioic acids selected from dimethyl-2-butyne-l,4dioate, diethyl-2-butyne-l,4-dioate, di-n-propyl-2butyne-l,4-dioate, di-n-butyl-2-butyne-l,4-dioate, bis(2ethylhexyl)2-butyne-l,4-dioate, diphenyl-2-butyne-l,4dioate and dicyclohexyl-2-butyne-l,4-dioate.

24. Process according to one of claims 1 to 23, characterised in that the alkali metal or alkaline earth metal alcoholate is used in an amount corresponding to the stoichiometric amount necessary to salify the hydroxy groups plus an amount that is from 1 to 5 times, preferably from 1 to 3 times, the stoichiometric amount necessary to convert the halogen atom or atoms into alkoxy groups.

25. Process according to one of claims 1 to 24, characterised in that the concentration of the alkali metal or alkaline earth metal alcoholate is higher than 1 mol/litre and is preferably between 1 and 5 mols/litre.

26. Process according to one of claims 1 to 25, characterised in that the molar ratio of copper compound to compound of formula (II) is from 1 % to 50 %, preferably from 2 % to 20 %.

27. Process according to one of claims 1 to 26, characterised in that the reaction is carried out in a solvent consisting of the alkanol corresponding to the alkali metal or alkaline earth metal alcoholate used.

28. Process according to claim 27, characterised in that the initial concentration of the compound of formula (II) - 54 relative to the mixture of compound (II) and solvent, is from 3 % to 40 % by weight and, preferably, from 10 % to 30 % by weight.

29. Process according to one of claims 1 to 28, characterised in that the molar ratio of co-catalyst to copper compound is from 1.0 to 20.0 and preferably from 1.0 to 10.0, most preferably from 1.0 to 5.0.

30. Process according to one of claims 1 to 29, characterised in that the alkoxylation reaction is carried out at a temperature of from 60°C to 220°C, preferably from 100°C to 180’C.

31. Process according to one of claims 1 to 5 and 7 to 30, characterised in that, in a following step, the Oalkylation of the hydroxy group or groups of the product obtained beforehand by reaction of an aromatic compound of formula (Ila) which contains at least one halogen atom and at least one hydroxy group with an alkali metal or alkaline earth metal alcoholate of formula (III), in the presence of a catalyst and a co-catalyst as defined, is carried out by adding directly to the organic reaction medium an alkylation agent selected from lower alkyl halides, dialkyl sulphates and dialkyl carbonates.

32. Process according to claim 31, characterised in that the alkylation agent in the O-alkylation reaction is dimethyl sulphate or dimethyl carbonate.

33. Process according to claim 31, characterised in that the alkylation agent is a lower alkyl halide correspondIE 904642 - 55 ing to the general formula (VI) : Rj-X (VI) in which formula X represents a bromine, chlorine or iodine atom and Rj represents a linear or branched alkyl radical containing from 1 to 6 carbon atoms.

34. Process according to claim 33, characterised in that the alkylation agent is methyl chloride, chloroethane, methyl bromide or bromoethane.

35. Process according to one of claims 31 to 34, characterised in that the amount of alkyl halide expressed in relation to the amount of compound of formula (II) varies from the stoichiometric amount to a possible excess of 200 %, but is preferably equal to the stoichiometric amount.

36. Process according to one of claims 31 to 35, characterised in that a salt in the form of an alkali metal iodide, preferably sodium iodide, is introduced before the alkylation agent.

37. Process according to one of claims 31 to 36, characterised in that the O-alkylation reaction is carried out at a pH of the reaction mixture of between 6 and 12, preferably between 9 and 11.

38. Process according to one of claims 31 to 37, characterised in that the O-alkylation reaction is carried out at between 80°C and 200°C, preferably at between 100°C and 160°C.

39. Process according to one of claims 1 to 38, characterised in that the mono- or poly-alkoxylated aromatic compound of formula (I) is one of the following compounds : - methoxybenzene - 1,2-dimethoxybenzene - 2-methoxyphenol - 4-methoxyphenol - 3,4,5-trimethoxybenzaldehyde - 3,4-dimethoxybenzaldehyde - 3,4-diethoxybenzaldehyde - 3-ethoxy-4-methoxybenzaldehyde.

40. A process according to claim 1 for the preparation of a polyalkoxylated aromatic compound of the general formula (I) given and defined therein, substantially as hereinbefore described and exemplified.

41. A polyalkoxylated aromatic compound of the general formula (I) given and defined in claim 1, whenever prepared by a process claimed in a preceding claim.