FR2669025A1 - Process for the preparation of alkoxybenzaldehydes - Google Patents

Abstract

The aim of the present invention is a process for the preparation of alkoxybenzaldehydes and more particularly of 3,4-dialkoxybenzaldehydes and 3,4,5-trialkoxybenzaldehydes. More precisely, the invention is a process for the preparation of an alkoxybenzaldehyde from a halo-4-hydroxybenzaldehyde, characterised in that the following stages are carried out: 1 - A halo-4-hydroxybenzaldehyde is reacted with an alkali metal alkoxide having from 1 to 4 carbon atoms in the presence of a copper catalyst and of a cocatalyst chosen from formamides or their acetals or carbon monoxide precursors. 2 - There is carried out at least one etherification in the 4-position of the product obtained above after alkoxylation, by directly adding an alkylating agent chosen from lower alkyl halides, dialkyl sulphates or dialkyl carbonates to the organic reaction mixture. 3,4,5-Trimethoxybenzaldehyde, which can be prepared according to this process, is used in particular for the preparation of pharmaceutical products.

Description

PROCESS FOR THE PREPARATION OF ALKOXYBENZALDEHYDES
The present invention relates to a process for the preparation of alkoxybenzaldehydes and more particularly of 3,4-dialkoxy benzaldehydes and of 3,4,5-trialkoxy benzaldehydes. The invention relates inter alia to the preparation of 3,4,5,5-trimethoxy benzaldehyde from 5-bromo-4-hydroxy-3-methoxy-benzaldehyde commonly known as "5-bromo-vanillin".

 A conventional route for preparing 3,4,5,5-trimethoxy benzaldehyde from 5-bromo-vanillin consists in hydrolyzing the bromine atom using an aqueous sodium hydroxide solution and in the presence of copper.

 After isolation of 4,5-dihydroxy-3-methoxy-benzaldehyde (or 5-hydroxy-vanillin), this leads to 3,4,5-trimethoxy-benzaldehyde after methylation using dimethyl sulphate or methyl chloride.

 Thus, patent FR-A 2 177 693 describes the methylation of hydroxy-5 vanillin by dimethyl sulfate, in the presence of an alkali metal carbonate.

 Hydroxy-5 vanillin is itself obtained by hydrolysis of bromo-5 vanillin and is then extracted, in particular, with toluene for 47 hours, recrystallized, washed and dried.

 The isolation phase of 5-hydroxy vanillin is therefore long and costly. In addition, the catalyst cannot be recovered and recycled.

 Before avoiding the intermediate separation of 5-hydroxy vanillin, there has been proposed according to patent FR-A 2 609 984, a process for the preparation of 4,5-dialkoxy-3-methoxy-benzaldehyde from 5-bromo vanillin which consists in carrying out successively, the hydrolysis of 5-bromo vanillin to 5-hydroxy vanillin, with an alkali metal hydroxide, in water and in the presence of a copper catalyst, then the etherification of 5-hydroxy vanillin using a lower alkyl halide, in an aqueous medium and maintaining the pH between 6 and 12, optionally in the presence of a catalyst.

 A major drawback of this process is that there is a formation, on hydrolysis of the bromo-5 vanillin, of a relatively large amount of vanillin approximately 10 to 15% which, after the etherification reaction, leads to the veratric aldehyde (3,4-dimethoxy benzaldehyde).

 Veratric aldehyde can be separated from 3,4,5 trimethoxy benzaldehyde by distillation. However, the recovery of 3,4,5,5-trimethoxy benzaldehyde from the reaction medium is made more complicated due to the presence of veratric aldehyde.

To overcome this drawback, the present invention provides a new process for the preparation of an alkoxybenzaldehyde of general formula (I)

in which R, R 'and R ", which are identical or different, represent a
linear or branched alkyl radical having from 1 to 4 atoms of
carbon; R "can also represent a hydrogen atom,
a linear or branched alkoxy radical having from 1 to 4 atoms of
carbon, characterized by the fact that one successively performs
the following steps 10 - A 4-hydroxy halo benzaldehyde of general formula (II) is reacted:

in which X represents a bromine, chlorine or
iodine; R1 represents a bromine, chlorine or iodine atom; a
hydroxyl group; a hydrogen atom; an alkyl radical li
nary or branched having from 1 to 4 carbon atoms; a radical
linear or branched alkoxy having from 1 to 4 carbon atoms, with an alkali metal alcoholate having from 1 to 4 carbon atoms, in the presence of a copper catalyst which is copper or / a copper compound and a effective amount of a co-catalyst chosen from formamides or their acetals or compounds that generate carbon monoxide.

20 - At least one etherification is carried out in position 4, of the product obtained previously after alkoxylation, by addition directly to the organic reaction medium of an alkylating agent chosen from lower alkyl halides, dialkylsulfates, dialkylcarbonates.

 In accordance with the process of the invention, the preparation of 3,4,5,5-trimethoxy benzaldehyde is carried out, from 5-bromo-4-hydroxy-3-methoxy-benzaldehyde, in an essentially homogeneous organic medium, without separation of the alkoxylated intermediate product, this which is very advantageous from an industrial point of view.

 Compared to the process described in FR-A 2 609 984, the separation of 3,4,5-trimethoxybenzaldehyde is simpler, since there is no formation of veratric aldehyde which must then be separated.

 According to the present invention, a 3,4-dialkoxy or a 3,4,5-trialkoxy-benzaldehyde is prepared from a 4-hydroxy halo-benzaldehyde of formula (II) by first subjecting it to an alkoxylation reaction then an etherification reaction.

 In the case where the compound of formula (II) has two halogen atoms or two hydroxyl groups, a dialkoxylation will be carried out at -3.5 respectively in the first step or a di-etherification at -3.4 in the second step , the only condition being only to adapt the amounts of reagents according to the number of groups to be substituted.

 Whether the compound of formula (II) carries one or two halogen atoms or hydroxyl groups, of an alkyl or alkoxy radical, it will be designated throughout the description of the present invention by the expression "4-hydroxy halo benzaldehyde".

 Among the 4-hydroxy halo benzaldehydes of formula (II) which serve as starting substrates in the present process, bromo-3, dibromo-3,5, iodo-3 and diodo-3,5 hydroxy-4 benzaldehydes are particularly suitable good.

As examples of such substrates, mention may be made of
- 3-bromo-4-hydroxy benzaldehyde,
- iodo-3 hydroxy-4 benzaldehyde
- 3,5-dibromo-4-hydroxy benzaldehyde
- 3,5-diiodo-4-hydroxy benzaldehyde
- 3-bromo-5-methoxy-4-hydroxy benzaldehyde
- 3-iodo-5-methoxy-4-hydroxy-benzaldehyde
- 3-bromo-5-ethoxy-4-hydroxy benzaldehyde
- 3-iodo-5-ethoxy-4-hydroxy benzaldehyde
- 3-bromo-4,5 dihydroxy benzaldehyde
- iodo-3 dihydroxy-4,5 benzaldehyde
In the first step of the process of the invention, a 4-hydroxy halo-benzaldehyde is therefore used, preferably corresponding to the general formula (II) in which X is a bromine atom and
R1 symbolizes a methoxy or ethoxy radical.

 A compound of general formula (II) is therefore reacted according to the invention, with an alkali metal alcoholate, in the presence of a copper catalyst and a co-catalyst such as a formamide or its acetals or a carbon monoxide generating compound, which thus makes it possible to conduct the alkoxylation reaction of the 4-hydroxy halo benzaldehyde without it being necessary to protect the aldehyde function, in the form of acetal. Such a process is the subject of French patent application no. 89/17213 in the name of the applicant.

 Among the alkali metal alcoholates used in the first step of the invention, the sodium or potassium alcoholates of the primary or secondary alkanols having 1 to 4 carbon atoms are particularly suitable.

 The most frequently used are sodium methylate and sodium ethylate.

 The copper compounds serving as catalysts are known. These are generally all the organic or inorganic compounds of copper I or copper II.

 Copper metal can be used, but its action is slower because it must first transform into copper I or copper II.

 As a non-limiting example, copper compound, cuprous chloride, cupric chloride, basic copper carbonate II, cuprous nitrate, cupric nitrate, cupric sulfate, cupric acetate, cupric trifluoromethylsulfonate, etc. cupric hydroxide, copper picolinate II, copper methylate I, copper methylate II, copper chelate II of 8-quinoline, copper compounds of formula ClCuOCH3, Cu2 (OCH3) 2 (acac) 2 .

dans laquelle
- n est égal à 1 ou à 2,
- R2 et R3, identiques ou différents, représentent
un atome d'hydrogène,
un radical alkyle, linéaire ou ramifié ayant 1 à 6
atomes de carbone,
un radical cycloalkyle ayant 5 à 12 atomes de carbone,
un radical aryle ayant 6 à 12 atomes de carbone,
un radical aralkyle ayant 7 à 14 atomes de carbone,
un radical aryle ayant 6 à 12 atomes de carbone portant
1 ou 2 substituants alkyle ayant 1 à 4 atomes de
carbone,
un radical hétérocyclique monocyclique saturé, insaturé ou
aromatique et comportant en tant qu'hétéroatome, un ou
plusieurs atomes d'oxygène, d'azote ou de soufre et contenant
4 à 6 atomes dans le cycle ; lesdits radicaux pouvant être
substitués par un ou plusieurs radicaux alkyle, notamment
méthyle.The formamides which are used in the process are more particularly compounds of general formula (III)

in which
- n is equal to 1 or 2,
- R2 and R3, identical or different, represent
a hydrogen atom,
an alkyl radical, linear or branched having 1 to 6
carbon atoms,
a cycloalkyl radical having 5 to 12 carbon atoms,
an aryl radical having 6 to 12 carbon atoms,
an aralkyl radical having 7 to 14 carbon atoms,
an aryl radical having 6 to 12 carbon atoms carrying
1 or 2 alkyl substituents having 1 to 4 atoms of
carbon,
a saturated, unsaturated or monocyclic heterocyclic radical
aromatic and comprising as heteroatom, one or more
several atoms of oxygen, nitrogen or sulfur and containing
4 to 6 atoms in the ring; said radicals being
substituted by one or more alkyl radicals, in particular
methyl.

R2 and R3 can form together and with the nitrogen atom of the formamide a saturated heterocycle optionally further comprising a nitrogen, oxygen or sulfur atom,
- when n is equal to 2, R2 and R3 represent an alkylene radical having 2 to 6 carbon atoms.

Among the formamides of formula (III), we will most often use those in the formula of which
- n is equal to 1 or 2,
- R2 and R3, identical or different, represent
a hydrogen atom,
a linear or branched alkyl radical having 1 r. 4
carbon atoms such as methyl, ethyl, isopropyl,
n-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl,
a cyclopentyl or cyclohexyl radical,
a phenyl or naphthyl radical,
a benzyl or phenethyl radical,
an alkylphenyl radical of which the alkyl part contains 1
with 4 carbon atoms,
a pyridinyl-2, pyridinyl-3 or pyridinyl-4 radical
R2 and R3 can form together and with the nitrogen atom of the formamide a piperidinyl ring, a morpholinyl ring, a piperazinyl ring, a pyrrolidinyl ring,
- R2 and R3 represent an ethylene radical when n is equal to 2.

dans laquelle R2 et R3 ont les significations indiquées précédemment pour les formamides de formule (III) et R4 représente un radical méthyle ou éthyle.The acetals of the formamides of formula (III) are more particularly those which correspond to the general formula (IV):

in which R2 and R3 have the meanings indicated above for the formamides of formula (III) and R4 represents a methyl or ethyl radical.

As non-limiting examples of formamides of formula (III), mention may be made of formamide, dimethylformamide, diethylformamide, N-phenylformamide (or formanilide), N-phenyl N-methylformamide (or N-methyl formanilide) , N-cyclohexylformamide,
N-pyridinyl-2 N-methyl formamide, N-hydrocarbonyl-morpholine,
N-hydrocarbonyl-piperazine, N-hydrocarbonyl-piperidine, N, N'-bis (hydrocarbonyl) piperazine.

 As regards the acetals of formula (IV), recourse may in particular be made to the acetals of the formamides mentioned above.

 As nonlimiting examples of compounds that generate carbon monoxide, mention may be made of dialkyl hydroxymethylenemalonates, in particular of dimethyl, diethyl, di-n-propyl, di-isopropyl, di-n-butyl, di-isobutyl , di-sec-butyl and di-tert-butyl and their alkali metal, especially sodium, salts.

 The sodium salt of diethyl hydroxymethylenemalonate is most commonly used.

 In accordance with the process of the invention, the alkoxylation of the 4-hydroxy halo-benzaldehyde corresponding to formula (II) is carried out in an organic medium consisting, most often, of the alkanol corresponding to the alkali metal alcoholate used .

 Methanol or ethanol is preferably chosen as solvent.

 The concentration of the compound of formula (II) expressed by weight of 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 amount of alkali metal alcoholate used is equal to or greater than the stoichiometric amount necessary, on the one hand to transform the compound of formula (II) into alkali metal phenate (that is to say to salify the one or more OH groups) and on the other hand to transform the halogen atom (s) into alkoxy groups.

 Generally the alkali metal alcoholate used will represent from 1 to 4 times the stoichiometric amount thus defined and preferably from 1.5 to 3 times.

 Conveniently, the alkali metal alcoholate is formed in situ, by reacting an excess of alkanol with the selected alkali metal.

 The amount of copper catalyst used in the process of the invention can vary widely.

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

 The quantity of formamide, of formamide acetal or of carbon monoxide generator used as co-catalyst in the process of the invention is such that there is generally a molar co-catalyst / catalyst to copper ratio of 1, 0 to 20.0 and preferably 1.0 to 10.

 This quantity of cocatalyst can also be expressed relative to the compound of formula (II), with regard to its upper limit.

 Thus, generally, at most 2 moles of cocatalyst will be used for 1 mole of compound of formula (II) and, preferably, 1 mole of c., - catalyst for 1 mole of compound of formula (II).

 The temperature of the alkoxylation reaction is generally between 900C and 2200C, and preferably between 1000C and 1800C.

 The pressure is not a critical parameter in itself, but to reach the temperatures indicated above and not to lose solvent, the process is usually carried out under autogenous pressure.

 Generally, this autogenous pressure of the reaction mixture is less than or equal to 5 MPa (50 bars).

 The duration of the alkoxylation reaction can vary widely between 2 and 10 hours, preferably between 3 and 5 hours.

 In the second step of the process of the invention, the etherification reaction of the 4-hydroxyalkoxy benzaldehyde previously obtained is carried out.

To this end, it is brought into contact with an alkylating agent. Use may be made of alkyl sulphates, preferably dimethyl sulphate or alkylcarbonates, in particular dimethylcarbonate or diethylcarbonate
However, it is preferred according to the invention to choose, as alkylating agent, a lower alkyl halide corresponding to the general formula (v):
RX (V) in said formula, X represents a bromine, chlorine or iodine atom and R represents a linear or branched alkyl radical having from 1 to 6 carbon atoms.

Among the halides of formula (V), it is preferred to use those corresponding to formula (V) in which X is a chlorine atom and
R a linear or branched alkyl radical having from 1 to 4 carbon atoms.

 Most often, a methyl halide or an ethyl halide is used.

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

 Due to their lower cost, it is preferred to use methyl chloride and chloroethane.

 The etherification reaction is advantageously carried out while maintaining the pH between 6 and 12 for the duration of the reaction.

 When operating at a pH below 6, a decrease in etherification is observed as well as a slowing down of this reaction.

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

 Regulation of the pH can be ensured if necessary by continuous addition of a base, preferably an aqueous solution of an alkali metal hydroxide. All alkali metal hydroxides can be used. However for economic reasons, soda is preferred.

 According to a preferred variant of the process of the invention, the reaction is carried out in the presence of a catalyst, in order to have higher kinetics and milder conditions, in particular of pressure.

 The catalyst is chosen from amines and quaternary ammonium salts.

 All primary, secondary or tertiary amines can be used.

 It is thus possible to use primary and secondary aliphatic, aromatic, arylaliphatic, cycloaliphatic or heterocyclic amines.

 By way of nonlimiting examples of such amines, mention may be made of ethylamine, propylamine, butylamine, hexylamine, octylamine, decylamine, laurylamine, dimethylamine, dipropylamine, diisopropylamine, dibutylamine, diisobutylamine, dihexylamine, aniline, piperidine, benzylamine, methylaniline, ethylaniline, pyrrolidine, imidazole.

 The tertiary amines which can be used are also very diverse, for example they are trialkylamines in which the alkyl radicals can be identical or different and have 1 to 24 carbon atoms; cycloalkylalkylamines; benzylalkylamines; phenylalkylamines cyclic amines: these amines can have other functions such as ether or hydroxyl functions.

There may be mentioned, without limitation, trimethylamine, triethylamine, tripropylamine, tributylamine, ethyldimethylamine, lauryldimethylamine, octadecyldimethylamine, propyldimethylamine, pentyldimethylamine, benzyldimethylamine, trioctylamine, triethanolamine, N, N -dimethylaniline, butyldimethylamine,
N, N-diethylaniline, N-methylpiperidine, N-ethylpiperidine,
N-methylpyrrolidine, N-methylimidazole, pyridine, 3-methyl pyridine, 2-methyl pyridine, 4-methyl pyridine, 2,4-dimethyl pyridine, 2,6-dimethyl pyridine, triethylenediamine.

 It is, of course, possible to use industrial mixtures (industrial cuts) available of different amines.

 In general, it is preferred to use the amines which are most easily quaternizable under the reaction conditions.

 The quaternary ammonium salts can also be used as catalyst. These are, for example, halides, hydroxides, alkyl, cycloalkyl or benzyl sulfates derived from the preceding amines.

 Generally preferred are quaternary ammonium chlorides or bromides.

 As regards the quantity of reagents to be used in the second step of the process of the invention, the preferred quantities are defined below.

 The amount of alkyl halide used is a function of the number of hydroxyl groups present on the aromatic nucleus of the 4-hydroxyalkyl benzaldehyde, that is to say at least one or two. It is preferably at least equal to a stoichiometric amount up to an excess of up to 500%. Even more preferably, it is chosen between the stoichiometric amount and an excess of up to 400%.

 The alkyl halide / 4-hydroxy hydroxy benzaldehyde molar ratio ranges from 1.0 to 4.0, preferably 1.5 to 3.0.

 The molar ratio of alkyl halide / 3,4-alkoxy dihydroxy benzaldehyde ranges from 2.0 to 8.0, preferably from 3.0 to 6.0.

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

 The amount of catalyst used in the preferred variant of the invention can vary within wide limits. Generally, from 0 to 30 mol% of catalyst are used relative to the 4-hydroxyalkoxy benzaldehyde present, preferably from 0 to 20%.

 With regard to the reaction conditions, the temperature of the etherification reaction is not critical; it has an influence on the kinetics of the reaction. Generally, one etherification is carried out between 900C and 2000 C. Preferably, one operates at a temperature of 1000C to 1500C.

 The pressure is not critical. It affects the kinetics of the reaction. It usually varies between atmospheric pressure and 50 bars.

 The choice to operate under a higher or lower pressure will be conditioned in particular by the presence or absence of catalyst. In the presence of catalyst, the higher the amount of said catalyst, the lower the pressure may be, that is to say for example be between atmospheric pressure and 20 bars.

 The pressure is usually created by the alkyl halide used for etherification when it is gaseous under the reaction conditions.

 The duration of the etherification reaction depends in particular on the reaction temperature. It most often varies between 1 hour and 8 hours. Generally, a duration of 1 to 4 hours is sufficient.

 According to a practical embodiment of the invention, it is possible to mix all the reactants of the first stage, namely the 4-hydroxy halo benzaldehyde, the copper catalyst and the co-catalyst such as a formamide or its acetals or a compound carbon monoxide generator and after heating for the time necessary for the alkoxylation reaction, add to the reaction medium, the alkylating agent optionally a base and the amine catalyst.

 A preferred mode of practicing the invention consists first of all in preparing a solution of the alkali metal alcoholate in the corresponding alkanol in an amount of, for example, 20 to 50% by weight.

 In the apparatus, nitrogen gas, 4-hydroxy halo benzaldehyde of formula (II), the copper catalyst and then the cocatalyst such as a formamide or its acetals are preferably charged under an inert gas atmosphere. or a carbon monoxide generating compound. The reaction medium is then brought to the temperature chosen between 900C and 2200C, preferably between 1000C and 1800C, for the pre-defined period.

 The alkyl halide, which may be liquid or gaseous, is then introduced and the alkali metal hydroxide solution is injected or poured in parallel, if this is necessary to adjust the pH in the aforementioned zone.

 Heating is maintained between 900C and 2000C, preferably between 1000C and 1500C, for the time necessary for the etherification reaction.

 At the end of the reaction, the alkoxy benzaldehyde of formula (I) obtained according to conventional separation techniques is separated, either by distillation or by extraction with an appropriate solvent, for example toluene in the case of 3,4-trimethoxy. , 5 benzaldehyde.

 It is possible to remove the copper catalyst from the reaction medium according to conventional treatments, in particular by acid treatment.

 One of the advantages of the process of the invention is that it makes it possible to carry out, in a row and in the same reactor, the alkoxylation and etherification reaction.

The process of the invention is particularly well suited to the preparation of the following alkoxybenzaldehydes
- 3,4,5-trimethoxy benzaldehyde
- 3,4-dimethoxy benzaldehyde.

- 3,4-diethoxy benzaldehyde
- 3-ethoxy-4-methoxy benzaldehyde
The 3,4,5-trimethoxybenzaldehyde which can be prepared according to the process of the invention is used in particular for the preparation of pharmaceutical products.

 The examples which follow illustrate the invention without however limiting it.

In the examples, the following abbreviations mean
BHMB: 5-bromo-4-hydroxy-3-methoxy benzaldehyde
TMBA: 3,4,5-trimethoxy benzaldehyde syringaldehyde: 4-hydroxy-3,5-dimethoxy benzaldehyde
Number of moles of BHMB transformed
TTBHMB = o
Number of moles of BHMB introduced
Number of moles of TMBA formed
RTTMBA =
Number of moles of BHMB transformed
Number of moles of syringaldehyde formed RTsyringaldehyde =
Number of moles of BHMB transformed
EXAMPLE 1
Nitrogen atmosphere is charged to a 3.9-liter stainless steel reactor with a heating system and a stirrer
- 170.5 g (0.738 mol) of 5-bromo-4-hydroxy-3-methoxy-benzaldehyde
(BHMB)
- 162 g of sodium methylate
-t 1785 cm3 (1428 g) of methanol
- 8.3 g (0.0377 mol) of basic copper II carbonate of formula CuC03, Cu (OH) 2
- 27.4 g (0.375 mol) of dimethylformamide
The mixture is heated with stirring for 3 hours at 1350C under autogenous pressure in order to carry out the methoxylation reaction.

 The reaction mixture is cooled to 1200C and then charged with 150 g of methyl chloride.

 The reaction mixture is kept at 1200C for 1 hour.

 Cool to room temperature.

 The insoluble part is filtered off.

 Dosing is carried out by high performance liquid chromatography, the unreacted BHMB and the 3,4,5 trimethoxybenzaldehyde obtained.

The results obtained are as follows
- transformation rate of BHMB (TTBHMB%) = 100%
- yield in TMBA (RTTMBA%) = 73.5%
- yield of syringaldehyde (RTsyringaldehyde%) = 16.9%

Claims (25)

 CLAIMS 1 - Process for the preparation of an alkoxybenzaldehyde of general formula (I)

 successively the following stages 10 - A 4-hydroxy halo benzaldehyde of general formula (II) is reacted  carbon atoms, characterized in that one performs  gene, a linear or branched alkoxy radical having from 1 to 4  carbon; R "can also represent a hydro atom  a linear or branched alkyl radical having from 1 to 4 atoms of  in which R, R 'and R ", which are identical or different, represent  carbon, with an alkali metal alcoholate having from 1 to 4 carbon atoms, in the presence of a copper catalyst which is copper and / or a copper compound and of an effective amount of a co-catalyst chosen from formamides or their acetals or compounds generating carbon monoxide, 20 - At least one etherification is carried out in position 4, of the product obtained previously after alkoxylation, by addition directly to the organic reaction medium of an alkylating agent chosen from lower alkyl halides, dialkylsulfates, dialkylcarbonates.  linear or branched alkoxy radical having from 1 to 4 atoms of  linear or branched having from 1 to 4 carbon atoms; a  a hydroxyl group; a hydrogen atom; an alkyl radical  iodine; R1 represents a bromine, chlorine or iodine atom  in which X represents a bromine, chlorine or 2 - Process according to claim 1 characterized in that the alkali metal alcoholate is a sodium or potassium alcoholate of a primary or secondary alkanol having 1 to 4 carbon atoms. 3 - Method according to one of claims 1 and 2, characterized in that the alkali metal alcoholate is sodium methylate or sodium ethylate. 4 - Method according to one of claims 1 to 3, characterized in that the catalyst is an organic or inorganic compound of copper I or copper II, chosen from cuprous chloride, cupric chloride, basic copper carbonate II , cuprous nitrate, cupric nitrate, cupric sulfate, cupric acetate, cupric trifluoromethylsulfonate, cupric hydroxide, copper picolinate II, copper methylate I, copper methylate II, copper chelate II of 8-quinoline, the copper compounds of formula ClCuOCH3, Cu2 (OCH3) 2 (acac) 2. 5 - Method according to one of claims 1 to 4, characterized in that the co-catalyst is a formamide of general formula (III)

 in which  - n is equal to 1 or 2,  R2 and R3, identical or different, represent  a hydrogen atom,  an alkyl radical, linear or branched having 1 to 6 atoms  of carbon,  a cycloalkyl radical having 5 to 12 carbon atoms,  an aryl radical having 6 to 12 carbon atoms,  an aralkyl radical having 7 to 14 carbon atoms,  an aryl radical having 6 to 12 carbon atoms carrying  1 or 2 alkyl substituents having 1 to 4 carbon atoms,  a saturated, unsaturated or monocyclic heterocyclic radical  aromatic and comprising as heteroatom, one or more  several atoms of oxygen, nitrogen or sulfur and  containing 4 to 6 atoms in the ring; said radicals  may be substituted by one or more alkyl radicals.  - when n is equal to 2, R2 and R3 represent an alkylene radical having 2 to 6 carbon atoms.  R2 and R3 can form together and with the nitrogen atom of the formamide a saturated heterocycle optionally further comprising a nitrogen, oxygen or sulfur atom, 6 - Method according to one of claims 1 to 5, characterized in that the co-catalyst is a formamide of general formula (III) in which  - n is equal to 1 or 2,  - R2 and R3, identical or different, represent  . a hydrogen atom,  an alkyl radical, linear or branched having 1 to 4  carbon atoms  . a cyclopentyl or cyclohexyl radical,  a phenyl or naphthyl radical,  a benzyl or phenethyl radical,  an alkylphenyl radical of which the alkyl part contains 1  with 4 carbon atoms,  . a pyridinyl-2, pyridinyl-3 or pyridinyl-4 radical ;;  R2 and R3 can form together and with the nitrogen atom of the formamide a piperidinyl cycle, a morpholinyl cycle, a piperazinyl cycle, a pyrrolidinyl cycle,  - R2 and R3 represent an ethylene radical when n is equal to 2. 7 - Method according to one of claims t to 6, characterized in that the co-catalyst is a formamide acetal of general formula (IV) in which

  in which R2 and R3 have the meanings indicated above for the formamides of formula (III) and R4 represents a methyl or ethyl radical. 8 - Method according to one of claims 1 to 7, characterized in that the cocatalyst is chosen from the following formamides or their acetals: formamide, dimethylformamide, diethylformamide, N-phenylformamide (or formanilide), N-phenyl N-methylformamide (or N-methyl formanilide), N-cyclohexylformamide, N-pyridinyl-2 N-methyl formamide, N-hydrocarbonyl-morpholine, N-hydrocarbonyl-piperazine, N-hydrocarbonyl-piperidina, N, N '-bis (hydrocarbonyl) piperazine. 9 - Method according to one of claims 1 to 8, characterized in that the amount of alkali metal alcoholate used is equal to or greater than the stoichiometric amount necessary to transform the compound of formula (II) into the corresponding alkaline phenate and to transform the halogen atom (s) it contains into alkoxy groups. 10 - Method according to one of claims 1 to 9, characterized in that the molar ratio of catalyst to copper / compound of formula (II) is from 1% to 50% and, preferably, from 2% to 20%. 11 - Method according to one of claims 1 to 10, characterized in that the reaction is carried out in a solvent consisting of the alkanol corresponding to the alkali metal alcoholate used. 12 - Process according to claim 11, characterized in that the initial concentration of compound of formula (II) relative to the mixture of compound of formula (II) / solvent is from 3% to 40% by weight by weight and, preferably , from 10% to 30%. 13 - Method according to one of claims I to 12, characterized in that the formamide or its acetal or carbon monoxide / catalyst to copper molar ratio is from 1.0 to 20 and, preferably, from 1, 0 to 10. 14 - Method according to one of claims 1 to 13, characterized in that one operates the alkoxylation reaction at a temperature of 900C to 2200C and, preferably, from 1000C to 1800C. 15 - Method according to one of claims 1 to 14, characterized in that the alkylating agent in the etherification reaction is dimethylsulfate or dimethylcarbonate. 16 - Method according to one of claims 1 to 15, characterized in that the alkylating agent is a lower alkyl halide corresponding to the general formula (V)  R-X (V) in said formula, X represents a bromine, chlorine or iodine atom and R represents a linear or branched alkyl radical having from 1 to 6 carbon atoms. 17 - Process according to claim 16, characterized in that the alkylating agent is methyl chloride, chloroethane, methyl bromide and bromoethane. 18 - Method according to one of claims 1 to 17, characterized in that the amount of alkyl halide expressed relative to the amount of 4-hydroxyalkoxy benzaldehyde varies from the stoichiometric amount to an excess of up to 500 %, preferably equal to 400%. 19 - 'Method according to one of claims 1 to 18, characterized in that one carries out the etherification reaction at a pH of reaction mixture between 6 and 12, preferably between 9 and 11. 20 - Method according to one of claims 1 to 19, characterized in that one operates the etherification reaction between 900C and 2000C and, preferably, between 1000C and 1500C. 21 - Method according to one of claims 1 to 20, characterized in that the etherification reaction is carried out under a pressure between atmospheric pressure and 50 bar and, preferably, between atmospheric pressure and 20 bar. 22 - Method according to one of claims 1 to 21, characterized in that one operates the etherification reaction in the presence of a catalyst chosen from primary, secondary or tertiary amines and quaternary ammonium salts. 23 - Process according to claim 22, characterized in that the catalyst is chosen from primary and secondary aliphatic, aromatic, arylaliphatic, cycloaliphatic or heterocyclic amines; tertiary amines such as trialkylamines in which the alkyl radicals can be identical or different and have 1 to 24 carbon atoms, cycloalkylalkylamines, benzylalkylamines, phenylalkylamines, cyclic amines which can have other functions such as ether functions or hydroxyl; quaternary ammonium salts such as halides, hydroxides, alkyl, cycloalkyl or benzyl sulfates derived from the preceding amines. 24 - Method according to one of claims 1, 22 and 23, characterized in that the molar ratio between the catalyst of the etherification reaction and the 4-hydroxyalkoxy benzaldehyde is between 0 and 30% and, preferably between 0 and 20%. 25 - Method according to one of claims 1 to 24, characterized in that the 4-hydroxy halo benzaldehyde of formula (II) is chosen from  - 3-bromo-4-hydroxy benzaldehyde,  - iodo-3 hydroxy-4 benzaldehyde  - 3,5-dibromo-4-hydroxy benzaldehyde  - 3,5-diiodo-4-hydroxy benzaldehyde  - 3-bromo-5-methoxy-4-hydroxy benzaldehyde  - 3-iodo-5-methoxy-4-hydroxy-benzaldehyde  - 3-bromo-5-ethoxy-4-hydroxy benzaldehyde  - 3-iodo-5-ethoxy-4-hydroxy benzaldehyde  - 3-bromo-4,5 dihydroxy benzaldehyde  - 3-iodo-4,5-dihydroxy benzaldehyde 26 - Application of the process described in one of claims 1 to 25, to the preparation of 3,4-dimethoxy benzaldehyde and 3,4,5-trimethoxy benzaldehyde.