FR2669024A1 - Process for the preparation of alkoxybenzaldehydes - Google Patents

Abstract

The subject 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 consisting of an aromatic compound carrying at least one substituent containing a nitrogen atom, such as an amine or nitrile group. 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 5-bromo-vanillin, of a relatively large amount of vanillin approximately 10 to 15 which, after the etherification reaction, leads to the aldehyde veratric (3,4-dimethoxy benzaldehyde).

 It is possible to separate the veratric aldehyde from the trimethoxy3,4,5 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 I to 4 carbon atoms, in the presence of a copper catalyst which is copper and / or a compound of copper and a cocatalyst consisting of an aromatic compound carrying at least one substituent containing a nitrogen atom such as an amine or nitrile group.

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-hydroxybenzaldehyde,
- 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 of a cocatalyst which is an aromatic compound carrying a group amine and / or nitrile, 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. 90/05655 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 .

 The co-catalyst involved in the first alkoxylation step is an aromatic compound carrying at least one substituent containing a nitrogen atom such as an amine or nitrile group.

 The generic term "amine" applies to radicals of the primary, secondary or tertiary amine type specified below.

By aromatic compound is meant the classic notion of aromaticity as defined in the literature, in particular by Jerry MARCH
Advanced Organic Chemistry, 3rd edition, John Wiley and Sons, 1985 p. 37 and following.

The aforementioned aromatic compound more particularly corresponds to the general formula (III)
R2 - Y (III) in said formula (III)
- Y represents one of the following groups of formula (IV) or (V)

in formula (IV), R3 and R4 which are 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 or unsaturated heterocyclic radical,
- R2 is an aromatic cyclic radical having at least 5 atoms in the ring, optionally substituted, and representing at least one of the following radicals
. an aromatic, monocyclic or polycy carbocyclic radical
click,
. an aromatic, monocyclic or polycy heterocyclic radical
click with at least one of the heteroatoms 0, N and S.

Said radical R2 can carry one of the groups R5, R6 and R7 which are identical or different which represent
. a hydrogen atom,
. a group of formula (IV),
. a group of formula (V),
. an -OH group,
. a linear or branched alkyl radical having from 1 to 6 atoms of
carbon,
. an alkoxy radical of the R8-O- type, where R8 represents a radical
linear or branched alkyl having from 1 to 6 carbon atoms,
. a -CHO group,
. an acyl group having from 2 to 6 carbon atoms,
. a group -COORg ', R8' representing a linear alkyl radical
or branched having from 1 to 6 carbon atoms,
. a group -NO2,
. a -CF3 group.

 The aromatic compound of general formula (III) preferably comprises at most two groups of formula (IV) and / or (V).

More precisely, the various symbols present in formulas (III) to (V) can take the following meanings:
Radical R,
The radical R2 more specifically represents 10 - An aromatic, monocyclic or polycyclic carbocyclic radical.

By "polycyclic carbocyclic radical is meant
. a radical consisting of at least 2 aromatic carbocycles
and forming between them orthocondensed or ortho systems and
pericondensed,
. a radical consisting of at least 2 carbocycles of which only one
of them is aromatic and forming between them ortho systems
or ortho and pericondensed.

20 - A heterocyclic aromatic, monocyclic or polycyclic radical.

By "polycyclic heterocyclic radical", we define
a radical consisting of at least 2 aromatic heterocycles
containing at least one heteroatom in each cycle of which at least
one of the two cycles is aromatic and forms between them
ortho or ortho and pericondensed systems,
a radical consisting of at least one hydrocarbon ring and at
minus a heterocycle of which at least one of the two cycles is
aromatic and forming between them ortho or ortho systems and
pericondensed.

30 - A radical formed by a chain of groups defined in paragraphs 1 and / or 2, linked together
. by a valential link,
. by an alkylene or alkylidene radical having from 1 to 4 atoms of
carbon1 preferably, a methylene or isopropylidene radical,
. by at least one of the following groups
-O-, -CO-, -COO-, -S-, -50-, 5021

in these formulas, Rg and Rg 'represent an alkyl radical
having from 1 to 4 carbon atoms, a cyclohexyl radical or
phenyl and R'g can represent a hydrogen atom.

Among the radicals which have just been mentioned, R2 represents more particularly
a - a phenyl, tolyl, xylyl radical,
b - an aromatic heterocyclic radical comprising, as heteroatom, one or more oxygen, nitrogen or sulfur atoms and containing 5 or 6 atoms in the ring,
By way of illustration, mention may be made of the furyl, pyrrolyl, thienyl, isoxazolyl, furazannyl, isothiazolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl radicals.

-N=N-, -COet/ou encore par un groupe alcoylène ou alcoylidène ayant de 1 à 4 atomes de carbone.c - a radical consisting of a chain of 2 to 4 groups as defined in paragraphs a and / or b and linked together by a valential bond and / or by at least one of the following groups -O-, -NH -, - COO-, -CO-NH-, -SO2-,

-N = N-, -COet / or also by an alkylene or alkylidene group having from 1 to 4 carbon atoms.

 By way of illustration, mention may be made of the biphenyl, methylene-1,1 'biphenyl, isopropylidene-1,1' biphenyl, oxy-1,1 'biphenyl, imino-1,1' biphenyl radicals.

 d - an aromatic radical consisting of a set of 2 to 3 carbocyclic and / or heterocyclic aromatic rings and forming between them orthocondensed systems.

 The aromatic rings are preferably benzene and pyridine rings.

 Examples of polycyclic aromatic radicals are given below by way of illustration: anthryl, quinolyl, naphthyridinyl, benzofuranyl, indolyl radicals.

 Preferably, the radical R2 represents - a phenyl1 tolyl, xylyl radical, - a pyridyl radical, - a radical formed by two phenyl radicals linked together by a valential bond, a methylene radical, an isopropylidene radical, an oxygen atom, a group -NH-, -SO2-, -CO-, -CO-NH-.

R3 and Ra radicals
The radicals R3 and R4 are the radicals carried by the nitrogen atom
R3 and R4 identical or different represent
. a hydrogen atom,
. an alkyl radical, linear or branched having 1 to 4 atoms of
carbon such as methyl 1 ethyl, propyl, isopropyl, butyl,
isobutyl, sec-butyl, tert-butyl,
. a cyclopentyl or cyclohexyl radical,
. a phenyl or naphthyl radical,
. a benzyl or phenethyl radical,
. an alkylphenyl radical, the alkyl part of which comprises 1 to 4
carbon tomes1
. a pyridinyl-2, pyridinyl-3 or pyridinyl-4 radical
Preferably, the identical or different radicals R3 and R4 represent
- a hydrogen atom1
- a linear or branched alkyl radical having from 1 to 4 carbon atoms.

 Even more preferably, the radical R3 is a hydrogen atom and the radical R4 represents a hydrogen atom or a linear or branched alkyl radical having from 1 to 4 carbon atoms.

Groups Rs, R6 and R7
The cyclic aromatic radical symbolized by R2 can carry one or more substituents R5, R6 and R7.

dans ladite formule (VI) : - Y a la signification donnée précédemment - les différents groupes R5, R6, R7 représentent plus particulièrement
Rs, R6 identiques ou différents représentent un atome d'hydro
gène ou un radical alkyle linéaire ou ramifié ayant de 1 à 4
atomes de carbone1
.R7 représente
- un atome d'hydrogène,
- un groupe de formule (IV) dans laquelle R3 et R4 identiques
ou différents représentent un atome d'hydrogène ou un radical
alkyle linéaire ou ramifié ayant de 1 à 4 atomes de carbone1
- un groupe de formule (V),
- un groupe -OH,
- un radical alkyle linéaire ou ramifié ayant de 1 à 4 atomes
de carbone,
- un radical alkoxy du type Rg-O- où R8 représente un radical
alkyle linéaire ou ramifié ayant de 1 à 4 atomes de carbone1
- un groupe -NO2,
- un groupe -CF3.10 - If the radical R2 symbolizes a monocyclic carbocyclic aromatic radical, the aromatic compound corresponds to the general formula (VI)

in said formula (VI): - Y has the meaning given above - the different groups R5, R6, R7 represent more particularly
Rs, R6, identical or different, represent a hydro atom
gene or linear or branched alkyl radical having from 1 to 4
carbon atoms1
.R7 represents
- a hydrogen atom,
- a group of formula (IV) in which R3 and R4 are identical
or different represent a hydrogen atom or a radical
linear or branched alkyl having 1 to 4 carbon atoms1
- a group of formula (V),
- a group -OH,
- a linear or branched alkyl radical having from 1 to 4 atoms
of carbon,
- an alkoxy radical of the Rg-O- type where R8 represents a radical
linear or branched alkyl having 1 to 4 carbon atoms1
- a group -NO2,
- a group -CF3.

 Even more preferably, the groups Rg, R6 and R7 which are identical or different represent a hydrogen atom or a linear or branched alkyl radical having from 1 to 4 carbon atoms, the group R7 possibly also being a group -NH2 , -CN or -CF3.

20 - If the radical R2 symbolizes a polycyclic aromatic carbocyclic radical or an aromatic, monocyclic or polycyclic heterocyclic radical, the groups Rg, R6 and R7 most often represent
- a hydrogen atom
- a methyl radical
- at most one group -NH2 or -CN
As an aromatic compound carrying an amine group corresponding to formula (III), use is made more particularly of the following compounds - GrouPe I (primary amine group)
. aniline
. o-toluidine
. m-toluidine
. p-toluidine
. 2,3-dimethyl aniline
. 2,4-dimethyl aniline
. 2,5-dimethyl aniline
. 2,6-dimethyl aniline
. 3,4-dimethyl aniline
. 3,5-dimethyl aniline
. 2-ethyl aniline
. 3-ethyl aniline
4-ethyl aniline. 2,6-diethyl aniline. 2-propyl aniline. propyl-4 aniline. isopropyl-2 aniline. isopropyl-4 aniline. 2,6-diisopropyl aniline. 4-butyl aniline. sec-butyl-4 aniline. tert-butyl-4 aniline. di-tert-butyl-2,5 aniline. o-anisidine. m-anisidine. p-anisidine. 2-methoxy-5-methyl aniline. 4-methoxy-2-methyl aniline. 2,4-dimethoxy aniline. 2,5-dimethoxy aniline. dimethoxy-3,4 aniline. 3,5-dimethoxy aniline. o-phenitidine. m-phenitidine. p-phenitidine. phenoxy-4 aniline. 2-amino phenol. 3-amino phenol. 4-amino phenol. amino-2-p-cresol. amino-3-o-cresol. amino-4-o-cresol. amino-4-m-cresol. amino-6-m-cresol. 4-amino resorcinol. 4-amino-2,5-dimethylphenol. 6-amino-2,4-dimethylphenol. 2-amino-4-tert-butylphenol. 5-amino-2-methoxy-phenol 2-amino-3-nitro-phenol. 2-amino-4-nitro phenol. 2-amino-5-nitro phenol. 4-amino-2-nitro phenol. 2-amino benzaldehyde. 2-amino acetophenone. amino-3 'acetophenone. amino-4 'acetophenone. 2-nitro aniline. nitro-3 aniline. 4-nitro aniline. nitro-3-o-toluidine. nitro-4-o-toluidine. nitro-5-o-toluidine. nitro-6-o-toluidine. nitro-2-p-toluidine. nitro-6-m-toluidine. 2-methoxy-4-nitro aniline. 2-methoxy-5-nitro aniline. 4-methoxy-2-nitro aniline. α,α,α -trifluoro-o-toluidine. α,α,α -trifluoro-m-toluidine. α,α,α; - trifluoro-p-toluidine. nitro-4- α,α,α -trifluoro-o-toluidine. nitro-2- α,α,α -trifluoro-p-toluidine. 1-amino-naphthalene. 2-amino naphthalene. amino-1 naphthol. 3-amino naphthol. 8-amino naphthol. 2-biphenyl amine. 3-biphenyl amine. 2-amino benzophenone. anino-4 benzophenone. 2-amino-4-methyl benzophenone. 2-amino-4 'methyl benzophenone 2-amino 5-nitro benzophenone. 4-amino-3-nitro benzophenone. 4-phenyl azoaniline. 2-amino benzimidazole. 2-amino-5,6 dimethyl benzimidazole 2-amino benzothiazole. 2-amino-4-methyl benzothiazole. 2-amino-6-methyl benzothiazole. 7-amino-4-methyl benzothiazole. 2-amino-5,6-dimethyl benzothiazole. 4-amino benzothiadiazole 2,1,3. 7-amino-4-methyl coumarin. amino-7 (trifluoromethyl) -4 coumarin. 3-amino quinoline. 5-amino quinoline. 6-amino quinoline. 8-amino quinoline. 5-amino isoquinoline. 4-amino quinaldine. 7-amino-2,4-dimethyl naphthyridine. 2-amino purine. (2-amino phenyl) -1 pyrrole. 5-amino-3-phenyl thiadiazole-1,2,4. 3-amino-5-methyl isoxazole. 5-amino-3-methyl isoxazole. 3-amino-triazole-1,2,4,. 3-amino pyrazole. 2-amino-thiadiazole-1,3,4. 2-amino-5-methylthiadiazole-113.4. 2-amino thiazole. 2-amino-4-methyl-thiazole. 2-amino pyridine. 3-amino pyridine. 4-amino pyridine. amino-2 picoline-3. amino-2 picoline-4. amino-2 picoline-5
. amino-2 picoline-6
. 2-amino-4,6-dimethyl pyridine
. 5-amino-2-methoxy pyridine
. 2-amino pyrimidine
. 4-amino pyrimidine
. 2-amino-4-methylpyrimidine
. 2-amino-4,6-dimethyl pyrimidine
. aminopyrazine
. 3-amino-triazine-1,2,4
. 3-amino-dimethyl-5,6 triazine-1,2,4
Group II (secondary amine group)
. N-methylaniline
. N-ethylaniline
. N-methyl 2-nitro aniline
. N-methyl nitro-4 aniline
. diphenyl amine
Group III (tertiary amine group)
. N, N-dimethylaniline
.N, N-diethylaniline
As examples of compounds with aromatic rings carrying plls of an amine group 1 there may be mentioned
Group IV (2 or more amine groups)
. 1,2-phenylene diamine
. 1,3-phenylene diamine
. 1,4-phenylene diamine
. 2,3-diamino toluene
. 2,4-diamino toluene
. diamino-2,5 toluene
. diamino-2,6 toluene
. diamino-3,4 toluene
. diamino-4,5-o-xylene
. 2,4-diamino phenol
. 2,4-diamino, 6-methylphenol
. 3-methoxy-1,3-phenylene diamine
. 2-nitro-1,4-phenylene diamine
. 3-nitro-1,2-phenylene diamine
4-nitro-1,2-phenylene diamine
. diamino-2,6 nitro-4 toluene
. 1.5 diamino naphthalene
. diamino-1,8 naphthalene
. 2,3-diamino naphthalene
. 2,3-diamino pyridine
. diamino-2,6 pyridine
. diamino-3,4 pyridine
. diamino-4,5 pyridine
. diamino-2,4-hydroxy-6 pyrimidine
. diamino-4,5 hydroxy-6 pyrimidine
. diamino-3,5 triazole-1,2,4,
. benzidine
. oxy-4,4 'dianiline
. 3,4-diamino benzophenone
. (phenylsulfonyl) -2 aniline
. 4,4 'methylene dianiline
. 4,4 'ethylene dianiline
. ethylene-4,4 '-m-toluidine
. N-phenylphenylene-1,2 diamine
. N-phenylphenylene-1,4 diamine
. diamino-3,3 'benzidine
As examples of aromatic compounds carrying one or two nitrile groups, mention may be made of
Group V (1 nitrile group)
. benzonitrile
. o-tolunitrile
. m-tolunitrile
. p-tolunitrile
. 2,5-dimethyl benzonitrile
. 2-methoxy benzonitrile
. 3-methoxy benzonitrile
. 4-methoxy benzonitrile
. 2,3-dimethoxy benzonitrile
. 2,4-dimethoxy benzonitrile
. 2,6-dimethoxy benzonitrile
. 3,4-dimethoxy benzonitrile
. 3,5-dimethoxy benzonitrile
. 2-cyano phenol
. cyano-3 phenol
. cyano-4 phenol
. acetylbenzonitrile
. 3-cyano benzaldehyde
. 4-cyano benzaldehyde
. cyano-1 naphthalene
. cyano-1 methoxy-2 naphthalene
. cyano-1 methoxy-4 naphthalene
. 2-cyano-6-methoxy naphthalene
. cyano-5 indole
. 2-cyano pyridine
. cyano-3 pyridine
. cyano-4 pyridine
GROUP VI (2 nitrile groups)
. 1,2-dicyano benzene
. 1,3-dicyano benzene
. 1,4-dicyano benzene (terephthalonitrile)
. 2,6-dicyano toluene
. dicyano-4,5 imidazole
It is also possible to use, in the alkoxylation step of the process of the invention, as co-catalyst, an aromatic compound carrying both an amine group and a nitrile group (Group VII).

There may be mentioned in particular cyano-2 aniline, cyano-3 aniline, cyano-4 aniline1 cyano-2 nitro-4 aniline, 2-amino-5-nitro benzonitrile1 4-amino 3-nitro benzonitrile, cyano-4 naphthyl-1 amine1 amino-3 cyano-4 pyrazole.

 Among all the aforementioned aromatic compounds carrying an amine or nitrile group, the following compounds are chosen in a completely preferential manner: aniline, toluidines, phenylenediamines, benzonitrile, tolunitriles, dicyanobenzenes.

 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 amount of aromatic compound carrying an amine and / or nitrile group used as cocatalyst in the process of the invention is such that there is generally a molar cocatalyst / copper compound ratio of 1.0 to 20.0 and preferably from 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 i mole of cocatalyst for 1 mole of compound of formula (II).

 The temperature of the alkoxylation reaction is generally between 900C and 2200C, and preferably from 100 C to 1800C.

 The pressure is not a critical parameter in itself but to reach the temperatures indicated above and not 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 (VII)
RX (VII) 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 (VII), it is preferred to use those corresponding to formula (VII) in which X is a chlorine atom and R is 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 considerations, 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, ethylaniline1 pyrrolidine, imidazole.

 The tertiary amines which can be used are also very diverse; these are, for example, trialkylamines in which the alkyl radicals can be identical or different and have 1 to 24 carbon atoms; cycloalkylalkylamines; benzylalkylamines; phenyl alkylamines; 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 pyridine1 4-methyl pyridine, 2,4-dimethyl pyridine1 2,6-dimethyl pyridine1 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 depends on 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 the 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, 0 to 30 mol% of catalyst is used relative to the 4-hydroxyalkoxy benzaldehyde present, preferably from 0 to 20 t.

 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, the etherification is carried out between 900C and 2000C. 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 reagents of the first step, namely the 4-hydroxy halo benzaldehyde, the copper catalyst and the cocatalyst carrying an amine and / or nitrile group. 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-type 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.

 The apparatus is charged under an inert gas atmosphere, preferably azete, 4-hydroxy halo benzaldehyde of formula (II), the copper catalyst and then the cocatalyst consisting of an aromatic compound carrying an amine and / or nitrile group, then the solution of the alkali metal alcoholate is introduced.

 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 examples1 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 mole) of 5-bromo-4-hydroxy-3-methoxy-benzaldehyde
(BHMB)
- 162 g of sodium methylate
- 1785 cm3 (1428 g) of methanol
- 8.3 g (0.0377 mol) of basic copper II carbonate of formula CuCO3, CU (OH) 2
- 38.6 g (0.375 mol) of benzonitrile
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 120 ° C. and then 150 g of methyl chloride are charged.

 The reaction mixture is kept at 120 ° C. 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
- -BHMB transformation rate (TTBHMB%) = 100%
- yield in TMBA (RTTMBA%) = 65%
- yield of syringaldehyde (RTsyringaldehyde%) = 24.4%

Claims (34)

CLAIMS 1 - Process for the preparation of an alkoxybenzaldehyde of general formula (I) in which R, R 'and R "identical or different represent a linear or branched alkyl radical having from 1 to 4 carbon atoms; R" can also represent a hydrogen atom, a linear or branched alkoxy radical having from 1 to 4 carbon atoms1 characterized in that the following steps are carried out successively 10 - A 4-hydroxy halo benzaldehyde of general formula (II) is reacted wherein X represents a bromine, chlorine or iodine atom; R1 represents a bromine, chlorine or iodine atom; a hydroxyl group; a hydrogen atom; a linear or branched alkyl radical having from 1 to 4 carbon atoms; a linear or branched alkoxy radical having from 1 to 4 carbon atoms1 with an alkali metal alcoholate having from 1 to 4 carbon atoms1 in the presence of a copper catalyst which is copper and / or a compound of copper and a cocatalyst consisting of an aromatic compound carrying at least one substituent containing a nitrogen atom such as an amine or nitrile group. 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. 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 copper compound I or copper II, chosen from cuprous chloride1 cupric chloride, basic copper carbonate II, cuprous nitrate1 cupric nitrate, cupric sulfate, cupric acetate, cupric trifluoromethylsulfonate, cupric hydroxide, picolinate copper II, copper methylate I, copper methylate II, copper chelate II of 8-quinoline, copper compounds of formula ClCuOCH3, Cu2 (0CH3) 2 (acac) 2 5 - Method according to one of claims 1 to 4 characterized in that the co-catalyst is an aromatic compound of general formula (III):  R2 - Y (III) in said formula (III)  - Y represents one of the following groups of formula (IV) or cl):

 in formula (IV), R3 and R4 which are 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 atoms1  . an aryl radical having 6 to 12 carbon atoms1  . an aralkyl radial having 7 to 14 carbon atoms1  . an aryl radical having 6 to 12 carbon atoms carrying 1 or  2 alkyl substituents having 1 to 4 carbon atoms1  . a saturated or unsaturated heterocyclic radical,  - R2 is an aromatic cyclic radical having at least 5 atoms in the ring, optionally substituted, and representing at least one of the following radicals  . an aromatic, monocyclic or polycy carbocyclic radical  click,  . an aromatic, monocyclic or polycy heterocyclic radical  click with at least one of the heteroatoms 0, N and S. 6 - Process according to claim 5 characterized in that the radical R2 carries one of the groups R5, R6 and R7 which are identical or different which represent  '. a hydrogen atom,  . a group of formula (IV),  . a group of formula (V),  . a grouse -OH,  . a linear or branched alkyl radical having from 1 to 6 atoms  carbon1  . an alkoxy radical of the Rg-O- type, where R8 represents a radical  linear or branched alkyl having 1 to 6 carbon atoms1  . a -CHO group,  . an acyl group having from 2 to 6 carbon atoms,  . a group -COORg ', R8' representing an alkyl radical li  nary or branched having from 1 to 6 carbon atoms,  . a group -NO2,  . a -CF3 group. 7 - Method according to one of claims 5 and 6 characterized in that the aromatic compound corresponds to the general formula (III) in which the radical R2 represents  10 - An aromatic, monocyclic or polycyclic carbocyclic radical.  20 - A heterocyclic aromatic, monocyclic or polycyclic radical.  30 - A radical formed by a sequence of groups defined in paragraphs 1 and / or 2, linked together  . by a valential link,  . by an alkylene or alkylidene radical having from 1 to 4 atoms  carbon, preferably a methylene or isopro radical  pylidene,  . by at least one of the following groups -O-, -CO-1 -COO-1  -S-, -SO-, -SO2-,

 in these formulas1 Rg and Rg 'represent an alkyl radical  having from 1 to 4 carbon atoms1 a cyclohexyl radical or  phenyl and R'g can represent a hydrogen atom. 8 - Process according to claim 7 characterized in that the aromatic compound corresponds to the general formula (III) in which the radical R2 represents  a - a phenyl1 tolyl, xylyl radical,  b - an aromatic heterocyclic radical comprising, as heteroatom, one or more oxygen, nitrogen or sulfur atoms and containing 5 or 6 atoms in the ring,  c - a radical consisting of a chain of 2 to 4 groups as defined in paragraphs a and / or b and linked together by a valential bond and / or by at least one of the following groups -o-, -NH-, - COO-, -CO-NH-, -S02-,

 -N = N-, -COet / or also by an alkylene or alkylidene group having from 1 to 4 carbon atoms.  d - an aromatic radical consisting of a set of 2 to 3 carbocyclic and / or heterocyclic aromatic rings and forming between them orthocondensed systems. 9 - Method according to one of claims 7 and 8 characterized in that the aromatic compound corresponds to the general formula (III) in which the radical R2 represents  - a phenyl, tolyl, xylyl radical,  - a pyridyl radical,  - a radical formed by two phenyl radicals linked to each other by a valential bond, a methylene radical, an isopropylidene radical, an oxygen atom, a group -NH-, -SO2-, -CO- ,. -CO-NH-. 10 - Method according to one of claims 7 to 9 characterized in that the aromatic compound corresponds to the general formula (III) in which Y represents a group of formula (IV):

 in which R3 and R4, which are identical or different, represent  . a hydrogen atom,  . an alkyl radical, linear or branched having 1 to 4 atoms of  carbon,  . a cyclopentyl or cyclohexyl radical,  . a phenyl or naphthyl radical,  . a benzyl or phenethyl radical,  . an alkylphenyl radical, the alkyl part of which comprises 1 to 4  carbon atoms,  . a pyridinyl-2, pyridinyl-3 or pyridinyl-4 radical 11 - Process according to claim 10 characterized in that the aromatic compound corresponds to the general formula (III) in which Y represents a group of formula (IV)

 in which R3 and R4, which are identical or different, represent  - a hydrogen atom,  - a linear or branched alkyl radical having from 1 to 4 carbon atoms. 12 - Method according to one of claims 10 and 11 characterized in that the aromatic compound corresponds to the general formula (III) in which Y represents a group of formula (IV):

 in which the radical R3 is a hydrogen atom and the radical R4 represents a hydrogen atom or a linear or branched alkyl radical having from 1 to 4 carbon atoms. 13 - Method according to one of claims 1 to 12 characterized in that the aromatic compound corresponds to formula (VI):

 in said formula (VI) - Y has the meaning given above, - R5, R6, and R7 represent  Rs, R6, identical or different, represent a dthy- atom  drogen or a linear or branched alkyl radical having from 1 to  4 carbon atoms,  .R7 represents  - a hydrogen atom,  - a group of formula (IV) in which R3 and R4 are identical  or different represent a hydrogen atom or a radical  linear or branched alkyl having 1 to 4 carbon atoms1  - a group of formula (V),  - a group -OH,  - a linear or branched alkyl radical having from 1 to 4 atoms  carbon1  - an alkoxy radical of the Rg-O- type where R8 represents a radical  linear or branched alkyl having 1 to 4 carbon atoms1  - a group -NO2,  - a group -CF3. 14 - Process according to claim 13 characterized in that the aromatic compound corresponds to the general formula (VI) in which the groups Rg, R6 and R7 identical or different represent a hydrogen atom or a linear or branched alkyl radical having 1 to 4 carbon atoms1 the group R7 can also be a group -NH2, -CN or -CF3. 15 - Method according to one of claims 1 to 14 characterized in that the aromatic compound corresponds to the general formula (III) in which the radical R2 symbolizes a polycyclic aromatic carbocyclic radical or an aromatic, monocyclic or polycyclic aromatic heterocyclic radical carrying groups Rg, R6 and R7 which represent  - a hydrogen atom  - a methyl radical  - At most one group -NH2 or -CN 16 - Method according to one of claims 1 to 15 characterized in that the aromatic compound corresponding to the general formula (III) and carrying an amine and / or nitrile group or of two amine or nitrile groups is chosen from one of the groups I to VII as defined above. 17 - Method according to one of claims 1 to 16 characterized in that the aromatic compound corresponding to the general formula (III) is chosen from aniline, toluidines, phenylenediamines, benzonitrile, tolunitriles, dicyanobenzenes. 18 - Method according to one of claims 1 to 17, 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 corresponding alkali phenate and to transform the halogen atom (s) it contains into alkoxy groups. 19 - Method according to one of claims 1 to 18, 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%. 20 - Method according to one of claims 1 to 19, characterized in that the reaction is carried out in a solvent consisting of the alkanol corresponding to the alkali metal alcoholate used. 21 - Process according to claim 20, 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%. 22 - Method according to one of claims 1 to 21, characterized in that the aromatic compound molar ratio carrying an amine and / or nitrile / catalyst to copper group is from 1 to 20 and, preferably, from i to 10. 23 - Method according to one of claims 1 to 22, characterized in that one operates the alkoxylation reaction at a temperature of 900C to 220C and, preferably, from 1000C to 1800C. 24 - Method according to one of claims 1 to 23 characterized in that the alkylating agent in the etherification reaction is dimethylsulfate or dimethylcarbonate. 25 - Method according to one of claims 1 to 24 characterized in that the alkylating agent is a lower alkyl halide corresponding to the general formula (VII):  R-X (VII) 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. 26 - Process according to claim 25 characterized in that the alkylating agent is methyl chloride, chloroethane, methyl bromide and bromoethane. 27 - Method according to one of claims 1 to 26 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%. 28 - Method according to one of claims 1 to 27 characterized in that one carries out the etherification reaction at a pH of reaction mixture between 6 and 12, preferably between 9 and 11. 29 - Method according to one of claims 1 to 28 characterized in that one operates the etherification reaction between 900C and 2000C and, preferably, between 1000C and 1500C. 30 - Method according to one of claims 1 to 29, 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. 31 - Method according to one of claims 1 to 30, 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. 32 - Method according to claim 31, characterized in that the catalyst is chosen from primary and secondary aliphatic, aromatic, arylaliphatic, cycloaliphatic or heterocyclic amines; tertiary amines such as trialkylamines, the alkyl radicals of which may be identical or different and have 1 to 24 carbon atoms, cycloalkylalkylamines, benzylalkylamines, phenylalkylamines, cyclic amines which may 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. 33 - Method according to one of claims 1, 31 and 32 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%. 34 - Method according to one of claims 1 to 33 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-hydroxybenzaldehyde,  - 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, 35 - Application of the process described in one of claims 1 to 34 to the preparation of 3,4-dimethoxy benzaldehyde and 3,4,5-trimethoxy benzaldehyde.