FR2799460A1 - PROCESS FOR THE PREPARATION OF HYDROXIMIC COMPOUND - Google Patents

Abstract

The invention concerns a method for preparing hydroximic compounds of formula (I) wherein the various substituents are as defined in the description, by condensation of an alkaline metal salt of 2-(hydroxymethyl)-phenylacetic acid with a compound of formula (A) wherein the various substituents are as defined in the description, and synthesis intermediates of said compounds.

Description

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 FIELD OF THE INVENTION The present invention relates to a process for the preparation of chemical compounds comprising a hydroximic function. The invention also includes certain new chemical compounds illustrated as intermediates in this process.

Technical context of the invention The process, object of the present invention, relates to the preparation of certain chemical compounds comprising a hydroximic function and described for their phytosanitary properties, in particular fungicides, in particular in the French applications, not yet published, filed on April 07, 1998, under number 98/04594 and on August 28, 1998 under number 98/10934.

Although embodiments of these compounds have already been presented in the French applications cited above, the available literature only provides few examples of the preparation of hydroximic compounds.

By way of example, mention may be made of patent applications EP-A-0 821 667 and WO 98/15512.

In the field of organic synthesis, it is nevertheless always desirable to have other methods of synthesis, for multiple reasons. Thus, for example, new processes allow: # thanks to the evolution of chemical synthesis techniques, to get rid of toxic, harmful or dangerous reagents; # obtain better yields; # reduce manufacturing costs; # reduce the number of steps required to obtain the final product; # improve the purity of the intermediate products and the desired final product;

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] Thus, an object of the present invention is to provide a new process for the synthesis of compounds comprising a hydroximic function, in particular for the reasons mentioned above.

Another object of the present invention is to provide a process for the synthesis of these compounds which is particularly suited to the requirements of industrial manufacturing.

Another object of the present invention is to provide a synthesis process using easily isolable, stable and easy handling intermediates.

General definition of the invention [0006] It has now been discovered that the method according to the present invention makes it possible to achieve these goals in whole or in part.

dans lesquels : # p représente 1 ou 2 ; # A représente un radical hétérocyclique aromatique, mono- ou bi- cyclique, comportant de 5 à 10 atomes, parmi lesquels 1 à 4 sont des hétéroatomes choisis parmi les atomes d'oxygène, de soufre ou d'azote, chaque atome de soufre ou d'azote étant éventuellement à l'état oxydé sous forme d'un groupe N-oxyde ou sulfoxyde, lequel radical étant rattaché à l'atome de carbone substitué par les radicaux
R, et R2, lequel radical étant éventuellement substitué par 1 à 5 radicaux X1 et/ou X2 et/ou X3 et/ou X4 et/ou X5, de préférence par 1 à 3 radicaux X, et/ou X2 et/ou X3 ; # X,, X2, X3, X4 et X5 représentent indépendamment les uns des autres un atome d'halogène ; ou le radical hydroxy, mercapto, nitro, thiocyanato, azido, cyano ou pentafluorosulfonyle ; ou Thus, the present invention describes a new process for the preparation of the compounds of general formula (I):

in which: # p represents 1 or 2; # A represents a heterocyclic aromatic radical, mono- or bi-cyclic, comprising from 5 to 10 atoms, among which 1 to 4 are heteroatoms chosen from oxygen, sulfur or nitrogen atoms, each sulfur atom or of nitrogen being optionally in the oxidized state in the form of an N-oxide or sulfoxide group, which radical being attached to the carbon atom substituted by the radicals
R, and R2, which radical being optionally substituted by 1 to 5 radicals X1 and / or X2 and / or X3 and / or X4 and / or X5, preferably by 1 to 3 radicals X, and / or X2 and / or X3 ; # X ,, X2, X3, X4 and X5 represent, independently of each other, a halogen atom; or the hydroxy, mercapto, nitro, thiocyanato, azido, cyano or pentafluorosulfonyl radical; or

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a lower alkyl, lower haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkoxyalkyl, haloalkoxyalkyl, alkylthioalkyl, haloalkylthioalkyl, cyanoalkyl, cyanoalkoxy, cyanoalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonylsulfonyl radical; or a lower cycloalkyl, lower halocycloalkyl, alkenyl, alkynyl, alkenyloxy, alkynyloxy, alkenylthio, alkynylthio radical; an amino, N-alkylamino, N, N-dialkylamino, acylamino, aminoalkyl, N-alkylaminoalkyl, N, N-dialkylaminoalkyl, acylaminoalkyl radical; or an acyl, carboxy, carbamoyl, N-alkylcarbamoyl radical,
N, N-dialkylcarbamoyl, lower alkoxycarbonyl; the radical X, possibly forming a 5 to 7-membered ring with
R1; # X6 represents a hydrogen atom, a halogen atom; or the cyano or nitro radicals; or a lower alkyl, lower haloalkyl, alkoxy, haloalkoxy radical; # R1 and R2 independently of one another represent a hydrogen atom, a lower alkyl radical, lower haloalkyl, a lower cycloalkyl radical, lower halocycloalkyl, an alkoxyalkyl, haloalkoxyalkyl, alkylthioalkyl, haloalkylthioalkyl, cyanoalkyl radical; or
R1 and R2 may together form a divalent radical such as an alkylene radical, optionally substituted by one or more halogen atoms and / or by one or more lower alkyl radicals; # R3 represents a hydrogen atom, a lower alkyl, lower haloalkyl radical, a lower cycloalkyl, lower halocycloalkyl, an alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkoxyalkyl, haloalkoxyalkyl, alkylthioalkyl, haloalkylthioalkyl, cyanoalkyl radical; or an alkenyl, alkynyl radical; an optionally substituted phenyl or benzyl radical; # R4 represents an alkoxy or haloalkoxy radical; and # R5 represents a lower alkyl or lower haloalkyl radical, by condensation of an alkali metal salt of 2- (hydroxymethyl) phenylacetic acid (substituted on the phenyl ring by a radical X6 as defined

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dans lequel R,, R2, R3, p et A sont tels que définis précédemment, et X représente un atome d'halogène, le radical CH3S(O)- ou le radical CH3S(O)2-' pour conduire au composé de formule (II) :

dans lequel R,, R2, R3, X6, p et A sont tels que définis précédemment, qui est lui-même estérifié, transformé par réaction de Claisen, puis éthérifié en composé de formule (I) telle que définie précédemment. previously) with a compound of formula (A):

in which R ,, R2, R3, p and A are as defined above, and X represents a halogen atom, the radical CH3S (O) - or the radical CH3S (O) 2- 'to lead to the compound of formula (II):

in which R ,, R2, R3, X6, p and A are as defined above, which is itself esterified, transformed by the Claisen reaction, then etherified into a compound of formula (I) as defined above.

Detailed definition of the invention The present invention relates to a process for the preparation of the compounds of general formula (I) as just defined. All of these compounds of formula (I) have characteristics which should be defined and which are valid throughout the present description, including for synthesis intermediates, when these characteristics apply. In general, therefore, the characteristics defined for the compounds of formula (I) apply, where appropriate, to the intermediates used for the synthesis of these compounds.

In the case of the compounds of formula (I), or their intermediates, for which p = 2, the radical - (CR1R2) 2- must be understood as being the radical - (CR1R2) - (CR'1R'2) - , where R'1 and R'2 have, independently of one another and independently of R, and R2, the same definitions as R, and R2; the couples of the radicals (R,; R2) and (R'1; R'2) can be identical or different.

Furthermore, the following generic terms are used with the following meanings: # the halogen atom means the fluorine, chlorine, bromine or iodine atom,

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 # the adjective "lower" qualifying an organic radical, means that this radical has from 1 to 6 carbon atoms, with the exception of the cycloalkyl radical where the adjective "lower" means from 3 to 6 carbon atoms, # les alkyl radicals may be linear or branched, # halogenated alkyl radicals may contain one or more identical or different halogen atoms, # the acyl radical means alkylcarbonyl, or cycloalkylcarbonyl, # the lower adjective qualifying the term acyl applies to the alkyl or cycloalkyl part of this radical, # the alkylene radical denotes the radical - (CH2) m- where m represents 2,3, 4 or 5, # when the amino radical is disubstituted, the two substituents may constitute a saturated nitrogen heterocycle or unsaturated, of 5 or 6 atoms, # when the carbamoyl radical is disubstituted, the two substituents can constitute a nitrogen heterocycle, saturated or unsaturated, of 5 or 6 atoms, # the expression "optionally t substituted "qualifying an organic group applies to the different radicals constituting this group, # the groups and radicals alkyl, alkenyl and alkynyl in the description and the corresponding claims are, unless otherwise indicated, linear or branched and contain up to 6 atoms of carbon.

The process according to the invention is particularly suitable for the preparation of the compounds of formula (I) having one or more of the following characteristics taken individually or in combination: # p represents 1 or 2; # R, is the hydrogen atom or the methyl radical, # R2 is the hydrogen atom or a lower alkyl, cyanoalkyl, or alkoxyalkyl radical, # R3 represents a hydrogen atom, a lower alkyl, haloalkyl radical lower, lower cycloalkyl, lower halocycloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkoxyalkyl, haloalkoxyalkyl, alkylthioalkyl, haloalkylthioalkyl, cyanoalkyl; or an alkenyl, alkynyl radical; or

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an optionally substituted phenyl or benzyl radical, # R4 represents an alkoxy or haloalkoxy radical, # R5 represents a lower alkyl or lower haloalkyl radical, # A represents a heterocyclic radical, optionally substituted by 1 to 5 radicals X1 and / or X2 and / or X3 and / or X4 and / or X5, preferably by 1 to 3 radicals XI and / or X2 and / or X3, A being chosen from the following list: furanyl; pyrolyl; thiophenyl; pyrazolyl; imidazolyl; oxazolyl; isoxazolyl; thiazolyl; isothiazolyl; 1,2,3-oxadiazolyl; 1,2,4-oxadiazolyl; 1,2,5-oxadiazolyle; 1,3,4-oxadiazolyl; 1,2,3-thiadiazolyl; 1,2,4-thiadiazolyl; 1,2,5-thiadiazolyl; 1,3,4-thiadiazolyle; 1,2,3-triazolyl; 1,2,4-triazolyl; tetrazolyl; pyridyle; pyrimidinyl; pyrazinyl; pyridazinyl;
1,2,3-triazinyl; 1,2,4-triazinyl; 1,3,5-triazinyl; 1,2,3,4-tetrazinyl; 1,2,3,5-tetrazinyl; 1,2,4,5-tetrazinyl; benzimidazolyl; indazolyl; benzotriazolyl; benzoxazolyl; 1,2-benzisoxazolyl; 2,1-benzisoxazolyl; benzothiazolyl; 1,2-benzisothiazolyl;
2,1-benzisothiazolyl; 1,2,3-benzoxadia-zolyle; 1,2,5-benzoxadiazolyl; 1,2,3-benzothiadiazolyl; 1,2,5-benzothiadiazolyle; quinoline; isoquinolinyl; quinoxazolinyl; quinazolinyl; cinnolyl or phthalazyl; pteridinyl; benzotriazinyl;
1,5-naphthyridinyl; 1,6-naphthyridinyl; 1,7-naphthyridinyl;
1,8-naphthyridinyl; imidazo [2,1-b] thiazolyl; thieno [3,4-b] pyridyl; purine; and pyrolo [l, 2-b] thiazolyl, # X ,, X2, X3, X4 and X5 represent independently of each other a halogen atom; or the hydroxy, mercapto, nitro, thiocyanato, azido, cyano or pentafluorosulfonyl radical; or a lower alkyl, lower haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkoxyalkyl, haloalkoxyalkyl, alkylthioalkyl, haloalkylthioalkyl, cyanoalkyl, cyanoalkoxy, cyanoalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl radical; or a lower cycloalkyl, lower halocycloalkyl, alkenyl, alkynyl, alkenyloxy, alkynyloxy, alkenylthio, or alkynylthio radical, and # X6 represents a hydrogen atom, a halogen atom; or the cyano or nitro radicals.

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] Advantageously, the process according to the invention is more particularly suitable for the preparation of the compounds of formula (I) having the following characteristics taken individually or in combination: # p represents 1; # R, represents the hydrogen atom, # R2 is the hydrogen atom or a lower alkyl radical, # R3 represents a hydrogen atom, a lower alkyl radical, lower haloalkyl, a lower cycloalkyl radical, or halocycloalkyl lower, or an alkenyl, alkynyl radical; an optionally substituted phenyl or benzyl radical, # R4 represents an alkoxy radical, # R5 represents a lower alkyl radical, # A represents a heterocyclic radical, optionally substituted by 1 to 3 radicals XI and / or X2 and / or X3, A being chosen from the following list: furanyl; pyrolyl; thiophenyl; pyrazolyl; imidazolyl; oxazolyl; isoxazolyl; thiazolyl; pyridyle; quinoline; or isoquinolinyl, # X1, X2 and X3 independently of one another represent a halogen atom; the hydroxy, mercapto, nitro, thiocyanato, azido, cyano or pentafluorosulfonyl radical; a lower alkyl, lower haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, and # X6 radical represents a hydrogen atom or a halogen atom.

In a particularly advantageous manner, the process according to the invention is still preferred for the compounds of formula (I) having the following characteristics: # p represents 1, # R1 is the hydrogen atom, # R2 represents the atom hydrogen or a lower alkyl radical, # R3 represents a hydrogen atom, a lower alkyl radical, lower haloalkyl, a lower cycloalkyl radical, or lower halocycloalkyl, # R4 represents an alkoxy radical, # R5 represents an alkyl radical, # A represents a pyridyl radical, # X6 represents a hydrogen atom.

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#le (E,E)- 2-(2- { -[(2-pyridyl)méthyloxyimino]-1 -cyclopropylméthyloxyméthyl}phényl)-3-méthoxypropénoate de méthyle, #le (E,E)-2-(2-{1-[1-(2-pyridyl)propyloxyimino]-1-cyclopropylméthyloxyméthyl}phényl)-3-méthoxypropénoate de méthyle, #le (E,E)-2-(2-{1-[1-(2-pyridyl)propyloxyimino]propyloxyméthyl} phényl) -3-méthoxypropénoate de méthyle, et # le (E,E)-2-(2-{ l-[l-(2-pyridyl)propyloxyimino]isobutyloxyméthyl} phényl)-3-méthoxypropénoate de méthyle. ] Finally, the process according to the invention is preferred for the preparation of the following compounds of formula (I):

#methyl (E, E) - 2- (2- {- [(2-pyridyl) methyloxyimino] -1 -cyclopropylmethyloxymethyl} phenyl) -3-methoxypropenoate, #le (E, E) -2- (2- {1- [1- (2-pyridyl) propyloxyimino] -1-cyclopropylmethyloxymethyl} phenyl) -3-methyl methoxypropenoate, #le (E, E) -2- (2- {1- [1- (2-pyridyl ) methyl propyloxyimino] propyloxymethyl} phenyl) -3-methoxypropenoate, and # le (E, E) -2- (2- {l- [l- (2-pyridyl) propyloxyimino] isobutyloxymethyl} phenyl) -3-methoxypropenoate methyl.

The preferred characteristics of the compounds of formula (I) which have just been defined above also correspond to the preferred characteristics of the synthesis intermediates which are discussed later in the present description.

By convention, in the case of the present invention, the names (E, E), (E, Z), (Z, E) and (Z, Z) denote by the first letter the configuration of the double bond carrying the groups OR5 and C (O) R4, and by the second letter the configuration of the hydroximic group.

The compounds of general formula (I) prepared according to the process of the present invention, as well as the synthesis intermediates described here, can exist in one or more forms of optical or chiral isomers depending on the number of asymmetric centers of the compound. The invention therefore also relates both to the preparation of all the optical isomers and to their racemic or scalemic mixtures (scalemic is a mixture of enantiomers in different proportions), as well as mixtures of all possible stereoisomers in all proportions. The separation of the diastereoisomers and / or of the optical isomers can be carried out according to the methods known per se (E. Eliel and S. Wilen "Stereochemistry of Organic Compounds" Ed. Wiley (1994).

The present invention therefore relates to the process for preparing the compounds of formula (I) as they have just been defined by condensation of an alkali metal salt of 2- (hydroxymethyl) phenylacetic acid of formula (B):

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dans lequel X6 est tel que défini précédemment et M représente un atome de métal alcalin ou alcalino-terreux, par exemple le sodium ou le potassium, avec un composé de formule (A) : @

dans lequel R,, R2, R3, p et A sont tels que définis précédemment, et X représente un atome d'halogène choisi parmi fluor, chlore, brome et iode, le radical CH3S(O)- ou le radical CH3S(O)2-, pour conduire au composé de formule (II) :

dans lequel R,, R2, R3, X6, p et A sont tels que définis précédemment.

in which X6 is as defined above and M represents an alkali or alkaline earth metal atom, for example sodium or potassium, with a compound of formula (A): @

in which R ,, R2, R3, p and A are as defined above, and X represents a halogen atom chosen from fluorine, chlorine, bromine and iodine, the radical CH3S (O) - or the radical CH3S (O) 2-, to lead to the compound of formula (II):

in which R ,, R2, R3, X6, p and A are as defined above.

A very particularly preferred compound of formula (A) is that for which X represents a chlorine atom. Another compound of formula (A) which can advantageously be used for this reaction is that for which X represents the CH3S (O) 2 radical.

This condensation reaction is carried out in the presence of a base, such as an alkali or alkaline-earth metal hydroxide, for example sodium, potassium or cesium hydroxide, or an alkali metal hydride or alcoholate, for example sodium or potassium hydride, sodium methylate, potassium methylate, sodium tert-butoxide or potassium tert-butoxide.

The base preferably used and an alkali or alkaline earth metal hydroxide, more preferably an alkali metal hydroxide, in particular potassium hydroxide.

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] The solvent used for this reaction is a polar aprotic solvent, for example chosen from dimethylsulfoxide, N-methylpyrrolidinone, N, N-dimethylformamide, tetrahydrofuran and sulfolane. The particularly preferred solvent for this condensation reaction is dimethyl sulfoxide.

The reaction is carried out under an inert atmosphere at an appropriate temperature depending on the reagents and the solvent used. Thus the reaction temperature will advantageously be between -20 ° C. and 100 ° C., preferably between 25 ° C. and 50 ° C., for example at 25 ° C. The duration of the reaction also varies depending on the reagents and the solvent used and is for example between 30 minutes and 12 hours, preferably 1.5 hours to 8 hours. As a rule, the reaction time is around 6 hours.

The condensation reaction can optionally be activated by the addition of a crown ether or by adding a salt such as potassium iodide, potassium chloride, sodium iodide, cesium fluoride and by a salt. ammonium such as tetraethylamonium bromide.

Depending on the operating conditions used and on the yield obtained, it may also be advantageous to recycle the compound of formula (A) which has not reacted in this condensation reaction.

dans laquelle X6 est tel que défini précédemment, et est traité, en milieu basique, par exemple un hydroxyde de métal alcalin, tel que l'hydroxyde de potassium, en solvant polaire, comme par exemple le diméthylsulfoxyde, puis chauffé à un température comprise entre 30 C et 80 C, de According to a variant of the process of the present invention, the condensation reaction defined above can also be carried out by directly reacting the compound of formula (A) with the isochromanone precursor of the compound of formula (B). This variant thus offers the advantage of avoiding the isolation of the monosal. This isochromanone precursor, explained later in the present description, admits for formula:

in which X6 is as defined above, and is treated, in basic medium, for example an alkali metal hydroxide, such as potassium hydroxide, in a polar solvent, such as for example dimethyl sulfoxide, then heated to a temperature between 30 C and 80 C, from

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 preferably at a temperature of about 50 C, before adding the compound of formula (A). The reaction time can vary between a few hours and two days, although it has been noted that after 12 to 17 hours, the reaction is complete. The compound of formula (II) is thus obtained and can be used in the rest of the process.

The compound of formula (II) obtained by condensation of compounds (A) and (B), or according to the variant described above, is most often obtained in the form of the Z isomer or a mixture of Z and E isomers, at the level of the double bond of the hydroximic group. Isomerization of these compounds, into the E isomer, can be carried out by the action of an acid, such as, for example, hydrochloric acid, para-toluene-trifluoroacetic acid or acetic acid according to known techniques.

The preferred acid for this type of isomerization is para-toluenetrifluoroacetic acid, although other acids may be used, depending on the knowledge of those skilled in the art.

de formule (111) : T\ /R4 (ni) dans laquelle R4 est tel que défini précédemment et T représente un atome d'halogène, choisi parmi chlore, fluor, brome et iode, ou un radical alkyle contenant de 1 à 6 atomes de carbone en chaîne droite ou ramifiée, éventuellement substitué par un plusieurs atomes d'halogène. The acid of formula (II) thus obtained is used in an esterification reaction according to conventional techniques. For example, the esterification can be carried out in an aprotic apolar solvent, such as dichloromethane, in the presence of a base such as triethylamine, at a temperature between -20 ° C. and 60 ° C., preferably between 0 ° C. and room temperature, by action of a compound

of formula (111): T \ / R4 (ni) in which R4 is as defined above and T represents a halogen atom, chosen from chlorine, fluorine, bromine and iodine, or an alkyl radical containing from 1 to 6 atoms of carbon in a straight or branched chain, optionally substituted by one or more halogen atoms.

A compound of formula (III) preferably used in the present invention is an alkyl chloroformate, for example methyl chloroformate.

The ester of formula (IV) thus obtained:

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puis directement isomérisé en composé de formule (VE) :

composés de formules (V) et (VE), dans lesquels R,, R2, R3, R4, X6, A et p sont tels que définis précédemment. in which R ,, R2, R3, R4, X6, A and p are as defined above, is then transformed by Claisen reaction, as described for example in US patent 5,606,095, into an enol of formula (V):

then directly isomerized to the compound of formula (VE):

compounds of formulas (V) and (VE), in which R ,, R2, R3, R4, X6, A and p are as defined above.

More particularly, the Claisen reaction defined above is carried out by adding methyl formate to the compound of formula (IV) defined above, in a solvent, such as an ether, for example tetrahydrofuran, dimethyl ether of ethylene glycol, di-isopropyl ether, dibutyl ether, methyltert-butylether, preferably methyl-tert-butyl ether, in the presence of a base, for example sodium hydride or sodium methylate in powder or in solution in the methanol, preferably sodium hydride. The reaction is carried out very particularly preferably using the sodium hydride / methyl-tert-butyl ether couple, at ambient temperature, and its duration is a few hours, approximately 3 hours.

This same reaction can be carried out in the methyl-tert-butyl ether / sodium methylate powder pair, also at room temperature, for periods of up to 12 hours or more.

The conversion to isomer (VE) of the compound of formula (V) is carried out in situ, by acidification of the reaction medium.

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The compound of formula (VE) thus obtained is finally engaged in an alkylation reaction of enol, in the presence of a compound of formula (R5) 2-SO4 or R5-Hal in which R5 is as defined above and Hal represents a halogen atom chosen from fluorine, chlorine, bromine or iodine, in a polar aprotic solvent, such as dimethylformamide and in the presence of a base, such as an alkali carbonate, for example potassium carbonate, for finally lead to the compound of formula (I).

The Claisen and alkylation reactions defined above can advantageously be carried out in a single step. In this case, the reaction will preferably be carried out in tetrahydrofuran solvent, in the presence of sodium hydride.

In this specific case, it will be preferable to alkylate the enol function with a compound of formula R5-Hal in which R5 is as defined above and Hal represents a halogen atom chosen from fluorine, chlorine, bromine or iodine, preferably the iodine.

According to a variant of the process of the present invention for the preparation of the compounds of formula (I) in which R4 represents the methoxy radical, the acid of formula (II) previously defined is engaged in an esterification enamination reaction to lead to the compound of formula (VE '):

] This reaction is advantageously carried out in the presence of dimethylformamide dimethylacetal and pyridinium tosylate, at reflux and for a period of approximately two hours. Other reagents can be used, such as for example Bredereck's reagents, such as methoxybis (dimethylamino) methane in toluene at 80 ° C., or tert-butoxybis (dimethylamino) methane, or tris (dimethylamino) methane, in the same conditions.

Another variant consists in carrying out the enamination described above from the esters of formula (IV) as defined above. In this case, the reaction is advantageously carried out with the Bredereck reagent, in particular the

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 methoxybis (dimethylamino) methane in toluene at 80 C, for a duration of approximately 2 hours The intermediate compounds of formulas (II), (IV), (V), (VE) and (VE ') are new and as such are also part of the present invention. Thus, as already indicated for the compounds of formula (I), preference will be given to the compounds of formulas (II), (IV), (V), (VE) and (VE ') in which: # p represents 1, # R1 is the hydrogen atom, # R2 represents the hydrogen atom or a lower alkyl radical, # R3 represents a hydrogen atom, a lower alkyl radical, lower haloalkyl, a lower cycloalkyl radical, or lower halocycloalkyl, # R4 represents an alkoxy radical, # R5 represents an alkyl radical, # A represents a pyridyl radical, and # X6 represents a hydrogen atom.

The compound of formula (VE ') is finally hydrolyzed to yield the compound of formula (I), optionally by first hydrolysis to the compound of formula (VE), the hydrolysis being carried out in an acid medium, hydrochloric acid for example, aprotic apolar solvent, such as toluene, generally at room temperature, for a period of approximately one hour.

It should be understood that the solvents and the operating conditions (temperatures and reaction times) used throughout the description of the process of the present invention (that is to say of the reactions described above but also in the remainder of this description), are given by way of example and can in no way limit the scope of the reactions described in this document. Those skilled in the art will appreciate, for each of the reactions and as a function of the various substituents present in the synthesis intermediates, as in the compounds of formula (I), the most appropriate operating conditions, that is to say in particular those leading to the best yields. In particular, the reaction times can be chosen according to the degree of progress of the reactions, by checking the quantities of the remaining reactants or of product formed.

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dans lequel X6 est tel que défini précédemment, selon, par exemple, les conditions opératoires décrites dans Organic Synthesis, (1961), 41, 53, c'est-à-dire en faisant réagir, à une température adaptée, par exemple entre 20 et 50 C, l'indène avec l'acide formique et l'eau, puis l'eau oxygénée et enfin en réalisant une addition d'acide sulfurique, à une température proche de 100 C. The present invention also relates to the process for the preparation of the compound of formula (B) defined above, characterized in that an oxidation of an indene to 2-indanone is carried out according to the following scheme:

in which X6 is as defined above, according to, for example, the operating conditions described in Organic Synthesis, (1961), 41, 53, that is to say by reacting, at a suitable temperature, for example between 20 and 50 C, indene with formic acid and water, then hydrogen peroxide and finally by carrying out an addition of sulfuric acid, at a temperature close to 100 C.

dans lequel X6 est tel que défini précédemment, par exemple selon le mode opératoire décrit dans J. Het. Chem., (1995), 32,73. La 2-indanone, placée en solvant aprotique apolaire, un solvant organo-chloré par exemple, comme le dichloorométhane, est mise au contact d'un agent d'oxydation bien connu du spécialiste èn synthèse organique. Cet agent d'oxydation peut, par exemple, être choisi parmi l'eau oxygénée, les sels de peroxydes métalliques, comme le permanganate de potassium, et les peracides organiques, comme l'acide méta-chloroperbenzoïque. 2-Indanone is then engaged in a Baeyer-Villiger reaction to lead to isochromanone according to the following synthetic scheme:

in which X6 is as defined above, for example according to the procedure described in J. Het. Chem., (1995), 32.73. 2-Indanone, placed in apolar aprotic solvent, an organo-chlorinated solvent for example, such as dichlooromethane, is brought into contact with an oxidizing agent well known to the specialist in organic synthesis. This oxidizing agent can, for example, be chosen from hydrogen peroxide, the salts of metal peroxides, such as potassium permanganate, and organic peracids, such as meta-chloroperbenzoic acid.

Finally, isochromanone is converted into the compound of formula (B) as defined above, by the action of an equivalent of a base, sodium hydroxide for example, at a temperature between 10 ° C. and 80 ° C., preferably between 25 C and 40 C, for example at 25 C.

The compound of formula is new and as such is also part of the invention. More particularly, the compound of formula (B) in which X6 represents hydrogen and M represents sodium will be preferred.

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dans lequel X6 est tel que défini précédemment et M représente un atome de sodium ou de potassium, composé de formule (B2) qui peut, dans les mêmes conditions que pour le composé de formule (B), être mis en #uvre dans la réaction de condensation avec le composé de formule (A) pour conduire au composé de formule (II). ] By adding two base equivalents to isochromanone, or alternatively according to the procedure described in patent application WO97 / 12864, this is converted into the compound of formula (B2):

in which X6 is as defined above and M represents a sodium or potassium atom, compound of formula (B2) which can, under the same conditions as for the compound of formula (B), be used in the reaction of condensation with the compound of formula (A) to yield the compound of formula (II).

formules dans lesquelles A, RI et R2 sont tels que définis précédemment et Hal représente un atome d'halogène choisi parmi fluor, chlore, brome et iode, la réaction étant effectuée en solvant halogéné, comme par exemple le 1,2-dichloroéthane, le tétrachlorométhane ou le n-chlorobutane, à une température comprise entre 50 C et la température d'ébullition du solvant. The compound of formula (A) defined above is prepared by halogenation of a compound of formula (al) into the compound of formula (a2), according to the following scheme:

formulas in which A, RI and R2 are as defined above and Hal represents a halogen atom chosen from fluorine, chlorine, bromine and iodine, the reaction being carried out in halogenated solvent, such as for example 1,2-dichloroethane, tetrachloromethane or n-chlorobutane, at a temperature between 50 C and the boiling point of the solvent.

The halogenating agent is chosen from the conventional agents known to a person skilled in the art and can be, for example, a halosuccinimide, for example N-bromosuccinimide. The reaction time is, in most cases, between 30 minutes and 10 hours, generally between 2 and 5 hours.

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composés de formules (a2), (a4) et (a5), dans lesquels A, R,, R2, R3 et p sont tels que définis précédemment, le composé de formule (a4) étant préparé directement in situ, et donc non isolé, à partir du composé de formule (a3) selon le schéma suivant :

schéma dans lequel R3 a la même définition que décrit précédemment, la préparation du composé de formule (a4) étant réalisée en présence de chlorhydrate d'hydroxylamine, en présence d'une base, comme un hydroxyde alcalin, l'hydroxyde de sodium par exemple, à une température comprise entre -20 C et 20 C, par exemple à une température d'environ 0 C à 2 C, réaction directement suivie par l'addition du composé de formule (a2), à température plus élevée, par exemple 60 C à 80 C, pour conduire au composé de formule (a5). ] The compound of formula (a2) previously defined is condensed on the compound of formula (a4) according to the following scheme:

compounds of formulas (a2), (a4) and (a5), in which A, R ,, R2, R3 and p are as defined above, the compound of formula (a4) being prepared directly in situ, and therefore not isolated , from the compound of formula (a3) according to the following scheme:

scheme in which R3 has the same definition as described above, the preparation of the compound of formula (a4) being carried out in the presence of hydroxylamine hydrochloride, in the presence of a base, such as an alkali hydroxide, for example sodium hydroxide , at a temperature between -20 ° C. and 20 ° C., for example at a temperature of approximately 0 ° C. to 2 ° C., reaction directly followed by the addition of the compound of formula (a2), at a higher temperature, for example 60 C to 80 C, to yield the compound of formula (a5).

dans lequel A, R,, R2, R3 et p sont tels que définis précédemment, et Hal représente un atome d'halogène, tel que fluor, chlore, brome ou iode, de préférence le chlore, cas particulier des composés de formule (A) pour lesquels X représente un atome d'halogène. The compound of formula (a5) thus formed is then treated with a phosphorus compound of formula POHal3, where Hal represents a halogen atom, such as fluorine, chlorine, bromine or iodine, preferably chlorine, to yield the compound of formula (a6):

in which A, R ,, R2, R3 and p are as defined above, and Hal represents a halogen atom, such as fluorine, chlorine, bromine or iodine, preferably chlorine, a special case of the compounds of formula (A ) for which X represents a halogen atom.

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(a@) dans lequel A, RI, R2, R3 et p sont tels que définis précédemment, par réaction, sur le composé de formule (a6) d'un thiométhylate de alcalin, par exemple le thiométhylate de sodium, dans un solvant polaire aprotique, comme le diméthylformamide. ] The compound of formula (a6) can itself be transformed into the compound of formula (a7):

(a @) in which A, RI, R2, R3 and p are as defined above, by reaction, on the compound of formula (a6) of an alkali thiomethylate, for example sodium thiomethylate, in a polar solvent aprotic, such as dimethylformamide.

dans lequel A, RI, R2, R3 et p sont tels que définis précédemment, cas particulier des composés de formule (A) pour lesquels X représente le radical CH3S(O)-, sous l'action d'un agent d'oxydation, tel que par exemple l'eau oxygénée en présence d'oxyde de sélénium, les sels de peroxydes métalliques, comme le permanganate de potassium, le periodate de sodium, l'ozone, et les peracides organiques, comme l'acide méta-chloroperbenzoïque, de préférence l'acide méta-chloroperbenzoïque, en solvant apolaire aprotique, le dichlorométhane par exemple, à une température comprise entre 0 C et la température ambiante, de ptréférence à une temlpérature d'environ 10 C. The compound of formula (a7) above can itself be oxidized to the corresponding sulfoxide of formula (a8):

in which A, RI, R2, R3 and p are as defined above, a special case of the compounds of formula (A) for which X represents the radical CH3S (O) -, under the action of an oxidizing agent, such as, for example, hydrogen peroxide in the presence of selenium oxide, the salts of metal peroxides, such as potassium permanganate, sodium periodate, ozone, and organic peracids, such as meta-chloroperbenzoic acid, preferably meta-chloroperbenzoic acid, in an aprotic apolar solvent, dichloromethane for example, at a temperature between 0 C and room temperature, preferably at a temperature of about 10 C.

dans lequel A, RI, R2, R3 et p sont tels que définis précédemment, cas particulier des composés de formule (A) pour lesquels X représente le radical CH3S(O)2-' dans les mêmes conditions opératoires que celles décrites précédemment pour la préparation du composé de formule (a8). Finally, the compound of formula (a8) above can itself be oxidized to the corresponding sulfonyl of formula (a9):

in which A, RI, R2, R3 and p are as defined above, special case of the compounds of formula (A) for which X represents the radical CH3S (O) 2- 'under the same operating conditions as those described above for the preparation of the compound of formula (a8).

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The set of compounds of formulas (a6), (a8) and (a9) forming the set of compounds of formula (A) as defined above. The synthesis intermediates of formula (A) and (a7) are new and, as such, are part of the present invention.

Preferred are the compounds of formula (A) and (a7) for which: # p represents 1, # R, is the hydrogen atom, # R2 represents the hydrogen atom or a lower alkyl radical, # R3 represents a hydrogen atom, a lower alkyl, lower haloalkyl, a lower cycloalkyl, or lower halocycloalkyl radical, and # A represents a pyridyl radical.

Thus, the method according to the present invention can be summarized on the following diagram:

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schéma dans lequel chacune des étapes est décrite dans la description précédente, chacun des groupements portés par les différents composés est tel que défini précédemment.

diagram in which each of the steps is described in the preceding description, each of the groups carried by the different compounds is as defined above.

composé dénommé (2E-2-[2-((E-cyclopropyl{[1-(2-pyridyl)propoxy]imino}- méthoxyméthyl) phényl]-3-méthoxy-2-propénoate de méthyle, selon le schéma suivant : More particularly the method according to the invention relates to the preparation of

compound called (2E-2- [2 - ((E-cyclopropyl {[1- (2-pyridyl) propoxy] imino} - methoxymethyl) phenyl] -3-methyl methoxy-2-propenoate, according to the following scheme:

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schéma dans lequel les étapes sont telles que définies dans la description précédente.

diagram in which the steps are as defined in the preceding description.

The following examples illustrate the present invention and do not limit it in any way.

 EXAMPLE 1: indene to 2-indanone In a 600 ml reactor, under a nitrogen atmosphere and at room temperature, are introduced successively 81.7 ml of indene (purity 95%; moles); ml of acid

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formic (9 moles); ml of water. The mixture is stirred and heated to 35-40 ° C. and then 70 ml of 30% hydrogen peroxide (0.7 moles) are added dropwise.
120 minutes. The temperature is maintained at 35 ° C. for 1 hour until complete transformation of the indene. The medium is then cooled to 20-25 C; the excess of peroxides is destroyed by the addition of an aqueous solution of sodium hydrogen sulfite and then the excess of formic acid is distilled under reduced pressure.

The intermediate reaction crude is then added to 200 ml of a 20% sulfuric acid solution (0.75 moles of sulfuric acid). The mixture is heated to 98-100 ° C. for 1.5 hours and then cooled to 20 ° C. After decantation, the aqueous phase is extracted with dichloromethane and the organic phases combined.

The yield (dosed in indanone) is 66%.

The indanone solution obtained previously is then used in the Baeyer-Villiger oxidation step to lead to isochromanone.

EXAMPLE 2 Preparation of isochromanone The above solution of 2-indanone (0.33 moles) in 500 ml of dichloromethane is placed in a 1 liter reactor and stirred at 40 ° C., then a solution of 125 g (0.5 moles) of metachloroperbenzoic acid (purity 70%) dissolved in dichloromethane is added dropwise to the mixture. After 6 hours of reaction, the mixture is cooled to 20 ° C. and the excess of metachloroperbenzoic acid destroyed by the addition of sodium hydrogen sulfite. The medium is neutralized with aqueous sodium carbonate. After decantation, the aqueous phase is extracted twice with 300 ml of dichloromethane. The organic phases are combined and the solvent removed under reduced pressure; 35.7 g of isochromanone are thus obtained.

Yield: 73%.

Melting point: 81 C.

 EXAMPLE 3 Sodium 2-hydroxymethylphenylacetate 1.48 g of isochromanone are placed in a 50 ml three-necked flask, then, with stirring at 25 ° C., 1 ml of sodium hydroxide (1M aqueous solution) is poured. After 2 hours of stirring at 25 ° C., the homogeneous medium is washed with 20 ml of toluene and then concentrated by azeotropic distillation. 1.47 g of sodium monosel (sodium 2-hydroxymethylphenylacetate) are obtained in the form of a white powder.

Yield: 78%.

Melting point:> 230 C.

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Under the same operating conditions, by replacing sodium hydroxide with potassium hydroxide, the corresponding potassium monosel is obtained with a yield of 86%.

EXAMPLE 4 Preparation of a compound of formula (a1) Example of preparation of 2- (n-propyl) pyridine by ethylation of a-picoline: Toluene (115 g) is charged into a 1 liter reactor and a suspension of sodium amide (125 g of a 50% solution in toluene, ie 1.6 moles) with stirring and inert atmosphere (nitrogen) at 25 C. Then 138 g (1.4 moles) of a -picoline are added in 30 minutes to the reaction medium. After 30 min. stirring at 25 ° C., the mixture is heated to 100 ° C. and a solution of chloroethane (142 g in 280 g of toluene) is added over 3 hours. After 3 hours of maintaining at this temperature, the medium is cooled to 25 ° C. and poured onto 270 g of water while keeping the temperature of the mixture below 45 ° C. After decantation, the organic phase is washed with 200 g of water. , then distilled under reduced pressure.

82 g of 2- (n-propyl) pyridine are thus obtained (boiling point: 75 ° C. to 50 mbar), ie a yield of 45% in isolated product.

EXAMPLE 5 Preparation of a compound of formula (a2) Example of preparation of 2-bromopropylpyridine from 2- (n-propyl) pyridine: In a 1 liter reactor, 1,2-dichloroethane (600 g), 2- (n-propyl) pyridine (121.9 g) and azo-bis-isobutyronitrile (AIBN) (4.95 g) are loaded with stirring at 25 ° C. and in an inert atmosphere (nitrogen). The reaction medium is heated to 70 C. N-bromosuccinimide (200 g; 1.1 eq.) Is gradually loaded in 5 g portions. At the end of the addition, the temperature of the reaction medium reaches 80 C. The medium is maintained for 3 h at reflux of dichloroethane, then cooled to 25 C and then filtered. An aqueous solution of sodium hydrogen sulfite (238 g of a 16% w / w solution) is added to the filtrate with stirring. After decantation, the organic phase is washed with 200 g of water and then dosed (yield: 90%) then concentrated under reduced pressure.

NMR (CDCl3): 1.00 (t, 3H); 2.3 (p, 2H); 4.95 (t, 1H); 7.25 (m, 1H); 7.45 (m, 1H); 7.70 (m, 1H), 8.60 (m, 1H).

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Exemple de préparation de N (1-(2 pyridyl)propoxyJcycloproparecarboxamide : Dans un réacteur de 1 litre à 25 C, on charge successivement et sous agitation 35 g de chlorhydrate d'hydroxylamine (0,5mole) ; 120 ml d'eau ; 50 g d'ester méthylique de l'acide cyclopropylcarboxylique et 60 ml de nitrométhane. Le mélange biphasique est refroidi à 0-2 C puis 182 g d'une solution aqueuse d'hydroxyde de sodium (2 éq.) à 22% poids/poids sont ajoutés en 45 minutes. Après 15 minutes de maintien à cette température, le milieu est ramené à 25 C en lh30. Après décantation, la phase organique est séparée. La phase aqueuse est chauffée sous agitation à 70 C et une solution de 10,2g de 2-bromopropylpyridine (de titre 78%) dans 60 ml de nitrométhane est ajoutée en 30 minutes. Le mélange est maintenu à cette température pendant 3 heures sous agitation puis refroidi à 20 C. On introduit alors successivement 100 ml d'éther di-isopropylique et 80 ml d'hydroxyde de sodium (solution aqueuse à 22% poids/poids). Après décantation, la phase organique est éliminée, la phase aqueuse est neutralisée par de l'acide chlorhydrique (solution aqueuse à 36% poids/poids) et extraite par 200 ml d'acétate d'éthyle. La phase organique obtenue après décantation est concentrée sous pression réduite pour donner un solide beige. EXAMPLE 6 Preparation of a compound of formula (a4)

Example of preparation of N (1- (2 pyridyl) propoxyJcycloproparecarboxamide: 35 g of hydroxylamine hydrochloride (0.5 mol) are charged successively with stirring at 25 ° C.; 120 ml of water; 50 g of methyl ester of cyclopropylcarboxylic acid and 60 ml of nitromethane The biphasic mixture is cooled to 0-2 C. and then 182 g of an aqueous solution of sodium hydroxide (2 eq.) at 22% w / w are added over 45 minutes, after 15 minutes of maintaining at this temperature, the medium is brought back to 25 ° C. in 1 hour 30 minutes, after decantation, the organic phase is separated off, the aqueous phase is heated with stirring to 70 ° C. and a solution of 10, 2 g of 2-bromopropylpyridine (78% titre) in 60 ml of nitromethane is added over 30 minutes, the mixture is maintained at this temperature for 3 hours with stirring and then cooled to 20 C. 100 ml of di ether are then successively introduced. -isopropyl and 80 ml of sodium hydroxide (solution a queuse at 22% w / w). After decantation, the organic phase is eliminated, the aqueous phase is neutralized with hydrochloric acid (aqueous solution at 36% w / w) and extracted with 200 ml of ethyl acetate. . The organic phase obtained after decantation is concentrated under reduced pressure to give a beige solid.

Melting point: 86 C.

Yield: 68%.

EXAMPLE 7 Preparation of a compound of formula (a6) Example of preparation of N - [(1- (2-pyridyl) propoxy] cyclopropanecarboximidoyl chloride: Introduced successively at 25 ° C. with stirring, 2.20 g of compound obtained in Example 6 (0.01 mole), 10 ml of 1,2-dichloroethane and then 1.11 ml of POCI3 (0.012 moles) The mixture is heated for 4 h 15 to 70 ° C. cooled to 0 ° C. and 50 ml of a saturated aqueous solution of sodium hydrogencarbonate is added dropwise After decantation, the organic phase is washed with 10 ml of water, dried over magnesium sulphate and then concentrated under reduced pressure to give 2.38 g of a yellow oil (yield 85%).

Crude NMR (CDCI,) 90/10 mixture of 2 isomers: 0.8-1.3 (m, 7H),; 1.8-2.1 (m, 3H); 5.20 (t, 1H); 7.25 (m, 1H); 7.35 (m, 1H); 7.45 (m, 0.1H); 7.70 (m, 1H); 7.85 (m, 0.1H); 8.10 (m, 0.1H); 8.60 (m, 1H); 8.70 (m, 0.1H).

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Exemple de préparation de N ((1-(2 pyridyl)propoxyJcyclopropanecarbimidothioate de méthyle : À 1,80 g (0,0075 moles) de composé obtenu dans l'exemple 7 dans 20 ml de diméthylformamide anhydre, sont additionnés 0,56 g (0,0080 moles) de thiométhylate de sodium par portions ; la température du mélange passe de 25 à 40 C.En fin d'addition, le milieu est agité 1 heure à température ambiante puis coulé dans 200 ml d'eau, extrait avec 100 ml d'acétate d'éthyle. La phase organique est lavée avec une solution aqueuse de chlorure de lithium, séchée sur sulfate de sodium, puis concentrée pour donner 1,67 g de composé attendu sous forme de miel jaune. EXAMPLE 8 Preparation of a compound of formula (a7)

Example of preparation of N ((1- (2 pyridyl) propoxy Methyl encyclopropanecarbimidothioate): To 1.80 g (0.0075 moles) of compound obtained in Example 7 in 20 ml of anhydrous dimethylformamide, are added 0.56 g ( 0.0080 moles) of sodium thiomethylate in portions; the temperature of the mixture increases from 25 to 40 C. At the end of the addition, the medium is stirred for 1 hour at room temperature then poured into 200 ml of water, extracted with 100 ml of ethyl acetate The organic phase is washed with an aqueous solution of lithium chloride, dried over sodium sulphate, then concentrated to give 1.67 g of the expected compound in the form of yellow honey.

Yield: 88%.

Refractive index (D, 24 C): 1.5440.

Exemple de préparation de cyclopropyl((1-(2 pyridyl)propoxyJimirco)méthyl- méthylsulfoxyde : On dissout 1,00 g (0,0040 moles) de composé obtenu dans l'exemple 8 dans 30 ml de dichlorométhane ; le milieu est refroidi à 5 C, puis additionné de 0,69 g (0,0028 moles) d'acide métachloroperbenzoïque à 70%, par portions. Après retour à température ambiante, le milieu est agité 1 heure, additionné de 50 ml de dichlorométhane. La phase organique est lavée avec une solution aqueuse de bicarbonate de sodium, puis à l'eau, séchée et concentrée. Après chromatographie sur silice, 0,46g de sulfoxyde correspondant est obtenu comme miel incolore. . EXAMPLE 9 Preparation of a compound of formula (a8)

Example of preparation of cyclopropyl ((1- (2 pyridyl) propoxyJimirco) methyl-methylsulfoxide: 1.00 g (0.0040 moles) of compound obtained in Example 8 is dissolved in 30 ml of dichloromethane; the medium is cooled to 5 C., then added with 0.69 g (0.0028 moles) of 70% metachloroperbenzoic acid, in portions, after returning to room temperature, the medium is stirred for 1 hour, supplemented with 50 ml of dichloromethane. is washed with an aqueous solution of sodium bicarbonate, then with water, dried and concentrated, after chromatography on silica, 0.46 g of corresponding sulfoxide is obtained as colorless honey.

Yield: 46%.

Refractive index (D, 24 C): 1.5450.

Exemple de préparation de cyclopropyl{[l-(2-pyridyl)propoxy]imino}méthyl- méthylsulfone : Le composé obtenu dans l'exemple 9 (9,40 g ; mmoles) est dissous dans 150 ml de dichlorométhane. Le milieu est refroidi à 10 C, puis additionné de 12,90 g (75 mmoles) d'acide métachloroperbenzoïque par portions. Après retour à température ambiante, le milieu est agité 2 heures, additionné de 100 ml de dichlorométhane, lavé avec une solution aqueuse de bicarbonate de sodium, puis à EXAMPLE 10: of a compound of formula (a9)

Example of preparation of cyclopropyl {[1- (2-pyridyl) propoxy] imino} methyl-methylsulfone: The compound obtained in example 9 (9.40 g; mmol) is dissolved in 150 ml of dichloromethane. The medium is cooled to 10 ° C., then added with 12.90 g (75 mmol) of metachloroperbenzoic acid in portions. After returning to ambient temperature, the medium is stirred for 2 hours, added with 100 ml of dichloromethane, washed with an aqueous solution of sodium bicarbonate, then at

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 the water. The organic phase is dried, concentrated. After chromatography on silica, 6.00 g of the expected compound are obtained in the form of yellow honey.

Yield: 57%.

Refractive index (D, 27 C): 1.5225.

EXAMPLE 11 Preparation of a compound of formula (II) by condensation of a compound of formula (A) with a compound of formula (B2) Example of preparation of the acid [2 - ((E) -cyclopropyl {[ 1- (2-pyridyl) propoxy] imino} methoxymethyl) phenyl] acetic: To 10.00 g (0.047 moles) of sodium disel of 2-hydroxymethylphenylacetic acid in 30 ml of dimethylformamide, 13 is added at room temperature, 4 g (0.047 moles) of compound obtained in Example 10 in 5 ml of dimethylformamide. The temperature of the medium goes from 23 to 32 C.

After 14 hours of stirring at room temperature, the medium is poured into 400 ml of water and then extracted with 50 ml of ethyl acetate, the aqueous phase is then brought to pH 4, then extracted with 2 times 50 ml of 'ethyl acetate ; the organic extracts are then washed with an aqueous solution of lithium chloride, then with water, then dried. After evaporation of the solvent, 11.6 g of a pale yellow honey are obtained, mixture of the Z and E isomers.

The honey obtained is dissolved in 100 ml of toluene, added with 1 ml of acetic acid and brought to reflux for 2 hours. After evaporation of the solvent under vacuum, the residue is kneaded in a heptane / ethyl acetate mixture (80:20). The white solid which crystallizes is dried under vacuum and 11.00 g of the expected compound are obtained.

Yield: 63%.

Melting point: 146 C.

EXAMPLE 12 Preparation of a compound of formula (II) by condensation of a compound of formula (A) with a compound of formula (B2) Example of preparation of the acid [2 - ((E) -cyclopropyl {[ l- (2-pyridyl) propoxy] - imino) methoxymethyl) phenyl] acetic: The reaction is carried out using the sulfoxide obtained in Example 9 as described above for Example 11; it is then necessary to cool the medium to 40 ° C., the yield is comparable.

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 EXAMPLE 13: of a compound of formula (II) by condensation of a compound of formula (A) with a compound of formula (B) Example of preparation of the acid [2 - ((E) -cyclopropyl {[1 - (2-pyridyl) propoxy] - iminomethoxymethyl) phenyl] acetic: 2.00 g (0.0106 moles) of sodium monosal 2-hydroxymethylphenylacetic acid in 10 ml of anhydrous dimethylformamide, under argon, at 10 C , 0.43 g (0.0106 moles) of 60% sodium hydride are introduced in portions. The reaction mixture is allowed to return to ambient temperature.

After 30 minutes of stirring, 2.99 g (0.0106 mol) of the compound obtained in Example 10, dissolved in 5 ml of anhydrous dimethylformamide, are poured in at room temperature. After 16 hours of stirring, the mixture is poured into 100 ml of water and washed with 10 ml of ethyl acetate. The aqueous phase is brought to pH 4 and extracted with 2 times 20 ml of ethyl acetate. The organic extracts are then washed with an aqueous solution of lithium chloride, then with water, to lead, after evaporation of the solvent, to 2.79 g of a pale yellow honey, mixture of the Z and E isomers.

Yield: 72%.

The isomerization of the Z isomer to the E isomer is carried out as described above in Example 11.

EXAMPLE 14 Preparation of a compound of formula (II) directly in the form of isomer E by condensation of a compound of formula (A) with a compound of formula (B) Example of preparation of the acid [2- ( (E) -cyclopropyl {[1- (2-pyridyl) propoxy] - imino) methoxymethyl) phenyl] acetic: Condensation: To a suspension of 7.9 g (2 eq.) Of ground potassium hydroxide, in 60 ml of dimethylsulfoxide, at 25 ° C. with stirring and under an inert atmosphere, a solution of 11.28 g (1 eq.) of sodium monosalt of 2-hydroxymethylphenylacetic acid and 20 g (1 eq.) of compound obtained in Example 7 (60%) in 60 ml of dimethyl sulfoxide. Stirring is continued for 6 hours at 25 ° C., then 150 ml of water and 150 ml of dichloromethane are successively added.

After decantation, the aqueous phase is washed with 2 times 100 ml of dichloromethane, then acidified to pH 6.5 with a 6M hydrochloric acid solution and extracted with 3 times 150 ml of ethyl acetate. After decantation, the combined organic phases

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 are washed with saturated sodium chloride solution, dried and evaporated.

 16.3 g of Zbrut acid are isolated in the form of a brown oil.

Isomerization: The oil obtained above is dissolved in 150 ml of dichloromethane at 25 ° C. and then 50 III of trifluroacetic acid are added and the medium is stirred at 25 ° C. for 3 hours. Then add a saturated aqueous solution of sodium hydrogencarbonate (about 4 ml, up to pH 6.5) and then 20 ml of water are added. After decantation and extraction of the aqueous phase with 100 ml of dichloromethane, the organic phases are combined, dried over magnesium sulphate, then concentrated under reduced pressure. The solid obtained is recrystallized from an 85:15 cyclohexane / ethyl acetate mixture, to give 6.14 g of acid E in the form of a white powder of 95% strength.

Melting point: 141 C.

Yield: 28% E acid.

EXAMPLE 15 Preparation of a compound of formula (II) by condensation of a compound of formula (A) with the isochromanone precursor of the compound of formula (B) Example of preparation of the acid [2 - ((E) -cyclopropyl {[1- (2-pyridyl) propoxy] imino) methoxymethyl) phenyl] acetic: Opening-Condensation: To a suspension of 19.8 g (3 eq.) of potassium hydroxide ground in 100 ml of dimethyl sulfoxide 24 C and under a nitrogen atmosphere, is poured in 5 minutes a solution of 14.88 g (1 eq.) Of isochromanone in 50 ml of dimethyl sulfoxide. The reaction medium is heated at 50 ° C. for 2 hours, then cooled to 30 ° C. A solution of 34.8 g (1.2 eq.) Of compound obtained in Example 7 (82%) is poured in over 5 minutes. in 50 ml of dimethyl sulfoxide. Stirring is then maintained for 5 hours at 50 ° C. and then 12 hours at 25 ° C. 200 ml of water and 200 ml of dichloromethane are then added successively. After decantation, the aqueous phase is washed with 2 times 150 ml of dichloromethane. The aqueous phase is then acidified to pH 6.5 with a 6M hydrochloric acid solution and extracted with 3 times 150 ml of dichloromethane.

After decantation, the combined organic phases are washed with 2 times 150 ml of water, dried and evaporated. 20 g of Zbrut acid are isolated in the form of an oil.

The isomerization is carried out as described for Example 14.

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 EXAMPLE 16 Preparation of a compound of formula (IV) by esterification of a compound of formula (II).

Example of preparation of [2 - ((E) -cyclopropyl {[1- (2-pyridyl) propoxy] imino} - methyl methoxymethyl) phenyl] acetate: At 9.55 g (0.026 moles) of compound obtained according to one of Examples 11 to 15 described above, dissolved in 150 ml of dichloromethane, 3.96 ml (0.029 moles) of triethylamine are added, then, at 10 ° C. and dropwise, 2.22 ml (0.029 moles) of methyl chloroformate. After returning to ambient temperature and continuing the reaction until gas evolution ceases, then concentration, the residue is taken up in 150 ml of ethyl acetate, washed with 50 ml of water. The organic phase, once dried and concentrated, provides 8.90 g of the expected ester.

Yield: 90%.

Refractive index (D, 23 C): 1.5432.

EXAMPLE 17 Preparation of a compound of formula (VE) from an ester of formula (IV).

Example of preparation of (2E) -2-2 - ((E) -cyclopropyll- (2 pyridyl) propoxyJimino) methoxymethyl) phenylJ-3-hydroxy-2 methyl propenoate: 1) In the solvent couple methyl-tert-butyl ether / sodium hydride: To a suspension of 134 mg (2.2 eq.) of sodium hydride 1.2 ml of tert-butyl methyl ether at 25 ° C. and under an inert atmosphere, a solution of 573 mg is poured in over 4 hours (1 eq.) Of ester obtained in Example 16 and 374 mg (4.2 eq.) Of methyl formate in solution in 1.5 ml of tert-butyl methyl ether. Stirring is then continued for 3 hours at 25 C. 20 ml of a saturated ammonium chloride solution are then added, then 20 ml of ethyl acetate. After decantation, the aqueous phase is extracted with 2 times 20 ml of ethyl acetate. The combined organic phases are washed with water, dried and evaporated. The expected crude compound is isolated in the form of a white powder.

2) In the methyl-tert-butyl ether / sodium methylate solvent couple: 0.28 g (0.0052 moles) of sodium methylate in powder in 5 ml of methyl-tert-butyl ether is poured slowly, and with vigorous stirring, a mixture composed of 1.00 g (0.0026 moles) of the ester previously prepared in Example 16 and 0.63 g (0.0105 moles) of methyl formate in 10 ml of methyl tert-ether -butyl.

<Desc / Clms Page number 30>

 After 12 hours of stirring at room temperature and concentration to dryness, the residue is taken up in 50 ml of water, washed with 20 ml of ethyl acetate and the aqueous phase is acidified to pH 4 with acetic acid concentrated. The expected compound is recovered in 2 times 20 ml of ethyl acetate. The organic phase is dried, concentrated to yield, after chromatography on silica (heptane / ethyl acetate solvent 7: 3) 1.20 g (80%) of a pale yellow honey which crystallizes over time.

Yield: 80%.

Melting point: 114 C.

EXAMPLE 18 Preparation of a compound of formula (I) from an ester of formula (VE).

((E)-cyclopropyl { [ 1-(2-pyridyl)propoxy]imino}méthoxyméthyl)phényl]-3-méthoxy- 2-propénoate de méthyle. Example of preparation of (2E) -2-j2 - ((E) -cyclopropyl (jl- (2 pyridyl) propoxyJ- imino) methoxymethyl) phenyl] -3-methyl-2-propenoate: At 0.130 g (0, 00032 moles) of compound obtained in the previous example, in 1 ml of dimethylformamide, 0.048 g (0.0035 moles) of potassium carbonate are added and, with vigorous stirring, at room temperature, 0.044 g (0.0035 moles) dimethyl sulfate; the reaction mixture is stirred for 2 hours, then poured into 10 ml of water, and extracted with twice 5 ml of ethyl acetate. The organic extracts are dried, concentrated and the honey obtained is chromatographed on silica, kneaded in diisopropyl ether, to obtain, after filtration and drying, 0.11 g of (2E) -2- [2-

((E) -cyclopropyl {methyl {[1- (2-pyridyl) propoxy] imino} methoxymethyl) phenyl] -3-methoxy-2-propenoate.

Yield: 90%.

Melting point: 75 C.

Exemple de préparation du (2E)-2-[2-((E)-cyclopropyl([l-(2-pyridyl)propoxyJ- imino)méthoxyméthyl)phércylJ-3-diméthylamiho-2 propénoate de méthyle : Un mélange de 1,00 g (0,00272 moles) d'acide E obtenu selon un des exemples 11à 15 décrits ci-dessus, dans 5 ml de diméthylformamide diméthylacétal et de 0,10 g de tosylate de pyridinium est porté 2 heures au reflux, concentré, le résidu chromatographié sur silice (solvant heptane/acétate d'éthyle 1: 1), pour donner 0,60 g d'énamine attendue, isomère EE, miel jaune pâle. EXAMPLE 19: of a compound of formula (VE ') from an ester (II).

Example of preparation of (2E) -2- [2 - ((E) -cyclopropyl ([l- (2-pyridyl) propoxyJ- imino) methoxymethyl) phercylJ-3-dimethylamiho-2-methyl propenoate: A mixture of 1, 00 g (0.00272 moles) of acid E obtained according to one of examples 11 to 15 described above, in 5 ml of dimethylformamide dimethylacetal and 0.10 g of pyridinium tosylate is brought to reflux for 2 hours, concentrated, the residue chromatographed on silica (heptane / ethyl acetate solvent 1: 1), to give 0.60 g of expected enamine, EE isomer, pale yellow honey.

Yield: 50%.

Refractive index (D; 23 C): 1.5675.

<Desc / Clms Page number 31>

Exemple de préparation du (2E)-2-[2-((E)-cyclopropyl{jjl -(2-pyridyl)propoxy]iminométhoxyméthyl)phénylJ-3-diméthylamino-2 propénoate de méthyle : À 0,50 g (0,0013 moles) d'ester E obtenu dans l'exemple 16 dans 3 ml de toluène est ajouté 0,34 g de méthoxybis(diméthylamino)méthane et le milieu porté 2 heures à 80 C. Après concentration, le résidu est chromatographié sur silice (solvant heptane/acétate d'éthyle 1:1), pour donner 0,60 g d'énamine attendue, isomère EE, sous forme de miel jaune pâle. EXAMPLE 20 Preparation of a compound of formula (VE ') from an ester of formula (IV).

Example of preparation of (2E) -2- [2 - ((E) -cyclopropyl {jjl - (2-pyridyl) propoxy] iminomethoxymethyl) phenylJ-3-2-dimethylamino-propenoate: At 0.50 g (0, 0013 moles) of ester E obtained in Example 16 in 3 ml of toluene is added 0.34 g of methoxybis (dimethylamino) methane and the medium brought to 2 hours at 80 C. After concentration, the residue is chromatographed on silica ( solvent heptane / ethyl acetate 1: 1), to give 0.60 g of expected enamine, EE isomer, in the form of pale yellow honey.

Yield: 50%.

Refractive index (D; 23 C): 1.5675.

EXAMPLE 21: of a compound of formula (VE) from an enamine of formula (VE ').

Example of preparation of methyl (2E) -2- [2 - ((E) -cyclopropyl [l- (2-pyridyl) propoxy] imino} methoxymethyl) phenyl] -3-hydroxy-2-propenoate: In 5 ml of toluene are dissolved 0.14 g (0.00032 moles) of enamine obtained in example 20, then added with 3.5 ml of hydrochloric acid N / 10. The medium is stirred for 1 hour at room temperature. After concentration and purification by chromatography on silica (heptane / ethyl acetate solvent 7: 3), g of expected enol of configuration EE is obtained in the form of a white solid.

Yield: 77%.

Melting point: 114 C.

Claims (26)

N, N-dialkylcarbamoyl, lower alkoxycarbonyl;  in which: # p represents 1 or 2; # A represents a heterocyclic aromatic radical, mono- or bi-cyclic, comprising from 5 to 10 atoms, among which 1 to 4 are heteroatoms chosen from oxygen, sulfur or nitrogen atoms, each sulfur atom or of nitrogen being optionally in the oxidized state in the form of an N-oxide or sulfoxide group, which radical being attached to the carbon atom substituted by the radicals R, and R2, which radical being optionally substituted by 1 to 5 radicals X, and / or X2 and / or X3 and / or X4 and / or X5, preferably by 1 to 3 radicals X, and / or X2 and / or X3; # X ,, X2, X3, X4 and X5 represent, independently of each other, a halogen atom; or the hydroxy, mercapto, nitro, thiocyanato, azido, cyano or pentafluorosulfonyl radical; or a lower alkyl, lower haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkoxyalkyl, haloalkoxyalkyl, alkylthioalkyl, haloalkylthioalkyl, cyanoalkyl, cyanoalkoxy, cyanoalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl radical; or a lower cycloalkyl, lower halocycloalkyl, alkenyl, alkynyl, alkenyloxy, alkynyloxy, alkenylthio, alkynylthio radical; or an amino, N-alkylamino, N, N-dialkylamino, acylamino, aminoalkyl, N-alkylaminoalkyl, N, N-dialkylaminoalkyl, acylaminoalkyl radical; or an acyl, carboxy, carbamoyl, N-alkylcarbamoyl radical,

 CLAIMS 1. Process for the preparation of compounds of general formula (I): <Desc / Clms Page number 33>  in which R1, R2, R3, X6, p and A are as defined above,

 in which R ,, R2, R3, p and A are as defined above, and X represents a halogen atom, the radical CH3S (O) - or the radical CH3S (O) 2-, to lead to the compound of formula (II):

R, and R2 can together form a divalent radical such as an alkylene radical, optionally substituted by one or more halogen atoms and / or by one or more lower alkyl radicals; # R3 represents a hydrogen atom, a lower alkyl, lower haloalkyl, a lower cycloalkyl, lower halocycloalkyl, an alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkoxyalkyl, haloalkoxyalkyl, alkylthioalkyl, haloalkylthioalkyl, cyanoalkyl radical; or an alkenyl, alkynyl radical; an optionally substituted phenyl or benzyl radical; # R4 represents an alkoxy or haloalkoxy radical; and # R5 represents a lower alkyl or lower haloalkyl radical, by condensation of an alkali metal salt of 2- (hydroxymethyl) phenylacetic acid (substituted on the phenyl ring by a radical X6 as defined above) with a compound of formula (A):  the radical X, optionally forming a 5 to 7-membered ring with R,; . X6 represents a hydrogen atom, a halogen atom; or the cyano or nitro radicals; or a lower alkyl, lower haloalkyl, alkoxy, haloalkoxy radical; # R, and R2 represent, independently of each other, a hydrogen atom, a lower alkyl, lower haloalkyl radical, a lower cycloalkyl, lower halocycloalkyl radical, an alkoxyalkyl, haloalkoxyalkyl, alkylthioalkyl, haloalkylthioalkyl, cyanoalkyl radical; or <Desc / Clms Page number 34>  which is itself esterified, transformed by the Claisen reaction, then etherified into a compound of formula (I) as defined above. 2. Method according to claim 1 for the preparation of compounds of formula (I) having one or more of the following characteristics taken individually or in combination: # p represents 1 or 2; # R1 is the hydrogen atom or the methyl radical, # R2 is the hydrogen atom or a lower alkyl, cyanoalkyl, or alkoxyalkyl radical, # R3 represents a hydrogen atom, a lower alkyl radical, lower haloalkyl , a lower cycloalkyl, lower halocycloalkyl, an alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkoxyalkyle, haloalkoxyalkyle, alkylthioalkyle, haloalkylthioalkyle, cyanoalkyle radical; or an alkenyl, alkynyl radical; or an optionally substituted phenyl or benzyl radical, # R4 represents an alkoxy or haloalkoxy radical,. R5 represents a lower alkyl or lower haloalkyl radical, # A represents a heterocyclic radical, optionally substituted by 1 to 5 radicals X1 and / or X2 and / or X3 and / or X4 and / or X5, preferably by 1 to 3 radicals X , and / or X2 and / or X3, A being chosen from the following list: furanyl; pyrolyl; thiophenyl; pyrazolyl; imidazolyl; oxazolyl; isoxazolyl; thiazolyl; isothiazolyl; 1,2,3-oxadiazolyl; 1,2,4-oxadiazolyl; 1,2,5-oxadiazolyle; 1,3,4-oxa-diazolyl; 1,2,3-thiadiazolyl; 1,2,4-thiadiazolyl; 1,2,5-thiadia-zolyle; 1,3,4-thiadiazolyle; 1,2,3-triazolyl; 1,2,4-triazolyl; tetrazolyl; pyridyle; pyrimidinyl; pyrazinyl; pyridazinyl; 1,2,3-triazinyl; 1,2,4-triazinyl; 1,3,5-triazinyl; 1,2,3,4-tetrazinyl; 1,2,3,5-tetrazinyl; 1,2,4,5-tetrazinyl; benzimidazolyl; indazolyl; benzotriazolyl; benzoxazolyl; 1,2-benzisoxazolyl; 2,1-benzisoxazolyl; benzothiazolyl; 1,2-benzisothiazolyl; 2,1-benzisothiazolyl; 1,2,3-benzoxadia-zolyle; 1,2,5-benzoxa-diazolyl; 1,2,3-benzothiadiazolyl; 1,2,5-benzothiadiazolyle; quinoline; isoquinolinyl; quinoxazolinyl; quinazolinyl; cinnolyl or phthalazyl; pteridinyl; benzotriazinyl; 1,5-naphthyridinyl; 1,6-naphthyridinyl; 1,7-naphthyridinyl; 1,8-naphthyridinyl; imidazo [2, 1-b] thiazolyl; <Desc / Clms Page number 35>  thieno [3,4-b] pyridyl; purine; and pyrolo [I, 2-b] thiazolyl, # X1, X2, X3, X4 and X5 represent independently of each other a halogen atom; or the hydroxy, mercapto, nitro, thiocyanato, azido, cyano or pentafluorosulfonyl radical; or a lower alkyl, lower haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkoxyalkyl, haloalkoxyalkyl, alkylthioalkyl, haloalkylthioalkyl, cyanoalkyl, cyanoalkoxy, cyanoalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl radical; or a lower cycloalkyl, lower halocycloalkyl, alkenyl, alkynyl, alkenyloxy, alkynyloxy, alkenylthio, or alkynylthio radical, and # X6 represents a hydrogen atom, a halogen atom; or the cyano or nitro radicals. 3. Method according to one of claims 1 or 2 for the preparation of compounds of formula (I) having one or more of the following characteristics taken individually or in combination: # p represents 1; # R, is the hydrogen atom; # R2 is a hydrogen atom or a lower alkyl radical; # R3 represents a hydrogen atom, a lower alkyl radical, lower haloalkyl, a lower cycloalkyl radical, or lower halocycloalkyl; or an alkenyl, alkynyl radical; oran optionally substituted phenyl or benzyl radical; # R4 represents an alkoxy radical; # R5 represents a lower alkyl radical; # A represents a heterocyclic radical, optionally substituted by 1 to 3 radicals X1 and / or X2 and / or X3, A being chosen from the following list: furanyl; pyrolyl; thiophenyl; pyrazolyl; imidazolyl; oxazolyl; isoxazolyl; thiazolyl; pyridyle; quinoline; or isoquinolinyl, # X1, X2 and X3 independently of one another represent a halogen atom; the hydroxy, mercapto, nitro, thiocyanato, azido, cyano or pentafluorosulfonyl radical; a lower alkyl, lower haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, and # X6 radical represents a hydrogen atom or a halogen atom. <Desc / Clms Page number 36>  4. Method according to one of claims 1 to 3 for the preparation of compounds of formula (I) having one or more of the following characteristics taken individually or in combination: # p represents 1; # R, is the hydrogen atom; . R2 is a hydrogen atom or a lower alkyl radical; # R3 represents a hydrogen atom, a lower alkyl radical, lower haloalkyl, a lower cycloalkyl radical, or lower halocycloalkyl; # R4 represents an alkoxy radical; # R5 represents an alkyl radical; # A represents a pyridyl radical; # X6 represents a hydrogen atom. 5. Method according to any one of claims 1 to 4 for the preparation of the following compounds of formula (I):

 #methyl (E, E) -2- (2- {1 - [(2-pyridyl) methyloxyimino] -1-cyclopropylmethyl-oxymethyl} phenyl) -3-methoxypropenoate, #le (E, E) -2- (2- {1- [1- (2-pyridyl) propyloxyimino] -1-cyclopropylmethyl-oxymethyl} phenyl) -3-methyl methoxypropenoate, #le (E, E) -2- (2- {1- [1 - (2-pyridyl) propyloxyiminoJpropyloxymethyl} phenyl) -3-methyl methoxypropenoate, and #le (E, E) -2- (2- {1- [1- (2-pyridyl) propyloxyimino] isobutyloxymethyl} phenyl) -3 -methyl methoxypropenoate. 6. Method according to any one of claims 1 to 5 characterized in that a condensation of an alkali metal salt of 2- (hydroxymethyl) phenylacetic acid of formula (B) is carried out:

 in which X6 is as defined in the preceding claims and M represents a sodium or potassium atom, with a compound of formula (A): <Desc / Clms Page number 37>  in which R ,, R2, R3, X6, p and A are as defined in the preceding claims, condensation carried out in the presence of a base, in a polar aprotic solvent, at a suitable temperature depending on the reagents and the solvent used .

 in which R1, R2, R3, p and A are as defined in the preceding claims, and X represents a halogen atom chosen from fluorine, chlorine, bromine and iodine, the radical CH3S (O) - or the radical CH3S ( O) 2-, to yield the compound of formula (II):

7. The method of claim 6 in which the compound of formula (A) is recycled. 8. Method according to one of claims 6 or 7, characterized in that the compound of formula (A) is reacted directly with the isochromanone precursor of the compound of formula (B) 9. Method according to any one of the preceding claims, characterized in that the acid of formula (II) according to claim 1 is engaged in an esterification reaction in aprotic apolar solvent, in the presence of a base, at a temperature between -20 C and 60 C, by the action of a compound of formula (III):

 in which R4 is as defined in one of claims 1 to 5 and T represents a halogen atom, chosen from chlorine, fluorine, bromine and iodine, or an alkyl radical containing from 1 to 6 carbon atoms in straight chain or branched, optionally substituted by one or more halogen atoms. <Desc / Clms Page number 38>  10. Method according to claim 9 characterized in that the compound of formula (III) is methyl chloroformate. 11. Method according to one of the preceding claims, characterized in that the ester of formula (IV):

 in which R ,, R2, R3, R4, X6, A and p are as defined in one of Claims 1 to 5, is then transformed by Claisen reaction, into an enol of formula (V):

 then directly isomerized to the compound of formula (VE):

 compounds of formulas (V) and (VE), in which R1, R2, R3, R4, X6, A and p are as defined in one of claims 1 to 5, the Claisen reaction defined above being carried out by adding methyl formate to the compound of formula (IV) defined above, in the presence of a base, preferably using the sodium hydride / methyl-tert-butyl ether couple, at room temperature, the conversion into isomer (VE ) of the compound of formula (V) being carried out in situ, by acidification of the reaction medium. <Desc / Clms Page number 39>  12. Method according to any one of the preceding claims, characterized in that the compound of formula (VE) according to claim 11 is engaged in an alkylation reaction of enol, in the presence of a compound of formula (R5) 2-SO4 or R5-Hal in which R5 is as defined above and Hal represents a halogen atom chosen from fluorine, chlorine, bromine or iodine, in a polar aprotic solvent, and in the presence of a base, to lead to the compound of formula (I). 13. Method according to one of claims 1 to 10 for the preparation of the compounds of formula (I) in which R4 represents the methoxy radical, characterized in that the acid of formula (II) is engaged in an esterification reaction enamination to lead to the compound of formula (VE '):

 this reaction being carried out in the presence of dimethylformamide dimethylacetal or of a Bredereck reagent, and of pyridinium tosylate, compound of formula (VE ') which is finally hydrolysed to yield the compound of formula (I), optionally by first hydrolysis into compound of formula (VE). 14. Composed of formulas:

<Desc / Clms Page number 40>  in which the set of substituent radicals is as defined in one of claims 1 to 5, useful as synthesis intermediates in the preparation of the compounds of formula (I) as described in any one of claims 1 to 5 .

15. Compounds according to Claim 14, characterized in that: # p represents 1, # R, is the hydrogen atom, # R2 represents the hydrogen atom or a lower alkyl radical, # R3 represents a d atom hydrogen, lower alkyl, lower haloalkyl, lower cycloalkyl, or lower halocycloalkyl, # R4 represents an alkoxy radical, # R5 represents an alkyl radical, # A represents a pyridyl radical, and # X6 represents a hydrogen atom . <Desc / Clms Page number 41> 16. Compounds of formula:

 in which the set of substituent radicals is as defined in one of claims 1 to 5, useful as synthesis intermediates in the preparation of the compounds of formula (I) as described in any one of claims 1 to 5 . 17. Compounds of formula:

 in which the set of substituent radicals is as defined in one of claims 1 to 5, useful as synthesis intermediates in the preparation of the compounds of formula (A) according to claim 16. 18. Compounds according to one of claims 16 or 17, characterized in that: # p represents 1, # R, is the hydrogen atom, # R2 represents the hydrogen atom or a lower alkyl radical, # R3 represents a hydrogen atom, a lower alkyl, lower haloalkyl, a lower cycloalkyl, or lower halocycloalkyl radical, and # A represents a pyridyl radical. 19. Process for preparing the compounds of formulas (A) and (a7) according to one of claims 16 to 18, characterized in that a halogenation of a compound of formula (al) is carried out into the compound of formula (a2 ), according to the following diagram:

 formulas in which A, R, and R2 are as defined in one of <Desc / Clms Page number 42>

 in which A, R1, K2, K3 and p are as defined in one of claims 1 to 5, and Hal represents a halogen atom, such as fluorine, chlorine, bromine or iodine, the compound of formula (a6 ) which can itself be transformed into a compound of formula (a7):

 Scheme in which R3 has the same definition as described in one of claims 1 to 5, the preparation of the compound of formula (a4) being carried out in the presence of hydroxylamine hydrochloride, in the presence of a base, reaction directly followed by the addition of the compound of formula (a2), at a higher temperature, for example 60 C to 80 C, to yield the compound of formula (a5) which is then treated with a phosphorus compound of formula POHal3, where Hal represents an atom of halogen, to lead to the compound of formula (a6):

 compounds of formulas (a2), (a4) and (a5), in which A, R ,, R2, R3 and p are as defined in one of claims 1 to 5, the compound of formula (a4) being prepared directly in situ, and therefore not isolated, from the compound of formula (a3) according to the following scheme:

 Claims 1 to 5, and Hal represents a halogen atom chosen from fluorine, chlorine, bromine and iodine, the compound of formula (a2) then being condensed on the compound of formula (a4) according to the following scheme: <Desc / Clms Page number 43>   in which A, R1, R2, R3 and p are as defined in one of claims 1 to 5, under the same operating conditions as those described above for the preparation of the compound of formula (a8).

 in which A, R ,, R2, R3 and p are as defined in one of claims 1 to 5, under the action of an oxidizing agent, the compound of formula (a8) above possibly being - even be oxidized to the corresponding sulfonyl of formula (a9):

 in which A, R1, R2, R3 and p are as defined in one of claims 1 to 5, by reaction, on the compound of formula (a6) of an alkali thiomethylate, the compound of formula (a7) above being itself oxidized to the corresponding sulfoxide of formula (a8): 20. Compound of formula (B):

 wherein X6 is as defined in one of claims 1 to 5 and M represents an alkali or alkaline earth metal atom. 21. A compound according to claim 20 in which X6 represents hydrogen and M represents sodium or potassium. 22. Process for the preparation of the compound of formula (B) according to one of claims 20 or 21, characterized in that an oxidation of an indene to 2-indanone is carried out according to the following scheme: <Desc / Clms Page number 44>  in which X6 is as defined in one of claims 1 to 5, the 2-indanone being brought into contact with an oxidizing agent, the isochromanone thus formed being finally converted into the compound of formula (B) by action an equivalent of a base.

 in which X6 is as defined in one of claims 1 to 5, 2-indanone then being engaged in a Baeyer-Villiger reaction to lead to isochromanone according to the following synthetic scheme:

23. Compounds of formula (I) substantially obtained according to the process of any one of claims 1 to 13. 24. Process for the preparation of the compounds of formula (I) characterized by the following synthetic scheme: <Desc / Clms Page number 45>  scheme in which each of the steps and each of the groups carried by the different compounds is as defined in any one of the preceding claims.

25. Compound called (E, E) -2- (2- {1- [1- (2-pyridyl) propyloxyimino] -

 Methyl 1-cyclopropylmethyloxymethyl} phenyl) -3-methoxypropenoate, substantially obtained according to the process of any one of claims 1 to 13. <Desc / Clms Page number 46>  26. Process for the preparation of the compound according to claim 25, characterized by the following synthetic scheme:

 scheme in which each of the steps is as defined in any one of the preceding claims.