METHOD FOR THE SYNTHESIS OF AN OXIM WITH AN IMIDAZOL GROUP AND METHOD FOR THE SYNTHESIS OF A NITRILE OXIDE FROM THIS OXIM

Description

[0001] The present invention relates to a method for the synthesis of an oxime bearing an imidazole group (hereinafter referred to as compound of formula (1)) and a method for the synthesis of a nitrile oxide bearing an imidazole group (hereinafter referred to as compound of formula (X)) via the synthesis of the compound of formula (I) according to the synthesis method of the invention.

[0002] Nitrile oxides containing an imidazole group are used as modifying agents for diene elastomers. Once grafted onto the carbon-carbon double bonds of these diene elastomers, they modify their structure and ultimately improve the mechanical properties of elastomeric compositions comprising such grafted diene elastomers and at least one reinforcing filler. These nitrile oxides are described in document WO2015059269.

[0003] Currently, during the synthesis of these nitrile oxides, it is necessary to carry out long and numerous steps of separation, purification, isolation and drying of each of the synthesis intermediates in order to avoid the presence of impurities which cause side reactions which have a negative impact on the selectivity of the reaction and on its yield.

[0004] Furthermore, the prior art synthesis process for these nitrile oxides uses raw materials and / or solvents that are very expensive to purchase. For example, the second step of the prior art process described in examples from WO2015059269 involves a formylation step in the presence of titanium tetrachloride and dichloromethyl methyl ether; the third step is carried out in the presence of N,N-dimethylformamide. This latter compound is used as a solvent and in large quantities. Moreover, its use is increasingly discouraged by national regulations. The use of these solvents imposes additional constraints in terms of safety, handling, and environmental treatment, making this synthesis process complex and costly, especially for industrial-scale synthesis.

[0005] Therefore, there is a need for an improved synthetic process for a nitrile oxide compound containing an imidazole group. More specifically, there is a need for a synthetic process for a nitrile oxide compound containing an imidazole group that is applicable on an industrial scale and that reduces the number of isolation steps for synthetic intermediates, reduces cycle times, reduces the quantity of solvents used, reduces the number of different solvents used, increases yields by limiting the formation of by-products, and ultimately reduces the production cost of these nitrile oxides.

[0006] The present invention aims to meet this need and to provide an improved synthesis process compared to that of the prior art.

[0007] Continuing her research, the applicant has developed a new process for the synthesis of an oxime bearing an imidazole group and a process for the synthesis of a nitrile oxide from said oxime synthesized according to the process of the invention; this process presenting a significantly improved synthesis yield compared to the prior art process and also allowing a reduction in the number and quantity of solvents.

[0008] Thus, the present invention relates to a method for synthesizing a compound of formula (I) in which: R1 represents, independently of each other, a C1-C6 alkyl, preferably a C1-C3 alkyl; R2 represents a hydrogen atom, a C1-C12 alkyl, preferably a C1-C6 alkyl, more preferably a C1-C3 alkyl; R3 and R4, independently of each other, represent a hydrogen atom, a C1-C12 alkyl, (preferably a C1-C6 alkyl, more preferably a C1-C3 alkyl) or together with the carbon atoms to which they are attached form a ring, in particular an aromatic ring, preferably phenyl; and n an integer equal to 0, 1, 2, 3 or 4; said synthesis process comprising the following successive steps A1, A2, A3: a step A1 of obtaining an intermediate compound of formula (V) by a halomethylation reaction of an aromatic aldehyde of formula (VI) in the presence of a halomethylating agent according to the following reaction scheme: with R1 and n as defined above; and X being a halogen atom, preferably a bromine or chlorine atom, more preferably a chlorine atom; a step A2 of obtaining an intermediate compound of formula (III) by nucleophilic substitution of the preceding intermediate compound of formula (V) with an imidazole compound of formula (IV) according to the following reaction scheme: with n, X, R1, R2, R3 and R4 as defined above; a step of obtaining A3 of the compound of formula (I) by a condensation reaction of the preceding intermediate compound of formula (III) with hydroxylamine (II) according to the following reaction scheme:] with R1, R2, R3, R4 and n as defined above; and steps A1, A2, A3 being carried out without isolation of at least one intermediate compound chosen from the group formed by the intermediate compound of formula (III) and the intermediate compound of formula (V).

[0009] Preferably, the halomethylating agent is preheated to a temperature T1 within a range of 23°C to 50°C, more preferably within a range of 30°C to 45°C, before being brought into contact with the compound of formula (VI).

[0010] Preferably, the compound of formula (VI) is added all at once after preheating the halomethylating agent.

[0011] Preferably, the halomethylating agent is a mixture of a formaldehyde donor and hydrochloric acid.

[0012] Preferably, the amount of formaldehyde donor is in the range of 1 molar equivalent to 7 molar equivalents, preferably from 1.2 molar equivalents to 6 molar equivalents, more preferably from 2 molar equivalents to 6 molar equivalents relative to the amount of compound of formula (VI).

[0013] Preferably, step A1 is carried out at a temperature T2 within a range of 60°C to 100°C, more preferably within a range of 70°C to 90°C.

[0014] Preferably, an organic solvent S1 is added at the end of step A1 and the organic phase is recovered, the organic solvent S1 being chosen from among the halogenated solvents.

[0015] Preferably, step A2 is carried out in the presence of an organic solvent S2 chosen from the group consisting of halogenated solvents, dimethyl sulfoxide, acetone, alcohols such as isopropanol, ethers such as tetrahydrofuran, ethyl acetate; preferably the organic solvent S2 is a halogenated organic solvent, more preferably a chlorinated organic solvent.

[0016] Preferably, the organic solvent S2 is identical to the organic solvent S1.

[0017] Preferably, the amount of compound of formula (IV) is in the range of 1.1 molar equivalents to 6 molar equivalents, more preferably in the range of 2 molar equivalents to 4 molar equivalents with respect to the compound of formula (V).

[0018] Preferably, step A2 is carried out at a temperature that is less than or equal to the reflux temperature of the organic solvent S2.

[0019] Preferably, the quantity of organic solvent S2 is at least 0.5 volume relative to 1 volume of organic solvent S1, more preferably is within a range of 1 volume to 10 volumes relative to 1 volume of organic solvent S1.

[0020] Preferably, step A3 is carried out in an organic solvent S3 chosen from the group consisting of halogenated solvents, acetone, alcohols such as isopropanol, ethers such as tetrahydrofuran, ethyl acetate preferably the organic solvent S3 a halogenated organic solvent, preferably is a chlorinated organic solvent.

[0021] Preferably, the organic solvent S3 is identical to the organic solvent S2.

[0022] The compounds of formula (I) obtained according to the synthesis process of the invention can be transformed into corresponding nitrile oxides while maintaining a good production yield and in particular a yield higher than the yield of the prior art synthesis processes of nitrile oxides.

[0023] The invention also relates to a method for synthesizing a compound of formula (X), said method comprising the following steps: a step (i) of synthesis of the compound of formula (I) according to the process described above, a step (ii) of transformation of the compound of formula (I) into the compound of formula (X) in the presence of at least one organic solvent S4 and at least one oxidant according to the following reaction scheme: with: R 1 represents, independently of each other, a C1-C6 alkyl, preferably a C1-C3 alkyl; R 2 represents a hydrogen atom, a C1-C12 alkyl, preferably a C1-C6 alkyl, more preferably a C1-C3 alkyl; R 3 and R 4, independently of each other, represent a hydrogen atom, a C1-C12 alkyl, (preferably a C1-C6 alkyl, more preferably a C1-C3 alkyl) or together with the carbon atoms to which they are attached form a ring, preferably an aromatic ring, preferably phenyl; and n an integer equal to 0, 1, 2, 3 or 4; and a step (iii) of recovery of the compound of formula (X).

[0024] The synthesis process according to the invention thus reduces the number of chemical steps compared to the prior art synthesis process, while using more acceptable solvents and achieving optimized synthesis yields. In particular, the use of an aromatic aldehyde as a starting material and appropriate solvents allows steps A1, A2, and A3 to be carried out sequentially without the need to isolate at least one synthetic intermediate obtained during steps A1 and A2.Thus, the halomethylation of compound (VI) is carried out, followed directly by a nucleophilic substitution with compound (IV), itself followed directly by a condensation reaction with hydroxylamine, resulting in the oxime (I) with a satisfactory level of purity and yield, without isolation of the intermediate compounds (V) and / or (III), preferably without isolation of the intermediate compounds (V) and (III). The synthesis process according to the invention advantageously avoids drying steps and limits the separation and purification steps of these synthetic intermediates. Finally, the overall cycle time is improved since no drying of the synthetic intermediates is required. The synthesis process according to the invention is therefore more economical, faster, and more environmentally friendly.

[0025] The process according to the invention is applicable on an industrial scale and makes it possible in particular to obtain cumulative yields of at least 60% for the chaining without isolation of the intermediates of steps A1 and A2.

[0026] Furthermore, the synthesis process according to the invention also has the advantage of reducing the number and quantity of solvents and also of using common solvents such as alcoholic solvents which are more environmentally friendly and operator-friendly than, for example, N,N-dimethylformamide.

[0027] In this application, unless expressly stated otherwise, all percentages (%) indicated are percentages (%) by mass.

[0028] On the other hand, any interval of values ​​designated by the expression "between a and b" represents the domain of values ​​going from more than a to less than b (that is, bounds a and b excluded) while any interval of values ​​designated by the expression "from a to b" means the domain of values ​​going from a to b (that is, including the strict bounds a and b).

[0029] The compounds mentioned in the description can be of fossil origin or bio-based. In the latter case, they may be partially or entirely derived from biomass or obtained from renewable raw materials derived from biomass. Obviously, the compounds mentioned can also come from the recycling of previously used materials; that is, they may be partially or entirely produced through a recycling process, or obtained from raw materials themselves derived from a recycling process. This includes, in particular, polymers, plasticizers, fillers, etc.

[0030] For the purposes of this invention, "C1-Cx alkyl" means a saturated hydrocarbon chain, linear or branched, comprising 1 to x carbon atoms. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl groups.

[0031] For the purposes of this invention, an "aromatic ring" is defined as an aromatic hydrocarbon group comprising 6 to 20 carbon atoms and including one or more fused rings, such as a phenyl or naphthyl group. Advantageously, this refers to phenyl (C6 aryl).

[0032] For the purposes of this invention, "ambient temperature" means a temperature in the range of 20°C to 25°C, more preferably a temperature of 23°C.

[0033] The terms "intermediate compound," "synthetic intermediate," and "intermediate compound for synthesis" are interchangeable and refer to a chemical compound intended to be chemically transformed to create another compound. In this sense, the intermediate should no longer be present in the final product, or at least only as a residual impurity.

[0034] For the purposes of this invention, "halogen atom" means an atom selected from the group consisting of chlorine, bromine, iodine, and fluorine. More preferably, it is a bromine or chlorine atom, and more preferably a chlorine atom.

[0035] A first object of the present invention relates to a method for synthesizing a compound of formula (I) in which: R1 represents, independently of each other, a C1-C6 alkyl, preferably a C1-C3 alkyl; R2 represents a hydrogen atom, a C1-C12 alkyl, preferably a C1-C6 alkyl, more preferably a C1-C3 alkyl; R3 and R4, independently of each other, represent a hydrogen atom, a C1-C12 alkyl (preferably a C1-C6 alkyl, more preferably a C1-C3 alkyl), or together with the carbon atoms to which they are attached form a ring, in particular an aromatic ring, preferably phenyl; and n an integer equal to 0, 1, 2, 3, or 4; and said synthesis process comprising the following successive steps A1, A2, A3: a step A1 of obtaining an intermediate compound of formula (V) by a halomethylation reaction of an aromatic aldehyde of formula (VI) in the presence of a halomethylating agent according to the following reaction scheme: with R1 and n as defined above; and X being a halogen atom, preferably a bromine or chlorine atom, more preferably a chlorine atom; a step A2 of obtaining an intermediate compound of formula (III) by nucleophilic substitution of the preceding intermediate compound of formula (V) with an imidazole compound of formula (IV) according to the following reaction scheme: with n, X, R1, R2, R3 and R4 as defined above; a step of obtaining A3 of the compound of formula (I) by a condensation reaction of the preceding intermediate compound of formula (III) with hydroxylamine (II) according to the following reaction scheme: with R1, R2, R3, R4 and n as defined above; and steps A1, A2, A3 being carried out without isolation of at least one intermediate compound chosen from the group formed by the intermediate compound of formula (III) and the intermediate compound of formula (V).

[0036] Preferably, the process of the invention comprises a sequence of reactions A1, A2, and A3, wherein the synthetic intermediate compound (V) resulting from the halomethylation reaction (step A1) is neither isolated nor dried before proceeding with the nucleophilic substitution reaction with an imidazole compound of formula (IV) (step A2). Preferably, the synthetic intermediate compound of formula (III) resulting from the nucleophilic substitution reaction with an imidazole compound (step A2) is neither isolated nor dried before proceeding with the condensation reaction with hydroxylamine (step A3). More preferably still, neither the synthetic intermediate compound of formula (V) nor the synthetic intermediate compound of formula (III) is isolated or dried during the sequence of steps A1 to A2 and A2 to A3.

[0037] The expression "without isolation" means, for the purposes of the present invention, that in a synthesis process or a chain of reactions, a synthesis intermediate undergoes several successive and / or simultaneous reactions in its reaction medium, limiting the separation steps and eliminating the purification and drying steps of the synthesis intermediate compounds.

[0038] The expression "reaction medium" refers to a medium in which chemical reactions take place.

[0039] "Isolation" refers to the separation of a synthetic intermediate from the reaction medium, possibly followed by its purification and / or drying. Methods for separating and / or purifying an intermediate are well known to those skilled in the art. Examples include filtration, chromatography, centrifugation, solvent extraction, distillation, etc. Washing with water is not considered a separation method or a purification method within the meaning of the present invention and therefore does not lead to the isolation of a synthetic intermediate.

[0040] In the synthesis process of the invention, the first step, step A1, allows obtaining an intermediate compound of formula (V) by a halomethylation reaction of an aromatic aldehyde of formula (VI) in the presence of a halomethylating agent according to the following reaction scheme: in which: R 1 represents, independently of each other, a C1-C6 alkyl, preferably a C1-C3 alkyl; n is an integer equal to 0, 1, 2, 3 or 4; and X is a halogen atom chosen from the group consisting of chlorine, bromine, fluorine, iodine; more preferably chosen from a chlorine atom and a bromine atom; more preferably still is a chlorine atom.

[0041] More preferably in compounds of formula (VI) and (V), n is an integer equal to 3; R1 represents, independently of each other, a C1-C6 alkyl, preferably a C1-C3 alkyl; and X is a halogen atom chosen from the group consisting of chlorine, bromine, fluorine, and iodine, more preferably chosen from a chlorine atom and a bromine atom, more preferably still is a chlorine atom. More preferably still, n is an integer equal to 3; R1 is a C1-C3 alkyl; and X is chosen from a chlorine atom or a bromine atom, preferably a chlorine atom. Even more preferably, n is equal to 3; the R1 groups are identical, located in the ortho- and para- positions of the aldehyde function, and are a C1-C3 alkyl, preferably methyl, ethyl, or propyl; and X is chosen to be a chlorine atom or a bromine atom, preferably a chlorine atom.

[0042] Step A1 is a halomethylation reaction. A halomethylation reaction is defined as an electrophilic substitution followed by a nucleophilic substitution in which an aromatic compound is alkylated with a halomethylating agent, with or without a catalyst. When the halomethylating agent contains at least one chlorine atom, the reaction is called chloromethylation. When the halomethylating agent contains at least one bromine atom, the reaction is called bromomethylation.

[0043] The halomethylating agent can be any known agent. Preferably, the halomethylating agent is a formaldehyde donor in a solution of hydrochloric acid or hydrobromic acid, with or without a Lewis acid such as zinc halides or a carboxylic acid such as acetic acid. More preferably, the halomethylating agent is a mixture of a formaldehyde donor and hydrochloric acid.

[0044] Preferably, in the synthesis process of the invention, the halomethylating agent is preheated to a temperature T1 in the range of 23°C to 50°C, more preferably in the range of 30°C to 45°C, before being brought into contact with the compound of formula (VI). The contacting of the halomethylating agent with the compound of formula (VI) is preferably carried out directly after its preheating.

[0045] When the halomethylating agent is a formaldehyde donor, the amount of formaldehyde donor in step A1 may be in the range of 1 molar equivalent to 7 molar equivalents, preferably 1.2 molar equivalents to 6 molar equivalents, more preferably 2 molar equivalents to 6 molar equivalents relative to the amount of compound of formula (VI).

[0046] Preferably, the formaldehyde donor can be chosen from paraformaldehyde and formaldehyde. Preferably, the formaldehyde donor is paraformaldehyde.

[0047] Preferably, the hydrochloric acid solution used in the context of the present invention can be a hydrochloric acid solution with a concentration in the range of 15% to 50% by volume, more preferably 27% to 42% by volume, more preferably 30% to 40% by volume.

[0048] Preferably, in the synthesis process of the invention, the compound of formula (VI) can be added in a single step, in particular directly, after preheating the halomethylating agent.

[0049] Preferably, step A1 can be carried out at a temperature T2 within a range of 60°C to 100°C, more preferably within a range of 70°C to 90°C.

[0050] According to one embodiment, an organic solvent S1 can be added at the end of step A1; then a recovery step of the organic phase can be carried out; the organic solvent S1 can be chosen from among halogenated solvents.

[0051] The term "halogenated solvent" or "halogenated organic solvent" refers to a solvent comprising at least one halogenated hydrocarbon, that is, a hydrocarbon containing one or more halogen substituents. Preferably, the halogenated solvent is a chlorinated solvent, that is, a solvent comprising at least one chlorinated hydrocarbon, that is, a hydrocarbon containing one or more chlorine substituents. As a chlorinated solvent, the organic solvent S1 may be chosen from the group consisting of dichloromethane, dichloroethane, and chloroform; preferably, the organic solvent S1 may be dichloromethane.

[0052] Preferably, the intermediate compound of formula (V) is not isolated, nor dried at the end of step A1.

[0053] The intermediate compound of formula (V) undergoes a nucleophilic substitution reaction with an imidazole compound of formula (IV) (this is step A2) directly in the same reaction medium as that of step A1.

[0054] Thus, the process of the invention comprises a step A2 of obtaining an intermediate compound of formula (III) by nucleophilic substitution of the preceding intermediate compound of formula (V) with an imidazole compound of formula (IV) according to the following reaction scheme: in which: R 1 represents, independently of each other, a C1-C6 alkyl, preferably a C1-C3 alkyl; n is an integer equal to 0, 1, 2, 3 or 4; X is a halogen atom chosen from the group consisting of chlorine, bromine, fluorine, iodine, more preferably chosen from a chlorine atom and a bromine atom, more preferably still is a chlorine atom; R 2 represents a hydrogen atom, a C1-C12 alkyl, preferably a C1-C6 alkyl, more preferably a C1-C3 alkyl; and R3 and R4, independently of each other, represent a hydrogen atom, a C1-C12 alkyl (preferably a C1-C6 alkyl, more preferably a C1-C3 alkyl), or together with the carbon atoms to which they are attached form a ring, preferably an aromatic ring, more preferably the phenyl.

[0055] Preferably in the compound of formula (V), n is an integer equal to 3; R1 represents, independently of each other, a C1-C6 alkyl, preferably a C1-C3 alkyl; and X is a halogen atom chosen from the group consisting of chlorine, bromine, fluorine, and iodine, more preferably chosen from a chlorine atom and a bromine atom, more preferably still is a chlorine atom. More preferably still, n is an integer equal to 3; R1 is a C1-C3 alkyl; and X is chosen from a chlorine atom or a bromine atom, preferably a chlorine atom. Even more preferably, n is equal to 3; the R1 groups are identical, located in the ortho- and para- positions of the aldehyde function, and are a C1-C3 alkyl, preferably methyl, ethyl, or propyl; and X is chosen to be a chlorine atom or a bromine atom, preferably a chlorine atom.

[0056] Preferably in the compound of formula (IV), R2 represents a hydrogen atom or a C1-C6 alkyl group, more preferably a C1-C3 alkyl group; and R3 and R4 represent a hydrogen atom or a C1-C6 alkyl group, more preferably a C1-C3 alkyl group, or together with the carbon atoms to which they are attached a phenyl group. More preferably still in the compound of formula (IV), R2 represents a C1-C3 alkyl group, preferably methyl, ethyl, or propyl; and R3 and R4 represent a hydrogen atom or a C1-C3 alkyl group (preferably methyl, ethyl, or propyl) or together with the carbon atoms to which they are attached a phenyl group. More preferably still, R 2 represents a C1-C3 alkyl, preferably methyl, ethyl or propyl; and R 3 and R 4 are identical and are a hydrogen atom.

[0057] Preferably in the compound of formula (III), n is an integer equal to 3; R1 represents, independently of each other, a C1-C6 alkyl, preferably a C1-C3 alkyl; R2 represents a hydrogen atom or a C1-C6 alkyl, more preferably a C1-C3 alkyl; and R3 and R4 represent a hydrogen atom or a C1-C6 alkyl, more preferably a C1-C3 alkyl, or together with the carbon atoms to which they are attached form a phenyl group. More preferably still, n is an integer equal to 3; R1 is a C1-C3 alkyl; R2 represents a C1-C3 alkyl, preferably methyl, ethyl, or propyl; and R3 and R4 represent a hydrogen atom or a C1-C3 alkyl (preferably methyl, ethyl or propyl) or together with the carbon atoms to which they are attached form a phenyl.Even more preferably, n is equal to 3; the R 1 groups are identical, located in the ortho- and para- positions of the aldehyde function and are a C1-C3 alkyl, preferably methyl, ethyl or propyl; R 2 represents a C1-C3 alkyl, preferably methyl, ethyl or propyl; and R 3 and R 4 are identical and are a hydrogen atom.

[0058] Step A2 can be carried out in the presence of an organic solvent S2 chosen from the group consisting of halogenated solvents, dimethyl sulfoxide, acetone, alcohols such as isopropanol, ethers such as tetrahydrofuran, and ethyl acetate. Preferably, the organic solvent S2 is a halogenated solvent, preferably a chlorinated solvent, and most preferably dichloromethane.

[0059] Preferably, the organic solvent S2 is identical to the organic solvent S1. Thus, when the organic solvent S1 is a halogenated solvent, preferably a chlorinated solvent, more preferably dichloromethane, then S2 is also a halogenated solvent, preferably a chlorinated solvent, more preferably dichloromethane.

[0060] Preferably, in step A2, the amount of compound of formula (IV) may be in the range of 1.1 molar equivalents to 6 molar equivalents, more preferably in the range of 2 molar equivalents to 4 molar equivalents relative to the compound of formula (V).

[0061] Preferably, step A2 is carried out at a temperature less than or equal to the reflux temperature of the organic solvent S2.

[0062] Preferably, the quantity of organic solvent S2 is at least 0.5 volume relative to 1 volume of organic solvent S1, more preferably is within a range of 1 volume to 10 volumes relative to 1 volume of organic solvent S1.

[0063] The process of the invention may optionally include, after step A2 and before step A3, at least one water washing step. Following this washing step, a step for recovering the organic phase may be carried out, and the process may continue directly with the execution of step A3.

[0064] Preferably, the intermediate compound of formula (III) is not isolated, and does not undergo any further purification steps other than optional water washes at the end of step A2.

[0065] The intermediate compound of formula (III) undergoes a condensation reaction with hydroxylamine (this is step A3) directly, in particular, in the same reaction medium as that of step A2.

[0066] The synthesis process of the invention comprises a step A3 of obtaining the compound of formula (I) by a condensation reaction of the preceding intermediate compound of formula (III) with hydroxylamine (II) according to the following reaction scheme: with R1, R2, R3, R4 and n as defined above, including their preferred modes,

[0067] Preferably in the compound of formula (III) and in the compound of formula (I), n is an integer equal to 3; R1 represents, independently of each other, a C1-C6 alkyl, preferably a C1-C3 alkyl; R2 represents a hydrogen atom or a C1-C6 alkyl, more preferably a C1-C3 alkyl; and R3 and R4 represent a hydrogen atom or a C1-C6 alkyl, more preferably a C1-C3 alkyl, or together with the carbon atoms to which they are attached form a phenyl group. More preferably still, n is an integer equal to 3; R1 is a C1-C3 alkyl; R2 represents a C1-C3 alkyl, preferably methyl, ethyl, or propyl; and R3 and R4 represent a hydrogen atom or a C1-C3 alkyl (preferably methyl, ethyl or propyl) or together with the carbon atoms to which they are attached form a phenyl.Even more preferably, n is equal to 3; the groups R 1 are identical, located in the ortho- and para- positions of the aldehyde function, respectively the oxime function, and are a C1-C3 alkyl, preferably methyl, ethyl or propyl; R 2 represents a C1-C3 alkyl, preferably methyl, ethyl or propyl; and R 3 and R 4 are identical and are a hydrogen atom.

[0068] Preferably, step A3 is carried out in an organic solvent S3 chosen from the group consisting of halogenated solvents, acetone, alcohols such as isopropanol, ethers such as tetrahydrofuran, and ethyl acetate. Preferably, the organic solvent S3 is a halogenated organic solvent, preferably a chlorinated organic solvent, and more preferably, the organic solvent S3 is dichloromethane.

[0069] Preferably, the compound of formula (II) is added to the reactor where step A3 takes place either as an aqueous solution or as a salt. Preferably, hydroxylamine is added as a salt.

[0070] Preferably, hydroxylamine in salt form is chosen from the group consisting of hydroxylamine sulfate salts, hydroxylamine chloride salts, and mixtures of these salts. When using hydroxylamine in salt form, a base may preferably be added to the reaction mixture. Examples of bases include sodium acetate and triethylamine. The amount of base added will be in the range of 1 to 2 molar equivalents relative to the hydroxylamine generated, preferably 1 to 1.2 molar equivalents relative to the hydroxylamine generated. "Hydroxylamine generated" refers to the cation (NH3+) of the hydroxylamine salt that is released upon contact of the salt with water. When using a base, the base is mixed with the hydroxylamine salt, and then the mixture is dissolved in water.

[0071] Preferably, the organic solvent S3 is identical to the organic solvent S2. Thus, when the organic solvent S2 is a halogenated solvent, preferably a chlorinated solvent, more preferably dichloromethane, then S3 is also a halogenated solvent, preferably a chlorinated solvent, more preferably dichloromethane.

[0072] Preferably, reaction A3 is carried out in the presence of a co-solvent, said co-solvent being chosen from the group consisting of alcohols such as ethanol or isopropanol. More preferably, the organic solvent S3 is a halogenated solvent and the co-solvent is an alcohol; more preferably, the organic solvent S3 is a chlorinated solvent and the co-solvent is an alcohol. Even more preferably, the organic solvent S3 is dichloromethane and the co-solvent is an alcohol, preferably isopropanol or ethanol.

[0073] The synthesis process of the invention may include an optional step A4 of isolating, purifying and drying the compound of formula (I) in order to recover the compound of formula (I).

[0074] Preferably, among the compounds of formula (I) which are synthesized according to the process of the invention described above, the compound of formula (la) is more particularly preferred

[0075] A second object of the present invention relates to a method for synthesizing a compound of formula (X), said method comprising the following steps: a step (i) of synthesis of the compound of formula (I) by the synthesis process as described above, a step (ii) of transformation of the compound of formula (I) into the compound of formula (X) in the presence of at least one organic solvent S4 and at least one oxidant according to the following reaction scheme: with: R 1 represents, independently of each other, a C1-C6 alkyl, preferably a C1-C3 alkyl; R 2 represents a hydrogen atom or a C1-C12 alkyl, preferably a C1-C6 alkyl, more preferably a C1-C3 alkyl; R 3 and R 4, independently of each other, represent a hydrogen atom, a C1-C12 alkyl, preferably a C1-C6 alkyl, more preferably a C1-C3 alkyl, or together with the carbon atoms to which they are attached form a ring, preferably an aromatic ring, more preferably phenyl; and n an integer equal to 0, 1, 2, 3 or 4; and a step (iii) of recovery of the compound of formula (X).

[0076] Preferably in the compound of formula (I) and in the compound of formula (III), n is an integer equal to 3; R1 represents, independently of each other, a C1-C6 alkyl, preferably a C1-C3 alkyl; R2 represents a hydrogen atom or a C1-C6 alkyl, more preferably a C1-C3 alkyl; and R3 and R4 represent a hydrogen atom or a C1-C6 alkyl, more preferably a C1-C3 alkyl, or together with the carbon atoms to which they are attached form a phenyl. More preferably still, n is an integer equal to 3; R1 is a C1-C3 alkyl; R2 represents a C1-C3 alkyl, preferably methyl, ethyl, or propyl; and R3 and R4 represent a hydrogen atom or a C1-C3 alkyl (preferably methyl, ethyl or propyl) or together with the carbon atoms to which they are attached form a phenyl.Even more preferably, n is equal to 3; the groups R 1 are identical, located in the ortho- and para- positions of the oxime function, respectively the nitrile oxide function, and are a C1-C3 alkyl, preferably methyl, ethyl or propyl; R 2 represents a C1-C3 alkyl, preferably methyl, ethyl or propyl; and R 3 and R 4 are identical and are a hydrogen atom.

[0077] Step (i) and these preferred modes have been described above.

[0078] Preferably in step (ii), the oxidant is chosen from the group consisting of sodium hypochlorite, N-bromosuccinimide in the presence of a base, N-chlorosuccinimide in the presence of a base, preferably the oxidant is sodium hypochlorite.

[0079] Preferably, the organic solvent S4 is chosen from the group formed by alcohols such as ethanol or isopropanol, chlorinated solvents such as chloroform or dichloromethane, ethyl acetate.

[0080] Advantageously, the quantity of oxidizing agent is 1 to 5 molar equivalents, preferably 1 to 2 molar equivalents, relative to the molar quantity of oxime of formula (I).

[0081] Preferably, among the compounds of formula (X) that are synthesized according to the process of the invention described above, the compound of formula (Xa) is most particularly preferred

[0082] The examples shown below are presented for illustrative purposes only and are not limiting to the invention. EXAMPLES Test 1:

[0083] 1.1-Synthesis of the compound of formula (la) 2,4,6-trimethyl-3-((2-methyl-1H-imidazol-1-yl)methyl)benzaldehyde oxime according to the process of the invention (process without isolation of the synthesis intermediates B and C))

[0084] The compound of formula (I) is synthesized according to the following reaction scheme:

[0085] In a 25 L reactor at 40°C, 5.58 L of hydrochloric acid solution (37% in aqueous solution) and 0.57 kg of paraformaldehyde (compound A, 18.82 mol, 2.5 eq. (eq. = molar equivalent)) are mixed. After 10 min of stirring at 40°C, the mixture becomes homogeneous, and 1.12 kg of mesitaldehyde (7.53 mol) are added. The mixture is stirred and gradually heated to 80°C at a rate of 2°C / min. After 4 hours of stirring at 80°C, the mixture is cooled to 40°C and diluted with dichloromethane (1.12 L). The organic phase is separated and used in the next step without further purification.

[0086] 1.75 kg of a 2-methyl-1H-imidazole solution ((2-Me-Im), 21.3 mol) in dichloromethane (5.92 L) is refluxed to achieve partial solubilization. Then, the previously prepared solution of 3-(chloromethyl)-2,4,6-trimethylbenzaldehyde (compound B) in dichloromethane (7.53 mol in 1.12 L of dichloromethane) is added to the 2-methyl-1H-imidazole solution. An orange mixture is obtained, which is refluxed with stirring for 2 hours. Heating is stopped, and the reaction mixture is washed 5 times with 5.25 L of water. The organic phase is separated and used in the next step without further processing (i.e., without purification or isolation).

[0087] In a 50 L reactor, 4.38 L of ethanol and 1.81 L of dichloromethane are added to the previously obtained solution of 2,4,6-trimethyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]benzaldehyde in dichloromethane. Then, 0.35 L of a 50% (w / w) aqueous solution of hydroxylamine in water (6 mol) is added. The mixture is heated to reflux and stirred for 7 hours. The suspension is then cooled to room temperature (23°C), concentrated, and filtered. The resulting solid is washed over a filter with the addition of 0.58 L of ethanol and then dried under vacuum for one day. After vacuum drying, a white solid is recovered with an overall yield of 65% (1.26 kg, 4.9 mol) for the three steps. [Table 1] N° δ 1< H (ppm) δ 13< C (ppm) 1 2,31 12,7 2 (-) 143,4 3 6,58 125,8 4 6,22 116,9 5 4,97 43,2 6 (-) 129,3 7 (-) 136,2 8 2,23 20,2 9 6,97 130 10 (-) 137,3 11 2,15 19,1 12 (-) 129,1 13 (-) 136,1 14 2,11 15,9 15 8,25 147,4 OH 11,11 (-) 1.2- Synthesis of the compound of formula (I) 2,4,6-trimethyl-3-((2-methyl-1H-imidazol-1-yl)methyl)benzaldehyde oxime according to a prior art process described in the examples of WO2015059269

[0088] 2,4,6-trimethyl-3-((2-methyl-1H-imidazol-1-yl)methyl)benzaldehyde oxime is synthesized by a prior art process according to the reaction scheme below. 1.2.1- Synthesis of 2-(chloromethyl)1,3,5-trimethylbenzene (compound D)

[0089] This compound can be obtained according to a procedure described in the following article: Zenkevich, IG; Makarov, AA; Russian Journal of General Chemistry; vol. 77; nb. 4; (2007); p. 611-619 (Zhurnal Obshchei Khimii; vol. 77; nb. 4; (2007); p. 653-662)

[0090] A mixture of mesitylene (100.0 g, 0.832 mol), para-formaldehyde (26.2 g, 0.874 mol), and hydrochloric acid (240 mL, 37%, 2.906 mol) in acetic acid (240 mL) is stirred and heated very slowly (1.5 hours) to 37°C. After returning to room temperature, the mixture is diluted with water (1.0 L) and CH₂Cl₂ (200 mL). The product is extracted with CH₂Cl₂ (4 times per 50 mL). The organic phases are collected, then washed with water (5 times per 100 mL) and evaporated to 11–12 mbar (bath temperature = 42°C). A colorless oil (133.52 g, 95% yield) is obtained. After 15–18 hours at +4°C, the oil crystallized. The crystals were filtered, washed with petroleum ether cooled to -18°C (40 mL), and then dried for 3–5 hours under atmospheric pressure at room temperature. A white solid (95.9 g, 68% yield) with a melting point of 39°C was obtained. The molar purity was greater than 96% (¹H NMR). [Table 2] N° δ 1< H (ppm) δ 13< C (ppm) 1 2,27 18,4 2 (-) 136,9 3 6,81 128,5 4 (-) 137,4 5 2,15 20,3 6 6,81 128,5 7 (-) 136,9 8 2,27 18,4 9 (-) 130,5 10 4,69 41,3 1.2.2- Synthesis of 3-(chloromethyl)-2,4,6-trimethylbenzaldehyde (compound B)

[0091] This compound can be obtained according to a procedure described in the following article: Yakubov, AP; Tsyganov, DV; Belen'kii, LI; Krayushkin, MM; Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation); vol. 40; nb. 7.2; (1991); p. 1427 - 1432 (Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya; nb. 7; (1991); p. 1609 - 1615)

[0092] A solution of 2-(chloromethyl)-1,3,5-trimethylbenzene (20.0 g, 0.118 mol) and dichloromethyl methyl ether (27.26 g, 0.237 mol) in dichloromethane (200 mL) is added under argon for 10–12 minutes. After stirring for 15–20 minutes at 17–20°C, water (1000 mL) and ice (500 g) are added to the reaction mixture. After 10–15 minutes of stirring, the organic phase is separated. The aqueous phase is extracted with CH₂Cl₂ (3 times per 75 mL). The combined organic phases are washed with water (4 times per 100 mL) and evaporated under reduced pressure to obtain a solid (bath temperature = 28°C). The target product (22.74 g) is obtained with a yield of 97%. Its melting point is 58°C. The molar purity estimated by 1H NMR is 95 mol%. [Table 3] N° δ 1< H (ppm) δ 13< C (ppm) 1 4,77 40,6 2 (-) 132.9 3 (-) 139,5 4 2,51 14,4 5 (-) 131,4 6 10,43 194,2 7 (-) 140,1 8 2,41 19,3 9 6,99 131,2 10 (-) 142,4 11 2,34 19,8 1.2.3 - Synthesis of 2,4,6-trimethyl-3-((2-methyl-1H-imidazol-1-yl)methyl)benzaldehyde (compound C):

[0093]

[0094] A mixture of 3-(chloromethyl)-2,4,6-trimethylbenzaldehyde (10.0 g, 0.051 mol) and imidazole (10.44 g, 0.127 mol) in DMF (10 ml) is stirred at 80°C for one hour.

[0095] After cooling to 40-50°C, the mixture is diluted with water (200 ml) and stirred for 10 minutes. The resulting precipitate is filtered and washed with water (4 times per 25 ml) and then dried at room temperature. A white solid (7.92 g, 64% yield) with a melting point of 161°C is obtained. The molar purity is 91% (¹H NMR). [Table 4] N° δ 1< H (ppm) δ 13< C (ppm) 1 10,45 194,2 2 (-) 131,5 3 (-) 139,5 4 2,44 19,6 5 7,04 131,2 6 (-) 142,5 7 2,19 19,5 8 (-) 131 9 (-) 139,5 10 2,34 14,6 11 5,02 42,5 12 6,24 116,9 13 6,59 125,9 14 (-) 143,5 15 2,32 12,7 1.2.4-Synthesis of 2,4,6-trimethyl-3-((2-methyl-1H-imidazol-1-yl)methyl)benzaldehyde oxime (compound la):

[0096]

[0097] To a solution of 2,4,6-trimethyl-3-((2-methyl-1H-imidazol-1-yl)methyl)benzaldehyde (20.3 g, 0.084 mol) in EtOH (110 mL) at 40°C, an aqueous solution of hydroxylamine (809 g, 0.134 mol, 50% in water, Aldrich) in EtOH (10 mL) is added. The reaction mixture is stirred for 2.5 hours at a temperature of 50–55°C. After cooling to 23°C, the resulting precipitate is filtered and washed twice through a filter with a mixture of EtOH / H₂O (10 mL / 15 mL) and dried for 15–20 hours under atmospheric pressure at room temperature. A white solid (19.57 g, 91% yield) with a melting point of 247°C is obtained. The molar purity is greater than 87% (1H NMR). [Table 5] N° δ 1< H (ppm) δ 13< C (ppm) 1 2,31 12,7 2 (-) 143,4 3 6,58 125,8 4 6,22 116,9 5 4,97 43,2 6 (-) 129,3 7 (-) 136,2 8 2,23 20,2 9 6,97 130 10 (-) 137,3 11 2,15 19,1 12 (-) 129,1 13 (-) 136,1 14 2,11 15,9 15 8,25 147,4 OH 11,11 (-) 1.3 - Comparison of the invention's process and the prior art process

[0098] [Table 6] Synthesis of the compound (the) according to the prior art process (process 1.2) Synthesis of the compound (the) according to the process of the invention (process 1.1) Number of isolated intermediaries 3 0 Overall performance 38 % 65 % Number of solvents used 4 2 Liters of solvent used / kg of final product dichloromethane 71,4 7 alcohol (ethanol, isopropanol) 7,2 3,9 petroleum ether 4,4 0 DMF 1,3 0 Liters of aqueous derivatives (water, HCl) used / kg of final product 190,2 25,5

[0099] In a completely unexpected turn of events, the synthesis process according to the invention of the compound of formula (la) allows for a reduction in the number of isolated intermediates while improving the process yield. It also reduces the number of solvents used, thus simplifying handling by an operator and improving the overall cycle time by eliminating the time required for purification and drying of the intermediates. Finally, it reduces effluents and therefore their treatment. Test 2:

[0100] 2.1 - Method for synthesizing the compound of formula (Xa) from the compound of formula (la) synthesized according to the method of the invention (according to the invention)

[0101] The compound of formula (Xa) is obtained from the compound of formula (la) obtained by the process without isolation of the intermediates of the invention and according to the following reaction scheme:

[0102] 1.26 kg of the oxime 2,4,6-trimethyl-3-((2-methyl-1H-imidazol-1-yl)methyl)benzaldehyde (4.9 mol), compound (la) obtained according to the process without isolation of intermediates of the invention as described in paragraph 1.1 above, is suspended in isopropanol / water (1.3 L / 1.3 L). The mixture is cooled to 0°C and 6.44 L of a 14% sodium hypochlorite solution in water (14.7 mol) is added over a period of 30 min. After the addition is complete, the mixture is kept under stirring at 2-3°C for 2 hours.

[0103] The product is then filtered, and the beige powder is resuspended in water (4.73 L) and stirred for 1 hour before being filtered again. This process is repeated four times. After the final filtration, the powder is ground and dried under vacuum (40 mbar) for 8 hours at 50°C, followed by overnight drying at 40°C under vacuum (50 mbar). 2,4,6-Trimethyl-3-((2-methyl-1H-imidazol-1-yl)methyl)benzonitrile N-oxide is obtained in a yield of 80% (1 kg, 3.92 mol) as a slightly yellow solid. [Table 7] N° δ 1< H (ppm) δ 13< C (ppm) 1 2,3 12,6 2 (-) 143,6 3 6,59 126,1 4 6,27 117,1 5 4,99 43 6 (-) 130,6 7 (-) 140,7 8 2,16 19,2 9 7,12 129,9 10 (-) 141 11 2,34 20 12 (-) 112,1 13 (-) 140,8 14 2,28 17,7 15 (-) NEITHER 2.2 - Synthesis of the compound of formula (Xa) according to a prior art process (not in accordance with the invention)

[0104] The N-oxide of 2,4,6-trimethyl-3-2((2-methyl-1H-imidazol-1-yl)benzonitrile (compound Xa) is prepared according to the following reaction scheme: 2.2.1 Synthesis of 2-(chloromethyl)1,3,5-trimethylbenzene (compound (D))

[0105] This compound can be obtained according to a procedure described in the following article: Zenkevich, IG; Makarov, AA; Russian Journal of General Chemistry; vol. 77; nb. 4; (2007); p. 611-619 (Zhurnal Obshchei Khimii; vol. 77; nb. 4; (2007); p. 653-662)

[0106] A mixture of mesitylene (100.0 g, 0.832 mol), para-formaldehyde (26.2 g, 0.874 mol), and hydrochloric acid (240 mL, 37%, 2.906 mol) in acetic acid (240 mL) is stirred and heated very slowly (1.5 hours) to 37°C. After returning to room temperature, the mixture is diluted with water (1.0 L) and CH₂Cl₂ (200 mL). The product is extracted with CH₂Cl₂ (4 times per 50 mL). The organic phases are collected, then washed with water (5 times per 100 mL) and evaporated to 11–12 mbar (bath temperature = 42°C). A colorless oil (133.52 g, 95% yield) is obtained. After 15–18 hours at +4°C, the oil crystallized. The crystals were filtered, washed with petroleum ether cooled to -18°C (40 mL), and then dried for 3–5 hours under atmospheric pressure at room temperature. A white solid (95.9 g, 68% yield) with a melting point of 39°C was obtained. The molar purity was greater than 96% (¹H NMR). [Table 8] N° δ 1< H (ppm) δ 13< C (ppm) 1 2,27 18,4 2 (-) 136,9 3 6,81 128,5 4 (-) 137,4 5 2,15 20,3 6 6,81 128,5 7 (-) 136,9 8 2,27 18,4 9 (-) 130,5 10 4,69 41,3 2.2.2 - Synthesis of 3-(chloromethyl)-2,4,6-trimethylbenzaldehyde (Compound (B))

[0107] This compound can be obtained according to a procedure described in the following article: Yakubov, AP; Tsyganov, DV; Belen'kii, LI; Krayushkin, MM; Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation); vol. 40; nb. 7.2; (1991); p. 1427 - 1432 (Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya; nb. 7; (1991); p. 1609 - 1615)]

[0108] A solution of 2-(chloromethyl)-1,3,5-trimethylbenzene (20.0 g, 0.118 mol) and dichloromethyl methyl ether (27.26 g, 0.237 mol) in dichloromethane (200 mL) is added under argon for 10–12 minutes. After stirring for 15–20 minutes at 17–20 °C, water (1000 mL) and ice (500 g) are added to the reaction mixture. After 10–15 minutes of stirring, the organic phase is separated. The aqueous phase is extracted with CH₂Cl₂ (3 times per 75 mL). The combined organic phases are washed with water (4 times per 100 mL) and evaporated under reduced pressure to obtain a solid (bath temperature = 28°C). The target product (22.74 g) is obtained with a yield of 97%. Its melting point is 58°C. The molar purity estimated by 1H NMR is 95 mol%. [Table 9] N° δ 1< H (ppm) δ 13< C (ppm) 1 4,77 40,6 2 (-) 132.9 3 (-) 139,5 4 2,51 14,4 5 (-) 131,4 6 10,43 194,2 7 (-) 140,1 8 2,41 19,3 9 6,99 131,2 10 (-) 142,4 11 2,34 19,8 2.2.3 - Synthesis of 2,4,6-trimethyl-3-((2-methyl-1H-imidazol-1-yl)methyl)benzaldehyde (Compound (C))

[0109]

[0110] A mixture of 3-(chloromethyl)-2,4,6-trimethylbenzaldehyde (10.0 g, 0.051 mol) and imidazole (10.44 g, 0.127 mol) in DMF (10 ml) is stirred at 80°C for one hour.

[0111] After cooling to 40-50°C, the mixture is diluted with water (200 ml) and stirred for 10 minutes. The resulting precipitate is filtered and washed with water (4 times per 25 ml) and then dried at room temperature. A white solid (7.92 g, 64% yield) with a melting point of 161°C is obtained. The molar purity is 91% (¹H NMR). [Table 10] N° δ 1< H (ppm) δ 13< C (ppm) 1 10,45 194,2 2 (-) 131,5 3 (-) 139,5 4 2,44 19,6 5 7,04 131,2 6 (-) 142,5 7 2,19 19,5 8 (-) 131 9 (-) 139,5 10 2,34 14,6 11 5,02 42,5 12 6,24 116,9 13 6,59 125,9 14 (-) 143,5 15 2,32 12,7 2.2.4 - Synthesis of 2,4,6-trimethyl-3-((2-methyl-1H-imidazol-1-yl)methyl)benzaldehyde oxime (compound (the))

[0112]

[0113] To a solution of 2,4,6-trimethyl-3-((2-methyl-1H-imidazol-1-yl)methyl)benzaldehyde (20.3 g, 0.084 mol) in EtOH (110 mL) at 40°C, an aqueous solution of hydroxylamine (809 g, 0.134 mol, 50% in water, Aldrich) in EtOH (10 mL) is added. The reaction mixture is stirred for 2.5 hours at a temperature of 50–55°C. After cooling to 23°C, the resulting precipitate is filtered and washed twice through a filter with a mixture of EtOH / H₂O (10 mL / 15 mL) and dried for 15–20 hours under atmospheric pressure at room temperature. A white solid (19.57 g, 91% yield) with a melting point of 247°C is obtained. The molar purity is greater than 87% (1H NMR). [Table 11] N° δ 1< H (ppm) δ 13< C (ppm) 1 2,31 12,7 2 (-) 143,4 3 6,58 125,8 4 6,22 116,9 5 4,97 43,2 6 (-) 129,3 7 (-) 136,2 8 2,23 20,2 9 6,97 130 10 (-) 137,3 11 2,15 19,1 12 (-) 129,1 13 (-) 136,1 14 2,11 15,9 15 8,25 147,4 OH 11,11 (-) 2.2.5 - Synthesis of 2,4,6-trimethyl-3-((2-methyl-1H-imidazol-1-yl)methyl)benzonitrile oxide (compound (Xa))

[0114]

[0115] To a mixture of 2,4,6-trimethyl-3-((2-methyl-1H-imidazol-1-yl)methyl)benzaldehyde oxime (8.80 g, 0.034 mol) in CH₂Cl₂ (280 mL) at 6°C, an aqueous solution of NaOCl (4% active chlorine, Aldrich, 49 mL) is added dropwise over 5 minutes. The temperature of the reaction mixture is maintained between 6 and 8°C. The reaction mixture is then stirred for 2 hours from 8°C to 21°C. The organic phase is separated. The organic phase is washed with water (3 times per 50 mL). After concentration under reduced pressure (bath temperature = 22-23°C, 220 mbar), petroleum ether (10 mL) is added, the solvent is evaporated to 8-10 mL, and the solution is maintained at -18°C for 10-15 hours to obtain a precipitate. The precipitate is filtered and washed through a filter with a mixture of CH₂Cl₂ / petroleum ether (2 mL / 6 mL), then with petroleum ether (2 x 10 mL), and finally dried for 10-15 hours under atmospheric pressure at room temperature.A white solid (5.31 g, yield 61%) with a melting point of 139°C is obtained.

[0116] The molar purity is greater than 95% mol (1H NMR). [Table 12] N° δ 1< H (ppm) δ 13< C (ppm) 1 2,3 12,6 2 (-) 143,6 3 6,59 126,1 4 6,72 117,1 5 4,99 43 6 (-) 130,6 7 (-) 140,7 8 2,16 19,2 9 7,12 129,9 10 (-) 141 11 2,34 20 12 (-) 112,1 13 (-) NEITHER 14 (-) 140,8 15 2,8 17,7

[0117] 2.3 - Comparison of the process for synthesizing nitrile oxide (compound Xa) obtained by transforming compound (la) obtained according to the process of the invention (paragraph 2.1) with respect to the process for synthesizing nitrile oxide (compound (Xa)) according to the prior art synthesis process (paragraph 2.2): [Table 13] Method for synthesizing compound (Xa) of the prior art (method 2.2) Method for synthesizing compound (Xa) according to the invention (method 2.1) Number of isolated intermediaries 4 1 overall yield 23 % 52% number of solvents used 4 2 Liters of solvent used / kg of final product dichloromethane 117,9 8,9 Alcohol (ethanol, isopropanol) 12 6,2 petroleum ether 7,3 0 DMF 2,2 0 Liters of aqueous derivatives (water, HCl) used / kg of final product 311 63,5

[0118] In a completely unexpected turn of events, the synthesis process of compound Xa from compound La, obtained according to the process of the invention, reduces the number of synthesis steps and the number of isolated intermediates while improving the yield. It also reduces the number of solvents used, thus simplifying handling by an operator. Finally, it reduces effluents and therefore their treatment.

Claims

1. Process for synthesizing a compound of formula (I) in which: - R1 represents, independently of one another, a C1-C6 alkyl, preferably a C1-C3 alkyl; - R2 represents a hydrogen atom, a C1-C12 alkyl, preferably a C1-C6 alkyl, more preferentially a C1-C3 alkyl; - R3 and R4, independently of one another, represent a hydrogen atom, a C1-C12 alkyl, (preferably a C1-C6 alkyl, more preferentially a C1-C3 alkyl) or form, together with the carbon atoms to which they are attached, a ring, preferably an aromatic ring, preferably phenyl; and - n is an integer equal to 0, 1, 2, 3 or 4; and said synthesis process comprising the following successive steps A1, A2 and A3: • a step A1 of obtaining an intermediate compound of formula (V) via a halomethylation reaction of an aromatic aldehyde of formula (VI) in the presence of a halomethylation agent according to the following reaction scheme: with R1 and n as defined above; and X being a halogen atom, preferably a bromine or chlorine atom, more preferentially a chlorine atom; • a step A2 of obtaining an intermediate compound of formula (III) via nucleophilic substitution of the preceding intermediate compound of formula (V) with an imidazole compound of formula (IV) according to the following reaction scheme: with n, X, R1, R2, R3 and R4 as defined above; • a step A3 of obtaining the compound of formula (I) via a condensation reaction of the preceding intermediate compound of formula (III) with hydroxylamine (II) according to the following reaction scheme: with R1, R2, R3, R4 and n as defined above; and steps A1, A2, A3 being carried out without isolation of at least one intermediate compound chosen from the group formed by the intermediate compound of formula (III) and the intermediate compound of formula (V).

2. Process according to Claim 1, in which the halomethylation agent is preheated to a temperature T1 within a range extending from 23°C to 50°C, more preferentially within a range extending from 30°C to 45°C, before bringing it into contact with the compound of formula (VI).

3. Process according to Claim 2, in which the compound of formula (VI) is added all at once after the preheating of the halomethylation agent.

4. Process according to any one of the preceding claims, in which the halomethylation agent is a mixture of a formaldehyde donor and hydrochloric acid.

5. Process according to Claim 4, in which the amount of formaldehyde donor is within a range extending from 1 molar equivalent to 7 molar equivalents, preferably from 1.2 molar equivalents to 6 molar equivalents, more preferentially still from 2 molar equivalents to 6 molar equivalents, relative to the amount of compound of formula (VI).

6. Process according to any one of the preceding claims, in which step A1 is carried out at a temperature T2 within a range extending from 60°C to 100°C, more preferentially within a range extending from 70°C to 90°C.

7. Process according to any one of the preceding claims, in which an organic solvent S1 is added at the end of step A1 and the organic phase is recovered; the organic solvent S1 being chosen from halogenated solvents.

8. Process according to any one of the preceding claims, in which step A2 is carried out in the presence of an organic solvent S2 chosen from the group consisting of halogenated solvents, dimethyl sulfoxide, acetone, alcohols such as isopropanol, ethers such as tetrahydrofuran, ethyl acetate; preferentially the organic solvent S2 is a halogenated organic solvent, more preferentially a chlorinated organic solvent.

9. Process according to Claim 7 or 8, in which the organic solvent S2 is identical to the organic solvent S1.

10. Process according to any one of the preceding claims, in which the amount of compound of formula (IV) is within a range extending from 1.1 molar equivalents to 6 molar equivalents, more preferentially extending from 2 molar equivalents to 4 molar equivalents, relative to the compound of formula (V).

11. Process according to any one according to any one of the preceding claims, in which step A2 is carried out at a temperature which is less than or equal to the reflux temperature of the organic solvent S2.

12. Process according to any one of Claims 8 to 11, in which the amount of organic solvent S2 is at least 0.5 volume relative to 1 volume of organic solvent S1, more preferentially is within a range extending from 1 volume to 10 volumes relative to 1 volume of organic solvent S1.

13. Process according to any one of the preceding claims, in which step A3 is carried out in an organic solvent S3 chosen from the group consisting of halogenated solvents, acetone, alcohols such as isopropanol, ethers such as tetrahydrofuran, ethyl acetate; preferentially the organic solvent S3 a halogenated organic solvent, preferably the solvent S3 is a chlorinated organic solvent.

14. Process according to Claim 13, in which the organic solvent S3 is identical to the organic solvent S2.

15. Process for synthesizing a compound of formula (X), said process comprising the following steps: • a step (i) of synthesizing the compound of formula (I) via the synthesis process according to any one of the preceding claims, • a step (ii) of converting the compound of formula (I) into a compound of formula (X) in the presence of at least one organic solvent S4 and at least one oxidant according to the following reaction scheme: where - R1 represents, independently of one another, a C1-C6 alkyl, preferably a C1-C3 alkyl; - R2 represents a hydrogen atom, a C1-C12 alkyl, preferably a C1-C6 alkyl, more preferentially a C1-C3 alkyl; - R3 and R4, independently of one another, represent a hydrogen atom, a C1-C12 alkyl, preferably a C1-C6 alkyl, more preferentially a C1-C3 alkyl, or form, together with the carbon atoms to which they are attached, a ring, preferably an aromatic ring, more preferentially phenyl, and - n is an integer equal to 0, 1, 2, 3 or 4; and • a step (iii) of recovering the compound of formula (X).